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United States Patent Office 3,506,642 United States Patent Office Patented Apr.3,506,642 14, 1970 2 3,506,642 inversely proportional to the cationic content of the salt. wv vs. However, the stability of these acid salts also decreases STABLE ORATE HEPARNOID with decreasing cationic content so that the formulation Teow Y. Koh and Kekhusroo R. Bharucha, Toronto, On- is necessarily a compromise between stability and tario, Canada, assignors to Canada Packers Limited, 5 heparinic activity. Toronto, Ontario, Canada No Drawing. Filed July 3, 1967, Ser. No. 650,621 SUMMARY OF THE INVENTION Int. C. C08b. 19/03, 19/08 O We have now discovered that heparinic acid forms U.S. C. 260-209 19 Claims salts or complexes (hereinafter collectively designated as 10 heparinoid complexes) with a number of weakly basic or amphoteric organic compounds to provide products ABSTRACT OF THE DISCLOSURE which are not only quite stable but which when orally This invention relates to new stable, orally active administered result in systemic anticoagulant effect of heparinoid complexes, prepared by reacting heparinic high order. o acid or other acid heparinoids with non-toxic organic 15 The expression "oral administration,” as used herein, compounds having weakly basic or amphoteric properties means administration by mouth and includes introduc and characterized by a base strength pKb in the range tion of therapeutic compositions containing the new of from about 7.0 to 12.5 or by an isoelectric point pI heparinoid complexes into the sublingual or buccal below about 9.7, to methods for preparing and using regions for absorption therefrom as well as the ad these new heparinoid complexes, and to therapeutic com- 20 ministration in the form of enteric-coated compositions positions containing them. Particularly suitable hepa- for release of the heparinoid substance in the intestine rinoid complexes are those prepared from heparinic acid for absorption through the intestinal walls. and amino acids having an isoelectric point pI below We have further discovered that there is a correlation about 9.7. The new complexes have utility as oral blood between the basicity of the basic or amphoteric reactant anticoagulant and/or lipemic agents. 25 and the stability-oral activity of the resulting heparinoid complex. Reactants which are too strongly basic, such as the alkali metal bases and the aliphatic amines provide BACKGROUND heparinoid complexes which are stable but not orally ac Natural heparin, heparin derivatives and synthetically 30 tive. Reactants which are too weakly basic, such as urea, sulfated polysaccharides, all of which will be referred pyrimidine and acetamide provide heparinoid complexes to hereinafter as heparinoids, have heretofore been pre- wnicn.hich are very active but unstable under normalv storage pared and used E. in the neutral sodium E. conditions, and quickly lose their hep arinic activity. form. This is the form of heparin which is presently em- We prefer to express the requisite basicity in terms of ployeduse of thesein anticoagulant materials is limited therapy. by theHowever, need to therapeuticadminister 35 EGEamphore findomp . Thi?E.d E. t them parenterally, since they are inactive or only slightly present invention, heparinic acid and re ated eparinoids active per se by the oral route. In view of the long es- having free acid groups are stabilized without Mr. tablished reputation of heparinoids as safe and effective tial loss of their oral effectiveness by forming complexes blood anticoagulants and/or antilipemicow agents, a great 40 Of the acidsw with certain non-toxic organic compounds deal of research has been devoted toward the develop- characterized by a base strength pK in the range of ment of adjuvants, derivatives and other expedients in an EG's 9t 7.0 to 12.5 or by an isoelectric point pI below effort to render the known heparinoids absorbable through the intestinal walls so that they can be orally DETAILED DESCRIPTION administered. However, this research has had limited 45 It will be understood that heparin is a very complex Success to date. molecule, with a structure which has not been com In the copending United States application Ser. No. pletely elucidated. It is tentatively identified as a sul 561,346 of Teow Yan Koh, filed June 29, 1966, it was fated copolymer consisting of alternating 1-4oz linked disclosed that heparinic acid per se readily passes through glucosamine and glucuronic acid residues. In accordance the intestinal walls to provide an extremely high anti- 50 with the invention, the acid form of heparin or related coagulant activity. The free acid form of heparin would, heparinoid is combined with one of a series of weak bases therefore, be an excellent anticoagulant, but unfortu- or amphoteric substances, which in themselves are not nately its stability is poor. Heparinic acid begins to de- simple. Therefore, the specific structure of the resulting compose almost immediately and is difficult to isolate product cannot be stated with certainty and for this rea or handle. It was found by Koh that by partially satis- son the word “complex” is used to embrace salts as well fying the free acid groups of heparinic acid by reaction as more complex structures which may be formed. with a base, e.g. sodium or potassium hydroxide or strong For purposes of simplification, a schematic representa organic bases, such as choline, to provide an acid salt, tion of the repeating tetrasaccharide heparin unit (sodium the stability was improved and some of the heparinic salt) is shown below: CH2OSONa COONa CHOSONa COONa) Kor),-O Kor),-0 Kr),-0 K.)