Oral Low Molecular Weight Heparin Absorption - Pharmaceutical ...

Oral Low Molecular Weight
Heparin Absorption
From Solution and Solid Dosage Forms
in Rat, Dog, and Monkey Models
Andrea Leone-Bay,* Catherina O’Shaughnessy, Rajesh Agarwal,
Theresa Rivera-Schaub, Connie Rosado-Gray, Linda Gerspach, and
Robert A. Baughman
EMISPHERE
Parenteral low molecular weight heparin (LMWH) is the standard
of care for the prevention of deep vein thrombosis in patients
undergoing joint replacement or abdominal surgery. LMWH is not
absorbed after oral dosing. This article describes the delivery
agent–mediated transport of LMWH across Caco-2 cells. These
agents are shown to facilitate oral LMWH absorption in rats, dogs,
and monkeys.
Andrea Leone-Bay is a senior
director of project management at
Emisphere Technologies, Inc.,
765 Old Saw Mill River Road, Tarrytown,
NY 10591, tel. 914.785.4733, fax
914.593.8281, aleone-bay@emisphere.
com. Catherina O’Shaughnessy
is a senior research associate; Rajesh
Agarwal is a director of pharmaceutics
R&D; Theresa Rivera-
Schaub is a project manager;
Connie Rosado-Gray is a project
coordinator; Linda Gerspach is a
research associate; and Robert A.
Baughman is a senior vice-president
of development at Emisphere
Technologies, Inc.
*To whom all correspondence should be
addressed.
Parenteral low molecular weight heparin (LMWH) has
replaced warfarin as the standard of care for the prevention
of deep vein thrombosis (DVT) and pulmonary
embolism in high-risk, hospitalized patients undergoing
joint replacement or abdominal surgery (1). LMWH is favored
over antivitamin K oral anticoagulants such as warfarin
because it produces a rapid onset of anticoagulant activity and
has a short physiological half-life (2). Compared with warfarin,
LMWH has a significantly lower incidence of drug–drug interaction.
Anticoagulation with LMWH typically is evidenced
by its effect on plasma LMWH concentrations measured by the
anti-Factor Xa assay. The target therapeutic range for DVT prophylaxis
is 0.1–0.2 IU/mL (2). With the use of fixed doses, continuous
monitoring generally is unnecessary, and untoward hemorrhage
rarely occurs. The major disadvantage of LMWH
therapy is that it must be parenterally administered because it
is ineffective when dosed orally (3,4). Thus, LMWH usually is
replaced by oral warfarin for outpatient therapy. Unfortunately,
this switch from parenteral LMWH to oral warfarin often requires
prolonged hospitalization for the patient because the delayed
onset of action, the prolonged half-life, and the variable
response to warfarin necessitate a gradual increase in dose as
the LMWH dose is slowly decreased. An oral LMWH formulation
would allow for continuous LMWH treatment of outpatients,
thereby eliminating the need to change to warfarin.
Several recent attempts to develop effective oral LMWH formulations
have been reported. For example, LMWH complexes
with tertiary diamines have shown limited oral bioavailability
38 Pharmaceutical Technology MARCH 2002 www.pharmtech.com

upon intraduodenal administration to rabbits (5). Administration
of LMWH in a lipid matrix composed of phosphatidylcholine
from soy protein and medium-chain monoacylglycerols
has improved absorption in the small intestine of
rabbits (6). Other approaches have included the use of glycerol
esters of fatty acids (7) and non-ionic surfactants (8) to increase
the absorption of orally dosed LMWH. Recently, studies have
been conducted in which high doses of LMWH alone have been
administered orally to rabbits (9,10). In general, these experiments
have met marginal success.
