Tablet, which is decomposed in mouth

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to tablet, which is decomposed in mouth, containing D-mannite, active ingredient, disintegrating preparation, selected from crospovidone and carmellose, lubricant, selected from sodium stearylfumarate and sucrose esters of fatty acids, binding agent and starch. D-mannite has average size of particles larger than 30 mcm and specific surface larger than 0.40 m2/g.

EFFECT: claimed tablet has time of decomposition in oral cavity within 30 seconds, excellent sensation in oral cavity and sufficient strength, as a result of which tablet is not decomposed in the process of distribution.

28 cl, 1 dwg, 12 tbl, 51 ex

 

Description

The technical field to which the invention relates.

The present invention relates to a rapidly disintegrating tablet which is capable of rapid disintegration or dissolution in the oral cavity with a small amount of water or even without it.

Prior art

Traditionally known for a variety of pharmaceutical dosage forms for oral administration. However, few dosage forms provide for easy ingestion by patients, and is especially desirable dosage forms suitable for the elderly, children and seriously ill patients for whom it is difficult to swallow the dosage form. For example, from the point of view of ability to dosing data quantities or physico-chemical stability and, in addition, from the viewpoint of the production cost, the most commonly used dosage forms are tablets and capsules; on the other hand, many patients do not like taking pills and capsules, as tablets and capsules less convenient to swallow, and they can become stuck in the throat. Powders and granules harder to swallow, but they remain in the mouth, giving long-lasting unpleasant aftertaste in the mouth. Solutions such as syrups, consider dosage forms that are suitable for older persons and children; the intake of fluids in measured volume is difficult for older persons, children and seriously ill patients, and therefore, cannot wait to receive the exact quantities. In addition, for liquids inherent problems with the physico-chemical stability. In recent years we have discovered many ways related to drugs, quickly disintegrating in the oral cavity, in such dosage forms that retain the ability to dosing data quantities and physico-chemical stability inherent in tablets and capsules, as well as easy to swallow as syrups (patent publications 1, 2, 3, and 4).

However, for the above methods are characterized by different problems caused by the use of relatively large quantities of water, which increases the probability of instability of medicines, lack of such dosage forms sufficient strength, as a result there is a risk of damage in the distribution process, as well as complications that are possible in the production process when pelletizing, such as blocking or destruction of the molded workpiece on the diagonal planes, which complicates the processing of this dosage form.

To solve the above problems were studied various combinations of additives and production methods; however, such methods of production, as, for example, the method of drying the tablets from moisture after pressing, the method of conducting nesnera lubrication, etc., in many cases complicates the necessity of special equipment.

The methods used relatively often include the methods described in patent publication 5, patent publication 6, etc. and any of these methods; further research should be conducted to provide tablets, disintegrating in the mouth, which will demonstrate the ability to rapid disintegration in the oral cavity and to have sufficient strength, and which does not depend on the specific production method.

In patent publication 7 disclosed tablet, which demonstrates not only the ability to rapid decay and an excellent feeling in the mouth after swallowing, but also sufficient strength, resulting tablet is not destroyed in the process of distribution. In addition, in patent publication 8 disclosed tablet which rapidly disintegrates in the mouth when using soluble diluent used in the form of a product molded by direct pressing.

On the other hand, in the field of medical practice, the last time requires a tablet with high strength, is not only desirable to prevent damages such as cracks and defects generated when removing the tablet from the blister RTR package, but also allows the packaging with the use of automatic machines for the manufacture of tablets.

Patent publication 1: Japanese laid patent No. Hei 9-309821

Patent publication 2: Japanese laid patent No. Hei 9-309822

Patent publication 3: WO 93/12769

Patent publication 4: Japanese unexamined patent publication No. Hei 7-501829

Patent publication 5: Japanese unexamined patent publication No. Hei 10-182436

Patent publication 6: Japanese laid patent No. Hei 9-71523

Patent publication 7: WO 00/47233

Patent publication 8: lined Japanese patent No. Hei 11-35450

The description of the present invention

The problems solved by the present invention

The aim of the present invention is the provision of a tablet, disintegrating in the mouth, having such excellent properties as (1) simple production on conventional equipment without the need for specialized pharmaceutical equipment, (2) possession of sufficient strength, whereby the tablet is not damaged in the process of distribution, (3) the ability to rapid disintegration in the oral cavity, and (4) excellent mouthfeel, remaining after its ingestion, which significantly weakens the sense of bitterness and mechanical irritation.

Means for solving the above problems

The authors of the present invention found that after making pill asadauskas mouth and having the above properties, the tablet disintegrates in the mouth for one minute and, more preferably, within 30 seconds, which is usually considered difficult to achieve using traditional machines for moulding pressing, and has a satisfactory hardness due to the combination of additives such as (1) D-mannitol, (2) crosspovidone and/or carmellose and (3) sodium fumarate and/or complex sugar ester of fatty acids.

Specifically, the present invention relates to a tablet, as listed below in the present description:

[1] the Disintegrating in the mouth tablet containing (1) D-mannitol, (2) an active ingredient, (3) one or more dezintegriruetsja means selected from the group consisting of crosspovidone and carmellose, and (4) one or more lubricants selected from the group consisting of sodium fumarate and complex sugar esters of fatty acids.

[2] the Disintegrating in the mouth tablet according to the above item [1], where dezintegriraat means is crosspovidone.

[3] the Disintegrating in the mouth tablet according to the above paragraphs [1] or [2], where the lubricant is sodium fumarate.

[4] the Disintegrating in the mouth tablet according to any of the above items [1]-[3], where dezintegriruetsja tool is present in an amount of from 1 to 10% by mass.

[5] the Disintegrating in the mouth tablet according to any one of the above paragraph is nktob [1]-[4], where the lubricant is present in an amount of from 0.01 to 5 mass%.

[6] the Disintegrating in the mouth tablet according to any of the above items [1]to[5], where D-mannitol has an average particle size greater than 10 μm and equal to or less than 500 microns.

[7] the Disintegrating in the mouth tablet according to any of the above items [1]to[6], where D-mannitol has an average particle size greater than 10 μm and equal to or less than 200 microns.

[8] the Disintegrating in the mouth tablet according to any of the above items [1]to[7], where D-mannitol has an average particle size greater than 30 μm and equal to or less than 150 microns.

[9] the Disintegrating in the mouth tablet according to any of the above items [1]to[8], where D-mannitol has an average particle size greater than 30 μm, and specific surface of greater than 0.40 m2/year

[10] the Disintegrating in the mouth tablet according to any of the above items [1]to[9], where D-mannitol is a β-type crystal.

[11] the Disintegrating in the mouth tablet according to any of the above items [1]to[10], further containing a binder.

[12] the Disintegrating in the mouth tablet according to the above item [11], where the binder is one or more members selected from the group consisting of hydroxypropylcellulose and pre gelatinizing starch (alpha-starch.

[13] the Collapse of the rpm die in the mouth tablet according to the above item [12], where 2% aqueous solution of hydroxypropylcellulose has a viscosity of from 2 to 10 MPa·s at 20°C.

[14] the Disintegrating in the mouth tablet according to any of the above items [11]-[13], where the binder is present in an amount of from 0.01 to 2% by mass.

[15] the Disintegrating in the mouth tablet according to any of the above items [1]to[14], further containing starch.

[16] the Disintegrating in the mouth tablet according to the above item [15], where the starch is one or more members selected from the group consisting of corn starch, potato starch, rice starch, wheat starch and partially pre-gelatinizing starch.

