JP2000247870A - Solid pharmaceutical preparation suppressed in whisker deposition and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a solid pharmaceutical preparation such as in the form of tablets or granules coated with no coating agent, suppressed in the deposition of whiskers of sublimable medicament such as caffeine, and to provide a method for producing the above pharmaceutical preparation. SOLUTION: This solid pharmaceutical preparation is such one as to contain at least a sublimable medicament, be in the form of tablets or granules coated with no coating agent, and be formulated with a polyvinylpyrrolidone to suppress whisker deposition. The other objective method for producing such a solid pharmaceutical preparation comprises formulating a sublimable medicament with a polyvinylpyrrolidone followed by forming the resultant formulation into a solid form such as tablets or granules to effect suppressing whisker deposition; wherein the polyvinylpyrrolidone is pref. a straight-chain or crosslinked polymerized product of 1-vinyl-2-pyrrolidone, or a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate; the sublimable medicament is pref. at least one kind selected from caffeines, menthols, benzoic acid compounds, salicylic acid compounds, ethenzamide, and carbamazepine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention is advantageous in the field of food and medicine for the production of solid preparations containing a sublimable drug such as caffeine, menthol, benzoic acid, salicylic acid, etensamide, carbamazepine and the like. The present invention relates to a solid preparation such as a tablet or a granule not coated with a coating agent, which suppresses whisker precipitation caused by these sublimable agents, and a method for producing the same.

[0002]

2. Description of the Related Art In foods and medicines, caffeines, menthols, benzoic acids, salicylic acids, etensamide, carbamazepine, etc., which are incorporated in solid preparations not coated with a coating agent, generally have sublimation properties. Therefore, whiskers (whiskers) are often precipitated and grown on the surface of the preparation or around the storage container by sublimation. As a result, there are many inconveniences such as loss of change in drug content and uniformity of quality during storage and discomfort to the consumers who use the formulation in appearance, which impairs commercial value. Could not be stored stably for a long time. Further, in the case of granules, whiskers are aggregated to cause deterioration of fluidity, or the content uniformity of tablets produced from granules is inconvenient, which has caused problems such as the inability to formulate the claimed formulation. .

Hitherto, in order to suppress whisker precipitation of caffeine and the like in a solid preparation, for example, a method of coating the surface of the preparation with a sugar coating layer having a sufficient thickness, or a method of film coating with a coating agent containing a polymer. For example, Japanese Patent Application Laid-Open No. S61-129138 proposes a method of performing coating, for example, coating with a coating agent containing cyclodextrins.
As a method of blending the adsorbent, Japanese Patent Publication No. Sho 56-5
Japanese Patent No. 3525 discloses a method of coexisting caffeine-containing powders or granules with charcoal, silicic anhydride and / or montmorillonite without mixing, and blending caffeine (hydrate) with activated carbon or bentonite. [Yamada et al., Pharmaceutical Magazine, 96 (10) 1223-1227 (197)
9)], and a production method using a raw material powder having a large particle diameter, a low tableting pressure, and a small compression rate [Yuasa et al. , Pharmaceutical Sciences, 41 (3) 161-17
1 (1981)]. Further, Japanese Unexamined Patent Application Publication
JP-A-85214 proposes a method of blending an antacid.

[0004] However, such coating with a coating agent has the disadvantage that it takes a long time to manufacture and requires raw materials for the coating agent, resulting in an increase in cost. Furthermore, coatings that delay disintegration are disadvantageous for drugs where fast disintegration is desired. Further, the compounding of the medicinal component may affect the desired medicinal effect, which is inconvenient in versatility.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a solid preparation such as a tablet or granule which is not coated with a coating agent, whereby whisker precipitation of a sublimable drug such as caffeine can be effectively suppressed. An object of the present invention is to provide a solid preparation having a high commercial value that has solved the above-mentioned disadvantages and a method for producing the same.

[0006]

DISCLOSURE OF THE INVENTION The present inventors have developed a method for suppressing whisker precipitation of a solid preparation containing a sublimable drug such as caffeine, and more particularly, a method of preventing whisker precipitation in a solid preparation without coating. As a result of various studies on the method, it was found that when polyvinylpyrrolidone was added to the solid preparation, whisker precipitation was unexpectedly suppressed, and the present inventors completed further studies and completed the present invention.