Oral unfractionated heparin (UFH) absorption in rats (11),
monkeys (12), and healthy human subjects (13) following the
administration of an aqueous solution containing UFH and a
delivery agent have been reported. These delivery agents are
low molecular weight compounds that can be dissolved in water
with UFH (11). Oral administration of this solution mixture
results in the gastrointestinal absorption of UFH. One of these
delivery agents, sodium 8-[N-(2-hydroxybenzoyl)amino]
caprylate (SNAC), is the subject of advanced clinical studies
(13). Thus, therapeutic levels of anticoagulation, as measured
by increased activated partial thromboplastin time (APTT)
and anti-Factor Xa activity, were obtained following single oral
doses of the SNAC–UFH combination as a flavored syrup. We
also have demonstrated the efficacy of this oral SNAC–UFH
combination for the prevention (14) and treatment (15) of
DVT in a rat model of venous thrombosis. These studies show
that orally delivered UFH is as effective as injectable UFH in
this model.
As part of our continued research in this therapeutic, we have
investigated the delivery agent–facilitated gastrointestinal absorption
of LMWH. In this article, we report on the effects of
oral LMWH delivery facilitated by SNAC and a more efficient
delivery agent, sodium 10-[N-(2 hydroxybenzoyl)amino]decanoate
(SNAD). SNAC and SNAD are compared for their abilities
to transport LMWH across Caco-2 cells in vitro as well as
to facilitate oral LMWH absorption in rats, dogs, and monkeys
from aqueous solutions and tablets.
Materials and methods
Materials. SNAC and SNAD were synthesized at Regis Laboratories
(Chicago, IL). LMWH (Parnaparin) (91 IU/mg) was purchased
from Opocrin Laboratories (Modena, Italy). Propylene
glycol was purchased from Aldrich Chemical Company (Milwaukee,
WI). Plasma samples and cell culture samples were analyzed
for anti-Factor Xa activity using an LMW heparin–UF
heparin assay (Coatest, Chromogenix Instrumentation Laboratory,
S.p.A, Milano, Italy). Heparin concentrations (IU/mL)
were extrapolated from a standard curve. Concentrations 0.05
IU/mL were considered significant (16). No interference resulted
from SNAC or SNAD in these assays.
Preparation of dosing solutions. Solutions of SNAC/LMWH
and SNAD/LMWH were prepared in either 25% (v/v) aqueous
propylene glycol or water as follows: Water or a solution of 25%
(v/v) aqueous propylene glycol was added to a dry mix of
SNAC/LMWH or SNAD/LMWH. The resulting suspension was
mixed by vortex and then placed in a 37 C ultrasonic water
bath for 10–15 min until a clear solution was obtained. The solution
was brought to its final volume with either water or 25%
v/v aqueous propylene glycol. Typically, the final solutions contained
100 mg/mL SNAC or SNAD and 91 IU/mL LMWH at
pH 7.5–8.5.
Preparation of tablets. SNAD/LMWH tablets were manufactured
at Elan Pharmaceutical Technologies (San Francisco, CA)
by direct compression. The SNAD/LMWH tablets each contained
275 mg SNAD and 45,000 U heparin.
Caco-2 cell culture. Caco-2 cells were obtained from American
Tissue Culture Collection (Rockville, MD). The cells were maintained
in Dulbecco’s modified eagle’s medium that contained
10% heat-inactivated fetal bovine serum, 1% nonessential amino
acids, penicillin (100 units/mL), and streptomycin (100 g/mL)
in an atmosphere of 95% air and 5% carbon dioxide as previously
described (17). All cell culture media were obtained from
GibcoBRL (Invitrogen Corp., Carslbad, CA). For transport studies,
the cells were seeded onto Costar Transwell (Corning Inc.,
Aeton, MA) polycarbonate filters (12-mm diameter, 0.4-m
pore size) at a density of 5 10 5 cells per filter. Cells between
passages 25 and 35 were used. The cells were fed every 48 h and
were allowed to grow and differentiate for as long as 20 days
before the monolayers were used in drug transport experiments.
Drug transport studies (Caco-2). Solutions of SNAC/LMWH
and SNAD/LMWH were prepared in Hank’s buffered saline
solution supplemented with 11 mM glucose and 25 mM N-[2-
hydroxyethyl]piperazine-N’-[2-ethanesulfonic] acid. Final concentrations
of the delivery agent (SNAC or SNAD) and LMWH
applied to the apical side of the monolayers were 5.0 mg/mL
and 60 mg/mL (5460 IU/mL), respectively. Basolateral samples
were taken every 30 min for 2 h and replaced with fresh
buffer. These were analyzed using the anti-Factor Xa activity
assay. The integrity of the cell monolayers was monitored by
measuring transepithelial electrical resistance (TEER) immediately
before the addition of donor solutions (apical side) and
again after 2 h. In addition, trypan blue staining of the monolayers
at the end of each experiment was used to verify monolayer
integrity.
