Note: Descriptions are shown in the official language in which they were submitted.
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4-20017/A
Pharmaceutical compositions for sparingly soluble therapeutic agents
The present invention relates to pharmaceutical compositions for sparingly
soluble
therapeutic agents as well as to processes for the preparation of said
compositions.
Generally, the oral administration of a therapeutic agent in solid dosage
forms such as
tablets, capsules or drag6es affords advantages over other, for example
parenteral, dosage
forms. Diseases that have to be treated by administering injections are felt
purely
subjectively to be more serious than other diseases in the treatment of which
the
administration of tablets, capsules or drag6es is little noticed. The
suitability of such
dosage forms for self-medication by patients themselves is especially
advantageous,
whereas parenteral dosage forms, aside from a few exceptions, have to be
administered by
the physician or paramedical staff.
After administration and dissolution of an oral dosage form, the
gastrointestinal fluid, e.g.
gastric or intestinal juice, acts on the therapeutic agents. Many therapeutic
agents for oral
administration have lipophilic properties and are therefore sparingly soluble
in the
aqueous environment of the gastrointestinal tract. Under these circumstances,
the amount
of therapeutic agent which can be resorbed is diminished, resulting in reduced
bioavailability. This generally necessitates the application of higher dosages
of the
therapeutic agent, resulting in biological variability and undesirable
variations in efficacy.
To enhance the solubility of sparingly soluble therapeutic agents, so-called
solubilisers
have been described in the literature, e.g. hydrophilic co-solvents, typically
ethanol,
propylene glycol, liquid polyethylene glycols, or lipophilic solubilisers,
typically lecithin,
fatty acid polyglycol ester or fatty acid glycerol polyglycol ester. The use
of such
solubilisers is problematical owing to reduced tolerance and lack of stability
of the dosage
form resulting, for example, in dehomogenisation.
Accordingly, DOS 40 05 190 proposes the use of glycerol fatty acid partial
esters or
partial esters of propylene glycol. The use of these excipients (co-
surfactants) is
disadvantageous because they are only obtainable in the narrow HLB range from
2 to 3,
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permitting only limited variation of the ratios of the
components present in the carrier composition for adjustment
to the different solubilities of the therapeutic agents to
be solubilised.
It is the object of this invention to enhance the
solubility, resorptive capacity and consequently also the
bioavailability of therapeutic agents for oral
administration by selecting particularly suitable
excipients.
This object is achieved by this invention, which
relates to a particularly useful pharmaceutical composition
for the enhanced solubilisation of a therapeutic agent which
is sparingly soluble in water and present in the carrier
composition. The composition of this invention consists of
the following components:
a) c. 10-50% by weight, based on the carrier
composition, of a co-surfactant which is substantially pure
or which is in the form of a mixture, having a hydrophilic-
lipophilic balance of less than 10 (HLB value according to
Griffin), selected from the group consisting of polyglycerol
fatty acid esters and sorbitan fatty acid esters;
b) c. 5-40% by weight, based on the carrier
composition, of a pharmaceutically acceptable oil which is
substantially pure or which is in the form of a mixture,
comprising a triglyceride as essential lipophilic component;
and
c) c. 10-50% by weight, based on the carrier
composition, of a nonionic surfactant which is substantially
pure or which is in the form of a mixture, having a HLB
value of more than 10;
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and further optional pharmaceutically acceptable excipients.
According to one aspect of the present invention,
there is provided a pharmaceutical composition for the
solubilization of a poorly water-soluble pharmaceutical
active agent in a carrier composition characterized in that
the carrier composition comprises the components: a) ca.
10-50% by weight, based on the carrier composition, of a
substantially pure co-surfactant, or one which is present as
a mixture, with a hydrophilic-lipophilic equilibrium of less
than 10(HLB value according to Griffin), selected from the
group of polyglycerol fatty acid esters and sorbitan fatty
acid esters; b) ca. 5-40% by weight, based on the carrier
composition, of a substantially pure, pharmaceutically
acceptable oil, or one which is present as a mixture, which
contains a triglyceride as lipophilic component; and c) ca.
10-50% by weight, based on the carrier composition, of a
substantially pure non-ionic surfactant, or one which is
present as a mixture, with a HLB value greater than 10; and,
optionally, further pharmaceutically acceptable excipients.
