JPS6354693B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a method for producing a solid drug for oral administration that has an excellent dissolution rate by adding specially treated water-swellable sodium carboxymethyl cellulose. Conventionally, efforts have been made to shorten the disintegration time of solid pharmaceuticals such as tablets, granules, and capsules filled with granules, and to increase the dissolution rate of medicinal ingredients. Improvements have been made in the form or disintegrant. Excipients used today to shorten the disintegration time of solid pharmaceuticals include l-HPC.
(low-substituted hydroxypropylcellulose; manufactured by Shin-Etsu Chemical), CMC-Ca (carboxymethylcellulose/calcium; manufactured by Nichirin Chemical, listed in the Japanese Pharmacopoeia), Polyplasdone XL (cross-linked
Polyvinylpyrrolidone), Explotab (chemically modified starch; manufactured by Edward Mondell Co.Inc.), Sta
−Rx 1500 (physically modified starch; Colorcon
Co.) and unmodified starch (listed in the Japanese Pharmacopoeia)
etc., but each has its advantages and disadvantages, and none of them are satisfactory. For example, l-HPC, Sta-
Rx 1500, unmodified starch requires relatively large addition to shorten disintegration time,
Polyplasdone XL and Explotad do not need to be added in large amounts, but when used in tablets and molded under high pressure, the disintegration time is significantly prolonged and the capping phenomenon occurs.
CMC-Ca has an outstanding effect as a disintegrant, but Ca salt may inhibit the stability of medicinal ingredients contained in solid pharmaceuticals, or it may be used in low pH ranges, such as artificial gastric fluid (PH approximately 1.2). etc., there is a problem that the swelling power is insufficient and the disintegrating effect is weakened. In the case of solid drugs that are orally administered, the length of the disintegration time is often reflected in the elution rate of the medicinal ingredient, and it is important to shorten the disintegration time in order to increase the bioavailability of the medicinal ingredient. often important. On the other hand, from a pharmaceutical engineering standpoint, it is desirable to add as few additives as possible that have a hygroscopic swelling effect in order to maintain the stability of the formulation, and this is also required in view of the recent trend toward miniaturization of formulations. Is Rukoto. Therefore, additives used to improve the disintegration rate of orally administered pharmaceuticals, that is, disintegrants, are effective when added in the smallest possible amount, and when applied to tablets, etc. It is desirable that the material also has a molding function that does not reduce hardness or cause capping. Based on the above viewpoint, the present inventors conducted various formulation studies for the purpose of searching for an excellent disintegrant, and as a result, discovered the following. That is, the present invention utilizes water-soluble carboxymethylcellulose, which has been used in the production of pharmaceuticals.
We have discovered that by using modified sodium, it is possible to produce the desired solid pharmaceutical product. Water-soluble sodium carboxymethylcellulose (abbreviated as CAC-Na) hardly causes disintegration effects even when added to solid pharmaceuticals as is. This applies not only to CMC-Na but also to water-soluble gums in general, but when a water-soluble gum that swells infinitely and completely dissolves in water is added to solid pharmaceuticals, the dissolution rate is too high. This is because a lump forms on the surface, impairing the rapid penetration of water. Therefore, in order to use CMC-Na as a disintegrant, it must be made water-insoluble and exhibit only a swelling effect. In order to make CMC-Na water-insoluble and give it only a swelling effect, there is a method of cross-linking CMC-Na with a cross-linking agent such as epichlorohydrin, formaldehyde, divinyl sulfone, etc., as described in Japanese Patent Publication No. 54-52189. . In addition, as a method for producing water-absorbing water-insoluble cellulose ether using a method similar to this, JP-A No. 50-85689,
There are JP-A-50-80376 and JP-A-51-136769.
These are intended to cause crosslinking by adding a crosslinking agent when alkali cellulose is etherified in isopropanol. The cross-linked CMC-Na obtained by these treatments has a significantly high water absorption and swelling ability, but when considering the production of solid pharmaceuticals that are orally administered to living organisms, the use of formaldehyde, epichlorohydrin, etc. is prohibited. It should be avoided if possible, and it is clear that if an attempt is made to purify the residual amount by washing with water or the like to reduce the residual amount to zero, it will lead to a significant increase in manufacturing costs. For these reasons, the use of water-insoluble CMC-Na using a crosslinking agent is limited to soil improvement materials,
Currently, its use is limited to napkins, sanitary products, etc. In view of the above circumstances, the inventors of the present application investigated a method for producing water-insoluble CMC-Na without using a crosslinking agent. We have discovered that it is possible to produce CMC-Na that is large and has a large swelling effect. The treatment method for CMC-Na will be described below. Fibrous or non-fibrous CMC-Na is dispersed in an aqueous medium to form a slurry, the pH of the slurry is adjusted to an acidic agent with mineral acid, and then the liquid is
