JP2541835B2 - Process for producing sustained-release pharmacological composition and composition obtained thereby - Google Patents

Description

Description: FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions of the type useful for the release of biologically active substances into the body over an extended period of time and methods of preparing such types of compositions. Regarding According to a particular aspect of the invention, the invention relates to a method of preparing a composition effective for releasing theophylline or a derivative thereof into the body over an extended period of time.

Theophylline and its derivatives are known biologically active substances used, for example, as bronchodilators.
It has long been known that theophylline tends to be problematic when administered in oral dosage forms. Gastrointestinal, CNS and cardiovascular side effects due to transient blood levels are not uncommon. To avoid or prevent problems such as those mentioned above, theophylline is administered in an enteric-coated and controlled-release form, which allows a predetermined dose of theophylline to release the enteric matrix and theophylline into the stomach. , And many attempts to administer it in a dosage form with a coating that allows it to pass through the intestine and at a controlled rate there over a relatively long period of time, eg 6-12 hours. It has been done.

Reported Developments Various dosage forms of enteric-coated, sustained-release medications (including theophylline) have been described in US Pat. Nos. 3,109,775 and 4,0.
83,949, 4,261,970 and PCT application publication No. WO83 /
00284 and the like. Generally speaking, said patent discloses a pharmacologically active substance which is slowly dissolving in a coating or enclosed in a porous substance which is insoluble in the acidic environment of the stomach and which is capable of passing the active substance and releasing it into the intestine. There is. For example, a typical sustained release formulation comprises an inert core, such as sugar granules, and an adhesive material coated with the pharmacologically active agent applied thereto. The amount of active substance can be increased by providing further layers on top of the layer of adhesive coating and active substance. Once the predetermined amount of active substance has been applied, the multilayer structure is coated with a permeable membrane. The membrane is resistant to dissolution (otherwise it is degraded in the stomach and intestine) and certain pharmacological agents such as theophylline, depending on their dissolution in the liquid solvent of the intestine, It can be passed through the pores of the membrane.

One problem with theophylline preparations is that they are significantly soluble in the acidic environment of the stomach, causing a relatively high concentration of theophylline to be released into the stomach, where it is absorbed locally and systemically as theophylline is absorbed. It has side effects. U.S. Pat. No. 4,083,949 discloses a film prepared from a liquid mixture of a film-forming material and an acid-insoluble and alkali-soluble material. Such a membrane is said to substantially prevent the early release of theophylline in the acidic environment of the stomach. However, the use of such membranes can lead to an unreasonably fast release of theophylline in the intestine. Problems of this type have been addressed by the preparation and use of sustained release compositions, which have been prepared in a number of ways.

Sustained-release compositions are generally prepared by utilizing a continuous coating of various materials, each of which is individually painstakingly applied to remove the pharmacologically active agent by successive peeling of the applied layers of the material. Ensures a gradual release. The coating method for obtaining such a composition can be carried out in a rotary coating plate (pam) which is usually used in the production of sugar-coated pills. In one of the conventional methods using coated dishes, a sustained release theophylline formulation is obtained by applying a liquid alkali-soluble adhesive substance to a batch of seed particles and then adding micronized particles of solid theophylline. . More specifically, this method included the following steps.

(A) forming a wet layer of an alkali-soluble adhesive substance on the seed, then contacting the wet seed particles with micronized theophylline; (B) drying the wet layer containing theophylline; (C) forming one or more layers of additional alkali-soluble adhesive material on the dried layer and then contacting it with micronized theophylline, wherein each of said one or more layers is first wet. Formed, and then each of said wetting layer or each of said plurality of wetting layers is dried before applying any top material thereto; (D) capable of forming pores and (1) acid-insoluble and alali-soluble material (2) coating the multilayer core with a film containing a water-soluble material; and (E) (1) an acid-insoluble and alkali-soluble material, and (2)
Applying a non-enteric coating containing an acid-insoluble and an alkali-insoluble material on the film.

Although the theophylline-containing compositions prepared by this dish-coating technique exhibit many of the desirable properties in sustained release formulations, the dish-coating process involved about 20 or more repeated and time-consuming layering and drying steps. .

Fluidized bed and column methods have also been utilized to prepare sustained release compositions. In these methods, the seed particles are suspended by a stream of air, coated by the addition of adhesive substances and powder components, and also involve a number of time-consuming and costly layer-forming steps. International publication No.
In WO / 83/00284, a Glatt column air suspension system is used to apply multiple layers of suspensions of theophylline and polyvinylpyrrolidone and isopropanol to airborne seed particles. This multi-layered product is then coated with a mixture of cellulosic materials. It has been reported that the product, which is believed to be prepared according to the above method, exhibits inhibited release when administered at the same time as or shortly after ingestion of food.

