JP4999297B2 - High content terbinafine hydrochloride small tablets - Google Patents

Description

The present invention relates to a terbinafine hydrochloride tablet used as an antifungal agent, and more particularly to a terbinafine hydrochloride small tablet having a high content of terbinafine hydrochloride and having excellent dissolution properties.

Terbinafine hydrochloride is marketed as an allylamine antifungal agent and is effective against dermatophytes by oral and topical administration. It also has high affinity for keratin and strong bactericidal properties for treating onychomycosis. Shows a high effect. Tablets are already on the market for oral administration.
Various studies have been made on pharmaceutical compositions for oral administration of terbinafine hydrochloride. For example, Patent Document 1 uses both normal hydroxypropylcellulose and low-substituted hydroxypropylcellulose as insoluble drugs such as terbinafine hydrochloride. A pharmaceutical composition for oral administration was described. A tablet composition containing 28% terbinafine hydrochloride with excellent dissolution characteristics is described. Patent Document 2 describes an external preparation that does not have a painful or pruritic sensation including terbinafine or a salt thereof and a local anesthetic such as lidocaine. Patent Document 3 describes a formulation such as a coated tablet containing 10 to 80% terbinafine and an additive such as microcrystalline cellulose.
Patent Document 4 describes a coated granule of terbinafine hydrochloride. Patent Document 5 describes a tablet that exhibits rapid disintegration and masks taste, including disintegrants such as maize starch and crosslinked polyvinylpyrrolidone, and a buffering component.

JP 2000-86503 A JP 2003-55205 A JP 2005-503399 Gazette JP 2005-503366 A Special table 2003-520252 gazette

The tablet of terbinafine hydrochloride currently on the market is a tablet with a dose of about 140 mg, a weight of 210 mg, a diameter of 9 mm, and a slightly large tablet. Therefore, patients who are difficult to take large tablets such as elderly people, patients who have to take a large number of tablets, and the like are required to have smaller and easier-to-handle tablets. Generally, the size is 7 to 8 mm. However, with the above prior art, the drug substance content in the tablet exceeds 80% when the drug substance content is kept small while keeping the content of the drug substance unchanged, so that a tablet having an appropriate release property can be obtained. It was difficult. Therefore, development of a small tablet having an appropriate release property and easy to handle is desired.

As a result of various studies, the present inventors can solve the above-mentioned problems by making tablets containing moderately low-substituted hydroxypropyl cellulose (hereinafter also referred to as L-HPC) and lactose , The present invention was also completed by finding that the storage stability was also good.

That is, the present invention
(1) for the entire plain tablet, low-substituted hydroxypropyl cellulose 5 to 10 wt%, lactose 20% by weight, 1 to 5% by weight of binder and 75 to 90 wt% including have a terbinafine hydrochloride A high content terbinafine hydrochloride small tablet having a tablet diameter of 7 to 8.2 mm ,
(2) carboxymethyl starch sodium, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, agar, above you containing at least one selected from the group consisting of calcium hydrogen phosphate and partially pregelatinized starch anhydride (1) Terbinafine hydrochloride small tablets as described in
(3) The high-content terbinafine hydrochloride small tablet according to the above (1) or (2) , wherein the tablet is a film-coated tablet,
(4) When the uncoated tablet is used, the amount of the low-substituted hydroxypropylcellulose is 5 to 10% by mass, lactose is 1 to 20% by mass, and terbinafine hydrochloride is 75 to 90 % by mass with respect to the whole uncoated tablet . The composition is wet granulated using an ethanol solution or an aqueous ethanol solution containing a binder in an amount of 1 to 5% by mass based on the whole uncoated tablet, and the resulting granule is tableted. A method for producing a high-content terbinafine hydrochloride small tablet,
It is about.

According to the present invention, in the case of a tablet having a terbinafine hydrochloride content of about 140 mg in one tablet, the total weight of the uncoated tablets can be 170 mg, the tablet diameter can be 8 mm or less, and a small terbinafine hydrochloride tablet that is easy to swallow is obtained. In addition, there is no decrease in tablet hardness due to the influence of humidity and temperature during storage, there is no problem in stability, etc., and the initial dissolution is completely inferior to currently marketed products. A good tablet can be obtained.

