JP2018104324A - Sustained-release preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a sustained-release preparation that controls simultaneously the elution properties of a plurality of medicines having different characteristics.SOLUTION: A sustained-release preparation contains a sustained-release granule that has a nuclear particle containing two or more medicines that differ at least in water solubility, and, on the surface of the nuclear particle, a sustained-release coating containing an acrylic water-insoluble polymer, a cellulose water-insoluble polymer, glycerol fatty acid ester and talc.SELECTED DRAWING: None

Description

  The present invention relates to a sustained-release preparation, particularly a sustained-release preparation in which the dissolution properties of a plurality of drugs are controlled simultaneously.

  Sustained-release preparations are devised so that the drug is gradually released. Since the drug is gradually released and absorbed gradually, the drug concentration in the blood is kept constant over a long period of time. Can do. Therefore, it can prevent rapid increase in blood drug concentration and significant decrease in blood drug concentration until the next dose, so it can not only reduce the number of daily doses but also reduce side effects. Can be sustained, improve compliance, stabilize and improve the effects, and maintain good adherence.

  As a sustained-release preparation of a pharmaceutical containing a plurality of drugs such as a rhinitis drug, (1) a sustained-release oral administration composition having a matrix core containing pseudoephedrine sulfate and a coating layer containing loratadine (Patent Document 1) (2) Oral rhinitis treatment composition containing pseudoephedrine as a sustained release matrix and ketotifen fumarate (Patent Document 2), (3) Slow release of decongestants such as prideephedrine and phenylpropanolamine A single oral dosage formulation containing antihistamines once a day (Patent Document 3), (4) Particles with a core containing a weakly basic drug and a sustained release coating are produced for each drug. A sustained-release preparation (Patent Document 4) that has been mixed is reported.

Japanese translation of PCT publication No. 8-502516 JP 2004-143160 A JP 2012-82212 A Japanese Patent Laying-Open No. 2015-98477

However, as in Patent Documents 1 and 2, the matrix-controlled release means has a problem that mechanical external force such as chewing and the like affects the dissolution property, and the designed release property cannot be obtained. Patent Document 3 does not describe any sustained release means. As in Patent Document 4, when a sustained release coating is applied to each of a plurality of drugs, the production process becomes complicated, the production cost increases, and a stable quality sustained release formulation cannot be obtained. there were.
Therefore, an object of the present invention is to gradually release a plurality of drugs having different properties, and the dissolution properties of these drugs are controlled in the same manner without being affected by changes in the oral cavity and digestive tract environment. The object is to provide a sustained-release preparation having releasability.

  Therefore, the present inventor has conducted various studies on means for sustained release of pseudoephedrine and dl-methylephedrine that are easily soluble in water and belladonna total alkaloids that are hardly soluble in water. Sustained-release granulated product containing drug in one core particle and coated on the particle surface with sustained-release film containing acrylic water-insoluble polymer, cellulose-based water-insoluble polymer, glycerin fatty acid ester and talc As a result, the elution properties are not affected by mechanical forces such as changes in the digestive tract environment such as pH, ion concentration, wetting characteristics, and chewing, and the elution properties of the plurality of drugs are controlled to be the same. The inventors have found that a releasable preparation can be obtained and completed the present invention.

  That is, the present invention provides the following [1] to [12].

[1] A sustained-release film containing an acrylic water-insoluble polymer, a cellulose-based water-insoluble polymer, a glycerin fatty acid ester and talc is provided on the surface of the core particle containing at least two types of drugs having different solubility in water. A sustained-release preparation containing a sustained-release granulated product.
[2] At least two kinds of drugs having different solubility in water are medicinal ingredients including pseudoephedrine or a salt thereof, and one or two kinds selected from dl-methylephedrine or a salt thereof, and a belladonna total alkaloid. A sustained-release preparation according to [1].
[3] At least two kinds of drugs having different solubility in water are medicinal ingredients including pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, and a belladonna total alkaloid [1] or [2] Sustained release formulation.
[4] The sustained-release preparation according to any one of [1] to [3], wherein the sustained-release film is a sustained-release film containing an ammonioalkyl methacrylate copolymer, ethyl cellulose, glycerin fatty acid ester and talc.
[5] The ammonioalkyl methacrylate copolymer is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride, and is a mixture of two types of copolymers having different contents of trimethylammonioethyl methacrylate chloride. 4] The sustained-release preparation according to the above.
[6] The sustained release preparation according to any one of [1] to [5], wherein the particles further contain a saccharide selected from a disaccharide and a sugar alcohol.
[7] The sustained release preparation according to any one of [1] to [6], wherein the core particles further contain sucrose.
[8] The sustained-release preparation according to any one of [1] to [7], further comprising a fast-soluble granulated product.
[9] The sustained release preparation according to [8], wherein the fast-dissolved granulated product contains an antihistamine.
[10] The sustained-release granule according to [8], wherein the fast-dissolved granulated product is a fast-dissolved granule containing pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, a belladonna total alkaloid, and an antihistamine. Formulation.
[11] The antihistamine is one or more selected from epinastine, fexofenadine, levocetirizine, loratadine, olopatadine, ebastine, cetirizine, pranlukast, emedastine, azelastine, ketotifen and salts thereof [9] or [9] [10] The sustained-release preparation according to [10].
[12] The sustained release preparation according to any one of [1] to [11], which is a capsule, tablet or granule.

