JP2004300150A - Oral fast disintegrating tablet and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a rapidly disintegrating tablet in the oral cavity which contains a high dose of a physiologically active substance and has strength and rapid disintegration with no problem in handling, and a method for producing the same.
SOLUTION: A physiologically active substance which exists in a free form as a free acid or a free base and a medically acceptable salt thereof are mixed or granulated, pressed at the minimum pressure at which molding is possible, humidified and wet, and then dried. A rapidly disintegrating buccal tablet containing a high dose of a physiologically active substance, which has a strength and a quick disintegration that can be handled without any problem.
[Selection diagram] None

Description

  The present invention relates to an orally rapidly disintegrating tablet and a method for producing the tablet.

WO93 / 12769 pamphlet WO95 / 20380 pamphlet JP-A-8-291051 JP-A-9-48726 JP-A-5-27054 WO93 / 15724 pamphlet

In recent years, in the treatment of diseases, the development of pharmaceutical preparations has been actively pursued with the aim of improving the quality of life (QOL) of patients, and rapidly disintegrating tablets in the oral cavity are the most developed pharmaceuticals. is there. Oral fast disintegrating tablets are easy to take because even a small amount of saliva in the oral cavity disintegrates instantly, and are the most suitable formulation for elderly people and children who have difficulty swallowing with ordinary tablets. In addition, since it can be taken without water, there is an advantage that the place and time for taking the drug are not limited.
Further, the rapidly disintegrating tablet in the oral cavity can be applied topically to oral diseases. In addition, if the physiologically active substance is directly absorbed from the oral mucosa, it is expected to avoid the first-pass effect in the liver and to have an immediate effect.

  Techniques for rapidly disintegrating tablets in the oral cavity that have been invented so far include, for example, a physiologically active substance and sugars such as lactose and mannitol are suspended in an aqueous agar solution, and the suspension is filled into a PTP (Press Through Package) sheet. Then, a method of obtaining a porous tablet by solidifying into a jelly-like form and then drying it [Patent Document 1], or a method of forming a powder composed of a saccharide having good disintegrability and a physiologically active substance into a saccharide having good moldability. After compression granulation at low pressure [Patent Document 2], a powder containing a saccharide as a main component and added with a water-soluble binder is compression-molded at low pressure, and the tablet is placed under humidification and wetted. A method for producing tablets by drying the tablets [Patent Document 3] and [Patent Document 4], and a method for compressing and molding wet granules mainly containing saccharides containing a small amount of water, followed by drying to produce tablets [Patent Patent Reference 5] and [Patent Document 6].

  However, the above-mentioned conventional orally rapidly disintegrating tablets according to the prior art need to use a large amount of additives in order to achieve both tablet strength that is not problematic in the distribution process or handling by patients and rapid disintegration. there were. Therefore, its functionality depends on the properties of the various additives, and depending on the properties of the physiologically active substance to be incorporated, a considerable amount of addition is required, and the content of the physiologically active substance in the preparation is limited. Particularly for a physiologically active substance having a low solubility in water and a high dose, a large amount of an additive is required, and the tablet shape becomes large, and the ingestibility is significantly impaired.

  The present inventors have conducted intensive studies to solve the above-mentioned problems of the prior art, and as a result, found that a physiologically active substance present as a free acid or a free base (hereinafter abbreviated as a free form) and a medically acceptable salt thereof Is mixed or granulated, pressed at the minimum pressure at which it can be molded, and after humidification and wetting, the dried tablet not only has both strength and rapid disintegration without any problem in handling, but also has essentially the same bioactive substance The present inventors have found that the tablet can be made to have an extremely high content of a physiologically active substance by constituting a tablet with the free form and a salt which are as follows.

That is, the present invention
(1) a rapidly disintegrating tablet in the oral cavity comprising a physiologically active substance existing in a free form and a medically acceptable salt thereof;

(2) a rapidly disintegrating tablet in the oral cavity containing a high dose of a physiologically active substance present in a free form, and a medically acceptable salt and additives thereof;

(3) The orally rapidly disintegrating tablet according to (1), wherein 1 to 19 parts by weight of a physiologically active substance existing in a free form is 1 part by weight of a medically acceptable salt thereof;

(4) The description of (2), wherein 1 to 19 parts by weight of the physiologically active substance existing as a free form comprises 1 part by weight of a pharmaceutically acceptable salt thereof and an additive of 10% or less based on the total weight of both. Orally rapidly disintegrating tablets of;