[17] the Disintegrating in the mouth tablet according to any of the above items [1]-[16], where the active ingredient is amlodipine or a pharmacologically acceptable salt.

[18] the Disintegrating in the mouth tablet according to any of the above items [1]to[17], where the active ingredient is amlodipine besylate.

[19] the Disintegrating in the mouth tablet according to any of the above items [1]to[18], where the active ingredient is a granulated particle or particle, which is applied to the floor covering tool.

[20] the Disintegrating in the mouth tablet according to any of the above items [1]to[19], where the active ingredient what is amlodipine or a pharmacologically acceptable salt, granulated or coated with a coating agent.

[21] the Disintegrating in the mouth tablet according to any of the above items [1]to[20], where the active ingredient is amlodipine besylate, granulated or coated with a coating agent.

[22] the Disintegrating in the mouth tablet containing (1) D-mannitol having an average particle size greater than 30 μm, and specific surface of greater than 0.40 m2/g, (2) from 0.1 to 50% by weight of active ingredient, (3) from 1 to 10% by weight of crosspovidone and/or carmellose, (4) 2% by weight or less of hydroxypropylcellulose and/or pre-gelatinizing starch, (5) from 5 to 20% by weight of starch and (6) 0.1 to 5% by weight of sodium fumarate.

[23] the Disintegrating in the mouth tablet according to any of the above items [1]to[22], where the tablet disintegrates in the mouth within 30 seconds and has an absolute hardness of 2.5 N/mm2or more.

[24] the Disintegrating in the mouth tablet according to any of the above items [1]to[23], where the tablet disintegrates in the mouth within 30 seconds and has an absolute hardness of 3.0 N/mm2or more.

[25] the Disintegrating in the mouth tablet according to any of the above items [1]to[24], wherein the tablet, disintegrating in the mouth, produced using granules, upon receipt of which a mixture containing at least the D-mannitol is dezintegriruetsja means, subjected to wet granulation.

[26] the Disintegrating in the mouth tablet according to any of the above items [1]to[25], where, in the case when the D-mannitol using D-mannitol for direct compression, the proportion of D-mannitol for direct compression is less than 50% by weight of the entire D-mannitol drug.

[27] the Disintegrating in the mouth tablet according to any of the above items [1]to[26], where, in the case when the D-mannitol using D-mannitol for direct compression, the proportion of D-mannitol for direct compression is less than 30% by weight of the entire D-mannitol drug.

The effects of the present invention

Because disintegrating in the mouth tablet according to the present invention contains (1) D-mannitol, (2) crosspovidone and/or carmellose and (3) sodium fumarate and/or complex sugar ester of fatty acids, tablet demonstrates excellent effects, showing the ability to rapid disintegration in the oral cavity, leaving it an excellent feeling after swallowing, and sufficient strength, and in consequence, it is not destroyed in the process of distribution.

Brief description of drawings

[Figure 1] figure 1 shows a graph showing the test results of the compositions of examples 1-8. The x-axis on this chart shows the absolute hardness, and the y-axis shows the time of disintegration of tablets, raspados the Xia mouth, defined by the tester. In figure 1, the black circles (●) represent the composition of example 1, black triangles (▲) represent the composition of example 2, white circles (○) represent the composition of example 3, white triangles (δ) represent the composition of example 4, white squares (□) represent the composition of example 5, white diamonds (◊) represent the composition of example 6, asterisks (*) represent the composition of example 7 and pluses (+) represent the composition of example 8.

Best mode for carrying out the present invention

The present invention will be explained more specifically in the present description below.

In the present invention, the term "disintegrating in the mouth pill" means swallow the tablet is able to disintegrate in the oral cavity under the action of only one saliva within 60 seconds, preferably within 45 seconds and, more preferably, within 30 seconds, and in oral tablet disintegrates without the intake of water. Such disintegration time in the oral cavity can be measured with good reproducibility when using the device (tester) for testing tablets, disintegrating in the mouth (Toyama Sangyo Co., Ltd., model ODT-101).

In the present invention, the term "absolute hardness is a value obtained by dividing the hardness of the tablets on the area of the fault surface. In addition to the, the term "practical hardness refers to the hardness corresponding to such a degree of strength, in which the tablet is not only not destroyed when extracted from RTR-packaging (blister plate), but such a degree of strength, which is applicable in the production and distribution process, even in a machine for the automatic packaging of tablets after the distribution of dosage forms. Specifically, the absolute hardness typically includes a value of 1.5 N/mm2or more, preferably 2.0 N/mm2or more, more preferably 2.5 N/mm2or more, and even more preferably 3.0 N/mm2or more. In the present invention the hardness of the tablets can be measured using, for example, tester) to determine the hardness of the tablets TH-203MP (manufactured by Toyama Sangyo Co., Ltd.). In addition, the area of the fault surface can be calculated from the form of tablets and thickness of the tablets.

"D-mannitol" tends to the fact that, if the size of its particles is too small, the ability to collapse dramatically reduced, whereas the compression formability is improved; and on the contrary, if the size of its particles is too large, deteriorating ability to molding under pressure and decreases the strength of the tablets, and it also gives the feeling of a mechanical irritation of the mouth, thereby reducing the feeling when swallowed, it is preferable to use the D-mannitol having an average particle size more than 10 μm and equal to or less than 500 μm. Accordingly, D-mannitol", used in the present invention has an average particle size of preferably more than 10 μm and equal to or less than 500 μm, more preferably greater than 10 μm and equal to or less than 200 μm, and even more preferably greater than 30 μm and equal to or less than 150 μm. The average particle size is defined in the present description as the median diameter calculated by the volume measured by the dry method using a laser diffraction analyzer distribution of particle sizes. For example, the average particle size can be measured using a laser diffraction analyzer distribution of particle sizes SALD-3000 (manufactured by Shimadzu Corporation).

"D-mannitol", used in the present invention has a specific surface area of preferably more than 0.20 m2/g, more preferably greater than 0.30 m2/g, even more preferably greater than 0.40 m2/g and less than 1.00 m2/g, and even more preferably greater than 0.40 m2/g and equal to or less than 0.80 m2/, In this case, in the present invention, the specific surface area is a value measured by the multi-point method BET specific surface can be measured using, for example, apparatus for metering is of specific surface Tristar 3000 (manufactured by Micromeritics).

Therefore, a preferred example, D-mannitol," includes "D-mannitol", having an average particle size greater than 30 μm, and specific surface of greater than 0.40 m2/year

In addition, it is known that D-mannitol exists in a crystalline polymorphic forms α-, β - and δ-type, and in the present invention, crystalline form is not specifically limited. However, since α - and β-types relatively easily undergo dependent on temperature and humidity the transformation of the crystalline form, it is preferable to use β-type, which represents the most stable form. The content in the preparation is not specifically limited, and such content is preferably 50% by mass or more, more preferably 60 mass% or more, and even more preferably 65 mass% or more, and such content is preferably 95 mass% or more, and more preferably 90 mass% or more. In the present invention as D-mannitol can use the D-mannitol for direct compression (also known as D-mannitol for direct tableting), and in this case, to maintain a favorable ability to collapse, it is preferable to use the D-mannitol for direct tabletting in combination with a powder D-mannitol. The share of D-mannitol for direct tabletting all D-mannitol in the drug prepact the tion, is less than 50 mass%, more preferably less than 30% by mass, even more preferably less than 10 mass%, and even more preferably, substantially in the absence of any number of D-mannitol for direct compression. The expression "direct pressure"used in the present description, refers to such materials which are converted into a form suitable mainly for tableting by direct tabletting, which receive, for example, by spray drying.

