WO1996013270A1

WO1996013270A1 - Heparin, compositions and methods of use therefore

Info

Publication number: WO1996013270A1
Application number: PCT/US1995/014021
Authority: WO
Inventors: Orville Horwitz; William T. M. Johnson
Original assignee: The Trustees Of The University Of Pennsylvania
Priority date: 1994-10-28
Filing date: 1995-10-27
Publication date: 1996-05-09
Also published as: AU4137996A

Abstract

A solid dosage form of heparin and compositions containing heparin are provided. Methods of using these solid dosage forms of heparin for treating a number of disorders are also disclosed.

Description

HEPARIN, COMPOSITIONS AND METHODS OF USE THEREFORE

BACKGROUND OF THE INVENTION

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. Injections of heparin have been characterized by a rapid response to provide a high level of systemic anticoagulant activity. However, this anticoagulant activity declines within a short time. Therefore, repeated injections are required where it is desired to maintain a therapeutic level of anticoagulant activity in the blood. Such repeated injections are both inconvenient and painful for chronic or long-term administration by an out-patient.

To address an acute situation in a hospital where anticoagulant activity is required, heparin is the prescribed drug of choice. However, once the patient is discharged from the hospital, and chronic or long-term anticoagulant therapy is required, coumadin, also known as sodium warfarin, has been the drug of choice because it is effective orally. However, 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.

Efforts have therefore been undertaken for providing heparin in a form suitable for effective oral administration, while providing significant anticoagulant activity and having fewer side effects than coumadin. These efforts have included preparing low molecular weight heparin derivatives, or combining the heparin with various complexing agents to increase absorbability of the heparin from the intestine. These approaches have been undertaken in view of the fact that unfractionated heparin is ineffective by an oral route of administration, as shown by the PDR as discussed above.

SUMMARY OF THE INVENTION

It has now been unexpectedly and surprisingly discovered by way of the present invention that unfractionated heparin in solid dosage form possesses significant therapeutic activities, as described hereinafter.

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.

By way of the present invention, a chronic maintenance or long-term antiatherogenic or antithrombotic therapy is also provided. Having a lower anticoagulant effect than heparin administered parenterally, such as by subcutaneous route, there is less likelihood of hemorrhage by way of the present invention. 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. Some of the advantages obtained by the 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.

These and other features, aspects, and advantages of the present invention will become better understood with reference to the following drawings, description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

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.

DETAILED DESCRIPTION

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. The term "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.

It has now thus been unexpectedly discovered that commercially available 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. 5,206,223, which patents are incorporated herein by reference. Accordingly, the present invention is advantageously easier and cheaper to practice. The commercially available 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. or "Panheprin" (Abbott Laboratories) can also be used in the practice of the present invention. Other examples of suitable commercially available heparins are disclosed in Table 5 of United States Patent No. 5,206,223, which patent is incorporated herein by reference.

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.

A variety of materials as carriers, adjuvants and vehicles, which are well-known to one of skill in the art, 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. In such solid dosage forms, 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 ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents, which agents are well-known.

Solid 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.

Furthermore, because of the well-known instability of heparin in acids, standard encapsulation procedure as set forth, for example, in Remington's Practice of Pharmacy, may be used to provide 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. Such 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. Accordingly, 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. The heparin utilized in the present invention can also be administered in the form of liposomes. As is known in the art, 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.

Methods to form liposomes are well-known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976) , p. 33 et seq. , which is incorporated herein by reference.

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. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g., two to four separate doses per day.

Another embodiment of the present invention is a composition 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. Alternatively, by providing this composition in the solid dosage form of, for example, a capsule, 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.

METHODS 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. As described above, the 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, which may be treated by way of the present invention, 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) . The compositions of the present invention, being in solid dosage form, are particularly suitable for administration to a human or lower mammal host by oral or sublingual routes. Alternatively, 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.

Because oral or sublingual administration do not have the disadvantages attendant with parenteral administration, administration of the heparin can be as frequent as required to effect a more closely controlled and sustained level of therapeutic activity in the blood. As shown by the data described hereinafter, due to the unexpectedly prolonged therapeutic effects achieved with the compositions of the present invention, it may be possible to less frequently administer the compositions by way of the methods of the present invention than heretofore previously accomplished.

By way of illustration, the unexpected therapeutic effects of the compositions of the present invention are demonstrated, as shown in FIG. 1. 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) . With those receiving heparin orally in the capsule (lower graph) , larger (greater than about 20%) and much more prolonged (for up to 3 days) decreases in serum triglycerides were observed, as compared with either oral heparin solution or subcutaneous heparin, which were relatively short-lived in effect (about 2-3 hours before triglycerides began to rise) , and having an effect of less than 20% with regards to decreasing serum triglycerides (upper graph) .

