KR870001374B1 - Process for preparing powder medicine products for oral and nasal - Google Patents

Abstract

Powdered medicine compn. contg. lower alkylester of cellulose as a base, steroid or glycyrrhizic acid as a antiinflammatory, and solid organic acid as a stabilizer is prepd. Thus, 100 part hydroxypropyl cellulose, 0.025 part beclomethasone dipropionate, and 0.5 part stearic acid is mixed thoroughly to give powd. compn., which is capsulated into tablets for oral use. Hydroxypropyl cellulose used in prepn. of the compn. has the viscosity of 1550cps in 2% aq. soln. at 37±0.2≰C and powder particles of 90% > has the particle diameter of 37-149 m.

Description

Method for preparing powdered pharmaceutical composition for oral or nasal mucosa

The present invention relates to a process for the preparation of powdered pharmaceutical compositions suitable for use in mucous membranes of the oral or nasal cavity.

More specifically, the oral or nasal mucosa containing (a) a lower alkyl ether of cellulose as a base, (b) a steroid or glycyric acid anti-inflammatory agent as a pharmaceutical ingredient, and (c) a low irritant solid organic acid as a stabilizer for the pharmaceutical ingredient. A process for the preparation of powdered pharmaceutical compositions suitable for use in

Powdered pharmaceutical compositions exhibit extremely good stability with the steroids or glycyrrhizinic acid type anti-inflammatory agents contained therein, and have low irritation to the mucous membranes of the oral or nasal cavity and impart long-term sustainability of the medicament.

Therefore, the powdered pharmaceutical composition according to the present invention can be used for oral diseases such as stomatitis, blisters or wounds caused by radiation contamination, nasal limbs, or allergic rhinitis and vasomotor rhinitis. It is effective when used to treat disease.

Various preparations such as buccal tablets, troche tablets, sublingual tablets and oral ointments are known in the oral treatment field, but the buccal tablets, troche tablets and sublingual tablets have a heterogeneity in the oral cavity and the patient must chew or swallow. Oral ointments also typically contain a mixture of beeswax or plaster and gelatin, pectin or sodium carboxymethyl cellulose.

These mixtures are not satisfactory because they lack sufficient adhesion to the oral mucosa and have an unpleasant taste. In addition, various preparations such as nasal ointments, jellies, cordrobes and sprays are known in the field of nasal administration, but nasal ointments and jellies are difficult to use in deep areas of the nasal cavity, such as the inside of the nasal cavity, In the case of a spray, the active ingredient does not last long in the nasal cavity.

Various sustained release formulations for oral or nasal administration are known in the art. The efficacy of these agents lasts for a long time as the active ingredient is gradually or continuously released from the formulation.

For example, Japanese Patent Application Laid-Open No. 57-118511 describes a slow-release powdery formulation bonded to oral adhesion.

These formulations use hydroxypropyl cellulose as base and the medicament has the advantage of having good sustainability and can be used extensively in the oral cavity.

Furthermore, U. S. Patent No. 4,294, 829 describes sustained-release powdery agents suitable for use in nasal passages, which contain the lower alkyl ethers of cellulose and agents and also have the advantage of agents having good sustainability. However, there was a further need to improve the stability of medicaments in the aforementioned sustained release formulations for use in mucous membranes of the oral or nasal cavity.

It is therefore an object of the present invention to provide a powdered pharmaceutical composition which is extremely stable in the medicament contained, ie steroids or glycyrrhizinic acid type anti-inflammatory agents, and suitable for use in the mucous membrane of the oral or nasal cavity.

Another object of the present invention is to provide a powdered pharmaceutical composition suitable for use in the mucous membrane of the oral or nasal cavity containing a lower alkyl ether of cellulose as a base, a steroid or glycyrrhizinic acid type anti-inflammatory agent as a medicament, and a special solid organic acid with low irritation as a pharmaceutical stabilizer. To provide.

It is another object of the present invention to provide a powdered pharmaceutical composition which gives a low irritation to the mucous membrane of the oral or nasal cavity. Another object of the present invention is to provide a powder composition containing a drug having excellent sustainability.

Another object of the present invention is to provide a powdered pharmaceutical composition having a particle diameter suitable for oral or nasal administration.

It is yet another object of the present invention to provide a method for providing a powdered pharmaceutical composition suitable for use in mucosal membranes of the oral or nasal cavity.

It is still another object of the present invention to provide a method for stabilizing powdered pharmaceutical compositions containing steroids or glycyrrhizin acid anti-inflammatory agents as medicaments. Other objects and advantages of the present invention are apparent as described below. The above objects and advantages according to the invention are: (a) a base selected from lower alkyl ethers of cellulose: (b) a pharmaceutically effective amount of a medicament selected from steroids or glycyric acid anti-inflammatory agents: (c) saturated with 12 or more carbon atoms Selected from higher aliphatic monocarboxylic acids, aliphatic polycarboxylic acids, hydroxy aliphatic polycarboxylic acids, aromatic carboxylic acids, unsaturated lower aliphatic monocarboxylic acids having up to 6 carbon atoms, and cellulose derivatives having carboxyl groups. It is achieved by a powdered pharmaceutical composition containing a stabilizer of a medicament of at least one solid organic acid with irritation.

