JPH01501936A - Method for producing sustained release pharmacological composition and composition obtained thereby - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Process for producing connected-release pharmacological compositions and compositions obtained thereby The present invention provides a type of drug useful for releasing biologically active substances into the body over an extended period of time. Certain Aspects of the Invention Relating to Pharmaceutical Compositions and Methods of Preparing Compositions of this Type According to The present invention relates to a method for preparing a composition effective for.

Theophylline and its derivatives are used in biology, e.g. as bronchodilators. It is a known substance that is actively active. For a long time, theophylline was used in a dosage form that is taken orally. It is known to have a tendency to cause problems when administered. excessive blood concentration Gastrointestinal, CNS, and cardiovascular side effects due to Theophylline in enteric-coated and controlled-release form to avoid or prevent administration, i.e., a predetermined dose of theophylline is added to the enteric matrix and theophylline. It allows the release of silane into the stomach and passes it through the intestines where it is controlled. releasing theophylline at a rate over a relatively long period of time, e.g. 6 to 12 hours. Many attempts have been made to administer the drug in a thorn-shaped form with a coating that allows for.

5 crush” 2ba] Taku l dog & Various dosage forms of enteric-coated, extended-release drugs (containing theophylline) are available in the United States. Patent No. 3.109.775, Patent No. 4.083.949, Patent No. 4.261.9 No. 70 and PCT Application Publication No. WO83100284.

Generally speaking, the above patents cover coatings that dissolve slowly or that are insoluble in the acidic environment of the stomach. , and the pharmacological activity is enclosed in a porous material that allows the active substance to pass through and be released into the intestine. Discloses sexual substances.

For example, a typical sustained release formulation includes an inert core, such as sugar granules, coated with and an adhesive substance to which a pharmacologically active substance is applied. The amount of active substance is , can be increased by providing further layers on top of the layer of adhesive coating and active substance. . - After applying the prescribed amount of active substance, this multilayer structure is covered with a permeable membrane; .

The membrane is resistant to dissolution (otherwise it would be degraded in the stomach and intestines) ) and a given pharmacological substance, e.g. theophylline, which dissolves in the liquid medium of the intestine. The membrane can be passed through the pores of the membrane depending on the nature of the membrane.

One problem with theophylline preparations is that they are highly soluble in the acidic environment of the stomach. relatively high concentrations of theophylline are released into the stomach, where it is absorbed. As a result, local and systemic side effects occur. The above US patent No. 4.083.949 is a film-forming material and a liquid form of an acid-insoluble and alkali-soluble material. A membrane prepared from the mixture is disclosed. Such a membrane protects the acidic environment of the stomach. It is said to substantially prevent premature release of theophylline. However However, the use of such membranes may result in an unduly rapid release of theophylline in the intestine. There is. This type of problem has been addressed by the preparation and use of sustained release compositions. The compositions have been prepared in a number of ways.

Sustained-release compositions are generally produced by utilizing successive coatings of various materials. The material is prepared by successively peeling off each painstakingly applied layer of the material. ensures a gradual release of the pharmacologically active substance. Obtain such a composition The coating method is a spin coating method commonly used in the manufacture of sugar-coated pills. It can be carried out with In one of the conventional methods using coated Phosphorus formulations involve applying a liquid alkali-soluble adhesive substance to a batch of seed particles and then obtained by adding micronized particles of solid theophylline. more specifically , this method included the following steps.

(^) forming a wet layer of alkali-soluble adhesive substance on the layer, then Contacting wet seed particles with micronized theophylline: (B) Drying the above-mentioned wet layer containing theophylline; (C) ti-dried Forming one or more additional layers of alkali-soluble adhesive material on top of the layer, which is then coated with a fine powder. contacting the chlorinated theophylline, wherein each of the layer or layers is first moistened with the wetting layer or each of the plurality of wetting layers is formed in a wet state, and then the wetting layer or each of the plurality of wetting layers The material is dried before being used; (D) a material capable of forming pores and +1lr11 insoluble and alkali soluble; and (2) water. coating the multilayer core with a film comprising a soluble material; and (E) +1+i insoluble and alkali soluble material and (2) acid insoluble and alkali Insoluble materials and non-Ii! Applying a soluble coating onto the membrane.

Theophylline-containing compositions prepared by this dish coating technique can be formulated into sustained release formulations. Although this dish coating method exhibits many desirable properties, it has been repeated approximately 20 times. It involved time-consuming layer formation and drying steps.

