JP2011506279A - Orally dispersible tablets - Google Patents

Abstract

  The present invention is directed to tablets that are dispersible in the oral cavity and exhibit disintegration ability in the oral cavity of 60 seconds or less. The tablet for oral administration comprises an effective amount of at least one active substance, a water-insoluble portion in an amount of at least 50% (w / w), such that the tablet is disintegratable or dispersible in the oral cavity. Includes surfactants and disintegrants.

Description

  The present invention is directed to tablets that are dispersible in the oral cavity and exhibit disintegration ability in the oral cavity of 60 seconds or less. The tablet for oral administration comprises an effective amount of at least one active substance, a water-insoluble portion in an amount of at least 50% (w / w), such that the tablet is disintegratable or dispersible in the oral cavity. Includes surfactants and disintegrants.

  Tablets that are dispersible in the oral cavity are in principle not different from general immediate release (IR) tablets. They should be mechanically stable to allow handling during technical operations and handling by the patient or customer. Their disintegration time in an aqueous environment should be rapid and complete. Softening under release conditions can be tolerated so that even weak mechanical stress is sufficient for complete dispersion.

Several principles are known for improving the disintegration properties. For example, a tablet containing a gas generating mixture consisting of at least one acid component (such as citric acid) and at least one base component in the form of a carbonate or bicarbonate. Such tablets for orally disintegrating ability are described, for example, in US 2002/0110578. Another known method is rapidly soluble, such as sugar alcohols (mannitol, sorbitol, xylitol, erythritol, etc.), sugars, or certain forms thereof such as Pharmaburst ^™ or F-Melt ^™ The use of tablet adjuvants. The rapid disintegration is the result of dissolution of these adjuvants.

  Several additional properties are desirable for tablets used for disintegration in the oral cavity. The solution or dispersion obtained after tablet disintegration should be easy to swallow and acceptable with respect to taste and mouthfeel. Thus, further measures (microencapsulation, coating, salt formation, ester formation, etc.) are often necessary to mask the taste of the active ingredient. In addition, aromas and / or sweeteners are used to improve taste and patient acceptance. The adjuvants used may also have a pleasant taste (sugar, sugar alcohol), 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 in the oral cavity is highly viscous. The amount of liquid and its viscosity are not constant. There are differences between different subjects, and even within one subject can vary depending on the time of day, the amount of liquid consumed (drinking condition), the food eaten, etc. Thus, highly porous tablet structures that can easily penetrate liquids are also common in the field of tablets that can be dispersed in the oral cavity. Several specialized manufacturing techniques ensure a highly porous tablet structure. The tablet geometry can also affect the disintegration time. A short path to liquid penetration is preferred. This requirement also affects the shape and contour of the tablet. The desired optimum profile must also take into account mechanical stability, as already mentioned.

  Cost is important in the manufacture of all tablets and for tablets that are dispersible in the oral cavity. Manufacturing costs should be as low as possible. This is best achieved by using established standard techniques and maintaining as lean a manufacturing method as possible. Any additional manufacturing steps will increase costs and should be avoided. The use of specialized adjuvants also tends to increase costs because they are more expensive than standard adjuvants.

  Target groups applying tablets that are dispersible in the oral cavity can be found in patients with difficulty swallowing tablets, or in groups where water for regular tablet intake is not readily available. In some markets, the convenience of taking tablets without water has a high priority. In all cases, the disintegration time of the tablet should be short and the patient / customer should have the impression that something is happening to the tablet in the mouth. This perception of disintegration helps the patient / customer expect a positive impact of the active ingredient on his / her condition or health.

  JP9071523 describes the formulation of tablets that are dispersible in the oral cavity. The use of crystalline cellulose (MCC) in combination with low substituted hydroxyl-propyl cellulose (L-HPC) is described. It has been found that a specific ratio of the two adjuvants provides the desired tablet properties.

  WO2004091585 describes the use of Prosolv (silicified crystalline cellulose) for the formulation of tablets dispersible in the oral cavity. Prosolv is a trademarked adjuvant and is further described in US 6471994 as a new tablet adjuvant for use in tablets that are dispersible in the oral cavity.

