JP2002154988A - Disintegrable tablet in oral cavity and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a tablet disintegrable in the oral cavity by finding a tableting technique capable of making a sufficient hardness compatible with disintegrability in the oral cavity even in the absence of water in a preparation and utilizing the technique. SOLUTION: This tablet disintegrable in the oral cavity comprises a partially amorphous saccharide containing a crystallized part and an amorphous part as a carrier in a preparation. This method for producing a tablet disintegrable in the oral cavity comprises formulating a physiologically active component with the partially amorphous saccharide containing a crystallized part and an amorphous part and tableting the mixture.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an orally disintegrating tablet which rapidly disintegrates in the oral cavity and a method for producing the same.

[0002]

2. Description of the Related Art At present, when orally administering a drug,
It is common to use tablets and capsules. But for example, for the elderly, children and patients with difficulty swallowing,
These preparations are difficult to take. Dry syrups and the like have also been provided to make them easier to take, but they have drawbacks such as poor usability and portability, such as the need to add water to the preparation upon taking.

For the purpose of solving such problems, there has been a demand for the development of a preparation which can be taken without water, and an orally disintegrating tablet which rapidly disintegrates in the oral cavity has been provided to satisfy this requirement.

[0004] As a method for producing this orally disintegrating tablet,
For example, a method of tableting a mixture containing water to such an extent that the surface of the particles becomes wet (Japanese Patent Laid-Open No. 5-27054), or a method of compressing and molding under a low pressure mainly comprising an amorphous saccharide, and then placing the tablet under humidification and wetting And further drying (Japanese Unexamined Patent Publication No.
162 and JP-A-11-349475) are known.

[0005] However, the orally disintegrating tablet obtained by the above-mentioned method can maintain the disintegration property in the oral cavity and the hardness required for carrying, but the manufacturing process is required to achieve both disintegration and hardness. It was not always satisfactory from the viewpoint of manufacturing process control, for example, it was necessary to control the amount of water in the inside, or it was necessary to leave it under high humidity. Further, since water is present in the preparation, there is a possibility that stability may be problematic depending on the physiologically active ingredient used, and there is also a problem that the range of use is limited.

[0006]

Accordingly, a tableting technique which can achieve both sufficient hardness and disintegration in the oral cavity even when water does not exist in the preparation has been found. It is an object of the present invention to provide disintegrating tablets.

[0007]

Means for Solving the Problems In order to solve the above problems, the present inventors have studied the components forming a tablet. As a result, as a saccharide used as a carrier component of the tablet, some sugars are not present in the crystalline material. By using saccharides containing a mixture of crystalline substances, it has been found that an orally disintegrating tablet which has a hardness such that there is no wear during the distribution process and which rapidly disintegrates in the oral cavity can be obtained, and completed the present invention. .

[0008] That is, the present invention provides, as a carrier in a preparation,
It is intended to provide an orally disintegrating tablet containing a partially amorphous saccharide containing a crystallized portion and an amorphous portion.

The present invention also provides an orally disintegrating tablet using a partially amorphous saccharide and a sugar alcohol containing a crystallized portion and an amorphous portion as a carrier in a preparation. is there.

The present invention further provides a method for producing the orally disintegrating tablet.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The orally disintegrating tablet of the present invention uses a partially amorphized saccharide containing a crystallized portion and an amorphous portion as a carrier in a preparation. It is manufactured by combining with a physiologically active ingredient which is an active ingredient of a preparation and formulating it as a tablet by a conventional method.

The partially amorphized saccharide used in the present invention refers to a mixture of a crystallized saccharide and an amorphous saccharide, which are substantially uniformly mixed. The mixing ratio between the crystallized saccharide and the non-crystallized saccharide is not particularly limited, but is, for example, 50 to 95:50 to
It is about 5, more preferably about 60 to 90:40 to 10.

Such partially amorphized saccharides are obtained by dissolving the saccharides in an appropriate solvent and spray-drying the saccharides, and by appropriately changing the conditions of the spray-drying, the desired degree of amorphization is obtained. Are obtained. Also, saccharides that have been completely amorphized by means such as freeze-drying and high-pressure grinding for a long time can be obtained by mixing with any amount of crystalline saccharides, and may be produced by other means. A partially amorphous saccharide obtained by spray drying is preferred.

