JP2007308492A - Intraoral disintegrating tablet for treating dysuria - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an intraoral disintegrating tablet intended to be used for administering an active component to treat dysuria and/or its related diseases. <P>SOLUTION: The intraoral disintegrating tablet contains the active component having 0.5-40μm average particle diameter and 15-60% (weight/weight) disintegration agent having 105-220μm average particle diameter. The tablet easily disintegrates in the mouth and gives no feeling of solid residue in the mouth. The tablet has sufficiently high hardness so that usual packaging and treating methods can be used. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention is for treating dysuria and / or related diseases having a hardness of 30 N or more and a disintegration time of 50 seconds or less and having an average particle diameter in the range of 0.5 to 40 μm. Orally disintegrating tablets, comprising a disintegrant in an amount of 15-60% (w / w) in the tablet and the active ingredient.

  Delivery systems that disintegrate or dissolve orally are known in the art. One such commercially marketed system is Zydis. Based on technology. The system is based on a tablet-shaped lyophilized solid gelatin or starch matrix network that also contains a water-soluble sugar such as mannitol.

  Despite the appearance of the tablet, such a form is not actually made by tableting, but is a wafer made by lyophilizing a solution of the ingredients in a tablet-shaped “pocket”. is there. Such techniques are complex and expensive requiring special equipment. A similar technique based on lyophilization is described in Lyoc. Technology (L. Lafon) or QuickSolv technology (Jansen).

  Orally disintegrating tablets produced by tableting are also known. In general, rapid disintegration is achieved by facilitating rapid uptake of water into the tablet matrix. The basic approach to making such tablets is to incorporate a suitable disintegrant and use highly water soluble excipients such as sugars or sugar alcohols to maximize the porous structure of the tablet matrix. Including. Many commercial orally dissolving tablets use pretreated excipients, among others.

  Patent Publication JP 102988062A, published in 1998, describes a rapidly disintegrating tablet containing 13% (weight / weight) of a water-insoluble excipient containing doxazosin mesylate and a shaping aid and a disintegrant for bonding. It is described. This tablet disintegrates in the oral cavity within 50 seconds and has a tablet hardness of 8.2 kgf.

  Patent publication JP2004175796A, published in 2004, describes an oral formulation for treating dysuria. This document discloses a tablet that, when administered, has no solid residue feel in the mouth and disintegrates rapidly in the mouth without an unpleasant taste, and is sufficiently hard to be packaged in a PTP container. There is a need. This document discloses tablets containing naphthopidil and a water-insoluble excipient. When included in an amount of 10% (weight / weight) or more, the excipient has an average particle diameter of 100 μm or less. This announcement teaches that limits on the particle diameter of water-insoluble excipients are necessary to prevent the feel and unpleasant taste of solid residues in the mouth when administered.

  It is an object of the present invention to provide another orally disintegrating tablet that treats dysuria containing a disintegrant without administration of a solid residue in the mouth upon administration and without an unpleasant taste. This object is achieved by incorporating a disintegrant in an amount of 15 to 60% (weight / weight) with an average particle diameter in the range of 105 to 220 μm into the tablet.

  According to the invention, active ingredients having an average particle diameter in the range of 0.5 to 40 μm for treating dysuria and / or related diseases, and 15 to 60 in which the average particle diameter of the disintegrant is in the range of 105 to 220 μm For the first time, orally disintegrating tablets for treating urination disorders, containing disintegrants in the amount of% (weight / weight) in the tablets are available. Surprisingly, such tablets containing disintegrants in an amount of 15 to 60% (weight / weight) having an average particle diameter in the range of 105 to 220 μm, contrary to the teaching of JP200417596A, Do not give the mouth a solid residue when administered.

  “Disintegrate orally” means that the tablet disintegrates or disperses within 50 seconds as measured by the in vitro disintegration test described in US Pharmacopeia 701 (without disk). Such disintegration test results are reasonably related to the actual disintegration time experienced by mammals when placed in the oral cavity.

