U.S. patent application number 09/579372 was filed with the patent office on 2002-06-06 for a cyclosporin-containing composition in the form of a gelatin capsule.
Invention is credited to Ambuhl, Michael, Haberlin, Barbara, Luckel, Barbara, Meinzer, Armin.
Application Number | 20020068083 09/579372 |
Document ID | / |
Family ID | 10854362 |
Filed Date | 2002-06-06 |
United States Patent
Application |
20020068083 |
Kind Code |
A1 |
Ambuhl, Michael ; et
al. |
June 6, 2002 |
A CYCLOSPORIN-CONTAINING COMPOSITION IN THE FORM OF A GELATIN
CAPSULE
Abstract
This invention provides composition comprising a cyclosporin and
a carrier medium.
Inventors: |
Ambuhl, Michael; (Mohlin,
CH) ; Luckel, Barbara; (Lorrach, DE) ;
Haberlin, Barbara; (Riehen, CH) ; Meinzer, Armin;
(Buggingen, DE) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
10854362 |
Appl. No.: |
09/579372 |
Filed: |
May 26, 2000 |
Current U.S.
Class: |
424/456 |
Current CPC
Class: |
A61K 38/13 20130101;
A61P 39/00 20180101; A61P 37/06 20180101; A61P 37/00 20180101; A61K
9/1075 20130101; A61P 41/00 20180101; A61P 19/02 20180101; A61P
29/00 20180101; A61K 9/4858 20130101; A61P 43/00 20180101 |
Class at
Publication: |
424/456 |
International
Class: |
A61K 009/00; A61K
009/64 |
Foreign Application Data
Date |
Code |
Application Number |
May 28, 1999 |
GB |
9912476.0 |
Claims
1. A cyclosporin-containing composition in the form of a capsule
comprising a polyoxyethylene sorbitan fatty acid ester, a reaction
product of a natural or hydrogenated castor oil and ethylene oxide,
a sorbitan fatty acid ester, and ethanol.
2. A cyclosporin-containing composition in the form of a capsule
comprising: (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.
3. A hard gelatine capsule containing the composition of claim 1 or
2.
4. A composition according to claim 1, 2 or 3 comprising the
cyclosporin in an amount of 1 to 20% by weight of the composition
centre fill.
5. A composition according to any one of claims 2 to 4 comprising
the lipophilic component in an amount of 5 to 35% by weight of the
composition centre fill.
6. A composition according to any one of claims 2 to 5 comprising
the hydrophilic surfactant in an amount of 25 to 70% by weight of
the composition centre fill.
7. A composition according to any one of claims 2 to 6 comprising
the lipophilic surfactant in an amount of 5 to 35% by weight of the
composition centre fill.
8. A composition according to any one of claims 1 to 7 comprising
the ethanol in an amount of 1 to 20% by weight of the composition
centre fill.
9. A composition according to any preceding claim wherein the
cyclosporin is Cyclosporin A.
10. A composition according to any preceding claim wherein a
hydrophilic co-component is present.
11. A method of reducing the variability of bioavailability levels
of a cyclosporin for patients during cyclosporin therapy, said
method comprising orally administering a composition according to
any preceding claim.
12. A method of orally administering a pharmaceutical composition,
said method comprising orally administering to a patient in need of
cyclosporin therapy a composition according to any preceding
claim.
13. The use of a composition according to any preceding claim in
the manufacture of a medicament for the treatment and prevention of
an autoimmune or inflammatory condition or for the treatment and
prevention of transplant rejection or for the treatment of
multi-drug resistance.
14. A process for the production of a composition according to any
one of claims 1 to 12, which process comprises bringing
cyclosporin, ethanol and other components into intimate admixture.
Description
[0001] 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.
[0002] 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.
[0003] The present invention provides in one aspect a cyclosporin
composition in the form of a capsule comprising a
polyoxyethylene-sorbita- n-fatty acid ester, for example
polyoxyethylene (20) sorbitan monooleate such as that available
under the trade name Tween.RTM.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.RTM.RH40 or EL; a sorbitan fatty acid ester,
for example Span.RTM. 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.