According to the present invention, it becomes possible to provide a sustained-release preparation with elution characteristics in which the release rate of a plurality of drugs does not change due to pH, ion concentration, stirring strength, mechanical stimulation, and wetting, and thus whether or not a meal is taken, Since it is less susceptible to influences between foods and drinks, solids, and individuals at the time of taking, since the drug acts stably and reliably, adherence is improved and the therapeutic effect of the drug can be maximized.
In addition, since multiple drugs are in the same core particle, there is no deviation in drug content, and multiple types of sustained-release parts are not required. Will be able to provide.
The sustained-release granule contains pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof and belladonna total alkaloid, and the fast-dissolved granule contains an antihistamine, pseudoephedrine or a salt thereof, dl-methylephedrine or The sustained-release preparation of the present invention containing the salt and the belladonna total alkaloid has an effect immediately after taking (about 5 minutes), and for a long time (12 to 24 hours), it is caused by pollen, house dust (indoor dust), etc. It can relieve nasal allergic symptoms such as sneezing, nasal congestion and nasal congestion, and is effective as a rhinitis drug that works immediately and works for a long time.

The influence by pH of the elution curve of pseudoephedrine hydrochloride is shown. The influence by pH of the elution curve of dl-methylephedrine hydrochloride is shown. The influence by pH of the elution curve of hyoscyamine in belladonna total alkaloid is shown. The influence by the ionic strength of the elution curve of pseudoephedrine hydrochloride is shown. The influence by the ionic strength of the elution curve of dl-methylephedrine hydrochloride is shown. The effect of ionic strength on the elution curve of hyoscyamine in belladonna total alkaloids is shown. The influence by the stirring intensity of the elution curve of pseudoephedrine hydrochloride is shown. The influence by the stirring intensity | strength of the elution curve of dl-methylephedrine hydrochloride is shown. The influence by the stirring intensity of the elution curve of hyoscyamine in the belladonna total alkaloid is shown. The influence by the mechanical stimulation of the elution curve of pseudoephedrine hydrochloride is shown. The influence by the mechanical stimulation of the elution curve of dl-methylephedrine hydrochloride is shown. The influence of mechanical stimulation on the elution curve of hyoscyamine in belladonna total alkaloids is shown. The influence by the wetting of the elution curve of pseudoephedrine hydrochloride is shown. The influence by the wetting of the elution curve of dl-methylephedrine hydrochloride is shown. The influence of wetting on the elution curve of hyoscyamine in belladonna total alkaloids is shown.

  The sustained-release preparation of the present invention comprises an acrylic water-insoluble polymer, a cellulose-based water-insoluble polymer, a glycerin fatty acid ester and talc on the surface of the core particle containing at least two kinds of drugs having different solubility in water. It contains a sustained-release granulated product having a sustained-release film.

The core particles in the sustained-release granulated product contain at least two kinds of drugs having different solubility in water. The plurality of drugs having different properties include a plurality of drugs having different water solubility, aqueous solution pH, crystal form, crystal water, molecular weight, molecular structure, acid (base) dissociation constant, oil-water partition coefficient, and the like. Although it is mentioned, it is preferable to use a plurality of drugs having different solubility in water that affects dissolution. In the present invention, the drug is a drug having a medicinal effect.
The plurality of drugs having different properties include a combination of one or two kinds of pseudoephedrine or a salt thereof easily soluble in water and dl-methylephedrine or a salt thereof, and a total belladonna alkaloid which is hardly soluble in water. Can be mentioned. More preferably, it is a drug containing three kinds of pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, and a belladonna total alkaloid.
Here, the pseudoephedrine salt includes pseudoephedrine hydrochloride. Examples of the salt of dl-methylephedrine include dl-methylephedrine hydrochloride. A particularly preferred drug combination is pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride and belladonna total alkaloid.

