TW200938233A - Oral dispersable tablet - Google Patents

Abstract

The present invention is directed to an oral disintegratable tablet which exhibits oral disintegratability of not more than 60 seconds. The tablet for oral administration, comprises an effective amount of at least one active agent, an amount of at least 50% (w/w) of a water insoluble parts, a surfactant and a disintegrant, such that said tablet is orally disintegretable or dispersable.

Description

200938233 VI. Description of the invention: [Technical field to which the invention pertains] 5 Ο 10 15 Ο 20 The present invention is directed to an orally disintegrable bond which exhibits no more than oral disintegratability. The orally administered dosage agent comprises: - having at least one active agent, at least 5 G% (Ww) of a water-insoluble portion: a surfactant and a disintegrating agent, so that the tablet is orally available Disintegrated or dispersible. [Prior Art] Orally dispersible lozenges are in principle not in general with general immediate release (IR) lozenges, and 4, 4, etc. should be physically stable, and can be used during industrial operations and can be Consumers are their own processors. The disintegration time of those who have a water ring should be prompt and complete. Softening treatment in the case of release so that weak physical pressure is sufficient to complete the dispersion, which is acceptable to * people. In order to improve the nature of the disintegration, there are some common principles. For example, a tablet comprises a 'package mixture, which is in the form of at least one acid component (having, for example, citric acid) and at least one component, in the form of a carbonate or a hydrogen carbonate. . Such a key for oral dispersibility has been disclosed, for example, in US 2002/0110578. Another common method is to use a fast-dissolving tablet excipient such as sugar alcohols (mannitol, sorbitol, xylitol, butyltetraol, etc.), sugars or these specialized forms. 1^11131) 1«^1^ or F-MeltTM. Rapid disintegration is the result of dissolution of this excipient. For tablets, for disintegration in the mouth, some additional properties are required 3 200938233 ι〇 15 2〇. The solution or dispersion formed after the disintegration of the tablet should be easily swallowed, and the taste and mouthfeel are acceptable. Therefore, there is a need for an additional measurement of the taste masking effect of the active component or component (e.g., microcapsule: envelope, salt formation, formation, etc.). In addition, the fragrance and/or sweetening position is used to improve the sputum; ^ and the patient can be incinerated. Sometimes the excipients used also have pleasant ice channels (sugars, sugar alcohols) and are used to improve patient acceptability. Rapid in the mouth (4) Another difficulty is that the domain is limited in liquid 、~, water comparison The liquid in the mouth is highly viscous. The amount of liquid and its adhesion # mutually set '. According to: the amount of liquid consumed at different times in the day (drinking food, etc., so that it can be changed between different subjects and even in: (4). The height of the multi-thief structure, the liquid can be accommodated! The field of dispersible tablets is common. The first manufacturing technology ensures a high degree of porous tablet construction. The disintegration time of the tablet. The shorter way to infiltrate the liquid: compared to #. This condition also affects the shape of the tablet. And geometry. The ideal geometry required also needs to consider physical stability, as already described. 2. Also for oral dispersible tablets, the cost is important 2, which should be as low as possible. Transfer the quasi-technique and keep the manufacturing process as lean as possible; to achieve the best U. Any additional manufacturing steps will increase the cost and the cost of the excipients of the Agency will increase the cost. Silver "Compared with the target group of oral dispersible tablets or when taken in normal aging, the water is not standing ❹ 4 200938233. In some markets, the convenience of taking tablets is the most convenient. Priority. In all cases The 'disintegration time of the tablet should be shortened and the patient/consumer should have an impression of what happens to the lozenge in his/her mouth. The perception of this disintegration can help the patient/consumer anticipate his/her One or more active principal components of physical condition or health may have a positive effect. JP 9071523 discloses formulations of orally dispersible troches which reveal microcrystalline cellulose (MCC) with low substituted hydroxypropyl cellulose (l - HPC) The use of the combination. Certain ratios of the two excipients are believed to produce the desired lozenge 10