"Dezintegriruetsja means includes crosspovidone and carmellose; preferably, it includes crosspovidone. The content in the preparation is not specifically limited, and such content includes, preferably, from 1 to 20% by weight, including, more preferably from 1 to 10% by weight, including, even more preferably from 2 to 10% by weight and including even more preferably, from 2 to 5% by weight. In that case, when used by one or more dezintegriruetsja tools, content in the product of the total number dezintegriruetsja funds is the same as above.

In addition, the tablet according to the present invention can be added dezintegriruetsja tool commonly used in the pharmaceutical field and distinct from the means stated above, within the range that does not influence the total effect of the present invention. This dezintegriruetsja means includes, for example, nitrocresols, calcixerollic, natrocarbonatite and nitrosamino hydroxypropylcellulose.

In addition, since the tablet according to the present invention further comprises starch, receive more preferred ability to collapse. Starch includes natural starches, such as corn starch, potato starch, rice starch and wheat starch; and partially pre-gelatinisation starches, in which a portion of the starch is pre-gelatinizing. In the present description, the term "pre-gelatinizing starch" named such materials, in which some portion of the starch is pre-gelatinizing, and in this part of content material, soluble in cold water, ranges from 0.5 to 20% by weight. The content of the material, soluble in cold water, measured by the method consisting in adding purified water to a weighed starch at room temperature (20°C) in an amount equal to 10 times the mass of the weighed starch, stirring the mixture at 1500 rpm for 2 minutes, centrifuging the resulting suspension at 1500 rpm for 15 minutes, drying the supernatant obtained in the above centrifugation, Poluchenie residue and retrieving the value of content in % by weight by dividing the specified residue on the total number of initially weighed starch. When starch is used in the above-mentioned purposes, it is added in such a way as to substantially maintain the shape of the particles of starch. The starch content in the preparation is not specifically limited, and such content includes, preferably, from 1 to 50% by weight, including, more preferably from 5 to 30% by weight, and including, even more preferably from 5 to 20% by mass.

"Lubricant" includes sodium fumarate and complex sugar ester of fatty acids, suitable from the point of view of monitoring complications pelletizing, especially in regard to the control of friction by forging, and including, preferably, sodium fumarate. The content in the preparation is not specifically limited, and the lubricant is usually used within a range from 0.01 to 5% by weight, and including, preferably, a range from 0.01 to 4% by weight. In addition, when the external lubricant, its content is preferably within the range from 0.01 to 0.5% by weight, and in the case where the lubricant is mixed with the composition for extrusion, its content preferably falls within a range from 0.5 to 4% by weight. In addition, in the case where the lubricant is sodium fumarate, its content is preferably from 1.5 to 4% by weight. In that case, when using one or more lubricants, the contents of their total number in the product is the same as specified above.

In addition, the tablet according to the present invention can be added to the lubricant normally used in the pharmaceutical field and distinct from the above, within the range not affecting the effects of the present invention. Such lubricants include, for example, stearic acid, magnesium stearate, calcium stearate, talc, Carnauba wax, L-leucine and macrogol.

If necessary, the tablet according to the present invention can be added are the "glue". Preferred binders include hydroxypropylcellulose and pre gelatinizing starch.

Hydroxypropylcellulose used as a binder for tablets according to the present invention, preferably includes hydroxypropylcellulose, 2%aqueous solution of which has a viscosity of from 2 to 10 MPa·s at 20°C, for example, HPC-L (manufactured by Nippon Soda Co., Ltd., viscosity in 2%aqueous solution: from 6.0 to 10.0 MPa·s). The content in the preparation is not specifically limited, and such content includes, preferably, 3% by mass or less. More preferably, the content is 2% by mass or less, including, even more preferably from 0.01 to 2% by weight and including even more preferably 0.1 to 1 mass%.

When the binder used pre gelatinizing Brahma is, natural starch such as corn starch or potato starch, or partially pre-gelatinizing starch is suspended in water and then the suspension is heated for pre-gilotinirovaniya, or can be dissolved and to use commercially available pre-gelatinizing starch, known under the trade name Amycol C (manufactured by NIPPON STARCH CHEMICAL CO., LTD.), or partially pre-gelatinizing starch. The content of pre-gelatinizing starch in the preparation is not specifically limited, and such content includes, preferably, 3% by mass or less. More preferably, the content is 2% by mass or less, including, even more preferably from 0.01 to 2% by weight and including even more preferably, 0.6 to 1.5% by mass.

When using one or more kinds of binder, the content of total amount of the binder in the preparation is preferably 3% by mass or less, more preferably 2% by mass or less and even more preferably from 0.01 to 2% by mass.

The tablet according to the present invention may be added a binder commonly used in the pharmaceutical field and different to the above, within the range not affecting the effects of the present invention. This binder includes, in the example, polyvinyl alcohols, polyvinylpyrrolidone (povidone), hypromellose (hypromellose), agar and gelatin.

As the "active ingredient" of the tablets according to the present invention can be applied to any drug that can be obtained in the form of conventional tablets. The drug used in the present invention may be in any form such as solid, crystalline, oil or dissolved form. For example, use one or more ingredients selected from the group consisting of food tonics, antipyretic analgesic anti-inflammatory drugs, psychotropic drugs, anxiolytics, antidepressants, tranquilizers sedatives, antispasmodics, drugs acting on the Central nervous system, tools, improving cerebral metabolism, improves cerebral blood circulation, anti-epileptics, sympathomimetics, tools, stimulating digestion, antacids, antiulcer funds, antitussive face means, antiemetics, respiratory stimulants center, bronchodilators, antiallergic agents, dental dental tools, antihistamines, cardiac funds, antiarrhythmic drugs diuretico is, antihypertensive drugs, stimulators of vascular tone, coronary vasodilators, peripheral vasodilators, antihyperlipidemic drugs, choleretic agents, antibiotics, chemotherapeutic agents, antidiabetic agents, drugs for the treatment of osteoporosis, Antirheumatic agents, skeletal muscle relaxants, antispasmodic drugs, hormonal drugs, narcotic alkaloids, sulfonamides, means for the treatment of gout, anticoagulant, anticancer agents, etc.

Specific examples of the active ingredient is not particularly limited, provided that the active ingredient is intended for oral administration, and drugs, it is highly suitable for such applications include antipyretic anti-inflammatory drugs such as indomethacin, ibuprofen, Ketoprofen, acetaminophen, aspirin and isopropylaniline; antihistamines, such as hydrochloride diphenylpyraline, maleate chlorpheniramine, cimetidine hydrochloride and isothipendyl; cardiovascular drugs, such as phenylephrine hydrochloride, procainamide hydrochloride, quinidine sulfate and nitrate isosorbide; antihypertensive agents such as amlodipine besylate and hydrochloride arotin the Lola; tranquilizers, such as sulpiride, diazepam, valproic acid, lithium carbonate and tandospirone citrate; antibiotics such as cephalexin and ampicillin; peptides or proteins, such as insulin, vasopressin, interferon, interleukin-2, urokinase, and various growth factors, such as human growth hormones; and other medicines such as theophylline, caffeine, citrate carbetapentane, hydrochloride phenylpropanolamine, denitrication, hydrochloride cetirizine and droxidopa; and their pharmaceutically acceptable salts (including inorganic salts and organic salts).

In addition, such active ingredients can be "particles coated", in which a portion of the surface or the entire surface of the active ingredient is covered with a covering agent such as water-insoluble polymer or a water-soluble polymer, for masking the bitter taste, control release, stabilization, etc.

