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WO1996013270A1 - Heparine, preparations d'heparine et leurs techniques d'utilisation - Google Patents

Heparine, preparations d'heparine et leurs techniques d'utilisation Download PDF

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Publication number
WO1996013270A1
WO1996013270A1 PCT/US1995/014021 US9514021W WO9613270A1 WO 1996013270 A1 WO1996013270 A1 WO 1996013270A1 US 9514021 W US9514021 W US 9514021W WO 9613270 A1 WO9613270 A1 WO 9613270A1
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WO
WIPO (PCT)
Prior art keywords
heparin
units
solid dosage
dosage form
effective amount
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1995/014021
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English (en)
Inventor
Orville Horwitz
William T. M. Johnson
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University of Pennsylvania Penn
Original Assignee
University of Pennsylvania Penn
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Pennsylvania Penn filed Critical University of Pennsylvania Penn
Priority to AU41379/96A priority Critical patent/AU4137996A/en
Publication of WO1996013270A1 publication Critical patent/WO1996013270A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/727—Heparin; Heparan

Definitions

  • Heparin was introduced to clinical medicine over fifty years ago on the basis of experimental work establishing its value in the prevention of venous thrombosis and as an essential aid for successful vascular surgery. During this time, heparin has been used as an essential drug in the treatment of diseases of the heart and blood vessels. However, the scope of its therapeutic use is limited by the need to administer it parenterally. It is inactive or only slightly active when introduced into the gastrointestinal tract and thus is not administered orally. See Physicians' Desk Reference (PDR) at pages 2538-40 (1994 edition) , which is incorporated herein by reference. At page 2539 of the PDR, it discloses that heparin sodium is not effective by oral administration. Accordingly, the drug is generally administered by intravenous or subcutaneous injection.
  • PDR Physicians' Desk Reference
  • heparin is the prescribed drug of choice.
  • coumadin also known as sodium warfarin
  • coumadin has been the drug of choice because it is effective orally.
  • coumadin is not without serious side effects.
  • the most serious risks reported for coumadin are hemorrhage, and necrosis and/or gangrenous skin and other tissues. Necrosis appears to be associated with local thrombosis and usually appears within a few days after commencing coumadin therapy. Hemorrhage and necrosis have, in some cases, been reported to result in death or permanent disability.
  • the present invention provides an effective amount of intact or unfractionated heparin formulated in a solid dosage form, which solid dosage form maintains a slight amount of its anticoagulant activity, while advantageously and unexpectedly exhibiting significant antilipe ic and antithrombotic activities not heretofore reported.
  • Such a solid dosage form of heparin, or compositions containing heparin thus unexpectedly provides an effective therapeutic in a convenient form for long-term or chronic use by the out-patient for treating a variety of lipemic and thrombotic disorders.
  • Another aspect then of the present invention provides compositions of the heparin and a pharmaceutically acceptable carrier, said compositions being formulated in solid dosage form for administration.
  • Another aspect then of the present invention unexpectedly provides a method of administering the heparin or the compositions of the present invention to a mammal, including humans, for treating conditions which may lead to atherosclerosis, such as those characterized by excess blood fats or lipemia, resulting in heart attack or stroke.
  • the methods of the present invention provide for routes of administration which are advantageously other than parenteral, for example, oral or sublingual.
  • a chronic maintenance or long-term antiatherogenic or antithrombotic therapy is also provided.
  • the compositions of the present invention may therefore be unexpectedly safer and more effective than parenterally administered heparin for long-term or chronic antiatherogenic or antithrombotic therapies.
  • Conditions advantageously and unexpectedly suitable for therapeutic treatment by way of the methods and compositions of the present invention include, but are not limited to, lipemia, thrombosis, hyperviscosity syndromes of the blood, and occlusive diseases of arteries and veins, such as atherosclerosis, venous thrombosis, and pulmonary embolism.
  • compositions and methods of the present invention include ease of administration and greater patient compliance, since no discomforting injections of heparin are required; greater reliability with regards to more certitude as to the amount of heparin administered in a solid dosage form, as compared with a liquid solution of heparin that must be measured using a hypodermic syringe; and greater stability and shelf-life, as compared with the liquid solution of heparin. Since the compositions and methods of the present invention advantageously and unexpectedly achieve a prolonged therapeutic effect, for example antilipemic effects, there is also unexpectedly achieved by way of this invention a less frequent need for administration of the compositions of the present invention, as favorably compared with other compositions of heparin and methods of administration.
  • the invention is also unexpectedly simpler and cheaper to practice, since there is no need to modify, derivatize, or complex heparin with other agents to achieve the therapeutic effects accomplished by the compositions and methods of the present invention.
  • Figure 1 shows changes in serum triglycerides after subcutaneous injection or oral administration (solution or powder) of heparin.
  • Figure 2 shows the effects of heparin taken orally in either a solution or powder form with regards to decreasing serum triglycerides.
  • Figure 3 shows the anticoagulant and antilipemic effects of sublingual and oral heparin by way of the present invention.
  • the present invention unexpectedly and surprisingly provides commercially available heparin formulated in a solid dosage form which may be administered in relatively pure form, or in combination with a pharmaceutically acceptable carrier as a composition for administration by a route other than parenteral.
  • the commercially available heparin may be unexpectedly and advantageously utilized as is by way of the present invention, without requiring fractionation or chemical modification.
