DESCRIPTION

ORAL PREPARATION HAVING IMPROVED QUALITY

Technical Field
[0001] The present invention relates to an oral preparation with which generation of an analogue resulting from a medicinal component is suppressed  the unpleasant taste such as bitterness resulting from the medicinal component is reduced  the dissolution behavior of the medicinal component is controlled  and which has reduced friability  and the present invention also relates to a production method therefor.
Background Art
[0002] Some medicinal components contained in oral preparations are problematic in that they are partially lost as time passes due to the decomposition reaction or the like caused by  for example  light. Also  some medicinal components contained in oral preparations are problematic in that the recipient suffers when taking a preparation because some medicinal components have a bitter taste. Furthermore  some oral preparations and  in particular  solid preparations are problematic in that they have a high level of friability that allows  for example  a part of solid preparations to be chipped off by  for example  an external impact received after being shaped. Accordingly  it is difficult to use an automatic packaging machine at the drug dispensing site  resulting in problems such as significantly poor drug dispensing efficiency.
[0003] One example of medicinal components that have such problems is donepezil. Donepezil is a therapeutic agent for Alzheimer-type dementia and has a structural formula as shown in Formula 1 below.
[0004] [Formula 1]

[0005] A tablet that contains donepezil hydrochloride as a medicinal component (hereinafter referred to as a donepezil hydrochloride-containing tablet) is already disclosed in Non-Patent Document 1. However  the donepezil hydrochloride-containing tablet described in Non-Patent Document 1 is problematic in that  in the case where it is stored for a long period of time  donepezil hydrochloride  which is a medicinal component unstable to light  is lost. Also  the donepezil hydrochloride-containing tablet described in Non-Patent Document 1 has a problem of a high level of friability.
[0006] Also  Patent Document 1 discloses an oral pharmaceutical composition containing an anionic high-molecular substance and a basic medicinal substance that has an unpleasant taste. Donepezil hydrochloride is described as one of the basic medicinal substances that have an unpleasant taste. Patent Document 1 describes  as the effect of the invention  that the unpleasant taste such as bitterness and numbness brought about by donepezil hydrochloride can be masked.
However  regarding the oral donepezil hydrochloride pharmaceutical composition disclosed in Patent Document 1  Patent Document 1 is silent as to the effect of the invention other than the unpleasant-taste masking effect.
Prior Art Documents
Patent Documents
[0007] Patent Document 1: Japanese Laid-Open Patent Publication No. H11-228450
Non-Patent Documents
[0008] Non-Patent Document 1: Package insert of Aricept (registered trademark) D tablets
Summary of Invention
Problems to be Solved by the Invention
[0009] An object of the present invention is to provide a donepezil hydrochloride-containing oral preparation having better qualities than donepezil hydrochloride-containing tablets produced by conventional techniques.
[0010] Specifically  for example  when the donepezil hydrochloride-containing tablet described in Non-Patent Document 1 is photo-irradiated at 300000 lux?hr  a donepezil analogue in the tablet is increased to about 0.73 % by weight  and accordingly an object is  for example  to make it possible to create a method for producing a novel donepezil hydrochloride-containing oral preparation with which this increase of the donepezil analogue can be suppressed at low cost  and in a simple manner and thus to provide a donepezil hydrochloride-containing oral preparation in which the donepezil hydrochloride content is not reduced over a longer period of time and which is safe for patients.
Means for Solving the Problems
[0011] The summary of the present invention is as follows.
(1) An oral preparation comprising a medicinal substance having an unpleasant taste  wherein the preparation is obtained through steps 1 to 6 below:
1. a step of obtaining a mixture containing a medicinal substance having an unpleasant taste and a first additive 
2. a step of dissolving or suspending a binder in a granulation liquid preparation solvent to obtain a granulation liquid 
3. a step of adding the granulation liquid to the mixture and carrying out granulation with an agitation granulator to obtain granules 
4. a step of dissolving or suspending a coating agent  a lubricant  and/or a low-viscosity binder in a spray liquid preparation solvent to obtain a spray liquid 
5. a step of spraying the spray liquid onto the granules to coat the granules to obtain coated granules  and
6. a step of mixing the coated granules with a second additive and a disintegrator that has a carboxymethyl group  and tableting the mixture.
(2) The oral preparation according to (1)  wherein the medicinal substance having an unpleasant taste contains one medicinal substance selected from donepezil hydrochloride  zolpidem tartrate  risperidone  or amlodipine besilate.