  The use of surfactants was studied in the development of new formulation approaches to tablets that are dispersible in the oral cavity. Surfactants and hydrophilic wet polymers (such as Poloxamer) are used to help hydrate the active ingredients (drug substances) or increase bioavailability by promoting their dissolution Is done. In the field of tablets dispersible in the oral cavity, surfactants can be used to reduce the viscosity of the aqueous medium in the oral cavity independent of the hydratability of the active ingredient. This effect can be facilitated by the use of one or more sweet-tasting substances inside the formulation. Salt (NaCl), acid components or strong flavors may have a similar effect, which will also reduce the viscosity of the aqueous medium in the oral cavity. These combinations can be used to enhance this effect.

  It has been found that rapid tablet disintegration is facilitated by a minimal amount of low hydrophobic lubricant, since the most commonly used magnesium stearate tends to slow the rate of tablet disintegration. Strong tablet disintegrants are also advantageous in combination with other insoluble materials in the formulation.

  The present invention provides an effective amount of at least one active substance, an amount of at least 50% (w / w) of a water-insoluble part, a surfactant and a disintegrant, wherein the tablet is disintegratable or dispersible in the oral cavity Intended for non-effervescent tablets for oral administration. The tablet exhibits an orally disintegrating ability for 60 seconds or less. Preferably, the tablet exhibits an orally disintegrating ability of 30 seconds or less. More preferably, the tablet exhibits an orally disintegrating ability for 5 seconds or more. Most preferably, the tablet exhibits an orally disintegrating ability for 2 seconds or more.

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

  The silicified crystalline cellulose contains 1-5% silicon dioxide. The tablet silicified crystalline cellulose in the tablet has an average particle size in the range of 20-300 μm.

  The disintegrant in the tablet is selected from the group consisting of low substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), sodium starch glycolate, starch and combinations thereof. Preferably, the disintegrant is low substituted hydroxypropyl cellulose or crospovidone (crosslinked polyvinyl pyrrolidone) or a combination thereof. The disintegrant is contained in the tablet in an amount of 0.5% to 50%.

  The surfactant in the tablet is selected from the group of sodium dodecyl sulfate, polyoxyethylene sorbitan fatty acid ester (Tweens), polyoxyethylene stearate, sorbitan fatty acid ester (Spans).

The tablets according to the invention have a tensile strength of 300 to 2000 kN / m ² (tensile strength = 2 * breaking load / (diameter * thickness * π; observed tensile fracture of the tablet to be measured) As calculated).

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

  The tablets according to the invention may further comprise at least one further adjuvant selected from the group consisting of taste masking agents, sweeteners, lubricants, stabilizers, preservatives and pH adjusting agents. The active substance in the tablets according to the invention is selected from the group consisting of pharmaceutically active substances, nutrients, nutriceuticals and cosmetics. The active substance can be one or more vitamins. The active substance can also be one or more pharmaceutically active substances.

  The pharmaceutically active substance can be present in the form of coated particles containing the pharmaceutically active substance. The coating can be a sustained release or enteric coating.

  In the tablet according to the present invention, the pharmaceutically active substance contains an anti-inflammatory agent, an anti-rheumatic agent, an antiemetic agent, an analgesic agent, an antiepileptic agent, an antipsychotic agent, an antidepressant agent, a sleeping agent, an antiulceric agent, a digestive tract. Tablets selected from the group consisting of exercise improving drugs, anti-asthma drugs, anti-parkinson drugs (antiparkinsonic), cardiovascular drugs, vasodilators, urologic drugs, lipid-lowering drugs, anti-diabetic drugs and anti-histamine drugs It is.

  The pharmaceutically active substances are ibuprofen, acetaminophen, piroxicam, leflunomide, ondansetron, granisetron, paracetamol, carbamazepine, lamotrigine, clozapine, olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zopicrimmezine, Ranitidine, omeprazole, metoclopramide, cisapride, domperidone, zafirlukast, montelukast, plarnipexol (prarnipexol), selegiline, zolpidem, zopiclone, doxazosin, terazosin, atenolol, bisoprolol, amlodipine, diltiazelpamipriprialpine , Glyceryl trinitrate, Alfuzosi , Finasteride, pravastatin, atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib, rifecoxib and rivastigmine, and pharmaceutically acceptable salts, esters, hydrates or solvates of the active substance It can be selected from a group.

