CN115803020A - Orally disintegrating tablet containing milobalin besylate - Google Patents
Orally disintegrating tablet containing milobalin besylate Download PDFInfo
- Publication number
- CN115803020A CN115803020A CN202180049600.5A CN202180049600A CN115803020A CN 115803020 A CN115803020 A CN 115803020A CN 202180049600 A CN202180049600 A CN 202180049600A CN 115803020 A CN115803020 A CN 115803020A
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- CN
- China
- Prior art keywords
- orally disintegrating
- disintegrating tablet
- weight
- besylate
- content
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KSCKTBJJRVPGKM-UHFFFAOYSA-N octan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-].CCCCCCCC[O-] KSCKTBJJRVPGKM-UHFFFAOYSA-N 0.000 description 1
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- 150000003839 salts Chemical class 0.000 description 1
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Abstract
An object of the present invention is to provide orally disintegrating tablets containing milopaline besylate having excellent stability. The embodiment of the present invention is an orally disintegrating tablet comprising (a) a granule containing milobaline besylate, and (B) a drug-free granule containing crystalline cellulose or a drug-free mixed powder containing crystalline cellulose.
Description
Technical Field
The present invention relates to orally disintegrating tablets containing milobaline besylate having excellent stability.
The orally disintegrating tablet of the present invention is one that disintegrates rapidly when contained in the mouth or placed in water, but has sufficient hardness in normal production, transportation and use.
The invention further relates to a preparation method thereof.
Background
Tablets, capsules, granules, powders and the like are known as dosage forms of oral solid preparations in the fields of pharmaceutical products and foods. However, as a dosage form which is more easily taken by the elderly, children and patients with dysphagia, there is a need to develop an orally disintegrating tablet which rapidly disintegrates when contained in the mouth or placed in water.
In addition to the property of rapidly disintegrating in the oral cavity, the orally disintegrating tablet is required to have sufficient hardness that can withstand physical impact in production, transportation and use, like ordinary tablets. Further, in view of drug compliance, it is also desirable to suppress unpleasant taste and irritation when contained in the mouth and to provide good taste.
Patent document 1 discloses an orally disintegrating tablet containing a drug and having a concentration of 0.23g/cm 3 Or less bulk density crystalline cellulose, sugar alcohols and pregelatinized starch. However, this document does not describe orally disintegrating tablets containing milobaline besylate.
Patent document 2 discloses a pharmaceutical solid composition containing, in addition to milobaline besylate, (i) one selected from the group consisting of D-mannitol, lactose, corn starch and crystalline cellulose, and (ii) calcium carboxymethylcellulose. However, this document does not describe orally disintegrating tablets containing milobaline besylate.
Patent document 3 discloses that stabilization of mirobalin besylate can be observed in a pharmaceutical solid preparation containing an excipient, a disintegrant, and a specific antioxidant in addition to mirobalin besylate. However, this document does not describe orally disintegrating tablets containing milobaline besylate.
Patent document 4 discloses a pharmaceutical solid composition containing, in addition to milbelin besylate, (i) one or more selected from the group consisting of D-mannitol, lactose, corn starch, and crystalline cellulose, (ii) calcium carboxymethylcellulose, and (iii) titanium oxide as a colorant, one or more other colorants. However, this document does not describe orally disintegrating tablets containing milobaline besylate.
CITATION LIST
Patent document
Patent document 1 U.S. patent application No. 2015/0110880A1
Patent document 2 U.S. patent application No. 2015/0079166A1
Patent document 3 U.S. patent application No. 2018/0042878A1
Patent document 4 U.S. patent application No. 2018/0243223A1.
Disclosure of Invention
Technical problem
An object of the present invention is to provide orally disintegrating tablets containing milopaline besylate having excellent stability.
The orally disintegrating tablet of the present invention is one that disintegrates rapidly when contained in the mouth or placed in water, but has sufficient hardness in normal production, transportation and use.
In addition, the invention also provides an excellent preparation method thereof.
Solution to the problem
In order to solve the above problems, as a result of diligent studies, the present inventors have found that the above problems are solved by combining (a) a granule containing milobaline besylate and (B) a drug-free granule containing crystalline cellulose or a drug-free mixed powder containing crystalline cellulose to produce an orally disintegrating tablet having excellent properties, and have completed the present invention.
That is, the present invention is as follows.
[1] An orally disintegrating tablet comprising (a) particles containing milobalin besylate and (B) drug-free particles containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose.
[2] The orally disintegrating tablet according to [1], wherein the average particle size of the milopalin besylate contained in (A) is 60 μm or less, and the content thereof as milopalin is 0.5 to 10% by weight relative to 100% by weight of the orally disintegrating tablet.
[3]According to [1]]Or [2]]The orally disintegrating tablet of (1), wherein the bulk density of the crystalline cellulose contained in (B) is 0.10 to 0.26g/cm 3 And the content thereof is 1.0 to 50% by weight with respect to 100% by weight of the orally disintegrating tablet.
[4] The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is a milobaline besylate-containing granule further containing low molecular weight hydroxypropylcellulose.
[5] The orally disintegrating tablet according to [4], wherein the content of the low molecular weight hydroxypropylcellulose contained in (A) is 0.1 to 2.0% by weight relative to 100% by weight of the orally disintegrating tablet.
[6] The orally disintegrating tablet according to any one of [1] to [3], wherein (A) is a milobalin besylate-containing granule further containing citric acid hydrate and tocopherol.
[7] The orally disintegrating tablet according to [6], wherein the content of citric acid hydrate contained in (A) is 0.2 to 1.0% by weight with respect to 100% by weight of the orally disintegrating tablet, and the content of tocopherol contained in (A) is 0.01 to 0.4% by weight with respect to 100% by weight of the orally disintegrating tablet.
[8] The orally disintegrating tablet according to [3], wherein (A) is a milobalin besylate-containing granule further containing D-mannitol and carboxymethylcellulose.
[9] The orally disintegrating tablet according to any one of [6] to [8], wherein (A) is a milobaline besylate-containing granule further containing hydroxypropylcellulose.
[10] The orally disintegrating tablet according to [9], wherein the content of the hydroxypropylcellulose in (A) is 0.1 to 3.0% by weight relative to 100% by weight of the orally disintegrating tablet.
[11] The orally disintegrating tablet according to any one of [6] to [10], wherein (B) is a drug-free granule further containing D-mannitol and pregelatinized starch.
