U.S. patent application number 10/781069 was filed with the patent office on 2004-08-19 for oil-free pharmaceutical compositions containing cyclosporin a.
Invention is credited to Haeberlin, Barbara, Meinzer, Armin.
Application Number | 20040161458 10/781069 |
Document ID | / |
Family ID | 26310891 |
Filed Date | 2004-08-19 |
United States Patent
Application |
20040161458 |
Kind Code |
A1 |
Meinzer, Armin ; et
al. |
August 19, 2004 |
Oil-free pharmaceutical compositions containing cyclosporin A
Abstract
The present invention provides a hard gelatine capsule
containing a pharmaceutical composition comprising cyclosporin A in
a mixture with a surfactant of HLB value at least 10, substantially
free of any oil and when a hydrophilic phase is present, the
hydrophilic phase being a polyethylene glycol and/or a lower
alkanol provided that any lower alkanol present is present in less
than 12% of the total weight of the composition absent the hard
gelatine capsule.
Inventors: |
Meinzer, Armin; (Buggingen,
DE) ; Haeberlin, Barbara; (Riehen, CH) |
Correspondence
Address: |
NOVARTIS
CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 430/2
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
26310891 |
Appl. No.: |
10/781069 |
Filed: |
February 18, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10781069 |
Feb 18, 2004 |
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09992584 |
Nov 6, 2001 |
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6723339 |
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09992584 |
Nov 6, 2001 |
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09284391 |
Apr 13, 1999 |
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6475519 |
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09284391 |
Apr 13, 1999 |
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PCT/EP98/00453 |
Jan 28, 1998 |
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Current U.S.
Class: |
424/456 ;
514/20.5 |
Current CPC
Class: |
A61P 29/00 20180101;
A61K 9/4866 20130101; A61P 37/00 20180101; Y10S 514/962 20130101;
A61P 37/06 20180101; A61K 9/4858 20130101; A61K 38/13 20130101;
A61P 19/02 20180101; A61P 37/02 20180101; A61K 9/1075 20130101 |
Class at
Publication: |
424/456 ;
514/011 |
International
Class: |
A61K 038/13; A61K
009/64 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 30, 1997 |
GB |
9701881.6 |
Feb 7, 1997 |
GB |
9702594.4 |
Claims
1. A hard gelatine capsule containing a pharmaceutical composition
comprising cyclosporin A in a mixture with a surfactant of HLB
value at least 10, substantially free of any oil and when a
hydrophilic phase is present, the hydrophilic phase being a
polyethylene glycol and/or a lower alkanol provided that any lower
alkanol present is present in less than 12% of the total weight of
the composition absent the hard gelatine capsule.
2. A hard gelatine capsule as defined in claim 1 wherein the lower
alkanol present is present in less than 8% of the total weight of
the composition absent the hard gelatine capsule.
3. A hard gelatine capsule as defined in claim 1 or 2 wherein the
surfactant is a polyoxyethylene-sorbitan-fatty acid ester.
4. A hard gelatine capsule as defined in any preceding claim
further comprising a thickening agent which is capable of
dissolving in the stomach juices or water.
5. A hard gelatine capsule as defined in any preceding claim
wherein cyclosporin is present in an amount of from 10 to 25% by
weight based on the total weight of the composition absent the hard
gelatine capsule.
6. A hard gelatine capsule as defined in any preceding claim
comprising further excipients apart from the surfactant and as
thickening agent in an amount of from 0.1 to 5% by weight based on
the total weight of the composition absent the hard gelatine
capsule.
7. A hard gelatine capsule as defined in any preceding claim
wherein the hydrophilic phase is present.
8. A hard gelatine capsule as defined in claim 7 claim wherein the
hydrophilic phase is polyethylene glycol and/or propylene
glycol.
9. A hard gelatine capsule as defined in claim 7 wherein the
hydrophilic phase is polyethylene glycol and/or ethanol.
10. A hard gelatine capsule as defined in claim 1 containing a
hydrophilic phase which comprises polyethylene glycol and/or a
lower alkanol as defined in claim 1 and when any polyethylene
glycol is present this polyethylene glycol is liquid when heated to
37.degree. and the surfactant is a polyoxyethylene sorbitan fatty
acid ester or a polyethyloxylated castor oil or a polyoxyethylene
fatty acid ester.