According to the present invention, non-effervescent tablets that can be disintegrated in the oral cavity of a medicament are essentially 20% to 90% silicified crystalline cellulose or cellulose or crystalline cellulose, 0% to 20% low substituted hydroxypropylcellulose, It consists of 0% to 20% cross-linked polyvinyl pyrrolidone, a lubricant, a surfactant and an effective amount of a pharmaceutically active substance, and the tablet exhibits a disintegration within 1-15 seconds when tested in an in vitro disintegration test. Show.
The tablets can further include flavoring agents, coloring agents, or both.

  The present invention is further directed to the use of a surfactant to produce a non-foamable pharmaceutical tablet that is disintegratable in the oral cavity.

  The present invention also provides a method for rapidly releasing an active substance from a solid tablet, which comprises disintegrating said tablet by placing the tablet in a water environment. The water environment is the oral cavity or a container filled with water.

  The proportion of insoluble part of the tablet mixture should exceed 30% by weight. Insoluble adjuvants are of inorganic origin (salts such as calcium phosphate, calcium sulfate, magnesium carbonate, calcium carbonate, silicates, etc., oxides such as titanium dioxide, aluminum oxide, magnesium oxide etc., or their respective Hydrates and / or polymorphs) or of organic nature (natural polymers such as cellulose, cellulose esters or ethers, chitin, chitosan, starches, starch esters or ethers, synthetic polymers such as alginates, such as , Polyethylene, polypropylene, polyvinyl chloride, polymethacrylate). If the active ingredients are insoluble or their solubility is low, they will also act as an insoluble part.

  Suitable disintegrants in this regard are, for example, swellable polymers, cross-linked swellable polymers, hydrophilic polymers, or other substances that increase in volume by incorporating water. Common in medicine are croscarmellose, cross-linked polyvinyl pyrrolidone, L-HPC or sodium starch glycolate. Other soluble adjuvants such as sugars (lactose, saccharose, glucose, fructose, maltose), sugar alcohols (mannitol, sorbitol, xylitol, erythritol) or soluble active substances are not too high in their proportions As long as the diameter remains above 50 μm, it can be used. The use of this soluble adjuvant is also common in the field of tablets dispersible in the oral cavity.

  For the incorporation of soluble active substances, it has been found that their particle size has an effect on the tablets. In this case, it is advantageous to have a particle size that is not too small. A particle size greater than 50 μm (average of distribution) was found to give the desired tablet properties. A larger average particle size is preferred when the solubility of the active substance is high or when the dissolution time is short. The method of increasing the particle size is not important. Larger crystals work as well as agglomerates formed by granulation (wet or dry granulation methods can be used).

  A direct compression manufacturing workflow can be used for the manufacture of the above formulations. Thus, manufacturing costs are low and standard techniques can be used, which keeps investment low.

  Desirable tablet properties include sufficient mechanical stability (expressed as tensile strength and friability), rapid disintegration (method described in the European Pharmacopoeia (European Pharmacopoeia 5th Edition 2007 (5.8) Method 2) 9.1, using 37 ° C. water and disk), expressed as disintegration time), acceptable mouth feel and taste.

  Pharmaceutical active substances (drug substances) with various solubilities can be formulated using the above formulation principle. The drug substance can be soluble (eg, oral antidiabetic agents such as acarbose or miglitol) or insoluble (eg, nifedipine). In the case of soluble drug substances, a special definition (percentage) of particle size may be advantageous with respect to disintegration time, content uniformity and tablet hardness. The particles of pharmaceutically active substance may be crystals or aggregates. The particle size of the pharmaceutically active substance may be 50 μm-1000 μm, preferably 100 μm-800 μm, more preferably 125 μm-630 μm, most preferably 125 μm-800 μm. Particularly useful at this particle size are the pharmaceutically active substances acarbose, miglitol and voglibose.

