Patent 6,462,093

A process for producing a solid dispersion of a sparingly water-soluble medical substance which comprises subjecting the sparingly water-soluble medical substance, an amorphous state-inducing agent and an amorphous state-stabilizing agent to heat treatment or mechanochemical treatment; and a process for producing a solid dispersion of a sparingly water-soluble medical substance which comprises high-frequency heating the sparingly water-soluble medical substance and an amorphous state-stabilizing agent. These processes make it possible to make sparingly water-soluble medical substance amorphous at a temperature lower than those employed in the conventional methods. The solid dispersions of the armorphous sparingly water-soluble medical substances thus obtained have an improved mucosal or rectal absorption rate, which makes it possible to elevate their bioavailability.

DISCLOSURE OF THE INVENTION

As a result of intensive investigation to overcome the problems of the conventional methods, the present inventors have found a method for converting a sparingly water-soluble medical substance to the amorphous state which comprises mixing these components of (1) a sparingly water-soluble medical substance, (2) an amorphous state-inducing agent and (3) an amorphous state-stabilizing agent, and subjecting the resulting mixture to heat treatment or mechanochemical treatment. Further, it has been found that high-frequency heating is preferred as the heat treatment to the conventional heating by a heater or steam.

In addition, the inventors have found a method of converting a sparingly water-soluble medical substance to the amorphous state which comprises mixing two components of (1) a sparingly water-soluble medical substance and (3) an amorphous state-stabilizing agent and subjecting the mixture to high-frequency heating.

Furthermore, it is possible to produce a pharmaceutical preparation of a sparingly water-soluble medical substance containing a solid dispersion obtained by the method of converting the medical substance to the amorphous sate according to the present invention.

The (1) sparingly water-soluble medical substance used in the present invention is a medical substance that has extremely low water-solubility and is hardly absorbed from the intestine, tunica mucosa nasi, rectum, and the like. It is difficult to improve absorptivity of such medical substances by the conventional techniques for formulating them into the pharmaceutical preparations. Absorptivity of these medical substances can be improved by converting them to the amorphous state. Examples of the sparingly water-soluble medical substances include dihydropyridine compounds such as nifedipine, nicardipine, hydrochloride, or the like, phenacetin, digitoxin, diazepam, phenytoin, tolbutamide, theophylline, griseofulvin, chloramphenicol, and the like.

The (2) amorphous state-inducing agent used in the present invention can be any compound capable of depressing the melting point of the mixture of it with a medical substance. A crystalline compound is particularly preferred. This is a compound having functions and properties to change crystal-lattice energy of a sparingly water-soluble medical substance to a direction of low energy and to increase fluctuation of crystal lattice at the same temperature in the presence of heat or mechanical energy. The amorphous state-inducing agent varies depending on the sparingly water-soluble medical substance to be used. For example, it is preferable to use a neutral substance or an acidic substance, particularly an acidic substance in the case of a) a basic sparingly water-soluble medical substance, and a neutral substance or a basic substance, particularly a basic substance in the case of b) an acidic sparingly water-soluble medical substance.

Specific examples of the amorphous state-inducing agents include amino acid or its salt (such as aspartic acid or its Na salt, Mg salt, or the like, glycine, alanine, glutamic acids, glutamic acid hydrochloride, or the like), Aspartame, erythorbic acid or its salt (such as an Na salt or the like), ascorbic acid or its salt (such as an Na salt or the like), stearic acid ester, aminoethylsulfonic acid, inositol, ethylurea, citric acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, dihydrogen Na salt, etc., a Ca salt or the like), glycyrrhizinic acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, etc., an ammonium salt, e.g., diammonium, monoammonium, etc., a K salt, or the like), gluconic acid or its salt (such as an Na salt, a Ca salt, an Mg salt, or the like), creatinine, salicylic acid or its salt (such as an Na salt or the like), tartaric acid or its salt (such as an Na salt, a K.Na salt, a hydrogen.K salt, or the like), succinic acid or its salt (such as Na salt, e.g., di Na salt, mono Na salt, etc.), calcium acetate, sodium saccharin, aluminum hydroxide, sorbic acid or its salt (such as a K salt or the like), dehydroacetic acid or its salt (such as an Na salt or the like), sodium thiomalate, nicotinic acid amide, urea, fumaric acid or its salt (such as an Na salt or the like), macrogols, maltose, maltol, maleic acid, mannitol, meglumine, sodium desoxycholate, phosphatidylcholine and the like.

