JP5605805B2 - Donepezil oral preparation - Google Patents

Description

  The present invention relates to an oral preparation containing donepezil or a salt thereof.

  Donepezil hydrochloride is a drug for the treatment of Alzheimer-type dementia, and its film-coated tablets have already been manufactured and sold. However, patients with Alzheimer-type dementia are mainly elderly, and since preparations that are easy to take are desired, sales of fine granules and orally disintegrating tablets have started.

  However, donepezil hydrochloride has a very unpleasant bitter taste, and numbness of the tongue may be felt when taking the fine granules or orally disintegrating tablets. Therefore, techniques for reducing the unpleasant taste of donepezil hydrochloride have been studied.

For example, Patent Document 1 describes that an unpleasant taste is suppressed by blending an anionic polymer substance such as carrageenan or dextran sulfate into a preparation of a basic drug having an unpleasant taste such as donepezil hydrochloride. Since these anionic polymer substances have a sulfate group (—OSO ₃ H group) in their structure, it is considered that they form a salt with a basic drug to reduce the unpleasant taste.

  In addition, Patent Document 2 describes that the bitterness could be reduced by blending a polyanionic polymer such as sodium carboxymethylcellulose or sodium alginate with a basic pharmaceutical ingredient having an unpleasant taste such as pioglitazone hydrochloride. ing.

Patent Document 3 discloses a technique for reducing the unpleasant taste of herbal medicines by blending celluloses or starches having a carboxymethyl group, such as carboxymethylcellulose.
JP 11-228450 A JP 2002-179558 A Japanese Patent Laid-Open No. 5-17372

  As described above, conventionally, a technique for suppressing an unpleasant taste of a drug by blending carboxymethyl cellulose or the like has been known. However, since donepezil hydrochloride has a particularly strong bitter taste, a technique capable of strongly reducing the unpleasant taste has been demanded.

  In addition, a technique for blending carrageenan to suppress the unpleasant taste of donepezil hydrochloride has also been known. However, carrageenan has a problem that it is difficult to handle as a pharmaceutical ingredient. For example, although carrageenan depends on the type, it generally dissolves in warm water but hardly dissolves in cold water. Therefore, when an aqueous solution is required during production, it may be necessary to use warm water. Furthermore, according to the results of the formulation studies by the present inventors, if donepezil hydrochloride and carrageenan were added to water at the same time, they could not be dissolved. I knew that I couldn't get it. Then, industrial mass production of the formulation containing both is difficult. Similarly, according to the findings by the present inventors, when donepezil hydrochloride and carrageenan are mixed and formulated in a powder state, a sufficient suppression effect of unpleasant taste cannot be obtained. It was also necessary to prepare a carrageenan solution.

  Under such circumstances, an object of the present invention is to provide an oral preparation of donepezil that has an unpleasant taste remarkably suppressed, is easy to be formulated, and is suitable for industrial mass production.

  The present inventors have intensively studied to solve the above problems. As a result, among the celluloses having a carboxy group, particularly those which are crosslinked or have a branched structure can remarkably reduce the unpleasant taste of donepezil and have excellent handleability at the time of preparation, and the present invention is completed. did.

  The oral preparation according to the present invention contains donepezil or a salt thereof, and one or more crosslinked / branched cellulose selected from the group consisting of cross carboxymethyl cellulose, carboxymethyl starch, and salts thereof. And

  In the above preparation, the amount of crosslinked / branched cellulose with respect to donepezil or a salt thereof is preferably 0.25 mass times or more. If the amount is 0.25 mass times or more, the unpleasant taste of donepezil can be more reliably suppressed.

  Compared with the conventional donepezil preparation, the oral preparation according to the present invention is remarkably reduced in unpleasant taste and easy to formulate and can be easily produced. Therefore, the oral preparation of the present invention is very useful as a donepezil preparation that can be taken comfortably because it is difficult to feel unpleasant taste as a fine granule or an orally disintegrating agent that is easier to take and can be efficiently mass-produced. .

  The oral preparation according to the present invention contains donepezil or a salt thereof, and one or more crosslinked / branched cellulose selected from the group consisting of cross carboxymethyl cellulose, carboxymethyl starch, and salts thereof. And

  Donepezil which is an active ingredient of the oral preparation according to the present invention is acetyl having a chemical structure of (±) -2-[(1-benzylpiperidin-4-yl) methyl] -5,6-dimethoxyindan-1-one. It is a cholinesterase inhibitor and is used as a therapeutic agent for Alzheimer's dementia.

  The salt of donepezil is not particularly limited as long as it is pharmaceutically acceptable. For example, inorganic salts such as hydrochloride, hydrobromide, sulfate, phosphate; acetate, maleate And organic acid salts such as tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, and trifluoroacetate; and amino acid salts such as aspartate and glutamine. Donepezil salt and donepezil may be used in combination.