Fluidized bed and column methods have also been utilized to prepare sustained release compositions. . In these methods, seed particles are suspended by an air stream and are separated from adhesive substances and powders. A large number of layers are coated by the addition of ingredients, which is also time consuming and cost disadvantageous. In International Publication No. 83100284, which includes the process of of theophylline and polyvinylpyrrolidone and isopropanol in the seed particles! ! ! (Glatt) Column Air Suspension System for Applying Multilayers of Suspended Liquids are using the system. This multi-layered product is then coated with a mixture of cellulosic materials. coated. The product supposedly prepared according to the above method should be prepared at the same time as the food is taken. have been reported to exhibit inhibited release when administered at or shortly after There is.

It is an object of the present invention to be relatively simple, include a minimum number of coating steps, and to minimize patient eating and drinking activity. Sustained release, giving compositions characterized by optimal time-delayed release properties according to An object of the present invention is to provide a method for producing a mold composition.

1Ib11! According to the invention, a sustained release drug comprising seed particles coated with a layer of pharmacologically active compound A method for producing a chemical composition is provided, which method comprises the following steps W1: (A) At the same time, centrifugal force, vertical gravitational force, and substantially opposite gravitational force are applied to the seed particle. Applying positive fluid pressure at the periphery in the opposite direction causes the fluidization ring of the seed particle to a step of forming, and (B) The above particles and the above pharmacological activation while maintaining the above ring-shaped suspended state. a liquid composition containing a compound and an alkali-soluble substance in an amount sufficient to coat the particles. a step of contacting the It is characterized by including.

According to another aspect of the invention, the invention relates to sustained release compositions, The substance releases the pharmacologically active ingredient at a predetermined rate under the action of gastrointestinal fluids, and the seed core, the pharmacologically active ingredient. Compositions of the Invention Comprising a Single Layer Containing an Active Ingredient and a Pore-formable Seal Coating A particularly favorable feature of is relatively low flux under fasting and/or fed conditions. It has release characteristics.

According to yet another aspect of the invention, the invention provides treatment for physiological diseases such as tracheal diseases such as asthma. Regarding the treatment of sub-diseases, this method involves oral intake by an individual of the above-mentioned pharmacological compositions. , where the formulation is predetermined regardless of whether there is food in the individual's gastrointestinal tract. Can be administered at regular time intervals.

Danri Risekosei R Base FIG. 1 shows an annular mixing and granulation process illustrating the fluidization and coating method of particles according to the present invention. FIG. 2 is a cross-sectional side view of the device.

1ri sitting pressure blue star■ more Unless otherwise specified, the following terms used herein shall have the definitions set forth below. It should be understood that

"Alkali-soluble material" refers to the intestinal soluble under alkaline conditions and during coating formation of the sustained release composition of the present invention. , refers to a substance that can function as a binder to agglomerate particles of pharmacologically active compounds. Taste.

“Enteric coated (enteric coated) J is essentially a substance that is released into the gastric fluid. Refers to a coating that allows medicine to pass through the stomach without being expelled.

A "membrane" is a semipermeable structure through which water and other molecules of similar size can pass. It means a structure.

“Non-lX! Soluble coating” means that it can release medicine into the stomach, and can be continuous, discontinuous, or irregular. Alternatively, it means a coating which may be a non-uniform coating.

"Pore" means an opening through which molecules larger than water can pass. Ru.

"Seeds" are those suitable for use in sustained release pharmacological compositions and have an average particle size of approximately They are small particles of material with a diameter of 600-850μ. An example of such a substance is sugar and cornstarch.

``Theophylline (theopheylll1ne) J is used to relieve asthma. refers to theophylline and its derivatives, which are effective bronchodilators for patients, such as Guaitirin (3,7-sihydro-1,3-dimethyl-III-purine-2,6 -1 of ion and 3-(2-methoxyphenoxy)-1,2-propanediol :l formulation).

