Pharmaceutical compositions containing a staurosporine

An orally administrable pharmaceutical composition comprising a solution or dispersion of a staurosporine active ingredient in a solid saturated polyalkylene glycol glyceride, such as a mixture of esters of C.sub.8 -C.sub.18 saturated fatty acids with glycerol and polyethylene glycol, is disclosed that may be administered in capsules or as a dispersion in an aqueous medium.

This invention relates to pharmaceutical compositions, particularly 
pharmaceutical compositions comprising a staurosporine as active 
ingredient. 
U.S. Pat. No. 5,093,330 describes staurosporine and N-substituted 
derivatives thereof as pharmaceuticals for use in tumour inhibition and 
inflammation inhibition, for antibacterial use and for use in combating 
arteriosclerosis, diseases of the cardiovascular system and of the central 
nervous system. 
Many staurosporines have low solubility in water. For example, 
N-benzoylstaurosporine, an especially preferred compound, has a solubility 
of less than 0.1 mg/liter. The staurosporines have been found to have low 
or negligible bioavailability. 
The formulation of an orally administrable preparation has proved 
problematic since formulation with materials which are conventionally used 
to improve bioavailability, including materials in which the 
staurosporines are soluble, has negligible or no effect on 
bioavailability. 
It has now been found that by dispersing a staurosporine active ingredient 
in a saturated polyglycolysed glyceride, i.e. a polyalkylene 
glycol-modified saturated fatty acid glyceride, bioavailability can be 
considerably increased and orally administrable formulations can be 
prepared. 
Accordingly, the present invention provides a pharmaceutical composition 
comprising a solution or dispersion of a staurosporine active ingredient 
in a saturated polyalkylene glycol glyceride. 
The staurosporine active ingredient may be any of those described in U.S. 
Pat. No. 5,093,330. Preferred compounds are N-acylstaurosporines including 
N-benzoylstaurosporine, N-(3-nitrobenzoyl)staurosporine, 
N-(3-fluorobenzoyl)staurosporine, N-trifluoracetylstaurosporine, 
N-phenylcarbamoylstaurosporine, N-(3-carboxypropionyl)staurosporine, 
N-methylaminothiocarbonylstaurosporine, 
N-tert-butoxycarbonylstaurosporine, N-(4-carboxybenzoyl)staurosporine, 
N-(3,5-dinitrobenzoyl)staurosporine, N-(2-aminoacetyl)staurosporine, 
N-alanylstaurosporine and their pharmaceutically acceptable salts. An 
especially preferred active ingredient is N-benzoylstaurosporine. 
The saturated polyalkylene glycol glyceride may be, for example, a mixture 
of glyceryl and polyethylene glycol esters of one or more long chain 
saturated fatty acids, usually C.sub.8 -C.sub.18 saturated fatty acids. 
The acid component of such esters may be, for example, caprylic acid, 
capric acid, lauric acid, myristic acid, palmitic acid, stearic acid or a 
mixture of two or more thereof. The polyethylene glycol component of such 
esters generally has a molecular weight of 200 to 2000, preferably 1000 to 
1800, especially 1400 to 1600. The glycerides, i.e. the glycol-modified 
glycerides, are usually mixtures of mono, di and triglycerides and 
polyethylene glycol mono and diesters. 
Preferred polyalkylene glycol glycerides are those having a high 
Hydrophilic-Lipophilic Balance (HLB) value. Further preferred are 
glycerides which are mixtures of esters of one or more C.sub.8 -C.sub.18 
saturated fatty acids with glycerol and a polyethylene glycol having a 
molecular weight of 1000 to 2000, preferably 1200 to 1800, especially 1400 
to 1600. An especially preferred material is available commercially from 
Gattefosse as Gelucire 44/14; this is a mixture of esters of C.sub.8 
-C.sub.18 saturated fatty acids with glycerol and a polyethylene glycol 
having a molecular weight of about 1500, the specifications for the 
composition of the fatty acid component being, by weight, 4-10% caprylic 
acid, 3-9% capric acid, 40-50% lauric acid, 14-24% myristic acid, 4-14% 
palmitic acid and 5-15% stearic acid. 
The saturated polyalkylene glycol glycerides are either commercially 
available or may be prepared by known procedures. For example they may be 
obtained by partial alcoholysis of hydrogenated vegetable oils using the 
polyalkylene glycol, or by esterification of the saturated fatty acid, or 
mixture of such acids, using glycerol and the polyalkylene glycol. 
In compositions of the invention, the staurosporine active ingredient is 
generally present in an amount from 1 to 30%, preferably 5 to 25%, 
especially 10 to 20%, by weight of the composition. 
The compositions of the invention may also contain carriers or adjuncts 
such as those described in U.S. Pat. No. 5,093,330 or other conventional 
excipients. For oral administration, the composition may be contained in 
capsules, usually hard capsules of gelatin or soft capsules of gelatin 
mixed with a plasticiser such as glycerol or sorbitol, or may be used as a 
dispersion in an aqueous medium, such as water, saline solution or a 
mixture of water with another, water-miscible, pharmaceutically acceptable 
solvent, for example in an amount of 0.5 to 70, preferably 5 to 50% by 
weight, optionally together with a preservative, for example a 
conventional preservative such as a benzoate, particularly an ester of 
p-hydroxybenzoic acid such as the methyl, ethyl, n-propyl, n-butyl or 
benzyl ester thereof or the sodium salt of the ester and other excipients 
such as dispersing agents and suspending agents. 
The present invention also provides a method of preparing a pharmaceutical 
composition as hereinbefore described which comprises melting a saturated 
polyalkylene glycol glyceride, mixing a staurosporine active ingredient 
with the molten glyceride and allowing the resulting mixture to solidify. 
The glyceride is conveniently melted by heating to a temperature 10.degree. 
to 20.degree. C. above its melting point before addition of the 
staurosporine active ingredient as a powder. Optional excipients may be 
added to the molten mixture. 
When a composition of the invention is to be administered in capsules, for 
example orally, the liquid mixture of the staurosporine active ingredient 
and glyceride may be poured into hard capsules or injected into soft 
capsules and allowed to solidify therein. Alternatively, the solid 
solution or solid dispersion obtained on cooling the liquid mixture of the 
staurosporine active ingredient and glyceride may be remelted for 
introduction into capsules. The capsules may contain, for example, from 1 
mg to 250 mg of the staurosporine active ingredient. 
When a composition of the invention is to be administered as a dispersion 
in an aqueous medium, e.g. water, a saline solution or mixture of water 
with a water-miscible pharmaceutically acceptable solvent, the solid 
solution or solid dispersion obtained on cooling the liquid mixture is 
conveniently broken up and dispersed in the aqueous medium by stirring or 
by ultrasonication. 
The compositions of the invention may be used in the treatment of the 
indications hereinbefore described. The compositions may be administered 
in prophylactically or curatively effective amounts. For example, 
compositions containing daily doses of 1 to 1000 mg of the active 
ingredient may be administered to warm-blooded animals having a body 
weight of about 70 kg. The compositions are particularly useful in the 
treatment of cancer.