According to the present invention, a preferred powdered pharmaceutical composition, i.e., a composition having extremely good drug stability, low irritation to the mucous membranes of the oral or nasal cavity, and good sustainability of the drug, is a lower alkyl ether of cellulose as a gas, steroid or glycyrizine as a drug. It can be obtained by using a special solid organic acid having low irritation as the stabilizer of the acid type anti-inflammatory agent and the drug, that is, the base and the drug can be obtained by mixing with the organic acid.

The lower alkyl ether of cellulose which can be used as a base in the present invention is obtained by at least partially replacing a plurality of hydroxyl groups of cellulose with the same or different lower alkyl ether groups.

The lower alkyl group in the lower alkyl ether group is preferably substituted with a substituent, and such a substituent is preferably a hydroxyl group, for example. Arbitrary substituted lower alkyl groups are preferred, for example hydroxy, lower alkyl groups having 2 to 3 carbon atoms with methyl groups. Optionally substituted lower alkyl groups are, for example, methyl, ethyl, n-propyl, iso-propyl, β-hydroxyethyl and β-hydroxy propyl.

Examples of lower alkyl ethers of optionally substituted cellulose are methyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose and hydroxy propyl methyl cellulose. Of the lower alkyl ethers of these cellulose, methyl cellulose, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are preferably used, because the lower alkyl ethers of these cellulose may cause odor and irritation. This is because when used in sensitive oral or nasal mucosa, the desired sustained efficacy of the drug can be obtained without actually exhibiting any smell and irritation. Particular preference is given to the use of hydroxypropyl cellulose in the lower alkyl ethers of these cellulose. Lower alkyl ethers of cellulose can be used alone or in combination thereof.

The use of the above-mentioned lower alkyl ethers of cellulose as a base in the powdered pharmaceutical composition according to the present invention will result in a long lasting and active pharmaceutical ingredient with adhesion in the mucous membranes of the oral or nasal cavity. Therefore, the affected area can be treated with long-term medication.

There is no restriction on the molecular weight of the lower alkyl ether of cellulose which can be used in the present invention, but it is preferable to use a lower alkyl ether having a viscosity of 2% aqueous solution of 3-10,000 cps at 37 ± 0.2 ° C, more preferably. It is time to use 1,000-4,000cps at 37 ℃ ± 0.2 ℃.

In preparing a unitary dosage form of a powdery contractive composition containing a lower alkyl ether of cellulose as a base, the composition is usually filled in a light capsule. These capsules are secured to specially designed sprayers. The spray device is equipped with a needle for spraying the pharmaceutical composition into the oral or nasal cavity.

In this case, if the moisture content of the lower alkyl ether of cellulose in the capsule is very small, the moisture contained in the capsule membrane is absorbed by the lower alkyl ether of cellulose, and the capsule is immediately solidified. Therefore, it is preferable to use as a base a lower alkyl ether of cellulose having a water content of 3-9% by weight, in particular 4-8% by weight.

Pharmaceutical agents that can be used in the powdered pharmaceutical composition of the present invention include steroids or glycyrrhizinic acid type anti-inflammatory agents, and examples of such steroidal anti-inflammatory agents include beclomethasone dipropionate, betamethasone, betamethasone allate, triamcinolone, triamcinolone acetonide, dexamethasone, Fluorinolo acetonide, fluorinide flumetason, hydrocollisone, prednisolone and prednisone. Examples of glycyrrhizinate type anti-inflammatory agents include glycyrrhizinate, disodium glycyrrhizin, trisodium glycyrrhinate, monopotassium glycyrinate, dipotassium glycyrrhinate and monoammonium glycyrrhinate. These agents can be used alone or in combination in the present powdered pharmaceutical compositions.

According to the present invention, the anti-inflammatory agent contained in the powdered pharmaceutical composition having the above-described lower alkyl ether of cellulose as a base is a special organic acid as a stabilizer, that is, a saturated higher aliphatic monocarboxylic acid or aliphatic poly having 12 or more carbon atoms. It can be advantageously recognized by mixing a carboxylic acid, a hydroxy polycarboxylic acid, an aromatic carboxylic acid, an unsaturated lower aliphatic monocarboxylic acid having up to 6 carbon atoms and a cellulose derivative having a carboxyl group.

