KR20100096140A

KR20100096140A - Oral dispersable tablet

Info

Publication number: KR20100096140A
Application number: KR1020107012467A
Authority: KR
Inventors: 토비아스 라이히; 토마스 스틴파스
Original assignee: 바이엘 쉐링 파마 악티엔게젤샤프트
Priority date: 2007-12-08
Filing date: 2008-11-25
Publication date: 2010-09-01
Also published as: TW200938233A; CN101888834A; BRPI0820861A2; RU2010128019A; JP2015038123A; WO2009071219A2; WO2009071219A3; MX2010005175A; EP2231126A2; JP2011506279A

Abstract

The present invention relates to oral disintegrating tablets exhibiting oral disintegration up to 60 seconds. Tablets for oral administration include an effective amount of at least one active agent, at least 50% (w / w) of water insoluble portion, surfactants and disintegrants such that the tablets are orally disintegratable or dispersible.

Description

Oral Dispersible Tablets {ORAL DISPERSABLE TABLET}

Oral dispersible tablets differ in principle from conventional immediate release (IR) tablets. They must be mechanically stable to allow handling during technical work and handling by patients or consumers. Their disintegration time in aqueous environments should be fast and complete. In addition, softening under release conditions is allowed so that the weak mechanical stress is sufficient for complete dispersion.

In order to improve the disintegration properties, several principles are used. For example, tablets contain a gas-generating mixture of at least one acid component (such as citric acid) and at least one basic component (in the form of carbonate or hydrogen-carbonate). Tablets for such oral dispersibility are described, for example, in US 2002/0110578. Another conventional method is, for example, sugar alcohols (mannitol, sorbitol, xylitol, erythritol, etc.), sugars or special forms thereof, such as Pharmaburst ™ or F-Melt ™. It is to use tablet excipients that dissolve rapidly. Rapid disintegration is due to the dissolution of these excipients.

For tablets used for disintegration in the oral cavity, some additional properties are desired. The resulting solution or dispersion after tablet disintegration should be easy to swallow and allow for taste and mouth-feel. Therefore, additional measures (such as micro-encapsulation, coating, salt-forming, ester-forming, etc.) are often necessary for the taste-blocking of the active ingredient or ingredients. Aroma and / or sweeteners are also used to improve taste and patient acceptability. Sometimes the excipients used (sugars, sugar-alcohols) also have a good taste and this property improves patient acceptance.

Another difficulty with rapid disintegration in the oral cavity is the limited amount of liquid present. Compared with water, the liquid inside the oral cavity is highly viscous. The amount and viscosity of the liquid are not constant. It varies between several subjects, even within one subject, depending on the time of day, the amount of liquid (drinking-state) consumed, the food consumed, and the like. Thus, highly porous tablet structures that allow liquid to penetrate easily are also common in the field of oral dispersible tablets. Several special manufacturing techniques ensure highly porous tablet structures. The geometry of the tablet can also affect the disintegration time. Short distances for liquid penetration are preferred. These prerequisites also affect the tablet form and geometry. The optimum geometry desired should also take into account the mechanical stability as described above.

In the manufacture of all tablets and also orally dispersible tablets, cost is important. Manufacturing costs should be as low as possible. This can be achieved at the maximum by using established standard techniques and keeping the manufacturing process as concise as possible. Any additional manufacturing steps will increase the cost and should be avoided. In addition, the use of special excipients tends to increase costs because special excipients are more expensive than standard excipients.

Target groups for the application of orally dispersible tablets can be found in patients having difficulty swallowing tablets or in groups where water is not readily available for taking ordinary tablets. In some markets, the convenience of taking tablets without water is highly preferred. In all cases, the disintegration time of the tablets should be short and the patient / consumer should be impressed with what happens by the tablets inside his mouth. Recognition of this disintegration action helps the patient / consumer to anticipate the positive impact of active ingredient (s) on his / her condition or health.

JP 9071523 describes the formulation of orally dispersible tablets. The use of microcrystalline cellulose (MCC) in combination with low substituted hydroxyl-propyl cellulose (L-HPC) is described. Certain proportions of two excipients have been found to produce the desired tablet properties.