The term "particles coated", the present invention relates to particles obtained in the coating solution or dispersion containing the covering means or molten liquid mixture on the surface of the active ingredients or compositions containing the active ingredient, thereby causing the coating on the entire surface of the particles or part of their surface.

Covering means on the em for example, water-soluble polymers, water-insoluble polymers, polymers soluble in the stomach and intestinal polymers. Water-soluble polymer is not specifically limited, and its examples include natural polymers and polysaccharides, such as gum Arabic powder (powdered gum acacia), gelatin, pullulan, dextrin, natrocarbonatite and sodium alginate and derivatives thereof; cellulose derivatives, such as carmellose, nutricology, calcixerollic, hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose and carboxymethylcellulose; and water-soluble vinyl derivatives, such as polyvinylpyrrolidone and polyvinyl alcohol. The water-insoluble polymer is not specifically limited, and its examples include ethylcellulose (especially aqueous dispersion of ethyl cellulose (for example, a product manufactured by FMC under the trade name AQUACOAT)), vinyl acetate polymer (for example, a product manufactured by BASF under the trade name Kollicoat SR30D), aminoalkylsilanes copolymer (especially of the aqueous dispersion (dispersion ammoniumnitrate copolymer) (for example, products produced by EVONIC under the trade names EUDRAGIT RL30D and EUDRAGIT RS30D)), the dispersion of a copolymer of acrylate and methyl methacrylate (e.g., product produced by EVONIC p is d trade name EUDRAGIT NE30D). Gastro-soluble polymer is not specifically limited and includes aminoacetanilide compounds such as polyvinylacetal-diethylaminoacetate (for example, a product manufactured by Mitsubishi-Called Foods Corporation under the trade name of AEA), aminoalkylsilanes copolymer E (for example, a product produced by EVONIC under the trade name EUDRAGIT E), and their mixture. Enteric polymer is not specifically limited and includes complex intestinal cellulose ethers, such as acetotrophic cellulose, acetylsuccinate hydroxypropylmethylcellulose, phthalate of hydroxypropylmethylcellulose (complex phthalic ester hypromellose), the phthalate of hydroxyethylmethylcellulose, karboksimetiltselljuloza and acetated cellulose; and enteric acrylic copolymers such as methacrylic acid copolymer LD (for example, a product produced by EVONIC under the trade name EUDRAGIT L30D-55, product of Sanyo Chemical Industries, Ltd., under the trade name POLYQUID PA30, and the product produced by BASF under the trade name Kollicoat MAE30DP), methacrylic acid copolymer L (for example, a product produced by EVONIC under the trade name EUDRAGIT L), methacrylic acid copolymer S (for example, products produced by EVONIC under the trade names EUDRAGIT S100 and EUDRAGIT FS30D).

Apparatus for coating includes granulators General type fluidized bed (including obroki Ivashina granulators fluidized bed, granulators with a Wurster fluidized bed and the like). To suppress the formation of coarse particles at this stage the preferred granulator, fluidized bed, using a method with improved Wurster air suspendirovanie, equipped with apparatus for enhanced circulation from the side surfaces (for example, SPC production Powrex Corporation, or the like) or complex granulator, fluidized bed supplied with the mechanism of sizing and grinding (sieve impeller, a bladed stator, a transverse screw feeder, crusher lumps or the like) (for example, the apparatus for coating and granulation SFP-01 production Powrex Corporation or the like), and a rotary granulator fluidized bed (e.g., OMNITEX production NARA MACHINERY CO., LTD., or the like). In an apparatus for drying spray you can use the spray dryer with General type product manufactured by OKAWARA CORPORATION, OKAWARA KAKOKI, YAMATO, NIRO or the like).

The concentration of active ingredient in the product may be different depending on the properties, and usually the content is 50% by mass or less, including, preferably, 30% by mass or less, and including, more preferably 10 mass% or less by weight of the tablet.

In the composition of the dosage form according to the present invention can also add non-toxic and inactive additives commonly used is in the pharmaceutical field and is different from the component as specified above, within the range not affecting the effects of the present invention.

Used additive can be any pharmaceutically acceptable additives, including, for example, excipients, plasticizers, sweeteners, corrigentov, perfumes and fragrances, colorants and stabilizers. Excipient includes, for example, sugars, such as lactose, refined sugar (refined sugar), sucrose, fructose, fructooligosaccharides, glucose, maltose, restored maltose, sugar, powdered crystalline sugar and restored lactose; sugar alcohols such as aritra, sorbitol ▫ maltitol, and xylitol; kaolin, calcium phosphate, calcium sulfate, calcium carbonate, and crystalline cellulose. The plasticizer includes, for example, light anhydrous silicic acid and alumosilicate magnesium. Sweetener and corrigent include, for example, sweeteners with high sladcasty, such as aspartame, saccharin, Nachrichten, dicliptera, stevia extract, thaumatin, Sucralose and Acesulfame K. Among them, preferred sweeteners with high sladcasty include aspartame, thaumatin and Sucralose. Perfume and flavor include, for example, peppermint, mint curly, menthol, lemon, orange, grapefruit, pineapple, fruits and yogurt. Depending on mixing the above sweetener, Corrie is enta, perfumes and flavoring, in some cases it is possible to obtain more preferable pleasant feeling left after swallowing the pills. These additives may be added suitably in an appropriate amount, individually or in combination of two or more types.

Method for the production of tablets according to the present invention is not specifically limited, and the tablet can be produced, for example, according to the following method. The tablet can be obtained by mixing D-mannitol, dezintegriruetsja tools and starch, granulating the mixture with water or an aqueous solution of a binder, drying the granulated product, mixing the dried product with the active ingredient and lubricant and compression molding the resulting mixture. The active ingredient can be mixed and pelletized with D-mannitol or the like In the case when there is a risk of compromising the content uniformity of the active ingredient, for example, due to the fact that each applicable component has the ability to aggregate or contains large crystals or granules, it is required to adjust each ingredient in size to the particle size, which can ensure the uniformity of content, through the use of a tool such as spraying, conducted before or after efficient when blended the I of each ingredient. Method of forming tablets not specifically limited, and when the tablet is produced commercially used method of compression molding using a rotary tablet press machine or tablet press machine single punch.

In this case, for tablets according to the present invention, the compression molding can be carried out without the application of the method with external lubrication; forming, of course, can be accomplished by way of external lubrication. In this case, the mixed components except for the lubricant and then spend tableting in the molds (dies and punches), injecting lubricant in them; or, alternatively, part of the lubricant is pre-mixed and then spend tableting in the mold, injecting them in the remaining lubricant.

The force with which perform compression molding is not specifically limited, provided that the forming force gives the tablet a sufficient strength, it is preferable to forming force 1 kN (about 100 kgf) or more. The shape of the obtained tablets in the present invention are not specifically limited, and the tablet may take any form, such as disc-shaped tablet, disc-shaped R-tablet-shaped tablets with beveled edges and various heteromorş tablets, and, alternatively, the tablet may be the tabla is some risk.

Examples

The present invention will be described below with specific examples, without intending to limit their scope of the present invention. In the measurement values of the physical properties, unless otherwise stated, the average particle size is a value which is obtained by measuring the dry method using laser diffraction analyzer distribution of particle sizes SALD-3000 (manufactured by Shimadzu Corporation) and by calculating the volume median diameter, which is defined as the average particle size and specific surface area is a value obtained by measurement by using an apparatus for measuring the specific surface Tristar 3000 (manufactured by Micromeritics) and carrying out the calculation according to the multi-point method BET, which determine the specific surface area.