According to the invention, a predetermined amount of seed particles 7 is deposited in a chamber l of the mixing and coating apparatus shown in FIG. while rotating the rotating disk 2 around the shaft 30 and as indicated by the arrow 8. A positive fluid pressure is applied through the clearance 4. Here, the fluid is an inert gas, For example, it preferably contains air, nitrogen or carbon dioxide, and is shown in FIG. The rotating disk 2, which rotates at 0 and is emitted from a gas source that does not rotate, exerts a centrifugal force on the seed particles. and move them towards the wall 5 of the chamber. Here, due to the fluid moving upward, The pressure exerted on the particle 7 is shown by arrow 8 and imparts an upward motion to the particle 7 that substantially opposes the force of gravity. Ru. The wall 5° of the chamber according to the embodiment of the device shown in FIG. The outwardly inclined portion 5a, including the sideward inclined portion 5b, moves up and down together with the rotating disk 2. can act to adjust the volume of fluid passing through the clearance 4. On the other hand, inside The sidewardly inclined portion 5b has the function of deflecting the particles 7 moving upward toward the center of the chamber l. 0 particle 7 rises in the chamber until gravity overcomes the reduction in force due to fluid pressure. 0 Then, the particles 7 descend toward the center of the rotating disk 2. The motion of the seed particle 7 is It is two-dimensionally depicted in Figure 1 by lines U%D and 0.

Also, the shape and motion of the resulting seed particle 7 will be referred to throughout this application as a “fluidization ring (f (luidized rig) J. Of course, particle 7 is bound in two dimensions. as well as rotation within the volume of the fluidizing ring as a result of rotation of the disk. Also do.

In the method of the present invention, a liquid containing a pharmacologically active ingredient and an alkali-soluble substance is used. The coating composition is introduced into chamber 1 by any suitable means, e.g. one or more spray nozzles. will be introduced in The liquid coating composition thereby causes the particles to rotate within the chamber and The coating composition comes into contact with the seed particles 7 as it passes through the space introduced into the ring. child A preferred method of coating the seed particles 7 is to mix air with the atomized liquid coating composition. spraying a fine atomized mixture through a nozzle 6, and the coating of particles is This occurs when the particles pass through the volume of the spray coating composition discharged from the introduction nozzle 6. Koru.

To simplify the spraying operation, liquid coating compositions may contain diluents such as lower alkyl alcohols. alcohol or low-boiling haloalkyl solvents, the preferred diluent being ethanol. isopropanol, methylene chloride and mixtures thereof. In addition, the coating process In order to control the amount of static electricity generated in the It can be included in the coating composition. A sustained release formulation that delivers an effective amount of water to prevent static electricity. can be used in the coating composition without adversely affecting the dissolution rate of the composition. It is known that The spray rate into the fluidizing ring is such that the rate of spraying the seed particles into the fluidizing ring is the coating composition should be sufficient to distribute the coating composition uniformly over the entire area; Moreover, the spray speed depends on the number of spray nozzles used in the nuclear process, the number of spray nozzles included in the fluidization ring, It depends on the amount of seed particles present and on the shape, viscosity and properties of the coating composition. Noriyoshi Typical spray rates range from about 50 to about 7008/min/nozzle.

In a particularly preferred embodiment of the method of the invention, the coating composition comprises a lower alkyl alcohol. comprising a suspended S solution in which solid particles of a pharmacologically active substance are suspended in a liquid dispersion containing a In addition, this suspension also contains liquid or solid alkali-soluble substances. The lukyl alcohol facilitates mixing of the suspension with the fluidizing ring of seed particles 7 and Clogging-free spraying of the suspension is achieved. This lower alkyl alcohol is ethano (modified and/or 200 proof), isopropanol, n-propanol or mixtures thereof.

The size of solid particles of pharmacologically active substances has a non-negligible influence on the sustained release properties of the final product. solid state of the pharmacologically active substance in order to optimize the release rate of the pharmacologically active substance. Particle size should be "micronized", i.e. based on micromerograph measuring equipment. Measured as about 100 to about 50 μ or about 300 mesh or more It is preferable that the size is as follows.

Advantageously, the suspension contains a proportion of solid pharmacologically active particles; 0g, which facilitates and accelerates the spraying of the suspension into the fluidizing ring. The dynamic amount of solid particles in the liquid can be from about 30 to about 60 g per 100 g of suspension, and is preferably Preferably, it is about 40 to about 55 g per 100 g of suspension. In addition, on the surface of the seed particle The nuclide particles are exposed to a certain amount of pharmacological activity to form a complete and continuous coverage of the aggregated particles. It is also advantageous to coat the material with synthetic particles. The total amount of pharmacological composition in the sustained release composition is The value should be sufficient to provide a source of active substance over the defined sustained release period. You should understand that. Achieving the above release rate of pharmacologically active substances in sustained release compositions Although there are many variables involved in the formulations and methods of the invention, the compositions from about 40 to about 90-t%, preferably about 50-t% of such active material, based on the total dry weight of ~65-t%.