[12] The orally disintegrating tablet according to [11], wherein the content of D-mannitol contained in (B) is 20 to 55% by weight with respect to 100% by weight of the orally disintegrating tablet, and the content of pregelatinized starch contained in (B) is 1.0 to 10% by weight with respect to 100% by weight of the orally disintegrating tablet.
[13] The orally disintegrating tablet according to [4] or [5], wherein (B) is a drug-free mixed powder further containing carboxymethylcellulose and potassium acetylaminosulfonate.
[14] The orally disintegrating tablet according to [13], wherein the content of carboxymethylcellulose contained in (B) is 2.0 to 20% by weight with respect to 100% by weight of the orally disintegrating tablet, and the content of potassium acetamidosulfonate contained in (B) is 1.0 to 5.0% by weight with respect to 100% by weight of the orally disintegrating tablet.
[15] A method for preparing an orally disintegrating tablet comprising: a step of mixing milopalin besylate, D-mannitol and citric acid hydrate and spraying a low molecular weight hydroxypropylcellulose binder solution to produce granules; a step of mixing granule a, crystalline cellulose, carboxymethylcellulose and potassium acetylaminosulfonate, then adding magnesium stearate to the mixed powder, followed by mixing to form a mixture for tableting; and a step of tableting using a tableting machine.
[16] A method for preparing an orally disintegrating tablet comprising: a step of mixing tocopherol and crystalline cellulose to produce a tocopherol powder; a step of mixing milobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, tocopherol powder and magnesium aluminum silicate and spraying a hydroxypropyl cellulose binder solution to produce granules; a step of mixing D-mannitol and crystalline cellulose and spraying the pregelatinized starch dispersion to produce particles; a step of mixing the two granules, crospovidone, and potassium acetamidosulfonate and then mixing magnesium stearate to form a mixture for tableting; and a step of tableting using a tableting machine.
Advantageous effects of the invention
The present invention can provide orally disintegrating tablets containing milobaline besylate having excellent stability.
Specifically, the orally disintegrating tablet of the present invention is an orally disintegrating tablet having good stability of milobalin besylate by containing citric acid hydrate and tocopherol.
The orally disintegrating tablet of the present invention rapidly disintegrates when contained in the mouth or placed in water, exhibits excellent solubility, and has a good taste.
The orally disintegrating tablet of the present invention is an orally disintegrating tablet having sufficient hardness in normal production, transportation and use, and having excellent storage stability.
The orally disintegrating tablet of the present invention can be prepared by normal compression molding without complicated steps and special equipment.
Description of the embodiments
An "orally disintegrating tablet" in the present invention is a molded substance that has rapid disintegration and solubility when contained in the mouth or placed in water. In particular, it refers to such tablets: in a disintegration test mainly by saliva in the oral cavity or a disintegration test by a device, it disintegrates within usually 5 to 180 seconds, preferably 5 to 60 seconds, further preferably about 5 to 40 seconds.
The orally disintegrating tablets of the invention have sufficient hardness during normal manufacture, transport and use. For example, in the hardness test, the orally disintegrating tablet usually has a hardness of 2kg or more, preferably 3kg or more, further preferably 5kg or more.
The orally disintegrating tablets of the invention retain leachability suitable for use in pharmaceutical products. For example, in a dissolution test, orally disintegrating tablets generally exhibit an average dissolution rate of 80% or more, preferably 85% or more, at 30 minutes.
Dissolution test 6.10 dissolution test method out of the formulation test methods described in 6. Eighteenth revised edition of japanese pharmacopoeia. This test was performed to determine whether the oral formulations met the dissolution test criteria, but also to prevent significant biological inequalities. The samples in this test correspond to the minimum dose and refer to one tablet for tablets, one capsule for capsules and the specified amount for other formulations. Examples of the apparatus to be used in this test include a spin basket apparatus, a paddle apparatus and a flow cell apparatus. The details thereof are described in the eighteenth revised edition of the japanese pharmacopoeia.
"Melobalin" as used in the present invention is a compound represented by the following formula (I):
[ formula 1]
"Melobalin besylate" as used in the present invention is a salt of Melobalin with benzenesulfonic acid and is represented by the following formula (Ia):
[ formula 2]
Milobalin used in the present invention is considered to exert analgesic effects by inhibiting calcium flow by binding to α 2 δ subunit, which plays an auxiliary role in the function of voltage-dependent calcium channel in nervous system.
In clinical trials conducted in japan and overseas, milobalin besylate used in the present invention has been approved for production and sale as a therapeutic agent for peripheral neuropathic pain.
To treat peripheral neuropathic pain, an adult typically orally administers an initial dose of 5mg milobalin each twice daily, then gradually increasing the dose by 5mg each at intervals of one week or more, and orally administers 15mg each twice daily. The dose is adjusted according to the age and symptoms of the patient, ranging from 10mg to 15mg, and is administered twice daily.
The method of producing the orally disintegrating tablet of the present invention and aspects thereof (aspect a and aspect B) will be described below.
Aspect A:
an orally disintegrating tablet containing a compound having a molecular weight of 0.26g/cm by compression molding 3 Or less, bulk density of drug-free granules of crystalline cellulose, D-mannitol, and pregelatinized starch, and granules comprising milobaline besylate.
In this respect, the drug-free granules act as a matrix of the formulation, which can impart the desired disintegration and moldability to the orally disintegrating tablet. The drug-free particles are prepared by only containing the particles with the concentration of 0.26g/cm 3 Or less of bulk densityCrystalline cellulose, D-mannitol, and pregelatinized starch (but may contain one or more other additives as needed) to exert excellent disintegration and excellent moldability.
Further, by adding citric acid hydrate and tocopherol to the granules containing milobalin besylate, the orally disintegrating tablet in this aspect exerts excellent stability.
The method for producing the orally disintegrating tablet of aspect a comprises (1) a step of preparing a drug-free granule, (2) a step of preparing a granule containing milobalin besylate, and (3) a step of mixing the drug-free granule, the granule containing milobalin besylate, and another extragranular mixed powder for compression molding.
(1) Step of preparing drug-free granules
Drug-free particles can be prepared using the following method 1) or 2).
1) Will contain with water the content of the active carbon particles with 0.26g/cm 3 Or less bulk density, of a mixture of crystalline cellulose, D-mannitol and pregelatinized starch.
2) It will have a viscosity of 0.26g/cm by a liquid (dissolving or dispersing pregelatinized starch in water or the like) 3 Or less bulk density, of a mixture of crystalline cellulose and D-mannitol.
Here, conventionally used extrusion granulation method, mixing and stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method, tumbling granulation method and the like may be used for granulation.
