JPH05255066A - Composition for pharmaceutical preparation, its preparation and its production - Google Patents

Abstract

PURPOSE:To readily obtain the subject preparation having a simple composition and capable of controlling elusion of a medicine. CONSTITUTION:In a preparation composed of a medicine exhibiting a pH- dependent solubility and a porous. cellulose, elusion of the medicine is controlled by supporting an acid or a base on the porous cellulose. The preparation may be carried out by supporting the medicine and an acid or a base on the porous cellulose or by using a coating film containing the medicine and an acid or a base. The composition for pharmaceutical preparation obtained by supporting an acid or a base on the porous cellulose is useful for controlling elusion of the medicine. The preparation may contain an additive such as a binder. A solid preparation such as powder, granule, tablet or capsule can be used as the dosage form.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a pharmaceutical composition capable of adjusting the solubility and dissolution of a physiologically active substance in the fields of food, pharmaceuticals, agricultural chemicals, etc., a pharmaceutical preparation using the pharmaceutical composition and a method for producing them.

[0002]

2. Description of the Related Art Generally, many studies have been conducted on drug release control systems (drug delivery systems) for drugs such as foods, pharmaceuticals and agricultural chemicals. For example, Japanese Unexamined Patent Publication No. 56-110612 proposes a compression molded product in which a poorly soluble drug is blended with a specific binder, a surfactant and the like to improve the solubility and dissolution of the drug. .. However, this compression molded product combines many components,
Moreover, since it has to be manufactured by the fluidized granulation method, there are many restrictions and the manufacturing work is complicated.

Japanese Patent Application Laid-Open No. 56-49314 proposes a formulation in which polyethylene oxide is added to a mixture of a drug and a specific base component to improve absorption and durability. However, this formulation also has many restrictions because it is necessary to combine many components and it is necessary to remove the organic solvent, and the manufacturing operation is complicated.

Japanese Patent Laid-Open No. 61-207343 proposes a preparation excipient in which finely divided crystalline cellulose and calcium carbonate are mixed at a specific ratio. However, in manufacturing this excipient, it is necessary to spray-dry the slurry of each component, which is complicated.

Japanese Patent Publication No. 2-60643 discloses a spherical core mainly composed of a water-soluble organic acid osmotic pressure adjusting agent.
There has been proposed a sustained-release granule prepared by coating an elementary granule to which a drug, an excipient and, if necessary, an osmotic pressure adjusting agent are adhered and bound, with a gastric juice insoluble film. In this granule,
Since it is necessary to prepare spherical granules of organic acid, the production efficiency of granules is likely to decrease. Moreover, in order to obtain spherical granules with high yield, it is necessary to control the production conditions with high precision.

Further, in JP-A-62-30709, in a coating agent in which a drug and a swelling agent are coated with a water-insoluble substance, the coating ruptures after a predetermined time due to expansion of the swelling agent accompanying absorption of water. A sustained release formulation has been proposed. However, the swelling agent used in this formulation is a disintegrant and a large amount of disintegrant is required to rupture the coating. When the amount of the disintegrant added is increased, the hardness of the tablet obtained by tableting decreases.

Further, Japanese Patent Application Laid-Open No. 2-105 proposes a tablet comprising a drug and a fine powdery, water-insoluble cellulosic polymer. However, in order to obtain this tablet, the cellulose-based polymer must be pulverized into an extremely fine powder of 5 μm or less, which is a workability problem.

On the other hand, when porous cellulose and ethenzamid are mixed and heat treated to amorphize ethenzamid,
It has been reported by Nakai et al. That the dissolution property is improved as compared with the case of using crystalline cellulose [The 6th Annual Meeting of the Pharmaceutical Society of Japan (September 26, 1990), Chiba Civic Center].
However, in this method, heat treatment at a high temperature of about 100 ° C. for about 2 hours is required to enhance the dissolution of ethenzamide, so that the productivity of the preparation is reduced. In addition, it has been reported that a drug is decomposed by heating a mixture of porous cellulose and aspirin under reduced pressure at 50 ° C. for 3 hours [Yonechimo et al., 1st Annual Meeting of the Japanese Hospital Pharmacy Society (1993). Kudan Kaikan, July 20). As is clear from this, the above methods limit the drugs that can be used.

Further, Japanese Patent Laid-Open No. 2-84401 discloses that
It is disclosed that when the porous cellulose particles and the sublimable drug are mixed to adsorb the drug, the drug dissolution property is improved. However, the heat treatment may be necessary to enhance the drug dissolution property, and the drug dissolution rate and duration cannot be controlled. Furthermore, the drug cannot be eluted after a predetermined time has elapsed.

Thus, none of the conventional preparations can easily adjust the drug dissolution property.

