DEVELOPMENT AND EVALUATION OF PULSATILE DRUG ...

DEVELOPMENT AND EVALUATION OF 

PULSATILE DRUG DELIVERY SYSTEM OF 

FLURBIPROFEN 

By 

PATEL VISHAL ASHOK 

Reg. No. 08 PU 251 

Dissertation submitted to the 

Rajiv Gandhi University of Health Sciences, Karnataka, Bangalore. 

In partial fulfillment 

of the requirements for the degree of 

MASTER OF PHARMACY 

in 

PHARMACEUTICS 

Under the guidance of 

Mr. M. NAJMUDDIN 

M. Pharm. (Ph. D.) 

Associate Professor 

DEPARTMENT OF PHARMACEUTICS 

LUQMAN COLLEGE OF PHARMACY 

GULBARGA. 585102 (KARNATAKA) 

2010 

i

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, 

KARNATAKA, BANGALORE 

DECLARATION BY THE CANDIDATE 

I hereby declare that this dissertation/thesis entitled 

“Development and Evaluation of Pulsatile Drug Delivery System 

of Flurbiprofen” is a bonafide and genuine research work carried out 

by me under the guidance of Mr. M. Najmuddin, Associate professor 

of Luqman college of Pharmacy Gulbarga. 

Date: 

Place: Gulbarga 

ii



CERTIFICATE BY THE GUIDE 

This is to certify that the dissertation entitled “Development 

and Evaluation of Pulsatile Drug Delivery System of 

Flurbiprofen” is a bonafide research work done by Mr. Patel Vishal 

Ashok in partial fulfillment of the requirement for the degree of 

“Master of Pharmacy” in Pharmaceutics. 

Date: M. Najmuddin 

M. Pharm (Ph.D.) 

Place: Gulbarga Associate Professor 

Luqman College of Pharmacy, 

Gulbarga.5851012 

iii



CERTIFICATE BY THE CO-GUIDE 




Ashok in partial fulfillment of the requirement for the degree of 

“Master of Pharmacy” in Pharmaceutics. 

Date: Mr. Aejaz Ahmed 

M. Pharm 

Place: Gulbarga Lecturer 


Gulbarga.5851012 

iv



ENDORSEMENT BY THE HOD, PRINCIPAL/ 

HEAD OF THE INSTITUTION 




Ashok under the guidance of Mr. M. Najmuddin, Research guide 

Luqman College of pharmacy Gulbarga. 

Date: Prof. Syed. Sanaullah 

Place: GULBARGA M. Pharm (PhD.) 


Gulbarga. 585102 

v



COPYRIGHT 

DECLARATION BY THE CANDIDATE 

I hereby declare that the Rajiv Gandhi University of Health Sciences, 

Karnataka shall have the right to preserve, use, and disseminate this 

dissertation/ thesis in print or electronic format for academic/ 

research purpose. 

Date: 

Place: GULBARGA Patel Vishal Ashok 

© Rajiv Gandhi University of Health Sciences, Karnataka 

vi

No work big or small can fructify without the grace and mercy of Almighty 

“JAI SAI NATH”, “The Honoror”. The most essentially humble solicitation and 

a lot of thanks to the Supreme Power for manifesting himself through the various 

helpful people I came across in my life. I bow my head to Him and ask for His 

blessings to be with me forever. 

I consider myself most lucky to work under the guidance of 

Mr. M.Najmuddin, Associate Professor, Luqman College of Pharmacy, 

Gulbarga. I take this opportunity to express my heartfelt gratitude to my reverend 

guide. His discipline, principles, simplicity, caring attitude and provision of 

fearless work environment will be cherished in all walks of my life. I am very 

much grateful to him for his invaluable guidance and ever-lasting encouragement 

throughout my course. 

Very special thanks to Dr. M.G Purohit, for their constant support in 

analytical work. 

I am immensely thankful to Dr. Syed Sanaullah, Principal,Luqman College of 

pharmacy, Dr. Mujeeb, Treasurer, Luqman college of pharmacy, Gulbarga. 

I owe my warmest and humble thanks to Dr. N.G. Raghvendra Rao, Dr. 

S.S.Bushetti, Mrs. Syeda Humaira, Mr. M. A. Saleem, Mr. Mohan Joshi, 

Prashant sir, Mr.Raghunandan Deshpande, Mr.Mahesh Bedre, Mr. Aejaz 

Ahmed, Mr. Sunil Firangi and other staff members of Luqman College of 

Pharmacy, Gulbarga, for their timely help, encouragement, boosting my 

confidence in the progress of my academics. 

I express my deepest and very special thanks to my batch mates Ram, 

Ganesh, Sachin, Ketan, Aniket, Vijay, Tousif, Azuruddin, Shahid, for their kind 

co-operation, help and encouragement throughout my course. 

I convey my thanks and well wishes to all my juniors Sudhir, Shrishail, 

Anaf, Vishal, Dinesh, Subhan, Izhar, Vahid, Mangesh, Hadi Jaspal, Jinesh and 

others who have contributed directly or indirectly during my dissertation 

I extended my special thanks to my dear friends & Brothers Ishwer, 

Nandakishor, Praful, Manoj, Anwar, Sunil, Amol Basgunde, Goutam, Rohit, 

Sachin, Rohit. 

vii

I render my grateful respect and sincere thanks to my beloved Parents. I 

would like to extend my gratitude to my ‘Jijaji’ Mr. Shailendra Patil and my 

sister Mrs. Deepu, Ms. Banti without whom it could not have been possible for 

me to complete this project work. 

I express my sincere thankful to non teaching staff Narendra, Peer Pasha, 

Suresh and Librarian Ms. Pratibha of Luqman college of pharmacy, Gulbarga, 

for their co-operation. 

Last but not the least, I would like to thank SUPER Computers, Gulbarga 

for making this thesis work in a reproducible manner. 

Date: 

Thankful I ever remain…………… 

Place: Gulbarga. VISHAL ASHOK PATEL 

viii

ix

Abs Absorbance 

ºC Temperature on Celsius Scale 

CAP Cellulose Acetate phthalate 

cm Centimetre 

cm 2 

Centimetre Square 

cps Centipoises 

EC Ethyl Cellulose 

o 

F Temperature on Faranide Scale 

FDA Food and Drug Administration 

gms Grams 

HPMC Hydroxypropyl methyl cellulose 

Hrs Hours 

IP Indian Pharmacopoeia 

IR Infrared 

kg/cm 2 

Kilogram per centimetre square 

L.R. Laboratory Grade 

mg Milligram 

g/mcg Microgram 

min Minutes 

mm Millimetre 

NASID Non-steroidal anti-inflammatory drug 

nm Nanometre 

P.G. Pharmaceutical Grade 

‘r’ Regression Coefficient 

rpm Resolutions per minute 

SEM Scanning Electron Microscopy 

SD Standard Deviation 

Sod. Alg. Sodium Alginate 

UV Ultraviolet 

v/v Volume/Volume 

w/w Weight/Weight 

% w/v Percentage weight by volume 

% w/w Percentage weight by weight 

x

FM-1 Flurbiprofen: Eudragit L-100: Eudragit S-100 




F-1 Flurbiprofen: Eudragit L-100: Eudragit S-100: Guar gum (20mg) 



F-4 Flurbiprofen: Eudragit L-100: Eudragit S-100: HPMC (20mg) 



F-7 Flurbiprofen: Eudragit L-100: Eudragit S-100: Sodium alginate (20mg) 



xi

In this study, investigation of an oral colon specific, pulsatile device to achieve 

time and/or site specific release of Flurbiprofen, based on chronopharmaceutical 

consideration. The basic design consists of an insoluble hard gelatin capsule body, 

filled with eudragit microcapsules of Flurbiprofen and sealed with a hydrogel plug. 

The entire device was enteric coated, so that the variability in gastric emptying time 

can be overcome and a colon-specific release can be achieved. The Flurbiprofen 

microcapsules were prepared by solvent evaporation method with Eudragit L-100 and 

S-100 (1:2) by varying drug to polymer ratio and evaluated for the particle size, angle 

of repose, percentage yield, drug content, SEM, IR and in-vitro release study. The 

drug content in the range of 75.9 ± 0.78 to 95.59 ± 0.68. The in-vitro, drug release 

studies were carried out using pH 6.8 phosphate buffer for 12 hrs. At the end of 12 th 

hrs the drug release in the range of 88.51 ± 1.53 to 95.58 ± 0.24 and from the obtained 

results; FM-3 was selected as an optimized formulation for designing pulsatile device. 

Different hydrogel polymers (Guar gum, HPMC, Sodium alginate) were used as plugs 

in different ratios, to maintain a suitable lag period. The entire device was coated with 

5% CAP. The formulated pulsatile device was evaluated weight variation, thickness 

of CAP, IR, and in-vitro release study. The in-vitro release study were carried out 

using pH 1.2 buffer for a period of 2 hrs then 7.4pH phosphate buffer for a period of 

3hrs then 6.8 pH phosphate buffer for a period of 10 hrs. At the end of 15 th hrs the 

drug releases were in the ranges of 62.28 ± 0.479 to 74.61 ± 0.408, 59.79 ± 0.363 to 

76.46 ± 0.802 and 70.25 ± 0.155 to 82.95 ± 0.239 with Guar gum, HPMC and Sodium 

alginate plugs respectively. From obtained results, it was found that the order of 

sustaining capacity of pulsatile device is, HPMC > Guar gum > Sodium alginate. 

Keywords: Pulsatile; Colon-specific device; Chronotherapeutics; Rheumatoid 

arthritis; Eudragit microcapsules 

xii

CHAPTER 

NO. 

 

CONTENTS 

PAGE 

NO. 

CHAPTER– 1 INTRODUCTION 01–32 

CHAPTER –2 OBJECTIVES 33–36 

CHAPTER – 3 REVIEW OF LITERATURE 37–66 

CHAPTER – 4 METHODOLOGY 67–82 

CHAPTER – 5 RESULTS 83–117 

CHAPTER – 6 DISCUSSION 118–125 

CHAPTER – 7 CONCLUSIONS 126–127 

CHAPTER – 8 SUMMARY 128–130 

CHAPTER – 9 BIBLIOGRAPHY 131–141 

ANNEXURES 142 – 147 

xiii

Sl. 

No. 

 

Title 

1. Circadian rhythm and manifestation of clinical diseases 05 

2. Average pH in the GI tract 26 

3. Average GI transit time 26 

4. Summary of colon-specific drug delivery strategies 30 

5. Materials / Chemicals used 67 

6. Equipments used and source 68 

7. Formulation of Flurbiprofen Microcapsules using Eudragit – L 100 

and Eudragit – S100 

8. Composition for modified pulsatile device on the basis of design 

summary 

9. Standard calibration data of Flurbiprofen in Ethanol 83 

10. Standard calibration data of Flurbiprofen in pH 1.2 buffer 84 



13. Micromeritic properties of Flurbiprofen Microcapsules 88 

14. Percentage yield and Drug content of Flurbiprofen microcapsules 88 

15. In-vitro release profile of Flurbiprofen microcapsules for FM-1 92 




19. Kinetic values obtained from in-vitro release profile for 

microcapsules 

Page 

No. 

20. Coating thickness 100 

72 

80 

96 

xiv

Sl. 

No. 

Title 

Page 

No. 

21. In-vitro release rate profile of F1 containing 20mg Guar Gum 102 



24. In-vitro release rate profile of F4 containing 20mg HPMC 105 



27. In-vitro release rate profile of F7 containing 20mg Sodium Alginate 108 



30. Kinetic values obtained from in-vitro release profile for 

microcapsules 

111 

xv

Sl. 

No. 

 

Title 

1 A 24-hours clock diagram of the peak time of selected human 

circadian rhythms with reference to the day-night cycle. 

2 Drug release profile of pulsatile drug delivery systems 20 

3 Different stages in drug release from pulsincap 22 

4 Structure of colon 25 

5 Classification of microparticles 32 

6 Overview of designed pulsatile device 79 

7 Standard calibration curve of Flurbiprofen in Ethanol 83 

8 Standard calibration curve of Flurbiprofen in pH 1.2 buffer 84 



11 Images of Flurbiprofen microcapsules for FM-1, FM-2, FM-3, FM-4 87 

12 Scanning electron microphotographs of FM-3 formulation 89 

13 I.R. Spectrum of Flurbiprofen (pure drug) 90 

14 I.R. Spectrum of Eudragit L-100 90 

15 I.R. Spectrum of Eudragit S-100 91 

16 I.R. Spectrum of Flurbiprofen microcapsules (FM-3) 91 

17 Comparative zero order plots for Flurbiprofen microcapsules 97 

18 Comparative first order plots for Flurbiprofen microcapsules 97 

19. Comparative Higuchi matrix model for Flurbiprofen microcapsules 98 

20. Comparative Peppas model for Flurbiprofen microcapsules 98 

Page 

No. 

21. I.R. Spectrum of Flurbiprofen + Sodium Alginate 101 

04 

xvi

Sl. 

No. 

Title 

Page 

No. 

22. I.R. Spectrum of Flurbiprofen + HPMC 101 

23. I.R. Spectrum of Flurbiprofen + Guar gum 101 

24. Comparative zero order plots of formulation containing Guar Gum as 

hydrogel plug 

25. Comparative first order plots of formulation containing Guar Gum as 

hydrogel plug 

26. Comparative Higuchi matrix model of formulation containing Guar 

Gum as hydrogel plug 

27. Comparative Peppas model of formulation containing Guar Gum as 

hydrogel plug 

28. Comparative zero order plots of formulation containing HPMC as 

hydrogel plug 

29. Comparative first order plots of formulation containing HPMC as 

hydrogel plug 

30. Comparative Higuchi matrix model of formulation containing HPMC 

as hydrogel plug 

31. Comparative Peppas model of formulation containing HPMC as 

hydrogel plug 

32. Comparative zero order plots of formulation containing Sodium 

Alginate as hydrogel plug 

33. Comparative first order plots of formulation containing Sodium 


34. Comparative Higuchi matrix model of formulation containing 

Sodium Alginate as hydrogel plug 

35 Comparative Peppas model of formulation containing Sodium 


112 

112 

113 

113 

114 

114 

115 

115 

116 

116 

117 

117 

xvii

CHAPTER-1 

 

Introduction 

Controlled drug delivery systems have acquired a centre stage in the area 

of pharmaceutical R &D sector. Such systems offer temporal &/or spatial control 

over the release of drug and grant a new lease of life to a drug molecule in terms 

of controlled drug delivery systems for obvious advantages of oral route of drug 

administration. These dosage forms offer many advantages, such as nearly 

constant drug level at the site of action, prevention of peak-valley fluctuation, 

reduction in dose of drug, reduced dosage frequency, avoidance of side effects and 

improved patient compliance. In such systems the drug release commences as 

soon as the dosage form is administered as in the case of conventional dosage 

forms. However, there are certain conditions, which demand release of drug after 

a lag time. Such a release pattern is known as “pulsatile release”. 1 

Traditionally, drug delivery has meant getting a simple chemical absorbed 

predictably from the gut or from site of injection. A second-generation drug 

delivery goal has been the perfection of continuous, constant rate (zero order) 

delivery of bioactive agents. However, living organisms are not “zero order” in 

their requirement or response to drugs. They are predictable resonating dynamic 

systems, which require different amounts of drug at predictably different times 

within the circadian cycle in order to maximize desired and minimize undesired 

drug effects. Due to advances in chronobiology, chronopharmacology and global 

DEPT. OF PHARMACEUTICS, LUQMAN COLLEGE OF PHARMACY, GULBARGA 

1

Introduction 

market constraints, the traditional goal of pharmaceutics (e.g. design drug delivery 

system with a constant drug release rate) is becoming obsolete. However, the 

major bottleneck in the development of drug delivery systems that match 

circadian rhythms (chronopharmaceutical drug delivery system: ChrDDS) may be 

the availability of appropriate technology. The diseases currently targeted for 

chronopharmaceutical formulations are those for which there are enough scientific 

backgrounds to justify ChrDDS compared to the conventional drug administration 

approach. These include asthma, arthritis, duodenal ulcer, cancer, diabetes, 

cardiovascular diseases, hypercholesterolemia, ulcer and neurological diseases. 2 

If the organization in time of living system including man is borne in 

mind, it is easy to conceive that not only must the right amount of the right 

substance be at right place but also this must occur at the right time. In the last 

decade numerous studies in animals as well as clinical studies have provided 

convicing evidence, that the pharmacokinetics &/or the drug’s effects-side effects 

can be modified by the circadian time &/or the timing of drug application within 

24 hrs of a day. 3 

Circadian variation in pain, stiffenss and manual and manual deyterity in 

patients with osteo and rheumatoid arthritis have been studied and has implication 

for timing antirheumatide drug treatment. 4 Morning stiffness associated with pain 

at the time of awakening is a diagnostic criterion of the rheumatoid arthritis and 

these clinical circadian symptoms are supposed to be outcome of altered 

functioning of hypothalamic–pitutary–adrenocortical axis. 


2

Introduction 

Chronopharmacotherapy for rheumatoid arthritis has been recommended 

to ensure that the highest blood levels of the drug coincide with peak pain and 

stiffness. 5 A pulsatile drug delivery system that can be administered at night 

(before sleep) but that release drug in early morning would be a promising 

chronopharmaceutic system. 5,6 

Drug targeting to colon would prove useful where intentional delayed drug 

absorption is desired from therapeutic point of view in the treatment of disease 

that have peak symptoms in the early morning such as nocturnal asthma, angina, 

arthritis. 1,4,7,8, 

Some orally administered drugs (E.g. Diclofenac, Theophyllin, Ibuprofen 

Isosorbide) may exhibit poor uptake in the upper regions of GIT or degrade in the 

presence of GIT enzymes. Better bioavailability can be achieved through colon- 

specific drug delivery. Colonic targeting is also advantageous where delay in 

systemic absorption is therapeutically desirable. 4,7 

1.1 Circadian rhythms and their implications: 

Circadian rhythms are self-sustaining, endogenous oscillation, exhibiting 

periodicities of about one day or 24 hours. Normally, circadian rhythms are 

synchronized according to the body ’ s pacemaker clock, located in the 

suprachiasmic nucleus of the hypothalamus. 


3

Introduction 

The physiology and biochemistry of human being is not constant during 

the 24 hours, but variable in a predictable manner as defined by the timing of the 

peak and through of each of the body’s circadian processes and functions. The 

peak in the rhythms of basal gastric and secretion, white blood cells (WBC), 

lymphocytes, prolactin, melatonin, eosinophils, adrenal corticotrophic hormone 

(ACTH), follicle stimulating hormone (FSH), and leuteinizing hormone (LH), is 

manifested at specific times during the nocturnal sleep span. The peak in serum 

cortisol, aldosterone, testosterone plus platelet adhesiveness and blood viscosity 

follows later during the initial hours of diurnal activity. Hematocrit is the greatest 

and airway caliber the best around the middle and afternoon hours, platelet 

numbers and uric acid peak later during the day and evening. Hence, several 

physiological processes in humans vary in a rhythmic manner, in synchrony with 

the internal biological clock, as shown in fig.1. 4,9 

Fig.1: A 24-hours clock diagram of the peak time of selected human circadian 

rhythms with reference to the day-night cycle. 


4

Introduction 

Through a number of clinical trials and epidemiological studies, it has 

become evident that the levels of disease activity of number of clinical disorders 

have a pattern associated with the body’s inherent clock set according to circadian 

rhythms. Infect just as the time of day influences normal biologic processes, so it 

affects the pathophysiology of disease and its treatment. Examples of some of the 

diseases are shown in Table 1. 4 

Table 1: Circadian rhythm and manifestation of clinical diseases 

Disease or syndrome Circadian rhythmicity 

Allergic Rhinitis Worse in the morning/upon rising 

Asthma Exacerbation more common during the sleep period 

Rheumatoid Arthritis Symptoms more common during the sleep period 

Osteoarthritis Symptoms worse in the middle/later portion of the day 

Angina Pectoris Chest pain and ECG changes more common in early 

morning 

Myocardial Infraction Incidence greatest in early morning 

Stroke Incidence higher in the morning 

Sudden cardiac death Incidence higher in the morning after awakening 

Peptic ulcer disease Worse in late evening and early morning hours 


5

Introduction 

1.2 Chronotherapeutic: Therapy in synchrony with biorhythms 

Chronotherapy coordinates drug delivery with human biological rhythms 

and holds huge promise in areas of pain management and treatment of asthma, 

heart disease and cancer. The coordination of medical treatment and drug delivery 

with such biological clocks and rhythms is termed chronotherapy. 10 

Chronotherapeutics, or delivery of medication in concentrations that vary 

according to physiological need at different times during the dosing period, is a 

relatively new practice in clinical medicine and thus many physicians are 

unfamiliar with this intriguing area of medicine. It is important that physicians 

understand the advantages of chronotherapy so that they can make well-informed 

decisions on which therapeutic strategies are best for their patients-traditional ones 

or chronotherapies. 

