Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-06-15
1999-12-07
Moezie, F. T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514885, 514937, 514938, 514963, 514964, 514970, 424455, 424489, A61K 3800, A61K 3813
Patent
active
059983655
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention is directed to pharmaceutical compositions which facilitate the administration of cyclosporins.
BACKGROUND ART
The term "cyclosporins" as used herein shall mean the class of nonpolar polypeptides. 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.
The term "composition" as used herein is to be understood as meaning any composition containing a drug along with inactive ingredients that are pharmaceutically acceptable by reason of not being excessively toxic in the quantities required.
The term "solvent system" as used herein is to be understood to mean the material in which the drug (i.e. a cyclosporin) is dissolved. The solvent system may be a single solvent or a combination or mixture of ingredients included as solvents, surfactants, diluents or for other purposes.
Cyclosporins are hydrophobic and have low solubility in aqueous media. This makes it difficult to design pharmaceutical compositions which exhibit satisfactory absorption into systemic circulation after oral administration, or absorption into the target tissue upon topical administration.
The cyclosporin can be dissolved in an organic solvent (e.g. ethanol or propylene glycol), but if the solvent is water-miscible, when the composition is mixed with gastrointestinal fluid or other aqueous media the cyclosporin will precipitate.
Various methods of overcoming this problem are known in the prior art, but all have certain limitations.
U.S. Pat. No. 4,388,307 discloses compositions comprising cyclosporine in an emulsion preconcentrate that is not water-miscible, but forms an emulsion upon being mixed into gastrointestinal fluids. A commercial product that has been sold under the trademark "Sandimmune" is made according to U.S. Pat. No. 4,388,307, and, more specifically, comprises cyclosporine dissolved in a solvent system comprising ethanol, a vegetable oil and a surfactant. Although this composition was superior to previously known compositions, it still exhibits absorption that is less than the maximum possible and is variable. Also, the use of ethanol has disadvantages, as ethanol is volatile, and the capsules of Sandimmune must be individually packaged in metallic pouches to avoid loss of ethanol by evaporation.
U.S. Pat. No. 5,342,625 discloses compositions that are said to be superior in certain respects to the compositions of U.S. Pat. No. 4,388,307. The compositions of U.S. Pat. No. 5,342,625 comprise, in addition to the cyclosporin, a hydrophilic phase, a lipophilic (i.e. hydrophobic) phase and a surfactant. The hydrophilic phase is either propylene glycol or a pharmaceutically acceptable alkyl or tetrahydrofurfuryl di- or partial-ether of a low molecular weight mono- or poly-oxy-alkanediol.
The lipophilic phase comprises a solvent which is non-miscible with the hydrophilic phase. and is preferably a fatty acid triglyceride.
It is disclosed that compositions according to U.S. Pat. No. 5,342,625, when added to water, disperse into emuisions with droplet size of less than 2000 .ANG., which is smaller than obtained with prior art compositions, thus leading to improved absorption.
Emulsions with droplet size of less than 2000 .ANG. are defined as "microemulsions". Compositions that, upon addition to water, disperse into microemulsions are called "microemulsion preconcentrates".
A composition made according to the disclosure of U.S. Pat. No. 5,342,625 is now marketed under the trademark "Neoral", in the form of both a soft gelatin capsule which encloses the microemulsion preconcentrate and an oral liquid which is a microemulsion preconcentrate intended to be diluted into an aqueous drink before ingestion.
For both the soft gelatin capsules and the oral liquid, the labelling indicates that the "Neoral" emulsion preconcentrate comprises cyclosporine dissolved in ethanol and propylene glycol as hydrophilic solvents, corn oil as lipophilic (hydro
REFERENCES:
patent: 5342625 (1994-08-01), Hauer et al.
Moezie F. T.
Sherman Bernard C.
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