JP3435464B2 - Aqueous dispersion for coating sustained-release preparations - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aqueous dispersion which is coated on a drug such as granules in order to impart sustained release.

[0002]

2. Description of the Related Art Medicinal products are digested in the body to dissolve medicinal components and exert a pharmacological action. A drug having a high dissolution rate of a medicinal component may have an excessively strong pharmacological action and cause a side effect to a patient. Therefore, sustained-release preparations having a function of suppressing the elution rate of the medicinal component, controlling the blood concentration at a constant level for a long time, and decreasing the number of doses are widely used as pharmaceuticals.

Sustained-release preparations include matrix type, coating type and tablet type. The matrix type is a mixture of a medicinal component with a water-soluble polymer or wax and tableted, and the coating type is a granule or tablet surface coated with a hydrophobic polymer, an enteric polymer or wax. The tablet type is a mixture of the sustained-released or enteric-coated coated granules and the immediate-release granules, which are encapsulated or tableted. Among them, a coating type sustained-release preparation is relatively easily produced, and therefore, many known examples are mentioned. Japanese Patent Publication No. 56-12614 discloses that a cellulose-based polymer having an average particle diameter of 10 μm or less is dispersed in water containing a gelling agent (plasticizer) and having a boiling point of 100 ° C. or more to form a coating liquid. Have been described. Japanese Patent Publication No. 57-53329 and Japanese Patent Publication No. 58-58
Japanese Patent No. 55125 describes that triacetin or triethyl citrate is used as the plasticizer. These water-based coating liquids have lower coating properties than organic coating liquids. For this reason, a large amount of water-based coating liquid is required when coating granules and the like.

Japanese Patent Publication No. 60-43334 and Japanese Patent Application Laid-Open No. 61-100527 describe an aqueous emulsion in which a coating base is a vinyl polymer. Since the emulsion may contain unreacted monomer, its coating property was low.

[0005]

The present invention has been made to solve the above-mentioned problems, and it is an object of the present invention to provide an aqueous dispersion capable of imparting excellent sustained-release property to pharmaceutical products such as granules with a small amount of coating. To aim.

[0006]

The aqueous dispersion for sustained-release preparation coating of the present invention made to achieve the above objects is selected from aliphatic alcohols having 10 or more carbon atoms, fatty acids and glycerin fatty acid esters. 100 parts by weight of at least one kind and 10 to 10 parts of anionic surfactant
And 30 parts by weight, a nonionic surfactant 30 parts by weight or less
And 10 to 30 parts by weight of water are heated to melt and mix,
A cellulose-based polymer is dispersed in an aqueous emulsion obtained by adding a solid substance obtained by cooling at a temperature to water .

100 at least one selected from aliphatic alcohols, fatty acids and glycerin fatty acid esters
When the weight ratio of the anionic surfactant to the weight part is less than 10 parts by weight, the emulsified state of the emulsion is deteriorated. If it exceeds 30 parts by weight, the water solubility of the surfactant may adversely affect the coating property of the emulsion.

When the weight ratio of the nonionic surfactant exceeds 30 parts by weight, the water solubility of the surfactant may adversely affect the coatability of the emulsion.
A particularly stable emulsion is obtained when the weight ratio is 10 to 15 parts by weight.

The weight ratio of at least one selected from aliphatic alcohols, fatty acids and glycerin fatty acid esters to the cellulosic polymer is 5 to 50 parts by weight: 100.
Parts by weight are preferred. When the amount of at least one selected from aliphatic alcohols, fatty acids and glycerin fatty acid esters is less than 5 parts by weight, the sustained release property of the aqueous dispersion for coating is lowered. If it exceeds 50 parts by weight, the effect obtained by increasing the ratio cannot be obtained.

The cellulosic polymer serves as a base for coating pharmaceuticals such as granules. Cellulosic polymers include ethyl cellulose, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, carboxymethyl ethyl cellulose. These may be used alone or in combination. Instead of the cellulosic polymer, polyvinyl acetate phthalate, methacrylic acid-ethyl acrylate copolymer, ethyl acrylate-methyl methacrylate copolymer, ethyl acrylate-methyl methacrylate-methacrylic acid trimethylammonium ethyl copolymer A vinyl-based polymer such as a polymer may be used as a coating base.

The average particle size of the cellulosic polymer is 10
μm or less is preferable. When it exceeds 10 μm, the film-forming property of the aqueous dispersion for coating is deteriorated, and a large amount of liquid is required for coating granules and the like.

Examples of the aliphatic alcohol having 10 or more carbon atoms include lauryl alcohol, cetyl alcohol and stearyl alcohol. Examples of the fatty acid having 10 or more carbon atoms include lauric acid, myristic acid, palmitic acid, and stearic acid. Examples of the glycerin fatty acid ester having 10 or more carbon atoms include glycerin esters of the above fatty acids, for example, glycerin monostearate. Of these, cetyl alcohol, stearyl alcohol, and stearic acid are particularly preferable. These aliphatic alcohols, fatty acids and glycerin fatty acid esters may be used alone or in combination.