That is, the present invention provides a solid preparation containing at least a sublimable drug and not coated with a coating agent, such as a tablet or a granule, in which the whisker precipitation obtained by blending polyvinylpyrrolidone is suppressed. A formulation,
Further, this solid preparation is filled in a transparent airtight container or PTP-packaged, and is a transparent airtight container-packed product in which fogging is prevented. As polyvinylpyrrolidones, 1-vinyl-2
It is preferably a linear or cross-linked polymer of pyrrolidone, or a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, the content of which is based on 100 parts by weight of the sublimable drug. It is preferably at least 10 parts by weight. Further, as the sublimable drug, one or more selected from caffeine, menthol, benzoic acid, salicylic acid, etensamide and carbamazepine are preferable.

The present invention also relates to a solid preparation containing at least a sublimable drug and not coated with a coating agent, such as a tablet or a granule, wherein at least the sublimable drug and polyvinylpyrrolidone are blended. Is formed into a solid preparation such as a tablet or a granule, which is a method for producing a solid preparation in which whisker precipitation is suppressed.

Hereinafter, the present invention will be described in detail. Examples of the polyvinylpyrrolidones to be added to the sublimable drug in the present invention include 1-vinyl-2-pyrrolidone linear polymer (Povidone, listed in the Japanese Pharmacopoeia) and 1-vinyl-2-pyrrolidone crosslinked polymer (additional drug) (Crospovidone), copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate (Copolyvidone, a drug excipient)
And the like.

Specific examples of the linear polymer of 1-vinyl-2-pyrrolidone include plasdone C-15, plasdone C-30, plasdone K-25 and plasdone K-29 /
32, Plasdone K-90, Plasdone K-90D, Plasdone K-90M (all manufactured by ASP Japan Co., Ltd.) and the like.

A specific example of a crosslinked polymer of 1-vinyl-2-pyrrolidone is polyplasdone INF-1.
0, polyplasdone XL-10, polyplasdone XL
(All manufactured by IS Japan Co., Ltd.). Since the crosslinked polymer itself has a function as a disintegrant, a rapid-acting solid preparation that requires a quick disintegration after oral administration is also possible.

Further, as a specific example of a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate, Plasdone S-630 (manufactured by ASP Japan Co., Ltd.) and the like can be mentioned.

These polyvinylpyrrolidones are all approved as pharmaceuticals and have no special medicinal properties. Therefore, unlike the case where medicinal ingredients such as antacids are compounded, desired ones are desired. It does not affect drug efficacy and does not impair versatility. Among these polyvinylpyrrolidones, a linear polymer or a crosslinked polymer of 1-vinyl-2-pyrrolidone is preferable from the viewpoint of the effect of suppressing whisker precipitation, and in particular, 1-vinyl-2 having a small particle diameter and a large specific surface area. A crosslinked polymer of pyrrolidone,
Specifically, polyplasdone INF-10 (manufactured by ISP Japan Ltd.) is suitable.

In the solid preparation of the present invention, when only the whisker precipitation of a sublimable drug such as caffeine is to be suppressed, the blending amount of polyvinylpyrrolidone (the total amount when two or more kinds are blended) is as follows. The amount is preferably 10 parts by weight or more based on 100 parts by weight of the sublimable drug. Depending on the content of the sublimable drug in the solid preparation, if the amount of the polyvinylpyrrolidone is less than 10 parts by weight, whisker precipitation due to the sublimable drug may not be sufficiently suppressed. Polyvinylpyrrolidone which functions as a disintegrant rather than a medicinal ingredient does not cause any problem even if it is blended in a large amount, but from the viewpoint of cost effectiveness, 10 to 1 part by weight per 100 parts by weight of the sublimable drug.
A blending amount of about 000 parts by weight is suitable.

On the other hand, the solid preparation of the present invention contains at least a sublimable drug as a medicinal ingredient. Examples of such sublimable agents include caffeine such as caffeine (monohydrate), anhydrous caffeine, caffeine citrate, and caffeine sodium benzoate, such as l-menthol, d-menthol, and dl-. Menthols such as menthol, for example, isoamyl benzoate, estradiol benzoate, ethyl benzoate, phenyl benzoate, propyl benzoate, benzyl benzoate, methyl benzoate, sodium benzoate, sodium benzoate, benzoic acids such as caffeine, for example, One or more of salicylic acids such as salicylic acid, aspirin, isobutyl salicylate, sodium salicylate, physostigmine salicylate, methyl salicylate, ethenzamide, carbamazepine and the like.

The solid preparation of the present invention can be applied to a wide range of drugs, quasi-drugs, foods, etc. containing sublimable drugs such as caffeine. Examples of the medicine include a cold medicine, an antipyretic / analgesic medicine, an antitussive expectorant, a cough medicine and the like.
For example, when applied to a cold remedy, the main drug may be, for example, acetaminophen, chlorpheniramine maleate, noscapine, dihydrocodine phosphate, dl-methylephedrine hydrochloride, tipepidine citrate, tipididine hibenzanate, odor Dextromethorphan hydrohydride, l-
Examples include sodium ascorbate, potassium guaiacolsulfonate, aspirin, kakkonto dried extract, licorice extract and the like.