Pregelatinized starch exhibits a viscosity suitable for granulation when dissolved or dispersed in a liquid such as water. Examples of the granulation method include a method of mixing pregelatinized starch with other components as they are in a powder form, followed by granulation with water, and a method of granulation with a liquid in which pregelatinized starch is dissolved or dispersed in water. Any method can produce tablets with the desired properties, but the latter method is preferred.
Further, in the case of granulation using a liquid in which pregelatinized starch is dissolved or dispersed, any of a high-speed stirring granulation method and a fluidized bed granulation method may be applied, but in the case of granules prepared by the fluidized bed granulation method, an orally disintegrating tablet having more excellent properties may be obtained. In case another additive, such as a conventional disintegrant, is mixed into the drug-free granules, it may be mixed with the mixture before granulation.
In the drug-free granules, D-mannitol has a concentration of 0.26g/cm 3 The proportion of the crystalline cellulose having a bulk density of less or more is 1 to 3 parts by weight of D-mannitol, preferably 1 to 2 parts by weight of D-mannitol, relative to 1 part of the crystalline cellulose.
(2) Process for the preparation of particles containing milobalin besylate
The milobaline besylate may be mixed with the drug-free particles as such, in powder form, or after it is granulated, if desired. For example, the milobailin besylate-containing granules can be prepared by a conventionally used extrusion granulation method, mixing and stirring granulation method, high-speed stirring granulation method, fluidized bed granulation method or tumbling granulation method.
For example, by dissolving or dispersing the hydroxypropylcellulose in water with a liquid, the powdery or granular milobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, 10% tocopherol powder (by mixing tocopherol and a powder having 0.26 g/cm) 3 Or less bulk density crystalline cellulose) and magnesium aluminum silicate, and a granule containing milobalin besylate can be obtained.
Further, by mixing powdery or granular milopalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, 10% tocopherol powder (by mixing tocopherol and a powder having 0.26 g/cm) 3 Or less bulk density crystalline cellulose), magnesium aluminum silicate and hydroxypropyl cellulose, and can be granulated to obtain granules containing the drug.
For example, by granulating a mixed powder of powdery or granular milopalin besylate, D-mannitol, and citric acid hydrate with a liquid in which low-molecular weight hydroxypropylcellulose is dissolved or dispersed in water, a granule containing milopalin besylate can be obtained. Further, drug-containing granules can be obtained by granulating a mixed powder of powdery or granular milobalin besylate, D-mannitol, citric acid hydrate, and low-molecular-weight hydroxypropylcellulose with water.
The particles containing milobaline besylate may be masked for unpleasant taste and odor, such as bitterness and irritation, or coated to control leachability. For the coating, a coating agent and a plasticizer may be suitably used. For example, the coating process is carried out using a fluid bed granulator/coater, a rolling fluid bed granulator/coater, a centrifugal fluidized granulator/coater or a Worcester-type fluid bed granulator/coater.
In case two or more drugs are used, they may be contained in the same granule or in different granules and compression molded, depending on the dosing suitability of the drugs.
(3) The step of mixing the drug-free granules, the milopaline besylate-containing granules, and other extragranular mixed powders for compression molding mixes the drug-free granules and the milopaline besylate-containing granules, and if necessary, a disintegrant, a lubricant, and other additives, followed by compression molding to produce orally disintegrating tablets. For example, mixing is carried out by using a drum mixer or a convection mixer.
Compression molding of the orally disintegrating tablet of the present invention can be performed using a common tablet press. The molding pressure of the tablet press may be the same as that of a conventional tablet, but is preferably from 2 to 20kN, more preferably from about 4 to 14kN, although it also depends on the shape and size of the tablet.
The proportion of the drug-free granules may be 30-90% relative to the total weight of the tablet components. In the case of a powder form, the ratio is 30-80%, preferably 45-70%. When the drug is used after granulation, the compounding ratio is 30 to 80%, preferably 45 to 70%. In addition, in the case of using the drug after granulation, the weight ratio of the formulation without drug particles to the drug-containing particles is preferably 1.0 to 3.5.
Aspect B:
an orally disintegrating tablet is prepared by mixing a mixture of a powder having a particle size of 0.26g/cm 3 Or less packingA drug-free mixed powder or another extra-granular mixed powder of crystalline cellulose, D-mannitol and pregelatinized starch in degrees is compression molded with the granules containing milobalin besylate.
In aspect B, the drug-free mixed powder or the other extragranular mixed powder imparts the desired disintegration and moldability to the orally disintegrating tablet.
The drug-free mixed powder is prepared by only containing the drug with the concentration of 0.26g/cm 3 Or less bulk density of the three components of crystalline cellulose, D-mannitol and pregelatinized starch (but may contain one or more other additives if desired) to exert excellent disintegration and excellent moldability.
Further, the other extragranular mixed powder exerts excellent disintegration and excellent moldability by containing only three components of crystalline cellulose, carboxymethylcellulose and potassium acetylaminosulfonate (but may contain one or more other additives if necessary).
The method for producing the orally disintegrating tablet of aspect B includes a step of preparing the milopalin besylate-containing granules and a step of mixing the milopalin besylate-containing granules with one or more other additives, followed by compression molding, if necessary. The procedure for preparing the milobaline besylate-containing particles is the same as in (2) of aspect a.
In the step of mixing the milobalin besylate-containing granules and one or more other additives, followed by compression molding, the mixing or compression molding process is the same as that in (3) of aspect a.
The orally disintegrating tablet of the present invention obtained as above has excellent disintegration and excellent solubility when placed in the oral cavity or in water, and has excellent physical and chemical stability.
The disintegration or solubility of the orally disintegrating tablet of the present invention means that the disintegration or dissolution time in the oral cavity (the time for which the tablet is completely disintegrated or dissolved only with saliva in the oral cavity of a healthy adult male in the absence of water in the mouth) is usually 5 to 180 seconds, preferably 5 to 60 seconds, and further preferably about 5 to 40 seconds.
The orally disintegrating tablet of the invention is gradually disintegrated or dissolved by saliva when contained in the mouth, but it disintegrates or dissolves in a shorter time due to the pressure in the mouth, i.e., the pressure generated by the palate and tongue, or the friction of the tongue, i.e., the "licking" action. For persons with dry mouth or little saliva, it can be disintegrated and dissolved in the oral cavity with water or hot water, or it can be taken with water as it is like an ordinary tablet.
Meanwhile, the hardness of the orally disintegrating tablet of the present invention is sufficient even after stability test under certain temperature and humidity conditions (for example, a temperature of 25 ℃ and a humidity of 75% held in an open system for one week).
