Note: Descriptions are shown in the official language in which they were submitted.
- 1338775
CASE 100-7207
~ATER SOLUBLE IIJ..J~Sl~S AS SOLUBILISERS FOR P~ARMACOLOGICALLY ACTIVE
COII~OUNUS AND P~ARMACRUTICAL ~ 1S
The invention relates to the use of water soluble monoesters of satu-
rated or unsaturated (C6_l8) fatty acids and polyols, preferably saccha-
rides, as solubilisers of pharmaceutically active compounds in intrave-
nously applicable solutions in aqueous media or in solvents which are
miscible with water, e.g. polyethylene glycol, ethanol, glycerin or
1,2-propylene glycol.
[By the term "water soluble" as used herein is meant: having a solu-
bility in water of at least 3.3 % at room temperature. Water soluble
monoesters as herein defined are thus monoesters dissolvable in water at
room temperature in an amount of at least 1 g monoester per 30 ml water.
The term "aqueous medium" is to be understood to include systems
comprising a liquid phase comprised entirely or substantially entirely
of water, as well as systems in which the liquid phase additionally
includes or comprises water miscible solvents such as hereinabove set
forth. Preferred aqueous media are such in which the liquid phase com-
prises at least 7S %, preferably at least 90 %, most especially at least
95 % water by weight.]
*
- 1338775
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The invention provides a combination of such a monoester and a substan-
tially water insoluble pharmaceutically active polypeptide, particularly
a cyclopeptide, preferably a cyclosporin.
[By the term "substantially water insoluble" is meant: having a solu-
bility in water of not more than 1 % at room temperature. Substantially
water insoluble polypeptides as defined above are thus polypeptides
requiring at least 100 ml water to effect dissolution of 1 g thereof at
room temperature. Preferably the term is applied to substances, e.g.
polypeptides having a solubility in water of not more than 0.1 %, in
particular not more than 0.01 %, e.g. not more than ca. 0.004 ~ at room
temperature.]
The mentioned monoesters are generally known. From UK-Patent 1.134.878
it is also known, to use water soluble raffinose monoesters of the same
category as solubilisers to stabilise specified non polypeptide agents,
e.g. the triterpenealcoholester of 3-methoxy-4-hydroxycinnamic acid in
solutions for injection or for oral application. However, and this is an
important feature, considerable amounts of several other excipients
(cosolubilisers) were necessary to guarantee a satisfactory stable
solution (cf. page 5, lines 2-18). Hence, it follows, that for the used
agent the applied monoesters alone were not satisfactory solubilisers.
Additionally it appeared that the saccharose monoesters were not
suitable as solubilisers at all for the used agent (cf. page 2, lines
70-73). The products obtained are indicated for e.g. intradermal
injection but not as suitable for intravenous injection (page 8, column
2, lines 3-4). Surprisingly liquid preparations according to the present
invention are suitable for intravenous injection.
UK-Patent 2.126.588 relates to the stabilisation of, e.g. injectable,
liquids containing tumor necrosis factor (TNF) against decomposition of
the active substance employing a wide variety of non-ionic solubilisers
(esters and ethers). In the examples many polyoxyethylene derivatives
are discussed including inter al. sorbitan monopalmitate and sorbitan
133877~
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oleate. Most solubilisers are not water soluble themselves and thus not
intravenously injectable. In particular the sorbitan esters are not
water soluble as herein defined. Again co-solubilisers must be used
(cf. page 3, lines 16-22). According to the instant invention no such
excipients are neccessary.
Saccharose fatty acid esters are also mentioned in the description (notin the examples) incidentally and only the monopalmitic and the mono-
stearic acid esters are specified (page 4, line 11). These compounds too
do not meet the requirement of the instant invention, that should they
be water soluble. No suggestion can be found to use water soluble mono-
esters for the improvement of the water solubility of pharmaceutically
active polypeptides.
UK-Patent 1.601.613 discloses mixtures of non-ionic solubilisers, amongothers saccharose monoesters generally (page 2, line 53) and saccharose
monopalmitate specifically (page 2, line 53), and agents, e.g. proteins
or insulin (page 2, line 24). The indicated solubilisers (the saccharose
monopalmitate is not water soluble) are used for the improvement of the
resorption of agents, which are badly resorbable after oral application.