Determination of the permeability coefficients and enhancement
ratios. The apparent permeability coefficient (P app
,cm/s) was
calculated according to Kotz et al. (18) using the following
equation:
in which dC/dt is the steady-state rate of change in the drug
concentration in the receiver chamber (g mL 1 s 1 ), V R
is the
volume in the receiver chamber (mL), A is the surface area of
the cell monolayer (1.13 cm 2 ), and C 0
is the initial concentration
in the donor chamber (g/mL). All experiments were carried
out under “sink” conditions. The enhancement ratio was
calculated by dividing the P app
of LMWH obtained in the presence
of the delivery agent by the control P app
of LMWH alone.
Animal studies. Animal protocols (rats and dogs) were reviewed
and approved, where appropriate, in advance by the
Institutional Animal Care and Use Committee. Animal protocols
(monkeys) were approved in advance by ITR Labora-
40 Pharmaceutical Technology MARCH 2002 www.pharmtech.com
[1]

Table I: Summary of Caco-2 studies.*
SNAC
SNAD
Delivery Agent LMWH P app
% TEER Enhancement LMWH P app
% TEER Enhancement
Concentration (mg/mL) (cm/s SEM) Remaining Ratio (cm/s SEM) Remaining Ratio
0 8.4 1.0 (10 9 ) 126.3 2.5 n/a 5.3 0.4 (10 9 ) 86.8 0.8 n/a
5 27.2 0.7 (10 9 ) 140.3 2.8 3.26 22.9 0.8 (10 9 ) 90.1 2.0 4.32
*% TEER percentage transepithelial electrical resistance remaining SEM. Enhancement ratio was calculated by dividing P app
of LMWH
in the presence of delivery agent by the P app
of LMWH alone. For each study, n 3.
tories Canada Inc. (Montréal, QC, Canada), Institutional Animal
Care and Use Committee.
Rat studies. Male Sprague-Dawley rats (Taconic Farms, Germantown,
NY), housed in the animal care facility at New York
Medical College (Valhalla, NY), were fasted for 12 h before dosing.
Groups of five or six rats weighing 300 to 350 g each were
anesthetized with 44 mg/kg ketamine hydrochloride (Fort
Dodge Laboratories, Inc., Fort Dodge, IA) intramuscularly.
One dose of either SNAC/LMWH or SNAD/LMWH in 25%
v/v aqueous propylene glycol was administered orally via an
8 fr. Nelaton catheter (Rusch, Kernen, Germany) attached to a
1-mL syringe. Control animals were dosed with 25% v/v aqueous
propylene glycol solution containing either LMWH, SNAC,
or SNAD alone. Citrated blood samples (0.5 mL) were collected
serially by cardiac puncture for 1.5 h, the plasma was
harvested, and the anti-Factor Xa activity was measured.
Monkey studies. Groups of four cynomolgus monkeys, two males
and two females, weighing 2–3 kg each and housed in the animal
care facility at ITR Laboratories Canada, Inc., were fasted
for 4 h before dosing and as long as 2 h after dosing. The animals
were sedated with an intramuscular injection of 10 mg/kg
ketamine hydrochloride immediately before dosing. Three
mL/kg or 1 mL/kg of the dosing solution was administered
to each animal via oral gavage. Citrated blood samples (1 mL
each) were collected by venipuncture at 1 h before dosing and
at 10, 20, 30, 40, and 50 min and 1, 1.5, 2, 3, 4, and 6 h after
dosing. The harvested plasma was frozen at 80 C and shipped
to Emisphere Technologies, Inc., for anti-Factor Xa analysis.
Dog studies. Conscious, male beagle dogs (Taconic Farms),
housed in the animal care facility at New York Medical College,
were fasted for 12 h before dosing. One oral dose of SNAD/
LMWH either as a solution in water (5 mL) or as one tablet was
administered to groups of six dogs weighing 15–18 kg each.
