U.S. patent application number 10/094781 was filed with the patent office on 2003-06-05 for pharmaceutical composition.
Invention is credited to Hauer, Birgit, Meinzer, Armin, Posanski, Ulrich, Vonderscher, Jacky.
Application Number | 20030104990 10/094781 |
Document ID | / |
Family ID | 27540011 |
Filed Date | 2003-06-05 |
United States Patent
Application |
20030104990 |
Kind Code |
A1 |
Hauer, Birgit ; et
al. |
June 5, 2003 |
Pharmaceutical composition
Abstract
Pharmaceutical compositions comprising a cyclosporin in a novel
galenic formulations for oral administration. The compositions
typically comprise a cyclosporin, 1,2-propylene glycol, a mixed
mono-, di- and tri-glyceride and a hydrophilic surfactant. Further
a refined glycerol-transesterified corn oil is provided
representing a mixed mono-, di- and tri-glyceride suitable for the
novel formulation. Dosage forms include in particular oral dosage
forms.
Inventors: |
Hauer, Birgit; (Lahr,
DE) ; Meinzer, Armin; (Freiburg-Munzingen, DE)
; Posanski, Ulrich; (Freiburg, DE) ; Vonderscher,
Jacky; (Riedisheim, FR) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
27540011 |
Appl. No.: |
10/094781 |
Filed: |
March 11, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10094781 |
Mar 11, 2002 |
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09871858 |
Jun 1, 2001 |
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09871858 |
Jun 1, 2001 |
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09690400 |
Oct 17, 2000 |
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6258808 |
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09690400 |
Oct 17, 2000 |
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09488215 |
Jan 19, 2000 |
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6262022 |
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09488215 |
Jan 19, 2000 |
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09312170 |
May 14, 1999 |
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09312170 |
May 14, 1999 |
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08979495 |
Nov 26, 1997 |
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08979495 |
Nov 26, 1997 |
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08490600 |
Jun 6, 1995 |
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08490600 |
Jun 6, 1995 |
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08233152 |
Apr 25, 1994 |
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08233152 |
Apr 25, 1994 |
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07906208 |
Jun 25, 1992 |
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Current U.S.
Class: |
554/227 ;
514/20.5; 514/21.1 |
Current CPC
Class: |
C11C 3/06 20130101; A61K
9/1075 20130101; B82Y 5/00 20130101; Y10S 514/962 20130101; Y10S
514/938 20130101; A61K 9/4866 20130101; A61K 9/4858 20130101; A61K
38/13 20130101; Y10S 514/943 20130101; A61K 47/44 20130101; Y10S
514/937 20130101 |
Class at
Publication: |
514/9 |
International
Class: |
A61K 038/13 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 1991 |
GB |
9113872 |
Claims
1. 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 surfactant.
2. A composition according to claim 1, wherein component (2)
comprises C.sub.12-20 fatty acid mono-, di- and tri-glycerides.
3. A composition according to claim 2, wherein component (2)
comprises linolenic, linoleic and oleic acids.
4. A composition according to claim 2, wherein component (2)
comprises a trans-esterification product of a vegetable oil.
5. A composition according to claim 4, wherein the vegetable oil is
corn oil.
6. A composition according to claim 4, wherein the vegetable oil is
transesterified with glycerol.
7. A composition according to claim 2, wherein the free glycerol
content is below 1%.
8. A composition according to claim 6, wherein component (2)
comprises Maisine.
9. A composition according to claim 6, wherein component (2)
comprises a "refined glycerol-transesterified corn oil".
10. A composition according to claim 9, wherein component (2)
comprises a composition which is a trans-esterification product of
corn oil and glycerol comprising predominately of linoleic acid and
oleic acid mono-, di- and tri-glycerides treated to enhance the
unsaturated fatty acid component content of mono-, di- and
tri-glycerides so that the linoleic acid and oleic acid mono-, di-
and tri-glyceride content is in total 85% or more of the whole
composition.
11. A composition according to claim 1, wherein component (2)
comprises from about. 30% to about 40% mono-glycerides, from about
45% to about 55% of di-glycerides and at least 5% of tri-glycerides
by weight based on the total weight of component (2).
12. A composition according to claim 11 wherein component (2)
comprises from about 32% to about 36% of mono-glycerides, from
about 45% to about 55% of di-glycerides, and from about 12% to
about 20% of tri-glycerides by weight based on the total weight of
component (2).
13. A composition according to claim 1, wherein component (3) gas
an HLB value of at least 10.
14. A composition according to claim 1, wherein component (3)
comprises a reaction product of a natural or hydrogenated castor
oil and ethylene oxide.
15. A composition according to claim 1, wherein (3) comprises
Cremophor RH40.
16. A composition according to claim 1, wherein the carrier medium
additionally comprises a hydrophilic phase co-component.
17. A composition according to claim 16, wherein the hydrophilic
phase co-component is ethanol.