The goal of chronotherapeutics is to synchronize the timing of treatment 

with the intrinsic timing of illness. Theoretically, optimum therapy is more likely 

to result when the right amount of drug is delivered to the correct target organ at 

the most appropriate time. In contrast, many side effects can be minimized if a 

drug is not given when it is not needed. Unlike homeostatic formulations, which 

provide relatively constant plasma drug levels over 24 hours,, chronotherapeutic 

formulations may use various release mechanisms. e.g., time-delay coatings 

(Covera-HS TM ), osmotic pump mechanisms (COER -24 TM ), and matrix systems 

(Geminex TM), that provide for varying levels throughout the day. 


6

Introduction 

A major objective of chronotherapy in the treatment of several diseases is 

to deliver the drug in higher concentrations during the time of greatest need 

according to the circadian onset of the disease or syndrome. The chronotherapy of 

a medication may be accomplished by the judicious timing of conventionally 

formulated tablets and capsules. In most cases, however, special drug delivery 

technology must be relied upon to synchronize drug concentrations to rhythms in 

disease activity. 4 

1.3 Arthritis 

11, 12, 13 

The term arthritis is used to describe changes in the joints which may be 

either inflammatory or degenerative in character. If only one joint is affected the 

condition is referred to as monoarticular arthritis; if several joints are involved 

it is called polyarticular arthritis or polyarthritis (Greek: poly= many). 

It is imperative for all adults to have at least a basic understanding of 

arthritis since most adults face some form of Arthritis. It is an extremely common 

and is among the oldest known disease among men and women. Only in recent 

years however, has the magnitude of the health problems associated with Arthritis 

been appreciated in the United States and throughout the world. As a result, a 

great deal of new knowledge, understanding, and treatment is available today. 

Medical scientists have discovered new leads in search for the causes of various 

forms of arthritis. Though cure is not yet available, treatment is generally 


7

Introduction 

satisfactory, especially if started within the first six months after onset. 

Fortunately, very few people today need to be crippled by arthritis. 

A Joint consists of the ends of the articulating bones which are covered 

with cartilage. It is surrounded and kept in position by a capsule and special 

ligaments which are lined by a membrane called the synovial membrane. 

Symptoms of arthritis: 

The joints ache and swell 

Pain and muscle-spasm are common features; and in the late stages very 

severe pain and gross destruction and deformity of the joints may develop. 

In children the condition tends to develop suddenly, many joints being 

affected from the beginning the small joint soft the hands and feet being as 

a rule affected first. 

Severe muscle wasting might also take place 

Patients of arthritis can only walk a certain distance after which they tend 

to feel pain and stiffness in their joints. 

Arthritis can also develop slowly starting as a slight restriction of 

movement in certain directions, with stiffness first thing in the morning 

and aches after exercises. 

Arthritis can be both of the infective variety as well as the chronic. 

In infective arthritis the patient feels ill and toxic with a swinging 

temperature and a furred tongue. Leucocytes are always evident, and a 

blood culture may confirm the presence of the septicaemia. 


8

Some common forms of Arthritis: 

Rheumatic arthritis(fibromyalgia) 

Rheumatoid arthritis(Still's Disease) 

Degenerative, e.g. osteo-arthritis 

Psoriatic arthritis 

Ankylosing Spondylitis 

Introduction 

The above mentioned are all different form of arthritis and they all have 

different cures and therapies as well as symptoms. The common strand binding 

them is that they are all marked by severe pain in the joints. 

1.3.1 Rheumatoid Arthritis: 

Rheumatoid arthritis is a form of chronic arthritis. This disease affects 

chiefly young adults, mainly women, and one or many joints may be involved; it 

also occurs in children (Still's Disease). It is generalized affection of joints, and 

their synovial membranes, cartilages, capsules and the muscles supplying them; 

but other connective tissues elsewhere in the body might also be affected. 

Rheumatoid arthritis is now a major cause of crippling in European countries, but 

it is not common in the tropics. 

Causes of Rheumatoid Arthritis: 

The causes of the conditions are not yet fully understood. While infection 

form the focus of the respiratory, alimentary, urinary or genital tracts is sometimes 


9

Introduction 

a factor, recent research has also demonstrated the importance of the endocrine 

glands as both as a cause and a therapy. 

1.3.2 Osteoarthritis 

This is a chronic and mild form of arthritis which is distinguished by 

degenerative changes affecting primarily the articular cartilage and adjacent bone 

which can usually be seen on x-ray. Sometime, only one joint is affected, and it is 

usually a large one such as the hip. Osteoarthritis is extremely common and 

usually constitutes a little more than a considerable and continuing nuisance. The 

chance of getting it increases with age. The weight-bearing joints are more 

commonly involved, but one hereditary form of osteoarthritis involves the end and 

middle joints of fingers. 

Causes of osteoarthritis: 

This disease is caused due to a gradual destruction of cartilage. Its precise 

cause is unknown but it is no longer known as a simple wear and tear 

disease. 

Hereditary seems to play a very important role in osteoarthritis. 

How can an osteoarthritis patient be treated? 

The treatment of osteoarthritis is simpler than that of the more severe 

forms of arthritis. 

The step in treatment is to assure the patient that it is not crippling, 

deforming disease. 


10

Introduction 

This is often a great relief to the patient since the patients usually think that 

they have a destructive form of arthritis. They often harbours more fear 

about their future regarding the course the disease would take in their life 

more than the disease warrants. 

Joint rest is important and special exercises are needed. 

Postural exercises are important aids in treatment. 

The body weight should be kept down 

Drug therapy is kept to a minimum. The principal drug is Aspirin and 

Paracetamol; the dose is to be decided by the doctor. 

Walking shoes with raised heel often help. The patient should also use a 

walking stick. 

Among the various surgeries available for arthritis, Osteotomy is the most 

successful. 

1.3.3 Fibromyalgia 

Fibromyalgia is a common condition. However it can get severe enough to 

start intruding into your day to day life. Fibromyalgia literally means, fibrous 

tissues (fibro -) and the muscles ( -my-) being affected by pain ( -algia). In this 

disease the whole body feels affected since the tendons and the ligaments both get 

affected. Fibromyalgia in fact affects the muscles and not the joints at all. Also, 

this form of arthritis never causes permanent damage to tissues though the 

symptoms may last for months or years. 


11

Introduction 

Fibromyalgia does not have any outward manifestation; therefore others 

might not understand your physical pain and tiredness. In the past fibromyalgia, 

was diagnosed as a form of rheumatism or generally also wrongly diagnosed as 

being a degenerative joint disease. It is only recently that we have a clearer picture 

of fibromyalgia. Subsequently medical practitioners have also streamlined various 

symptoms, signs and therapies specially suited to fibromyalgia. Tennis elbow is a 

localized condition of this same disease. Fibromyalgia however can lead to 

tenderness in various points of the body. 

Causes fibromyalgia: 

Fibromyalgia is a functional disturbance which implies that its causes 

cannot purely be categorized as being physical or mental. 

Both the person's mind as well as body is involved in this ailment. 

Sleep being vital to both the good health of the body as well as the mind, it 

comes as no surprise that a major cause of fibromyalgia is sleep disorders. 

If a person has more light sleep than deep sleep then he is likely to be 

inflicted by Fibromyalgia. 

Any stress that the person is feeling might interfere with his/her deep or 

restorative sleep and therefore end up in fibromyalgia. 

Sleeping in uncomfortable positions and places could also be a leading 

cause of this disease. 

Once fibromyalgia sets in, it becomes a vicious cycle; since the person now 

already afflicted by pain loses sleep as a result of which his/her condition 

automatically intensifies the condition. 


12

1.3.4 Ankylosing Spondylitis 

Introduction 

This is a chronic inflammatory form of arthritis which affects the spinal 

joints. The main and the most important feature is that in this form of arthritis the 

joints between the spine and the pelvis get inflicted. This form of arthritis causes 

back ache and stiffness in the back as well as a hunched up body posture. In very 

severe cases there might be inflammations around the tendons and ligaments that 

connect and provide support to joints that lead to pain and tenderness in the 

shoulder blades and the spinal cord. Ankylosing Spondylitis can also impair 

mobility by creating inflammation of the vertebra. 

This ailment can have confusing symptoms since there can be varied kinds 

of manifestations. While some individuals suffer gouts of transient back ache only 

while others suffer chronic back aches that lead to differing degrees of back ache 

and stiffness. 

Colloquially, Ankylosing Spondylitis is referred to as poker back and 

rheumatoid Spondylitis. It is only about five decades back that this ailment got the 

name that is now prevalent. Since this ailment belongs to the family of diseases 

that attack the spine it is also referred to as, in medical jargon as 

spondylarthropathies. 

You must keep in mind that men are three times more at a risk of acquiring 

this disease than women. This ailment also attacks youngster’s more than older 

people, contrary to popular belief. 


13

Causes Ankylosing Spondylitis: 

Introduction 

Ankylosing spondylitis is believed to be hereditary since it depends on 

tissue type and we genetically inherit tissue types. 

The exact cause of this ailment is however still not known. 

Some researches also believe that environmental interaction with certain 

tissue types might result in Ankylosing spondylitis. 

What are the signs and symptoms of Ankylosing spondylitis? 

Recurring inflammation in the eyes which cause pain, redness, blurred 

vision and sensitivity to bright light. People also experience inflammation 

of the joints. 

Chronic back ache that lasts for years 

Pain and tenderness in the ribs, shoulder blades, hips, thighs and along the 

shins. 

Pronounced back pain 

Youngsters who are afflicted will experience pain in the heels and waist. 

1.3.5 Psoriatic arthritis 

Psotiaric arthritis is a less common form of arthritis which affects, men 

and women in an equal ratio, and usually strikes when they are between the ages 

of 20 to 50. It is marked by scaly growth of rough tissues around the joints. There 

are several types of psoriatic arthritis, with symptoms that range from mild to 

severe. In general, the disease isn't as crippling as other forms of arthritis, but if 

left untreated it can cause discomfort, disability and deformity. Although no cure 


14

Introduction 

exists for psoriatic arthritis, medication, physical therapy and lifestyle changes 

often can relieve pain and slow the progression of joint damage. Psotiaric arthritis 

causes swelling in the joints. It affects a number of joints including the fingers, 

wrists, toes, knees, ankles, elbows and shoulder joints, the spine and joints in the 

lower back (called sacroiliac joints). Pso riatic arthritis also affects tissues 

surrounding the joints including tendons and ligaments and causes inflammation 

and swelling and pain in and around the joints. This ailment usually affects the 

wrists, knees, ankles, fingers and toes. It also affects the back. 

One of these conditions is psoriatic arthritis, which may affect as many as 

1 million of the approximately 6 million Americans who have psoriasis. In fact 

30% of the people who have psoriasis later go onto have psoriatic arthritis. 

Causes of Psoriatic arthritis: 

The exact cause of psoriatic arthritis is unknown 

As mentioned before psoriasis generally develops into psoriatic arthritis 

It has been observed that people who have psoriatic arthritis patients in the 

house generally get inflicted by this ailment. 

Exposure to infection, stress, alcohol, poor nutrition 

Reaction to a medication or vaccine 

Overexposure to the sun or prolonged exposure to irritating chemical such 

as disinfectants and pain thinners. 


15

1.4 Chronopharmaceutics: 2 

Introduction 

Chronopharmaceutics is a branch of pharmaceutics devoted to design and 

evaluation of drug delivery system that release a bioactive agent at a rhythm that 

ideally matches the biological requirement of a given disease therapy. Ideally 

chronopharmaceutical drug delivery system (ChrDDS) should embody time - 

controlled and site specific drug delivery system. Evidence suggests that an ideal 

ChrDDS should: 

Be non-toxic within approved limits of use, 

Have a real-time and specific triggering biomarker for a given disease 

state. 

Have a feed-back control system (ex: self -regulated and adaptive 

capability to circadian rhythm and individual patient to differentiate 

between awake-sleep status), 

Be biocompatible and biodegradable, especially for parentral 

administration, 

Be easy to manufacture at economic cost and 

Be easy to administer to patients and enhances compliance to dosage 

regimen. 

When treating human diseases, the overall goal is to cure or manage the 

disease while minimizing the negative impact of side effects associated with 

therapy. In this respect, chronopharmaceutics will be a clinically relevant and 

reliable discipline if pharmaceutical scientists could delineate a formal and 


16

Introduction 

systemic approach to design and evaluate drug delivery system that matches the 

biological requirement. 

1.5 Pulsatile drug delivery systems 

1.5.1 New global trends in drug discovery and development 

In this century, the pharmaceutical industry is caught between pressure to 

keep prices down and the increasing cost of successful drug discovery and 

development. The average cost and time for the development of a new chemical 

entity are much higher (app $500 million and 10-12 years) than those required to 

develop a novel drug delivery system (NDDS or ChrDSS) ($20-$50 million and 3 

to 4 years). In the form of an NDDS or ChrDDs, an existing drug molecule can 

“get a new life” thereby increasing its market value and competitiveness and 

extending patent life. 2 

Among modified-release oral dosage forms, increasing interest has 

currently turned to systems designed to achieve time specific (delayed, pulsatile) 

and site-specific delivery of drugs. In particular, systems for delayed release are 

meant to deliver the active principle after a programmed time period following 

administration. These systems constitute a relatively new class of device the 

importance of which is especially connected with the recent advances in 

chronopharmacology. It is by now well-known that the symptomatology of a large 

number of pathologies as well as the pharmacokinetics and pharmacodynamics of 

several drugs follow temporal rhythms, often resulting in circadian variations. 

Therefore, the possibility of exploiting delayed release to perform chronotherapy 


17

Introduction 

is quite appealing for those diseases, the symptoms of which recur mainly at night 

time or in the early morning, such as bronchial asthma, angina pectoris and 

rheumatoid arthritis. The delay in the onset of release has so far mainly been 

achieved through osmotic mechanisms, hydrophilic or hydrophobic layers, coating 

a drug-loaded core and swellable or erodible plugs sealing a drug containing 

insoluble capsule body. 14 

Delivery systems with a pulsatile release pattern are receiving increasing 

interest for the development of dosage forms, because conventional systems with 

a continuous release are not ideal. Most conventional oral controlled release drug 

delivery systems release the drug with constant or variable release rates. A 

pulsatile release profile is characterized by a time period of no release rates (lag 

time) followed by a rapid and complete release. These dosage forms offer many 

advantages such as 

Nearly constant drug levels at the site of action. 

Avoidance of undesirable side effects. 

Reduced dose and 

Improved patient compliance. 

Used for drugs with chronopharmacological behaviour, a high first pass 

effect, the requirement of night-time dosing and site-specific absorption in 

GIT. 


18

The conditions that demand pulsatile release include: 

Introduction 

Many body functions that follow circadian rhythm i.e. their waxes and 

wanes with time. Ex: hormonal secretions. 

Diseases like bronchial asthma, myocardial infraction, angina pectoris, 

rheumatoid diseases, ulcer and hypertension display time dependence. 

Drugs that produce biological tolerance demand for a system that will 

prevent continuous present at the biophase as this tend to reduce their 

therapeutic effect. 

The lag time is essential for the drugs that undergo degradation in gastric 

acidic medium (ex: peptide drugs) irritate the gastric mucosa or induce 

nausea and vomiting. 

Targeting to distal organs of GIT like the colon requires that the drug 

release is prevented in the upper two-third portion of the GIT. 

All of these conditions demand for a time-programmed therapeutic scheme 

releasing the right amount of drug at the right time. This requirement is fulfilled 

by pulsatile drug delivery system, which is characterized by a lag time that is an 

interval of no drug release followed by rapid drug release. 1 

Pulsatile systems are basically time-controlled drug delivery systems in 

which the system controls the lag time independent of environmental factors like 

pH, enzymes, gastrointestinal motility, etc. these time-controlled systems can be 

classified as single unit (tablet or capsule) or multiple unit (e.g., pellets) 

systems. 1,15 


19

Fig 2: Drug release profile of pulsatile drug delivery systems 

A: Ideal sigmoidal release 

1) Single Unit Systems 15,16,17,18 

B & C: Delayed release after initial lag time 

i) Drug delivery systems with eroding or soluble barrier coatings 

Introduction 

Most pulsatile delivery systems are reservoir devices coated with a barrier 

layer. The barrier dissolves or erodes after a specify lag period, after which the 

drug is released rapidly from the reservoir core. In general, the lag time prior to 

drug release from a reservoir type device can be controlled by the thickness of the 

coating layer. E.g. The Time Clock ® system (West Pharmaceutical Services Drug 

Delivery & Clinical Research Centre), and chronotropic ® system consists of a 

drug containing core coated by hydrophilic swellable hydroxypropylmethyl 

cellulose (HPMC), which is responsible for a lag phase in the onset of release. 


20

ii) Drug delivery systems with rupturable coatings 

Introduction 

In this the drug is released from a core (tablet or capsule) after rupturing 

the surrounding polymeric layer, caused by inbuilt pressure within the system. 

The pressure necessary to rupture the coating can be achieved with gas-producing 

effervescent excipients, osmotic pressure or swelling agents. 

iii) Capsular shaped systems 

Several single unit pulsatile dosage forms with a capsular design have 

been developed. Most of them consist of an insoluble capsule body, containing the 

drug and a plug, which gets removed after a predetermined lag time because of 

swelling, erosion or dissolution. E.g., Pulsincap ® system and Port ® system. 

The Pulsincap ® system consists of a water-insoluble capsule body 

(exposing the body to formaldehyde vapor which may be produced by the addition 

of trioxymethylene tablets or potassium permanganate to formalin or any other 

method), filled with the drug formulation and plugged with a swellable hydrogel 

at the open end. Upon contact with dissolution media or gastrointestinal fluid, the 

plug swells and comes out of the capsule after a lag time, followed by a rapid 

release of the contents. The lag time prior to the drug release can be controlled by 

the dimension and the position of the drug. In order to assure a rapid release of the 

drug content, effervescent agents or disintegrants were added to the drug 

formulation, especially with water-insoluble drug. Studies in animals and healthy 

volunteers proved the tolerability of the formulation (e.g., absence of 


21

Introduction 

gastrointestinal irritation). In order to overcome the potential problem of variable 

gastric residence time of a single unit dosage forms, the Pulsincap ® system was 

coated with an enteric layer, which dissolved upon reaching the higher pH regions 

of the small intestine. 

The plug consists of 

Swellable materials coated with insoluble, but permeable polymers (e.g., 

polymethacrylates) 

Erodible compressed materials (e.g., HPMC, polyvinyl alcohol, 

polyethylene oxide) 

Congealed melted polymers (e.g., saturated polyglycoated glycerides or 

glyceryl monooleate). 

Fig. 3: Different stages in drug release from pulsincap 


22

2) Multiparticulate Pulsatile Drug Delivery Systems: 

Introduction 

These have various advantages, when compared to single unit dosage 

forms, which include, a reproducible gastric residence time, no risk of dose 

dumping and the flexibility to blend with different compositions or release 

patterns e.g., pellets. 

However, drug loading in these systems is low because of higher need of 

excipients (e.g. sugar cores). Multiparticulate with pulsatile release pr ofiles are 

usually reservoir-type devices with a coating, which either ruptures or changes its 

permeability. 

1.6 Colon specific drug delivery systems (CSDDS) 16,17 

The colonic region of the gastrointestinal tract is one area that would 

benefit from the development and use of such modified release technologies. 

Although considered by many to be an innocuous organ that has simple functions 

in the form of water and electrolyte absorption and the formation, storage and 

expulsion of faecal material, the colon is vulnerable to a number of disorders 

including ulcerative colitis, crohn’s disease IBS and carcinomas. In addition, 

systemic absorption from the colon also be used as a means of achieving 

chronotherapy for diseases that are sensitive to circadian rhythms such as asthma, 

angina and arthritis. 


23

1.6.1 Structure and function of the Colon: 16 

Introduction 

The colon forms the lower part of the gastrointestinal tract and extends 

from the ileocecal junction at the anus. The colon is upper five feet of the large 

intestine and the rectum is the lower six inches. While the colon is mainly situated 

in the abdomen, the rectum is primarily a pelvic organ. The first portion of the 

colon is spherical and is called cecum. The appendix hangs off the cecum. The 

next portion of the colon, in the order in which contents flow, is the ascending 

(proximal) colon, just under the liver, the angle or bend is known as the hepatic 

flexure, located just beneath the rib cage. The colon then turns to a long horizontal 

segment, the transverse colon. Beneath the left rib cage, the colon turns downward 

at the haustra, to become the descending (distal) colon. In the left lower portion of 

the abdomen, the colon makes an S-shaped curve from the hip over the midline 

known as the sigmoid colon. The colon and rectum have an anatomic blood 

supply. Along these blood vessels are lymph nodes. Lymph nodes are structures 

found in the circulating lymphatic system of the body that produce and store cells 

that fight infection, inflammation, foreign proteins and cancer. 


