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Title: Cyclosporin-based pharmaceutical compositions
United States Patent: 6,979,672
Issued: December 27, 2005
Inventors: Legora; Michela (Como, IT);
Mailland; Federico (Milan, IT)
Assignee: Polichem, S.A. (Luxembourg, LU)
Appl. No.: 327646
Filed: December 20, 2002
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Abstract
A pharmaceutical formulation for the oral administration of cyclosporin
is described, which formulation is capable of providing substantially
constant and foreseeable plasma levels of the active ingredient. The
formulation has the following quali-quantitative composition by weight:
- (a) cyclosporin in the amount of from about 8 to about 12% of the
total weight;
- (b) ethanol in the amount of from about 12 to about 18% of the total
weight;
- (c) a polyoxyethylene/polyoxypropylene block copolymer in the amount
of from about 8 to about 12% of the total weight;
- (d) water in the amount of from about 4 to about 6% of the total
weight;
- (e) a solubilizer having an HLB from 13 to 15 in the amount of from
about 28 to about 40% of the total weight;
- (f) an ester of a C1-C6 alkyl alcohol and a C14-C18
saturated fatty acid in the amount of from about 20 to about 30%
of the total weight.
Description of the Invention
The present invention relates to a pharmaceutical formulation for the oral
administration of cyclosporin, which formulation is capable of providing
substantially constant and foreseeable plasma levels of the active
ingredient.
BACKGROUND OF THE INVENTION
Cyclosporin is a drug having immunosuppressant activity, which is used to
prevent graft rejection in transplant patients and for the treatment of a
series of autoimmune diseases characterized by an abnormal reaction of the
immune system. The clinical availability of cyclosporin has greatly
improved the prognosis of transplant patients, considerably increasing
their survival. However, the drug has an intrinsic toxicity which limits
its therapeutic window, requiring the achievement of defined plasma
levels. Outside the therapeutic window the patient's life is threatened,
both when plasma levels attained are lower than those needed—due to lack
of efficacy and the consequent increased risk of rejection—and when plasma
levels exceed the safe levels—due to the specific risk of toxicity,
particularly renal and/or liver toxicity.
In its therapeutic use as an immunosuppressant, cyclosporin is currently
administered either orally or by injection. However, since the solubility
of cyclosporin in water is extremely low, (e.g. 20 μg/ml to 30 μg/ml), an
oily solution containing ethanol has been recognized to be a suitable
vehicle. Even so, the bioavailability of oral preparations of cyclosporin
is extremely low, generally below 30%. This is believed to be due to the
separation of cyclosporin as a solid immediately after it comes into
contact with water, e.g. in the mouth and on contact with gastric fluids.
It is generally accepted that cyclosporin cannot be absorbed following
oral administration unless it is first solubilized in gastrointestinal
fluids by appropriate excipients.
The first cyclosporin formulations available for therapeutic use (SANDIMMUN®)
were characterized by a high degree of intra- and interindividual
variability with respect to absorption, so that it was necessary to
frequently titrate the plasma levels in the individual patients in order
to continuously adjust the administered dosage.
Subsequently, in order to avoid the described disadvantage, and thus to
obtain less variable plasma levels of the drug, formulations that are
based on preconcentrates for microemulsions and that have demonstrated
less individual variability, or compositions that are difficult to produce
and just as complex, were described. One of those formulations, (in the
form of a preconcentrate for a microemulsion) was introduced onto the
market (NEORAL®) as an improvement over the previous oily solution of
cyclosporin in ethanol.
The prior art is rich in complex compositions which, nevertheless, lead to
absorption profiles of the active ingredient which are extremely variable
in quantitative terms.
U.S. Pat. No. 4,388,307, relating precisely to SANDIMMUN®, describes a
cyclosporin-based composition containing (a) a non-ionic ester of a
triglyceride and a polyalkylene polyol, (b) a saturated fatty acid
triglyceride, and (c) a mono- or di-glyceride having improved physical and
absorption properties.
