WO2007086457A1

WO2007086457A1 - Quickly disintegrating tablet produced by direct dry-tabletting

Info

Publication number: WO2007086457A1
Application number: PCT/JP2007/051156
Authority: WO
Inventors: Misa Tateda; Satoshi Sakuma; Itsumi Enomoto
Original assignee: Toa Pharmaceuticals Co., Ltd.
Priority date: 2006-01-26
Filing date: 2007-01-25
Publication date: 2007-08-02
Also published as: KR101386022B1; CN101374503A; JP2007197357A; CN101374503B; KR20080108227A; JP4965130B2

Abstract

It is intended to provide a quickly disintegrating tablet, which has a practically appropriate tablet hardness while sustaining the disintegrability, and a process for producing the same by the direct dry-tabletting method wherein a material mixture powder before tabletting has a high flowability owing to well designed combination of an active ingredient with auxiliary ingredient(s) and, therefore, can be smoothly flown out from the hopper of a tabletting machine, no capping occurs during tabletting and the obtained tablets show little deviation in weight. Namely, a quickly disintegrating tablet produced by the direct dry-tabletting method characterized by containing (a) an active ingredient and (b)as a dissolution aid, at least one member selected from the group consisting of acid selected from among citric acid, tartaric acid, malic acid, lactic acid and ascorbic acid or alkali metal salts thereof; alkali metal hydrogencarbonates; and alkali metal carbonates, together with (c) a filler, (d) a binder, (e) a disintegrating agent, (f) a fluidizer, and (g) as a lubricant, a lubricant comprising a combination of magnesium stearate with a sucrose fatty acid ester.

Description

Specification

Dry type quick-disintegrating tablet

Technical field

TECHNICAL FIELD [0001] The present invention relates to a dry-type direct-disintegrating tablet having a practical tablet hardness while maintaining fast disintegration by devising a combination of an active ingredient and a compounding ingredient, and a method for producing the same. .

Background art

[0002] In recent years, in medical solid preparations, there has been an increasing demand for the development of an orally rapidly disintegrating tablet due to reasons such as taking a dose. Tablets as fast-disintegrating tablets in the oral cavity include (1) disintegration within 30 seconds according to the disintegration test method of the Japanese Pharmacopoeia, (2) disintegration property of disintegrating within 60 seconds in the oral cavity, ( 3) Wornness test Hardness, etc., that no noticeable damage is observed at 200 revolutions, is required.

[0003] Conventionally, a wet granulation method and a dry granulation method have been proposed as methods for producing such an intraorally rapidly disintegrating tablet. As the wet granulation method, for example, the surface of the saccharide particles is moistened with 0.3 to 7% by weight of water to a tablet component containing (1) a medicinal ingredient and a saccharide as an excipient. The disintegration time according to the disintegration test method described in the Japanese Pharmacopoeia 12th Amendment by compressing the mixture containing the medicinal ingredient, saccharide and water and then drying is 0.05 to 3.0 minutes. A method for producing an orally disintegrating tablet (Patent Document 1) has been reported.

[0004] In addition, as the dry granulation method, for example, (2) tablets that are orally administered without being dispersed in water before administration, and in the form of microcrystals or fine particles coated so as to mask the taste A rapidly disintegrating multiparticulate tablet obtained by directly compressing a mixed material of an active substance and a mixture containing an excipient has been proposed (Patent Document 2). In this case, the mixture containing the excipient is selected from at least one disintegrant and starch, modified starch, or microcrystalline cellulose, and at least one swelling agent that does not produce high viscosity when contacted with water, or It contains at least one solubilizing agent, and tablets do not contain effervescent agents and free organic acids, and rapidly disintegrate in the oral cavity in the presence of saliva and in less than 60 seconds without chewing. It is a particle tablet. [0005] Further, as a composition by a dry granulation method, for example, (3) Meloxicam as an active ingredient; Oligosaccharide and / or polysaccharide; Surfactant, hydrotropic agent, alcoholic agent, no, id mouth Proposed pharmaceutical composition (Patent Document 3) comprising one or more pharmaceutically acceptable additives selected from the group consisting of colloids and polymers; and any excipients, carriers and / or auxiliaries It has been done.

