JP5563841B2 - Oral pharmaceutical composition masking unpleasant taste of drug - Google Patents

Description

  The present invention relates to an oral pharmaceutical composition in which the unpleasant taste of drugs such as donepezil hydrochloride is masked.

  Pharmaceutical preparations such as orally disintegrating tablets, granules, and powders are easy to take by elderly people and patients with low swallowing ability. However, drugs such as donepezil hydrochloride are known to cause bitterness and numbness of the tongue when taken, and in the case of the above-mentioned preparations containing these drugs, the drug is released into the mouth, which causes drug-induced discomfort. The patient's compliance may be reduced due to poor taste and poor taking. Various techniques have been studied as a method for masking such an unpleasant taste.

  Patent Document 1 discloses an oral pharmaceutical composition that conceals an unpleasant taste by blending carrageenan, dextran sulfate, and salts thereof. However, since these substances have a strongly acidic functional group, the interaction with the drug becomes too strong, and the solubility and dissolution property of the preparation may be deteriorated.

  Patent Document 2 discloses a granular pharmaceutical composition in which an unpleasant taste is masked by containing a wax-like substance and a sugar alcohol. Patent Document 3 discloses a method for isolating bitterness by melt extrusion of a drug and a specific (meth) acrylate copolymer. However, these methods require an apparatus for melt granulation and cannot be applied to unstable drugs that are decomposed by heat during melting.

  Patent Document 4 discloses a pharmaceutical composition that suppresses the discomfort of a drug that exhibits an unpleasant taste by mixing sucralose, but because sucralose is highly water soluble, the active ingredient is easily released in the mouth, Depending on the drug, there is a possibility that unpleasant taste cannot be concealed only by adding sucralose.

  As described above, the conventional method for masking a drug having an unpleasant taste may be difficult to implement technically or may not be masked depending on the drug, and thus further methods are required. .

JP 11-228450 A JP 2000-327590 A JP 2005-526731 A JP 2001-342151 A

  The object of the present invention is to provide an oral pharmaceutical composition in which the unpleasant taste of drugs such as donepezil hydrochloride is masked.

  As a result of studies to solve the above problems, the present inventors have found that the unpleasant taste of the drug is masked by including carmellose calcium and / or methacrylic acid copolymer in the preparation, The present invention has been completed.

That is, the features of the present invention are as follows.
(1) An oral pharmaceutical composition comprising a drug having an unpleasant taste and carmellose calcium and / or methacrylic acid copolymer.
(2) The oral pharmaceutical composition according to claim 1, wherein the drug having an unpleasant taste is donepezil hydrochloride.
(3) The oral pharmaceutical composition according to claim 1, wherein the oral pharmaceutical composition is an orally disintegrating tablet.
(4) The oral pharmaceutical composition according to claims 1 to 3, wherein the methacrylic acid copolymer is a dry methacrylic acid copolymer LD.
(5) An orally disintegrating tablet containing donepezil hydrochloride and carmellose calcium and / or methacrylic acid copolymer.

  The oral pharmaceutical composition of the present invention suppresses not only the bitterness derived from drugs such as donepezil hydrochloride but also the numbness of the tongue that occurs after taking. The present invention can be applied to an orally disintegrating tablet that can be easily taken even by patients with dysphagia. Furthermore, since the oral pharmaceutical composition of the present invention exhibits the effect of suppressing bitterness and numbness only by adding carmellose calcium and / or methacrylic acid copolymer to the main drug, regardless of the production method, Not restricted by manufacturing equipment.

FIG. 1 is a graph showing the bitterness masking effect according to the present invention by measurement using a taste recognition apparatus. (Test Example 3)

  The oral pharmaceutical composition of the present invention contains a drug having an unpleasant taste. As the drug, donepezil hydrochloride is particularly suitable.

  The oral pharmaceutical composition of the present invention contains either carmellose calcium, methacrylic acid copolymer, or both. Either of them produces an effect of suppressing bitterness and numbness, but it is more effective when both are contained.

  Carmellose calcium used in the present invention may be used as a pharmaceutical disintegrant. Carmellose calcium in the present invention exerts an effect of masking an unpleasant taste in a dose-dependent manner, but has a high hygroscopic property and absorbs water and swells. Therefore, it is necessary to appropriately adjust the blending amount to such an extent that the strength required for the pharmaceutical preparation can be ensured and the physical properties are not impaired. The blending amount of carmellose calcium is desirably 0.2 to 5 parts by weight with respect to 1 part by weight of the drug having an unpleasant taste.