[0004] The capsule composition may be preferably a hard gelatine
capsule.
[0005] As will be appreciated by a man skilled in the art the
present invention extends to variants.
[0006] For example the compositions of the invention may contain
lower alkanols, e.g. propylene glycol and polyethylene glycol.
[0007] A cyclosporin-containing composition of the invention in the
form of a capsule if desired may comprise:
[0008] (a) a hydrophilic surfactant,
[0009] (b) a lipophilic component,
[0010] (c) a lipophilic surfactant, and
[0011] (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.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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%.
[0017] 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.
[0018] 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.
[0019] 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.
[0020] 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.
[0021] 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.
[0022] 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.
[0023] 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.
[0024] 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.
[0025] In a further aspect the present invention provides a capsule
having a composition centre fill comprising
[0026] 1-20% by weight of Cyclosporin A,
[0027] 5-35% by weight of a lipophilic component, e.g.,
Miglyol.RTM.812 or Span.RTM.80,
[0028] 25-70% by weight of a hydrophilic surfactant, e.g.,
Cremophor.RTM.RH40 or EL and
[0029] Tween.RTM.80,
[0030] 5-35% by weight of a lipophilic surfactant, e.g.,
Span.RTM.80,
[0031] 1-20% by weight of ethanol.
[0032] 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].sup.8-Ciclosporin, and
[3'-deshydroxy-3'-keto-MeBmt].sup.1-[Val].sup.2-Ciclosporin.
Cyclosporin A is preferred.
[0033] In one aspect the present invention provides a composition
of the invention wherein the cyclosporin is Cyclosporin A.
[0034] 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.RTM. from e.g. ICI, UK, including the products Tween.RTM.
[0035] 20 [polyoxyethylene(20)sorbitanmonolaurate],
[0036] 21 [polyoxyethylene(4)sorbitanmonolaurate],
[0037] 40 [polyoxyethylene(20)sorbitanmonopalmitate],
[0038] 60 [polyoxyethylene(20)sorbitanmonostearate],
[0039] 65 [polyoxyethylene(20)sorbitantristearate],
[0040] 80 [polyoxyethylene(20)sorbitanonooleate],
[0041] 81 [polyoxyethylene(5)sorbitanmonooleate],
[0042] 85 [polyoxyethylene(20)sorbitantrioleate].
[0043] Especially preferred products of this class are Tween.RTM.40
(HLB value of about 15 to 16) and Tween.RTM.80 (HLB value of about
15).
[0044] 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 polyethylene glycol
component from the products. Various such surfactants are
commercially available. The hydrogenated-hydrogenated castor oils
available under the trade name Cremophor.RTM. are especially
suitable. Particularly suitable are Cremophor.RTM.RH40, which has a
saponification value of about 50 to 60, an acid value less than
about 1, a water content ( Fischer) less than about 2%, an
n.sub.D.sup.60 of about 1.453 to 1.457 and an HLB of about 14 to
16; and Cremophor.RTM.RH60, which has a saponification value of
about 40 to 50, an acid value less than about 1, an iodine value of
less than about 1, a water content (Fischer) of about 4.5 to 5.5%,
an n.sub.D.sup.60 of about 1.453 to 1.457 and an HLB of about 15 to
17. An especially preferred product of this class is
Cremophor.RTM.RH40. Also suitable are polyethyleneglycol castor
oils such as that available under the trade name Cremophor.RTM.EL,
which has a molecular weight (by steam osmometry) of about 1630, a
saponification value of about 65 to 70, an acid value of about 2,
an iodine value of about 28 to 32 and an n.sub.D.sup.25 of about
1.471.
[0045] Similar or identical products which may also be used are
available under the trade names Nikkol.RTM. (e.g. Nikkol.RTM.