18. A composition according to claim 1, which is a micro-emulsion
preconcentrate.
19. A composition according to claim 1, in unit dosage form.
20. A composition according to claim 19, comprising a gelatine
encapsulated form.
21. A composition according to claim 1 additionally comprising
water or an aqueous phase and which is a microemulsion.
22. A composition according to claim 1, wherein component (1) plus
any hydrophilic phase co-component present comprises from 10 to 35%
by weight of the hydrophilic phase component (1) plus components
(2) and (3).
23. A composition according to claim 22, wherein the hydrophilic
phase co-component is present in an amount of from about 25 to 75%
of the total weight of component (3) and the hydrophilic phase
co-component.
24. A composition according to claim 1, wherein the component (2)
is present in an amount of from 20 to 40% based on the total weight
of hydrophilic phase component(s) plus component (2) and (3).
25. A composition according to claim 1, wherein the component (3)
is present in an amount of from 30 to 60% based on the total weight
of hydrophilic phase component(s) plus component (2) and (3).
26. A composition according to claim 1 containing from 7.5 to 15%
of cyclosporin.
Description
[0001] This is a continuation of U.S. application Ser. No.
09/690,400, filed Oct. 17, 2000, which is a continuation of U.S.
application. Ser. No. 09/488,215, filed Jan. 19, 2000, which is a
continuation of J.S. application. Ser. No. 09/312,170, filed May
14, 1999, which is a continuation of U.S. application. Ser. No.
08/979,495, filed Nov. 26, 1997, now abandoned, which is a
continuation of U.S. application. Ser. No. 08/490,600, filed Jun.
6, 1995, now abandoned, which is a continuation of U.S.
application. Ser. No. 08/233,152, filed Apr. 25, 1994, now
abandoned, which is a continuation of U.S. application. Ser. No.
07/906,208, filed Jun. 25, 1992, now abandoned. The entire contents
of each application are incorporated herein by reference.--
[0002] 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.
[0003] 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.
[0004] 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.
[0005] 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.
[0006] 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.
[0007] 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:
[0008] A pharmaceutical composition comprising a cyclosporin as
active ingredient in a carrier medium comprising:
[0009] 1) 1,2-propylene glycol;
[0010] 2) a mixed mono-, di-, tri-glyceride; and
[0011] 3) a hydrophilic surfactant.
[0012] 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.
[0013] 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].sup.8-Ciclosporin, and
[3'-deshydroxy-3'-keto-MeBmt].sup.1-[Val].sup.2-Ciclosporin.
[0014] Components (2) in the compositions of the invention
preferably comprise mixtures of C.sub.12-20 fatty acid mono-, di-
and tri-glycerides, especially C.sub.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.sub.1
8 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.sub.1 8 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.
[0015] 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).
[0016] 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).
[0017] 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 48 to 50%, di-glycerides, based on the
total weight of component (2).
[0018] 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.
[0019] 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.
[0020] 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
tiransestrification 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.
[0021] 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.
[0022] 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):
[0023] Mono-glycerides: 25 or 30 to 50%, especially 30 to 40%.
[0024] Di-glycerides: 30 or 40 to 60%, especially 40 to 55%, e.g.
45 to 55%.
[0025] Mono- plus di-glycerides: >75%, especially >80%, e.g.
ca. 85%.
[0026] Tri-glycerides: at least 5%.
[0027] Free glycerol: <5%, preferably <2% or <1%.
[0028] 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 Gattefoss, of 36, Chemin
de Genas, P.O. Box 603, 69804 Saint-Priest, Cedex (France)] are:
approximate composition
1 free glycerol 10% max. (typically 3.9-4.9% or, in "substantially
glycerol free" batches, ca. 0.2%) mono-glycerides ca. 35%
(typically 30-40% or, in "substantially glycerol free" batches,
e.g. 32-36, e.g. ca. 36%) di-glycerides ca. 50% (or, in
"substantially glycerol free" batches ca. 46-48%) tri-glycerides
ca. 10% (or, in "substantially glycerol free" batches, ca. 12-15%)
free oleic acid content ca. 1%
[0029] Further physical characteristics for Maisine are: acid
value=max. ca. 2, iodine no.=ca. 85-105, saponification no.=ca.
150-175 (Fiedler "Lexikon der Hilfsstoffe", 3rd revised and
expanded edition (1989) Vol. 2, p.768). The fatty acid content for
Maisine is typically: palmitic acid--ca. 11%; stearic acid--ca.
2.5%; oleic acid--ca. 29%; linoleic acid--ca. 56%; others--ca.
1.5%.
[0030] It is especially preferred that the component (2) e.g. a
glycerol transesterified corn oil is clear, e.g. after keeping a
sample in a refrigerator, e.g. between 2 and 8.degree. C., for 24
hours, the sample is clear at room temperature 1 hour after taking
the sample out of the refrigerator.