U.S. Pat. No. 5,047,396 discloses an intravenous pharmaceutical
formulation composed of a) 1 part by mass of one or more cyclosporins, b)
8 to 13 parts by mass of a monoester of a saturated hydroxylated fatty
acid formed with polyethylene glycol or the mixture of said monoesters, c)
4 to 10 parts by mass of one or more intravenously administerable mono- or
polivalent alcohols.
U.S. Pat. No. 5,756,450 discloses a combination of cyclosporin and a water
soluble monoester of a saturated or unsaturated fatty acid and a polyol,
especially a saccharide.
German patent application DE-4418115 discloses an at least ternary vehicle
formed by the transesterification product of a vegetable oil and mono-, di-
or triglyceride of oleic acid and/or linoleic acid, and/or of
polyoxyethylenated vegetable oil, propylene glycol and ethanol.
U.S. Pat. No. 5,342,625, which relates to NEORAL®, describes a composition
which allows a more homogeneous absorption of the active ingredient by
means of a formulation which consists of a preconcentrate for
microemulsion, that does not contain alkanols.
U.S. Pat. No. 5,639,724 discloses pharmaceutical compositions comprising a
cyclosporin as active ingredient, a fatty acid triglyceride, a glycerol
fatty acid partial ester or propylene glycol or sorbitol complete or
partial ester, preferably, and a tenside having an HLB of at least 10,
without ethanol.
U.S. Pat. No. 6,258,808 describes a composition containing a cyclosporin,
1,2-propylene glycol, a mixed mono-, di- and tri-glyceride and a
hydrophilic surfactant.
U.S. Pat. No. 6,420,355 discloses a pharmaceutical composition in the form
of an emulsion preconcentrate for oral administration and containing a
cyclosporin. The pharmaceutical composition has a carrier medium for the
cyclosporin that contains a hydrophilic organic solvent; a mixed mono-, di-,
and tri-glyceride or a transesterified and polyethoxylated vegetable oil;
and a polyoxyethylene-sorbitan-fatty acid ester surfactant.
U.S. Pat. No. 4,990,337 relates to a pharmaceutical composition comprising
a cyclosporin in admixture with a monoglyceride or diglyceride of a C6-C10
fatty acid in an amount sufficient to dissolve the cyclosporin.
U.S. Pat. No. 5,589,455 discloses a microemulsion free from ethanol and
containing (1) cyclosporin as the active ingredient; (2) polyethylene
glycol having a molecular weight from 200 to 600 Da as cosurfactant; (3) a
mixture comprising the esterification product of a fatty acid and a
primary alcohol, the triglyceride of a medium-chain fatty acid nd the
monoglyceride of a fatty acid; and (4) a surfactant having an HLB value
from 10 to 17.
United States patent application US2002/0107183A1 describes a
pharmaceutical composition containing (a) cyclosporin as the active
ingredient, (b) an alkylene polyether and/or an alkylene polyester as
vehicles, in which the HLB of component (b) is at least 10.
Pharmaceutical compositions containing water insoluble active ingredients
are also disclosed in US2002120015, WO02/45696, WO00/37050, WO96/03113 and
WO00/03753. DESCRIPTION OF THE INVENTION
The object of the present invention is to provide a novel orally
administrable formulation based on cyclosporin, which formulation, unlike
SANDIMMUN®, is capable of providing substantially constant and foreseeable
plasma levels and is at least bioequivalent to NEORAL®.
The formulation according to the present invention contains the following
components in the following proportions by weight:
- (a) cyclosporin in the amount of from about 8 to about 12% of the
total weight;
- (b) ethanol in the amount of from about 12 to about 18% of the total
weight;
- (c) a polyoxyethylene/polyoxypropylene block copolymer in the amount
of from about 8 to about 12% of the total weight;
- (d) water in the amount of from about 4 to about 6% of the total
weight;
- (e) a solubilizer having an HLB from 13 to 15 in the amount of from
about 28 to about 40% of the total weight;
- (f) the ester of a C1-C6 alkyl alcohol and C14-C18
saturated fatty acids in the amount of from about 20 to about 30%
of the total weight;
- where the sum of compounds (a), (b), (c), (d), (e) and (f) is 100%.
Preferably, the cyclosporin is cyclosporin A.