The high-content terbinafine hydrochloride small tablet of the present invention contains 75% (mass) of terbinafine hydrochloride or more (hereinafter the same unless otherwise specified) and low-substituted hydroxypropylcellulose with respect to the uncoated tablet, and if necessary, for pharmaceutical use Various additives acceptable as additives can be included. The tablet contains 75% (mass) or more of terbinafine hydrochloride and low-substituted hydroxypropylcellulose, and if necessary, a tablet containing various additives acceptable as pharmaceutical additives is tableted by a conventional method. As a result, an uncoated tablet can be obtained. Various additives may be mixed from the beginning, or may be appropriately added in the preparation process. The high-content terbinafine hydrochloride small tablet of the present invention may remain as an uncoated tablet, but it is preferable to coat the uncoated tablet.

The content of terbinafine hydrochloride in the tablet of the present invention is not particularly limited as long as it is 75% or more with respect to the uncoated tablet, but is usually preferably about 75 to 90%, more preferably 80 to 85%. The content of L-HPC in the tablet is not particularly limited as long as the object of the present invention is achieved, but it may be usually 3% or more, preferably 4% or more, and more preferably 5% or more. The upper limit can be up to 25%, but is usually 20% or less, preferably 16% or less, more preferably about 10% or less. The balance is an additive other than both, and can include a disintegrant, a binder, a lubricant, an excipient, and the like. A preferable tablet in the present invention contains an excipient in addition to L-HPC, and the content of the excipient is about 1 to 20%, preferably about 1.5 to 12%, as a ratio to the uncoated tablet. It is. The excipient is more preferable when it is contained in a specific ratio with respect to L-HPC. A preferred ratio of L-HPC to the excipient is about 9: 1 to 3: 7 (mass ratio). In a preferred embodiment of the present invention, a disintegrant, a binder, a lubricant and the like can be further contained. The content of the disintegrant is about 0 to 10%, preferably 0.1 to 10%, more preferably 1 to 5% with respect to the uncoated tablet. The binder is about 0 to 10%, preferably about 1 to 5%. The lubricant is 0 to the balance, usually 10% or less, preferably 5% or less. Further, if necessary, other additives such as stabilizers, surfactants, sweeteners, flavoring agents, antioxidants, brighteners, coloring agents, fragrances, sugar-coating agents, disintegrating aids, storage An agent, a moisture-proofing agent, etc. can be added. These other additives can be appropriately added within a range of about 0 to 10% with respect to the uncoated tablet.

As the L-HPC used in the present invention, any commercially available low-substituted hydroxypropylcellulose can be used. Usually, it refers to those substituted with a hydroxypropyl group in the degree of molar substitution in the glucose ring in cellulose (normal hydroxypropyl cellulose has a molar substitution degree of 3). The product number LH-11, LH-21, LH-22, LH-31, LH-32 etc. in Shin-Etsu Chemical Co., Ltd. can be mentioned. Any of them can be used, so that an optimal L-HPC may be selected and used as appropriate according to the desired preparation or the like. LH-11, LH-31, LH-32 and the like are preferable, and LH-31 is one of the more preferable ones. The particle size of L-HPC is not so problematic, and any of the above commercially available products can be used.

As the excipient used in the present invention, any excipient conventionally used in pharmaceutical preparations can be used. Typical examples thereof include crystalline cellulose, dextran, corn starch, sucrose, lactose, powdered cellulose, maltose, D-mannitol and the like. Of these, lactose is a preferred excipient. When the ratio of L-HPC and lactose is in the range of 9: 1 to 3: 7, the initial elution rate is high, which is more preferable.

The disintegrant used in the present invention is not particularly limited, but sodium carboxymethyl starch, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, agar, anhydrous calcium hydrogen phosphate, or partially pregelatinized starch is preferred. It is preferable to use 1 type, or 2 or more types of these. In particular, sodium carboxymethyl starch is one of the more preferred ones, and a preparation containing sodium carboxymethyl starch as a disintegrant is one of the more preferred preparations. In the case of a preparation containing sodium carboxymethyl starch, the content thereof is preferably from 0.1 to 10%, more preferably from 1 to 5%, based on the uncoated tablet.

As the binder used in the present invention, any of those used in pharmaceutical preparations can be used. Among them, preferred are hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, Arabic Examples include gum, sodium alginate, guar gum, gelatin, pregelatinized starch, tragacanth, bull run, and polyvinyl alcohol. Hydroxypropyl methylcellulose is a more preferred binder. These may be added in the form of powder or in the form of a solution during granulation.