11. A hard gelatine capsule as defined in claim 10 wherein the
pharmaceutical composition is semi-solid or liquid with the
cyclosporin dissolved therein.
Description
[0001] The present invention relates to novel pharmaceutical
compositions comprising cyclosporin A, also known as ciclosporine,
as active agent (hereinafter referred to as cyclosporin).
[0002] 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.
[0003] These formulations are available in the form of a drink
solution or a soft gelatine capsule. Such soft gelatine capsules
require special manufacturing techniques.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.degree. C. e.g. having a M.W. 200 to 600 daltons.
[0010] 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.
[0011] 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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] The present compositions are of a small volume, yet stable,
thereby increasing patient compliance.
[0016] The surfactant is preferably approved by the FDA, e.g. a
GRAS surfactant, e.g.
[0017] 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.sub.D.sup.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.sub.D.sup.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.sub.D.sup.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.sub.2O content (%,
KF)=ca. 0.03;
[0018] 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 Muller, Tenside, Year 3, Issue 2, p. 37-45.
[0019] Preferably the surfactant is a polyethoxylated hydrogenated
castor oil Cremophor RH.
[0020] 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
[0021] 20 [polyoxyethylene(20)sorbitanmonolaurate],
[0022] 40 [polyoxyethylene(20)sorbitanmonopalmitate],
[0023] 60 [polyoxyethylene(20)sorbitanmonostearate],
[0024] 80 [polyoxyethylene(20)sorbitanmonooleate],
[0025] 65 [polyoxyethylene(20)sorbitantristearate],
[0026] 85 [polyoxyethylene(20)sorbitantrioleate],
[0027] 21 [polyoxyethylene(4)sorbitanmonolaurate],
[0028] 61 [polyoxyethylene(4)sorbitanmonostearate], and
[0029] 81 [polyoxyethylene(5)sorbitanmonooleate].
[0030] Especially preferred products of this class for use in the
compositions of the invention are the above products Tween 40 and
Tween 80;
[0031] 1.3 Polyoxyethylene fatty acid esters, e.g. produced by
reacting fatty acids with ethylene oxide, e.g. polyoxyl 40
stearate, for example polyoxyethylene stearic acid esters of the
type known and commercially available under the trade name Myrj
(c.f. Fiedler, loc. cit., p. 834) as well as polyoxyethylene fatty
acid esters known and commercially available under the trade name
Cetiol HE. (c.f. Fiedler, loc. cit., p. 284); an especially
preferred product of this class for use in the compositions of the
invention is the product Myrj 52 having a D.sup.25=ca. 1.1.,
m.p.=ca. 40-44 C., an HLB=ca. 16.9., an acid no.=ca. 0-1 and a
saponification no.=ca. 25-35;
[0032] 1.4 Polyethoxylated glyceryl fatty acid mono esters, e.g. of
lauryl, stearic, oleyl, or isostearic acid, e.g. those obtainable
under the name Tagat O or L.
[0033] 1.5 Polyoxyethylene mono esters of a saturated C.sub.10 to
C.sub.22, e.g. C.sub.18 substituted e.g. hydroxy fatty acid; e.g.
12 hydroxy stearic PEG acid, e.g. of PEG about e.g. 600-900 e.g.
660 daltons MW, e.g. SOLUTOL H515 from BASF, Ludwigshafen,
Germany.
[0034] 1.6 Polyoxyethylene-polyoxypropylene co-polymers,
poloxamers, e.g. of the type known and commercially available under
the trade names Pluronic and Emkalyx (c.f. Fiedler, loc. cit., pp.
956-958). An especially preferred product of this class for use in
the compositions of the invention is the product Pluronic F68
(poloxamer 188).
[0035] 1.7 Propylene glycol mono- and di-fatty acid esters such as
propylene glycol dicaprylate, propylene glycol dilaurate, propylene
glycol hydroxystearate, propylene glycol isostearate, propylene
glycol laurate, propylene glycol ricinoleate, propylene glycol
stearate and so forth (c.f. Fiedler, loc. cit., pp. 1013 et seq.).
Especially preferred is propylene glycol caprylic-capric acid
diester as known and commercially available under the trade name
Miglyol 840 (c.f. Fiedler, loc. cit., p. 809). Miglyol 840 has a
fatty acid content=C.sub.6 max. ca. 3%, C.sub.8 ca. 65-80%,
C.sub.10 ca. 15-30%, C.sub.12 max. 3%. Acid no.=max. 0.1, iodine
no.=ca. 320-340, iodine no.=max. 1.