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. With regards to FIG. 3, herein is shown that heparin, in either an oral capsule or sublingual pellet form, provided significant decreases in serum triglycerides. Also note the relatively small increase in measured APTT (Activated Partial Thro boplastin Time) clotting time (about 6%) with these solid dosage forms, which is indicative of their safety with regards to hemorrhage. While sublingual heparin exhibited about the same time frame as subcutaneous heparin in decreasing triglycerides (data not shown) , the sublingual form is advantageously easier to administer.

These results demonstrate that a solid dosage form of heparin, as either a powder in a capsule or pelleted for sublingual administration, surprisingly and unexpectedly possesses significant antilipemic activity in human subjects. Furthermore with the oral capsule, this antilipemic effect is advantageously and unexpectedly prolonged (from about 1 to about 3 days) , as compared with either an oral solution of heparin or heparin administered subcutaneously.

In summary, with regards to the advantages achieved by the compositions and methods of the present invention, these 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.

The following example is merely for further illustrating the present invention, and should not be construed in any manner whatsoever as limiting the scope of the present invention.

EXAMPLE 1 Clinical Data

Standard, unfractionated heparin powder from Diosynth, Inc. was used to prepare gelatin capsules filled with heparin. Capsules utilized were Nos. 3 and 4 from Eli Lilly, Inc. Each capsule contained 240 mg of heparin (40,000 units) . Five people in overall good health participated in the study.

The Protocol was as follows:

Day One 8:30 AM Draw Blood

8:45 AM Take Heparin Powder

Capsule (40,000 Units)

10:45 AM Draw Blood

Day Two 8:30 AM Draw Blood Day Three 8:30 AM Draw Blood

Day Four 8:30 AM Draw Blood

Day Five 8:30 AM Draw Blood

8:45 AM Take Subcutaneous Heparin (5,000 Units) 10:45 AM Draw Blood 11:45 AM Draw Blood 12:45 AM Draw Blood

Each morning blood was drawn after fasting overnight. The blood specimens were analyzed for APTT

Clotting Time, Platelet count, and Lipids (Cholesterol (CHOL) ; Triglycerides (TRIG) ; HDL and LDL lipoproteins) . Days Two, Three, and Four were added after the first two subjects were run (M71J and F40S) . Results

There were no adverse health effects suffered by any of the five subjects. There was little or slight increase in the APTT clotting time; little or slight anticoagulant effect from the heparin. Subcutaneous heparin showed the expected APTT clotting time increases. This advantageously indicates that the solid dosage forms of heparin are unexpectedly safer than subcutaneous heparin with regards to potentially causing serious hemorrhage. Here again, the decrease in blood Triglycerides was the most sensitive indicator of oral heparin absorption into the blood. There was little change in any of the parameters studied within a few hours after taking heparin (one exception) .

Subject F40S showed large decreases in Cholesterol and LDL on Day Five; these changes were the order of 50 and 80 percent, respectively. This finding suggested that the oral heparin powder was having an effect on the fasting blood lipids between Days One and Five. In the next three subjects, large and prolonged decreases in Triglycerides as shown in Figure 1 were observed. Note that these decreases in Triglycerides are significantly greater in magnitude and longer lasting (1-3 days) , than from either oral heparin solution (40,000 units) or from subcutaneous heparin (5,000 units) , which decrease Triglycerides for at most only about 2- 3 hours. These results show that oral heparin powder, taken in a gelatin capsule, has an unexpectedly prolonged effect, with regards to providing a significant decrease in Triglycerides. A patient may therefore only have to take it every other day to treat lipemia. From this clinical data, we conclude that heparin powder in a gelatin capsule appears to be strongly antilipemic and long lasting. Furthermore, significant antilipemic effects were also obtained with the sublingual form.

It is to be understood that the foregoing detailed description and accompanying example are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications, including without limitation those relating to the substituents, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

What we claim is:

1. A therapeutic method of decreasing blood fats in a mammal in need thereof which comprises administering to said mammal an effective amount of unfractionated heparin,

5 said heparin being formulated in a solid dosage form.

2. The therapeutic method of claim 1 wherein the heparin is administered orally or sublingually.

3. The therapeutic method of claim 2 wherein the heparin is administered orally.

10 4. The therapeutic method of claim 2 wherein the heparin is administered sublingually.

5. The therapeutic method of claim 2 wherein the solid dosage form is selected from the group consisting of a powder, a capsule, a pellet, a suppository, a tablet, a pill,

15 a troche, a lozenge, and a granule.