The kind of the saccharide of the partially amorphized saccharide is not particularly limited as long as it is solid at normal temperature and is water-soluble, and is not limited to monosaccharides, oligosaccharides, polysaccharides and saccharide derivatives. Is mentioned. More specifically, for example, sucrose,
Coupling sugar, fructooligosaccharide, palatinose, glucose, maltose, lactose, fructose and the like are used, among which lactose is preferred, and alpha-lactose-hydrate is particularly preferred.

The amount of the partially amorphized saccharide in the orally disintegrating tablet of the present invention varies depending on the required amount of the physiologically active ingredient to be added and the amount of other optional ingredients described below.
It is used in an amount of about 20 to about 99% by weight per tablet weight (hereinafter simply referred to as "%"), preferably about 50 to about 95%.

The partially amorphized saccharide used in the present invention may further be used in combination with a sugar alcohol in order to improve the mouthfeel in the oral cavity when taken. Examples of the sugar alcohol include sorbitol, xylitol, erythritol, mannitol, maltitol, lactitol, paranit and the like. These sugar alcohols can be granulated and used by a conventional method. The amount of sugar alcohol used in this case is 1 to 60%, preferably 2 to 40%, based on the weight of the preparation.

On the other hand, in the present invention, the physiologically active ingredient to be partially combined with the amorphized saccharide is not particularly limited in its structure, action and use.
Nourishing tonic health drugs, antipyretic analgesics and anti-inflammatory drugs, psychotropic drugs, anti-anxiety drugs, antidepressants, hypnotic sedatives, antispasmodics, gastrointestinal drugs, antacids,
Laxatives, antitussive expectorants, dental oral medicines, antihistamines, inotropics, arrhythmias, diuretics, hypotensives, vasoconstrictors,
Selected from coronary vasodilators, peripheral vasodilators, bile drugs, antibiotics, antivirals, chemotherapeutics, diabetes, osteoporosis, skeletal muscle relaxants, antihyperlipidemic agents, etc. One or more components are used. These physiologically active ingredients may be generally diluted with a diluent or the like used in the field of medicine, foods, etc.
Those mixed with binders, disintegrants, masking agents, etc.
Alternatively, it may be refined, refined, refined, or granulated. Further, at least one of the medicinal ingredients may be oily.

[0018] Of the above, nourishing tonics include, for example, vitamin A, vitamin D, vitamin E (acetate d-α).
- tocopherol), vitamin B ₁ (dibenzoyl thiamine, etc. fursultiamine hydrochloride), vitamin B
Vitamins such as ₂ (such as riboflavin butyrate), vitamin B ₆ (such as pyridoxine hydrochloride), vitamin C (such as ascorbic acid and sodium L-ascorbate), and vitamin B ₁₂ (such as hydroxocobalamin acetate);
Minerals such as magnesium and iron; proteins; amino acids; oligosaccharides;

Examples of antipyretic analgesics and anti-inflammatory drugs include aspirin, acetaminophen, etensamide, ibuprofen, diphenhydramine hydrochloride, dl-chlorpheniramine maleate, dihydrocodeine phosphate, noscapine, methylephedrine hydrochloride, phenylpropanolamine hydrochloride, caffeine , Serrapeptase, lysozyme chloride, tolfenamic acid, mefenamic acid, diclofenac sodium, flufenamic acid, salicylamide, aminopyrine, ketoprofen, indomethacin, bucolome,
Pentazocine and the like.

Examples of the psychotropic drug include chlorpromazine, reserpine and the like. Examples of the anxiolytic include chlordiazepoxide, diazepam and the like. Examples of the antidepressant include imipramine, maprotiline, amphetamine and the like.
Examples of the hypnotic sedative include estazolam, nitrazepam, diazepam, phenobarbital sodium and the like. Antispasmodics include, for example, scopolamine hydrobromide, diphenhydramine hydrochloride, papaverine hydrochloride and the like.

Gastrointestinal drugs include, for example, gastrointestinal drugs such as diastase, sugar-containing pepsin, funnel extract, lipase AP, and calyx oil; intestinal drugs such as berberine chloride, resistant lactic acid bacteria, and bifidobacteria; H ₂ blockers; cetraxate, gefarnate, teprenone, sofalcone, mucosal protective agents such as rebamipide; omeprazole, and the like proton pump inhibitors such as lansoprazole. Examples of the antacid include magnesium carbonate, sodium hydrogencarbonate, magnesium aluminate metasilicate, synthetic hydrotalcite, precipitated calcium carbonate, magnesium oxide, and the like. Examples of the laxative include sodium picosulfate, bisacodyl and the like.