24

1.6.2 pH in colon: 7,16 

Fig. 4: Structure of colon 

Introduction 

Radiotelemetry shows the highest pH levels (7.5 0.5) in the terminal 

ileum. On entry into the colon, the pH drops to 6.40.6. The pH in the mid colon 

is 6.60.8 and in the left colon 7.00.7. There is a fall in pH on entry into the 

colon due to the presence of short chain fatty acids arising from bacterial 

fermentation polysaccharides. For example lactose is fermented by the colonic 

bacteria to produce large amounts of lactic acid resulting in pH drop to about 5.0. 


25

Table 2: Average pH in the GI tract 

Location pH 

Oral cavity 6.2-7.4 

Oseophagus 5.0-6.0 

Stomach Fasted condition:1.5-2.0 

Fed condition: 3.0-7.5 

Small intestine Jejunum:5.0-6.5 

Ileum: 6.0-7.5 

Large intestine Right colon: 6.4 

1.6.3 Gastrointestinal transit: 7 

Mild colon and left colon:6.0-7.6 

Introduction 

Gastric emptying of dosage form is highly variable and depends primarily 

on whether the subject is fed or fasted and on the properties of the dosage forms 

such as size and density. The arrival of an oral dosage form at the colon is 

determined by the rate of gastric emptying and the small intestinal transit time. 

Although the surface area in the colon is low compared to the small intestine, this 

is compensated by the markedly slower rate of transit. 

Table 3: Average GI transit time 

Oral Transit time (hr) 

Stomach 3(fed) 

Small intestine 3-4 

Large intestine 20-30 


26

1.6.4 Methods for targeting drug into the colon: 7,14,16,19,20 

Introduction 

By definition, an oral colonic delivery system should retard drug release in 

the stomach and small intestine but allow complete release in the colon. The fact 

that such a system will be exposed to a diverse range of gastrointestinal conditions 

on passage through the gut makes colonic delivery via the oral route a challenging 

proposition. Nevertheless a number of approaches have been used and systems 

have been developed for the purpose of achieving colonic targeting. These 

applications are either drug specific (prodrug) or formulations specific (coated or 

matrix preparations). The most commonly used targeting mechanisms are: 

1 pH-dependent delivery 

2 Time dependent delivery 

3 Pressure dependent delivery 

4 Bacteria- dependent delivery 

1) pH- Triggering Drug Delivery Systems: 

Use of pH-dependent polymers is based on the differences in pH levels 

throughout GIT. The polymers described as pH- dependent in colon specific drug 

delivery are insoluble at low pH levels but become increasingly soluble as pH 

rises. The principle group of polymers utilized for the preparation of colon 

targeted dosage forms has been the Eudragits (registered trademark of Rohm 

Pharma, Darmstadt, Germany), more specifically Eudragit L100 and S100 are 

copolymers of methacrylic acid and methyl methacrylate. The ratio of the 


27

Introduction 

carboxyl ester groups is approximately 1:1 in Eudragit L100 and 1:2 in Eudragit 

S100. The polymers form salts and dissolve above pH 6 and 7 respectively. This 

approach is based on the assumption that gastrointestinal pH increases 

progressively from the small intestine to colon. In fact, the pH in the distal small 

intestine is usually around 7.5, while the pH in the proximal colon is closer to 6. 

The pH-sensitive delivery systems commercially available for mesalazine 

(5-aminosalicylic acid) (Asacol ® and Salofalk ® ) and budesonide (Budenofalk ® and 

Entocort ® ) for the treatment of ulcerative colitis and Chron’s disease respectively. 

2) Time-Dependent Delivery System: 

As discussed earlier, although gastric emptying tends to be highly variable, 

small intestinal transit times are less (3 1 h). So various attempts are made to 

prevent the release of drug until 3-4 h after leaving the stomach. These systems 

release their drug load after a pre-programmed time delay. To attain colonic 

release, the lag time should equate to the time taken for the system to reach the 

colon. This time is difficult to predict in advance, although a lag time of five hours 

is usually considered sufficient, given that small intestinal transit time is reported 

to be relatively constant at three to four hours. 

The drug delivery systems, Pulsincap ® and Time Clock ® are time 

dependent formulations. 


28

3) Pressure-Controlled Drug Delivery Systems: 

Introduction 

Gastrointestinal pressure has also been utilized to trigger drug release in 

the distal gut. This pressure, which is generated via muscular contractions of the 

gut wall for grinding and propulsion of intestinal contents, varies in intensity and 

duration throughout the gastrointestinal tract, with the colon considered to have a 

higher luminal pressure due to the processes that occur during stool formation. 

Systems have therefore been developed to resist the pressures of the upper 

gastrointestinal tract but rupture in response to the raised pressure of the colon. 

The system can be modified to withstand and rupture at different pressures by 

changing the size of the capsule and thickness of the capsule shell wall. 

Takaya et al. have developed pressure-controlled colon-delivery capsules 

prepared using an ethyl cellulose, which is insoluble in water. 

4) Microflora-Activated Drug Delivery Systems: 

The resident gastrointestinal bacteria provide a further means of effecting 

drug release in the colon. These bacteria predominantly colonize the distal regions 

of the gastrointestinal tract where the bacterial count in the colon is 10 11 per 

gramme, as compared with 10 4 per gramme in the upper small intestine. Moreover 

400 different species are present. Colonic bacteria are predominantly anaerobic in 

nature and produce enzymes that are capable of metabolizing endogenous and 

exogenous substrates, such as carbohydrates and proteins that escape digestion in 

the upper gastrointestinal tract. Both prodrugs and dosage forms from which the 

release of drug is triggered by the action of colonic bacteria enzymes have 


29

Introduction 

devised. Enzymes produced by the colonic bacterial are capable of catalyzing a 

number of metabolic reactions, which includes reduction (of double bonds, nitro 

groups, azo groups, aldehydes, sulphoxides, ketones, alcohols, N-oxides and 

arsenic acid), hydrolysis (of glycosides, sulphates, amides, esters, nitrates and 

sulphonates), deamination, decarboxylation, dealkylation, acetylation, nitrosamine 

formation, heterolytic ring fission and esterification. 

Design 

strategy 

Table 4: Summary of colon-specific drug delivery strategies 16,19,20 

Drug release triggering 

mechanisms 

Prodrugs Cleavage of the linkage 

bond between drug and 

carrier via reduction and 

hydrolysis by enzyme from 

colon bacteria. Typical 

enzymes include 

azoreductase, glycosidase, 

and glucuronidase. 

pHdepedent 

systems 

Timedependent 

system 

Microfloro 

activated 

system 

Combination of polymers 

with pH-dependent 

solubility to take advantage 

of the pH changes along the 

GI tract. 

The onset of drug release is 

aligned with positioning the 

delivery system in the colon 

by incorporating a time 

factor simulating the system 

transit in upper GIT. 

Primarily fermentation of 

non-starch polysaccharides 

by colon anaerobic bacteria. 

The polysaccharides are 

incorporated into the 

delivery system via film 

coating and matrix 

formation. 

Advantages Disadvantages 

Able to achieve 

site specificity. 

Formulation 

well protected 

in the stomach 

Small intestine 

transit time 

fairly 

consistent. 

Good site 

specificity with 

prodrugs and 

polysaccharides. 

It will be considered as a 

new chemical entity 

from regulatory 

prespective. So far this 

approch has been 

primarily constricted to 

achives releated to the 

treatment of IBD. 

Unpredictable sitespecificity 

of drug 

release because of 

inter/intra subject 

variation of pH between 

small intestine and the 

colon. 

Substantial variation in 

gastric retention times 

make it complicated in 

predicting the accurate 

location of drug release. 

Diet and disease can 

affect colonic 

microflora; enzymatic 

degredation may be 

excessively slow. 


30

1.7 Microencapsulation: 7 

Introduction 

A microcapsule is a tiny capsule and its preparation produced, called 

microcapsulation, can endow various traits to core material in order to add 

secondary functions and/or compensate for shortcomings. 

Microencapsulation is a technique to prepare tiny packaged materials 

called microcapsules that have many interesting features. This technique has been 

employed in a diverse range of fields from chemicals and pharmaceuticals to 

cosmetics and printing. For this region widespread interest has developed in 

microencapsulation technology. Microcapsules are tiny microparticles with 

diameters in the range of nanometres or millimetres that consist of core materials 

and convering membranes (sometime also called walls). The most significant 

features of microcapsules is their size that allows for a huge surface or interface 

area. Through selection of the composition materials (sometimes also called 

walls). The most significant feature of microcapsules is their microscopic size that 

allows for a huge surface or interface area. Through selection of composition 

materials (core material and membrane), we can endow microcapsule with a 

variety of functions. Generally, membrane materials are chosen in order to 

pronounce the effects of microencapsulation. Therefore, not only synthetic and 

natural polymers but also lipids and inorganic materials are used for the 

preparation of microcapsules. 


31

Introduction 

Microcapsules have a number of interesting advantages and the main 

reasons for microencapsulation cap be exemplified as 

1. Controlled release of en encapsulating drugs, 

2. Protection of the encapsulated materials against oxidation or deactivation due 

to reaction in the environment 

3. Masking of odour and/or taste of encapsulating materials. 

4. Isolation of encapsulating materials from undesirable phenomena, and 

5. Easy handling as powder-like materials. 

Microcapsule can also be classified into three basic categories according to 

their morphology as mono-cored, poly-cored and matrix type as shown in Fig 8 

Morphological control is important and much effort has been given to controlling 

internal structures, which largely depend on protocol and the microcapsulation 

methods employed. 

Fig 5: Classification of microparticles. 


32

2.1 Need for the study: 

CHAPTER-2 

 


Objectives 

The development of oral sustained and controlled release formulation 

offer benefits like controlled administration of therapeutic dose at the delivery 

rate, constant blood levels of the drug, reduction of side effects minimizations 

of dosing frequency and enhancement of patient compliance. 21 

Among modified-release oral dosage form increasing interest has 

currently turned to system designed to achieve time-specific (delayed, pulsatile) 

and site-specific delivery of drug. The possibility of exploiting delayed release 

to perform chronotherapy, is quite appealing for those diseases, the symptoms 

of which recur mainly at night time or in the early morning, such as bronchial 

asthma, angina pectoris and rheumatoid arthritis. 22,23,24 

Flurbiprofen [1,1’-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, is an 

important analgesic and non-steroidal anti-inflammatory drug (NSAID) also 

with anti-pyretic properties whose mechanism of action is the inhibition of 

prostaglandin synthesis. It is used in the therapy of rheumatoid disorders. 

Flurbiprofen is rapidly eliminated from the blood, its plasma elimination half- 

life is 3-6 hours and in order to maintain therapeutic plasma levels. The drug 

must be administered approximately 150-200mg daily by oral in divided 

doses. 25 

33


Objectives 

The aim of this work is to design site-specific (pulsatile) drug delivery 

system with pH sensitive methacrylic acid co-polymers and Flurbiprofen as 

model drug, whose drug delivery system. 

2.2 Objective of the study 

To design and characterize an oral, drug delivery system of Flurbiprofen 

intended to approximate the chronobiology of arthrities, proposed for colonic 

targeting. It is a chronopharmaceutical approach for the better treatment of 

rheumatoid arthritics. 

Based on the concept that a formulation on leaving the stomach, arrives at 

the ileocaecal junction in about 6 hours after administration and difference in pH 

throughout GIT, a time and pH dependent pulsatile ( or modified pulsincap), 

controlled drug delivery system was designed. 

This capsule consists of a non-disintegrating body and a soluble cap. The 

drug formulations is contained within the capsule body and separated from the 

water-soluble cap by a hydrogel polymer plug. The entire capsule is enteric coated 

to prevent variable gastric emptying. The enteric coating prevents disintegration 

of the soluble cap in the gastric fluid. On reaching the small intestine the capsule 

will lose its enteric coating and the polymer plug inside the capsule swells to 

create a lag phase that equals the small intestinal transit time. This plug ejects on 

swelling and releases the drug from the capsule in the colon. 

34

2.3 Plan of Research Work 


Objectives 

1. Selection of polymers and its combinations suitable for the colonic drug 

delivery. 

2. Preparation of Flurbiprofen microcapsules. 

3. Evaluation of microcapsules: 

a) Particle size 

b) Study of flow properties 

c) Percentage yield 

d) Drug content 

c) Drug-Polymer interaction 

d) External morphology 

c) In-vitro drug release kinetics 

4) Preparation of cross-linked gelatine capsules. 

a) Formaldehyde treatment of capsule bodies 

b) Test for formaldehyde treated empty capsule 

Physical test 

Identification attributes 

Visual defect 

Dimensions 

Solubility studies of treated capsules 

35

Chemical test 

Qualitative test for free formaldehyde 

5) Development of pulsatile drug delivery system. 

6) Evaluation of pulsatile drug delivery system 

a) Thickness of cellulose acetate phthalate coating 

b) Weight variation 

c) In-vitro drug release kinetics 


Objectives 

36

3.1 Literature Survey 

CHAPTER-3 

Review Of Literature 

 

Listair CR, et al. 26 developed a chronopharmaceutical capsule drug 

delivery system capable of releasing drug after predetermined time delays. The 

drug formulation is sealed inside the capsule body by an erodible table (ET). The 

release time is determined by an ET erosion rate and increases as the content of an 

insoluble excipient (dibasic calcium phosphate) and of gel forming excipient 

(HPMC) increases. Programmable pulsatile release has been achieved from a 

capsule over a 2-12 hrs period, consistent with the demands of chronotherapeutic 

drug delivery. 

Samantha MK, et al. 27 designed and evaluated Pulsincap drug delivery 

system of Salbutamol sulphate for drug targeting to colon in disease condition like 

asthma. Empty gelatin capsule was coated with ethycellulose keeping the cap 

portion as such. A hydrogel plug made of gelatin was suitably coated with 

Cellulose Acetate Phthalate in such a way that it was fixed to the body under the 

cap. Eudragit microcapsule containing Salbutamol sulphate were prepared and 

incorporated into this specialized capsule shell. The in-vitro dissolution studies 

indicated that the onset of drug release was after 7 to 8 hrs of the experiment and 

revealed its better sustaining efficacy over a period of 24hrs. 


37


Young-II Jeong, et al. 28 evaluated pressure-controlled colon delivery 

(PCDCS) capsules prepared by a dipping method. Empty PCDCS are composed 

of two polymer membranes. The inner one was a water-insoluble polymer 

membrane, ethycellulose (EC) and the outer one was an enter ic polymer 

membrane. Hydroxypropyl methylcellulose phthalate (HPMCAS). By 

consequently dipping in an ethanolic EC solution and alkalized enteric polymer 

solution, PCDCS were obtained after both the capsule body and cap were adjusted 

to the size of #2 capsules. 

Seshasayan A, et al. 29 studied release of Rifampicin from modified 

pulsincap preparation, using different preparation of various hydrophilic polymer 

such as guar gum, cabapol-940, sodium alginate, hydroxypropyl methylcellulose, 

gum karaya and poly vinyl alcohol. Among all the polymers tested guar gum 

showed better sustaining capacity even at low concentration. 

Julie Binns, et al. 18 studied the tolerability of multiple oral dose of 

pulsincap ® capsule in a healthy volunteers. Twelve healthy subjects entered a 

double-blind placebo-controlled parallel group study to evaluate the tolerability of 

a 28 days course of twice daily dosage with pulsincap ® capsules having the plug 

set for separation after 6 hrs. 

Sangalli ME, et al. 30 performed in-vitro and in-vivo evaluation of an oral 

system (Chronotropic TM ) designed to achieve time & /or site specific release. 

Cores containing antipyrine as the model drug were prepared by tableting and 

both the retarding and enteric coatings were applied in fluid bed. The release test 


38


was carried out in a USP 24 paddle apparatus. The in-vitro testing, performed on 

healthy volunteers, envisaged the HPLC determination of antipyrine salivary 

concentration and γ-scintigraphic investigation. 

Zahirul Khan MI, et al. 31 formulated a pH-dependent colon targeted oral 

drug delivery system using methacrylic acid copolymers. Drug release was 

manipulated using Eudragit ® 100-55 and Eudragit ® S100 combinations. The 

coated tablets were tested in-vitro for their sutability for pH dependent colon 

targeted oral delivery. 

Howard Stevens NE, et al. 32 designed pulsincap ® formulations to delivery 

a dose of drug following 5 h delay and evaluated the capability of the formulation 

to deliver defetilide to the lower GIT. The combination of scintigraphic and 

pharmacokinetic analysis permits identification of the site of drug release from the 

dosage form and pharmacokinetic parameters to be studied in man in a non- 

invasive manner. 

Libo Yang, et al. 33 reviewed the new approaches in-vitro and in-vivo 

evaluation of colon specific drug delivery systems. 

Ying-huan Li, et al. 34 developed a multifunctional and multiple unit 

system, which contains versatile mini-tablets in a hard gelatin capsule, as Rapid- 

release Mini-tablets (RMTs), Sustained -release Mini-Tablets (SMTs), Pulsatile 

Mini-Tablets (PMTs) and Delayed onset Sustained- release Mini tablets (DSMTs), 

each with various lag times of release. 


39


Tomohiro Takaya, et al. 35 studied the importance of dissolution process 

on systemic availability of drugs delivered by colon delivery system. The 

relationship between in-vitro drug release characteristics from colon delivery 

systems and in-vivo drug absorption was investigated using three kinds of 

delayed-release systems. Pressure controlled colon delivery capsules for liquid 

preparations, time controlled colon delivery capsules for liquid and solid 

preparations and Eudragit S coated tablets for solid preparations were used in this 

study. 

Takashi Ishibashi, et al. 36 evaluated colonic absorbability of drugs dog 

using a novel colon-targeted delivery capsule (CTDC). A series of dog studies 

were performed to examine the in- vitro/in-vivo relationship of drug release 

behaviour of the newly developed CTDC. The 4 kinds of CTDCs containing 

theophylline, each of which has a different in-vitro dissolution lag time, were 

orally administered to 4 beagle dogs under fasted condition and the onset time of 

drug absorption were compared. 

Jonathan CDS, et al. 37 investigated the coating-dependent release 

mechanism of a pulsatile capsule using Nuclear Resonance microscopy. 

Chrononopharmaceutical capsules, ethycellulose-coated to prevent water ingress, 

exhibited clearly different characteristic when coated by organic or aqueous 

processes. 


40


Mastiholimath, et al. 38 attempt was made to that of the small intestine 

(7.0–7.8). So, by using the deliver theophylline into colon by taking the advantage 

of the fact that colon has a lower pH value (6.8) than mixture of the polymers, i.e. 

Eudragit L and Eudragit S in proper proportion, pH dependent release in the colon 

was obtained. 

Abraham S, et al. 39 reported modified pulsincap dosage form of 

metronidazle to target drug release in colon by using extrusion-spheronization 

method. 

Sungthongjeen S, et al. 40 reported development of pulsatile release tablets 

with swelling and rupturable layers. Finally concluded that pulsatile release tablets 

with a swelling layer and rupturable ethyl cellulose coating were developed. The 

system released the drug rapidly after a certain lag time due to the rupture of ethyl 

cellulose film. 

Krishnaiah YSR, et al. 41 development of colon targeted drug delivery 

systems for mebendazole The tablets were evaluated for drug content uniformity, 

and were subjected to in vitro drug release studies. Differential scanning 

calorimetry (DSC). 

Satyanarayana S, et al. 42 presented the delivery of drugs to the colon for 

local effects, including drug candidates, methods used for studying colonic drug 

absorption and colon-specific drug delivery systems, role of absorption enhancers 


41


in colonic drug delivery, and the use of prodrugs, drugs coated with pH dependent 

or pH independent biodegradable polymers, or polysaccharide matrices 

Ram Prasad YV, et al. 43 assessed the utility of guar gum as a carrier for 

colon specific drug delivery using indomethacin as model drug from an oral 

matrix tablet formulation containing 40 mg of drug and 340 mg of guar gum in 0.1 

M HCl for 2 hrs and pH 7.4 phosphate buffer for 3 hrs in albino rat cecal content 

after 5 hrs of testing under conditions mimicking mouth to colon transit, guar gum 

was found to be susceptible to colon bacterial enzyme action with the consequent 

release of indomethacin. 

