Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-10-27
1998-12-01
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
A61K 3813
Patent
active
058438912
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/CA94/00222 filed Apr. 22, 1994.
TECHNICAL FIELD
This invention is directed to pharmaceutical compositions which facilitate the in vivo absorption of hydrophobic drugs, including but not limited to polypeptide and protein drugs.
BACKGROUND ART
The hydrophobic nature of some drugs causes them to be insoluble or poorly soluble in aqueous media. This reduces the absorption of the drug into systemic circulation after a composition containing the drug is swallowed, or the absorption into the target tissues upon topical application.
Previous attempts to deal with this problem have included forming a solution, either liquid or solid, incorporating the drug, whereby the drug is disseminated as molecular size particles within the solvent. If the solvent is water-soluble, upon ingestion of the composition the solvent dissolves and releases the drug as individual molecules which are more readily available for absorption than larger particles would be.
Problems previously encountered with this approach include: require large quantities of solvent. This limits the amount of the drug that can be contained in a tablet or capsule of acceptable, swallowable size; consequence the drug is precipitated and the efficacy diminishes; and dissolves in the gastrointestinal fluids, the drug may precipitate and agglomerate into larger particles that are poorly absorbed.
Among the drugs that are hydrophobic and give rise to such problems are nonpolar polypeptides, including cyclosporins, as defined in the Merck Index, Eleventh Edition. One such cyclosporin is cyclosporin A, also known as cyclosporine, and hereinafter referred to as "cyclosporine", known to be therapeutically active as an immunosuppressant.
U.S. Pat. No. 4,388,307 discloses a composition comprising cyclosporine in an emulsion preconcentrate that is not water-soluble, but upon being mixed into gastrointestinal fluids forms an emulsion. The advantage of such compositions is that the cyclosporine in the emulsion is absorbed to a substantially greater extent than from other compositions previously known.
However, such compositions still suffer from certain disadvantages;
Although the absorption is superior to that of some compositions, the absorption is still less than the maximum possible and is variable.
Further, the concentration of cyclosporine in such compositions is limited to about 10 percent by weight. Hence, a capsule containing 100 mg of cyclosporine weighs about 1 gram. Capsule strengths are thus limited to about 100 mg, as higher strength capsules would be too large to be swallowed.
Others have attempted to solve the formulation problems by developing solutions of cyclosporine (either liquid or solid solutions) that are entirely water-soluble and form a clear solution upon being dispersed in aqueous media such as gastrointestinal fluids.
European Patent Application No. 88305138.5 discloses use of a surfactant or solubilizing agent which is alphacyclodextrin or a derivative thereof.
Other publications and patent applications disclose compositions comprising cyclosporine together with surfactants, which also form clear solutions upon their addition to aqueous media.
However, such compositions have been generally impractical, as the quantities of surfactant needed to render cyclosporine entirely water-soluble have been unacceptably large. Typical therapeutic doses of such compositions would require toxic quantities of the surfactants.
Others have provided compositions in which surfactants are used in quantities less than sufficient to entirely solubilize the cyclosporine in water. Japanese Patent No. 1038029 discloses preparation of powders by dissolving cyclosporine and surfactants in organic solvents and evaporating the solvents. However, the compositions described do not fully solubilize the cyclosporine, and organic solvents are costly and more difficult to use than water in the manufacturing process.
U.K. Patent Application No. 8920597.5 discloses "microemulsion preconcentrates" which are stated to be improved over compo
REFERENCES:
patent: 4388307 (1983-06-01), Cavanak
Physicians' Deck Reference, 46.sup.th ed. (1992) pp. 2024-2027.
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