Examples of the anionic surfactant include sodium fatty acid, potassium fatty acid, sodium lauryl sulfate and dioctyl sodium sulfosuccinate. Among these, sodium lauryl sulfate and dioctyl sodium sulfosuccinate are particularly preferable from the viewpoint of emulsification.

Examples of the nonionic surfactant include polyoxyethylene fatty acid ester, glycerin ester, polyoxyethylene sorbitan fatty acid ester and polyoxyethylene alkyl ether. The hydrophilic-lipophilic ratio (hereinafter referred to as HLB), which is an index showing the balance between the hydrophilicity and the lipophilicity of the surfactant, is preferably 4-18. HL
When B is out of this range, the nonionic surfactant is
It becomes impossible to incorporate the aliphatic alcohol particles or the fatty acid particles as a micelle structure.

The weight ratio of water in the aqueous emulsion is 1 with respect to 100 parts by weight of at least one selected from aliphatic alcohols, fatty acids and glycerin fatty acid esters.
In the case of 0 to 30 parts by weight, the emulsion becomes a solid when cooled. The solid matter is formed into pellets by a pelleter or the like. The pellets revert to emulsions when added to water. When the pellets are put into water and re-emulsified, it is preferable to add talc. The weight ratio of talc is 5 with respect to 100 parts by weight of at least one selected from aliphatic alcohols, fatty acids and glycerin fatty acid esters.
The amount is preferably 0 to 200 parts by weight, particularly preferably 70 to 150 parts by weight. When it is less than 50 parts by weight, the effect of re-emulsifying the pellet is small. If it exceeds 200 parts by weight, the concentration of the obtained emulsion will be low.

The aqueous dispersion for sustained-release preparation coating can be obtained by the following method. A predetermined amount of anionic surfactant or nonionic surfactant is added to at least one selected from the aliphatic alcohol, fatty acid and glycerin fatty acid ester, and the mixture is heated to a temperature above the melting point of the additive to obtain a molten mixture. To do. Water and talc are added to this molten mixture and cooled to room temperature with stirring to obtain an emulsion. The obtained emulsion is diluted with water, and the cellulosic polymer is dispersed in this diluted aqueous solution to prepare an aqueous dispersion for sustained-release preparation coating. Incidentally, an emulsion may be added to an aqueous solution in which a cellulose-based polymer is dispersed to form an aqueous dispersion for sustained-release preparation coating.

The coating treatment is completed by spraying an aqueous dispersion for coating on a drug such as granules by a coating device and then drying the liquid to form a film. A pharmaceutically acceptable drug or additive such as a plasticizer, a colorant, a pigment or an anti-adhesive agent may be added to the dispersion liquid. Examples of the plasticizer include triethyl citrate and triacetin. These may be used alone or in combination. Examples of the coating device include a fluidized bed coating device, a pan coating device, and a ventilated rotary drum coating device. After spraying an aqueous dispersion for coating on a drug with these devices and then blowing in hot air, the water in the liquid is diffused to obtain a film for coating granules and the like.

[0018]

INDUSTRIAL APPLICABILITY The aqueous dispersion for coating a sustained-release preparation of the present invention can impart excellent sustained-release properties only by coating a small amount on granules or the like.

[0019]

EXAMPLES Examples of the present invention will be described in detail below.

Example 1 100 parts by weight of cetyl alcohol, 10 parts by weight of sodium lauryl sulfate, 10 parts by weight of polysorbate 80, 100 parts by weight of talc and 20 parts by weight of water were mixed and then heated to 80 ° C. to obtain a molten mixture. While gently stirring with a stirrer, the mixture was allowed to cool to 40 ° C. at room temperature and solidified. The obtained solid is dome gran DG-L1 type (screen: 0.8 m
m Fuji Paudal) and extruded into pellets.

The pellets (57.3 g) were added to water (2622 g) and gently stirred to re-emulsify the mixture, and then triethyl citrate (72 g) was added. Ethyl cellulose (N-1
0-F: manufactured by Shin-Etsu Chemical Co., Ltd., average particle size 6 μm)
180 g and 30.1 g talc are dispersed in this liquid,
This was an aqueous dispersion for coating.

This aqueous dispersion for coating was sprayed onto 1.5 kg of malm granules containing 10% of propantheline bromide. For the spraying process, a fluidized bed coating device (Flow Coater FLO-1) manufactured by Freund Sangyo Co., Ltd. is used.
Intake temperature 80 ℃, exhaust temperature 38 ℃, spray speed 60g
Per minute. After the spray treatment, the granules were dried at 80 ° C. for 60 minutes by a blow dryer. A sustained-release preparation having a coating amount of 4, 8, 10, 12% by weight with respect to the granules was obtained.

The coating film of the granules thus obtained was broken by gastric juice, and the amount of propantheline bromide inside the film was eluted according to the Japanese Pharmacopoeia 12th revised method using a dissolution tester. I investigated by law. Specifically, the first liquid (artificial gastric juice) having a pH of 1.2 was rotated at a speed of 100 times per minute while maintaining the temperature at 37 ° C., and the coated granules were immersed in the first liquid. Immersion time 15,
The amount of propatherin bromide eluted outside from the granules at 30, 60, 90 and 120 minutes was measured. The results are shown in Table 1.