Krishnaiah YSR, et al. 44 used guar gum as a carrier for colon specific and 

studied influence of metronidazole and tinidazole on in-vitro release of 

albendazole from guar gum matrix tablet and it was found that the release of drug 

from guar gum formulations increased with a decrease in the dose of 

metronidazole / tinidazole. 

Leopold CS, et al. 45 carried out in-vitro study for the assessment of poly 

(Laspartic acid) as a drug carrier for colon specific drug delivery, using 

dexamethasone as model drug. It was concluded that poly (L -aspartic acid) 

appears to be a suitable drug carrier for colon specific drug delivery. 

Rubinstein et al. 46 (1995) showed that calcium pectinate -indomethacin 

tablets of both types, i.e. compression coated and matrix tablets give no release of 

indomethacin at a pH-1.5 for 2 hrs.When these tablets were shaken at a pH-7.4 a 


42


drug leak was seen in plain matrix tablets but not in compression coated tablets. In 

the presence of pectinolytic enzymes, a sudden release of indomethacin was seen 

in both, the types of tablets but the rate and the percentage of release were lower 

(only 57.6#2.5% ) in compression coated tablets as compared to plain matrix 

tablets (74.2#4%) after 12hrs. 

Turkoglu, et al. 47 evaluated the pectin-HPMC system for compression 

coated core tablets of 5-aminosalicylic acid (5 -ASA) for colonic delivery. Drug 

dissolution/system erosion/degradation studies were carried out in pH 1.2 and 6.8 

phosphate buffers using a pectinolytic enzyme. The system was designed based on 

the gastrointestinal transit time concept, under the assumption of colon arrival 

times of 6 hrs. It was found that pectin alone was not sufficient to protect ate core 

tablets and HPMC addition was required to control the solubility of pectin. The 

optimum HPMC concentration was 20% and such system would protect the 

course up to 6 h that corresponded to 25-35% erosion and after that under the 

influence of pectinase the system would degrade faster and delivering 5-ASA to 

the colon. The pectin-HPMC envelope was found to be a promising drug delivery 

system for those drugs to be delivered to the colon. 

Rama Prasad et al. 48 evaluated the suitability of guar gum as a carrier in 

colonic drug delivery. In this study, matrix tablet of indomethacin with guar gum 

were prepared. These tablets were found to retain their integrity in 0.1M HCl for 2 

hrs and in Sorensen’s phosphate buffer (pH-7.4) for 3 hr releasing only 21% of the 

drug in these 5 hrs. However, in presence of 2% rat cecal contents the drug 


43


release increased and further increased with 4% concentration of cecal contents. 

The drug release improved to about 91% in 4% cecal content medium after 

enzyme induction of rats. This study suggests the specificity of these matrices for 

enzyme trigger in the colon to release the drug. 

Krishnaiah, et al. 49 evaluated guar gum as a compression coating to protect 

the drug core of 5- ASA in upper GIT. Percent drug release from tablet increased 

considerably from 11 hr and the tablets were completely disintegrated in 26 hr in 

the presence of the rat cecal medium. The results of drug release studies on 

compression coated tablets suggested that the thickness of guar gum coating in the 

range of 0.61-0.91 mm was sufficient to deliver the drugs selectively to the colon. 

Krishnaiah et. al. 50 studied to develop colon targeted drug delivery systems 

for metronidazole using guar gum as a carrier. Matrix, multilayer and compression 

coated tablets of metronidazole containing various proportions of guar gum were 

prepared. Matrix tablets and multilayer tablets of metronidazole failed to control 

the drug release within 5 hrs of the dissolution study in the physiological 

environment of stomach and small intestine. The compression coated formulations 

released less than 1% of metronidazole in the physiological environment of 

stomach and small intestine. The results of the study show that compression 

coated metronidazole tablets with either 275 or 350 mg of guar gum coat is most 

likely to provide targeting of metronidazole for local action in the colon owing to 

its minimal release of the drug in the first 5 hrs. 


44


Shinha, et al. 51 evaluated polysaccharide (combined xanthan gum and guar 

gum) matrices for microbially triggered drug delivery to the colon. Matrix tablets 

were prepared using xanthan gum and guar gum in vary in proportions using 

indomethacin as model drug. The ability of the prepared matrices to retard drug 

release in the upper gastrointestinal tract and to undergo enzymatic hydrolysis by 

the colonic bacteria was evaluated in the presence of rat cecal content. Guar gum 

alone as a drug release retarding excipient in the matrices does not achieve the 

desired retardation. Presence of xanthan gum in the tablets not only retard the 

initial drug release from the tablets, but due to high swelling, make them more 

vulnerable to digestion by the microbial enzymes in the colon. 

Lorenzo-lamosa, et al. 52 prepared and demonstrated the efficacy of a 

system, which combines specific biodegradability and pH dependent release 

behaviour. The systemconsists of chitosan microcores entrapped within acrylic 

microspheres containing diclofenac sodium as model drug. The drug was 

efficiently entrapped within the chitosan microcores using spray drying and then 

microencapsulated into Eudragit L100 using and Eudragit S100 using an oil-in-oil 

solvent evaporation method. Release of the drug from chitosan multi-reservoir 

system was adjusted by changing the chitosan molecular weight or the type of 

chitosan salt. No release was seen in acidic pH for 3hr, but at higher pH Eudragit 

dissolved and swelling of chitosan started leading to continuous drug diffusion 

which completed in the next 4hr. Furthermore, by coating the chitosan microcores 

with Eudragit ® perfect pH-dependent release profiles were attained. 


45


Brondsted et al. 53 investigated the application of glutaraldehyde cross 

linked dextran as a capsule material for colon-specific drug delivery. These 

capsules were loaded with hydrocortisone and drug release studies were 

conducted in vitro. Ten percent of drug was released in initial 3h and only about 

35% in 24 h at pH 5.4. Addition of dextranase enzyme after 24 h resulted in a 

rapid degradation of the capsule leading to fast and complete release of 

hydrocortisone. However, these results reflect only an experimental condition and 

not the in vivo situation. 

Vervoort, et al. 54,55 synthesized methacrylated insulin and aqueous 

solutions of methacrylated insulin upon free radical polymerization, were 

converted to cross-linked hydrogels. Rheological studies and characterization of 

there hydrogels showed that higher substituted insulin had better network and 

higher mechanical strength. These hydrogels were there studied for their swelling 

properties and degradation in vitro. Degradation studies carried out in presence of 

insulinase showed that increasing enzyme concentration and incubation time 

degraded insulin faster. However, increasing the substitution on insulin molecules 

resulted in stronger hydrogels with less enzyme diffusion thereby less 

degradation. 

Rubinstein, et al 56 developed cross-linked chondroitin as a drug carrier for 

colon-specific delivery. Chondroitin sulphate was cross-linked with 1,12- 

diaminododecane via dicyclohexylcarbodiimide activation. Cross-linked 


46


chondroitin sulphate was used to form a matrix tablet with indomethacin. Release 

ofindomethacin from the tablet was studied in the presence of rat cecal contents 

ascompared to release in phosphate buffer saline. A significant difference in drug 

release was observed after 14 hrs in the two dissolution media. Also, different 

degreesof cross-linked chondroitin sulphate were used to study their effect on 

drug releasefrom the matrices. The cumulative percent release of indomethacin 

from cross-linked chondroitin matrix tablet showed that release was increased in 

the presence of rat cecal contents. Studies on rat cecal contents with various cross- 

linked chondroitin sulphate showed greater cumulative drug release when cross- 

linking was less and as crosslinking increased the cumulative release decreased 

i.e. a linear relationship was found between the degree of cross-linking of polymer 

and the amount of drug released in rat cecal content. 

Milojevic, et al. 57 evaluated Amylose-Ethocel ® system for their potential 

as microbial degradable colon drug carrier. Amylose-Ethocel ® coating system 

resistant to gastric acid and small intestinal enzymes, but degradable by colonic 

bacteria. Varying concentration of Amylose and Ethocel ® in the form of aqueous 

dispersions were use to coat 5-ASA pellets. Coating formulation comprising 

Amylose and Ethocel ® in the ratio of 1:4 w/w showed optimum drug release 

retarding properties in gastric and intestinal fluids. 

Shantha KL, et al. 58 developed azo polymeric hydrogels for colon targeted 

drug delivery and studied various physicochemical properties such as FT-IR, 

SEM, Equilibrium swelling studies, In-vitro release. 


47


Takashi Ishibashi, et al. 59 developed new capsule-type dosage form for 

colon-targeted delivery of drugs The system was designed by imparting a timed- 

release function and a pH-sensing function to a hard gelatin capsule. The technical 

characteristics of the system are to contain an organic acid together with an active 

ingredient in a capsule coated with a three-layered film consisting of an acid- 

soluble polymer, a water-soluble polymer, and an enteric polymer. In order to find 

the suitable formulation, various formulation factors were investigated through a 

series of in vitro dissolution studies. As a result, it was found that: (1) various 

organic acids can be used for this system: (2) a predictable timed -release 

mechanism of a drug can be attained by adjusting the thickness of the Eudragit ® E 

layer: and (3) the outer enteric coating with HPMC ® -AS provided acceptable acid- 

resistibility. All these results suggested that this approach can provide a useful and 

practical means for colon-targeted delivery of drugs. 

Anita L et. al. 60 reviewed the ability to deliver therapeutic agents to a 

patient in a pulsatile or staggered release profile has been a major goal in drug 

delivery research recently. This review will cover methods that have been 

developed to control drug delivery profile with different polymeric systems. 

Externally and internally controlled system will be considered including a range 

of technologies like pre-programmed systems as well as systems that are sensitive 

to modulated enzymatic or hydrolytic degradation, pH, magnetic fields, 

ultrasounds, electric fields, temperature, light and mechanical stimulation. These 

systems have the potential to improve the quality of life for patients undergoing 

therapy with a variable dosing regimen. 


48


Morta Rodriguez, et al. 61 presented a new multiparticulate system to 

deliver active molecules to colonic region, which combines pH-dependent and 

controlled drug release properties. This system was constituted by drug loaded 

cellulose acetate butyrate (CAB) microspheres coated by an enteric polymer 

(eudragit ® S). Both, CAB cores and pH-sensitive microcapsules were prepared by 

the emulsion solvent evaporation technique in an oil phase. The in-vitro drug 

release studies of pH-sensitive microcapsules containing the hydrophobic cores 

showed that no drug was released below pH 7. 

Lorenzo- Lamosa ML, et al. 62 designed the microcapsulated chitoson 

microspheres for colonic drug delivery. Sodium diclofenac(SD) used as a model 

drug, was effectively entrapped within chitoson (CS) microcores using spray - 

drying and then microcapsulated into Eudragit ® L-100 and S-100 using an oil-in- 

oil solvent evaporation method. A combined mechanism of release is proposed, 

which considers the dissolution of eudragit coating, the swelling of the CS 

microcores and the dissolution of SD and its further diffusion through the CS gel 

cores. 

Shivkumar HN, et al. 63 designed the multiparticulate system comprising of 

nonpareil seeds coated with a mixture of Eudragit S-100 and L-100 for 

chronopharmaceutical delivery of diclofenac sodium. The in-vitro dissolution test 

showed that the release of drug from coated pellets depended on the pH of the 

dissolution fluid and the coat weights applied. 


49


Kristmudsodottir T, et al. 64 prepared microcapsule containing diltiazem 

hydrochloride by the Spray drying technique using Acrylate-methaacrylate 

copolymers, Eudragit RS and RL as coating materials and studied the drug release 

rate and concluded that the drug release rate can be controlled by choice of 

polymer type and production condition during spray-drying. 

Hideki Ichikawa, et al. 65 designed the prolonged-release microcapsules 

containing diclofenac sodium for oral suspension and their preparation by the 

wurster process. 

Giovanni FP, et al. 66 prepared controlled release of ketoprofen by emulsion 

solvent evaporation method. The prepared microspheres were characterized by 

scanning electron microscopy, x-ray diffractometry, and in-vitro dissolution 

studies and then used for the preparation of tablets. 

Alf Lamprecht, et al. 67 designed the microsphere for the colonic delivery 

of 5-fluorouracil prepared by a simple and fast o/w emulsification method. A 

relatively high drug load even for the hydrophilic drug 5-FU can be achieved. A 

pH-dependent release can be provided in a range of pH 6.8, where the main drug 

load is retained, and pH 7.4, where a fast dissolution of the carrier occurs. The 

enlargement of the particle results in a slight retardation effect on the drug release. 

When polymer combinations were applied for the microsphere preparation 

(Eudragit RS100 and Eudragit P-4581F) at different mixing ratios, only minor 

influences on particle size and drug load are observed. These simple polymer 


50


mixtures can prolong the release only for a relatively short period due to the 

exceptional structural arrangements of the carrier system. 

Lars hovgaard, et al. 68 developed dextran hydrogel for colon-specific drug 

delivery. Degradation of the hydrogels has been studied in vitro using dextrose, in 

vivo in rate and in human fermentation model. It was found that by changing the 

chemical composition of hydrogels it is possible to control the equilibrium degree 

of swelling, mechanical strength and degradability. The dextran hydrogel were 

degraded in vivo in the cecum of rat but not in stomach. Furthermore, the dextran 

hydrogel were degraded in human colonic fermentation model, indicating that 

dextranases are indeed present in human colonic contents. Finally, releases of 

hydrocortisone from the hydrogels were evaluated. It was found to depend on the 

presence of dextranases in the release medium. the result suggest that the dextran 

hydrogels are promising as drug carries for colon-specific drug deliver. 

Mine Orlu, et. al. 69 designed and evaluated colon specific drug delivery 

system containing flurbiprofen microsponges Microsponges containing FLB 

(Flurbiprofen) and EudragitRS100 were prepared by quasi-emulsion solvent 

diffusion method. Additionally, FLB was entrapped into a commercial 

Microsponge ® 5640 system using entrapment method. Afterwards, the effects of 

drug: polymer ratio, inner phase solvent amount, stirring time and speed and 

stirrer type on the physical characteristics of microsponges were investigated. The 

thermal behaviour, surface morphology, particle size and pore structure of 

microsponges were examined. 


51

3.2 Drug profile: 25,70,71 

Flurbiprofen 

Molecular Formula : C15H13FO2 

Average Molecular Weight : 244.2609 

Drug Category: Analgesics 

Chemical Structure: 

Anti-Inflammatory Agents 

Non-Steroidal Anti-inflammatory Agents 

Carbonic Anhydrase Inhibitors 

Cyclooxygenase Inhibitors 

Chemical Name: 2-(3-fluoro-4-phenylphenyl) propanoic acid 

Description: 

Physical state and appearance: Solid. (Solid crystalline powder.) 

Odor : Practically odourless 

Taste : Not available. 



52

Molecular Weight : 244.27 g/mole 

Color : White to yellowish. 

Melting Point : 110°C (230°F) 

Solubility: 

Partially soluble in methanol. 

Very slightly soluble in cold water. 

Insoluble in diethyl ether. 

Stability: The product is stable. 


Storage: Keep container tightly closed. Keep container in a cool, well-ventilated 

area. 

Indication: Flurbiprofen tablets are indicated for the acute or long-term treatment 

of the signs and symptoms of rheumatoid arthritis and osteoarthritis 

Pharmacology: 

Flurbiprofen, a non- steroidal anti-inflammatory drug (NSAID) of the 

propionic acid class, is used for the relief of pain an inflammatioassociated with 

rheumatoid arthritis and osteoarthritis and for the inhibition of intraoperative 

miosis. Flurbiprofen exhibits anti-inflammatory, analgesic, and antipyretic 

activities 


53

Mechanism of Action: 


The anti-inflammatory effect of flurbiprofen may result from the 

reversible inhibition of cyclooxygenase, causing the peripheral inhibition of 

prostaglandin synthesis. Flurbiprofen also inhibits the migration of leukocytes into 

sites of inflammation and prevents the formation of thromboxane A2, an 

aggregating agent, by the platelets 

Absorption: 

The mean oral bioavailability of flurbiprofen from tablets is 96% relative 

to an oral solution. 

Toxicity : LD50=10 mg/kg (orally in dogs). 

Protein Binding : > 99% 

Biotransformation: 

Hepatic. Cytochrome P450 2C9 plays an important role in the metabolism 

of flurbiprofen to its major metabolite, 4’-hydroxy-flurbiprofen. The 4’-hydroxy- 

flurbiprofen metabolite showed little anti-inflammatory activity in animal models 

of inflammation 

Dose : 150-200mg daily by oral in divided doses. 

Half Life : 4.7-5.7 hours 


54

Interactions: 

Drug Interaction 


Acenocoumarol The NSAID increases the anticoagulant effect 

Alendronate Increased risk of gastric toxicity 

Anisindione The NSAID increases the anticoagulant effect 

Cyclosporine Monitor for nephrotoxicity 

Dicumarol The NSAID increases the anticoagulant effect 

Methotrexate 

The NSAID increases the effect and toxicity of 

methotrexate 

Warfarin The NSAID increases the anticoagulant effect 


55

3.3 Polymer Profile 

1. EUDRAGIT L 100 AND EUDRAGIT S 100: 72 

Synonyms : Methacrylic acid, Eudragit 

Functional category : Film former, tablet binder 


Chemical name: Copolymers synthesized from dimethylaminoethyl methacrylate 

and other neutral methacrylic esters 

Basic structure: 

Eudrgit ® L 100 and S 100 are anionic copolymers based on methacrylic 

acid and methyl methacrylate. The ratio of the free carboxyl groups to the ester 

groups is approx. 1:1 in eudragit ® L 100 and approx. 1:2 in eudrgit ® S 100.The 

average molecular weight is approx. 135,000. 

Description : White powders with a faint characteristic odour 


56


Solubility: 1 g of eudragit ® L 100 or eudragit ® S 100 dissolves in 7 g methanol, 

ethanol, in aqueous isopropyl alcohol and acetone (containing approx. 3 % water), 

as well as in 1 N sodium hydroxide to give clear to slightly cloudy solutions. 

EUDRAGIT ® L 100 and S 100 are practically insoluble in ethyl acetate, 

methylene chloride, petroleum ether and water. 

Stability and storage condition: 

Eudragit S 100 and L 100 polymers are stable at room temperature. 

Safety: Acute toxicity studies have been performed in rats, rabbits and dogs. No 

toxic effects were observed. Chronictoxicity studies were performed in rats over a 

period of 3 months. No significant changes were found in the animal organs. 

Applications in Pharmaceutical Formulation or Technology: 

Eudragit L 100 and S 100 are employed as film coating agents resistant 

to gastric fluid with solubility above pH 6.0 and 7.0 respectively, for enteric 

coating of formulations. 

Comments: 

For spray coating, the lacquer solutions and dispersions and must be 

thinned with suitable solvents. Suitable solvents are ethanol, isopropyl alcohol, 

diethyl ether, acetone, methylene chloride and water. Suitable plasticizers are 

glyceryl triacetate, phthalic acid esters, polyethyiene glycols, triacetin, dibutyl 

phthalate and citric acid esters. 


57

2. CELLULOSE ACETATE PHTHALATE 73,74,75 


Cellulose Acetate phthalate is cellulose, some of the hydroxyl groups of 

which are esterified by acetyl groups and others by hydrogen phthaloyl groups. 

Nonproprietary: Cellacephate; Cellacefate 

Synonyms: CAP, Cellulose acetophthalate 

Category: Pharmaceutical aid (for enteric coating of tablets). 

Structure: 

Description: 

White, free-flowing powder or colorless flakes; odorless or with a faint 

odor of acetic acid; hygroscopic 

Solubility: 

Freely soluble in acetone; soluble in diethylene glycol and in dioxan; 

practically insoluble in water, in ethanol (95), in toluene and in chlorinated and 

non-chlorinated aliphatic hydrocarbons. It dissolves in dilute solutions of alkalis. 


58

Storage: 

Viscosity: 


Store in tightly-closed containers at a temperature between 8 and 15 o C. 

A 15% solution in acetone with a moisture content of 0.4% has viscosity 

of 50-90 cps. This is a good coating solution with honey-like consistency, but the 

viscosity is influenced by the purity of the solvent. 

Incompatibilities: 

CAP is incompatible with ferrous sulfate, ferric chloride, silver nitrate, 

sodium citrate, aluminum sulfate, calcium chloride, mercuric chloride, barium 

nitrate, basic lead acetate, strong alkalis and acids. 

Applications in pharmaceutical formulation: 

CAP is used as an enteric coating material for tablets or capsules. Such 

coating resists simulated gastric fluid, and dissolves in the intestinal fluid. The 

addition of plasticizers improves the water resistance of this coating material and 

such plasticizers are more effective than when CAP is used alone. 

Comments: 

The CAP should always be added to solvent; not the reverse. 