The invention also relates to the process for the
preparation of a pharmaceutical composition containing a
solubilised therapeutic agent which is sparingly soluble in
water and present in a carrier composition comprising the
indicated components. This pharmaceutical composition is
suitable for filling into oral dosage units, e.g. into
starch or hard or soft gelatin capsules.
According to another aspect of the present
invention, there is provided a process for production of a
pharmaceutical composition as described herein, wherein
components a), b) and c) and, optionally, further
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pharmaceutically acceptable, water-soluble excipients are
mixed together in any order to form a mixture; the
pharmaceutical active agent which is poorly soluble in water
is dispersed in the mixture; and, optionally, the dispersion
is brought to a suitable, orally administrable form.
Within the scope of the description of this
invention, the terms used above and hereinafter are defined
as follows:
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The term "pharmaceutical composition" defines the mixture of a solubilised
pharmaceutical therapeutic agent, or a combination of therapeutic agents,
which is
sparingly soluble in water and present in a carrier composition comprising the
indicated
components, which mixture can be processed to oral dosage forms, preferably
starch or
hard or soft gelatine capsules.
The term "solubilised" or "solubilisation" of a therapeutic agent or
therapeutic agent
mixture which is sparingly soluble in water defines a dispersion process
induced by the
action of a suitable solubiliser which enhances the dispersibility of the
therapeutic agent to
such a degree that a therapeutically effective dosage is completely dissolved
or made at
least bioavailable by a partial dissolution process. The term "dispersibility"
defmes a
measure for the formation of micro-emulsions, of genuine molecular solutions
of the
therapeutic agents and the excipients in water, and of colloidal solutions,
typically
solutions of association colloids or molecular colloids which are clear or
opalescent, and
which contain no solid particles at all after optional filtration, preferably
with sterile filters
having a pore diarneter of c. 5-10 m, or of e.g. micellar solutions or
spherocolloids which
can only be separated in an ultracentrifuge. The dispersibility can be given,
for example,
in mg or mmol per litre of water.
A therapeutic agent or therapeutic agent mixture which is sparingly soluble in
water has a
solubility in water of less than 500 mgl1000 ml, preferably of less than 200
mg/ml.
Particularly suitable sparingly soluble therapeutic agents are
immunosuppressants having
a macrolide structure, typically cyclosporin A, cyclosporin G, rapamycin,
tacrolimus,
deoxyspergualin, mycophenolate-mofetil, gusperimus, non-steroidal
antiphlogistic agents,
typically acetylsalicylic acid, ibuprofen or S(+)-ibuprofen, indomethacin,
diclofenac,
piroxicam, meloxicam, tenoxicam, naproxen, ketoprofen, flurbiprofen,
fenoprofen,
felbinac, sulindac, etodolac, oxyphenbutazone, phenylbutazone, nabumetone;
dihydro-
pyridine derivatives having cardiovascular activity, e.g. nifedipine,
nitrendipine,
nimodipine, nisoldipine, isradipine, felodipine, amlodipine, nilvadipine,
lacidipine,
benidipine, masnidipine, furnidipine, niguldipine; depressants and stimulants,
typically a-
liponic acid, muramyl peptides, e.g. muramyl dipeptide or muramyl tripeptide,
romurtid,
fat-soluble vitamins, typically vitamin A, D, E or F; alkaloids, e.g.
vincopectin,
vincristine, vinblastin, reserpine, codeine, ergot alkaloids, typically
bromocriptine,
dihydroergotamine, dihydroergocristine; antitumour agents, e.g. chlorambucil,
etoposide,
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teniposide, idoxifen, tallimustin, teloxantron, tirapazamine, carzelesin,
dexniguldipine,
intoplicin, idarubicin, miltefosin, trofosfamide, teloxantrone, melphalan,
lomustine, 4,5-
bis(4'fluoroanilino)phthalimide; 4,5-dianilinophthalimide; immunomodulators,
typically
thymoctonan, prezatid copper acetate; antiinfectives, e.g. erythromycin,
daunorubicin,
gramicidin, doxorubicin, amphotericin B, gentamycin, leucomycin, streptomycin,
ganefromycin, rifamexil, ramoplanin, spiramycin; antimycotic agents, typically
fluconazole, ketoconazole, itraconazole; H2-receptor antagonists, typically
famotidine,
cimetidine, ranitidine, roxatidine, nizatidine, omeprazole, proteinkinase
inhibitors, e.g.