There is no teaching to use the esters as solubilisers for the produ-
ction of aqueous solutions, since the agents already have relatively
good water solubility by nature (cf. page 1, lines 17-21 and page 2,
lines 19-20). The obtained aqueous mixtures are not solutions (page 1,
lines 33-39), but dispersions (page 2, line 3 and page 2, lines 63-page
3, line 4) and are recommended for rectal and not for intravenous
application.
Takada, Japanese patent JP 071682, issued 11/12/86 relates to the preparation ofaqueous dispersions of cyclosporins for oral use. Monoesters which are applied are
mostly not water soluble solubilisers, e.g. saccharose monopalmitate, saccharosemonostearate or a sorbitan fatty acid ester. Saccharose monooleate was also used,
but it was not found that this ester gives a clear solution.
-
13~8775
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In one of the examples a dispersion of a saccharose mono fatty acid
ester and Ciclosporine is sonicated, to provide an oral liquid prepa-
ration. No indication can be found to use the obtained dispersion for
intraveneous administration. For a dispersion containing 0.35~ of
Ciclosporine in water (3,5 mg/ml) a concentration of 0.2X monoester is
employed. According to the instant invention solutions comprising 0.35X
of Ciclosporine by weight are obtainable using a 2.3% solution of the
water soluble saccharose monolaurate in water.
The present invention also provides compositions, in particular pharma-
ceutical compositions, comprising combinations of saccharose monolaurate
or raffinose monolaurate with polypeptides. Such compositions may
optionally include pharmaceutical excipients, which are substantially
insoluble in water. Such excipients include e.g. benzene derivatives,
e.g. p-hydroxybenzoic acid methyl ester.
The invention also provides solid solutions comprising pharmaceutically
active, particularly substantially water insoluble pharmaceutically
active compounds in the said water soluble monoesters.
Pharmaceutically active, substantially water insoluble compounds often
suffer from a loss of bioavailability if applied orally. This is because
they are insufficiently rapidly dissolved in the aqueous medium of the
gastro-intestinal tract and are eliminated from the body, in substantial
amount in undissolved form.
It is difficult to find water soluble excipients, which solubilise the
pharmaceutically active compounds in aqueous media to provide solutions
which are stable at all dilution stages without forming a precipitate,
and which are additionally pharmaceutically acceptable. Liquid galenical
forms, which are satisfactory from a pharmaceutical and medical view-
point and which contain, in particular, substantially water insoluble
polypeptides, especially cyclopeptides such as the cyclosporins, have
long been sought. Excipients used in available commercial forms possess
1338775
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poor palatability or are associated with a risk of anaphylactic shock.
Tensides containing ethylene oxide units or such having amine or amide
structures are no longer acceptable from a pharmaceutical or medical
viewpoint.
Surprisingly, it has now been found that in this respect unobjectionable
water soluble monoesters of saturated or unsaturated (C6_l8) fatty acids
and polyols, especially saccharides, are extremely well suited solubili-
sers, especially for pharmaceutically active, substantially water insoluble
compounds. It has further been observed, that the said monoesters form
solid solutions with pharmaceutically active compounds. These monoesters
can dissolve the active compound sufficiently. By addition of water or
other aqueous media, aqueous micellar solutions are obtained from which the
active compound is readily bioavailable. The active compound is completely
solubilized in the colloidal solution.
The invention in particular provides solid solutions comprising polypeptide
agents, particularly substantially water insoluble polypeptide agents in
water soluble monoesters of saturated or unsaturated (C6_l8) fatty acids
and polyols, especially saccharides. The fatty acid residues in the said
esters may be substituted e.g. by hydroxyl.
Hydrotropic substances or cosolubilisers are not essential in the solidsolutions of the invention. The used solubilisers do not contain ethylene
oxide, amine or amide structural units, which are pharmaceutically or medi-
cally objectionable.
In accordance with the present invention solid solutions are obtainable in
which the pharmaceutically active, e.g. substantially water insoluble,
pharmaceutically active agent, e.g. polypeptide, for example cyclosporin
(i.e. the dissolved or disperse phase) is entirely or substantially enti-
rely present in molecular distribution, or in which the water soluble fatty
acid ester (i.e. the solvent or continuous phase) and the water insoluble
pharmaceutically active agent are each in entirely or substantially
133877~
- 6 - 100-7207
entirely amorphous state, e.g. as verifiable by X-ray structure ana-
lysis. Solid solutions meeting the above criteria are preferred.
The water soluble fatty acid esters employed in the compositions of theinvention are themselves pharmaceutically acceptable.
