WO2001034114A1

WO2001034114A1 - Liquid heparin formulation

Info

Publication number: WO2001034114A1
Application number: PCT/US2000/030890
Authority: WO
Inventors: Rajesh Agarwal; George F. Klein; Kiran Chaudhary
Original assignee: Emisphere Technologies, Inc.
Priority date: 1999-11-12
Filing date: 2000-11-10
Publication date: 2001-05-17
Also published as: MXPA02004741A; AU1594801A; DE20022960U1

Abstract

The present invention provides an aqueous composition comprising (a) from about 0.075 to about 0.160 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate(SNAC) or other salt thereof, (b) from about 0.01 to about 0.05 g/mL of heparin, and (c) from about 0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose. Generally, the aqueous composition is a liquid at temperatures of from about 5 to about 30 °C. Another embodiment of the invention is an aqueous composition comprising (a) from about 0.075 to about 0.160 g/mL of SNAC or other salt thereof, (b) from about 33,000 to about 41,000 U (units) of heparin per gram of SNAC, and (c) from about 0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose.

Description

LIQUID HEPARIN FORMULATION

FIELD OF THE INVENTION

The present invention relates to liquid compositions of heparin.

BACKGROUND OF THE INVENTION

U.S. Patent No. 5,650,386 discloses compositions for the oral delivery of active agents, such as heparin, with modified amino acids, such as sodium N-(8-[2- hydroxybenzoyl]amino)caprylate (SNAC). Current commercial formulations of heparin are delivered by routes other than the oral route. Formulations delivered orally are typically easier to administer than by other routes and improve patient compliance.

Oral liquid dosage forms containing SNAC and heparin, however, were found to be unpalatable. Accordingly, sweeteners, such as polysaccharides, and other flavorants were added to the formulation to improve the flavor ofthe dosage form.

Aqueous compositions containing polysaccharides. SNAC, and heparin were found to be in the liquid phase at 22° C and above. However, at temperatures below 22° C, these compositions sometimes haze and become gels after a few days. Therefore, there is a need for aqueous compositions containing a polysaccharide, SNAC, and heparin which remain in the liquid phase between 15 and 30° C.

SUMMARY OF THE INVENTION

The present invention provides an aqueous composition comprising (a) from about 0.075 to about 0.160 g/mL of sodiumN-(8-[2-hydroxybenzoyl]amino)caprylate (SΝAC) or other salt thereof, (b) from about 0.01 to about 0.05 g/mL of heparin, and (c) from about

0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose. Generally, the aqueous composition is a liquid at temperatures of from about 5 to about 30° C. Another embodiment ofthe invention is an aqueous composition comprising

(a) from about 0.075 to about 0.160 g/mL of SNAC or other salt thereof, (b) from about

33,000 to about 41,000 USP heparin units (U) (or from about 33,000 to about 41,000

International Units (IU)) of heparin per gram of SNAC, and (c) from about 0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose.

Yet another embodiment is a method of administering heparin to an animal in need thereof by orally administering the composition ofthe present invention.

Yet another embodiment is a method of treating thrombosis in an animal in need thereof by orally administering an anti-thrombosis effective amount ofthe composition of the present invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graphic illustration ofthe time for an aqueous composition ofthe present invention to become a gel at 5° C. Figure 2 is a graphic illustration of the time for an aqueous composition to become a gel.

Figure 3 is a graphic illustration of clotting time in cynomolgus monkeys after oral administration of aqueous compositions containing heparin.

Figure 4 is a graphic illustration of heparin activity in cynomolgus monkeys after oral administration of aqueous compositions containing heparin.

Figure 5 is a graphic illustration of heparin activity in healthy human subjects after oral administration of aqueous compositions containing heparin.