  The methacrylic acid copolymer used in the present invention is usually often used as a pharmaceutical coating agent, but in the present invention, it is used in the form of coexisting with the main drug in the oral pharmaceutical composition. As the methacrylic acid copolymer used in the present invention, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, and methacrylic acid copolymer S are desirable. Among them, dry methacrylic acid copolymer LD, which has a particularly good bitterness-inhibiting effect and has little powderiness when taken, is preferred. The methacrylic acid copolymer in the present invention is dose-dependent and exhibits the effect of suppressing bitterness and numbness of the tongue. However, if the amount is too large, the characteristic odor and sourness become stronger, and the feeling of taking becomes worse. Therefore, the blending amount of the methacrylic acid copolymer is desirably 0.2 to 5 parts by weight with respect to 1 part by weight of the drug having an unpleasant taste.

  The oral pharmaceutical composition of the present invention is optionally added with an excipient, a binder, a disintegrant other than carmelulose calcium, a lubricant, a surfactant, a sweetener, a corrigent, a fragrance, a colorant and the like. An agent can be contained. For example, starches such as corn starch, lactose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, crystalline cellulose, magnesium carbonate, calcium carbonate, magnesium aluminate metasilicate, light anhydrous silicic acid, Excipients such as anhydrous calcium hydrogen phosphate; sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, carboxymethylcellulose, crystalline cellulose / sodium carboxymethylcellulose, dextrin, pullulan, Binding agents such as tragacanth, sodium alginate, pregelatinized starch; crospovidone, carmelo Disintegrants such as sodium, croscarmellose sodium, carmellose, low-substituted hydroxypropylcellulose, crosslinked carmellose sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch; magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, light anhydrous Lubricants such as silicic acid, hydrous silicon dioxide, sucrose fatty acid ester, hydrogenated oil; glycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, sodium lauryl sulfate , Surfactants such as polyoxyethylene polyoxypropylene glycol; aspartame, saccharin, saccharin sodium, acesulfameca Um, sucralose, sorbitol, sucrose, glucose, maltitol and other sweetening agents; citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, DL-alanine and other flavoring agents; strawberry, lemon, lemon lime, orange, Fragrances such as l-menthol and mint oil; and coloring agents such as yellow ferric oxide, ferric oxide, edible tar dye, natural dye, and the like.

  The dosage form of the oral pharmaceutical composition of the present invention includes not only solid preparations such as tablets, orally disintegrating tablets, granules, fine granules, powders, capsules, troches, chewable tablets, but also liquids, suspensions, Includes jelly and soft capsules.

  The method of the oral pharmaceutical composition of the present invention is not particularly limited, but it is necessary to uniformly mix carmellose calcium, methacrylic acid copolymer, or both with the main drug. At that time, the main agent, carmellose calcium, and methacrylic acid copolymer may each be pre-granulated. The granulated product may contain additives such as an excipient, a binder, a disintegrant other than carmelulose calcium, a surfactant, a sweetener, a corrigent, a fragrance, and a colorant as necessary. The granulation method may be any conventional method, such as stirring granulation method, fluidized bed granulation method, rolling granulation method, compression granulation method, extrusion granulation method, melt granulation method, spray granulation method. Among them, the stirring granulation method or the fluidized bed granulation method is simple and preferable.

  For example, when manufacturing tablets, the composition containing the active ingredient, excipients, and other necessary additives is mixed and kneaded and granulated with a high-speed agitation granulator, then dried and sized, as necessary. And a method of mixing a lubricant and tableting with a tableting machine. In this case, the carmellose calcium and / or methacrylic acid copolymer may be added before the granulation process or during the mixing process before tableting.

  EXAMPLES Hereinafter, although a test example and an Example demonstrate this invention in detail, the scope of the present invention is not limited to the following Example.

[Test Example 1]
The bitterness masking effects of various additives applicable to oral pharmaceutical compositions including orally disintegrating tablets were compared.
Donepezil hydrochloride 10 mg, D-mannitol 260 mg, and bitterness masking candidate substance 10 mg, which are drugs having an unpleasant taste, were mixed in a mortar and kneaded and granulated with purified water. The granulated product was dried to obtain a powder.