(5) It is characterized by mixing or granulating a physiologically active substance present in a free form and a medically acceptable salt thereof, tableting at the minimum pressure at which molding is possible, humidifying and wetting, and then drying. )) A method for producing a rapidly disintegrating tablet in the oral cavity;

(6) 1 to 19 parts by weight of a physiologically active substance existing in a free form is mixed or granulated with 1 part by weight of a medically acceptable salt, and the mixture is tabletted at the minimum pressure at which molding is possible, and after humidification and wet Drying the tablet in the oral cavity according to (2), wherein the tablet is dried;

(7) Mixing or granulating a physiologically active substance present in a free form and its medically acceptable salt and additives, tableting at the minimum pressure at which molding is possible, humidifying wet, and then drying. (1) a method for producing an orally rapidly disintegrating tablet according to (1);

(8) 1 to 19 parts by weight of a physiologically active substance existing in a free form, 1 part by weight of a pharmaceutically acceptable salt thereof and an additive of 10% or less based on the total weight of both, are mixed or granulated, (2) The method for producing a rapidly disintegrating tablet in the oral cavity according to (2), wherein the tablet is pressed at the minimum pressure at which the tablet can be molded, wetted and wetted, and then dried.

(9) The orally rapidly disintegrating tablet according to (1) to (4), wherein the physiologically active substance existing in a free form is L-carbocysteine.

(10) The method for producing a rapidly disintegrating tablet in the oral cavity according to (5) to (8), wherein the physiologically active substance existing in a free form is L-carbocysteine.
The present invention based on such knowledge can be applied to a physiologically active substance in which a free form and a medically acceptable salt thereof exist.

Physiologically active substances that can exist in a free form and in the form of a medically acceptable salt thereof generally differ in physicochemical properties, stability and properties (taste), but have essentially the same physiological activity. Show.

  Since the orally rapidly disintegrating tablet in the present invention is essentially composed of a free form having the same physiological activity and a pharmaceutically acceptable salt, the content of the physiologically active substance in the tablet can be extremely high. Even when the free form of the physiologically active substance has a low solubility in water, if the salt is present, it has tablet strength and rapid disintegration with no problem in handling, when properly combined.

  In the present invention, the compounding ratio of the free form of the physiologically active substance and the medically acceptable salt thereof is not particularly limited, but the free form is about 99 parts by weight per 1 part by weight of the sodium salt and / or other salts. Parts by weight or less, particularly preferably about 1 to 19 parts by weight. The compounding ratio may be appropriately set in consideration of the balance between physicochemical properties, stability, taste, and the like of the tablet. When one or more medically acceptable salts are blended, they may be blended as an aqueous salt solution.

In the present invention, the term "rapid disintegration in the oral cavity" refers to disintegration such that the tablet disintegrates in the oral cavity without taking water within 2 minutes, preferably within 1 minute, and more preferably within 40 seconds. That means.
In the present invention, the minimum moldable pressure may be any tableting pressure that does not cause any problem in the manufacturing process, such that the tablet strength maintains a strength of 0.1 kg or more.

  The internal structure having a high porosity of the tablet of the present invention is formed by tableting at the minimum pressure at which molding is possible, and then humidifying wet and drying. Due to this internal structure, prompt infiltration of saliva into the inside of the tablet at the time of ingestion promotes good disintegration in the oral cavity.

The tablet of the present invention has tablet strength with no problem in handling due to the dense structure formed in the tablet surface layer. This dense structure is obtained by humidifying and wetting after tableting, the wet form of the free form of the physiologically active substance and a part of its salt being dissolved and then recrystallized by drying.
The tablet strength which does not have a problem in handling specifically depends on the shape of the tablet, but refers to 1 kg or more for a tablet diameter of about 8 mm and 2 kg or more for a tablet diameter of about 10 mm in PTP packaging.
The tablet of the present invention thus obtained is characterized in that the free form of the physiologically active substance and a pharmaceutically acceptable salt thereof are used as the basic constituents of the tablet, and the content of the physiologically active substance in the tablet is extremely high, while the inside of the tablet is high. By having a porosity, it has a rapid disintegration property in the oral cavity, and by forming a dense structure on the surface layer portion of the tablet, tablet strength that is not problematic in handling is ensured.

