JPH1135451A - Intraoral dissolving type tablet and its production - Google Patents

Abstract

PURPOSE: To provide tablets soluble in the oral cavity that shows rapid disintegration and dissolution in the oral cavity, readily can be produced by means of conventionally used medicine-producing installations, can avoid the tableting troubles because the tablets has a proper hardness, even when they are tableted with a low pressure, and can be applied to masking particles and releasing particles, too. CONSTITUTION: The tablets soluble in the oral cavity contains active ingredients, saccharides and low-melting substance and has a porous structure where the low-melting substance crosslinks via particle-bridges between the active ingredients and the saccharide. The tablets are produced by mixing the active ingredients, the saccharide and the low-melting substance, tableting the mixture in a low pressure, the resultant tablets are heated at such a temperature that the low-melting substance melts and allowed to stand thereby cooling down.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an orally dissolvable tablet having rapid disintegration and dissolving properties in the oral cavity and having an appropriate hardness even when compressed at a low pressure. Orally dissolvable tablets are practically sufficient disintegration by saliva without taking water in the oral cavity,
It is a tablet that has solubility. Here, practically sufficient disintegration and dissolving means disintegration or dissolution in the oral cavity in about 5 to 120 seconds.

[0002]

2. Description of the Related Art Conventionally, various pharmaceutical dosage forms for oral use have been known, but there are few dosage forms in consideration of the ease of drinking for patients.
In particular, there has been a demand for the development of a dosage form suitable for elderly people and children who have many problems in taking drugs.

For example, tablets and capsules, when taken by elderly people or children with weak swallowing power, have problems such as difficulty in swallowing and sticking to the pharynx and esophagus. In the case of powders and granules, the drug remains in the oral cavity and it is difficult to swallow, discomfort remains in the mouth, and when taken by elderly people,
In some cases, granules may enter between dentures and cause discomfort. Furthermore, since these oral preparations require water when taken, elderly people and children have problems with urination at night, and it is often difficult to prepare water. A syrup is a preferred dosage form for elderly people and children, but it is difficult to take a correct amount by measurement and it is not always suitable for elderly people and children.

[0004] In view of these circumstances, development of orally dissolving tablets has been promoted as a dosage form suitable for the elderly and children. Conventional oral dissolution type tablets include those manufactured through a freeze-drying process and those manufactured by tableting. As an example of the former, Japanese Patent Publication No. Sho 58-2441.
No. 0 publication discloses mixing the tablet contents with a solvent which is inert to the tablet contents and which is frozen at -30 to + 25 ° C.
The solvent is adjusted to 5 to 80% by weight of the total mixture, the mixture is solidified by placing the mixture in an inert cooling medium, compressed at a temperature lower than the freezing point of the solvent into tablets, and the solvent is further freeze-dried or air-dried. A method for producing a porous tablet with good disintegration by volatilization is described.

As an example of the latter, Japanese Patent Application Laid-Open No. 5-27
Japanese Patent No. 1054 discloses a porous material which has a suitable strength when it is compressed and dried when a mixture containing a medicinal ingredient, a saccharide, and water enough to moisten the surface of the saccharide particles, and which rapidly disintegrates and dissolves in the oral cavity. It is disclosed that an orally dissolving tablet having a sex structure can be obtained. Further, Japanese Patent Application Laid-Open No. 5-31055
No. 8 discloses that mannitol or lactose having poor moldability is mixed with sorbitol powder having a bulk specific gravity of less than 60 g / 100 ml to form other additives having high moldability, such as a cellulose compound, an acrylic acid compound, It describes that the amount of gelatin and the like can be reduced, and a solid pharmaceutical composition having excellent disintegration properties can be obtained.

[0006]

However, freeze-dried oral dissolving tablets are excellent in disintegration and dissolution in the oral cavity, but are not used in ordinary tablets due to insufficient tablet hardness. PTP (Press Through Pack) packaging etc. cannot be used, and when the product is delivered, carried or taken out for taking, etc.
Cracks were easily generated and handling was difficult. Furthermore, in the production process, a new freeze-dryer must be purchased, and the freeze-dryer cannot process a large amount of medicine at one time, and has disadvantages such as a long processing time.

[0007] On the other hand, the tablet-type oral dissolving tablet solves various problems of the freeze-dried oral dissolving tablet.
Not enough yet. The usual preparation is prepared by applying granules or powder for tablet preparation to a tablet machine and obtaining a tablet having a certain hardness by pressing.
The molding is performed at a high pressure of g / punch. However, depending on the physicochemical properties and the amount of the medicinal ingredient and additives, there is a problem that tableting trouble such as capping may occur. The particles could be destroyed, impairing their properties.

In view of the above, these problems of freeze-dried orally dissolving type tablets and tableting orally dissolving type tablets have been solved, and rapid disintegration and solubility in the oral cavity have been solved. It has been desired to develop an orally dissolvable tablet having appropriate strength in the distribution process, compatibility with the conventional production process, and the like.

[0009]

The present inventors have conducted various studies to develop an orally dissolving tablet having the above-mentioned properties and a method for producing the same. Once the tablet is obtained, once the low-melting substance is melted and then re-solidified, it quickly disintegrates in the mouth, has solubility, and becomes a porous orally dissolvable tablet with appropriate strength. We have found that we have completed the present invention. That is, according to the present invention, a medicinal ingredient, an orally dissolving tablet containing a saccharide and a low-melting substance, and the low-melting substance forms an interparticle crosslink between the medicinal ingredient and the saccharide. An orally dissolving tablet having a porous structure is provided. According to the present invention, a medicinal component,
A saccharide and a low-melting substance are mixed, the mixture is compressed at a low pressure, the resulting tablet is heated to a temperature at which the low-melting substance is melted, and then left to cool to form a porous structure. A method for producing an orally dissolvable tablet is provided.