Examples of the antitussive expectorants include cloperastine hydrochloride, dextromethorphan hydrobromide, theophylline, potassium guaiacol sulfonate, guaifenesin, ambroxol hydrochloride, and bromhexine hydrochloride. Examples of the oral medicine include oxytetracycline, triamcinolone acetonide, chlorhexidine hydrochloride, lidocaine and the like.

Examples of the antihistamine include diphenhydramine hydrochloride, promethazine, isotipendyl hydrochloride, dl-chlorpheniramine maleate and the like. Examples of the cardiotonic agent include, for example, ethylephrine hydrochloride and the like. Examples of the agent for arrhythmia include procainamide hydrochloride, propranolol hydrochloride, pindolol and the like. Examples of the diuretic include isosorbide, furosemide and the like. Examples of the antihypertensive include nifedipine, delapril hydrochloride, captopril, hexamethonium bromide, hydralazine hydrochloride, labetalol hydrochloride, methyldopa and the like.

Examples of the vasoconstrictor include phenylephrine hydrochloride. Examples of the coronary vasodilator include carbochromene hydrochloride, molsidomine, verapamil hydrochloride and the like. Examples of the peripheral vasodilator include cinnarizine and the like. As a bolus,
For example, dehydrocholic acid, trepibutone, etc. are exemplified.

Antibiotics include, for example, cephalexin,
Examples include cephem, penem, carbapenem, macrolide, aminoglycoside, new quinolone, and polypeptide antibiotics such as amoxicillin, pivmecillinam hydrochloride, and cefotiam hydrochloride. Chemotherapeutic agents include, for example, sulfamethizole, thiazosulfone and the like. Examples of the antiviral agent include acyclovir, vidarabine and the like. Examples of the antidiabetic agent include tolbutamide, voglibose and the like. Examples of the agent for osteoporosis include ipriflavone and the like. Skeletal muscle relaxants include methocarbamol and the like. Examples of the antihyperlipidemic agent include pravastatin, simvastatin and the like.

Preferred physiologically active ingredients used in the present invention include, for example, the above-mentioned vitamins, crude drugs, antipyretic analgesics and anti-inflammatory drugs, anxiolytics, hypnotics and sedatives, gastrointestinal drugs, laxatives, antitussive expectorants, antihypertensives, Diabetes agents, osteoporosis agents, skeletal muscle relaxants, antihyperlipidemic agents, and the like.

The orally disintegrating tablet of the present invention is prepared by blending the above-mentioned physiologically active ingredient, partially amorphized saccharide and, if necessary, sugar alcohol by a conventional method, preferably by compression molding at a low pressure.

More specifically, for example, at least one of the following suitable additives is mixed with a physiologically active ingredient,
Alternatively, after kneading and granulating, the mixture is partially mixed with an amorphous saccharide, and then compression-molded (tableting).
Alternatively, before or after the mixing or kneading / granulating step of mixing or kneading / granulating the physiologically active ingredient and the partially amorphized saccharide, it can be obtained by compression molding (tableting).

The pressure (tablet pressure) in compression molding is 50
About 2500 kg / cm ² , and 500 to 1500
It is more preferably about kg / cm ² . Further, the humidity of the tableting environment is preferably about 70% or less, particularly preferably about 50% or less.

In preparing the orally disintegrating tablet of the present invention, various additives generally used for tablet production can be used as long as the effects of the present invention are not hindered.

The additives include, for example, disintegrants, binders, extenders, lubricants, flavoring ingredients, masking agents, fragrances and auxiliaries.

More specifically, examples of the disintegrant include corn starch, potato starch, partially pregelatinized starch, sodium carboxymethyl starch, camellose, carmellose calcium, carmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, crystal Examples include cellulose and hydroxypropyl starch. Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, carmellose sodium, pregelatinized starch, polyvinylpyrrolidone, gum arabic powder, gelatin, pullulan, copolyvidone, and the like. Examples of the bulking agent include sucrose, glucose, lactose, sugars such as maltose, calcium hydrogen phosphate, calcium sulfate, and light anhydrous silicic acid other than those partially amorphized.

Examples of the flavoring component include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include baking soda. Examples of artificial sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like. Examples of the masking agent include water-insoluble polymers such as ethyl cellulose, and anti-saliva gastrosoluble polymers such as methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer.