Preferred fatty acid esters for use in practicing the invention are
monoesters of disaccharides, e.g. maltose, or, especially, saccharose,
as well as of trisaccharides, e.g. raffinose. Preferred are saccharides
which contain glucose, fructose and/or galactose units.
The fatty acid esters for use in practicing the invention are preferably
caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid
(Cl2), myristic acid (Cl4), palmitic acid (Cl6), oleic acid (Cl8),
ricinoleic acid (Cl8) or 12-hydroxystearic acid (Cl8) esters.
In the fatty acid esters used in practicing the invention the lipophili-
city of the acid moiety is, by the choice of its length, in balance with
the hydrophilicity of the polyol, e.g. saccharide, moiety. Preferably
(C6_l4) acid residues are connected with disaccharides and (C8_l8) acid
residues with trisaccharides.
In general the HLB-value of the fatty acid ester is preferably at least10. Suitable fatty acid esters are in particular saccharose monocaproate,
saccharose monolaurate, saccharose monomyristate, saccharose monooleate
and saccharose monoricinoleate, raffinose monocaproate, raffinose monolau-
rate, raffinose monomyristate, raffinose monopalmitate and raffinose mono-
oleate. Saccharose monolaurate and raffinose monolaurate are especially
preferred.
The monoester content of fatty acid esters used in practicing the inven-
tion is preferably at least 80 X, more preferably at least 90 X by weight,
i.e. the said fatty acid esters preferably contain less than 20 %, more
preferably less than 10 % of di- or poly-ester impurities. The esters can
133877~
- 7 - 100-7207
be produced in a manner known per se, e.g. as described in the Journal of
the Society of Cosmetic Chemists (1956) 7 249-255 and are preferably puri-
fied by column chromatography in order to obtain a maximal monoester
content.
Pharmaceutically active compounds comprised in the solid solutions of
the invention are water soluble or, preferably, substantially water
insoluble, e.g. Proquazone (= l-isopropyl-7-methyl-4-phenyl-2(1H)-quina-
zolinone) which has a water solubility of below 0.1 g/100 ml; xanthine
derivatives, e.g. theophyllin; tricyclic compounds, for example tricy-
clic antidepressiva or e.g. ketotifen; azulene derivatives, e.g. guaja-
zulene, or steroids, e.g. Prednisone.
Uater soluble pharmaceutically active compounds are included in the
invention of the solid solution, since such agents are as advantageous
as substantially water insoluble agents in combination with water so-
luble monoesters, since their bioavailability becomes improved.
Preferred pharmaceutically active compounds in the mixtures, as well asin the solid solutions of the invention, are polypeptides, especially
substantially water insoluble polypeptides having a molecular weight of
from 500 to 10'000, e.g. of from 500 to 1'500.
To this class of compounds especially belong the cyclopeptides, e.g. the
cyclosporins, particularly Ciclosporine, which has a water solubility of
below 0.004 g/100 ml.
The cyclosporins comprise a class of structurally distinct cyclic, poly-
N-methylated undecapeptides having valuable pharmaceutical, in particular
immunosuppressive, anti-inflammatory and anti-parasitic, in particular
anti-protozoal activity. The first of the cyclosporins to be isolated and
the "parent" compound of the class, is the naturally occurring fungal
metabolite Ciclosporine, also known as Cyclosporin A, the production and
properties of which are described e.g. in US Patent No. 4,117,118.
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Since the original discovery of Ciclosporine a wide variety of naturally
occurring cyclosporins have been isolated and identified and many
further non-natural cyclosporins have been prepared by synthetic or
semi-synthetic means or by the application of modified culture tech-
niques. The class comprised by the cyclosporins is thus now substantial
and includes, for example, the naturally occurring cyclosporins (Thr2)-,
(Val2)- and (Nva2)- Ciclosporine (also known as cyclosporins C, D and G
respectively), as well as various semi-synthetic derivatives thereof,
such as their dihydro derivatives (e.g. as disclosed in US Patents Nos.
4,108,985; 4,210,581 and 4,220,641) including e.g. (Dihydro-MeBmtl)-
(Val2)-Ciclosporine (also known as dihydrocyclosporin D) and other na-
tural and artificial cyclosporins such as those disclosed in European
Patent Publication No. 0,058,134 Bl, for example [(D)-Ser8]-Ciclospo-
rine; UK Patent Application No. 2,115,936 A, published October 2, 1985, for
example [O-Acetyl-(D)-Ser3]-Ciclosporine; and European Patent Publication No.