Hereinafter, the present invention will be described in more detail. The orally dissolving tablet of the present invention has a medicinal ingredient, a saccharide and a low-melting substance as main components, and the low-melting substance forms an interparticle crosslink with the medicinal ingredient and the saccharide, and has a porous structure. It has become. As a form of the present invention, when the medicinal ingredient and the saccharide form particles separately, when the medicinal ingredient and the saccharide form particles in a mixed state, the medicinal ingredient is masked particles or sustained release And the like, for example.

Granules obtained by heating and melting a water-soluble low-melting substance such as polyethylene glycol and / or a wax-like substance have been widely used for masking bitter drugs, sustained-release preparations, and the like. . For example, Japanese Patent Application Laid-Open No. 5-194193 discloses a granular material using polyethylene glycol and masking an unpleasant taste by melt granulation. Japanese Patent Application Laid-Open No. 223533/1990 discloses matrix-controlled release granules after heating and melting a polyglycerol fatty acid ester as a wax, followed by spray cooling. However, these are all
In the process of resolidification, the drug forms a matrix structure in which the drug is dispersed in wax or polyethylene glycol, and controls the release rate of the drug. The structure is completely different from that of the tablet obtained by increasing the tablet strength by making the structure in which the particles are bonded by re-solidification.

The low-melting substance used in the present invention is not particularly limited as long as it is pharmaceutically acceptable and can form a porous structure by forming an interparticle cross-link between a pharmaceutically active ingredient and a saccharide. The purpose of the addition of the low melting point substance is to obtain a porous structure for rapid disintegration and dissolution in the oral cavity, and to obtain a desired tablet strength (hardness) while maintaining the porous structure. Therefore, the low melting point substance is preferably a pharmaceutically acceptable additive having a melting point of 40 ° C. or more, more preferably a substance having a melting point of 40 to 90 ° C. For those exhibiting a melting point lower than 40 ° C., there is a concern that the desired effect cannot be expected, such as re-melting of the low-melting substance depending on the storage location during indoor storage, and changes in tablet properties. Those having a melting point higher than 90 ° C. cannot be applied to medicinal ingredients which are unstable to heat. Particularly preferred are those having a melting point of 50 to 80 ° C.

The "melting point" as used herein refers to a temperature at which a solid phase slowly transitions to a liquid phase. The low-melting substance used in the present invention is not particularly limited as long as it is in a solid state, for example, a particle state, a powder state, or a flake state, but is preferably a powder state or a particle state. Here, the powder of the low-melting substance refers to an aggregate of a large number of solid fine particles, and the particles of the low-melting substance refer to the powder as a fluidized bed granulator,
It refers to granules granulated by a tumbling granulator or the like, or granules prepared by spray drying, spray congealing or the like. When a flaky material is used, it may be used in the form of the powder by a general process such as pulverization and spray drying.

Specific examples of the low-melting substance include waxes, surfactants, and polyethylene glycol. These low-melting substances may be used alone or in combination of two or more. Wax has a melting point of 40
To 90 ° C., preferably 50 to 90 ° C., such as myristic acid (melting point 54 ° C.), palmitic acid (melting point 63 ° C.), stearic acid (melting point 69 to 7 ° C.).
Higher fatty acids such as 0 ° C.); cetanol (melting point 49 ° C.);
Higher alcohols such as stearyl alcohol (melting point 56-60 ° C), various hardened oils such as hardened castor oil (melting point 85-87 ° C), hardened rapeseed oil (melting point 69 ° C); paraffin wax (melting point 50-57 ° C) And paraffins such as microcrystalline wax (melting point 60-75 ° C); carnauba wax (melting point 72-86 ° C), beeswax (melting point 61-6)
And natural waxes such as beeswax wax (melting point 61-65 ° C).

It is desirable to use a surfactant having a melting point of 40 to 90 ° C., preferably 46 to 69 ° C. For example, polyoxyethylene [160] polyoxypropylene [30] glycol (melting point of 46 to 56 ° C.) ), Polyoxyethylene [196] polyoxypropylene [67]
Various polyethylene polyoxypropylene glycols such as glycol (melting point: 50 to 62 ° C) and polyoxyethylene [105] polyoxypropylene [5] glycol (melting point: 50 to 54 ° C); sucrose stearic acid ester (melting point: 55 to 69 ° C) ), Sucrose oleate (melting point 5
(0 to 54 ° C.).

A feature of the present invention is to obtain a desired tablet strength (hardness) while maintaining a porous structure by causing powder-to-particle adhesion through the process of melting and re-solidification of a low-melting substance. is there. Therefore, the surfactant is not particularly limited as long as it has a melting point of 40 ° C. or higher without depending on the surfactant action such as HLB. It is desirable to use polyethylene glycol having a melting point of 40 to 70 ° C, preferably 53 to 64 ° C. For example, Macrogol 1540 (melting point 42 to 46 ° C, British Pharmacopoeia (BP) 1988), Macrogol 4000
(Melting point 53-57 ° C, molecular weight 2600-3800, Japanese Pharmacopoeia XII revision), macrogol 6000 (melting point 56
~ 61 ° C, molecular weight 7300-9300, Japanese Pharmacopoeia XI
Macrogol 20000 (melting point 56-64)
° C, molecular weight 15000-25000, Japanese Pharmacopoeia XII
Revised) and the like.