By adjusting the rotational speed of the rotating shaft 30 and the positive fluid pressure 8, the "fluidization reaction" of the solid particles 7 is achieved. conditions suitable for the formation of a coating material and the formation of a uniform layer of coating material on the seed particles. obtain. Typical rotor speeds are from about 100 to about 30 rpm, preferably about 120 ~20 Orpm and can be varied within this range during the coating process.

The fluid pressure varies depending on the amount of material introduced into chamber 1 and ranges from about 30 to about 60 psi. It can be a range.

The temperature of the inert gas passing through chamber 1 and clearance 4 is regulated throughout the coating process. be done. To make this adjustment, the fluidization ring and inert gas are brought to a certain temperature. heated and maintained at that temperature. The temperature is such that the diluent contained in the coating composition is at a temperature in a range sufficient to volatilize the seed particles at a rate that allows uniform coverage of the seed particles. Ru. In many applications, the advantageous temperature for the inert gas is from about 30 to about 75°C, preferably The preferred temperature for the fluidization ring is from about 35°C to about 50°C, while the preferred temperature for the fluidization ring is from about 20°C to about 45°C. ℃, preferably about 25 to about 35℃.

An example of a device that may be used in the present invention is the Graft Air Technique Inc. Commercially available by Glatt Air Technique, Inc. Rotor Granulators and by Vector Corporation Commercially available Vector/Freu In the latter spill flow device, including nd 5pir-a-F1oi=) Provides additional force to the coating process. Nuclear force is generated through numerous holes inside the rotating disk. This is due to the air being forced in. This additional force creates a vortex inside the fluidization ring. and flow and help improve the efficiency and speed of coating operations. .

For some applications, providing an additional coating on top of the coated seed particles 7 is advantageous. This additional coating includes a porous membrane, the wire membrane containing a pharmacologically active compound, e.g. (C) has pores of sufficient size to allow theophylline to pass through; (C) is alkali insoluble; A porous membrane-forming solution containing a mixture of acid-insoluble and water-insoluble components is prepared as described above. filling a fluidization ring containing the coated seed particles prepared by step (B); It can be obtained by Preferably, the mixture forming the porous membrane is acid insoluble. and alkali-insoluble (otherwise it would be degraded in both the gastric and intestinal environments) substances and water-soluble substances that dissolve in the aqueous environment of the stomach and intestines to form pores in the membrane. nothing.

In a preferred form, the film-forming substance versus the water-soluble substance in the membrane and film-forming solution. The ratio is from about 5=1 to about 20:1, more preferably from about 8:1 to about 15:1. child Examples of porous film-forming solutions such as or about 6 to about 8 g of acid-insoluble and alkali-insoluble material and 100 g of coating solution. contains about 0.5 to about 1 g, preferably about 0.6 to about 0.8 g of water-soluble material per It is something. The amount of film-forming material combined with the coated particles in step (B) above is from about 0.1 to about 2%, preferably from about 0.3 to about 1.3%, based on the total dry weight of the composition It can be in the range of .

In many applications, a homogeneous film is desirable; It is believed to provide reproducible and controlled dissolution rates. Dilute film forming solution It has been found that the use of a more uniform membrane results in a more uniform film than a more concentrated solution.

Also, compositions that have more uniform films and contain smaller amounts of film-forming substances can be used for a given retention period. Compositions with extended release properties and conversely more heterogeneous films may also have a given release profile. It was also found that a larger amount of film-forming substance is required to show this. Therefore, the book For many applications of the invention, by using a porous membrane-forming solution at a low concentration, Membrane forms necessary to incorporate into sustained release compositions of the present invention to obtain their desired sustained release characteristics. It is possible to reduce the total amount of constituent substances.

- M, and as detailed below, the membrane comprises a mixture of the coated seed particles and the substance. It can be formed by combining the compound with a solution containing a solvent in which the compound is dissolved. of solvent Examples are lower alkyl alcohols such as ethanol (denatured and 200 proof) , isopropanol or n-propatool or haloalkyls, e.g. salts A solid pore-forming membrane containing methylene chloride or carbon tetrachloride evaporates the solvent from the solution. It is formed when

Using cellulose ether as an acid-insoluble and alkali-insoluble film-forming substance are preferred, most preferably lower alkyl cellulose ethers, such as ethyl cellulose. Regarding water-soluble substances, lower alkylene glycols, e.g. In a more preferred form, it is preferred to use ropylene glycol. The porous membrane of the sustained release composition is made of ethyl cellulose and propylene glycol. The following solutions can be advantageously used, containing the amounts of the components based on 100 g of solution: It is.