  The physiologically active substance in the present invention is not particularly limited as long as the free form and a medically acceptable salt thereof can be orally administered. Such physiologically active substances include chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents, drugs for autonomic nerves, drugs for psychiatric nerves, local anesthetics, muscle relaxants, drugs for digestive organs, Antihistamines, addiction treatments, hypnotics, sedatives, antiepileptics, antipyretic analgesics and anti-inflammatory drugs, inotropics, arrhythmias, diuretics, vasodilators, antilipidemics, nutrient tonics, anticoagulants, liver drugs, Hypoglycemic agents, hypotensive agents, cerebral circulation metabolism improving agents, and the like.

  The medically acceptable salt in the present invention is an alkali metal salt (for example, sodium salt, potassium salt and lithium salt), calcium salt, magnesium salt or aluminum salt when the physiologically active substance forms an alkali salt. No. When the physiologically active substance forms an acid addition salt, an inorganic acid salt (eg, hydrochloride, sulfate, hydrobromide, etc.) or an organic acid salt (eg, maleate, fumarate, acetate) Oxalate, tartrate and benzenesulfonic acid).

In the present invention, in addition to the free form of the physiologically active substance and its medically acceptable salt, additives generally used in the field of formulation technology are used, and the tablet of the present invention has strength and rapid disintegration that can be handled without problems. Can be added as appropriate within a range that does not impair. Such additives include, for example, lactose and crystalline cellulose as excipients, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, corn starch, potato starch, sodium carboxymethyl starch as disintegrants. And stearic acid and its metal salts as lubricants, such as talc, light anhydrous silicic acid, hydrated silicon dioxide, sucrose fatty acid esters, and the like, and sugars, sugar alcohols, aspartame, saccharin and the like as sweeteners. Salts, glycyrrhizic acid and its salts, stevia, and acesulfame potassium, etc., as a flavoring agent, citric acid, sodium citrate, succinic acid, tartaric acid and fumaric acid, and a coloring agent. Ferric oxide Te, yellow ferric oxide, caramel, riboflavin and aluminum lakes, etc., menthol and orange oil, and the like as a perfume.
The method for producing a rapidly disintegrating tablet in the oral cavity according to the present invention can be sufficiently produced by appropriately combining conventional production apparatuses which have been conventionally used, and there is no need to use a special production apparatus.
In the present invention, the free form of the physiologically active substance and its medically acceptable salt can be tableted after granulation by a usual stirring granulation method or fluidized bed granulation method.

  In the present invention, the shape of the tablet to be molded is not particularly limited as long as it does not impair tablet strength and rapid disintegration that have no problem in handling. For example, special shapes such as hollow, polygonal and concave shapes can be used. In addition, in order to increase the contact area of the tablet on the tongue, quickly penetrate the water in the oral cavity into the tablet, and increase the rapid disintegration in the oral cavity, a flat tablet with a small tablet thickness and a large tablet diameter It can also be molded.

In the present invention, the humidification conditions are not particularly limited, and a mixture of a physiologically active substance and a pharmaceutically acceptable salt thereof, which are present in a free form, or a granulated product is pressed at the minimum pressure at which molding is possible. It is sufficient that the humidity is such that the surface layer portion or the whole inside of the tablet is wet and sufficient tablet strength is obtained after drying. The humidification can shorten the processing time as the temperature and the humidity become higher. Furthermore, if a mixture of a physiologically active substance and its salt existing as a free form, or a water adsorption isotherm of a granulated substance is determined, more optimal conditions can be set.
The means for humidification is not particularly limited, and an existing device such as a spray humidifier, a warming humidifier (constant temperature / humidifier, Tabaispec) may be used.
The means for drying is not particularly limited, and is performed for removing and solidifying water from the wetted portion of the tablet after tableting and humidification, and is performed by appropriately combining conditions such as normal temperature or heating, reduced pressure, or ventilation. Can be.

  The present invention has a problem in handling by mixing or granulating a physiologically active substance present in a free form and a medically acceptable salt thereof, compressing the mixture under the minimum pressure at which it can be molded, humidifying and moistening, and then drying. It is a rapidly disintegrating tablet in the oral cavity containing a high dose of 90% or more of a physiologically active substance, having no tablet strength and rapid disintegration, and has a limited chewing and swallowing function for infants and the elderly or water intake. It is the optimal formulation for patients. Moreover, since it is excellent in portability and can be taken without water, the time and place of taking it are not limited. Furthermore, it is a technique capable of formulating a physiologically active substance, which has been difficult to formulate as a rapidly disintegrating tablet in the oral cavity because of its high dose so far, and its usefulness is extremely high.

  Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited by these Examples.