Blood samples (0.9 mL) were removed via a saphenous vein
catheter before dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, and
6 h after dosing. Anti-Factor Xa assays were conducted.
Results and discussion
Both SNAC and SNAD previously were identified as effective
oral and colonic delivery agents for UFH (11). To test their abilities
to facilitate oral LMWH absorption across intestinal tissue,
the SNAC/LMWH and SNAD/LMWH combinations were evaluated
in vitro (cell culture studies) and in vivo (rats, dogs, and
monkeys).
Cell culture studies. Both SNAC and SNAD were effective at increasing
the permeation of LMWH across Caco-2 cell monolayers
compared with controls run with LMWH alone. Data in
Table I show that the apparent permeability coefficient of LMWH
alone was 5.3–8.4 10 9 0.7. In the presence of SNAC, P app
of LMWH (27.2 10 9 0.7) was increased greater than threefold
in comparison with the value of the control study. In the
presence of SNAD, P app
of LMWH (22.9 10 9 0.8) was increased
more than four-fold in comparison with the value of the
control study. In both cases, the monolayers were not adversely
affected. Thus, no significant decreases in Caco-2 TEER were
observed by the end of the experiments (see Table I).
Caco-2 monolayer integrity was verified by trypan blue staining
after each experiment. No increase in dye uptake was observed
at the conclusion of the control, SNAD/LMWH, or
SNAC/LMWH studies. These studies indicate that SNAC and
SNAD do not behave as classical penetration enhancers (e.g.,
sodium dodecylsulfate). Absorption that occurs as a result of
traditional penetration enhancement is accompanied by significant
reductions in TEER and significant increases in trypan blue
uptake (19–22). The data show that SNAC and SNAD do not
cause these changes. The enhancement ratio for LMWH in the
presence of SNAD (4.32) was higher than that obtained in the
presence of SNAC (3.26). These studies suggest that SNAD is a
more efficient oral delivery agent for LMWH. The following animal
experiments were conducted to test this observation in
vivo.
In vivo administration of SNAC/LMWH and SNAD/LMWH solutions.
Having verified that SNAC and SNAD were effective at promoting
the membrane transport of LMWH, in vivo studies were initiated.
Thus, either SNAC/LMWH or SNAD/LMWH as an aqueous
propylene glycol solution was orally administered to rats.
Following a single oral dose, both the SNAC/LMWH and
SNAD/LMWH combinations produced increased plasma LMWH
concentrations as measured by anti-Factor Xa assay (see Figure
1). Mean peak anti-Factor Xa levels of 2.0 0.3 IU/mL and 2.2
0.2 IU/mL were observed following oral administration of
solutions containing SNAC/LMWH and SNAD/LMWH, respectively.
The SNAC-facilitated bioavailability (relative to subcutaneous
injection [23]) of LMWH was 5%, and the SNADfacilitated
bioavailability of LMWH was 9%. Control animals
dosed with either LMWH, SNAC, or SNAD alone did not show
any increase in plasma LMWH concentrations.
To confirm the abilities of SNAC and SNAD to facilitate oral
LMWH delivery in a second species, single oral doses of either
the SNAC/LMWH or SNAD/LMWH heparin combinations as
aqueous solutions were administered to monkeys. Both combinations
caused significant elevations in plasma LMWH concentrations.
In the presence of a constant dose of LMWH, a
dose-dependent response was evident for SNAC delivery agent
42 Pharmaceutical Technology MARCH 2002 www.pharmtech.com

Figure 1: LMWH delivery to rats. The graphs indicate the responses
following a single oral dose of SNAC/LMWH or SNAD/LMWH and the
response following a single subcutaneous injection of LMWH. The dose
of SNAC or SNAD was 300 mg/kg. The dose of LMWH was 3000 IU/kg
(oral) or 200 IU/kg (subcutaneous). The dosing vehicle was 25%
aqueous propylene glycol. The bioavailability of LMWH was 5% when
dosed with SNAC and 9% when dosed with SNAD.
Figure 2: Oral LMWH delivery to monkeys, SNAC dose–response study.
