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)
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.
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.
An object of the present invention is to provide medicaments which comprise a sialic acid derivatives disclosed in Japanese Patent Unexamined Publication No.
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:
As preferred embodiments of the present invention, there are provided the aforementioned solid dispersion wherein R1 represents
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 R14O- (in the formula, R14 represents hydrogen atom or acetyl group) or R15NH- {in the formula, R15 represents a C2-C7 acyl group, R16O(CH2)p-CO-(in the formula, R16 represents hydrogen atom, a C1-C4 alkyl group or a phenyl-(C1-C3) alkyl group, and symbol "p" 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 R14O- (in the formula, R14 represents hydrogen atom) or R15NH- {in the formula, R15 represents a C2-C5 acyl group, R16O(CH2)p-CO-(in the formula, R16 represents hydrogen atom and symbol "p" represents 1)}; the aforementioned solid dispersion, wherein R5 represents R15NH- (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 α -[N-(5-acetamido-3,5-dideoxy-2-O-methyl-α -D-glycero-D-galacto-2-nonulo pyranosonyl)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.
Fig. 1 shows results of a dissolution test of a solid dispersion of the present invention. The results shown in the figure are averages of experiments performed in triplicate. The line with ■ represents the results obtained from a solid dispersion of the present invention (Example 1); and the line with □ from the solid powder of Comparative Example 1.Fig. 2 shows results of an absorption test (rat) of a solid dispersion of the present invention. The results shown in the figure are averages of experiments performed in triplicate. The line with ■ represents the results obtained from a solid dispersion of the present invention (Example 2); and the line with □ from the suspension of Comparative Example 2.Fig. 3 shows results of an absorption test (dog) of solid dispersions of the present invention. The results shown in the figure are averages of experiments performed in triplicate. The line with ■ represents the results obtained from a solid dispersion of the present invention (Example 3); the line with ◆ from a solid dispersion of the present invention (Example 4), the line with ● from a solid dispersion of the present invention (Example 5), and line with □ from the capsule (solid powder) of Comparative Example 3.
The sialic acid derivative contained in the solid dispersion of the present invention is represented by the aforementioned general formula (I). Examples of the C1-C4 alkyl group defined in the aforementioned general formula (I) include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group and the like. Examples of the C1-C15 alkyl group include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, n-decyl group, n-pentadecyl group and the like. Examples of the C1-C6 alkyl group include those C1-C6 alkyl groups exemplified above for the C1-C15 alkyl group. Examples of the halogen atom include fluorine atom, chlorine atom, bromine atom and the like. Examples of the phenyl-(C1-C3) alkyl group include benzyl group, phenethyl group and the like. Examples of the C2-C7 acyl group include acetyl group, propionyl group, butyryl group, valeryl group, benzoyl group and the like. Examples of the C1-C4 alkylsulfonyl group include methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, n-butylsulfonyl group and the like.
Further, examples of the C1-C4 alkylamino group include methylamino group, ethylamino group, butylamino group and the like. Examples of the C2-C8 dialkylamino group include dimethylamino group, diethylamino group, dibutylamino group and the like. Examples of the C7-C11 aroyl group include benzoyl group, toluoyl group, naphthoyl group and the like. Examples of the phenyl-(C1-C3) alkylcarbonyl group include benzylcarbonyl group, phenylethylcarbonyl group, phenylpropylcarbonyl group and the like.
A specific example of the steroid compound residue defined by R1 in the formula (I) includes a group represented by the following formula:
A preferred example of R1 include a steroid compound residue represented by the following formula:
R2 is preferably hydrogen atom or a methyl group, and hydrogen atom is most preferred. R3 is preferably a C1-C8 alkyl group,
R4 is preferably hydrogen atom or acetyl group, and hydrogen atom is most preferred. R5 is preferably R14O- (in the formula, R14 represents hydrogen atom or acetyl group) or R15NH- {in the formula, R15 represents a C2-C5 acyl group, R16O(CH2)p-CO- (in the formula, R16 represents hydrogen atom, a C1-C4 alkyl group, or a phenyl-(C1-C3) alkyl group, and symbol "p" represents an integer of from 0 to 4), a C7-C11 aroyl group, a C1-C4 alkylsulfonyl group, or a phenylsulfonyl group}}, more preferably R14O- (in the formula, R14 represents hydrogen atom) or R15NH- {in the formula, R15 represents a C2-C5 acyl group, R16O(CH2)p-CO- (in the formula, R16 represents hydrogen atom, and symbol "p" represents 1)}, most preferably R15NH- (in the formula, R15 represents acetyl group). X is most preferably an oxygen atom.