  • parenteral as used herein includes subcutaneous, intravenous, intra-arterial injection, or infusion techniques, without limitation. These other than parenteral routes preferably encompass, for instance, oral and/or sublingual. Other routes of administration also contemplated by way of the present invention include topical applications such as rectal and vaginal.
  • An effective amount of the heparin is provided in a solid dosage form, which solid form advantageously and unexpectedly maintains its therapeutic activity.
  • This therapeutic activity encompasses slight anticoagulant activity, while unexpectedly and surprisingly exhibiting other therapeutic activities, such as antilipemic and antithrombotic effects, as compared with those activities achieved by injection or oral administration of a heparin solution.
  • An effective amount of heparin may be broadly defined as that amount necessary to achieve the desired therapeutic effect, which may be readily ascertained in practice by one of skill in the art or the attendant physician in the clinical setting.
  • heparin which is intact or unfractionated, and chemically unmodified, may be utilized in a solid dosage form, which is suitable for administration by routes other than parenteral. It has further been unexpectedly and advantageously discovered that heparin exhibits its beneficial therapeutic effects in such solid dosage form, while providing a lower risk of hemorrhage, without requiring further processing to low MW derivatives, as disclosed in United States Patent Nos. 4,533,549, 4,687,765 and 4,777,161, combining with various complexing agents, such as disclosed in United States Patent Nos. 3,548,052 and 4,510,135, or chemically modifying the heparin, as disclosed in United States Patent No.
  • heparin may be employed in any physiologically acceptable non-toxic form, including metal salts, preferably as the sodium salt. All of these are embraced in the term "heparin" as used in the present specification and claims. Intact or unfractionated heparins of various origins are considered suitable in the practice of the present invention. However, those heparins derived from porcine intestinal mucosa appear to have fewer side effects than bovine lung heparin. For best results, standard, unfractionated heparin powder from Diosynth, Inc. is preferred, but heparin from other sources, such as Hepar, Inc.
  • a therapeutic embodiment of the present invention may comprise a solid dosage form of U.S.P. heparin.
  • the compositions of the present invention in solid dosage form may also provide heparin in combination with one or more non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles, which are described hereinafter.
  • compositions of this invention can be used in the compositions of this invention, so long as they are suitable for formulation into a solid dosage form for administration by way of the present invention.
  • Such solid dosage forms for administration include capsules, tablets, pills, suppositories, dragees, troches, lozenges, powders and granules.
  • the active heparin is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or, a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as microcrystalline cellulose, carboxy ethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary am
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms can be prepared with coatings and shells such as enteric coatings and other coatings well- known in the pharmaceutical formulating art. They may optionally contain opacifying agents, and can also be of a composition that releases the heparin in a certain part of the intestinal tract or, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • compositions for rectal or vaginal administration are suitably suppositories which can be prepared by mixing heparin with appropriate non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at room temperature but liquifies at body temperature. Therefore, the suppositories melt in the rectum or vaginal cavity, and subsequently release the active heparin. Additional topical applications include inhalation spray and transdermal application.
  • a capsule such as an enteric-coated gelatin capsule, which is resistant to the acid medium of the stomach for advantageously dissolving and releasing the heparin in the alkaline medium of the intestine.
  • encapsulation of the heparin in an enteric coating by means well-known in the art, provides another example of a suitable form for oral administration.
  • Heparin can also be provided in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • heparin can be encapsulated, for instance, within proteinoid microspheres by dissolving or suspending the heparin in a pharmaceutically acceptable liquid, such as water or dimethyl sulfoxide, that interacts with the proteinoid to form microspheres, as described in United States Patent No. 4,925,673, which is incorporated herein by reference.
  • a pharmaceutically acceptable liquid such as water or dimethyl sulfoxide
  • the heparin utilized in the present invention can also be administered in the form of liposomes.
  • liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are disbursed in an aqueous medium.
  • any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to heparin, stabilizers, preservatives, excipients and the like. Suitable examples of such lipids are the phospholipids and the phosphatidyl cholines (lecithins) , both natural and synthetic.
  • the therapeutically-effective amount of heparin that may be combined with the above materials to produce a solid dosage form will vary depending upon various factors, as described below. Actual therapeutic dosage levels of heparin utilized alone or in the pharmaceutical compositions of this invention may vary so as to provide an amount of heparin that is effective to achieve the desired therapeutic response for a particular patient and mode of administration. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including body weight, general health, sex, diet, time and route of administration, rates of absorption and excretion, combination or interactions with other drugs, and the severity of the particular disease being treated. However, it is well within the skill of the art to commence with doses of heparin at levels lower than required to achieve the desired therapeutic effect, and then to gradually increase the dosage until the desired effect is achieved.
