KR830002614B1 - Process for preparation of actived pharmaceutical compounds - Google Patents

Abstract

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Description

Preparation of activated pharmaceutical composition

1 shows the dissolution test results of Example 1,

2 shows the dissolution test results of Example 2,

Figure 3 shows the test results by the adult male of Example 4,

Figure 4 shows the test results for the rat of Example 8,

5 shows the test results of Example 10,

6 shows the test results of Example 11,

Figure 7 shows the test results of Example 14,

8 shows the test results of Example 15,

9 shows the test results of Example 16.

The present invention relates to the preparation of a pharmaceutical composition which is easily absorbed in the stomach and shows high efficacy. The technical field of this invention belongs to US patent classification 424. The prior art of this invention is Japanese Unexamined-Japanese-Patent 35-5798.

This document describes a method of adding Carbo Wax to chloramphenicol palmitate, dissolving them in a hot hydrophilic organic solvent and then quenching to obtain a fine amorphous product of chloramphenicol palmitate. However, the composition obtained by the above method has poor redispersibility for water because it contains carbowax with a low melting point. Another prior art is Japanese Patent Laid-Open No. 54-2316. Said document discloses a composition in which nifedipine is dissolved in an organic solvent, and a combination in which a first component selected from glycerin, vegetable oil, etc., and a second component selected from polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl cellulose, and the like are dissolved in an organic solvent. A method of preparing is provided. However, this method uses a large amount of organic solvents and thus has a dangerous process defect. The above disclosed method is fundamentally different from the method of the present invention using water in that both use organic solvents. In addition, as a prior art similar to the present invention, there is a Japanese Patent Application No. 46-42390. Here, a method of preparing a suspension of chloramphenicol palmitate by mixing chloramphenicol palmitate, which is insoluble in water, with a surfactant, is pulverized with a colloid mill in a water-soluble high molecular material such as methylcellulose solution. However, the mixture of chloramphenicol palmitate and surfactant used in this method is closely bound to each other and is not chloramphenicol palmitate itself. Also, since this technique is a preparation of suspension, the novelty of the present invention cannot be denied. Another prior art similar to the present invention is Japanese Patent Application No. 45-33676, where an organic acid ester of chloramphenicol, which is difficult to be dissolved in water, is mixed with a surfactant and dispersed in hot water, and cooled in the presence of polyvinyl alcohol or the like. V) producing a fine particle suspension of an organic acid ester of chloramphenicol. In the case of the above technique, a chloramphenicol organic acid ester is used which is suspended with a surfactant. In this case, the chloramphenicol organic acid ester is in close contact with the surfactant and may be regarded as a material other than the chloramphenicol organic acid ester. In addition, since the micelle of the surfactant is surely formed in the suspension of the similar technology, it is remarkably different from the method of the present invention in which the micelle is not formed. This analogous technique also suggests the preparation of a suspension. Therefore, the novelty of the present invention cannot be denied by these prior arts. It is an object of the present invention to provide a new method for preparing a drug composition that is insoluble in water, and has a good redispersibility for water and high drug efficacy and bioavailability. Summary of the Invention A method of preparing a particulate pharmaceutical composition coated with a water-soluble high molecular material by dispersing a drug that is insoluble in water in the presence of a water-soluble high molecular material into a fine particle having a diameter of 10 μm or less in water and then evaporating water. to be.

When the water-soluble polymer used in the present invention is thermogelable, a drug that is insoluble in water is dispersed in a particulate state in an aqueous solution of the water-soluble polymer material, and then the dispersion solution is heated to gel the water-soluble polymer material to be contained in the gel. The cost of evaporating the solvent can be greatly reduced by separating it from the water layer with the reagent and drying it.

In the present invention, there are various methods for dispersing a drug that is poorly soluble in water in the form of fine particles. In the first method, when a drug is dissolved in an aqueous alkali solution, the drug is dissolved in an aqueous alkali solution and then neutralized with an acid to precipitate. When the second method is dissolved in an acidic aqueous solution, the drug is dissolved in an acidic aqueous solution and then neutralized with alkali to precipitate. In the third method, when a drug is dissolved in a non-hydrophilic organic solvent, the drug is dissolved in a non-hydrophilic organic solvent and the solution is emulsified with water. The fourth method is a method of pulverizing and dispersing a drug that is insoluble in water in water.

In the present invention, the term "activating agent" refers to a drug that has been improved in water absorption by atomizing and having high redispersibility.

It is an object of the present invention to propose a new method for preparing an active pharmaceutical composition with good redispersibility in the digestive tract as described above. Poorly soluble drugs that do not dissolve well in water, the superiority of the drug is not evaluated only by the pharmacological effect alone. It was recognized that the physical properties conferred in the formulation process, in particular, the particle size and the size, were actively studied for the preparation of the drug with fine particles. In particular, the micronization of the organic acid salt of chloramphenicol has been studied and many patent applications have been published. For example, Japan Special Public Office 35-5798, East 45-33676, East 46-15286, East 46-17153, East 46-21671, East 46-42390. The present invention is a method for preparing a particulate drug coated with a water-soluble polymer material by dispersing a poorly soluble drug in water in the presence of a water-soluble polymer material and then evaporating water.

