Pharmaceutical compositions containing cyclosporins

Details Pharmaceutical compositions containing cyclosporins Pharmaceutical compositions containing cyclosporins

2001-04-05

2002-07-16

Weddington, Kevin E. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S937000, C514S951000

Reexamination Certificate

active

06420355

ABSTRACT:

This invention relates to galenic formulations which contain one or more members selected from the cyclosporin class.
Cyclosporins comprise a class of structurally distinct, cyclic, poly-N-methylated undecapeptides, generally possessing immunosuppressive, anti-inflammatory, anti-viral and/or anti-parasitic activity, each to a greater or lesser degree. The first of the cyclosporins to be identified was the fungal metabolite Cyclosporin A, or Ciclosporin, and its structure is given in The Merck Index, 11th Edition; Merck & Co., Inc.; Rahway, N.J., USA (1989) under listing 2759. Large numbers of other cyclosporins are also known and examples are disclosed in UK patent application No 2 222 770 A.
Cyclosporins are generally very insoluble in aqueous media. Consequently, severe difficulties have arisen in developing stable pharmaceutically acceptable formulations which allow delivery of the drug in sufficiently high concentrations to permit convenient use and which allow efficient and consistent absorption of the drug by the body. Problems also arise with regard to drug bioavailability and variability in patient dose response. Cyclosporins also have side effects at higher doses and therefore their concentration in the blood must be kept within certain therapeutic ranges. It is therefore desirable for the bioavailability of the cyclosporin drug to be as predictable and constant as possible.
In order to meet these and related difficulties, UK patent application 2 222 770 (the disclosure of which is incorporated by reference), discloses galenic formulations comprising a cyclosporin and which take the form of a microemulsion or microemulsion pre-concentrate. These formulations comprise a hydrophilic phase, a lipophilic phase and a surfactant. The following components for the hydrophilic phase are proposed: Transcutol, Glycofurol and 1,2-propylene glycol. Medium chain fatty acid triglycerides are disclosed as being suitable for the lipophilic phase. Reaction products of natural or hydrogenated vegetable oils and ethylene glycol are given as surfactants.
UK patent application 2 228 198 proposes an alternative means for meeting difficulties in relation to cyclosporin administration. Specifically it discloses oil based formulations in which the oily component comprises a combination of tri-glyceride and (i) glycerol partial esters or (ii) 1,2-propylene glycol complete or partial esters or (iii) sorbitol complete or partial esters. The products known and commercially available under the trade name MAISINE are proposed as suitable tri- and partial glyceride components. The disclosed compositions additionally comprise a surfactant component, for example Cremophor RH40. These may be preferably free of any hydrophilic components such as ethanol.
It has now surprisingly been found that simple, stable cyclosporin formulations that have improved bioavailability characteristics, reduced variability in inter- and intra-subject bioavailability parameters, are obtainable.
Accordingly this invention provides a pharmaceutical composition in the form of an emulsion preconcentrate and comprising a cyclosporin in a carrier medium, the carrier medium comprising: 1) a hydrophilic organic solvent, 2) (a) a mixed mono-, di-, and tri-glyceride or (b) a transesterified and polyethoxylated vegetable oil, and 3) a polyoxyethylene-sorbitan-fatty acid ester surfactant.
The pharmaceutical compositions are simple, stable, and provide surprisingly high bioavailabilities. For example, in clinical trials in which healthy volunteers each received three times 200 mg cyclosporin A in soft gelatin capsules under fasted and fed conditions, the pharmaceutical compositions resulted in at least a 150% increase in bioavailability as compared to the Cyclosporin market form which is disclosed in U.S. Pat. No. 4,388,307. Also, in the same trials, the relative bioavailability under fasted and fed conditions differed by less than 5%. This indicates very low inter-subject variability. Moreover intra-subject variability is reduced more than two fold. Hence the pharmaceutical compositions have very surprising properties which offer great advantages over the Cyclosporin market form.
The pharmaceutical composition is an emulsion preconcentrate; that is it has the characteristics of a stable emulsion preconcentrate system and spontaneously forms an emulsion in an aqueous medium, for example, in water or in the gastric juices after oral application. The emulsion formed is opaque, thermodynamically stable and contains dispersed droplets of a size greater than about 100 nm, more usually greater than about 200 nm. The pharmaceutical compositions are preferably emulsion preconcentrates of the type providing o/w (oil-in-water) emulsions.
The term “pharmaceutical composition” as used in this specification means compositions of which the individual components or ingredients are themselves pharmaceutically acceptable. For example, where oral administration is foreseen, the components are suitable or acceptable for oral application.
The cyclosporin may be any cyclosporin having pharmaceutical utility as, for example, an immunosuppressive agent, an anti-parasitic agent or an agent for the reversal of multi-drug resistance. In particular the cyclosporin may be Cyclosporin A (also known as and referred to as Ciclosporin), and Cyclosporin G.
Suitably the pharmaceutical composition comprises from about 1 or 2 to 30%, preferably from 5 to 25% (more preferably from 7.5 to 15%, for example about 10%) by weight of cyclosporin based on the total weight of the pharmaceutical composition.
The hydrophilic organic solvent preferably comprises pharmaceutically acceptable, hydrophilic organic solvents which are suitable for oral administration. Examples are Transcutol, Glycofurol, ethyl acetate, propylene glycol and lower alkanols, or mixtures thereof. Preferred solvents are 1,2-propylene glycol and mixtures of 1,2-propylene glycol and ethanol. If the component (2) is a mixed mono-, di- and tri-glyceride, 1,2-propylene glycol and mixtures of 1,2-propylene glycol and ethanol are particularly preferred.
Suitably the hydrophilic organic solvent is present in an amount of from 1.0 to 50% (preferably from 5 to 40%, more preferably from 10 to 35%, and even more preferably from about 15 to about 30%) by weight based on the total weight of the carrier medium.
When the hydrophilic organic solvent comprises a mixture of 1,2-propylene glycol and ethanol, the co-component, that is the ethanol, is suitably present in an amount of up to about 20% (preferably up to about 15%, more preferably from about 5 to 15% and even more preferably 5 to 10%) by weight based in the total weight of the pharmaceutical composition. Thus the co-component is suitably present in an amount of from about 25 to 85% by weight based on the total weight of the organic solvent (for example 1,2-propylene glycol plus ethanol). More preferably the co-component is present in an amount of from 50% to 85%, for example from 70 to 80% based on the total weight of the hydrophilic organic solvent.
If component (2) comprises mixed mono-, di-, and tri-glycerides, the mixed mono-, di-, and tri-glycerides preferably comprise a mixture of C
12-20
fatty acid mono-, di- and tri-glycerides. C
16-18
fatty acid mono-, di- and triglycerides are especially preferred. The fatty acid component of the mixed mono-, di- and tri-glycerides may comprise both saturated and unsaturated fatty acid residues. Preferably however the mixed glycerides are predominantly comprised of unsaturated fatty acid residues, in particular C
18
unsaturated fatty acid residues such as linolenic, linoleic and oleic acid residues. Suitably the mixed glycerides comprise at least 60%, preferably at least 75%, more preferably 85% or more by weight C
18
unsaturated fatty acid mono-, di- and tri-glycerides. Suitably the mixed glycerides comprise less than 20%, for example about 15% or 10% by weight, saturated fatty acid mono-, di- and tri-glycerides (for example palmitic and stearic acid mono-, di- and tri-glycerides).
The mixed mono-, di-, and tri-glycerides

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