As described above, waxes such as hardened oils have conventionally been used as a base for controlling the release of sustained-release preparations, a masking agent for drugs having bitterness, and a lubricant for tableting. Have been. In addition, surfactants such as sucrose fatty acid esters have conventionally been solubilizers for poorly soluble drugs, absorption enhancers,
It has been used as a lubricant for tableting. Conventionally, polyethylene glycol has been used as a plasticizer of a coating base for imparting flexibility to a coating film in a drug, as a masking agent for melt-granulating a bitter drug and relieving bitterness, or as a tableting agent. It has been used as a binder to be added during granulation to ensure fluidity during tableting, and as a stabilizer to stabilize by heat coating a heat-stable and water-unstable drug. Was. However, these waxes, surfactants, and low-melting substances such as polyethylene glycol obtain a porous structure for rapid disintegration and solubility in the oral cavity, and are desired in a state where the porous structure is maintained. This is the first use of the present invention in an orally dissolving tablet for the purpose of obtaining tablet strength (hardness).

In the orally dissolving tablet of the present invention, the amount of the low-melting substance to be added is 0.5 to 25% by weight based on the total amount.
Is preferred. If the amount of the low-melting substance is less than 0.5% by weight, it is difficult to satisfy the desired tablet hardness and porosity at the same time, while if it exceeds 25% by weight, rapid disintegration and solubility in the oral cavity are not achieved. It is difficult to achieve.

The medicinal component applied to the present invention is not particularly limited, and those who have difficulty swallowing tablets, the elderly,
Drugs intended for children or drinkable without water, drugs that need to be administered in daily life, preparations for patients with restricted drinking water, drugs for single use, and the like are preferred. The following are specific examples of drugs of high utility value.

(R) -5-[(1-methyl-3-indolyl) carbonyl] -4,5,6,7-tetrahydro-
IH-benzimidazole hydrochloride and salts thereof, serotonin 5HT3 receptor antagonists such as ondansetron and granisetron, indomethacin, ibuprofen, ibufenac, alclofenac, diclofenac, mefenamic acid, flurbiprofen, flufenamic acid, ketoprofen, phenyl Non-steroidal anti-inflammatory drugs such as butazone and methyl salicylate. Steroidal anti-inflammatory agents such as cortisone, hydrocortisone, prednisolone, dexamethasone, betamethasone dipropionate, betamethasone valerate, prednisolone, triamcinolone, and fluocinoloacetonide.

Diuretics such as bendroflurothiazide comma polythiazide, methycloazide, trichlormethiazide, ticlobenzazide, pentylhydrochlorothiazide, hydrochlorothiazide, and bumetanide. Emonapride,
Antipsychotics such as diazepam, nitrazepam, flunitrazapam, lorazepam, prazepam, fludiacepam, clonazepam, chlorpromazine, reserpine, clofluberyl, trifluperidol, haloperidol, moperonpromperidol, etizolam. Barbital,
Hypnotics such as thiopental, phenobarbital, and cyclobarbital.

Ethosuccinimide, sodium palproate,
Antiepileptic drugs such as acetazolamide and meprobamate. Anti-perkins agents such as chlorzoxazone and levodoba. Antiemetics such as metoclopramide and metoclopramide hydrochloride. Hormonal agents such as insulin, testosterone, methyltestosterone, progesterone, and estradiol. Analgesics, such as morphine, aspirin, codeine, acetaminophen, acetanilide, aminopyrine, and lochyliprofen; Sulfa drugs such as sulfamine, sulfamonomethoxine and sulfamethizole;

Coronary vasodilators such as nitroglycerin, isosorbide dinitrate, pentaerythritol tetranitrate, propanyl nitrate, dipyridamole and papaverine hydrochloride. H2 receptor antagonists such as famotidine, cimetidine, ranitidine hydrochloride, and loxazine acetate hydrochloride. Antiarrhythmic therapeutic agents such as ajmaline, pindolol, propranolol, quinidine, amrinone and milrinone. Cardiotonic agents such as caffeine, digoxin, digitoxin. Nicardipine hydrochloride,
Calcium antagonists such as diltiazem hydrochloride, nivadipine, nifedipine, nitredipine, nizoldipine, nimodipine and nildipine.

Antihistamines such as diphenhydramine hydrochloride, carbinoxamine, diphenylpyraline, fenbenzamine, chlorpheniramine maleate, brompheniramine maleate, diphenylimidazole, clemizole and the like. Tetracycline, oxytetracyline,
Metacycline, doxycycline, minocycline,
Antibiotics such as chloramphenicols, erythromycins, lincomycin, penicillin G, clingmycin, kanamycin, chloramphenicol, fradiomycin, streptomycin and gentamicin; Anti-neoplastic agents such as 5-fluorouracil, uracil, cytarabine, broxuridine, busulfan, actinomycin, bleomycin, and mitomycin.

Diabetic drugs such as glibenclamide and epalrestat. Gout remedies such as allopurinol, colchicine and benzbromarone. Antiallergic agents such as ketotifen fumarate, sodium cromoglycate, and amlexanox. Clonidine, atenolol, doxazosin, bilibrolol, cilazapril, lisinopril, nilvalnidipine, manidipine, isosorbide dinitrate, diltiazem,
Antihypertensive agents such as nicolarezyl, guanethidine sulfate, amosulalol hydrochloride, alacepril, delapril hydrochloride, and enalapril maleate.

Indeloxazine hydrochloride, thiabride hydrochloride,
Central nervous system drugs such as bifemelane hydrochloride. Skeletal muscle relaxants such as dantrolene sodium. Antispasmodics such as everidine hydrochloride, tizanidine hydrochloride, butylscopolamine, methylatropine bromide. Hyperlipidemia agents such as simvastatin and bravastatin sodium. Bronchodilators such as formoterol fumarate, salbutamol sulfate, and procaterol hydrochloride.