Comparative Example 1 72 g of triethyl citrate was added to 2319 g of water and gently stirred, and then ethyl cellulose N-10-F180 was used.
g and 54 g of talc were dispersed in this solution to obtain an aqueous dispersion for coating.

The aqueous dispersion for coating was coated to 10% by weight of Malmö granules, and the amount of propatherin bromide eluted from the coated granules to the outside was determined according to the Japanese Pharmacopoeia 12th revised method. It was measured by the basket method. The results are shown in Table 1.

[0026]

[Table 1]

In the coated granules of Example 1, the elution rate of propatherin bromide decreased as the coating amount of ethyl cellulose increased. Since the coated granules of Comparative Example 1 were coated with the aqueous dispersion containing no cetyl alcohol, the elution rate of propatherin bromide was higher than that of the coated granules of Example 1.

Example 2 100 parts by weight of cetyl alcohol, 10 parts by weight of sodium lauryl sulfate, 10 parts by weight of polysorbate 80, 100 parts by weight of talc and 200 parts by weight of water were mixed and then heated to 80 ° C. to obtain a molten mixture. The mixture was stirred with a homomixer and cooled to room temperature.

104 g of the obtained emulsion was added to water 297.
After being added to 7 g and gently stirred, 67 g of triethyl citrate was added. Add to this emulsion hydroxypropylmethylcellulose acetate succinate (A
S-MF: Shin-Etsu Chemical Co., Ltd., average particle size 4μ
m) 240 g and talc 47.2 g were dispersed to obtain an aqueous dispersion for coating.

The above aqueous dispersion for coating was applied to 1.5 kg of columnar granules containing 60% of pancreatin.
Was coated in the same manner as in. After the coating treatment, the granules were dried at 80 ° C. for 60 minutes with a blow dryer. The coating amount for granules is 10, 12,
Sustained-release preparations of 14, 16 and 18% by weight were obtained.

The coated granules were immersed in the first liquid (artificial gastric juice) having a pH of 1.2 for 2 hours, and the amount of pancreatin eluted outside was measured by the basket method according to the 12th revised method of the Japanese Pharmacopoeia. The results are shown in Table 2.

Comparative Example 2 67 g of triethyl citrate was added to 3081 g of water and gently stirred, and then 240 g of hydroxypropylmethyl cellulose acetate succinate was dispersed in this solution.
This was an aqueous dispersion for coating.

Pancreatin columnar granules were coated with the above aqueous dispersion for coating in the same manner as in Example 1, and the coating amounts were 10% by weight, 12% by weight and 14% by weight.
%, 16% and 18% by weight of sustained release preparation were obtained.

The amount of pancreatin eluted from the coated granules to the outside was measured by the basket method according to the 12th revised method of the Japanese Pharmacopoeia. The results are shown in Table 2.

[0035]

[Table 2]

The coated granules of Example 2 had a smaller amount of pancreatin eluted outside than Comparative Example 2.
It is considered that the function of filling the pinhole portion of the film layer where cetyl alcohol is formed and the fact that cetyl alcohol itself is hydrophobic suppresses the permeation of the drug solution inside from the film.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-2-11526 (JP, A) JP-A-2-178222 (JP, A) JP-A-6-157313 (JP, A) JP-A-7- 10756 (JP, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 47/38 A61K 9/28 A61K 9/52

Claims (4)

(57) [Claims] 1. An aliphatic alcohol having 10 or more carbon atoms,
And at least one kind of 100 parts by weight selected from fatty acids and glycerol fatty acid ester, 10 to 30 parts by weight of anionic surfactant, and 30 parts by weight or less of a nonionic surfactant, and water 10-30 parts by weight By heating and melting
An aqueous dispersion for sustained-release preparation coating, characterized in that a cellulose-based polymer is dispersed in an aqueous emulsion obtained by adding a solid obtained by cooling and cooling at room temperature . 2. The weight ratio of at least one selected from the aliphatic alcohols, fatty acids and glycerin fatty acid esters to the cellulosic polymer is 5 to 50 parts by weight: 100 parts by weight. 1. An aqueous dispersion for coating a sustained-release preparation according to 1. 3. The cellulose-based polymer is at least one selected from ethyl cellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, cellulose acetate trimellitate, and carboxymethylethylcellulose, and the average particle thereof. The diameter is 10 μm or less, and the aqueous dispersion for sustained-release preparation coating according to claim 1 or 2. 4. At least one selected from the aliphatic alcohols, fatty acids and glycerin fatty acid esters is lauryl alcohol, cetyl alcohol, stearyl alcohol, lauric acid, myristic acid, palmitic acid,
At least one selected from stearic acid and glycerin monostearate.
3. An aqueous dispersion for coating a sustained-release preparation according to any one of 3 above.