20 W02004091585 discloses the use of a formulation for oral dispersible tablets, Prosolv® (through Shihua crystallized microcrystalline cellulose). It is a trade name for an excipient and is further disclosed as a novel tablet excipient in US Pat. No. 647,1994, and may also be used with an orally dispersible lozenge. In the development of novel formulations that have begun to work on orally dispersible tablets, we have investigated the use of surfactants. The surfactant and the hydrophilic, humidifying polymer, such as prosham (p〇1〇xamer), may be used to assist the active component ("seed" or "four" Such as bioavailability. In the field of oral dispersibles, surfactants can be used to reduce the viscosity of aqueous media in the oral cavity: the wettability of sexual substances - standing. By (4) - one or more

With this effect. Salt (10) bismuth, acid component or = can be used as a knife, has similar effects and can also reduce J. These combinations can have a strong effect. (4) μ" viscous viscous people find that the rapid ingot (four) solution can be reduced to a minimum amount of less 5 200938233 water I · raw, π agent promoted, and the most commonly used magnesium stearate tends to have effect Tablets disintegrating agent in the formulation and other insoluble substances [Summary of the Invention] The present invention is directed to at least one kind of medicinal efficacy of at least one kind of ramie 丨〇匕 3. There are eight, - instead, at least 〇 ( ( W/W) water insoluble part

\ I 'tongue agent and a disintegration agent, causing the tablet to be orally disintegratable I 10 15

In (10), the current disintegration = / /, ... super-present oral disintegration. More preferably, the tablet exhibits oral disintegratability within 1 second. Preferably, the key exhibits oral disintegration in less than 2 seconds. The water-insoluble carrier is selected from the group consisting of cellulose, microcrystalline cellulose or smectic microcrystalline cellulose or a mixture thereof. (4) The microcrystalline cellulose system is included in the range of 2G% to 90%, preferably in the range of 25% to the sail.

The crystallization of the microcrystalline cellulose comprises from 5% to 5%. The tablet has a mean particle size in the range of 2 () • Lion A. The disintegrating agent in the key is selected from the group consisting of low-substituted propyl cellulose, m-methyl cellulose, parent-linked methyl slow-sodium cellulose, cross-linked Pwesome (cross-linked polyethylene lycopene), and temple Sodium acetate, starch and combinations thereof. Preferred disintegrating agents are low substituted hydroxypropyl cellulose or crosslinked Pvillon (crosslinked polyethylene pyrrolidine) or a combination thereof. The amount of the agent is included in the amount of 镜 5% to 50%. The surfactant in the tablet is selected from the group consisting of sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester (Tweens), polyoxyethylene stearate, sorbose 20 200938233 Alcohol fatty acid ester (Spans) Group of groups. The tablet of the present invention is a tensile strength of 3 〇〇 to 2 〇〇〇 kN/m 2 (calculated as tensile strength = 2 * breaking load / (diameter * thickness * redundancy); observed ingots are observed) Agent pull damage). 5 ❹ 10 15 ❹ 20 The tablet of the present invention has a friability of less than 1%. The lozenge of the present invention does not include a water-soluble adhesive. The tablet according to the present invention may further comprise at least one added excipient selected from the group consisting of a taste masking agent, a sweetener, a lubricant, a stabilizer, a preservative, and a pH adjusting agent. The active agent in the tablet according to the present invention is selected from the group consisting of pharmaceutically active agents, nutraceuticals, nutraceuticals, and cosmetics. The active agent can be one or more vitamins. The active agent can be one or more pharmaceutically active agents. The pharmaceutically active agent may be in the form of a coated particle comprising the pharmaceutically active agent. The envelope may be an extended release or an enteric coating. The tablet according to the present invention, wherein the pharmaceutically active agent is selected from the group consisting of an anti-inflammatory agent, an anti-rheumatic agent, an anti-emetic agent, an analgesic agent, an anti-epileptic agent, an antipsychotic agent, an antidepressant, a hypnotic agent, and an anti-cancer agent. (antiuicerics), gastrointestinal motility agents, anti-asthmatic agents, anti-Parkinson's agents, cardiovascular agents, vasodilators, urological agents, hypolipidemic agents, anti-diabetic agents and antihistamines. The pharmaceutically active agent may be selected from the group consisting of ibuprofen, acetominophen, piroxicam, leflunomide, ondansetron, glas Granisetron, paracetamol, carbamazepin, lamotrigine, clozapine, 7 200938233 olanzapine, risperidone , citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zopiclon, zolpidem, west Cimetidine, ranitidine, omeprazole, metoclopramide, cisapride, domperidon, jafirlukast ), montelukast, prarnipexol, selegiline, zolpidem, zopiclon, doxazosin, orthodontic ingot Ίο (terazosin), atenolol, bisoprolol, ang Amlodipine, nifedipine, diltiazem, enalapril, captopril, ramipril, losartan, Glycerol trinitrate, alfuzosin, finasteride, Pravastatin, atorvastatin, simvastatin, gemfibrozil ), metf〇rmin, terfenadine, 1〇ratadine, celecoxib, dfecoxib, and memory The rivastigmine is a group, and a pharmaceutically acceptable salt, ester, hydrate or solvate of the active agent. According to the present invention, a pharmaceutically acceptable orally disintegrable non-effervescent agent is one of 20% to 9% by weight of microcrystalline cellulose or cellulose microcrystalline cellulose, G% to 20% low substitution (4) Cellulose, (4) to cross-linked polyscale bitumen, lubricant, surfactant and effective amount of pharmaceutically active agent 200938233 1 to see = in-tube disintegration test test, the tablet contains spices, colorants Or both. 5 ❹ 10 15 ❹ 20 The use of a disintegrable non-effervescent active agent is used to make a mouth, a self-solids agent that rapidly releases the active agent over collapse; the agent is in an aqueous environment, as described above The key agent male is used for oral or water-filled containers. The percentage of the insoluble portion of the tablet mixture should be high (such as salts: for example • two = magnesium strontium calcium, strontium salts, oxides such as dioxide towns or the respective hydrates and domains are the same, == Species: for example, cellulose, fiber sputum, 4 Τ glycan, house powder, starch __, alginate, human polymer: such as polyethylene, polypropylene, polyvinyl chloride;