On the other hand, Japanese Examined Patent Publication No. 56-44777 discloses a process for producing effervescent tablets which is excellent in moldability and rapidly disintegrates by adding magnesium aluminometasilicate and further crystalline cellulose. .. This prior art document describes a combination of a carbonate or bicarbonate and an organic acid such as citric acid or tartaric acid as a foaming component. However, as described in the above-mentioned prior art documents, the foaming component is apt to cause sticking during compression molding. Therefore, a large amount of lubricant is required.

In order to enhance the gastric and enteric properties of the drug, it is preferable to add an acid or base to the drug-containing preparation. However, the addition of acids and / or bases
Tabletability is significantly impaired by acids and / or bases. In particular, the greediness, which is the most problematic problem with tableting, that is, since the powder has no lubricity, the friction force between the tableting powder and the punches and dies during tableting becomes strong, making it difficult for the punches and dies to separate. A phenomenon occurs and productivity is greatly reduced. In order to improve the stickiness, it is necessary to add a large amount of a lubricant as described above, and therefore, there are great restrictions on the design of the preparation.

[0013]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a pharmaceutical composition which can easily control the dissolution of a drug.

Another object of the present invention is to provide a preparation in which the dissolution rate and duration of the drug are controlled.

Still another object of the present invention is to provide a pharmaceutical composition having the above-mentioned excellent properties and a method capable of easily producing a pharmaceutical composition with a simple composition.

Another object of the present invention is to provide a method capable of efficiently obtaining a preparation despite containing an acid or a base.

[0017]

As a result of intensive studies, the present inventors have found that when a composition containing a porous cellulose and an acid or a base is formulated together with a drug, the action of the porous cellulose and the acid or the base causes The present inventors have completed the present invention by discovering that the solubility and dissolution of a drug can be easily controlled.

That is, according to the present invention, the solubility of a drug is controlled by supporting an acid or a base on the porous cellulose in a preparation in which a drug having a different solubility depending on pH is mixed with the porous cellulose. Provide a formulation.

The present invention also provides a method for producing a preparation in which a porous cellulose is coated with a film containing a drug and an acid or a base, or the porous cellulose is loaded with the drug and an acid or a base.

The present invention further relates to porous celluloses,
There is also provided a pharmaceutical composition supporting an acid or a base; a method for producing a pharmaceutical composition supporting an acid or a base on porous cellulose.

The present invention also provides a solid preparation containing the above preparation.

In the present specification, the terms "support" and "support layer" are not limited to the entire surface of the porous cellulose, but may be partially supported, adsorbed, absorbed, or coated. It is used to include the case. The “coating” is not limited to a continuous layer that covers the entire surface of the porous cellulose and is used to include a case where the coating is partially performed.

The above-mentioned porous celluloses can be obtained, for example, by adding a mixed liquid of viscose and a foaming agent such as calcium carbonate to a coagulating liquid, and condensing / regenerating cellulose and decomposing the foaming agent at the same time. Porous Cellulose [Fujita et al., Proceedings of the 23rd Autumn Meeting of the Chemical Engineering Society of Japan (Heisei 2)
October 21, 2010), Kanazawa University], Japanese Patent Laid-Open No. 64-4353
0, JP-A-1-167345, JP-A-1-
188839, Japanese Patent Laid-Open No. 1-272643,
JP-A-2-84401, JP-A-2-208330
Examples thereof include porous celluloses disclosed in JP-A No. 2-2081331, and further, for example, porous celluloses obtained by treating hemp cellulose with an enzyme or a mineral acid. These porous celluloses may be crystalline or non-crystalline.

The pore structure of these porous celluloses is not particularly limited, but, for example, a structure in which a large number of radially small pores are formed in the cross section (hereinafter sometimes referred to as A type), large It may have any structure such as a structure in which holes are formed (hereinafter sometimes referred to as B type), a structure in which fine holes and large holes are mixed. The holes may be connected continuously or may be independent.

The shape of the porous celluloses can be selected according to the application of the preparation. When the preparation is a solid oral administration agent, it may have any shape such as granular shape, angular shape, spherical shape, elliptical shape, flat shape, cylindrical shape, hollow cylindrical shape and the like.
Usually, granular porous celluloses are frequently used.

The size, pore size and distribution of the granular porous celluloses can be selected according to the desired floating property, sustained drug release property and the like. The average particle size of the preferable granular porous celluloses is, for example, about 0.001 to 10 mm, and the average pore size distribution is about 0.0001 to 150 μm, preferably about 0.001 to 150 μm. The apparent specific gravity of the preferable porous celluloses is 0.01 to 0.8.
It is about g / ml. The composition of the porous cellulose is not limited to cellulose alone, but may be composite particles with chitin, cellulose having various functional groups (for example, diethylaminoethylated cellulose, carboxymethylated cellulose, etc.).