N-[4-methyl-3-(4-pyridin-3-ylpyrimidin-2-ylamino)phenyl]benzamide, N-benzoyl-
staurosporin; HIV-1-protease inhibitors, e.g. BOC-PhecPhe-Val-Phe-morpholine
or its
O-[2-(2-methoxyethoxy)acetoxy] derivative; leucotriene antagonists, typically
N-[4-(5-
cyclopentyloxycarbonylamino-l-methylindol-3-ylmethyl)-3-methoxybenzoyl]-2-
vinyloxy] benzenesulfonamide.
Particularly preferred therapeutic agents are cyclosporins, rapamycin,
tacrolimus,
deoxyspergualin, mycophenolate-mofetil, nifedipine, nimodipine, etoposide,
ibuprofen
and a-liponic acid.
Instead of being in the form of a free acid or in basic form, the therapeutic
agent may be
present in the pharmaceutical composition in the form of a pharmaceutically
acceptable
salt, typically as hydrobromide, hydrochloride, mesylate, acetate, succinate,
lactate,
tartrate, fumarate, sulfate, maleate, and the like.
The concentration of the therapeutic agent or combination thereof is
determined by the
dosage to be administered and can be in the range from 1 to 30% by weight,
preferably
from 5 to 20% by weight, more particularly from 5 to 12% by weight, based on
the weight
of the carrier composition.
The carrier composition for one of the cited therapeutic agents or for a
therapeutic agent
combination is defined as follows:
The requirement "substantially pure" with respect to a component present in
the carrier
composition defines a degree of purity higher than 90 %, preferably higher
than 95 %, of
this component, prior to being mixed with the other components of the
therapeutic agent
combination. A component defined as "substantially pure" preferably has a
uniformly
defined structure and composition.
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Components present as mixture in the carrier composition can be mixtures of
natural
substances whose composition depends on the raw material itself, on its
isolation and its
further processing. The components of such mixtures are indicated in the
specifications of
the producer.
The polyglycerol fatty acid ester of component a) consists of a substantially
pure
polyglycerol fatty acid ester or of a mixture of different polyglycerol fatty
acid esters,
wherein the polyglycerol chain preferably contains up to and including 10
units of
glycerol which are esterified with 1-10 acid radicals of saturated or
unsaturated carboxylic
acids having an even number of 8-20 carbon atoms.
The acid radical of a saturated carboxylic acid having an even number of 8-20
carbon
atoms which esterifies the polyglycerol chain is preferably straight-chain and
contains 12,
14, 16 and 18 carbon atoms, typically n-dodecanoyl, n-tetradecanoyl, n-
hexadecanoyl or
n-octadecanoyl.
The acid radical of an unsaturated carboxylic acid having an even number of 8-
20 carbon
atoms, which esterifies the polyglycerol chain, is preferably straight-chain
and contains
12, 14, 16 and 18 carbon atoms and 1 double bond, typically 9-cis-dodecenoyl,
9-cis-tetra-
decenoyl, 9-cis-hexadecenoyl or 9-cis-octadecenoyl.
The following names are also conventionally used for the cited acid radicals:
9-cis-dodecenoyl (lauroleoyl), 9-cis-tetradecenoyl (myristoleoyl), 9-cis-
hexadecenoyl
(palmitoleoyl), 6-cis-octadecenoyl (petroseloyl), 6-trans-octadecenoyl
(petroselaidoyl),
9-cis-octadecenoyl (oleoyl), 9-trans-octadecenoyl (elaidoyl), 11-cis-
octadecenoyl
(vaccenoyl), 9-cis-icosenoyl (gadoleoyl), n-dodecanoyl (lauroyl), n-
tetradecanoyl
(myristoyl), n-hexadecanoyl (palmitoyl), n-octadecanoyl (stearoyl), n-
icosanoyl
(arachidoyl).