Α-adrenergic receptor blockers such as tamsulosin hydrochloride and brazosin, hypoglycemic agents, and oral contraceptives. Analgesic and anti-inflammatory agents such as loxoprofen. Gastrointestinal motility improvers such as Dombellidone and Cisapride. Anti-gastritis and anti-gastric ulcer agents such as deprenone. Osteoporosis agents such as alfacalcidol.
Prostatic hyperplasia agents such as chlormasisone. Expectorants such as amproxol. Allergic rhinitis agents such as oxatomodo and ketotifen. Asthmatics such as azelastine, procaterol, and terfenadine. Or an animal drug having antipyretic analgesic / inflammation activity, peptic anti-ulcer activity, etc. or an animal drug for each organ such as a reproductive organ.

In addition, the present invention makes use of the properties of the present preparation, not limited to pharmaceuticals, such as diagnostic agents such as contrast agents, health foods and functional foods, and oral agents such as halitosis removers and plaque stains. It can be applied to various uses, and the range of the active ingredient is not particularly limited. The compounding amount of the active ingredient is preferably 90% by weight or less based on the whole solid ingredient, though it depends on its properties. In general,
The active ingredients applied are preferably those which do not give an unpleasant taste when dissolved. When applied to a component exhibiting an unpleasant taste, it is preferable to perform an appropriate masking treatment. Further, it is preferable that the active ingredient for which sustained release is desired is subjected to an appropriate sustained release treatment by a known method so as to obtain particles with controlled release of the active ingredient.

The orally dissolving tablet of the present invention usually contains about 90% by weight or less, preferably about 80% by weight or less of the active ingredient based on the total amount. In addition, the content of the medicinal component may be an amount that exhibits the desired medicinal effect.
For example, for a medicinal ingredient that is effective at a low dose, 0.0
Since the usefulness of the tablet of the present invention can be enjoyed even at about 01% by weight, the lower limit of the active ingredient is not particularly limited. In addition, for those that are effective at high doses, the size of tablets is a problem in the usual formulation process, but by formulating according to the present invention, almost all of the tablets are medicinal ingredients. However, it can be manufactured into an orally dissolving tablet, and the usefulness of the present invention is extremely large.

The saccharide used in the present invention is not particularly limited as long as it is water-soluble and has no adverse effect on the pharmaceutically active ingredient. For example, sucrose, coupling sugar, fructooligosaccharide, palatinose, glucose, maltose, fructose ,
Examples include sugars such as lactose, isomerized lactose (lactulose), and reduced lactose (lactitol), and sugar alcohols such as sorbitol, mannitol, maltitol, xylitol, and reduced palatinose. These saccharides may be used alone or in combination of two or more.

The tablet of the present invention further comprises a disintegrant, a binder,
It may contain one or more components selected from the group consisting of acidulants, foaming agents, artificial sweeteners, flavors, lubricants and coloring agents. Examples of the disintegrant include starch such as corn starch and potato starch, carmellose calcium and the like. Examples of the binder include synthetic polymers such as polyvinylpyrrolidone, hydroxypropylcellulose and hydroxypropylmethylcellulose, and gum arabic powder. And natural polymers such as gelatin, polysaccharides such as pullulan and saccharides such as maltose, maltitol and sorbitol.

Examples of the acidulant include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include:
Baking soda and the like. Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like. As the flavor, for example, lemon, lemon lime, orange, menthol and the like, and as a lubricant,
For example, magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like are exemplified. As the coloring agent, for example, food yellow 5
Food colors such as No. 2, Edible Red No. 2, and Edible Blue No. 2; edible lake dyes;

The orally soluble tablet of the present invention has a porous structure. The “porous structure” referred to here is
It usually means that the porosity is 10 to 50%, preferably 20 to 40%. For this reason, the tablet of the present invention has rapid disintegration / solubility in the oral cavity and has an appropriate tablet strength (hardness).

Next, a method for producing the tablet of the present invention will be described. First, a medicinal component, a saccharide, and an additive are mixed, and if necessary, granulation is performed. Alternatively, the medicinal ingredient and the saccharide, and in some cases, the additive may be separately granulated and then mixed. Next, a low-melting substance in the form of particles or powder is blended, and tableting is performed at a low pressure to adjust the shape. Finally, the added low-melting substance is once melted by heating or the like, and then solidified by cooling.

FIG. 1 is a schematic diagram showing the inside of the tablet before and after the melting of the low-melting substance particles in one embodiment of the tablet of the present invention. 2 represents low melting point particles or powder. At the stage before the low-melting substance 2 is melted, the particles in the tablet are dispersed while maintaining the gap between the particles. For this reason, unlike a normal tablet having a porous structure but having a dense particle, the tablet has no hardness and is extremely easily disintegrated. However, once the low-melting substance 2 is melted and then re-solidified, the low-melting substance forms a crosslink 3 between the medicinal ingredient and the saccharide particles and contributes to the adhesion between the particles. It is growing.
In addition, the melting of the low melting point substance 2 has an effect of increasing the porosity of the tablet. The tablet preferably has a porous structure in order to have rapid disintegration and dissolution in the oral cavity.However, in order to obtain a porous structure in the tablet of the present invention, the low-melting-point substance must be in the form of powder or particles. It is extremely important to add.