[0006] Similarly, as a dry tableting method, for example, (4) it disintegrates rapidly in the oral cavity containing at least one of mannitol, disintegrants, celluloses, lubricants, and starches and lactose, which is practically sufficient. Orally disintegrating composition (Patent Document 4), or (5) meloxicam or a pharmaceutically acceptable salt, starch or various types of starch, a glidant and at least one additional excipient A tablet that disintegrates rapidly in water, consisting essentially of the agent, in which at least one of the additional excipients is water soluble, such as a direct dry press method (direct compression method), such as meloxicam, ratatose, starch and silicon dioxide water A Japanese blend is prepared by mixing the ingredients in a conventional mixer for 30 minutes, then adding magnesium stearate and adding 5 more of the composition. Method of blending between (Patent Document 5) have been reported.

[0007] Patent Document 1: Japanese Patent No. 3069458

Patent Document 2: Japanese Patent No. 2820319

Patent Document 3: Japanese Patent Publication No. 2001-513563

Patent Document 4: Japanese Patent Laid-Open No. 2000-273039

Patent Literature 5: Special Table 2004-525975

[0008] However, these conventional methods, for example, in the wet granulation method (1) described above, 0.3 to 7% by weight of moisture with respect to the tablet component containing a medicinal component and a saccharide. This requires a complicated process of moistening and drying the surface of the saccharide particles. In the dry granulation method (2), when the active ingredient (active ingredient) is coated and is in a microcrystalline state, the fine granule is coated, and when the active ingredient is in a fine granule state not coated. In this method, the effective component is formed into a fine condylar shape by a method such as extrusion granulation, processing in a bread, air fluidized bed, etc. Further, in the above (3), in the ceramic ball minole Meloxicam and oligosaccharides and Z or polysaccharides (eg cyclodextrins, microcrystals This is an effervescent tablet using a composition obtained by co-powdering cellulose, latatose, starch) and a method for producing the same, and requires complicated operations.

[0009] The dry tableting method is a method in which after mixing a drug and other excipients, the mixture is directly tableted (direct compression method) to form a tablet. This is a simple preparation method. However, depending on the combination of the type of drug, mixing components, etc., for example, the fluidity of the mixture will be low, so that the powder mixture will not flow out of the hopper of the tableting machine, and it will be impossible to compress the tablet, It was observed that the rate declined and the tablet weight deviation significantly increased, or that the tablet hardness could not be maintained if the tablet disintegration was improved.

[0010] In fact, in the case of tablets used in the dry method, for example, tablets by the dry method of meloxicam, the smaller the particle size of meloxicam, the faster the dissolution rate of meloxicam from the obtained tablet. However, they have experienced that tableting troubles such as sticking are more likely to occur.

Disclosure of the invention

Problems to be solved by the invention

[0011] The present invention relates to a caving that improves the flowability of the mixed powder before tableting by devising the combination of the active ingredient and the compounding ingredient, and therefore has good spillability from the hopper of the tableting machine. As a result, a rapidly disintegrating tablet having a practical tablet hardness while maintaining the disintegration of the tablet with a small tablet weight deviation and a production method by the dry direct compression method The purpose is to provide.

Means for solving the problem

[0012] As a result of intensive studies to solve the above problems, the present inventors have devised a combination of active ingredients and compounding ingredients, in particular, selected specific ones as solubilizers, and specific slips. The inventors have newly found that these problems can be solved by selecting a pesticide, and have completed the present invention.

In particular, the present invention can select meloxicam which is a non-steroidal anti-inflammatory / analgesic agent as an active ingredient and provide an effective fast disintegrating tablet containing meloxicam.