0,194,972, published 17/09/86, for example [Val]2-[(D)Methylthio-Ser]3- and
[Dihydro-MeBmt]'-[Val~2-[(D)Methylthio-Sar]3-Ciclosporine.
[In accordance with now conventional nomenclature-for the cyclosporins,these are definded herein by reference to the structure of Ciclosporine
(i.e. Cyclosporin A). This is done by first indicating those residues in
the molecule which differ from those present in Ciclosporine and then
Applying the term "Ciclosporine" to characterise the remaining residues
which are identical to those present in Ciclosporine. Ciclosporine has
the formula I
A-B-Sar-MeLeu-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal -
1 2 3 4 5 6 7 8 9 10 11 (I)
133877~
- 9 - 100-7207
wherein A represents the [N-methyl-(4R)-4-but-2E-en-l-yl-4-methyl-(L)-
threonyl] residue of formula II
ICH3
x
CH2
(II)
H0 \(R) / CH
CH (R ~
CH3
-N-CH-C0-
I(s)
CH3
in which -x-y- is -CH=CH- (trans), which residue is abbreviated as
-MeBmt-, and
B is the alpha-aminobutyric acid residue, abbreviated as -Abu-.
Accordingly (Thr2)-Ciclosporine (cyclosporin C) is the compound of
formula I, wherein A has the meaning given above and B is -Thr-, and
(Dihydro-MeBmt1)-(Val2)-Ciclosporine (dihydrocyclosporin D) is the
compound of formula I, wherein A represents the -dihydro-MeBmt- residue
of formula II above in which [x-y- is -CH2-CH2-, and B is -Val-].
As the "parent" compound of the class, Ciclosporine has so far receivedthe most attention. The primary area of clinical investigation for Ciclo-
sporine has been as an immunosuppressive agent, in particular in rela-
tion to its application to recipients of organ transplants, e.g. heart,
lung, combined heart-lung, liver, kidney, pancreatic, bone marrow,
133877~
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skin and corneal transplants and, in particular, allogenic organ
transplants. In this field Ciclosporine has achieved a remarkable
success and reputation and is now commercially available and widely
employed in clinic.
At the same time, applicability of Ciclosporine to various autoimmune
diseases and to inflammatory conditions, in particular inflammatory
conditions with an aetiology including an autoimmune component such as
arthritis (for example rheumatoid arthritis, arthritis chronica pro-
grediente and arthritis deformans) and rheumatic diseases, has been
intensive and reports and results in vitro, in animal models and in
clinical trials are wide-spread in the literature. Specific autoimmune
diseases for which Ciclosporine therapy has been proposed or applied
include autoimmune hematological disorders (including, e.g. hemolytic
anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombo-
cytopaenia), systemic lupus erythematosus, polychondritis, sclerodoma,
Wegener granulamatosis, dermatomyositis, chronic active hepatitis,
myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue,
autoimmune inflammatory bowel disease (including e.g. ulcerative colitis
and Crohn's disease) endocrine opthalmopathy, Graves disease, sarcoi-
dosis, multiple sclerosis, primary billiary cirrhosis, primary juvenile
diabetes (diabetes mellitus type I), uveitis (anterior and posterior),
conjunctivitis (e.g. keratoconjunctivitis for example, vernal kerato-
conjunctivitis and keratoconjunctivitis sicca), interstitial lung
fibrosis, psoriatic arthritis and glomerulonephritis (with and without
nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or
minimal change nephropathy).
A further area of investigation has been potential applicability as an
anti-parasitic, in particular anti-protozoal agent, with possible uses
suggested including treatment of malaria, coccidiomycosis and schisto-
somiasis.
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Other cyclosporins exhibit equivalent pharmacological utility as
Ciclosporine and various proposals for application, in indications, as
set forth above are prevelant in the literature.
Dosaging for Ciclosporine (which is commerciable available under the
Registered Trade mark SANDIMMUN) varies considerably from subject to
subject and with condition to be treated, as well as with the course of
therapy and use of concommitant therapy. In general, dosaging is
monitored by HPLC, RIA or equivalent assay of blood levels and indivi-
dual subject dosaging is adjusted to maintain desired serum levels.
Commonly, oral dosaging starts at 10 or 15-20 mg/kg day for initating
therapy, reducing to 3/5 - 10 mg/kg day. Intravenous infusion is at ca.
