HK1024185A - Rapidly releasing and taste-masking pharmaceutical dosage form - Google Patents

Description

Pharmaceutical dosage form with rapid release and taste masking

Technical Field

The present invention relates to pharmaceutical dosage forms that rapidly release and mask taste sensation, and methods for their preparation. More particularly, the present invention relates to a pharmaceutical dosage form which can be orally administered without bitter taste and has improved drug release properties in the gastrointestinal tract.

Background

The bitter taste of many oral drugs has several negative effects. For example, the unpleasant taste of the drug can make it difficult to swallow, or cause the patient to avoid medication, thereby resulting in poor compliance by the patient. Therefore, taste masking techniques are considered to be of great importance and many researchers are conducting research and development. Taste masking is typically achieved by forming a taste-masking layer on the particles with the active ingredient. However, the taste-masking layer may lead to poor drug release. Therefore, it is difficult to provide an oral dosage form with good taste masking properties and good drug release properties by formulation design.

European patent application EP 0409254 discloses a fast-release oral particulate medicament that masks an unpleasant taste. The oral particulate medicament comprises a core containing at least an unpleasant-tasting drug and a water-swelling agent, and a film layer covering the core containing at least ethylcellulose and a water-soluble substance. However, this technique typically requires heating the final product (e.g., at 60-75 ℃ for 10-20 hours) to achieve good drug release properties. This heat treatment is undesirable for heat sensitive drugs, which decompose or melt at such high temperatures. In addition, in this technique, the effective taste masking time is said to be more than 20 seconds. For some patients, such as those with dentures, this time is not sufficient to provide a complete taste masking effect. Also, the prior art cannot avoid the use of acetone and chlorine solvents (e.g., dichloromethane) harmful to the human body to provide sufficient taste masking effect.

Japanese laid-open patent publication No. S63-258809 discloses a fine particle prepared by forming an outer layer of 1-10 wt.% on a core particle of an active ingredient having a bitter taste, and forming a saliva-insoluble layer of 3-10 wt.% on the outer layer. However, this technique cannot provide fine particles having a rapid release property in neutral and alkaline pH media. This is because the solubility of the polymer constituting the outer layer is strongly influenced by the pH of the medium and cannot be dissolved and split in neutral and alkaline pH media.

Accordingly, it would be desirable to provide oral dosage forms having improved drug release and taste masking properties.

Summary of The Invention

The present invention provides a pharmaceutical dosage form (or pharmaceutical preparation) for rapid release and taste masking comprising a core containing a pharmaceutically active ingredient, low-substituted hydroxypropyl cellulose and microcrystalline cellulose in an amount of at least 26.0% by weight of the total weight of the core; an inner coating layer formed on the core, which contains a water-soluble polymer; and an outer coating layer formed on the inner coating layer, which contains a saliva-insoluble polymer. In the dosage form of the present invention, the contents of the core, the inner coating layer and the outer coating layer are preferably 49.9 to 95.1, 0.1 to 45.3 and 4.8 to 50.0% by weight, respectively, based on the total weight of the dosage form. The dosage form may further comprise a sugar coating layer formed on the outer coating layer. The core is preferably spherical and has an average particle diameter of 80-400 microns, more preferably 100-300 microns.

Suitable inner coating layers comprise 70.0 to 100% by weight of a water soluble polymer such as hydroxypropyl methylcellulose and no more than 30.0% by weight of a water insoluble polymer such as (1) ethyl acrylate/methyl methacrylate copolymer, (2) ethyl acrylate/methyl methacrylate/trimethylaminoethyl methacrylate copolymer. Suitable outer coating layers comprise from 70.0 to 100% by weight of a saliva-insoluble polymer, such as (3) a butyl methacrylate/(2-dimethylaminoethyl) methacrylate/methyl methacrylate copolymer, and not more than 30.0% by weight of a water-soluble or water-insoluble copolymer.

According to the present invention, an oral dosage form having improved drug release properties and taste masking properties (e.g., over 50 seconds) can be provided.

The invention also provides a preparation method of the dosage form, which comprises the steps of mixing core materials containing the pharmaceutical active ingredients, the low-substituted hydroxypropyl cellulose and the microcrystalline cellulose, carrying out wet stirring granulation on the mixed core materials, drying and screening to obtain core particles; an inner coating layer is formed on the core particle by spraying an aqueous solution containing a water-soluble polymer, and then an outer coating layer is formed on the inner coating layer by spraying an aqueous solution containing a saliva-insoluble polymer. The method can be carried out in the absence of a solvent harmful to the human body (for example, acetone and a chlorine solvent such as dichloromethane, chloroform and methyl chloride). Therefore, this method is advantageous from the safety and ecological points of view.