[0036] Examples of ionic surfactants include:
[0037] 2.1 Dioctylsuccinate, dioctylsodiumsulfosuccinate,
di-[2-ethylhexyl]-succinate or sodium lauryl sulfate.
[0038] 2.2 Phospholipids, in particular lecithins (c.f. Fiedler,
loc. cit., pp. 731-733). Lecithins suitable for use in the
compositions of the invention include, in particular, soya bean
lecithins.
[0039] 2.3 Bile salts, e.g. alkali metal salts, for example sodium
taurocholate.
[0040] Examples of further lipophilic surfactants for use as
surfactant component are, e.g.:
[0041] 2.1 Trans-esterification products of natural vegetable oil
triglycerides and polyalkylene polyols. Such trans-esterification
products are known from the art and may be obtained e.g. in
accordance with the general procedures described in U.S. Pat. No.
3,288,824. They include trans-esterification products of various
natural (e.g. non-hydrogenated) vegetable oils for example, maize
oil, kernel oil, almond oil, ground nut oil, olive oil and palm oil
and mixtures thereof with polyethylene glycols, in particular
polyethylene glycols having an average molecular weight of from 200
to 800. Preferred are products obtained by trans-esterification of
2 molar parts of a natural vegetable oil triglyceride with one
molar part of polyethylene glycol (e.g. having an average molecular
weight of from 200 to 800). Various forms of trans-esterification
product of the class defined are known and commercially available
under the trade name Labrafil [see Fiedler, loc. cit., 707].
Especially useful as components of the compositions of the
invention are the products: Labrafil M 1944 CS, a
trans-esterification product of kernel oil and polyethylene glycol
having an acid no.=ca. 2, a saponification no. ca. 145-175 and an
iodine no.=ca. 60-90; and Labrafil M 2130 CS, a
trans-esterification product of a C.sub.12- to C.sub.18-glyceride
and polyethylene glycol having a melting point=ca. 35-40 C., an
acid no.=<2, a saponification no.=ca. 185-200 and an iodine
no.=<3;
[0042] 2.2 Mono-, di- and mono/di-glycerides, especially
esterification products of caprylic or capric acid with glycerol.
Preferred products of this class are e.g. those comprising or
consisting mainly or essentially of caprylic/capric acid mono- and
di-glycerides such as are commercially available under the trade
name Imwitor (c.f. loc. cit., pp. 645). A particularly suitable
product of this class for use in the compositions of the invention
is the product Imwitor 742, which is the esterification product of
a mixture of ca. 60 p.p.w. caprylic acid and ca. 40 p.p.w. capric
acid with glycerol. Imwitor 742 is typically a yellowish
crystalline mass, liquid at ca. 26 C.; acid no.=max. 2; iodine
no.=max. 1; saponification no.=ca. 235-275: % monoglycerides=ca.
40-50%; free glycerol=max. 2%; m.p.=ca. 24-26 C.;
unsaponifiables=0.3% max.; peroxide no.=max. 1;
[0043] 2.3 Sorbitan fatty acid esters e.g. of the type known and
commercially available under the trade name Span, for example
including sorbitan-monolauryl, -monopalmityl, -monostearyl,
-tristearyl, -monooleyl and -trioleyl esters--(c.f. Fiedler, loc.
cit., pp. 1139-1140);
[0044] 2.4 Pentaerythritol fatty acid esters and polyalkylene
glycol ethers, for example pentaerythrite- -dioleate, -distearate,
-monolaurate, -polyglycol ether and -monostearate as well as
pentaerythrite-fatty acid esters (c.f. Fiedler, loc. cit. pp.
923-924);
[0045] 2.5 Monoglycerides, e.g. glycerol monooleate, glycerol
monopalmitate and glycerol monostearate, for example as known and
commercially available under the trade names Myvatex, Myvaplex and
Myverol (c.f. Fiedler, loc. cit., pp. 836), and acetylated, e.g.
mono-and di-acetylated monoglycerides, for example as known and
commercially available under the trade name Myvacet (c.f. Fiedler,
loc. cit., pp. 835);
[0046] 2.6 Glycerol triacetate or (1,2,3)-triacetin (c.f. Fiedler,
loc. cit., pp. 952); and
[0047] 2.7 Sterols and derivatives thereof, for example
cholesterols and derivatives thereof, in particular phytosterols,
e.g. products comprising sitosterol, campesterol or stigmasterol,
and ethylene oxide adducts thereof, for example soya sterols and
derivatives thereof, such as known under the trade name Generol
(c.f. Fiedler loc. cit., p.p. 554 and 555) in particular the
products Generol 122, 122 E5, 122 E10, and 122 E25.