The organic acid which can be used as a stabilizer for pharmaceuticals in the present invention is selected from the above-mentioned organic acids which are solid at room temperature and which do not irritate the mucous membranes of the oral or nasal passages and have practically no smell or almost no smell. The term "organic acid" refers to an acid having an organic and free carboxyl group. The use of organic acids that are solid at room temperature allows the preparation of desired powdered pharmaceutical compositions with uniform particle sizes, and the use of non-irritating organic acids gives higher stability when the compositions are used in oral or nasal mucosa. Examples of preferred saturated higher fatty buckles mono carboxylic acids are saturated higher aliphatic hydrocarbon monocarboxylic acids having 12 to 24 carbon atoms such as stearic acid, palmitic acid, lauric acid and myristic acid. Examples of preferred aliphatic polycarboxylic acids are aliphatic hydrocarbon dicarboxylic acids having 4-6 carbon atoms, such as succinic acid, fumaric acid and maleic acid, and examples of hydroxy aliphatic polycarboxylic acids such as tartaric acid and citric acid. Preference is given to hydroxy aliphatic hydrocarbondi- or tri-carboxylic acids having -8 carbon atoms, benzoic acid and derivatives thereof such as, for example, parahydroxy benzoic acid and salicylic acid. Examples of unsaturated lower aliphatic monocarboxylic acids are unsaturated lower aliphatic hydrocarbon monocarboxylic acids having 4 to 6 carbon atoms such as sorbic acid, and examples of cellulose derivatives having carboxyl groups include, for example, carboxymethylcellulose and Carboxymethylethyl cellulose is preferred. These organic acids can be used individually or in mixture.

Preference is given to using saturated lower aliphatic monocarboxylic acids, aliphatic polycarboxylic acids, aromatic carboxylic acids and cellulose derivatives having carboxyl groups having at least 12 carbon atoms in the organic acid.

In powdered pharmaceutical compositions for use in the nasal cavity, the use of saturated higher aliphatic monocarboxylic acids having at least 12 carbon atoms and cellulose derivatives having carboxyl groups is particularly preferred in view of low irritation and no smell. The amount of the organic acid in the present pharmaceutical composition is not particularly limited. The amount of organic acid in the present pharmaceutical composition is preferably 0.05-5% by weight, especially 0.1-3% by weight, based on the total amount of the composition. The particle size of the organic acid is not critical, but in order to obtain a powdered pharmaceutical composition that can be effectively administered to the mucous membranes of the oral or nasal cavity, the organic acid has at least about 90% by weight of powder particles of about 75 μm or less, especially about 20-75 μm. Such particle size with an effective particle diameter of is preferred.

As described above, the powdered pharmaceutical composition according to the present invention contains, as a main component, a lower alkyl ether, steroid or glycyrrhizinic acid type anti-inflammatory agent of the cellulose and an organic acid stabilizer. The particle size of the present pharmaceutical composition is not particularly limited, but the particle size of the present pharmaceutical composition preferably has at least about 90% by weight of powder particles having an effective particle diameter of about 20-250 μm. Powdered pharmaceutical compositions of the present invention having such a particle size distribution are preferred because the amount of powder particles adhered to the mucous membranes of the oral or nasal cavity becomes large. That is, when the pharmaceutical composition having the above preferred particle size distribution is used in the oral cavity or the nasal cavity, the amount of the pharmaceutical composition that reaches the lung is small, and also the amount of the pharmaceutical composition distributed in the oral cavity or the nasal cavity is small. Moreover, the pharmaceutical composition having the above preferred particle size adheres well to the oral or nasal mucosa and has a progressive sustained release.

Powdered pharmaceutical compositions according to the present invention are more preferred for such particle size distributions where at least about 90% by weight of powder particles have an effective particle diameter of about 20-150 μm. As used herein, the term "effective particle diameter" means measured by the sieve pore size.

44의 유효직경(d)을 갖는 분말은 44미크론의 구멍크기를 갖는 체에는 통과되나, 37미크론의 구멍크기를 갖는 체에는 통과하지 못한다.For example, 37 <d

The powder having an effective diameter (d) of 44 passes through a sieve having a hole size of 44 microns, but does not pass through a sieve having a hole size of 37 microns.

If the effective particle diameter of the powder is 37 microns or more, a vibrating body is used. If the effective particle diameter of the powder is 37 microns or less, a sound wave body (a micro hand shifter SWM-2, manufactured by Juju Rigakaku Co., Ltd.) is used. The sieves used have hole sizes of 500, 420, 350, 297, 250, 210, 177, 149, 125, 105, 88, 74, 63, 53, 44, 37, 25 and 20 microns respectively.

Powdered pharmaceutical compositions of the present invention may optionally contain conventional ingredients in addition to the lower alkylters, anti-inflammatory agents and organic acids of cellulose described above to improve the physical properties, visual appearance or odor of the formulation. Lubricants such as talc and wax; Binders such as starch, dextrin, tragacanth rubber, gelatin, polyvinylpyrrolidone and polyvinyl alcohol; Diluents such as starch cellulose crystals, deck screens, lactose, mannitol, sorbitol and calcium phosphate anhydride; Fragrance-improving agents such as menthol and citrus flavors; Preservatives such as methyl p-hydroxybenzoate, propyl p-hydroxybenzoate and various hardeners.