There are some kinds of such porous celluloses that shrink in a dry state and have a small specific gravity, and swell when contacted with water to have a large volume.

The pharmaceutical composition of the present invention contains the above-mentioned porous cellulose and an acid or a base. The pharmaceutical composition is
It may contain both an acid component and a base component, and may contain an appropriate amount of additives described below.

As the acid and base, various pharmaceutically acceptable compounds can be used.

Examples of the acid include mineral acids such as hydrochloric acid; organic acids such as acetic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid and ascorbic acid; viscous minerals such as acid clay, silica alumina, cations. Examples thereof include exchange resins, enteric bases and solid acids such as aluminum oxide. Examples of the enteric base include acidic polymers such as hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, carboxymethyl ethyl cellulose (trade name CMEC AQ manufactured by Kojin Co., Ltd.), methacrylic acid-methyl methacrylate copolymer [Rohm Pharma (Rohm Pharma Pharma) (Germany), trade name Eudragit L100-55, Eudragit L
100, Eudragit S100] and the like. At least one of these acids is used. Preferred acids include solid acids.

The amount of the acid added to the porous celluloses can be selected according to the acidity of the acid, the desired drug dissolution rate, and the like. Usually, the total amount of the porous celluloses and the acid is
It is about 0.1 to 95% by weight, preferably about 1 to 90% by weight. If the amount of the acid added is less than 0.1% by weight, the control of the solubility and dissolution by the acid is not sufficient, and
When it exceeds the weight%, it becomes an excessive amount.

As the base, there are I, II and III of the periodic table.
Mention may be made of solid bases such as metal oxides, hydroxides, carbonates, hydrogen carbonates, inorganic acid salts or organic acid salts. Specific examples of the base include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, aluminum hydroxide, calcium oxide, barium oxide, magnesium oxide, sodium carbonate, potassium carbonate, calcium carbonate. , Barium carbonate, magnesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium silicate, aluminum silicate, silicic acid (cyloid, aerosyl), magnesium aluminometasilicate (neusilin), magnesium stearate, aluminum stearate, stearic acid Examples thereof include sodium and the like, and mixtures thereof. At least one of these bases can be used. Preferred bases include solid bases.

The amount of the base added to the porous cellulose can be selected according to the basicity of the base, the desired drug dissolution rate, etc., and is usually 0.1 to 0.1% of the total amount of the porous cellulose and the base. 80% by weight, preferably 1-75% by weight
It is a degree. When the addition amount of the base is less than 0.1% by weight, it is not sufficient to control the solubility and dissolution of the drug, and when it exceeds 80% by weight, not only the excess amount but also the porous cellulose are obtained. The porous structure of the class may be destroyed.

A formulation using such a pharmaceutical composition is
It brings various advantages.

For example, when the above-mentioned pharmaceutical composition is formulated together with a drug, not only the solubility of the drug can be controlled, but also when a drug soluble in an acid and an organic acid are blended in combination, the gastric composition becomes organic. The acid elutes quickly. Therefore, even an acid-free person, who is generally considered to be poorly absorbed, can absorb the drug in the same manner as an ordinary person.
On the other hand, when a drug that is difficult to dissolve in an acid is mixed, the dissolution property in the stomach is reduced, but since the dissolution property of the drug is improved by the porous celluloses, the dissolution and absorption of the drug are sustained. be able to. When a soluble drug or a drug which is difficult to dissolve is mixed with a base, the dissolution and absorption of the drug can be controlled in the intestine in the same manner as described above.

The use of an acid in combination with a basic drug or a base in combination with an acidic drug can facilitate the dissolution of the drug in the drug, both in the stomach and in the intestine. Further, the combination of an acid and an acidic drug can suppress dissolution of the drug in the stomach and promote dissolution of the drug in the intestine. The combination of a base and a basic drug can accelerate the dissolution of the drug in the stomach and suppress the dissolution of the drug in the intestine. When a neutral drug is used, the drug may be stabilized by the acid or base.

Further, although the above-mentioned porous celluloses, the above-mentioned pharmaceutical composition and the drug-containing preparation are contracted when dried, there are some cases where the volume of the porous celluloses rapidly increases when contacted with water or the like. is there. Utilizing this property, for example, when the porous celluloses, the pharmaceutical composition or the formulation is coated with a water-insoluble coating, the water permeating through the coating and penetrating the inside makes the porous cellulose remarkably It expands, and the large expansion force causes the film to burst. Also, the rupture of this coating may occur explosively. Therefore, in oral administration, a drug can be dissolved after a lapse of a predetermined time, or a targeting drug capable of dissolving and absorbing the drug at a specific site in the digestive tract.