DETAILED DESCRIPTION OF THE INVENTION The aqueous composition of the present invention comprises (a) from about

0.075 to about 0.160 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate (SΝAC), (b) from about 0.01 to about 0.05 g/mL of heparin or from about 33,000 to about 41 ,000 U (units) of heparin per gram of SΝAC, and (c) from about 0.01 to about 0.15 g/mL of a polysaccharide, such as sucrose. The term "heparin" as used herein includes all forms of heparin including, but not limited to, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, and any combination of any of the foregoing. The heparin incorporated in the composition preferably is heparin sodium, such as heparin sodium USP available from Scientific Protein Labs of Waunakee, WI. Generally, the concentration of heparin in the composition ranges from about 1,000 to about 12,000 U/mL, preferably from about 4,000 to about 8,000 U/mL, and more preferably from about 5,000 to about 6,000 U/mL. Typically, the potency (by weight) ofthe heparin is greater than about 140 U/mg and preferably ranges from about 150 to about 210 U/mg.

The concentration of SNAC in the composition preferably ranges from about 0.120 to about 0.150 g/mL and more preferably from about 0.130 to about 0.140 g/mL. The concentration of heparin preferably ranges from about 0.02 to about 0.04 g/mL and more preferably from about 0.025 to about 0.035 g/mL. The concentration of sucrose preferably ranges from about 0.05 to about 0.15 g/mL and more preferably from about 0.075 to about 0.125 g/mL. According to a preferred embodiment, the composition contains about 0.135 g/mL of SNAC, about 0.028 g/mL of heparin, and about 0.1 g/mL of sucrose. Generally, the concentration of SNAC and polysaccharide is less than the saturation solubility of the composition. Liquid polysaccharides may be included in the composition to increase the palatability of the composition and to increase the solubility of the composition. According to one embodiment, the composition comprises a liquid polysaccharide and has a total polysaccharide concentration (which may include solids) of from about 0.01 to about 0.65 g/mL. In such an embodiment, the concentration of sucrose in the composition may be greater than 0.15 g/mL.

Generally, the composition contains from about 33,000 to about 41,000 U of heparin per gram of SNAC. The composition preferably contains from about 35,000 to about 39,000 U of heparin per gram of SNAC. According to one preferred embodiment, the composition contains about 37,000 U of heparin per gram of SNAC.

Generally, the amount of heparin in the composition is an amount effective to accomplish the purpose for which it is being used. The amount of heparin is typically a pharmacologically or biologically effective amount. However, the amount can be less than a pharmaceutically or biologically effective amount when the composition is used in a dosage unit form, such as a capsule or a liquid, because the dosage unit form may contain a multiplicity of SNAC/heparin compositions or may contain a divided pharmacologically or biologically effective amount. The total effective amount can then be determined in cumulative units containing, in total, a pharmacologically or biologically effective amount of heparin. The total amount of heparin may be determined by those skilled in the art. Preferably, the dosage unit form is an oral dosage unit form, i.e., a dosage unit form to be delivered by the oral route. The composition may contain a pH adjuster, such as sodium hydroxide or hydrochloric acid, to adjust the pH. The pH ofthe composition is typically greater than about 7.2. Preferably, the pH ofthe composition is from about 7.6 to about 8.6. According to one preferred embodiment, the pH is about 8.2.

The composition ofthe present invention typically is a liquid and substantially clear at temperatures ranging from about 5 to about 40° C. Preferably, the composition remains a liquid and does not substantially gel, i. e. , non-gelling, at temperatures ranging from about 15 to about 30° C.

The composition preferably contains less than about 1 g/mL of solids. The composition may contain other adjuvants as known in the art, such as preservatives; flavorants, including sweeteners; fragrances; humectants; tonicifiers; colorants; surfactants; plasticizers; lubricants; dosing vehicles; solubilizers; excipients; and any combination of any ofthe foregoing.