Therefore, it has a hardness that does not collapse during the preparation process and distribution process of the formulation, has a practical hardness even when stored under constant temperature and humidity conditions, and is excellent in storage stability and disintegration.
The orally disintegrating tablet of the present invention can be used as a preparation which is easy to take even for the elderly, children and patients with dysphagia, and as a safe preparation for ordinary adults, for the treatment of diseases.
The "milobaline besylate" used in the present invention suitably has an average particle diameter of 60 μm (further suitably 40 μm) or less. The "average particle diameter" of the present invention refers to a particle diameter at an integrated value of 50% in a particle diameter distribution determined by a laser diffraction/light scattering method.
The milopaline besylate used in the present invention is suitably 0.5 to 40% by weight, more suitably 0.5 to 25% by weight, particularly suitably 0.5 to 10% by weight as milopaline, relative to 100% by weight of the orally disintegrating tablet.
As the "D-mannitol" used in the present invention, those conforming to the pharmacopoeias of Japan, europe, and the United states can be generally used. The crystal form, particle size and specific surface area of the D-mannitol to be contained are not particularly limited, but the crystal form may be any of the α form, β form, δ form and amorphous form, the particle size is preferably 10 μm or more and 250 μm or less, more preferably 20 μm or more and 150 μm or less, and the specific surface area is preferablyIs 0.1m 2 (ii)/g or more and 4m 2 A,/g or less, more preferably 0.1m 2 A number of moles of 2m and/g or greater 2 (iv) g or less. For example, the crystal form, the particle diameter and the specific surface area can be measured by X-ray diffraction, a laser diffraction particle diameter measuring method and a BET specific surface area measuring method (multipoint method), respectively. Examples of commercially available products include D-mannitol manufactured by Merck KGaA, roquette fress, towa Kasei Co., ltd., and Kao Corporation.
In the case of using D-mannitol, the content thereof is usually 20 to 95% by weight, preferably 20 to 55% by weight, relative to 100% by weight of the orally disintegrating tablet.
The D-mannitol may be mixed with other components as a tablet powder as it is in a powder form and then compression molded, or may be granulated together with other components using a suitable binder and then compression molded.
The "carboxymethylcellulose" used in the present invention is usually 1 to 20% by weight, preferably 2 to 20% by weight, relative to 100% by weight of the orally disintegrating tablet.
The "citric acid hydrate" used in the present invention is citric acid hydrate that can be used as a pharmaceutical additive (for example, a product conforming to japanese pharmacopoeia), and is usually citric acid monohydrate. Alternatively, citric acid anhydride may be used instead of citric acid hydrate.
"citric acid hydrate" and "tocopherol" used in the present invention act as stabilizers. The content of the citric acid hydrate of the present invention is suitably 0.01 to 10% by weight, more suitably 0.1 to 5.0% by weight, and still more suitably 0.2 to 1.0% by weight, relative to 100% by weight of the orally disintegrating tablet.
Further, the content of the tocopherol of the present invention is suitably 0.01 to 10% by weight, more suitably 0.01 to 1.0% by weight, and still more suitably 0.01 to 0.4% by weight, relative to 100% by weight of the orally disintegrating tablet.
The "crystalline cellulose" used in the present invention is usually 0.10 to 0.46g/cm 3 Preferably 0.10 to 0.42g/cm 3 More preferably 0.10 to 0.26g/cm 3 The level of bulk density of. Examples of commercially available products include CEOLUS KG-1000 (having 0.10-0.15 g/cm) 3 Bulk density of), CEOLUS KG-802 (having a density of 0.13-0.23 g/cm) 3 (iii) bulk density), CEOLUS UF-711 (having a density of 0.20-0.26 g/cm) 3 Bulk density) (both manufactured by Asahi Kasei Chemicals Corporation). Furthermore, it is also possible to combine two or more crystalline celluloses having different bulk densities and adjust them to obtain the desired bulk density.
The content of crystalline cellulose is preferably 1.0 to 50% by weight relative to 100% by weight of the orally disintegrating tablet. When it exceeds 50% by weight, the fluidity may deteriorate, and the manufacturability may decrease. The content is more preferably 5.0 to 30% by weight.
The ratio of D-mannitol to crystalline cellulose is 1.0 to 10 parts by weight, preferably 1.0 to 8.5 parts by weight, and more preferably 1.0 to 3.0 parts by weight, based on 1 part of crystalline cellulose.
The orally disintegrating tablet of the present invention may contain an inorganic excipient, and examples of the inorganic excipient may include one or a combination of two or more selected from the group consisting of synthetic hydrotalcite, precipitated calcium carbonate, hydrous silicon dioxide, light anhydrous silicic acid, magnesium aluminum silicate and magnesium hydroxide.
The "hydroxypropylcellulose" used in the present invention is not limited as long as it maintains the desired properties (disintegration time, hardness and extractability) as an orally disintegrating tablet.
In view of moldability and disintegration/suspension in water, the content of hydroxypropylcellulose in the orally disintegrating tablet of the invention is usually preferably 0.1 to 3.0% by weight relative to 100% by weight of the orally disintegrating tablet. When the content of the hydroxypropylcellulose is too large, the time required for suspension is prolonged, and the suitability for an orally disintegrating tablet is reduced.
The "low molecular weight hydroxypropylcellulose" used in the present invention is hydroxypropylcellulose having a molecular weight of 140,000 (GPS method) or less. Uncoated tablets containing low molecular weight hydroxypropylcellulose exhibit both suppression of the production of similar substances and suppression of the prolongation of disintegration time, which are desirable properties for orally disintegrating tablets.
The content of the low-molecular weight hydroxypropylcellulose in the orally disintegrating tablet of the invention is preferably 0.1 to 2.0% by weight relative to 100% by weight of the orally disintegrating tablet.
"analogous substances" as used in the present invention are lactam compounds of milobaline and other related substances with undefined structure.
In addition to the aforementioned components, the orally disintegrating tablet of the present invention further contains crospovidone (e.g., a product conforming to the japanese pharmacopoeia) and pregelatinized starch as a "disintegrant".
Pregelatinized starch is obtained by heating starch to pregelatinize it, and comprises a part of pregelatinized starch. In addition, those described in the japanese pharmaceutical additive standards may be used as the pregelatinized starch. The average degree of pregelatinization is preferably 90% or less, more preferably 70 to 80%. As a commercially available product, for example, pregelatinized starch SWELSTAR PD-1 (manufactured by Asahi Kasei Chemicals Corporation) can be used.