Specific examples of the substituents defined in the aforementioned general formula (I) and specific examples of the sialic acid derivatives represented by the formula (I) are mentioned in Japanese Patent Unexamined Publication No.
Most preferred sialic acid derivatives include 3 α -[N-(3-deoxy-2-O-methyl-α -D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α -isomer of Compound No. 367 mentioned in Japanese Patent Unexamined Publication No.
- 3 α -[N(3-deoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulo-pyranosonyl)amino]-5-cholestene (α -isomer of Compound No. 507 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α -[N-(5-acetamido-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 4 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α -[N-(5-acetamido-3,5-dideoxy-2-O-phenyl-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 19 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α-[N-(5-acetamido-3,5-dideoxy-2-O-benzyl-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 21 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α-[N-(5-acetamido-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]-5-cholestene (α-isomer of Compound No. 234 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α-[N-(5-acetamido-3,5-dideoxy-2-S-phenyl-2-thio-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 260 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α-[N-(5-acetamido-3,5-dideoxy-2-O-methyl-β-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 268 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995 - 3 α-[N-(5-acetamido-3,5-dideoxy-2-O-benzyl-β-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (α-isomer of Compound No. 281 mentioned in Japanese Patent Unexamined Publication No.
7-228592/1995
Examples of salts formed with the carboxyl groups of the compounds represented by the general formula (I) include, for example, salts with alkali metals such as sodium or potassium, and salts with ammonia, organic amines such as tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, and L-glucamine.
Examples of salts formed with the compounds represented by the general formula (I) include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, hydroiodides, sulfates, and phosphates, and organic acid salts such as oxalates, maleates, fumarates, lactates, malates, citrates, tartrates, benzoates, methanesulfonates and camphorsulfonates. However, the salts which can be used for the solid dispersion of the present invention are not limited to these examples, and any of physiologically acceptable salts can be utilized.
The compound of the aforementioned formula (I) or a salt thereof may exist in the forms of a hydrate or a solvate, and therefore, the hydrate or the solvate can also be used for the manufacture of the solid dispersion of the present invention.
Solvents for forming the solvates are not particularly limited, and include, for example, methanol, ethanol, isopropanol, acetone, ethyl acetate, methylene chloride and the like. Further, the compounds of the aforementioned formula (I) have one or more asymmetric carbon atoms, and many isomers thereof may exist. Any of such isomers can be used for the manufacture of the solid dispersion of the present invention. The compounds falling within the aforementioned general formula (I) can be produced according to the method described in Japanese Patent Unexamined Publication No.
The types of the water-soluble macromolecules used for the manufacture of the solid dispersion of the present invention are not particularly limited, and any kinds of macromolecules may be used so long as they are pharmaceutically acceptable. Examples include, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol and the like. Furthermore, macromolecules having pH-dependent solubility may also be used, and examples include carboxymethylethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, methacrylic acid copolymer and the like. Where the water-soluble macromolecules form a salt, any salts may be used. Two or more of the water-soluble macromolecules can be used in combination. The amount of the water-soluble macromolecules is not particularly limited, and may be appropriately chosen by those skilled in the art. For example, the amount may be 0.5 to 20 parts by weight, preferably 1 to 7 parts by weight based on the aforementioned substance as an active ingredient.