HCO-40 and HCO-60), Mapeg.RTM. (e.g. Mapeg.RTM. CO-40h),
Incrocas.RTM. (e.g. Incrocas.RTM. 40), Tagat.RTM. (for example
polyoxyethylene-glycerol-fatty acid esters e.g. Tagat.RTM. RH40;
and Tagat.RTM. TO, a polyoxyethylene-glycerol-triol- eate having a
HLB value of 11.3; Tagat.RTM. RH40 is preferred) and Simulsol OL-50
(PEG-40 castor oil, having a saponification value of about 55 to
65, an acid value of max. 2, an iodine value of 25 to 35, a water
content of max. 8%, and an HLB of about 13, available from Seppic).
These surfactants are further described in Fiedler "Lexikon der
Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete",
Editio Cantor Verlag Aulendorf, Aulendorf, 4th revised and expanded
edition (1996), and "Handbook of Pharmaceutical Excipients", 2nd
Edition, Editors A. Wade and P. J. Weller (1994), Joint publication
of American Pharmaceutical Association, Washington, USA and The
Pharmaceutical Press, London, England.
[0046] The polyoxyethylene-sorbitan-fatty acid ester and the
reaction product of a natural or hydrogenated castor oil and
ethylene oxide may e.g comprise 25-70% by weight of the centre
fill.
[0047] Preferred sorbitan fatty acid esters include sorbitan mono
C.sub.12-18 fatty acid esters, or sorbitan tri C.sub.12-18 fatty
acid esters as known and commercially available under the trade
mark Span.RTM. from e.g. ICI. An especially preferred product of
this class is e.g. Span.RTM.20 (sorbitan monolaurate, HLB value of
about 8) or Span.RTM.80 (sorbitan monooleate, HLB value of about 4)
(Fiedler, loc. cit., 2, p. 1430; Handbook of Pharmaceutical
Excipients, loc. cit., page 473).
[0048] The sorbitan fatty acid esters may e.g comprise 10-70% by
weight of the centre fill. Examples of polyalkylene glycol
materials are polyethylene glycols, in particular polyethylene
glycols having a molecular weight of from ca. 500 to ca. 4,000,
e.g. from ca. 1,000 to ca. 2,000.
[0049] In a further alternative aspect of the invention there are a
plurality of alkanols. For example the ethanol may be replaced or
partially replaced by an alkanol which may be hydrophilic, e.g.
selected from Transcutol (which has the formula
C.sub.2H.sub.5-[O-(CH.sub.2).sub.2- ].sub.2-OH), Glycofurol (also
known as tetrahydrofurfuryl alcohol polyethylene glycol ether), and
1,2-propylene glycol.
[0050] Quantities of liquid and/ or solid polyethylene glycols,
e.g. polyethylene glycol (PEG) 3350 or PEG 1450, as known and
commercially available from e.g. Union Carbide, USA, may also be
included in the composition of the invention.
[0051] GB 2 222 770 A discloses a wide variety of lipophilic
components suitable for use in a composition of the invention.
Typical examples for lipophilic components are:
[0052] (i) medium chain fatty acid triglycerides, e.g.
C.sub.6-C.sub.12, e.g. Miglyol.RTM. 812, and/or
[0053] (ii) mixed mono-, di-, tri-glycerides, e.g.
C.sub.6-C.sub.20, e.g. C.sub.16-C.sub.18, e.g. Maisine.RTM.,
and/or
[0054] (iii) transesterified ethoxylated vegetable oils, e.g.
Labrafil.RTM., and/or
[0055] (iv) propylene glycol mono fatty acid esters, e.g.
C.sub.14-C.sub.18, e.g. propylene glycol hydroxystearate, propylene
glycol isostearate, propylene glycol ricinoleate, propylene glycol
stearate, and/or
[0056] (v) propylene glycol di fatty acid esters, e.g.
C.sub.6-C.sub.20, e.g. C.sub.8-C.sub.12, e.g. propylene glycol
dicaprylate, e.g. Miglyol.RTM.840, or propylene glycol dilaurate,
and/or
[0057] (vi) esterified compounds of fatty acid and primary alcohol,
e.g. C.sub.8-C.sub.20 fatty acids and C.sub.2 C.sub.3 alcohols,
e.g. ethyl linoleate, and/or
[0058] (vii) mono- and/or di-glyceride, e.g. a mixture of mono- and
di-glycerides with e.g. a monoglyceride of C.sub.18 fatty acid as
its main component, e.g. GMOrphic.RTM.-80 or Tegin.RTM. O.
[0059] Preferred lipophilic components are medium chain fatty acid
triglycerides, mixed mono-,di-, tri-glycerides, sorbitan fatty acid
esters and transesterified ethoxylated vegetable oils. Accordingly,
in one aspect the present invention provides a composition of the
invention wherein the lipophilic component is a medium chain fatty
acid triglyceride, or a sorbitan fatty acid ester.
[0060] In another aspect the lipophilic component may comprise a
medium chain triglyceride and/or a mono-and di-glyceride or a
mixture thereof.
[0061] As the medium chain fatty acid triglyceride in the
lipophilic component a triglyceride of saturated fatty acid having
6 to 12, e.g. 8 to 10, carbon atoms can be used. Suitable medium
chain fatty acid triglycerides are those known and commercially
available under the trade names Acomed.RTM., Myritol.RTM.,
Captex.RTM., Neobee.RTM.M 5 F, Miglyol.RTM.810, Miglyol.RTM.812,
Miglyol.RTM.818, Mazol.RTM., Sefsol.RTM.860, Sefsol.RTM.870;
Miglyol.RTM.812 being the most preferred. Miglyol.RTM.812 is a
fractionated coconut oil comprising caprylic-capric acid
triglycerides and having a molecular weight of about 520 Daltons.
Fatty acid composition =C.sub.6 max. about 3%, C.sub.8 about 50 to
65%, C.sub.10 about 30 to 45%, C.sub.12 max 5%; acid value about
0.1; saponification value about 330 to 345; iodine value max 1.
Miglyol.RTM. 812 is available from Condea. Neobee.RTM. M 5 F is a
fractionated caprylic-capric acid triglyceride available from
coconut oil; acid value max. 0.2; saponification value about 335 to
360; iodine value max 0.5, water content max. 0,15%, D..sup.20
0,930-0,960, n.sub.D.sup.20 1,448-1,451 (manufacturer information).
Neobee.RTM. M 5 F is available from Stepan Europe.
[0062] These triglycerides are described in Fiedler, H. P., loc
cit, the contents of which are hereby incorporated by
reference.
[0063] In a further alternative aspect triglycerides suitably
comprise at least 5% but less than about 25%, based on the total
weight of the lipophilic component. More preferably from about 7.5
to about 20% (for example from about 9 to 12%) triglycerides are
present. Suitable mixed mono-, di-, tri-glycerides are those known
and commercially available under the trade name Maisine.RTM. from
Gattefosse. They are transesterification products of corn oil and
glycerol.
[0064] In a composition of the invention, in a further alternative
aspect the constitutional ratio of the lipophilic component to
cyclosporin is preferably 1-30:1 and more preferably 2-30:1, on the
basis of weight.
[0065] It is to be appreciated that the components may be complex
mixtures containing side products or unreacted starting products
involved in the preparation thereof, e.g. surfactants made by
polyoxyethylation may contain another side product, e.g.
polyethylene glycol. A surfactant having a hydrophilic-lipophilic
balance (HLB) value of 8 to 17 is conveniently present. The HLB
value is preferably the mean HLB value.
[0066] According to the invention a hydrophilic surfactant may be
mixed with a lipophilic surfactant. Under a hydrophilic surfactant
is to be understood a surfactant having an HLB value of greater
than or equal to 10, whereas under a lipophilic surfactant is to be
understood a surfactant having an HLB value of less than 10.
[0067] A hydrophilic surfactant selected preferably has a
hydrophilic-lipophilic balance (HLB) of greater than or equal to
10, for example Cremophor.RTM.RH40 or EL.
[0068] One component selected preferably has a
hydrophilic-lipophilic balance (HLB) of less than 10, for example
Span.RTM.80.
[0069] If desired the relative proportion of the lipophilic
components, the surfactants and the ethanol lie within the
"microemulsion" region on a standard three-way plot. The
compositions thus obtained are microemulsion preconcentrates of
high stability that are capable, on addition to water, of providing
microemulsions having a mean particle size of <200 nm.