Detailed description of the invention

In the present invention, the oral dosage form comprises at least three layers, namely: a core (also referred to as core particle) comprising a pharmaceutically active ingredient, low-substituted hydroxypropylcellulose and microcrystalline cellulose, an inner coating layer comprising a water-soluble polymer, and an outer coating layer comprising a saliva-insoluble polymer.

The active ingredients commonly used in the present invention have a bitter taste, although those without a bitter taste may also be used. For example, active ingredients useful in the present invention include: antifungal agents such as fluconazole, analgesic agents such as acetaminophen and acetylsalicylic acid, antihistamines such as diphenhydramine, phenicolamine succinate and meclizine, decongestants such as pseudoephedrine hydrochloride, anti-impotence agents such as sildenafil, antibiotics such as azithromycin, erythromycin and cephalosporin, penicillins such as sultam tosylate and amoxicillin trihydrate, enzyme inhibitors such as sulbactam sodium, antihypertensive agents such as nifedipine, doxazosin mesylate and amlodipine sulfonate, antidiabetic agents such as glipizide, bronchodilators such as pirbuterol hydrochloride and theophylline, anti-inflammatory agents such as piroxicam and tenidap, antidepressants such as sertraline hydrochloride, antacids such as calcium carbonate and magnesium oxide, and non-sedating antihistamines such as cetirizine, cardiotonic agents such as digitoxin and digoxin.

The term "microcrystalline cellulose" as used herein refers to pure, partially depolymerized cellulose made by treating alpha cellulose. Examples of such microcrystalline cellulose are: under the trade name Avicel^TM(manufactured by Asahi chemical industries, Ltd.), Ceolus^TM(manufactured by Asahi chemical industries, Ltd.), Vivacel^TM(by J Rettenmaier&Manufactured by Sohne GmbH), and Emcocel^TM(manufactured by Edward Mendell corporation). Suitable microcrystalline cellulose includes Avicel^TMThose sold under the names PH-101, PH-102, PH-301 and PH-302 (manufactured by Asahi chemical industries, Ltd.), and mixtures of two or more of these celluloses. Most preferably Avicel^TM PH-101。

As used herein, "low-substituted hydroxypropylcellulose" means poly (hydroxypropyl) ether of low-substituted cellulose containing not less than 5.0% and not more than 16.0% of hydroxypropoxyl groups in its dry state. Examples of the low-substituted hydroxypropylcellulose include a product sold under the trade name LH-31 (manufactured by Shin-Etsu Co., Ltd.).

If desired, other additives may be added to the core material. Such additives include binders such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, masking agents such as calcium gluconate, magnesium oxide, and lubricants such as talc and magnesium stearate.

The core particles used in the present invention are preferably spherical and have an average particle diameter of 80 to 400 microns, more preferably 100 to 300 microns. Preferably, the core has a sphericity of 0.85 to 1.0, more preferably 0.9 to 1.0. The spherical core particles used in the present invention have an advantage in that the coating efficiency in the subsequent inner and outer coating processes can be improved.

Suitable cores (also referred to as core particles) for use in the present invention comprise 0.1 to 73.5 wt%, more preferably 20.0 to 40.0 wt% of the active ingredient, 26.0 to 99.4 wt%, more preferably 28.0 to 80.0 wt%, most preferably 30.0 to 60.0 wt% of microcrystalline cellulose, and 0.5 to 34.0 wt%, more preferably 3.0 to 30.0 wt% of low substituted hydroxypropyl cellulose, the wt% being based on the total weight of the core material. Good drug release profiles can be obtained using cores with such compositions. When the amount of microcrystalline cellulose exceeds the above-mentioned limit, the sphericity of the resulting core particle may decrease, resulting in a decrease in coating efficiency.

In the present invention, an inner coating layer is formed on the above core particles. The purpose of forming the inner coating layer is to smooth the surface of the core and to make the outer coating layer easily separable from an acidic solution of an active ingredient such as sildenafil citrate (about ph 3.85). Suitable inner coating layers comprise 70.0 to 100 wt.% of a water-soluble polymer, and not more than 30.0 wt.% of a water-insoluble polymer.