Preferable examples thereof include amino acid or its salt (such as aspartic acid or its Na salt, Mg salt, or the like, glycine, alanine, glutamic acids, glutamic acid hydrochloride, or the like), ascorbic acid or its salt (such as an Na salt or the like), stearic acid ester, aminoethylsulfonic acid, ethylurea, citric acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, dihydrogen Na salt, etc., a Ca salt, or the like), glycyrrhizinic acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, etc., an ammonium salt, e.g., diammonium, monoammonium, etc., a K salt, or the like), creatinine, tartaric acid or its salt (such as an Na salt, a K.Na salt, a hydrogen.K salt, or the like), succinic acid or its salt (such as an Na salt, e.g., di Na salt, mono Na salt, etc.), urea, fumaric acid or its salt (such as an Na salt or the like), macrogols, maltose, maltol, mannitol, meglumine, and the like.

More preferably, the amorphous state-inducing agents include amino acid or its salt (such as aspartic acid or its Na salt, Mg salt, or the like salt, glycine, alanine, glutamic acids, glutamic acid hydrochloride, and the like), ethylurea, glycyrrhizinic acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, etc., an ammonium salt, e.g., diammonium, monoammonium, etc., a K salt, or the like), tartaric acid or its salt (such as an Na salt, a K.Na salt, a hydrogen.K salt, or the like), succinic acid or its salt such as an Na salt (e.g., di Na salt, mono Na salt, etc.), urea, maltose, maltol, mannitol, meglumine, and the like.

Most preferably, the agents are glycyrrhizinic acid or its salt (such as an Na salt, e.g., tri Na salt, di Na salt, etc., an ammonium salt, e.g., diammonium, monoammonium, etc., a K salt, or the like), succinic acid or its salt (such as an Na salt, e.g., di Na salt, mono Na salt, etc.), urea, maltol, mannitol, and the like.

Depression of melting point of the mixture of the amorphous state-inducing agent and the sparingly water-soluble medical substance varies depending on the sparingly water-soluble medical substance to be mixed. It is preferable to use a compound which can depress the melting point of the mixture to 5^oC. or more from that of the sparingly water-soluble medical substance.

It is more preferable to use a compound which can depress the melting point of the mixture of the amorphous state-inducing agent and the sparingly water-soluble medical substance to 15^oC. or more, particularly 25^oC. or more, from the melting point of the sparingly water-soluble medical substance.

In the case of the high-frequency heating, the sparingly water-soluble medical substance can be converted to the amorphous state by heating the mixture of the sparingly water-soluble medical substance and the amorphous state-stabilizing agent under high frequency without using the amorphous state-inducing agent. As a matter of course, the mixture of the three components containing the amorphous state-inducing agent can also provide satisfactory results when subjected to high-frequency heating.

Following that the crystalline structure of the sparingly water-soluble medical substance is fluctuated by the amorphous state-inducing agent, the amorphous state-stabilizing agent interacts with the fluctuated state of the crystal lattice to stabilize the amorphous state.

Accordingly, any amorphous state-stabilizing agent can be used in the present invention as long as it has the above-described function. In other words, any compound having a functional group capable of interacting with the sparingly water-soluble medical substance can be used as the amorphous state-stabilizing agent. It is preferable to use a highly thermostable compound having a functional group that is flexible and highly miscible with the sparingly water-soluble medical substance, for example, the following amorphous polymer base. The compound miscible with the sparingly water-soluble medical substance means the compound having solubility parameter (Solubility Parameter: Encyclopedia of Polymer Science and Engineering, vol. 15, p. 393, John Wiley & Sons,Inc. 1989) close to that of the sparingly water-soluble medical substance. More preferably, the amorphous state-stabilizing agent is highly miscible with not only the sparingly water-soluble medical substance but also the amorphous state-inducing agent.