Example 1

Eighty grams of hydroxypropylcellulose (HPC-L, the viscosity of a 2%aqueous solution: from 6.0 to 10.0 MPa·s, manufactured by Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) was loaded to 69.3 g of amlodipine besylate, 936,7 g of D-mannitol (crystals of β-type, average particle size: 43 μm, specific surface area: 0,51 m2/g), 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 50 g to the of opovidan (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 240-g portion of the above binder liquid and held granulation and drying, which gave 1000 g of the granules formed by granulation.

To 116,4 g of the granules formed by granulation, with stirring, was added 1.2 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) under a compressive force of approximately 7 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Example 2 (production of particles of amlodipine besylate, coated)

In 667,8 g of purified water was dissolved 37,35 g of Polysorbate 80 (Polysorbate 80 (HX), production NOF Corporation), and then it was mixed 88,12 g of talc (TALCAN HAYASHI, production Hayashi-Kasei Co., Ltd.) and 63,01 g nutritionnelles (Ac-Di-Sol, FMC production) and the resulting mixture was mixed with a liquid mixture obtained by previously adding 83,99 g 1N aqueous solution of sodium hydroxide to 840 g of methacrylic acid copolymer LD (POLYQUID PA-30S, production Sanyo Chemical Industries, Ltd.), getting opaque liquid.

Four hundred grams of amlodipine besylate and 1.6 g of light anhydrous PU glue the eve acid (Aerosil 200, production Nippon Aerosil Co., Ltd.) thoroughly mixed in a polyethylene bag, and the mixture was introduced into the granulator Wurster fluidized bed, equipped with apparatus for enhanced circulation (advanced granulator Wurster fluidized bed MP-01 SPC, production Powrex Corporation), and there was injected above the covering liquid. At the point when the injected amount was $ 1595, conducted phase drying/film formation in the fluidized bed. Particles of amlodipine besylate, coated, had an average size of 88 μm.

Example 3 (particles of anhydrous caffeine, coated)

In 188,5 g of purified water was dissolved to 31.5 g of Polysorbate 80 (Polysorbate 80 (HX), production NOF Corporation) and then under stirring was added 700 g of methacrylic acid copolymer LD (POLYQUID PA-30S, production Sanyo Chemical Industries, Ltd.), getting opaque liquid.

In a polyethylene bag thoroughly mixed 346,6 g of anhydrous caffeine and 3.5 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and the mixture is introduced into the granulator Wurster fluidized bed, equipped with apparatus for enhanced circulation (advanced granulator Wurster fluidized bed MP-01 SPC, production Powrex Corporation), and there was injected above the covering liquid. At the point when the injected amount was 751,3 g, conducted phase drying/plank the education in the fluidized bed. Particles of anhydrous caffeine, coated, had a medium size 127 μm.

Example 4

Eighty grams of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) downloaded 864,25 g of D-mannitol (crystals of β-type, average particle size: 43 μm, specific surface area: 0,51 m2/g), 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 50 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then to the mixture was injected 240-g portion of the above binder liquid and held granulation and drying, getting about 1000 g of the granules formed by granulation.

To 102,23 g of the granules formed by granulation, with stirring, was added 14,18 g particle of amlodipine besylate, coated tablets obtained in example 2, 1.2 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) under a compressive force of approximately 7 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 the m and a weight of 120 mg

Comparative examples 1 and 2

The tablet having a diameter of 7 mm and a weight of 120 mg, was obtained by the similar procedure of example 4, except that instead of D-mannitol with an average particle size of 43 μm and a specific surface area of 0.51 m2/g used D-mannitol (crystals of β-type), specified in table 1.

[Table 1]
The average particle size (µm)Specific surface area (m2/d)
Comparative example 191,56
Comparative example 22360,12

Example 5 and comparative examples 3-6

The tablet was obtained by the similar procedure of example 4, except that 2.4 g of sodium fumarate was replaced by the lubricant specified in table 2 together with its insertion number.

[Table 2]
LubricantInsertion amount (g)The mass of the tablet and (mg)
Example 5Complex sugar ester of fatty acids (SURFHOPE SE PHARMA J-1803F, manufactured by Mitsubishi Called)2,4120
EUR. example 3Magnesium stearate (light) stearate, vegetable production Taihei Chemical Industrial Co., Ltd.)1,2118,8
EUR. example 4Magnesium stearate (light) stearate, vegetable production Taihei Chemical Industrial Co., Ltd.)2,4120
EUR. example 5Stearic acid (stearic acid A, manufactured by NIPPON FINE SEIKA CO., LTD.)1,2118,8
EUR. example 6Stearic acid (stearic acid A, manufactured by NIPPON FINE SEIKA CO., LTD.)2,4120

Example 6

The tablet having a diameter of 7 mm and a weight of 120 mg, was obtained by the similar method of example 4, except that 50 g of crosspovidone was replaced by 50 g carmellose (NS-300, manufactured GOTOKU CHEMICAL COMPANY LTD.).

Example 7

Tablet, having the second diameter of 7 mm and a weight of 120 mg, received, similar to the method of example 4, except that the binder liquid was replaced with 240 g of a liquid consisting of 8 g of pre-gelatinizing starch (Amycol C, manufactured by NIPPON STARCH CHEMICAL CO., LTD.) and 232 g of purified water.

Example 8

The tablet having a diameter of 7 mm and weight to 121.6 mg, was obtained by the similar method of example 4, except that 14,18 g particle of amlodipine besylate, coated, replaced 15,79 g of particles of anhydrous caffeine, coated as described in example 3.

Test example 1

The presence or absence of complications during the pelletizing was evaluated for the compounds of examples 1 and 4-8 and comparative examples 1-6 in three ranks. (○: excellent, (∆):small complications, and ×: significant complications). The results are shown in table 3. If there were complications, complications are given in the parentheses.

[Table 3]
Evaluation of the results
Example 1
Example 4
EUR. example 1æ(pollution punch)
Cf is EXT. example 2
Example 5æ(pollution punch)
EUR. example 3× (friction in the matrix)
EUR. example 4æ(friction in the matrix)
EUR. example 5× (friction in the matrix)
EUR. example 6× (friction in the matrix)
Example 6
Example 7
Example 8

Test example 2

Disintegration time was measured for tablets prepared according to examples 1 and 4 to 8 and comparative examples 1, 2 and 4, using a testing device (tester) for tablets, disintegrating in the mouth (Toyama Sangyo Co., Ltd., model ODT-101)in the following conditions: the test solution was water (37±1°C), the weight was 10 g and the rotation speed was 25 rpm in Addition, a tester for determining the hardness of tablets (Toyama Sangyo Co., Ltd., TH-203MP) was measured hardness. The obtained hardness values were expressed as absolute hardness as quotient izmereno what about the hardness values in the area of the fault surface tablets. Additionally, in three ranks (○: excellent, (∆):well and ×: poor) assessed the feeling after keeping the tablet in the mouth until complete dissolution; evaluation (∆)and × is shown with a detailed description of the sensations given in parentheses. The results are shown in table 4.