After washing so that the pH becomes 6 to 7, heat treatment is performed. The preferred PH range is approximately PH2-5. This is because CMC-Na has a flocculating property on the acidic side, making cleaning easier. A method of insolubilizing and post-washing after heat treatment is also a method for facilitating washing, but in this case there is no need to adjust the pH to acidity. In the above treatment method, the aqueous medium refers to an aqueous solution in which methanol, ethanol, propanol, isopropanol, acetone, dioxane, etc. are compatible with water in a free ratio, and the blending ratio of organic solvent/water is determined in the aqueous solution. It is sufficient to add an organic solvent to the solution at a rate that prevents CMC-Na from infinitely swelling and dissolving.
It is 20/80 or more, preferably 50/50 or more. The mineral acids used include hydrochloric acid, nitric acid, boric acid, and carbonic acid, with hydrochloric acid being preferred. This is because the Na ⁺ produced when a part of the COONa group in CMC-Na becomes the free acid form -COOH reacts with hydrochloric acid, resulting in the formation of common salt, which is harmless to the human body.
This is because it becomes NaCl. Purification by washing after acidifying the aqueous medium slurry is performed to remove useful acids such as hydrochloric acid and nitric acid, but CMC-Na that has only been acid-treated is still soluble in water. It is preferable to use an aqueous medium or an organic solvent alone that is capable of gelling or coagulating and precipitating Na as the cleaning liquid. After washing until the pH is about 6 to 7, it is moistened.
CMC-Na is dried at a temperature below its boiling point while the wetting medium remains, and after the wetting medium has evaporated away, it is heated to a temperature of 100°C or higher, preferably in the range of 120 to 200°C. When CMC-Na is completely dried at 230 to 240°C, it becomes brown or pale yellow, which is not preferable, so the upper limit of heating is 220°C. Among the heating conditions, time can be selected within a relatively wide range. It is true that the higher the heating temperature, the faster the desired CMC-Na can be obtained by heating, but no thermodynamic or kinetic correlation between heating temperature and heating time has been found. Not yet. If you simply describe the heating time range, the number
The range is from 10 seconds to several hours, and to give a specific example, when the heating temperature is 200℃, it is 50 seconds, and when the heating temperature is 120℃.
In this case, it takes about 3 hours. These heat treatments can be performed in the air or in an inert gas atmosphere. The heat treated CMC-Na (hereinafter HT-
CMC-Na) becomes water-insoluble and water-absorbing, but this alone is not sufficient to obtain HT-CMC-Na that is effective in a small amount and has a molding function as intended by the present invention. There is a need to regulate its shape. HT-CMC-Na itself is amorphous, and when it is compressed into tablets, for example, it tends to leave an elastically deformed part along with the plastic deformation, which causes the capping phenomenon of the tablets. There is. In order to reduce this, HT-CMC-Na can be shredded and pulverized to a certain particle size or less, but the particle size (more precisely, fiber length) of HT-CMC-Na, which is a swollen product,
There is a strong correlation between the disintegrating effect on tablets or granules, and if the powder is too finely divided, a rapid and strong disintegrating effect cannot be obtained. Of course, if the fiber length of HT-CMC-Na is too long, the disintegration effect (meaning that the tablet or granule will disintegrate) will be weakened, and other disadvantages include the fact that fibrous HT-CMC-Na
-Na makes the formulation itself difficult. Therefore, HT-CMC-Na has an optimum particle size suitable for the formulation, and the amount remaining on a Tyler 42 mesh sieve is essentially zero, and at least 50% by weight passes through a Tyler 200 mesh sieve. , and the amount passing through the 325 mesh sieve must be less than 30% by weight. If there is a lot of residue on the Tyler 42 mesh sieve, it will pass through the sieve,
Tableting processes such as mixing, kneading, and tabletting, sieving, mixing,
This causes various difficulties or obstacles in the granulation process such as kneading. These include, for example, prolonged sieving time, non-uniform mixing, non-uniform kneading, and capping during tabletting. The amount that passes through the Tyler 200 mesh sieve has some correlation with the amount that passes through the 325 mesh sieve, but if the amount that passes through the Tyler 200 mesh sieve is less than 50% by weight, in other words, if the particles are too coarse, the amount that passes through the Tyler 200 mesh sieve may be partially correlated with the amount that passes through the Tyler 325 mesh sieve. Because the number of HT-CMC-Na particles present in