59

3. HYDROXYPROPYL METHYLCELLULOSE 74,76 

Non-proprietary names: 


Hypomellus, hydroxyl propyl methylcellulose 2208, 2906, 2910. 

Synonyms: Methyl hydroxypropylcellulose, Propylene glycol ether of 

methylcellulose, methylcellulose propylene glycol ether. 

Chemical Name & CAS Registry number: Cellulose, 2-hydroxypropylmethyl 

ether Cellulose Hydroxypropylmethylether [9004-65-3]. 

Empirical formula : C8H15 – (C10H18O6) n – C8 H15 O5 

Molecular weight : Approximately 86,000 

Structure: 

Description: An odourless, tasteless, whit or creamy coloured fibrous or granular 

powder. 

Functional category: 

Coating agent, film former, tablet binder, stabilizing agent, suspending 

agent, viscosity agent and emulsion stabilizer. 

Apparent Density: 0.25 – 0.75 g/cm 3 


60

Solubility: 


Soluble in cold water forming viscous colloidal solution, insoluble in 

chloroform, alcohol and ether, but soluble in mixture of methanol and methylene 

chloride. 

Viscosity: HPMC K4M: 4,000 cps 

Stability and Storage Condition: 

Very stable in dry conditions, Solutions are stable at pH 3.0 – 11.0. Store 

in a tight container, in a cool place. 

Incompatibility: Extreme pH conditions, oxidizing materials. 

Safety: Human and animal feeding studies have shown Hydroxypropyl 

methylcellulose to be safe. 

4. GUAR GUM 74,77 

Synonyms: Guar flour, Buratoin V-7-E; Supercol Guar Gums; jaguar. 

Functional Category: 

USP : Tablet binder; suspending and/or viscosity- increasing agent 

Other : Tablet disintegrant. 

Chemical Name & CAS Registry number: 

Chemical type : Galactomannan polysaccharide [9000-30-0] 

Botanical origin : Cyamopsis tetragonolobus (L) Taub. 

Empirical formula: (C6H12O6) n 


61

Structure: 

Description: White to yellowish- white powder. or nearly so with 

Physical state and appearance: Solid. 

Odour : Odorless 

Taste : bland test. 

Melting Point : Decomposes. 


Properties: It forms viscous colloidal dispersion when hydrated in cold water. 

Incompatibility: Acetone, alcohol, tannins, strong acids and alkalis, borate ions, 

if present in the dispersing water, will prevent hydration of guar gum. The 

addition borate ions to hydrated solutions produce cohesive gels, which prevents 

further hydration. The gel can be liquefied by reducing the pH below 7. 

Safety: 

Guar gum is recognized by the FDA as a substance added directly to 

human food and has been affirmed as generally as safe. Specific limits in yours 

foods are established; however alkylated guar gums are not covered by 

appropriate FDA regulations. 


62

5. SODIUM ALGINATE 74,78 


Synonyms: Alginc acid; Sodium salt; sodium polymannuronate satialgine S 20; 

Album S 160 and S 15/600; Kelcosol, Keltone, Kelco-gel LV, HV; Sodium 

Alginate. 

Functional Category: 

binder. 

Suspending and/or viscosity- increasing agent, disintegrating agent; tablet 


Sodium alginate is the purified carbhydrate product extracted form brown 

sea weed by the use of dilute alkali. It consists chiefly of the sodium salt of alginic 

acid, a polyuronic acid composed of β-D-mannuronic acid, residues linked so that 

the carboxyl group of each unit is free while the aldehyde group is shielded by a 

glycosidic linkage. [9005-38-3] 

Structure: 


63

Description: 

Physical state and appearance: Solid. (Powdered solid.) 

Odor : Odorless. 

Taste : Tasteless. 

Color : White to Off-white (cream) 

Boiling Point : Not available. 

Melting Point : >300°C (572°F) 

Solubility: 


It is slowly soluble in water, forming a viscous, colloidal solution. It is 

insoluble in alcohol and in hydro-alcoholic solutions in which the alcohol content 

is grater than 30% by weight. It is also insoluble in other organic solvents. 

Stability and Storage conditions: 

It is hygroscopic. Dry storage stability is excellent when the powder is 

stored in a well-closed container at temperatures of 25 o C or less. 

Precautions: 

Keep away from heat. Keep away from sources of ignition. Empty 

containers pose a fire risk, evaporate the residue under a fume hood. Ground all 

equipment containing material. Do not ingest. Do not breathe dust. If ingested, 

seek medical advice immediately and show the container or the label. Keep away 

from incompatibles such as oxidizing agents, acids, alkalis. 


64


Storage: Keep container tightly closed. Keep container in a cool, well-ventilated 

area. 

Safety: 

The incorporation of 5 to 15% sodium alginate in the diet of purebreed 

beagle dogs for one year caused no harmful effects. It is found not allergenic. 

6. ETHYL CELLULOSE 74,79 

Synonyms : Ethyl cellulose; Ehocel. 

Functional Category : Tablet binder; coating agent. 


Structure: 

Cellulose, ethyl ether 

Cellulose ethyl ether [9004-57-3] 

Description: A tasteless, free-flowing, white to light tan powder. 


65

Solubility: 


Insoluble in water, glycerine and propylene glycol, but soluble in varying 

degrees in certain organic solvents, depending upon the ethoxyl content. The 

addition of 10-20% of a lower aliphatic alcohol to solvents, such as ketons, esters 

and hydrocarbons, can improve the solubility. 

Stability and Storage conditions: 

It is resistant to alkalis, both dilute and concentrated and to salt solutions. 

It is more sensitive to acidic materials than are cellulose esters. It should be stored 

between 7 o and 32 o C in a dry area away from all sources of heat. Store in a well 

closed container. 

Incompatibility: Incompatible with paraffin wax and microcrystalline. 

Safety: Essentially non-toxic. 

Application in pharmaceutical formulation or technology: 

Binder in tablet, coating materials for tablets, coating material for 

stabilization, coating to prevent unpleasant taste, thickness agent in creams, 

lotions and gels. 


66

4.1 Materials 

follows: 

Sr. 

No. 

CHAPTER-4 

 

Methodology 

The following materials/chemicals were used in the work which are as 

Table-5: Materials / Chemicals used 

Materials/ Chemicals Grade Name Of Supplier 

1. Flurbiprofen - 

2. Eudragit L-100 Degussa India Pvt. Ltd., Mumbai 

3. Eudragit S-100 Degussa India Pvt. Ltd., Mumbai 

4. Guar gum L.R. S.D. Fine Chem. Ltd., Mumbai. 

5. Sodium alginate L.R. S.D. Fine Chem. Ltd., Mumbai. 

6. HPMC (K4M L.R. Ozone international Mumbai. 

7. Cellulose acetate phthalate L.R. Sisco Research Lab. Pvt. Mumbai 

8. Ethyle cellulose L.R. Loba Chemical, India. 

9. Dibutyl phthalate L.R. S.D. Fine Chem. Ltd., Mumbai. 

10. Span-80 L.R. Loba Chemical, India. 

11. Acetone L.R. S.D. Fine Chem. Ltd. Mumbai. 

12. Liquid paraffin(heavy) L.R. S.D. Fine Chem. Ltd. Mumbai. 

13. Petrolium ether 60-80 C L.R. S.D. Fine Chem. Ltd. Mumbai. 

14. Potassium dihydrogen 

phosphate 

L.R. S.D. Fine Chem. Ltd. Mumbai. 

15. Sodium hydroxide L.R. S.D. Fine Chem. Ltd. Mumbai. 

16. Potassium Chloride L.R. S.D. Fine Chem. Ltd. Mumbai. 

17. Hydrochloric acid L.R. S.D. Fine Chem. Ltd. Mumbai. 

18. Empty gelatin capsules - - 


67

4.2 Equipments 

The equipments used in the present work are as follows: 

Table-6: Equipments used and source 

Sr. No. Instruments Source 

1. Electronic balance 

2. UV/Visible spectrophotometer 

Methodology 

Shimadzu Corporation--BL-220H, 

Japan 

Shimadzu 1700, Shimadzu 

Corporation. Japan 

3. Scanning electron microscopy JEOL–6360A, Japan. 

4. FTIR spectrophotometer 

Shimadzu, Shimadzu Corporation. 

Japan 

5. Magnetic stirrer Remi Motor Equipments, Mumbai 

6. 

Electrolab dissolution apparatus 

(USPXXIII) 

7. Oven 

Electro lab. 

Shital Scientific Industries, 

Mumbai 

8. pH meter Elico II-122 

9. Distillation unit Biotech India, Mumbai 


68

4.3 Evaluation of Flurbiprofen 

4.3.1 Preparation of Calibration Curve in Ethanol 

Methodology 

An accurately weighted amount of Flurbiprofen equivalent to 100 mg was 

dissolved in 100ml of ethanol. A series of standard solution containing Beer’s 

Lambert’s range of concentration from 2 to 16 µg/ml of Flurbiprofen were 

prepared and absorbance was measured at 247 nm against reagent blank. All 

spectral absorbance measurement was on Shimadzu 1700 UV-visible 

spectrophotometer. 

4.3.2 Preparation of Calibration Curve in 1.2 pH buffer 


dissolved in small volume of ethanol, in 100 ml volumetric flask and the volume 

was adjusted to 100 ml with 1.2 pH buffer and further dilution were made with 1.2 

pH buffer. A series of standard solution containing Beer’s Lambert’s range of 

concentration from 2 to 16 µg/ml of Flurbiprofen were prepared and absorbance 

was measured at 247 nm against reagent blank. All spectral absorbance 

measurement was on Shimadzu 1700 UV-visible spectrophotometer. 

4.3.3 Preparation of Calibration Curve in 6.8 pH phosphate buffer 



was adjusted to 100 ml with 6.8 pH phosphate buffer and further dilution were 


69

Methodology 

made with 6.8 pH phosphate buffer. A series of standard solution containing 

Beer’s Lambert’s range of concentration from 2 to 16 µg/ml of Flurbiprofen were 




4.3.4 Preparation of Calibration Curve in 7.4 pH phosphate buffer 



was adjusted to 100 ml with 7.4 pH phosphate buffer and further dilution were 

made with 7.4 pH phosphate buffer. A series of standard solution containing 

Beer’s Lambert’s range of concentration from 2 to 16 µg/ml of Flurbiprofen were 




4.4. Microcapsulation of Flurbiprofen 

4.4.1 Rationale for selection of ingredients and process: 39,40 

From literature review, it was evident that the pH in the proximal colon 

ranges from 6.6 to 7.0. So the Eudragit L-100 and S-100 were combined in 

different ratios and solubility of these combinations was found that Eudragit L- 

100 and S-100 in the ratio 1:2 was soluble in pH range of 6.6 to 7.0. Hence this 

combination was selected for preparation of microcapsules 


70

Methodology 

Pure acetone did not dissolve Eudragit; however acetone with 2% water fitted 

the criterion well. Liquid paraffin was used was used as the dispersion media or 

external phase. Petroleum ether was used to clean the microparticles since it 

removes liquid paraffin without the integrity of the microparticles. 

Solvent evaporation O/O (oil in oil) emulsification method of 

microencapsulation was chosen since it yields more uniform particles. The 

method is correctly referred as O/O instead of W/O (water in oil) since a 

polymeric solution in organic solvent is considered as oil in microencapsulation 

terminology. 

4.4.2 Preparation of Flurbiprofen microcapsule: 80,81 

Emulsification-solvent evaporation. 

Accurately weighted amount of Drug, Eudragit L-100 and S-100 as shown 

in Table-7 were dissolved in 50ml of acetone to form a homogenous polymers 

solution. Core material, i.e. Flurbiprofen was dispersed in it and mixed 

thoroughly. This organic phase was slowly poured at 15°C into liquid paraffin 

(100 ml) containing 1% (w/w) of Span -80 with stirring at 1000 rpm to form a 

uniform emulsion. Thereafter, it was allowed to attain room temperature and 

stirring was continued until residual acetone evaporated and smooth-walled, rigid 

and discrete microcapsules were formed. The microcapsules were collected by 

decantation and the product was washed with petroleum ether (40 –60°C) and 

dried at room temperature for 3 hrs. The microcapsules were then stored in a 

desiccators over fused calcium chloride. 


71

Sl. 

No. 

Table-7: Formulation of Flurbiprofen Microcapsules using Eudragit – L 100 and Eudragit – S100 

Ingredients 

Formulation Code 


Methodology 

FM-1 FM-2 FM-3 FM-4 

1. Drug (mg) 1000 1000 1000 1000 

2. Eudragit L-100 (mg) 166 333 500 666 

3. Eudragit S-100 (mg) 332 666 1000 1332 

4. Span-80 (ml) 0.5 0.5 0.5 0.5 

5. Acetone (ml) 50 50 50 50 

72

4.5 Evaluation of Flurbiprofen Microcapsule 

parameters. 

Methodology 

Prepared microcapsules of Flurbiprofen were evaluated for the following 

4.5.1 Particle size 82 

Determination of average particle size of Flurbiprofen microcapsule was 

carried out by using optical microscopy. A minute quantity of microcapsules was 

spread on a clean glass slide and average size of 600 microcapsules was 

determined in each batch. 

4.5.2 Study of flow properties of microcapsules 83 

Angle of repose (θ) of the microspheres, which measures the resistance to 

particle flow, was determined by a fixed funnel method. The height of the funnel 

was adjusted in such a way that the tip of the funnel just touches the heap of the 

blends. Accurately weighed microspheres were allowed to pass through the funnel 

freely on to the surface. The height and diameter of the powder cone was 

measured and angle of repose was calculated using the following equation 

θ = tan -1 

h 

r 

Where h/r is the surface area of the free standing height of the 

microspheres heap that is formed on a graph paper after making the microspheres 

flow from the glass funnel. 


73

4.5.3 Percentage yield 84 

Methodology 

The measured weight was divided by total amount of all non-volatile 

components which were used for the preparation of microcapsule. 

% yield = 

Actual weight of product 

Total weight of excipient and drug 

4.5.4 Drug Content Uniformity 85 

x 100 

In 100ml volumetric flask 25mg of crushed microcapsules were taken and 

dissolved with small quantity of ethanol and the volume was made up to mark 

with pH 6.8 and stirred for 12 hrs. After stirring the solution was filtered through 

whatman filter paper and from the filtrate appropriate dilutions were made and 

absorbance was measured at 247 nm by using Shimadzu 1700 UV- 


4.5.5 Scanning Electron Microscopy 86 

It has been used to determine particle size distribution, surface topography, 

texture and examine the morphology of fractured or sectioned surface. 

The samples for SEM analysis were prepared by following method. Dry 

microcapsules brass stub a coated with gold in an ion sputter. Then picture of 

microcapsules were taken by random scanning of the stub. The SEM analysis or 

the microcapsules was carried out by using JEOL–6360A analytical scanning 

electron microscope. The microcapsules were viewed at an accelerating voltage of 

20KV. 


74

4.5.6 Drug-polymer Interaction 87 

Methodology 

FT-IR spectra of the Flurbiprofen, FM3 formulation, Eudragit L-100, 

Eudragit S-100 were determined by using KBr pellet technique. Samples were 

scanned over the 500-4000cm -1 Spectral region at a resolution of 4cm -1 . The ratio 

of the sample in KBr disc was 1% (shimadzu FT-IR spectrometer). To ensure no 

interaction has been occurred between the drug and polymers. 

4.5.7 In-vitro dissolution study 38,80 

In vitro dissolution profile of each formulation was determined by 

employing USP XXIII rotating basket method (900 ml of p H 6.8-phosphate 

buffer, 100 rpm and 37±0.5 o C). Microcapsules equivalent to 150 mg of 

Flurbiprofen was loaded into the basket of the dissolution apparatus. Dissolution 

study carried out for 12 hrs. 5 ml of the sample was withdrawn from the 

dissolution media at suitable time intervals and the same amount was replaced 

with fresh buffer. The absorbance was measured at 247 nm by using Shimadzu 

1700 UV–Vis spectrophotometer, against pH 6.8 as blank. 

4.6 Preparation of Cross-Linked Gelatine Capsules 

Formaldehyde treatment 

38, 39 

Formalin treatment has been employed to modify the solubility of gelatine 

capsules. Exposure to formalin vapours results in an unpredictable decreases in 

solubility of gelatine owing to the crosslinkage of the amino group in the gelatine 

molecular chain aldehyde group of formaldehyde by Schiff’s base condensation. 


75

Methodology 

Procedure: Hard gelatine capsule of size 00 and 100 in number taken. Their 

bodies were separated from the caps. 25 ml of 15% (v/v) formaldehyde was taken 

into desiccators and a pinch of potassium permanganate was added to it, to 

generate formalin vapours. The wire mesh containing the empty bodies of capsule 

was then exposed to formaldehyde vapours. The caps were not exposed leaving 

them water-soluble. The desiccators were tightly closed. The reaction was carried 

out for 12 h after which the bodies were removed and dried at 50 O C for 30 min to 

ensure completion of reaction between gelatine and formaldehyde vapours. The 

bodies were then dried at room temperature to facilitate removal of residual 

formaldehyde. 

polythene bag. 

These capsule bodies were capped with untreated caps and stored in a 

4.7 Tests for Formaldehyde Treated Empty Capsules 

Various physical and chemical test were carried out simultaneously for 

formaldehyde treated and untreated capsules. 

4.7.1 Physical tests: 

Identification attributes: The ‘00’ capsule were one with a red cap and red 

colored body. They were lockable type, odorless, softy and sticky when 

treated with wet fingers. After formaldehyde treatment, there were no 

significant changes in the capsules. They were non-tacky when touched with 

wet fingers. 


76

Methodology 

Visual defect: In about 100 capsule bodies treated with formaldehyde, about 

ten were found to be shrunk or distorted. 

Dimensions: Variations in dimensions between formaldehyde, treated and 

untreated capsules were studied. The length and diameter of the capsules were 

measured before and after formaldehyde treatment, using dial caliper. 

Solubility studies of treated capsules: The solubility test was carried out for 

normal capsules and formaldehyde treated capsules for 24 hrs. Ten capsules 

were randomly selected and then subjected to solubility studies at room 

temperatures in buffers of pH 1.2, 7.4 and 6.8. 100 ml solution and stirred for 

24 hrs. The time at which the capsule dissolves or forms a soft fluffy mass was 

noted. 

4.7.2 Chemical test: 

Qualitative test for free formaldehyde: 73 

Standard formaldehyde solution used is formaldehyde solution (0.002, 

w/v) and sample solution is formaldehyde treated bodies (about 25 in number) 

were cut into small pieces and taken into a beaker containing distilled water. This 

was stirred for 1 hrs with a magnetic stirrer, to solubilize the free formaldehyde. 

The solution was then filtered into a 50 ml volumetric flask, washed with distilled 

water and volume was made up to 50 ml with the washings. 


77

Procedure: 

Methodology 

1ml of sample solution, 9ml of water was added. One millilitre of resulting 

solution was taken into a test tube and mixed with 4ml of water and 5ml of 

acetone reagent. The test tube was warmed in a water bath at 40 o C and allowed to 

stand for 40 min. The solution was not more intensely colored than a reference 

solution prepared at the same time and in the same manner using 1ml of standard 

solution in place of the sample solution. The comparison should be made by 

examining tubes down their vertical axis. 

4.8 Formulation of Pulsatile (modified pulsincap) Drug Delivery 

System: 18,38,39,88 

Microcapsule equivalent to 150mg of Flurbiprofen were accurately weighted 

and filled into the previously formaldehyde treated bodies by hand filling. 

The bodies containing the microsphere were then plugged with different 

amounts of polymers like guar gum, hydroxylpropylmethylcellulose and 

sodium alginate as shown in Table-8. Then join the capsule body and cap and 

sealed with a small amount of the 5% ethyl cellulose ethanolic solution. 

The sealed capsules were completely coated with 5% Cellulose Acetate 

Phthalate (CAP) to prevent variable gastric emptying. The whole system thus 

produced is modified pulsincap. 


78

4.8.1 Coating of pulsincap 

Methodology 

5 % w/w solution of CAP was prepared by using acetone: ethanol (8.:2) as a 

solvent and dibutyl phthalate as plasticizer (0.75%) as a plasticizer. Dip coating 

method was fallowed to develop the pulsincap. The capsules were alternatively 

dipped in 5 % CAP solution and dried. Coating was repeated until an expected 

weight gain of.8-12% was obtained and the capsule resists disintegration in 0.1 N 

HCL for a minimum period of 2 hrs. 

