The present invention relates to a solid dispersion containing a substance useful for therapeutic and/or preventive treatment of various diseases resulting from impairment of cholinergic nerve cells, and a pharmaceutical composition containing said solid dispersion.
In order to utilize hardly soluble and/or hardly absorbable substances as a pharmaceutical preparation, it has been attempted to improve their solubility and absorbability. As a physicochemical method for such attempt, amorphization is known. In this technique, crystalline structures of the substances are destroyed and pulverized into a size of molecular level. An example of amorphized states includes solid dispersion. The solid dispersion contains a substance dispersed in a size of molecular level in a carrier, and the dispersion is such a state that a solid is dissolved in a solid. In the solid dispersion, a dispersed substance does not contact with each other. and accordingly, crystallization hardly occurs and stability of the substance in the amorphized state is generally improved.
It is known that solubility and absorbability of a hardly soluble compound can be improved by dispersing the substance in a water-soluble macromolecule to form an amorphous solid dispersion. For example, Japanese Patent Unexamined Publication (Kokai) 58-77811/1983 discloses that solubility and absorbability of nifedipine, which is useful as a therapeutic drug for angina pectoris, can be improved by dispersing said drug in hydroxypropylmethylcellulose to form a solid dispersion. As methods for preparing a solid dispersion, there are known, for example, the solvent method wherein a substance and a water-soluble macromolecule are dissolved in a suitable solvent, and then the solvent is removed (Chem. Pharm. Bull., 34 (8), 3408 (1986)), the fusion method wherein a substance and a water-soluble macromolecule are fused and solidified by cooling (J. Pharm. Sci., 59, 937 (1970)), the mixed grinding method wherein a substance and a water-soluble macromolecule are mixed and pulverized by a ball mill or the like (Yakuzaigaku (Pharmaceutics), 45 (4), 291 (1985)), the spray drying method wherein a solution of a drug and a water-soluble macromolecule is spray-dried (Chem. Pharm. Bull., 44 (3), 568 (1996)) and the like.
Gangliosides, which are glycosphingolipids including sialic acid, are components of biomembranes and abundantly contained in brains of higher animals. Variety of functions of gangliosides have recently been reported. Since gangliosides are present highly locally in membranes of the nerve system, their role in the nerve system have been focused. Sialic acid is an important component of gangliosides, and various sialic acid derivatives have been synthesized to investigate correlation between sialic acid and the functions of gangliosides and from a viewpoint of clinical applications (Japanese Patent Unexamined Publication Nos. 55-89298/1980, 61-243096/1986, 61-282390/1986, 63-41492/1988, 63-41494/1988, 63-63697/1988, 63-68526/1988, 64-52794/1989, 1-190693/1989, 3-151398/1991, WO93/10134, WO094/03469 etc.). Some reports have also been made on the activity of sialic acid derivatives (Japanese Patent Unexamined Publication Nos. 62-265229/1987, 1-93529/1989, 3-77898/1991, 3-81287/1991, and Brain Research, 438, 277-285 (1988)).
The applicants of the present application discovered previously sialic acid derivatives having an activity for activating an acetylcholine synthetase, i.e., choline acetyltransferase (ChAT) (Japanese Patent Unexamined Publication No. 7-228592/1995). These sialic acid derivatives have actions of improving central nervous system disorders such as dysmnesia in senile dementia including Alzheimer""s disease and peripheral nerve system disorders such as diabetic neuropathy, and therefore they are very useful as active ingredients of drugs. Since the compounds of said invention activate ChAT activity in cholinergic nerve cells, their prophylactic or therapeutic efficacy for dementia, dysmnesia and symptoms resulting therefrom is expected. Specifically, they are considered to be useful for prophylactic and therapeutic treatments of senile dementia including Alzheimer""s disease; cerebrovascular dementia accompanying apoplectic stroke, encephalorrhagy, cerebral infarction etc.; and dysmnesia, hypoprosexia, allophasis, hypobulia, emotional disorder, hallucination, paranoid state, behavioral abnormality and the like resulting from head injury, postencephalitis, cerebral paralysis, Huntington disease, Pick""s disease, Down""s syndrome, Parkinson""s disease etc. They are also useful for prophylactic and therapeutic treatments of tardive dyskinesia; glaucoma; dysgryphia; peripheral nerve disorders of motor nerve, sensory nerve, autonomic nerve etc. including traumatological and inflammatory neuropathiesi alcoholic nerve disorder, drug induced nerve disorder caused by carcinostatic agents etc., metabolic nerve disorder resulting from diabetes mellitus etc. or idiopathic peripheral nerve disorder induced by carcinostatic agents etc.; facial nerve palsy: ischiadic nerve palsy; myelopathic muscular atrophy; muscular dystrophy; myasthenia gravis; multiple sclerosis; a myotrophic lateral sclerosis; acute disseminated encephalomyelitis; Guillain-Barre syndrome: postvaccinal encephalitis; subacute myelo-optic neuropathy (SMON disease) and the like. However, these sialic acid derivatives are almost insoluble in water and hardly absorbable, and for this reason, drugs prepared by ordinary formulation techniques fail to sufficiently exert efficacy.