Suitable preservatives include, but are not limited to, parabens, such as methylparaben, butylparaben, propylparaben, and any combination of any of the foregoing. The composition preferably contains from about 0.0001 g/mL to about 0.001 g/mL of preservative and more preferably contains from about 0.0002 g/mL to about 0.0008 g/mL of preservative. According to one preferred embodiment, the composition comprises about 0.0005 g/mL of butylparaben and about 0.0002 g/mL of propylparaben.

Suitable flavorants include, but are not limited to, sodium saccharin, ammonium glycyrrhizinate, sodium chloride, maltol, menthol, anise oil, chocolate flavor, chocolate mint flavor, and any combination of any ofthe foregoing.

According to one preferred embodiment, the composition comprises about 0.004 g/mL of sodium saccharin, about 0.05 g/mL of ammonium glycyrrhizinate, about 0.001 g/mL of maltol, about 0.001 g/mL of peppermint oil, about 0.0007 g/mL of menthol, and about 0.0002 g/mL of anise oil.

Suitable fragrances include, but are not limited to, menthol. Sui table solubilizers include, but are not limited to, propylene glycol. According to one preferred embodiment, the composition includes about 0.02 g/mL of propylene glycol.

Suitable tonicifiers include, but are not limited to, sodium chloride. According to one preferred embodiment, the composition includes about 0.005 g/mL of sodium chloride.

The aqueous composition ofthe present invention may be prepared as follows. Water is heated to and maintained at from about 45 to about 55° C. Sucrose and other flavorants are added to the water and mixed. SNAC is added to the solution and mixed for from about 30 minutes to about 2 hours. SNAC may be prepared as described in U.S. Patent No. 5,650,386. While the solution is stirred, heparin is added to the solution, preferably to the vortex ofthe solution. The solution is mixed for from about 30 to about 60 minutes and then allowed to cool to between about 25 and about 35° C to form a first solution.

In a separate container, additional flavorants, preservatives, and other adjuvants are mixed while the container is maintained at a temperature of between about 25 and 35 ° C. The solution in the container is mixed to form a uniform second solution.

The second solution is added to the first solution. The combined solution is mixed and maintained at between about 25 and about 35 ° C. The pH ofthe solution may be adjusted as appropriate with sodium hydroxide and hydrochloric acid. Water may be added to dilute the solution and obtain the desired concentrations for the ingredients. The solution is then mixed for from about 10 to about 30 minutes and filtered to form the aqueous composition. The solution is preferably filtered through a filter having a pore size of from about 0.5 to about 10 microns, and more preferably a pore size of about 4.5 microns to remove any foreign materials.

The compositions of the present invention may be orally administered to deliver heparin to any animal in need thereof, including but not limited to birds, such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.

Also, an anti-thrombosis effective amount of the composition may be administered to an animal in need thereof to treat thrombosis. The total amount of heparin and SNAC needed to treat thrombosis in an animal may be determined by any method known in the art. Generally, for humans, from about 90,000 to about 350,000 USP heparin units and from about 1.5 to about 9.0 g of SNAC and preferably from about 180,000 to about 270,000 USP heparin units and from about 4.5 to about 6.75 g of SNAC are administered daily.

According to one embodiment of the invention, from about 30,000 to about 120,000 USP heparin units and from about 0.5 to about 3.0 g of SNAC and preferably from about 60,000 to about 90,000 USP heparin units and from about 1.5 to about 2.25 g of SNAC are administered per dose. Generally, from about 5 to about 20 mL and preferably from about 12 to about 18 mL of the composition are administered per dose. Typically, about 2 to 4 doses of the composition are administered daily. According to a preferred embodiment, 3 doses ofthe composition are administered daily. Dosages for non-human primates may be adjusted according to weight.

The following examples are intended to describe the present invention without limitation.