WO 2004091585 describes the use of Prosolv (silicated microcrystalline cellulose) for the formulation of orally dispersible tablets. Prosolve is an excipient brand name and is further described in US 6471994 as a novel tablet excipient for use in oral dispersible tablets.

In the development of new formulation approaches for orally dispersible tablets, the use of surfactants has been studied. Surfactants and hydrophilic wetting polymers, such as Poloxamers, are used to increase the bioavailability by aiding the wettability of the active ingredients (drug substance (s)) or by enhancing their dissolution. In the field of oral dispersible tablets, surfactants can be used to reduce the viscosity of aqueous media inside the oral cavity regardless of the wettability of the actives. This effect can be facilitated by the use of one or more sweeteners in the formulation. Salts (NaCl), acid components or strong flavoring agents can have a similar effect and will also reduce the viscosity of the aqueous medium inside the oral cavity. Combinations of these will be used to increase the effect.

It has been found that rapid tablet disintegration can be facilitated by minimal amounts of less hydrophobic lubricants, since the most commonly used magnesium-stearate tends to slow tablet disintegration. Strong tablet disintegrants are also advantageously combined with other insoluble materials in the formulation.

The present invention provides a non-effervescent for oral administration comprising an effective amount of at least one active agent, at least 50% (w / w) of water insoluble portion, surfactant and disintegrant to be orally disintegratable or dispersible. Relates to tablets. The tablets show oral disintegration up to 60 seconds. Preferably, the tablet exhibits oral disintegration up to 30 seconds. More preferably, the tablets exhibit oral disintegration of 5 seconds or more. Most preferably, the tablets exhibit oral disintegration of 2 seconds or more.

The water insoluble carrier in the tablet is selected from the group of cellulose, microcrystalline cellulose or silicified microcrystalline cellulose or mixtures thereof. The silicified microcrystalline cellulose is contained in an amount in the range of 20% to 90%, preferably in the range of 25% to 60%.

The silicified microcrystalline cellulose contains 1% to 5% silicon dioxide. The silicified microcrystalline cellulose in the tablets has an average particle size in the range of 20 μm to 300 μm.

Disintegrants in tablets are selected from the group consisting of low substituted hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), sodium starch glycolate, starch and combinations thereof do. Preferably, the disintegrant is low substituted hydroxypropyl cellulose or crospovidone (crosslinked polyvinylpyrrolidone) or a combination thereof. Disintegrants are contained in tablets in amounts of 0.5% to 50%.

Surfactants in tablets are selected from the group of sodium dodecyl sulfate, polyoxyethylene sorbitan fatty acid esters (Tween), polyoxyethylene stearate, sorbitan fatty acid esters (Span).

Tablets according to the present invention have a tensile strength of 300 kN / m² to 2000 kN / m² (tensile strength = 2 * break load / (diameter * thickness * π; calculated from the observed tensile failure of the measured tablets)).

Tablets according to the invention have a friability of less than 1%. Tablets according to the invention do not contain a water soluble binder.

Tablets according to the invention may further comprise one or more additional excipients selected from the group consisting of taste blockers, sweeteners, lubricants, stabilizers, preservatives and pH-adjusting agents. The active agent in the tablet according to the invention is selected from the group consisting of pharmaceutical actives, nutrients, nutritional improvers and cosmetic preparations. The active agent may be one or more vitamins. The active agent may also be one or more pharmaceutical active agent (s).

The pharmaceutical active may be in the form of coated particles containing the pharmaceutical active. The coating can be a sustained release or enteric coating.

Tablet according to the present invention, the pharmaceutical active agent is anti-inflammatory, anti-rheumatic, anti-emetic, analgesic, antiepileptic, antipsychotic, antidepressant, sleeping, anti-ulcer, gastrointestinal motility, anti-asthma, anti-Parkinson's, cardiovascular It is a tablet selected from the group consisting of vasodilators, urological preparations, hyperlipidemic agents, antidiabetic agents and antihistamines.