An object of the present invention is to provide medicaments which comprise a sialic acid derivatives disclosed in Japanese Patent Unexamined Publication No. 7-228592/1995 and can sufficiently take sufficient effects. More specifically, the object of the present invention is to provide medicaments which achieve superior solubility and absorbability of the sialic acid derivative.
The inventors of the present invention made extensive studies to achieve the foregoing object. As a result, they found that the object was achievable by preparing a solid dispersion in which an active ingredient such as the aforementioned sialic acid derivatives or salts thereof in a water-soluble macromolecule, and that medicaments superior in solubility and absorbability of the active ingredient and capable of exerting high efficacy were successfully provided. The present invention was accomplished on the basis of these findings.
The present invention thus provides a solid dispersion which comprises a water-soluble macromolecule and a substance dispersed in the water-soluble macromolecule, wherein said substance is selected from the group consisting of a sialic acid derivative represented by the following general formula (I) and a salt thereof, and a hydrate thereof and a solvate thereof: 
[in the above general formula (I), R1 represents a steroid compound residue, R2 represents hydrogen atom or a C1-C4 alkyl group, R3 represents a C1-C15 alkyl group, 
{in the formula, R6 and R7 independently represent hydrogen atom, a halogen atom, a C1-C4 alkyl group, hydroxyl group, R8Oxe2x80x94 (in the formula, R8 represents a C1-C4 alkyl group, phenyl group or a phenyl-(C1-C3) alkyl group), nitro group, amino group, a C1-C4 alkylamino group, a C2-C8 dialkylamino group or R9Oxe2x80x94COxe2x80x94 (in the formula, R9 represents hydrogen atom, a C1-C4 alkyl group, phenyl group or a phenyl-(C1-C3) alkyl group), and symbol xe2x80x9cLxe2x80x9d represents an integer of from 0 to 6}, R10O(CH2)mxe2x80x94 (in the formula, R10 represents hydrogen atom; a C1-C4 alkyl group; a phenyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and a carboxyl group; or a phenyl-(C1-C3) alkyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and carboxyl group, and symbol xe2x80x9cmxe2x80x9d represents an integer of from 2 to 6), or (R11)(R12)Nxe2x80x94(CH2)nxe2x80x94 {in the formula, R11 represents hydrogen atom or a C1-C4 alkyl group, R12 represents hydrogen atom; a C1-C4 alkyl group; a C2-C7 acyl group; a C1-C4 alkylsulfonyl group; a phenylsulfonyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, halogen atom, hydroxyl group, nitro group, amino group, and a carboxyl group; or R13Oxe2x80x94COxe2x80x94 (in the formula, R13 represents a C1-C4 alkyl group, phenyl group or a phenyl-(C1-C3) alkyl group) and symbol xe2x80x9cnxe2x80x9d represents an integer of from 2 to 6}, R4 represents hydrogen atom or a C2-C7 acyl group, R5 represents R14Oxe2x80x94 (in the formula, R14 represents hydrogen atom or a C2-C7 acyl group) or R15NHxe2x80x94 {in the formula, R15 represents a C2-C7 acyl group: R16O(CH2)pxe2x80x94COxe2x80x94 (in the formula, R16 represents hydrogen atom, a C1-C6 alkyl group, phenyl group, or a phenyl-(C1-C3) alkyl group, and p represents an integer of from 0 to 4); a C7-C11 aroyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and a carboxyl group; a phenyl-(C1-C3) alkylcarbonyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and a carboxyl group; a C1-C4 alkylsulfonyl group; or a phenylsulfonyl group which may have one or more substituents selected from the group consisting of a C1-C4 alkyl group, a halogen atom, hydroxyl group, nitro group, amino group, and a carboxyl group}, and X represents an oxygen atom or a sulfur atom].