Further, examples of the flavor include lemon, lemon lime, orange, menthol, peppermint oil, vanillin and the like, and powdered flavor obtained by adsorbing these on dextrin or cyclodextrin.
As the lubricant, for example, magnesium stearate,
Examples include sucrose fatty acid esters, polyethylene glycol, talc, stearic acid and the like. As auxiliary agents,
Examples include a coloring agent, a stabilizer for a physiologically active ingredient, and a solubilizing agent. For example, examples of the colorant include food colors such as Food Yellow No. 5, Food Red No. 2, Food Blue No. 2, etc .; Food Lake Dye; Stabilizers or solubilizers vary depending on the physiologically active ingredient used, for example, ascorbic acid, antioxidants such as tocopherol,
Surfactants such as polysorbate 80.

[0035]

The present invention will be described in more detail with reference to the following examples and test examples, but the present invention is not limited by these examples.

EXAMPLE 1 2742 g of D-mannitol was put into a fluidized bed granulator,
D-mannitol granulated product was obtained by granulating with a solution in which 164.5 g of maltose was dissolved in 1000 mL of purified water. 581.3 g of this D-mannitol granulated product was sprayed with lactose (FlowLac100 manufactured by MEGGLE) at 1365.
46 g, crospovidone 33.3 g, aspartame
10 g and 1.64 g of powdered fragrance are added and mixed for 20 minutes with a V-type mixer, and then 8.3 calcium stearate is added.
g was added to obtain tableting granules. The granules for tableting are compression-molded by a rotary tableting machine to make one tablet 200 m.
g, a tablet having a diameter of 8 mm and a tablet thickness of 3.0 mm were obtained.

Example 2 The granules for tableting obtained in Example 1 were compression-molded with a rotary tableting machine to obtain tablets each having a size of 60 mg, a diameter of 5 mm and a tablet thickness of 2.3 mm.

Example 3 The granules for tableting obtained in Example 1 were compression-molded with a rotary tableting machine to obtain tablets each having 500 mg, a diameter of 11 mm and a tablet thickness of 5.3 mm.

Comparative Example 1 2742 g of D-mannitol was put into a fluidized bed granulator.
Granulation was performed using a solution in which 164.5 g of maltose was dissolved in 1000 mL of purified water to obtain a granulated D-mannitol. This D
-Lactose (DMV p-type) was added to 581.3 g of granulated mannitol.
harmatose 100M) 1365.46 g, crospovidone 33.3 g, aspartame 10 g and powdered flavor 1.64 g were added, mixed for 20 minutes with a V-type mixer, and further 8.3 g of calcium stearate was added to obtain granules for tableting. Was. The tableting granules were compression-molded by a rotary tableting machine to obtain tablets each having a size of 60 mg, a diameter of 5 mm and a tablet thickness of 2.3 mm.

Comparative Example 2 The granules for tableting obtained in Comparative Example 1 were compression-molded with a rotary tableting machine to obtain tablets each having a size of 500 mg, a diameter of 11 mm and a tablet thickness of 5.3 mm.

Comparative Example 3 2742 g of D-mannitol was put into a fluidized bed granulator,
Granulation was performed using a solution in which 164.5 g of maltose was dissolved in 1000 mL of purified water to obtain a granulated D-mannitol. This D
-Granulated mannitol 58.13 g of lactose (DMV p
harmatose 200M) in water and freeze-dried lactose 136.5 g, crospovidone 3.3 g, aspartame 1 g and powdered flavor 0.164 g were added.
The mixture was mixed for 20 minutes using a mold mixer, and 0.83 g of calcium stearate was further added to obtain granules for tableting. The granules for tableting are compression molded by a rotary tableting machine to obtain
A tablet having a size of 200 mg, a diameter of 8 mm and a thickness of 3.0 mm was obtained.

Test Example 1 The tablet having a diameter of 8 mm of Example 1 and the tablet having the same diameter of Comparative Example 3 were compared in terms of hardness and disintegration time in the oral cavity. The hardness of each tablet was determined by measuring five tablets using a TH-203 tablet breaking strength meter manufactured by Toyama Sangyo Co., Ltd., and calculating the average value. The intraoral rapid disintegration time was determined by measuring the time required for disintegration in a bite state by having six tablets each containing the tablet in the mouth and calculating the average time. Table 1 shows the results.

(Result)

[Table 1]

Test Example 2 The tablet having a diameter of 5 mm of Example 2 and the tablet of the same diameter of Comparative Example 1 were compared in hardness and disintegration time in the oral cavity. The hardness and oral disintegration time of each tablet were determined in the same manner as in Test Example 1. Table 2 shows the results.