During disintegration, tablets or granules form many coarse block-like masses, which do not contribute to improving dissolution rate, etc., and also prolong the disintegration time itself. When the amount passing through the Tyler 325 mesh exceeds 300% by weight, that is, when the HT-CMC-Na is too fine, the disintegration effect is extremely reduced. When applying HT-CMC-Na to pharmaceutical preparations, there is another point to keep in mind in addition to particle size distribution. Whether it is a tablet or a granule, it is always treated as a powder in each unit operation of sieving, weighing, and mixing during the manufacturing process. Particularly in the case of tablets, there is a direct tableting method (hereinafter referred to as direct compression) in which the powder is compression-molded, and there is a method in which a disintegrant is added after the granules have been created and then a disintegrant is added before compression molding. As mentioned above, the powder remains as is.
In formulation processes that involve handling HT-CMC-Na, the bulk of the powder has a significant impact on the handling (workability) of the powder and the physical properties of the product. For example, in the mixing process which is usually carried out in batches, if the powder is too bulky, the amount charged per batch is reduced and it is not efficient. In addition, if the powder is too bulky, it becomes difficult to fill and mold the powder by direct compression, increasing the variation in tablet filling weight. This difficulty in compression molding is the same in the non-additive method. Also, considering the case of manufacturing granules, if the bulk of the powder is too high, extrusion granulation becomes difficult or the bulk of the granules obtained by fluidized bed granulation becomes high, so it is preferable. do not have. On the other hand, the drawbacks when the bulk is too low are often not so serious, but direct injection and late addition methods can lead to capping phenomena. In addition, the bulk is often determined by itself, depending on the particle size distribution of the powder itself. Especially in the case of the claimed invention, it is too small.
HT-CMC-Na is disliked, and the content passing through the Tyler 325 mesh sieve is specified to be 30% by weight or less, but this constraint, the heat treatment conditions, and the CMC-Na
The minimum value of the bulk is almost determined by factors such as the degree of substitution, and the only remaining factor is the particle shape. In the case of the present invention, the range of the volume of HT-CMC-Na is determined by the various factors mentioned above, and the crude specific volume value must be in the range of about 1.8 to 3.4 cc/g. In order to guarantee the disintegration ability of HT-CMC-Na obtained by heat treatment, it is necessary that the degree of substitution of CMC-Na, which is the starting material, is within a certain range. When the degree of substitution is less than 0.4, the decay ability of HT−CMC−Na is extremely reduced, and when the degree of substitution exceeds 2.0, CMC−
In addition to the increase in the production cost of Na, the hydrophilicity is too strong and the mako phenomenon remains, resulting in a decrease in disintegration ability. And CMC with too high degree of substitution
When -Na is used, moldability decreases when used for direct punching, perhaps because cleaning after acid treatment becomes difficult or the amount of plastic deformation during compression molding decreases. Why is HT-CMC-Na mentioned above different from normal CAC-?
The mechanism of action is not clear whether it has a disintegrating ability that is unimaginable for Na, but the following mechanism is thought to be possible. (1) The heat treatment partially crystallizes the CMC-Na surface, which delays the solubility of CMC-Na. (2) -COOH group generated by mineral acid treatment,
It undergoes dehydration condensation with other -COOH or -OH groups present in the CMC-Na molecular chain. In any case, it has a degree of substitution of about 0.4-2.0
HT-CMC-Na obtained by once placing CMC-Na under acidic conditions, then washing, drying and heating,
Tyler42 mesh sieve residue is virtually zero and the same
HT--, in which the amount passing through the 200 mesh sieve is 50% by weight or more, the amount passing through the 325 mesh sieve is 30% by weight or less, and the gross specific volume value is in the range of about 1.8 to 3.4 cc/g. The white powder of CMC-Na exhibits good functionality as a disintegrant for tablets and granules. The above HT-CMC-Na can be used for tablets produced by direct compression and wet tableting (wet compression), as well as by extrusion granulation method.
It can be used as a disintegrant for granules produced by centrifugal granulation, crushing granulation, fluidized bed granulation, etc. The method for producing a pharmaceutical product with an excellent dissolution rate according to the present invention can be carried out as follows. First, regarding the manufacturing method of tablets, there are direct compression, wet compression, and a powder addition method as a modified method of wet compression, and these can be carried out by known procedures. In the case of direct compression, HT-CMC-Na is added to the medicinal ingredients, and additives such as excipients, binders, lubricants, and fluid thickeners are added as necessary, and after mixing, the powder is Compression mold the raw material to obtain tablets. In the case of wet application, HT-CMC-Na is added to the medicinal ingredient, an excipient (solid) binder, etc. is added and mixed, water or binder liquid is added and granulated, and after drying, it is sieved. The resulting granules may be compression molded. Of course, the lubricant may be added during powder mixing and/or before compression molding. The powder addition method is similar to wet pulverization, and after making dry granules, HT-CMC-Na alone or HT-CMC