Fig. 6: Overview of designed pulsatile device 


79

Formulation 

code 

Table- 8: Composition for modified pulsatile device on the basis of design summary 

Wt.of empty 

body 

(mg*) 

Wt.of micro 

capsule (mg) 

Polymer used 

Wt.of polymer 

used (mg) 


Total weight 

with cap (mg) 

Methodology 

Wt. after CAP 

coating (mg) 

F-1 68.8 355 Guar gum 20 443.8 454.7 

F-2 67.9 355 Guar gum 30 452.9 462 

F-3 68.5 355 Guar gum 40 463.5 470.18 

F-4 67.5 355 HPMC 20 442.5 451.34 

F-5 67.4 355 HPMC 30 452.4 460.8 

F-6 68.5 355 HPMC 40 463.5 473.25 

F-7 68.0 355 Sod. Alg. 20 443.0 454 

F-8 67.7 355 Sod. Alg. 30 452.7 462.35 

F-9 67.6 355 Sod. Alg. 40 462.6 471.95 

HPMC: Hydroxy Propyl Methylcellulose. 

Sod.Alg: Sodium Alginate 

* Microcapsule equivalent to 150 mg of drug used 

80

4.9 Evaluation of Modified Pulsincap 39,40 

4.9.1 Thickness of cellulose acetate phthalate coating 

Methodology 

The thickness of cellulose acetate phthalate coating was measured using 

screw gauge and expressed in mm. 

4.9.2 Weight variation 

10 capsules were selected randomly from each batch and weight 

individually for weight variation. 

4.9.3 Drug Polymer Interaction 

FT-IR spectra of physical mixture of Flurbiprofen+Guargum, 

Flurbiprofen+HPMC, Flurbiprofen+Sodium alginate was carried out by using KBr 

pellet technique. Samples were scanned over the 500-4000cm -1 Spectral region at 

a resolution of 4cm -1 . The ratio of the sample in KBr disc was 1% (shimadzu FT- 

IR spectrometer). 

4.9.4 In vitro release profile 

Dissolution studies were carried out by using USP XXIII dissolution 

test apparatus (Basket) method. Capsules were placed in a basket so that the 

capsule should be immersed completely in dissolution media but not float. In 

order to simulate the pH changes along the GI tract, three dissolution media with 

pH 1.2, 7.4 and 6.8 were sequentially used referred to as sequential pH change 

method. When performing experiments, the pH 1.2 medium was first used for 2 

hrs (since the average gastric emptying time is 2 hrs) then removed and the fresh 


81

Methodology 

pH 7.4 phosphate buffer saline (PBS) was added. After 3 hrs (average small 

intestinal transit time is 3 hrs) the medium was removed and fresh pH 6.8 

dissolution medium was added for subsequent hrs. 900ml of the dissolution 

medium was used at each time. Rotation speed was 100 rpm and temperature was 

maintained at 37±0.5 ◦C. five millilitres of dissolution media was withdrawn at 

predetermined time intervals and fresh dissolution media was replaced. The 

withdrawn samples were analyzed at 247 nm, by UV absorption spectroscopy. 


82

CHAPTER-5 


 

 

Standard Calibration Curve of Flurbiprofen 

Solvent………………………………….Ethanol 

Wavelength……………………………..247nm 

Unit for concentration………………......mcg/ml 

Table-9: Standard calibration data of Flurbiprofen in Ethanol 

SI.NO. 

Concentration 

(mcg/ml) 

Absorbance 

(nm) 

1 0.000 0.000 

2 2.000 0.118 

3 4.000 0244 

4 6.000 0.371 

5 8.000 0.496 

6 10.000 0.609 

7 12.000 0734 

8 14.000 0858 

9 16.00 0.976 

*Average of triplicate sets 

Fig-7: Standard calibration curve of Flurbiprofen in Ethanol 

 

 

 

 

 

 


Results 

 

 

 

 

 

83


 


Solvent………………………….............pH 1.2 buffer 




Results 

Table-10: Standard calibration data of Flurbiprofen in pH 1.2 buffer 

SI.NO. 

Concentration 

(mcg/ml) 

Absorbance 

(nm) 

1 0.000 0.000 

2 2.000 0.085 

3 4.000 0.165 

4 6.000 0.242 

5 8.000 0.335 

6 10.000 0.419 

7 12.000 0.505 

8 14.000 0.583 

9 16.00 0.654 


Fig-8: Standard calibration curve of Flurbiprofen in pH 1.2 buffer 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

84


 


Solvent………………………….............pH 6.8 phosphate buffer 




Results 


SI.NO. 

Concentration 

(mcg/ml) 

Absorbance 

(nm) 

1 0.000 0.000 

2 2.000 0.078 

3 4.000 0.152 

4 6.000 0.228 

5 8.000 0.308 

6 10.000 0.386 

7 12.000 0.454 

8 14.000 0.538 

9 16.00 0.612 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

85


 


Solvent………………………….............pH 7.4 phosphate buffer 




Results 


SI.NO. 

Concentration 

(mcg/ml) 

Absorbance 

(nm) 

1 0.000 0.000 

2 2.000 0.115 

3 4.000 0.23 

4 6.000 0.345 

5 8.000 0.455 

6 10.000 0.576 

7 12.000 0.688 

8 14.000 0.803 

9 16.00 0.917 



 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

86

Fig-11 Image showing microcapsule of Flurbiprofen formulations 

(A) FM-1 (B) FM-2 (C) FM-3 (D) FM-4 

A B 

C D 


Results 

87

5.5 Evaluation of Flurbiprofen Microcapsules: 

5.5.1 Micrometric properties 

Table-13: Micromeritic properties of Flurbiprofen Microcapsules 

Formulation code Mean particles size (m) Angle of repose 

FM-1 163.68 1.14 18° 80” 3.89 

FM-2 167.32 1.01 18° 55” 1.93 

FM-3 196.77 3.49 21° 39” 2.78 

FM-4 251.84 2.01 22° 76” 3.39 

All values are represented as mean standard deviation (n=3) 

5.5.2 Percentage yield and drug content 


Results 

Table-14: Percentage yield and Drug content of Flurbiprofen microcapsules 

Formulation code Percentage yield Drug content uniformity 

FM-1 87.21 0.50 82.89% 0.68 

FM-2 88.41 0.37 89.23% 0.85 

FM-3 90. 24 0.08 95.59% 0.68 

FM-4 85.85 0.29 75.9% 0.78 


88

5.5.3 Scanning Electron Microscopy (SEM) 


Results 

Morphology of microcapsules was examined by scanning electron 

microscopy. The view of the microcapsules showed smooth surface morphology 

exhibited range of sizes within each batch. The outer surface of microcapsules 

was smooth and dense, while the internal surface was porous. The shell of 

microcapsules also showed some porous structure it may be caused by 

evaporation of solvent entrapped within the shell of microcapsules after forming 

smooth and dense layer. 

Fig. 12: Scanning electron microphotographs of FM-3 formulation. 

A B 

C D 

89

5.5.4 Infrared spectroscopy: 


Results 

The FT-IR spectra study showed no change in the finger print of pure drug 

spectra, thus confirming absence of drug and polymer interaction. The result 

shown in Fig. 13 to 156 

Fig. 13: I.R. Spectrum of Flurbiprofen (pure drug) 

Fig. 14: I.R. Spectrum of Eudragit L-100 

90

Fig. 15: I.R. Spectrum of Eudragit S-100 

Fig. 16: I.R. Spectrum of Flurbiprofen microcapsules (FM-3) 


Results 

91

Time (T) 

Hrs 

5.5.5 Evaluation of In-vitro drug release of Prepared Flurbiprofen Microcapsules 

Square root 

of Time 

Table-15: In-vitro release profile of Flurbiprofen microcapsules for FM-1 

Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

0.5 0.70 -0.301 43.93 29.29 ± 1.48 70.71 1.466 1.849 

1 1.00 0.000 52.14 34.96 ± 1.41 65.04 1.543 1.813 

2 1.41 0.301 62.82 41.88 ± 1.50 58.12 1.622 1.764 

3 1.73 0.477 72.26 48.17 ± 0.36 51.83 1.682 1.714 

4 2.00 0.602 84.62 56.41 ± 0.70 43.59 1.751 1.639 

5 2.23 0.698 92.85 60.92 ± 1.20 39.08 1.784 1.591 

6 2.44 0.778 96.15 64.10 ± 0.84 35.90 1.806 1.555 

7 2.64 0.845 102.3 68.22 ± 0.71 31.79 1.833 1.502 

8 2.82 0.903 112.2 74.83 ± 1.42 25.17 1.874 1.400 

9 3.00 0.954 119.1 79.42 ± 0.53 20.58 1.899 1.313 

10 3.16 1.000 128.5 85.17 ± 0.58 14.29 1.933 1.155 

11 3.31 1.041 136.3 90.91 ± 0.85 9.090 1.958 0.958 

12 3.46 1.079 143.3 95.58 ± 0.24 4.420 1.980 0.645 


92

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

0.5 0.70 -0.301 41.14 27.43 ± 1.88 72.57 1.438 1.860 

1 1.00 0.000 53.38 35.58 ± 0.35 64.42 1.551 1.809 

2 1.41 0.301 60.73 40.48 ± 1.50 59.52 1.607 1.774 

3 1.73 0.477 67.40 44.93 ± 0.46 55.07 1.652 1.740 

4 2.00 0.602 72.33 48.22 ± 0.98 51.78 1.683 1.714 

5 2.23 0.698 81.46 54.31 ± 0.61 45.69 1.734 1.659 

6 2.44 0.778 94.64 63.09 ± 2.35 36.91 1.799 1.567 

7 2.64 0.845 101.9 67.99 ± 2.16 32.01 1.832 1.505 

8 2.82 0.903 113.1 75.45 ± 1.54 24.55 1.877 1.390 

9 3.00 0.954 125.5 83.69 ± 1.06 16.13 1.922 1.212 

10 3.16 1.000 133.5 89.05 ± 1.07 10.95 1.949 1.039 

11 3.31 1.041 136.1 90.76 ± 1.35 9.240 1.957 0.965 

12 3.46 1.079 138.7 91.96 ± 0.51 8.040 1.963 0.905 


93

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

0.5 0.70 -0.301 40.44 26.96 ± 0.15 73.04 1.430 1.863 

1 1.00 0.000 45.10 30.07 ± 1.16 69.93 1.478 1.844 

2 1.41 0.301 52.90 35.27 ± 0.81 64.73 1.547 1.811 

3 1.73 0.477 61.65 41.10 ± 0.13 58.90 1.613 1.770 

4 2.00 0.602 70.60 47.08 ± 0.83 52.92 1.672 1.723 

5 2.23 0.698 80.19 53.16 ± 0.97 46.54 1.728 1.667 

6 2.44 0.778 89.39 59.60 ± 0.25 40.4 1.775 1.606 

7 2.64 0.845 94.53 63.02 ± 0.26 36.98 1.799 1.567 

8 2.82 0.903 102.0 66.37 ± 0.41 33.63 1.821 1.526 

9 3.00 0.954 107.2 71.49 ± 0.25 28.51 1.854 1.406 

10 3.16 1.000 119.2 79.50 ± 0.47 20.5 1.900 1.311 

11 3.31 1.041 124.6 83.06 ± 0.89 16.93 1.919 1.228 

12 3.46 1.079 133.3 88.87 ± 1.68 11.13 1.948 1.046 


94

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.00 0.000 0.000 

0.5 0.70 -0.301 37.05 24.70 ± 0.46 75.3 1.392 1.876 

1 1.00 0.000 46.15 30.77 ± 0.39 69.23 1.488 1.840 

2 1.41 0.301 54.77 36.36 ± 0.39 63.64 1.560 1.803 

3 1.73 0.477 62.28 41.52 ± 0.19 58.48 1.618 1.767 

4 2.00 0.602 70.63 47.09 ± 0.84 52.91 1.672 1.723 

5 2.23 0.698 80.42 53.61 ± 0.47 46.39 1.729 1.666 

6 2.44 0.778 91.26 60.84 ± 0.47 39.16 1.784 1.592 

7 2.64 0.845 100.7 67.14 ± 0.24 32.86 1.826 1.516 

8 2.82 0.903 108.6 72.42 ± 0.35 27.58 1.859 1.440 

9 3.00 0.954 116.5 77.70 ± 0.37 22.43 1.890 1.348 

10 3.16 1.000 120.8 80.58 ± 0.49 19.42 1.906 1.288 

11 3.31 1.041 126.2 84.39 ± 0.01 15.61 1.926 1.193 

12 3.46 1.079 132.7 88.51 ± 1.53 11.49 1.946 1.060 


95

Zero order kinetic 

data 

Formulation Code Regression 

coefficient 

(r) 

Table-19: Kinetic values obtained from in-vitro release profile for microcapsules 

First order kinetic 

data 

Regression 

coefficient 

(r) 

Higuchi Matrix 

kinetic data 

Regression 

coefficient 

(r) 

Regression 

coefficient 

(r) 


Peppas kinetic data 

Results 

Slope ‘n’ 

FM-1 0.9160 0.073 0.985 0.974 0.200 

FM-2 0.930 0.065 0.963 0.945 0.23 

FM-3 0.936 0.010 0.973 0.951 0.26 

FM-4 0.937 0.017 0.983 0.968 0.26 

96

Fig. 17: Zero order plots of Flurbiprofen microcapsules 


Results 

 

 

 

 

 

 

 

 

 

Fig. 18: First order plots of Flurbiprofen microcapsules 

 

 

 

97

Fig. 19: Higuchi diffusion plots of Flurbiprofen microcapsules 

 

 

 

 

 

 

 


Results 

 

 

 

Fig. 20: Peppas exponentional plots of Flurbiprofen microcapsules 

 

 

 

 

 

 

 

 

 

98

5.6 Evaluation of formulation treated empty capsules 

5.6.1 Dimension 

Average capsule length 


Results 

Before formaldehyde treatment (untreated cap and body) : 23.5 mm 

After formaldehyde treatment (treated body and untreated cap) : 22.5 mm 

Average diameter of capsule body 

Before formaldehyde treatment : 7.9 mm 

After formaldehyde treatment : 7.5 mm 

Average length of capsule body 

Before formaldehyde treatment : 20.5 mm 

After formaldehyde treatment : 19.5 mm 

5.6.2 Solubility studies for the treated capsules 

When the capsules were subjected to solubility studies in different buffers 

for 24 hrs, the following observation were made 

a) In all the case of normal capsules, both cap and body dissolved within 

fifteen minutes. 

b) In the case of formaldehyde treated capsules, only the cap dissolved within 

15minutes, while the capsule remained intact for about 24 hours. 

99

Quantity test for free formaldehyde 

Results 

The formaldehyde capsules were tested for the presence of free 

formaldehyde. The sample solution was not more intensely colored than the 

standard solution inferring that less than 20µg free formaldehyde is present in 25 

capsule 

5.7 Evaluation of Modified Pulsincap 

5.7.1 Weight variation 

The filled capsules pass the weight variation test as their weights are 

within the specified limits. 

5.7.2 Thickness of Cellulose Acetate Phthalate 

Table-20: Coating thickness 

Formulation Thickness of Coating (mm) 

F-1 0.060 


5.7.3 IR- Study 

F-2 0.054 

F-3 0.063 

F-4 0.067 

F-5 0.056 

F-6 0.059 

F-7 0.057 

F-8 0.061 

F-9 0.066 

From the spectra of pure drug and the combination of drug with polymers, 

it was observed that all the characteristics peaks of Flurbiprofen were present in 

the combination spectrum, thus indicating compatibility of the drug and polymer. 

DEPT. OF PHARMACEUTICS, LUQMAN COLLEGE OF PHARMACY, GULBARGA 100

Fig. 21: I.R. Spectrum of Flurbiprofen + Guargum 

Fig. 22: I.R. Spectrum of Flurbiprofen + HPMC 

Fig. 23: I.R. Spectrum of Flurbiprofen + Sodium Alginate 

Results 


5.7.3 Evaluation of In-vitro drug release of Prepared Pulsatile Capsule Device 

Time (T) 

Hrs 

Square root 

of Time 

Table 21: In-vitro release rate profile of F1 containing 20mg Guar Gum 

Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 0.098 0.06 ± 0.042 99.93 -1.184 1.999 

5 2.23 0.698 9.073 6.05 ± 0.034 93.95 0.781 1.972 

6 2.44 0.778 30.31 20.20 ± 0.315 78.80 1.305 1.902 

7 2.64 0.845 38.23 25.50 ± 0.130 74.50 1.406 1.872 

8 2.82 0.903 51.05 34.04 ± 0.310 60.96 1.531 1.819 

9 3.00 0.954 61.40 40.93 ± 0.650 59.06 1.612 1.771 

10 3.16 1.000 75.85 50.56 ± 1.767 49.18 1.703 1.697 

11 3.31 1.041 81.29 54.19 ± 0.317 45.81 1.730 1.660 

12 3.46 1.079 95.40 63.94 ± 0.358 36.09 1.805 1.557 

13 3.60 1.113 101.2 67.51 ± 0.239 32.49 1.829 1.511 

14 3.74 1.146 107.3 71.50 ± 0.536 28.50 1.854 1.454 

15 3.87 1.176 111.9 74.61 ± 0.408 25.39 1.872 1.404 


102

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 0.000 0.000 100 0.000 2.000 

5 2.23 0.698 4.160 2.777 ± 0.216 97.22 0.443 1.987 

6 2.44 0.778 32.25 20.82 ± 0.625 79.18 1.318 1.898 

7 2.64 0.845 38.38 25.59 ± 0.319 74.41 1.408 1.871 

8 2.82 0.903 53.08 35.39 ± 0.092 64.61 1.548 1.810 

9 3.00 0.954 58.90 39.27 ± 0.086 60.73 1.594 1.783 

10 3.16 1.000 68.15 45.44 ± 0.631 54.56 1.657 1.736 

11 3.31 1.041 84.71 56.47 ± 0.092 43.53 1.751 1.638 

12 3.46 1.079 89.76 59.84 ± 0.160 40.16 1.776 1.603 

13 3.60 1.113 93.41 62.27 ± 0.473 37.73 1.794 1.576 

14 3.74 1.146 98.62 65.73 ± 0.408 34.25 1.817 1.534 

15 3.87 1.176 104.1 69.43 ± 0.234 30.57 1.841 1.485 


103

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 0.000 0.000 100 0.000 2.000 

5 2.23 0.698 3.330 2.213 ± 0.577 97.78 0.344 1.990 

6 2.44 0.778 12.18 8.200 ± 0.080 91.88 0.909 1.963 

7 2.64 0.845 23.39 15.59 ± 0.546 84.41 1.192 1.926 

8 2.82 0.903 33.88 22.59 ± 0.240 77.41 1.353 1.888 

9 3.00 0.954 47.01 31.34 ± 0.086 68.66 1.496 1.836 

10 3.16 1.000 56.27 37.51 ± 0.239 62.49 1.574 1.795 

11 3.31 1.041 68.70 45.80 ± 0.323 54.20 1.660 1.733 

12 3.46 1.079 82.53 55.02 ± 0.155 44.98 1.740 1.653 

13 3.60 1.113 85.56 57.04 ± 1.123 42.96 1.756 1.633 

14 3.74 1.146 88.52 59.01 ± 0.387 40.99 1.770 1.612 

15 3.87 1.176 93.41 62.28 ± 0.479 37.72 1.794 1.576 


104

Time (T) 

Hrs 

Square root 

of Time 

Table 24: In-vitro release rate profile of F4 containing 20mg HPMC 

Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 3.746 2.497 ± 0.205 97.50 0.397 1.989 

5 2.23 0.698 8.990 5.990 ± 0.043 94.01 0.777 1.973 

6 2.44 0.778 42.82 28.54 ± 0.768 71.46 1.455 1.854 

7 2.64 0.845 50.35 33.57 ± 0.680 66.43 1.525 1.822 

8 2.82 0.903 58.44 38.96 ± 0.321 61.04 1.590 1.785 

9 3.00 0.954 64.96 43.31 ± 0.735 56.69 1.636 1.753 

10 3.16 1.000 71.26 47.51 ± 0.092 52.49 1.676 1.720 

11 3.31 1.041 84.71 56.47 ± 0.239 43.53 1.751 1.638 

12 3.46 1.079 96.44 64.30 ± 0.629 35.70 1.808 1.552 

13 3.60 1.113 99.32 66.10 ± 0.465 33.79 1.820 1.528 

14 3.74 1.146 108.9 72.64 ± 0.450 27.36 1.861 1.437 

15 3.87 1.176 114.7 76.46 ± 0.802 23.54 1.883 1.371 


105

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 0.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 0.000 0.000 100 0.000 2.000 

