Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-12-29
2002-10-01
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S450000, C424S451000, C424S455000, C424S456000, C424S463000, C424S489000, C424S499000, C424S502000, C424S435000, C424S464000, C424S434000, C514S937000, C514S938000, C514S939000, C514S940000, C514S941000, C514S942000, C514S943000, C514S975000, C514S056000
Reexamination Certificate
active
06458383
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to drug delivery, and more specifically relates to novel dosage forms, methods and drug delivery systems for enhancing the absorption and therefore the bioavailability of hydrophilic drugs, particularly polysaccharide drugs such as heparin, including low molecular weight heparin. The invention has utility in the fields of pharmaceutical formulation, pharmacology, and medicine.
BACKGROUND
Hydrophilic therapeutic agents frequently present difficult challenges with respect to both formulation and delivery. While these therapeutic agents can be readily soluble in water and easily dissolvable from a given dosage form in the gastrointestinal environment, the absorption of these drugs, because of their high molecular weight and/or hydrophilicity, is severely hampered by the permeation barrier imposed by the intestinal epithelial cell membrane as well as the junctional structure between the epithelial cells. In addition, chemical degradation in the acidic environment of the stomach, enzymatic inactivation, and binding or interference by mucous and other contents of the gastrointestinal (GI) tract can also contribute to the reduced availability of hydrophilic drugs in the GI tract for absorption. As a result, the administration of these hydrophilic drugs such as polysaccharides, peptides, and proteins frequently calls for invasive approaches such as subcutaneous or intravenous injection, resulting in severe restrictions in clinical use and problems with patient compliance.
Heparin is a polysaccharide drug of particular interest and importance because it is a potent anticoagulant drug widely used in the prevention and treatment of thrombosis. It decreases the rate of coagulation by increasing the rate at which antithrombin (also termed “heparin cofactor” or “antithrombin III”) inhibits activated coagulation factors, particularly thrombin, a key enzyme in the coagulation cascade. Heparin is a glycosaminoglycan present in the secretory granules of mast cells, and is characterized as a polymer of alternating D-glucuronic acid and N-acetyl-D-glucosamine residues (Bourin et al. (1993), “Glycosaminoglycans and the Regulation of Blood Coagulation,”
Biochem. J
. 289:313-330). Heparinoids—derivatives, analogs, fragments, salts, esters, etc. of heparin or heparin like glycosaminoglycan such as chrondroitin, dermatan sulfate, sulfomucopolysaccharide, mesoglycan, sulodexide, etc.—are also of paramount interest as anticoagulants.
Among all the heparins and heparinoids, low molecular weight heparin is of particular interest from a clinical standpoint. The potential advantages of low molecular weight heparin over unfractionated heparin include are numerous. For example, it has been suggested that low molecular weight heparin may be associated with a reduced risk of bleeding complications, possibly due to its more specific action on clotting factor Xa and relatively low action on factor IIa. In addition, low molecular weight heparin has a longer half-life so dosing frequency can be reduced. Because low molecular weight heparin exhibits reduced binding to platelets, the incidence of thrombocytopenia is substantially reduced. Furthermore, the likelihood of bone loss is reduced because low molecular weight heparin tends to bind less strongly to osteoblasts. See Hirsch et al. (1998), “Heparin and Low-Molecular-Weight Heparin. “
Chest
114:489S-510S.