  Orally disintegrating dosage forms for drug delivery are known in the art. The purpose of such a system is to allow administration of beneficial therapeutic agents in solid dosage forms, such as tablets, to a patient without having to swallow the dosage form. Orally disintegrating tablets should disintegrate and possibly dissolve directly in the oral cavity using saliva or possibly small amounts of water. The resulting liquid or dispersion is then easily swallowed. This introduces the dissolved or dispersed beneficial therapeutic agent easily and quickly into the gastrointestinal tract. Orally disintegrating tablets should disintegrate in the oral cavity within a period not exceeding about 1 minute.

  The tablets of the present invention disintegrate rapidly when placed in the oral cavity without the feel of solid residues and unpleasant taste in the mouth. After the drug disintegrates in the mouth, the active ingredient is not completely dissolved before it is swallowed with saliva.

  The disintegration time of the tablets of the present invention was evaluated using a disintegration test performed as described in US Pharmacopoeia 701 using water as the test solution. Disintegration preferably takes 50 seconds or less, more preferably 30 seconds or less, and particularly preferably 20 seconds or less. The hardness of the tablet is determined with Pharmatest PTB301 or equivalent.

  The tablet hardness is high enough so that conventional packaging and handling methods can be used. Preferably the tablet has a hardness of 30N and more preferably 70N or more.

  Active ingredients having alpha-1 adrenergic receptor blocking activity, cholinergic agents and active ingredients having muscarinic receptor antagonistic activity are active ingredients for treating dysuria and / or related diseases. Typically known. Preferred active ingredients for the present invention are naphthopidil, tamsulosin, bunazosin, urapidil, moxisylite, doxazosin, alfuzin, alfuzin, alfuzin Prazosin, metazocine, fiduxosin, indrazosin, and pharmaceutically acceptable salts, esters, hydrates or solvates of the active ingredients.

  YM-905 (Solifenacin succinate; (+)-(1S, 3′R) -quinuclidin-3′-yl-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate International publications WO 96/20194) and KMD-3213 (silodosin) (-)-(R) -1- (3-hydroxypropyl) -5- [2- [2- [2- (2,2 , 2-trifluoroethoxy) phenoxy] ethylamino] propyl] indoline-7-carboxamide: described in US Pat. No. 5,387,603).

  Naftopidyl, prazosin hydrochloride and urapidil are more preferred for the present invention. Naphtopidyl [4- (2-methoxyphenyl) piperazinyl] -3- (1-naphthyloxy) propan-2-ol] is most preferred.

  Conventional naphthopidyl tablets are already on the market in Japan. The initial daily dosage of naphthopidyl for a once daily dosage schedule in adults with dysuria with benign prostatic hyperplasia is 25 mg naphthopidyl. If the patient shows an inadequate response, the daily dose is gradually increased to 50-75 mg at 1-2 week intervals.

  The initial daily dosage of prazosin hydrochloride in adults with dysuria with enlarged prostate is 1-1.5 mg (2-3 times daily, 0.5 mg each). If the patient shows an inadequate response, the dose is gradually increased to 1.5-6 mg at 1-2 week intervals on a daily 2 to 3 dose schedule.

  The initial daily dosage of urapidil in adults with dysuria with enlarged prostate is 30 mg. If the patient shows an inadequate response, the dose is gradually increased to 60-90 mg at 1-2 week intervals on a twice daily dose schedule.

  The average particle diameter of the active ingredient is obtained by suspending the active ingredient in water with a surfactant and using a laser diffraction apparatus. The active ingredient preferably has an average particle diameter in the range of 0.5-40 μm, more preferably in the range of 1-35 μm, and most preferably in the range of 2-30 μm.

  The active ingredient in the tablets of the present invention generally does not exceed 50% by weight of the tablet, preferably from about 0.5 to about 35%.

