Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-11-23
2000-04-04
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514183, 514461, A61K 3800, A61K 3133, A61K 3134
Patent
active
060461632
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a pharmaceutical formulation comprising a cyclosporin as active ingredient. The invention relates to formulations for internal use and also to topical formulations.
Cyclosporins are immunosuppressive cyclic undecapeptides which are used particularly in relation to organ transplants. Cyclosporins are also used for treatment of autoimmune diseases and inflammatory conditions such as arthritis and rheumatic diseases. Further applications include antiparasitic treatments and cancer therapy. Certain Cyclosporins which are devoid of immunosuppressive activity have been found to exhibit an inhibitory effect towards replication of the HIV-1 virus and these compounds can be employed in therapy for treatment and prevention of AIDS or AIDS related diseases.
A wide variety of cyclosporins has been identified. Cyclosporins are highly hydrophobic and are consequently difficult to formulate in dosage forms providing adequate bioavailability. Solubility of cyclosporins in water typically does not exceed 25 mg/l. The high lipophilicity of cyclosporins is indicated by the value of the partition coefficient P in the system n-octanol/water. For ciclosporin, values of log P=2.08 to 2.99 have been reported.
Dispersion systems characterised by the presence of a hydrophilic phase, a hydrophobic phase and a tensoactive component have been used to afford acceptable bioavailability for cyclosporin formulations. Commercially available compositions for oral administration are available under the trade marks Sandimmun, Sandimmun-Neoral, Consupren, Implanta and Imusporin. These formulations are disclosed in GB-A-2015339, GB-A-2222770, GB-A-2270842 and GB-A-2278780. A modification wherein the hydrophilic phase is omitted and replaced by partial esters of fatty acids with polyols such as propylene glycol, glycerol or sorbitol is disclosed in GB-A-2228198.
DE-A-4322826 discloses a carrier system for drugs which are poorly soluble in water, comprising a composition containing polyglyceryl esters of fatty acids as a co-tenside to non-ionic tensides having HLB higher than 10, in the presence of a triacyl glycerol as the lipophilic component. Use of dimethyl iso-sorbide as a co-tenside is mentioned in GB-A-650721.
Compositions for external treatment of inflammatory skin diseases containing, as accelerators of percutaneous absorption, a combination of N-acyl sarcosine and salts thereof with fatty acid amides prepared as reaction products of aliphatic carboxylic acids with mono- and di-ethanolamides are disclosed in JP-A2-07025784.
It has been surprisingly found that it is possible to prepare cyclosporin formulations having advantages over prior compositions by modification of the lipidic components and omission of ethyoxylated tensides from the formulation. While the solubility of cyclosporin in olive oil or corn oil does not exceed 50 mg/ml, we have discovered that solubility of cyclosporin in glyceryl monoesters is higher by approximately an order of magnitude.
According to the present invention a pharmaceutical composition containing cyclosporin for internal or external use is characterised in comprising from 0.1 to 20% by weight of a cyclosporin (I) and a vehicle comprising: formula IIa ##STR1## wherein R is C.sub.1 -C.sub.3 alkyl; (iii) and from 1 to 60% by weight of a mixture of one or more glyceryl monoesters of C.sub.8 -C.sub.22 fatty acids (III) and one or more polyglyceryl esters selected from hexaglyceryl to pentadecaglyceryl monoesters of C.sub.8 -C.sub.22 fatty acids (IV) in a ratio of components (III)/(IV) of 1:2 to 1:6.
We have found that mixtures of polar lipids formed by monoesters of fatty acids with glycerol and of pseudolipids formed by monoesters of fatty acids with polyglycerols for example from hexaglycerol to pentadecaglycerol are particularly suitable for formulation of cyclosporin.
Cyclosporins which may be employed comprise one or more of: ciclosporin, [NVa].sup.2 -ciclosporin, [MeIle].sup.4 ciclosporin, [3'-O-acylMeBmt].sup.1 -ciclosporin.
The polyether IIa is preferably selected from: ethox
REFERENCES:
patent: 5589455 (1996-12-01), Woo
Andrysek Tomas
Husek Ales
Jegorov Alexander
Matha Vladimir
Stuchlik Josef
Galena As
Weddington Kevin E.
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