- Add Na and lubricant, mix with granules and compression mold. In the case of the above tablets, the amount of HT-CMC-Na added is preferably in the range of 0.5 to 10% by weight, preferably 1.0 to 3.0% by weight, based on the weight of the tablet. If it is less than 0.5% by weight, the disintegration effect is insufficient, and if it exceeds 10% by weight,
It is uneconomical because it does not have a disintegrating effect commensurate with the amount added. Next, granules (including pills) are manufactured as follows. Adding HT-CMC-Na to the medicinal ingredients,
Excipients added as necessary are blended, mixed, and granulated. After drying, the mixture is sieved to obtain granules. For granulation, various known granulators can be used. The use of a binder (liquid or solid) during granulation is free. In the case of the above granules, the amount of HT-CMC-Na added is 0.5 to 8% by weight, preferably 1.0 to 3.0% by weight.
It is desirable that The above-described method for producing tablets and granules significantly improves the disintegration rate or dissolution rate. Therefore, the present invention is particularly effective when using medicinal ingredients that are difficult to dissolve in water and have a solubility in water of 1.0 g/100 ml (20°C) or less. The disintegration time of tablets and granules obtained by conventional formulation methods using CMC-Na or CMC-Na as a disintegrant was sometimes extended depending on the PH of the disintegrating liquid, but this Since the obtained drug is not dependent on pH, it is thought that it will contribute to improving the availability of the preparation. Note that the tablets and granules obtained according to the present invention may be coated with a film or coated with sugar according to a conventional method. Example 1 Commercially available CMC-Na (degree of substitution 0.3 to 2.5) was dissolved in a liquid with a ratio of n-propanol and water of 80:20 at a solid concentration of 5.
% by weight slurry. While stirring, a small amount of 5% hydrochloric acid was added to adjust the pH to about 2 to 5, and the mixture was left to stand for 30 minutes. Next, the supernatant was discarded by centrifugation, re-slurried in an aqueous medium with a ratio of n-propanol and water of 80:20, and the process of discarding the supernatant by centrifugation was repeated until the pH of the liquid was approximately 6.2.
The solid content was collected by centrifugation. The solid content was treated in an oven at 100°C for 20 minutes to completely evaporate the wetting medium, then heated at 170°C for 15 minutes and cooled to obtain HT-CMC-Na. Since the obtained HT-CMC-Na had a large particle size distribution, it was subjected to an air flow mill to adjust the average particle size to about 45 to 60μ. Obtained HT−CMC−
Table 1 shows the powder physical properties of Na. In addition, each measurement is
This was done by the following method. Particle size distribution Take 100 grams of sample and pass through a Tyler standard sieve (42200,
After shaking for about 30 minutes using a low-tap sieve shaking tester, each fraction was measured using a 100 ml graduated cylinder. Deposit a small amount under the order. After injecting all the samples, use a brush to smooth the top surface of the deposited powder, and divide the deposited volume shown at that time by the sample weight. Degree of substitution of HT-CMC-Na (1) Accurately weigh 2 g of HT-CMC-Na, incinerate, cool, and moisten with 1:1 sulfuric acid (2) Heat until no sulfuric acid fume is generated. (3) Completely bake in an atmosphere of 800 to 850℃ (approximately 30
(4) Leave the sample as above to cool in a desiccator. (5) Weigh accurately and calculate the ash content: C using the following formula: Residue weight/sample weight (100-%H ₂ O/100) x 100 = C
(1) (6) Accurately weigh about 1 g of HT-CMC-Na and transfer it to a ground glass Erlenmeyer flask (500 ml volume) with a stopper. (7) Add 300 ml of 10% NaCl solution. (8) Accurately weigh 25 ml of 0.1N NaOH. (9) Seal tightly and leave for 5 minutes while shaking occasionally. (10) Add 5 drops of metacresol purple indicator (0.1 g of metacresol purple dissolved in 13 ml of 0.01N NaOH and diluted with water to 100 ml). . (11) Next, add approximately 15 ml of 0.1N HCl using a beer bottle (12) Seal the bottle tightly and shake. If the solution is purple, add 1 ml of 0.1N HCl until the solution turns yellow.
Add them one by one. Shaking is required after each addition of acid. Since 0.1N HCl is added in 1 ml increments, it is necessary to back-titer with 0.1N NaOH to correct for excess HCl (13).
(14) Record the number of ml required for back titration, combine it with the previous 25 ml, and calculate M (m, eq/g;
Calculate (ml x N NaOH) - (ml x N HCl) / sample weight (100-%
_H2O /100)=M(2) (15) Using C and M obtained above, the free acid type carboxymethyl substitution degree: A and the salt type sodium carboxymethyl substitution degree: S are calculated. 162+80S) M/1000-(58×M)=A (3) (162×58A)C/7102-(80×C)=S (4) However, 162=Molecular formula weight of anhydroglucose unit of cellulose 80=Sodium・Molecular weight value that increases each time a carboxymethyl group is added 58 = Molecular weight value that increases each time a carboxymethyl group is added 7102 = Formula weight of sodium sulfate multiplied by 100 The degree of CMC-Na substitution is based on (1) above. ~(14)
Measure using.