  The tablets according to the invention further comprise a disintegrant to reduce the disintegration time. The disintegrant may be one or a combination of two or more disintegrants. In general, the disintegrant comprises water-insoluble cellulose, preferably the cellulose is microcrystalline cellulose. These celluloses are preferably combined with a super disintegrant.

  This disintegrant is present in the tablet in an amount of 15% (weight / weight) or more, and the average particle diameter of the disintegrant ranges from 105 to 220 μm. More preferably, the average particle diameter is in the range of 150 to 210 μm. Most preferably, the average particle diameter is in the range of 160 to 200 μm.

  The tablets preferably comprise 15-60% (w / w) and more preferably 25-50% (w / w) and most preferably 35-45% (w / w) disintegrant.

  In tablets comprising a combination of a water-insoluble cellulose and a disintegrant from the group of superdisintegrants, the superdisintegrant is 10% (weight / weight) or less, more preferably 8% (weight / weight) or less, in particular 5% (weight). / Weight) is preferably present in the following amounts.

  The disintegrants of the group of water-insoluble cellulose consist of essentially purified cellulose or essentially organically modified cellulose. Examples of these disintegrants are crystalline cellulose, microcrystalline cellulose (Avicel PH101, Avicel PH102, Avicel PH301, Avicel PH302, Avicel PH200, Vivapur), purified wood cellulose, low substituted hydroxypropylcellulose and ethylcellulose. Examples of water-insoluble disintegrants that can be used that do not belong to the group of cellulose are superdisintegrations such as starch, partially gelatinized starch (Starch 1500) and cross-linked polyvinyl pyrrolidone, sodium starch glycolate, carboxymethyl starch, etc. It is an agent.

  The “average particle diameter” of the disintegrant means the diameter when the cumulative percentage of sieving is 50% when measuring 75 g of powder using a Retsch sieve.

  A further advantage of using more than 15% (weight / weight) disintegrant having an average particle diameter in the range of 105 to 220 μm, and preferably in the range of 150 to 210 μm is that the disintegrant treats dysuria To improve the flow characteristic value of granules containing the active ingredient.

  A further advantage of using more than 15% (weight / weight) disintegrant with an average particle diameter in the range of 105 to 220 μm and preferably in the range of 150 to 210 μm is that the produced tablets are higher than the tablets It is to disintegrate rapidly due to porosity.

  The tablets according to the invention can contain commonly used diluents (fillers) or extenders, as known by those skilled in the art, which are water-insoluble calcium phosphates (dibasic and tribasic). , Calcium sulfate dihydrate and calcium carbonate. A water-soluble diluent comprising sugar and sugar alcohol is preferably used. Water soluble diluents can be used both intragranular, extragranular, and intragranular. Sugars and sugar alcohols are preferred dry excipients for milling with active ingredients to form a finely milled mixture prior to granulation. Examples of sugars and sugar alcohols that can be used are saccharose, glucose, fructose, lactose, mannitol, sorbitol, xylitol, erythritol, trehalose and maltitol. Lactose is the most preferred diluent for intragranular application in amounts ranging from 10 to 60% (weight / weight) in the tablet.

  In wet granulation, the material that binds the powders together is the binder. For granulation, the binder can be added dry and blended with the mixture. Binders used alone or in combination with other binders dissolved in the granulating liquid are preferred.

  Examples of binders are gelatin, agar, alginic acid, sodium alginate, xanthan gum, powdered acacia gum, polyethylene glycol, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, partially saponified polyvinyl alcohol, methylcellulose, pullulan, modified starch, sugar and sugar alcohol It is. A preferred binder is hydroxypropylcellulose in an amount ranging from 0.01 to 1% (w / w) in the tablet.

  Tablets according to the present invention can further comprise materials for improving the flow characteristic values and are called lubricants. By way of example, silicon dioxide, magnesium lauryl sulfate, magnesium aluminum silicate, magnesium oxide, talc or clay are incorporated into the formulation to reduce the friction between the microparticles and the material from large to small openings in the tablet press The problems associated with the flow of data can be reduced.