Further, when coated with a tough film or a film having a high elasticity, water passing through the film is absorbed by the porous celluloses, and due to the high expansion force, a sustained-release preparation in which the drug is gradually released is also obtained. be able to. The preparation having such properties can be used not only for oral preparations but also for suppositories. In this case, the preparation swells in the rectal portion and stays in the same position for a long time, and the drug effect can be enhanced.

Further, for example, when an enteric coating is applied to a porous cellulose compounded with a base, the permeated water dissolves the base compounded together with the porous cellulose compound, and the dissolution of the drug and the high osmotic pressure, The coating can be dissolved from the inside of the coated formulation. Therefore, the drug is rapidly released in the small intestine. On the contrary, when a gastric-soluble coating and an acid are combined and formulated into a formulation, for example, the gastric-soluble coating coated for masking is rapidly destroyed, and the drug is rapidly eluted.

Further, the addition of the acid and / or base may stabilize the drug. Furthermore, when the drug and the acid and / or base are poorly compounded, each of them is combined individually or with a composition containing a stabilized drug,
It is also possible to add it to porous cellulose and mix it into a formulation.

The formulation of the present invention contains at least the above-mentioned porous cellulose, drug and acid or base. More specifically, a drug having different solubilities depending on pH is mixed with porous cellulose, and an acid or a base is carried on the porous cellulose. This allows the solubility of the drug to be controlled.

The above-mentioned drugs having different solubility depending on pH include
Various substances having physiological activity, for example, food or feed additives such as various vitamins, minerals and amino acids; pesticides such as insecticides and fungicides; and medicines are included.
The preferred drug is a drug.

Examples of the drug include central nervous system drugs such as diazepam, idebenone, aspirin, ibuprofen, piroxicam, diclofenac, indomethacin, sulindac, lorazepam, nitrazepam, acetaminophen, and ketoprofen; cardiovascular drugs such as molsidomine, Vinpocetine, methyldopa, atenolol, metoprolol, captopril, etc .; as a respiratory drug, 3- (imidazo [1,2-b] pyridazine-6-yl) oxy-2,2-dimethylpropanesulfonamide hydrochloride (hereinafter referred to as compound A)), amlexanox, dextromethorphan, theophylline, pseudoephedrine, etc .; and benzimidazo, such as lansoprazole and omeprazole, as digestive system drugs Drugs, bisacodyl, 5-aminosalicylic acid, etc .; antibiotics and chemotherapeutic agents, cefoam hexetyl hydrochloride, cephalexin, cefaclor, cefradine, amoxicillin, dicloxacillin, etc .; metabolic drugs, lysozyme chloride, adenosine triphosphate, Glypenclamide, potassium chloride, etc .; As vitamin-based drugs, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin C, fursultiamine, etc .; oil-like drugs such as vitamin A, vitamin E; liquids such as crude drug extracts Or a slurry-like drug; and other drugs such as metabolic drugs, vitamins, crude drugs, extracts, and antacids, which have different solubilities depending on pH. These drugs may be used alone or in combination of two or more.

The drug may be used in combination with an additive. As an additive, a conventional component generally used in producing an oral solid preparation, for example, lactose, corn starch,
Sucrose, talc, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate, L-
Excipients such as cysteine; hydroxypropylcellulose (hereinafter sometimes referred to as HPC), hydroxypropylmethylcellulose, pregelatinized starch, partially pregelatinized starch, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan,
Binders such as dextrin and gum arabic; carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose (hereinafter sometimes referred to as L-HPC), starches, cross-linked carboxymethyl cellulose sodium, cross-linked insoluble polyvinylpyrrolidone, etc. Disintegrators; anionic surfactants such as sodium alkylsulfate; nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters and polyoxyethylene castor oil derivatives; titanium oxide , Red iron oxide, tar pigments and the like; and flavoring agents such as 1-menthol and peppermint oil. Furthermore, the additive may be enteric-coated, gastric-soluble or insoluble for imparting taste masking, barrier for controlling water and water migration, separation between drug and / or additive, enteric property, gastric solubility, etc. The film forming base and the like are also included. You may use 2 or more types of these additives. The addition of the surfactant has the effect of enhancing the drug dissolution property.

The formulation of the present invention, in various aspects, comprises a drug,
Acids and / or others include bases. That is, porous celluloses may be used as a carrier such as an adsorbent, and porous celluloses may be loaded with a drug and an acid and / or a base to form a carrier layer.

It is also possible to use porous cellulose as a core and coat the porous cellulose with a film containing a drug and an acid and / or a base.