  The core particles containing these drugs contain these drugs and formulation additives. The formulation additive used for the core particles is preferably at least one selected from disaccharides and sugar alcohols from the viewpoint of making the dissolution properties of a plurality of drugs the same. Examples of the disaccharide include sucrose (sucrose), lactose, maltose and the like, and sucrose, particularly purified sucrose is preferable. Examples of the sugar alcohol include erythritol, xylitol, mannitol and the like. Among these saccharides, disaccharide is preferably used from the viewpoint of making the elution properties of a plurality of drugs the same, more preferably sucrose, and particularly preferably purified sucrose.

The total amount of the plurality of drugs in the core particles is preferably 20 to 60% by mass, more preferably 30 to 40% by mass, and further preferably 32 to 38% by mass.
Particularly preferred forms of the core particles include pseudoephedrine hydrochloride 10-20% by mass, dl-methylephedrine hydrochloride 10-20% by mass, belladonna total alkaloid 0.02-1.5% by mass, and sucrose 58.5-89. Preferably it is .98% by mass, pseudoephedrine hydrochloride 12-20% by mass, dl-methylephedrine hydrochloride 12-20% by mass, belladonna total alkaloid 0.05-1.2% by mass, and sucrose 58.8- More preferably, it is 75.95 mass%.

  The core particles of the preparation of the present invention can be produced by a conventional method such as rolling granulation, high-speed stirring granulation, extrusion granulation by measuring the plurality of drugs and formulation additives. The shape of the core particle is not particularly limited, but it is preferably a spherical or substantially spherical particle. In particular, rolling granulation is mentioned as an optimal manufacturing method. That is, rolling 1 mass part of the core of white sucrose spherical granules and spraying 4 parts by mass of powder composed of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, belladonna total alkaloid, and sucrose while spraying purified water. It is preferable to granulate into a spherical shape and dry in a fluidized bed or the like.

Pseudoephedrine hydrochloride is a white crystalline or crystalline powder sympathomimetic drug that has a molecular formula: C ₁₀ H ₁₅ NO · HC, molecular weight: 201.69, and is a water-soluble sympathomimetic drug that locally contracts blood vessels in the nasal mucosa. , Has the action of relieving nasal congestion. The daily blending amount is blended in the total amount of the sustained-release preparation of the present invention such that the sustained-release part and the fast-dissolving part are totaled to be 30 mg to 180 mg / day. Most preferably, it is 60 mg / day.

dl-Methylephedrine hydrochloride is a sympathomimetic excitatory drug of colorless crystals or white crystalline powder that has a molecular formula: C ₁₁ H ₁₇ NO · HCl, molecular weight: 215.72 and is easily dissolved in water. It has the action of calming coughing while removing breathlessness. The daily compounding amount is 22 mg to 110 mg / day in the total amount of the sustained-release preparation of the present invention. Most preferably, it is 60 mg / day.

The belladonna total alkaloid is a total alkaloid obtained by purifying an extract extracted from rhizome of the solanaceous plant: belladonnacone with water or water-containing ethanol, and is a white crystal or crystalline powder that is hardly soluble in water. It is a parasympatholytic agent containing hyoscyamine (atropine) and scopolamine, which are anticholinergic components, and has the effect of decreasing secretion of nasal fluid and tears. Further, belladonna total alkaloids, with respect to the dry matter in terms, hyoscyamine (molecular formula: C ₁₇ H ₂₃ NO _3, molecular weight: 289.37) 95.0 to 99.0%, scopolamine (molecular formula: C ₁₇ H ₂₁ NO ₄ , molecular weight: 303.35) 1.3-3.9% and total alkaloids (hyoscyamine and scopolamine) 99.0-102.0%. The daily compounding amount is 0.12 mg to 0.6 mg / day in the total amount of the sustained-release preparation of the present invention. Most preferably, it is 0.3 mg / day.

  The sustained-release film covering the surface of the core particles contains an acrylic water-insoluble polymer, a cellulose water-insoluble polymer, a glycerin fatty acid ester and talc. By coating the core particles with a sustained-release film containing these four components, even if a plurality of drugs having different properties are contained in the core particles, the dissolution properties of these drugs are made the same. Can do.