-O - N NHSONaY- Y - ".O-SO3Na "/-O-NESO3Na " OH -O- activity on oral administration could be retained. The Treatment of sodium heparinate with an acidic ion ex acid salts of heparinic acid, such as the sodium, potassium change resin removes the sodium and gives heparinic acid. and choline acid salts, are absorbable from the mam- to The conversion to heparinic acid confers oral activity on malian intestine to a useful extent, though less readily the molecule but at the same time makes it unstable. We than heparinic acid, with the amount of absorption being believe that this instability probably arises by autocatalytic 3,506,642 3. 4. destruction of the acid labile O- and/or N-sulfate and Compound: pKb glycosidic linkages. However, whatever the cause of such 2-aminoquinazoline ----------------------- 9.3 instability, we have found that stabilization can be 1,4-dihydro-1-methyl-4-oxo-quinazoline ------ 10.9 achieved without destruction of the oral activity by re 1,2,4-triazole ---------------------------- 11.7 action of the acid heparin with selected weakly basic 2-aminopyrimidine ----------------------- 10.6 or amphoteric substances. It is found that heparinic acid, 5 5-amino-4-methylpyrimidine --------------- 10.9 being a strong acid, forms stable complexes even with the 1-phenylpyrrolidine ---------------------- 9.7 relatively weakly basic substances. Salt or complex forma Methylindanylamino-indan ----------------- 9.4 tion is believed to be involved with at least the sulfonic O-aminohydroxymethane ------------------ 9.4 acid group of heparinic acid. In pertinent cases, as with Semicarbazide --------------------------- 10.4 amino-amides (e.g. nicotinamide), stability may be fur O N-methyl-1,4-benzoquinone-imine ---------- 10.1 ther increased by hydrogen bond formation through the 1,4-benzoquinoneimine -------------------- 10.1 amide linkages. N-benzyl-1,4-benzoquinoneimine ------------ 11.2 In aqueous solution all such compounds may dissociate, Thioflavine T---------------------------- 1.3 releasing heparinic acid. On the other hand, salts of hepa 15 N-methylcytidin ------------------------- 10.1 rinic acid with strong bases, and in particular the neutral Biliverdine ------------------------------ 9.0 salts of the strong bases, apparently do not release hepa 2,4,2,4,2'-pentamethoxytriphenylcarbinol --- 12.2 rinic acid in aqueous Solution in a form in which it can Rhodamine B---------------------------- 10.8 be absorbed through the mucous membranes of the mam It will be understood that the invention is not limited malian body. We believe that the absorption of heparinic 20 to these specific examples and that those skilled in the acid from the mouth or intestine, in the present instance, art will be able to select many related complexing agents takes place by the process of passive diffusion of that having a base strength or isoelectric point Within the fraction of heparinic acid, which, after release from the ranges given. heparinoid complex, remains in the unionized form. Compounds such as urea, pyrimidine and acetamide It is to be understood, however, that this invention is 25 are weak bases with a pK value above the limit of 12.5. not to be limited to any particular theory of operation. These weak bases readily form complexes with heparinic The complexing agents suitable for the purposes of acid which provide significant increases in blood clot the present invention, and which yield complexes with ting time by absorption through the mucous membranes. heparinic acid and other acid heparinoids, resulting in However, the stability of these complexes is quite low, good stability coupled with high oral activity, are those 30 decomposition and loss of heparinic activity at room tem organic bases which have a base strength pKb in the perature beginning within 20 days. Dimethylamine and range of from about 7.0 to 12.5, preferably about 9.0 choline, on the other hand, are stronger bases with a pKb to 12.5, and those organic amphoteric compounds which value below the limit of 7.0. While these compounds form have an isoelectric point pI below about 9.7. Amphoteric stable complexes with heparinic acid, the resulting com substances over the range of from about 2.7 to 9.7 have 35 plexes do not provide a significant rise in the level of blood been successfully tested and the criticality of the lower clotting time. Likewise, lysine which is an amino acid limit has not been determined.
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