As the water-soluble polymer material used in the present invention, a heat gelling water-soluble polymer material can be used. In this case, when the solid drug is dispersed in water and the dispersion system is heated, the high molecular material gels by containing the dispersed fine drug. This gel can be separated from water and dried. In this case, since the amount of heat required for evaporation can be reduced, it is very preferable. In the present invention, as described above, there are the first to fourth methods for dispersing poorly soluble solid medicaments in water into water particulates.

Conventionally, low melting agents such as fatty acid esters of chloram phenicol have been proposed to be melted by heating to make them liquid and emulsified by physical methods by mechanical stirring or shearing. However, this method is insufficient in the degree of atomization because the molten chemical is high in viscosity and hardly subjected to shear force. That is, in this method, the particle size is often about 10 μm or more. Moreover, the method of using surfactant at the time of emulsification is also performed normally. Surfactants used include polysorbate 80, which is particularly recognized for its use as a medicament, and has a high emulsifying and soluble ability, and HCO-60, in which ethylene oxide is added and polymerized with hydrogenated castor oil. . These nonionic surfactants are commonly used because they have little interaction with the drug and have no taste or smell. However, in the case of using a surfactant when emulsifying, a problem of hemolytic action has recently been caused. Furthermore, depending on the amount of surfactant added, it is clearly atomized and in vitro, i.e., in the dissolution test, when the dissolution rate is high or when administered to humans in the biological test, the bioavailability is not always high, the absorption is slow, and the area under the blood concentration curve It is reported that this is sometimes small.

These causes are considered to be because microparticles of a chemical | medical agent bind to the micelle of surfactant, and absorption is suppressed and the distribution ratio to a lipid is low. In addition, there are polymorphs in fatty acid esters of chloramphenicol, barbital, sulfanamide, and steroids such as crotisone acetate, methylprednisolone, riboflavin, and ubidecaranone. Occurs. Therefore, it is necessary to fully consider this problem in preparing an active agent with high bioavailability. The pharmaceuticals used in the present invention also have many polymorphs. In general, it is known that the smaller the particle size of the drug is, the more the surface area thereof is increased and the absorption thereof is faster. However, if the drug is poorly soluble in water, even if the primary particles of the drug are finely formulated into fine granules, granules, tablets, etc., the primary particles aggregate and behave like large particles without being redispersed in the summon tube. a lot of works. Therefore, as a result, it may not be easily absorbed by a living body.

In view of the relationship between the gastric emptying time and the particle size of the drug, the present inventors orally administer a slurry obtained by dispersing fine particles of arsenic sulfate in water and granules of various sizes of barium sulfate to orally move the stomach and the intestine. As a result of X-ray observation, when the barium sulfate slurry dispersed in water in the form of fine particles is transferred to the intestines regardless of the food in the stomach, the molded fine granules, granules and tablets of barium sulfate have a long retention time in the stomach. It was found to be long and not easily transitioned to the intestines. Absorption of the drug occurs in part of the stomach, but most of the absorption occurs in the upper or small intestine with the largest absorption area, so it is very important how quickly the drug is transferred to the small intestine after oral administration. Therefore, in oral preparations, the time to move to the small intestine, which is the largest surface absorbent, without being affected by the presence or absence of food in the stomach is highlighted as the first factor to increase the bioavailability.

As described above, drugs that reach the absorption site vary depending on the pharmacological and physicochemical characteristics of each drug in mucosal permeation, but are often transported manually. In addition, active transport is not small. In any case, what is desired for a drug that is poorly soluble in water should be dispersed particulate in the absorbing part so that each of the particulates should be oily in the distribution ratio. As described above, many studies on atomization of solid pharmaceuticals have been reported, but many reports have been compared in the order of several tens of microns.

According to the experiments of the present inventors, 10 μm or less is preferable and preferably 0.5 μm or less in order to quickly pass into the gastrointestinal tract and reach the small intestine with or without food in the stomach. Most of the poorly water-soluble drugs are thought to be absorbed through the aliphatic pathway of the small intestine mucosa, so it is best to disperse them into so-called colloidal particles of 0.5 micron or less. The method of the present invention, in particular, in a non-hydrophilic organic solvent, dissolves a drug that is insoluble in water and examines the concentration in the water-soluble high molecular organic solvent, and the dispersed particles in the digestive tract are about 0.5 mu (measured by electron microscope). It was confirmed that it can be done.

The drug composition of the drug composition composed of the ultra-fine particles of the drug can be seen that can be absorbed directly through the fatty path of the small intestinal mucosa without passing through the phase of water even in consideration of the diameter of the small pores of the mucosa.