In addition, the functional group of the amorphous state-stabilizing agent which conducts interacting action with and is selected depending on the sparingly water-soluble medical substance to be used. For example, it is preferably to select a neutral substance or an acidic substance, particularly an acidic substance, in the case of a) a basic sparingly water-soluble medical substance and a neutral substance or a basic substance, particularly a basic substance, in the case of b) an acidic sparingly water-soluble medical substance.

Examples of (3) the amorphous state-stabilizing agents used in the present invention include cellulose derivatives (such as hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose-acetate succinate (HPMC-AS), methylcellolose, ethylcellulose, carboxymethylcellulose, phthalic acetate cellulose, or the like), polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, ethylene/vinyl acetate copolymer, polyethylene oxide derivatives (such as polyethylene glycol, polyoxy ethylene polyoxy propylenecetyl ether, polyoxy ethylene alkyl ether, polyoxy ethyleneoctyl phenyl ether, polyoxy ethyleneoleyl amine, polyoxy ethyleneoleyl ether, polyoxy ethyleneoleyl ether sodium phosphate, polyoxy ethylene hydrogenated castor oil, polyoxy ethylene stearyl ether, polyoxy ethylene stearyl ether phosphoric acid, polyoxy ethylene cetyl ether, polyoxy ethylene cetyl ether sodium phosphate, polyoxy ethylene sorbitol bees wax, polyoxy ethylenenonyl phenyl ether, polyoxy ethylene castor oil, polyoxy ethylenebehenyl ether, polyoxy ethylene polyoxy propyleneglycol, polyoxy ethylene polyoxy propylenecetyl ether, polyoxy ethylene lauryl ether, polyoxyethylene. lanoline, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, or the like), sodium polystyrene sulfonate, gelatin, soluble starch, pullulan, dextran, gum arabic, chondroitin sulfuric acid or its Na salt, hyaluronic acid, pectin, chitin, chitosan, .alpha., .beta. or .gamma.-cyclodextrin, alginic acid derivatives (such as alginic acid, its Na salt, propylene glycol ester, or the like), acryl resins (such as homopolymer of methacrylic acid derivative and/or acrylic acid derivative, e.g., methacrylic acid, methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, ethyl trimethyl chloride ammonium methacrylate, acrylic acid, ethyl acrylate, etc. and copolymer of methacrylic acid derivative and/or acrylic acid derivative, e.g., aminoalkyl/methacrylate copolymer, methylmethacrylate/methacrylic acid copolymer, methacrylic acid/ethyl acrylate copolymer, methacrylic acid/n-butyl acrylate copolymer, acrylic acid ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/vinyl pyrrolidone copolymer, starch acrylate, etc.) and polyvinyl acetal diethylaminoacetate and the like.

In addition, compounds capable of forming gel, such as silicon dioxide, aluminum hydroxide, or the like, can be also used as the amorphous state-stabilizing agent according to the present invention.

Preferable examples of the amorphous state-stabilizing agents include hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose-acetate succinate (HPMC-AS), polyvinyl pyrrolidone, sodium polystyrenesulfonate, dextran, .alpha., .beta. or .gamma.-cyclodextrin, acrylic resins (such as homopolymer and/or copolymer of methacrylic acid derivative and/or acrylic acid derivative, e.g., methacrylic acid, methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, ethyl trimethyl chloride ammonium methacrylate, acrylic acid, ethyl acrylate, etc.), and polyvinyl acetal diethylamino acetate and the like.

More preferably, the amorphous state-stabilizing agents include hydroxypropylmethylcellulose (HPMC), hydroxypropylmethyl cellulose-acetate succinate (HPMC-AS), polyvinyl pyrrolidone, acrylic resins (such as homopolymer and/or copolymer of methacrylic acid derivative and/or acrylic acid derivative, e.g., methacrylic acid, methyl methacrylate, butyl methacrylate, dimethylaminoethyl methacrylate, ethyl trimethyl chloride ammonium methacrylate, acrylic acid, ethyl acrylate, etc.), and polyvinyl acetal diethylamino acetate and the like.