[0031] Preferably components (2) have a low saturated fatty acid
content. Components (2) meeting these requirements may, for example
be obtained from commercially available products, e.g. obtained
therefrom by methods such as separative techniques as known in the
art, e.g. freezing procedures coupled with separative techniques,
e.g. centrifugation, to remove the saturated fatty acid
components/enhance the unsaturated fatty acid component content.
Typically the total saturated fatty acid component content will be
<15%, e.g. <10%, or <5% by weight based on the total
weight of component (2). A reduction of the content of saturated
fatty acid component in the mono-glyceride fraction of components
(2) may be observed after the separative technique.
[0032] Components (2) thus preferably contain lesser quantities of
saturated fatty acids (e.g. palmitic and stearic acids) and
relatively greater quantities of unsaturated fatty acids (e.g.
oleic and linoleic acids) than for the starting material.
[0033] Typical preferred components (2) may according to the
preferred embodiment of this invention contain:
2 32-36% mono-glycerides, 45-55% di-glycerides and 12-20%
tri-glycerides
[0034] by weight based on the total weight of component (2).
[0035] Further preferred characteristics include the following:
[0036] Fatty acid content as determined as the methyl ester by
chromatography
3 Methyl linoleate 53-63% Methyl oleate 24-34% Methyl linolenate
0-3% Methyl arachate 0-3% Methyl palmitate 6-12% Methyl stearate
1-3% Relative Density 0.94-0.96 Hydroxyl Value 140-210 Iodine Value
110-120 Peroxide Value <4.0 Free Glycerol <1.0 Acid value
max. ca. 2 Saponification no. ca. 150-185
[0037] Components (2) complying with the above outlined features
are referred to hereafter as "refined glycerol-transesterified corn
oils". Freshly prepared components (2) according to the preferred
embodiments are of clear appearance and stay clear at storage
temperature of 20.degree. C.-25.degree. C. for more than 20
days.
[0038] The "refined glycerol-transesterified corn oils" have
especially been proposed for the preparation of the compositions of
this invention. They may also have uses for the solubilization of
other active agents and have the advantage of remaining stable,
e.g. clear, for a long time. They constitute another aspect of
present invention. The invention accordingly provides in another
aspect a trans-esterification product of corn oil and glycerol
comprising predominately of linoleic acid and oleic acid mono-, di-
and tri-glycerides treated to enhance the unsaturated fatty acid
component content of mono-, di- and tri-glycerides so that the
linoleic acid and oleic acid mono-, di- and tri-glyceride content
is in total 85% or more of the whole composition.
[0039] Components (3) in the compositions of the invention
preferably have an HLB of at least 10.
[0040] Examples of suitable components (3) in the compositions of
the invention are:
[0041] 3.1 Reaction products of a natural or hydrogenated castor
oil and ethylene oxide. Such products may be obtained in known
manner, e.g. by reaction of a natural or hydrogenated castor oil
with ethylene oxide, e.g. in a molar ratio of from about 1:35 to
about 1:60, with optional removal of the polyethyleneglycol
component 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 number of ca. 50-60, an
acid number <1, an iodine number <1, a water content
(Fischer) <2%, an n.sub.D.sup.60 of ca. 1,453-1,457 and an HLB
of ca. 14-16; Cremophor RH 60 having a saponification number of ca.
40-50, an acid number <1, an iodine number <1, a water
content (Fischer) 4.5-5.5%, and an n.sub.D.sup.25 of ca.
1.453-1.457 and an HLB of ca. 15-17; and Cremophor EL having a
molecular weight (by steam osmometry) of ca. 1630, a saponification
number of ca. 65-70, an acid number of ca. 2, an iodine number of
ca. 28-32 and an n.sub.D.sup.25 of ca. 1.471.(c.f. Fiedler,
"Lexikon der Hilfstoffe", 3rd revised and expanded edition (1989),
Vol. 1,p.326). Also suitable for use in this category are the
various tensides available under the trade name Nikkol (e.g. Nikkol
HCO-40 and HCO-60), Emulgin (e.g. Emulgin RO40), Mapeg (e.g. Mapeg
CO-40h) and Incrocas (e.g. Incrocas 40) (c.f. Fiedler). The said
product Nikkol HC0-60 is a reaction product of hydrogenated castor
oil and ethylene oxide exhibiting the following characteristics:
acid value ca. 0.3; saponification number of ca. 47.4; hydroxy
value of ca. 42.5; pH (5%) of ca. 4.6; color APHA=ca. 40; m.p.=ca.
36.0.degree. C.; freezing point=ca. 32.4.degree. C.; H.sub.2O
content (%, KF)=0.03.