  • a total daily dose of heparin administered by way of the present invention to a mammalian host may be provided in single or divided dosages, as may be suitable, and may range, for example, from about 5,000 units to about 50,000 units; preferably, from about 10,000 units to about 40,000 units; more preferably from about 20,000 units to about 30,000 units, and, most preferably, from about 10,000 units to about 20,000 units per day.
  • These units are calculated on the basis of approximately 170 units of anticoagulant activity present per mg of heparin, and may, of course, be varied and tailored accordingly by calculation of units per mg of heparin preparation. Accordingly, these units above correspond to a range of from about 30 mg to about 300 mg of heparin.
  • the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.
  • compositions in solid dosage form containing an effective amount of heparin and an effective amount of the anticoagulant coumadin.
  • a pharmaceutically acceptable carrier may also be included.
  • the composition is suitable for sublingual administration in a pellet form, which is readily obtained by compressing the powder form of the active ingredients into a pellet.
  • the composition is suitable for oral administration.
  • the amounts of coumadin and heparin may be readily varied based upon the considerations for treatment discussed above. With regards to amounts, the coumadin may generally be present in an effective anticoagulant amount of from about 1 mg to about 5 mg.
  • Heparin may be provided in an amount ranging from about 10,000 units to about 20,000 units. Such a composition provides significant anticoagulant activity by way of coumadin, while unexpectedly providing additional antilipemic and antithrombotic activities via heparin, which antilipemic and antithrombotic activities coumadin lacks.
  • RESULTS OF TREATMENT Intact or unfractionated heparin in solid dosage form utilized either alone or in combination with the compositions of the present invention unexpectedly and surprisingly exhibits a number of beneficial therapeutic effects. These effects include, but are not limited to, preventing and treating of venous and/or coronary thrombi
  • antithrombotic thus decreasing the likelihood of coronary thrombosis, stroke, and pulmonary embolus; decreasing blood fats such as cholesterol and triglycerides (treating lipemia) ; altering cholesterol metabolism by advantageously increasing HDL to LDL ratio and retarding development of atherosclerosis; reducing platelet adhesiveness post-operatively; reducing blood viscosity in postoperative and chronic heart disease (CHD) patients; reducing anti-tPa activity; having high affinity for the vascular endothelium; and reducing of the incidence of post-operative phlebitis. It is contemplated by way of the present invention that methods of treating these conditions are advantageously and unexpectedly provided by the solid dosage forms of heparin and the compositions of this invention.
  • compositions of the present invention are therefore suitable for a number of therapeutic treatments. These include, e.g., for antilipemic treatment, and antithrombotic therapy, particularly in prophylaxis of postoperative thrombosis in mammals or preventing blood clots from forming in and on the wall of the blood vessel, which could lead to stroke.
  • the advantageous properties achieved by this invention also provide for the treatment of various hyperviscosity syndromes of the blood where, until now, reliance was placed essentially on techniques of hemodilution of limited short-term effects.
  • the hyperviscosity syndromes associated with a certain number of diseases include particular arteriopathies relating to chronic cerebral insufficiencies in elderly patients, hyperviscosity problems encountered in burn patients, hyperviscosity syndromes associated with conditions of sub- acute arterial insufficiency, for example, in the case of cerebral ischemia (localized thromboses in the brain) or cardiac insufficiency (condition of anginal pain) .
  • compositions of the present invention are particularly suitable for administration to a human or lower mammal host by oral or sublingual routes.
  • the compositions may be utilized topically in the form of suppositories for rectal or vaginal administration.
  • Such solid dosage forms advantageously avoid many of the problems of a liquid solution, such as measuring out volumes with a syringe.
  • Solid dosage forms are also much more convenient with regards to ease of use by the patient, who may otherwise be reluctant to undertake a long-term basis of daily heparin injection.
  • FIG. 1 shows the overall changes in serum triglycerides of eight patients who were administered heparin subcutaneously (5,000 units) or orally (ten patients receiving solution, 40,000 units, or three patients receiving powder in a gelatin capsule, 40,000 units) .
  • FIG. 2 additionally demonstrates the significant reduction or decrease in serum triglycerides obtained by heparin powder in a capsule over either an oral solution of heparin or subcutaneous heparin.
  • heparin in either an oral capsule or sublingual pellet form, provided significant decreases in serum triglycerides.
  • APTT Activated Partial Thro boplastin Time
  • clotting time about 6%
  • compositions and methods of the present invention include ease of administration and therefore greater patient compliance over a course of long-term treatment, since no discomforting injections of heparin are required; greater reliability with regards to more certitude as to the amount of heparin administered in a solid dosage form, as compared with a liquid solution of heparin, which must be measured by syringe; and better stability and shelf-life, as compared with the liquid solution of heparin.
  • the invention is also unexpectedly more convenient, simpler and less expensive to practice, since the unfractionated, commercial heparin utilized in the present invention need not be modified, derivatized, or complexed with other agents to unexpectedly and advantageously achieve the therapeutic effects accomplished by the compositions and methods of the present invention.
  • the invention would also advantageously increase the number of patients willing to take heparin, since no daily injections are necessary.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention porte sur une forme posologique solide d'héparine et sur des compositions la contenant. Il est également question des techniques d'utilisation de ces formes posologiques solides d'héparine pour traiter un certain nombre de troubles.
PCT/US1995/014021 1994-10-28 1995-10-27 Heparine, preparations d'heparine et leurs techniques d'utilisation Ceased WO1996013270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41379/96A AU4137996A (en) 1994-10-28 1995-10-27 Heparin, compositions and methods of use therefore

