Oral Delivery of Heparin - American Chemical Society

Chapter 6

Oral Delivery of Heparin 1

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Andrea Leone-Bay , Theresa Rivera-Schaub , Rajesh Agarwal , Mark Gonze , Sam Money , Connie Rosado-Gray , and Robert A. Baughman 2

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Emisphere Technologies, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591 Ocshner Medical Institutes, New Orleans, LA 70121

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During the past decade, dramatic progress in the field of biotechnology has resulted in a large increase in the number of commercially available macromolecular drugs that require parenteral dosing. These new drugs have enormous therapeutic potential, but their use is often limited by their invasive route of administration and with it the complications of patient discomfort and noncompliance. Nonparenteral macromolecular drug delivery has obvious benefits but represents a major clinical challenge because these drugs are plagued by poor absorption, rapid metabolism, and biological and chemical instability. A variety of noninvasive routes of administration for these new therapeutics are currently under investigation including pulmonary, nasal, transdermal, buccal, and oral. Of these methodologies, the most desirable route is the oral route, but it is also the most difficult because the gastrointestinal tract is designed to degrade large molecules and to prevent their absorption.

Heparin Heparin is a heterogeneous mixture of oligosaccharides with an average molecular weight of about 20,000 Da. It is an anticoagulant drug administered parenterally to hospitalized patients to prevent deep venous thrombosis (DVT) and pulmonary embolism (PE), two common post-surgical complications. Heparin is favored over antivitamin Κ oral anticoagulants because it produces a rapid onset of anticoagulant activity and has a short physiological half-life (1). Heparin therapy also results in a significantly lower incidence of drug-drug interactions. These pharmacological properties facilitate uncomplicated dose adjustment and contribute to heparin=s relatively large margin of safety. The biological response to heparin is increased blood clotting time typically measured by the activated partial thromboplastin time (APTT) assay. The therapeutic target range is 1.5-2.5 times baseline. Heparin levels in the systemic circulation are measured by the anti-Factor Xa assay. Adequate anticoagulation is achieved when plasma heparin levels are 0.1-0.2 IU/mL. 54

© 2000 American Chemical Society

In Controlled Drug Delivery; Park, K., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2000.


55 The major disadvantage of heparin therapy is the requirement for parenteral administration. Oral heparin is ineffective because its highly anionic character and large molecular weight preclude its absorption from the gastrointestinal tract (2). Thus, heparin is usually replaced by the oral anticoagulant warfarin for outpatient therapy. Warfarin has an extended physiological half-life, is almost completely bound to plasma proteins (3), and requires multiple days for the onset or termination of its activity. Due to its high protein binding, warfarin is the source of numerous unfavorable drug interactions. The switch from heparin to warfarin therapy requires 5-6 days because the delayed onset of action and the prolonged half-life of the latter necessitates a gradual increase in dose as the heparin dose is slowly decreased. Throughout this period of multiple drug exposure, careful patient monitoring is imperative (1). In adddition, establishing an appropriate dose can be a long process because equilibration of clotting time may not be achieved for 1-2 weeks after dose adjustment. Daily monitoring is ultimately reduced to several times per month in well-controlled pateints receiving long-term therapy. Given these therapeutic problems associated with the current oral anticoagulants, and given that heparin is considered the therapy of choice for preventing DVT and PE, an oral heparin formulation could have tremendous clinical importance. Oral Heparin Numerous attempts to develop oral heparin formulations have been reported. Formulations using enteric-coated heparin-amine combinations, heparin complexes or salts prepared with organic acids, heparin derivatives produced by partial desulfation and methylation, mixed micelles, oil/water emulsions, and absorption enhancers such as EDTA have been described (4). Dosage forms based on hydrophobic organic bases (5, 6), spermine and lysine salts (7), liposomes (8, 9), hydrogel nanospheres (10), or bile salts (11, 12) have also been investigated. These approaches have been largely unsuccessful. Consequently, the need for an oral heparin dosage form remains. We have chosen a new approach to oral heparin delivery that can be described as the design and synthesis of novel, peptide-like delivery agents that facilitate the gastrointestinal absorption of macromolecular drugs including interferon (13), recombinant human growth hormone (14), and heparin (15). These delivery agents can be administered in combination with macromolecular drugs to effect their oral absorption. We previously demonstrated limited absorption of heparin in rats (16) following the oral administration of microsphere-encapsulated heparin. These microspheres were prepared from either complex, uncharacterized mixtures of thermally condensed α-amino acids (17) or acylated α-amino acids, both of which undergo spontaneous molecular self-assembly to form microspheres under acidic conditions. To improve the efficiency of this oral heparin delivery, we have now developed novel delivery agents based on ηοη-α-amino acids. These compounds promote the oral absorption of heparin at physiological pH and offer several advantages over our earlier systems. Most importantly, these current delivery agents are well-characterized chemical entities, and the preparation of microsphere


