JPH09100226A - Production of sustained release enteric coating preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sustained release enteric coating preparation having excellent appearance, strength and safety. SOLUTION: An enteric substance having an average particle diameter of <=10μm and pH or 5-8 (e.g. hydroxypropyl methyl cellulose acetate succinate) is applied to the surface of a formed solid material containing a drug-active substance while spraying a wax in melted state. The spraying of wax melt is carried out by a conventional rotary granulator while fluidizihng the formed solid material and the addition of the fine powder of the enteric substance is performed by manual operation or with a powder-supplying and scattering apparatus. There is no particular restriction on the mixing weight ratio of the meltable substance and the enteric substance. It has high rate of dissolution of the drug component in the 2nd liquid of the Japanese Pharmacopoeia. The sustained release effect can be imparted in addition to the enteric property without applying an additional coating layer simply by decreasing the weight of the enteric substance relative to the meltable substance.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an enteric coated / sustained release coating preparation.

[0002]

2. Description of the Related Art The method of coating a preparation with an enteric substance is a method of dissolving the enteric substance in an organic solvent, spray-coating it on the surface of a granular material, and then drying it. Further, fine particles of the enteric substance are dispersed in water with a plasticizer. The method using the thing is widely used. However, these methods have environmental problems and manufacturing problems. As a method that does not use a solvent such as an organic solvent or water, JP-A-4-290817 discloses a fusible substance while rolling a core substance containing a pharmaceutical compound under a temperature condition in which the fusible substance melts. There is disclosed a manufacturing method in which a mixed powder of an enteric substance and is mixed with the core substance to form an enteric substance around the core substance using the molten substance as a binder. However, as described in this publication, this method is not always satisfactory because there are restrictions on the weight mixing ratio of the meltable substance and the enteric substance used.

[0003]

The present invention has been made in view of the above circumstances, and is not limited to the weight mixing ratio of the meltable substance and the enteric substance, and it can be used in the second liquid of the Japanese Pharmacopoeia. It is an object of the present invention to provide an enteric-coated / sustained-release preparation which has a fast drug elution and is capable of imparting a sustained-release effect in addition to the enteric-coating property.

[0004]

Means for Solving the Problems As a result of intensive studies to achieve the above object, the present inventors have found that by adding fine powder of an enteric substance while spraying the meltable substance in a molten state. The inventors have found that a good enteric coated / sustained release coating preparation can be obtained, and completed the present invention.

Next, the method of the present invention will be described in detail.
The method of melting and spraying waxes is not particularly limited, but the methods disclosed in JP-A-5-309314 and JP-A-7-24369 are preferably exemplified. In order to spray waxes in a molten state onto the surface of a solid molded article containing a pharmacologically active substance, it is preferable that the solid molded article be in a fluid state, and a production apparatus known per se, for example, a fluidized bed granulator. , A composite fluidized bed granulator, a stirring granulator, a tumbling granulator, a spheroidizing granulator, a sugar-coated bread, an aerated sugar-coated bread and the like. It is not necessary to maintain the solid molded article containing the pharmacologically active substance under the temperature condition in which the waxes are melted, and the temperature condition is not limited. For example, in order to lower the temperature of the solid molded article, the production used The equipment can be cooled, and conversely, the solid molded article can be heated.

Examples of the method for adding the fine powder of the enteric substance include a manual addition method and a method using a powder supply / dispersion device. For example, as the powder supplying / dispersing means, there are a method of mixing and conveying powder and compressed air and then dispersing together with the compressed air, and a method of conveying powder by a rotary displacement type screw pump and gradually sprinkling it. Further, the order of adding the powder can be selected from a method of performing the spray of wax alternately and a method of performing the spray spray simultaneously. The fine powder of the enteric substance used preferably has an average particle diameter of 10 μm or less. The component constituting the solid molded product containing the pharmacologically active substance may be any one generally added as a pharmaceutical additive, such as an excipient, a binder, a disintegrating agent, a coating agent, a lubricant, an anti-agglomeration agent, Adsorbents, preservatives, wetting agents, antistatic agents, etc. are exemplified, and the form of the solid molded product is not particularly limited, and various forms such as fine particles, granules, tablets, pills, tablets and capsules Can be preferably used, and a method known per se can be selected as a method for producing these solid molded products.