3-5 mg/kg day for initiating therapy reducing to ca. 2-3 mg/kg day for
maintenance therapy (where infusion is required, e.g. in the case of
rejection crisis).
Solid solutions in accordance with the present invention preferably com-
prise at least 7%, particularly at least 10% by weight of pharmaceuti-
cally active, substantially water insoluble pharmaceutically active,
compound.
Solid solution in accordance with the invention comprising a cyclosporin
as active ingredient preferably comprise up to 30% of weight of cyclo-
sporin based on the total weight of ester plus cyclosporin. Lowest
concentration is only determined in relation to the therapy to be
applied but should not be below 1~ by weight.
Solid solutions comprising a cyclosporin in saccharose monolaurate or in
raffinose monolaurate are preferred. In the first - pure - monoester
solid solutions containing up to 16%, in the second monoester solutions
up to 13,5% cyclosporin are preferred since they can be diluted with
water without forming a cyclosporin precipitate. It is generally
preferred to use as high a concentration as possible.
- 12 - 100-7207
1338775
The solid solutions of the invention may be employed as, or as compo-
nents of, pharmaceutical compositions. In a further aspect the present
invention thus also provides: a pharmaceutical composition comprising a
solid solution as herein described or defined.
Such pharmaceutical compositions include dosage forms suitable for
direct administration, for example unit dosage forms for oral admini-
stration, for example tablets, capsules or the like comprising or con-
taining a solid solution in accordance with the invention. Such compo-
sitions can be prepared in accordance with conventional techniques, e.g.
by appropriate forming of the solid solution or by grinding or milling
of the solid solution and compounding of the obtained particulate, e.g.
fine particulate, product, optionally together with other ingredients,
e.g. fillers, carriers, diluents and so forth, for tabletting or for
filling into capsule shells.
The solid solutions of the invention may equally be employed in the
manufacture of other conventional solid dosage forms, e.g. oral dosage
forms such as pellets and granulates, topical dosage forms such as
creams, gels, ointments and the like, e.g. for application to the skin
or eye; and rectal dosage forms such as suppositories.
Oral unit dosage forms as aforesaid comprising a cyclosporin as active
ingredient, for example Ciclosporine, suitably comprise from 20 to 250,
preferably 25 to 100, e.g. about 50 mg cyclosporin per unit dosage.
Suitably the ratio of water soluble fatty acid ester to cyclosporin in
such compositions is of the order of from 10:0.5 to 10:3.0, especially
from 10:1.0 to 10:2.0, e.g. about 10:1.2 to 10:1.6 parts by weight.
Such pharmaceutical compositions also include dosage forms intended fordilution in aqueous media prior to administration, for example infusion
concentrates comprising or consisting of said solid solutions, to be
dissolved in an appropriate aqueous infusion medium such as physiologi-
cal saline, for administration i.v., as well as preparations for disso-
13~8775
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lution in aqueous media, e.g. drink preparations and the like, prior to
ingestion. To aid dissolution, such compositions will preferably com-
prise the solid solution in particulate, especially fine particulate,
form, optionally together with other excipents or additives. Uhere such
compositions comprise a cyclosporin as active ingredient the ratio of
ester to ciclosporin will appropriately be as described above in rela-
tion to unit oral dosage forms.
Compositions of this type will conveniently be presented in an
appropriate container e.g. ampoule, phial bottle or the like.
The solid solutions of the invention are readily soluble in aqueous
media to provide solutions which may be further diluted to any desired
concentration without clouding or precipitation. At high concentrations
increase in viscosity is observed. On further dilution clear micellar
solutions are formed. Such solutions are also novel and form part of the
invention.
More particularly the invention provides: a solution obtained by dissolving
a solid solution as herein described or defined in an aqueous medium or in
a solvent which is miscible with water;
as well as: a solution comprising a substantially water insoluble, pharmac-
eutically active polypeptide and a water soluble monoester of saturated or
unsaturated (C6_13) fatty acid and a polyol (as solubiliser for said
peptide) in an aqueous medium or in a solvent which is miscible with water.
If such a liquid solution is formed by simultaneous mixing of the threecomponents monoester, active compound and water, a liquid solution of
active compound, especially in higher concentration, is only possible
after vigorous agitation. For this reason, the most simple method is,
firstly preparing the solid active compound solution in the monoester,
-after which diluting with water can be carried out without problems.