Example 1

A 250 mL batch ofthe aqueous composition having the formulation in Table 1 below was prepared as follows. 150 g of water was heated in a stainless steel container affixed with an overhead mixer to and maintained at about 50 ° C. Sucrose, sodium saccharin, ammonium glycyrrhizinate, sodium chloride, and maltol were added to the water and mixed to form a clear solution. 17.5 mL of IN sodium hydroxide was added. SNAC was added to the solution and mixed for about 1 hour to form a clear solution. While the solution was stirred, heparin was added to the vortex ofthe solution. Then the solution was mixed for 30- 60 minutes to form a clear solution. The solution was allowed to cool to between about 25 and about 35 ° C to form a first solution. In a separate container, propylene glycol, methylparaben, and propylparaben were mixed by gentle swirling in a water bath at or below about 35 ° C until a clear solution was formed. Pepperment oil, menthol, anise oil, liquid NorVan flavor, chocolate mint flavor, chocolate flavor, and chocolate mousse color were added to the solution and mixed in a water bath at or below about 35° C until a uniform second solution was obtained. The second solution was added to the first solution. The combined solution was mixed and maintained at between about 25 and about 35 ° C. The pH ofthe solution was adjusted to about 8.2 with sodium hydroxide. The appropriate amount of water was added to bring the total weight ofthe solution up to about 275 g. The solution was mixed for about 15 minutes and filtered through a 4.5 micron filter to form the aqueous composition.

Table 1

¹ - Sucrose NF and sodium saccharin USP are available from Bioclinical Labs of Philhpsburg, NJ.

² - Magnasweet 110™ is ammonium glycyrrhizinate in glycerin and is available from MAFCO Worldwide of Camden, NJ. ³ - Maltol is available as Maltol Veltol, FCC from Cultor Food Science, Inc., of New York, NY. ⁴ - Natural Peppermint Oil and Anise Oil are available from Mane, USA of Wayne, NJ.

⁵ - Liquid NorVan Flavor and N & A Chocolate flavor are available from Flavors of North America, Inc., of Carol Stream, IL.

⁶ - L-Menthol USP is available from Bioclinical Labs of Philhpsburg, NJ. ⁷ - N&A Chocolate mint flavor is available from H & R Florasynth of Teterboro, NJ.

⁸ - SNAC is available from Emisphere Technologies, Inc., of Tarrytown, NY.

⁹ - Heparin sodium USP is available from Scientific Protein Labs of Waunakee, WI.

¹⁰ - Chocolate mousse color is available from Warner- Jenkinson Co., Inc., of St. Louis, MO.

Comparative Example 1A

A 500 mL batch ofthe aqueous composition having the formulation in Table 2 below was prepared as follows. 225 g of water was heated in a stainless steel container affixed with an overhead mixer to and maintained at about 50° C. Sucrose, aspartame, sodium chloride, and maltol were added to the water and mixed to form a clear solution. 22.5 mL of IN sodium hydroxide was added. Ammonium glycyrrhizinate was added to the solution and mixed to form a clear solution. SNAC was added to the solution and mixed for about 1 hour to form a clear solution. While the solution was stirred, heparin was added to the vortex of the solution. Then the solution was mixed for 30-60 minutes to form a clear solution. The solution was allowed to cool to between about 25 and about 35° C to form a first solution.

In a separate container, propylene glycol and menthol were mixed by gentle swirling in a water bath at or below about 35 ° C until a clear solution was formed. Peppermint oil and anise oil were added to the solution and mixed gently in a water bath at or below about 35° C until a uniform second solution was obtained. The second solution was added to the first solution. The combined solution was mixed and maintained at between about 25 and about 35 ° C. The pH ofthe solution was adjusted to about 7.8 with sodium hydroxide. The appropriate amount of water was added to bring the total weight ofthe solution up to about 605 g. The solution was mixed for about 15 minutes and filtered through a 4.5 micron filter to form the aqueous composition. Table 2

Example 2 A 10% sucrose aqueous composition prepared as in Example 1 was tested as follows. 1 mg/mL of SNAC was added to about 10 mL aqueous composition and mixed to form a seeded composition. The aqueous composition was stored at 5° C. The number of days until the composition became a gel was observed.