Powdered pharmaceutical compositions according to the invention can be prepared by conventional methods. For example, the pharmaceutical composition may be prepared by mechanically mixing the three main components described above, ie lower alkyl ethers of cellulose, an anti-inflammatory agent and a solid organic acid with the above components.

Mixing of the composition can be carried out using conventional methods such as bowl and V-type mixers, and the desired pharmaceutical composition can also be mechanically mixed with all the components of the above-mentioned composition, for example produced under a pressure of 0.2-0.4 soils. The compacted mixture may be prepared by crushing the compacted mixture to a desired particle size distribution. The mixed or ground powder particles are sieved to form a powdery composition having the desired particle size distribution. In addition, the desired pharmaceutical composition may be prepared by impregnating a lower alkyl ether of cellulose in a solution or dispersion in which an anti-inflammatory agent, an organic acid, and optional components are dissolved or dispersed in an organic solvent (for example, methanol, ethanol, ethyl cellosolve, and dichloromethane). The impregnated product can then be prepared by drying. Water may be contained in this organic solvent. Impregnation can be carried out by spraying, for example, the aforementioned solution or dispersion with a lower alkyl ether of cellulose in the form of powder particles with an atomizer. The particle size distribution of the lower alkyl ether of cellulose can be adjusted to the desired range prior to impregnation. In addition, the powder particles of the impregnated product may be pulverized and sieved after impregnation to have a desired particle size distribution. Furthermore, the desired pharmaceutical compositions can be prepared by dissolving or dispersing cellulose lower alkyl ethers, anti-inflammatory agents, solid organic acids in organic solvents such as methanol, ethanol ethyl cellosolve and dichloromethane, water or mixtures thereof and then evaporating off the organic solvent. Can be. The resulting composition is ground and sieved to have the desired particle size distribution.

The present invention provides a powdered preparation in unit dosage form comprising the powdered pharmaceutical composition, and the pharmaceutical composition can be directly converted to a powdered preparation in unit dosage form.

The dosage unit of the powdered preparation according to the invention is preferably about 10-400 mg, especially about 30-300 mg when used in the oral cavity and about 5-200 mg, particularly about 10-100 mg when used in the nasal cavity. The amount of steroid or glycyrrhizin acid anti-inflammatory agent in the unit dosage form depends on the pharmaceutically effective amount of the anti-inflammatory agent to be used and the number of doses of the preparation.

For example, when beclomethasone dipropionate is mixed into a powdered formulation for use in the nasal or oral cavity, a typical amount is about 200-400 μg / day whereas a suitable amount is about 25-200 μg / day. When dipotassium glycyrrhinate was mixed with powdered preparations for oral use, a typical amount was about 10-30 mg / day, while a suitable amount was about 0.1-15 mg / day.

This is because the lower alkyl ethers of cellulose can be used in the pharmaceutical compositions of the present invention to obtain the desired sustained drug component.

The powdered formulation of the invention is preferably filled in a capsule, such as a hard gelatin capsule, in a preferred dosage form.

The powdery preparation of the present invention may be used for oral or nasal passages. For example, a capsule filled with the powdered formulation is fixed to a nebulizer equipped with a needle, and the hole is punched with a needle to make several holes at the top and the bottom. The rubber ball is then blown into the capsule to spray or spray the powder formulation.

As described above, the water content in the lower alkyl ether of the cellulose of the powdered formulation filled in the light gelatin capsule is preferably 3-8.5% by weight, particularly 4-8.5% by weight.

The powdered formulations of the present invention can be widely used to treat oral diseases such as stomatitis, blisters or wounds caused by radiation therapy, and nasal diseases such as squamous or allergic rhinitis and vasomotor rhinitis.

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in detail by way of examples, which are not to be construed as limiting the scope of the present invention, unless otherwise indicated and all percentages and parts are by weight.

Example 1

100 parts of hydroxypropyl cellulose are used, having a viscosity of 2% aqueous solution at 1550 cps at 37 ° C. ± 0.2 ° C. and having a particle size of 90% or more powder particles having a particle diameter of 37-149 μm.

One part hydroxypropyl cellulose and 0.025 parts beclomethasone dipropionate are mixed thoroughly in a bowl, and then nine times hydroxypropyl cellulose is added gradually. The resulting mixture is mixed thoroughly, then residual hydroxypropyl cellulose is added and mixed in a mixer, followed by 0.5 parts of stearic acid and mixed thoroughly. Thus, a powdered oral composition containing orally dispersed beclomethasone dipropionate is prepared, and the powdered composition is filled into a # 2 trans gelatin capsule in an amount of 200 mg each to make the powdered formulation into unit dosage form for oral use. .

Example 2

Except for using palmitic acid instead of stearic acid, powdered formulations in unit dosage form for oral preparations were prepared in the same manner as in Example 1.

Example 3

Powdery preparations in unit dosage form for oral cavity are prepared in the same manner as in Example 1 except for using citric acid instead of stearic acid.