Sort and ratio of compounding (1) the sparingly water-soluble medical substance, (2) the amorphous state-inducing agent, and (3) the amorphous state-stabilizing agent used in the present invention can be appropriately selected depending on the sparingly water-soluble medical substance to be used. The weight ratio of (1):(2):(3) is generally 1:(0.1-10):(0.1-10), preferably the (1):(2):(3) being 1:(0.3-3):(0.3-8), and more preferably the (1):(2):(3) being 1:(0.3-2):(0.5-5).

The solid dispersion of the sparingly water-soluble medical substance according to the present invention can be obtained by granulating (mixing) the essential components, (1) the sparingly water-soluble medical substance, (2) the amorphous state-inducing agent, and (3) the amorphous state-stabilizing agent, by means of the wet or dry method, at the same time or after the mixing, heat-treating the mixture at the temperature that is not less than the temperature at which the amorphous state-induction initiates and that the sparingly water-soluble medical substance is not deteriorated by decomposition, or subjecting the mixture to the mechanochemical treatment under the same energic conditions as the heat treatment. In this occasion, the mixture is preferably heated at the temperature not more than the melting point of the sparingly water-soluble medical substance. The temperature is closest to the amorphous state-induction initiating temperature as much as possible. If the heating temperature is lower, for example, 5 to 10^oC. lower than the amorphous state-induction initiating temperature, conversion to the amorphous state does not proceed sufficiently.

The amorphous state-induction initiating temperature means the endothermic reaction initiating temperature (peak rise temperature) which is observed when 10 mg of the sample of the mixture (1:1) of the sparingly water-soluble medical substance and the amorphous state-inducing agent is measured at the temperature rising rate 10^oC./minute using a differential scanning calorimeter (DSC).

The granulation (mixing) does not require any special means and is conducted using a universal mixer, a fluidized bed granulation machine, a dash mill, a wet granulation machine, a roller compacted granulation machine or the like. The heat treatment may be carried out together with the granulation. Alternatively, the heat treatment may be carried out after the granulation by the usual heating method, such as heating by a heater, steam, infrared rays, extreme infrared rays, or the like, using, for example, a hot air dryer, a fluidized bed dryer, a gyro-dryer, a powder dryer, or the like.

The conversion to the amorphous state can be conducted also by the mechanochemical treatment with not only the heat in the heat treatment, but also mechanical energy of compression, shearing, friction or the like as an energy to be added. For example, the conversion to the amorphous state can also be conducted, without heating the above-mentioned essential components, only through the mechanochemical treatment such as pulverization with a ball mill, treatment with a planetary mill, treatment with a compression press, treatment with a shear roll, treatment with a kneader or the like. This method makes it easy to control formation of thermal decomposed substance.

In addition, it is possible to apply oscillation energy such as ultrasonic wave, or electromagnetic energy such as electrical field, magnetism, or the like, as energy to fluctuate the crystal lattice of the sparingly water-soluble medical substance in the three-component mixture.

Either the heat treatment or the treatment with the mechanical energy under the same energy conditions as the heat treatment can be carried out at the amorphous state-induction temperature. The treatment time required for conversion to the amorphous state ranges generally from 20 to 120 minutes, preferably 30 to 90 minutes, in the case of the heat treatment, and generally from 1 to 20 minutes, preferably 3 to 10 minutes, in the case of the mechanical energy treatment, in view of quality control, homogeneity, and energy saving.

The heat treatment can be effected by using high frequency heating as well as the above-described heating methods.

The high-frequency heating according to the present invention can be carried out by any of high-frequency dielectric heating, radiofrequency inductive heating, plasma heating, and the like, with being high-frequency dielectric heating particularly preferred.

The frequency zone can be selected depending on a substance to be heated. Microwave heating using a microwave zone is especially preferable. Four frequencies which are distributed as ISM (Industrial, Scientific and Medical) frequencies under the Wireless Telegraphy Act, namely, 915, 2450, 5800 and 22125 MHz can be used as the frequency in the microwave heating. Generally, the frequency, 915 or 2450 MHz can be used.

The microwave heating can be conducted using an oven system (electronic oven system or conveyor system) or a wave guide system depending on a shape of a substance to be heated.