This procedure was repeated with the aqueous composition of Example 1 , except the concentration of sucrose was changed to 0.25 and 0.4 g/mL. The results are shown in Figure 1.

Comparative Example 2A A 40% sucrose aqueous composition prepared as in Comparative Example 1 A was tested as follows. 1 mg/mL of SNAC was added to about 10 mL aqueous composition and mixed to form a seeded composition. The aqueous composition was stored at 5, 10, and 25° C. The number of days until the composition became a gel was observed. This procedure was repeated without the addition of 1 mg/mL of SNAC (unseeded). The results are shown in Figure 2.

Example 3 Cynomolgus monkeys received oral doses of 1.2 mL/kg of an aqueous composition prepared as in Example 1. Heparin activity was determined by utilizing the activated partial thromboplastic time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; W.B. Saunders (1979). The results are shown in Figure 3. The mean peak APTT was about 200 seconds. Also, the heparin activity level was measured with an antiFactor Xa assay kit available from Chromogenix A.B., Sweden. The results are shown in Figure 4. The mean peak antiFactor Xa activity level was 1.63 ± 0.44 IU/mL.

Comparative Example 3 A Cynomolgus monkeys received oral doses of 1 mL/kg of an aqueous composition prepared as in Comparative Example 1A. Heparin activity was determined as described in Example 3. The results are shown in Figures 3 and 4. The mean peak APTT was about 185 seconds and the mean peak antiFactor Xa activity level was 1.43 ± 0.39 IU/mL.

Example 4

A 10% sucrose aqueous composition was prepared having the formula described in Table 1 above, except 0.00050 g/mL of butylparaben was substituted for the 0.0020 g/mL of methylparaben.

A single oral dose of 18 mL of the 10% sucrose aqueous composition was administered to healthy human subjects. Heparin activity was determined with an antiFactor Xa assay kit available from Chromogenix A.B., Sweden. The results are shown in Figure 5. The mean peak antiFactor Xa activity level was 0.26 ± 0.06 IU/mL.

Comparative Example 4A A 40% sucrose aqueous composition was prepared having the formula described in Table 2 above. A single oral dose of 15 mL of the 40% sucrose aqueous composition was administered to healthy human subjects. Heparin activity was determined as described in Example 4. The results are shown in Figure 5. The mean peak antiFactor Xa activity level was 0.25 ± 0.05 IU/mL.

Examples 5-12 Aqueous compositions having the formulations in Table 3 below were prepared.

Table 3

Example 13

Each aqueous composition prepared in Examples 5-12 was tested as follows.

About 10 mL ofthe aqueous composition was seeded with 10 mg of SNAC. A sample of the seeded aqueous composition was stored at room temperature for 28 days.

Another sample ofthe seeded aqueous composition was stored at 2-8° C for 28 days. After

7 and 28 days, the samples were observed for precipitate and gel.

This procedure was repeated with the aqueous compositions in Examples 5-12 without seeding. The results are shown in Table 4 below. Table 4

All patents, publications, applications, and test methods mentioned above are hereby incorporated by reference. Many variations of the present matter will suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations are within the patented scope ofthe appended claims.

Claims

What is claimed is:

1. An aqueous composition comprising

(a) from about 0.075 to about 0.160 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate;

(b) from about 0.01 to about 0.05 g/mL of heparin; and

(c) from about 0.01 to about 0.15 g/mL of sucrose.

2. The composition of claim 1, wherein the heparin is heparin sodium.

3. The composition of claim 1, wherein the concentration of heparin in the composition is from about 1,000 to about 12,000 U/mL.

4. The composition of claim 3, wherein the concentration of heparin in the composition is from about 4,000 to about 8,000 U/mL.

5. The composition of claim 4, wherein the concentration of heparin in the composition is from about 5,000 to about 6,000 U/mL.