[0013] That is, the present invention has, as its basic aspect, (a) an active ingredient and (b) a solubilizing agent. An acid selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid or an alkali metal salt thereof; an alkali metal bicarbonate; and at least one selected from the group consisting of alkali metal carbonates, and (c Contains lubricants consisting of a combination of magnesium stearate and sucrose fatty acid ester as excipients), (d) binders, (e) disintegrants, (f) glidants, and (g) lubricants. It is a dry-type direct hitting disintegrating tablet characterized by the above.

[0014] More specifically, the present invention relates to alkali metal salt strength of acids sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate, potassium malate, sodium lactate, potassium lactate, ascorbic acid A dry direct-disintegrating tablet that is sodium or potassium ascorbate, the alkali metal bicarbonate is sodium bicarbonate or potassium bicarbonate, and the alkali metal carbonate is sodium carbonate or potassium carbonate.

[0015] More specifically, in the present invention, the solubilizing agent (b) is a combination of both sodium citrate and sodium bicarbonate, and the excipient (c) is Group consisting of sugar, lactose, erythritol, D-mannitol, xylitol, maltitol, etc., synthetic quinoleminium, hydroxypropyl starch sodium, crystalline cellulose, hydroxypropinole starch, anhydrous calcium hydrogen phosphate, reduced maltose water solution It is a dry direct-disintegrating tablet that is one or more types selected from.

[0016] In the present invention, the binder in (d) is at least one selected from the group consisting of crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and carmellose, A dry straightener in which the agent is at least one selected from the group consisting of crospovidone, carmellose, carmellose calcium, sodium carboxymethyl starch, and the fluidizing agent (f) is light anhydrous caustic acid (silicon dioxide). It is a quick-disintegrating tablet.

[0017] Most specifically, the present invention relates to a dry-type direct-disintegrating tablet in which the active ingredient (a) is meloxicam, and specifically includes the following components:

(a) active ingredient, caloxicam,

(b) the solubilizing agent is sodium citrate and sodium bicarbonate,

(c) the excipient is lactose and erythritol,

the binder of (d) is crystalline cellulose, (e) disintegrant is crospovidone,

(f) fluidizing agent is light anhydrous caustic anhydride (silicon dioxide),

(g) lubricant is magnesium stearate and sucrose fatty acid ester,

It is a powerful dry-type direct-disintegrating tablet.

[0018] Further, the present invention provides, as another aspect, (a) meloxicam, (b) sodium taenoate and sodium bicarbonate as a solubilizer, (c) an excipient, (d) a binder, (e) Disintegrating agent and (f) fluidizing agent are mixed, and (g) magnesium stearate and sucrose fatty acid ester are added and mixed as a lubricant, and then the resulting mixture is directly compressed into tablets. This is a method for producing a dry-type quick-disintegrating tablet.

That is, the present invention provides an acid selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid or an alkali metal salt thereof as a solubilizing agent to be blended in addition to the active ingredient Z excipient and the like. A lubricant comprising at least one selected from the group consisting of alkali metal bicarbonates; and alkali metal carbonates, and further comprising a combination of both magnesium stearate and sucrose fatty acid ester as lubricants Therefore, a dry-type quick-disintegrating tablet having a desired rapid disintegration property and appropriate hardness is provided.

The invention's effect

[0020] According to the present invention, the flowability of the mixed powder containing the active ingredient before tableting is good, and therefore, the occurrence of cabbing with good flowability of the mixed powder from the hopper of the tableting machine is suppressed, and as a result A rapidly disintegrating tablet having almost no tablet weight deviation and a method for producing the tablet by the dry direct compression method are provided.

The fast disintegrating tablet obtained by the present invention has a desired disintegration rate and a practical tablet hardness, and its manufacturing method has the advantage of being an inexpensive and simple manufacturing method. Have.

BEST MODE FOR CARRYING OUT THE INVENTION

[0021] The medicinal ingredients used in the dry direct-disintegrating tablet of the present invention are not particularly limited, for example, non-steroidal antipyretic analgesic / anti-inflammatory agents, vitamins, antihistamines, antitussives, fungicides, antacids, Herbal medicine, gastric mucosa repair agent, analgesic antispasmodic agent, constipation treatment agent, H2 receptor antagonist, Examples include ulcer treatment agents, antihypertensive agents, antibiotics, arrhythmia treatment agents, gastrointestinal drugs, expectorants, antipruritic drugs (vehicle sickness drugs), and central nervous stimulants.