Methods for manufacturing the solid dispersion of the present invention are not particularly limited, and any methods that can be utilized as a method to prepare a solid dispersion may be applied. Specifically, examples include the solvent method (
When the solid dispersion of the present invention is manufactured by the solvent method, a substance selected form the group consisting of the sialic acid derivative represented by the aforementioned formula (I) and a salt thereof, and a hydrate thereof and a solvate thereof can be dissolved in a suitable solvent, and the solvent can be removed from the solution by a suitable method. The types of the solvents are not particularly limited so long as they can dissolve the aforementioned substance, and it is preferred to use an organic solvent having high volatility and low toxicity. For example, ethanol, methanol, isopropanol, acetone and the like can be suitably used. Two or more of these solvents may be used in combination.
Methods to remove the solvent from the solution containing the aforementioned substance as an active ingredient and the water-soluble macromolecule dissolved therein are not particularly limited, and commonly used methods such as distillation by heating and vacuum distillation can be applied. After a solvent is removed, dried residue can be pulverized and sized by using a screen mill, hammer mill, jet mill or the like, and if necessary, the resulting product can be subjected to secondary drying and further sizing to produce a solid dispersion of the present invention. The aforementioned solution can also be spray-dried by using a spray dryer or the like, and the resulting product may optionally be subjected to secondary drying and then further sizing to produce a solid dispersion. Drying conditions may vary depending on a type of a water-soluble macromolecule, a solvent, or an apparatus be used, as well as to a type of the aforementioned substance as the active ingredient. Generally, the drying can be performed under heating at 200°C and under ordinary pressure or high vacuum of 1 torr or less for several seconds to ten and several hours.
The solid dispersion of the present invention per se can be used as a medicament. Generally, however, a pharmaceutical formulation in the form of subtilized granule, granule, tablet, capsule, dry syrup or the like may be prepared and subjected to administration. The pharmaceutical preparation can be manufactured by subjecting the aforementioned solid dispersion to ordinary formulation processes such as, for example, mixing, granulation, sizing, tablet compression, coating, capsule filling and the like utilizing pharmaceutical manufacturing apparatuses. If necessary, a pharmaceutical composition may be prepared by using one or more suitable pharmaceutical additives, and then the pharmaceutical composition may be formulated in the aforementioned formulations.
The pharmaceutical additives include, for example, excipients (e.g., lactose, mannitol, crystalline cellulose, corn starch, potato starch etc.), disintegrating agents (e.g., sodium carboxymethyl starch, carboxymethylcellulose calcium, croscarmellose sodium, polyvinylpyrrolidone, low substituted hydroxypropylcellulose, carboxymethylcellulose etc.), fluidization improving agents (e.g., light anhydrous silicic acid, hydrated silicon dioxide etc.), coloring agents (e.g., titanium oxide, yellow ferric oxide etc.), flavoring agents (e.g., tartaric acid, ascorbic acid, citric acid etc.), surface active agents (e.g., sodium laurylsulfate, polysorbate 80, polyethylene hydrogenated castor oil etc.), dispersing agents (e.g., crystalline cellulose, carboxyvinyl polymer etc.), lubricants (e.g., magnesium stearate etc.) and the like, and the amounts of these pharmaceutical additives can be suitably chosen by those skilled in the art. The pharmaceutical additives can be added during any one or more of the steps. For example, they may be added during the production of the solid dispersion, or during the steps of preparing the pharmaceutical preparation from the solid dispersion.
The present invention will be explained more specifically with reference to examples.
5 g of 3 α-[N-(5-Acetamido-3,5-dideoxy-2-O-methyl-α-D-glycero-D-galacto-2-nonulopyranosonyl)amino]cholestane (hereinafter referred to as Compound A) and 15 g of hydroxypropylcellulose were dissolved in 2.5 liter of methanol and spray-dried at 140°C by using a spray dryer. The resulting solid was subjected to vacuum dehydration at 70°C for 6 hours using a vacuum desiccator, and sized through a 32# mesh sieve to obtain a solid dispersion.