The term "water-soluble polymer" as used herein refers to conventional pharmaceutical polymers having a solubility in water of above 10 mg/ml. For example, suitable water-soluble polymers include: hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (polyvinylpyrrolidone), and polyvinyl alcohol. The most preferred water-soluble polymers for use in the present invention are hydroxypropyl methylcellulose and hydroxypropyl cellulose. The term "water-insoluble polymer" as used herein refers to a conventional pharmaceutical polymer having a solubility in water of not more than 10 mg/ml. For example, suitable water-insoluble polymers include ethylcellulose, methacrylate copolymers and aminoalkyl methacrylate copolymers, such as ethyl acrylate/methyl methacrylate copolymer and ethyl acrylate/methyl methacrylate/trimethylaminoethyl methacrylate copolymer. Commercially available water-insoluble polymers may also be used. Such water-insoluble polymers are those sold under the tradenames Aquacoat (manufactured by Asahi chemical industries Co., Ltd.), Eudragit NE and Eudragit RS (manufactured by Rohm Pharma Co., Ltd.).

Other additives may also be added to the inner coating material if desired. Such additives include, for example, lubricants such as magnesium stearate or talc.

Then, an outer coating layer is formed on the inner layer. The outer coating layer has mainly a taste-masking effect to prevent the release of the active ingredient of the coated drug in the mouth of the patient. Suitable outer coating layers comprise 70.0 to 100 wt.% of a saliva-insoluble polymer, and not more than 30.0 wt.% of a water-soluble or water-insoluble polymer, these wt.% being based on the total weight of the outer coating layer. As used herein, the term "saliva-insoluble polymer" refers to a conventional pharmaceutical synthetic polymer having a solubility of less than 10mg/ml at neutral pH (6.0-7.5) and a solubility of greater than 10mg/ml at acidic pH (1.2-5.0). For example, suitable saliva-insoluble polymers include: aminoalkyl methacrylate copolymers, such as butyl methacrylate/(2-dimethylaminoethyl) methacrylate/methyl methacrylate copolymers and the polyvinyl acetal diethylaminoacetate. Commercially available polymers may also be used. Such polymers are those sold under the trade names of Eudragit E (manufactured by Rohm Pharma) and AEA (Sankyo) (manufactured by Sankyo). Suitable water-soluble polymers for use as the outer coating material include, for example, hydroxypropylmethyl cellulose and hydroxypropyl cellulose. Suitable water-insoluble polymers for use as the inner coating material include, for example, ethyl cellulose and Eudragit RS.

In the oral dosage form of the present invention, the core, the inner coating layer and the outer coating layer are contained in amounts of 49.9 to 95.1 (more preferably 60.0 to 87.0), 0.1 to 45.3 (more preferably 4.0 to 31.0, most preferably 4.0 to 10.0) and 4.8 to 50.0 (more preferably 9.0 to 36.0) wt%, respectively, based on the total weight of the dosage form. The ratio of the components may be determined according to the kind of active ingredient used, the kind of polymer used, the expected drug release profile, and the like. In general, the resulting coated drug having the above-mentioned component ratios can achieve a good drug release profile and taste-masking effect.

The following will describe a method for preparing the above oral dosage form.

First, a core material containing a pharmaceutically active ingredient, low-substituted hydroxypropylcellulose and microcrystalline cellulose is mixed, and the mixed core material is subjected to warm stirring granulation, drying and sieving to prepare a core or core granules in this order. The method for producing core particles usable in the present invention is described in detail in laid-open publication H06-56700. For example, in the container of a granulator, a powder of an active ingredient such as sildenafil citrate is mixed with microcrystalline cellulose, L-HPC and other additives such as a masking agent (e.g. calcium gluconate), a binder (e.g. hydroxypropyl methylcellulose), a lubricant (e.g. talc), etc. The mixture is then granulated at room temperature with water for 10-60 minutes using wet stirred granulation methods well known to those skilled in the art. The granulated core particles are dried with a fluidized bed dryer and sieved to obtain substantially spherical core particles. Preferably, the core particles are classified to give fine particles having an average particle size of 80-400, preferably 100-300 microns.

Then, an inner coating layer is coated on the thus-prepared core particles by spraying an aqueous solution containing a water-soluble polymer, and thereafter, an outer coating layer is coated on the inner coating layer by spraying an aqueous solution containing a saliva-insoluble polymer.

The core particles may be coated in a centrifugal fluidization granulator (e.g., a CF-granulator manufactured by Freund under the trade name CF-360) by spraying an aqueous solution consisting of a water-soluble polymer, a water-insoluble polymer, water and other additives such as talc. The conditions for coating may be determined according to the kind of the granulator used, the kind of the ingredients, the ratio of the ingredients, and the like. Suitable conditions are, when using the above-mentioned CF-granulator, a slit air temperature of 30-70 ℃ and a slit air rate of 200-350 l/min; the rotating speed is 100-200 rpm; the spraying speed is 2-7 g/min; the pressure of the spraying air is 2-4kg/cm². For example, after the spraying operation, the granules may be dried using a fluid bed dryer or a tray dryer.

Further, the core particles may be coated in a centrifugal fluidization granulator (e.g., a CF-granulator manufactured by Freund under the trade name CF-360) by spraying an aqueous ethanol solution (e.g., 80% ethanol) consisting of a saliva-insoluble polymer, ethanol, water and other additives such as talc. The conditions for coating may be determined according to the kind of the granulator used, the kind of the ingredients, the ratio of the ingredients, and the like. Similar conditions as mentioned above may be used. After the spraying operation, the particles may be dried, for example, using a fluid bed dryer, and then oven cured (oven-cured) to provide tri-layer core particles of the present invention.

In addition, in order to obtain good taste and mouthfeel, a sugar coating layer may be formed on the outer coating layer of the thus-prepared three-layered granule. Such sugar coating layers can be prepared by known coating methods. For example, a solution consisting of sucrose and D-mannitol dissolved in water is sprayed onto the three-layered granules under appropriate conditions. Xanthan gum (a polysaccharide produced from natural sources) may be added to obtain good mouthfeel. The amount of the sugar coating layer may be 15.0 to 270.0% by weight of the total weight of the coated granule consisting of the core, the inner coating layer and the outer coating layer. The pharmaceutical dosage form of the present invention may be used in the form of fine granules, tablets, POS (oral suspension powder), capsules or the like.

Examples and proportions in time

The present invention will be described in more detail based on the following examples and comparative examples. (materials used)

The following materials were used in these examples and comparative examples. Core material:

active ingredients: sildenafil citrate

L-HPC: low-substituted hydroxypropyl cellulose (LH-31, Shin-Etsu)

MCC: microcrystalline cellulose (Avicel PH101, Asahi Chemical Industry)

HPMC: hydroxypropylmethylcellulose 2910 as a binder (TC-5E, Shin-Etsu)

Calcium gluconate (Tomita Pharmaceuticals) inner coating layer:

water-soluble polymer: HPMC: hydroxypropyl methylcellulose 2910(TC-5E, Shin-Etsu)

Water-insoluble polymer: methacrylate copolymer (Eudragit NE30D, rohm pharma) outer coating layer:

saliva insoluble polymer: aminoalkyl methacrylate copolymer (Rohm Pharma) under the trade name Eudragit E100.

Other excipients, such as talc and magnesium stearate, hydroxypropyl methylcellulose and ethylcellulose, may also be added as desired.

Example 1(1) preparation of core particles:

in the container of the granulator, the active ingredient (sildenafil citrate, 210.66g) was mixed with microcrystalline cellulose (300g), L-HPC (97.2g), calcium gluconate (64.8g) and hydroxypropylmethylcellulose 2910(7.2g) as binder. Table 1 shows the amount ratio of each component used. Then, after adding water (699.0g) at room temperature, the mixture was granulated for 30 minutes (blade speed, 200 rpm; cross-rotation speed, 3600rpm) using a wet stirring granulation method (vertical granulator, VG-05, Powrex). The granulated core was dried with a Fluidized Bed Dryer (FBD) (Multiplex, MP-01, Powrex, Japan) and sieved to obtain core particles with an average diameter of 177-.