The lubricant used in the present invention is not particularly limited, but a stearic acid type lubricant is usually used. Examples of the stearic acid lubricant include stearic acid, sodium stearate, and magnesium stearate. Of these, magnesium stearate is one of the preferred ones. The content of the stearic acid lubricant with respect to the uncoated tablet is about 0 to 10, preferably about 2 to 7%.

The production method of the high-content terbinafine hydrochloride small tablet of the present invention is not particularly limited, and may be tableted by any method as long as the object of the present invention is achieved. Usually, a composition containing terbinafine hydrochloride, L-HPC and, if necessary, excipients and other additives is granulated by a conventional method to form granules, and the granules are compressed into tablets. If necessary, it can be obtained by coating. As the granulation method, either dry granulation or wet granulation may be used, but wet granulation is preferred. Moreover, when using a lubricant, it is preferable to mix the lubricant with the granulated granules and tablet them. The size of the tablet is not particularly limited, but it is about 6 to 8.5 mm, more preferably about 7 to 8.2 mm from the viewpoint of easy drinking and easy handling.
As the liquid used in the wet granulation, water, an organic solvent-water mixed solution, an organic solvent such as alcohol, and the like can be used, but an ethanol solution or an ethanol aqueous solution is preferable. When ethanol or an aqueous ethanol solution is used, the ethanol concentration is preferably 10% or more, preferably 30% or more, more preferably 45% or more. The liquid may be added to a composition containing a binder by a method such as spraying and granulated, or the binder may be dissolved in the liquid and added as a binder solution by a method such as spraying. May be granulated. In the present invention, the latter is preferred. When used as a binder solution, the concentration of the binder may be appropriately selected. When an aqueous ethanol solution is used, a binder that dissolves in the solution, such as hydroxypropylmethylcellulose, is 20 to 85%, preferably about 40 to 80%. It is preferable to use it as a concentration.
An example of a preferred wet granulation is described as follows: L-HPC, terbinafine hydrochloride, and, if necessary, an excipient, and a terbinafine hydrochloride content of 75% by mass or more based on the total composition For tableting, the product is stirred and mixed with ethanol or aqueous ethanol solution in which the binder is dissolved, preferably sprayed, wet granulated, and the resulting granules are sized as necessary. Granules can be obtained. An uncoated tablet (uncoated tablet) of the present invention can be obtained by blending a tableting granule with a tableting tablet if necessary and tableting. Tableting may be performed by a conventional tableting machine.

The uncoated tablets obtained as described above can be used as they are, but by coating the uncoated tablets, the effects of light, humidity, etc. are reduced, and the preparation is stable to light and has little or no discoloration. Furthermore, by taking masking such as taste, it is possible to make it easy to take.
The coating material is not particularly limited as long as it is used in pharmaceutical preparations. For example, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), ethyl acrylate / methyl methacrylate copolymer, aminoalkyl methacrylate Copolymers, carboxyvinyl polymers, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, stearyl alcohol, cetanol, shellac, triacetin, polyethylene glycol, polysorbate, and the like can be used. A cellulose derivative-based coating agent is preferable, and HPMC is more preferable. Further, it is preferable to use polyethylene glycol in combination. When HPMC and polyethylene glycol are used in combination, the ratio of the two is not particularly limited, but is usually 1 to 100 parts, preferably 10 to 60, more preferably about 20 to 40 parts with respect to 100 parts (mass) of HPMC. As HPMC, Shin-Etsu Chemical Co., Ltd. product numbers TC-5S, TC-5E, TC-5EW, TC-5R, TC-5RW, TC-5MW, and the like are used. Preferably, low viscosity HPMC (for example, TC-5E, TC-5EW) is used. These coating materials are usually dissolved in water to form an aqueous solution and sprayed onto tablets. These concentrations in the coating liquid are not particularly limited, but from the viewpoint of viscosity and the like, when HPMC and polyethylene glycol are used in combination, the coating material concentration is preferably 4 to 20%, and preferably about 7 to 15%. As a coating method, the coating can be carried out by a conventional method used for general tablet coating, such as spray coating. Further, since terbinafine hydrochloride is known to be colored by light, a general coating formulation containing titanium oxide can be used in order to improve the light shielding ability and hiding ability of the coating layer. There are two types of titanium oxide, rutile type and anatase type, which have different crystal forms. In the present invention, both the rutile type and the anatase type are used, but the rutile type is more preferable. Titanium oxide is about 10 to 80 parts, preferably about 20 to 75 parts, more preferably about 30 to 65 parts with respect to 100 parts (mass) of the coating material. The coating amount of the coating agent is a solid content in the coating agent and is desirably 5% or less with respect to the uncoated tablet.