The pharmaceutically active agent is ibuprofen, acetominophene, pyroxicam, leflunomide, ordansetron, granistron, paracetamol, carbamazepine, lamotrigine, clozapine, olanzapine, risperidone, citalopram, paroxetine, ser Traline, Fluoxetine, Fluvoxamine, Zopiclone, Zolpidem, Cimetidine, Lanitidine, Omeprazole, Metoclopramide, Cisapride, Domperidone, Zapirlucaste, Montelukast, Pranipexole, Selegiline, Zolpidem , Zopiclone, doxazosin, terrazosin, atenolol, bisoprolol, amlodipine, nifedipine, diltiazem, enalapril, captopril, ramipril, losartan, glycerol trinitrate, alfuzosin, finasteride, pravastatin, atorvastatin , Simvastatin, gemfibrozil, metformin, terpenadine, loratadine, celecoxib, lipcoxib, and rivastigmine, as well as pharmaceutically acceptable active agents Salts, may be selected from the group consisting of esters, hydrates or solvates.

According to the invention, the pharmaceutical oral disintegrating non-foamable tablets consist essentially of 20% to 90% silicified microcrystalline cellulose or cellulose or microcrystalline cellulose, 0% to 20% low substituted hydroxypropyl cellulose, 0% to 20 It is composed of% crosslinked polyvinylpyrrolidone, a lubricant, a surfactant and an effective amount of a pharmaceutical active, and exhibits disintegration within 1 to 15 seconds when tested in an in vitro disintegration test.

The tablet may further comprise a flavourant, a colorant or both.

The present invention also relates to the use of surfactants for preparing orally disintegrating non-foamable pharmaceutical tablets.

The invention also provides a method of rapidly releasing an active agent from a solid tablet, which comprises disintegrating by placing the tablet as described above in an aqueous environment. The aqueous environment is an oral or water filled container.

The percentage of insoluble portion in the purification mixture should be greater than 30 weight percent. Insoluble excipients may be of inorganic origin (such as salts such as calcium phosphate, calcium sulfate, magnesium carbonate, calcium carbonate, silicate (s), oxides such as titanium dioxide, aluminum oxide, magnesium oxide or Each of these hydrates and / or polymorphic forms) or organic nature (eg, natural polymers such as cellulose, cellulose esters or ethers, chitin, chitosan, starch, starch esters or ethers, alginates, synthetic polymers, eg Polyethylene, polypropylene, polyvinylchloride, polymethacrylate). If the active ingredient (s) are insoluble or have low solubility, they will also act as insoluble moieties.

Suitable disintegrants in this respect are, for example, expandable polymers, crosslinked expandable polymers, hydrophilic polymers or other materials which increase the volume by absorbing water. Croscarmellose, crosslinked polyvinylpyrrolidone, L-HPC or sodium starch glycolate are pharmaceutically customary. Other soluble excipients such as sugars (lactose, saccharose, glucose, fructose, maltose), sugar alcohols (mannitol, sorbitol, xylitol, erythritol) or soluble actives do not increase their ratio but It can be used as long as the average particle size is maintained above 50 μm. The use of such soluble excipients is also common in the field of oral dispersible tablets.

For incorporation of soluble actives, their particle size has been found to affect tablet disintegration. In this case, it is advantageous that the particles do not become small. Particle sizes (average distribution values) of greater than 50 μm have been found to produce the desired tablet properties. If the solubility of the active (s) is high or the dissolution time is short, a larger average particle size is preferred. The method of increasing the particle size is not important. Larger crystals act as agglomerates prepared by granulation (wet- or dry-granulation methods may be used).

For the preparation of the described formulations, direct compression manufacturing processes can be used. Thus, manufacturing costs are reduced and standard techniques can be used that keep the investment low.

The desired tablet properties are described in sufficient mechanical stability (expressed in tensile strength and friability), rapid disintegration (European Pharmacopia 5 ^th edition 2007 (5.8) Method 2.9.1, using water and discs at 37 ° C.). Expressed as time of disintegration using the method), permissible texture and taste.