Sour vinegar). If the miscellaneous domain ("the kind of money" is insoluble or its degree of decompression is low", it will also act as an insoluble part. Suitable disintegrating agents in this regard are, for example, swellable polymers, fluorinated cross-linked swellable polymers, hydrophilic polymers or other materials, 2 which absorb water and thereby increase the volume. In pharmacy, it is common to be conjugated, mercapto carboxycellulose, crosslinked polyvinylpyrrolidone 'L-HPC or starch 臬 醋酸 sodium acetate. Other soluble thief-shaped agents can be used such as sugars (lactose, saccharose, grape vine, candied fruit, maltose), sugar alcohols (mannitol sorbitol, xylitol, butyl alcohol) or soluble The active material, as long as the ratio of 9 200938233 is not excessive and its average particle size is maintained above 5 〇 μιη. The use of such soluble excipients is also common in the field of oral dispersible tablets. For the combination of soluble active substances, we have found that the particle size has a certain degree of influence on the disintegration of the tablet. In this case, it is advantageous to make the particles less than 5 small. Particle sizes greater than 50 (average of distribution) are believed to produce the desired lozenge properties. If the solubility of the active substance or substances is high, or when the dissolution time is short, the size is preferably larger than the average particle, and the manner in which the particle size is increased is not important. Large crystals are better than those made by granulation methods (wet or dry granulation methods). 〇 10 In order to manufacture the above formulation, a direct compression purple, * process can be used. Therefore, the manufacturing cost is low and standard techniques can be used, and then it can be used. The properties of the lozenges required are: sufficient physical stability (in terms of tensile strength and brittleness), rapid disintegration (using the method disclosed in European Blood 15th, Fifth Edition 2007 (5.8)) 2.9", expressed in 3n: using the disintegration time of water and disc), acceptable mouthfeel and taste. The pharmaceutically active substance (drug substance) having different solubility can be formulated with the above-mentioned main components of the formulation. The drug substance is not soluble (for example, the oral antidiabetic agent or the miglitol (Miglit(R) 1) or insoluble (e.g., nitrobenzoate). In the case of soluble drug substances, the specific definition (fraction) of particle size is extremely advantageous for disintegration time, content uniformity and tablet hardness. The particles of the pharmaceutically active substance may be crystalline or agglomerated. The particle size of the pharmaceutically active substance may be 5 〇 μηη - ΙΟΟΟμιη, preferably 1 〇〇 μιη _ 800 μηι, more preferably 125 μηη - 630 μηη, and most preferably 125 μπι - 800 μιη. 200938233 In this particle size, especially those which are particularly useful are the pharmaceutically active substances, lycopene, miglitol and voglibose. [Embodiment] 5 Example: By mixing a known component (except the lubricant stearyl sulfoxylate) in a suitable mixing device (for example, a three-dimensional mixer (Turbula® mixer) or a rolling flap Mixer), can be obtained in W minutes. Thereafter, the lubricant was added and mixed for 5 minutes. The 10 conjugate is a 9 mm flat end bevel set of a stamper which is then pressed into a tablet to produce a tablet of known quality. For double dose tablets, a 13 mm flat end bevel punch is used and doubled to a known mass. The bond should be compatible with the known tensile strength range (breaking load between 20 and 60 N). 15 In the case where the sugar lozenge is used as an active material, the sugar lozenge is previously mixed with 0.5% (w/w) stearyl-based sodium butadisulfate and densified. The dense body 破裂 is broken and sieved (dried granulation or compacted by a roller machine). After the sieving, the use of 125 μιη - 800 μΓη was used. Using the above-mentioned European method, the tablet is disintegrated in 5 to 10 seconds. 20 The total amount of the substance of Example 1 [mg/synthesis mass [%1 active substance*) _ I-**·*" 50, 25 30,15% Prosolv (SMMC 90) _ — -------—" 101,00 60,61% 11 200938233 L-HPCB1 type 13,3〇7,98% sodium lauryl sulfate 0 , 42 0,25% gasification nano 0,50 0,30% saccharin sodium stearin brewing base anti-succinic acid sodium 0,17 0,10% 1,00 0,60% bond agent 166,64 100,00 % *) used as 99,5 ° / 〇 (m / m) sugar Lu and 0.5% (m / m) Sodium stearyl flimerat or miglitol