  About each obtained powder, it was compared by the sensory test whether the bitter taste of the donepezil hydrochloride raw material powder was suppressed. The sensory test evaluated the degree of bitterness in three stages. The results are shown in Table 2.

Degree of bitterness +: bitter (no change from the original powder), ±: slightly suppressed bitterness,-: significantly suppressed bitterness

  As a result of the sensory test, bitterness was suppressed in the samples using sodium alginate, dry methacrylic acid copolymer LD, methacrylic acid copolymer L, methacrylic acid copolymer S, carmellose calcium, and xanthan gum. Of these, sodium alginate and xanthan gum are highly viscous, and tablets produced at the above weight ratio (donepezil hydrochloride: sodium alginate or xanthan gum = 1: 1) have poor disintegration and dissolution, and oral pharmaceutical compositions It was unsuitable for.

  From the above, it was suggested that methacrylic acid copolymer and carmellose calcium are useful as bitterness masking substances applicable to oral pharmaceutical compositions including orally disintegrating tablets.

(Comparative Example 1)
In a high speed agitation granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 5.0 g, D-mannitol 136.9 g, low substituted hydroxypropylcellulose 18.5 g, light anhydrous silicic acid 1.6 g And kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 3.2 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

  In a high speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 5.0 g, D-mannitol 131.9 g, carmellose calcium 5.0 g, low substituted hydroxypropylcellulose 18.5 g, 1.6 g of light anhydrous silicic acid was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 3.2 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

  In a high speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 5.0 g, D-mannitol 126.9 g, methacrylic acid copolymer LD 10.0 g, low substituted hydroxypropylcellulose 18.5 g, 1.6 g of light anhydrous silicic acid was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 3.2 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

  In a high speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 5.0 g, D-mannitol 121.9 g, carmellose calcium 5.0 g, methacrylic acid copolymer LD 10.0 g, low substitution degree 18.5 g of hydroxypropylcellulose and 1.6 g of light anhydrous silicic acid were mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 3.2 g of magnesium stearate to obtain a pre-tablet powder. . This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

Table 2 shows the formulations of the orally disintegrating tablets of Comparative Example 1, Example 1, Example 2, and Example 3.

[Test Example 2]
A sensory test was performed using the orally disintegrating tablets of Comparative Example 1, Example 1, Example 2, and Example 3 as samples. The evaluation items of the sensory test were bitterness and numbness, and the degree was evaluated in five levels. The results are shown in Table 3.

Bitterness ++++: Very bitter, ++: Bitter, +: Slightly bitter,-: Slight numbness +++: Very numb, ++: Sucked, +: Slightly numb,-: Almost numb do not feel

  As a result of the sensory test, in Examples 1 to 3 which are orally disintegrating tablets using dry methacrylic acid copolymer LD which is carmellose calcium and / or methacrylic acid copolymer, bitterness and numbness derived from donepezil hydrochloride are remarkable. Was suppressed. In particular, it was found that both bitterness and numbness were remarkably suppressed by using both as in Example 3.

[Test Example 3]
The bitterness suppressing effect of carmellose calcium and methacrylic acid copolymer was evaluated using a taste recognition device (Incent Co., Ltd .: TS-5000Z).

  This taste recognition device is a device capable of taking out a change in membrane potential of an artificial lipid membrane as a signal, and it is known that an index called a CPA value shows a good correlation with the strength of bitterness (Takashi Uchida). Hiroshi, PHARM TECH JAPAN, 18 (12), pp 133-146, 2002).

  The test method is as follows.

  The orally disintegrating tablets of Comparative Example 1, Example 1, Example 2, and Example 3 were added to a 10 mM KCl solution so that the concentration of donepezil hydrochloride was 0.03 mg / mL, and stirred with a stirrer for 1 minute. The suspended matter was filtered with a paper filter to obtain a sample solution. Further, a 10 mM KCl solution was used as a control solution.

  In the taste recognition apparatus, the CPA values in the control solution and each sample solution were measured after stabilization with a reference solution (30 mM KCl and 0.3 mM tartaric acid). The sensor used for the measurement was BTO specific for basic bitterness.

The CPA value is defined as follows.
Vr (mV): Measured value of reference solution before measuring control solution or sample solution Vr ′ (mV): Measured value of reference solution measured again after measuring control solution or sample solution CPA: Vr′−Vr. Change of membrane potential caused by Adoption.