It is an object of the present invention to provide a process for the preparation of sustained release compositions which is relatively simple, comprises a minimum number of coating steps and gives a composition characterized by optimum time delayed release properties according to the eating and drinking behavior of the patient. To provide.

SUMMARY OF THE INVENTION According to the present invention, there is provided a method for producing a sustained release type pharmaceutical composition comprising seed particles coated with a pharmacologically active compound-containing layer, which method comprises the following steps: (A) Simultaneously with the above seed particles. A centrifugal fluid, a vertical gravity, and a positive fluid pressure at a peripheral portion substantially in the direction opposite to the gravity to form a fluidized ring of the seed particles, and (B) in the ring shape. A step of bringing the particles into contact with the liquid composition containing the pharmacologically active compound and the alkali-soluble substance for a sufficient time to coat the particles while maintaining the floating state.

According to another aspect of the present invention, the present invention relates to a sustained release composition, which composition releases a pharmacologically active ingredient at a predetermined rate under the action of gastrointestinal fluid and has a seed core, said pharmacologically active ingredient. A single layer containing the components and a pore-forming seal coating. Particularly preferred features of the compositions of the invention are fasting and / or
Or, it has a relatively poor release profile under dietary intake conditions.

According to yet another aspect of the present invention, the present invention relates to a method for treating physiological disorders, for example bronchial diseases such as asthma, which method comprises the oral ingestion of the above-mentioned pharmaceutical composition by an individual, wherein the formulation. Can be administered at pre-determined time intervals regardless of whether there is food in the digestive tract of the individual.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a cross-sectional side view of an annular mixing and granulating apparatus illustrating the fluidization and coating method of particles according to the present invention.

DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used herein should be understood to have the definitions set out below.

The "alkali-soluble substance" is soluble under intestinal alkaline conditions, which is suitable for use in forming a sustained-release drug, and, in forming a coating of the sustained-release composition of the present invention,
It means a substance that can function as a binder for aggregating particles of a pharmacologically active compound.

By "enteric coating" is meant a coating that allows a drug to pass through the stomach without being substantially released into the gastric juices.

"Membrane" means a semipermeable structure through which water and other molecules of similar size can pass.

By "non-enteric coating" is meant a coating capable of releasing the drug into the stomach and which may be continuous, discontinuous, irregular or non-uniform.

By "pore" is meant an opening through which molecules of a size larger than water can pass.

A "seed" is a small particle of material suitable for use in sustained release pharmaceutical compositions and having an average particle size of about 600-850 [mu]. One example of such a substance is a combination of sugar and corn starch.

“Theopheylline” means theophylline and its derivatives, which are bronchodilators effective for the relief of asthma, such as guaitilin (3,7-dihydro-1,3-dimethyl-1H-purine-2, 6-dione and 3-
(2-methoxyphenoxy) -1,2-propanediol in a 1: 1 formulation).

According to the invention, a predetermined amount of seed particles 7 is introduced into the chamber 1 of the mixing and coating device shown in FIG. 1, while the rotating disc 2 is rotated around the shaft 3 and is indicated by the arrow 8. A positive fluid pressure is applied through the clearance 4. here,
The fluid preferably comprises an inert gas such as air, nitrogen or carbon dioxide and is emitted from a gas source not shown in FIG. The rotating rotating disc 2 exerts a centrifugal force on the seed particles to move them towards the wall 5 of the chamber.
Here, the pressure due to the upwardly moving fluid is indicated by the arrow 8 and gives the particle 7 an upward movement that is substantially opposite to gravity. The chamber wall 5 according to the embodiment of the device shown in FIG. 1 comprises an outwardly inclined portion 5a and an inwardly inclined portion 5b.
The outwardly inclined portion 5a can act to adjust the volume of fluid passing through the clearance 4 together with the rotating rotating disc 2. On the other hand, the inwardly inclined portion 5b has a function of deflecting upwardly moving particles 7 to the center of the chamber 1. The particles 7 rise in the chamber 1 until gravity overcomes the fluid force reduction. Then, the particles 7 descend toward the center of the rotating disc 2. The movement of the seed particles 7 is two-dimensionally depicted by lines U, D and O in FIG. Also, the resulting shape and movement of seed particles 7 is referred to as a "fluidized ring" throughout this application. Of course, the particles 7 are not only two-dimensionally constrained, but also rotate within the volume of the fluidizing ring as a result of the rotation of the disc.