Example 4

Powdery preparations in unit dosage form for oral cavity are prepared in the same manner as in Example 1 except for using benzoic acid instead of stearic acid.

Example 5

Powdery formulations in unit dosage form for oral cavity are prepared in the same manner as in Example 1 except for using sorbic acid instead of stearic acid.

Example 6

A powdery composition for oral cavity was prepared in the same manner as in Example 1 except that the amount of stearic acid was changed to 0,0.1,0.3,0.5 and 0.7 parts.These powdery compositions were prepared in the amount of # 2 light gelatin capsules in amounts of 200 mg each. To charge. The capsule thus prepared is left at a temperature of 60 ° C. for one month and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 1 below.

TABLE 1

Example 7

Except for changing the amount of palmitic acid to 0, 0.1, 0.3 and 0.5 parts, oral powdery compositions are prepared in the same manner as in Example 2, and these powdery compositions are filled in a # 2 trans gelatin capsule in an amount of 200 mg each. . The capsule thus prepared is left at a temperature of 60 ° C. for one month and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 2 below.

TABLE 2

Example 8

Except for changing the amount of citric acid to 0, 0.05, 0.1, 0.5, 1 and 3 parts, oral powder compositions were prepared in the same manner as in Examples, and these powder compositions were prepared in a # 2 trans gelatin capsule in an amount of 200 mg each. Charge it.

The capsule prepared here is left at a temperature of 60 ° C. for one month and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 3 below.

TABLE 3

Example 9

A powdery composition for oral cavity was prepared in the same manner as in Example 4, except that the amount of benzoic acid was changed to 0, 0.05, 0.1 and 0.5 parts.

These powdery compositions are filled in a # 2 gelatin capsule in an amount of 200 mg each.

The capsule thus prepared is left at a temperature of 60 ° C. for one month and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 4.

TABLE 4

Example 10

Powder compositions for oral cavity were prepared in the same manner as in Example 5, except that the amount of sorbic acid was changed to 0, 0.1, 0.3 and 0.5 parts, and these powder compositions were filled in a # 2 gelatin capsule in an amount of 200 mg each. .

The prepared capsule is left at a temperature for one month, and the percentage of beclomethasone dipropione remaining in the capsule is measured.

The results are shown in Table 5 below.

TABLE 5

Example 11

Oral powder form except for using 100 parts of methyl cellulose and 0.025 parts of triamcinolone having a viscosity of 2% aqueous solution of 1335 cps at 37 ° C. ± 0.2 ° C. and changing the amount of stearic acid to 0, 0.1, 0.3, and 0.5 part. The detergent is prepared in the same way.

The formulation of the capsules is left at a temperature of 60 ° C. for one month before the residual percent of triamcinolone acetonide is measured.

The results are shown in Table 6.

TABLE 6

Example 12

100 parts of hydroxypropyl cellulose are used with a viscosity of 2% aqueous solution at 37 ° C. ± 0.2 ° C., with a particle size of 90% or more powder particles with a particle diameter of 37-149 μm.

10 parts of hydroxypropyl cellulose and 0.17 parts of beclomethasone dipropionate are thoroughly mixed in a mixer, then residual hydroxypropyl cellulose is gradually added thereto, and the resulting mixture is mixed, followed by 0.5 parts of stearic acid. Add and mix thoroughly. Therefore, a nasal powdery composition containing homogeneously dispersed beclomethasone dipropionate was prepared, and the powdery composition was filled in a # 2 diameter gelatin capsule in an amount of 30 mg each to prepare a powdery preparation in nasal unit dosage form. do.

Example 13

100 parts of methyl cellulose are used with a viscosity of 2% aqueous solution at 37 ° C. ± 0.2 ° C. of 1335 cps.

10 parts methyl cellulose and 0.17 parts beclomethasone dipropionate are mixed thoroughly in a bowl, followed by gradually adding the residual hydroxypropyl cellulose. After the resulting mixture is mixed thoroughly, 0.5 part of stearic acid is added and mixed.

In this way, a nasal powder composition containing beclomethaneson dipropionate uniformly dispersed was prepared, and the powder composition was filled in a # 2 light gelatin capsule in an amount of 30 mg each to prepare a nasal powder-type powder formulation. Manufacture.

Example 14

The same method as in Example 13 was carried out in the same manner as in Example 13, except that hydroxypropylmethyl cellulose having a viscosity of 2% aqueous solution of 20 cps at 37 ° C. ± 0.2 ° C. was used instead of methyl cellulose. To manufacture.

The powdered composition is filled in a # 2 trans gelatin capsule in an amount of 30 mg each to prepare a powdered formulation in unit dosage form for nasal use.

Example 15

Powdered compositions were prepared in the same manner as in Example 12 except that the amount of stearic acid was changed to 0, 0.01, 0.1, 0.3, 0.5 and 0.7 parts, and these powdered compositions were added to the # 2 gelatin capsules in an amount of 30 mg each. To charge.

The capsule thus prepared is left at a temperature of 60 ° C. for one month and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 7 below.