Examples of the acrylic water-insoluble polymer include ammonioalkyl methacrylate copolymers. Ammonioalkyl methacrylate copolymers include copolymers of alkyl acrylates, alkyl methacrylates and trialkylammonioalkyl methacrylate halides, with copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride being more preferred. Furthermore, it is more preferable to use a mixture of copolymers of alkyl acrylate, alkyl methacrylate and trialkyl ammonio alkyl methacrylate chloride, wherein the contents of the trialkyl ammonio alkyl methacrylate halides are different. More preferred is a mixture of two copolymers of ethyl acrylate, methyl methacrylate and trimethylammonio methacrylate chloride, wherein the contents of trimethylammonioethyl methacrylate chloride are different.
Examples of commercially available acrylic water-insoluble polymers include ammonioalkyl methacrylate copolymer type A and ammonioalkyl methacrylate copolymer type B. A mixture of ammonioalkyl methacrylate copolymer type A and ammonioalkyl methacrylate copolymer type B is used. Is preferred. Examples of commercially available products include EUDRGIT (registered trademark) RS type A and EUDRAGIT (registered trademark) RS type B.
The mass ratio of ammonioalkyl methacrylate copolymer type A and ammonioalkyl methacrylate copolymer type B is preferably 0.1: 99.9 to 5:95, and most preferably 1:99.
The content of the acrylic water-insoluble polymer in the sustained-release film is preferably 76 to 90% by mass, more preferably 80 to 85% by mass, and further 81.9% by mass. Is more preferable.

As the cellulose water-insoluble polymer, alkyl cellulose is preferable, and ethyl cellulose is more preferable. Further, ethyl cellulose having a property of a viscosity of 9 to 11 mPa · s (5% solution, 25 ° C., toluene: ethanol = 8: 2) containing 48.5 to 49.5% of ethoxy groups is particularly preferable.
The content of the cellulose-based insoluble polymer in the sustained-release film is preferably 6 to 10% by mass, more preferably 7 to 9% by mass, and still more preferably 8.1% by mass.

Glycerin fatty acid ester is one in which fatty acids are ester-bonded to one to two of the three hydroxy groups of glycerin. Here, as for carbon number of the constituent fatty acid of glycerol fatty acid ester, 8-20 are preferred. The glycerin fatty acid ester used in the present invention is preferably a liquid product at room temperature having a degree of acetylation of 96% or more and a melting point of about 4 to 12 ° C. produced using vegetable oil such as soybean oil as a raw material fat and oil, its hydroxyl value: 0 to 15, Saponification value: 370-382, acid value: 3, iodine value: 43-53.
1-5 mass% is preferable, as for content of the glycerol fatty acid ester in a sustained-release film | membrane, 3-4 mass% is more preferable, and 3.75 mass% is further more preferable.

The average particle diameter of talc is preferably 0.1 to 20 μm, more preferably 1 to 12 μm, and further preferably 2 to 8 μm. Further, the particle size of talc is preferably 0.3% by mass or less when the particle size exceeds 45 μm (that does not pass through a sieve having an opening of 45 μm).
The content of talc in the sustained-release film is preferably 3 to 9% by mass, more preferably 5 to 7% by mass, and further preferably 6.25% by mass.
The amount of the sustained-release coating varies depending on the particle size and shape of the core particles containing the drug, and is appropriately increased or decreased. However, when the average particle size of the core particles is 500 to 1000 μm, the core particle 100 containing the drug is used. It is preferable that it exists in 5-20 mass parts with respect to a mass part, 7.5-15 mass parts is more preferable, and 11.8 mass parts is further more preferable.
The sustained-release granulated product is prepared by weighing each component of the sustained-release film by a conventional method, dissolving and dispersing it in a solvent such as alcohol to adjust the coating liquid, and causing the core particles to flow in the fluidized bed coating apparatus. It can be produced by spray coating the coating liquid.

In the sustained-release preparation of the present invention, the dissolution property of a plurality of drugs in the sustained-release granulated product is controlled to be the same, but the dissolution property is controlled in combination with a fast-dissolved granulated product. preferable.
It is preferable that the fast-melting granulated product contains a drug used in combination with a plurality of drugs contained in the sustained-release granulated product. When the drug in the sustained-release granule is a drug containing pleuephedrine or a salt thereof and one or two selected from dl-methylephedrine or a salt thereof and a belladonna total alkaloid, fast dissolving The granulated product preferably contains an antihistamine, and more preferably contains an antihistamine, pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, and a total belladonna alkaloid.