The content of pregelatinized starch is usually 1.0 to 15% by weight, preferably 1.0 to 10% by weight, relative to 100% by weight of the orally disintegrating tablet.
The pregelatinized starch may be mixed with the other components as it is in the form of powder as tablet powder and then subjected to compression molding, or may be granulated together with the other components and then subjected to compression molding.
In the orally disintegrating tablet of the present invention, pregelatinized starch is used as a disintegrant. Meanwhile, when it is dissolved or dispersed in a liquid such as water during the preparation process, it becomes viscous, and thus when it is sprayed on the raw material in the form of powder, granulation is performed, and particles may be formed. Using this property, the starch granules were prepared by spraying a solution or dispersion in which pregelatinized starch was dissolved or dispersed in water to a spray having a viscosity of 0.26g/cm 3 Or less bulk density of crystalline cellulose and D-mannitol, and mixing with other components as required, followed by compression molding, thereby obtaining good moldability and desired disintegration in the oral cavityThe tablet of (4). Such an advantage is hardly obtained in the preparation when conventional disintegrants such as low-substitution hydroxypropylcellulose or crospovidone are used, and this is a characteristic property of pregelatinized starch.
The content of crospovidone is usually 0.5 to 20% by weight, preferably 2.0 to 20% by weight, relative to 100% by weight of the orally disintegrating tablet.
The orally disintegrating tablets of the invention may contain various "additives" conventionally used in tablet preparation, as long as the effects of the invention are not hindered.
Examples of the additives may include binders, lubricants, coating agents, plasticizers, colorants, flavors, sweeteners, flavors, fluidizing agents, foaming agents, and surfactants.
Examples of the "binder" may include one or a combination of two or more selected from the group consisting of gum arabic, sodium alginate, carboxyvinyl polymer, gelatin, dextrin, pectin, sodium polyacrylate, pullulan, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, and polyethylene glycol.
Examples of the "lubricant" may include one or a combination of two or more selected from magnesium stearate (e.g., a product conforming to the japanese pharmacopoeia), calcium stearate (e.g., a product conforming to the japanese pharmacopoeia), sodium stearyl fumarate (e.g., a product conforming to the standards of pharmaceutical additives), and talc (e.g., a product conforming to the japanese pharmacopoeia), with magnesium stearate being particularly preferred.
The content of the lubricant is preferably 0.1 to 5.0% by weight with respect to 100% by weight of the orally disintegrating tablet.
Examples of the "coating agent" may include one or a combination of two or more selected from the group consisting of ethylcellulose, aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L, dried methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer, polyvinyl acetal-diethylaminoacetate, and polyvinyl acetate resin as a coating agent to coat the surface of the powdery medicine (the surface of the crystals) or the surface of the particles of the granulated medicine.
The "plasticizer" is usually used in combination with a coating agent, and examples thereof may include one or a combination of two or more selected from the group consisting of diethyl sebacate, dibutyl sebacate, triethyl citrate, stearic acid, polyethylene glycol and triacetin.
Examples of "colorants" may include one or a combination of two or more selected from the following: edible pigments such as edible yellow No. 5, edible red No. 2, and edible blue No. 2; edible lake pigments, yellow iron oxide, ferric oxide, titanium oxide, beta-carotene, and riboflavin.
Examples of "flavors" may include one or a combination of two or more selected from orange, lemon, strawberry, mint, menthol, micro-menthol and various flavors.
Examples of "sweeteners" may include one or a combination of two or more selected from sodium saccharin, aspartame, potassium acesulfame, dipotassium glycyrrhizinate, sucralose, steviol glycosides, and thaumatin.
Examples of "flavoring agents" may include one or a combination of two or more selected from the group consisting of sodium chloride, magnesium chloride, disodium inosinate, monosodium L-glutamate, and honey.
Examples of the "fluidizing agent" may include one or a combination of two or more selected from the group consisting of hydrous silica, light anhydrous silicic acid and talc.
Examples of "frother" may include tartaric acid.
Examples of the "surfactant" may include one or a combination of two or more selected from the group consisting of polyoxyethylene stearate 40, sorbitan fatty acid ester, polyoxyethylene hardened castor oil, polysorbate, glycerin monostearate and sodium lauryl sulfate.
Examples
Hereinafter, the present invention will be described by way of embodiments thereof.
Example 1 molecular weight of hydroxypropyl cellulose and stability of the formulation
(1) Preparation of granule A
Melobalin besylate, D-mannitol and citric acid hydrate were weighed at the ratios shown in Table 1, mixed using a PE bag for 3 minutes, and sieved at 1100rpm using a Comil (U-10, diameter: 1.143mm, QUADRO) to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (FL-labo 2L, FREUND) and a low molecular weight hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was sprayed at a feed air temperature of 77 ℃ at about 8g/min in the formulation shown in table 1, followed by drying to a product temperature of 50 ℃ after the spraying was finished.
Screening was carried out at 1100rpm using Comil (U-10, diameter: 1.143mm, QUADRO) to produce particles A.
(2) Preparation of granules for tabletting
Granule a, crystalline cellulose, carboxymethylcellulose, and potassium acetylaminosulfonate were weighed at the compounding ratios shown in table 1, and mixed using a V-type mixer (5L) at a rotation speed of 34rpm for 10 minutes to produce a mixed powder.
Then, magnesium stearate was weighed at the compounding ratio shown in table 1 and added to the mixed powder, followed by mixing for 10 minutes at a rotation speed of 34rpm using a V-type mixer (5L) to produce granules for tableting.
(3) Preparation of tablets
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI seisakuho ltd.) and uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a compression pressure of 5.5 kN.
Comparative example 1 molecular weight of hydroxypropyl cellulose and stability of formulation
(1) Preparation of granule A
Melobalin besylate, D-mannitol and citric acid hydrate were weighed at the ratios shown in Table 1, mixed using a PE bag for 3 minutes, and sieved using Comil (U-10, diameter: 1.143mm, QUADRO) at 1100rpm to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (FL-labo 2L, FREUND) and a hydroxypropyl cellulose binder solution (7 wt/wt% dissolved in purified water) was sprayed at a feed air temperature of 80 ℃ at about 8g/min in the proportions shown in table 1, followed by drying to a product temperature of 50 ℃ after the spraying was finished.
Screening was carried out at 1100rpm using Comil (U-10, diameter: 1.143mm, QUADRO) to produce particles A.