Of these, non-steroidal antipyretic analgesic / anti-inflammatory agents can be preferably applied.

[0022] Hereinafter, the dry-type direct hit disintegrating tablet of the present invention will be described using, for example, meloxicam as a representative example.

Meloxicam is a pale yellow powder that is extremely insoluble in methanol and ethanol, is almost insoluble in water, and has a melting point of 241 ° C. It is also a non-steroidal anti-inflammatory agent with no bitterness, as a rheumatoid arthritis, osteoarthritis, low back pain, shoulder periarthritis, scapulohumeral disease group disease and anti-inflammatory analgesic, as a tablet containing lOmg Oral administration once a day after meals.

[0023] In consideration of the fact that the smaller the particle size of the drug substance of meloxicam used for the dry-type direct-disintegrating tablet of the present invention, the better the solubility when the tablet is preferred, the appropriate particle size Can be used. Preferably, an average particle size of 20 μΐη or less is used.

[0024] Examples of the solubilizing agent used together with the above active ingredients include acids or alkali metal salts, alkali metal hydrogen carbonates or alkali metal carbonates thereof. In the present invention, such acids are selected from the group consisting of citrate, tartaric acid, malic acid, lactic acid, and ascorbic acid. Therefore, as alkali metal salts of acids, Examples thereof include sodium acid, potassium citrate, sodium tartrate, potassium tartrate, sodium malate, potassium malate, sodium lactate, potassium lactate, sodium ascorbate, and potassium ascorbate.

[0025] Further, examples of the alkali metal hydrogen carbonate as the solubilizing agent include sodium hydrogen carbonate or potassium hydrogen carbonate, and examples of the alkali metal carbonate include sodium carbonate or potassium carbonate.

[0026] These solubilizing agents can be used in combination of one or more. A combination of both sodium citrate and sodium bicarbonate is particularly preferred.

[0027] The blending amount of the solubilizing agent in the present invention is the active ingredient used, the type of solubilizing agent, etc. However, for example, when meloxicam is used as an active ingredient and sodium citrate and sodium bicarbonate are combined in combination as a solubilizer for this, When the blending amount of the solubilizing agent is expressed in terms of% by weight, the total amount of sodium quenate and sodium bicarbonate is preferably about 0.5 to 6% by weight per tablet.

[0028] When both sodium citrate and sodium hydrogen carbonate are combined and mixed, the most preferable mixing ratio of sodium citrate and sodium hydrogen carbonate is as follows. Sodium hydride 0.3 to 1.9 monole, preferably 0.57 to 1.72 monole, more preferably f 0.7 to 1.6 monole.

[0029] The amount of sodium citrate and sodium hydrogencarbonate to be blended by the combination based on the above molar ratio is such that when one tablet is dissolved in 900 mL of distilled water, the pH of the solution is 4-8. Combine them so that they are between 5. More preferably, the pH ranges from pH 5.0 to 8.0, and particularly preferably pH 6.5 to 7.5.

It has been found that when meloxicam is used as an active ingredient, it should be blended so that this pH is somewhat alkaline.

[0030] Even when a solubilizing agent other than sodium citrate and sodium bicarbonate is employed as the solubilizing agent, the preferred blending amounts of the respective components as the solubilizing agent are the same as described above. When one solution is dissolved in 900 mL of distilled water, the pH of the solution is 4 to 8.5, preferably 5 · 0 to 8 · 0, particularly preferably pti 6.5 to 5 · 7.5. The power of being combined, S.

[0031] In the rapidly disintegrating tablet provided by the present invention, excipients include lactose, erythritol, D-mannitol, xylitol, maltitol and other sugars, synthetic aluminum silicate, hydroxypropyl starch sodium, crystalline cellulose , Hydroxypropyl starch, water-free calcium hydrogen phosphate, reduced maltose starch and the like. Of these, lactose and erythritol which can be used as a flavoring agent are preferably used.