When the solid preparation of the present invention is produced, a commonly used additive such as lactose, starch, crystalline cellulose or the like is used in an amount not to impair the suppression of whisker precipitation of sublimable drugs such as caffeine. Excipients such as talc, granulated sugar and the like; binders such as povidone, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose and pullulan; disintegrants such as carboxymethylcellulose calcium, cross-linked sodium carboxymethylcellulose and partially pregelatinized starch; For example, a lubricant such as magnesium stearate and the like, a coloring agent such as tar dye, caramel, red bean, titanium oxide and riboflavin, and a flavoring agent such as a sweetener and a flavor may be appropriately added to the preparation.

In the solid preparation of the present invention, the sublimable drug and polyvinylpyrrolidone may be allowed to coexist, and the two need not necessarily be mixed or mixed. When mixing both components, it can be carried out by a conventional method. Usually, a solid preparation such as an uncoated tablet or an uncoated granule of the present invention can be prepared by mixing the sublimable drug and polyvinylpyrrolidone and then granulating. In this case, if necessary, another main drug or the above-mentioned additives may be added at an appropriate stage. For example, the sublimable agent and the polyvinylpyrrolidone are mixed in a dry state and / or a wet state together with other base agents and additives, if necessary, and then into tablets or granules together with other base agents and additives, if necessary. On the other hand, only the sublimable drug may be mixed with other main drugs and additives, and then mixed with polyvinylpyrrolidone. Further, polyvinylpyrrolidones may be treated by a general method of preparation such as coating or granulation to the extent that the effect of suppressing whisker precipitation is not impaired. Further, needless to say, an embodiment in which a sublimable agent is mixed with a polyvinylpyrrolidone with another base agent and an additive, if necessary, and then treated with a coating agent is also one embodiment of the present invention. Further, the sublimable drug and the polyvinylpyrrolidone may be separated and, for example, individually tableted or granulated, or compounded as a known preparation such as a dry coated tablet and a laminated tablet.

The solid preparation containing a sublimable drug such as caffeine of the present invention has a great feature that coating with a coating agent is not required. Thus, the final coating forming step can be omitted in the production of the solid preparation, and the production cost can be reduced.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION When the preparation of the present invention is filled in a glass bottle transparent airtight container or a PTP package, the effect of the present invention can be sufficiently exhibited since the container is not clouded by whisker precipitation. A transparent airtight packaged product in which the solid preparation of the present invention is filled in a transparent airtight container and fogging is prevented is also an object of the present invention.

The preparation of the present invention in which a polyvinylpyrrolidone is blended with the sublimable agent is stable even without being coated with a coating agent, and whisker precipitation caused by the sublimable agent is suppressed during storage, so that the temporal change in quality is suppressed. Very few. In this way, the suppression of whisker precipitation caused by the sublimable drug is due to the fact that polyvinylpyrrolidones in the same container as the sublimable drug compress fine particles to form pores formed in the tablet. It is presumed that the diameter becomes small, and the amount of the sublimable drug sorbed by capillary condensation becomes extremely large.

[0022]

EXAMPLES Next, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to these examples.

Example 1 2 g of 1-menthol as a sublimable agent and 0.3 g of polyplasdone INF-10 (Cross Popidone, manufactured by IS Japan Co., Ltd.) as polyvinylpyrrolidones
(15 parts by weight with respect to 100 parts by weight of the sublimable drug) and 6 g of lactose as an excipient were placed in a plastic bag and mixed for 5 minutes.
400 mg is weighed and put into a mold having a cross section of 1 cm ² ,
Universal Tensile Compression Tester (Minebea Co., Ltd., TCM-50
00C), molding pressure 100 MPa, compression speed 50
It was compression molded at mm / min. The obtained compression-molded product was filled with tablets of a number corresponding to a drug content of 10 mg / ml in the container in a volume of 3 mg / ml.
The mixture was placed in a 0 ml glass container, stored at room temperature for 28 days, and the state of whisker precipitation was observed by an optical microscope. As a result, no whisker was observed.

Comparative Example 1 A tablet obtained by compression-molding in the same manner as in Example 1 except that the polyplasdone INF-10 was not blended was stored in the same manner as in Example 1. As a result, several whiskers of 2 to 7 mm were deposited. It was recognized that it was.

Example 2 A tablet was compression-molded in the same manner as in Example 1 except that the amount of polyplasdone INF-10 was changed to 8 g (400 parts by weight with respect to 100 parts by weight of the sublimable drug). When the tablets were stored at room temperature or at 40 ° C., no whisker deposition was observed at room temperature or at 40 ° C.