(2) Preparation of granules for tabletting
Granule a, crystalline cellulose, carboxymethylcellulose, potassium acetaminosulfonate were weighed in the compounding ratios shown in table 1 and mixed using a V-type mixer (5L) at a rotation speed of 34rpm for 10 minutes to produce a mixed powder. Then, magnesium stearate was weighed at the compounding ratio shown in table 1 and added to the mixed powder, followed by mixing for 10 minutes at a rotation speed of 34rpm using a V-type mixer (5L) to produce granules for tableting.
(3) Preparation of tablets
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI SEISAKUSHO ltd. And uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a compression pressure of 6 kN.
(evaluation method and results) molecular weight of hydroxypropylcellulose and stability of preparation
After allowing the uncoated tablets of example 1 and comparative example 1 to stand in an aluminum bag for 1 month under the conditions of 40 ℃/75% RH, the amounts of the produced similar substances were measured using HPLC (Agilent definition 1290) under the conditions shown in Table 2. Further, the disintegration test was according to the disintegration test method of the japanese pharmacopoeia revised seventeenth time, and the initial product and uncoated tablets after being left in an aluminum bag for 3 months under the condition of 40 ℃/75% rh were evaluated without a pan.
Table 3 shows the results of the amounts of similar substances produced. In the uncoated tablets using low molecular weight hydroxypropylcellulose having a molecular weight of 140,000 (GPS method) or less, it was confirmed that the amount of the similar substance produced was about 1/2 of the amount in the uncoated tablets using normal hydroxypropylcellulose having a molecular weight of 1,000,000 (GPS method) or less.
Table 4 shows the results of the disintegration test. In the uncoated tablets using normal hydroxypropyl cellulose (having a molecular weight of 1,000,000 (GPS method) or less), the disintegration time after standing for 3 months at 40 ℃/75 RH was extended by 38 seconds, but in the uncoated tablets using low molecular weight hydroxypropyl cellulose (having a molecular weight of 140,000 (GPS method) or less), the extension of the disintegration time was as little as 12 seconds.
As seen from the foregoing results, the uncoated tablet containing low-molecular weight hydroxypropylcellulose has the properties desired for the orally disintegrating tablet in terms of suppressing the production of similar substances and suppressing the prolongation of the disintegration time.
[ Table 1]
[ Table 2]
[ Table 3]
Difference in amount of similar substances produced
| Example 1 | Comparative example 1 |
| 0.19％ | 0.39％ |
。
[ Table 4]
Results of disintegration test
Example 2 content of crystalline cellulose and stability of the preparation
(1) Preparation of granule A
The tocopherol and crystalline cellulose were weighed in the proportions shown in table 5 and mixed using a high speed stirring granulator (VG-50, powrex) at a blade rotation speed of 180rpm and a shear blade (chopper) rotation speed of 3000rpm for 15 minutes to produce a 10% tocopherol powder.
Melobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, 10% tocopherol powder, and magnesium aluminum silicate were weighed at the ratios shown in Table 5, mixed using a V-type mixer (30L) at a rotation speed of 27rpm for 5 minutes, and sieved using Comil (QC-194S, diameter: 1.143mm, QUADRO) at 600rpm to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (FLO-5) and a hydroxypropyl cellulose binder solution (7 wt/wt% dissolved in purified water) was sprayed at a ratio as shown in table 5 at a supply air temperature of 80 ℃ at about 40g/min, followed by drying to a product temperature of 55 ℃ after spraying was finished.
Screening was performed using Comil (QC-194S, diameter: 1.143mm, QUADRO) at 1400rpm to produce particles A.
(2) Preparation of granule B
D-mannitol and crystalline cellulose were weighed in the proportions indicated in Table 5 and placed in a fluid bed granulator (GPCG-15, POWREX) and the pregelatinized starch dispersion (8% w/w dissolved in purified water) was sprayed in the proportions indicated in Table 5 at a supply air temperature of 85 ℃ at approximately 140g/min and subsequently dried after the end of the spraying to a discharge gas temperature of 45 ℃.
Screening was performed at 600rpm using a Comil (QC-194S, diameter: 1.143mm, QUADRO) to produce particles B.
(3) Preparation of granules for tabletting
Granule a, granule B, crospovidone, and potassium acetamidosulfonate were weighed in the compounding ratios shown in table 5 and mixed using a V-type mixer (10L) at a rotation speed of 32rpm for 5 minutes to produce a mixed powder. Then, magnesium stearate was weighed at the compounding ratio shown in table 5, added to the mixed powder, and mixed for 10 minutes at a rotation speed of 32rpm using a V-type mixer (10L) to produce granules for tableting.
(4) Preparation of tablets
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI SEISAKUSHO ltd. And uncoated tablets (. Phi.10.0 mm) were obtained by molding at a compression pressure of 8 kN.
(comparative example 2) content of crystalline cellulose and stability of formulation
(1) Preparation of granule A
Tocopherol and crystalline cellulose were weighed in the proportions shown in Table 5 and mixed for 15 minutes using a high speed stirring granulator (VG-50, POWREX) at a blade rotation speed of 180rpm and a shear blade rotation speed of 3000rpm to produce a 10% tocopherol powder.
Melobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, 10% tocopherol powder, and magnesium aluminum silicate were weighed at the ratios shown in Table 5, mixed using a V-type mixer (30L) at a rotation speed of 27rpm for 5 minutes, and sieved using Comil (QC-194S, diameter: 1.143mm, QUADRO) at 600rpm to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (FLO-5, freund) and a hydroxypropyl cellulose binder solution (7 wt/wt% dissolved in purified water) was sprayed at a ratio as shown in table 5 at a supply air temperature of 80 ℃ at about 40g/min, followed by drying to a product temperature of 55 ℃ after the spraying was finished.
Screening was carried out at 1400rpm using Comil (QC-194S, diameter: 1.143mm, QUADRO) to produce granules A.
(2) Preparation of granules for tabletting
Granules a, D-mannitol, crospovidone, and potassium acetaminosulfonate were weighed at the compounding ratios shown in table 5 and mixed using a V-type mixer (10L) at a rotation speed of 32rpm for 5 minutes to produce a mixed powder. Then, magnesium stearate was weighed at the compounding ratio shown in table 5, added to the mixed powder, and mixed for 10 minutes at a rotation speed of 32rpm using a V-type mixer (10L) to produce granules for tableting.
(3) Preparation of tablets
The tablet mass was adjusted to 300mg using a tablet press (Vela 5, manufactured by KIKUSUI SEISAKUSHO ltd.) and uncoated tablets (. Phi.9.5 mm) were obtained by compression molding at a compression pressure of 7 kN.