The blending amount of the excipient to be blended per tablet is 20 to 70% by weight, preferably 30 to 70% by weight, and more preferably about 60% by weight.

[0032] In the rapidly disintegrating tablet provided by the present invention, as the binder, crystalline cellulose, powder Examples thereof include powdered cellulose, low-substituted hydroxypropylcellulose, and carmellose. Preferred is crystalline cellulose, for example, CELUS PH101, CELUS PH302 [manufactured by Asahi Kasei Chemicals Corporation].

The amount of binder used per tablet is 5 to 20% by weight, preferably about 10% by weight.

[0033] In the rapidly disintegrating tablet provided by the present invention, examples of the disintegrant include one or more selected from the group consisting of crospovidone, carmellose, carmellose calcium, and sodium carboxymethyl starch. Preferably, crospovidone is used.

The amount of disintegrant added per tablet is 5 to 20% by weight, preferably about 15% by weight.

[0034] Examples of the fluidizing agent include light anhydrous silicic acid (silicon dioxide) strength S. Preferably, Ad Solida 101 [trade name, manufactured by Freund Sangyo Co., Ltd.] can be used.

The blending amount of the fluidizing agent per tablet is 0.5 to 3% by weight, preferably about 0.5 to 1.5% by weight.

[0035] The fast disintegrating tablet provided by the present invention is characterized in that both magnesium stearate and sucrose fatty acid ester are used in combination as lubricants. Examples of the sucrose fatty acid ester include sugar ester B-370F, or Surf Hope J 2 203F [Sucrose behenic acid ester used as lubricant for B-370; Mitsubishi Chemical Foods, Inc. ) Made] and the like.

The blending ratio of magnesium stearate and sucrose fatty acid ester is about 1 :: ~ 2 in weight ratio, preferably about 1: 1 ~!

The blending amount per tablet as the total amount of the lubricant is 1.0 to 3% by weight, preferably about 1.0 to 2.0% by weight.

[0036] When the active ingredient has bitterness, a masking agent for masking strong bitterness can be blended according to a conventional method. Examples of such a masking agent include sweeteners such as aspartame and tautiman, and fragrances such as les or 1_menthol, dry coat cocoon, brown sugar flavor, dry coat peppermint, and grapefruit coat. The amount of these masking agents can be increased or decreased as appropriate depending on the active ingredient to be included. The power to do S.

[0037] The dry direct hit disintegrating tablet provided by the present invention can be prepared, for example, by a manufacturing method according to the following steps.

This method is generally composed of two steps: a first step of mixing each component constituting the tablet, and then a second step of tableting. Each step itself is simple and efficient that can be performed according to a conventional method. It is a preparation method of a tablet.

The details are as follows.

[0038] [First step]

First, a predetermined amount of the following components, (a) an active ingredient, (b) a solubilizer, (c) an excipient, (d) a binder, (e) a disintegrant, and (f) a fluidizing agent are usually added. According to the method, for example, mixing is performed using a mixer [trade name, Bore container mixer; manufactured by Kotopuki Giken Kogyo Co., Ltd.].

The mixing time at this time varies depending on the type of additive to be used, the amount used, etc., and is not particularly limited, but is preferably 5 to 40 minutes, more preferably 5 to 30 minutes.

[0039] Next, (g) a lubricant is further added to the above mixture and mixed.

The mixing time at this time is not particularly limited depending on the amount of the mixture used as long as the lubricant can be sufficiently mixed, but usually 2 to 10 minutes, preferably 2 to 4 minutes. In mixing, a taste-masking agent such as erythritol may be added if desired.

[0040] [Second step]

Using the mixture prepared by force, direct dry tableting can be used to prepare the intended dry direct compression fast disintegrating tablet of the present invention.

[0041] The perfume used in the fast disintegrating tablet provided by the present invention is a force that can be added in either the first step or the second step, preferably in the second step. In addition, the sweetener used in the tablet of the present invention can be applied with any of the first step or the second step.