[0048] It is to be appreciated that surfactants may be complex
mixtures containing side products or unreacted starting products
involved in the preparation thereof made by e.g. polyoxyethylation
may contain another side product, e.g. polyethylene glycol.
[0049] The compositions of the invention may also comprise a
thickening agent (also referred to as a viscosity increasing
agent).
[0050] Suitable thickening agents may be of those known and
employed in the art, including e.g. pharmaceutically acceptable
polymeric materials and inorganic thickening agents which enable
the compositions to be filled easily and resists leakage, e.g.
thixotropic agents. These should also have the property of
dissolving quickly (e.g. within 5 minutes) in the stomach juices or
water or at pH 1 to 2, for example, of the following types:
[0051] 3.1 Water soluble tocopheryl polyethylene glycol succinic
acid esters (TPGS), e.g. with a polymerisation number ca 1000, e.g.
available from Eastman Fine Chemicals Kingsport, Texas, USA.
[0052] 3.2 Water soluble celluloses and cellulose derivatives
including; alkyl celluloses, e.g. methyl-, ethyl- and
propyl-celluloses; hydroxyalkyl-celluloses, e.g.
hydroxypropyl-celluloses and hydroxypropylalkyl-celluloses such as
hydroxypropyl-methyl-celluloses; acylated celluloses, e.g.
cellulose-acetates, cellulose-acetatephthallate- s,
cellulose-acetatesuccinates and hydroxypropylmethyl-cellulose
phthallates; and salts thereof such as sodium-carboxymethyl-
-celluloses. Examples of such products suitable for use in
accordance with the present invention are those known and
commercially available, e.g. under the trade names Klucel and
Methocel (c.f. Fiedler, loc. cit., pp. 688 and 790),
[0053] 3.3 Water soluble polyvinylpyrrolidones, including for
example poly-N-vinylpyrrolidones and vinylpyrrolidone co-polymers
such as vinylpyrrolidone-vinylacetate co-polymers, especially of
low molecular weight. Examples of such compounds suitable for use
in accordance with the present invention are those known and
commercially available, e.g. under the trade name Kollidon (or, in
the USA, Povidone) (c.f. Fiedler, loc. cit., pp. 694-696), in
particular the products Kollidon 30 and 90;
[0054] 3.4 Low amounts of inorganic thickening agents such as
atapulgite, bentonite and silicates including hydrophilic silicon
dioxide products, e.g. alkylated (for example methylated) silica
gels, in particular colloidal silicon dioxide products as known and
commercially available under the trade name Aerosil [c.f. Handbook
of Pharmaceutical Excipients, loc. cit., p.p. 253-256] in
particular the products Aerosil 130, 200, 300, 380, O, OX 50, TT
600, MOX 80, MOX 170, LK 84 and the methylated Aerosil R 972.
[0055] The compositions may also include one or more further
ingredients e.g. in an amount of from 0.1 to 5%, in particular
anti-oxidants [e.g. ascorbyl palmitate, butyl hydroxy anisole
(BHA), butyl hydroxy toluene (BHT) and tocopherols, e.g.
-tocopherol (vitamin E)], flavouring agents and so forth. Use of an
anti-oxidant, in particular a tocopherol, is particularly
advantageous.
[0056] The relative proportion of ingredients in the compositions
of the invention will, of course, vary considerably depending on
the particular type of composition concerned. Determination of
workable proportions in any particular instance will generally be
within the capability of the man skilled on the art. All indicated
proportions and relative weight ranges described below are
accordingly to be understood as being indicative of preferred or
individually inventive teachings only and not as not limiting the
invention in its broadest aspect.
[0057] a) The cyclosporin will generally be present in an amount of
from 5 to 30%, suitably from about 10 to about 25% by weight based
on the total weight of the composition absent the hard gelatine
capsule.