5 2.23 0.698 6.920 4.613 ± 0.115 95.38 0.663 1.979 

6 2.44 0.778 41.08 27.38 ± 0.311 72.62 1.437 1.861 

7 2.64 0.845 46.55 31.03 ± 0.086 68.97 1.491 1.838 

8 2.82 0.903 53.31 35.54 ± 0.239 64.46 1.550 1.890 

9 3.00 0.954 65.32 43.42 ± 0.240 56.58 1.637 1.752 

10 3.16 1.000 74.68 49.79 ± 0.086 50.21 1.697 1.700 

11 3.31 1.041 84.95 56.09 ± 0.532 43.91 1.748 1.642 

12 3.46 1.079 94.73 63.08 ± 0.370 36.90 1.799 1.567 

13 3.60 1.113 97.74 64.97 ± 0.310 30.03 1.812 1.544 

14 3.74 1.146 103.4 68.96 ± 0.086 31.04 1.832 1.491 

15 3.87 1.176 107.5 71.71 ± 0.358 28.29 1.855 1.451 


106

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 2.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 0.000 0.000 100 0.000 2.000 

5 2.23 0.698 0.720 0.483 ± 0.063 99.51 -0.315 1.997 

6 2.44 0.778 7.950 5.300 ± 0.088 94.70 0.724 1.976 

7 2.64 0.845 27.58 18.39 ± 0.239 81.66 1.264 1.911 

8 2.82 0.903 43.52 29.01 ± 0.086 70.99 1.462 1.851 

9 3.00 0.954 50.66 33.78 ± 0.327 66.22 1.528 1.820 

10 3.16 1.000 56.96 37.97 ± 0.323 62.03 1.579 1.792 

11 3.31 1.041 64.42 42.95 ± 0.387 57.05 1.632 1.756 

12 3.46 1.079 75.38 50.25 ± 0.319 49.75 1.701 1.696 

13 3.60 1.113 81.76 54.45 ± 0.392 45.55 1.735 1.658 

14 3.74 1.146 85.56 57.04 ± 0.536 42.96 1.756 1.633 

15 3.87 1.176 89.68 59.79 ± 0.363 40.21 1.776 1.604 


107

Time (T) 

Hrs 

Square root 

of Time 

Table 27: In-vitro release rate profile of F7 containing 20mg Sodium Alginate 

Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 2.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 6.13 4.127 ± 0.361 95.875 0.615 1.981 

5 2.23 0.698 13.95 9.303 ± 0.057 90.697 0.968 1.957 

6 2.44 0.778 44.37 29.58 ± 0.239 70.42 1.470 1.847 

7 2.64 0.845 51.91 34.61 ± 0.392 65.39 1.539 1.815 

8 2.82 0.903 59.92 39.68 ± 0.092 60.32 1.598 1.780 

9 3.00 0.954 70.10 46.73 ± 0.086 53.27 1.669 1.726 

10 3.16 1.000 79.65 53.10 ± 0.327 46.90 1.725 1.671 

11 3.31 1.041 90.15 60.10 ± 0.086 39.90 1.778 1.600 

12 3.46 1.079 99.16 66.11 ± 0.626 33.98 1.820 1.530 

13 3.60 1.113 109.7 73.16 ± 0.729 26.84 1.864 1.428 

14 3.74 1.146 118.8 79.22 ± 0.450 20.78 1.898 1.317 

15 3.87 1.176 124.4 82.95 ± 0.239 17.05 1.918 1.231 


108

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 2.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 1.874 1.247 ± 0.105 98.75 0.095 1.994 

5 2.23 0.698 9.130 6.087 ± 0.011 93.91 0.784 1.972 

6 2.44 0.778 35.20 23.47 ± 0.542 76.53 1.370 1.883 

7 2.64 0.845 45.55 30.36 ± 0.171 69.64 1.482 1.842 

8 2.82 0.903 54.47 36.32 ± 0.184 63.68 1.560 1.804 

9 3.00 0.954 63.45 42.33 ± 0.179 57.60 1.626 1.760 

10 3.16 1.000 83.70 55.80 ± 0.406 44.20 1.746 1.645 

11 3.31 1.041 94.81 63.21 ± 0.392 36.79 1.800 1.565 

12 3.46 1.079 96.68 64.45 ± 0.315 35.55 1.809 1.550 

13 3.60 1.113 99.32 66.21 ± 0.315 33.79 1.809 1.528 

14 3.74 1.146 102.8 68.60 ± 0.502 31.40 1.836 1.496 

15 3.87 1.176 105.3 70.25 ± 0.155 29.75 1.846 1.473 


109

Time (T) 

Hrs 

Square root 

of Time 


Log Time 

Cum. Drug 

release (mg) 

Cum.% Drug 

release ± SD 

Cum.% Drug 

retained 


Log Cum. % 

drug released 

Results 

Log Cum. % 

Drug retained 

0 0.00 0.000 0.000 0.000 0.000 0.000 2.000 

1 1.00 0.000 0.000 0.000 100 0.000 2.000 

2 1.41 0.301 0.000 0.000 100 0.000 2.000 

3 1.73 0.477 0.000 0.000 100 0.000 2.000 

4 2.00 0.602 5.777 3.600 ± 0.398 96.44 0.556 1.984 

5 2.23 0.698 6.760 4.436 ± 0.057 95.56 0.646 1.980 

6 2.44 0.778 36.99 24.66 ± 0.023 75.34 1.391 1.877 

7 2.64 0.845 41.34 27.56 ± 0.473 72.44 1.440 1.859 

8 2.82 0.903 47.25 31.50 ± 0.392 68.50 1.498 1.835 

9 3.00 0.954 60.61 40.41 ± 0.155 59.59 1.606 1.775 

10 3.16 1.000 74.84 49.89 ± 0.265 50.11 1.698 1.699 

11 3.31 1.041 83.39 55.59 ± 0.239 44.41 1.744 1.647 

12 3.46 1.079 98.00 65.33 ± 0.701 34.64 1.815 1.539 

13 3.60 1.113 104.9 70.00 ± 0.645 30.00 1.845 1.477 

14 3.74 1.146 112.8 75.33 ± 0.551 24.76 1.876 1.392 

15 3.87 1.176 116.0 77.36 ± 1.166 22.64 1.888 1.354 


110

Table 30: Kinetic values obtained from in-vitro release profile for microcapsules 

Zero order kinetic 

data 

First order kinetic 

data 

Higuchi Matrix 

kinetic data 

Peppas kinetic data 

Formulation Code Regression Regression Regression Regression 

coefficient coefficient coefficient coefficient Slope ‘n’ 

(r) 

(r) 

(r) 

(r) 

F1 0.955 0.950 0.917 0.717 2.500 

F2 0.947 0.958 0.913 0.887 2.644 

F3 0.930 0.929 0.875 0.920 2.609 

F4 0.958 0.957 0.930 0.915 2.504 

F5 0.950 0.945 0.923 0.880 2.622 

F6 0.929 0.943 0.930 0.821 2.724 

F7 0.967 0.943 0.937 0.926 2.459 

F8 0.943 0.954 0.918 0.899 2.593 

F9 0.957 0.938 0.910 0.971 2.500 


Results 

111

Results 

Fig. 24: Zero order plots of formulation containing Guar Gum as hydrogel 

 

 

 

 

 

 

 

 

 

 

plug 

 

 

 

Fig. 25: First order plots of formulation containing Guar Gum as hydrogel 

 

 

 

 

 

 

plug 

 

 

 


Results 

Fig. 26: Higuchi diffusion plots of formulation containing Guar Gum as 

 

 

 

 

 

 

 

 

 

hydrogel plug 

 

 

 

Fig. 27: Peppas exponentional plots of formulation containing Guar Gum as 

 

 

 

 

 

 

hydrogel plug 

 

 

 


Results 

Fig. 28: Zero order plots of formulation containing HPMC as hydrogel plug 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 29: First order plots of formulation containing HPMC as hydrogel plug 

 

 

 

 

 

 

 

 

 


Results 

Fig. 30: Higuchi diffusion plots of formulation containing HPMC as hydrogel 

 

 

 

 

 

 

 

 

 

 

 

plug 

 

 

 

Fig. 31: Peppas exponentional plots of formulation containing HPMC as 

 

 

 

 

 

 

hydrogel plug 

 

 

 


Results 

Fig. 32: Zero order plots of formulation containing Sodium Alginate as 

 

 

 

 

 

 

 

 

 

 

hydrogel plug 

 

 

 

Fig. 33: First order plots of formulation containing Sodium Alginate as 

 

 

 

 

 

 

hydrogel plug 

 

 

 


Results 

Fig. 34: Higuchi diffusion plots of formulation containing Sodium Alginate as 

 

 

 

 

 

 

 

 

 

 

 

hydrogel plug 

 

 

 

Fig. 35: Peppas exponentional plots of formulation containing Sodium 

 

 

 

 

 

 


 

 

 


CHAPTER-6 

 

Discussion 

In the present study, an attempt was made to develop and evaluate 

pulsatile drug delivery system containing eudragit microcapsules with 

subsequently lower dose of Flurbiprofen for colon specific delivery and for better 

treatment of early morning symptoms in rheumatoid arthritis and prevent 

unwanted systemic side effects. 

Calibration curve for the estimation of Flurbiprofen was constructed in 

Ethanol, 1.2 pH 7.4 pH and 6.8 pH buffer at 247 nm the method obeyed Beer’s 

Lambert law in the range of 2-16 mcg/ml. 

Microcapsules of Flurbiprofen using Eudragit L-100/S-100 as a polymer 

by emulsion solvent evaporation method as shown in Table-7. In this method, the 

organic phase was slowly poured in liquid paraffin and the emulsion was 

stabilized by Span- 80. The organic phase evaporated and finally spherical, 

smooth–walled, rigid and discrete microcapsules were formed. 

Particle size 

The mean particle size of the microcapsules significantly increased with 

increase in polymer concentration and was ranged in between 163.68 to 251.84 

m. The reason must be, the viscosity of medium which increase as the polymer 

concentration increase resulting in enhanced interfacial tension. Shearing 


Discussion 

efficiency is also diminished at higher viscosities. This may be resulting in the 

formation of large particles. (as shown in Table-13) 

Flow properties: 

The value of between 18 – 22° indicates reasonable flow and all the 

batches were found to fit with respect of flow ability. (as shown in table-13) 

Percentage yield: 

Percentage yield of the formulation was carried out and was found to be 

within the range between 85.85 to 90.24 %. (as shown in Table-14) 

Drug Content: 

Drug content of the formulation was carried out and was found to be 

within the range between 75.9 to 95.59 %. (as shown Table-14) 

Scanning Electron Microscopy: 

Scanning electron microscopy was performed to characterize the surface 

of the formed microcapsules. The outer surface of FM-3 formulation was smooth 

and dense, while the internal surface was porous. The shell of microcapsules also 

showed some porous structure it may be caused by evaporation of solvent 

entrapped within the shell of microcapsules after forming smooth and dense 

layer.(as shown in Fig-12) 

IR Studies 

Drug-polymer interaction study was carried out for pure drug, eudragit L- 

100 and S-100 and FM-3. 


Discussion 

Flurbiprofen was used in this study which contains carboxylic acid 

function responsible for a broad hump 3200 cm -1 .The aromatic C-H peaks was 

observed at 3076, 3063, 3032 cm -1 . The broad carboxylic acid absorption is 

noticed at 1701 cm -1 . These data are in concurrent with the structure of the drug 

molecular. .(as shown in Fig-13) 

Polymer eudragit L-100 and S-100 gave the broad carboxylic acid peak 

3500 cm -1 and C=0 absorption at 1724 cm -1 . These are the characteristics of the 

polymer under study. .(as shown in Fig-14,15) 

The formulation FM-3 which was subjected to IR. The formulated product 

is showed identical spectrum with respect to the spectrum of the pure drug and 

polymers, indicating there is no chemical interaction between the drug molecule 

and polymers.(as shown in Fig-16) 

In-vitro release studies: 

The In-vitro release studies of Flurbiprofen from prepared microcapsules 

were carried in pH 6.8 buffer as a diffusion medium for a period of 12 hrs. The 

drug release from the formulations decreased with increase in the amount of 

polymer added in each formulation. The release showed a biphasic release with an 

initial burst effect. In the first 30 min. drug release was 29.29%, 27.43%, 26.96% 

and 24.70% for FM-1 to FM-4 respectively. The mechanism for the burst release 

can be attributed to the drug loaded on the microcapsule or imperfect entrapment 

of drug. 


Discussion 

The overall cumulative % release for FM-1, FM-2, FM-3 and FM-4 were 

found to be 95.58%, 91.96%, 88.87%, and 88.51% at the end of 12 th hrs. ( as 

shown in Table-15 to 18 ) 

The ‘r’ values for zero order kinetics of FM-1, FM-2, FM-3 and FM-4 

were 0.916, 0.930, 0.936 and 0.937 respectively. The ‘r’ values for first order of 

FM-1, FM-2, FM-3 and FM-4 were 0.073, 0.065, 0.010 and 0.017 respectively. 

The ‘r’ values indicate the drug release follows zero order. 

To ascertain the drug release mechanism, the in-vitro data were also 

subjected to Higuchi diffusion. The ‘r’ values of Higuchi diffusion was 0.985, 

0.963, 0.973 and 0.983 for formulation FM-1, FM-2, FM-3 and FM-4 

respectively. It suggests that the Higuchi diffusion plots of all the formulations 

were fairly linear because ‘r’ values near about 1 in all the cases. So it confirms 

the drug release by Higuchi diffusion mechanism. 

The formulations were subjected to peppas plots by taking log cum % drug 

released versus log time. The plots are found fairly linear and slope value was 

calculated (n value) which was in ranges of 0.20 to 0.26 indicating the drug was 

released by Fickian diffusion mechanism. (as shown in Table-19) 

Formaldehyde treatment of hard gelatine capsules: 

The bodies of hard gelatine capsules were made insoluble by 

formaldehyde treatment. This was done by exposing the bodies of the capsules to 

vapours of formaldehyde; the caps were not exposed leaving them water-soluble. 


Discussion 

The capsules were tested for physical and chemical changes caused by exposure to 

vapours of formaldehyde. 

Dimensions: 

On formaldehyde treatment, the ‘00’ size capsule bodies showed a 

significant decrease in length and diameter. 

Solubility studies: 

When the capsules were subjected to studies in different buffers, the 

untreated caps disintegrated within 10 mins in all the media whereas the treated 

bodies remained intact for about 24 hrs. 

Qualitative test for free formaldehyde: 

Limit test for the presence of residual formaldehyde was carried. The 

sample solution was less intensively coloured when compared with standard 

inferring that less than 20 g/ml of free formaldehyde is present in 25 capsules 

bodies) as per the I.P. 

Formulation of modified pulsincap: 

Microcapsules equivalent to 150 mg of Flurbiprofen were filled into the 

treated bodies and plugged with different polymers like guar gum, sodium 

alginate, HPMC at different concentrations. The filled capsules were completely 

coated with 5% CAP solution. These pulsatile drug delivery systems were further 

evaluated for :( as shown in Table-8) 


Thickness: 

Discussion 

The thickness of the CAP coating was measured by using screw gauge. 

The values ranged from 0.05-0.067 mm.(as shown in Table-20) 

IR studies: 

Drug-polymer interaction study was carried out for physical mixture of 

pure drug and polymers (i.e. Flurbiprofen + Guar Gum, Flurbiprofen + HPMC and 

Flurbiprofen + Sodium Alginate). From the results, it was observed that all the 

characteristic peaks of Flurbiprofen were present in the combination spectrum, 

thus indicating compatibility of the drug and polymer in pulsatile device. (as 

shown in Fig-21 to 23) 

In-vitro release studies: 

In-vitro drug release profiles of pulsatile device were found to have very 

good sustaining efficacy. During dissolution studies, it was observed that, the 

enteric coat of the cellulose acetate phthalate was intact for 2 hours in pH 1.2, but 

dissolved in intestinal pH, leaving the soluble cap of capsule, which also dissolved 

in pH 7.4 phosphate buffer and then the exposed polymer plug which absorbed the 

surrounding fluid, swelled and released the drug through the swollen matrix. 

After complete wetting of the plug, it formed a soft mass, which was then easily 

ejected out of the capsule body; releasing the eudragit microcapsules into 

simulated colonic fluid (pH 6.8 phosphate buffer). 


Discussion 

With all the formulations, there was absolutely no drug release in pH 1.2, 

thus indicating the efficiency of 5% CAP for enteric coating. Very slight release 

was observed in pH 7.4 phosphate buffer. 

a) Formulations with guar gum as hydrogel plug: 

With formulations F1 (20mg), F2 (30mg) and F3 (40mg) at the end of 5 th 

hrs there was 6.050%, 2.777% and 2.212% drug was released respectively and at 

the end of 15 th hrs 74.61%, 69.43% and 62.28% drug release was found in F1, F2 

and F3 respectively. (as shown in Table-21to 23) 

b) Formulation with HPMC as hydrogel plug: 

With formulation F4 (20mg), F5 (30mg) and F6 (40mg) at the end of 5 th 

hrs 5.990%, 4.613% and 0.483% drug was released respectively and at the end of 

15 th hrs 76.46%, 71.71% and 59.79% drug released respectively. (as shown in 24 

to 26) 

c) Formulations with sodium alginate as hydrogel plug: 

With formulations F7 (20 mg), F8 (30 mg) and F9 (40 mg), at the end of 

5 th hrs around 9.303%, 6.087% and 4.436% drug released respectively and at the 

end of 15 th hrs 82.95%, 70.25% and 77.36% drug was released respectively.(as 

shown in Table-27 to 29) 

From all the above observations, it was found that the order of sustaining 

capacity of polymer is HPMC > Guar gum > Sodium alginate. 


Discussion 

The ‘r’ values for zero order kinetics of F-1, F-2, F-3, F-4, F-5, F-6, F-7, 

F-7, F-8 and F-9 were 0.955, 0.947, 0.930, 0.958, 0.950, 0.929, 0.967, 0.967, 

0.943 and 0.957 respectively. The ‘r’ values of the first order kinetics of F-1, F-2, 

F-3, F-4, F-5, F-6, F-7, F-7, F-8 and F-9 were 0.950, 0.958, 0.929, 0.957, 0.945, 

0.943, 0.943, 0.954, and 0.938 respectively. The ‘r’ value indicates drug release 

follows mixed order kinetics. 

To ascertain the drug release mechanism, the in-vitro data were also 

subjected to Higuchi diffusion. The ‘r’ values of Higuchi diffusion was 0.917, 

0.913, 0.875, 0930, 0.923 0.930, 0.937, 0918 and 0.910for formulation F-1 to F-9, 

respectively. It suggests that the Higuchi diffusion plots of all the formulations 

were fairly linear because ‘r’ values near about 1 in all the cases. So it confirms 

the drug release by Higuchi diffusion mechanism. 

The formulations were subjected to peppas plots by taking log cum % drug 

released versus log time. The plots are found fairly linear and the ‘r’ values are 

near to 1 and also slop value was calculated (n value) which was in ranges of 2.45 

to 2.72, indicating the drug was released by Super Case II transport diffusion 

mechanism. 


CHAPTER-7 

 

Conclusion 

The aim of this study was to explore the feasibility of time and pH 

dependent colon specific, pulsatile drug delivery system of Flurbiprofen to treat 

the rheumatoid arthritis. A satisfactory attempt was made to develop 

microcapsules by using pH dependent polymers (eudragit L/S100) and further the 

time dependent, pulsatile device was designed for the microcapsules and 

evaluated. 

The data obtained from the study of “Development and evaluation of 

pulsatile drug delivery system of Flurbiprofen” reveals following conclusion: 

Eudragit L-100 and S-100 in the ratio 1:2 are suitable for preparation of 

microcapsules for colonic targeting. 

The mean particle size of microspheres was in the range of 163.68 – 

251.84 m depending upon the type of polymer used. The particle size 

increased significantly as the amount of polymer increased. 

The flow properties of all the prepared microspheres were good as 

indicated by low angle of repose ( < 40º).The good flow properties 

suggested that the microspheres produced were non-aggregated. 

The entrapment efficiency was good in all the cases. This suggested that 

optimized parameters were used in the method of preparations. 


Conclusion 

In-vitro drug release of microcapsules showed biphasic release pattern for 

all microcapsules with initial burst release effect, which may be attributed 

to the drug loaded onto the surface of the particles. 

On the basis of, particle size, drug content, Scanning Electron Microscopy, 

IR-study, in-vitro release studies and its kinetic data, FM-3 was selected as 

an optimized formulation for designing pulsatile device. 

The solubility studies of empty gelatine capsule bodies, which where 

crosslinked with formaldehyde treatment, revealed that they are intact for 

24 hrs, and hence suitable for colon targeting. 

From all obtained results, it was found that the order of sustaining capacity 

of polymer is HPMC > Guar gum > Sodium alginate. 

