JP2003183181A - Pharmaceutical preparation containing sublimable component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a solid pharmaceutical preparation containing a sublimable component, especially a pharmaceutical preparation containing ibuprofen, which is stable with time because the sublimation of the sublimable component is suppressed, is easy to take with less bitterness, and can be manufactured at a lower cost. <P>SOLUTION: The preparation containing the sublimable component is coated with a film coating solution containing propylene glycol, glycerol or copolyvidone and an aqueous polymeric base agent. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sublimable ingredient-containing preparation. More particularly, the present invention relates to formulations containing ibuprofen with suppressed sublimation.

[0002]

2. Description of the Related Art Conventionally, film coating has been carried out for the purpose of improving the appearance and ingestability of tablets. As a base for this film coating, a water-soluble polymer base, which has the advantage that an organic solvent need not be used, is widely used. However, when the drug component has sublimability, it is difficult to suppress sublimation due to the coating layer being porous depending on such a coating method.For example, when stored in a bottle, the phenomenon that the inner surface of the bottle becomes cloudy is observed the next day. To be done. For this reason, countermeasures can be taken by using a base other than the water-soluble polymer base, but in this case it is necessary to use an organic solvent, and in order to suppress sublimation, thicken the coating layer or use a multi-layer coating. Therefore, there is a problem that the manufacturing method becomes extremely complicated.

Examples of the sublimable drug component include ibuprofen, that is, 2- (4-isobutylphenyl) propionic acid. This ibuprofen has anti-inflammatory, analgesic, antipyretic and other effects and is widely used as a medicine. However, since ibuprofen has an irritating bitterness, it is desired to suppress the bitterness from the viewpoint of improving the taking property. Regarding such suppression, JP-A-63-101321 discloses a method of adding aluminum hydroxide.
No. 2 discloses a method for producing fine granules or powder by kneading ibuprofen with a gastric soluble polymer compound. A method is also known in which the ibuprofen-containing granular material is coated with a water-insoluble polymer compound and the surface thereof is further coated with sugar alcohol or sugar to suppress bitterness. However, since the melting point of ibuprofen is as low as 75 to 77 ° C. and it has sublimability as described above, the formulation as described above has a less bitterness masking effect, and also causes wetting, solidification, and discoloration, resulting in a bottle-like appearance. There is a problem in that the container sealed at 1 becomes cloudy and the commercial value is reduced. On the other hand, when a water-soluble polymer base is used as a base for film coating, the film coating liquid contains a water-soluble polymer base, a concealing agent, a lubricant, as well as flexibility to give strength to the film layer. And a plasticizer is added to improve the spreadability and appearance of the formulation. As such a plasticizer, Macrogol 6000 is excellent and widely used. However, uncoated tablets containing a low melting point substance such as ibuprofen and Macrogol 600 in the film layer
There is a problem that 0 reacts with the interface to reduce the content, the tablet surface is colored to cause a problem with stability over time, and it is difficult to suppress sublimation. As described above, various problems remain when formulating a preparation containing ibuprofen.

[0004]

Therefore, an object of the present invention is to suppress sublimation of a sublimable component and to have excellent stability over time, and to reduce bitterness and the like, which makes it easy to take.
Further, it is an object of the present invention to provide a solid preparation containing a sublimable component which has a low manufacturing cost, particularly a solid preparation containing ibuprofen.

[0005]