[0070] Standard three way plots, e.g. phase diagrams, can be
generated in a conventional manner as described in e.g. GB patent
publication no. 2 222 770 or WO 96/13273.
[0071] The emulsion, e.g. microemulsion, preconcentrate
compositions, e.g. those in the examples hereinafter, may show good
stability characteristics as indicated by standard stability
trials, for example having a shelf life stability of up to one, two
or three years, and even longer. The microemulsion preconcentrate
compositions of this invention produce stable microemulsions, e.g.
for up to one day or longer, e.g. one day.
[0072] The composition of the invention may also include further
additives or ingredients, for example antioxidants (such as
ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy
toluene (BHT) and tocopherols) and/or preserving agents. In a
further alternative aspect these additives or ingredients may
comprise about 0.05 to 1% by weight of the total weight of the
composition centre fill. The composition of the invention may also
include sweetening or flavoring agents in an amount of up to about
2.5 or 5% by weight based on the total weight of the composition
centre fill. Preferably the antioxidant is .alpha.-tocopherol
(vitamin E).
[0073] Details of excipients for use in a composition of the
invention are described in Fiedler, H. P., loc cit; "Handbook of
Pharmaceutical Excipients", loc cit; or may be obtained from the
relevant manufacturers, the contents of which are hereby
incorporated by reference.
[0074] Any carbon chain not otherwise specified herein conveniently
contains 1 to 18 carbon atoms, e.g. 10 to 18 carbon atoms, when a
terminal group or 2 or 3 carbon atoms when a polymer moiety.
[0075] The compositions of the invention exhibit especially
advantageous properties when administered orally; for example in
terms of consistency and high level of bioavailability obtained in
standard bioavailability trials, e.g. 2 to 4 times higher than
known emulsions. These trials are performed in animals e.g. rats or
dogs or healthy volunteers using HPLC or a specific or nonspecific
monoclonal kit to determine the level of the cyclosporin in the
blood. For example, the composition of Example 1 administered p.o.
to dogs may give surprisingly high C.sub.max values as detected by
ELISA using a specific monoclonal antibody.
[0076] In one aspect the present invention provides a method of
orally administering a pharmaceutical composition, said method
comprising orally administering to a patient in need of
cyclosporin-therapy a composition of the invention.
[0077] Pharmacokinetic parameters, for example absorption and blood
levels, also become surprisingly more predictable and problems in
administration with erratic absorption may be eliminated or
reduced. Additionally the compositions of the invention are
effective with tenside materials, for example bile salts, being
present in the gastro-intestinal tract. That is, the compositions
of the invention are fully dispersible in aqueous systems
comprising such natural tensides and thus capable of providing
microemulsion systems in situ which are stable and do not exhibit
precipitation of the active agent or other disruption of fine
particulate structure. The function of the compositions of the
invention upon oral administration remain substantially independent
of and/or unimpaired by the relative presence or absence of bile
salts at any particular time or for any given individual. The
compositions of the invention reduce variability in inter- and
intra-patient dose response.
[0078] In one aspect the present invention provides a method of
reducing the variability of bioavailability levels of a cyclosporin
for patients during cyclosporin therapy, said method comprising
orally administering an oral pharmaceutical composition according
to the present invention.
[0079] In a further alternative aspect the invention also provides
a process for the production of a composition of the invention,
which process comprises bringing cyclosporin, ethanol and other
components into intimate admixture. When required, the composition
may be compounded into unit dosage form, for example filling the
composition into gelatine capsules.
[0080] Optionally further components or additives may be mixed with
the components with or after addition of active agent.
[0081] The composition may be combined with water or an aqueous
solvent medium such that an emulsion, e.g. microemulsion, is
obtained.