  The dose of donepezil may be adjusted as appropriate, but it is usually administered to an adult at about 3 mg to 10 mg per day. Therefore, what is necessary is just to mix | blend about 0.5 mg or more and 10 mg or less per tablet or 1 bag. In terms of one preparation, a proportion of about 0.5% by mass or more and 5% by mass or less may be blended.

  In the oral preparation according to the present invention, one or more cross-linked / branched cellulose selected from the group consisting of cross carboxymethyl cellulose, carboxymethyl starch, and salts thereof is blended.

  Conventionally, in order to suppress the unpleasant taste of donepezil, a polysaccharide having a sulfate group has been blended. Such polysaccharides are believed to inhibit the binding of tongue bitter receptors to donepezil by interacting with donepezil in saliva and reducing free form. In addition, carboxymethyl cellulose and salts thereof are considered suitable for suppressing the unpleasant taste of common drugs. In contrast, in the present invention, a specific crosslinked / branched cellulose is used. Since such crosslinked / branched cellulose is a planar polymer having a crosslinked structure or a branched structure, it does not only ionically bind donepezil, but it can be considered to significantly suppress the unpleasant taste by inclusion of donepezil. It is done. On the other hand, it has also been confirmed that the preparation according to the present invention can release donepezil well in simulated intestinal fluid.

Cross sodium carboxymethyl cellulose is generally obtained by cross-linking sodium carboxymethyl cellulose obtained by reacting alkali cellulose with monochloroacetic acid with glycolic acid (HOCH ₂ CO ₂ H) and then extracting with aqueous alcohol. Cross carboxymethyl cellulose is obtained by treating the obtained sodium salt with dilute sulfuric acid. Moreover, salts other than a sodium salt are obtained by neutralizing free cross carboxymethylcellulose.

  In general, carboxymethyl starch can be produced by carboxymethylating starch using sodium monochloroacetate as in the production method of carboxymethylcellulose. In addition, the molecules may be further crosslinked by a physical method or a chemical method such as phosphorus oxytrichloride or sodium trimetaphosphate.

  Examples of the metal constituting the salt of cross carboxymethyl cellulose and carboxymethyl starch include alkali metals such as lithium, sodium and potassium; alkaline earth metals such as calcium and barium; first transition metals such as manganese, iron, nickel and zinc; Light metals such as aluminum; Of these, monovalent metal salts are preferable, and alkali metal salts are particularly preferable.

  The ratio of the crosslinked / branched cellulose to donepezil or a salt thereof is preferably 0.25 mass times or more. If the said ratio is 0.25 mass times or more, the unpleasant taste of donepezil can be suppressed more reliably. On the other hand, since the effect of suppressing unpleasant taste by the crosslinked / branched cellulose is improved in a dose-dependent manner, the upper limit of the ratio is not particularly limited. However, since there is a limit to the allowable intake of the above-mentioned crosslinked / branched cellulose, it is preferably 100 mass times or less.

  The preparation of the present invention is an oral preparation. The dosage form is not particularly limited, and can be, for example, an orally disintegrating tablet, a fine granule, a film-coated tablet, a granule, a liquid, and a jelly.

  You may mix | blend another additive with this invention formulation according to a dosage form. For example, excipients such as crystalline cellulose, lactose, mannitol; bases or binders such as corn starch, hydroxypropylcellulose, silicic acid, polyethylene glycol, talc, titanium oxide, hydroxypropylmethylcellulose; aspartame, xylitol, simple syrup, etc. Sweeteners such as iron sesquioxide and yellow sesquioxide; lubricants such as magnesium stearate and calcium stearate; solubilizers such as polyvinyl alcohol; and the like.

  The preparation of the present invention can be produced by a known method according to the dosage form. For example, in the case of a tablet, after mixing donepezil or a salt thereof, cross-linked / branched cellulose and other excipients, etc., granulate with adding purified water, and after drying, mix lubricant. You can tablet with.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

Production Example 1
Donepezil hydrochloride (200 mg) and the amount of additives shown in Table 1 were added to purified water (about 70 mL), and dissolved by shaking while applying ultrasonic waves.

  The added additives are as follows.

  At this time, the temperature of the purified water was not particularly adjusted and kept at room temperature, and additives other than carrageenan and high-dose carboxymethylcellulose sodium were added to the purified water at the same time as donepezil hydrochloride. And was able to. On the other hand, in the case of carrageenan, since it could not be dissolved by the same method, purified water was added little by little with stirring, and a solution of donepezil hydrochloride was added to obtain a mixed solution. However, high doses of carrageenan and sodium carboxymethyl cellulose could still not be completely dissolved.