  Prior to compressing tablets, lubricants are often added during processing to prevent friction and wear. Some lubricants also exhibit anti-adhesion properties that can be related to the sticking of tablet granules to the mating surface of the punch and the die wall. Examples of groups of lubricants are magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, polyethylene glycol, stearic acid, hydrogenated vegetable oil, high melting point wax, sodium stearyl fumarate.

  Aspartame, saccharin sodium, dipotassium glycyridinate, stevia, thaumatin can be used as a sweetening agent. These are used alone or in combination of two or more.

  The method for producing an orally disintegrating tablet according to the present invention comprises a wet preparation of a first mixture comprising an active ingredient for treating dysuria and / or related diseases having an average particle diameter in the range of 0.5 to 40 μm. The first step of producing granules by granules, and the amount of granules, disintegrant in the tablet in an amount of 15% (weight / weight) or more (where the average particle diameter of the disintegrant is in the range of 105 to 220 μm). And preparing a second mixture comprising water-insoluble cellulose at 15% (weight / weight), after which the second mixture is compressed into tablets in a third step.

  Methods for processing active ingredients to particle diameters within the scope of the present invention are well known in the art. Various methods of pulverization and pulverizers including, for example, pin mill pulverizers, ball mill pulverizers and hammer mill pulverizers are available. Further processing for a uniform particle diameter can be carried out, for example, by sieving.

  The dry excipient and finely ground active ingredient are mixed in a suitable mixer, preferably a mixer capable of performing both mixing and granulation, for example a Gral high shear mixer. General mixing methods are described in Pharmaceutical Dosage Forms (Volume 2). Edit. H. A. Lieberman, L.M. Lachman, J .; B. Schwartz (1990), Marcel Dekker Inc. New York and Basel pages 1-71.

  Granules can be prepared by dry granulation and wet granulation. In dry granulation, a mixture of dry excipients and active ingredients, and optionally a lubricant (eg, magnesium stearate or stearic acid) is compressed, preferably using slugging or roller condensate. After compression, a plate or disk of the mixture is obtained, which is optionally ground into dry granules.

  A preferred method of preparing the granules is wet granulation. A mixture comprising the granulating liquid, binder and finely ground active ingredient is prepared and the wetted material is dried. A common method for preparing granules is for example Pharmaceutical Dosage Forms: Tablets (Volume 1). Edit. H. A. Lieberman, L.M. Lachman, J .; B. Schwartz (1989), Marcel Dekker Inc. New York and Basel pages 131-190.

  The advantages of wet granulation include powder agglomeration and compressibility, good distribution of finely divided or finely ground active ingredients and homogeneous content, most reduction of contamination from dust and air, ingredients Includes prevention of segregation.

  The total amount of disintegrant can be added to the granulation just before compression, can be added to the total amount of powdered material before the wet granulation process occurs, or simply added before wet granulation Can be divided into one part to be added and one part added to the granules in a dry state.

  Tableting and other solid or dry drug preparation methods are well known. For example, in the standard English text, Gennaro et al., Remington's Pharmaceutical Sciences, (see 20th edition, Mack Publishing Company, 2000, in particular, Part 5: Pharmaceutical Manufacturing, methods of making tablets, capsules and pills). Each component of is described.

  Granules and tablets prepared by granulation generally consist of several inert materials that can be found in conventional solid oral dosage forms. This component includes excipients that help provide satisfactory processing and compression property values for formulation, such as diluents, sugars and sugar alcohols, binders, lubricants, sweetening agents and lubricants, and disintegrants and It can be classified into excipients to give desirable physical property values such as color.

  The amount of water can vary and depends on the drying conditions used. However, tablets always contain a small amount of water, usually less than 10% by weight and preferably about 0.5 to 10% by weight.

  The invention is further illustrated by the following non-limiting examples.