(Result)

[Table 2]

Test Example 3 The hardness and the oral disintegration time of the tablet of Example 3 having a diameter of 11 mm and the tablet of Comparative Example 2 having the same diameter were compared. Test Example 1 shows the hardness of each tablet and the oral rapid disintegration time.
As well as sought. Table 3 shows the results.

(Result)

[Table 3]

Example 4 766.5 g of D-mannitol and 125 g of sodium picosulfate were placed in a fluidized bed granulator, and purified water 500
The mixture was granulated with a solution in which 46 g of maltose was dissolved in mL to obtain a picosulfate granulated product. 187.5 g of the granulated sodium picosulfate was added to FlowLa manufactured by MEGGLE.
1023.3 g of c100, 25 g of crospovidone, 6.7 g of aspartame and 1.25 g of powdered flavor were added, mixed for 20 minutes with a V-type mixer, and further 6.3 g of calcium stearate was added to obtain granules for tableting. . The tableting granules are compression-molded by a rotary tableting machine to give 125 mg per tablet, 6.5 mm in diameter, and 2.95 mm in tablet thickness.
Tablets were obtained. At this time, the tablet hardness was 3.5 kg, and the oral disintegration time was 20 seconds.

Example 5 975 g of FlowLac100 manufactured by MEGGLE and 20 g of crospovidone were mixed in a V-type mixer for 20 minutes, and 5 g of calcium stearate was added to obtain granules for tableting. The granules for tableting were compression-molded by a rotary tableting machine to obtain tablets each having a size of 200 mg, a diameter of 8 mm and a tablet thickness of 3.0 mm. The tablet hardness at this time is 4.
2 kg and the oral disintegration time was 10 seconds. that's all

 ──────────────────────────────────────────────────続 き Continuation of front page (72) Inventor Naoko Iwasaki 39-2-411, Kamiyabecho, Totsuka-ku, Yokohama-shi, Kanagawa F-term (reference) 4C076 AA36 BB01 DD41 DD66 DD67 EE16 EE30 EE41 GG01

Claims (15)

[Claims] An orally disintegrating tablet comprising a partially amorphous saccharide containing a crystallized portion and an amorphous portion as a carrier in a preparation. 2. The orally disintegrating tablet according to claim 1, wherein the partially amorphized saccharide is solid at room temperature and water-soluble. 3. The partially amorphized saccharide is a monosaccharide, an oligosaccharide,
The orally disintegrating tablet according to claim 1, which is one or more compounds selected from a sugar alcohol, a polysaccharide and a sugar derivative. 4. The orally disintegrating tablet according to claim 1, wherein the partially amorphized saccharide is obtained by spray drying. 5. The orally disintegrating tablet according to claim 1, wherein the partially amorphized saccharide is lactose. 6. The orally disintegrating tablet according to claim 1, wherein the ratio of the amorphous portion and the crystallized portion of the partially amorphous saccharide is from 1: 1 to 1:19. 7. The orally disintegrating tablet according to claim 1, further comprising a sugar alcohol in combination. 8. The orally disintegrating tablet according to claim 6, wherein the sugar alcohol is selected from mannitol, xylitol, sorbitol, erythritol, maltitol, lactitol and paranit. 9. A method of mixing a physiologically active ingredient, a partially amorphous saccharide containing a crystallized portion and an amorphous portion,
Then, the method is tableted to produce an orally disintegrating tablet. 10. The method for producing an orally disintegrating tablet according to claim 9, wherein the partially amorphized saccharide is solid at room temperature and water-soluble. 11. The oral cavity according to claim 9, wherein the partially amorphized saccharide is one or more compounds selected from monosaccharides, oligosaccharides, sugar alcohols, polysaccharides and sugar derivatives. A method for producing a disintegrating tablet. 12. The method for producing an orally disintegrating tablet according to claim 9, wherein the partially amorphized saccharide is obtained by spray drying. 13. The method for producing an orally disintegrating tablet according to claim 9, wherein the partially amorphized saccharide is lactose. 14. The method for producing an orally disintegrating tablet according to claim 9, wherein the ratio of the amorphous portion and the crystallized portion of the partially amorphous saccharide is from 1: 1 to 1:19. . 15. An oral cavity, comprising mixing a physiologically active ingredient, a partially amorphous saccharide and a sugar alcohol containing a crystallized portion and an amorphous portion, and then tableting the mixture. A method for producing a disintegrating tablet.