The pharmacologically active substance contained is not particularly limited, and includes antipyretic and antiphlogistic agents such as indomethacin, ibuprofen, ketoprofen, acetaminophen, aspirin, and isopropylantipyrine, for example, diphenylpyraline hydrochloride, chlorpheniramine maleate, cimetidine, hydrochloric acid. Antihistamines such as isothipendyl, for example phenylephrine hydrochloride, procainamide hydrochloride, quinidine sulfate, cardiovascular agents such as isosorbide, for example sulpiride,
Metabilizers such as diazepam, valproic acid, lithium carbonate, antibiotics such as cephalexin and ampicillin, peptides such as insulin, vasopressin, interferon, interleukin-2, urokinase, or various growth factors such as human growth hormone or There are various drugs such as protein, theophylline, caffeine, carbetapentane citrate, and phenylpropanolamine hydrochloride.

The waxes used in the present invention are not particularly limited as long as they achieve the object of the present invention. For example, higher alcohols such as cetyl alcohol and stearyl alcohol, behenic acid, myristic acid, palmitic acid,
Higher fatty acids such as stearic acid, monoglycerides, diglycerides, triglycerides and polyglycerides which are glycerin esters thereof, hydrogenated soybean oil, hydrogenated castor oil,
Hardened beef tallow, hydrogenated rapeseed oil, oils and fats such as mokuro, whale wax,
Examples include waxes such as carnauba wax, candelilla wax, beeswax and shellac, higher hydrocarbons such as paraffin and ceresin, and polyethylene glycol. These waxes may be used alone or in combination of two or more. Is also possible.

The enteric substance is not particularly limited as long as it is a substance which is substantially insoluble in water having a pH of 4 or less but is soluble in water having a pH of 5 to pH 8, and which achieves the object of the present invention. Examples thereof include methacrylic acid copolymer L, cellulose acetate phthalate, carboxymethylethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, and hydroxypropylmethyl cellulose phthalate. These enteric substances may be used alone or in combination of two or more. It is also possible to use together. Further, within the scope of achieving the object of the present invention,
It is also possible to previously mix and use those generally added as pharmaceutical additives as described above. Also,
It is also possible to carry out pharmaceutical preparations such as coating the surface of the pharmaceutical preparation subjected to the method of the present invention with other pharmaceutical additives.

[0010]

The method of the present invention forms a coating layer by adding fine powder of an enteric substance while spraying waxes in a molten state on the surface of a solid molded article containing a pharmacologically active substance. The mixing ratio by weight of the meltable substance and the enteric substance used is not limited. Further, in the case of imparting a sustained-release effect in addition to the enteric property, it is possible by simply reducing the weight of the enteric substance as compared with the meltable substance without providing another coating layer. Therefore, the method of the present invention makes it possible to provide an enteric-coated / sustained-release preparation.

[0011]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto. (Examples 1 and 2) Manufacturing method: 2000 g of non-pareil 101 (registered trademark: manufactured by Freund Sangyo Co., Ltd.) having 24-32 mesh,
Charged in a tumbling granulator and used as a binder, an alcohol / water solution of 10% polyvinylpyrrolidone K-30 (alcohol:
While spraying 600 g of purified water = 8: 2 weight ratio,
Phenylpropanolamine hydrochloride (80
0 g) of the powder was gradually sprinkled and then dried to prepare a solid molded product. 2000 g of this solid molded product was placed in a centrifugal fluidizer (CF-360, manufactured by Freund Sangyo Co., Ltd.),
While melting glycerin distearate and spraying it using an Atmax CN-200 type nozzle manufactured by Seito Kyoritsu Shokai, a fine powder of hydroxypropylmethylcellulose acetate succinate having an average particle size of 10 μm or less (Shin-Etsu AQOAT AS-MF ( Shin-Etsu Chemical Co., Ltd.))
Was added to give a coating.

[0012]

[Table 1] (Evaluation example): Tables 2 and 3 show the results of dissolution tests of the prepared samples in the 12th revised Japanese Pharmacopoeia 1st liquid and the 2nd liquid.
Shown in

[0013]

[Table 2]

The preparation obtained in Example 1 has almost no drug elution even after 60 minutes in the first liquid and has resistance to the first liquid, but in the second liquid, almost no drug is eluted in 1 hour. From the fact that it is released, it is understood that it has the performance as an enteric coated preparation.

[0015]

[Table 3]

The preparation obtained in Example 2 has a resistance to the first liquid, which hardly dissolves the drug even after 1 hour in the first liquid, but gradually releases the drug in the second liquid. Therefore, it can be seen that it has the performance as an enteric coated sustained-release preparation.

Claims (2)

[Claims] 1. An enteric-coated / sustained-release coating preparation, characterized in that a fine powder of an enteric substance is added while waxes are sprayed in a molten state onto the surface of a solid molded article containing a pharmacologically active substance. Manufacturing method. 2. The fine powder of the enteric substance has an average particle diameter of 10 μm.
The method according to claim 1, which is not more than m.