KR100858631B1 - Controlled release of Indapamide using pellet-tape dosage form - Google Patents

Abstract

The present invention relates to a sustained release formulation containing indafamid, more specifically, crystalline nucleus (A); A pharmacologically active ingredient layer (B) formed on the surface of the crystalline nucleus (A) and including a drug including indafamid and a binder composed of a water-insoluble polymer and a water-soluble polymer; And a sustained release layer (C) formed on the surface of the pharmacologically active ingredient layer (B) and comprising a sustained release film forming material.

The sustained-release pellets containing indafamid according to the present invention can more precisely control drug release compared to tablets, and can be administered once a day to increase patient compliance.

In addition, the present invention is to prepare a granule by mixing the indamide and the water-insoluble polymer or water-soluble polymer that is a drug that requires sustained release, and to produce a sustained-release pellet by coating the water-insoluble polymer on the prepared granules or granules containing the drug Provided is a sustained release pellet for multilayer coating with a water insoluble material.

Inda Pamide, Water Insoluble Polymer, Sustained Release Pellets, Fluidized Bed Coating

Description

Controlled release of Indapamide using pellet-tape dosage form

FIG. 1-A graph showing the release rate of indafamide over time of the sustained-release drug delivery vehicle containing indaphamide prepared according to Example 1 and the commercially available FLUDEX SR (Servie Korea Co., Ltd., 06SE008). .

FIG. 2-A graph showing the release of indamide release with time of the sustained-release drug delivery vehicle containing inindapamide prepared according to Example 2 and the commercially available FLUDEX SR (Servie Korea Co., Ltd., 06SE008). .

3-A graph showing the release of indamide release with time of the sustained-release drug delivery vehicle containing indamide, prepared according to Example 3, and the commercially available FLUDEX SR (Servie Korea Co., Ltd., 06SE008). .

The present invention relates to a sustained release formulation containing indafamid, more specifically, crystalline nucleus (A); A pharmacologically active ingredient layer (B) formed on the surface of the crystalline nucleus (A) and including a drug including indafamid and a binder composed of a water-insoluble polymer and a water-soluble polymer; And a sustained release layer (C) formed on the surface of the pharmacologically active ingredient layer (B) and comprising a sustained release film forming material.

Indafamid is represented by the following formula (1), and the chemical name of the compound is 4-chloro-N- (2-methyl-1-indolinyl) -3-sulfamoylbenziamide, and is a polar sulfamoylchlorobenzamide group and methyl As an oral antihypertensive and diuretic drug of the indole system with protuberances, thiazid diuretics acting on the distal tubule are recommended as the first choice for patients with high blood pressure without complications. Unlike other diuretics, it increases calcium resorption, such as spironolactone and amiloride. Potassium-preserving diuretics, which act on the late distal tubules and aggregates, exhibit mild diuretic activity and prevent the loss of potassium, a side effect of other diuretics. The diuretic effect of indafamid is mainly due to the O -chlorobenzenesulfonamide group, has a free-radical scavenging activity, and exhibits direct vasodilation by blocking calcium channels.

[Formula 1]

If the drug is absorbed too slowly in the body and the drug's bioavailability is low or the drug is rapidly absorbed and lost out of the body too quickly, the rate of drug delivery should be controlled. For this purpose, a mechanical device or a pump using osmotic pressure, a device for controlling diffusion using a membrane, a device using a polymer material that does not decompose or decompose in vivo, and various combinations thereof are used.

Korean Patent Publication No. 2000-69800 provides a method for preparing a porous matrix drug delivery agent by an emulsion method, which method disperses an aqueous solution containing a drug after dissolving a polymer compound and a surfactant in an organic solvent. After the emulsion is prepared in the form of a desired matrix, immediately lyophilized and dried at room temperature for a certain time, i.e. until the surface of the matrix starts to harden, or by using a lyophilizer to prepare a porous matrix. There is a disadvantage in that the manufacturing method is complicated and the manufacturing cost of the product is expensive, and the production of the porous membrane is not homogeneous according to the conditions of freeze drying in the manufacturing process. In addition, there is a problem that the prepared polymer membrane is unstable or the pore size becomes large.