Suitable polyglycerol fatty acid esters having a uniformly defined structure
are typically
diglycerol monocaprate, diglyceryl monolaurate, diglycerol diisostearate,
diglycerol
monoisostearate, diglycerol tetrastearate (polyglyceryl 2-tetrastearate),
triglycerol
monooleate (polyglyceryl 3-monooleate), triglycerol monolaurate, triglycerol
mono-
stearate (polyglyceryl 3-stearate), triglycerol monoisosterate, hexaglycerol
dioleate
(polyglycerol 6-dioleate), hexaglycerol distearate (polyglycerol 6-
distearate), decaglycerol
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dioleate (polyglycerol 10-dioleate), decaglycerol tetraoleate (polyglycerol 10-
tetraoleate),
decaglycerol decaoleate (polyglycerol 10-decaoleate), decaglycerol
decastearate
(polyglycerol l0-decastearate). The CTFA nomenclature is given within the
brackets.
These products are commercially available under the registered trade mark
Caprol (trade
mark of Karlshamns USA Inc., Columbus Ohio). Specific product names: CAPROL
2G4S, 3G0, 3GS, 6G20, 6G2S, lOG2O, 10G40, 1OG100, 1OG10S. Further products are
available under the names of DGLC-MC, DGLC-ML, DGLC-DISOS, DGLC-MISOS,
TGLC-ML and TGLC-MISOS from Solvay Alkali GmbH, D-3002 Hannover.
The mixture of different polyglycerol fatty acid esters is specified under
names such as
decaglycerol monooleate, dioleate, polyglycerol ester of mixed fatty acids,
polyglycerol
ester of the fatty acids, polyglycerol caprate, cocoate, laurate, lanolinate,
isostearate or
rizinolate and are commercially available under the registered trade mark
Triodan and
Homodan (trade mark of Grindsted Products, Grindsted Denmark), specific
product
names: TRIODAN 20, 55, R90 and HOMODAN MO; Radiamuls (trade mark of
Petrofina (FINA), Bruxelles Belgium), specific product name: RADIAMULS Poly
2253;
under the name CAPROL PGE 860 or ET, or under the registered trade mark
Plurol (trade mark of Gattefoss6 Etablissements, Saint-Priest, France),
specific product
name: PLUROL Stearique WL 1009 or PLUROL Oleique WL 1173. Further products are
available under the names PGLC-C 1010 S, PGLC-C 0810, PGLC 1010/S,
PGLC-L T 2010, PGLC-LAN 0510/S, PGLC-CT 2010/90, PGLC-ISOS T UE,
PGLC-R UE, PGLC-ISOS 0410 from Solvay Alkali GmbH, D-3002 Hannover.
The cited polyglycerol fatty acid esters conform to the specifications listed
in the
Foodchemical Codex FCC III under "Monographs", p.232 regarding "description",
"requirements" and "tests". Applicable are especially the product
specifications published
by the indicated producers on the data sheets of the specified product, in
particular
specifications such as monoester content, drop point, free glycerol, free
fatty acid, iodine
value, form, antioxidants, HLB value, properties and stability.
The cited polyglycerol fatty acid esters in particular conform to the
requirements of
number E 475 of the EC food additives directive (EC directive 74/329) as well
as the
regulation of U.S. FDA Code 21 CFR 172.854.
The sorbitan fatty acid ester of component a) preferably consists of a
sorbitan fatty acid
ester which is substantially pure, or of a mixture of different sorbitan fatty
acid esters, and
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the sorbitan skeleton is esterified with 1-3 acid radicals of a saturated or
unsaturated
straight-chain carboxylic acid having an even number of 8-20 carbon atoms.
The acid radical of a saturated carboxylic acid having an even number of 8-20
carbon
atoms which esterifies the sorbitan skeleton is preferably straight-chain with
12, 14, 16
and 18 carbon atoms, typically n-dodecanyol, n-tetradecanoyl, n-hexadecanoyl
or
n-octadecanoyl.
The acid radical of an unsaturated carboxylic acid having an even number of 8-
20 carbon
atoms is preferably straight-chain with 12, 14, 16 and 18 carbon atoms,
typically oleoyl.