Hence, finally it was concluded that the prepared pulsatile drug delivery 

system can be considered as one of the promising formulation technique 

for preparing colon specific drug delivery systems and hence in 

chronotherapeutic management of arthritis. 


CHAPTER-8 

 

Summary 

Over the past two decades there has been a growing appreciation on the 

importance of circadian rhythms on GIT physiology and on disease states, 

together with the realization of the significance of time-of-day of the 

administration on resultant pharmacodynamics and pharmacokinetics parameters. 

The significance of these day-light variations has not been over looked from the 

drug-delivery perspective and pharmaceutical scientists have displayed 

considerable ingenuity in the development of time delayed drug delivery system 

to address emerging chronotherapeutic formulation. 

The colon is a site where both local and systemic delivery of drug can 

take place. Treatment could be made more effective if it were possible for drug to 

be targeted directly on the colon. Colon-specific system could also be used in 

diseases that have diurnal rhythms. In the present study, an attempt was made to 

design and characterize pulsatile, colon specific drug delivery system in order to 

target the drug to the colon, and intentionally delaying the drug absorption from 

therapeutic point of view in the treatment of rheumatoid arthritis, where peak 

symptoms are observed in the early morning. 

Eudragit L/S 100 in ratio 1:2 was employed to prepare microcapsule of 

Flurbiprofen by 0/0 emulsion solvent evaporation method. Four formulations 

(FM-1 to FM-4) were prepared by varying the ratio of the drug and polymer. 


Summary 

These formulations were subjected to various evaluation parameters like particle 

size, flow properties, percentage yield, drug content, scanning electron 

microscopy, IR-study and in-vitro drug release studies using pH 6.8 phosphate 

buffer as dissolution medium. Based on the results obtain, the FM-3 was 

considered as the optimum formulation to design time and pH dependent, pulsatile 

drug delivery system. 

In the next step, the capsule bodies were made insoluble by 

formaldehyde treatment and these were subjected to various physical and 

chemical test such as dimension measurement, solubility studies and qualitative 

for free formaldehyde. 

The microcapsules equivalent to 150 mg of drug was filled in to the 

formaldehyde treated capsule bodies and plugged with different polymers, at 

different concentration (20, 30 and 40 mg). The polymers used as hydrogel plugs 

were Guar gum, HPMC and Sodium alginate. The joint of the capsule body and 

cape was sealed with small amount of 5 % ethycellulose ethanolic solution. Then 

these filled capsules were completely coated with 5 % cellulose acetate phthalate 

solution. These pulsatile formulations were subjected to various tests such as 

thickness of CAP coating, weight variation and in vitro release studies. 

From the in vitro release studies of pulsatile device, it was observed that 

with all the formulations, there was absolutely no drug release in simulated gastric 

fluid (acidic pH 1.2) for 2 hrs. Negligible amount of drug release was observed in 

simulated intestinal fluid (pH 7.4 phosphate buffer), where the dissol ution were 


Summary 

carried out for 3 hrs. In remaining hours dissolution was continued in simulated 

colonic medium (pH 6.8 phosphate buffers) and here the drug release was found 

to be 76.61, 69.43, 62.28 from F-1, F-2, F-3 respectively. 74.46, 71.71, 59.79 from 

F-4, F-5, F-6 respectively and 82.95, 70.25, 77.36 from F-7, F-8, F-9 respectively 

at the end of 15 hrs. 

All the polymers employed in study are suitable for colon targeting. The 

order of sustaining capacity of the polymer was HPMC > guar gum > sodium 

alginate. The obtained results showed the capability of the system in dealing drug 

release for programmable period and time and possibility of exploiting such delay 

to attain colon targeting. 

. 


Bibliography 

1. Gothaskar, AV, Joshi AM, Joshi, NH, 2004. Pulsatile drug delivery 

system—a review. Drug Del. Technol. 4, http://www.drugdeliverytech. 

com/id article=250. 

2. Bi-Botti CY. Chronopharmaceutics: Gimmick or clinically relevant 

approach to drug delivery—a review. J Control Rel 2004; 98(3):337– 

353. 

3. Bjorn, L. 1996. The clinical relevance of chronopharmacology in 

therapeutics. Pharmacological Res.1996; 33:107–115. 

4. Suresh S, Pathak S. Chronopharmaceutics: Emerging role of bio- 

rhythms in optimizing drug therapy. Indian J Pharm Sci 2005; 

67(2):135-140. 

5. Sharma S, Pawar SA, Low density multiparticulate system for pulsatile 

release of meloxicam. Int J Pharm 2006; 313: 150-158. 

6. Fan TY, Wei SL, Yan WW Chen DB, Li J. An investigation of pulsatile 

release tablets with ethycellulose and eudragit-L as film coating 

materials and cross-linked polyvinyl pyrolidone in the core tablets. J 

Control Rel 2001; 77:245-251. 

7. Krishainah YSR, Satyanarayan S. Colon-specific drug delivery system. 

In: Jain NK, editor. Advances in controlled and novel drug delivery. 1 st 

Ed. New Delhi: CBS publishers and distributors; 2001:89-119. 


Bibliography 

8. Bhavana V, Khopade AJ, Jain VVD, Jain NK. Oral pulsatile drug 

delivery. Eastern pharmacist 1996 Aug; 39 (464): 21-6. 

9. Smolensky MH, Peppas AN. Chronobiology drug delivery and 

Chronopharmaceutics. Adv Drug Delivery 2007; 59:825-851. 

10. Hrushesky WJM, 1994. Timing is everything. The Sci, 32–37. 

11. Roger Walker and Cate Whittlsea. Clinical pharmacy and Therapeutics. 

Elsevier Health Sci 4 th Ed. 2008:759-776. 

12. Harsh Mohan. Textbook of Pathology. Jaypee Brothers, Medical 

Publishers Ltd. New Delhi, 4 th Ed. 2003:832-838. 

13. http://www.arthritiestreatmentandrelief.com 

14. Libo Y, James SC, Joseph AF. Colon specific drug delivery: new 

approaches and in-vitro/in-vivo evaluation—review. Int J Pharm 2002; 

235:1–15. 

15. Shivkumar HG, Promod KTM, Kashappa GD. Pulsatile drug delivery 

systems .Indian J Pharma Edu 2003 July-Sep : 37(3) : 125:8. 

16. Sarasija S, Stutie P. Chronotherapeutics: emerging role of biorhythms in 

optimizing drug therapy. Indian J Phrma Sci 2000; 67:135–140. 

17. Wiwattanapatapee R, Luelak Lomlim, Krisanee Saramunee. Dendrimers 

conjugates for colonic delivery of 5-aminosalicylic Acid. J Control Rel 

2003; (88): 1–9 

18. Julie B, Howard, NES, John ME, Gillian P, Fran MB. The tolerability of 

multiple oral doses of Pulsincap ® capsules in healthy volunteers. J 

Control Rel.1996; 38: 151–158. 


Bibliography 

19. Sachin Survase, Neeraj Kumar. Pulsatile drug delivery: Current scenario 

crips 2007; 8:33 

20. Krishnaiah YSR, Reddy PBR, Satyanarayana V, Karthikeyan RS. 

Studies on the development of oral colon targeted drug delivery systems 

for metronidazole in the treatment of amoebiasis. Int J Pharm 2002; 

236: 43-55. 

21. Chien YW. Controlled and Modulated Release Drug Delivery System in 

Swarbrik J, Boylan JC Eds. Encyclopedia of Pharmaceutical 

Technology, Marcel Dekker, New York, 1990:281-313. 

22. Sangalli ME, Maroni A, Zema L, Busetti C, Giordano F, Gazzaniga A. 

In-vitro and in-vivo evaluation of an oral system for time and / or site- 

specific drug delivery. J Control Rel 2001; 73:103-110. 

23. Gupta SK, Atkinson L, Theeuwes F, Wong P, Gilbert PJ, Longstreth J. 

Pharmacokinetics of verapamil from an osmotic system with delayed 

onset. Eur J Pharm and Biopharma1996; 42 (1):74-81 

24. Ross AC, Macrae RJ, Walther M, Stevens HNE. Chronopharmaceutical 

drug delivery from a pulsatile capsule device based on programmable 

erosion. J Pharm Pharmacol. 2000; 52:903-909. 

25. Sweetman SC. Martindale The complete drug reference, 33 rd Edn. 

Pharmaceutical Press: Great Britain; 2002:41-42. 

26. Listair CR, Ross JM, Mathias W, Howard NES. Chronopharmaceutical 

drug delivery from a pulsatile capsule device based on programmable 

erosion. J Pharm. Pharmacol 2002; 52:903–909. 


Bibliography 

27. Samanta MK, Suresh NV, Suresh B. Development of Pulsincap Drug 

Delivery of salbutamol sulphate for drug tareting. Indian. Pharma Sci 

2000; 62(2):102-7. 

28. Young-II J, Tomoya O, Zhaopeng Hu. Evaluation of an intestinal 

pressure-controlled colon delivery capsules prepared by dipping method. 

J Control Rel 2001; 71:75-82. 

29. Seshasayan A, Sreenivasa RB, Prasanna R, Ramana Murthy KV. Studies 

on release of Rifampicin from Modified Pulsincap Technique. Indian J 

Pharma Sci 2001:337-9. 

30. Sangalli ME, Maroni A, Zema L, Busetti C, et al. 2001. In vitro and in 

vivo evaluation of an oral system for time and/or site-specific drug 

delivery. J Control Rel 2001; 73:103–110. 

31. Zahirul Khan MI, Zeljko P, Nevenka K. A pH-dependent colon targeted 

oral drug delivery system using methacrylic acid copolymers. I. 

Manipulation of drug release using Eudragit ® L100-55 and Eudragit ® 

S100 combinations. J Control Rel 1999; 58:215–222. 

32. Howard NES, Clive GW, Peter GW, Massoud B, Julei SB, Alan CP. 

Evaluation of Pulsincap TM to provide regional delivery of dofetilide to 

the human GI tract. Int J Pharm2002; 236:27–34. 

33. Libo Y, James SC, Joseph AF. Colon specific drug delivery: new 

approaches and in vitro/in vivo evaluation—review. Int J Pharm 2002; 

235:1–15. 


Bibliography 

34. Ying-huan Li, Jia-bi Zhu. Modulation of combined release behaviours 

from a novel “tablets-in-capsules system”. J Control Rel 2004; 50:111- 

22. 

35. Tomohiro Takaya, Kiyoshi N, Motoki M, Ikuo Ogita, Norko N, Ryo- 

ichi Y, et al. Importance of dissolution process on systemic availability 

of drugs delivered by colon delivery system. J Control Rel 1998; 

50:111-22. 

36. Takashi Ishibashi, Kengo I, Hiroaki Kubo, Masakazu M, Hiroyuki Y. 

Evalution of colonic absorbability of drugs in dogs using a novel colon- 

targeted delivery capsules(CTDC) J Control Rel 1999; 59:361-76. 

37. Jonathan CDS, Alistair CR, Walter K, Richard WB, Ross JM, Howard 

NES, et al. Investigating the coating-dependent release mechanism of a 

pulsatile capsule using NMR microscopy. J Control Rel 2003; 92:341-7. 

38. Matiholimath VS, Dandagi PM, Jain SS , Gadad AP, Kulkarni AR. 

Time and pH dependent colon specific, pulsatile delivery o theophylline 

for nocturnal asthma. Int J Pharm 2007; 328:49-56. 

39. Abraham S, Srinath MS. Development of modified pulsincap drug 

delivery system of metronidazole for drug targeting Indian J Pharm Sci 

2007; 69(1):18-23. 

40. Srisagul Sungthongjeen, Satit Puttipipatkhachorn, Ornlaksana 

Paeratakul, Andrei Dashevsky, Roland Bodmeier. Development of 

pulsatile release tablets with swelling and rupturable layers. J Control 

Rel 2004:147–159. 


Bibliography 

41. Krishnaiah YSR, Veer Raju P, Dinesh Kumar B, Bhaskar P, 

Satyanarayana V. Development of colon targeted drug delivery systems 

for Mebendazole. J Control Rel 2001; 77: 87–95 

42. Satyanarayana S, Rama Prasad YV, Krishnaiah YSR, Trends in colonic 

drug delivery- a review. Indian Drugs 1996; 33(1):1-10. 

43. Rama Prasad YV, Krishnaiah YSR, Satyanarayana S. In-vitro evaluation 

of guar gum as a carrier for colon-specific drug delivery. J Control Rel 

1998; 51:281-87. 

44. Krishnaiah YSR, Seetha DA. Guar gum as a carrier for colon specific 

delivery; influence of metronidazole tinidazole on in-vitro release of 

albendazole from guar gum matrix tablets. And J Pharm. Sci 2001; 4(3): 

235-43. 

45. Leopold CS, Friend DR. In-vitro study for the assessment of poly (L - 

aspartic acid) as a drug carrier for colon-specific drug delivery. Int J 

Pharm 1995; 126:139-45. 

46. Rubinstein A,Radai R. In vitro and in vivo analysis of colon specificity 

of calcium pectinate formulations. Eur J Pharm Biopharm 1995; 41:291- 

295. 

47. Turkoglu M, Ugurlu T. In vitro evaluation of pectin-HPMC compression 

coated 5-aminosalicylic acid tablets for colonic delivery. Eur J Pharm 

Biopharm 2002; 53:65-73. 


Bibliography 

48. Rama Prasad YV, Krishnaiah YSR, Satyanarayana S. In vitro evaluation 

of guar gum as a carrier for colon-specific drug delivery. J Control Rel 

1998; 51:281-287. 

49. Krishnaiah YSR, Satyanaryana S, Rama Prasad YV. Studies of guar 

gum compression-coated 5-aminosalicylic acid tablets for colon-specific 

drug delivery. Drug Dev Ind Pharm 1999; 25:651-657. 

50. Krishnaiah YSR, Bhaskar Reddy PR, Satyanarayana V, Karthikeyan RS. 

Studies on the development of oral colon targeted drug delivery systems 

for metronidazole in the treatment of amoebiasis. Int J Pharm 2002; 

236:43-55. 

51. Shinha VR, Kumaria R. Polysaccharide matrix for microbially triggered 

drug delivery to the colon. Drug Dev Ind Pharm 2004; 30(2):143-150. 

52. Lorenzo-Lamosa ML, Remunan-Lopez C, Vila-Jato JL, Alonson MJ. 

Design of microencapsulated chitosan microspheres for colonic drug 

delivery. J Control Rel 1998; 52:109-118. 

53. Brondsted H, Andersen C, Hovgaard L. Crosslinked dextran – a new 

capsule material for colon targeting of drug. J Control Rel 1998; 53:7- 

13. 

54. Vervoort L, Van den Mooter G, Augustijns P, Kinget R, Inulin 

hydrogels. I.Dynamic and equilibrium swelling properties. Int J Pharm 

1998; 172:127-135. 


Bibliography 

55. Vervoort L, Rambant P, Van den Mooter G, Augustijns P, Kinget R. 

Inulin hydrogels. II. In vitro degradation study. Int J Pharm 1998; 

172:137-145. 

56. Rubinstein A, Nakar D, Sintov A. Chondroitin sulphate: a potential 

biodegradable carrier for colon-specific drug delivery. Int J Pharm 1992; 

84:141-150. 

57. Milojevic S, Newton JM, Cummings JH, Gibson GR, Botham RL, Ring 

SG, Stockham M, Allwood MC Amylose as a coating for drug delivery 

to the colon: preparation and in vitro evaluation using 5-aminosalicylic 

acid pellets. J Control Rel 1996; 38:75-84. 

58. Shantha KL, Ravichandran P, Rao KP. Azo polymeric hydrogels for 

colon targeted drug delivery. Biomaterids 1995; 16: 1313-1318. 

59. Takashi Ishibashi, Harumi Hatano, Masao Kobayashi, Masakazu 

Mizobe, Hiroyuki Yoshino. Design and evaluation of a new capsule- 

type dosage form for colon-targeted delivery of drugs. Intl J Pharm 168 

(1998) 31–40. 

60. Lalwani A, Santani DD. Pulsatile drug system. A-review Indian J Pharm 

Sci 2007; 69(4):487-497. 

61. Morta R, Jose L, Vila J. Design of new multiparticulate system for 

potential site-specific and controlled drug delivery to the colonic region. 

J Control Rel 1998; 55: 67–77. 


Bibliography 

62. Lorenzo-Lamosa ML, Remun˜a´n-Lo´pez C, Vila-Jato JL, Alonso MJ. 

Design of microencapsulated chitosan microspheres for colonic drug 

delivery. J Control Rel 1998; 52: 109–118. 

63. Shivakumar HN, Sarasija S, Venkataram S. Design and evaluation of a 

multiparticulate system for chronotherapeutic delivery of Diclofenac 

sodium. Indian J Pharm Sci 2002; 64(2): 133-137. 

64. Kristmundsdottir T, Gudmundsson OS, Ingvarsdottir K. Release of 

diltiazem from eudragit microparticles prepared by spray-drying. Int J 

Pharm 1996; 137: 159-65. 

65. Hideki Ichikawa, Yoshinob F, Christianah, Moji, Adeyeye. Design of 

prolonged release microcapsules containing diclofenac sodium for oral 

suspension and their preparation by the wuster process. Int J Pharm 

1997; 156:39-48. 

66. Giovani FP, Giulia B, Piera DM, Sante M. Microcapsulation of 

semisolide ketoprofen/polymer microspheres. Int J Pharma 2002; 242: 

175-78. 

67. Alf Lamprecht, Hiromitsu Yamamoto, Hirofumi Takeuchi, Yoshiaki 

Kawashima. Microsphere design for the colonic delivery of 5- 

fluorouracil. J Control Rel 2003; 90: 313–322. 

68. Havgaard L, Brondsted H. Dextran hydrogels for colon-specific drug 

delivery. J Control Rel 1995; 36: 159-166. 


Bibliography 

69. Mine Orlu, Erdal Cevher, Ahmet Araman. Design and evaluation of 

colon specific drug delivery system containing flurbiprofen 

microsponges. Int J Pharm 2006; 318: 103–117. 

70. http://www.drugbankcom./flurbiprofen. 

71. http://www.sciencelab.com/flurbiprofen. 

72. http://www.roehm.com 

73. Government of India Ministry of Health & Family Welfare. Indian 

Pharmacopoeia. Delhi: Controller of Publications; 1996.p: 750, 151. 

74. Ainley W, Paul JW. Handbook of pharmaceutical excipients: 

monograph. 2 ed Ed. . London: The pharmaceutical Press; 2000: P.51-2, 

128, 138-9, 257, 113, 119. 

75. http://www.tradeindia.com 

76. http://www.huasu.en.chemnet.com 

77. http://www.adarshguargum.com 

78. http://www.chemicalbook.com 

79. http://www.ronasgroup.com 

80. Dandagi PM, Matiholimath VS, Gadad AP, Kulkarni AR, Jain SS. pH 

Sensitive mebeverin microspheres for colon delivery Indian J Phrm Sci 

2009; 71 (4): 264-268. 

81. Mehat KA. Formulation of enterosoluble microparticles for an acid 

labile Protein. J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 2002; 

5(3):234-244. 


Bibliography 

82. D Nagasamy Venkatesh, Reddy AK, Samanta MK, Suresh B. 

Development and In Vitro Evaluation of Colonic Drug Systems for 

Tegaserod Maleate. Asian J Pharm 2009; Jan – Mar: 50-53. 

83. Manavalan ramasamy. physical pharmaceutics. 2nd ed. india :vignesh 

publisher;2004. 

84. Patel A, Ray S, Thakur RM. In vitro evaluation and optimization of 

controlled release floating drug delivery system of metformin 

hydrochloride. DARU 2006; 14(2): 57-64. 

85. Kothawade KB, Gattani SG, Surana SJ and Amrutkar JR. Colonic 

Delivery of Aceclofenac Using combination of pH and Time Dependent 

Polymers. Indian Drugs Nov 2009; 46 (11): 67-70. 

86. Saravanan M, Bhaskar K, Srinivasa Rao G, Dhanaraju MD. Ibuprofen 

loaded ethylcellulose / polystyrene microsphers an approch to get 

prolonged drug release with reduced burst effect and low ethycellulose 

content J Microencapsulation 2003; 20 (3): 289-302. 

87. Nizar Al-Zoubi, Alkhatib HS, Yasser Bustanji, Khaled Aiedeh, Starros 

Malamataris. Sustained-release of buspirone HCL by co spray-drying 

with aqueous polymeric dispersion. Eur J Pharma and Biopharm 2008 

;(69): 735-742. 

88. Seshasayan A, Sreenivasa RB, Prasanna R., Ramana Murthy KV. 

Studies on Release of Rifampicin from modified pulsincap technique. 

Indian J Pharm Sci 2001:337–339. 


Annexure 


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