Component (c), that is to say, the polyoxyethylene/polyoxypropylene block
copolymer, is preferably poloxamer 407 (CAS No. 9003-11-6) which is
marketed by BASF under the mark Lutrol® F 127 and whose use for the
preparation of transmucosal release formulations is described in
international patent application WO 94/03157.
As regards component (e), that is to say, the solubilizer, it preferably
has an HLB value from 13.5 to 14.5 and, even more preferably, it is
caprylocaproyl macrogol-8-glyceride (CAS No. 85536-07-8 and 84963-88-2).
This is a mixture of mono-, di- and triesters of glycerol and of PEG 400
with medium-chain fatty acids (C8-C10) which is
marketed, for example, by Gattefossé under the mark Labrasol®; Labrasol®
has an HLB value of 14 and has the following composition by weight:
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C8-C10 monoglycerides |
approximately 4%; |
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C8-C10 diglycerides |
approximately 17%; |
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C8-C10 triglycerides |
approximately 6%; |
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C8-C10 monoesters of PEG 400 |
approximately 14%; |
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C8-C10 diesters of PEG 400 |
approximately 36%; |
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free PEG 400 |
approximately 20%; |
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free glycerol |
approximately 3%. |
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For the purposes of the present invention, with the term solubilizer it is
intended a component in a mixture which is able to enhance the affinity to
the solvent of a molecule which is poorly soluble in that solvent.
As regards component (f), that is to say, the ester of a C1-C6
alkyl alcohol and C14-C18 saturated fatty acids, it
is preferably isopropyl myristate.
In the more preferred embodiment, the ratios range from about 9% to about
11% for cyclosporin, from about 9% to about 11% for poloxamer 407, from
about 13.5% to about 16.5% for ethanol, from about 4.5% to about 5.5% for
water, from about 31.5% to about 38.5% for caprylocaproyl
macrogol-8-glyceride and finally from about 22.5% to about 27.5% for
isopropyl myristate; even more preferably, they are about 10% for
cyclosporin, about 15% for ethanol, about 5% for water, about 10% for
poloxamer 407, about 35% for caprylocaproyl macrogol-8-glyceride and about
25% for isopropyl myristate.
The formulation according to the present invention can be obtained by
dissolving cyclosporin in ethanol at room temperature; the poloxamer 407,
the water, the caprylocaproyl macrogol-8-glyceride and, the isopropyl
myristate are then added, under stirring; after 10 to 20 minutes the
mixture is heated to a temperature from 25 to 55° C. (preferably from 25
to 45°, even more preferably from 25 to 35° C.) and maintained at that
temperature, under stirring, for a period from 80 to 120 minutes; then is
cooled to room temperature (approximately 21-24° C.) The thus-obtained
mixture is then filled into soft gelatin capsules under stirring. The
process for the preparation of the present formulation constitutes a
further subject of the invention.
Contrarily to the formulations known in the art, that according to the
present invention is neither an emulsion, nor a microemulsion, nor a
preconcentrate for microemulsions: it is a biphasic system consisting of
two visibly separated mixtures, one lipophilic and one hydrophilic,
wherein the concentration of cyclosporin is substantially equal between
the two phases.
The preferred pharmaceutical form for the administration of the medicament
is a soft gelatin single-dose capsule in which the liquid biphasic system
is homogeneously distributed.
Claim 1 of 20 Claims
1. A pharmaceutical formulation of compounds (a)-(f) for
oral administration comprising by weight:
(a) cyclosporin in the amount of from about 8 to about 12% of the total
weight;
(b) ethanol in the amount of from about 12 to about 18% of the total weight;
(c) a polyoxyethylene/polyoxypropylene block copolymer in the amount of from
about 8 to about 12% of the total weight;
(d) water in the amount of from about 4 to about 6% of the total weight;
(e) a solubilizer having an hydrophilic lipophilic balance (HLB) from 13 to
15 in the amount of from about 28 to about 40% of the total weight; and
(f) an ester of a C1-C6alkyl alcohol and a C14-C18
saturated fatty acid in the amount of from about 20 to about 30% of the
total weight.
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