6. The therapeutic method of claim 5 wherein the solid dosage form is a powder.

7. The therapeutic method of claim 5 wherein the solid dosage form is a capsule.

20 8. The therapeutic method of claim 5 wherein the solid dosage form is a pellet.

9. The therapeutic method of claim 1 wherein the effective amount of the heparin is sufficient to decrease blood fats for about 1 to about 3 days . 25

10. The therapeutic method of claim 9 wherein the effective amount ranges from about 5,000 units to about 50,000 units .

11. The therapeutic method of claim 10 wherein the effective amount ranges from about 10,000 units to about

30 40,000 units.

12. The therapeutic method of claim 11 wherein the effective amount ranges from about 20,000 units to about 30,000 units.

13. An unfractionated heparin having antilipemic 35 activity which comprises an effective amount of said heparin being formulated in a solid dosage form.

14. The heparin of claim 13 wherein the solid dosage form is selected from the group consisting of a powder, a capsule, a pellet, a tablet, a suppository, a pill, a troche, a lozenge, and a granule.

15. The heparin of claim 14 wherein the solid dosage form is a powder.

16. The heparin of claim 14 wherein the solid dosage form is a capsule.

17 The heparin of claim 14 wherein the solid dosage form is a pellet.

18. The heparin of claim 13 wherein the amount of the heparin is sufficient to treat lipemia for about 1 to about 3 days

19. The heparin of claim 18 wherein the effective amount ranges from about 5,000 units to about 50,000 units.

20. The heparin of claim 19 wherein the effective amount ranges from about 10,000 units to about 40,000 units.

21. The heparin of claim 20 wherein the effective amount ranges from about 20,000 units to about 30,000 units.

22. The heparin of claim 19 wherein the effective amount ranges from about 10,000 units to about 20,000 units.

23. The heparin of claim 13 which further comprises an anticoagulant amount of coumadin.

24. The heparin of claim 23 wherein the amount of the coumadin ranges from about 1 to about 5 mg.

25. A therapeutic method of treating thrombosis in a mammal in need thereof which comprises administering to said mammal an effective amount of unfractionated heparin, said heparin being formulated in a solid dosage form.

26. The therapeutic method of claim 25 wherein the heparin is administered orally or sublingually.

27. The therapeutic method of claim 26 wherein the heparin is administered orally.

28. The therapeutic method of claim 26 wherein the heparin is administered sublingually.

29. The method of claim 26 wherein the solid dosage form is selected from the group consisting of a powder, a capsule, a pellet, a tablet, a suppository, a pill, a troche, a lozenge, and a granule.

30. The therapeutic method of claim 29 wherein the solid dosage form is a powder.

31. The therapeutic method of claim 29 wherein the solid dosage form is a capsule.

32. The therapeutic method of claim 29 wherein the solid dosage form is a pellet.

33. The therapeutic method of claim 25 wherein the effective amount ranges from about 5,000 units to about 50,000 units.

34. The therapeutic method of claim 33 wherein the effective amount ranges from about 10,000 units to about

40,000 units.

35. The therapeutic method of claim 34 wherein the effective amount ranges from about 20,000 units to about 30,000 units.

36. An unfractionated heparin having antithrombotic activity which comprises an effective amount of said heparin being formulated in a solid dosage form.

37. The heparin of claim 36 wherein the solid dosage form is selected from the group consisting of a powder, a capsule, a pellet, a suppository, a tablet, a pill, a troche, a lozenge, and a granule.

38. The heparin of claim 37 wherein the solid dosage form is a powder.

39. The heparin of claim 37 wherein the solid dosage form is a capsule.

40. The heparin of claim 37 wherein the solid dosage form is a pellet.

41. The heparin of claim 36 wherein the amount of the heparin is sufficient to treat lipemia for about 1 to about 3 days.

42. The heparin of claim 41 wherein the effective amount ranges from about 5,000 units to about 50,000 units.

43. The heparin of claim 42 wherein the effective amount ranges from about 10,000 units to about 40,000 units.

44. The heparin of claim 43 wherein the effective amount ranges from about 20,000 units to about 30,000 units.

45. The heparin of claim 42 wherein the effective amount ranges from about 10,000 units to about 20,000 units.

46. A therapeutic composition having antilipemic activity which comprises the effective amount of the heparin of claim 13 and a pharmaceutically acceptable carrier.

47. A therapeutic composition having antithrombotic activity which comprises the effective amount of the heparin of claim 36 and a pharmaceutically acceptable carrier.