Since the coating preparation obtained as described above is excellent in storage stability and dissolution, and has a high content of terbinafine hydrochloride, the size of the tablet can be reduced. For example, in the case of a tablet having a terbinafine hydrochloride content of about 140 mg in one tablet, the total weight of the uncoated tablets can be 170 mg and the tablet diameter can be 8 mm or less. Since the weight of the tablet of the present commercial product is 210 mg and the tablet diameter is 9 mm, the weight can be reduced by about 20% and the size can be reduced by 10% or more compared with the tablet currently marketed in the form of an uncoated tablet. Therefore, according to the present invention, a terbinafine hydrochloride tablet that can be easily swallowed can be obtained.
If necessary, the coating preparation can be further polished to give gloss. As the polishing, any conventionally used polishing for pharmaceutical tablets and the like can be used. As typical examples, carnauba wax or paraffin may be mentioned, and paraffin is more preferable. The addition amount of the polishing agent may be about 0.01 to 0.1% with respect to the coating preparation.
Next, the present invention will be described more specifically with reference to examples and comparative examples.

According to the formulation shown in Table 1 below, the tablet of the present invention was produced as follows.
Terbinafine hydrochloride, lactose (manufactured by HMS: lactose (200)), low-substituted hydroxypropylcellulose (L-HPC product number LH-31, manufactured by Shin-Etsu Chemical Co., Ltd.) were charged into a stirring and mixing granulator, and hydroxy What was spray-granulated with a 75% solution (solvent: 50% ethanol solution) of propylmethylcellulose (product number TC-5R, manufactured by Shin-Etsu Chemical Co., Ltd.) was dried and further sized with a 20 mesh sieve. Magnesium stearate was added to and mixed with the obtained granules to obtain granules for tableting. The granules for tableting were tableted to produce a bare tablet having a WR type having a weight of 170 mg and a diameter of 8 mm.

A plain tablet in the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 2 below was used.

A plain tablet in the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 3 below was used.

A plain tablet of the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 4 below was used.

A plain tablet in the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 5 below was used.

得られた錠剤につき、初期の溶出性をみるため、最初から５分間での溶出率を、後記試験例１に記載の方法と同様にして、調べたところ、試験開始から５分後における溶出率は、４０％で有り、初期溶出率の良好なものであった。

In order to check the initial dissolution properties of the obtained tablets, the dissolution rate after 5 minutes from the beginning was examined in the same manner as described in Test Example 1 below, and the dissolution rate after 5 minutes from the start of the test. Was 40%, and the initial dissolution rate was good.

A plain tablet of the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 6 below was used.

実施例５と同様にして、試験開始から５分後における溶出率を調べたところ、該溶出率は約３８％で有り、初期溶出率の良好なものであった。

When the elution rate after 5 minutes from the start of the test was examined in the same manner as in Example 5, the elution rate was about 38%, and the initial elution rate was good.

A plain tablet in the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 7 below was used.

実施例５と同様にして、試験開始から５分後における溶出率を調べたところ、該溶出率は約４３％で有り、初期溶出率の良好なものであった。

When the elution rate after 5 minutes from the start of the test was examined in the same manner as in Example 5, the elution rate was about 43% and the initial elution rate was good.

A plain tablet in the present invention was produced in the same manner as in Example 1 except that the formulation shown in Table 8 below was used.

実施例５と同様にして、試験開始から５分後における溶出率を調べたところ、該溶出率は約４５％で有り、初期溶出率の良好なものであった。

When the elution rate after 5 minutes from the start of the test was examined in the same manner as in Example 5, the elution rate was about 45%, and the initial elution rate was good.

Comparative Example A
A plain tablet in Comparative Example A was produced in the same manner as in Example 1 except that the formulation shown in Table 9 below was used.