(3) The oral preparation according to (1)  wherein the medicinal substance having an unpleasant taste is donepezil hydrochloride.
(4) The oral preparation according to (1)  wherein the first additive is an excipient.
(5) The oral preparation according to (1)  wherein the coating agent is an acrylic polymer-based coating agent.
(6) The oral preparation according to (1)  wherein the coating agent is Eudragit NE.
(7) The oral preparation according to (1)  wherein the disintegrator that has a carboxymethyl group is carmellose  carmellose sodium  carmellose calcium  croscarmellose sodium  sodium carboxymethyl starch  or carboxy methyl ethyl cellulose.
(8) A method for producing an oral preparation containing a medicinal substance having an unpleasant taste  which comprises steps 1 to 6 below:
1. a step of obtaining a mixture containing a medicinal substance having an unpleasant taste and a first additive 
2. a step of dissolving or suspending a binder in a granulation liquid preparation solvent to obtain a granulation liquid 
3. a step of adding the granulation liquid to the mixture and carrying out granulation with an agitation granulator to obtain granules 
4. a step of dissolving or suspending a coating agent  a lubricant  and/or a low-viscosity binder in a spray liquid preparation solvent to obtain a spray liquid 
5. a step of spraying the spray liquid onto the granules to coat the granules to obtain coated granules  and
6. a step of mixing the coated granules with a second additive and a disintegrator that has a carboxymethyl group  and tableting the mixture.
[0012] The present invention will now be described in detail below.
[0013] Donepezil herein refers to the compound represented by Formula 1 above. Donepezil suppresses decomposition of acetylcholine in the brain by inhibiting acetylcholinesterase. Due to this effect  donepezil exhibits a pharmacological effect of preventing a decrease of the activity of the cholinergic nervous system in the brain  and has been used as a therapeutic agent of Alzheimer-type dementia.
[0014] Examples of the medicinal substance that has an unpleasant taste usable in the oral preparation of the present invention include medicinal substances that exhibit a strong bitter taste when administered  which makes it difficult to take them.
Specific examples include donepezil hydrochloride  zolpidem tartrate  risperidone  amlodipine besilate  and the like.
The medicinal substance most preferable in the present invention that has an unpleasant taste is donepezil hydrochloride.
[0015] Examples of the first additive usable in the oral preparation of the present invention include diluting agents  binders  lubricants  disintegrators  plasticizers  antioxidants  antistatic agents  pH adjustors  fluidizers  surfactants  coloring agents  and the like.
[0016] Examples of the second additive usable in the oral preparation of the present invention include diluting agents  lubricants  disintegrators  antioxidants  antistatic agents  pH adjustors  fluidizers  surfactants  coloring agents  and the like.
[0017] Examples of diluting agents usable in the oral preparation of the present invention include sugar alcohols  saccharides  starches or derivatives thereof  and the like.
[0018] Specific examples of sugar alcohols usable in the oral preparation of the present invention include mannitol  erythritol  xylitol  maltitol  sorbitol  and the like. More preferable are mannitol and xylitol  and most preferable is mannitol.
[0019] Specific examples of saccharides usable in the oral preparation of the present invention include hydrates  non-hydrates  or the like of lactose  sucrose  saccharose  trehalose  fructose  glucose  and the like. More preferable are lactose and sucrose  and most preferable is lactose.
[0020] Specific examples of starches or derivatives thereof usable in the oral preparation of the present invention include corn starch  potato starch  and the like.
[0021] Specific examples of binders usable in the oral preparation of the present invention include sodium alginate  ethylcellulose  carrageenan  gelatin  hydroxypropylcellulose  polyvinylpyrrolidone  carboxy vinyl polymer  agar  copolyvidone  purified shellac  dextrin  hydroxyethyl cellulose  hydroxyethyl methyl cellulose  hydroxypropyl starch  hydroxypropyl cellulose  vinylpyrrolidone-vinyl acetate copolymer  hypromellose  partially pregelatinized starch  pullulan  pectin  polyvinyl alcohol-polyethylene glycol graft copolymer  povidone  polyvinyl alcohol  methacrylic acid copolymer L  methacrylic acid copolymer LD  methacrylic acid copolymer S  methylcellulose  and the like.
Examples of binders preferably used during the preparation of the granulation liquid of the present invention include hydroxypropyl cellulose  polyvinylpyrrolidone  hypromellose  and polyvinyl alcohol
[0022] Examples of lubricants used in the present invention include talc  titanium oxide  glycerine  glycerol fatty acid ester  wheat starch  sucrose fatty acid ester  stearyl alcohol  stearic acid and salts thereof  cetanol  gelatin  polyoxyethylene-polyoxypropylene glycols  polysorbates  macrogols  glyceryl monostearate  sodium lauryl sulfate  and the like.
Examples of lubricants preferably used during the preparation of the spray liquid of the present invention include magnesium stearate  talc  and titanium oxide.
[0023] Examples of disintegrators used in the present invention include corn starch  starch  crystalline cellulose  stearic acid and salts thereof  talc  crospovidone  cellulose or derivatives thereof  and the like.
Examples of disintegrator preferably used in the present invention include crystalline cellulose and corn starch.
[0024] Examples of plasticizers used in the present invention include triacetin  triethyl citrate  polypropylene glycol  polyethylene glycol  glycerine  polysorbate 80  diethyl sebacate  dibutyl sebacate  stearic acid  and the like.
[0025] Examples of antioxidants used in the present invention include tocopherol  ascorbic acid  sodium hydrogen sulfite  sodium sulfite  sodium edetate  erythorbic acid  cysteine hydrochloride  dried sodium sulfite  citric acid hydrate  dibutylhydroxytoluene  soybean lecithin  natural vitamin E  tocopherol  sodium pyrosulfite  butylhydroxyanisol  propyl gallate  and the like.
[0026] Examples of antistatic agents used in the present invention include hydrous silicon oxide  light anhydrous silicon  talc  and the like.
[0027] Examples of pH adjusters used in the present invention include citric acid and salts thereof  phosphoric acid and salts thereof  carbonic acid and salts thereof  tartaric acid and salts thereof  fumaric acid and salts thereof  acetic acid and salts thereof  amino acids and salts thereof  succinic acid and salts thereof  lactic acid and salts thereof  and the like.
[0028] Examples of fluidizers used in the present invention include light anhydrous silicic acid  hydrous silicon oxide  titanium oxide  talc  stearic acid and salts thereof  heavy silicic acid anhydride  and the like.
Examples of fluidizers preferably used in the present invention include light anhydrous silicic acid  titanium oxide  talc  and the like.
[0029] Examples of surfactants used in the present invention include phospholipid  glycerol fatty acid ester  polyoxyethylene fatty acid ester  sorbitan fatty acid ester  polyethylene glycol fatty acid ester  polyoxyethylene hydrogenated castor oil  polyoxyethylene alkyl ether  sucrose fatty acid ester  sodium lauryl sulfate  polysorbates  sodium hydrogen phosphates  potassium hydrogen phosphates  and the like.
[0030] Examples of coloring agents used in the present invention include iron sesquioxide  yellow iron sesquioxide  tar-based color  aluminum chelate  titanium oxide  talc  and the like.
Examples of coloring agents preferably used in the present invention include titanium oxide  talc  iron sesquioxide  tar-based color  and the like.
[0031] Examples of solvents for the preparation of the granulation liquid usable in the oral preparation of the present invention include water  ethanol  isopropyl alcohol  and the like.
[0032] Specific examples of coating agents usable in the oral preparation of the present invention include ethyl acrylate-methyl methacrylate copolymer  aminoalkyl methacrylate copolymer  ethyl cellulose  carboxyvinyl polymer  methacrylic acid copolymer  dimethylaminoethyl methacrylate-methyl methacrylate copolymer  and the like.
Examples of coating agents preferably used in the present invention include acrylic polymer-based coating agents such as Eudragit NE30D and Eudragit L.
[0033] Specific examples of low-viscosity binders usable in the oral preparation of the present invention include sodium alginate  ethyl cellulose  carrageenan  gelatin  hydroxypropyl cellulose  polyvinylpyrrolidone  carboxyvinyl polymer  agar  copolyvidone  purified shellac  dextrin  hydroxyethyl cellulose  hydroxyethyl methyl cellulose  hydroxypropyl starch  hydroxypropyl cellulose  vinylpyrrolidone-vinyl acetate copolymer  hypromellose  partially pregelatinized starch  pullulan  pectin  polyvinyl alcohol-polyethylene glycol graft copolymer  povidone  polyvinyl alcohol  methacrylic acid copolymer L  methacrylic acid copolymer LD  methacrylic acid copolymer S  methylcellulose  and the like.
Examples of low-viscosity binders preferably used in the present invention include methylcellulose  hypromellose  and the like.
[0034] Specific examples of disintegrators that have a carboxymethyl group usable in the oral preparation of the present invention include carmellose  carmellose sodium  carmellose calcium  croscarmellose sodium  sodium carboxymethyl starch  carboxy methyl ethyl cellulose  and the like.
Examples of disintegrators that have a carboxymethyl group preferably used in the present invention include carmellose  croscarmellose sodium  carmellose calcium  and sodium carboxymethyl starch.
[0035] Examples of solvents for the preparation of the spray liquid usable in the oral preparation of the present invention include water  ethanol  and the like.
[0036] Specific examples of the oral preparation in the present invention include tablets  powders  capsules  granules  and the like. The oral preparation most preferably used in the present invention is a tablet.
[0037] It is possible to carry out agitation and granulation in the present invention with a generally known agitation granulator. Examples of generally known agitation granulators include vertical granulators  high-speed mixers  and the like.
[0038] The tableting method for tablets to be provided by the present invention is not particularly limited as long as the effect of the present invention is demonstrated. Examples of the tableting method in the present invention include dry indirect compression method  wet indirect compression method  dry direct compression method  and the like.
[0039] Tablets provided by the present invention are shaped using  for example  a single-punch tableting machine  a rotary tableting press machine  or the like. The pressure for tableting is usually 4 to 20 kN/cm2. The shape of the solid preparation of the present invention is not particularly limited  and specific examples include shapes such as round  caplet  doughnut and oblong as well as multilayered tablets and cored tablets. Moreover  the tablets may be provided  if necessary  with distinguishing characters  symbols  or marks and  moreover  may be provided with a line along which tablets can be broken.
[0040] The donepezil analogue  which can be reduced by the present invention  can be quantified as follows.
[0041] From a chromatogram obtained by HPLC  the sum of the peak areas excluding the main-peak area and the additive-derived peak areas is calculated  the resulting value is divided by the value of the main-peak  the obtained value is regarded as the amount of the analogue  and comparison/evaluation is carried out. More specifically  comparison/evaluation can be carried out using the test method described in paragraph [0055].
Effects of Invention
[0042] The present invention has made it possible to obtain a donepezil hydrochloride-containing tablet with which generation of a donepezil analogue in the tablet  which occurs through photo-irradiation for a long period of time  can be less than with conventional donepezil hydrochloride-containing tablets.
Also  the present invention has made it possible to reduce an unpleasant taste such as bitterness resulting from donepezil hydrochloride felt after taking a donepezil hydrochloride-containing tablet in a sensory test.
Also  the present invention has made it possible to obtain a donepezil hydrochloride-containing tablet with which the dissolution behavior of donepezil hydrochloride immediately after taking the donepezil hydrochloride-containing tablet can be more controlled compared with conventional donepezil hydrochloride-containing tablets.
Also  the present invention has made it possible to obtain a donepezil hydrochloride-containing tablet having a lower level of friability than conventional donepezil hydrochloride-containing tablets.
Also  the present invention has made it possible to obtain a donepezil hydrochloride-containing tablet having a lower level of porosity.
Mode for Carrying Out the Invention
[0043] The best mode for carrying out the invention will now be disclosed below.
Examples
[0044] Example 1:
After 65 parts by weight of donepezil hydrochloride and 110 parts by weight of D-mannitol were mixed to give a mixture  the mixture was introduced into an agitation granulator (VG-05  manufactured by Powrex Corporation)  and a granulation liquid composed of 2 parts by weight of hypromellose and 20 parts by weight of purified water was added  to give granules. The granules were dried in a fluidized-bed drier (Multiplex MP-01  manufactured by Powrex Corporation)  and pulverization and particle size regulation were carried out with a power mill. The dried granules were sprayed with a spray liquid composed of 150 parts by weight of Eudragit NE30D  25 parts by weight of talc  25 parts by weight of titanium oxide  10 parts by weight of methylcellulose  and 200 parts by weight of purified water to give coated granules. Two parts by weight of light anhydrous silicic acid  10 parts by weight of carmellose  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the prepared coated granules  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0045] Example 2:
Two parts by weight of light anhydrous silicic acid  10 parts by weight of carmellose calcium  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the coated granules as prepared in Example 1  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0046] Example 3:
Ten parts by weight of sodium carboxymethyl starch  2 parts by weight of light anhydrous silicic acid  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the coated granules as prepared in Example 1  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0047] Example 4:
After 65 parts by weight of donepezil hydrochloride and 110 parts by weight of D-mannitol were mixed to give a mixture  the mixture was introduced into an agitation granulator (high-speed mixer FS-02  manufactured by Fukae Seisakusho)  and a granulation liquid composed of 2 parts by weight of hydroxypropyl cellulose and 20 parts by weight of purified water was added  to give granules. The granules were dried in a fluidized-bed drier (Multiplex MP-01  manufactured by Powrex Corporation)  and pulverization and particle size regulation were carried out with a power mill. The dried granules were sprayed with a spray liquid composed of 150 parts by weight of Eudragit NE30D  50 parts by weight of titanium oxide  10 parts by weight of hypromellose  and 200 parts by weight of purified water to give coated granules. Two parts by weight of light anhydrous silicic acid  10 parts by weight of carmellose  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the prepared coated granules  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0048] Example 5:
After 50 parts by weight of zolpidem tartrate and 50 parts by weight of lactose hydrate were mixed to give a mixture  the mixture was introduced into an agitation granulator (VG-05  manufactured by Powrex Corporation)  and a granulation liquid composed of 2 parts by weight of methylcellulose and 20 parts by weight of purified water was added  to give granules. The granules were dried in a fluidized-bed drier (Multiplex MP-01  manufactured by Powrex Corporation)  and pulverization and particle size regulation were carried out with a power mill. The dried granules were sprayed with a spray liquid composed of 150 parts by weight of Eudragit L30D55  50 parts by weight of titanium oxide  5 parts by weight of triethyl citrate  and 200 parts by weight of purified water to give coated granules. Thirty parts by weight of croscarmellose sodium  2 parts by weight of magnesium stearate  and 90 parts by weight of D-mannitol were added to and mixed with 30 parts by weight of the prepared coated granules  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0049] Comparative Example 1:
Ten parts by weight of crospovidone  2 parts by weight of light anhydrous silicic acid  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the coated granules as prepared in Example 1  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0050] Comparative Example 2:
Ten parts by weight of crystalline cellulose  2 parts by weight of magnesium stearate  and 118 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the coated granules as prepared in Example 1  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0051] Comparative Example 3:
Two parts by weight of magnesium stearate  and 128 parts by weight of F-Melt Type C were added to and mixed with 20 parts by weight of the coated granules as prepared in Example 1  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0052] Comparative Example 4:
After 65 parts by weight of donepezil hydrochloride and 110 parts by weight of D-mannitol were mixed to give a mixture  the mixture was introduced into a fluidized-bed drier granulator (Multiplex MP-01  manufactured by Powrex Corporation)  and a granulation liquid composed of 3 parts by weight of hydroxypropyl cellulose and 50 parts by weight of purified water was added  to give granules. Next  the granules were subjected to pulverization and particle size regulation in a power mill. The granules after pulverization and particle size regulation were sprayed with a spray liquid composed of 150 parts by weight of Eudragit NE30D  50 parts by weight of talc  and 200 parts by weight of purified water to give coated granules. Two parts by weight of light anhydrous silicic acid  10 parts by weight of carmellose  2 parts by weight of magnesium stearate  10 parts by weight of corn starch  5 parts by weight of crystalline cellulose  and 101 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the prepared coated granules  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0053] Comparative Example 5:
Thirty parts by weight of carmellose sodium  2 parts by weight of magnesium stearate  and 98 parts by weight of D-mannitol were added to and mixed with 20 parts by weight of the dried coated granules as prepared in Example 5  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0054] Comparative Example 6:
Thirty parts by weight of carmellose  5 parts by weight of magnesium stearate  and 155 parts by weight of D-mannitol were added to and mixed with 30 parts by weight of the dried coated granules as prepared in Example 4  and tableting was carried out with a rotary tableting machine (VIRGO  manufactured by Kikusui Seisakusho Ltd.).
[0055] Comparative Example 7:
Aricept (registered trademark) 10 mg D tablets (produced and distributed by Eisai Co.  Ltd.) were used.
[0056] Test Example 1: Test for measurement of analogue content after long-term storage under photo-irradiated conditions
The donepezil hydrochloride-containing oral preparations obtained in Examples 1 to 4 and Comparative Example 7 were each placed in a photostability test chamber (LTB-180C type  manufactured by Nagano Science Co.  Ltd.)  and irradiated at an illuminance of 1000 lux/hr under a D65 lamp so as to attain a cumulative illuminance of 300000 lux/hr. Thereafter  each sample was dissolved in a solution for use as a mobile phase such that the concentration of donepezil hydrochloride was 1 mg/mL. The used mobile phase was a solution prepared by mixing an aqueous 1-decanesulfonic acid solution and acetonitrile and perchloric acid in a ratio of 1300 : 700 : 1. The peak area ratio of analogue to donepezil hydrochloride was calculated using a test instrument (high-speed liquid chromatograph: LC-20A  manufactured by Shimadzu Corporation) and a UV detector as a detector while maintaining the temperature of a column (Mightsil ODS RP-18 GP 150-4.6)  into which a sample was introduced  at 40°C under conditions of the amount of sample introduced into the column of 10 µL  the flow rate of 1.3 mL/min  and the measurement wavelength of 271 nm to quantify the analogue. Test results are shown in Table 1.
[0057] [Table 1]