Using the formulation principles described, it is possible to formulate pharmaceutically active substances (drug substances) of different solubility. The drug substance can be soluble (eg acarbose or miglitol, an oral antidiabetic agent) or insoluble (eg nifedipine). In the case of soluble drug substances, particular defined (fractional) particle sizes may be advantageous for disintegration time, content uniformity and tablet hardness. Particles of pharmaceutically active substance may be crystals or aggregates. The particle size of the pharmaceutically active substance may be between 50 μm and 1000 μm, preferably between 100 μm and 800 μm, more preferably between 125 μm and 630 μm and most preferably between 125 μm and 800 μm. Pharmaceutically active substances acarbose, miglitol and boglybose are particularly useful at such particle sizes.

Example

Tablets can be obtained by mixing a given component (excluding the lubricant Na-stearyl-fumarate) for 10 minutes in a suitable mixing device (e.g. Turbula mixer or tumble blender). . The lubricant was then added and mixed for an additional 5 minutes.

The mixture was then compressed into tablets using a punch of 9 mm flat-faced beveled edged set to give tablets of a given mass. For double dose tablets, a 13 mm flat planar oblique rim punch was used and compressed to twice the given mass. Tablets should fit within a given tensile strength range (20 N to 60 N breaking load).

In the case of acarbose as active, acarbose was premixed with 0,5% (w / w) Na-stearyl-fumarate and compressed. The compact was broken and sieved (dry-granulated or roller-compressed). After sieving, a fraction of 125 μm to 800 μm was used.

Tablets disintegrated within 5 to 10 seconds using the European Pharmacopoeia method described.

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Claims

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, a surfactant, and a disintegrant to be orally disintegratable or dispersible.

The tablet of claim 1, wherein the tablet exhibits oral disintegration up to 60 seconds.

The tablet according to claim 1 or 2, wherein the water insoluble carrier is selected from the group of cellulose, microcrystalline cellulose or silicified microcrystalline cellulose or mixtures thereof.

The tablet according to claim 6, wherein said silicified microcrystalline cellulose is contained in an amount within the range of 20% to 90%.

The tablet according to claim 6, wherein the silicified microcrystalline cellulose has an average particle size in the range of 20 μm to 300 μm.

The disintegrant according to any one of claims 1 to 5, wherein the disintegrant is a low substituted hydroxypropyl cellulose, carboxymethyl cellulose, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), sodium starch glycolate Tablets selected from the group consisting of starch and combinations thereof.

The method according to any one of claims 1 to 6, wherein the surfactant is sodium dodecyl sulfate, polyoxyethylene sorbitan fatty acid ester (Tween), polyoxyethylene stearate, sorbitan fatty acid ester (span Span)).

The tablet according to any one of claims 1 to 7, wherein the active agent is selected from the group consisting of pharmaceutical actives, nutrients, nutritional improvers and cosmetic preparations.

The method according to any one of claims 1 to 8, wherein the pharmaceutical active agent is an anti-inflammatory agent, anti-rheumatic agent, anti-emetic agent, analgesic agent, antiepileptic agent, antipsychotic agent, antidepressant agent, sleeping agent, anti-ulcer agent, gastrointestinal motility agent, anti-asthma agent Tablets selected from the group consisting of anti-Parkinson's disease, cardiovascular agents, vasodilators, urological agents, hyperlipidemia, antidiabetic agents and antihistamines.

The pharmaceutical active according to any one of claims 1 to 8, wherein the pharmaceutically active agent is ibuprofen, acetominophene, pyricampam, leflunomide, ordansetron, granisetrone, paracetamol, carbamazepine, lamotrigine. , Clozapine, olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zodiclodine, zolpidem, cimetidine, ranitidine, omeprazole, metoclopramide, cisapride, domperidone, zaphyllucast , Montelukast, pranipexole, selegiline, zolpidem, zodiaclone, doxazosin, terrazosin, atenolol, bisoprolol, amlodipine, nifedipine, diltiazem, enalapril, captopril, ramipril, losartan, Glycerol trinitrate, alfuzosin, finasteride, pravastatin, atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib, lipoxibib and riba Purification TIG Min, that not only selected from the group consisting of a pharmaceutically acceptable salt of the active agent, ester, hydrate or solvate.

Use of a surfactant for the manufacture of orally disintegrating non-foamable pharmaceutical tablets.