Example 3 Except for using microcrystalline cellulose (Avicel PH301) in place of lactose as an excipient, a tablet obtained by compression-molding in the same manner as in Example 1 was stored in the same manner as in Example 1. No precipitation was observed.

Example 4 A tablet obtained by compression-molding in the same manner as in Example 2 except that dry aluminum hydroxide gel was used instead of lactose as an excipient was stored in the same manner as in Example 2. No whisker deposition was observed at room temperature or at 40 ° C.

Example 5 Except for using magnesium aluminate metasilicate instead of lactose as an excipient, a tablet pressed in the same manner as in Example 2 was stored in the same manner as in Example 2, and the storage temperature was reduced. No whisker deposition was observed at room temperature or at 40 ° C.

Example 6 Polyplasdone K-in place of polyplasdone INF-10
90 (Popidone, manufactured by ASP Japan Co., Ltd.)
0.3 g (typical molecular weight 1.3 million) (sublimable drug 10
Example 1 except that 0 parts by weight) was used.
When the tablet obtained by compression-molding was stored in the same manner as in Example 1, no whisker was observed.

Example 7 Polyplasdone S-in place of polyplasdone INF-10
630 (manufactured by ISP Japan Co., Ltd., copolyvidone, typical molecular weight: 58,000), except that 0.3 g (15 parts by weight per 100 parts by weight of the sublimable drug) was used. Example 1 molded tablets
As a result, no whiskers were precipitated.

[0031]

According to the solid preparation of the present invention, whisker precipitation caused by a sublimable drug can be efficiently suppressed by blending polyvinylpyrrolidone which is approved for use in medicine. Since the polyvinylpyrrolidones do not have a special medicinal effect, without affecting the medicinal effect desired for the solid preparation, various pharmaceuticals,
It has versatility such as being applicable to quasi-drugs and foods. Further, since coating with a coating agent is not required, there is an effect that the cost is low and the disintegration of tablets and granules can be accelerated. Furthermore, the solid preparation of the present invention does not show contamination (especially clouding) of the storage container due to whisker precipitation of sublimable drugs such as caffeine even when stored in an airtight transparent container or the like for a long time, and the essence immediately after production is This has the effect of being stably maintained for a long time. In addition, the solid preparation of the present invention prevents whisker precipitation of the sublimable drug, particularly when a crosslinked polymer of 1-vinyl-2-pyrrolidone is blended, and does not require the addition of a further disintegrant / binder. In addition, it is also possible to provide a preparation that can be easily formulated.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/32 A61K 47/32 J (72) Inventor: Tsutomu Morinaga 41-12 Nihonbashi Hakozakicho, Chuo-ku, Tokyo Nihonbashi Daini Bldg. 2nd FP Japan Stock Company In-house F-term (reference) 4C076 AA31 AA36 BB01 CC01 DD30 DD67 EE07 EE16 EE31 EE45 EE48 FF06 FF36 FF63 GG12 GG14 4C086 AA01 AA02 BC32 CB07 DA17 MA01 MA02 MA05 MA03 MA52 MA52 MA52 ZA08 4C206 AA01 AA02 CA03 DA19 GA07 MA01 MA02 MA05 MA17 MA55 MA61 MA72 NA03 NA11 NA20 ZA06 ZA07 ZA08

Claims (6)

[Claims] 1. A solid preparation containing at least a sublimable drug and not coated with a coating agent, such as a tablet or a granule, containing a polyvinylpyrrolidone and suppressing whisker precipitation. 2. The whisker according to claim 1, wherein the polyvinylpyrrolidone is a linear or crosslinked polymer of 1-vinyl-2-pyrrolidone or a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate. A solid preparation with reduced precipitation. 3. The solid preparation according to claim 1, wherein the content of the polyvinylpyrrolidone is at least 10 parts by weight based on 100 parts by weight of the sublimable drug. 4. The whisker according to claim 1, wherein the sublimable drug is one or more selected from caffeines, menthols, benzoic acids, salicylic acids, etensamide and carbamazepine. Suppressed solid preparation. 5. A transparent airtight packaged product in which the solid preparation according to claim 1 is filled in a transparent airtight container or PTP-packaged, and the container is prevented from fogging. 6. In a solid preparation such as a tablet or granule containing at least a sublimable drug and not coated with a coating agent, at least the sublimable drug and polyvinylpyrrolidones are blended, and the blend is converted into a tablet or granule. A method for producing a solid preparation in which whisker precipitation is suppressed, characterized by molding into a solid preparation such as an agent.