[0042] The above provides a dry-type direct-disintegrating tablet that is the object of the present invention. The obtained tablet has a practical tablet hardness while maintaining a desired rapid disintegrating property. It is. Example [0043] Hereinafter, the present invention will be described in more detail with reference to the following examples.

In Examples:! To 9, meloxicam having an average particle size of 4 to 15 μm obtained by grinding with a flour mill according to a conventional method was used, and sodium citrate and hydrogen carbonate as dissolution aids. Although the preparation method of the tablet added using sodium in combination is illustrated, the present invention is not limited to these examples.

Also in the comparative examples, meloxicam having each particle size is prepared and used.

[0044] Examples:! To 9:

According to the formulation shown in Table 1 below, each component was mixed and tableted to obtain a dry-type direct-disintegrating tablet.

[0045] [Table 1]

In the table, (a) is the active ingredient, (b) is a solubilizer, (c) is an excipient, (d) is a binder, (e) is a disintegrant, and (f) is fluidized. (G) is a lubricant, (h) is a corrigent, (i) is a sweetener, ( j) is a fragrance.

[0047] A typical production operation example is shown in the formulation of Example 1.

(a) Meloxicam (active ingredient; 8.00 g), (b) sodium quenate (dissolution aid; 8.00 g), sodium bicarbonate (dissolution aid; 2.00 g), (c) lactose (excipient 62.00 g), (d) Crystalline cellulose [Binder; 20.00 g, Colas PH302, manufactured by Asahi Kasei Chemicals Corporation], (e) Crospovidone [Disintegrant; 30.00 g, Crospovidone XL, ISP ( Co., Ltd.) and (f) Light anhydrous Caustic acid [Fluidizer; 2. 60 g, Freund Sangyo Co., Ltd.] for 30 minutes, and then (g) Magnesium stearate (lubricant; 1. 40 g ) And sucrose fatty acid ester [lubricant; 2.00 g, sugar ester B_370F, manufactured by Mitsubishi Kasei Foods Co., Ltd.] and mixed for 3 minutes. Upon mixing, erythritol (flavoring agent; 60.00 g), aspartame (sweetening agent; 4.00 g), and 1-menthol (fragrance; 0.10 g) were added.

The obtained mixture was directly tableted to obtain a tablet weighing 375 mg containing 15 mg of the active ingredient.

[0048] For each of the examples, each tablet was prepared according to the above. However, in Examples 8 and 9, the tablets are 250 mg in weight containing 10 mg of the active ingredient.

[0049] About the obtained tablets, the hardness of the tablets, the disintegration time (minutes) according to the disintegration test method of the Japanese Pharmacopoeia, and the friability test were measured at 200 revolutions, and are shown in the table.

[0050] Example 10:

A tablet containing 15 mg of active ingredient (total weight: 375 mg) was prepared in the same manner as in the production method of Example 7, except that 4 parts by weight of meloxicam and sodium citrate was used, and 1 part by weight of sodium bicarbonate. did.

As a result, dissolution was faster than the tablet of Comparative Example 3 described later, but a slight bitterness was felt.

[0051] Example 11:

A tablet containing 15 mg of the active ingredient (total weight: 375 mg) was prepared in the same manner as in the production method of Example 7, except that 3 parts by weight of meloxicam and sodium citrate was used, and 2 parts by weight of sodium bicarbonate. did.

As a result, elution is faster than the tablet of Comparative Example 4 to be described later, but some bitterness is felt. there were.

[0052] Example 12:

In the tablet preparation method of Example 3, the mixture obtained in the same manner except that brown sugar flavor (0.2 g) or dry coat peppermint (0.2 g) was added as a fragrance was effective by tableting. A tablet containing 15 mg of the ingredient (total weight: 375 mg) was prepared. The characteristics such as dissolution behavior of these tablets were not different from those of Example 3, and the taste of these tablets was good.