The classified core fine particles (177-. (2) Coating an inner layer:

the core granules (360.0g) prepared in step (1) above were coated by spraying a coating solution consisting of TC-5E (30.2g), Eudragit NE30D (20.1g) and 378.2g of water in a centrifugal fluidization granulator (CF-granulator, CF-360, Freund). Talc and magnesium stearate were added to prevent electrostatic aggregation of the individual particles. The amount ratio of each component used is shown in table 1. The conditions used were as follows: slit air temperature, 70 ℃; slit air rate, 250 l/min; rotation rate, 150 rpm; the spraying rate is 3.4 g/min; air pressure of spray, 3.0kg/cm². After the spraying operation, the granules were dried with a fluidized bed dryer (Multiplex, MP-01, Powrex) for 25 minutes (inlet, 80 ℃ C.; outlet, 50 ℃ C.). (3) Coating an outer layer:

eudragit E100(66.5g) dissolved in 950.2g of an aqueous ethanol solution (80% EtOH) was coated on the inner layer-coated granules (190.0g) using a CF-granulator (slit air temperature, 34 ℃; slit air rate, 300 l/min; rotation rate, 140 rpm; spray rate, 5.0 g/min). The coating concentration of the outer layer was adjusted as shown in table 1. After the spraying operation, these granules were transferred to the FBD and oven hardened under the same conditions as above to enhance the protective effect, thereby obtaining a three-layer product. (4) Coating a sugar layer:

in some examples and comparative examples, an additional sugar coating was formed on the three-layered product obtained in the above step (3). More specifically, a sugar layer was formed on these coated granules (137.8g) by spraying a solution consisting of sucrose (170.5g) and D-mannitol (55.0g) dissolved in water (138.0g) into a CF-granulator to adjust the taste. The conditions used were the same as when the protective coating was applied, except that the slit air temperature was 50 ℃. Aspartame (11.5g) was added to give sweetness to the fine particles. The polysaccharide xanthan gum produced from nature is used to provide good mouthfeel. In the spraying process, titanium dioxide (7.7g) and a seasoning (0.4g) were used in a powder state. After drying in FBD (outlet air 67 ℃) and sieving (< 500mm), a sugar-coated product was obtained. The amounts of the respective components used are shown in table 1 (a).

Examples 2 to 5 and comparative example

Oral dosage forms were prepared in the same manner as described in example 1, except that the amounts of the ingredients were varied as shown in tables 1(a) -1 (c).

TABLE 1(a)

Example 1 example 2

Ingredient dosage core ingredient coating product

(Mg/g)%% core material sildenafil 70.2230.9919.53170.22033.40328.575 talc- - -5.5002.6162.238L-HPC 32.4014.309.0126.5003.0922.645 MCC 100.0044.1327.81388.00041.86135.811 HPMC 2.401.060.668- - -calcium gluconate 21.609.536.00840.00019.02816.277 total amount 226.62100.0063.032210.220100.00085.546 inner layer HPMC 19.005.2843.7701.534 NE-30D 3.801.0577.8193.182 Mg-St- - -talc 3.801.057 total amount 26.607.39811.5894.716 outer layer E10088.6224.64822.7309.25TC-5E- - -talc 17.704.923 Mg-St- - -1.2000.488 total amount 106.3229.57123.930 839.738 subtotal 359.54100.00245.739100.000 sugar layer sucrose 444.96123.758-D-mannitol 143.5039.91227.00010.987 Primojel 3.8001.546 xanthan gum 1.000.2780.0400.016 Aspartame 30.008.34410.7004.355 flavoring agent 1.000.278- -TiO 8584₂20.005.563- -Total amount 640.46178.13341.54016.904 Total 1000.00278.134287.279116.904

TABLE 1(b)

Example 3 example 4

Ingredient dosage core ingredient coating product

(mg/g)%% of core material sildenafil 70.2232.35625.54871.8430.53118.857 talc 4.402.0281.601-L-HPC 9.404.3313.42057.9724.63715.216 MCC 110.4050.87140.16776.5732.54120.099 HPMC1.000.4610.3646.822.8981.790 Total amount of calcium gluconate 21.609.9537.85922.109.3935.801 217.02100.00078.959235.30100.00061.763 inner HPMC 18.106.58418.914.964 NE-30D 3.621.3173.790.995 Mg-St- -0.160.042 Talc- -3.790.995 Total amount 21.727.90126.656.996 outer layer E10035.8113.03091.6824.065TC-5E- - -Talc- -26.206.877 Mg-St 0.300.1101.140.299 Total amount 36.1113.140119.0231.241 Small 274.85100.000380.97100.000 sugar layer sucrose 533.15193.979427.03112.090D-mannitol 140.0050.937140.0036.748 Primojel- - -Xanthan Gum 1.000.3641.000.263 Aspartame 30.0010.91530.007.875 seasoningAgent 1.000.3641.000.263 TiO₂20.007.27720.005.250 Total 725.15263.836619.03162.49 Total 1000.00363.8361000.00262.489