実施例５と同様にして、試験開始から５分後における溶出率を調べたところ、該溶出率は約２１％で有った。本比較例Ａにおいては、Ｌ−ＨＰＣの含量が少ないため、初期の溶出性の点で、実施例に比して劣るものであった。

When the elution rate after 5 minutes from the start of the test was examined in the same manner as in Example 5, the elution rate was about 21%. In this comparative example A, since a small amount of L-HPC, in terms of early dissolution was poor shall than the actual施例.

Coated tablets were prepared on the uncoated tablets of Preparation Examples 1 to 4 according to the following method.
In 87.27 parts of water, 7 parts of hydroxypropylmethylcellulose (TC-5EW) and 1.99 parts of macrogol 6000 were stirred and dissolved, and a coating liquid was prepared by stirring and dispersing 3.82 parts of titanium oxide in the mixed solution. . Thereafter, the coating solution was passed through a No. 200 sieve (aperture 75 μm) to coat the bare tablets (coated with 8 mg as a solid component per tablet) to obtain about 178 mg of coated tablets.

Comparative Example 1
In the present invention, the same manner as in Example 1 except that the formulation of Table 10 below (same as the formulation of Example 1 except that carboxymethyl starch sodium is used instead of L-HPC in the formulation of Example 1) is used. Bare tablets were produced.

Comparative Example 2
In the same manner as in Example 1 except that the formulation shown in Table 11 below (same as the formulation of Example 1 except that carmellose calcium is used instead of L-HPC in the formulation of Example 1), Tablets were manufactured.

Comparative Example 3
In the present invention, the same manner as in Example 1 except that the formulation shown in Table 12 below (same as the formulation of Example 1 except that croscarmellose sodium is used instead of L-HPC in the formulation of Example 1) is used. Bare tablets were produced.

Comparative Example 4
In the same manner as in Example 1 except that the formulation shown in Table 13 below (same as the formulation of Example 1 except that agar is used instead of L-HPC in the formulation of Example 1), Manufactured.

Test Example 1 (Dissolution test up to 240 minutes at pH 4)
The tablets obtained in Example 1 and Comparative Examples 1 to 4 obtained above were tested for dissolution of terbinafine hydrochloride up to 240 minutes by the following method, and the results are shown in FIG.
Dissolution test method: Dissolution test was conducted according to the 14th revised Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method). Sampling was 10 mL, and the sample was filtered using a 0.45 μm membrane filter (initial 3 mL was discarded).
Test solution: Water, first solution of disintegration test and diluted McIlvaine buffer (pH 4.0)
Measurement: A sample solution was prepared by separating 2 mL from each sample and adding 2 mL of methanol to it. Also, weigh accurately about 15.625 mg of terbinafine hydrochloride, dissolve it by adding a mixture of methanol and each test solution (1: 1), and then add the mixture to make exactly 200 mL. did. Using the obtained sample solution and standard solution, the absorbance at a wavelength of 283 nm was measured, and the elution rate was calculated. (*: Prepared for each test solution)

Elution rate (%) = {absorbance of sample solution (abs) / (collected amount of terbinafine hydrochloride (mg) /15.625 mg × absorbance of standard solution (abs))} × 100 (%)

FIG. 1 shows dissolution of a tablet of the present invention containing L-HPC (plain tablet) and an aqueous solution of PH 4.0 in a comparative tablet containing only other disintegrants instead of L-HPC, up to 240 minutes. It is a curve.

Claims (4)

For the entire plain tablet, 5-10 wt% low-substituted hydroxypropyl cellulose, lactose 20% by weight, binder 1-5% by weight and terbinafine hydrochloride have 75 to 90 wt% free tablets High content terbinafine hydrochloride small tablets having a diameter of 7-8.2 mm . Carboxymethyl starch sodium, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, agar, high according to claim 1 you at least one selected from the group consisting of calcium hydrogen phosphate and partially pregelatinized starch anhydrous Content Terbinafine hydrochloride small tablets. The high-content terbinafine hydrochloride small tablet according to claim 1 or 2 , wherein the tablet is a film-coated tablet. When uncoated tablets, on the entire plain tablet, 5-10 wt% low-substituted hydroxypropylcellulose, containing in an amount comprised lactose 1 to 20 mass%, and terbinafine hydrochloride and 75 to 90 wt% composition High content, characterized by wet granulating the product using an ethanol solution or an aqueous ethanol solution containing a binder in an amount of 1 to 5% by mass based on the whole uncoated tablet, and tableting the resulting granule Method for producing terbinafine hydrochloride small tablets.

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