However, because low molecular weight heparin is still a fairly large molecule and has prominent negative charges, the epithelial cell membrane in the intestine is practically impermeable to the drug, precluding effective oral delivery. As a result, there are several low molecular weight heparins commercially available for various anti-coagulating indications, but only through an invasive delivery approach, subcutaneous injection. Enoxaprin sodium is currently marketed under the trade name Lovenox® by Rhone-Poulenc Rorer. It is obtained by alkaline degradation of heparin benzyl ester derived from porcine intestinal mucosa. Its average molecular weight is about 4500 daltons, characterized by a distribution of no more than 20% less than 2000 daltons, no more than 15% greater than 8000 daltons, and greater that 68% between 2000 to 8000 daltons. It is formulated as a sterile solution for subcutaneous injection that contains 10 mg enoxaparin sodium per 0.1 ml water for injection in each dosage unit. Ardeparin sodium is currently marketed under the trade name Normiflo® by Wyeth-Ayerst Laboratories. It is a partially depolymerized porcine mucosal heparin that has the same molecular subunits as heparin sodium, USP and is available in concentrations of 5000 and 10000 anti-Factor Xa units/0.5 ml for deep (intra-fat) subcutaneous injection. It has an average molecular weight range of 6000±350 daltons. Dalteparin sodium is currently marketed under the trade name Fragmin® by Pharmacia. It is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. Its average molecular weight is about 5000 daltons and about 90% of the material within the range of 2000-9000 daltons. It is available as a single-dose, prefilled syringes containing 32 mg dalteparin sodium in 0.2 ml and a multiple-dose vial containing 64 mg per ml for subcutaneous injection.
Clearly, then, there is a need in the art for a pharmaceutical dosage form for non-invasive (e.g., oral) administration of heparin, heparinoids, and particularly low molecular weight heparin, wherein a therapeutically effective amount of the active agent is provided, the dosage form is chemically and physically stable, and patient compliance is improved relative to prior, injectable formulations.
The following references pertain to one or more aspects of the invention and may provide useful background information:
U.S. Pat. No. 3,510,561 to Koh et al. describes a method for enhancing heparin absorption through mucous membranes by co-administering a sulfone and a fatty alcohol along with the heparin.
U.S. Pat. No. 4,156,719 to Sezaki et al. describes a pharmaceutical formulation for rectal administration of a poorly absorbable drug. The formulation is a micellar solution containing the drug, a C
6
-C
8
fatty acid and/or the mono- or di-glyceride thereof, a bile acid and/or a non-ionic surfactant, and water.
U.S. Pat. No. 4,239,754 to Sache et al. describes liposomal formulations for the oral administration of heparin, intended to provide for a prolonged duration of action. The heparin is retained within or on liposomes, which are preferably formed from phospholipids containing acyl chains deriving from unsaturated fatty acids.
U.S. Pat. No. 4,654,327 to Teng pertains to the oral or other enteral administration of heparin in the form of a complex with a quaternary ammonium ion.
U.S. Pat. No. 4,656,161 to Herr describes a method for increasing the enteral absorbability of heparin or heparinoids by orally administering the drug along with a non-ionic surfactant such as polyoxyethylene-20 cetyl ether, polyoxyethylene-20 stearate, other polyoxyethylene (polyethylene glycol)-based surfactants, polyoxypropylene-1 5 stearyl ether, sucrose palmitate stearate, or octyl-&bgr;-D-glucopyranoside.
U.S. Pat. No. 4,695,450 to Bauer describes an anhydrous emulsion of a ydrophilic liquid containing polyethylene glycol, a dihydric alcohol such as propylene glycol, or a trihydric alcohol such as glycerol, and a hydrophobic liquid, particularly an animal oil, a mineral oil, or a synthetic oil.
U.S. Pat. No. 4,703,042 to Bodor describes oral administration of a salt of polyanionic heparinic acid and a polycationic species.
U.S. Pat. No. 4,994,439 to Longenecker et al. describes a method for improving the transmembrane absorbability of macromolecular drugs such as peptides and proteins, by co-administering the drug along with a combination of a bile salt or fusidate or derivative thereof and a non-ionic detergent (surfactant).
U.S. Pat. No. 5,688,761 to Owen et al. focuses primarily on the delivery o
Chen Feng-Jing
Fikstad David T.
Patel Mahesh V.
Channavajjala Lakshmi
Lipocine Inc.
Page Thurman K.
Reed Dianne E.
Reed & Associates
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