Further, since the tablet of the present invention is molded at a low pressure, it is difficult for tableting trouble to occur, the physicochemical properties of medicinal components to be added and the amount to be added are hardly restricted, and masking particles, sustained release It is also a feature of the present invention that it can be applied to particles. When tableting sustained-release particles subjected to controlled release, it is generally known that tableting pressure causes damage to the controlled-release mechanism and accelerates the dissolution rate. Thus, for example, a tableting technique using porous crystalline cellulose (JP-A-5-32542), or a technique in which formulation aids and the like are preliminarily laminated on sustained-release granules (JP-A-63-398).
No. 11) is known. Further, according to the above-mentioned technique, the tablet is made into a normal tablet in the form of granules, and it is difficult to have both rapid disintegration and solubility in the oral cavity, which is one of the effects of the present invention. However, the present invention enables tableting of sustained-release particles without changing the dissolution rate of the sustained-release particles, without requiring the above-mentioned technology, since tableting can be performed at a low pressure. In the production of the tablet of the present invention, mixing of the active ingredient, saccharides, additives and the like is performed by a method used in the production of general pharmaceutical preparations. Specifically, V
This is carried out using a mold mixer (manufactured by Tokuju Kosakusho Co., Ltd.), a W-type mixer (manufactured by Tokuju Kosakusho Co., Ltd.), a cross rotary mixer (manufactured by Meiwa Kogyo Co., Ltd.), or the like. The same applies when a low-melting substance is mixed with this mixture.

For tableting, devices generally used for tablet molding are used. For example, a single-shot tableting machine (manufactured by Kikusui Seisakusho Co., Ltd.) and a rotary tableting machine (Hata Iron Works Co., Ltd.) )) Is used. The molding pressure at the time of tableting is desirably low and is usually 300 kg / punch or less, preferably 200 kg / punch or less. The hardness of the tablet after tableting is 2 kg or less. If the fluidity of the powder is required at the time of tableting, the medicinal component, saccharides and additives can be granulated individually or as a mixture. For example, a fluid bed granulator (Okawara Seisakusho Co., Ltd.) Using a vertical mixer (manufactured by Sanei Seisakusho Co., Ltd.), an agitation granulator (manufactured by Fukae Sangyo Co., Ltd.), etc., using an aqueous solution of a saccharide or a water-soluble polymer as a binder, and granulating. Do.

Heating is generally used as a method for melting the low-melting substance, but a drying apparatus such as a ventilation drying apparatus (manufactured by Matsui Seisakusho Co., Ltd.) is used. The heating temperature and the heating time are not particularly limited as long as the low-melting-point substance can be melted.
One hour or the like. The preparation of the present invention has sufficient strength in handling the preparation and can be used practically like ordinary tablets. Here, “sufficient strength for handling the preparation” means a strength that is at least applicable to ordinary PTP packaging, and if it has this strength, it can withstand other handling such as delivery and carrying. it is conceivable that.

As a measure of the strength applicable to the PTP packaging, that is, the strength at which the preparation can be extruded from the cover sheet of the ordinary PTP packaging, the hardness in the longitudinal direction of the tablet can be mentioned. The hardness varies depending on the size and shape of the tablet, for example, 1.0 kg when the diameter is about 8.0 mm.
As described above, the weight is preferably 1.5 kg or more when the diameter is about 10.0 mm, and 2.0 kg or more when the diameter is about 12.0 mm. The preparation of the present invention has strength enough to withstand removal from the PTP package in any size. The “rapid disintegration and solubility” of the present invention means that the saliva has practically sufficient disintegration or solubility even without taking water in the oral cavity. Here, practically sufficient disintegration or dissolution may vary depending on individuals, but usually disintegrate or dissolve in the oral cavity in about 5 to 120 seconds, preferably about 10 to 60 seconds, more preferably about 10 to 40 seconds. It indicates that

The sugar-based structure of the preparation of the present invention is rapidly weakened by saliva in the oral cavity and gradually disintegrates or dissolves. In addition, the intraoral pressure, that is, the pressure by the upper jaw and tongue Alternatively, when a “licking” operation or the like is performed by the lower part, the substance disintegrates or dissolves in a shorter time.

For a person who has a dry or little saliva in the oral cavity, the present preparation can be applied by using water or hot water that is sufficient to moisten the mouth. In addition, the present formulation can be taken together with a small amount of water after it has been disintegrated or dissolved in the oral cavity, or in a partially disintegrated or dissolved state. Ease of swallowing even in this way of taking,
Alternatively, the advantages of the preparation of the present invention, such as the use of a small amount of water, can be enjoyed. It should be noted that there is no problem even if the preparation of the present invention is taken with water as it is in the same manner as ordinary tablets. The dosage form of the present invention can be selected according to the taste of the patient or according to the situation, as long as there is no restriction by the contained active ingredient.

[0042]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

(Test Example) In order to further explain the effects of the present invention, the tablets obtained in the examples were measured in the following manner. (1) Hardness test It was measured using a tablet hardness tester (Schleunigel).
The test was performed 3 to 10 times (n = 3 to 10), and the average value is shown. (2) Disintegration and dissolution test without water in the oral cavity The compression molded product is contained in the oral cavity of a healthy adult male without water (without water), and the compressed molded product is completely composed of only saliva in the oral cavity. The time until disintegration and dissolution was measured.

(3) Porosity The porosity of the tablet was determined by the following equation. V; volume of tablet W; weight of tablet ρ; specific gravity of powder constituting tablet The test was performed on 10 samples except for Example 8 (3 times), Example 9 (4 times), and Example 10 (4 times). And the average was shown.

Example 1 400 g of mannitol (Towa Kasei Kogyo Co., Ltd.) was added to maltose (San malt green,
Using a maltose aqueous solution obtained by dissolving 20 g of Hayashibara Shoji Co., Ltd. in 180 g of water, granulation was performed with a fluidized bed granulator (manufactured by Okawara Seisakusho Co., Ltd.). Up to 10 g of maltose, fine particle coating is performed with a spray pressure of 3 kg / cm ² ,
Thereafter, granulation was performed at a spray pressure of 0.5 kg / cm ² . After the granules were dried, 154.8 g of polyethylene glycol 6000 (PEG 6000: Sanyo Chemical Co., Ltd.) (molecular weight: 6000) and 0.2 g of magnesium stearate were blended with 184.8 g, and a rotary tableting machine (Hata Tekko) 1 tablet 300mg, φ10mm,
Tableting was performed with a pressure of 72 kg / punch using a 10 mmR punch.
Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour, and then allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 17 seconds and the hardness was 3.3 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 37%.