TABLE 1(c)

Example 5 comparative example 1

Ingredient dosage core ingredient coating product

(mg/g)%% core material sildenafil 71.8430.53119.58970.2230.80115.865 talc- - -L-HPC 57.9724.63715.80721.609.4754.880 MCC 76.5732.54120.879110.4048.42524.944 HPMC 6.822.8981.8601.300.5700.294 calcium gluconate 22.109.3936.02521.609.4754.880 Tween 80- - -0.760.3330.172 citric acid- - -2.100.9210.474 total amount 235.30100.00064.160227.98100.00051.509 inner layer HPMC 18.915.15618.914.272 NE-30D3.791.0333.790.856 Mg-St 0.160.044- -Talc 3.791.0331.370.310 Total 26.657.26624.075.438 outer layer E10073.3520.001189.0542.714TC-5E 18.345.001- -Talc 13.103.572- -Mg-St- -1.500.339 Total 104.7928.574190.5543.053 Small 366.74100.000442.60100.000 sugar layer sucrose 441.26120.320365.4082.558D-mannitol 140.0038.174140.0031.631 Primojel- - - -Xanthan Gum 1.000.2731.000.226 Aspartame 30.008.18030.006.778 flavor 1.000.2731.000.226 TiO 1.000.2731.000.226 TiO 2₂20.005.45320.004.519 Total 633.26172.673557.40125.94 Total 1000.00272.6731000.00 225.938

Experiment (1) bitterness test:

please five (5) panelists placed 1g of the three-or four-layered product prepared by the above procedure in their mouths for 1 minute, and measured the time when they felt bitter. The average time (in seconds) was used for evaluation. The expected masking time is 50 seconds or more. The results are shown in Table 2. (2) The release time of the drug is as follows:

dissolution experiments were carried out with three media (ph1.2, 4.0 and 6.5) each according to the guidelines published by the Ministry of Health and Welfare (MHW) of japan. Additionally, dissolution experiments in media at ph5.0, 5.5, 6.0 were also investigated to predict dissolution in humans with low or no gastric acidity. The experiment of release from the particles was carried out according to the Japanese Pharmacopoeia (JP) with stirring in 900ml of medium at 37 ℃. The three-or four-layer product obtained by the above procedure was dispersed in the medium with constant stirring at 100 rpm. The media used in this study were fluid 1 (disintegration test fluid, japanese pharmacopoeia 13, ph1.2), 0.1M acetate buffer (ph4.0) and 0.05M phosphate buffer (ph5.5, 6.0, 6.5). Drug release performance was assessed as the amount of drug released after 5, 10 and 15 minutes of addition to each medium. The results are shown in Table 2.

TABLE 2

EXAMPLES comparative examples expected values

12345 bitterness test (sec) > 120 > 55 > 75 > 120 > 53 > 120 > 50 sec (drug release test) RA (%, pH1.2 after 5 minutes) 103.1RA (%, pH1.2 after 10 minutes) 101.6RA (%, pH1.2 after 20 minutes) 102.2 > 75% RA (%, pH4.0 after 5 minutes) 87.771.390.4 RA (%, pH4.0 after 10 minutes) 98.886.783.598.790.4 RA (%, pH4.0 after 20 minutes) 100.095.795.599.399.7 > 75% RA (%, pH5.5) RA (%, pH5.5 after 10 minutes (pH 5.5) 95.8RA (%, pH5.5 after 20 minutes) 95.690.586.690.593.974.3 > 75% RA (%, pH6.0 (%, RA (%, pH6.0) after 5 minutes, pH6.0) after 10 minutes) 87.0RA, pH6.0) after 20 minutes 87.7 > 75% pHRA (%, pH 6.5% RA (%, pH 56% RA (%, pH 5% RA after 5 minutes) 30.5 minutes, 30.5% RA after 5 minutes, 5.5% RA 30.5

As shown in table 2, it was confirmed that: the oral dosage forms of the invention (examples 1-5) have good taste masking properties and good drug release profiles.

More specifically, for all examples, the time for the test member to perceive a bitter taste was above 50 seconds. Furthermore, it was found that: the oral dosage form of the invention is capable of rapid onset of release in a medium (gastric fluid) at a pH in the range of 1.2 to 5.5. It is reported that: the pH of the evacuated stomach of 30 subjects varied from less than 2 to 5.5. It can also be confirmed that: the release of the product of the invention in a medium with a pH of 1.2 to 5.5 is satisfactory even for persons with low or no gastric acidity.