[Means for Solving the Problems] In order to solve the above problems, the inventors of the present invention have conducted extensive studies as to a plasticizer for film coating and a substitute for Macrogol 6000. As a result, unexpectedly, propylene was obtained. By adding glycol, glycerin or copolyvidone, it was found that the sublimation of ibuprofen from the film-coated tablet can be suppressed in addition to the function as the original plasticizer.
As a result of further studies, the present invention has been completed. That is, the present invention provides (1) a sublimable ingredient-containing preparation coated with a film coating solution containing propylene glycol, glycerin or copolyvidone and a water-soluble polymer base; (2) blending of propylene glycol, glycerin or copolyvidone. The formulation according to (1) above, wherein the amount is 1 to 50 parts by weight relative to 100 parts by weight of the water-soluble polymer base; (3) The formulation according to (1) above, wherein the sublimable component is ibuprofen; (4) The present invention relates to a film coating liquid for sublimable component-containing preparations, which contains propylene glycol, glycerin or copolyvidone and a water-soluble polymer base.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The sublimable component used in the present invention is not particularly limited as long as it is a compound that has sublimability and is used in a solid preparation, and it may be an active ingredient or an additive such as a fragrance. Good. Examples of the sublimable component include ibuprofen, 1-menthol, anhydrous caffeine, cyclanderate, guaifenesin and the like. Above all,
Ibuprofen is preferably used. The water-soluble polymer base used in the present invention is not particularly limited as long as it is a water-soluble polymer used as a base for film coating of a solid agent. Examples of the water-soluble polymer base include hydroxypropylcellulose, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylmethylcellulose 2910, methylserose and the like.

Examples of the dosage form of the pharmaceutical preparation of the present invention include, but are not limited to, tablets, capsules, powders, granules, fine granules and pills. According to the dosage form, the preparation of the present invention contains propylene as a plasticizer in powder, granules, fine granules or uncoated tablets containing the sublimable components, drug components, and components generally used in the production of solid preparations. It can be produced by film-coating with a commercially available film-coating device according to a conventional method using a coating liquid containing glycol, glycerin or copolyvidone and a water-soluble polymer base. The preparation of the preparation of the present invention is carried out according to the dosage form, according to the granulation handbook (edited by Japan Powder Industrial Technology Association, Ohmsha Co., Ltd.), prescription design of orally administered preparation (edited by Mitsuhashi Hashida, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University) It may be carried out by using a general method described in publications such as Housekihosha), powder compression molding technology (powder engineering / formulation and particle design group, edited by Nikkan Kogyo Shimbun). For example, the above granules and fine granules may be produced by a general stirring granulation method, fluidized bed granulation method, dry granulation method, or the like. Further, the plain tablet can be produced by a general wet granule compression method, a dry granule compression method, a direct powder compression method, or the like.

Ingredients commonly used in the production of solid preparations include excipients, binders, disintegrants and lubricants. As the excipient and the binder, crystalline cellulose, powdered cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, corn starch, dextrin, pregelatinized starch, partially pregelatinized. Starch, hydroxypropyl starch, sodium carboxymethyl starch, cyclodextrin, polyvinylpyrrolidone, aminoalkylmethacrylate copolymer E, methacrylic acid copolymer L, aminoalkylmethacrylate copolymer RS, methacrylic acid copolymer S, carboxyvinyl polymer, polyvinyl alcohol, Polyvinyl acetal diethylamine acetate, , Trehalose, lactose, mannitol, sorbitol, xylitol, maltitol, erythritol, powdered hydrogenated maltose starch syrup, and the like.

Examples of the disintegrant include croscarmellose sodium, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, sucrose fatty acid ester and the like.