Example 2 Maltose (San Malt S,
Hayashibara Shoji Co., Ltd.) 184.8g, PEG6000
Was mixed with 15 g of magnesium stearate and 0.2 g of magnesium stearate.
Tableting was performed at a pressure of 103 kg / punch with a 0 mm, 10 mmR punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 20 seconds and the hardness was 3.5 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 33%.

Example 3 154.8 g of PEG 6000 and 0.2 g of magnesium stearate were blended with 184.8 g of lactose (Dilactose, Freund Corporation).
Using a rotary tableting machine, 1 tablet 300mg, φ10m
The tablet was pressed at a pressure of 112 kg / punch with a 10 mmR punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 17 seconds and the hardness was 4.1 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 32%.

Example 4 Lactose (388 g) was replaced with hydroxypropylcellulose (HPC-SL, Nippon Soda) (12 g).
Was granulated with a fluidized bed granulator using an aqueous solution of HPC dissolved in 118 g of water. After drying the granulate, 184.8
15 g of PEG 6000 and 0.2 g of magnesium stearate were added to the mixture, and the mixture was mixed with a rotary tableting machine.
Tablets were pressed at a pressure of 62 kg / punch using a punch of 300 mg, φ10 mm, 10 mmR. Furthermore, the obtained tablets were
After being air-dried at 0 ° C. for 1 hour and allowed to cool, a tablet of the present invention was obtained. The dissolution time of the tablet in the oral cavity was 20 seconds, and the hardness was 3.0 kg (the number of hardness tests (n =
3)). The porosity of this tablet was 38%.

Example 5 Using 800 g of mannitol and 65 g of water, granulation was carried out using a vertical granulator. After drying the granules, PEG6000 was added to 184.8 g.
Was mixed with 15 g of magnesium stearate and 0.2 g of magnesium stearate.
The tablets were pressed at a pressure of 195 kg / punch using a 10 mmR punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and then allowed to cool to obtain a tablet of the present invention. The dissolution time in the mouth of the tablet is 22 seconds and the hardness is 3.9 kg
(Number of hardness tests (n = 3)). The porosity of this tablet was 23%.

Example 6 500 g of mannitol was added to maltose (San malt midori, Hayashibara Shoji Co., Ltd.)
Using a maltose aqueous solution in which 3 g was dissolved in 218.7 g of water, the mixture was granulated by a fluidized bed granulator. Maltose amount 10g
Until then, fine particle coating was performed at a spray pressure of 3 kg / cm ² . Famotidine 1 was added to 485.8 g of this coated product.
7.6 g, aspartame 5.2 g, malic acid 10.5
g, and the mixture was granulated with a spray pressure of 0.5 kg / cm ² using the above maltose aqueous solution by a fluidized bed granulator.
After drying the granulated product, 11.3 g of PEG 6000 and 0.16 g of magnesium stearate were blended with 150 g, and 318 mg / tablet and 1 tablet of φ1 were mixed with a rotary tableting machine.
Tableting was performed with a 0 mm, 10 mmR punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and then allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 20 seconds, and the hardness was 6.0 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 40%.

Example 7 A mixture of 396.9 g of mannitol and 3.5 g of glibenclamide was granulated with a fluid bed granulator using an aqueous maltose solution in which 21 g of maltose was dissolved in 189 g of water. Fine particle coating was performed at a spray pressure of 3 kg / cm ² up to a maltose amount of 8 g, and thereafter granulation was performed at a spray pressure of 0.6 kg / cm ² . After drying the granules, 149.8 g of PE
7.5 g of G6000 and 0.15 g of magnesium stearate were blended, and one tablet was prepared using a rotary tableting machine.
3mg, φ10mm, pressure 86 using a 10mmR punch
The tablet was compressed with a kg / punch. Further, the obtained tablet was air-dried at 80 ° C. for 10 minutes and allowed to cool, whereby a tablet of the present invention was obtained. The dissolution time in the mouth of the tablet was 30 seconds, and the hardness was 4.5 kg (the number of hardness tests (n = 1)
0)). The porosity of this tablet was 38%.

Example 8 Maltose (Sunmalt S,
Hayashibara Shoji Co., Ltd.) 179.8g, PEG6000
Was mixed with 20 g of magnesium stearate and 0.2 g of magnesium stearate.
Tableting was performed with a 0 mm, 10 mm R punch at a pressure of 111 kg / punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 20 seconds, and the hardness was 3.8 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 37%.

Example 9 20 g of PEG 6000 and 2 g of sugar ester (manufactured by Mitsubishi Kasei Food Co., Ltd.) were mixed with 178 g of glucose (Japan Food Processing Co., Ltd.), and the mixture was mixed with a rotary tableting machine. Tablets 300mg, φ1
Tableting was carried out with a punch of 0 mm and 10 mmR at a pressure of 157 kg / punch. Furthermore, the obtained tablet was air-dried at 70 ° C. for 1 hour and allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 32 seconds, and the hardness was 3.8 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 35%.