Suitable sorbitan fatty acid esters are preferably sorbitan monolaurate,
sorbitan
monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan
monooleate, sorbitan
sesquioleate and sorbitan trioleate. These products are commercially available
under the
registered trade mark Span (trade mark of Atlas, Wilmington USA), specific
product
names: SPAN 20, 40, 60, 65, 80 and 85; Arlacel (trade mark of Atlas),
specific product
names: ARLACEL 20, 40, 60, 80, 83, 85 and C; Crill (trade mark of Croda
Chemicals
Ltd., Cowick Hall, Snaith Goole GB), specific product names: CRILL 1, 3 and 4;
Dehymuls (trade mark of Henkel, Dusseldorf DE), specific product names:
DEHYMULS SML, SMO, SMS, SSO; Famodan (trade mark of Grindsted Products,
Grindsted Denmark), specific product names: FAMODAN MS and TS; Capmul (trade
mark of Karlshamns USA Inc., Columbus Ohio), specific product names: CAPMUL S
and
0; Radiasurf (trade mark of Petrofina (FINA), Bruxelles Belgium), specific
product
names: RADIASURF 7125, 7135, 7145 and 7155.
The cited sorbitan fatty acid esters and the polyglycerol fatty acid esters
conform to the
specifications listed in the British Pharmacopeia (special monography) or in
Ph.Helv.VI.
Applicable are especially the product specifications published by the
indicated producers
on the data sheets of the specified product, in particular specifications
regarding e.g. form,
colour, HLB value, viscosity, ascending melting point and solubility.
Component a) has a HLB value of less than 10. Component a) is present in the
carrier
composition in an amount of 10-50% by weight, preferably 15-40% by weight,
more
particularly 15-20% by weight, based on the total weight of the carrier
composition.
Component a) can also consist of product mixtures of the cited polyglycerol
fatty acid
esters with each other or of the cited sorbitan fatty acid esters with each
other, or of
20ti
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product mixtures of said polyglycerol fatty acid esters with said sorbitan
fatty acid esters.
A pharmaceutically acceptable oil b) is a triglyceride of natural origin or a
synthetic or
semi-synthetic substantially pure triglyceride. It is preferred to use a
triglyceride of natural
origin wherein the glycerol is esterified by acid radicals of saturated or
unsaturated
carboxylic acids having an even number of 8-20 carbon atoms. Such acid
radicals are
defined above and are typically n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl,
n-octadecanoyl or oleoyl.
Suitable triglycerides of natural orgin are, for example, ground nut oil,
sesame oil,
sunflower oil, olive oil, corn oil, soybean oil, castor oil, cottonseed oil,
rape-seed oil,
thistle oil, grape-seed oil, fish oil or neutral oil.
Component b) is present in the carrier composition in an amount of c. 5-40% by
weight,
preferably 10-35% by weight, based on the total weight of the carrier
composition.
Component b) can also consist of product mixtures of the indicated
pharmaceutically
acceptable oils.
The nonionic surfactant of component c) having a HLB value of more than 10 is
preferably an amphiphilic substance whose hydrophilic component consists of
polyethylene oxide, the average molecular weight of the polyethylene oxide
component
being c. 600-2500, corresponding to 15-60 units of ethylene oxide.
Suitable nonionic surfactants are typically reaction products of natural or
hydrogenated
castor oil and ethylene oxide. Such products are commercially available, e.g.
under the
registered trade mark Cremophor , Niccol and Emulgin . Suitable nonionic
surfactants
are also polyoxyethylene (POE) sorbitan fatty acid esters (polysorbates),
typically
POE-(20)sorbitan monolaurate, POE-(20)sorbitan monopalmitate, POE-(20)sorbitan
tristearate, POE-(20)sorbitan monooleate or POE-(20)sorbitan trioleate as well
as
polyoxyethylene fatty acid esters, typically POE-(20, 30, 40, 50)stearate.
Such products
are commercially available e.g. under the registered trade marks Tween and
Myrj .
Component c) is present in the carrier composition in an amount of c. 10-50%
by weight,
preferably 20-45% by weight, based on the total weight of the carrier
composition.
Component c) can also consist of product mixtures of the indicated
pharmaceutically
acceptable nonionic surfactants.
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Suitable pharmaceutically acceptable additional excipients are added to the
carrier
composition in such an amount as to make up 100% by weight together with the
amounts
of components a), b) and c) as well as of the therapeutic agent or combination
thereof.
Additional excipients can be present in the carrier composition in amounts of
0 % to
c.75% by weight. Additional excipients depend on the choice of the
pharmaceutical
dosage form. Pharmaceutically acceptable diluents are added to liquid dosage
forms, such
as drops, suspensions or capsule fillings, typically ethanol, propanol,
isopropanol,
propylene glycol, polyethylene glycol, glycerol or water, or mixtures thereof.