The invention is illustrated by the following Examples, in which parts are 
by weight. 
EXAMPLE 1 
Gelucire 44/14 (82 parts) is melted by heating to 60.degree. C. Powdered 
N-benzoylstaurosporine (18 parts) is added to the molten material. The 
resulting mixture is homogenised and the dispersion obtained is introduced 
into hard gelatin capsules of different size, so that some contain a 25 mg 
dosage and others a 75 mg dosage of the staurosporine. The resulting 
capsules are suitable for oral administration. 
EXAMPLE 2 
Gelucire 44/14 (86 parts) is melted by heating to 60.degree. C. Powdered 
N-benzoylstaurosporine (14 parts) is added to the molten material. The 
mixture is homogenised and the dispersion obtained is introduced into hard 
gelatin capsules of different size, so that some contain a 25 mg dosage 
and others a 75 mg dosage of the staurosporine. The resulting capsules are 
suitable for oral administration. 
EXAMPLE 3 
The bioavailability of N-benzoylstaurosporine dispersed in Gelucire 44/14 
is tested as follows: 
Dosages of 100 mg of N-benzoylstaurosporine dispersed in 500 mg of Gelucire 
44/14 are administered orally in size O gelatine capsules to two healthy 
random bred pedigree male beagle dogs weighing 10-15 kg. 
Blood samples (4 ml) are collected from each dog prior to administration 
and at various time intervals after administration. Each sample is 
immediately centrifuged and the separated plasma is protected from light, 
frozen and stored in the dark at -20.degree. C. until analysed. The 
concentration of N-benzoylstaurosporine in each plasma sample is 
determined by high performance liquid chromatography using UV detection. 
The results are as follows: 
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Concentration of N-benzoylstaurosporine 
in Plasma (.mu. mol/l) 
Time (hours) Dog 1 Dog 2 
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0 0 0 
1 0.27 0.23 
2 0.38 0.30 
3 0.36 0.45 
4 0.31 0.41 
6 0.27 0.40 
8 0.24 0.28 
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