U.S. Patent 5,334,392 describes a process for preparing matrix tablets using two polymers of different chemical groups, and U.S. Patent Publication No. 2005/0202086 describes hydroxypropylmethyl as a polymer for controlling release of copovidone as a binder. Provided are methods for preparing tablets with sustained release using cellulose. Its manufacturing method is a method of drug delivery by the expansion of polymer material, which regulates drug release due to the expansion rate of hydrogel. During in vivo experiments, the tablet is attached to the mucous membrane of the gastrointestinal tract, resulting in the burst effect of the drug. There is an increasing problem.

Therefore, in the present invention, it is possible to control the release of the drug to a constant release form for 16 hours by adjusting the concentration of the pharmacologically active ingredient layer containing indamide, prepared by pellets to supplement the above problems, tablets One of the problems of the present invention is to provide a sustained release pellet which can reduce the dosage bumping of the drug which may occur when the coating is incomplete, thereby increasing patient compliance and achieving uniform drug release.

The present invention provides a crystalline nucleus (A); A pharmacologically active ingredient layer (B) formed on the surface of the crystalline nucleus (A) and including a drug including indafamid and a binder composed of a water-insoluble polymer and a water-soluble polymer; And a sustained release pellet formed on the surface of the pharmacologically active ingredient layer (B) and comprising a sustained release layer (C) including a sustained release film forming material.

It is another object of the present invention to provide a sustained release drug delivery system which effectively releases a pharmacologically active substance at a constant rate for 16 hours.

The present invention to achieve the above object is a crystalline nucleus (A); A pharmacologically active ingredient layer (B) formed on the surface of the crystalline nucleus (A) and including a drug including indafamid and a binder composed of a water-insoluble polymer and a water-soluble polymer; And a sustained release pellet (C) formed on the surface of the pharmacologically active ingredient layer (B) and comprising a sustained release film forming material.

In addition, the sustained-release pellets containing the indafamid of the present invention may be formed between the pharmacologically active ingredient layer (B) and the sustained release layer (C) by forming a surface of the pharmacologically active ingredient layer (B). It may be further coated with a lipidic material.

Hereinafter, the present invention will be described in more detail.

FIELD OF THE INVENTION The present invention relates to sustained-release pellets containing indamide, wherein the pharmacologically active ingredient layer (B) containing indamide is composed of a drug containing indamide and at least one water-insoluble polymer and a water-soluble polymer. By using together, granules can be prepared in one step without going through a two-step process, and also the types and thicknesses of the water-soluble and water-insoluble polymers constituting the pharmacologically active ingredient layer (B) comprising indamide; The release rate of the drug can be controlled efficiently and continuously according to the type and thickness of the sustained release layer constituting the sustained release layer (C), mass production is possible through a simple process, and time is shortened during mass production. have. In addition, a fluidized bed coater can be used to produce granules of constant size and shape.

As used herein, the term "water insoluble polymer" refers to a polymer (pH-independent polymer) that exhibits insolubility even in acid or basic regardless of pH.

The sustained-release pellets containing inindapamide of the present invention comprise a crystalline nucleus (A); A pharmacologically active ingredient layer (B) formed on the surface of the crystalline nucleus (A) and including a drug including indafamid and a binder composed of a water-insoluble polymer and a water-soluble polymer; And a sustained release layer (C) formed on the surface of the pharmacologically active ingredient layer (B) and comprising a sustained release film forming material.

As the crystalline nucleus (A), as a granular material, a crystalline material having a specific gravity of 1 or more may be used, and pellets made of sugar, granules prepared using sugar, nonpareil, and susgasphere are used. Can be used. The size of the whole granule can be determined according to the size of the pellet used as the crystalline nucleus. Preferred crystalline nucleus material pellets that can be used are from 100 to 800 μm in diameter, more preferably from 300 to 710 μm. If the crystalline material is smaller than 100 ㎛, the amount of excipient used when coating is increased, and the coating material is not adhered to the crystalline nucleus material much, so there is a problem in yield of the coating phase. The size of the granules increases, making it difficult to fill the gelatine hard capsules, and the filling amount may be insufficient, which may cause production problems. If the size of the crystalline nucleus material is small, the content of the active ingredient of the pharmacologically active ingredient of the individual granules is very small, causing a problem that a large amount of granules should be administered. That is, the crystalline nucleus is sieved to a constant size in the range of 300-710 μm using a sieve. When the size of the crystalline substance is small, the effective amount of the pharmaceutically active ingredient of the individual granules is very small, so that a large amount of granules Since there is a problem to be administered, the size of the granules to be orally administered together with the hard capsule is in the above range.

The pharmacologically active ingredient layer (B), which is formed on the surface of the crystalline nucleus (A) and comprises a pharmacologically active ingredient and a binder composed of a water-insoluble polymer and a water-soluble polymer, is referred to as a drug and its equivalent as a pharmacologically active ingredient. Compounds, including physiological or pharmacologically active ingredients produced by the passage of drugs in the body.

In the present invention, indamide is used as the pharmacologically active ingredient, and the content thereof is contained in an amount of 0.1 to 4% by weight of the total weight of the sustained-release pellet containing inindapamide. If the use amount of the indamide is less than 0.1% by weight, the concentration of the indamide is small, and the amount of granules to be administered is increased. .

In addition, the pharmacologically active ingredient layer (B) may include indamide as a pharmacologically active ingredient, and if necessary, a pharmacologically acceptable carrier or plasticizer may be used, and as the carrier, excipients, lubricants, pigments and Sweeteners. The brothers include lactose or corn starch, and the lubricant is selected from the group consisting of talc, magnesium stearate, magnesium silicate, calcium stearate, glyceryl behenate, polyethylene glycol, mineral oil, silicic anhydride and stearic acid. One or more species may be used, and the carrier may not be used if necessary, and may be used up to 80% by weight.

In addition, the pharmacologically active ingredient layer (B) further contains a binder made of a water-insoluble polymer and a water-soluble polymer, in addition to indaphamide, and the binder made of the insoluble polymer and a water-soluble polymer further comprises indamide and a carrier as a crystalline nucleus ( It can be combined to A). The binder is contained in 2 to 30% by weight of the total weight of the sustained-release pellet containing inda pamide, if the content exceeds 30% by weight of the coating liquid increases the viscosity of the coating liquid is difficult to transport, and also does not dry well The granules stick together.

The water-insoluble polymer is selected from water-insoluble cellulose and derivatives thereof, polymethacrylate, or a mixture of two or more kinds of polyalkyl acrylate and polymethacrylate, preferably cellulose acetate, cellulose acetate phthalate, ethyl cellulose, It is 1 or more types chosen from the group which consists of hydroxypropylene methylcellulose phthalate, methylcellulose, polymethacrylate, or polyalkylacrylate.

The polymethacrylate or a mixture of two or more kinds of polyalkylacrylate and polymethacrylate is selected from the group consisting of Eudragit RS PO, RS100, RS 30D, RL100, RL 30D, and NE 30D. Can be used.

The water-soluble polymer is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, pullulan, gelatin, collagen, casein, agar, gum arabic, dextrin, chitin, chitosan, mannan, carboxymethylethyl cellulose, carboxy One or more types selected from the group consisting of methyl cellulose sodium, polyethylene glycols, sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, silicone, polyvinyl acetal diethylamino acetate or albumin can be used.

In addition, the sustained-release pellets containing the indafamid of the present invention may be formed between the pharmacologically active ingredient layer (B) and the sustained release layer (C) by forming a surface of the pharmacologically active ingredient layer (B). It may be further coated with a lipidic material.

The lipophilic substance includes fat, fatty alcohol or wax, and preferably beeswax, polyethoxylated beeswax, single, double or triple substituted glycerides, diethylene glycol palmitostearate, glyceryl palmito Stearate, polyethylene glycol stearate, polyoxyethylene glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, polyethylene glycol palmitostearate, mono- or di-glyceryl behenate, polyethoxylate One or more selected from the group consisting of fatty alcohols, cetyl alcohols, cetostearyl alcohols, stearic acid, hydrogenated castor oils or dibutyl phthalate associated with fatty alcohols can be used.

The sustained release layer (C) formed on the surface of the pharmacologically active ingredient layer (B) and including the sustained release film forming material to slowly release indapamid may form a sustained release film on the active ingredient layer surface. It may further include a plasticizer, a disintegrating agent or a lubricant as necessary. By using a plasticizer, the drug is released in a sustained release as the plasticizer and disintegrant are dissolved out of the membrane in an aqueous solution or human body fluid (gastric fluid, intestinal fluid, etc.).

The sustained release film forming material may be a material that can be used in the preparation of a sustained release formulation, wherein the sustained release film forming material is selected from the group consisting of cellulose acetate, polymethyl methacrylate copolymer and polyvinylacetate 1 or more types can be used. Commercially available Eudragit RS, RL, NE30D, and NE40D may be used as the polymethyl methacrylate copolymer, and Kollicoat SR 30D, Kollidon, which is commercially available as polyvinyl acetate. SR can be used. The sustained release film forming material is preferably used in an amount of 1 to 30% by weight based on the total weight of the sustained release pellet containing indaphamide. Outside of the above range, there is a problem in that the sustained release drug is difficult to deliver. Preferably, as the amount of Eudragit RS increases, the drug is released slowly. Also, in the case of Eudragit NE 30D and Colicoat SR 30D, as the sustained release film forming material increases, the drug is released slowly. Indicated.

As the plasticizer, low molecular weight polymers, oligomers, copolymers, oils, small organic molecules, low molecular weight polyols of aliphatic hydroxy species, ester types, and glycol esters may be used. Preferably triethyl citrate, dibutyl sebacate, acetyl triethyl citrate, tributyl citrate, butyryl-n-hexyl citrate, acetyl triethyl citrate, triacetin, glycerol, propylene glycol, average molecular weight 200 to 8,500 polyethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, monopropylene glycol, monoisopropyl ether, propylene glycol One or more selected from the group consisting of monoethyl ether, ethyl ether, sorbitol lactate, ethyl lactate, butyl lactate or ethyl glycolate can be used. The amount of the plasticizer used is preferably 0.05 to 0.3% by weight of the total weight of the sustained-release pellet containing indaphamide. If the amount of the plasticizer is out of the range, it is difficult to form the sustained-release film.

The disintegrant is used for dispersing the drug, and can be used conventionally pharmaceutically acceptable, for example, lactose, starch, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or polyprastone, etc. Can be used.

The glidants are used to prevent sticking of granules and to smooth and gloss the surface, and are commonly used talc, magnesium stearate, magnesium silicate, calcium stearate, glyceryl behenate, polyethylene glycol, mineral oil, anhydrous One or more types selected from the group consisting of silicic acid and stearic acid can be used.

The pharmacologically active ingredient layer (B) and the sustained release layer (C) composition may include one or more solvents such as ethanol, acetone, 2-propanol, methylene chloride or water to perform a coating process.

The sustained-release pellets containing inindapamide of the present invention are released in a sustained-release form as the plasticizer and disintegrant are dissolved out of the membrane in aqueous solution or human body fluid (gastric juice, serous fluid, etc.).

Hereinafter, the method of manufacturing the sustained release pellet containing the inda pamide of this invention is demonstrated.

The crystalline nucleus (A) material was placed in a fluidized bed coater and first coated with a pharmacologically active ingredient layer (B) composition containing indapamid as a pharmacologically active material. ). According to this coating process, the crystalline nucleus material is spherical. Sustained release layer on the surface of the pharmacologically active ingredient layer by secondary coating with a sustained release layer (C) composition comprising a sustained release film forming material on the pharmacologically active ingredient layer first coated on the surface of the crystalline nuclear material as described above To form.

As the coater, a fluidized bed coater is generally used, and various coaters may be used in some cases, but the conditions of the fluidized bed coater are not particularly limited in order to prepare respective coating layers.

Although this invention is demonstrated further more concretely based on an Example, this invention is not limited by the following Example.

Example 1 In case of using a water-insoluble polymer in the pharmacologically active ingredient layer

1) Pharmacologically active ingredient layer coating

26.74% by weight of sugar (pellet size 300-710 μm) was placed in a fluidized bed coater and coated with a pharmacologically active ingredient layer composition. The pharmacologically active ingredient layer composition comprises 0.31% by weight of indamide, 3.34% by weight of hydroxypropylcellulose, 2.67% by weight of ethyl cellulose, and 0.13% by weight of dibutyl sebacate as a plasticizer, respectively, 53.45% of dichloromethane and isopropanol. Prepared by dissolving or dispersing in wt%, 13.36 wt%. The coating process was carried out under conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 34 ℃, inlet air temperature 35 ℃, flow 8, outlet air flat 30%, the flow rate is injected starting from 0.8, Was increased by 0.2 in 10 minute increments.

2) Sustained release membrane layer coating

51.74 wt% of the coated pellets (450-800 μm) were coated with a sustained release film forming material. The material used was prepared by mixing 17.23% by weight Eudragit NE30D, 25.86% by weight purified water, and 5.17% by weight talc, a lubricant. The coating process was carried out under the conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 28 ℃, inlet air temperature 29 ℃, flow 6, outlet air flat 35%.

Example 2 In case of using a water-insoluble polymer in the pharmacologically active ingredient layer

1) Pharmacologically active ingredient layer coating

26.74 wt% of sugar (pellet size 300-710 μm) was placed in a fluidized bed coater and coated with a pharmacologically active ingredient layer composition. The pharmacologically active ingredient layer composition comprises 0.29% by weight of indafamid, 3.34% by weight of hydroxypropyl cellulose and 2.67% by weight of ethylcellulose, and 0.13% by weight of dibutyl sebacate as a plasticizer, 53.46% by weight of dichloromethane and isopropanol, respectively. %, 13.37% by weight was prepared by dissolving or dispersing. The coating process was carried out under conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 34 ℃, inlet air temperature 35 ℃, flow 8, outlet air flat 30%, the flow rate is injected starting from 0.8, Was increased by 0.2 in 10 minute increments.

2) Sustained release membrane layer coating

60.49 wt% of the coated pellets (450-800 μm) were coated with a sustained release film forming material. The material used was prepared by mixing 14.11% by weight Eudragit NE 30D, 21.17% by weight purified water, and 4.23% by weight talc, a lubricant. The coating process was carried out under the conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 28 ℃, inlet air temperature 29 ℃, flow 6, outlet air flat 35%.

Example 3 In the case of using a water-soluble polymer in the pharmacologically active ingredient layer

1) Pharmacologically active ingredient layer coating

26.74 wt% of sugar (pellet size 300-710 μm) was placed in a fluidized bed coater and coated with a pharmacologically active ingredient layer composition. The pharmacologically active ingredient layer composition comprises 0.29% by weight of indafamid, 6.01% by weight of hydroxypropyl cellulose as a binder, 0.13% by weight of plasticizer triethyltyl citrate, 53.46% by weight of dichloromethane and isopropanol, and 13.37% by weight, respectively. Prepared by dissolving or dispersing. The coating process was carried out under the conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 34 ℃, inlet air temperature 35 ℃, flow 8, outlet air flat 30%, the flow rate is injected starting from 0.8, Was increased by 0.2 in 10 minute increments.

2) fatty alcohol or wax layer coating

64.52% by weight of the coated pellets (450-800 μm) was coated with fatty alcohol. The material used was prepared by mixing 3.23 wt% cetyl alcohol and 32.25 wt% ethanol. The coating process was carried out under the conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 33 ° C, inlet air temperature 35 ° C, outlet air flat 35%.

3) Sustained release membrane layer coating

The coated pellets (500-850 μm) were coated with 68.19 wt% of a sustained release film forming material. The material used was prepared by mixing 11.35% by weight of Eudragit NE 30D, 17.05% by weight of purified water, and 3.41% by weight of talc, a lubricant. The coating process was carried out under the conditions of inlet air 5.8 bar, spray air 1.5 bar, outlet air temperature 28 ℃, inlet air temperature 29 ℃, flow 6, outlet air flat 37.5%.

Comparative Example 1

As a comparative example, FLUDEX SR (Servie Korea Co., Ltd.) containing indapamid, which is a commercially available hypertension treatment agent, was used. The FLUDEX SR is a tablet prepared by mixing indafamid with polyvidone, hydroxypropylmethyl cellulose, lactose, magnesium stearate, and colloidal silica, and includes 1.5 mg of indafamid per tablet.

In the case of FLUDEX SR, eluting was performed with 500 ml of purified water using USP No. 2 method (paddle, 50 rpm). The dissolution rate was 17-28% for 4 hours, 35-56% for 8 hours, and the dissolution rate was over 75% for 16 hours.

Experimental Example 1

In order to measure the elution amount of the indamide of the multi-layered granules containing the indamide, prepared according to Examples 1 to 3, the following analysis conditions were used using HPLC. 1 to 3 show the dissolution rate graphs with time, FIG. 1 shows the results of Example 1, FIG. 2 shows the results of Example 2, and FIG. 3 shows the results of Example 3. FIG.

Mobile phase: phosphate buffer solution / acetonitrile / methanol = 55/40/5 volume ratio

Column: SC-04 (125 * 4.0mm), PRONTOSIL EUROBOND C18 5.0μm

Flow rate: 1.0 ml / min

Detector: 240 nm

Elution condition: 37.5 ℃, 500 ml of purified water

TABLE 1

From Table 1 and FIGS. 1 to 3, the sustained-release pellets containing the indaphamide of Examples 1 to 3 were slowly released at a constant rate for 16 hours, and thus, it was a very suitable formulation for sustained-release formulations. Can be.