- Bottom - 1 minute - 100 hits Ethyl cellulose 10cps 7g Propylene glycol 0.8g Appropriate amount of denatured ethanol This porous membrane-forming solution is prepared by converting it into a stream containing the seed particles coated in step (B) above. The coated seed particles are applied by spraying onto the mobilization ring. This spray speed is , the differences between these two liquid spray formulations, including the amount of material in each liquid composition. and due to differences in the predetermined thickness of each layer or coating, the coating of step (B) This rate may be different from that used, and this rate may be different from that used in the above chamber. can also vary as a function of batch size. In preferred applications, this membrane form The solution is applied at a rate within the range of about 20 to about 1000 g/min/nozzle, most In preferred applications, rates of about 20 to about 500 g/min/nozzle are acceptable.

At the completion of each coating operation, the fluidization ring of the coated particles is maintained in motion and heated. Subsequently, the coated particles are dried and the volatile diluent contained in the spray composition is removed. Remove. Complete drying of the coated particles is carried out subsequent to the coating operation carried out in chamber 1. This is accomplished through the following operations. However, given the nature of the diluent, the given thickness of the coating and This includes mechanical limitations on mixing equipment (some considerations may include other drying operations). These considerations may be useful in some applications that may require The dried coated particles are removed from chamber 1 and their drying is carried out in another drying device, e.g. Complete with an air dryer.

Particular B of the present invention includes a composition having an outermost coating as follows: The coating allows the aqueous contents of the stomach to pass through and retains less than the amount that constitutes the linear membrane from the underlying membrane. It is possible to dissolve a small amount of water-soluble substances. This non-I! Soluble coating The coating is discontinuous, irregular or non-uniform film shape, and only part of the surface of the membrane is covered. as a thin continuous film with minimal structural integrity. can exist. Thus, within the acidic environment of the stomach, pharmacologically active ingredients, such as theophyte, Phosphorus is released only in small amounts, most of which is retained within the globules.

The outermost and preferably non-enteric coating is formed from a mixture of substances. and one of the substances is acid-insoluble and alkali-insoluble, otherwise the stomach Another substance in the mixture that is degraded in both the intestinal and intestinal environments is alkaline Soluble but acid insoluble. Typically, this coating consists of a solid material in a suitable solvent. The resulting solution is sprayed onto the membrane-coated particles mentioned above. will be accomplished. As the solvent evaporates, a coating consisting of a matrix of each of the substances is also formed on the above film from alkali-soluble and acid-insoluble substances; To a limited extent, the water-soluble components of the membrane are kept from dissolving in the aqueous environment of the stomach. be protected. The acid-insoluble, alkali-insoluble material of the coating includes cellulose ether. the acid insolubility of the coating, most preferably comprising ethyl cellulose; Alkali-soluble substances include seven lacs, cellulose acetate phthalate, and methacrylate. Contains a copolymer of acid and methacrylic acid ester, and is used as a pharmaceutical glaze. 7 is most preferred.

Also, the ratio of acid-insoluble, alkali-insoluble substances to acid-insoluble, alkali-soluble substances is approximately 0. Preferably from 1:1 to about 1:1, non-I! An example of a soluble coating solution is coating solution. About 0.05 to about 0.5 g, preferably about 0.08 to about 0.3 g per 100 g of liquid from about 0.05 to about 100 g of acid-insoluble, alkali-insoluble material and coating solution. 0.8 g, preferably about 0.1 to about 0.4 g of acid-insoluble and alkali-soluble material including.

The weight percent of material coated by this coating solution, based on the total weight of the coated particles, is e.g. It may range from about 0.05% to about 0.7% (W/W). This non-Ii soluble coating solution Two example formulations of liquids have the following formulations, where the amounts of ingredients are 100% of the solution. It is given in amounts per gram.