Analogue Content
(% by weight)
Example 1 0.36
Example 2 0.32
Example 3 0.32
Example 4 0.25
Comparative Example 7 0.73

[0058] It is clear from these results that  with donepezil hydrochloride-containing tablets of the present invention  the analogue content can be lower than that with a conventional donepezil hydrochloride-containing tablet.
[0059] Test Example 2: Sensory test of oral preparation
The taste of a tablet until it completely dissolved in saliva in the mouth of healthy male adults (27 years old  175 cm height  65 kg body weight) was evaluated. The test was carried out twice  and results of comprehensive evaluation of the test that was carried out twice are shown in Table 2.
-: Absolutely no unpleasant taste or bitterness was felt.
±: Slight unpleasant taste or bitterness was felt.
+: Unpleasant taste or bitterness was felt.
++: Considerable unpleasant taste or bitterness was felt.
[0060] [Table 2]

Evaluation of Bitterness Disintegration Time (sec.)
Example 1 ± 20
Example 2 - 18
Example 3 - 21
Example 4 ± 23
Example 5 - 24
Comparative Example 1 + 20
Comparative Example 2 ++ 25
Comparative Example 3 + 30
Comparative Example 4 + 29
Comparative Example 5 ++ 112
Comparative Example 6 + 30
Comparative Example 7 + 20