[0042] 3.2 Polyoxyethylene-sorbitan-fatty acid esters, 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. p.1300-1304) including the products
Tween
[0043] 20 [polyoxyethylene(20)sorbitanmonolaurate],
[0044] 21 [polyoxyethylene(4)sorbitanmonolaurate],
[0045] 40 [polyoxyethylene(20)sorbitanmonopalmitate],
[0046] 60 [polyoxyethylene(20)sorbitanmonostearate],
[0047] 65 [polyoxyethylene(20)sorbitantristearate],
[0048] 80 [polyoxyethylene(20)sorbitanmonooleate],
[0049] 81 [polyoxyethylene(5)sorbitanmonooleate],
[0050] 85 [polyoxyethylene(20)sorbitantrioleate].
[0051] Especially preferred products of this class for use in the
compositions of the invention are the above products Tween 40 and
Tween 80.
[0052] 3.3 Polyoxyethylene fatty acid esters, for example
polyoxyethylene stearic acid esters of the type known and
commercially available under the trade name Myrj (c.f. Fiedler,
loc. cit., 2, p.834-835); 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.degree. C., an
HLB value=ca. 16.9., an acid value=ca. 0-1 and a saponification
no.=ca. 25-35.
[0053] 3.4 Polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers, e.g. of the type known and commercially available
under the trade names Pluronic, Emkalyx and Poloxamer (c.f.
Fiedler, loc. cit., 2, p. 959). An especially preferred product of
this class for use in the compositions of the invention is the
product Pluronic F68, having an m.p.=ca. 52.degree. C. and a
molecular weight of ca. 6800-8975. A further preferred product of
this class for use in the compositions of the invention is the
product Poloxamer 188.
[0054] 3.5 Dioctylsulfosuccinate or di-[2-ethylhexyl]-succinate
(c.f. Fiedler, loc. cit., 1, p. 107-108).
[0055] 3.6 Phospholipids, in particular lecithins (c.f. Fiedler,
loc. cit., 2, p. 943-944). Lecithins suitable for use in the
compositions of the invention include, in particular, soya bean
lecithins.
[0056] 3.7 Propylene glycol mono- and di-fatty acid esters such as
propylene glycol dicaprylate (also known and commercially available
under the trade name Miglyol 840), 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., 2, p.
808-809).
[0057] 3.8 Sodium lauryl sulfate.
[0058] For use in relation to the present invention, components as
set out under (3.1) above are most preferred.
[0059] Components (1), (2) and (3) are preferably present in the
compositions of the invention in relative proportions such that the
composition is a "micro-emulsion preconcentrate", i.e. having the
characteristics of a micro-emulsion preconcentrate system as
described in GB patent publication no. 2 222 770 A at pages 11 to
12, the contents of which are, for the purposes of defining such
systems, incorporated herein by reference. Compositions of the
invention are thus preferably "microemulsion preconcentrates", in
particular of the type providing o/w (oil-in-water) microemulsions.
The present invention is also to be understood as including
compositions comprising components (1), (2) and (3) together with
(4) water and which are microemulsions.
[0060] As also indicated in GB patent publication no. 2 222 770 A
the hydrophilic phase of microemulsion preconcentrate systems, i.e.
component (1) in compositions of the present invention may include
one or more additional ingredients as hydrophilic phase component,
for example lower (e.g. C.sub.1-5) alkanols, in particular ethanol.
Such components will generally be present in partial replacement of
component (1). While the use of ethanol in compositions of the
present invention is not essential, it has been found to be of
particular advantage when the compositions are to be manufactured
in soft gelatine encapsulated form, e.g. as a means of improving
storage characteristics, in particular to reduce risk of
cyclosporin precipitation following encapsulation procedures. Thus
the shelf life stability may be extended by employing a lower
alkanol as an additional ingredient of the hydrophilic phase.
[0061] Suitably the hydrophilic phase component, i.e. component
(1), 1,2-propylene glycol, or component (1) plus any hydrophilic
phase co-component(s), e.g. ethanol, will be present in the
compositions of the invention in an amount of from 1.0 or 2.5 to
50%, preferably from 5 to 40%, more preferably from 10 to 35%, e.g.
above 15%, e.g. from about 20 to about 30% by weight based on the
total weight of hydrophilic phase component(s) plus components (2)
and (3).
[0062] When a hydrophilic phase co-component is employed, the
co-component, e.g. ethanol, is suitably present in an amount of up
to about 20%, preferably up to about 10 or 15%, e.g. from about 5
to 10 or 15% by weight based in the total weight of the
composition. Such co-component is thus suitably present in an
amount of from about 25 to 75% by weight based on the total weight
of hydrophilic phase components (e.g. 1,2-propylene glycol plus
ethanol) more preferably it is present in an amount of less than
50%, e.g. from 25 to 50%, for example about 30, 40 or 50%.
[0063] Suitably component (2) will be present in the compositions
of the invention in an amount of from 5 to 65%, preferably from 15
to 45%, more preferably from 20 to 40%, e.g. from about 25 to about
35%, based on the total weight of hydrophilic phase component(s)
plus components (2) and (3).