[0082] The utility of all the pharmaceutical compositions of the
invention may be observed in standard clinical tests in, for
example, known indications of cyclosporin using dosages giving
equivalent blood levels of cyclosporin; for example using dosages
in the range of 2.5 mg to 1000 mg of active agent per day for a 75
kilogram mammal, e.g. adult and in standard animal models. The
increased bioavailability of the cyclosporin provided by the
compositions may be observed in standard animal tests and in
clinical trials, e.g. as described above.
[0083] The optimal dosage of cyclosporin to be administered to a
particular patient must be considered carefully as individual
response to and metabolism of the cyclosporin may vary. It may be
advisable to monitor the blood serum levels of the active agent by
radioimmunoassay, monoclonal antibody assay, or other appropriate
conventional means.
[0084] Cyclosporin dosages may be e.g. 25 to 1000 mg per day
(preferably 50 mg to 500 mg) The compositions of the invention are
preferably compounded in unit dosage form, for example by filling
them into orally administrable capsule shells. The capsule shells
may be soft or hard gelatine capsule shells. Where the composition
of the invention is in unit dosage form, each unit dosage will
suitably contain between 10 and 100 mg of the cyclosporin, more
preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg.
Such unit dosage forms are suitable for administration 1 to 5 times
daily depending upon the particular purpose of therapy, the phase
of therapy and the like.
[0085] However, if desired, the compositions of the invention may
be in drink solution form and may include water or any other
aqueous system, to provide emulsion, e.g. microemulsion, systems
suitable for drinking.
[0086] The compositions of the invention are particularly useful
for:
[0087] a) treatment and prevention of organ or tissue transplant
rejection, for example for the treatment of the recipients of
heart, lung, combined heart-lung, liver, kidney, pancreatic, skin
or corneal transplants. The compositions of the invention are also
indicated for the prevention of graft-versus-host disease, such as
sometimes occurs following bone marrow transplantation;
[0088] b) treatment and prevention of autoimmune disease and of
inflammatory conditions, in particular inflammatory conditions with
an aetiology including an autoimmune component such as arthritis
(for example rheumatoid arthritis, arthritis chronic progrediente
and arthritis deformans) and rheumatic diseases; and
[0089] c) treatment of multi-drug resistance (MDR).
[0090] In a further aspect the present invention provides the use
of a composition of the invention in the manufacture of a
medicament for the treatment and prevention of an autoimmune or
inflammatory condition or for the treatment and prevention of
transplant rejection or for the treatment of multi-drug
resistance.
EXAMPLES
[0091] Following is a description by way of example only of
compositions of the invention. Unless otherwise indicated,
components are shown in % by weight based on each composition
centre fill.
[0092] Miglyol.RTM.812 is from the Condea Company, Germany.
[0093] Cremophor.RTM.RH40 is from BASF, Germany.
[0094] Span.RTM.80 is from ICI, UK.
[0095] Tween.RTM.80 is from ICI, UK.
EXAMPLE 1
[0096] A composition is made up with the following components:
[0097] 40% by volume of a Cremophor.RTM.RH40
[0098] 32% by volume of a Miglyol.RTM.812
[0099] 8% by volume of Span.RTM.80
[0100] 10% of volume cyclosporin A
[0101] 10% of volume ethanol
EXAMPLE 2
[0102] A composition is made up with the following components:
[0103] 56% by weight of Cremophor.RTM.EL
[0104] 16% of Miglyol.RTM.812
[0105] 8% of Span.RTM.80
[0106] 10% of cyclosporin A
[0107] 10% of ethanol
[0108] Other Examples may be made by omitting Miglyol.RTM.812 and
replacing the Miglyol.RTM.812 by Span.RTM.80.
[0109] Further Examples may be made by replacing part (e.g. 30 to
70%) of the Cremophor.RTM.EL by an equivalent amount of
Tween.RTM.80.
[0110] These compositions may be encapsulated in hard and soft
gelatine capsules.
[0111] The examples illustrate compositions useful for example in
the prevention of transplant rejection or for the treatment of
autoimmune disease, on administration of from 1 to 5 unit
dosages/day at a dose of 2 to 5 mg/kg per day.
[0112] On visual inspection after dilution, each of the
compositions may form a clear and stable microemulsion or
emulsion.
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