Conventional excipients can also be added, for example preservatives,
typically benzyl
alcohol, ethanol, p-hydroxybenzoate, sorbic acid; antioxidants, typically
tocopherols,
butylhydroxyanisol, butylhydroxytoluene, ascorbic acid, ascorbylpalmitate;
stabilisers,
typically citric acid, tartaric acid, EDTA, flavourings or fragrances.
Gelatin capsules are suitably filled with conventional plasticisers to
stabilise the gelatin
shell. Such excipients are typically sorbitol, sorbitan, polyvinylpyrrolidone,
hydroxy-
propylmethyl cellulose (HPMC), hydroxypropyl cellulose, methyl cellulose or
colloidal
silicon dioxide.
The invention also relates to the process for the preparation of the above-
defined
pharmaceutical composition, which comprises mixing components a), b) and c)
and
optional further pharmaceutically acceptable excipients in any order,
dispersing in this
mixture the pharmaceutical therapeutic agent which is sparingly soluble in
water and, if
desired, processing the dispersion to a suitable dosage form for oral
administration.
Dispersion of the therapeutic agent or therapeutic agent combination can be
carried out
after blending components a), b) and c) and the other excipients.
Alternatively, the
therapeutic agent or therapeutic agent combination can be dispersed in a
single component
or in a mixture of two of the indicated components, and the remaining
components can
then be added. Solubilisation or dispersion processes can be accelerated by
heating single
components or mixtures thereof. Preferred reaction conditions are those
promoting the
formation of a colloidally dispersed phase.
The process is carried out in an inert gas atmosphere, typically under
nitrogen, helium or
argon, in the presence of therapeutic agents susceptible to oxygen.
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Before carrying out said process, the oxygen present in the liquid components
can be
removed by application of low pressure, typically of 50-100 mbar, or by
ultrasonication.
This process is suitably carried out using a double-walled reaction vessel
equipped with
stirrer.
The conversion into a dosage form for oral administration is carried out in
per se known
manner. Dosage forms for oral administration, such as drops, suspensions,
emulsions and
the like, can be prepared by conventional methods described in standard text
books such
as in Hagers Handbuch der Pharmazeutischen Praxis or Remington's
Pharmaceutical
Sciences.
Capsules are preferably dry-filled capsules made of gelatin and, in some
cases, with the
addition of glycerol or sorbitol, and which dissolve without delay under the
action of
gastric juice. Alternatively, capsules made of starch can be used, e.g. those
available under
the registered trade mark Capill , supplied by Capsugel/Warner Lambert. The
capsules
may be blended with further excipients and fillers, typically lactose, starch,
lubricants, e.g.
starch or magnesium stearate. Soft capsules can additionally contain liquids
such as
lecithin, fats, oils, paraffin oil or liquid polyethylene glycol. Depending on
the dosage,
dry-filled capsules are suitably of size 0-4 and, preferably, of size 0-2.
Suitable
commercially available capsules are those supplied by Shionogi, Capsugel or
Scherer.
The following Examples illustrate the invention in more detail without
restricting the
general scope defined above. The cited therapeutic agents are representative
of all the
therapeutic agents indicated above. Temperatures are given in degrees
centigrade.
Example 1
Composition for fclling into soft gelatin capsules; amounts in mg per fclled
capsule; size of
soft gelatin capsules: 22 minims oblong.
1 Ciclosporin A (USP XXII/Pharm.Eur.) 100.0
2 POE-(40) hydrogenated castor oil 400.0
(CREMOPHOR RH 40, NICCOL HCO 40, SIMULSOL 1293)
3 Di/tri/tetraglycerol fatty acid ester 238.0
(FCC/ TRIODAN 20)
4 Sesame oil (DAB 10) 160.0
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alpha-Tocopherol (DAB 10) 2.0
6 Ethanol (DAB 10) 100.0
Components 2-4 are mixed in a stainless steel vessel equipped with stirrer,
while heating
to 40 . The solution is then degassed by applying low pressure. Antioxidant 5
is added to
the clear solution, and the therapeutic agent ciclosporin A is then dispersed
therein. After
addition of the ethanol, the entire composition is stirred until a clear
solution is obtained.
This solution is cooled to c. 20 and then filled into soft gelatin capsules.
To compensate
for evaporation, the amount of ethanol added is 30-60 mg higher than in the
above
composition.