The pharmaceutical composition of the pharmaceutical composition prepared according to the method of the present invention is redispersed in water, and after oral administration, quickly reaches the small intestine and is easily absorbed into the blood to increase blood concentration. Examples of the water-soluble high-molecular substance used in the present invention include cellulose derivatives such as hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, and carboxymethyl cellulose salts and α-starch, Hydroxypropyl starch, carboxymethyl starch, pullulan, gum arabic, tragacand rubber, gelatin, polyvinyl alcohol, polyvinylpyrrolidone and the like. Among these water-soluble high molecular substances, thermogelability includes hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl ethyl cellulose, hydroxypropyl amylose and hydroxypropyl pullulan. These can be used individually or in combination. On the other hand, when a water-soluble high molecular material such as carboxy wax having a low melting point (100 ° C. or lower) is used, it is not good because the redispersibility is poor in the case of using a solid medicine.

Next, the present invention will be described in detail with respect to a case where the drug of the present invention is dissolved in an aqueous alkali solution and then neutralized with an acid to disperse the drug. First, the case where the water-soluble high molecular substance used is not gelatinized is demonstrated. A drug that dissolves in an aqueous alkali solution as a poorly water-soluble solid at room temperature, for example, phenytoin is dissolved in an aqueous alkali solution in which gum arabic is dissolved, neutralized by addition of an acid and stirred, and the drug is precipitated in a particulate form. The acid is good and the active pharmaceutical composition can be obtained. The components of the pharmaceutical composition obtained when, for example, phenytoin is used as a drug soluble in water are phenytoin and gum arabic, in which the former fine particles are coated with the latter.

Instead of the spray drying described above, fine granules or granules may be prepared by spraying an excipient such as lactose, starch, microcrystalline cellulose, and hard silicic acid with a fluidized bed spray dryer. When a solid drug which is hard to dissolve in water is dissolved in the acidic aqueous solution, the same procedure as described above may be performed except that the drug is dissolved in the acidic aqueous solution and neutralized using alkali.

Examples of solid pharmaceuticals soluble in aqueous alkali solution include ipananoic acid, iotalamic acid, indomethacin, nalidic acid, trichloromethiazide, barbital, hydrochlorothiazide, phenytoin, phenylbutazone, phenobarbital, prosemide, Hydrocholic acid, propylthiouracil, methylthiouracil, methotrexate, folic acid, iodide, riboflavin and the like.

Acid soluble solvents include ethyl amino benzoate, ethionamide, azimalin, sulfamomethazole, sulfamomethoxine, sulfisoxazole, tetracycline, 1-tryptophan, maleic acid perfenazine, norepinephrine, methyldopa, and levadopa. Etc. In the case of using a thermogelable compound such as hydroxypropyl cellulose as a water-soluble high molecular material used in the method of neutralizing as described above to precipitate the drug and dispersing it in the particulate form in water, the method is carried out as follows according to the method of the present invention. can do.

A drug which is solid at room temperature, poorly soluble in water and soluble in an aqueous alkali solution is dissolved in an aqueous alkali solution, and then heat-gelling water-soluble high molecular substance, for example, hydroxypropyl cellulose having a thermal gelation temperature of 60 ° C. Stir and dissolve. Next, when the acid is added and neutralized with stirring, the above-mentioned agent precipitates in a fine shape. Subsequently, if the solution is heated to 80 ° C. or higher, hydroxypropyl cellulose gels and precipitates. At this time, the particulate drug is contained in the gel. This precipitate is separated by filtration, washed with warm water of 80 ° C. or higher to remove the salt produced by the above-mentioned neutralization, and dried. The drug thus obtained is extremely fine, but is contained in the gel ring water-soluble high molecular material, and thus is easily filtered without filling the filter medium.

The drug which dissolves in the aqueous solution of an acid can also be implemented by the same method using a heat-gelling water soluble high molecular material (alkali is used for medium sulfur). In general, in the case of precipitation of a drug in a solution, at first, particles in which fine particles are formed gradually become larger, grow into crystals, and fine particles disappear. However, since the fine drug particles of the present invention are in a state of being stacked with a water-soluble high molecular material, the growth of such particles does not occur and can maintain a very stable fine phase. This is also a big feature of the present invention.

Next, a method of preparing an active pharmaceutical composition by dissolving a solid pharmaceutical agent insoluble in water in a non-hydrophilic organic solvent, emulsifying the solution in the presence of a water-soluble polymer, and evaporating the solvent of the emulsion, will be described. In this method, any method may be used to evaporate the water and the organic solvent which are solvents of the emulsion. However, it is desirable to follow the method of evaporating as quickly as possible, for example spray drying, flow spraying. Fine powders of the drug obtained by evaporation of solvent are piled up into water-soluble high molecular material immediately after production. As a result, the fine powder does not clump or grow to be a coarse crystal, and once introduced into water, the water-soluble polymer is dissolved in water, and the medicine is easily redispersed in water. In this method, "dispersing an organic solvent in water in the presence of a water-soluble high molecular material" means that the water-soluble high molecular material may be present in either water or in an organic solvent or may be added during an emulsification operation. .