[0064] Suitably component (3) will be present in the compositions
of the invention in an amount of from 25 to 75%, preferably from 30
to 60%, e.g. from about 55 or 60% based on the total weight of
hydrophilic phase component(s) plus components (2) and (3).
[0065] Suitably the compositions of the invention will comprise
from about 1 or 2 to 30%, preferably from 5 to 20 or 25%, more
preferably from 7.5 to 15%, e.g. about 10% by weight of cyclosporin
based on the total weight of the composition.
[0066] Accompanying Figure I represents a three-way plot for
relative concentrations of hydrophilic phase component, i.e.
1,2-propylene glycol, component (2), e.g. "refined
glycerol-transesterified corn oil", and component (3), e.g.
Cremophor RH40, in compositions in accordance with the invention
and comprising 10% cyclosporin (e.g. Ciclosporin) by weight.
Relative concentrations of the carrier components increase in the
directions indicated by the arrows from 0 to 100%.
[0067] For compositions in accordance with the present invention
the relative proportion of hydrophilic phase component(s),
component (2) and component (3) will suitably lie within the shaded
area X. Compositions thus defined are microemulsion preconcentrates
of high stability, capable on addition to water, of providing
microemulsions having an average particle size of <1,500.ANG.
and stable over periods in excess of 24 hrs. In contrast
compositions in the region A, B and C give aqueous systems subject
to (A) discoloration, (B) phase separation and (C) turbidity
respectively. Compositions in accordance with the invention
comprising hydrophilic phase component(s) and components (2) and
(3) in relative proportion as defined by the line X of FIG. 1 are
accordingly especially preferred.
[0068] In the event that the 1,2-propylene glycol component is
partially replaced by ethanol as hereinbefore described, the area X
of FIG. 1 is shifted slightly upwards within the plot, i.e. in the
direction of higher component (3) concentration. This shift however
represents an upwards displacement of a few percent only and does
not substantially alter the obtained plot.
[0069] The compositions of the invention show good stability
characteristics, e.g. as indicated by standard stability trials,
e.g. having a shelf life stability of up to three years, and even
longer.
[0070] Compositions in accordance with the present invention may
also include further additives or ingredients, for example [e.g.
antioxidants ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl
hydroxy toluene (BHT) and tocopherols, e.g. .alpha.-tocopherol
(vitamin E)] and/or preserving agents, e.g. in an amount of from
about 0.05 to 1% by weight based on the total weight of the
composition, or sweetening or flavoring agents, e.g. in an amount
of up to about 2.5 or 5% by weight based on the total weight of the
composition.
[0071] Compositions in accordance with the present invention 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 indicated in standard
bioavailability trials e.g. in healthy patients using a specific
monoclonal kit to determine cyclosporin levels, e.g. as described
in the Examples hereinafter. In particular the compositions in
accordance with the present invention provide an improved oral
administration form for cyclosporins (e.g. Ciclosporin) as it
exhibits absence of significant food interaction, which we have
observed with the commercially available oral form of Ciclosporin
especially with fat rich food. Moreover, inter-subject and
intra-subject variability of pharmacokinetic parameters may be
significantly lower with the compositions according to the present
invention than with the commercial oral form of Ciclosporin.
Specifically the difference between the pharmacokinetic parameters
with food intake and without food intake, or even between day time
absorption and night time absorption, may be eliminated by
administering the composition in accordance with the present
invention. Thus with the novel composition according to present
invention the pharmacokinetic parameters, e.g. absorption and blood
levels, become surprisingly more predictable and this new galenic
form may eliminate problems in administration with erratic
absorption of Ciclosporin. Additionally the composition according
to present invention, may exhibit an improved bioavailability in
patients having malabsorption, e.g. liver transplantation patients
or pediatric patients. In particular it has been found that such
compositions are compatible with tenside materials, e.g bile salts,
present in the gastro-intestinal 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 of the cyclosporin 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.
[0072] The compositions of the invention are well tolerated, e.g.
as indicated by clinical trials over 4 weeks.
[0073] Compositions in accordance with the present invention will
preferably be compounded in unit dosage form, e.g. by filling into
orally administerable capsule shells, e.g. soft or hard gelatine
capsule shells but if desired may be in drink solution form. Where
compositions are in unit dosage form, each unit dosage will
suitably contain between 10 and 200 mg cyclosporin, more suitably
between 10 and 150 mg, e.g. 15, 20, 25, 50 or 100 mg cyclosporin.
Such unit dosage forms are 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.).
[0074] The compositions of the invention containing Ciclosporin are
indicated to be administered at the same dosage for renal
transplant patients as the commercial forms as described
hereafter.
[0075] Alternatively compositions in accordance with the present
invention suitable for oral administration may include (4) water or
any other aqueous system, to provide microemulsion systems suitable
for drinking.
[0076] In addition to the foregoing the present invention also
provides a process for the production of a pharmaceutical
composition as hereinbefore defined, which process comprises
bringing a component (1), a component (2) and a component (3) as
hereinbefore defined into intimate admixture and, when required
compounding the obtained composition in unit dosage form, for
example filing said composition into gelatine, e.g. soft or hard
gelatine, capsules.