Dissolving the active compound in the liquified monoester and subse-
quently diluting the obtained mixture, after an optional intermediate
1338775
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treatment with hot ethanol, with water is known from the GB-Patent
1.134.878 (page 3, lines 22-32 and page 6, lines 34-39). However, there
is no teaching, that an intermediate cooling is practised and that a
solid solution would have been formed.
Liquid solutions of the invention are clear or perfect or substantiallyclear or perfect. The pharmaceutically active component, e.g. substan-
tially water insoluble peptide component is preferably present entirely
or substantially entirely in true solution. Solutions of the invention
are free or substantially free of pharmaceutically active component in
colloidal or other associated or particulate form. They are free or sub-
stantially free of turbidity or clouding as may be evidenced by freedom
from formation of precipitate or deposit on ultracentrifugation.
Solutions in accordance with the invention in aqueous media may of
course comprise or be present together with further components other
than water. They may for example also incorporate water miscible compo-
nents. Such solutions equally include solutions as defined in which
other non water soluble, e.g. colloidal components are present, e.g. in
dispersion, for example, in the case of solutions for oral administra-
tion, flavouring agents and so forth. For the purposes of i.v. admini-
stration solutions in accordance with the invention will preferably
comprise the active ingredient and the fatty acid component in an
intravenously administrable aqueous medium such as isotonic saline and
be free or substantially free of water insoluble additives. Liquid
solutions in accordance with the invention may also be employed as or as
components of occular formulations, e.g. eye drops.
The present invention accordingly also provides: a pharmaceutical compo-
sition (for example for intravenous, oral or occular administration)
comprising a solution in an aqueous medium as herein described or
defined.
In the drawings which illustrate this invention:
Fig. 1 is a plot of concentrations v. time for three different solutions, and
Fig. 2 is a plot of solubilizing capacity v. concentration of a solubilisation solution.
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The invention also provides using the liquid solubilisate solution as
well as the solid solution orally, buccally, lingually, occularly,
cutaneously, intracutaneously, percutaneously, vaginally or rectally.
The solubilisate solution can additionally be applied parenterally.
Solid solutions of Ciclosporine in accordance with the present invention
and aqueous solutions derived from the use are usable as alternative for
the existing intravenous Ciclosporine infusion concentrate in alcohol in
the presence of CremophorR EL, a polyoxyethylated castor oil, or the oral
solution in olive oil, which are the state of the art for Ciclosporine.
A comparison of Ciclosporine and saccharose or raffinose monolaurate con-
taining aqueous solutions of the invention with the mentioned CremophorR
EL containing Ciclosporine infusion concentrate in a test in which dogs
were injected intravenously with these solutions, did not show different
Ciclosporine plasma concentrations. This means that the distribution of
the active compound in the body is the same. In Figure l the concentra-
tions are plotted in ng/ml and the time t in hours. Curve l presents the
saccharose monolaurate solution, curve 2 the raffinose monolaurate solu-
tion and curve 3 the commercial solution.
A comparison of a saccharose monolaurate containing Ciclosporine solution
with the commercial solution in olive oil in a test in which these solu-
tions were administered orally to rats resulted in a bioavailability im-
provement of 26% of the solution according to the invention.
The invention also provides a solid solution of a water soluble pharma-
ceutically active compound in a monoester, used according to the inven-
tion, since an improvement of bioavailability is also obtained with this
type of agent.
The production of the solid solution is preferably carried out in such
manner, that the agent and the sugar ester are dissolved together in a
liquid solvent and the solvent is volatilised from the obtained mixture.
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Volatilising can be realised by evaporation or by freeze drying. As a vo-
latile solvent water or preferably ethanol are used. If water is used,
volatilising is preferably effected by freeze drying. The invention also
provides a process for the production of the solid solution, comprising
dissolving the active compound and the monoester together in a volatile
solvent, volatilising the solvent and recovering the obtained solid so-
lution.
The invention additionally provides a process comprising melting the
monoester by heating, dissolving the active compound in the melt, soli-
difying by cooling and recovering the obtained solid solution. Additional
pharmaceutical excipients can be added to the solid solution, e.g. to
lubricate, to thicken or to dye it. Excipients which are substantially
water insoluble are solubilised under the influence of the monoester and
can also be incorporated in the solid solution.