U-Σ circle--where"--prescription-"- Ethyl cellulose 10cps 0.1g 2.4g Pharmaceutical glaze 0.6g 13.8 g (total shellac solids content) (0.2 g) (4.8 g) modified eta Nol 0.6g suitable place In situ methylene 1 quantity Another particular embodiment of the invention provides that the core seed particles of the sustained release composition have pharmacological properties. In many applications of the present invention relating to compositions which also contain active substances and processes for their preparation. , the use of particles of a pharmacologically active substance with an average particle size of about 600 to about 850μ as seed particles 0, for example from about 10 to about 1, providing advantageous higher doses of the compositions of the invention. 00% more pharmacologically active substance in a standard volume sustained release using pharmacologically active species material Can be included in pellets. Such a composition has a higher assay) It can be referred to as a sustained release composition.

The present invention relates to the preparation of sustained release compositions containing theophylline as a pharmacologically active ingredient. We believe that it has been found that it can be used extremely widely. The following examples are in accordance with the invention. A method for preparing a sustained release pharmacological composition of theophylline is described.

Team Ooka Preferred theophylline-containing compositions are prepared using the following ingredients in the amounts indicated below. Ru.

1 litter, 1, 1, 1, 1, 1, 1, 1, 1 Theophylline υSP 60g (m powdered anhydrous powder) Non-pareil seed (25/30 mephistication fraction) 24g pharmaceutical glaze (4 bottles) fraction) 46g (total shellac solids content > (16g) Ethyl cellulose 10 cps 0.4 g Propylene glycol υSP 0.0 4g denatured ethanol amount Anhydrous powder of powdered theophylline was mixed with about 40 g of pharmaceutical glaze and about 37 g of modified ester. Disperse in ethanol using a mixer or homogenizer. Grand CPCG 5/ 9 A graft rotor equipped with a coating device and having parts such as those shown in the device of FIG. Granulator CGlatt Rotor Graaulator (Model R GR-5)) is used to coat the non-bareille variety charged in chamber 1. B The motor speed remains set at 150 rpm. Air pressure is 1.100c per hour d, the temperature of the introduced air is set to about 40℃, and the temperature of the fluidization ring is about Set to 30°C. The theophylline slurry was passed through two nozzles at approximately 50 ml of The flow rate varies between ~500 g/min and averages around 200 g/min. Spray inside the chemical ring.

About 5 g of pharmaceutical glaze containing 35% shellac solids and about 4 g of denatured alcohol. Add the remaining 10% to the slurry and then spray into the fluidization ring. All slurry After spraying, continue rotating to raise the temperature and guide the theophylline-selanx perleft. Dry for about 10 to about 30 minutes by adjusting the amount of air introduced. Remove this pellet from the offering , sieved and 12/20i! Collect the i-minute amount and dry it in a hot air dryer at about 70℃ for about 15 minutes. Dry for ~24 hours. The 12/200 fraction of dried Pelle 7) was re-rotagged. Introduced into the lanulator and fluidized by adjusting temperature, rotor speed, and introduced air volume. form a ring. 7g ethylcellulose and 0.8g per 100g solution Coating particles of ethyl cellulose with an alcohol solution containing propylene glycol The fluidization ring is sprayed until the content is about 0.4 wt%. This spray is complete Once done, the temperature of the introduced air is increased to about 50°C while rotation continues for about 5-10 minutes.

1 gong 5l Preferred high-potency theophylline-containing compositions are prepared using the following ingredients in the amounts listed below. make

Pharmaceutical glaze (4-hont fraction) 46g (total shellac solid content) (16g) Ethyl cellulose 10cps O, 4g Propylene glycol USP 0.04 　g Denatured ethanol　Quantity Approximately 46 g of anhydrous micronized theophylline powder was added in a mixer or homogenizer. Disperse in pharmaceutical glaze and approximately 42 g of denatured ethanol. Graft CP Grass 7 equipped with a CG5/9 coating device and having parts as shown in the device of FIG. Glatt Rotor Granulator (Motor 24 g of theophylline 25/3 charged in chamber 1 using a Dell RGR-5)) Coat with 0 mefushi powder. Set and maintain the rotor speed at 1'50 rpm and The pressure was set to 100 Or/h, the introduced air temperature was set to approximately 40°C, and the flow Set the heating ring temperature to approximately 30°C. Theophylline slurry is passed through two nozzles. through the fluidization at an increasing rate varying within the range of about 50 to about 500 g/min. Spray the ring. After spraying all the slurry, continue rotating and spray the theophylline-cera. By raising the temperature and reducing the introduced air volume by 1 g, the temperature of Fukubere 7 is about 50 to about 500. Dry for a minute. This pellet was removed from the specimen, sieved, and the 12/200 fraction was collected. This is dried in a hot air dryer at about 70° C. for about 15 to about 24 hours. dry bae Re-introduce the 12/20 fraction of the letto into the rotor granulator and adjust the temperature and rotor speed. Adjust the temperature and volume of air introduced to form a fluidized ring. per 100g of solution Contains 7g of ethylcellulose and 0.8g of propylene glycol.