【table】 # # #
+42, -200, -325 are 42 each
Example 2 showing the amount remaining on a mesh sieve, the amount passed through a 200 mesh sieve, and the amount passed through a 325 mesh 2 Commercially available aspirin powder (pharmaceutical product) 40% by weight, microcrystalline cellulose 30% by weight, DMV 100 mesh lactose
24.5% by weight of magnesium stearate, 0.5% by weight of magnesium stearate, and 5% by weight of HT-CMC-Na obtained in Example 1 (total amount 1 kg) were mixed for 30 minutes in a 10-volume V-type blender, and then processed into a rotary tablet press manufactured by Kikusui Seisakusho. (RT
The molding pressure was varied in the range of 200 to 600 Kg/cm 2 and the molding pressure was varied in the range of 200 to 600 Kg/cm ² . The physical properties of the direct compression tablets are shown in Table 2.

【table】

[Table] Example 3 CMC-Na was produced using a normal etherification method in which purified linter (DP800) was used to make alkali cellulose, reacted with monochloroacetic acid, and then isopropanol was added to precipitate CMC-Na. After that, the isopropanol/water ratio is 50/50.
After washing with an aqueous medium, repeating centrifugal dehydration and washing, adjust the CMC-Na-isopropanol/water slurry to pH 4 using nitric acid, leave it to stand for 2 hours, repeat centrifugal dehydration and washing, and then repeat centrifugal dehydration and washing. After dehydration as in 1, it was heated in an oven. The heating conditions are
The temperature was 145°C for 30 minutes. It was taken out of the oven and allowed to cool to obtain HT-CMC-Na. The degree of substitution of CMC-Na sampled in advance was 0.75, and the ratio of acid type substitution to salt type substitution of the final HT-CMC-Na was 0.8. The above HT-CMC-Na had large particles (long fiber length) reflecting the shape of the starting material and a large crude specific volume of 4.6 cc/g, so a pin-type hammer mill was used to discharge it. Adjust the screen hole diameter,
Particle size distribution and coarse specific volume were reduced. Some of the obtained powder was classified using an air mini-separator to cut out coarse particles to obtain the samples shown in Table 3.

【table】

[Table] Using these samples (#8 to #11), tablets were manufactured with the same composition and the same direct compression formulation as in Example 2, and were evaluated. The evaluation results are shown in Table 4.