The graphs indicate the responses following a single oral dose of SNAC
(300–50 mg/kg doses) in combination with LMWH (1000 IU/kg). The
dosing vehicle was 25% aqueous propylene glycol. The bioavailability
of LMWH was 35% at 300 mg/kg SNAC, 20% at 100 mg/kg SNAC, and
3.1% at 50 mg/kg SNAC.
Figure 3: LMWH delivery to monkeys, comparison of SNAC with SNAD.
The graphs indicate the responses following single oral doses of
SNAC/LMWH or SNAD/LMWH and the response following a single
subcutaneous injection of LMWH. The dose of SNAC or SNAD was
50 mg/kg. The dose of LMWH was 1000 IU/kg (oral) or 200 IU/kg
(subcutaneous). The dosing vehicle was 25% aqueous propylene
glycol. The bioavailability of LMWH was 3.1% when dosed with SNAC
and 38.2% when dosed with SNAD.
doses ranging from 50 to 300 mg/kg (see Figure 2). Mean peak
anti-Factor Xa levels for all monkey studies were achieved between
0.5 and 1.5 h after dosing. Mean peak plasma LMWH
concentrations were 0.17–0.96 IU/mL. A similar dose–response
relationship was observed with SNAD at lower delivery agent
doses. Figure 3 shows a comparison of the responses following
single oral doses of the SNAC/LMWH and SNAD/LMWH combinations
at a delivery agent dose of 50 mg/kg and a LMWH
dose of 1000 IU/kg. The relative bioavailability of LMWH was
3.1% with SNAC and 38.2% with SNAD. Thus, SNAD is 10
times more effective than SNAC for oral LMWH delivery in the
monkey model.
Solid dose formulation in vivo studies. Having confirmed in both
in vitro cell culture and in vivo models that SNAD is more effective
than SNAC for facilitating oral LMWH absorption from
unformulated aqueous solutions, studies were initiated to evaluate
a SNAD/LMWH solid dose form. Dogs were selected as
the large-animal model for this work. Single oral doses of either
aqueous solutions or tablets containing SNAD (275 mg)
in combination with LMWH (45,000 IU) were administered to
groups of six dogs. Figure 4 shows the response following a single
oral dose of the SNAD/LMWH solutions or the SNAD/
LMWH tablets. Both dosage forms produced increases in anti-
Factor Xa activity. Similar pharmacokinetic profiles were obtained
from the aqueous dosing solution and the tablets, both
producing a peak response at 0.5 to 1.5 h. The area under the
curve of plasma LMWH concentration versus time indicates
that the solution elicited a 1.5-fold greater response than did
the tablets. Oral administration of LMWH or SNAD alone did
not produce elevations in anti-Factor Xa activity. The bioavailability
of LMWH, administered orally as a solid dose form, relative
to subcutaneous injection was 3%.
Conclusion
The studies presented in this article have shown that both SNAC
44 Pharmaceutical Technology MARCH 2002 www.pharmtech.com

Figure 4: SNAD/LMWH capsule administration to dogs. The graphs
represent the responses following a single oral dose of SNAD/LMWH
as an aqueous solution or following a single oral dose of SNAD/LMWH
as one tablet. The dose of SNAD was 275 mg/dog, and the dose of
LMWH was 45,000 IU/dog.
and SNAD facilitate the transport of LMWH across Caco-2 epithelial
cells without opening the tight junctions or adversely
affecting the structural integrity of the cell monolayer. Administration
of aqueous solutions of the SNAC/LMWH and
SNAD/LMWH combinations to rats and monkeys indicated
that the Caco-2 cell model correctly predicted the relative transport
abilities of both SNAC and SNAD. Thus, these delivery
agents were effective at promoting oral LMWH absorption in
these animal models, and SNAD was more effective than SNAC.
The SNAD/LMWH combination was evaluated further as a
tablet formulation. Increased plasma LMWH concentrations
also were measured following the oral administration of these
tablets to dogs. Overall, these studies demonstrate that SNAC
and SNAD facilitate oral LMWH absorption in two species, and
that the SNAC/LMWH and SNAD/LMWH combinations are
not cytotoxic in a Caco-2 cell culture model.
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