Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-17
2001-07-10
Carr, Deborah D. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S962000
Reexamination Certificate
active
06258808
ABSTRACT:
The present invention relates to novel galenic formulations, in particular novel galenic formulations in which the active ingredient comprises one or more members selected from cyclic poly-N-methylated undecapeptides of the cyclosporin class—see e.g. GB patent publications nos. 2 222 770 A and 2 228 198 A and equivalents world-wide.
As discussed in the said GB patent publications, the cyclosporins present highly specific difficulties in relation to administration generally and galenic formulation in particular, including in particular problems of drug bioavailability and variability in patient dose response.
In order to meet these and related difficulties, in GB patent publication no. 2 222 770 A, galenic formulations are disclosed comprising a cyclosporin as active ingredient and which take the form of, inter alia, a microemulsion or microemulsion pre-concentrate. Such compositions typically comprise 1) a hydrophilic phase, 2) a lipophilic phase and 3) a surfactant. Specifically recited hydrophilic phase components are the products known and commercially available under the trade names Transcutol and Glycofurol as well as 1,2-propylene glycol. Preferred lipophilic phase components are medium chain fatty acid triglycerides such as known and commercially available under the trade names Miglyol, Captex, Myritol, Capmul, Captex, Neobee and Mazol, Miglyol 812 being the most preferred.
Suitable surfactant components include, in particular, reaction products of natural or hydrogenated vegetable oils and ethylene glycol such as those known and commercially available under the trade names Cremophor and Nikkol, the products Cremophor RH40 and Nikkol HCO-40 being indicated as especially preferred.
GB patent publication no. 2 228 198 A 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 tradename Maisine are proposed as suitable tri- and partial glyceride components. The disclosed compositions additionally comprise a surfactant component, for example Cremophor RH40, but are preferably free of any hydrophilic components such as ethanol. Described and exemplified compositions are free of such components.
In accordance with the present invention it has now surprisingly been found that particularly stable cyclosporin galenic formulations having particularly interesting bioavailability characteristics and reduced variability in inter- and intra-subject bioavailability parameters, are obtainable. Such compositions being new, the present invention provides in its broadest aspect:
A pharmaceutical composition comprising a cyclosporin as active ingredient in a carrier medium comprising:
1) 1,2-propylene glycol;
2) a mixed mono-, di-, tri-glyceride; and
3) a hydrophilic surfactant.
The term “pharmaceutical composition” as used herein and in the accompanying claims is to be understood as defining compositions of which the individual components or ingredients are themselves pharmaceutically acceptable, e.g. where oral administration is foreseen, suitable or acceptable for oral application.
Cyclosporins to which the present invention applies are any of those having pharmaceutical utility, e.g. as immunosuppressive agents, anti-parasitic agents and agents for the reversal of multi-drug resistance, as known and described in the art, in particular Cyclosporin A (also known as and referred to hereinafter as Ciclosporin), Cyclosporin G, [0-(2-hydroxyethyl)-(D)Ser]
8
-Ciclosporin, and [3′-deshydroxy-3′-keto-MeBmt]
1
-[Val]
2
-Ciclosporin.
Components (2) in the compositions of the invention preferably comprise mixtures of C
12-20
fatty acid mono-, di- and tri-glycerides, especially C
16-18
fatty acid mono-, di- and triglycerides. The fatty acid component of said mixed mono-, di- and tri-glycerides may comprise both saturated and unsaturated fatty acid residues. Preferably however they will predominantly be comprised of unsaturated fatty acid residues in particular, C
18
unsaturated fatty acid residues for example linolenic, linoleic and oleic acid residues. Suitably component (2) will comprise at least 60%, preferably at least 75%, more preferably 85% or more by weight C
18
unsaturated fatty acid, e.g. linolenic, linoleic and oleic acid mono-, di- and tri-glycerides. Suitably they will comprise less than 20%, e.g. ca. 15% or 10% by weight or less, saturated fatty acid, e.g. palmitic and stearic acid mono-, di- and tri-glycerides.
Components (2) in the compositions of the invention will preferably be predominantly comprised of mono- and di-glycerides, e.g. comprise at least 50%, more preferably at least 70%, e.g. 75%, 80%, 85% by weight or more, mono- and di-glycerides, based on the total weight of component (2).
Components (2) in the compositions of the invention will suitably comprise from about 25 to about 50%, preferably from about 30 to about 40%, e.g. 35 to 40%, monoglycerides, based on the total weight of component (2).
Components (2) in the composition of the invention will suitably comprise from about 30 to about 60%, preferably from about 40 to about 55%, e.g. about 48to 50%, di-glycerides, based on the total weight of component (2).
Components (2) in the compositions of the invention will suitably comprise at least 5%, e.g. from about 7.5 to about 15%, e.g. 9 to 12%, by weight of triglycerides.
Components (2) in the compositions of the invention may be prepared by admixture of individual mono-, di- or tri-glycerides in appropriate relative proportion. Conveniently however they will comprise transesterification products of vegetable oils, for example almond oil, ground nut oil, olive oil, peach oil, palm oil or, preferably, corn oil, sunflower oil or safflower oil and most preferably corn oil, with glycerol.
Such transesterification products are generally obtained by heating of the selected vegetable oil with glycerol, at high temperature in the presence of an appropriate catalyst under an inert atmosphere with continuous agitation, e.g. in a stainless steel reactor, to effect trans-esterification or glycerolysis. In addition to their mono-, di- and tri-glyceride components, such transestrification products will also generally comprise minor amounts of free glycerol. The amount of free glycerol present in components (2) for use in the compositions of the invention will preferably be less than 10%, more preferably less than 5%, most preferably ca. 1 or 2% by weight based on the total weight of free glycerol plus mono-, di- and tri-glycerides.
Preferably some of the glycerol is first removed e.g. by distillation (to give a “substantially glycerol free batch”), when soft gelatine capsules are to be made.
Especially suitable components (2) for use in the compositions of the invention will thus comprise the following components in the indicated amounts by weight based on the total weight of component (2):
Mono-glycerides: 25 or 30 to 50%, especially 30 to 40%.
Di-glycerides: 30 or 40 to 60%, especially 40 to 55%, e.g. 45 to 55%.
Mono- plus di-glycerides: >75%, especially >80%, e.g. ca. 85%.
Tri-glycerides: at least 5%.
Free glycerol: <5%, preferably <2% or <1%.
Particularly suitable components (2) for use in the compositions of the invention are trans-esterification products of corn oil and glycerol, for example as commercially available under the trade name Maisine. Such products are comprised predominantly of linoleic and oleic acid mono-, di- and tri-glycerides together with minor amounts of palmitic and stearic acid mono-, di- and tri-glycerides (corn oil itself being comprised of ca. 56% by weight linoleic acid, 30% oleic acid, ca. 10% palmitic and ca. 3% stearic acid constituents). Physical characteristics for Maisine [available from the company Etablissements Gattefossé, of 36, Chemi
Hauer Birgit
Meinzer Armin
Posanski Ulrich
Vonderscher Jacky
Carr Deborah D.
Novartis AG
Thallemer John D.
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