(evaluation method and results) content of crystalline cellulose and stability of preparation
After the uncoated tablets of example 2 and comparative example 2 were allowed to stand for 6 months in a plastic bottle under the conditions of 40 ℃/75% RH, the amounts of the similar substances produced were measured using HPLC (Agilent definition 1290) under the conditions shown in Table 2.
Table 6 shows the results. It was confirmed that in the uncoated tablet (example 2) using D-mannitol, crystalline cellulose and pregelatinized starch as granule B, the total amount of the similar substances produced was about 1/3 of that of the uncoated tablet (comparative example 2) using no granule B or crystalline cellulose and pregelatinized starch.
[ Table 5]
[ Table 6]
| Example 2 | Comparative example 2 |
| 0.27％ | 0.74％ |
。
(example 3) content of crystalline cellulose and disintegration time, extent of abrasion and hardness of formulation (1) preparation of tablet
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI SEISAKUSHO ltd., and uncoated tablets (phi 10.0 mm) were obtained from the granules for tableting prepared in example 2 by compression molding at compression pressures of 6, 8 and 10 kN.
Comparative example 3 content of crystalline cellulose and disintegration time, extent of abrasion and hardness of the formulation (1) preparation of tablet
The tablet mass was adjusted to 300mg using a tablet press (Vela 5, manufactured by KIKUSUI SEISAKUSHO ltd.) and uncoated tablets (9.5 mm) were obtained from the granules for tableting prepared in comparative example 2 by compression molding at compression pressures of 6, 8 and 10 kN.
(evaluation method and results) content of crystalline cellulose and disintegration time, degree of abrasion and hardness of preparation
Tables 7 to 9 show the evaluation results of the uncoated tablets prepared. The hardness of the tablets was measured using a fully automatic tablet measuring device (Type WHT-2, PHARMA TEST APPRATEABAU GmbH). Further, the disintegration test was according to the disintegration test method of the japanese pharmacopoeia revised seventeenth time, and the evaluation was made without a disc. The measurement of the abrasion degree test was carried out using a tablet abrasion degree tester (SZ-03, rinkan).
Although the hardness of example 3 was lower than that of comparative example 3, the degree of wear was low, and it was shown that a good degree of wear was imparted. Further, it was confirmed that the disintegration time of example 3 was shortened by about 1/2 compared to the uncoated tablet of comparative example 3 having almost the same hardness.
From the foregoing results, it can be seen that uncoated tablets containing D-mannitol, crystalline cellulose and pregelatinized starch as the B granules have the desired properties for orally disintegrating tablets in terms of both low degree of wear and short disintegration time.
[ Table 7]
[ Table 8]
[ Table 9]
Example 4 stability of tocopherol and formulations
(1) Preparation of granule A
The tocopherol and crystalline cellulose were weighed in the proportions shown in table 10 and mixed for 15 minutes using a high speed stirring granulator (VG-50, powrex) at a blade rotation speed of 180rpm and a shear blade rotation speed of 3000rpm to produce a 10% tocopherol powder.
Melobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, 10% tocopherol powder, and aluminum magnesium silicate were weighed at the ratios shown in Table 10, mixed using a V-type mixer (2L) at a rotation speed of 39rpm for 5 minutes, and sieved using a Comil (U-10, diameter: 1.143mm, QUADRO) at 2200rpm to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (FLO-5) and a hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was sprayed at a ratio as shown in table 10 at a supply air temperature of 78 ℃ at about 7g/min, followed by drying to a product temperature of 55 ℃ after the spraying was finished.
Screening was carried out at 2200rpm using Comil (U-10, diameter: 1.143mm, QUADRO) to produce granules A.
(2) Preparation of granule B
D-mannitol and crystalline cellulose were weighed in the proportions shown in Table 10 and placed in a fluid bed granulator (NFLO-5, FREUND) and the pregelatinized starch dispersion (8% by weight dissolved in purified water) was sprayed in the proportions shown in Table 10 at a supply air temperature of 85 ℃ at about 45g/min, followed by drying to an exhaust gas temperature of 45 ℃ after the spraying was finished.
Screening was performed at 800rpm using Comil (QC-197, diameter: 1.143mm, QUADRO) to produce particles B.
(3) Preparation of granules for tabletting
Granule a, granule B, crospovidone, and potassium acetamidosulfonate were weighed at the compounding ratios shown in table 10, and mixed using a V-type mixer (2L) at a rotation speed of 39rpm for 5 minutes to produce a mixed powder. Then, magnesium stearate was weighed at the compounding ratio shown in table 10, added to the mixed powder, and mixed for 5 minutes at a rotation speed of 39rpm using a V-type mixer (2L) to produce granules for tableting.
(4) Preparation of tablets
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI SEISAKUSHO ltd. And uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a compression pressure of 6 kN.
Comparative example 4 stability of tocopherol and formulation
(1) Preparation of granule A
Melobalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate and magnesium aluminum silicate were weighed at the ratios shown in Table 10, mixed using a V-blender (5L) at a rotational speed of 34rpm for 5 minutes, and sieved using a Comil (QC-197, diameter: 1.143mm, QUADRO) at 2200rpm to produce a sieved powder. The sieved powder was placed in a fluid bed granulator (NFLO-5, freund) and a hydroxypropyl cellulose binder solution (7 wt/wt%, dissolved in purified water) was sprayed at a feed air temperature of 80 ℃ at about 7g/min in the formulation shown in table 10, followed by drying to a product temperature of 55 ℃ after the spraying was finished.
Screening was carried out at 2200rpm using Comil (QC-197, diameter: 1.143mm, QUADRO) to produce particles A.
(2) Preparation of granule B
D-mannitol and crystalline cellulose were weighed in the proportions shown in Table 10 and placed in a fluid bed granulator (NFLO-5, FREUND) and the pregelatinized starch dispersion (8% by weight dissolved in purified water) was sprayed in the proportions shown in Table 1 at a supply air temperature of 85 ℃ at about 45g/min, followed by drying to an exhaust gas temperature of 45 ℃ after the spraying was finished.
Screening was carried out at 800rpm using Comil (QC-197, diameter: 1.143mm, QUADRO) to give granules B.
(3) Preparation of granules for tabletting
Granule a, granule B, crospovidone, and potassium acetamidosulfonate were weighed at the compounding ratios shown in table 10, and mixed using a V-type mixer (5L) at a rotation speed of 34rpm for 5 minutes to produce a mixed powder. Then, magnesium stearate was weighed at the compounding ratio shown in table 10, and the mixed powder was added, followed by mixing for 10 minutes at a rotation speed of 34rpm using a V-type mixer (5L) to produce granules for tableting.