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suspensions is no longer required to elicit enhanced absorption. Following oral administration of a solution containing a combination of heparin and a selected delivery agent to rats, monkeys, or healthy, human subjects therapeutic levels of anticoagulation can be obtained (18, 19). Oral SNAC/Heparin A family of delivery agents (Figure 1) was prepared and screened for their ability to facilitate the gastrointestinal absorption of heparin in rats. These data are reported in Figure 2 in which mean peak APTT values are plotted against the number of methylene units in the acid chain. The data show that the delivery agents having 7 (SNAC), 8, or 9 methylenes connecting the amide and acid functions are the most efficient at promoting oral heparin absorption. The compounds having either a fewer or a greater number of carbons do not effect the oral delivery of heparin as well. One possible explanation for this observation is that the delivery agents are acting as surfactants or "traditional penetration enhancers" (20-22). However, surfactants cause damage to the gastrointestinal membranes at the concentrations required to effect drug delivery. Here, however, the increased absorption of heparin in the presence of delivery agents was not the result of frank damage to the intestinal tissue (23). Histological evaluation of the gastrointestinal tracts of rats was performed following a single oral administration of SNAC to ensure that the increased absorption of heparin observed in these studies was not due to tissue damage. At no time point was there detectable pathology caused by SNAC. These data confirm that the increased absorption of heparin in the presence of SNAC was not due to disruption of the intestinal epithelium. Based on these studies, the SNAC/heparin combination was selected to confirm oral heparin delivery in a second species, cynomolgus monkeys. Monkeys that received a single oral dose of 150 mg/kg SNAC in combination with 30 mg/kg heparin had APTT levels above the detectable range of the assay (>240 sec). This response is about 12 times the baseline value of 20 seconds. In humans, therapeutic anticoagulation is achieved at 1.5-2.5 times baseline. The pharmacodynamic response following oral administration of 150 mg/kg SNAC and 30 mg/kg heparin is shown in Figure 3 a. A large increase in clotting time demonstrated that significant absorption of heparin was achieved in the presence of SNAC. Neither SNAC (300 mg/kg) nor heparin (100 mg/kg) dosed alone elicited any change in APTT. When the dose of heparin was reduced by one-half (150 mg/kg SNAC and 15 mg/kg heparin), the pharmacodynamic response was greatly reduced (Figure 3a). However, the direct plasma heparin measurement by anti-Factor Xa activity showed that drug levels were approximately half those measured following a heparin dose of 30 mg/kg (Figure 3b). The dependence of the pharmacological response (clotting time) to increasing heparin concentration is not a linear function due to heparin's dose-dependent clearance (24,25). At higher heparin doses, relatively small changes in plasma heparin concentrations will lead to proportionately larger changes in APTT. Given the effective oral delivery of heparin in the presence of SNAC in two species, the safety of this combination dosing solution was evaluated in monkeys. Cynomolgus monkeys dosed orally with SNAC and heparin (30 mg/kg) in


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Figure I. Chemical Structures of Oral Heparin Delivery Agents

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Figure 2. APTT response in rats following a single, colonic dose of heparin in combination with one of the delivery agents 1-11. The data are plotted as mean SEM.


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Oral Delivery of Heparin - American Chemical Society

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