  Rapid disintegrating tablets were prepared on a 1 kg scale with the compositions described in Table 1 (Batch A, B, C and D).

Particle Diameter Naftopidil and lactose milled mixture: Naftopidil was mixed with lactose (1: 1) and milled in a hammer mill. The average particle diameter of naphthopidyl in the pulverized mixture was 12 μm. This ground mixture was used in the production of batches A, B, C and D.

  The average particle diameter of the microcrystalline cellulose used (Avicel ph200) was 195 μm.

  The process for preparing Batch A was as follows. A portion of the ground mixture of naphthopidyl and lactose was transferred to a high shear mixer and dry mixed for about 1 minute. After mixing, the mixture was granulated with a 2 wt / wt% solution of HPC in water for about 7 minutes. The wet granulation was transferred to a fluid bed and dried for about 20 minutes at an inlet temperature of 60 ° C. until the desired water content was achieved. The dried lactose / naphthopidyl granules were then transferred into Comil and sieved to remove lumps. The sieved granules and other excipients were then transferred into Rhonrad and mixed for about 15 minutes. Finally, magnesium stearate was added to the mixture in Ronrad and mixed for about 2 minutes. Tablets were produced from the granule mixture using a rotary press.

  The process for preparing Batch B was as follows. Tablets were produced from portions of the ground mixture of naphthopidyl and lactose, after which the tablets were broken in a high shear mixer. The resulting mixture of naphthopidyl and lactose and other excipients was then transferred into Ron Rad and mixed for about 15 minutes. Finally, magnesium stearate was added to the mixture in Ronrad and mixed for about 2 minutes. Tablets were produced from the granule mixture using a rotary press.

  The process for preparing Batch C was as follows. A portion of the ground mixture of naphthopidyl and lactose was transferred to a high shear mixer and dry mixed for about 1 minute. After mixing, the mixture was granulated with a 2 wt / wt% solution of HPC in water for about 7 minutes. The wet granulation was transferred to a fluid bed and dried for about 20 minutes at an inlet temperature of 60 ° C. until the desired water content was achieved. The dried lactose / naphthopidyl granules were then transferred into Comil and sieved to remove lumps. The sieved granules and other excipients (including calcium silicate) were then transferred into Ron Rad and mixed for about 15 minutes. Finally, magnesium stearate was added to the mixture in Ronrad and mixed for about 2 minutes. Tablets were produced from the granule mixture using a rotary press.

  The process for preparing Batch D was as follows. A portion of the ground mixture of naphthopidyl and lactose was transferred to a high shear mixer and dry mixed with polyethylene glycol for about 1 minute. After mixing, the mixture was granulated at a high 600 rpm where the polyethylene glycol melted and formed granules. When the desired granule size distribution was obtained, the granules were allowed to cool and the polyethylene glycol solidified. The granules were then transferred into a comil and sieved to remove lumps. The sieved granules and other excipients were then transferred into Ron Rad and mixed for about 15 minutes. Finally, magnesium stearate was added to the mixture in Ronrad and mixed for about 2 minutes. Tablets were produced from the granule mixture using a rotary press.

  The disintegration time for all formulations was within 20 seconds according to tests described in US Pharmacopeia 701. The physical properties of the produced tablets are shown in Table 2.

  The method for producing a rapidly disintegrating tablet according to the present invention is a dry mixing method. Preferred methods of manufacture are melt granulation and dry mixing / smashing and wet granulation with the addition of calcium silicate. The most preferred method of preparing fast disintegrating tablets according to the present invention is a wet granulation method.

  Production of rapidly disintegrating tablets of 108 kg scale by wet granulation method.

  As in Example 1, a rapidly disintegrating tablet according to the present invention with a batch size of 108 kg was produced with the composition described in Table 3. Naftopidyl was mixed with lactose and ground in a hammer mill. Subsequently, the ground mixture was transferred into a high shear mixer (Gral. 300) and dry mixed for about 1 minute. After mixing, the mixture was granulated with a 2 wt / wt% solution of HPC in water for about 6 minutes. The wet granulate was transferred to a fluid bed dryer (FLO 120) and dried at an inlet temperature of 60 ° C. until the desired moisture content was reached. The naphthopidyl / lactose mixture was then transferred along with other excipients to a sieve device (Comil conical sieve) and sieved to remove lumps. The ground mixture of naphthopidyl and lactose was then transferred to a V blender (V-300) and mixed for about 15 minutes. Finally, magnesium stearate was added to the mixture in the V blender and mixed for about 3 minutes. Tablets were manufactured from the granules using a rotary press (Libra (Kikusui) tableting press). Tablets containing naphthopidyl 50 and 75 mg were prepared.

  The physical properties of the produced tablets are shown in Table 4.

  The feel and taste of the solid residue in the mouth upon administration was tested on the rapidly disintegrating tablets produced by the formulation of Example 2. Batch E, F and G tablets were compressed with different tableting pressures (Table 5). The tablets were put on the tongues of six healthy adult men as panelists. After disintegrating on the tongue, the feel and bitterness of the solid residue in the mouth upon administration was evaluated.

No feel of solid residue in mouth: None Slight feel of solid residue in mouth: S
Mouth feel of solid residue in mouth: Yes Bitterness: No Slight bitterness: S
Significant bitterness: A certain average is calculated from the results obtained and shown in Table 5.

Claims (13)

An active ingredient having a hardness of 30 N or more and a disintegration time of 50 seconds or less, and an average particle diameter in the range of 0.5 to 40 μm for treating dysuria and / or related diseases, and Containing disintegrant in an amount of 15 to 60% (weight / weight) in the tablet;
An orally disintegrating tablet, wherein the disintegrant has an average particle diameter in the range of 105 to 220 μm.   The orally disintegrating tablet of claim 1, wherein the disintegrant has an average particle diameter in the range of 150 to 210 μm.   The orally disintegrating tablet of claim 1, wherein the disintegrant has an average particle diameter in the range of 160 to 200 μm.   The orally disintegrating tablet according to any one of claims 1 to 3, wherein the amount of the disintegrant in the tablet is 25 to 50% (weight / weight).   The orally disintegrating tablet according to any one of claims 1 to 4, wherein the amount of disintegrant in the tablet is 35 to 45% (weight / weight).   6. The disintegrant according to any one of claims 1 to 5, wherein the disintegrant comprises a water-insoluble cellulose consisting essentially of purified cellulose or consisting essentially of organically modified cellulose, and a superdisintegrant. Orally disintegrating tablets.   The orally disintegrating tablet according to claim 6, wherein the water-insoluble cellulose is microcrystalline cellulose.   The orally disintegrating tablet according to claim 6 or 7, wherein the super disintegrant is crospovidone.   The orally disintegrating tablet according to any one of claims 1 to 8, wherein the tablet comprises lactose.   The orally disintegrating tablet according to any one of claims 1 to 9, wherein the active ingredient is naphthopidyl.   The orally disintegrating tablet according to any one of claims 1 to 10, which is obtained by producing granules containing an active ingredient, preparing a mixture containing the granules and a disintegrant, and compressing the mixture into tablets.   12. An orally disintegrating tablet according to claim 11, wherein the granules are produced by wet granulating a finely divided mixture comprising the active ingredient and a water soluble diluent.   In a first step, the granules are produced by wet granulation of a first mixture having an active ingredient for treating dysuria and / or related diseases and having a particle diameter in the range of 0.5 to 40 μm, In a second step, a second mixture comprising the granules and 15% (weight / weight) or more disintegrant in a tablet is prepared, and the average particle diameter of the disintegrant ranges from 105 to 220 μm. The method for producing an orally disintegrating tablet according to any one of claims 1 to 12, wherein the second mixture is compressed into a tablet in the third step.