Especially when the solid solution is obtained according to the firstlydescribed process, an anti-microbiological treatment is possible before
the solid solution is formed and filled in ampoules. The anti-microbio-
logical treatment can be easily integrated in the process of production,
if the solid solution is formed according to the secondly described
process by raising the liquefaction temperature.
The weight ratios of the amount of active compound to the amount of
monoester can be varied up to the maximum solubilisation capacity of the
monoester.
The saccharose ester of lauric acid is an excipient, widely distributed in
the food industry and is easily biodegradable. The solubilisation capacity
of the monoester, having a mono ester content of >80%, for Ciclosporine in
aqueous solutions at room temperature and at different monoester concen-
trations was as follows:
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TABLE I
Saccharose monolaurate concentration Solubilising capacity for
in water, containing 0.9~ of weight Ciclosporine in mg/ml at room
of NaCl. temperature.
1 % 1,5 mg/ml
3,5 5,5
8,0
6,5 10,0
8 13,0
16,0
35~0
The solubilising capacity in mg/ml and the concentration of the
solubilisator solution in % of weight are plotted in Fig. 2; a constant
ratio is shown. The Ciclosporine solid solution can thus be diluted
with the brine to every desirable extent, without destabilisation and
precipitation of the drug compound or the solution becoming opalescent.
From table 1 it is seen that a maximum concentrated aqueous solution ofCiclosporine can be obtained if the weight ratio of the monoester to
Ciclosporine is 100:16.
The present invention yet further provides a solid solution or solutionin an aqueous medium as hereinbefore defined or described, for use as a
pharmaceutical; as well as a method for effecting therapy employing a
pharmaceutically active substance in a subject requiring treatment with
said substance, which method comprises administering a solid solution
or solution in an aqueous medium as herein defined or described and
comprising said substance as active ingredient, in an amount sufficient
to effect therapy.
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As applied to the solid solutions of the invention and solutions of theinvention in aqueous media comprising a cyclosporin as active ingre-
dient the present invention accordingly provides:
a) use thereof as immunosuppressants, for the treatment of inflamma-
tory conditions or for the treatment of parasitic disease, e.g.
use in any of the diseases or conditions hereinbefore described
in relation to cyclosporin, e.g. Ciclosporine, therapy, as well
as
b) methods of immunosuppressive, anti-inflammatory or anti-parasitic
treatment, e.g. methods of treatment of any of the specific
diseases or conditions hereinbefore described in relation to
cyclosporin, e.g. Ciclosporine, therapy, comprising use thereof
in immunosuppressive, anti-inflammatory or anti-parasitic
effective amounts.
As will be apppreciated, all components of solid solutions and solu-
tions in aqueous media for use as defined above will themselves be
pharmaceutically acceptable, e.g., in relation to intravenous admini-
stration, intravenously applicable.
The following examples are illustrative of the present invention:
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A) Preparation of solid solution and their use
Example 1
A suitable saccharose monolaurate is, since it has a monoester weight
content of >80%, the commercially available product L-1695 of Mitsubishi-
-Kasei Food Corporation, Tokyo 104, Japan. The product has an HLB-value
of at least 12.3. The purity of the lauryl ester residue is about 95%.
The melting point is about 35C, the decomposition temperature is about
235C. The surface tension of an aqueous solution containing an amount of
0.1% of weight of monoester is about 72.0 dyn/cm at 25C.
lO00 mg of this saccharose monolaurate product and 160 mg of Ciclosporine
are dissolved in 20ml of ethanol and the solvent evaporated in a Rotava-
porisator to yield the desired solid solution.. The residue is pulverised
in a mortar under dry conditions, since the monoester is hygroscopic.
Example 2
lO00 mg of the saccharose monolaurate of Example 1 are mixed with 160 mg
of Ciclosporine and the mixture heated to 150C while stirring. The ob-
tained clear solution is cooled to room temperature to yield the desired
solid solution and then processed further as described in Example l.
Example 3
a) lO00 mg of the saccharose monolaurate employed in Example 1 and 30 mg
of Proquazone (Biarison~) are dissolved in 20ml of 100 ~ ethanol and
the solvent evaporated completely in a Rotavaporisator to yield the
desired solid solution. The residue is reduced to a fine powder in a
mortar and is mixed with lO mg of magnesium stearate as a lubricator.
b) A similar solid solution is obtained by substituting the Proquazone
ingredient with 30 mg of Progesterone.
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Example 4
Solid solutions having the following compositions are obtainable
analogously to Example 1.
