Oil-free pharmaceutical compositions containing cyclosporin A

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules

Reexamination Certificate

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Details

C424S451000, C424S452000, C424S455000, C514S785000, C514S962000

Reexamination Certificate

active

06475519

ABSTRACT:

The present invention relates to novel pharmaceutical compositions comprising cyclosporin A, also known as ciclosporine, as active agent (hereinafter referred to as cyclosporin).
Hitherto few pharmaceutical compositions containing cyclosporin have been accepted for commercial use for humans. Thus in the USA only SANDIMMUNE and NEORAL (cyclosporin for microemulsion) have been approved.
These formulations are available in the form of a drink solution or a soft gelatine capsule. Such soft gelatine capsules require special manufacturing techniques.
The compositions of the present invention are compositions containing cyclosporin which meet the requirements for approval in the US or elsewhere, yet can be produced in a form administrable as a hard gelatine capsule. Such capsules are well known in the art and may be made and filled in conventional manner.
In one aspect to present invention provides an oral pharmaceutical composition comprising cyclosporin A in a mixture with (i) a surfactant of HLB value at least 10, and optionally (ii) a viscosity increasing agent and/or (iii) a hydrophilic phase, the hydrophilic phase being a polyethylene glycol and/or a lower alkanol provided that any lower alkanol present is present in less than 12%, preferably less than 10 or 8% of the total weight of the composition, the composition being adapted for filling into, and serving as a centre-fill for, a hard gelatine capsule, and being substantially free of any additional oil.
The present compositions are based on the use of very few components, e.g. a surfactant (including associated side products normally arising from its preparation), optionally a viscosity increasing agent (thickener) and if desired an additional hydrophilic phase (additional to that present in the surfactant) chosen from polyethylene glycol and/or a lower alkanol which said lower alkanol is present in an amount of less than 12%, e.g. 8% by weight of the composition.
Cyclosporin compositions which have been proposed before suffer from the disadvantage that they are not stable in hard gelatine capsules, e.g. over 2 to 3 years and have bioavailability or variability similar to SANDIMMUNE OR NEORAL. The present compositions have excellent stability. The capsules do not become brittle.
Preferably the composition contains few other excipients. This has the advantage of reducing bulk. Thus preferably less than 5%, preferably less than 2% or 1% of lipophilic moieties (oils) apart from those present in the surfactant, or hydrophilic moieties, e.g. alkanols such as ethanol or propylene glycol are present.
The compositions may contain polyethylene glycol. This may be a part of the surfactant for example if this is produced by polyethoxylation or added separately. This may be present from e.g. 1 to 40% of the formulation. Preferably the polyethylene glycol is liquid at 37° C. e.g. having a M.W. 200 to 600 daltons.
The cyclosporin may be present in the usual dosage form for a cyclosporin formulation e.g. 25 mg; 50 mg; 100 mg per weight dosage form. The dosage form is e.g. a hard gelatine capsule as known in the art.
By the present invention there are provided novel cyclosporin galenic formulations, which meet or substantially reduce difficulties in cyclosporin, therapy hitherto encountered in the art. In particular it has been found that the compositions of the invention permit the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in sufficiently high concentration to permit convenient oral administration, while at the same time achieving improved efficacy, e.g. in terms of bioavailability characteristics.
More particularly it has been found that compositions in accordance with the present invention enable effective cyclosporin dosaging with concomitant enhancement of resorption/bioavailability levels, as well as reduced variability in resorption/bioavailability levels achieved both for individual patients receiving cyclosporin therapy as well as between individuals. By application of the teachings of the present invention cyclosporin dosage forms are obtainable providing reduced variability in achieved cyclosporin blood/blood serum levels between dosages for individual patients as well as between individuals/ individual patient groups. The invention thus enables reduction of cyclosporin dosage levels required to achieve effective therapy. In addition it permits closer standardisation as well as optimisation of on-going daily dosage requirements for individual subjects receiving cyclosporin therapy as well as for groups of patients undergoing equivalent therapy.
By closer standardisation of individual patient dosaging rate and blood/blood-serum level response, as well as dosaging and response parameters for patient groups, monitoring requirements may be reduced, thus substantially reducing the cost of therapy.
By reduction of required cyclosporin dosaging/standardisation of achieved bio-availability characteristics, the present invention also offers a means permitting reduction in the occurrence of undesirable side-effects, in particular nephrotoxic reaction, in patients undergoing cyclosporin therapy.
The present compositions are of a small volume, yet stable, thereby increasing patient compliance.
The surfactant is preferably approved by the FDA, e.g. a GRAS surfactant, e.g.
1.1 Polyethyloxylated castor oil, e.g. reaction products of natural or hydrogenated vegetable oils and ethylene glycol, i.e. polyoxyethylene glycolated natural or hydrogenated vegetable oils, for example polyoxyethylene glycolated natural or hydrogenated castor oils. Such products may be obtained in known manner, e.g. by reaction of a natural or hydrogenated castor oil or fractions thereof with ethylene oxide, e.g. in a molar ratio of from about 1:35 to about 1:60, with optional removal of free polyethyleneglycol components from the product, e.g. in accordance with the methods disclosed in German Auslegeschriften 1,182,388 and 1,518,819. Especially suitable are the various tensides available under the trade name Cremophor. Particularly suitable are the products Cremophor RH 40 having a saponification no. ca. 50-60, an acid no.=<1, an iodine no.=<1, a water content (Fischer)=<2%, an n
D
60
=ca. 1,453-1,457 and an HLB=ca. 14-16; Cremophor RH 60 having a saponification no.=ca. 40-50, an acid No.=<1, an iodine no.=<1, a water content (Fischer)=ca. 4.5-5.5%, an n
D
25
=ca. 1,453-1,457 and an HLB=ca. 15-17; and Cremophor EL having a molecular weight (by steam osmometry)=ca. 1630, a saponification no.=ca. 65-70, an acid no.=ca. 2, an iodine no.=ca. 28-32 and an n
D
25
=ca. 1.471 (c.f. Fiedler loc. cit. pp. 326-327). Also suitable for use in this category are the various tensides available under the trade name Nikkol, e.g. Nikkol HC0-60. The said product Nikkol HC0-60 is a reaction product of hydrogenated castor oil and ethylene oxide exhibiting the following characteristics: Acid no.=ca. 0.3; Saponification no.=ca. 47.4; Hydroxy value=ca. 42.5; pH (5%)=ca. 4.6; Color APHA=ca. 40; m.p.=ca. 36.0 C.; Freezing point=ca. 32.4 C.; H
2
O content (%, KF)=ca. 0.03;
Such products contain a “hydrophilic portion” of ca. 70 to 90% of fatty acid esters of glycerol polyethylene glycol, as well as fatty acid esters of polyethylene glycols and a hydrophilic portion of polyethylene glycol and glycerol ethoxylates. See for example Karl Müller, Tenside, Year 3, Issue 2, p. 37-45.
Preferably the surfactant is a polyethoxylated hydrogenated castor oil Cremophor RH.
1.2 Polyoxyethylene-sorbitan-fatty acid esters (polysorbates) e.g. produced by co-polymerising ethylene oxide with fatty acid esters of a sorbitol and its anhydrides of e.g. mono- and tri-lauryl, palmityl, stearyl and oleyl esters e.g. of the type known and commercially available under the trade name Tween (c.f. Fiedler, loc. cit. pp. 1300-1304) including the products Tween
20 [polyoxyethylene(20)sorbitanmonolaurate&r

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