The ethyl cellulose content of the coated particles is about 0.4 wt. % onto the fluidizing ring. After the completion of this spraying, the temperature of the introduced air The temperature is increased to about 50° C. and rotation is continued for about 5-10 minutes.

1 gong 5l Once the final spraying step is completed, the pellets prepared according to Example 2 above are Remain in the rotor granulator for approximately 5 minutes, at which point 100 g of denatured alcohol Contains ethylcellulose (2.4g) and pharmaceutical glaze (13.8g>) in the bottle. of the alcoholic solution until the solid content of the outermost coating becomes 0.15 wt%. Spray into the mixing chamber. Once this spraying operation is complete, the temperature of the introduced air should be about 50°C. Turn up and continue rotating for about 5-10 minutes.

The coated pellets prepared in Examples 1.2 and 3 can be encapsulated or formed into tablets. Wear.

The dissolution properties of pellets prepared according to the method of the invention were determined in the laboratory. On this occasion , the concentration of the dissolved drug substance as a function of pl of the environmental fluid and as a function of time. A dissolution apparatus was used that was installed to measure Those described in Examples 1 and 2 method and containing about 0.4@/w% ethylcellulose in the porous membrane layer. The time-dependent dissolution properties (pH-constant) of filin-containing compositions are shown in Table 1 below. Table 2 below shows the theophylline pellets prepared according to Example 1 above. shows time- and pH-dependent solubility properties of.

The data in the table below is expressed as the percentage of theophylline dissolved in the pellet. indicated, and the theophylline is constantly released from the composition and is in the patient's bloodstream for a period of time. It has been demonstrated that it provides a constant supply of theophylline over a period of time.

LL! L Knee H's - Ophirin Perate's)'3.5 51 49 5 9 10 87 B7 96 24 98 3B a): The paddles of the device attempt to dissolve 6 capsules of the composition set at 50 rpm. The solution initially contained 900 Ml of Pamphur at pH 3, which was added to water after 3.5 hours. Add sodium oxide p)! Changed to 7.4.

Ball 11: As H's - Offy 1 Impere To's "" LthI Le Lff2 1 red coin 5 gold coin 5 rumu 3,5515550524549474 9596456267586156605B60 697310 8387 7 981 7880 8080 B992a: Dissolution medium is 0.11i11c J including.

b: Dissolution medium is 0.05M sodium chloride and 0.05M monobasic f4 Contains #1 potassium, and by adding HCj or NaOH to it, each pH Adjust to

The controlled release properties and bioreceptivity of preferred theophylline-containing compositions of the present invention The dosage characteristics are such that patients suffering from asthma can take a predetermined dose approximately once or twice a day. ingestion, thereby maintaining therapeutic levels of the active ingredient in the bloodstream. and make it possible.

Additionally, the present invention provides a controlled release method that maintains a relatively constant concentration of active ingredient in the blood. It is also possible to formulate a composition to provide an extract composition. Fluctuations in blood concentration of active ingredients is reduced, resulting in increased therapeutic efficacy and reduced side effects.

In aspects of the compositions of the invention, the invention provides that a pharmacologically active agent, such as theophylline, is present in multiple layers. Contained within a single layer of coated pellets and providing sustained release of the active substance over approximately 12 hours The present invention relates to a sustained release composition.

A special embodiment of the compositions of the invention are high potency compositions, in which pharmacological The active substance also constitutes the seed core of the pellet. A preferred S type of the composition of the present invention is T. This is a pharmaceutical composition containing ophylline, which is useful for bronchial diseases such as asthma. It is particularly suitable for treating individuals with This is because this is the time of food intake, for example. or therapeutically active substances in the bloodstream for extended periods of up to 12 hours, regardless of their frequency. This is because it provides a means to maintain a suitable amount of theophylline. This preferable Mr. B is Compositions prepared by the above methods include a non-enteric coating of the outermost layer.