[0061] It is clear from these results that an unpleasant taste such as bitterness resulting from the medicinal component donepezil hydrochloride or zolpidem tartrate is reduced in oral preparations of the present invention.
[0062] Test Example 3: Dissolution test of oral preparation
Three tablets prepared in each of Examples 1 to 3 and Comparative Examples 1 to 3 were subjected to a comparison of the dissolution rate (%) of the medicinal component by the upright-inverted syringe method. Values measured 30 seconds after the beginning of the test were regarded as dissolution rates and shown in Table 3.
[0063] The "upright-inverted syringe method" herein uses a simple dissolution test method (the upright-inverted syringe method) of Nakamura et al. that mimics the oral cavity. This method enables a measurement of the amount of a drug dissolved and an evaluation of bitter taste masking in comparison with a threshold of feeling a bitter taste (Reference: Yasuhiko Nakamura et al.  "Ryuushi Sekkei To Seizai Gijyutsu (Particle Designing and Formulation Technique)" 121-128 (1993)). The upright-inverted syringe method herein is carried out as follows.
(Test on donepezil hydrochloride-containing particles)
Provide a 10 mL plastic syringe (manufactured by Nipro) to the end of which a 25 mm size filter having a pore size of 0.22 µm to 0.45 µm (Ekicrodisc manufactured by Pall Corporation) is attached  with the fluid outlet at the end of the filter being wrapped and blocked with a thermoplastic film (PARAFILM (registered trademark) M) to prevent fluid leakage. Introduce into this 10 mL glass syringe a tablet corresponding to 15 mg of donepezil hydrochloride and 10 mL of water maintained at 37 ± 1°C. Attach a plunger at the same time  turn the syringe into an upright or inverted position at a rate of every 3 seconds for 30 seconds for a total of 10 times so that the PARAFILM detaches and filtration is carried out with the filter; discard the first 5 mL of the filtrate; recover the remaining filtrate; and measure the amount of donepezil hydrochloride.
[0064] Measurement of the amount of donepezil hydrochloride can be carried as follows.
The recovered filtrate is used as a test solution. Separately  about 150 mg of a donepezil hydrochloride reference standard that has been dried at 105°C for 2 hours under reduced pressure is precisely weighed out  water as used for dissolution in this test is added  ultrasonic irradiation is carried out to dissolve the reference standard  and water is further added to attain 100 mL precisely  thus giving a standard solution. Using this standard solution and test solution and a UV-Vis absorption spectrometer (U-3300  manufactured by Hitachi  Ltd.) as a detector  4 mL of a sample is introduced into a 10 mm × 10 mm quartz cell  and spectrophotometry is carried out at a measurement wavelength of 271 nm. Using the numerical value of the detected donepezil hydrochloride  the amount of dissolution by a simple dissolution test (the syringe upright-inverted method) is calculated by Equation (1) below. The obtained test results are shown in Table 3.
Rate (%) of dissolution by upright-inverted syringe method = Ws × At/As × 2/3 (1)
where
Ws: Amount of donepezil hydrochloride reference standard (mg)
At: Absorbance of test solution
As: Absorbance of standard solution
[0065] [Table 3]