Next, a method of using the gelling phenomenon using a thermal gelling material as the water-soluble polymer in the above-described method will be described. The emulsion is prepared according to the method described above using a heat gelable water soluble high molecular material. Next, this emulsion is heated. The heating temperature is preferably 80 ° C. or higher since it gelled reliably. The gelled water-soluble high molecular material is sedimented or floated together with the colloidal organic solution and separated from water. This is divided by a method such as filtration and dried to obtain an activated pharmaceutical composition.

The method of drying the separated gel can be vacuum dried while maintaining the gelation temperature. It may also be cooled to room temperature, sprayed and dried. In either case, the emulsification of the water and the non-hydrophilic organic solution is maintained while drying. Also in the method including this gelation process, the fine particles of the drug are accumulated in the water-soluble polymer immediately after precipitation. The resulting fine particles do not lump or grow afterwards. In the method including the gelling process, since the gel and the liquid can be easily separated, the amount of heat for evaporating the solvent can be saved, which is very advantageous. The non-hydrophilic organic solvent used in these methods is preferably formed when the water is mixed to form a different layer from water, among which chloroform, methylene chloride, trichloroethylene, trichloroethane, carbon tetrachloride, benzene, benzine, and n Low melting point organic solvents such as hexane, toluene, xylene, ethyl ether, isopropyl ether, methyl ethyl ketone, ethyl acetate and the like are easily removed upon drying.

A hydrophilic low melting organic solvent (for example, ethanol, isopropyl alcohol, acetone, etc.) may be added to the hydrophilic organic solvent for the purpose of improving solubility or promoting emulsification. As a non-hydrophilic organic solvent, it can be used as a harmless and orally administrable oily substance such as glyceride, liquid paraffin, squalane, squaraine, pristane and low HLB sorbitan fatty acid ester and sucrose fatty acid ester which remain after drying. In general, amorphous drugs are known to be more soluble and more easily absorbed than crystalline ones.

In particular, an amorphous amorphous drug can be easily obtained by using the above-mentioned oily substance as a non-hydrophilic organic solvent as a poorly soluble drug in water used in the present invention or by adding it to the low-melting non-hydrophilic organic solvent described above. One of the characteristics of the method using an aqueous organic solvent. In the case of non-polymorphic drugs, bioavailability can be increased by changing the distribution rate in this way. In the method of dissolving a drug that is insoluble in water in a non-hydrophilic organic solvent and emulsifying and dispersing it in water in the presence of a water-soluble polymer, the ratio of the water-soluble polymer to water is preferably 5% by weight or more. In consideration of the dosage form, the dosage, and the like, an excipient such as starch, lactose, mannite, cellulose powder, and silicon dioxide may be added to water, if necessary.

The amount of the non-hydrophilic organic solvent may be equal to or greater than the amount that the poorly soluble drug can dissolve or uniformly disperse in colloidal form. When the water is removed in the process of evaporating water with a low melting organic solvent, dilution to several times to several tens of times is preferable because the particle diameter of the solid pharmaceutical agent in the product is small. Usually, it can be made into fine particles having a particle size of 1 μm or less by dissolving at the same weight or more, preferably 5 to 20 times (weight) of the drug.

The above-described method is a method that substantially does not use a surfactant, and a small amount of the surfactant may be added for the purpose of promoting dispersion in the digestive tract. At this time, dioctyl sodium sulfosuccinate or sucrose fatty acid ester without hemolytic action is used.

Solid agents dissolved in the above non-hydrophilic organic solvents include azmalin, isopropyl anthylphyrin, ethyl sulphine quinine, ethenamide, erythromycin, erythromycin fatty acid esters, chitasamycin, chloropropamide, and chloromezzanone. , Cortisone acetate, diazepam, digroxine, cyclophosphamide, spironolactone, nalidixic acid, amobarbital, indomethacin, probemycin, nifedipine, ubidecarenone, chloramphenicol palmitate and the like.

In the present invention, a method for preparing an activated pharmaceutical composition by pulverizing the drug in an aqueous solution of a water-soluble high molecular material in order to disperse the drug which is poorly soluble in water in an aqueous solution of water is then evaporated.

In this method, an aqueous solution of a water-soluble high molecular material is used, but a hydrophilic organic solvent may be added to the aqueous solution unless a water-soluble high molecular material is precipitated. Usually methanol, ethanol, isopropyl alcohol, acetone, etc. are used. By adding these, there is an effect of rapidly drying and depending on the drug, promoting the atomization during grinding. The solid pharmaceutical agent dissolving in the organic solvent and poorly soluble in water may be prepared by pulverizing the drug in the organic solvent of the organic solvent of the water-soluble polymer material after evaporating the solvent to prepare the activated pharmaceutical composition. The pulverizer used for pulverization in liquid can be pulverized in a liquid using a wet mill such as various ball mills, vibration pulverizers, attritors and polytrons manufactured by Kinematik Co., Ltd. of Switzerland, to obtain sufficiently fine powder. These wet mills have a stronger refining function than dry mills. It is preferable to pulverize the powder in advance before putting the drug in the wet grinder, and it is advantageous to use the raw material that has undergone such a preliminary atomization process because the grinding is smooth. Grinding by a wet grinding machine yields a solid pharmaceutical agent of fine particles having a particle size of 0.5 to 5 mu or less. The drying of the solid pharmaceuticals dispersed in water may be performed by spraying and drying by spray drying, or by adding to an excipient such as lactose, starch, microcellulose, hard silicic anhydride, etc. with a fluidized granulator. When the solid drug is pulverized in an aqueous solution in which the thermogelable water-soluble polymer material is dissolved, the thermogelable water-soluble polymer material may be gelated by dispersing the drug in an aqueous solution and then heating the dispersion system. The heating is sufficient to cause gelation and is generally preferred to be heated to 80 to 90 ° C. The solid drug gelled and dispersed in the liquid is separated from the liquid contained in the gel. In drying this gel, the liquid can be sufficiently separated in advance to save the amount of heat required for drying. Filtration or the like can be used to separate the gel from the liquid. In the filtration, the gel acts as a filter aid to prevent the blockage of the filter agent by the fine particles of the drug to facilitate filtration. It is preferable to keep the temperature of the gel above the gelation temperature during the separation process such as filtration. If the temperature of the gel cannot be maintained above the gelation temperature, it is preferable to spray and instantaneously dry, because it prevents the growth or aggregation of the primary particles of the drug. The above method of pulverizing the solid drug in a solution of a water-soluble high molecular material and dispersing it in a liquid is advantageous because it can be washed with a liquid containing a crab active agent to make a product that is soluble in water. For this purpose, it is preferable to use a surfactant such as dioctylsodium sulfosuccinate that does not form micelles well as described above. However, if a large amount of the surfactant is used, even if the dispersibility of the poorly water-soluble drug in water can be improved, the biovailability of the drug may be deteriorated.

The activator composition prepared according to the method of the present invention exhibits high bioavailability in the form of powder, granules, granules, tablets, and the like.

Example 1

50 g of sodium hydroxide mu was dissolved in 1.51 of water. In this solution, 200 g of Japanese pharmacy room phenytoin and 20 g of hydroxy propyl cellulose (Japanese-made L-type) are dissolved. While the aqueous solution of phenytoin, sodium hydroxide and hydroxy propyl cellulose is heated and stirred, a solution of 100 g of citric acid dissolved in 0.51 of water is gradually added to neutralize to precipitate phenytoin. The white liquor is heated to about 90 ° C. to gel hydroxy propyl cellulose, and the precipitate is filtered to wash the precipitate with 3 l of hot water of 80 ° C. or higher.

After washing, the precipitate is transferred to a hot air dryer already heated to 110 ° C. and dried. It is then powdered with a grinder. The powdered phenytoin obtained is quickly dispersed in water to give a white suspension.

Using powdered phenytoin, commercially available phenytoin A, and commercially available phenytoin B obtained in Example 1 as samples, 0.05 wt% of polysorbate 80 was added to the sealing solution method 1 of the Japanese pharmacy room. The results of the elution test at 100 rpm and phenytoin 50 mg / l) are shown in FIG. Line I-I shows the sample of Example 1, line II-II shows the commercial item A, and line III-III shows the commercial item B. FIG.

Commercially available product A of Nihon Pharmacy Phenytoin, Commercially available product B of Nitrogen Pharmacy Phenytoin and the phenytoin of the present invention obtained by Example 1 above were orally administered at 4 mg / kg body weight, and the blood concentration was measured every hour over 8 hours after administration. Is shown in the first table below.

In the above sealing test, it is seen that the commercial item A has a low sealing speed and a low sealing rate. In addition, as shown in Table 1, phenytoin hardly enters the blood.

=212μg/ml로 표시한다. 투여 3 내지 4시간 후에는 약 5 내지 6μg/ml의 최고치에 달하고, 시판품 A, B에 비교하여 현저하게 높은 생물학적 이용도를 나타내며, Aμc도 의의적으로 높다.Commercially available product B, as shown in Table 1, has a prolonged delay due to a significant increase in blood concentration. In comparison, activated phenytoin obtained by the method of the present invention has an elevated blood concentration within 1 hour after administration,

= 212 μg / ml. After 3 to 4 hours of administration, a peak of about 5 to 6 μg / ml is reached, showing a significantly higher bioavailability compared to commercially available products A and B, and A μc is also significantly higher.

[Table 1]

Blood concentration of commercially available phenytoin and activated phenytoin μg / ml

Example 2

50 g of sulfisoxazole is dissolved in 51 N of 0.1 N hydrochloric acid, and 10 g of methyl cellulose (SM-25 from Shinwol Chemical Co., Ltd.) is dissolved in this solution, 1.0 l of 0.5 N sodium hydroxide is slowly added dropwise to precipitate sulfisoxazole. This suspension is heated to 80 ° C. or higher to gelatinize methyl cellulose. The precipitate is filtered, washed well with 3 l of boiling water, and added to 20 g of hard silicic anhydride in Japanese pharmacy. The mixture is made into a dough, extruded using a 40 mesh sieve, and dried to obtain a product. When this dry granule is put into water, it disintegrates quickly and disperses again in water.

The dry granules obtained in Example 2 were compared with commercially available sulfisoxazoles, and eluted with a paddle method (100 rpm, sulfisoxazole 200 mg / l) using the first solution of the disintegration test method of the Japanese Drug Administration. The results of the test are shown in FIG.

Line IV-IV is the invention of Example 2, and line V-V is a case of a commercial item.

Example 3

10 g of naridic acid is dissolved in 100 ml of 1N sodium hydroxide solution, and 1 g of hydroxypropyl methylcellulose (60 SH50 manufactured by Shinwol Chemical) is added to dissolve it. 100 ml of 1N hydrochloric acid is added to the solution to neutralize the precipitate, and naridic acid is precipitated and dispersed in water, followed by heating to 80 deg. C to precipitate hydroxy propylmethyl cellulose. The precipitate is filtered and washed well with hot water of 90 ° C. or higher, dried in a hot air drier in the same manner as in Example 1, and powdered with pestle to obtain a product.

This powder is dispersed and suspended in water and the first and second liquids of the Japanese Pharmacopoeia Disintegration Test at a fairly high rate.

Example 4

A solution of 60 g of erythromycin stearate and 15 g of Migriol 812 (manufactured by West Germany Dynamite Nobel) in 200 ml of chloroform was added to 100 ml of water in which 35 g of gum arabic was dissolved and emulsified using Poltron (form PT-45 from Guinea Matica, Switzerland). The solvent is evaporated from the emulsion using a spray dryer (F8 type manufactured by Freund Industrial Co., Ltd.). The powder obtained was redispersed very well in water so that the particle size at the time of redispersion was measured by a scanning electron microscope (type MSM-101 manufactured by Hitachi) (particles in the Examples below) Size measurement using the scanning electron microscope described above).

Commercial drug A containing erythromycin stearate powder and erythromycin stearate obtained in this Example was orally administered 4 mg / kg as erythromycin stearate to six adult males, and the blood concentration of erythromycin was changed over time. Measure what happens. Administration is done as a cross-over of one week apart. The results are shown in FIG. The VI-VI line shows the sample of Example 4, and the X-X line shows commercial item A. FIG.

Example 5

A solution obtained by dissolving 5 g of azmarin and 2 g of soybean oil in 20 ml of chloroform was added to 20 ml of water containing 5 g of trikacanda rubber, followed by emulsification in the same manner as in Example 4, followed by emulsification of chloroform and water in the same manner as in Example 4. To obtain. The powder is redispersed very well in water so that the particle size during redispersion is 0.5-2.5μ as measured by electron microscope.

Example 6

을 사용하여 유화하고 수득된 유화액을 실시예 4와 동일하게 분무건조기로 용매를 증발시켜 분말을 수득한다. 이 분말은 물에 재분산이 매우 잘 되므로 재분산시 입자의 크기를 측정한 결과 0.1 내지 1.5μ이다.50% ethanol aqueous solution of 5 g of hydroxypropyl cellulose (produced by Japan Procurement Corporation) was added to a solution in which 10 g of indomethane was dissolved in 50 ml of methylene chloride.

Emulsified using and the obtained emulsion liquid in the same manner as in Example 4 by evaporation of the solvent in a spray dryer to obtain a powder. This powder has a very good redispersion in water, so the particle size of the redispersion is 0.1-1.5 μm.

Example 7

A solution obtained by dissolving 20 g of chitasamycin in 250 ml of carbon tetrachloride was added to 300 ml of water in which 10 g of gum arabic and 10 g of α-starch were dissolved, thereby treating in the same manner as in Example 4 to obtain a powder. This powder has a very good redispersibility in water, so the particle size during the redispersion is 0.8 to 3.5 mu.

Example 8

2 g of nifedipine and 0.3 g of squaran were dissolved in 10 ml of chloroform, and a solution of 0.5 g of gum arabic and 0.5 g of gelatin in 130 ml of water was added to the solution. The emulsion obtained in the same manner as in Example 4 was treated with a spray dryer, followed by treatment with chloroform. And water is evaporated to obtain a powder. This powder is very excellent in redispersibility in water and has a particle size of 0.1 to 3.0 mu as a result of determining the size of particles during redispersion.

The liquid capsules of the powder and nifedipine commercial drug obtained in this Example were orally titrated to 4 μg / kg rats with nifedipine in crossover at 1 week intervals to measure blood concentration of nifedipine. The results are shown in FIG. X-ray represents the sample of Example 8, and X-ray represent the commercial nifedipine.

Example 9

10 g of flufenamic acid was dissolved in 100 ml of chloroform, and this solution was mixed with a solution of 10 g of hydroxypropyl methylcellulose (TC-5 from Shinwol Chemical TC-5) in 100 ml of water, and then emulsified in the same manner as in Example 4 with a spray dryer. Water and chloroform are evaporated to give a powder. Since the powder has good redispersibility with respect to water, the particle size is 0.4 to 1.8 mu when redispersed in water.

Example 10

20 g of chloram phenicol palmitate and 10 g of migriol 812 are dissolved in 100 ml of chloroform, 30 ml of ethanol and 15 g of hydroxypropyl cellulose are added thereto, and 250 ml of water is separately added to emulsify and dry in the same manner as in Example 4. To obtain. This powder has good redispersibility with respect to water and has a particle size of 0.1 to 1.2 mu when redispersed.

Using the powder of Example 10 (chloramphenicol palmitate) and commercially available chloram phenicol palmitate in 4 mice, oral administration of 250 mg / kg as chloramphenicol was performed once, followed by Blood concentration was measured. The results are shown in FIG. X-X ray is a sample of Example 10, XI-XI ray is commercially available chloram phenicol palmitate.

Comparative Example 1

Instead of dissolving chloramphenicol palmitate in a hydrophobic organic solvent, it is instead melted and emulsified in an aqueous solution, and the emulsion is redispersed in water and redispersed in water by evaporating water with a spray dryer. The particle size is measured and used as a comparative example. To 20 g of chloram phenicol palmitate, 5 g of hydroxy methylcellulose (manufactured by Hellcress, USA) and 280 ml of water are added, and when heated at 95 ° C to melt the chloram phenicol palmitate, it becomes a liquid phase. 10 min at 20,000 rpm. The obtained emulsion was treated with Found spray dryer of Found Pharmaceutical Co., Ltd. to evaporate water. When the obtained powder is dispersed in water, redispersibility is not so good that it is vigorously stirred to disperse. The size of the dispersed particles is more than 15μ.

Example 11

100 g of 1-isopropyl-7-methyl-4-phenyl-2 (1H) -quinazolinone (1 MPQ) and 3 g of the above-mentioned migriol 812 were dissolved in 250 ml of chloroform, and 50 ml of ethanol and methyl cellulose (new moon) in this solution. 40 g of chemical agent SH-25) and 400 ml of water were added to emulsify in the same manner as in Example 4, and treated with a spray dryer to evaporate chloroform, ethanol and water to obtain a powder. This powder has excellent redispersibility for water and the size of the dispersed particles is 1 μm or less.

A powder containing 1MPQ as a main ingredient of Example 11 and 1MPQ purchased as a control are administered orally in two sets of seven adult males (average weight 61 kg). Dosage is 200 mg as 1 MPQ. This was orally administered at a crossover interval of one week, and the blood concentration of 1 MPQ was measured. The result is shown in FIG. XII-XII line is the target of Example 11, XIII-XIII line is a control product.

Example 12

4 g of ubide carenone was dissolved in a mixed solvent of 50 ml of chloroform and 50 ml of ethanol. To this solution, 2 g of hydroxypropyl cellulose (L-formed by Japan Procurement) was added, and 100 ml of water was added separately, followed by Sonifier (US Branson Corporation) ultrasonic homogenizer. Emulsification was carried out using 200 for 15 minutes, and the emulsion was sprayed into 80 g of lactose using a fluidized bed spray granulator (F10-Coater Mini) to obtain granules. Chloroform, ethanol and water are evaporated in the preparation of the granules. The granulated medicament thus prepared has good redispersibility in water and has a particle size of 0.1 to 0.5 mu.

Example 13

Dissolve 10 g of indomethane in 50 g of methylene chloride, and add 100 ml of water containing 5 g of hydroxypropyl cellulose (L-type from Japan Procurement Co., Ltd.), emulsify it using the above poritorone, and warm the emulsion to The methylene is removed and then warmed to 80 ° C. to gel. After 10 minutes, the gelled portion is separated from the liquid layer and dried in an oven previously heated to 105 ° C. Since the dried drug has good redispersibility with respect to water, the particle size of the dried drug is examined by electron microscopy, and the particle size is 0.1 to 0.5 mu.

Example 14

72 g of phenytoin, 8 g of hydroxypropyl cellulose (GPC-L manufactured by Japan Procurement Company), and 100 ml of water were purchased from a pot of a vibrating mill (a horizontal production small product, stainless steel pot diameter 13 cm x length 10 cm), and the mill was vibrated for 60 minutes. After pulverizing phenytoin, the resulting dispersion was transferred to a beaker, heated to 80 to 90 ° C. to precipitate hydroxypropyl cellulose gelled and filtered as it was maintained at that temperature to separate the precipitate from the liquid, and mill Place in a hot air dryer warmed to 105 ° C and dry. The dried product is pulverized with an atomizer (Fuji Powdelco., LTD). Since the powdered medicine is very well dispersed in water, the particle size at the time of redispersion is 0.5 to 5 mu as observed by an electron microscope.

The powder of phenytoin and commercially available phenytoin crystal powder coated with the water-soluble polymer material obtained in Example 14 are orally administered to 6 adult males as phenytoin as 4 mg / kg (body weight). Administration is by cross-over at 1 week intervals. The seventh result is shown. 7 is the time elapsed after administration (Hrs) and the vertical axis is blood concentration of phenytoin (mcg / ml). XIV-XIV line is a sample of Example 14, XV-XV line is a commercially available phenytoin,

Example 15

)를 부착하고, 이 원판을 모터를 사용하여 400rpm으로 90분간 회전시켜 펜아세틴을 습식분쇄하여 미립화시킨다. 수득한 분산액을 30멧쉬체를 사용하여 유리 알맹이를 분별하고, 분산액에 에어로졸(일본 에어로졸사제)40g을 가하고, 교반하여, 물을 흡착시켜서, 건조 과립상 물질을 수득한다. 이 과립상 물질을 80 내지 90℃의 열풍 건조기에서 60분간 건조후 30멧쉬체를 손으로 놀러서 과립의 크기를 조절한다.32 g of phenacetin, 8 g of hydroxypropylmethyl cellulose, and 200 ml of water are placed in a 300 ml ordinary beaker, which is covered with hard glass kernels of 2 to 5 mm (diameter). In this container, place a stainless disc with a diameter of 5 cm and a thickness of 3 mm from the bottom of the beaker at 3 cm.

), And the disc is rotated at 400 rpm for 90 minutes using a motor to atomize penacetin by wet grinding. Glass granules were fractionated using a 30 mesh sieve, 40 g of aerosol (manufactured by Japan Aerosol Co., Ltd.) was added to the dispersion, stirred, and water was adsorbed to obtain a dry granular material. The granular material was dried in a hot air dryer at 80 to 90 ° C. for 60 minutes, and then the size of the granules was adjusted by playing with 30 mesh bodies by hand.

The dissolution rate of 1 g of granulated penacetin powder (500 mg as penacetin) coated with the water-soluble high molecular material obtained in this Example was measured by a US pharmaceutical defense dissolution tester (in the form of a basket manufactured by Fuji Chemical Industries). By contrast, the dissolution rate was measured for 500 mg of commercial penacetin crystals in the same manner, and both results are shown in FIG. The abscissa in Fig. 8 is the elapsed time (minutes) of the elution and the vertical axis is the elution (%). XVI-XVI line is a sample of Example 15, XVII-XVII line is a commercial penacetin.

Example 16

160 g of chloram phenolic palmitate, 40 g of hydroxypropyl cellulose (manufactured by Japan Procurement), 0.16 g of dioctyl sodium sulfosuccinate, and 1,000 ml of ethanol were put in a beaker, and polytron (made by Kinematik Co., Switzerland) was used. After wet grinding for 30 minutes, the obtained suspension is spray dried using a spray dryer (type FS-20, manufactured by Freund Industries). The redispersibility of the obtained dry powder with respect to water is very good.

Powder of chloramphenicol palmitate and commercially available chloramphenicol palmitate crystals coated with the water-soluble high molecular material obtained in Example 16 were each administered orally to 500 adult male titers as chloramphenicol. Administration is by crossover of one week intervals. The results are shown in FIG. 9 is the elapsed time after administration (Hrs) and the vertical axis is the blood concentration of chloramphenicol (mcg / ml). XVIII-XVIII line is a sample of Example 16, and XIX-XIX line is a commercial chloramphenicol palmitate.

Example 17

50 g of glyceroprene, 6,000 5 g of polyethylene glycol, 5 g of methyl cellulose, and 100 ml of water were wet pulverized with Geni wheat flour for 8 hours according to Example 1. After grinding, the mixture was heated in the same manner as in Example 1 to gel methyl cellulose and filtered as the temperature was maintained to separate the gel from the liquid. The gel was dried in a hot air dryer previously heated at 105 ° C. The dried product is ground with an atomizer. This powder is very good in redispersion in water, artificial gastric juice and artificial intestinal fluid. When the particle | grains of the glycer offbine of a dispersion are observed with the electron microscope, the diameter is almost 0.5 micrometer or less.

Example 18

30 g of hydrocortisone acetate, 10 g of ethylene oxide-propylene oxide copolymer (pluronine F68), 100 ml of water, 50 ml of ethanol After wet grinding for 30 minutes with polytron according to Example 16, the resulting suspension was sprayed using a spray dryer. To dry. The powder obtained is redispersed very quickly in water, artificial gastric juice and artificial intestinal fluid at 37 ° C.

Claims (1)

A method for producing a dried and activated pharmaceutical composition, characterized by separating and removing a dispersion medium from a dispersion system obtained by dispersing a poorly soluble drug in water in the form of fine particles having a diameter of 10 μm or less in the presence of a water-soluble high molecular material.

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