Example 10 400 g of mannitol was added to
Maltose (San Malt Midori, Hayashibara Shoji Co., Ltd.) 20
g in water 180 g of maltose aqueous solution,
Granulation was performed with a fluid bed granulator. Fine particle coating was performed at a spray pressure of 3 kg / cm ² up to a maltose amount of 10 g, and thereafter granulation was performed at a spray pressure of 0.5 kg / cm ² . After drying the granulated product, 12 g of acetaminophen (Yoshitomi Pharmaceutical Co., Ltd.) and PEG6 were added to 18 g of the granulated product.
000 and 1.5 g each, and 30 tablets per oil press.
Tablets were punched using a 0 mg, φ10 mm, 10 mmR punch. The tablet hardness at this time was 0 on a Schleuniger tablet hardness tester.
kg. Further, the obtained tablet was air-dried at 80 ° C. for 15 minutes and allowed to cool to obtain a tablet of the present invention. The dissolution time in the mouth of the tablet is 15 seconds and the hardness is 5.
It was 7 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 33%.

Example 11 Granulation was performed on 8 kg of mannitol using a maltose aqueous solution using a fluidized bed granulator (Okawara Seisakusho Co., Ltd., FLO-5). At this time, using a 10% maltose aqueous solution up to a maltose amount of 0.2 kg,
Fine particle coating was performed at a spray pressure of 2.5 kg / cm ² , and then granulation was performed at a spray pressure of 1.5 kg / cm ² using a 20% maltose aqueous solution having a maltose amount of 0.4 kg. To 190 g of the granulated mannitol, 10 g of polyethylene glycol 4000 (PEG4000) (molecular weight: 4000) (Nippon Oil & Fats Co., Ltd.) and 0.2 g of magnesium stearate were mixed, and 300 mg of one tablet was prepared using a rotary tableting machine. Tableting was performed with a φ10 mm, 10 mmR punch at 76 kg / punch. 8 tablets
The tablet of the present invention was obtained by allowing to cool at 0 ° C. for 10 minutes and then allowing to cool. The dissolution time of the tablet in the oral cavity is 20 seconds,
The hardness was 4.0 kg (the number of hardness tests (n =
3)). The porosity of this tablet was 35%.

Example 12 Granulation was performed on 8 kg of mannitol using a maltose aqueous solution using a fluidized bed granulator (Okawara Seisakusho Co., Ltd., FLO-5). At this time, using a 10% maltose aqueous solution up to a maltose amount of 0.2 kg,
Fine particle coating was performed at a spray pressure of 2.5 kg / cm ² , and then granulation was performed at a spray pressure of 1.5 kg / cm ² using a 10% maltose aqueous solution having a maltose amount of 0.2 kg. Separately, PEG 20000 flakes
(Nippon Oil & Fats Co., Ltd.) 150 g was dissolved in 850 g of methanol and 100 g of water, spray-dried, and powdered polyethylene glycol 20000 (PEG 20000)
(Molecular weight 20,000) was prepared. Next, PEG 20000 in the form of powder was added to 237.25 g of the granulated product.
12.5 g and magnesium stearate 0.25 g were mixed, and using a rotary tableting machine, one tablet 300 mg,
Tableting was performed with a pressure of 80 kg / punch using a 10 mmR punch with a diameter of 10 mm. Further, the obtained tablet was allowed to cool at 80 ° C. for 10 minutes and then allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 20 seconds, and the hardness was 4.3 kg (number of hardness tests (n = 3)). The porosity of this tablet was 38%.

Example 13 40 g of PEG 6000 (Nippon Oil & Fats Co., Ltd.) and 0.2 g of magnesium stearate were added to 160 g of the granulated mannitol prepared in Example 11.
And using a rotary tableting machine, one tablet 300 m
g, φ10mm, pressure 128kg /
It was compressed with a pestle. Further, the obtained tablet was allowed to cool at 80 ° C. for 10 minutes and then allowed to cool to obtain a tablet of the present invention. The tablet has a dissolution time in the mouth of 25 seconds and a hardness of 6.
It was 2 kg (the number of hardness tests (n = 3)). The porosity of this tablet was 35%.

Example 14 Acetaminophen 225
g, hydroxypropyl methylcellulose (Shin-Etsu Chemical Co., Ltd., TC-5E) 22.5 g was dissolved in a mixed solution of methanol and water (4: 1, w / w). In a fluidized bed granulator, this acetaminophen solution was
(Asahi Kasei Corporation) 450 g was coated to obtain fine granules. Further, in order to control drug release, a coating solution of methanol / methylene chloride (4: 1, w / w) in which 97.2 g of ethyl cellulose and 20.7 g of TC-5E were dissolved was coated on 575 g of the fine particles. Performed to obtain sustained release fine granules. Next, with respect to 60 g of the obtained sustained-release fine granules containing acetaminophen, 224.7 g of the mannitol granules prepared in Example 11 and 1 PEG6000 were added.
5 g and 0.3 g of magnesium stearate were mixed and, using a rotary tableting machine, 300 mg per tablet, φ10 m
The tablet was pressed at a pressure of 43 kg / punch with a 10 mmR punch.
Further, the obtained tablet was allowed to cool at 80 ° C. for 10 minutes and then allowed to cool to obtain a tablet of the present invention. The dissolution time of the tablet in the oral cavity was 15 seconds, and the hardness was 2.2 kg (number of hardness tests (n = 5)). The porosity of this tablet is
38%.

Example 15 Acetaminophen 600
Using a 30% aqueous solution in which 30 g of maltose was dissolved, granulation was performed with a vertical mixer (Sanei Seisakusho Co., Ltd.). The obtained acetaminophen granulated product 25
25.2 g, 25.2 g of the granulated mannitol prepared in Example 11, 22.5 g of PEG 6000, and 0.75 g of magnesium stearate were mixed, and using a rotary tableting machine, 1 tablet 300 mg, φ10 mm, 10mm
The tablet was pressed with a R punch at a pressure of 76 kg / punch. Furthermore, the tablet of the present invention was obtained by air-drying the obtained tablet at 80 ° C. for 20 minutes and then allowing it to cool. The dissolution time of the tablet in the oral cavity was 15 seconds, and the hardness was 2.2 kg (number of hardness tests (n = 4)). The porosity of this tablet was 30%.