<Example 1>
To 1 part by weight of sodium L-carbocysteine (particle size: 200 μm or less), 4 parts by weight of L-carbocysteine was added and mixed in a mortar. This mixed powder was tableted using a single punch tableting machine (N-30E, manufactured by Okada Seiko) using a 12φ-15R punch and die so that the tablet weight was 500 mg at the minimum moldable pressure. After humidifying and moistening for 1 day under the condition of 40 ° C.-75% RH, it was dried for 3 days under the condition of 25 ° C.-60% RH to produce an orally rapidly disintegrating tablet.

<Example 2>
1.5 parts by weight of L-carbocysteine was added to 1 part by weight of sodium L-carbocysteine (particle size: 200 μm or less) and mixed in a mortar. This mixed powder was tableted using a single punch tableting machine (N-30E, manufactured by Okada Seiko) using a 12φ-15R punch and die so that the tablet weight was 500 mg at the minimum moldable pressure. After humidifying and moistening for 1 day under the condition of 40 ° C.-75% RH, it was dried for 3 days under the condition of 25 ° C.-60% RH to produce an orally rapidly disintegrating tablet.

<Example 3>
To 1 part by weight of sodium L-carbocysteine (particle size: 150 μm or less), 9 parts by weight of L-carbocysteine was added and mixed in a mortar. This mixed powder was tableted with a single-shot tableting machine (N-30E type, manufactured by Okada Seiko) using a 9.5 φ-12R punch and die so that the tablet weight became 273 mg at the minimum moldable pressure. After humidifying and moistening for 6 minutes at 60 ° C.-90% RH, the mixture was dried at 60 ° C. for 15 minutes (30C type, ventilation dryer, manufactured by Fuji Paudal) to produce an orally rapidly disintegrating tablet.

<Example 4>
To 1 part by weight of sodium L-glutamate (particle size: 150 μm or less), 9 parts by weight of L-glutamic acid was added and mixed in a mortar. This mixed powder was tableted with a single-shot tableting machine (N-30E type, manufactured by Okada Seiko) using a 9.5 φ-12R punch and die so that the tablet weight became 273 mg at the minimum moldable pressure. After humidifying and moistening for 6 minutes at 60 ° C.-90% RH, the mixture was dried at 60 ° C. for 15 minutes (30C type, ventilation dryer, manufactured by Fuji Paudal) to produce an orally rapidly disintegrating tablet.

<Example 5>
34.5 g of sodium hydroxide was added to 490.5 g of water and dissolved with cooling. Further, 150 g of L-carbocysteine was added and dissolved while cooling to prepare an L-carbocysteine sodium hydroxide solution. Using a fluidized bed granulator (Flow Coater, FBG-1 type, manufactured by Freund Corporation), 900 g of L-carbocysteine was sprayed with 450 g of sodium L-carbocysteine hydroxide solution and granulated (granulated material). Separately, 2.55 g of hydrated silicon dioxide, 0.47 g of fragrance and 25.50 g of aspartame were mixed in a mortar to prepare a fragrance and aspartame dispersed powder. To 409.2 g of the granulated product, 26.84 g of a fragrance and aspartame dispersed powder were added, and the mixture was mixed with a V-type mixer (15 L type, manufactured by Nippon Pharmaceutical Machinery) for 10 minutes. Further, 4.4 g of magnesium stearate was added, and mixed with a V-type mixer (15 L type, Nippon Pharmaceutical Machinery Co., Ltd.) for 10 minutes to prepare granules for tableting. The granules for tableting were tableted using a single-shot tableting machine (Model N-30E, manufactured by Okada Seiko) using a 9.5 φ-12R punch and die so that the tablet weight would be 275 mg at the minimum moldable pressure. After humidifying and moistening for 6 minutes at 60 ° C.-90% RH, it was dried at 60 ° C. for 20 minutes (30C type, ventilation dryer, manufactured by Fuji Paudal) to produce a rapidly disintegrating tablet in the oral cavity.

<Comparative Example 1>
1 part by weight of sucrose was added to 4 parts by weight of sodium L-carbocysteine (particle size: 200 μm or less) and mixed in a mortar. This mixed powder was tableted using a single punch tableting machine (N-30E, manufactured by Okada Seiko) using a 12φ-15R punch and die so that the tablet weight was 500 mg at the minimum moldable pressure. After humidifying and moistening for 1 day under the condition of 40 ° C.-75% RH, it was dried for 3 days under the condition of 25 ° C.-60% RH to produce an orally rapidly disintegrating tablet.