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33106894A 1994-10-28 1994-10-28
US08/331,068 1994-10-28

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WO1996013270A1 true WO1996013270A1 (fr) 1996-05-09

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3574832A (en) * 1968-05-29 1971-04-13 American Cyanamid Co Therapeutic heparin-surfactant compositions
US3574831A (en) * 1968-05-29 1971-04-13 American Cyanamid Co Therapeutic heparin-sodium taurocholate compositions
US4745107A (en) * 1986-08-20 1988-05-17 Foley Kevin M Heparin derivatives with improved permeability
US5264425A (en) * 1988-06-03 1993-11-23 Italfarmaco S.P.A. Glycosaminoglycan salts and pharmaceutical compositions containing them
US5346701A (en) * 1993-02-22 1994-09-13 Theratech, Inc. Transmucosal delivery of macromolecular drugs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3574832A (en) * 1968-05-29 1971-04-13 American Cyanamid Co Therapeutic heparin-surfactant compositions
US3574831A (en) * 1968-05-29 1971-04-13 American Cyanamid Co Therapeutic heparin-sodium taurocholate compositions
US4745107A (en) * 1986-08-20 1988-05-17 Foley Kevin M Heparin derivatives with improved permeability
US5264425A (en) * 1988-06-03 1993-11-23 Italfarmaco S.P.A. Glycosaminoglycan salts and pharmaceutical compositions containing them
US5346701A (en) * 1993-02-22 1994-09-13 Theratech, Inc. Transmucosal delivery of macromolecular drugs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FOUNDATION FOR VASCULAR-HYPERTENSION RESEARCH, issued November 1993, HORWITZ et al., "Twenty Second Annual Report", pages 1-16. *
PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE, Volume 77, No. 2, issued June 1951, LITWINS et al., "Sublingual Administration of Heparin", pages 325-326. *

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Publication number Publication date
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