SOLID SOLUTION CICLOSPORINE SACCHAROSE MONOESTER
CONTENT CONTENT *
A 120 mg 1000 mg Saccharose
monocaproate
B 130 mg 1000 mg Saccharose
monomyristate
C 250 mg 1500mg Saccharose
monooleate
*Monoester content for all listed esters >80 ~.
The obtained solid solutions are completely soluble in water.
Example 5
Solid solutions containing Ciclosporine in 1000 mg of raffinose mono-
laurate and in 1000 mg of raffinose monooleate respectively (monoester
content >80%) are prepared using the evaporation method. In the
raffinose monolaurate 135 mg of Ciclosporine and in raffinose monooleate
200 mg of Ciclosporine could be dissolved. The obtained solid solutions
are completely soluble in water.
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Example 6
2000 mg of saccharose monolaurate (monoester content >80X) and 320 mg of
Ciclosporine are dissolved in 50 ml of an aqueous solution containing
lOX of weight of ethanol and the liquid micellar solution is filled in
ampoules for injection and lyophilised under sterile conditions. The
thus obtained solid solution in the ampoule can be dissolved within 30
seconds by sh~k~ng in a 0.9% NaCl containing aqueous solution to yield a
clear solution as product.
EXAMPLE 7
362 mg of a solid solution prepared according to the method of Example 1
are mixed with 375 mg of water free citric acid and 150mg of sodium bi-
carbonate and the mixture pressed. The thus obtained effervescent tablet
contains 50mg of Ciclosporine and dissolves within 2.5 minutes in water
without leaving a residue. The obtained solution is adminsterable orally
to provide effective Ciclosporine therapy, e.g. on administration of one
or several such dosages, e.g. 2 to 4x per day.
Example 8
181.25 mg of a solid solution, prepared according to the method of Exam-
ple 1 containing 25 mg of Ciclosporine are mixed while stirring with
198.75 mg of viscous liquid paraffin and filled into hard gelatine
capsules. The release rate of Ciclosporine from the obtained oral unit
dosage form is measured in water at 37C:
. . --
-
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Time (min.)~ of weight of Ciclosporine standard
dissolved deviation
mean value (n=3)
3 2,2
14 3,5
29 6,8
7,0
98 0,6
120 98 0,6
180 98 0,6
Example 9
1000 mg of saccharose monolaurate (monoester content >80~) and 30 mg
of Proquazone (BiarisonR) are processed according to the evaporation
method to a solid solution. The powder is moulded with 1.0 g of Adeps
solidus Ph. Eur. to a suppository, thus diminishing the hygroscopi-
city.
B) Preparation of a liquid micellar solution and its use
For human application the solid solution is preferably transformed
into a liquid (aqueous) micellar solution, of which generally a dosis
is used corresponding to an amount of 40 to 2000 mg of Ciclosporine
for oral or intravenous application. For the oral application the
higher dosage and for intravenous application the lower dosage within
the range are taken.
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Example 10
16 mg of Ciclosporine are solubilised in 1 ml of an isotonic aqueous
solution of 10~ of weight of saccharose monolaurate with a monoester
amount of >80% of weight. The solution is used for the treatment of
Psoriasis by intralesional injection. Repeated injection is effective
in the treatment of Psoriasis.
Example 11
1000 mg of saccharose monolaurate having a monoester content of >80~
by weight and 160 mg of Ciclosporine are dissolved in a liquid mixture
of 16 ml of 1,2-propylene glycol and 91 ml of distilled water,
sterilised by filtration and filled in an ampoule for injection. The
dosage of 1.5 mg of Ciclosporine pro ml of solubilisate solution
corresponds to the average dosage range and a dilution to a ratio of
1:33 of the normal Ciclosporine infusion concentrate of 50 mg/ml.
Example 12
With p-hydroxy benzoic acid methyl ester as a substantially water
insoluble excipient, Proquazone (BiarisonR) and Progesterone as
substantially water insoluble pharmaceutically active compounds, clear
solubilisate solutions are prepared with saccharose monolaurate having
a monoester content of >80~. In an aqueous solution of solubilisate
(10~ by weight) 8 mg of p-hydroxybenzoic acid methyl ester, 3 mg of
Proquazone and 3 mg of Progesterone can be solubilised per ml. The
solubilisate solutions are stable over a long period of time at room
temperature. A solid solution is obtained by removing the water by
freeze drying.