Further, at least one supporting layer and a coating may be formed on the porous cellulose in any order. In these cases, it is preferable that at least one of the supporting layer and the coating contains a drug and an acid and / or a base, but at least one of the supporting layer and the coating contains a drug and the other contains an acid. And / or may contain a base. Furthermore, the porous celluloses may be coated with a plurality of coatings. In this case, at least one film may contain a drug and an acid and / or a base, or the drug and an acid and / or a base may be contained in different films.

The porous celluloses may be used as an additive, and the porous celluloses, the drug, the acid and / or the base may be mixed.

In these cases, the carrier layer, the coating and the mixture may contain the additive or the base for forming the coating.

Further, such a formulation has gastric solubility,
An enteric or water-insoluble coating, a coating of the above-mentioned sustained-release preparation utilizing the swelling property of porous cellulose with water, a coating of the above-mentioned targeting preparation and the like may be applied.

The drug, the acid and / or the base can be supported by adsorption on the porous cellulose or coating on the porous cellulose. Further, the mixing can be performed by mixing or kneading the porous cellulose, the drug, the acid and / or the base. In these cases, the above additives and bases may be used in combination, if necessary.

The coating film can be formed by using a coating agent containing a film-forming base according to the purpose. As the base, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, HP
C, L-HPC, polyoxyethylene glycol, Tween 80, Pluronic F68, castor oil, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate succinate, acrylic acid copolymer, carboxymethylethyl cellulose, polyvinyl acetal diethylaminoacetate, shellac, Examples thereof include waxes and pigments such as talc, titanium oxide and red iron oxide.
At least one of these bases can be used.

The content of the drug in the preparation can be selected depending on the form of the preparation and the presence or absence of combined use with additives. When the carrier layer contains a drug, the content of the drug is, for example, 0.0
It is about 1 to 100% by weight, preferably about 0.1 to 100% by weight. When the film contains a drug, the content of the drug is 0.01 to 97% by weight, preferably 0.1.
It is about 95% by weight.

The size of the preparation of the present invention can be selected according to the intended use, but when it is a powder, its particle size is usually substantially 500 μm or less. Even in the case of a preparation having a small particle diameter, by combining the above-mentioned porous celluloses with an acid and / or a base, the solubility and dissolution of the drug can be controlled.

Hereinafter, the pharmaceutical composition of the present invention and the method for producing the pharmaceutical preparation will be described in detail. The method for producing a pharmaceutical composition and the method for producing a pharmaceutical preparation are substantially different in the presence or absence of a drug. Therefore, the method for producing a pharmaceutical composition will be described below together with the pharmaceutical composition.

In these production methods, the porous cellulose can be used as a carrier as an adsorbent, an additive or a core.

When the porous cellulose is used as an adsorbent, at least the drug and the acid and / or base may be supported by adsorption, absorption or coating. It is advantageous to dissolve the water-soluble drug, acid and / or base in water and add them to the porous cellulose in order to reduce the variation in the content of the drug, acid and / or base. A drug or acid and / or base having low solubility in water may be dissolved in a solvent composed of an organic solvent such as ethanol or a solvent such as a pH buffer solution and used as a mixed solution. In these cases, the mixed solution containing the drug may contain acid and / or base, other drugs or additives, and may be supported on the porous cellulose. The mixed solution containing the drug and the acid and / or base You may make it carry | support by using the mixed liquid containing etc. individually. Further, the loading of the drug or the like on the porous celluloses may be repeated by using a dilute mixed solution.

In order to carry a drug or the like on the porous celluloses, the above-mentioned mixture is added to the porous celluloses put in a tumbling granulator, a stirring granulator, a fluidized granulator, a centrifugal tumbling granulator or the like. The liquid may be added. When using a tumbling and stirring type granulator, a liquid amount is used that does not exceed the adsorption ability of the porous celluloses. The adsorption ability of the porous celluloses varies depending on the type of the mixed liquid, but when the solvent is water or an organic solvent, for example, 1 to 1 of the porous celluloses.
It is about 3 times. On the other hand, a fluidized and centrifugal tumbling fluidized type granulator may spray the mixed liquid under the condition that the porous celluloses flow in a wet state.

The wet porous celluloses after the supporting treatment are dried by a conventional method such as vacuum, fluidization, freezing and heating to obtain a pharmaceutical composition or a pharmaceutical preparation.

When the drug, the acid and / or the base has low solubility in water, the components may be supported by adsorption or the like by a method such as ordered mixing by mechanical impact. When a drug or the like is loaded by mechanical impact, an adsorption powder can be produced by using a ball mill type, a hammer mill type, or a rolling compaction type device and adsorbing it in a dry manner or by adding an appropriate solvent.

When the porous cellulose is used as an additive, by mixing the porous cellulose, the drug, the acid and / or base, and the additive, if necessary,
A formulation is obtained. This method is advantageous when the content of the drug, the acid and / or the base, the additive is large, or when it is difficult to apply the above method.

