chitosan and plga microspheres as drug delivery ... - UniCA Eprints

More documents

Recommendations

Info

1. General Introductionof numerous endogenous or exogenous compounds. All metabolizing enzymes found in theliver are also found in the lung, although in smaller amounts. The rate at which a drug iscleared and absorbed from the respiratory tract depends on the dynamic interaction of severalfactors, predominantly: (1) the mucociliary clearance rate, (2) site of deposition along theairways, (3) biopharmaceutical factors (particulates vs drug in solution), (4) drug release rate,and (5) the physicochemical properties of the drug, such as molecular weight, partitioncoefficient, and charge.1.4.7. Mucociliary ClearanceMucociliary clearance is a physiologic function of the respiratory tract to clear locallyproduced debris, excessive secretions, or unwanted inhaled particles. It consists of ciliatedepithelial cells reaching from the naso/oropharynx and the upper tracheobronchial regiondown to the most peripheral terminal bronchioles. Beating of the cilia, together with mucussecreted by the goblet cells, contributes to an efficient clearance mechanism.For normal mucociliary clearance to occur it is necessary that the epithelial cells are intact,the ciliary activity and the rheology of mucus is normal, and that the depth and chemicalcomposition of the periciliary fluid layer is optimal. Thus, the mucociliary escalator can beimpaired by altering the volume of mucus secretion, the mucus viscosity and elasticity, or theciliary beat frequency. Mucociliary clearance is known to be impaired in smokers (104), inpatients with chronic bronchitis (102), and in acute asthmatics (105). Certain diseases havethe opposite effect that of enhancing clearance rates (106).1.5. RifampicinEach year, there are 8–10 million new cases of TB, which is the leading cause of death inadults by an infectious agent (107, 108).Rifampicin (RFP), 3-(4-methyl-l-piperazinyl-irninomethyl) rifamycin (109, 110) is one of themost potent and broad spectrum antibiotics against bacterial pathogens and is a keycomponent of anti-TB therapy. The introduction of RFP in 1968 greatly shortened theduration of TB chemotherapy. RFP diffuses freely into tissues, living cells, and bacteria,making it extremely effective against intracellular pathogens like M. tuberculosis (108).However, bacteria develop resistance to RFP with high frequency, which has led the medicalcommunity in the United States to commit to a voluntary restriction of its use for treatment ofTB or emergencies.24
1. General IntroductionRFP is an amphiphilic compound. It is extensively recycled in the enterohepatic circulation,and metabolites formed by deacetylation in the liver are eventually excreted in the faeces.Formula: C43H58N4O12;Molecular Weight: 822.95.Log P: 4,24pKa 1: 1,7pKa 2: 7,9Figure 1.6: Chemical Structure of Rifampicin.The bactericidal activity of RFP stems from its high affinity binding to, and inhibition of, thebacterial DNA-dependent RNA polymerase (RNAp) (111). The essential catalytic core RNApof bacteria (subunit composition α 2 ββ’ϖ) has a molecular mass of around 400 kDa and isevolutionarily conserved among all cellular organisms (112).Mutations conferring RFP resistance map almost exclusively to the rpoB gene (encoding theRNAp β-subunit) in every organism tested, including E. coli (113, 114, 115) and M.tuberculosis (116, 117). Comprehensive genetic analyses have provided molecular details ofamino acid alterations in β conferring RFP resistance (118, 119, 120, 121, 122, 123).Variable bioavailability of RFP from separate as well as fixed dose combination formulationshas been perceived as a major bottleneck in successful treatment of TB (124). In eachformulations important factor that may affect rate and/or extent of dissolution is physicalcharacteristics of rifampicin raw material such as polymorphic form, particle size, etc., whichin turn have a direct impact on drug substance processability, drug product manufacturability,and quality of dosage forms, including stability, dissolution, and bioavailability (125).Therefore, a complete physical characterization and its biopharmaceutic implication isessential in order to determine the influence of polymorphism/physical form onbioavailability. RFP due to its complex structure exhibits polymorphism and exists in twopolymorphic forms (126). It also exists as hydrates and various solvates, which eventuallyconvert into amorphous form at room temperature or after desolvation (127).RFP is well tolerated by most patients at currently recommended doses, althoughgastrointestinal tolerance can be unacceptably severe. Other adverse effects (skin rashes,fever, influenza-like syndrome and thrombocytopenia) are more likely to occur with25
Page 1: European Union Ministero dell’Uni
Page 5 and 6: Table Of Contents1. GENERAL INTRODU
Page 7: 7.1.4. Release Studies/Stability St
Page 10 and 11: 1. General Introduction1.1. Pulmona
Page 12 and 13: 1. General Introductionmucosa, and
Page 14 and 15: 1. General Introductionis the fact
Page 16 and 17: 1.3. Lung Anatomy1. General Introdu
Page 18 and 19: 1. General Introductionhighly vascu
Page 20 and 21: 201. General Introductionliquid (84
Page 22 and 23: 1. General IntroductionAerosol size
Page 26 and 27: 1. General Introductionintermittent
Page 28 and 29: 1. General Introductionsphere prepa
Page 30 and 31: 1. General Introductionit, respecti
Page 32 and 33: 1. General Introductionthe subject
Page 34 and 35: 1. General IntroductionA. zahoor et
Page 36 and 37: 2. Chitosan And PLGA2.1. Chitosan a
Page 38 and 39: 2. Chitosan And PLGAfor the prepara
Page 40 and 41: 2. Chitosan And PLGAmainly controll
Page 42 and 43: 2. Chitosan And PLGAAt present, a n
Page 44 and 45: 2. Chitosan And PLGAneed to be a go
Page 46 and 47: 2. Chitosan And PLGAdichloromethane
Page 49 and 50: 3. Aim of the Work49
Page 51: 3. Aim of the WorkBiodegradable mic
Page 54 and 55: 4. RFP Loaded Chitosan Microspheres
Page 71 and 72: 5. Rifampicin Loaded ChitosanMicros
Page 75 and 76:
5. RFP Loaded Chitosan Microspheres
Page 77 and 78:
Page 79 and 80:
Page 81 and 82:
Page 83:
Page 86 and 87:
6. RFP Loaded PLGA Microspheres Pre
Page 88 and 89:
Page 90 and 91:
Page 92 and 93:
Page 94 and 95:
Page 96 and 97:
Page 98 and 99:
Page 100 and 101:
100
Page 102 and 103:
7. RFP Loaded PLGA Coated Chitosan
Page 104 and 105:
Page 106 and 107:
Page 108 and 109:
Page 110 and 111:
Page 112 and 113:
Page 114 and 115:
Page 116 and 117:
Page 118 and 119:
118
Page 120 and 121:
8. Final Discussion and Conclusions
Page 122 and 123:
9. References9. References1. Fred S
Page 124 and 125:
9. References40. Wayne L.G., Good R
Page 126 and 127:
1269. References88. Carpenter R.L.
Page 128 and 129:
1289. References135. Fukushima S.;
Page 130 and 131:
9. References173. Zeng X.M., Martin
Page 132 and 133:
9. References219. Berthold A., Crem
Page 134:
9. Referencesmediates target gene e
show all

chitosan and plga microspheres as drug delivery ... - UniCA Eprints

Create successful ePaper yourself

Delete template?

Save as template?