As the antihistamine, it is preferable to use an antihistamine that is administered once a day or twice a day. Specific examples include one or more selected from epinastine, fexofenadine, levocetirizine, loratadine, olopatadine, ebastine, cetirizine, pranilcast, emedastine, azelastine, ketotifen, and salts thereof. In addition, epinastine hydrochloride, fexofenadine hydrochloride, levocetirizine hydrochloride, cetirizine hydrochloride, loratadine, ebastine, olopatadine hydrochloride, pranlukast hydrate, emedastine fumarate, azelastine hydrochloride, ketotifen fumarate Of these, epinastine hydrochloride, fexofenadine hydrochloride, levocetirizine hydrochloride, cetirizine hydrochloride, loratadine, and ebastine are more preferable. One or more of these can be mixed and used.
The daily blending amount is blended as follows when blending alone. Epinastine hydrochloride is preferably 5 to 20 mg, more preferably 10 to 20 mg. 30-120 mg is preferable and, as for fexofenadine hydrochloride, 60-120 mg is more preferable. The levocetirizine hydrochloride is preferably 2.5 to 10 mg, more preferably 5 to 10 mg. Loratadine is preferably 5 to 10 mg, and more preferably 10 mg. Ebastine is preferably 2.5 to 10 mg, more preferably 5 to 10 mg. Cetirizine hydrochloride is preferably 5 to 10 mg, more preferably 10 mg. The olopatadine hydrochloride is preferably 5 to 10 mg, more preferably 10 mg. Pranlukast hydrate is preferably 225 to 450 mg, more preferably 450 mg. The emedastine fumarate is preferably 0.5 to 2 mg, more preferably 1 to 2 mg. The azelastine hydrochloride is preferably 1 to 2 mg, more preferably 2 mg. The ketotifen fumarate is preferably 1.38 to 2.76 mg, more preferably 2.76 mg.
The method for producing the immediate-release granulated product is not particularly limited, and it may be produced by a conventional method by adding a formulation additive as necessary to the drug. For example, a common formulation method (Tsusuke Tsuda and Toshi Ueno, “Pharmaceutical Development Basic Course XI Pharmaceutical Production Law (above), (below)”, Jinshokan, 1971; Nakano Yoshinobu Written, "Formulation Engineering Handbook", Jinshokan, published in 1983; Nakano Yoshinobu, "Latest Powder Material Design", Techno System, 1988; Arakawa Masafumi, "Pharmaceutical Development 11 And Machine ", Yodogawa Shoten, 1989; Mitsuru Hashida," Design and Evaluation of Orally Administered Products ", Pharmaceutical Industry Timeline, 1995, Mitsuru Hashida," Prescription Design of Orally Administered Products ", Pharmaceutical Industry Time Report発 行, published in 1995). In addition, when it is necessary to adjust the granulation powder, a commonly used granulation method (spray granulation method using a solution or dispersion containing water or an organic solvent, stirring granulation method, fluidized granulation method, rolling) For example, a wet granulation method such as a granulation method or a rolling fluidized granulation method, or a dry granulation method such as a compaction granulation method using a powdery binder.
The formulation additives used for the formulation include pharmaceutically acceptable carriers such as stabilizers, surfactants, lubricants, lubricants, solubilizers, buffers, sweeteners. , Base, adsorbent, flavoring agent, binder, suspending agent, antioxidant, brightening agent, perfume, coating agent, wetting agent, wetting regulator, filler, antifoaming agent, cooling agent , Flavoring agent / fragrance, colorant, tonicity agent, softening agent, emulsifier, thickening agent, foaming agent, pH adjusting agent, excipient, dispersant, disintegrant, disintegration aid, fragrance , Desiccants, preservatives, preservatives, solubilizers, solubilizers, solvents, fluidizing agents, etc. Specific examples of these formulation additives include, for example, bookbinding (Japan Pharmaceutical Additives Association, “Pharmaceutical Additives” The materials described in “Executive Encyclopedia 2016”, Pharmaceutical Daily Report, issued in 2016) can be used.