[Table 4]
Disintegration time (sec)Hardness (H)Absolute hardness (N/mm2)The feeling when swallowing
Example 118452,5
Example 420512,7
EUR. example 134643,3∆ (poor solubility in the mouth)
EUR. example 220392,1× (feeling mehanicheskij the irritation)
Example 517502,7
EUR. example 438482,6∆ (poor solubility in the mouth)
Example 624472,5
Example 714492,6
Example 825532,8

As shown in table 4, all the tablets of examples 1 and 4-7 showed excellent hardness (2,5 N/mm2or more) and disintegration time (30 seconds or less) and left superior feeling after swallowing. On the other hand, the tablet of comparative example 1 showed a slow disintegration time, though, and showed excellent hardness. In addition, the tablet of comparative example 2 had a low hardness and after swallowing felt mechanical irritation, although pokazala great time decay. The tablet of comparative example 4 had a slow time of the collapse, though, and showed excellent hardness.

Example 2-1 (sample 1)

Eighty grams of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) was loaded to 69.3 g of amlodipine besylate, 936,7 g of D-mannitol (crystals of β-type, average particle size: 43 μm, specific surface area: 0,51 m2/g), 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 50 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 240-g portion of the above binder liquid and held granulation and drying, receiving granules formed by granulation.

To 116,4 g of the granules formed by granulation, with stirring, was added 1.2 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when efforts compression 7 kN 9 kN and 11 kN, respectively, receiving the tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 10 mg In this case, the tablet obtained by pelletizing when the compressing force 7 kN is the tablet equivalent of the tablet of example 1.

Example 2-2 and comparative examples (2-1)to(2-6) (compounds of examples 2-8)

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg, was obtained by the same methodology for the composition of example 1, except that 50 g of crosspovidone was replaced dezintegriraat means specified in table 5.

[Table 5]
Dezintegriruetsja toolThe amount applied (g)
Example 2-1The composition of example 1Crosspovidone (Polyplasdone XL-10)50
Example 2-2The composition of example 2Carmellose (NS-300)50
EUR. example 2-1The composition of example 3Nizkozameshhennoj hydroxypropylcellulose (L-HPC (LH-21))50
EUR. example 2-2The composition with the EPA 4 Calcicoles (ECG-505)50
EUR. example 2-3The composition of example 5Nutricology (Ac-Di-Sol)50
EUR. example 2-4The composition of example 6Pre partly gelatinizing starch (PCS)50
EUR. example 2-5The composition of example 7Natrocarbonatite (EXPLOTAB)50
EUR. example 2-6The composition of example 8Hydroxypropylmethyl (HPS-101)50

Example 2-3 (sample 9)

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg, was obtained by the same methodology for the composition of example 1, except that 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) replaced the same amount of D-mannitol (crystals of β-type, average particle size: 43 μm, specific surface area: 0,51 m2/g) and tableting was carried out at the efforts compression 6 kN and 9 kN.

Comparative example 2-7 (composition of example 10)/p>

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg, was obtained by the same methodology for the composition of example 1, except that 936,7 g of D-mannitol was replaced with the same amount of lactose (Pharmatose 200M) and tableting was carried out at the efforts compression 7 kN and 9 kN.

Test example 3

For dosage forms of the compositions of examples 1-10 were measuring the hardness and, in the same manner as in test example 2, was calculated absolute hardness. In addition, in the same manner as in test example 2, measured time decay. The results are shown in table 6, table 7 and figure 1.

[Table 6]
7 kN9 kN11 kN
Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolue is Naya hardness (N/mm 2)
Example 2-1The composition of example 1182,5173,7174,4
Example 2-2The composition of example 2242,0252,8264,1
EUR. example 2-1The composition of example 3222,1312,8423,0
EUR. example 2-2The composition of example 4302,2 363,4444,2
EUR. example 2-3The composition of example 5262,1343,2454,3
EUR. example 2-4The composition of example 6271,5332,5454,1
EUR. example 2-5The composition of example 7181,8342,6414,0
EUR. example 2-6SOS is AB example 8 221,5262,342the 3.8
[Table 7]
6 kN7 kN9 kN
Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)
Example 2-3The composition of example 9282,5-- 343,3
EUR. example 2-7The composition of example 10--431,6382,5

According to the results of tables 6 and 7, each of the dosage forms of the composition of example 1, molded when the compressing force 7, 9 or 11 kN, each of the dosage forms of the composition of example 2, molded when the compressing force 8 or 11 kN, and dosage form of the composition of example 9, a molded when the compressing force of 6 kN, had the strength at which the absolute hardness was 2.5 N/mm2and at the same time, they had an excellent ability to collapse, at which disintegration time was 30 seconds. Particularly, each of the dosage forms of the composition of example 1, molded when the compressing force 9 or 11 kN dosage form of the composition of example 2, molded when the compressing force 11 kN, suddenly had such strength, in which the absolute hardness was 3.0 N/mm2or more, with an excellent ability to collapse, at which disintegration time was 30 seconds.

On the other hand, each of the dosage forms of the compositions p is Kerov 3-8, which used dezintegriruetsja means other than crosspovidone and carmellose, and dosage form of the composition of example 10, in which instead of D-mannitol was used lactose, were not those dosage forms that showed such excellent properties, in which the absolute hardness was not less than 2.5 N/mm2and disintegration time was 30 seconds.

Figure 1 presents a graph showing the test results of the compositions of examples 1-8, where the x-axis shows the absolute hardness, and the y-axis shows the time decay according to the test apparatus tablets, disintegrating in the mouth. In the dosage forms of the compositions of examples 3-8 observed an increase in decay time with increasing hardness; on the other hand, in the composition of example 1, in which as dezintegriruetsja tools used crosspovidone, and in the composition of example 2, which used carmellose, extension of time decay with increasing hardness of the tablets was observed. Due to these unexpected events, it was noted that the dosage form, in which as dezintegriruetsja tools used crosspovidone or carmellose, can simultaneously possess high strength tablets and an excellent ability to collapse.

Example 3-1 (sample 11)

Eighty of gramma is hydroxypropylcellulose (HPC-L, production Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) downloaded 864,25 g of D-mannitol (crystals of β-type, average particle size: 43 μm, specific surface area: 0,51 m2/g), 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 50 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 240-g portion of the above binder liquid and held granulation and drying, getting about 1000 g of the granules formed by granulation.

To 102,23 g of the granules formed by granulation, with stirring, was added 14,18 g particle of amlodipine besylate, coated tablets obtained in example 2, 1.2 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when efforts compression 7 kN and 9 kN, respectively, receiving the tablet having a diameter of 7 mm, a curvature radius of 100 mm and a weight of 120 mg

Example 3-2 and comparative examples 3-1)to(3-6) (compounds of examples 12-18)

The tablet having a diameter of 7 mm, a curvature radius of 100 mm and the Assu 120 mg, received the same methodology for the composition of example 11, except that 50 g of crosspovidone was replaced dezintegriraat means, as indicated in table 8, and tableting was carried out at the force of the compression ratio specified in table 9.

[Table 8]
Dezintegriruetsja toolThe amount applied (g)
Example 3-1The composition of example 11Crosspovidone (Polyplasdone XL-I0)50
Example 3-2The composition of example 12Carmellose (NS-300)50
EUR. example 3-1The composition of example 13Nizkozameshhennoj hydroxypropylcellulose (L-HPC (LH-21))50
EUR. example 3-2The composition of example 14Calcixerollic (ECG-505)50
EUR. example 3-3The composition of example 15Nitric carmellose (Ac-Di-Sol) 50
EUR. example 3-4The composition of example 16Pre partly gelatinizing starch (PCS)50
EUR. example 3-5The composition of example 17Natrocarbonatite (EXPLOTAB)50
EUR. example 3-6The composition of example 18Hydroxypropylmethyl (HPS-I01)50

Example 3-3 (composition of example 19)

The tablet having a diameter of 7 mm and weight to 121.6 mg, was obtained by the same methodology for the composition of example 11, except that 14,18 g particle of amlodipine besylate, coated, replaced 15,79 g of particles of anhydrous caffeine, coated as described in example 3.