As described above, the sustained-release pellets containing inindapamide according to the present invention are used in the pharmacologically active ingredient layer at the same time by using a binder composed of indaphamide and a water-soluble polymer and a water-insoluble polymer simultaneously. It can be manufactured simply and mass production is possible.

In addition, according to the type and thickness of the water-soluble and water-insoluble polymer constituting the pharmacologically active ingredient layer containing indaphamide, and the type and thickness of the sustained release film-forming material constituting the sustained release layer and controlling drug release Indamide can be released continuously, and the prepared granules can have a uniform particle to increase the sustained release of the drug.

Claims (14)

Crystalline nucleus (A); It is formed on the surface of the crystalline nucleus (A), at least one water-insoluble polymer and hydroxy selected from the group consisting of indamide, cellulose acetate, ethyl cellulose, methyl cellulose, polymethacrylate or polyalkyl acrylate Propyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, furan, gelatin, collagen, casein, agar, gum arabic, dextrin, chitin, chitosan, mannan, carboxymethylethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol Pharmacologically active ingredient layer comprising a binder comprising at least one water-soluble polymer selected from the group consisting of sodium alginate, polyvinyl alcohol, polyvinylpyrrolidone, silicone, polyvinyl acetal diethylamino acetate or albumin (B). ); At least one lipophilic material coating layer formed on the surface of the pharmacologically active ingredient layer (B) and selected from the group consisting of fats, fatty alcohols or waxes; And Sustained release layer (C) formed on the surface of the lipophilic material coating layer and comprising one or more sustained release film forming materials selected from the group consisting of cellulose acetate, polymethyl methacrylate copolymer, and polyvinylacetate ; Sustained-release pellets containing inindapamide. delete The method of claim 1, Crystalline nucleus (A) is a granular material, sugar, granules produced using sugar, sustained-release pellets containing indamide, characterized in that selected from non-pareil and sugaspeare. The method of claim 3, wherein The crystalline nucleus (A) is a sustained-release pellet containing inda pamide, characterized in that the circular granules of 100 to 800 ㎛ size. The method of claim 1, The indamide is a sustained-release pellet containing indamide, characterized in that contained in 0.1 to 4% by weight of the total weight of the sustained-release pellet containing the indamide. The method of claim 1, The binder is a sustained-release pellet containing indamide, characterized in that it contains 2 to 30% by weight of the total weight of the sustained-release pellet containing the inda pamide. delete delete The method of claim 1, The lipophilic materials include beeswax, polyethoxylated beeswax, single, double or triple substituted glycerides, diethylene glycol palmitostearate, glyceryl palmitostearate, polyethylene glycol stearate, polyoxyethylene glycol palmito Stearate, glyceryl monopalmitostearate, cetyl palmitate, polyethylene glycol palmitostearate, mono- or di-glyceryl behenate, polyethoxylate fatty alcohols, cetyl alcohol, cetostearyl alcohol, stearic acid, An indamide sustained-release pellet containing at least one member selected from the group consisting of saturated or unsaturated fatty acids or hydrogenated derivatives thereof, hydrogenated castor oil or dibutyl phthalate. The method of claim 1, The sustained release film-forming material is an indamide release-containing sustained release pellet, characterized in that it is contained in 1 to 30% by weight of the total weight of the sustained release pellet containing inda pamide. delete The method of claim 1, The pharmacologically active ingredient layer (B) and the sustained release layer (C) further contain at least one additive selected from the group consisting of excipients, disintegrants, lubricants and plasticizers. Sustained release pellets. The method of claim 12, The lubricant is characterized in that the lubricant is at least one selected from the group consisting of talc, magnesium stearate, magnesium silicate, calcium stearate, glyceryl behenate, polyethylene glycol, mineral oil, silicic anhydride and stearic acid. Sustained release pellets containing pamide. The method of claim 12, The plasticizer has triethyl citrate, dibutyl sebacate, acetyl triethyl citrate, tributyl citrate, butyryl-n-hexyl citrate, acetyl triethyl citrate, triacetin, glycerol, propylene glycol, average molecular weight 200 to 8,500 polyethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, monopropylene glycol, monoisopropyl ether, propylene glycol An indamide sustained-release pellet containing at least one member selected from the group consisting of monoethyl ether, ethyl ether, sorbitol lactate, ethyl lactate, butyl lactate or ethyl glycolate.

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