Claims (21)

[Claims] 1. A sustained release pharmacological composition comprising seed particles coated with a pharmacologically active compound-containing layer. A manufacturing method, (A) simultaneously exerting a centrifugal force, a vertical gravitational force, and a force substantially opposing the gravitational force on the seed particle; The seed particles are fluidized by applying positive fluid pressure at their periphery in the direction of a step of forming a (B) The pharmacologically active compound is added while the seed particles are kept in the ring-shaped suspended state. and the particles are coated with a liquid mixture containing an alkali-soluble substance. contact for a sufficient period of time to The above method, characterized in that it includes. 2. The fluidizing ring of the seed particles is placed in a dispersion medium containing lower alkyl alcohol. It is characterized by being filled with a suspension of bioactive particles and alkali-soluble substances. The method according to claim 1. 3. characterized in that the fluid used to form the fluidized ring includes an inert gas; The method according to claim 2, characterized in that 4. The inert gas is maintained at a temperature sufficient to volatilize the dispersion medium. The method according to claim 3, wherein: 5. 5. The method of claim 4, wherein the temperature of said gas is from about 30 to about 75<0>C. 6. A suspension of the above pharmacologically active compound and an alkali-soluble substance is flowed through the above seed particles. 6. The method according to claim 5, characterized in that the oxidation ring is sprayed. 7. A claim characterized in that the diluent is substantially volatilized to form coated particles. The method described in item 6. 8. (C) The coated seed particles were suspended in a fluidized ring shape and maintained in this state. porous, containing a mixture of alkali-insoluble and acid-insoluble components and water-soluble components By contacting the coated seed particles with a membrane forming solution, a porous membrane is formed on the coated particles. 8. A method according to claim 7, characterized in that: 9. The above porous membrane forming solution is lower alkylene glycol and lower alkyl cell. 9. A method according to claim 8, characterized in that it comprises a rose ether material. 10. characterized in that the pharmacologically active compound contains theophylline or a derivative thereof; The method according to claim 9. 11. Claims characterized in that the alkali-soluble substance includes Sierrac. The method according to item 10. 12. The seed particles have an average particle size of about 600 to about 725 u. The method described in item 11. 13. (A) At the same time, the seed particle is subjected to centrifugal force, vertical gravitational force, and substantially compatible with said gravitational force. Applying positive fluid pressure at the periphery in the opposite direction to form a fluidized ring of the seed particles death, (B) Fill the ring with an alcoholic suspension of theophylline particles and shellac. and the seed particles suspended in the ring are coated with theophylline-coated core particles. in contact with the suspension for a sufficient period of time to form; and (C) The coated core particles are suspended in a fluidized ring shape and maintained in this state. , a solution containing a mixture of an alkali-insoluble and acid-insoluble component and a water-soluble component, and the coating. A method of producing a sustained release theophylline composition comprising the step of contacting the composition with a core particle. . 14. The suspension of theophylline in the lower alkyl alcohol is about 14 to about 17 Pharmaceutical glaze comprising from about 52 to about 65 wt% shellac and average particle size Claim 13 comprising from about 1 to about 20 u of theophylline powder. Method described. 15. The above coated core particles are coated with lower alkyl glycol and lower alkyl cellulose. - Claim No. 1 characterized in that it is coated with an alcoholic solution of an ether substance The method described in item 14. 16. A sustained release Asahi composition obtained according to claim 1. 17. Seed particle core, monolayer containing pharmacologically active substance, and alkali-insoluble and acid-insoluble Sustained release pharmacological composition comprising a porous film-forming coating containing a mixture of a water-soluble component and a water-soluble component A product. 18. including an outermost coating formed from a mixture of materials, one of which is an acid One is insoluble and alkali-insoluble, the other is alkali-soluble and acid-insoluble. The composition according to claim 17, characterized in that: 19. The pharmacologically active substance is theophylline or a derivative thereof. 19. The composition according to claim 18. 20. Claim 17, characterized in that the seed particles contain a pharmacologically active substance. composition. 21. blood in patients with bronchial disease, regardless of the time and frequency of food intake. maintaining a therapeutically effective and substantially unaltered amount of theophylline in the blood stream. A method of treating a patient comprising: a composition prepared according to claim 19; The above characterized in that the therapeutically effective dosage is administered to said patient about twice per day. Treatment.