Example 3-4 (composition of example 20)

Forty-eight grams of triethylcitrate (CITROFLEX 2) were carefully dispersible 700 g of purified water and dispersed solution was mixed 1400 g of aqueous dispersion of ethyl cellulose (AQUACOAT, production FMC), then there was added 63 g of talc (TALCAN HAYASHI, production Hayashi-Kasei Co., Ltd.), getting opaque liquid.

Four hundred grams of amlodipine besylate and 1.6 g of light anhydrous PU glue the eve acid (Aerosil 200, production Nippon Aerosil Co., Ltd.) thoroughly mixed in a polyethylene bag, and the mixture was introduced into the granulator Wurster fluidized bed, equipped with apparatus for enhanced circulation (advanced granulator Wurster fluidized bed MP-01 SPC, production Powrex Corporation), and there was injected above the covering liquid. At the point when the injected amount was $ 907, conducted phase drying/film formation in the fluidized bed, receiving particles of amlodipine besylate and ethyl cellulose coated.

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 117,5 mg, was obtained by the same methodology for the composition of example 11, except that 14,18 g particle of amlodipine besylate, coated, replaced of 11.69 g of particles of amlodipine besylate and ethyl cellulose, coated, and tableting was carried out at the force of the compression ratio specified in table 9.

Test example 4

For dosage forms of the compositions of examples 11-20 were measuring the hardness and in the same manner as in test example 2, was calculated absolute hardness. In addition, in the same manner as in test example 2, measured time decay. The results are shown in table 9.

[Table 9]
7 kN9 kN11 kN
Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)
Example 3-1The composition of example 11202,7193,6--
Example 3-2The composition of example 12242,5253,7--
EUR. example 3-1The composition of example 13432,7----
EUR. example 3-2The composition of example 14512,7----
EUR. example 3-3The composition of example 15472,7----
EUR. example 3-4The composition of example 16452,4----
EUR. example 3-5The composition of example 17382,7----
EUR. example 3-6The composition of example 18412,7----
Prima is 3-3 The composition of example 19252,822a 3.9
Example 3-4The composition of example 20282,6--283,3

According to the results of table 9, each of the dosage forms of the compositions of examples 11, 12, 19 and 20, molded when the compressing force 7 kN, had the strength at which the absolute hardness was 2.5 N/mm2or more, and at the same time had an excellent ability to collapse, at which disintegration time was 30 seconds. In addition, each of the dosage forms of the compositions of examples 11, 12 and 19, molded when the compressing force 9 kN, and dosage form of the composition of example 20, molded when the compressing force 11 kN, suddenly had such strength, in which the absolute hardness was 3.0 N/mm2or more, and they had an excellent ability to collapse, at which disintegration time was 30 seconds.

On the other hand, each of the dosage forms of the compositions of examples 13 and 18, which used disintegrity the developing means, other than crosspovidone and carmellose did not belong to medications that had such excellent properties, in which the absolute hardness was 2.5 N/mm2or more, and disintegration time was 30 seconds.

Comparative example 4-1 (composition of example 21)

In 623,7 g of purified water were dispersively 6.3 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and the dispersion was heated to obtain a paste, which gave 630 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) downloaded 869,4 g of D-mannitol (crystals of β-type, average particle size: 46 μm, specific surface area: 0.46 m2/g), 90 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 32.4 g nitrosamines hydroxypropylcellulose (L-HPC LH-22, manufactured by Shin-Etsu Chemical Co., Ltd.) and the content was stirred. Then there was injected 630 g of the above binder liquid and held granulation and drying, receiving granules formed by granulation.

To 99,81 g of the granules formed by granulation, with stirring, was added 14,18 g particle of amlodipine besylate, coated tablets obtained in example 2, 1.2 g of light anhydrous silicic acid (AerosiI 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA), receiving granules to table the tests.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when efforts compression 6 7 kN and kN, respectively, receiving the tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Test example 5

For dosage forms of the composition of example 21 was performed measuring the hardness and in the same manner as in test example 2, was calculated absolute hardness. In addition, in the same manner as in test example 2, measured time decay. The results are shown in table 10.

[Table 10]
6 kN7 kN
Disintegration time (sec)Absolute hardness (N/mm2)Disintegration time (sec)Absolute hardness (N/mm2)
EUR. example 4-1The composition of example 21362,7463,1

According to the results table is s 10, dosage form of the composition of example 21, even when it was formed when the efforts of the grips 6 and 7 kN, showed the absolute hardness of not less than 2.5 N/mm2but the time of its disintegration exceeded 30 seconds.

Example 5-1 (composition of example 22)

Eighty grams of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In the granulator, fluidized bed (Multiplex MP-01, manufactured Powrex Corporation) downloaded 906 g of D-mannitol (crystals of β-type, average particle size: 46 μm, specific surface area: 0.46 m2/g), 100 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 50 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 240-g portion of the above binder liquid and held granulation and drying, receiving granules formed by granulation.

To 106,4 g of the granules formed by granulation, with stirring, was added 10 g of amlodipine besylate (average particle size: 20 μm), 1.2 g of light anhydrous silicic acid (Aerosil 200, manufactured by Nippon Aerosil Co., Ltd.) and 3.6 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) in Wuxi the AI compression 9 kN getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 121,2 mg.

Examples (5-2)-(5-5) (compounds of examples 23-26)

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 121,2 mg, was obtained by the same methodology for the composition of example 22, except that 10 g of amlodipine besylate replaced the active ingredient indicated in table 11, and tableting was carried out at the force of the compression ratio specified in table 11.

[Table 11]
The active ingredientThe amount applied (g)The compressing force when pelletizing (kN)
Example 5-1The composition of example 22Besylate amlodipine509
Example 5-2The composition of example 23Hydrochloride Metformin5011
Example 5-3The composition of example 24Acetaminophen5011
Example 5-4The composition of example 25Sodium ascorbate5011
Example 5-5The composition of example 26Ibuprofen5011

Example 6-1 (sample 27)

Eighty grams of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) was dissolved in 2320 g of purified water, getting 2400 g of binder liquid.

In a universal mixer (5DMr, production San-ei Seisakusho) was loaded 34,65 g of amlodipine besylate, 468,35 g of D-mannitol (crystals of β-type, average particle size: 46 μm, specific surface area: 0.46 m2/g), 5 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 25 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 120-g portion of the above binder liquid was added 20 g of purified water and the mixture was mixed until a homogeneous mass. Zameshannuu the mixture was dried on a shelf aerated drying overnight at 60°C and the dried mixture was subjected to sorting by size, receiving granules formed by granulation.

To 116,4 g of the granules formed by granulation, with stirring, was added 1.2 g is egcoa anhydrous silicic acid (AerosiI 200, production Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production JRS PHARMA)to give granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when the compressing force 9 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Example 6-2 (sample 28)

In a universal mixer (5DMr, production San-ei Seisakusho) was loaded 432,1 g of D-mannitol (crystals of β-type, average particle size: 46 μm, specific surface area: 0.46 m2/g), 50 g of corn starch (Corn Starch (XX16)W, manufactured by NIHON SHOKUHIN KAKO CO., LTD.) and 25 g of crosspovidone (Polyplasdone XL-10, production ISP) and the contents stirred. Then there was injected 120-g portion of the above-described binder liquid was added 20 g of purified water and the mixture was mixed until a homogeneous mass. Zameshannuu the mixture was dried on a shelf aerated drying overnight at 60°C and the dried mixture was subjected to sorting by size, receiving granules formed by granulation.