[0053] In Examples 11 and 12, when aspartame was added as a sweetener and 1_menthol was added as a flavor, unpleasant bitterness was alleviated.

[0054] Comparative examples:! -6:

According to the formulation shown in Table 2 below, each component was mixed and tableted to obtain a dry-type direct hitting collapsible tablet.

Each of the obtained tablets was tested in the same manner as in the above Examples, and the results are also shown in the table.

[0055] [Table 2]

Component Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6

(a) Meloquicam 8.00 S.00 8.00 8.00 8.00 8.00

Particle size m) 60-80 60-80 80 60-80 60-80 7-15 7-15

Cb) Sodium quenate 1 S.00 20.00 40.00 8.00 10.00

Cb) Sodium bicarbonate 2.00 1 1 1 1 1

Cc) Lactose 70.00 66.00 47.00 27.00 65.00 69.00

(d) Crystalline cellulose 20.00 20.00 20.00 20.00 20.00 20.00

(e) Crospovidone 30.00 30.00 30.00 30.00 30.00 28.00

(f) Light anhydrous carboxylic acid 1.00 1.00 1.00 1.00 1.00 2.00

Cg) Magnesium stearate 1.00 1.00 1.00 1.00 1.00 1.00

Cg) Shochu fatty acid ester 2.00 2.00 2.00 2.00 2.00 2.00

Ch) Erisri! Le 68.00 64.00 70.00 70.00 64.00 60.00

(i) Aspartame 1 1.00 1.00 1.00 1

Ci) Tauchiman 1 1 1 1 1 1

Cj) I—Menthol

Cj) Dry coat ヮ leek 1 1 1 1 1 1

(j) Black Panther Flavor 1 1 1 1 1 1

(j) Dry coat peppermint 1 1 1 1 1 1

Cj) Grapeful 1 ton 1 1 1 1 1 1 1

Dissolution test (compared to commercial products)

Hardness (KP) 4.30 4.00 3.30 3.00 3.90 4.30 Disintegration time (min) 0.30 0.63 0.61 0.56 0.43 0.49 Friction (%) 0.21 0.15 0.48 1.01 0.20 0.42 Active ingredient weight (mg) 10mg 10mg 1 Omg 1 Omg 10mg 10mg Total tablet weight ( mg) 250mg 250mg 250mg 250mg 250mg 250mg In the table, “” means that the average did not elute more than 85¾ within 6 hours. Commercial products eluted on average more than 85¾ within 60 minutes.

[0056] Comparative Examples 1 to 4 use meloxicam having an average particle size of 60 to 80 μm, and in Comparative Example 1, only sodium bicarbonate was added in an amount of 0.25 parts by weight to 1 part by weight of meloxicam. Comparative Examples 1 to 4 are tablets obtained by adding 1, 2.5 and 5 parts by weight, respectively, of 1 part by weight of meloxicam to sodium quenate.

[0057] For each of these tablets, the dissolution behavior was confirmed according to the "V. Dissolution Test" section of "Guidelines for Bioequivalence Testing of Generic Drugs" in comparison with a commercially available tablet containing meloxicam. .

As a result, it was confirmed that commercially available tablets had an average dissolution of 85% or more within 60 minutes. Each of Comparative Examples:! To 4 did not dissolve more than 85% on average within the specified time of 6 hours.

As a cause of the difference in dissolution behavior from commercially available tablets, the difference in the physical properties of meloxicam bulk was first considered. Then, it was examined whether it could be improved by reducing the particle size. [0058] In Comparative Examples 5 and 6, meloxicam having an average particle size of 7 to 15 / im was used, and 1 and 1.25 parts by weight of sodium quenate as a solubilizer was added to 1 part by weight of meloxicam, respectively. Each tablet. As a result, it was found that by using meloxicam with a small average particle size and adding a solubilizing agent, the dissolution behavior resembles that of a commercially available product. The average elution of 85% or more was not observed within the specified time of 6 hours according to V. Dissolution test.

Tableting was performed using magnesium stearate or sucrose fatty acid ester alone as a lubricant, but cabbing occurred, yield decreased, and was not practical.