[0058] b) Any polyethylene glycol amount when present will
generally be present in an amount of from about 15% to about 30%,
by weight based on the total weight of the composition absent the
hard gelatine capsule;
[0059] c) Any further excipient apart from the surfactant and as
thickening agent is preferably present from an amount from 0.1% to
5%, by weight based on the total weight of the composition absent
the hard gelatine capsule.
[0060] The compositions above may additionally include a thickening
agent, though, as previously indicated, this will generally be less
preferred. The amount of thickening agent present may vary e.g.
depending on the required consistency of the end product, e.g.
whether it is to be in a thickened flowable form, for example for
filling into a capsule. The amount will of course also depend on
the nature of the thickening agent chosen. In general the
thickeners components (4), when present will be present in an
amount of up to about 25% by weight based on the total weight of
the composition, more suitably in an amount of up to about 15 or
20% by weight, e.g. in an amount of from 0.5 or 5 up to 15 or 20%
by weight based on the total weight of the composition.
[0061] The compositions may also include further additives or
ingredients, e.g. as hereinbefore described. In particular they may
comprise antioxidants, e.g. in an amount of up to about 0.5 or 1%
by weight based on the total weight of the composition, and
sweetening or flavouring agents, e.g. in an amount of up to about
2.5 or 5% by weight based on the total weight of the
composition.
[0062] Preferably no other excipients are present. Thus the volume
may be kept low and the composition may be filled into a capsule
size, 1, 2 or 3.
[0063] The compositions have been found to exhibit especially
advantageous properties when administered orally, e.g. in terms of
both the consistency and high level of bioavailability achieved as
defined in standard tests in humans or e.g. beagle dogs. In
particular, and in contrast with other galenic systems, e.g. as
known from the art, it has been found that such compositions are
compatible with tenside materials, e.g. bile salts, present in the
gastrointestinal tract. That is, they are fully dispersible in
aqueous systems comprising such natural tensides and are thus
capable of providing microemulsion systems in situ which are stable
and do not exhibit precipitation or other disruption of fine
particulate structure. Function of such systems on oral
administration remains independent of and/or unimpaired by the
relative presence or absence of bile salts at any particular time
or for any given individual. Such compositions accordingly
represent an especially preferred embodiment of the invention. The
bioavailability characteristics may be observed in standard
clinical trials or in dogs using standard radioimmunoassays for
cyclosporins. Preferred capsules have a short Tmax. Preferably the
compositions form, on dilution with water, micellar solutions, in
which one may be able to detect droplets of, e.g. from 10 to 150 nm
in diameter.
[0064] The compositions above will preferably be compounded in
orally administerable hard gelatine capsule shells to be unit
dosage forms. Where the compositions are in unit dosage form, each
unit dosage will suitably contain between about 5 or 10 and about
200 mg cyclosporin, more suitably between about 15 or 25 and about
150 mg, e.g. 25, 50 or 100 mg cyclosporin. Thus unit dosage forms
in accordance with the invention, suitable for administration
1.times., 2.times. or 3.times. up to 5.times. daily (e.g. depending
on the particular purpose of therapy, the phase of therapy etc . .
. ) will appropriately comprise e.g. about 25 mg, about 50 mg or
about 100 mg cyclosporin per unit dosage.
[0065] Further details of the excipients are given in Fiedler.
[0066] The following non-limitative Examples illustrate the
invention.
EXAMPLE 1
[0067]
1 Hard gelatine capsules Cyclosporin A 100 mg Surfactant (Cremophor
300 mg RH or Tween)
EXAMPLE 2
[0068] As for Example 1 but containing additionally 10 mg of
TPGS.
[0069] Each composition shows a bioavailability profile in humans
and dogs similar to that of NEORAL, e.g. in terms of AUC, Tmax and
Cmax.
[0070] The hard gelatine capsules are stable for at least 2 years
and maintain an excellent condition.
EXAMPLE 3
[0071]
2 Hard gelatine capsules Cyclosporin A 50 mg Surfactant (Cremophor
300 mg RH or Tween) 1,2-Propylene glycol or Ethanol 8% by weight of
the total composition
EXAMPLE 4
[0072]
3 Hard gelatine capsules Cyclosporin A 50 mg Surfactant (Cremophor
300 mg RH or Tween) PEG 300 30% by weight of the total
composition
* * * * *