To 102,2 g of the granules formed by granulation, with stirring, was added 14,18 g particle of amlodipine besylate, coated tablets obtained in example 2, 1.2 g of light anhydrous silicic acid (AerosiI 200, manufactured by Nippon Aerosil Co., Ltd.) and 2.4 g of sodium fumarate (PRUV, production is odstv JRS PHARMA), receiving granules for tableting.

The obtained granules for tableting were subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when the compressing force 9 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Example 6-3 (composition of example 29)

The tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg, was obtained by the same methodology for the composition of example 28, except that 25 g of crosspovidone was replaced by 25 g carmellose.

Example 6-4 (sample 30)

Granules for tabletting of example 5 was subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when the compressing force 9 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Example 6-5 (composition of example 31)

Granules for tabletting of example 7 was subjected to pelletizing using tablet press machine single punch (EKO, production KORSCH) when the compressing force 9 kN, getting a tablet having a diameter of 7 mm, a curvature radius of 10 mm and a weight of 120 mg

Test example 6

For dosage forms of the compositions of examples 22 and 31 measurements of hardness and in the same manner as in test example 2, was calculated absolute hardness. In addition, in the same manner as in test example 2, was measured BP is me collapse. The results are shown in table 12.

[Table 12]
Disintegration time (sec)Absolute hardness (N/mm2)
Example 5-1The composition of example 22193,5
Example 5-2The composition of example 23303,2
Example 5-3The composition of example 24143,5
Example 5-4The composition of example 25303,5
Example 5-5The composition of example 26193,0
Example 6-1The composition of example 27204,1
Example 6-2The composition of example 28243,7
Example 6-3The composition of example 29263,4
Example 6-4The composition of example 30204,0
Example 6-5The composition of example 31163,7

According to the results in table 12, all dosage forms of the compositions of examples 22-31 showed absolute hardness of 3.0 N/mm2or more and disintegration time within 30 seconds.

Industrial utility

Disintegrating in the mouth tablet according to the present invention has some excellent properties: (1) its production on conventional equipment, without requiring the use of specialized pharmaceutical equipment, (2) it has sufficient strength to prevent collapse in the distribution process, (3) the tablet is capable of rapidly disintegrating in the oral cavity, and (4) after swallowing it leaves a superb feeling, greatly weakening the bitter taste and sense mechanical stimuli; therefore, this tablet can be used for use as a dosage form, suitable for elderly persons who, children and seriously ill patients.

1. Disintegrating in the mouth tablet containing (1) D-mannitol, (2) an active ingredient, (3) one or more dezintegriruetsja means selected from the group consisting of crosspovidone and carmellose, (4) one or more lubricants selected from the group consisting of sodium fumarate and complex sucrose esters of fatty acids, (5) a binder and (6) starch.

2. Disintegrating in the mouth tablet according to claim 1, where dezintegriraat means is crosspovidone.

3. Disintegrating in the mouth tablet according to claim 1, where the lubricant is sodium fumarate.

4. Disintegrating in the mouth tablet according to any one of claims 1 or 2, where dezintegriruetsja tool is present in an amount of from 1 to 10 wt.%.

5. Disintegrating in the mouth tablet according to any one of claims 1 or 3, where the lubricant is present in an amount of from 0.01 to 5 wt.%.

6. Disintegrating in the mouth tablet according to claim 1, where D-mannitol has an average particle size greater than 10 μm and equal to or less than 500 μm,

7. Disintegrating in the mouth tablet according to claim 2, where the lubricant is sodium fumarate.

8. Disintegrating in the mouth tablet according to claim 7, where D-mannitol has an average particle size greater than 10 μm and equal to or less than 500 microns.

9. Disintegrating in the mouth tablet according to claim 1, where D-mannitol has an average particle size greater than 30 μm, and specific surface of more than 0.40 m2/year

10. Disintegrating in the mouth tablet according to claim 1, where D-mannitol is a β-type crystal.

11. Disintegrating in the mouth tablet according to claim 1, where the binder is one or more members selected from the group consisting of hydroxypropylcellulose and pre gelatinizing starch.

12. Disintegrating in the mouth tablet according to claim 11, where 2%aqueous solution of hydroxypropylcellulose has a viscosity of from 2 to 10 MPa·s at 20°C.

13. Disintegrating in the mouth tablet according to claim 1, where the binder is present in an amount of from 0.01 to 2 wt.%.

14. Disintegrating in the mouth tablet according to claim 1, where the starch is one or more members selected from the group consisting of corn starch, potato starch, rice starch, wheat starch and partially pre-gelatinizing starch.

15. Disintegrating in the mouth tablet according to claim 1, where the active ingredient is amlodipine or its pharmaceutically acceptable salt.

16. Disintegrating in the mouth tablet indicated in paragraph 15, where the active ingredient is amlodipine besylate.

17. Disintegrating in the mouth tablet according to claim 1, where the active ingredient is a particle, granule or covered with a covering agent.

18. Disintegrating in the mouth tablet 17, where the active ingredient is amlodipine or its pharmaceutically acceptable salt, granular, the traveler or covered with a covering agent.

19. Disintegrating in the mouth tablet p, where the active ingredient is amlodipine besylate, granulated or coated covering means.

20. Disintegrating in the mouth tablet containing (1) D-mannitol having an average particle size greater than 30 μm, and specific surface of more than 0.40 m2/g, (2) 0.1 to 50% by weight of active ingredient, (3) 1-10% by weight of crosspovidone, carmellose or their combination, (4) 2% by weight or less of hydroxypropylcellulose, pre gelatinizing starch, or a combination of (5) 5-20% by weight of starch and (6) 0.1 to 5% by weight of sodium fumarate.

21. Disintegrating in the mouth tablet according to any one of claims 1 or 2, where the tablet disintegrates in the mouth within 30 seconds and has an absolute hardness of 2.5 N/mm2or more.

22. Disintegrating in the mouth tablet containing (1) D-mannitol, (2) an active ingredient, (3) crosspovidone, (4) sodium fumarate, (5) a binder and (6) starch, where the active ingredient is a particle, granule or covered with a covering agent.

23. Disintegrating in the mouth tablet p.22, where the active ingredient is amlodipine or its pharmaceutically acceptable salt, granulated or coated covering means.

24. Disintegrating in the mouth tablet according to claim 1, where the tablet contains granules obtained by mixing D-mannitol, desintegrates the th tools and starch, the active ingredient and lubricant.

25. Disintegrating in the mouth tablet according to claim 1, where the tablet contains granules obtained by mixing the active ingredient, D-mannitol, dezintegriruetsja tools and starch, and a lubricant.

26. Disintegrating in the mouth tablet according to claim 1, characterized in that the disintegrating in the mouth tablet containing granules, are due to exposure to mixtures containing at least the D-mannitol and dezintegriruetsja tool, wet granulation.

27. Disintegrating in the mouth tablet p, where in the case when the D-mannitol using D-mannitol for direct compression, the proportion of D-mannitol for direct compression is less than 50% by weight of the entire D-mannitol drug.

28. Disintegrating in the mouth tablet according to item 27, where in the case when the D-mannitol using D-mannitol for direct compression, the proportion of D-mannitol for direct compression is less than 30% by weight of the entire D-mannitol drug.



 

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10 cl, 11 ex, 6 dwg

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17 cl, 4 tbl, 21 ex

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29 cl, 10 dwg, 23 tbl, 8 ex

.

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