TABLE 7

Example 16

The same evaluation test as in Example 15 was conducted except that palmitic acid was used instead of stearic acid.

The results are shown in Table 8 below.

TABLE 8

Example 17

Powdered compositions were prepared in the same manner as in Example 12, except that 0, 1, 2 and 3 parts of carboxymethyl cellulose were used instead of stearic acid, and these powdered compositions were prepared in an amount of # 2 light gelatin in an amount of 30 mg each. Fill the cap slot.

The capsule thus prepared is left at a temperature of 60 ° C. for one month, and beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 9.

TABLE 9

Example 18

Powdered compositions were prepared in the same manner as in Example 13 except that the amount of stearic acid was changed to 0, 0.01, 0.05, 0.1 and 0.5 parts, and these powdered compositions were filled in a # 2 gelaline capsule in an amount of 30 mg each. do.

The capsule thus prepared is left at a temperature of 60 ° C. for one month, and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 10 below.

TABLE 10

Example 19

90 parts of hydroxypropyl cellulose and 10 parts of dipotassium glycyrrhinate are mixed in a mixer having a viscosity of 2% aqueous solution at 1550 cps at 37 ° C. ± 0.2 ° C. and having a particle size of at least 90% having a particle diameter of 37-149 μm. After complete mixing, 0.1, 0.3, 0.5 and 0.7 parts of stearic acid are added to the resulting mixture to prepare a powder composition for oral cavity.

The prepared powdery composition is filled into a # 2 gelatin capsule in an amount of 100 mg each, and the obtained capsule is left at a temperature of 60 ° C. for one month, and the percentage of glycyrizine remaining in the capsule is measured.

The results are shown in Table 11 below.

TABLE 11

Example 20

100 parts of hydroxypropyl cellulose are used with a viscosity of 2% aqueous solution at 37 ° C. ± 0.2 ° C. and a particle size of at least 90% of powder particles of 37-149 μm.

Mix 1 part hydroxypropyl cellulose and 0.025 parts beclomethasone dipropionate thoroughly in a bowl, then gradually add 9 parts hydroxypropyl cellulose to the mixture and mix the resulting mixture thoroughly Add hydroxypropyl cellulose and mix in a mixer, then add 0.5 parts of stearic acid and mix thoroughly. In this way, a powdery composition for oral cavity containing homogeneously dispersed beclomethasone dipropionate is prepared, and the powdery composition is filled into a # 2 light gelatin capsule in an amount of 200 mg each to prepare a powdery formulation in unit dosage form for oral use. Manufacture.

The capsules thus prepared are left at 60 ° C. for one month and 40 ° C. for six months.

TABLE 12

Comparative Example 1

100 parts of hydroxypropyl cellulose are used in a 2% aqueous solution at 1550 cps at 37 ° C. ± 0.2 ° C. and having a particle size of at least 90% of the powder particles having a particle diameter of 37-149 μm.

Mix 1 part hydroxypropyl cellulose and 0.025 parts beclomethasone dipropionate thoroughly in a bowl, then gradually add 9 parts hydroxypropyl cellulose, mix the resulting mixture and then mix the residue Roxypropyl cellulose is added and mixed in a mixer.

Next, an unsaturated lower aliphatic monocarboxylic acid having up to 6 carbon atoms used in the present invention and another 0.5 parts of ascorbic acid are added and mixed thoroughly.

In this way, a powdery composition for oral cavity containing homogeneously dispersed beclomethasone dipropionate is prepared, and the powdery composition is filled into a # 2 light gelatin capsule in an amount of 200 mg each to prepare a powdery formulation in unit dosage form for oral use. Manufacture.

The capsule thus prepared is left at a temperature of 60 ° C. for 30 days, and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 13 below.

TABLE 13

Comparative Example 2

Except for using aliphatic polycarboxylic acid and glutamic acid used in the present invention in place of ascorbic acid, a powdery formulation in the unit dosage form for oral use is prepared in the same manner as in Comparative Example 1.

The cap obtained above is left at a temperature of 60 ° for 30 days, and the percentage of beclomethasone dipropionate remaining in the cap is measured.

The results are shown in Table 14 below.

TABLE 14

Comparative Example 3

Sodium carboxymethyl cellulose having carboxyl groups and other carboxylate groups is used in place of ascorbic acid.

The capsule obtained here is left to stand at the temperature of 60 degreeC for 30 days. The percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 15 below.

TABLE 15

Comparative Example 4

Unit dosage form for oral use, except that the steroid or glycyrrhizinic acid type anti-inflammatory agent used in the present invention and other aspirin are used in place of beclomethasone dipropionate, and the stearic acid used as a stabilizer in this invention is used instead of ascorbic acid. Powdery formulation of was prepared in the same manner as in Comparative Example 1.

The capsule obtained above is left at 60 degreeC for 30 days, and the percentage of the aspirin which remained in the capsule is measured.

The results are shown in Table 16 below.