  By adding further purified water to the solution, the amount was adjusted to 100 mL (solution A). The solution (10 mL) was accurately weighed and purified water was added to make exactly 100 mL. Further, the solution (7 mL) was accurately weighed, and purified water was added to make exactly 100 mL (solution B).

Test Example 1 Measurement of Free Donepezil in Simulated Mouth Each liquid A prepared in Production Example 1 was analyzed by high performance liquid chromatography, and the peak intensity was measured when the peak intensity was 100 when no additive was added. In addition, the purified water which is a solvent of each A liquid assumes the case where the formulation is taken with water. The analysis conditions are as follows. Under these conditions, the flow rate of the mobile phase was adjusted so that the donepezil peak appeared 5 minutes after injection of the sample.

Analytical instrument: “2695 Separation Module” manufactured by Nippon Waters
Column: Octadecylated silica gel 4.6 × 150 mm Intersil ODS-3
Measurement wavelength: 271 nm
Mobile phase: acetonitrile / water / 70% perchloric acid = 400/600/1
Column temperature: 25 ° C
Flow rate: 1.075 mL / min
Sample injection volume: 20 μL

  The results are shown in Table 3. In addition, "-" in Table 3 indicates that the analysis could not be performed because the concentration was too high for the solubility of the additive to be dissolved.

  As described above, the peak intensity of donepezil does not change even when sodium carboxymethylcellulose and cross polyvinylpyrrolidone are added. On the other hand, the peak intensity particularly when sodium carboxymethylcellulose is added is significantly reduced in a dose-dependent manner. This is probably because the amount of free donepezil was significantly reduced by physically including donepezil in addition to ionic bonds. Therefore, it was found that if sodium carboxymethylcellulose sodium was added to the donepezil oral preparation, the amount of free donepezil in the oral cavity was reduced, and the unpleasant taste could be remarkably suppressed.

Test Example 2 Measurement of free donepezil in simulated intestinal fluid Potassium dihydrogen phosphate (34.0 g) and disodium hydrogen phosphate (35.5 g) were dissolved in purified water (20 L), and phosphoric acid was added dropwise. The pH of the solution was adjusted to 6.8 to obtain a simulated intestinal fluid. Donepezil hydrochloride (500 mg) was added to the simulated intestinal fluid (about 350 mL) and dissolved. Furthermore, simulated intestinal fluid was added to make exactly 500 mL to obtain a 1000 μg / mL simulated intestinal fluid solution of donepezil hydrochloride.

  10 mg, 20 mg, or 40 mg of sodium carboxymethylcellulose, carboxymethyl starch sodium or carrageenan used in Production Example 1 was weighed, and the simulated intestinal fluid (80 mL) was added. Subsequently, the simulated intestinal juice solution of donepezil hydrochloride (20 mL, containing 20 mg of donepezil hydrochloride) was added and shaken for 1 hour. The solution was centrifuged at 3000 rpm for 20 minutes, 7 mL of the supernatant was accurately weighed, and the simulated intestinal fluid was added to make exactly 100 mL. The solution was filtered through a 0.45 μm membrane filter, the first 5 mL was discarded, and the next filtrate was analyzed under the same conditions as in Test Example 1 above. The same test was performed when no additive was added. The results are shown in Table 4.

  As described above, in the simulated intestinal fluid, the addition of cross carboxymethyl cellulose sodium is probably due to high ionic strength, but the amount of free donepezil is not reduced. Therefore, it was found that the oral preparation according to the present invention can release donepezil in the intestinal tract and therefore does not inhibit the intestinal absorption.

Test Example 3 Sensory Test Two subjects were allowed to include the solution A (5 mL) obtained in Production Example 1 in their mouths for about 10 seconds, and bitterness and numbness were evaluated. Bitterness and numbness were evaluated on an eight-point scale, with the bitterness or numbness when no additive was added being “7” and the case where no bitterness or numbness was felt at all being “0”. The results of bitterness evaluation are shown in Table 5, and the results of numbness evaluation are shown in Table 6.

  As described above, sodium carboxymethylcellulose and cross polyvinyl pyrrolidone cannot suppress the unpleasant taste of donepezil. On the other hand, when cross sodium carboxymethylcellulose or sodium carboxymethyl starch was added, it was found that the unpleasant taste of donepezil can be suppressed to the same or higher level than carrageenan.

Production Example 2 Preparation of Granules Granules were prepared according to the formulation shown in Table 7. Specifically, each component other than purified water was weighed and mixed, and granulated by stirring while adding purified water. The obtained granulated product was dried at 60 ° C. for 5 hours, and then passed through a 30 mesh sieve to obtain granules.