6. The composition of claim 1, wherein the heparin has a potency greater than about 140 U/mg.

7. The composition of claim 6, wherein the heparin has a potency of from about 150 to about 210 U/mg.

8. The composition of claim 1 , wherein the composition comprises from about 0.120 to about 0.150 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

9. The composition of claim 8, wherein the composition comprises from about 0.130 to about 0.140 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

10. The composition of claim 1 , wherein the composition comprises from about 0.02 to about 0.04 g/mL of heparin.

11. The composition of claim 10, wherein the composition comprises from about 0.025 to about 0.035 g/mL of heparin.

12. The composition of claim 1, wherein the composition contains from about 33,000 to about 41,000 U of heparin per gram of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

13. The composition of claim 12, wherein the composition contains from about 35,000 to about 39,000 U of heparin per gram of sodium

N-(8-[2-hydroxybenzoyl]amino)caprylate.

14. The composition of claim 13, wherein the composition contains about 37,000 U of heparin per gram of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

15. The composition of claim 1 , wherein the composition comprises from about 0.05 to about 0.15 g/mL of sucrose.

16. The composition of claim 15, wherein the composition comprises from about 0.075 to about 0.125 g/mL of sucrose.

17. The composition of claim 1 , wherein the composition comprises

(a) about 0.135 g/mL of SΝAC;

(b) about 0.028 g/mL of heparin; and (c) about 0.1 g/mL of sucrose.

18. The composition of claim 1 , wherein the composition further comprises (d) a pH adjuster.

19. The composition of claim 1 , wherein the pH adjuster is sodium hydroxide.

20. The composition of claim 1, wherein the pH ofthe composition is greater than about 7.2.

21. The composition of claim 20, wherein the pH of the composition is from about 7.6 to about 8.6.

22. The composition of claim 21, wherein the pH is about 8.2.

23. The composition of claim 1, wherein the composition is a liquid at temperatures ranging from about 5 to about 40° C.

24. The composition of claim 23, wherein the composition is a liquid at temperatures ranging from about 15 to about 30° C.

25. The composition of claim 1, wherein the composition does not substantially gel at temperatures ranging from about 15 to about 30° C.

26. The composition of claim 1 , wherein the composition contains less than about 1 g/mL of solids.

27. The composition of claim 1 , wherein the concentration of SNAC and the polysaccharide is less than the saturation solubility ofthe composition.

28. The composition of claim 1, wherein the composition further comprises: (e) a preservative;

(f) a flavorant;

(g) a fragrance; (h) a humectant; (i) a tonicifier;

(j) a colorant;

(k) a surfactant;

(1) a plasticizer; (m) a lubricant; (n) a dosing vehicle;

(o) a solubilizer;

(p) an excipient; or

(q) any combination of any ofthe foregoing.

29. The composition of claim 28, wherein the composition further comprises a preservative.

30. The composition of claim 29, wherein the preservative comprises one or more parabens.

31. The composition of claim 30, wherein the preservative is selected from the group consisting of butylparaben, propylparaben, and any combination of any of the foregoing.

32. The composition of claim 29, wherein the composition comprises from about 0.0001 g/mL to about 0.001 g/mL of preservative.

33. The composition of claim 32, wherein the composition comprises from about 0.0002 g/mL to about 0.0008 g/mL of preservative.

34. The composition of claim 28, wherein the flavorant is selected from the group consisting of

(i) sodium saccharin;

(ii) ammonium glycyrrhizinate; (iii) maltol;

(iv) menthol;

(v) anise oil;

(vi) chocolate flavor;

(vii) chocolate mint flavor; and (viii) any combination of any of the foregoing.