The sustained-release preparation of the present invention can be produced by adding a fast-dissolved granule to the sustained-release granule produced by the above-described method as necessary. Examples of the final dosage form include capsules, tablets, granules and the like.
Here, the tablets include ordinary tablets and OD tablets. Capsules include hard capsules and soft capsules (solid filling).

  Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1
Hard capsule 360 gram of pseudoephedrine hydrochloride, 360 g of dl-methylephedrine hydrochloride, 1.8 g of belladonna total alkaloids, and 958.2 g of purified white sugar were used to produce 1680 g of a spraying agent by a conventional method. 420 g of refined sucrose spherical granules (Nonparel 103) were put into a CF granulator, and sprayed with an ethanol-purified water mixture to granulate by spraying. The obtained granulated particles were dried with a fluidized bed dryer, and those passing through a No. 16 sieve and not passing through a No. 32 sieve were selected to obtain core particles.
2000 g of core particles are weighed and fluidized in a fluidized bed, ammonioalkyl methacrylate copolymer RS type A 0.108% by mass, ammonioalkyl methacrylate copolymer RS type B 9.72% by mass, ethyl cellulose 0.972% by mass, glycerin fatty acid ester 0 Spray coating liquid consisting of .45% by mass, talc 0.75% by mass, and JP JP 88% by mass until the increase in the mass of the core particles is 11.8%, followed by drying to obtain sustained release granules. .
Pseudoephedrine hydrochloride 240 g, dl-methylephedrine hydrochloride 240 g, belladonna total alkaloid 1.2 g, epinastine hydrochloride 100 g, lactose 2345.8 g, hydroxypropylcellulose 84 g, magnesium stearate 28 g, and ethanol 300 g Wet granulation was performed with a granulator and dried in a fluidized bed to obtain immediate release granules.
Weigh out 2100 g of sustained-release granules, 2718 g of immediate-release granules, and 11.6 g of talc, and use a capsule filling machine to fill the Nikko hard capsule (No. 2) so that the filling mass per capsule is 270 mg. As a capsule, the sustained-release preparation of the present invention was obtained.

Test example 1
Dissolution test (effect of pH)
Using the capsules obtained in Example 1, the dissolution test was conducted with the paddle method 50 rpm test solution amount 500 mL according to the Japanese Pharmacopoeia 17 revised dissolution test method. Quantification was performed by HPLC method. The test solution used was a test solution of water, pH 1.2, pH 4.0, and pH 6.8. The results are shown in FIGS. The elution of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, and belladonna total alkaloids was not affected by pH.

Test example 2
Dissolution test (effect of ionic strength)
In the same manner as in Test Example 1, the influence of ionic strength was tested. Water (ion concentration 0), 0.025 mol / L, 0.05 mol / L, 0.1 mol / L was used as the test solution. The results are shown in FIGS. The elution of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, and belladonna total alkaloids was not affected by ionic strength.

Test example 3
Dissolution test (effect of stirring strength)
In the same manner as in Test Example 1, the rotational speed of the paddle was set to 25, 50, 100, 200 r. p. m. Then, the influence of the stirring strength was tested. Water was used as the test solution. The results are shown in FIGS. The elution of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, and belladonna total alkaloids was not affected by stirring intensity.

Test example 4
Dissolution test (effect of mechanical stimulation)
In the same manner as in Test Example 1, the effect of mechanical stimulation was tested using a test solution with 500 polyethylene beads added and a test solution with no polyethylene beads added. Set the paddle speed to 100 r. p. m. The test solution was water. The results are shown in FIGS. The elution of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, and belladonna total alkaloids was not affected by mechanical stimulation.

Test Example 5
Dissolution test (effect of wetting)
In the same manner as in Test Example 1, the effect of wetting was tested using a test solution with a surfactant added (0.5% polysorbate 80, 0.1% polysorbate 80) and a test solution not added. Rotate the paddle at 50 r. p. m. The test solution was water. The results are shown in FIGS. The elution of pseudoephedrine hydrochloride, dl-methylephedrine hydrochloride, and belladonna total alkaloids was not affected by wetting.

Example 2
Segmented granules As in Example 1, sustained-release granules and immediate-release granules were obtained.
Weigh out 210g of sustained-release granules, 271.8g of immediate-release granules, and 1.16g of talc, and use an aluminum heat seal packaging machine to fill and seal so that the filling mass per package is 540mg. The sustained-release preparation of the present invention was obtained as a packaged granule.