(4) Preparation of tablets
Tablet mass was adjusted to 300mg using a tablet press (Virgo 0524SS1AX, manufactured by KIKUSUI SEISAKUSHO ltd. And uncoated tablets (12.1 x 6.4 mm) were obtained by molding at a compression pressure of 6 kN.
(evaluation methods and results) stability of tocopherol and formulations
After the uncoated tablets of example 4 and comparative example 4 were left without packaging under the conditions of 25 ℃/75% rh, the amounts of the similar substances produced were measured using HPLC (Agilent definition 1290) under the conditions shown in table 2.
Table 11 shows the results. It was confirmed that in the uncoated tablet using tocopherol, the total amount of the similar substances produced was about 1/2 of that of the uncoated tablet without using tocopherol.
[ Table 10]
[ Table 11]
| Example 4 | Comparative example 4 | |
| 25 ℃/75% RH6 months | 0.71％ | 1.64％ |
。
Claims (16)
1. An orally disintegrating tablet comprising:
(A) Particles containing milobaline besylate; and
(B) Drug-free granules containing crystalline cellulose or drug-free mixed powder containing crystalline cellulose.
2. The orally disintegrating tablet of claim 1, wherein
The average particle diameter of the milopalin besylate contained in (A) is 60 μm or less, and
the content thereof as milobalin is 0.5 to 10% by weight relative to 100% by weight of the orally disintegrating tablet.
3. Orally disintegrating tablet according to claim 1 or 2, wherein
The bulk density of the crystalline cellulose contained in (B) is 0.10 to 0.26g/cm 3 And is and
the content thereof is 1.0 to 50% by weight relative to 100% by weight of the orally disintegrating tablet.
4. The orally disintegrating tablet of any one of claims 1 to 3, wherein
(A) Is a granule containing milobalin besylate, which further contains low molecular weight hydroxypropyl cellulose.
5. The orally disintegrating tablet of claim 4, wherein
The content of the low-molecular weight hydroxypropylcellulose contained in (a) is 0.1 to 2.0% by weight relative to 100% by weight of the orally disintegrating tablet.
6. The orally disintegrating tablet of any one of claims 1 to 3, wherein
(A) Is a particle comprising milobalin besylate, further comprising citric acid hydrate and tocopherol.
7. The orally disintegrating tablet of claim 6, wherein
The content of citric acid hydrate contained in (A) is 0.2-1.0% by weight with respect to 100% by weight of the orally disintegrating tablet, and
the content of the tocopherol contained in (a) is 0.01 to 0.4% by weight relative to 100% by weight of the orally disintegrating tablet.
8. The orally disintegrating tablet of claim 3, wherein
(A) Is a granule containing milopaline besylate, which further contains D-mannitol and carboxymethylcellulose.
9. The orally disintegrating tablet of any one of claims 6 to 8, wherein
(A) Is a granule containing milobaline besylate, which further contains hydroxypropyl cellulose.
10. The orally disintegrating tablet of claim 9, wherein
The content of the hydroxypropylcellulose in (a) is 0.1 to 3.0% by weight relative to 100% by weight of the orally disintegrating tablet.
11. The orally disintegrating tablet of any one of claims 6 to 10, wherein
(B) Is a drug-free granule further comprising D-mannitol and pregelatinized starch.
12. The orally disintegrating tablet of claim 11, wherein
The content of D-mannitol contained in (B) is 20 to 55% by weight with respect to 100% by weight of the orally disintegrating tablet, and the content of pregelatinized starch contained in (B) is 1.0 to 10% by weight with respect to 100% by weight of the orally disintegrating tablet.
13. Orally disintegrating tablet according to claim 4 or 5, wherein
(B) Is a drug-free mixed powder further containing carboxymethylcellulose and potassium acetamido sulfonate.
14. The orally disintegrating tablet of claim 13, wherein
The content of carboxymethylcellulose contained in (B) is 2.0-20% by weight with respect to 100% by weight of the orally disintegrating tablet, and
the content of the potassium acetaminosulfonate contained in (B) is 1.0 to 5.0% by weight relative to 100% by weight of the orally disintegrating tablet.
15. A method for producing an orally disintegrating tablet comprising:
a step of mixing milopalin besylate, D-mannitol and citric acid hydrate and spraying a low molecular weight hydroxypropylcellulose binder solution to produce granules;
a step of mixing granule a, crystalline cellulose, carboxymethylcellulose and potassium acetylaminosulfonate, then adding magnesium stearate to the mixed powder, followed by mixing to form a mixture for tableting; and
and (3) tabletting by using a tabletting machine.
16. A method for producing an orally disintegrating tablet comprising:
a step of mixing tocopherol and crystalline cellulose to produce a tocopherol powder;
a step of mixing milopalin besylate, D-mannitol, carboxymethylcellulose, citric acid hydrate, tocopherol powder and magnesium aluminum silicate and spraying a hydroxypropylcellulose binder solution to produce granules;
a step of mixing D-mannitol and crystalline cellulose and spraying the pregelatinized starch dispersion to produce particles;
a step of mixing the two granules, crospovidone, and potassium acetaminosulfonate and then mixing magnesium stearate to form a mixture for tableting; and
and (3) tabletting by using a tabletting machine.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2020126311 | 2020-07-27 | ||
| JP2020-126311 | 2020-07-27 | ||
| PCT/JP2021/027505 WO2022024979A1 (en) | 2020-07-27 | 2021-07-26 | Orally disintegrating tablet containing mirogabalin besilate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115803020A true CN115803020A (en) | 2023-03-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180049600.5A Pending CN115803020A (en) | 2020-07-27 | 2021-07-26 | Orally disintegrating tablet containing milobalin besylate |
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| Country | Link |
|---|---|
| JP (1) | JPWO2022024979A1 (en) |
| KR (1) | KR20230044355A (en) |
| CN (1) | CN115803020A (en) |
| BR (1) | BR112023000403A2 (en) |
| TW (1) | TW202220643A (en) |
| WO (1) | WO2022024979A1 (en) |
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| KR20230044355A (en) | 2023-04-04 |
| BR112023000403A2 (en) | 2023-02-07 |
| WO2022024979A1 (en) | 2022-02-03 |
| JPWO2022024979A1 (en) | 2022-02-03 |
| TW202220643A (en) | 2022-06-01 |
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