Propylene glycol and glycerin used in the film coating liquid are colorless and clear viscous liquids which are easily miscible with water and are conventionally used as plasticizers, as listed in the regulations of medicines. Copolyvidone is listed in the drug regulations and 1-vinyl-2
A copolymer of pyrrolidone and vinyl acetate, the weight ratio of which is 3: 2. It is a white to yellowish white powder, and it is very soluble in ethanol and easily soluble in water. Copolyvidone is commercially available [Plasdone S-6
30 (trade name) ISP, Kollidon VA64 (trade name)
BASF]. Although copolyvidone is widely used as a binder, it also functions as a plasticizer. The amount of propylene glycol added is 1 to 50 parts by weight, preferably 5 to 30 parts by weight, and more preferably 15 to 25 parts by weight, based on 100 parts by weight of the water-soluble polymer base material. The amount of glycerin or copolyvidone added is also the same as that of propylene glycol. Two or more selected from propylene glycol, glycerin and copolyvidone may be used in combination. The film coating liquid may contain additives (e.g., an additive usually used in the film coating liquid) as needed.
Talc, pigment, precipitated calcium carbonate, calcium phosphate, calcium sulfate, titanium oxide, etc.) can be added. In addition, a scent and taste may be imparted to the preparation of the present invention by blending a flavoring agent, a fragrance, or a flavoring agent in order to improve the ingestability. Examples of flavoring agents or fragrances that can be used in the present invention include peppermint oil, eucalyptus oil, cinnamon oil, fennel oil, clove oil, orange oil, lemon oil, rose oil, fruit flavor, banana flavor, strawberry flavor. , Mint flavor, peppermint flavor, dl-menthol, 1-menthol and the like. Examples of the corrigent include sugar (eg, sucrose, trehalose, lactose, etc.),
Sugar alcohols (eg, mannitol, sorbitol, xylitol, maltitol, erythritol, etc.), high-potency sweeteners (eg, aspartame, stevia, saccharin, glycyrrhizin dipotassium, thaumatin, sucralose, acesulfame K, etc.), acidulants (eg, citric acid,
Malic acid, tartaric acid, ascorbic acid, etc.).

The thus-obtained preparation of the present invention can be administered in the same manner as a usual preparation for oral administration.

[0012]

EXAMPLES The present invention will now be described in detail with reference to Examples, Controls and Tests, but the present invention is not limited thereto.

Example 1 An ibuprofen-containing granulated powder and a mequitazine-containing granulated powder were produced, respectively. The granulated powder containing ibuprofen was 1125 g of ibuprofen, dihydrocodeine phosphate 60.
g, hesperidin 127.5 g, and lactose 1142.5 g,
Corn starch 375g, crystalline cellulose 325
g and croscarmellose sodium 150 g,
It was put in a fluidized bed granulator (FD-5S type fluidized bed granulator, manufactured by Powrex) and sprayed with 2000 g of a 6% aqueous solution of hydroxypropyl cellulose as a binder at a rate of 50 g / min. On the other hand, the granulated powder containing mequitazine contained 16 g of mequitazine, 19.2 g of trimethoquinol hydrochloride, 300 g of anhydrous caffeine, 156 g of hesperidin and 2068.
8 g, corn starch 700 g, crystalline cellulose 400 g, croscarmellose sodium (HPC-
L) 200 g was mixed and put in a fluidized bed granulator (FD-5S type fluidized bed granulator, manufactured by Paulec), and 2333 g of 6% aqueous solution of hydroxypropyl cellulose was used as a binder.
It was prepared by spraying at a rate of g / min. Table 1 shows the formulations of the granulated powders by the theoretical amount charged per 9 tablets. Power granules for both granules (Showa Kagaku Kikai, screen size 2
mmφ) to obtain a sized powder.

Next, sized powder 2740 containing ibuprofen
g, 2000 g of sized powder containing mequitazine, 110 g of croscarmellose sodium, 10 magnesium magnesium stearate
After adding g and performing rough mixing, the mixture was placed in a tumbler mixer (TM-60S type, manufactured by Showa Kagaku Kikai) and mixed at 10 rpm for 3 minutes. Tablets are collected by Collect 12 HUK (Kikusui Seisakusho, 3
0 pm) 8.5 mm φ R surface plain punches 270 per tablet
Tablets were obtained by tableting under the conditions of weight of mg and compression pressure of 1200 kg / punch. Table 2 shows the formulation of plain tablets by the theoretical amount charged per 9 tablets.

4050 g of the obtained uncoated tablets was applied to a film coating apparatus (Dowa Co., Ltd., DRC-manufactured by Paulec).
500 type), and using the film coating liquid having the formulation shown in Table 3, rotation speed 8 rpm, air supply temperature 70 ° C., air supply amount 4 m ³ / min, spray air amount 4000 Nl / h
The film-coated tablet was obtained by operating under the conditions of r and the film-coating liquid supply rate of 12 g / min. Table 3 shows the formulation of the film coating solution by the theoretical amount charged per 9 tablets.