Test Example 4 Measurement of Free Donepezil in Simulated Mouth Granules (56 mg) of Production Example 2 above were weighed, purified water (70 mL) was added, and dissolved by shaking while applying ultrasonic waves. 7 mL of the solution was accurately weighed and purified water was added to make exactly 10 mL. The solution was analyzed by high performance liquid chromatography under the same conditions as in Test Example 1 above, and the ratio of the same peak intensity to the free donepezil peak intensity of the same donepezil hydrochloride solution was measured. The results are shown in Table 8.

  As described above, in the aqueous solution assuming that the preparation is taken with water, the amount of free donepezil is remarkably suppressed when croscarboxymethylcellulose sodium (croscarmellose sodium) is blended. Therefore, when taking the oral formulation which concerns on this invention, the bitter taste resulting from donepezil can be suppressed.

Production Example 3 Preparation of Tablets Tablets were prepared according to the formulation shown in Table 9. Specifically, each component other than purified water and a lubricant (magnesium stearate) was weighed and mixed, and granulated by stirring while adding purified water. The obtained granulated product was dried at 60 ° C. for 5 hours and then sieved with 20 mesh. Further, a lubricant (magnesium stearate) was added and mixed. Tablets were obtained from the obtained mixture by tableting so that the mass of 1 tablet was 280.0 mg using a 9 mm-diameter plane scissors.

Test Example 5 Measurement of free donepezil in simulated mouth The dissolution behavior of donepezil in the simulated mouth of each tablet prepared in Production Example 3 above is described in “Fifteenth revised Japanese Pharmacopoeia Manual” Tokyo Yodogawa Shoten, B-588-501 ( 2006). Specifically, one tablet was added to purified water (900 mL), and the paddle was rotated at a speed of 50 times / minute. The eluate (10 mL) was accurately weighed at predetermined intervals, and purified water (10 mL) heated to 37 ± 0.5 ° C. was immediately added. The eluate was filtered through a membrane filter having a pore size of 0.45 μm or less, the first filtrate (5 mL) was removed, and the next filtrate was obtained as a sample solution. Separately, donepezil hydrochloride (22 mg) for quantification was accurately weighed and purified water was added to obtain exactly 100 mL of solution, which was used as a standard solution. The obtained sample solution and standard solution (each 20 μL) were analyzed by liquid chromatography, and the peak area of free donepezil was measured. The obtained measured value was substituted into the following equation, and the dissolution rate (%) of free donepezil relative to the contained donepezil hydrochloride in each tablet was calculated.

［式中、Ａ_T(n)は試料溶液中の遊離ドネペジルのピーク面積を示し；Ａ_Sは標準溶液中の遊離ドネペジルのピーク面積を示し；Ｗ_Sは定量用の塩酸ドネペジルの量（ｍｇ）を示し；１／９０は（採取液量／試験液量）×１００であり；１／１０は１／１錠中の塩酸ドネペジル含量であり；４５は［（試料液量×試料溶液の希釈率）／標準溶液の希釈率］×１００である］

[Wherein A _{T (n)} represents the peak area of free donepezil in the sample solution; A _S represents the peak area of free donepezil in the standard solution; W _S represents the amount of donepezil hydrochloride for determination (mg) 1/90 is (collected liquid volume / test liquid volume) × 100; 1/10 is the content of donepezil hydrochloride in 1/1 tablet; 45 is [(sample liquid volume × sample solution dilution rate) ) / Dilution ratio of standard solution] × 100]

  The results are shown in Table 10.

  As can be seen from the above results, in the case of Formulation 4 containing no special additive component, the tablet rapidly disintegrates and free donepezil is released.

  On the other hand, in the case of Formulation 3, disintegration of the tablet was delayed although it was probably due to the action of carrageenan. As a result, the initial amount of free donepezil is relatively suppressed, but the amount of free donepezil after the tablet disintegrates is increased. In Test Example 1, the formulation containing carrageenan produced such a result even though the amount of free donepezil was small. In Production Example 3, the formulation was prepared without dissolving carrageenan. It is thought that.

  On the other hand, the amount of free donepezil is suppressed, although the preparation 1 containing croscarboxymethylcellulose sodium (croscarmellose sodium) and the preparation 2 containing carboxymethyl starch sodium disintegrate relatively quickly. In particular, the inhibitory effect on the amount of free donepezil in the preparation 1 is remarkably high. This is believed to be due to the inclusion / inclusion of these cross-linked / branched celluloses with donepezil.

  From the above results, it was found that the oral preparation according to the present invention containing cross-linked / branched cellulose significantly suppresses the unpleasant taste caused by donepezil even when it disintegrates in the mouth.

Claims (2)

Donepezil or a salt thereof, and orally disintegrating tablets, characterized in that it contains carboxymethyl starch sodium (except those containing low substituted hydroxypropylcellulose or hydroxypropyl starch). The orally disintegrating tablet according to claim 1, wherein the amount of sodium carboxymethyl starch relative to donepezil or a salt thereof is 1 mass times or more.