Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Patent
1995-06-06
1997-07-08
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
424456, 514784, 514785, 514786, 514975, 514937, A61K 910, A61K 948
Patent
active
056458568
DESCRIPTION:
BRIEF SUMMARY
This invention relates to oral drug delivery systems for hydrophobic drugs, and in particular is concerned with improving the bioavailability of hydrophobic drugs from such systems.
As is well known, many pharmaceutically active compounds intended for oral administration are poorly soluble in water. This hydrophobic property often makes it difficult to formulate a drug so that it exhibits a satisfactory bioavailability profile in vivo. Poor bioavailability may lead to ineffective therapy, the need for higher dosing and/or undesirable side effects.
Over the years the drug formulation art has developed numerous oral delivery systems for hydrophobic drugs. Many such systems are oil-based, the hydrophobic drug being dispersed or dissolved in an oil which may sometimes contain a co-solvent. For such formulations the oil appears to be an important component for promoting drug absorption. However, the administration of a drug in oil alone is not advantageous because of the poor miscibility of the oil with the aqueous environment of the gastrointestinal tract. This poor miscibility can lead to highly variable gastric emptying which, in turn, produces variable absorption of drug from the small intestine.
Accordingly, in order to increase the dispersibility of the oil in aqueous fluids it is the normal practice in oil-based pharmaceutical formulations to include a surfactant component. Lipophilic surfactants (i.e. HLB<10) are capable of promoting some emulsification of the oil but the resulting emulsions are normally too crude, in terms of size, to be useful. Hydrophilic surfactants (i.e. HLB>10) are much superior with respect to forming oil-in-water (o/w) emulsions and can be used to produce fine, uniform emulsions which are more likely to empty rapidly and uniformly from the stomach and coupled with a very large surface area will promote faster and more complete absorption. However, hydrophilic surfactants, by themselves, are often not sufficiently miscible with the oil component to ensure good homogeneity, and consequently the surfactant component of an oil-based drug formulation usually consists of a mixture of lipophilic and hydrophilic surfactants.
For convenience of storage and use by the patient, oil-based drug formulations are generally filled into hard or soft capsules.
A few examples of oil-based formulations of hydrophobic drugs which have appeared in the recent patent literature will now be briefly described, by way of illustration.
GB-A-2015339 discloses pharmaceutical compositions in which the drug is cyclosporin, a valuable immuno-suppressive agent, and the carrier for the cyclosporin comprises the following components: oil triglyceride and a poly-alkylene polyol,
GB-A-2228198 in contrast seeks to provide an ethanol-free formulation of cyclosporin. The carrier formulation which this specification discloses comprises: complete or partial ester, and
It is suggested that these compositions enable absorption of cyclosporins in a manner that is at least substantially independent of the relative availability of bile acids or salts in the patient's gastrointestinal tract.
Another carrier system for cyclosporin is proposed in GB-A-222770. This takes the form of a microemulsion or microemulsion pre-concentrate which may typically comprise:
Yet another cyclosporin carrier system is disclosed in GB-A-2257359. This consists essentially of:
W092/10996 is concerned with improving the bioavailability of probucol, a serum cholesterol lowering agent. It proposes that the probucol be dissolved in a propylene glycol ester of fatty acids of the formula C.sub.x H.sub.2x O.sub.2 wherein x is 4, 6, 8, 10, 12, 14, 16.
Finally, W092/21348 discloses a pharmaceutical formulation for a specific benzodiazapine, viz 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N, -(3-methylphenyl)-urea, in which the carrier comprises a pharmaceutically acceptable oil selected from the esterification or polyether products of glycerides with vegetable oil fatty acids of chain length C.sub.8 -C.sub.10 and a pharmaceu
REFERENCES:
patent: 3932634 (1976-01-01), Kardys
patent: 5028432 (1991-07-01), Chopra et al.
patent: 5190748 (1993-03-01), Bachynsky et al.
patent: 5342625 (1994-08-01), Hauer et al.
Database WPI, Section CH, Week 8440, Derwent Publications Ltd., London, GB; Class B04, AN 84-246919 & JP-A-59 148 718 (Fujisawa Pharm KK), 10 Feb. 1983.
Chemical Abstracts, vol. 90, No. 10, 5 Mar. 1979, Columbus, Ohio, US; abstract No. 76504, Bobbe D. et al.: "Effects of Some Excipients and Adjuvants on the Dissolution Rate of Amidopyrine Present in Soft Capsules" & Bobbe D. et al. Expo-Congr. Int. Technol. Pharm., 1977, Aassoc. Pharm. Galenique Ind., Chatenay Malabry, Fr.
Chemical Abstracts, vol. 106, No. 16, 20 Apr. 1987, Columbus, Ohio, US; abstract No. 125904, Kimura K. et al.: "Menatetrenone Soft Capsules", & Patent Abstracts of Japan, vol. 11, No. 136 (C-419) 30 Apr. 1987 & JP A 61 275214 (Kimura K. et al.) 5 Dec. 1986.
Embleton Jonathan Kenneth
Lacy Jonathan Ernest
Page Thurman K.
R. P. Scherer Corporation
Spear James M.
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