[0077] In a more particular embodiment the present invention
provides a process for the production of a pharmaceutical
composition as hereinbefore defined in the form of a "microemulsion
preconcentrate" or microemulsion, which method comprises bringing a
component (1), a component (2) and a component (3), optionally
together with further components or additives, in particular with a
hydrophilic phase co-component, for example ethanol, into intimate
admixture in relative proportions of components (1), (2) and (3),
such that a microemulsion preconcentrate is obtained and, when
required, compounding the obtained composition in unit dosage form
or combining said obtained composition with sufficient water or
sufficient of an aqueous solvent medium such that a microemulsion
is obtained.
[0078] The following examples are illustrative of compositions in
accordance with the invention, in unit dosage form, suitable for
use, e.g. in the prevention of transplant rejection or for the
treatment of autoimmune disease, on administration of from 1 to 5
unit dosages/day. The examples are described with particular
reference to Ciclosporin. However equivalent compositions may be
obtained employing any other cyclosporin, in particular
[0-(2-hydroxyethyl)-(D)-Ser].sup.8-Ciclosporin (hereinafter
referred to as Compound Z).
EXAMPLE 1
[0079] Preparation of "refined glycerol-transesterified corn
oil".
[0080] Substantially-glycerol free glycerol-transesterified corn
oil (if necessary after heating to give a clear mixture) is slowly
cooled to a temperature of +20.degree. C. and kept at this
temperature for one night. In a first-step centrifugation, at an
acceleration of 12 000 G and a flow rate of 103 kg/h in a
continuous flow centrifuge, a liquid phase (62 kg/h) and a
sediment-containing phase (41 kg/h) are obtained. The liquid phase
is slowly cooled to +8.degree. C. and kept at this temperature for
one night. In a second-step centrifugation at an acceleration of 12
000 G and a flow rate of 112 kg/h a liquid phase (76.2 kg/h) and a
sediment-containing phase (35.8 kg/h) are obtained. The liquid
phase is "refined glycerol-transesterified corn oil". Alternatively
an improved product may be obtained by effecting the centrifugation
in three steps, e.g. at +20.degree. C., +10.degree. C. and
+5.degree. C.
[0081] The process is characterised by a slight percentage
reduction in the mono-glyceride component in the refined glycerol
transesterified corn oil as compared to the starting material (e.g.
35.6% compared to 38.3%).
[0082] A typical analytical comparison between the sediment and
clear solution is as follows:
4 Compound Sediment (%) Clear Solution (%) 1. Mono palmitate 19.1
3.4 2. Mono linoleate + 23.4 27.0 Mono oleate 3. Mono stearate 5.7
<2 4. Dilinoleate + 35.4 44.7 Dioleate 5. Other di-glycerides
7.7 10.4 6. Tri-glycerides 8.7 12.5
[0083] In a variant of this refining procedure similar "refined
glycerol-transesterified corn oil" compositions may be obtained by
heating the starting material to +80.degree. C. for one hour under
nitrogen, cooling it down with slight agitation and with a
1.degree. C. difference between temperature of the product and
temperature of the cooling fluid to +16.degree. C., maintaining
+16.degree. C. for about 12 hours with slight agitation, cooling it
down to about +8.degree. C. and separating the precipitate by means
of a band filter under vacuum.
[0084] In a further variant similar "refined
glycerol-transesterified corn oil" compositions may be obtained by
heating the starting material to +75.degree. C. under nitrogen and
cooling it down to +8.degree. C. within a period of 5 to 6
hours.
[0085] In yet a further variant similar "refined
glycerol-transesterified corn oil" compositions may be obtained by
heating the starting ,material to +80.degree. C. for 1 hour,
cooling it down to +8.degree. C. in a stepwise cooling procedure
comprising: cooling to +25.degree. C. in 1 hour, maintaining at
+25.degree. C. for 8 hours, cooling to +20.degree. C. in 0.5 hours,
maintaining at +20.degree. C. for 1 hour, cooling to +15.degree. C.
in 0.5 hours, maintaining at +15.degree. C. for 1 hour, cooling to
+10.degree. C. in 0.5 hours, maintaining at +10.degree. C. for 1
hour, cooling to +8.degree. C. in 0.5 hours, staying at 8.degree.
C. for 2 hours, and filtering the batch on a 0.5 .mu.m mesh filter
under a pressure of 0.5 bars.