In addition, since the pH of normal human saliva is about 6.5, it is preferable that the amount of drug released is small after 2.5 minutes of stirring in a medium having a pH of 6.5. The release profile of the product of the invention at pH6.5 shows an S-shaped release profile, i.e. a delay of a few minutes before rapid release begins. This is a good drug release profile since some elderly patients have gastric juices with a pH of about 6.5. In this case, it is preferable that the drug should be released more than 30% after stirring for 20 minutes. The expected dissolution value at 20 minutes is 30% (ph6.5) instead of 75% (ph1.2, 4.0, 5.5, 6.0) because the solubility of sildenafil at ph6.5 is low. All products of the invention showed a drug release percentage of greater than 30% after 20 minutes of stirring at ph6.5, whereas the product prepared in the comparative example showed a drug release percentage of only 5.4.

In summary, the oral dosage forms of the present invention do have good drug release properties and good taste masking properties.

Claims (11)

1. A pharmaceutical dosage form for rapid release and taste masking comprising a core containing a pharmaceutically active ingredient, low-substituted hydroxypropylcellulose and microcrystalline cellulose in an amount of at least 26.0% by weight based on the total weight of the core; an inner coating layer formed on the core and comprising a water-soluble polymer; and an outer coating layer formed on the inner coating layer and containing a saliva-insoluble polymer.

2. The dosage form according to claim 1, wherein the contents of the core, the inner coating layer and the outer coating layer are 49.9 to 95.1, 0.1 to 45.3 and 4.8 to 50.0% by weight, respectively, based on the total weight of the dosage form.

3. The dosage form according to claim 1, wherein the contents of the core, the inner coating layer and the outer coating layer are 60.0 to 87.0, 4.0 to 31.0 and 9.0 to 36.0% by weight, respectively, based on the total weight of the dosage form.

4. The dosage form according to claim 1, which is further coated with a sugar coating layer on the outer coating layer in an amount of 15.0 to 270.0% by weight based on the total weight of the coated granule composed of the core, the inner coating layer and the outer coating layer.

5. A dosage form according to claim 1 wherein the core is spherical and the mean particle diameter is from 80 to 400 microns.

6. A dosage form according to claim 1, wherein the core comprises 0.1 to 73.5% by weight of the active ingredient, 26.0 to 99.4% by weight of microcrystalline cellulose and 0.5 to 34.0% by weight of low substituted hydroxypropyl cellulose, the% by weight being based on the total weight of the core material.

7. A dosage form according to claim 1, wherein the core comprises 20.0-40.0 wt% of the active ingredient, 30.0-60.0 wt% of microcrystalline cellulose and 30-30.0 wt% of low substituted hydroxypropyl cellulose, the wt% being based on the total weight of the core material.

8. A dosage form according to claim 1, wherein the inner coating layer comprises from 70.0 to 100% by weight of a water-soluble polymer selected from the group consisting of: hydroxypropyl methylcellulose and hydroxypropyl cellulose; and not more than 30.0 wt.% of a water-insoluble polymer selected from the group consisting of: ethyl cellulose, methacrylate copolymer and aminoalkyl methacrylate copolymer, these weight percents being based on the total weight of the inner coating layer.

9. A dosage form according to claim 1, wherein the outer coating layer comprises from 70.0 to 100% by weight of a saliva-insoluble polymer selected from the group consisting of: polyvinyl acetal diethylaminoacetate and butyl methacrylate/(2-dimethylaminoethyl) methacrylate/methyl methacrylate copolymers; and not more than 30.0 wt.% of a water-soluble or water-insoluble polymer selected from the group consisting of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, ethyl acrylate/methyl methacrylate/triaminoethyl methacrylate copolymer, the weight percents being based on the total weight of the outer coating layer.

10. A process for preparing a dosage form according to claim 1, which comprises mixing a core material comprising the pharmaceutically active ingredient, low-substituted hydroxypropylcellulose and microcrystalline cellulose, and subjecting the mixed core material to wet granulation with stirring, drying and sieving to obtain core particles in this order; forming an inner coating layer on the core particle by spraying an aqueous solution containing a water-soluble polymer; then, an outer coating layer is formed on the inner coating layer by spraying an aqueous solution containing a saliva-insoluble polymer.

11. The process according to claim 10, which is carried out in the absence of solvents harmful to humans.