[0059] From the above results, it was confirmed that the use of meloxicam with a small particle size and the addition of a solubilizing agent were effective in making the dissolution behavior similar to that of a commercially available product, but still The result was that sufficient elution behavior could not be obtained.

[0060] In contrast, the tablets of Examples:! To 9 use meloxicam having an average particle size of 4 to 15 μm, and both sodium citrate and sodium bicarbonate are used as a solubilizer. Since the desired dissolution behavior can be obtained thereby, the specific force of the present invention is well understood.

Industrial applicability

[0061] As described above, the present invention provides a dry-type direct-disintegrating tablet having a practical tablet hardness while maintaining rapid disintegration, particularly a direct-disintegrating tablet containing meloxicam. Since the dissolution behavior is also good, the medical value is tremendous.

Claims

The scope of the claims

[1] (a) active ingredient, (b) acids selected from citrate, tartaric acid, malic acid, lactic acid and ascorbic acid as a solubilizer or alkali metal salts thereof; alkali metal bicarbonates; and alkali metals At least one selected from the group consisting of carbonates, and (c) an excipient, (d) a binder, (e) a disintegrant, (f) a fluidizing agent, and (g) stearin as a lubricant. A dry direct disintegrating tablet characterized by containing a lubricant comprising a combination of acid magnesium and sucrose fatty acid ester.

[2] Alkaline metal salt strength of acids Sodium citrate, potassium citrate, sodium tartrate, potassium tartrate, sodium malate, potassium malate, sodium lactate, potassium lactate, sodium ascorbate or potassium ascorbate 2. The dry direct-disintegrating tablet according to claim 1, wherein the hydrogen salt is sodium hydrogen carbonate or potassium hydrogen carbonate, and the alkali metal carbonate is sodium carbonate or potassium carbonate.

3. The dry direct-disintegrating tablet according to claim 1, wherein the solubilizing agent (b) comprises a combination of sodium quenate and sodium hydrogen carbonate.

[4] The excipient in (1) above is lactose, erythritol, D-mannitol, xylitol, maltitol and other sugars, synthetic aluminum silicate, hydroxypropyl starch sodium, crystalline cellulose, hydroxypropyl starch, anhydrous calcium hydrogen phosphate The dry direct-disintegrating tablet according to any one of claims 1 to 3, which is at least one selected from the group consisting of reduced maltose and starch.

[5] The binder according to any one of claims 1 to 4, wherein the binder (d) is at least one selected from the group consisting of crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, and carmellose. Dry direct-disintegrating tablets.

[6] The dry direct impact according to any one of claims 1 to 5, wherein the disintegrant of (e) is one or more selected from the group consisting of crospovidone, carmellose, carmellose calcium, and sodium carboxymethyl starch. Fast disintegrating tablet.

[7] The dry direct-disintegrating tablet according to any one of [1] to [6], wherein the fluidizing agent of (f) is light anhydrous caustic acid (silicon dioxide).

8. The dry direct strike according to any one of claims 1 to 7, wherein the active ingredient (a) is meloxicam. Fast disintegrating tablet.

[9] The following ingredients:

The active ingredient of (a) is meloxicam,

(b) the solubilizing agent is sodium citrate and sodium bicarbonate,

(c) the excipient is lactose and erythritol,

the binder of (d) is crystalline cellulose,

(e) disintegrant is crospovidone,

The fluidizing agent in (f) is light caustic anhydride (silicon dioxide),

(g) lubricant is magnesium stearate and sucrose fatty acid ester,

A dry direct-disintegrating tablet consisting of

[10] (a) meloxicam, (b) sodium citrate and sodium bicarbonate as a solubilizer,

Mix (c) excipient, (d) binder, (e) disintegrant, and (f) fluidizing agent, and (g) add magnesium stearate and sucrose fatty acid ester as lubricant. 10. The method for producing a dry-type direct-disintegrating tablet according to claim 8 or 9, wherein the obtained mixture is directly compressed.