35. The composition of claim 28, wherein the fragrance comprises menthol.

36. The composition of claim 28, wherein the solubihzer is propylene glycol.

37. The composition of claim 28, wherein the tonicifer is sodium chloride.

38. A dosage unit form comprising a composition of claim 1.

39. An oral dosage unit form comprising a composition of claim 1.

40. An aqueous dosage unit form comprising

(a) about 0.135 g/mL of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate;

(b) about 0.028 g/mL of heparin; and

(c) about 0.1 g/mL of sucrose.

41. The dosage unit form of claim 40, wherein the heparin is heparin sodium.

42. The dosage unit form of claim 40, wherein the concentration of heparin in the dosage unit form is from about 5,000 to about 6,000 U/mL.

43. The dosage unit form of claim 40, further comprising (d) a pH adjuster.

44. The dosage unit form of claim 43, wherein the pH adjuster is sodium hydroxide.

45. The dosage unit form of claim 40, further comprising a preservative.

46. The dosage unit form of claim 45, wherein the preservative comprises one or more parabens.

47. The dosage unit form of claim 46, wherein the preservative is selected from the group consisting of butylparaben, propylparaben, methylparaben, and any combination of any ofthe foregoing.

48. The dosage unit form of claim 47, further comprising

(e) about 0.0005 g/mL of butylparaben; and

(f) about 0.0002 g/mL of propylparaben.

49. The dosage unit form of claim 40, further comprising a flavorant.

50. The dosage unit form of claim 49, wherein the flavorant comprises (g) sodium saccharin; (h) ammonium glycyrrhizinate;

(i) maltol; 0⁾ peppermint oil;

(k) menthol;

(1) anise oil;

(m) chocolate flavor;

(n) chocolate mint flavor; or

(o) any combination of any of the foregoing.

51. The dosage unit form of claim 50, wherein the flavorant comprises

(g) about 0.004 g/mL of sodium saccharin; (h) about 0.05 g/mL of ammonium glycyπhizinate;

(i) about 0.001 g/mL of maltol;

(j) about 0.001 g/mL of peppermint oil;

(k) about 0.0007 g/mL of menthol; and

(1) about 0.0002 g/mL of anise oil.

52. The dosage unit form of claim 51 , wherein the flavorant further comprises

(m) about 0.015 g/mL of chocolate flavor; and (n) about 0.02 g/mL of chocolate mint flavor.

53. The dosage unit form of claim 40, further comprising a solubihzer.

54. The dosage unit form of claim 53, wherein the solubihzer is propylene glycol.

55. The dosage unit form of claim 54, wherein the solubihzer comprises (n) about 0.02 g/mL of propylene glycol.

56. The dosage unit form of claim 40, further comprising a tonicifier.

57. The dosage unit form of claim 56, wherein the tonicifer is sodium chloride.

58. The dosage unit form of claim 57, wherein the tonicifier comprises (o) about 0.005 g/mL of sodium chloride.

59. The dosage unit form of claim 40, wherein the dosage unit form has a pH greater than about 7.2.

60. The dosage unit form of claim 59, wherein the dosage unit form has a pH of from about 7.6 to about 8.6.

61. The dosage unit form of claim 60, wherein the dosage unit form has a pH of about 8.2.

62. The dosage unit form of claim 40, wherein the dosage unit form is a liquid.

63. An aqueous composition comprising (a) from about 0.075 to about 0.160 g/mL of sodium

N-(8-[2-hydroxybenzoyl]amino)caprylate or other salt thereof;

(b) from about 33,000 to about 41 ,000 U of heparin per gram of sodium N-(8-[2-hydroxybenzoyl]amino)caprylate; and

(c) from about 0.01 to about 0.15 g/mL of a polysaccharide.

64. The aqueous composition of claim 63, wherein the polysaccharide is sucrose.

65. A method of administering heparin to an animal in need thereof, the method comprising orally administering the composition of claim 1.

66. A method of treating thrombosis in an animal in need thereof, the method comprising orally administering an anti-thrombosis effective amount ofthe composition of claim 1 to the animal.