[Table] Calculated as a percentage, usually 3% or less is desirable.
Example 4 According to the method of Example 1, CMC- with a degree of substitution of 0.8
HT-CMC-Na was produced using Na powder. However, the pH was adjusted to PH3.5 for 30 minutes, and the heat treatment conditions were 120° C. for 2 to 180 minutes. Obtained HT−
CMC-Na is lightly ground with a pin-type hammer mill and passed through a Tyler 42 mesh sieve with zero residue.
The content passing through the mesh sieve was controlled at 75 to 85% by weight, and the content passing through the 325 mesh sieve was controlled at 20 to 28% by weight. Pharmacopoeia phenacetin powder 40% by weight, crystalline cellulose
30% by weight, DMV100 mesh lactose 24.5% by weight, magnesium stearate 0.5% by weight, HT- as above
Create a prescription of CMC-Na 5% by weight (total amount 1.5Kg),
The mixture was mixed for 30 minutes in a 10-volume V-type blender, and then a direct formulation was prepared under the conditions of Example 2. The evaluation results are shown in Table-5.

[Table] Example 5 A wet compression formulation was prepared according to the formulation shown in Table 6, and the physical properties of the tablet were evaluated. In Table 6, l-
HPC (A), CMC−Ca (B), Explotab (C), STa
-Rx 1500(D), Cornstarch (E), HT-CMC
−Na(F) was selected. However, as HT-CMC-Na(F), No. 3 of Example 4 was used.

[Table] The formulation method is as follows. First, the three components, phenacetin, crystalline cellulose, and disintegrant, were thoroughly mixed and mixed in a 5-volume planetary mixer (Shinagawa Kogyo Co., Ltd.).
After adding the binder solution and kneading for 5 minutes,
The mixture was crushed and granulated using a FL-200 flat mill manufactured by Fuji Paudal Co., Ltd. using a perforated plate with a hole diameter of 3 mm as a screen. The obtained granules were dried in a hot air dryer at 60°C for 8 hours, and passed through a 12-mesh and 100-mesh sieve to remove coarse granules and fine powder, and the weight of the granules was 0.5% by weight.
of magnesium stearate was added, mixed and formulated using the tablet press described in Example 2. Table 7 shows the evaluation results of the obtained tablet physical properties.

【table】

[Table] Example 6 Phenacetin 40% by weight, crystalline cellulose 5% by weight, DMV200 mesh lactose 40% by weight, methylcellulose 2% by weight, cornstarch 8% by weight,
After mixing the powders at a blending ratio of 5% by weight of HT-CMC-Na (using No. 3 in Example 4), water was added and kneaded by a conventional method, and the mixture was heated using a vertical extruder (manufactured by Fuji Powdal Co., Ltd.). After granulation and drying,
The mixture was sieved through a 12-mesh sieve to obtain granules. This product is
Although it had a particle size that met the Japanese Pharmacopoeia granule specifications, it was confirmed that it disintegrated quickly in pure water at 37°C within 3 minutes. On the other hand, granules obtained by granulation in the same manner using a system in which HT-CMC-Na was removed and corn starch was increased in its place had a very long disintegration time of 18 minutes.

Claims (1)

[Scope of Claims] 1 Sodium carboxymethyl cellulose with a degree of substitution of 0.4 to 2.0 is treated with mineral acid, washed, heated and pulverized, and the particle size is such that the residual amount of Tyler 42 mesh is zero, 50% by weight or more passes through 200 mesh, and 325 mesh. A white powder of heat-treated sodium carboxymethyl cellulose having a passing content of 30% by weight or less and a gross specific volume of 1.8 to 3.4 cc/g is added to a composition containing a medicinal ingredient and then shaped. Characteristic manufacturing method of pharmaceutical products. 2 Heat-treated carboxymethylcellulose sodium with a degree of substitution of 0.4 to 2.0 is dispersed in an aqueous medium,
Add mineral acid and place under acidic conditions, then wash so that the pH is 6 to 7, and then heat to a temperature of 100 to 200.
2. The method for producing a pharmaceutical according to claim 1, wherein the pharmaceutical product is heat-treated at ℃. 3 The aqueous medium is a mixed solution of at least one selected from methanol, ethanol, propanol, and isopropanol and water, the mineral acid is hydrochloric acid or nitric acid alone or a mixture, and the heating temperature is
The method for producing a pharmaceutical according to claim 2, characterized in that the temperature is 120 to 200°C. 4. The method for producing a pharmaceutical according to claim 1, wherein the medicinal ingredient has a solubility of 1.0 g/100 ml or less at 20°C.