In the case of high-frequency heating, the amorphous state-inducing agent is not an essential component. Sort and rate of compounding the other two components, (1) the sparingly water-soluble medicl substance and (3) the amorphous state-stabilizing agent, are generally (1):(3)=1:(0.1-10), preferably the (1):(3) being 1:(0.3-8), more preferably the (1):(3) being 1:(0.5-5) though they are appropriately selected depending on the sparingly water-soluble medical substance to be used.

In this case, the solid dispersion of the sparingly water-soluble medical substance can be obtained by granulating (mixing) (1) the sparingly water-soluble medical substance and (3) the amorphous state-stabilizing agent by the wet or dry method, and simultaneously or thereafter, conducting high-frequency heating.

The treatment time required for conversion to the amorphous state ranges from 3 to 40 minutes, preferably 5 to 30 minutes, in the case of the batch treatment, in view of quality control, homogeneity, and the like though it varies depending on high frequency power. The treatment required in the continuous treatment using the conveyer system can be calculated from the energy necessary for converting to the amorphous state in the batch treatment. In the case of the high-frequency heating, a highly homogeneous solid dispersion can be obtained for a short period of time compared with the usual heat treatment.

The granulation (mixing) is conducted by using a universal mixer, a fluidized bed granulation machine, a dash mill, a wet granulation machine, a roller compacted granulation machine or the like, without the necessity of special measures. The granulation may be effected simultaneously with the usual heat treatment or the above-described mechanochemical treatment, such as pulverization with a ball mill, treatment with a planetary mill, treatment with a compression press, treatment with a shear roll, treatment with a flow coater, treatment with a kneader, or the like. Alternatively, after granulation, the usual heat treatment using a hot air dryer, a fluidized bed dryer, a gyro-dryer, a powder dryer, and the like, or the above-described mechanochemical treatment may be carried out.

Further, it is possible to perform. the heat treatment, the high-frequency heating, and the mechanochemical treatment in combination.

For the conversion of the sparingly water-soluble medical substance to the amorphous state according to the present invention, it is possible to contain water, a surfactant, an antioxidant, a preservative, a stabilizer, and the like components other than the three components, (1) the sparinly water-soluble medical substance, (2) the amorphous state-inducing agent, and (3) the amorphous state-stabilizing agent to effect the conversion to the amorphous state. Further, with respect to (2) the amorphous state-inducing agent and (3) the amorphous state-stabilizing agent, it is possible to incorporate one component or two or more components to allow the conversion to the amorphous state.

In the process for producing the solid dispersion obtained by the method of conversion to the armorphous state and the oral administration containing the solid dispersion in the. present invention, it is possible to add a pharmaceutical excipient (for example, crystalline cellulose and lactose), a disintegrant, a lubricant and/or a colorant which are generally known in the field of preparations, as required.

Claim 1 of 12 Claims

What is claimed is:

1. A method for producing a solid dispersion of a sparingly water-soluble medical substance comprising

heat treating a sparingly water-soluble medical substance, an amorphous state-inducing agent selected from the group consisting of amino acid or its salt, Aspartame, erythorbic acid or its salt, ascorbic acid or its salt, stearic acid ester, aminoethylsulfonic acid, inositol, ethylurea, citric acid or its salt, glycyrrhizinic acid or its salt, gluconic acid or its salt, creatinine, salicylic acid or its salt, tartaric acid or its salt, succinic acid or its salt, calcium acetate, sodium saccharin, aluminum hydroxide, sorbic acid or its salt, dehydroacetic acid or its salt, sodium thiomalate, nicotinic acid amide, urea, fumaric acid or its salt, macrogols, maltose, maltol, maleic acid, mannitol, meglumine, sodium desoxycholate and phosphatidylcholine, and an amorphous state-stabilizing agent selected from the group consisting of cellulose derivatives, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, vinyl alcohol/vinyl acetate copolymer, ethylene/vinyl acetate copolymer, polyethylene oxide derivatives, sodium polystyrene sulfonate, gelatin, soluble starch, pullulan, dextran, gum arabic, chondroitin sulfuric acid or its sodium salt, hyaluronic acid, pectin, chitin, chitosan, .alpha., .beta., .gamma.-cyclodextrin, alginic acid derivatives, acryl resins, polyvinyl acetal diethylaminoacetate, silicon dioxide and aluminium hydroxide,

wherein the method excludes a solvent method and a mechanochemical method.

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