  The measurement was performed three times, and an average value was calculated for each CPA value of the control solution and each sample solution. FIG. 1 is a graph showing the value obtained by subtracting the average CPA value of the control solution from the average CPA value of each sample solution.

  As a result, the CPA values of Examples 1 to 3 were smaller than the CPA value of Comparative Example 1. From this, even in a test using a taste recognition device, the bitter taste derived from donepezil hydrochloride can be remarkably suppressed by using carmellose calcium and / or dry methacrylic acid copolymer LD which is a methacrylic acid copolymer. confirmed.

  In a high speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 5.0 g, D-mannitol 121.9 g, methacrylic acid copolymer LD 10.0 g, low substituted hydroxypropyl cellulose 18.5 g, 1.6 g of light anhydrous silicic acid was mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve is dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 5.0 g of carmellose calcium and 3.2 g of magnesium stearate. A powder before tableting was obtained. This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

  In a fluidized bed granulator (multiplex: FD-MP-01D), 5.0 g of donepezil hydrochloride, 121.9 g of D-mannitol, 10.0 g of methacrylic acid copolymer LD, 18.5 g of low substituted hydroxypropylcellulose, light 1.6 g of silicic anhydride was mixed and fluidized bed granulated with purified water. This was subsequently dried with a fluid bed granulator, sized with No. 30 sieve, and finally mixed with 5.0 g of carmellose calcium and 3.2 g of magnesium stearate to obtain a pre-tablet powder. This powder was tableted with a single tableting machine to prepare 165.2 mg orally disintegrating tablets per tablet.

  The orally disintegrating tablets of Example 4 and Example 5 contain the same prescription ingredients as in Example 3 in the same amount. Using these as samples, a sensory test was performed using the same evaluation items as in Test Example 2. The results are shown in Table 4.

  From the above results, according to the present invention, it was confirmed that the effect of suppressing bitterness and numbness can be obtained regardless of the production method.

  In a high-speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 3.0 g, D-mannitol 124.4 g, carmellose calcium 5.0 g, methacrylic acid copolymer LD 10.0 g, low substitution degree 18.5 g of hydroxypropylcellulose and 1.6 g of light anhydrous silicic acid were mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally 3.2 g of sodium stearyl fumarate was mixed to obtain a pre-tablet powder. . This powder was tableted with a single tableting machine to produce 165.7 mg orally disintegrating tablets per tablet.

  In a high speed stirring granulator (high speed mixer: LFS-GS-2J), donepezil hydrochloride 10.0 g, D-mannitol 199.6 g, carmellose calcium 8.3 g, methacrylic acid copolymer LD 20.0 g, low substitution degree 30.8 g of hydroxypropylcellulose and 2.7 g of light anhydrous silicic acid were mixed and kneaded and granulated with purified water. The granulated product obtained by sieving this with a No. 16 sieve was dried in a mini jet oven, sized with a No. 30 sieve, and finally mixed with 5.3 g of sodium stearyl fumarate to obtain a pre-tablet powder. . This powder was tableted with a single tableting machine to prepare 276.7 mg orally disintegrating tablets per tablet.

  Table 5 shows the formulations of the orally disintegrating tablets of Example 6 and Example 7.

  A sensory test was performed on the same evaluation items as in Test Example 2 using the orally disintegrating tablets of Example 6 and Example 7 as samples. The results are shown in Table 6.

  In a high speed stirring granulator (high speed mixer: FS-GS-10), 125 g of donepezil hydrochloride, 3068 g of D-mannitol, 250 g of methacrylic acid copolymer LD, 462 g of low-substituted hydroxypropylcellulose, and 40 g of light anhydrous silicic acid were mixed. And kneaded and granulated with purified water. This is crushed using a wet granulator, and the resulting granulated product is dried with a vented shelf dryer, further sized with a power mill, and finally carmellose calcium 125 g, aspartame 50 g, stearyl fumarate. Sodium 80g was mixed with a V-type mixer (VM-30) to obtain 4.2kg of powder before tableting. This powder was tableted with a rotary tableting machine to prepare 168.0 mg orally disintegrating tablets per tablet.

  When the sensory test was conducted using the orally disintegrating tablet of Example 8 as a sample and the same evaluation items as in Test Example 2, a result of “−” was obtained for both bitterness and numbness.

Claims (1)

An orally disintegrating tablet containing donepezil hydrochloride, carmellose calcium and methacrylic acid copolymer.

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