TABLE 16

Comparative Example 5

Unit dosage form for oral use, except that steroid or glycyrrhizinic acid type anti-inflammatory agent used in the present invention and other azulenes are used in place of beclomethasone dipropionate and palmitic acid used as a stabilizer in the present invention instead of ascorbic acid Powdery formulation of was prepared in the same manner as in Comparative Example 1.

The capsule obtained above is left at a temperature of 60 ° C. for 30 days and the percentage of azulene remaining in the capsule is measured.

The results are shown in Table 17 below.

TABLE 17

Comparative Example 6

A powdery formulation in unit dosage form for oral use is prepared in the same manner as in Comparative Example 1, except that stearic acid and other magnesium stearate used in the present invention are used instead of ascorbic acid.

The capsule obtained above is left to stand at the temperature of 60 degreeC for 30 days. The percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 18 below.

TABLE 18

Comparative Example 7

100 parts of hydroxypropyl cellulose are used with a viscosity of 2% aqueous solution of 1550 cps and a particle size distribution in which at least 90% of the powder particles have a particle diameter of 37-149 μm.

10 parts of hydroxypropyl cellulose and 0.17 parts of beclomethasone dipropionate are thoroughly mixed in a mixer, followed by adding residual hydroxypropyl cellulose to the mixture.

Then add 0.5 part ascorbic acid and mix. This produces a pharmaceutical powder composition for oral cavity containing beclomethasone dipropionate uniformly dispersed.

The powder composition obtained above is filled in a # 2 gelatin capsule in an amount of 30 mg each to prepare a powdery preparation in unit dosage form for oral use. The capsules are left at a temperature of 60 ° C. for 30 days to determine the percentage of residual beclomethasone dipropionate.

The results are shown in Table 19 below.

TABLE 19

Comparative Example 8

A powdery formulation in unit dosage form for oral use was prepared in the same manner as in Comparative Example 7, except that glutamic acid was used instead of ascorbic acid.

The cap obtained above is left at a temperature of 60 ° C. for 30 days, and the percentage of beclomethasone dipropionate remaining in the cap is measured.

The results are shown in Table 20 below.

TABLE 20

Comparative Example 9

Aspirin is used in place of beclomethasone dipropionate and stearic acid is used in place of ascorbic acid, except that powdered formulations in nasal dosage form are prepared in the same manner as in Comparative Example 7.

The capsule obtained above is left at a temperature of 60 ° C. for 30 days and the percentage of aspirin remaining in the capsule is measured.

The results are shown in Table 21 below.

TABLE 21

Comparative Example 10

A powdery formulation in unit dosage form for oral use is prepared in the same manner as in Comparative Example 7, except that magnesium stearate is used instead of ascorbic acid.

The capsule obtained above is left at a temperature of 60 ° C. for 30 days and the percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 22 below.

Table 22

Example 21

100 parts of hydroxypropyl cellulose are used with a viscosity of 2% aqueous solution at 37 ° C. ± 0.2 ° C. and a particle size of at least 90% of powder particles of 37-149 μm.

10 parts of hydroxypropyl cellulose and 0.17 parts of beclomethasone dipropionate are mixed thoroughly in a mixer, and then the remaining hydroxypropyl cellulose is gradually added. After the resulting mixture is mixed thoroughly, 0.5 part of stearic acid is added and mixed.

In this way, the nasal powder composition containing the uniformly dispersed beclomethasone dipropionate is manufactured. This powdery composition is filled in a # 2 light gelatin capsule in an amount of 30 mg each to prepare a powdery dosage form in unit dosage form for nasal cavity use. The capsules thus prepared are left at a temperature of 60 ° C. for 30 days or at 40 ° C. for 6 months.

The percentage of beclomethasone dipropionate remaining in the capsule is measured.

The results are shown in Table 23 below.

TABLE 23

Comparative Example 11

A powdery formulation for oral cavity is prepared in the same manner as in Example 1, except that capric acid (e.g., saturated higher aliphatic monocarboxylic acid having 10 carbon atoms) is used instead of stearic acid.

However, the powdery formulations obtained above are not suitable as powdery formulations because the powdery formulations filled in the capsules are too strong in odor when administered to the oral cavity with the above-described nebulizer.

Example 22

100 parts of hydroxypropyl cellulose are used with a viscosity of 2% aqueous solution at 1550 cps at 37 ° C. ± 0.2 ° C. and a particle size of at least 90% of the powder particles having a particle diameter of 37-149 μm.

Completely mix 10 parts hydroxypropyl cellulose and 1.7 parts triamscelon acetonide with a mixer, then gradually add residual hydroxypropyl cellulose to the mixture, thoroughly mix the resulting mixture and mix 0.5 parts of stearic acid with 0.3 Negative magnesium stearate is added and mixed.

In this way, a nasal powder composition containing a uniformly dispersed triamcinolone acetonide is prepared.