Example 3
Hard capsule A sustained release granule was obtained in the same manner as in Example 1.
Using pseudoephedrine hydrochloride 140 g, dl-methylephedrine hydrochloride 140 g, belladonna total alkaloid 0.7 g, fexofenadine hydrochloride 400 g, lactose 679 g, hydroxypropylcellulose 33.3 g, magnesium stearate 11.3 g, and ethanol 100 g Then, wet granulation was performed with a high-speed stirring granulator and dried in a fluidized bed to obtain immediate-release granules.
Weigh out 234.8 g of sustained-release granules, 140.4 g of immediate-release granules, and 1.3 g of talc, and use a capsule filling machine to fill a Nikko hard capsule (No. 2) with a filling mass of 270 mg per capsule. Thus, the sustained-release preparation of the present invention was obtained as a hard capsule.

Example 4
Hard capsule A sustained release granule was obtained in the same manner as in Example 1.
240 g pseudoephedrine hydrochloride, 240 g dl-methylephedrine hydrochloride, 1.2 g belladonna total alkaloid, 200 g epinastine hydrochloride, 2245.8 g lactose, 84 g hydroxypropylcellulose, 28 g magnesium stearate, and 300 g ethanol are stirred at high speed. Wet granulation was performed with a granulator and dried in a fluidized bed to obtain immediate release granules.
Weigh out 2100 g of sustained-release granules, 2718 g of immediate-release granules, and 11.6 g of talc, and use a capsule filling machine to fill the Nikko hard capsule (No. 2) so that the filling mass per capsule is 270 mg. As a capsule, the sustained-release preparation of the present invention was obtained.

Example 5
Tablets Sustained release granules were obtained in the same manner as in Example 1.
Sustained release granules 234.8 g, pseudoephedrine hydrochloride 24 g, dl-methylephedrine hydrochloride 24 g, belladonna total alkaloid 0.12 g, epinastine hydrochloride 10 g, crystalline cellulose 190 g, low-substituted hydroxypropylcellulose 28.4 g, lactose 20. 08 g, light anhydrous silicic acid 3 g, magnesium stearate 2.8 g and talc 2.8 g were mixed to produce a tableting powder, and tableted with a 10 mm diameter mortar so that the mass per tablet was 270 mg. The sustained release preparation of the present invention was obtained as a tablet.

Claims (12)

  Sustained release having a sustained release film containing an acrylic water-insoluble polymer, a cellulose-based water-insoluble polymer, a glycerin fatty acid ester and talc on the surface of a core particle containing at least two kinds of drugs having different solubility in water A sustained-release preparation containing a granulated product.   The at least two kinds of drugs having different solubility in water are medicinal ingredients containing pseudoephedrine or a salt thereof and one or two kinds selected from dl-methylephedrine or a salt thereof and a belladonna total alkaloid. 1. The sustained release preparation according to 1.   The sustained-release preparation according to claim 1 or 2, wherein at least two kinds of drugs having different solubility in water are medicinal ingredients including pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, and a belladonna total alkaloid.   The sustained-release preparation according to any one of claims 1 to 3, wherein the sustained-release film is a sustained-release film containing an ammonioalkyl methacrylate copolymer, ethyl cellulose, glycerin fatty acid ester and talc.   5. The ammonioalkyl methacrylate copolymer is a copolymer of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride, which is a mixture of two copolymers having different contents of trimethylammonioethyl methacrylate chloride. Sustained release formulation.   The sustained-release preparation according to any one of claims 1 to 5, wherein the particles further contain a saccharide selected from disaccharides and sugar alcohols.   The sustained release preparation according to any one of claims 1 to 6, wherein the core particles further contain sucrose.   The sustained-release preparation according to any one of claims 1 to 7, further comprising a fast-dissolved granulated product.   The sustained-release preparation according to claim 8, wherein the fast-dissolved granulated product contains an antihistamine.   The sustained-release preparation according to claim 8, wherein the fast-dissolving granule is a fast-dissolving granule containing pseudoephedrine or a salt thereof, dl-methylephedrine or a salt thereof, a belladonna total alkaloid, and an antihistamine.   The gradual agent according to claim 9 or 10, wherein the antihistamine is one or more selected from epinastine, fexofenadine, levocetirizine, loratadine, olopatadine, ebastine, cetirizine, pranlukast, emedastine, azelastine, ketotifen and salts thereof. Release formulation.   It is a capsule, a tablet, or a granule, The sustained release formulation in any one of Claims 1-11.