The mixing of the porous celluloses with the drug is preferably carried out by stirring granulation or tumbling granulation. The content of the porous celluloses in the mixture is, for example, preferably 5% by weight or more. If it is less than 5% by weight, the swelling force of the mixture is small and it is difficult to control the solubility and dissolution of the drug.

When the porous cellulose is used as a nucleus, a coating agent containing a base, a drug, an acid and / or a base is used, and the porous cellulose is coated with a film containing the drug, an acid and / or a base. Good. Further, a coating solution for forming a film and a mixed liquid for forming a supporting layer may be sprayed onto the porous cellulose in any order to cover the porous cellulose to form the film and the supporting layer. in this case,
At least one of the coating solution for forming a film and the mixed solution for forming the supporting layer contains a drug and / or (acid and / or
Or a base). The mixed solution may contain an acid and / or a base, a binder or an additive, and may be a solution or a dispersion. In the process of spraying and coating the coating agent or the mixed solution, the adsorption of a drug or the like also occurs.

In another method, the powder-dispersing agent may be sprayed while spraying the mixed liquid on the core. In this case, at least one of the mixed solution and the powder-dispersing agent may contain a binder and the other may contain a drug and an acid and / or a base. Alternatively, a mixed solution containing a drug together with a binder and a powder spray containing an acid and / or a base may be used, and a mixed solution containing an acid and / or a base together with a binder and a powder spread containing a drug. May be used. Moreover,
Other additives may be added to the mixed solution or powder dispersion.
In these methods, the coating can be formed by a simple operation of spraying the powdery spraying agent. Further, when spraying a powdery spraying agent containing at least one drug and an acid and / or a base while spraying a liquid containing at least a binder and not containing a drug, stability to the solvent contained in the liquid mixture is obtained. Even if the drug is easily damaged, a film can be easily formed. The particle size of the spray is usually 100 μm or less, preferably about 50 μm.
m or less. Further, without using the mixed liquid, a powder spraying agent in which a drug, an acid and / or a base and, if necessary, an additive are mixed may be added, and the porous cellulose may be coated by a dry method.

On the other hand, when coating two or more drugs or acids and / or bases having poor compounding properties, coating is carried out simultaneously or separately by using respective mixed solutions containing additives and powder spraying agents if necessary. Alternatively, the support layer and / or the coating may be blocked by a coating. Further, porous celluloses carrying a drug or the like by adsorption or the like may be coated with a mixed liquid or a powder-dispersing agent containing at least a drug having a poor compoundability with the drug. This method has different elution times.
It is also advantageous when obtaining formulations containing more than one drug.

The amount of the binder added to the mixed solution varies depending on the amount of the drug or the additive added, but is usually 0.1 to 7
It is 0% by weight, preferably about 0.5 to 30% by weight.
If the added amount of the binder is less than 0.1% by weight, the binding force of the drug or acid and / or base to the core is small, and if the added amount exceeds 70% by weight, the viscosity of the mixed solution increases and the workability of production deteriorates. easy.

Further, the porous cellulose may be coated with a plurality of coating layers by using a coating agent containing a base material, a mixed solution containing a binder or a powder spraying agent. In this case, select grades of bases with different content ratios and viscosities,
Sequential coating using a mixed solution or the like in which the ratio of the drug, acid and / or base and other additives is changed, the content ratio of the base or the like in the core supporting layer and / or the coating, the drug or acid and / or The concentration of the base and the like may be changed continuously or stepwise. In this case, for example, as the mixed liquid, a solution or dispersion liquid in which the content of the binder is out of the range of 0.1 to 70% by weight may be used.

When acids and / or bases, other drugs and other additives are dissolved or dispersed in the coating agent or the mixed solution, the compounding ratio thereof may be varied.

These methods can be carried out by using a conventional apparatus such as a centrifugal tumbling type fluid granulator, a fluid granulator, and a stirring granulator.

Furthermore, the above-mentioned methods may be repeated or the above-mentioned methods may be appropriately combined to produce a pharmaceutical composition or a pharmaceutical preparation. For example, the porous celluloses may be previously coated with a coating agent containing a base and then subjected to an adsorption treatment of a drug, an acid and / or a base, etc., adsorption powder after adsorption treatment or drying, admixture The product or the granulated powder coated with the powder mixture with the powder mixture may be coated with the coating agent. In addition, coating with a coating agent may be performed during the adsorption treatment. Further, in order to block and separate the drug, the acid and / or the base, a coating layer made of a coating agent containing a base may be formed between the plurality of coatings or between the coating and the supporting layer.
Furthermore, the resulting formulation may be admixed with acids and / or bases, other drugs and / or additives.