The powdered composition obtained above is pulverized with a grinder and then compressed to prepare a tablet having a Monsanto hardness of 3-4 kg. The tablets are ground with a grinder to produce powder particles, which are sieved to obtain powder particles having a particle size of 60-400 mesh.

Next, the powder particles are filled in a # 2 light gelatin capsule in an amount of 30 mg each to prepare a powder dosage form in unit dosage form for nasal cavity.

Example 23

100 parts of hydroxypropyl cellulose having a viscosity of 1550 cps at 37 ° C. ± 0.2 ° C. and having a particle size of 90% or more powder particles having a particle diameter of 37-149 μm were charged into a fluidized bed granulator and then 0.025 parts Spray the granulator with 50 parts of ethanol mixture containing 5 parts of hydroxypropyl cellulose and 0.5 parts of stearic acid having beclomethasone dipropionate having a viscosity of 2% aqueous solution at 7 ° C. at 37 ° C. ± 0.2 ° C. Spray with a nozzle and then dry. Thus, powder particles impregnated with the ethanol mixture as a solid component are obtained. Sieve the powder particles to produce particles having a particle size of 60-400 mesh. The powder particles thus prepared are filled in a # 2 gelatin capsule in an amount of 200 mg to prepare a powdery preparation in unit dosage form for oral use.

Example 24

80 parts of hydroxypropyl cellulose and 0.2 parts of dissolved becloro having a viscosity of 2% aqueous solution at 37 ° C. ± 0.2 ° C. of 1550 cps and having a particle size of 90% or more powder particles having a particle diameter of 37-149 μm. A 1000 part ethanol suspension containing metason dipropionate and 0.4 part suspended stearic acid is sprayed onto the surface of the screening paper. When dried, a film is obtained.

The film obtained above is finely pulverized with a pulverizer and sieved to make powder particles having a particle size of 60-400 mesh.

The powder particles are filled in a # 2 trans gelatin capsule in an amount of 200 mg each to prepare a powdery preparation in unit dosage form for oral use.

Claims (4)

Bases selected from lower alkyl ethers of cellulose; Beclomethasone, dipropionate, betamethasone, betamethasone valerate, triamcinolone, triamcinolone acetonide, dexamethasone, fluorocylone acetonide, fluorinide, flumethasone, hydrocollisone, prednisolone and plednisone A pharmaceutically effective amount of a drug selected from the selected steroid anti-inflammatory agents or glycyrrhizin acid anti-inflammatory agents; And saturated higher aliphatic monocarboxylic acids, aliphatic polycarboxylic acids, hydroxy aliphatic carboxylic acids, aromatic carboxylic acids having 12 or more carbon atoms, and unsaturated lower aliphatic monocarboxylic acids having up to 6 carbon atoms and carboxyl groups. A method of producing a powdered pharmaceutical composition for oral or nasal mucosa, characterized by mechanically mixing at least one low irritant solid organic acid selected from cellulose derivatives. The method according to claim 1, wherein the mixed composition is pressed under pressure and then the compacted mixture is ground. Beclomethasone dipropionate, betamethasone, betamethasone valerate, triamcinolone, triamcinolone aceronide, dexamethasone, fluorcinolone aceronide, fluorinoneide, flumethasone, hydrocollisone, prednisolone and prednisone A pharmaceutically effective amount of a medicament selected from a steroid anti-inflammatory agent or a glycyrrhinic acid type anti-inflammatory agent, a saturated higher aliphatic monocarboxylic acid having at least 12 carbon atoms, a hydroxy aliphatic polycarboxylic acid, an aliphatic carboxylic acid, up to 6 unsaturated lower aliphatic monocarboxylic acids. Oral cavity characterized in that it is prepared by impregnating a lower alkyl ether of cellulose in a solution in which at least one low irritant solid organic acid selected from an cellulose derivative having an acid and a carboxyl group is dissolved in an organic solvent, and then drying the impregnation. ratio Process for the preparation of powdered pharmaceutical compositions for steel mucosa. Lower alkyl ethers of cellulose; Selected from the group consisting of beclomethasone dipropionate, betamethasone, betamethasone valerate, triamcinolone, triamcinolone, acetonide, dexamethasone, fluorcinolone, acetonide, fluorinoneide, flumethasone, hydrocollisone, prednisolone and prednisone Pharmaceutically effective amount of medicament selected from steroid anti-inflammatory agents or glycyrrhinic acid type anti-inflammatory agents; and saturated higher aliphatic monocarboxylic acids, aliphatic polycarboxylic acids, hydroxy aliphatic polycarboxylic acids, aromatic carboxylic acids, 6 having more than 12 carbon atoms At least one low irritant solid organic acid selected from unsaturated lower aliphatic monocarboxylic acids having the following carbon atoms and cellulose derivatives having a carboxyl group is dissolved in an organic solvent, and then the organic solvent is evaporated from the resulting solution, followed by evaporation. Method of producing a powder for oral or mucosal steel, characterized in that the pharmaceutical compositions prepared by grinding the water.