In addition to gelatin, the shells of the soft gelatin capsules contain
excipients which
influence the consistency, typically glycerol and/or propylene glycol, or
sorbitol and/or
mannitol. The shells can additionally contain pigments or colourants,
typically titanium
dioxide, iron oxide, quinoline yellow, or cochenille red A.
Example 2
Composition for filling into hard gelatin capsules or starch capsules; amounts
in kg per
preparation.
1 Nifedipine (DAB 10) 20.0
2 POE-(20) sorbitan monooleate 168.0
(Polysorbate 20 Pharm.Eur., TWEEN 20)
3 Triglycerol mono/dioleate (FCC - CAPROL 3G0) 28.0
4 Neutral oil (MIGLYOL 812, CAPTEX 300/400) 84.0
All components of the composition are mixed at 45 in a double-walled heating
vessel
having a volume of 300 1 and are stirred until a clear solution is obtained.
300 mg each of
the cooled clear solution are filled into hard gelatin capsules of size 1 made
opaque with
titanium dioxide/iron oxide.
The filled capsules are banded. Owing to the susceptibility of nifedipine to
light, all
process steps must be carried out excluding daylight.
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Example 3
Composition for filling into glass bottles. The composition is suitable for
oral
administration as drop solution and is filled into a brown 40 ml dropping
bottle. Amounts
are given in gram.
1 Nimodipine 3.0
2 POE-(60) hydrogenated castor oil 15.0
(CREMOPHOR RH 60, NICCOL HCO 60, SIMULSOL 1294)
3 Sorbitan monolaurate (BPC 1973, SPAN 20) 8.5
4 Sunflower oil (DAB 10) 8.5
Propylene glycol 5.0
The solution is prepared in general accordance with the procedure of Example
2.
Example 4
Composition for filling into soft gelatin capsules; amounts in mg per filled
capsule; size of
soft gelatin capsule: 4 minims oblong.
1 Tacrolimus 10.0
2 POE-(35) castor oil (CREMOPHOR EL) 72.0
3 Sorbitan monooleate (SPAN 80) 72.0
4 Neutral oil 32.0
5 alpha-Tocopherol 1.0
6 Propylene glycol (DAB 10) 5.0
The capsules are prepared in general accordance with the procedure of Example
1.
Propylene glycol is particularly suitable as plasticiser for the capsule
shell.
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Example 5
Composition for filling into hard gelatin capsules; amounts relate to the
filling of one
size 0 capsule.
1 alpha-Liponic acid 100.0
2 POE-(40) stearate (US/NF, MYRJ 52 S) 80.0
3 Tetraglycol stearate (FCC, TRIODAN 55) 215.0
4 Sesame oil 160.0
Butylhydroxyanisol 0.5
The solution is prepared in general accordance with the procedure of Example
2,
additionally observing the susceptibility of the liponic acid to oxygen.
Example 6
Composition for filling into soft gelatin capsules; amounts in mg per filled
capsule, size of
soft gelatin capsules: 6 minims, oblong.
1 Rapamycin 20.0
2 POLYSORBAT 80 (TWtEN 80) 150.0
3 Sorbitan monoleate 25.0
4 Neutral oil 75.0
5 Ascorbylpalmitate 0.5
6 Benzyl alcohol (DAB 10) 5.0
The composition is prepared in general accordance with the procedure of
Example 1,
adding the benzyl alcohol as last component.
Example 7
Composition for filling into soft gelatin capsules; amounts in mg per filled
capsule.
1 Etoposide 100.0
2 POE-(40) hydrogenated castor oil 400.0
3 Di/tri/tetraglycerollaurate 160.0
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(TGLC-Laurat T2010 Solvay Alkali GmbH)
4 Corn oil 230.0
Ethanol 100.0
The composition is prepared in general accordance with the procedure of
Example 1.
Example 8
Composition for use in soft gelatin capsules; amounts in mg per filled
capsule; size of soft
gelatin capsule: 9.5 minims, oblong.
1 S(+)-Ibuprofen 100.0
2 POLYSORBAT 60 (TWEEN 60) 210.0
3 Hexaglycerol dioleate (CAPROL 6G20) 130.0
4 Castor oil (DAB 10) 60.0
The composition is prepared in general accordance with the procedure of
Example 1.