[0086] Typical contents of components in the refined product
obtained from these preparations are listed in the following
Table:
5 COMPOSITION OF COMPONENTS (% w/w) refined glycerol-trans-
Components esterified corn oil Glycerides: mono 33.3 di 52.1 tri
14.6 Fatty acids: palmitic acid (C16) 7.8 stearic acid (C18) 1.7
oleic acid (C18:1) 31.6 linoleic acid (C18:2) 57.7 Glycerol content
<1%
EXAMPLE 2
[0087] Preparation of oral unit dosage forms
6 COMPONENT QUANTITY (mg/capsule) Cyclosporin, e.g. Ciclosporin 100
1) 1,2-propylene glycol 200 2) refined oil 320 3) Cremophor RH40
380 Total 1,000
[0088] The cyclosporin is dissolved in (1) with stirring at room
temperature and (2) and (3) are added to the obtained solution
again with stirring. The obtained mixture is filled into size 1
hard gelatine capsules and sealed e.g. using the Quali-Seal
technique.
[0089] Compositions comprising 50 and 100 mg Ciclosporin, are
prepared analogously employing the following indicated ingredients
in the indicated amounts.
[0090] In this Example, refined oil="refined
glycerol-transesterified corn oil" as described in Example 1 or
Maisine, e.g. substantially glycerol free Maisine.
7 COMPOSITIONS COMPRISING 100 mg cyclosporin, e.g. Ciclosporin
COMPOSITION 2 3 4 5 6 COMPONENT QUANTITY (mg/capsule) 1)
1,2-Propylene glycol 200 270 180 180 90 2) refined oil 350 180 180
360 360 3) Cremophor RH40 350 450 540 360 450 COMPOSITION 7 8 9 10
COMPONENT QUANTITY (mg/capsule) 1) 1,2-Propylene glycol 150 100 200
200 1a) ethanol 100 100 100 100 2) refined oil 345 320 320 290 3)
Cremophor RH40 405 380 380 360 COMPOSITIONS COMPRISING 50 mg
Ciclosporin COMPOSITION A B C D E F COMPONENT QUANTITY (mg/capsule)
1) 1,2-Propylene glycol 100 135 45 90 100 50 1a) ethanol 50 2)
refined oil 160 90 180 180 67 160 3) Cremophor RH40 190 225 225 180
167 190
[0091] As indicated above equivalent compositions may be made
containing Compound Z instead of Ciclosporin. Thus composition D
may be made containing 50 mg Compound Z instead of Ciclosporin.
EXAMPLE 3
Bioavailability in Dogs
[0092] The biopharmaceutical properties of compositions in
accordance with the present invention we compared with the marketed
soft-gelatine capsule of Ciclosporin. The forms were compared after
oral administration to 12 male beagle dogs in a cross-over design.
The pharmacokinetic profile of Ciclosporin was determined in whole
blood over 24 hours. the areas under the curve of the blood
concentration versus time curves (AUC), C.sub.max and T.sub.max
were determined.
[0093] Forms: Dose 100 mg Ciclosporin/dog
8 Composition X (commercial form, soft gelatin capsule) Ciclosporin
100 mg Labrafil 300 mg ethanol 100 mg Maize oil 416 mg Total 926
mg/dosage Composition I according to present invention (a soft
gelatin capsule): Ciclosporin 100 mg 1) 1,2-propylene glycol 75 mg
1a) ethanol 150 mg 2) refined glycerol-transesterified corn oil 345
mg 3) Cremophor RH40 405 mg Total 1075 mg/dosage
[0094] Drug Administration:
[0095] 10 male beagle dogs weighing around 12 kg completed the
trial successfully. Twenty hours before the drug administration the
food was withdrawn but the animals were allowed free access to
water until the beginning of the experiment. The dosage forms were
administered by gavage to the animals, early in the morning
(approx. 8.00 am), and followed by 20 ml NaCl 0.9% solution. Three
hours after the administration, the animals were again allowed free
access to water and food. A 1 week wash-out period was necessary
between 2 administrations to the same animal.
[0096] Blood Sampling:
[0097] Blood samples of 2 ml (or 5 ml for the blank sample) were
taken from the vena cephalica (forearm) with a sterile needle
(diameter ca. 1.2 mm) and collected into 5 ml plastic tubes
containing EDTA at -15 min, 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12 and
24 hours after the oral administration of the drug. The blood
samples were stored at ca. -18.degree. C. until drug assay. The
blood samples were analysed by Ciclosporin-specific
radioimmunoassay (RIA). The median blood concentrations of
Ciclosporin in dogs are plotted in the accompanying Figure II. The
areas under the blood drug concentration versus time curves (AUC)
were calculated using the trapezoidal rule. An analysis (CV) of
variance was performed and the mean AUCs, Cmax and Tmax were
compared statistically by the Tukey test. The results obtained are
shown in the following table.
9 AUC.sub.0-24 h C.sub.max T.sub.max Mean CV Mean CV Mean CV
Composition [ng .multidot. h/ml] [%] [ng/ml] [%] [h] [%] X 6695 27
1053 25 1.3 20 I 10064 24 1539 18 1.6 29
[0098] The behaviour and body weight of the animals were controlled
during the study. No body weight loss could be detected.