Dissolution Rate (%)
Example 1 22
Example 2 7
Example 3 16
Comparative Example 1 54
Comparative Example 2 53
Comparative Example 3 49

[0066] It is clear from these results that with donepezil hydrochloride-containing tablets of the present invention  the dissolution behavior of donepezil hydrochloride immediately after administration can be controlled.
[0067] Test Example 4: Test for measurement of friability of oral preparations
The donepezil hydrochloride-containing oral preparations obtained in Examples 1  4  and 5 and Comparative Example 7 were subjected to a test in accordance with a tablet friability testing method (The Japanese Pharmacopoeia Fifteenth Edition) to compare their level of friability (%). The results are shown in Table 4.
[0068] [Table 4]

Level of Friability (%)
Example 1 0.07
Example 4 0.08
Example 5 0.08
Comparative Example 7 0.34

[0069] These results made it clear that oral preparations of the present invention have a lower level of friability than a conventional oral preparation.
[0070] Test Example 5: Test for determination of porosity of oral preparations
Enlarged images of granules and coated granules obtained in both Example 4 and Comparative Example 4 are presented in Figs. 1 to 4 below.
[0071]
[0072]
[0073]
[0074]
[0075] These results made it clear that the donepezil hydrochloride-containing tablets of the present invention have reduced porosity.
Industrial Applicability
[0076] The present invention has made it possible to provide a novel oral preparation that has better qualities from a number of different perspectives compared with conventional oral preparations having an unpleasant taste. Accordingly  it has become possible to provide an oral preparation having an unpleasant taste that is safer to patients who receive the preparation.

CLAIMS

1. An oral preparation comprising a medicinal substance having an unpleasant taste  wherein the preparation is obtained through steps 1 to 6 below:
1. a step of obtaining a mixture containing a medicinal substance having an unpleasant taste and a first additive 
2. a step of dissolving or suspending a binder in a granulation liquid preparation solvent to obtain a granulation liquid 
3. a step of adding the granulation liquid to the mixture and carrying out granulation with an agitation granulator to obtain granules 
4. a step of dissolving or suspending a coating agent  a lubricant  and/or a low-viscosity binder in a spray liquid preparation solvent to obtain a spray liquid 
5. a step of spraying the spray liquid onto the granules to coat the granules to obtain coated granules  and
6. a step of mixing the coated granules with a second additive and a disintegrator that has a carboxymethyl group  and tableting the mixture.

2. The oral preparation according to claim 1  wherein the medicinal substance having an unpleasant taste contains one medicinal substance selected from donepezil hydrochloride  zolpidem tartrate  risperidone  or amlodipine besilate.

3. The oral preparation according to claim 1  wherein the medicinal substance having an unpleasant taste is donepezil hydrochloride.

4. The oral preparation according to claim 1  wherein the first additive is an excipient.

5. The oral preparation according to claim 1  wherein the coating agent is an acrylic polymer-based coating agent.

6. The oral preparation according to claim 1  wherein the coating agent is Eudragit NE.

7. The oral preparation according to claim 1  wherein the disintegrator that has a carboxymethyl group is carmellose  carmellose sodium  carmellose calcium  croscarmellose sodium  sodium carboxymethyl starch  or carboxy methyl ethyl cellulose.

8. A method for producing an oral preparation containing a medicinal substance having an unpleasant taste  which comprises steps 1 to 6 below:
1. a step of obtaining a mixture containing a medicinal substance having an unpleasant taste and a first additive 
2. a step of dissolving or suspending a binder in a granulation liquid preparation solvent to obtain a granulation liquid 
3. a step of adding the granulation liquid to the mixture and carrying out granulation with an agitation granulator to obtain granules 
4. a step of dissolving or suspending a coating agent  a lubricant  and/or a low-viscosity binder in a spray liquid preparation solvent to obtain a spray liquid 
5. a step of spraying the spray liquid onto the granules to coat the granules to obtain coated granules  and
6. a step of mixing the coated granules with a second additive and a disintegrator that has a carboxymethyl group  and tableting the mixture.