Preparation of Aqueous Clear Solution Dosage Forms with Bile Acids

Abstract

Compositions for pharmaceutical and other uses comprising clear aqueous solutions of bile acids which do not form any detectable precipitates over selected ranges of pH values of the aqueous solution and methods of making such solutions. The compositions of the invention comprise water; a bile acid in the form of a bile acid, bile acid salt, or a bile acid conjugated with an amine by an amide linkage; and either or both an aqueous soluble starch conversion product and an aqueous soluble non-starch polysaccharide. The composition remains in solution without forming a precipitate over a range of pH values and, according to one embodiment, remains in solution for all pH values obtainable in an aqueous system. The composition, according to some embodiments, may further contain a pharmaceutical compound in a pharmaceutically effective amount. Non-limiting examples of pharmaceutical compounds include insulin, heparin, bismuth compounds, amantadine and rimantadine

Description

[0001] This application is a divisional of U.S. patent application Ser. No. 09 / 778,154 filed Feb. 5, 2001; which claims the benefit of provisional application No. 60 / 180,268, filed Feb. 4, 2000 and is a continuation in part of application Ser. No. 09 / 357,549 filed Jul. 2, 1999; and which claims the benefit of provisional application No. 60 / 094,069, filed Jul. 24, 1998, all of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Bile acids salts which are organic acids derived from cholesterol are natural ionic detergents that play a pivotal role in the absorption, transport, and secretion of lipids. In bile acid chemistry, the steroid nucleus of a bile acid salt has the perhydrocyclopentano phenanthrene nucleus common to all perhydrosteroids. Distinguishing characteristics of bile acids include a saturated 19-carbon sterol nucleus, a beta-oriented hydrogen at position 5, a branched, saturated 5-carbon side chain terminating in a carboxylic acid, and an alpha...

AI Technical Summary

Benefits of technology

[0048] The invention further relates to solution dosage forms of bile acid compositions. Advantages of these solution dosage forms include improved bioavailability and absorbability of a bile acid. Additional advantages of solution dosage forms include improved bioavailability and absorbability of a pharmaceutical compound.

[0050] In some embodiments of the invention, a combination therapy composition is provided which may increase intensity of response to or efficacy of a pharmaceutical. Such a composition may permit administration of lower dosages of a pharmaceutical compound, attack a disease complex at different points, affect elimination and / or alter absorption of a pharmaceutical compound. Such a composition may lead to or contribute to a reduction in toxicity and / or side effects of a pharmaceutical.

Problems solved by technology

However, in the gastric pH range, certain bile acids such as UDCA and CDCA are no longer soluble.

However, this revolutionary nasal spray solution dosage form with bile acids (salts) as an adjuvant could not be developed further and commercialized, because the nasal spray solution must be prepared immediately prior to use due to the precipitation of bile acid salt and the instability of insulin at pH levels between 7.4 and 7.8.

Bile acid salts and insulin, thus, appear to be chemically and physically incompatible.

Dosage forms of bile acid salts prepared by conventional techniques have been unable to overcome problems with bile precipitation at these pH levels and insulin is unstable at a pH of 7.4 or higher.

However, heparin treatment is usually limited to hospitalized patients since this drug is given only by injection.

However, heparin is only stable under acidic conditions.

Bile acids are particularly not soluble in acidic conditions.

Therefore, due to their incompatible characteristics, commercial dosage forms of bile acids with heparin are not presently available.

Drug delivery systems involving bile acids can provide liver-specific drug targeting which is of major interest for drug development since standard pharmacological approaches to liver diseases have been frustrated by the inadequate delivery of active agents into liver cells as well as non specific toxicity towards other organs.

Even if bile acid salts and their derivatives act as shuttles for specific delivery of a drug to the liver, as already mentioned above, there are enormous risks to the development of the derivatives of bile acids or bile acid salts as carriers because new derivatives of bile acids or bile acid salts formed by covalent linkages of a drug to bile acid must be tested for its pharmacology, toxicity and clinical effectiveness.

In spite of the extremely valuable therapeutic activities and the long historic medical uses of bile acids as therapeutically active agents and as carriers and / or adjuvants based on the already mentioned biological properties and functions of bile acids, the commercial administration of bile acids is limited to pharmaceutical formulations with a solid form of bile acid which are in tablet, capsule and suspension.

This is also due to bile's extremely bitter taste and equally bitter after-taste which lasts several hours.

The few aqueous dosage forms that are available are unstable, and have very limited uses because of pH control and maintenance problems.

Bile acid, especially ursodeoxycholic acid is poorly soluble in the gastro-duodeno jejunal contents of fasted subjects.

However, the solubility of bile acids increase with the increase of the pH in the intestine very slowly and incompletely, and eventually the bile acids become soluble at pH between 8 and 9.5.

However, it is extremely difficult and very costly to prepare the precise delayed release dosage forms which can release therapeutically active components by disintegration, dissolution and diffusion at the desired area within a limited time.

Unpredictable variations in the extent and rate of release of bile acids by the disintegration, dissolution and diffusion of delayed or immediate release dosage forms having pH-dependent instability result in the slow and inefficient bile absorption and reduced bioavailability.

In addition, mucinogenesis is reduced and the mucosa becomes susceptible to the erosive effects of acid.

This condition may lead to gastritis and peptic ulcers.

Yet when tested as single agents in clinical studies, they do not succeed in eradicating the organism.

Failure of therapy and relapse are very common.

The efficacy of this course of therapy is hindered by poor patient compliance due to adverse effects such as diarrhea, nausea, retching and breakdown of normal intestinal flora.

Another reason for incomplete eradication may be that the residence time of antimicrobial agents in the stomach is so short that effective antimicrobial concentrations cannot be achieved in the gastric mucous layer or epithelial cell surfaces where H. pylori exist.

However, no in vivo eradication trials with dosage forms that prolong the gastric residence times for topical activity and have the high absorption rate in the gastro-intestinal tract have been reported.

But clearly, therapy for H. pylori infections is still suboptimal.

But unfortunately, intramucus bismuth concentrations often fall below the mean inhibitory concentration of bismuth compounds for H. pylori, because of the diluting effects of food, long disintegration time of commercial tablets at pH<1.1, and bismuth precipitation due to insolubility in acidic environment.

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