Example 16 A rotary tableting machine was prepared by mixing 284.7 g of the granulated mannitol prepared in Example 11, 15 g of stearic acid (Kawaken Fine Chemical Co., Ltd.) and 0.3 g of magnesium stearate. Using 1
Tablets were pressed with a 300 mg tablet, φ10 mm, 10 mmR punch. The tablet hardness after tableting was 1.4 kg with a Schleunigel tablet hardness tester. Further, the obtained tablet was heated at 80 ° C.
And then allowed to cool for 15 minutes, to give tablets of the present invention. The dissolution time of the tablet in the oral cavity was 20 seconds and the hardness was 3.6 kg (the number of hardness tests (n = 5)). The porosity of this tablet was 37%.

(Example 17) 229.75 g of a granulated product of mannitol prepared in Example 11, sucrose fatty acid ester (sugar ester S770, Mitsubishi Kasei Food Co., Ltd.)
20 g and magnesium stearate (0.25 g) were mixed, and using a rotary tableting machine, one tablet (300 mg, φ1)
The tablets were pressed with a 0 mm, 10 mmR punch (tablet pressure: 130 kg
/ Pestle). Furthermore, the obtained tablet was air-dried at 80 ° C. for 10 minutes, and then allowed to cool to obtain a tablet of the present invention.
The tablet has a dissolution time in the mouth of 20 seconds and a hardness of 3.
5 kg (the number of hardness tests (n = 5)). The porosity of this tablet was 28%.

(Example 18) 237.25 g of the granulated mannitol prepared in Example 11, 12.5 g of coarsely crushed polyoxyethylene polyoxypropylene glycol (Pluronic F68, Asahi Denka Kogyo KK), stearic acid 0.25 g of magnesium was mixed, and the mixture was tableted with a rotary tableting machine using a punch of 300 mg per tablet, φ10 mm, 10 mmR (tabletting pressure 122 kg / punch). Furthermore, the obtained tablet was air-dried at 60 ° C. for 15 minutes, and then allowed to cool to obtain a tablet of the present invention. The dissolution time of this tablet in the oral cavity was 15 seconds, and the hardness was 3.0 kg (number of hardness tests (n = 5)). The porosity of this tablet is 3
1%.

(Example 19) 244.75 g of the granulated mannitol prepared in Example 11 and hydrogenated rapeseed oil (Laburi wax 103, Kawaken Fine Chemical Co., Ltd.) 5
g, magnesium stearate 0.25 g, and using a rotary tableting machine, 1 tablet 300 mg, φ10 m
tablet with a 10 mmR punch (tablet pressure 103 kg /
Pestle). Further, the obtained tablet was air-dried at 80 ° C. for 15 minutes, and then allowed to cool to obtain a tablet of the present invention. The dissolution time in the mouth of this tablet is 35 seconds and the hardness is 3.3.
kg (hardness test frequency (n = 5)). The porosity of this tablet was 32%.

[0064]

The orally-dissolvable tablet of the present invention shows rapid disintegration and dissolution in the oral cavity, and can be produced using equipment conventionally used in the production of drugs. Since it has an appropriate hardness even when pressed at a low pressure, tableting trouble can be avoided, and it can be applied to masking particles and sustained-release particles.

[Brief description of the drawings]

FIG. 1 is a schematic diagram showing a state inside a tablet before and after melting of powder or particles of a low-melting substance in one embodiment of the tablet of the present invention.

[Explanation of symbols]

1 ... particles of saccharides or medicinal ingredients, 2 ... powders or particles of low melting point substance, 3 ... crosslinking by low melting point substance

Claims (11)

[Claims] An orally dissolving tablet containing a pharmaceutically active ingredient, a saccharide and a low-melting substance, wherein the low-melting substance forms an interparticle crosslink between the pharmaceutically active ingredient and the saccharide. An orally dissolving tablet having a structure. 2. The orally soluble tablet according to claim 1, wherein the low melting point substance is a pharmaceutically acceptable additive and has a melting point of 40 ° C. or higher. 3. The orally dissolving tablet according to claim 1, wherein the low-melting substance comprises one or more selected from waxes, surfactants and polyethylene glycol. 4. The oral dissolving tablet according to claim 1, wherein the low melting point substance is contained in an amount of 0.5 to 25% by weight based on the total amount. 5. The orally soluble tablet according to claim 1, which has a porous structure having a porosity of 10 to 50%. 6. A medicinal component comprising 0.001 to 90 based on the total amount.
The orally-dissolvable tablet according to claim 1, which is contained by weight. 7. A disintegrant, a binder, an acidulant, a foaming agent,
The oral dissolving tablet according to any one of claims 1 to 6, comprising one or more components selected from the group consisting of artificial sweeteners, flavors, lubricants, and coloring agents. 8. A medicinal component, a saccharide and a low-melting substance are mixed, the mixture is tabletted at a low pressure, the resulting tablet is heated to a temperature at which the low-melting substance melts, and then left to cool. A method for producing an orally dissolvable tablet, comprising forming a porous structure. 9. The method according to claim 8, wherein the low-melting substance is added in the form of powder or particles. 10. The method for producing an oral dissolvable tablet according to claim 8, wherein the tablet is compressed at a low pressure of 300 kg / punch or less. 11. The composition of claim 1, further comprising one or more components selected from the group consisting of disintegrants, binders, acidulants, foaming agents, artificial sweeteners, flavors, lubricants and coloring agents. The method for producing an orally-soluble tablet according to any one of 8 to 10.