Example 2 Total amount of substance [mg/bond] Mass [%] Active substance*) 50,25 30,15% Prosolv (SMMC 90) 75,00 45,01% Avicel PH200 26,08 15,65% L-HPCB1 Type 13,3〇7,98% sodium lauryl sulfate 0,42 0,25% gasification nano 0,50 0,30% sodium saccharin 0,09 0,05% stearyl thioglycolic acid Sodium 1,00 0,60% Lozenges 166,64 100,00% *) Used as 99.5% (m/m) sugar sulphate and 0.5% (m/m) sodium stearyl sulphate or Miglitol Example 3 Total amount of substance [mg/ingot] Quality "%] Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% 12 200938233

Avicel PH200 26,08 ______ 15,68% Arbocel P290 25,00 L-HPCB1 type 18,00 10,82% sodium lauryl sulfate 0,42 0,25% one__ sodium chloride 0,50 0 ,30% _- Sodium saccharin 0,09 0,05%___- Sodium stearyl succinimide 1,00 0,60%__One bond agent 166,34 100,00%__ *) 99.5% (m/m) 餹Lu ingot and 0.5% (m/m) stearyl succinimide or miglitol. Example 4 5 Total amount of substance [mg/bond] Mass [%] Activity Substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 20,00 12,02% Kollidon CL 49,08 29,51% Sodium lauryl sulfate 0,42 0 , 25% sodium gas 0,50 0,30% sodium saccharin 0,09 0,05% sodium stearyl sulfonate 1,00 0,60% tablets 166,34 100,00% -- -~~~_ *) 1 Do 99.5% (m/m) sugar sulphate and 0.5% (m/m) stearyl succinate or sodium glutamate. Example 5 Total amount of substance [mg/ Ingot] quality [%] 13 10 200938233

Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Arbocel 290 30,00 18,04% Kollidon CL 39,08 23,49% sodium lauryl sulfate 0,42 0,25% sodium chloride 0,50 0,30% sodium saccharin 0,09 0,05% sodium stearyl sulfonate 1,00 0,60% tablets 166,34 100,00% * ) used as 99.5% (m / m) sugar sulphate and 0.5% (m / m) stearyl sulfonate sodium or miglitol Example 6 total amount of substance [mg / ingot 1 mass [% Active substance*) 50,25 30,21% Prosolv (SMMC 90) 45,00 27,05% Aqualon EC T10 38,00 22,84% Kollidon CL 15,08 9,07% L-HPCB1 type 16,00 9,62% sodium lauryl sulfate 0,42 0,25% gasification nano 0,50 0,30% saccharin-nano 0,09 0,05% sodium-stearyl sulfonyl-fumarate 1,00 0,60% lozenges 166,34 100,00% *) used as 99.5% (m/m) sugar sulphate and 0.5% (m/m) stearyl sulphate sodium or rice Glycerol 14 200938233 [Simple description of the diagram] No [Main component symbol description] None 5

Claims (1)

200938233 VII. Patent application scope: 1. A non-effervescent tablet for oral administration, comprising an effective amount of at least one active agent, at least 50% (w/w) of water-insoluble portion, and an interfacial activity The agent and a disintegrating agent cause the tablet to be orally disintegratable or dispersible. 5 2. The bonding agent of claim 1, wherein the tablet exhibits oral disintegratability in less than 60 seconds. 3. The bonding agent according to claim 1 or 2, wherein the water insoluble carrier system is selected from the group consisting of cellulose, microcrystalline cellulose or sillimanite microcrystalline cellulose or a mixture thereof.锭 10 4. The tablet of claim 6, wherein the deuterated microcrystalline cellulose is included in an amount ranging from 20% to 90%. 5. The tablet of claim 6 to 9, wherein the deuterated microcrystalline cellulose has an average particle size in the range of from 20 to 300 μm. 6_such as the tablet of claim 1 to 5, wherein the disintegrating agent is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose, crosscarmelose sodium, A group consisting of cross-povidone (cross-linked polyvinyl ketone), transamidyl acetate, canine, starch, and combinations thereof. 7. The tablet of claim 1 to 6, wherein the surfactant 20 is selected from the group consisting of sodium lauryl sulfate, Tweens, and polyoxyethylene stearin. a group consisting of acid esters and sorbitan fatty acid vinegars (Spans). The tablet of claim 1 to 7, wherein the active agent is selected from the group consisting of pharmaceutically active agents, nutrients, nutriceuticals, and cosmetics. 5 Ο 10 15 ❹ 20 9. The tablet of claim 1 to 8, wherein the pharmaceutically active agent is selected from the group consisting of an anti-inflammatory agent, an anti-rheumatic agent, an anti-emetic agent, an analgesic agent, an anti-epileptic agent, Psychotropic agents, antidepressants, hypnotics, antiulcer agents, prokinetic agents, anti-asthmatic agents, anti-Parkinsonics, cardiovascular agents, vasodilators, urology agents (urologies) a group of hypolipidemic agents, anti-diabetic agents, and antihistamines. 10. The tablet of claim 1 to 8, wherein the pharmaceutically active agent is selected from the group consisting of ibUprofen, acetominophen, piroxine, yanoxi Influx (leflunomide), ondansetron _ (ondansetron), granisetron (granisetron), acetaminophen (paracet; amol), carbamazepin, lamorrigine, nitrozapine (clozapine) ), olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, Zopiclon, zolpidem, cimetidine, ranitidine, omeprazole, metoclopramide, 希Cisapride, domperidon, zafirlukast, montelukast, prarnipexol, selegiline, tyros 17 200938233 (zolpidem), piri隆 (zopicl〇n), 达萨坐辛 (d〇xaz〇sin), serving veins (terazosin), Atenolol (aten〇i〇1), bisoprolol, amlodipine, nifedipine, diltiazem, enalapril, cato Captopril, ramiprii, losartan, glycerol trinitrate, alfuzosin, finasteride, pravastatin, ado Atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib , a group consisting of rifecoxib, and rivastigmine', and a pharmaceutically acceptable salt, ester, hydrate or solvate of the active agent. 11. A surfactant for the manufacture of an orally disintegrable non-effervescent pharmaceutical lozenge. 18 200938233 IV. Designation of Representative Representatives: (1) The representative representative of the case is: (No). (2) A brief description of the symbol of the representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: