HK1036220B - Multiple-unit sustained release tablets - Google Patents
Multiple-unit sustained release tablets Download PDFInfo
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- HK1036220B HK1036220B HK01106865.8A HK01106865A HK1036220B HK 1036220 B HK1036220 B HK 1036220B HK 01106865 A HK01106865 A HK 01106865A HK 1036220 B HK1036220 B HK 1036220B
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Description
Technical Field
The present invention relates to a multiple unit sustained release tablet comprising a granule portion and a powder portion.
Background
The pharmaceutical preparation controlling the dissolution rate of the active ingredient can be divided into a single unit pharmaceutical preparation and a multiple unit pharmaceutical preparation. The single unit pharmaceutical preparation is mainly in the form of tablets, and the multiple unit pharmaceutical preparation is mainly in the form of capsules or granules. The multiple unit pharmaceutical formulation is superior to the single unit pharmaceutical formulation in the following characteristics: (1) less change in absorption of the active ingredient, (2) more reproducible dissolution, and (3) applicability to two or more active ingredients. Due to these excellent properties, multiple unit pharmaceutical formulations are desirable as sustained release formulations. Multiple unit pharmaceutical formulations in the form of tablets are preferred over multiple unit pharmaceutical formulations in the form of capsules or granules because tablets are easier to take.
However, the conventional multiple unit sustained-release tablet is prepared by the following method: the core granules are coated with a drug layer, the surface of the coated granules is coated with a controlled-release agent to form sustained-release granules, and the granules are mixed with a powder portion and then compressed into tablets. During compression into tablets, the sustained release film of the granules often breaks, making it difficult to control the dissolution of the drug. In order to solve these problems, there have been proposed multiple-unit tablets comprising indefinite-form granules consisting of uncoated granules containing ｃA low-melting oil or fat and an active ingredient, and ｃA controlled-release film (JP- ｃA-7-316042), or sustained-release compressed tablets prepared by tableting ｃA large number of microcapsules consisting of fine particles of an active ingredient coated with ｃA sustained-release polymeric composition, wherein the microcapsules have an inconsistent particle diameter of between about 5 μm and about 400 μm and are immediately disintegrable in an aqueous solution to disperse into individual microcapsules (japanese patent No. 2601660). However, the prior art sustained-release granules have uncertainty, and the uneven shape makes it difficult to coat them with a uniform coating film, and to prepare sustained-release tablets having a stable dissolution rate.
The object of the present invention is to provide a multiple unit sustained-release tablet which shows little change in dissolution rate due to compression during the tabletting step.
Disclosure of the invention
We have found that the above problems can be solved by using particles comprising a matrix composed of a water-insoluble polymer and an active ingredient (hereinafter, referred to as matrix particles), or the matrix particles further coated with a controlled-release film (hereinafter, referred to as coated particles), thereby completing the present invention.
More specifically, the present invention includes the following inventions:
(1) a multiple unit sustained release tablet characterized in that the tablet is composed of a granule part and a powder part, each granule in the granule part comprising a matrix composed of a water-insoluble polymer and an active ingredient.
(2) The multiple unit sustained-release tablet according to (1), wherein the granules comprise core granules and a matrix layer composed of a water-insoluble polymer and an active ingredient for coating the core granules.
(3) The multiple unit sustained-release tablet according to (1) or (2), wherein the weight ratio of the water-insoluble polymer to the active ingredient is from 0.7: 1 to 3: 1.
(4) The multiple unit sustained-release tablet according to any one of (1) to (3), wherein the water-insoluble polymer is ethyl cellulose.
(5) The multiple unit sustained-release tablet according to (4), wherein the ethylcellulose has a viscosity of not less than 15cps when dissolved in a mixed solution of toluene and ethanol (8: 2w/w) at 5% by weight at 25 ℃.
(6) The multiple unit sustained-release tablet according to any one of (1) to (5), wherein the granules are coated with a controlled-release film.
(7) The multiple unit sustained-release tablet according to (6), wherein the controlled-release film is a water-insoluble polymer.
(8) The multiple unit sustained-release tablet according to (6) or (7), wherein the water-insoluble polymer is ethyl cellulose.
(9) The multiple unit sustained-release tablet according to any one of (6) to (8), wherein the granule has a granule strength of not less than 3000g/mm when the granule is not coated with the controlled-release film2。
The water-insoluble polymer used in the present invention refers to a water-insoluble polymer used as a sustained-release coating agent, an enteric coating agent, a gastric coating agent, and the like in the pharmaceutical field, and includes, for example, ethyl cellulose, purified shellac, white shellac, aminoalkyl methacrylate copolymer RS, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate-succinate, carboxymethylethylcellulose, cellulose acetate-phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, and the like, among which ethyl cellulose is most preferable.
The type, substitution degree, and molecular weight of the water-insoluble polymer are preferably selected for proper use according to the solubility of the active ingredient in water or alcohol, the desired sustained-release level, and the like. These water-insoluble polymers may be used alone or in combination. Hydrogenated oil, stearic acid, cetyl alcohol, etc. may also be added as coating auxiliary agents, and medium-chain fatty acid triglyceride, triacetin, triethyl citrate, cetyl alcohol, etc. may also be added as plasticizers.
The ethylcellulose used in the present invention preferably has an ethoxy content of from 43 to 50% (degree of substitution of from 2.2 to 2.6). For the practice of the present invention, the ethylcellulose has a viscosity of not less than 15cps, more preferably 20 to 50cps when dissolved in a mixed solution of toluene and ethanol (8: 2w/w) at 5% by weight at 25 ℃.
The solvent for the water-insoluble polymer may vary depending on the type of polymer. Mixtures of water and lower alcohols or lower alcohols are generally preferred. For ethyl cellulose, an aqueous ethanol solution of 60% or more is preferable. The water-insoluble polymer must be soluble in such a solvent, and the active ingredient must be soluble or uniformly dispersed in the water-insoluble polymer solution. When the active ingredient is in a dispersed form, in order to improve adhesion to the core particles and ensure uniformity, it is effective to maintain the average particle diameter below 20 μm and to perform sufficient stirring to achieve uniformity.
The present invention can be applied to various active ingredients including water-soluble drugs by changing the type of water-insoluble polymers or the mixing ratio thereof, or by additionally coating the matrix particles with a controlled-release film. Therefore, the kind of the active ingredient usable in the present invention is not particularly limited. Examples of active ingredients that can be used in the present invention are as follows: diprophylline, dextromethorphan hydrobromide, phenylpropanolamine hydrochloride, belladonna (total) alkaloid, paracetamol, theophylline, sodium salicylate, aspirin, ibuprofen, noscapine, dl-methylephedrine hydrochloride, dihydrocodeine phosphate, ethenzamide, bromhexine hydrochloride, d-chlorpheniramine maleate, aminophylline, propylhydrotheophylline, caffeine and the like. These active ingredients may be used in combination of two or more.
According to the present invention, the dissolution rate of the active ingredient can be freely controlled depending on the solubility of the active ingredient in water, the type of the water-insoluble polymer forming the matrix particles, the mixing ratio of the water-insoluble polymer to the active ingredient, and other factors. The dissolution rate of the active ingredient can also be controlled by changing the composition of the solvent used to dissolve the water-insoluble polymer. The mixing ratio of the water-insoluble polymer forming the matrix particle and the active ingredient is appropriately selected within the range in which the dissolution of the active ingredient can be controlled, and the ratio thereof is usually 0.7: 1 to 3: 1, preferably 0.75: 1 to 1.25: 1, wherein the ratio is a weight ratio. In the preparation according to the present invention, the amount of the water-insoluble polymer added to the matrix particles is preferably 3 times or less than 3 times that of the active ingredient. However, if it is difficult to secure a desired dissolution rate of the active ingredient using the amount, the dissolution rate of the active ingredient can be more efficiently controlled by coating the matrix granules with a controlled-release film. In this case, the particle strength of the matrix particles is maintained at preferably not less than 3000g/mm2More preferably not less than 3500g/mm2. This results in coated granules that are hardly broken during mixing with the powder fraction and compression into tablets. Thus reducing the variation in the dissolution rate of the coated particles.
The particle strength can be controlled by selecting the type, substitution degree and molecular weight of the water-insoluble polymer used, and appropriately selecting the mixing ratio of the water-insoluble polymer and the active ingredient.
The following examples illustrate embodiments of the present invention, but the present invention is not limited thereto.
If it is desired to control the dissolution of the active ingredient contained in the matrix granules in a short time or if it is desired to control the dissolution of the active ingredient slightly dissolved in water or alcohol, the matrix granules can be used in their own form because the dissolution can be easily controlled without coating them with a controlled-release film. On the other hand, if it is desired to control the dissolution of the active ingredient contained in the matrix granules over a long period of time, it is necessary to coat the granules with a controlled-release film in an amount suitable for the desired dissolution rate. The controlled-release film usable in the present invention comprises a water-insoluble polymer such as the above-exemplified water-insoluble polymers, and ethyl cellulose is preferable.
The core particles optionally used for the matrix particles may be spherical particles of crystalline cellulose or spherical particles of lactose-crystalline cellulose (e.g., Celphere; manufactured by Asahi Kasei Co., Ltd., Nonpareil; manufactured by Freund industries, Ltd.). The average particle diameter of the core particles is preferably 100-1000 μm.
Methods for preparing the matrix particles using the core particles include methods using a complex coating machine, a rotary fluidized coating machine, a fluidized bed coating machine, and the like. Granulation methods without using core particles include wet cylinder granulation using a kneader or granulator, and hot melt, stirred granulation using a leader Mixer, a HighSpeed Mixer, or the like. For coating the matrix granules with the controlled-release film, a conventional fluidized bed coating machine or vented pan coating machine or the like can be used. If desired, a curing operation may also follow. The curing operation is preferably carried out at a temperature of 70 ℃ or higher.
The powder portion as used in the present invention means a portion containing a component other than the active ingredient (drug) and, if necessary, the same and/or different active ingredient as the active ingredient contained in the matrix particles, and the powder portion can be disintegrated immediately after administration so that the active ingredient (drug, if contained) starts to dissolve. The component other than the active ingredient (drug) may be an excipient, a disintegrant, a lubricant, etc. which are commonly used in tablets, such as microcrystalline cellulose, light silicic anhydride, low-substituted hydroxypropylcellulose, lactose, corn starch, magnesium stearate, etc., and they may be used in a mixture.
In the tablet of the present invention, the weight mixing ratio of the granule portion to the powder portion is preferably 1: 0.5 or more. If the proportion of the powder portion is less than 0.5, rapid disintegration into sub-units may be prevented or the workability of the tablet may be deteriorated due to the contact of the granule portions with each other. There is no upper limit for the amount of powder fraction used. There is no particular limitation in mixing the granule portion with the powder portion and compressing into tablets, and it can be carried out according to a conventional method using any conventional mixer or tablet press. The present invention can provide sustained-release tablets with little change in dissolution rate even when a higher pressure is used. The pressure used is generally not less than 0.6t, preferably from 1.0 to 2.5 t.
Brief description of the drawings
FIG. 1 shows the results of dissolution test of the sustained-release granules and tablets prepared in example 1.
FIG. 2 shows the results of dissolution testing of the sustained-release granules and tablets prepared in example 2.
FIG. 3 shows the results of dissolution test of the sustained-release granules and tablets prepared in example 3.
FIG. 4 shows the results of dissolution testing of the sustained release granules and tablets prepared in example 4.
FIG. 5 shows the results of dissolution testing of the sustained-release granules and tablets prepared in example 5.
FIG. 6 shows the results of dissolution test of the sustained-release granules and tablets obtained in comparative example 1.
FIG. 7 shows the results of dissolution test of the sustained-release granules and tablets obtained in comparative example 2.
FIG. 8 shows the results of dissolution test of the sustained-release granules and tablets obtained in comparative example 3.
FIG. 9 shows the results of dissolution test of the sustained-release granules and tablets obtained in comparative example 4.
FIG. 10 shows the results of dissolution test of the sustained-release granules and tablets obtained in comparative example 5.
Best mode for carrying out the invention
The present invention is illustrated in more detail by the following examples and test examples.
Example 1
500g of diprophylline was dispersed in 4000g of 95% ethanol, and the dispersion was milled with a colloid mill to adjust the average particle diameter so as not to exceed 20 μm. Then, 500g of ethyl cellulose (having a viscosity of 20cps when dissolved in a toluene-ethanol mixed solvent (8: 2w/w) at 5% by weight at 25 ℃ and an ethoxy content of 48.0 to 49.5% (degree of substitution of 2.41 to 2.51)) (hereinafter referred to as "ethyl cellulose-20 cps") was dissolved in the dispersion. The thus-prepared dispersion was then coated on 1000g of core particles (Celphere CP-305) by a bottom spray type fluidized bed coater (Powrex co., ltd., GPCG-1) to prepare matrix particles (ethylcellulose: diprophylline ═ 1: 1 (w/w)). A part of the thus-prepared matrix granules was mixed with a part of granules for molding prepared by granulating a powder part obtained by mixing lactose and corn starch in a ratio of 7: 3, using a fluidized bed granulator (Freund industries, model FLO-1), 571.4g of 7% hydroxypropylcellulose/purified water to 800g of lactose. Magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5t pressures) to produce tablets weighing 290mg per tablet.
Example 2
500g of dextromethorphan hydrobromide and 500g of ethylcellulose, which has a viscosity of 45cps when dissolved in a toluene-ethanol mixed solvent (8: 2w/w) at 5% by weight at 25 ℃ and an ethoxy content of 48.0 to 49.5% (degree of substitution of 2.41 to 2.51) (hereinafter referred to as "ethylcellulose-45 cps"), were dissolved in 9000g of 95% ethanol. The thus-prepared solution was then coated on 1000g of core particles (Celphere CP-305) by a bottom spray type fluidized bed coater (Powrex co., ltd. production, GPCG-1) to prepare matrix particles (ethylcellulose: dextromethorphan hydrobromide 1: 1 (w/w)). A part of the thus-prepared matrix particles was mixed with a part of the particles for molding prepared in the same manner as described in example 1. Magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5t pressures) to produce tablets weighing 290mg per tablet.
Example 3
The substrate particles prepared in example 2 were coated with a coating solution prepared by dissolving 300g of ethylcellulose-20 cps and 15g of triethyl citrate in 7185g of 76% ethanol by a bottom spray type fluidized bed coater (Powrex co., ltd., product, GPCG-1) to prepare coated particles. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
Example 4
The matrix solution was prepared by dissolving 600g phenylpropanolamine hydrochloride and 600g ethylcellulose-20 cps in 8800g 76% ethanol. The thus-prepared matrix solution was coated on 1000g of core particles (Celphere CP-305) by a bottom spray type fluidized bed coater (powrexco, ltd. production, GPCG-1) to prepare matrix particles (ethylcellulose: phenylpropanolamine hydrochloride ═ 1: 1 (w/w)).
The coating solution was prepared by dissolving 440g of ethylcellulose-20 cps and 22g of triethyl citrate in 10537g of 76% ethanol. The coating solution thus prepared was applied to the base particles using a bottom spray type fluidized bed coating machine (Powrex co., ltd., GPCG-1) to prepare coated particles. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
Example 5
Coated granules having the compositions described in table 1 were prepared in the same manner as shown in example 4. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
Comparative example 1
Matrix particles having the compositions shown in table 2 were prepared in the same manner as described in example 1. A part of the thus-prepared matrix granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (under pressures of 1.5t and 2.5 t), to prepare tablets weighing 290mg per tablet.
Comparative example 2
Matrix particles having the compositions shown in table 2 were prepared in the same manner as described in example 2. A part of the thus-prepared matrix granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (under pressures of 1.5t and 2.5 t), to prepare tablets weighing 290mg per tablet.
Comparative example 3
1129g of phenylpropanolamine hydrochloride and 71g of hydroxypropyl cellulose (hydroxypropyl cellulose content 53.4-77.5%) were dissolved in 2188g of purified water. This solution was coated on 1000g of core particles (Celphere CP-305) by a bottom spray type fluidized bed coater (Powrex Co., Ltd., manufactured by GPCG-1) to prepare uncoated particles. 440g of ethylcellulose-20 cps and 22g of triethyl citrate were then dissolved in 10531g of 76% ethanol, and the resulting solution was applied to uncoated granules to prepare coated granules. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
Comparative example 4
Coated granules having the compositions shown in table 2 were prepared in the same manner as described in example 3. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
Comparative example 5
Coated granules having the compositions shown in table 2 were prepared in the same manner as described in example 3. A part of the thus-prepared coated granules was mixed with a part of the granules for molding prepared in the same manner as described in example 1, magnesium stearate was added to the mixture in an amount of 0.2%, and the resulting mixture was compressed into tablets using a rotary tablet press (at 1.5t and 2.5 t) to prepare tablets weighing 290mg per tablet.
The formulations of the examples and comparative examples are summarized in tables 1 and 2.
TABLE 1
| (Unit: gram) | Examples | ||||
| 1 | 2 | 3 | 4 | 5 | |
| Matrix particle Celphere CP-305 dihydroxypropyl theophylline hydrobromide dextromethorphan hydrochloride phenylpropanolamine ethyl cellulose-20 CPs ethyl cellulose-45 CPs 95% ethanol purified water | 1000500--500-4000- | 1000-500--5009000- | 1000-500--5009000- | 1000--600600-70401760 | 1000--600450-60001500 |
| Coating film ethyl cellulose-20 cps triethyl citrate 95% ethanol purified water | ---- | ---- | 3001557481437 | 4402284302107 | 4102078561964 |
TABLE 2
| (Unit: gram) | Comparative examples | ||||
| 1 | 2 | 3 | 4 | 5 | |
| Matrix particle Celphere CP-305 diprophylline hydrochloride phenylpropanolamine hydroxypropyl cellulose ethyl cellulose-7 CPs ethyl cellulose-45 CPs 95% ethanol purified water | 1000500--500-4000- | 1000-600--180033600- | 1000-112971---2188 | 1000-600-600-4800- | 1000-600--3005100- |
| Coating film ethyl cellulose-20 cps triethyl citrate 95% ethanol purified water | ---- | ---- | 4402284252106 | 4402284252106 | 3801972811820 |
Test example 1
The granules and tablets obtained in examples 1 to 5 and comparative examples 1 to 5 were subjected to dissolution test. The dissolution test was carried out according to dissolution measurement method 2 of the general measurement method of the Japanese pharmacopoeia.
The results of the dissolution test are shown in FIGS. 1 to 10.
Test example 2
The matrix granules (uncoated granules) prepared according to examples 1 to 5 and comparative examples 1 to 5 were subjected to a granule strength test. The test was performed using a GURANO pellet Strength tester (Ooka Seiki Co., Ltd.) using a 2kg pressure cell at a compression rate of 0.10 μm/sec. The pellet strength was calculated according to the following formula, wherein the weight of the load when the pellets were broken was defined as p (peak):
(particle Strength) ═ 2.8 p/(particle Cross-sectional area)
The test results are shown in tables 3 and 4.
TABLE 3 results of the Strength test of the particles of examples 1-5 (uncoated particles)]
| Examples | |||||
| 1 | 2 | 3 | 4 | 5 | |
| Particle Strength (g/mm)2) | 3,500 | 3,800 | 3,800 | 3,650 | 3,300 |
TABLE 4 results of the strength test of comparative examples 1-5 granules (uncoated granules)]
| Comparative examples | |||||
| 1 | 2 | 3 | 4 | 5 | |
| Particle Strength (g/mm)2) | 2,700 | 4,800 | 1,600 | 2,600 | 2,800 |
The above results reveal the following facts.
Matrix granules prepared with 1: 1 blend ratio of diprophylline and ethylcellulose-20 cps as a model drug allowed 50% dissolution of the active ingredient in 100 minutes and showed little change in dissolution rate due to tableting (example 1). On the other hand, the matrix granules prepared with diprophylline and ethylcellulose-7 cps at a mixing ratio of 1: 1 achieved 50% dissolution of the active ingredient in 30 minutes and showed an increase in dissolution rate due to tabletting (comparative example 1). The 50% dissolution time of the matrix granules of comparative example 1 was reduced compared to the matrix granules of example 1, which is considered to be due to the viscosity level of ethyl cellulose decreasing from 20cps to 7 cps. The increase in dissolution rate due to flaking is considered to be due to the fact that the particle strength of the matrix particles of example 1 was 3500g/mm2While the particle strength of the matrix particles of comparative example 1 was as low as 2700g/mm2。
Matrix granules prepared with 1: 1 ratio of dextromethorphan hydrobromide and ethylcellulose-45 cps as a model drug allowed 50% dissolution of the active ingredient in 60 minutes and showed little change in dissolution rate due to tableting (example 2). The coated granules prepared by coating the above matrix granules with 15% ethylcellulose-20 cps achieved 50% dissolution of the active ingredient in 180 minutes and showed little change in dissolution rate due to tableting (example 3).
Matrix granules prepared with phenylpropanolamine hydrochloride and ethylcellulose-45 cps at a mixing ratio of 3: 1 as a model drug allowed 50% dissolution of the active ingredient within 20 minutes and provided almost no satisfactory sustained release (comparative example 2). Coated particles prepared by coating matrix particles prepared by mixing ethylcellulose-45 cps and a drug in a mixing ratio of 1: 1 with 20% ethylcellulose-20 cps can achieve 50% dissolution of the active ingredient within 100 minutes and show little change in dissolution rate due to tableting (example 4).
Uncoated granules were prepared using a conventional binder (HPC-L) without ethyl cellulose and then coated with ethyl cellulose-20 cps to form coated granules. The coated granules showed 50% dissolution in 100 minutes, but the dissolution rate by tableting varied greatly (comparative example 3). The coated granules of examples 3 and 4 showed little change in dissolution rate due to tableting, while the granules of comparative example 3 showed great change. This is considered to be because the particle strength of the uncoated particles (matrix particles) of the former two was 3500g/mm, respectively2And 3500g/mm2And the particle strength of the latter is as low as 1600g/mm2。
In the coated granule (comparative example 4) prepared in the same manner as described in example 4 except that ethylcellulose-7 cps was used instead of ethylcellulose used in the uncoated granule (matrix granule), the 50% dissolution time of the coated granule was almost the same as that of the coated granule of example 4. However, the change in dissolution rate due to tableting was increased compared to the coated granules of example 4. This is probably because the granule strength of the sustained-release granules of comparative example 4 was as low as 2600g/mm2。
In the coated granules prepared in the same manner as described in example 3 except that the mixing ratio of ethylcellulose-45 cps to the drug for the uncoated granules (matrix granules) was changed to 0.75: 1, little change in dissolution rate due to tableting was exhibited (example 5). However, in the coated granules prepared in the same manner as described in example 3 except that the mixing ratio of ethylcellulose-45 cps to the drug for the uncoated granules (matrix granules) was changed to 0.5: 1, a somewhat increased change in dissolution rate by tableting was exhibited (comparative example 5). This is probably because the granule strength of the uncoated granule of example 5 was as high as 3300g/mm2While comparative example 5 uncoated pellets had a pellet strength as low as 2800g/mm2。
Industrial applicability
The multiple unit sustained-release tablet of the present invention is different from the conventional granules in which the surface of the active ingredient is coated with the sustained-release matrix because in the tablet of the present invention, each granule comprises a matrix composed of a mixture of a water-insoluble polymer and an active ingredient. This allows the granules of the invention to be hardly broken during mixing with the powder fraction and compression into tablets. Therefore, the dissolution rate changes little. In addition, coated granules prepared by coating uncoated granules (wherein the core-coated granules consist of a hard matrix) with a water-insoluble polymer can prevent the coating from being broken when compressed into tablets. Therefore, the tablet of the present invention can provide a stable dissolution rate.
Claims (7)
1. A multiple unit sustained release tablet characterized in that it is composed of a granule part and a powder part, each granule in the granule part comprising a matrix composed of a water-insoluble polymer and an active ingredient, the granule having a granule strength of 3000g/mm2Or above, the weight ratio of the water-insoluble polymer to the active component is 0.7: 1-3: 1.
2. The multiple unit sustained-release tablet according to claim 1, wherein the granules comprise a core granule and a matrix layer composed of a water-insoluble polymer and an active ingredient for coating the core granule.
3. The multiple unit sustained release tablet of any one of claims 1 to 2, wherein the water-insoluble polymer is ethyl cellulose.
4. The multiple unit sustained release tablet according to claim 3, wherein the ethylcellulose has a viscosity of 15cps or more when dissolved in a mixed solution of toluene and ethanol (8: 2w/w) at 5% by weight at 25 ℃.
5. The multiple unit sustained release tablet of claim 1, wherein the granules are coated with a controlled release film.
6. The multiple unit sustained release tablet according to claim 5, wherein the controlled release film is a water-insoluble polymer.
7. The multiple unit extended release tablet of claim 5, wherein said water insoluble polymer is ethyl cellulose.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP107349/1998 | 1998-04-17 | ||
| JP10734998 | 1998-04-17 | ||
| PCT/JP1998/003537 WO1999053905A1 (en) | 1998-04-17 | 1998-08-07 | Multiple-unit sustained release tablets |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1036220A1 HK1036220A1 (en) | 2001-12-28 |
| HK1036220B true HK1036220B (en) | 2005-02-18 |
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