Compound A (1 g) and 5 g of polyvinylpyrrolidone were dissolved in 0.7 liter of ethanol. 0.3 g of light anhydrous silicic acid was then added to the solution and suspended, and then the solvent was removed by heating at 80°C with stirring. The resulting solid was ground by using a grinding mill, subjected to vacuum dehydration at 70°C for 6 hours, and sized through a 32# mesh sieve to obtain a solid dispersion. 3.78 g of polyvinylpyrrolidone was added to 1.26 g of this solid dispersion, and mixed in a conventional manner. The resulting mixture was suspended in 1000 ml of purified water to obtain a uniform suspension, of which concentration of Compound A was 1 mg/5 ml.
Compound A (5 g) and 35 g of hydroxypropylcellulose were dissolved in 2.5 liter of methanol and spray-dried at 140°C by using a spray dryer. The resulting solid was subjected to vacuum dehydration at 70°C for 6 hours using a vacuum desiccator, and sized through a 32# mesh sieve to obtain a solid dispersion. This solid dispersion was dissolved in a 5% aqueous solution of sodium laurylsulfate to obtain a formulation in the form of a solution, of which concentration of Compound A was 5 mg/ml.
Compound A (5 g) and 35 g of hydroxypropylcellulose were dissolved in 2.5 liter of methanol, and 20 g of polyvinylpyrrolidone was added and suspended in the solution. The suspension was then spray-dried at 140°C by using a spray dryer. The resulting solid was subjected to vacuum dehydration at 70°C for 6 hours using a vacuum desiccator, and sized through a 32# mesh sieve to obtain a solid dispersion. This solid dispersion was filled into a capsule to obtain a formulation in the form of a capsule containing 5 mg of Compound A.
12.0 g of the solid dispersion obtained in Example 4 was added with 6.06 g lactose, 5.6 g of sodium carboxymethyl starch, 4.2 g of hydrated silicon dioxide and 0.14 g of magnesium stearate, and the mixture was mixed and compressed into a tablet in a conventional manner to obtain a tablet containing 5 mg of Compound A.
Compound A (5 g) and 15 g of hydroxypropylcellulose were mixed to obtain solid powder.
Compound A (1 g), 5 g of polyvinylpyrrolidone and 0.3 g of light anhydrous silicic acid were mixed to obtain solid powder. 3.78 g of polyvinylpyrrolidone was added to 1.26 g of this solid powder, and mixed in a conventional manner. The resulting mixture was suspended in 1000 ml of purified water to obtain a uniform suspension, of which concentration of Compound A was 1 mg/5 ml.
Compound A (5 g), 35 g of hydroxypropylcellulose and 20 g of polyvinylpyrrolidone were mixed to obtain solid powder. This solid powder was filled into a capsule to obtain a formulation in the form of a capsule containing 5 mg of Compound A.
Residual solvent in each of the solid dispersions obtained in Examples 1, 2, 3 and 4 was measured by gas chromatography. As a result, the residual solvent in the solid dispersions obtained in Examples 1, 2, 3 and 4 was less than the detection limit (50 ppm).
A dissolution test was performed for the solid dispersion and the solid powder obtained in Example 1 and Comparative Example 1, respectively. Each sample corresponding to 10 mg of Compound A was added to 100 ml of distilled water at 37°C with stirring using a stirrer, and the solution was sampled after a given period. The dissolution amount of Compound A in the sampled solution was quantified. The results are shown in
Absorption tests were performed using rats for the suspensions obtained in Example 2 and Comparative Example 2. Compound A (1 mg/kg/5 ml of suspension) was forcibly administered to rats. Blood was collected after a given period, and plasma concentration of Compound A was quantified. The results are shown in
Absorption tests were performed using dogs for formulations obtained in Examples 3, 4, 5 and Comparative Example 3. Each formulation containing 5 mg of Compound A was forcibly administered to dogs. Blood was collected after a given period, and plasma concentration of Compound A was quantified. The results are shown in
By using the solid dispersion of the present invention, solubility and absorbability of the sialic acid derivatives of the formula (I) and salts thereof, which have superior efficacy as medicaments, can be improved, and the problems accompanied with conventional methods, i.e., residual solvent, decomposition, contamination of foreign substances and the like, can be eliminated.