<Comparative Example 2>
One part by weight of D-mannitol was added to 4 parts by weight of sodium L-carbocysteine (particle size: 200 μm or less) and mixed in a mortar. This mixed powder was tableted using a single punch tableting machine (N-30E, manufactured by Okada Seiko) using a 12φ-15R punch and die so that the tablet weight was 500 mg at the minimum moldable pressure. After humidifying and moistening for 1 day under the condition of 40 ° C.-75% RH, it was dried for 3 days under the condition of 25 ° C.-60% RH to produce an orally rapidly disintegrating tablet.

<Comparative Example 3>
1 part by weight of lactose was added to 4 parts by weight of sodium L-carbocysteine (particle size: 200 μm or less) and mixed in a mortar. This mixed powder was tableted using a single punch tableting machine (N-30E, manufactured by Okada Seiko) using a 12φ-15R punch and die so that the tablet weight was 500 mg at the minimum moldable pressure. After humidifying and moistening for 1 day under the condition of 40 ° C.-75% RH, it was dried for 3 days under the condition of 25 ° C.-60% RH to produce an orally rapidly disintegrating tablet.

(Measurement of tablet hardness)
It was measured using a tablet hardness tester (TS-50N, manufactured by Okada Seiko).

(Measurement of oral disintegration time)
The time until the tablet completely disintegrated in the mouth of a healthy adult male was measured.

(Bioactive substance content)
The physiologically active substance content per tablet was determined by the following formula.

  The hardness, the oral disintegration time and the bioactive substance content of each of the orally rapidly disintegrating tablets of Examples 1 to 5 and Comparative Examples 1 to 3 were measured. The results are shown in Table 1.

  As shown in Table 1, a free physiologically active substance represented by L-carbocysteine or L-glutamic acid and a sodium salt thereof are mixed or granulated, and the mixture is tableted at the minimum moldable pressure and humidified. By drying after wetting, an orally rapidly disintegrating tablet having a physiologically active substance content of 90% or more having tablet strength and good orally rapid disintegration without any problem in handling could be obtained. On the other hand, in place of the sodium salt of L-carbocysteine, the tablets obtained in Comparative Examples 1 to 3, which were manufactured using saccharides, which are general additives, did not have tablet strength with no problem in handling. .

Claims (10)

An orally rapidly disintegrating tablet comprising a physiologically active substance present in a free form and a pharmaceutically acceptable salt thereof. An orally rapidly disintegrating tablet containing a high dose of a physiologically active substance comprising a physiologically active substance present in a free form, and a medically acceptable salt and additives thereof. 2. The orally rapidly disintegrating tablet according to claim 1, comprising 1 to 19 parts by weight of a physiologically active substance existing in a free form and 1 part by weight of a medically acceptable salt thereof. The oral cavity according to claim 2, comprising 1 to 19 parts by weight of the physiologically active substance present as a free form, 1 part by weight of a pharmaceutically acceptable salt thereof, and 10% or less of an additive based on the total weight of both. Quick disintegrating tablets. 2. The method according to claim 1, wherein the physiologically active substance present as a free form and a pharmaceutically acceptable salt thereof are mixed or granulated, tableted at a minimum pressure capable of molding, humidified and wet, and then dried. A method for producing a rapidly disintegrating tablet in the oral cavity. 1 to 19 parts by weight of the physiologically active substance present in the free form is mixed or granulated with 1 part by weight of a medically acceptable salt, tableted at the minimum pressure at which molding is possible, humidified and wet, and then dried. The method for producing an orally rapidly disintegrating tablet according to claim 1, characterized in that: A method comprising mixing or granulating a physiologically active substance present in a free form, a medically acceptable salt thereof, and an additive, compressing the mixture under the minimum pressure at which it can be molded, humidifying and wetting, and then drying. 2. The method for producing an orally rapidly disintegrating tablet according to item 2. It is possible to mix or granulate 1 to 19 parts by weight of the physiologically active substance existing as a free form and 1% by weight of a pharmaceutically acceptable salt thereof and an additive of 10% or less with respect to the total weight of both to form. 3. The method for producing a rapidly disintegrating tablet in the oral cavity according to claim 2, wherein the tablet is compressed at a minimum pressure, humidified and wet, and then dried. The orally rapidly disintegrating tablet according to any one of claims 1 to 4, wherein the physiologically active substance present in a free form is L-carbocysteine. The method for producing a rapidly disintegrating tablet in the oral cavity according to any one of claims 5 to 8, wherein the physiologically active substance existing in a free form is L-carbocysteine.