[0099] Conclusion: The composition according to the present
invention (composition I) has a significantly higher
bioavailability (factor 1.5) than the commercial soft-gelatin
capsule of Ciclosporin.
[0100] Figure II shows the average whole blood Ciclosporin
concentrations as determined by a specific monoclonal RIA following
single oral administration of Composition X and Composition I each
in 100 mg dosage. Blood concentration (in ng/ml) is recorded
vertically and time horizontally.
EXAMPLE 4
Bioavailability in Humans
[0101] The bioavailability of Ciclosporin is compared as it is
determinable after administration of the commercial Ciclosporin
soft gelatine capsule and of a composition according to present
invention.
[0102] Administered form: 100 mg Ciclosporin per capsule
10 Composition X (commercial form, soft gelatine capsule)
Ciclosporin 100 mg Labrafil 300 mg Ethanol 100 mg Maize oil 426 mg
Total 926 mg/Capsule
[0103] Composition No. 8 (according to Example 2 containing
"refined glycerol-transesterified corn oil") in a soft gelatine
capsule.
[0104] Method:
[0105] Forty eight healthy male subjects completed the study. Each
of the participants received four of the eight administrations (two
doses of composition 8 and the same two doses of composition
X).
[0106] The participants were randomly allocated to two subgroups
consisting of twenty four subjects each according to a parallel
design. Subjects in Group I received doses of 200 mg and 600 mg
Ciclosporin and subjects in Group II received 400 mg and 800
mg.
[0107] Within each of the two groups the trial was conducted on the
basis of a balanced 4-way cross-over design with a wash-out period
of two weeks between each treatment.
[0108] Blood samples for determination of Ciclosporin in whole
blood were taken 1 minute before drug intake and then 15 min, 30
min. 45 min, 1 h, 1.5h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 6
h, 8 h, 20 h, 12 h, 16 h, 20 h, 24 h, 28 h, 32 h, 36 h, 40 h, and
48 h after drug intake.
[0109] The individual concentrations of Ciclosporin in whole blood
were determined for each blood sample by a specific RIA-method.
[0110] The limit of quantification was 12.5 ng/ml.
[0111] Blood concentrations and corresponding AUC.sub.(0-48
h)-values of Ciclosporin were significantly higher after
administration of Composition 8 than after administration of
Composition X at all dosage strengths. Peak concentrations
(C.sub.max) of the 200 mg, 400 mg, and 600 mg dose levels appeared
somewhat earlier after administration of Composition 8 (see
following table).
11TABLE Bioavailability of Ciclosporin in Humans Mean (.+-.SD)
values of AUC.sub.(0-48 h), C.sub.max and T.sub.max after single
oral administration of different dosages of Composition X and
Composition 8 AUC.sub.(0-48 h) C.sub.max T.sub.max Form [ng
.multidot. h/ml] [ng/ml] [h] 200 mg Comp X 2028 .+-. 608 558 .+-.
228 2.1 .+-. 0.7 200 mg Comp 8 3468 .+-. 1000 1025 .+-. 218 1.5
.+-. 0.4 400 mg Comp X 3326 .+-. 1115 785 .+-. 252 2.1 .+-. 0.9 400
mg Comp 8 6944 .+-. 1468 1557 .+-. 286 1.4 .+-. 0.4 600 mg Comp X
4501 .+-. 1217 917 .+-. 236 2.3 .+-. 1.0 600 mg Comp 8 9689 .+-.
2282 1812 .+-. 400 1.7 .+-. 0.6 800 mg Comp X 5209 .+-. 1554 1045
.+-. 264 2.4 .+-. 1.0 800 mg Comp 8 12162 .+-. 3059 2143 .+-. 576
2.1 .+-. 0.8
[0112] Based on the mean ratios of AUC .sub.(0-48 h)-values the
relative bioavailability of Composition 8 vs Composition X was
estimated between 170% and 233%, depending on the dose administered
(see following table).
12TABLE Relative bioavailability of Composition 8 vs. Composition X
Dose of Mean ratio of AUC.sub.(0-48 h) Conversion Factor: [mg] Comp
8 vs. Comp X Comp X vs. Comp 8 200 1.70 0.59 400 2.09 0.48 600 2.15
0.47 800 2.33 0.43
[0113] Conclusion: The composition according to the present
invention (Composition 8) has a significantly higher
bioavailability in humans be at least factor 1.7 when compared to
the commercial form (Composition X).
[0114] The accompanying Figure III provides a graphical plot of the
mean AUC.sub.(0-48 h)-values of composition X (open triangles)
versus those of Composition 8 (solid Circles). AUC-values (in
ng.h/ml) of Ciclosporin vertically and dose horizontally as
obtained from Example 4.
[0115] The extent of absorption of Composition 8 (in terms of
AUC.sub.(0-48 h)-values) seemed to be independent of dose, whereas
the extent of absorption of Composition X declined with increasing
doses (see Figure III).
* * * * *