The thus-obtained preparation may be coated with a coating agent by a conventional method in order to impart taste masking, enteric properties, gastric solubility, etc., and to control the drug dissolution properties. Good.

For the solid preparation of the present invention, the above-mentioned preparation can be used as it is as a powder. Further, the solid preparation may be a granule or tablet in which the preparation is added to granules or tablets, or a capsule filled in capsules according to a conventional method. Alternatively, the preparation may be put in a container in advance, and water or the like may be added as necessary to prepare a solid agent for use.

[0073]

Since the pharmaceutical composition of the present invention contains porous cellulose and an acid or a base, the drug dissolution property in the pharmaceutical preparation can be easily controlled.

The formulation of the present invention comprises porous celluloses and
Since the drug and the acid and / or base are contained, the dissolution rate and duration of the drug can be controlled.

In the production method of the present invention, a pharmaceutical composition having excellent properties as described above can be prepared by a simple operation such as supporting an acid and / or a base or a drug on a porous cellulose or applying a film. The formulation can be manufactured easily and with a simple composition.

Furthermore, in the production method of the present invention, acid and / or
Alternatively, despite containing a base, the tableting property is excellent and the preparation can be efficiently obtained.

[0077]

The present invention will be described in more detail based on the following examples, comparative examples and experimental examples, but the present invention is not limited thereto.

Example 1 Spherical porous cellulose (pore structure A type, apparent specific gravity of 0.
2 g / ml, diameter 0.3 mmφ) 12.5 g was put in a mortar, and a solution prepared by previously dissolving 12.25 g of citric acid and 0.25 g of vinpocetine in 20 ml of water was added, and mixed gently with a spatula for adsorption treatment. Then 40 ° C,
It was dried under vacuum for 16 hours to obtain an adsorbed powder.

The adsorbed powder obtained expanded 3 to 4 times in the wet state, but was restored to the original diameter by drying.

Example 2 Spherical porous cellulose (void structure B type, apparent specific gravity of 0.
2g / ml, diameter 0.3mmφ) 25g in a mortar,
A solution prepared by dissolving 50 g of citric acid in 90 ml of water was added in advance, lightly mixed with a spatula, and subjected to adsorption treatment. Then, it was dried at 40 ° C. under vacuum for 16 hours to obtain an adsorbed powder.

The adsorbed powder obtained expanded 3 to 4 times in the wet state, but was restored to its original diameter by drying.

Example 3 An adsorption powder was obtained in the same manner as in Example 2 except that sodium carbonate was used instead of citric acid, and the adsorption treatment was carried out by dividing the solution into three times.

Example 4 Spherical porous cellulose (void structure A type, apparent specific gravity of 0.
1 g / ml, diameter 2.0 mmφ) 380 g was put in a fluidized coating granulator (manufactured by Paulec, Inc .: FD-3S), and the air temperature was controlled at 70 ° C. and the product temperature at about 40 ° C., while using the bottom spray method in advance. The prepared bulk liquid having the following composition was sprayed and coated. When a predetermined amount of the bulk liquid was sprayed, the spraying was stopped, dried for 1 minute as it was, and then sifted through a 32 mesh round sieve to obtain 480 g of granules.

[Bulk liquid] Compound A 5 g Tartaric acid 5 g Lactose 20 g Talc 20 g L-HPC 20 g HPC (type M, viscosity 300 cps) 6 g HPC (type L, viscosity 8 cps) 44 g Water 1080 g Comparative example 1 lactose 100 kg, starch 20 kg and vinpocetine. 5 kg of fluidized granulation dryer (made by Paulec: STRE-
60 kg of an aqueous solution in which 5 kg of hydroxypropylcellulose was previously dissolved by the top spray method while controlling the blowing temperature to 90 ° C and the product temperature to about 40 ° C.
While spraying, the mixture was granulated and dried to obtain a granulated powder.

Comparative Example 2 52 mg of the granules obtained in Comparative Example 1 was mixed with 100 mg of citric acid to prepare a mixed powder.

Comparative Example 3 Crystalline cellulose (Avicel, manufactured by Asahi Kasei Corporation) 12.5
g, citric acid 12.25 g, and vinpocetine 0.2
5 g was placed in a mortar, 5 ml of water was added, and the mixture was kneaded using a pestle. Then, it was dried at 40 ° C. under vacuum for 16 hours to obtain a kneaded powder.

Comparative Example 4 25 g of crystalline cellulose (Avicel, manufactured by Asahi Kasei Corporation),
50 g of citric acid was placed in a mortar, 10 ml of water was added, and kneaded with a pestle. Then, it was dried at 40 ° C. under vacuum for 16 hours to obtain a kneaded powder.