[0016]

[Table 1]

[0017]

[Table 2]

[0018]

[Table 3]

Example 2 4860 g of tablets obtained by the same method as in Example 1 was applied to a film coating apparatus (manufactured by Paulec, DRC-500).
The mixture was placed in a mold) and coated with the coating liquid having the formulation shown in Table 4 under the same conditions as in Example 1 to obtain a film-coated tablet.

[0020]

[Table 4]

Example 3 972 g of tablets obtained by the same method as in Example 1 was used as a film coating apparatus (HCT-30, manufactured by Freund).
The coating solution having the formulation shown in Table 5 was used for coating under the same conditions as in Example 1 to obtain a film-coated tablet.

[0022]

[Table 5]

Control Example 1 4860 g of the tablets obtained by the same method as in Example 1 was placed in a film coating device (Dowa Kouba DRC-500 type, manufactured by Paulec Co.), and the coating solution having the formulation shown in Table 6 was used. Coating was performed under the same conditions as in Example 1 to obtain a film-coated tablet.

[0024]

[Table 6]

Control Example 2 4860 g of the tablet obtained by the same method as in Example 1 was placed in a film coating device (Dower Coater DRC-500 type manufactured by Paulec Co.) and the same coating solution as shown in Table 7 was used. The film was coated under the conditions to obtain a film-coated tablet.

[0026]

[Table 7]

Test Example 1 (Stability Test) Eighty tablets each of the film-coated tablets prepared in Example 1, Example 2, Example 3, Control Example 1 and Control Example 2 were each divided into bottles, and the bottles were tightly sealed at room temperature. , 40 ° C., 50 ° C., respectively, and taken out with time to measure the appearance change of the tablet as a color difference ΔE (manufactured by Suga Test Instruments Co., Ltd.). In addition, the surface of the bottle was observed and the sublimation state of ibuprofen was evaluated in the following 5 grades. (+++): Large cloudiness in the bottle (++): Large cloudiness (+): Cloudy (±): Slightly cloudy (-): No change

As a result, as shown in Tables 8 and 9,
The formulations produced in Examples 1, 2 and 3 were:
Compared with the preparations produced in Control Example 1 and Control Example 2, the appearance change was small under any storage conditions, and the sublimation of ibuprofen was also suppressed.

[0029]

[Table 8]

[0030]

[Table 9]

[0031]

As is apparent from the above, according to the present invention, the sublimation of the sublimable component is suppressed and the stability over time is excellent, and the bitterness and the like are reduced, and it is easy to take and the production cost is low. A solid preparation containing a sublimable component having a low content, particularly a solid preparation containing ibuprofen is provided.

   ─────────────────────────────────────────────────── ─── Continued front page    F-term (reference) 4C076 AA44 BB01 CC04 CC47 DD29                       DD38 DD50 DD60 DD67 DD69                       EE16 EE31 EE32 EE38 FF22                       FF27 FF36 FF52 FF63                 4C206 AA10 DA24 MA03 MA05 MA28                       MA29 MA30 MA55 MA72 NA03                       NA09 ZA07 ZA08 ZB11

Claims (4)

[Claims] 1. A sublimable component-containing preparation obtained by coating with a film coating solution containing propylene glycol, glycerin or copolyvidone and a water-soluble polymer base. 2. The preparation according to claim 1, wherein the blending amount of propylene glycol, glycerin or copolyvidone is 1 to 50 parts by weight based on 100 parts by weight of the water-soluble polymer base. 3. The preparation according to claim 1, wherein the sublimable component is ibuprofen. 4. A film coating liquid for a sublimable component-containing preparation, which contains propylene glycol, glycerin or copolyvidone and a water-soluble polymer base.