As preferred embodiments of the present invention, there are provided the aforementioned solid dispersion wherein R1 represents 
(in the formula,/ represents a single bond or a double bond); the aforementioned solid dispersion, wherein R1 represents 
and the aforementioned solid dispersion, wherein R1 represents 
in the sialic acid derivative and a salt thereof, and a hydrate thereof and a solvate thereof.
As other preferred embodiments of the present invention, there are provided the aforementioned solid dispersion wherein, as for the substance selected from the sialic acid derivative and a salt thereof, and a hydrate thereof and a solvate thereof, R2 represents hydrogen atom or methyl group; the aforementioned solid dispersion, wherein R2 represents hydrogen atom; the aforementioned solid dispersion, wherein R3 represents a C1-C8 alkyl group, 
{in the formula, R6 and R7 independently represent hydrogen atom, a halogen atom, or R9Oxe2x80x94COxe2x80x94 (in the formula, R9 represents hydrogen atom or a C1-C4 alkyl group), and symbol xe2x80x9cLxe2x80x9d represents an integer of from 0 to 3}, R10O(CH2)mxe2x80x94 (in the formula, R10 represents hydrogen atom, a C1-C4 alkyl group, phenyl group, or a phenyl-(C1-C3) alkyl group, and symbol xe2x80x9cmxe2x80x9d represents an integer of from 2 to 4), or (R11)(R12)Nxe2x80x94(CH2)nxe2x80x94 {in the formula, R11 represents hydrogen atom, R12 represents hydrogen atom, a C2-C7, acyl group, a C1-C4 alkylsulfonyl group or R13Oxe2x80x94COxe2x80x94 (in the formula, R13 represents a phenyl-(C1-C3) alkyl group) and symbol xe2x80x9cnxe2x80x9d represents an integer of from 2 to 4}; and the aforementioned solid dispersion, wherein R3 represents a C1-C8 alkyl group or 
(in the formula, symbol xe2x80x9cLxe2x80x9d represents an integer of from 0 to 3).
As further preferred embodiments of the present invention, as for the substance selected from the sialic acid derivative and a salt thereof, and a hydrate thereof and a solvate thereof, there are provided the aforementioned solid dispersion, wherein R3 represents a C1-C3 alkyl group; the aforementioned solid dispersion, wherein R4 represents hydrogen atom or acetyl group; the aforementioned solid dispersion, wherein R4 represents hydrogen atom; the aforementioned solid dispersion, wherein R5 represents R14Oxe2x80x94 (in the formula, R14 represents hydrogen atom or acetyl group) or R15NHxe2x80x94 {in the formula, R15 represents a C2-C7 acyl group, R16O(CH2)pxe2x80x94COxe2x80x94 (in the formula, R16 represents hydrogen atom, a C1-C4 alkyl group or a phenyl-(C1-C3) alkyl group, and symbol xe2x80x9cpxe2x80x9d represents an integer of from 0 to 4), a C7-C11 aroyl group, a C1-C3 alkylsulfonyl group or a phenylsulfonyl group}; the aforementioned solid dispersion, wherein R5 represents R14Oxe2x80x94 (in the formula, R14 represents hydrogen atom) or R15NHxe2x80x94 {in the formula, R15 represents a C2-C5 acyl group, R16O(CH2)pxe2x80x94COxe2x80x94 (in the formula, R16 represents hydrogen atom and symbol xe2x80x9cpxe2x80x9d represents 1)}; the aforementioned solid dispersion, wherein R15 represents R15NHxe2x80x94(in the formula, R15 represents acetyl group); and the aforementioned solid dispersion, wherein X represents oxygen atom.
As particularly preferred embodiments, there are provided the aforementioned solid dispersion, wherein the sialic acid derivative is 3 xcex1-[N-(5-acetamido-3,5-dideoxy-2-O-methyl-xcex1-D-glycero-D-galacto-2-noneuropyranosonyl)amino]cholestane; the aforementioned solid dispersion, which comprises the aforementioned substance in substantially amorphous state; and the aforementioned solid dispersion, which does not substantially comprise said substance in crystallized state. As another aspect, there is provided a pharmaceutical composition comprising the aforementioned solid dispersion and a pharmaceutically acceptable carrier.