Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-05-26
2002-08-13
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S451000, C424S452000, C424S456000, C424S463000
Reexamination Certificate
active
06432445
ABSTRACT:
The present invention relates to novel galenic compositions, e.g. substantially oil-free, galenic compositions containing a cyclosporin as an active agent and also comprising a plurality of alkanols.
Cyclosporins present highly specific difficulties in relation to administration generally and galenic compositions in particular, including in particular problems of stability, drug bioavailability, and variability in inter- and intra-patient dose response. The present invention allows the production of a particularly convenient form, namely a capsule. The present invention provides in one aspect a cyclosporin composition in the form of a capsule comprising a polyoxyethylene-sorbitan-fatty acid ester, for example polyoxyethylene (20) sorbitan monooleate such as that available under the trade name Tween®80; a reaction product of a natural or hydrogenated castor oil and ethylene oxide, for example polyethylene glycol castor oil such as that available under the trade name Cremophor®RH40 or EL; a sorbitan fatty acid ester, for example Span® 80 (sorbitan monooleate), and ethanol. Hereinafter these cyclosporin compositions with particular reference to the centre fill (e.g. when referring to weights and amounts) are referred to as compositions of the invention.
The capsule composition may be preferably a hard gelatine capsule. As will be appreciated by a man skilled in the art the present invention extends to variants. For example the compositions of the invention may contain lower alkanols, e.g. propylene glycol and polyethylene glycol.
A cyclosporin-containing composition of the invention in the form of a capsule if desired may comprise:
(a) a hydrophilic surfactant,
(b) a lipophilic component,
(c) a lipophilic surfactant, and
(d) ethanol,
characterized by the presence of a polyoxyethylene sorbitan fatty acid ester, a reaction product of a natural or hydrogenated castor oil and ethylene oxide, and a sorbitan fatty acid ester.
It will also be appreciated by a man skilled in the art that the same component may serve as both the lipophilic component and the lipophilic surfactant.
If desired a composition of the invention may be so formulated that on treatment with water it produces a particularly stable emulsion, e.g. microemulsion, or emulsion, e.g. microemulsion.
Compositions of the invention may have particularly interesting bioavailability characteristics and reduced variability in inter- and intra-subject bioavailability parameters. Preferably the composition is in the form of an “emulsion, e.g. microemulsion, preconcentrate” of the type providing o/w (oil-in-water) emulsions, e.g. microemulsions.
An “emulsion, e.g. microemulsion, preconcentrate” is defined in this specification as being a composition which spontaneously forms an emulsion, e.g. microemulsion, in an aqueous medium, for example, in water, for example on dilution of the centre fill 1:1 to 1:100, e.g. 1:10, or in the gastric juices after oral application.
A microemulsion is thermodynamically stable and contains dispersed particles of a mean size less than about 200 nm. Generally microemulsions comprise droplets or particles having a mean diameter of less than about 150 nm; typically less than 100 nm, generally greater than 10 nm, and stable over periods in excess of 24 hours. A “microemulsion” may be a non-opaque or substantially non-opaque, alternatively it may be a translucent colloidal dispersion that is formed spontaneously or substantially spontaneously when its components are brought into contact. Further characteristics can be found in British patent application 2 222 770, the disclosure of which is incorporated herein by reference.
In a further aspect the present invention provides a composition of the invention, the relative proportion of the cyclosporin, the lipophilic component, the hydrophilic surfactant, the lipophilic surfactant and the ethanol in said composition being such that upon dilution with water to a ratio of 1 part by weight of said composition centre fill to 1 to 100, e.g. 10 to 100 parts by weight of water, an oil-in-water microemulsion having particles of a mean size of less than 200 nm, is spontaneously formed.
In the centre fill, the cyclosporin may be present in an amount by weight of up to about 20% by weight of the composition of the invention. The cyclosporin is preferably present in an amount of 1 to 15% by weight of the composition of the invention, for example about 2 to 10%.
In a further alternative aspect the lipophilic component may comprise 5 to 35% by weight of the composition centre fill, e.g. 10 to 30%; preferably 15 to 25% by weight, more preferably about 20% or 30% by weight.
In a composition of the invention, in a further alternative aspect the constitutional ratio of the lipophilic component to the cyclosporin is preferably 1-30:1 and more preferably 2-30:1, on the basis of weight.
In a further alternative aspect the hydrophilic surfactant may comprise 25 to 70% by weight of the composition centre fill; preferably 30 to 65% by weight, more preferably 40 to 60% by weight and even more preferably about 50% by weight.
In a composition of the invention, in a further alternative aspect the constitutional ratio of the hydrophilic surfactant to the cyclosporin is preferably 1-60:1 and more preferably 2-60:1, on the basis of weight.
In a further alternative aspect the lipophilic surfactant may comprise 5 to 35% by weight of the composition centre fill, e.g. 5 to 30%; preferably 5 to 20% by weight, more preferably about 10% by weight.
In a composition of the invention, in a further alternative aspect the constitutional ratio of the lipophilic surfactant to the cyclosporin is preferably 1-30:1 and more preferably 2-30:1, on the basis of weight.
In a further alternative aspect the ethanol may comprise 1 to 20% by weight of the composition centre fill, e.g. 5 to 15%; preferably about 10% by weight.
In a composition of the invention, in a further alternative aspect the constitutional ratio of the ethanol to the cyclosporin is preferably 10:1 to 1:10 and more preferably 5:1 to 1:5, on the basis of weight.
In a further aspect the present invention provides a capsule having a composition centre fill comprising
1-20% by weight of Cyclosporin A,
5-35% by weight of a lipophilic component, e.g., Miglyol®812 or Span®80, 25-70% by weight of a hydrophilic surfactant, e.g., Cremophor®RH40 or EL and Tween®80,
5-35% by weight of a lipophilic surfactant, e.g., Span®80,
1-20% by weight of ethanol.
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, Cyclosporin G, [0-(2-hydroxyethyl)-(D)Ser]
8
-Ciclosporin, and [3′-deshydroxy-3′-keto-MeBmt]
1
-[Val]
2
-Ciclosporin. Cyclosporin A is preferred.
In one aspect the present invention provides a composition of the invention wherein the cyclosporin is Cyclosporin A.
Polyoxyethylene-sorbitan-fatty acid esters may comprise for example mono- and tri-lauryl, palmityl, stearyl and oleyl esters of the type known and commercially available under the trade name Tween® from e.g. ICI, UK, including the products Tween®
20 [polyoxyethylene(20)sorbitanmonolaurate],
21 [polyoxyethylene(4)sorbitanmonolaurate],
40 [polyoxyethylene(20)sorbitanmonopa Imitate],
60 [polyoxyethylene(20)sorbitanmonostearate],
65 [polyoxyethylene(20)sorbitantristearate],
80 [polyoxyethylene(20)sorbitanmonooleate],
81 [polyoxyethylene(5)sorbitanmonooleate],
85 [polyoxyethylene(20)sorbitantrioleate].
Especially preferred products of this class are Tween®40 (HLB value of about 15 to 16) and Tween®80 (HLB value of about 15).
In the reaction products of a natural or hydrogenated castor oil and ethylene oxide, the natural or hydrogenated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1:35 to about 1:60, with optional removal of the polyet
Ambuhl Michael
Haberlin Barbara
Lückel Barbara
Meinzer Armin
Novartis AG
Spear James M.
Thallemer John D.
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