Example:
Tablets can be obtained by mixing the prescribed ingredients (excluding the lubricant stearyl Na fumarate) for 10 minutes in a suitable mixing device (eg a Turbula mixer or rotary blender). The lubricant is then added and mixed for an additional 5 minutes.
This mixture is then compressed into tablets using a 9 mm flat face beveled set of punches to obtain tablets of a given mass. For double dose tablets, use a punch with a beveled edge on a 13 mm flat surface and compress to twice the predetermined mass. Tablets should correspond to a predetermined tensile strength range (breaking load 20-60 N).
In the case of acarbose as the active substance, the acarbose is premixed with 0.5% (w / w) Na stearyl fumarate and compressed. The compact is crushed and sieved (dry granulation or roller compaction). After sieving, the fraction of 125 μm-800 μm is used.
These tablets disintegrate within 5-10 seconds using the European Pharmacopoeia method described above.

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 1

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 2

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 3

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 4

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 5

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

＊）９９．５％（ｍ／ｍ）アカルボースおよび０．５％（ｍ／ｍ）フマル酸ステアリルナトリウムまたはミグリトールとして使用 Example 6

*) Used as 99.5% (m / m) acarbose and 0.5% (m / m) sodium stearyl fumarate or miglitol

Claims (11)

  An effective amount of at least one active substance, an amount of water-insoluble part, surfactant and disintegrant in an amount of at least 50% (w / w), such that the tablet is disintegratable or dispersible in the oral cavity, Non-effervescent tablet for oral administration.   The tablet according to claim 1, wherein the tablet exhibits an orally disintegrating ability for 60 seconds or less.   The tablet according to any one of claims 1 to 2, wherein the water-insoluble carrier is selected from the group of cellulose, crystalline cellulose or silicified crystalline cellulose or a mixture thereof.   The tablet according to claim 3, wherein the silicified crystalline cellulose is contained in an amount in the range of 20% to 90%.   The tablet according to any one of claims 3 to 4, wherein the silicified crystalline cellulose has an average particle size in the range of 20-300 µm.   The disintegrant is selected from the group consisting of low-substituted hydroxypropylcellulose, carboxymethylcellulose, croscarmellose sodium, crospovidone (crosslinked polyvinylpyrrolidone), sodium starch glycolate, starch and combinations thereof. Item 6. The tablet according to any one of Item 5.   7. The surfactant according to any one of claims 1 to 6, wherein the surfactant is selected from the group of sodium dodecyl sulfate, polyoxyethylene sorbitan fatty acid ester (Tweens), polyoxyethylene stearate, sorbitan fatty acid ester (Spans). The tablet described.   The tablet according to any one of claims 1 to 7, wherein the active substance is selected from the group consisting of pharmaceutically active substances, nutrients, nutritional supplements and cosmetics.   The pharmaceutically active substance is an anti-inflammatory agent, anti-rheumatic agent, antiemetic agent, analgesic agent, antiepileptic agent, antipsychotic agent, antidepressant agent, sleep agent, antiulcer agent, gastrointestinal motility improver, antiasthma agent, anti The tablet according to any one of claims 1 to 8, which is selected from the group consisting of Parkinson's disease drug, cardiovascular drug, vasodilator, urinary drug, lipid lowering drug, antidiabetic drug and antihistamine.   The pharmaceutically active substance is ibuprofen, acetaminophen, piroxicam, leflunomide, ondansetron, granisetron, paracetamol, carbamazepine, lamotrigine, clozapine, olanzapine, risperidone, citalopram, paroxetine, sertraline, fluoxetine, fluvoxamine, zopicrimmezine, Ranitidine, omeprazole, metoclopramide, cisapride, domperidone, zafirlukast, montelukast, plarnipexol, selegiline, zolpidem, zopiclone, doxazosin, terazosin, atenolol, bisoprolol, amlodipine, nifedipine, diltiazem, enalapril tapril Glycerin, alfuzosin, finaster , Pravastatin, atorvastatin, simvastatin, gemfibrozil, metformin, terfenadine, loratadine, celecoxib, rifecoxib and rivastigmine, and pharmaceutically acceptable salts, esters, hydrates or solvates of the active substance The tablet according to any one of claims 1 to 8.   Use of a surfactant to produce a non-foamable pharmaceutical tablet that is disintegratable in the oral cavity.