Experimental Example 1 The dissolution properties of 200 mg of the adsorbed powder obtained in Example 1, 52 mg of the granulated powder obtained in Comparative Example 1 and 152 mg of the mixed powder obtained in Comparative Example 2 were evaluated according to the 11th revised Japanese Pharmacopoeia / general test. Method 46 Dissolution test Method 2 The method (75 rpm) was tested. As the test liquid, 500 ml of the second liquid of the Japanese Pharmacopoeia General Test Method 38 disintegration test method was used. The test results are shown in Table 1.

[0089]

[Table 1] As is clear from Table 1, the formulation obtained in Example 1
Despite the fact that the drug was not readily soluble (solubility: about 4 μg / ml), it eluted faster than the granulated powder of Comparative Example 1 and the mixed powder of Comparative Example 2. On the other hand, no significant difference was found in the elution rate between the granulated powder of Comparative Example 1 and the mixed powder of Comparative Example 2 in which citric acid was simply added to this granule.

Experimental Example 2 500 m of the adsorption powder obtained in Examples 1 and 2, the granulation powder obtained in Comparative Example 1 and the kneading powder obtained in Comparative Examples 3 and 4 respectively.
g is an autograph (manufactured by Shimadzu Corporation: AG-5000)
According to B), the punch diameter is 9.5 mmφ and the tableting pressure is 1000 kg /
Tablets were obtained by tableting under the condition of cm ² . In addition, as controls, the porous cellulose used in Example 1, the crystalline cellulose used in Comparative Example 3, Examples 1 and 2, and Comparative Examples 3 and 4 were used.
The citric acid used in 1. was tableted alone in the same manner as above. The degree of greediness was evaluated by the ejection pressure for extracting the tablet from the die at the time of tableting, by utilizing the fact that the ejection pressure becomes larger as the greediness phenomenon becomes more severe, and the ejection pressure can be evaluated. The results are shown in Table 2.

[0091]

[Table 2] As is clear from Table 2, the granulated powder and kneaded powder of Comparative Example
While the tablets were compressed while being pressed during tableting, the adsorption powders obtained in Examples 1 and 2 were free from problems such as cracking during tableting, and compared with the granulated powder and kneaded powder of Comparative Example. Tabletability is significantly improved. When citric acid alone was tableted, capping occurred.

Example 5 Spherical porous cellulose (void structure B type, apparent specific gravity of 0.
120 g of 1 g / ml, diameter 0.3 mmφ) was put into a stainless steel ball, and methacrylic acid-methyl methacrylate copolymer [Rohm Pharma (Germany), trade name Eudragit L100-
55] A dispersion of 7.5 g of vinbocetin was added to a solution of 22.5 g of ethanol and 120 g of ethanol and mixed. After vacuum-drying the mixture at 40 ° C. for 20 hours, the dried product was passed through a 32 mesh round sieve to obtain 150 g of an adsorbed powder.

100 g of the adsorbed powder was placed in a fluidized coating granulator (FD-3S, manufactured by Paulec), and the blast temperature was 6
8 parts by weight of ethyl cellulose (viscosity type 10 cp) and 2 parts by weight of polyethylene glycol 60 by bottom spray method while controlling the temperature at 0 ° C. and the product temperature at about 35 ° C.
An ethanol solution containing 0 and 10 (concentration 10% by weight) was sprayed to obtain a coated preparation in which 30% by weight of the adsorbed powder was coated.

Experimental Example 3 150 mg of the adsorption powder obtained in Example 5 and the coated preparation 1
The drug dissolution properties were examined in the same manner as in Experimental Example 1 except that 95 mg and the first and second solutions were used as test solutions. The results of the adsorption powder are shown in Table 3, and the results of the coated preparation are shown in Table 4.

[0095]

[Table 3]

[0096]

[Table 4] As is clear from Tables 3 and 4, in the adsorption powder and the coated preparation obtained in Example 5, vinvocetin was easily dissolved in the first liquid (solubility: 100 mg / ml or more) and in the second liquid. Despite being sparingly soluble (solubility: about 4 μg / ml), they all show the same dissolution property, and the dissolution property of the drug can be controlled by adding an acid (enteric polymer).

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Claims (6)

[Claims] 1. A formulation in which a drug having different solubility depending on pH is mixed with a porous cellulose, and the solubility of the drug is controlled by supporting an acid or a base on the porous cellulose. 2. A method for producing a preparation, which comprises coating a porous cellulose with a film containing a drug and an acid or a base. 3. A method for producing a preparation in which a drug and an acid or a base are supported on porous celluloses. 4. A pharmaceutical composition in which an acid or a base is supported on porous celluloses. 5. A method for producing a pharmaceutical composition in which an acid or a base is carried on porous celluloses. 6. A solid preparation containing the preparation according to claim 1.