In the method of the present invention, the liquid coating composition containing the pharmacologically active substance and the alkali-soluble substance is introduced into the chamber 1 by a suitable means, for example, one or more spray nozzles. Thereby the liquid coating composition comes into contact with the seed particles 7 as the particles roll in the chamber and pass through the space where the coating composition is introduced into the ring. This seed particle 7
The preferred method for coating the particles comprises spraying a fine spray mixture of air and an atomized liquid coating composition through a nozzle 6, and the coating of the particles is first sprayed from an inlet nozzle 6. It occurs as the particles pass through the volume of the coating composition.

To simplify the spraying operation, the liquid coating composition contains a diluent, such as a lower alkyl alcohol or a low boiling haloalkyl solvent, with a preferred diluent being ethanol,
Isopropanol, methylene chloride and mixtures thereof. Water can also be included in the coating composition in an amount effective for this purpose to control the amount of static electricity generated during the coating process. Use an effective amount of water to prevent static electricity
It has been found that it can be used in the coating composition without adversely affecting the dissolution rate of the sustained release composition. The spray rate into the fluidizing ring must be sufficient to distribute the coating composition evenly throughout the fluidizing ring of seed particles. Moreover, the spray rate depends on the number of spray nozzles used in the process, the amount of seed particles contained in the fluidizing ring and the shape, viscosity and properties of the coating composition. Typical spray rate is about 50 to about 700g
The range is / min / nozzle.

In a preferred embodiment of the method of the present invention, the coating composition comprises a suspension of solid particles of the pharmacologically active substance in a liquid dispersion containing a lower alkyl alcohol. The suspension also contains a liquid or solid alkali-soluble substance. The lower alkyl alcohol facilitates mixing of the suspension with the fluidizing ring of seed particles 7 and provides a clog-free spray of the suspension. The lower alkyl alcohol can be ethanol (denatured and / or 200 proof), isopropanol, n-propanol or mixtures thereof.

The size of the solid particles of the pharmacologically active substance has a considerable effect on the sustained release properties of the final product. In order to optimize the release rate of the pharmacologically active substance, the solid particle size of the pharmacologically active substance should be "micronized", that is, from less than about 1 to about 50μ or about 300 mesh based on the micromerograph measuring device. Alternatively, it is preferable that the size is measured as being larger than that.

Advantageously, this suspension contains a certain amount of solid pharmacologically active particles, which facilitates and facilitates atomization of the suspension into the fluidizing ring. An effective amount of solid particles in the suspension can be from about 30 to about 60 g per 100 g suspension, preferably from about 40 to about 55 g per 100 g suspension. It is also advantageous to coat the seed particles with an amount of pharmacologically active particles so as to form a complete and continuous coating of the agglomerated particles on the surface of the seed particles. It should be understood that the total amount of the pharmaceutical composition in the sustained release composition should be sufficient to provide the source of active agent over the entire sustained release period. There are many variables involved in the formulations and methods of the present invention that can achieve the above release rates of the pharmacologically active agent in a sustained release composition, the composition being about 40 to about 40 such active agent on a total dry weight basis. 90wt%, preferably about 50 ~
About 65 wt% can be included.

The rotation speed of the rotating shaft 3 and the positive fluid pressure 8 are adjusted to obtain a state suitable for forming a "fluidizing ring" of the solid particles 7 and forming a uniform layer of coating material on the seed particles. Typical rotor speeds range from about 100 to about 300 rpm, preferably from about 120 to about 200 rpm, and can be varied within this range during the coating process. Fluid pressure will vary depending on the amount of material introduced into chamber 1 and may range from about 30 to about 60 psi.

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

An example of a device that may be used in the present invention is Glatt Air Techniqu
e., Inc.) and Rotor Granulators marketed by Vector Corpotation and Vector / Freund Spir-
a-Flow). In the latter spill-aflow system, an additional force is applied to the coating process. The force is due to the air being pressed in through a large number of perforations provided inside the rotating disc. This incidental force creates vortices and flow inside the fluidizing ring and helps improve the efficiency of the coating operation and increase its speed.

For some applications it is advantageous to provide an additional coating on the coated seed particles 7. This additional coating comprises a porous membrane having pores of sufficient size to allow the passage of pharmacologically active compounds such as theophylline,
(C) A porous film-forming solution containing a mixture of an alkali-insoluble and acid-insoluble component and a water-insoluble component is added to the above step (B).
It can be obtained by filling a fluidizing ring containing the coated seed particles prepared by. Preferably, the porous membrane-forming mixture is acid-insoluble and alkali-insoluble (a substance that would otherwise be degraded in both the gastric and intestinal environment and dissolved in the gastric and intestinal aqueous environment to form pores in the membrane). In a preferred form, the ratio of film-forming material to water-soluble material in the membrane and film-forming solution is from about 5: 1 to about 20: 1, more preferably from about 8: 1 to about 1.
It is 5: 1. Examples of such porous film-forming solutions are about 5 to about 10 g, preferably about 6 to about 8 g of acid-insoluble and alkali-insoluble material per 100 g of coating solution and about 0.5 to about 1 g, preferably about 0.6, per 100 g of coating solution. To about 0.8 g of water soluble material. The amount of film-forming material combined with the particles coated in step (B) above may range 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.

A uniform film is desirable in many applications. Such membranes are believed to provide a reproducible and controlled rate of dissolution of the underlying pharmacologically active substance. It has been found that the use of a dilute thin film forming solution results in a more uniform film than a more concentrated solution, and that a composition having a more uniform film and containing a smaller amount of film forming material has a predetermined content. It has also been found that compositions having sustained release characteristics, and conversely having a more heterogeneous film, also require higher amounts of film forming material to exhibit the desired release characteristics. Therefore, for many applications of the present invention, a low concentration of the porous film forming solution is used to formulate the sustained release composition of the present invention to achieve the film formation required to achieve its desired sustained release properties. It is possible to reduce the total amount of substance.

Generally, and as described in detail below, the film can be formed by combining the coated seed particles with a solution containing a solvent in which a mixture of the materials is dissolved. Examples of solvents include lower alkyl alcohols such as ethanol (denatured and 200 proof), isopropanol or n-propanol or haloalkyls such as methylene chloride or carbon tetrachloride. The solid pore-forming film is formed when the solvent is evaporated from the solution.

Cellulose ethers are preferably used as acid-insoluble and alkali-insoluble film-forming substances, most preferably lower alkyl cellulose ethers such as ethyl cellulose. For water-soluble substances, it is preferred to use lower alkylene glycols, such as propylene glycol. In a more preferred form, the resulting sustained release composition porous membrane comprises ethyl cellulose and propylene glycol. The following solutions can be advantageously used, the amounts of the components are the values based on 100 g of the solution. Amount per 100 g of component Ethyl cellulose 10 cps 7 g Propylene glycol 0.8 g Modified ethanol Suitable amount This porous film-forming solution was prepared by spraying the solution on the fluidizing ring containing the seed particles coated in the step (B). Applied to coated seed particles. This spray rate is due to the differences between these two liquid spray formulations, including the amount of the substance in each liquid composition, as well as the difference in the predetermined thickness of each layer or coating from the coating of step (B). It may be different from that used for. This rate can also be varied as a function of the size of the batch of material processed in the chamber. In a preferred application, the film-forming solution contains about 20-
It is applied at a temperature in the range of about 1000 g / min / nozzle, and in the most preferred application at a rate of about 20 to about 500 g / min / nozzle.

At the completion of each coating operation, the fluidized ring movement of the coated particles is maintained and heating is continued to dry the coated particles and remove the volatile diluent contained in the spray composition. . Complete drying of the coated particles is achieved by the operation following the coating operation carried out in the chamber 1. However, some considerations, including the nature of the diluent, the desired thickness of the coating and the mechanical limitations of the mixing equipment, may require a separate drying operation. For applications in which these considerations are valid, the partially dried coated particles are removed from chamber 1 and these dried in a separate drying device,
For example, it is completed with a hot air dryer or the like.

Certain aspects of the invention include compositions having an outermost layer coating as follows. That is, the coating allows the aqueous contents of the stomach to pass through and dissolves less of the water-soluble substance from the underlying membrane than that which constitutes the membrane. This non-enteric coating can be present as a discontinuous, irregular or non-uniform film shape, covering only a portion of the surface of the membrane, or as a thin continuous film with minimal structural integrity. Thus, in the acidic environment of the stomach, pharmacologically active ingredients, such as theophylline, are released only in small amounts, the majority of which are retained within the globules.

The outermost, and preferably non-enteric, coating described above can be formed from a mixture of substances, one of which is acid-insoluble and alkali-insoluble, otherwise in both the gastric and intestinal environment. Will be decomposed by. Another material of the mixture is alkali soluble but acid insoluble. Typically, this coating dissolves the solid material in a suitable solvent,
It is formed by spraying and applying the resulting solution to the membrane-coated particles described above. As the solvent evaporates, a film consisting of each matrix of the substance is also formed on the membrane from the alkali-soluble and acid-insoluble substance, which causes the water-soluble components of the membrane to a limited extent to the stomach. Protected against dissolution in an aqueous environment. The acid-insoluble, alkali-insoluble material of the coating preferably comprises cellulose ethers, most preferably ethyl cellulose. The acid-insoluble, alkali-soluble substance of the coating comprises shellac, cellulose acetate phthalate, a copolymer of methacrylic acid and methacrylic acid ester, with shellac as the pharmaceutical glaze being most preferred.

It is also preferred that the ratio of acid insoluble, alkali insoluble material to acid insoluble, alkali soluble material is about 0: 1 to about 1: 1. An example of a non-enteric coating solution is about 0.
05 to about 0.5 g, preferably about 0.08 to about 0.3 g of acid-insoluble, alkali-insoluble substance and about 0.05 to about 100 g per 100 g of coating solution.
It contains 0.8 g, preferably about 0.1 to about 0.4 g of acid insoluble and alkali soluble material. Based on the total weight of the coated particles, the weight% of material applied by this coating solution is, for example, about 0.05.
Can range from about 0.7% (w / w). Two exemplary formulations of this non-enteric coating solution have the following formulations, where the amounts of ingredients are given per 100 g of solution.

Another particular aspect of the invention relates to compositions and methods of making the same, wherein the seed particles that form the core of the sustained release composition also include a pharmacologically active agent. In many applications of the present invention, the use of particles of pharmacologically active agent having an average particle size of about 600 to about 850μ as seed particles provides an advantageous higher dose dosage form of the compositions of the present invention. For example, about 10 to about 100% more pharmacologically active agent can be included in a standard volume sustained release pellet obtained with the pharmacologically active species agent. Such compositions can be referred to as "higher assay" sustained release compositions.

It is believed that the present invention has been found to have significantly broader utility in the preparation of sustained release compositions containing theophylline as the pharmacologically active ingredient. The following examples describe methods of preparing theophylline sustained release pharmaceutical compositions according to the present invention.

Example 1 A preferred theophylline-containing composition is prepared using the following ingredients in the amounts shown below. Ingredients per 100 g Theophylline USP (micronized anhydrous powder) 60 g Nonpareil seeds (25/30 mesh fraction) 24 g Pharmaceutical glaze (4 pound fraction) 46 g (total shellac solids content) (16 g) Ethyl cellulose 10 cps 0.4 g propylene glycol USP 0.04 g denatured ethanol qs anhydrous powder of micronized theophylline is dispersed in about 40 g pharmaceutical glaze and about 37 g modified ethanol with a mixer or homogenizer. It is installed in the chamber 1 using a Glatt Rotor Granulator (Model RGR-5) equipped with the Glatt GPCG 5/9 coating apparatus and having the parts shown in the apparatus of FIG. Cover non-pareil seeds. Rotor speed set and maintained at 150 rpm. The air pressure is set at 1,100 m ^{3 /} hour, the temperature of the introduced air is set at about 40 ° C, and the temperature of the fluidizing ring is set at about 30 ° C. Varying the slurry of theophylline through two nozzles in the range of about 50 to about 500 g / min,
And spray into the fluidizing ring at a rate of averaging about 200 g / min.

About 5g and about 4g of pharmaceutical glaze with 35% shellac solids
Of denatured alcohol is added to the remaining 10% slurry and then sprayed onto the fluidizing ring. After spraying all the slurry, continue to spin and dry theophylline-shellac pellets for about 10 to about 30 minutes by increasing the temperature and adjusting the amount of air introduced. The pellets are removed from the chamber, screened to collect the 12/20 fraction, and dried in a hot air oven at about 70 ° C. for about 15 to about 24 hours. The 12/200 fraction of the dried pellets is reintroduced into the rotor granulator and the temperature, rotor speed and air volume introduced are adjusted to form a fluidization ring. solution
An alcoholic solution containing 7 g ethyl cellulose and 0.8 g propylene glycol per 100 g is sprayed onto the fluidizing ring until the coated particles have an ethyl cellulose content of about 0.4 wt%. When the atomization is complete, the temperature of the inlet air is raised to about 50 ° C, while rotation is continued for about 5-10 minutes.

Example 2 The following ingredients are used in the following amounts to prepare a preferred high potency theophylline-containing composition. Ingredients per 100 g Theophylline USP (micronized anhydrous powder) 60 g Anhydrous theophylline USP (25/30 mesh fraction) 24 g Pharmaceutical glaze (4 pound fraction) 46 g (total shellac solids content) (16 g) Ethyl cellulose 10 cps 0.4 g Propylene glycol USP 0.04 g denatured ethanol qs Anhydrous powder of micronized theophylline is dispersed in about 46 g pharmaceutical glaze and about 42 g denatured ethanol in a mixer or homogenizer. The Glatt Rotor Granulat equipped with a Glatt GPCG 5/9 coating device and having parts as shown in the apparatus of FIG.
or (model RGR-5)] was used to load 24g into chamber 1.
Of theophylline 25/30 mesh powder. The rotor speed is set and maintained at 150 rpm, the air pressure is set at 1000 m ³ / h, the inlet air temperature is set at about 40 ° C, and the fluidizing ring temperature is set at about 30 ° C. A slurry of theophylline is sprayed through the two nozzles onto the fluidizing ring at increasing rates that vary within the range of about 50 to about 500 g / min.
After spraying all the slurry, continue to rotate the theophylline-
The shellac pellets are dried for about 10 to about 300 minutes with increasing temperature and adjusting the volume of air introduced. The pellets are removed from the chamber, screened to collect 12/200 fractions, which are dried in a hot air oven at about 70 ° C. for about 15 to about 24 hours. The 12/20 fraction of the dried pellets is reintroduced into the rotor granulator and the temperature, rotor speed and air volume introduced are adjusted to form a fluidizing ring. The fluidized ring is sprayed with an alcoholic solution containing 7 g of ethyl cellulose and 0.8 g of propylene glycol per 100 g of solution until the ethyl cellulose content of the coated particles is about 0.4 wt%. After the atomization is complete, the temperature of the introduced air is raised to about 50 ° C and the rotation is continued for about 5-10 minutes.

Example 3 Pellets prepared according to Example 2 above were maintained in the rota-granulator for about 5 minutes after the last spraying step indicated, at which point ethyl cellulose (2.4 g) and pharmaceutical grade in 100 g denatured alcohol. Glaze (13.8
An alcoholic solution containing g) is sprayed into the mixing chamber until the solids content of the outermost coating is 0.15 wt%. When this spraying operation is completed, raise the temperature of the introduced air to about 50 ° C,
Continue spinning for about 5 to about 10 minutes.

The coated pellets prepared in Examples 1, 2 and 3 can be encapsulated or formed into tablets.

The dissolution properties of pellets prepared according to the method of the invention were measured in the laboratory. In this case, a dissolution apparatus was used, which was installed so as to measure the concentration of the dissolved drug substance as a function of the pH of the environmental fluid and as a function of time. Prepared by the method described in Examples 1 and 2 and about 0.4 w / w for the porous membrane layer.
The time-dependent dissolution properties (pH = constant) of theophylline-containing compositions containing 10% ethyl cellulose are shown in Table 1 below. Table 2 below shows the time- and pH-dependent dissolution characteristics of theophylline pellets prepared according to Example 1 above. The data presented in the table below is expressed as a percentage of dissolved theophylline in the pellet, which provides a steady release of theophylline from the composition and a consistent supply of theophylline over time in the patient's bloodstream. Has proved to bring.

The controlled release and bioreceptive properties of the preferred theophylline-containing compositions of the present invention allow asthma suffering patients to take a predetermined dose about once or twice a day, resulting in It makes it possible to maintain therapeutic levels of the active ingredient in the bloodstream. Further, the present invention provides
It may also be formulated to give a controlled release composition, which maintains a relatively constant concentration of active ingredient in the blood. Fluctuations in the blood concentration of the active ingredient are reduced, so that the therapeutic effect is increased and side effects are reduced.

In an aspect of the composition of the present invention, the present invention provides a pharmacologically active substance,
For example, it relates to a sustained release composition in which theophylline is contained within a single layer of a multi-layer coated pellet and which releases the active substance over a period of about 12 hours. A particular embodiment of the composition of the present invention is a high titer composition in which the pharmacologically active substance also constitutes the seed core of the pellet. A preferred embodiment of the composition according to the invention is a theophylline-containing pharmacological composition, which is particularly suitable for the treatment of individuals with bronchial diseases, such as asthma. This is because it provides a means of maintaining a therapeutically effective amount of theophylline in the bloodstream for extended periods of time, for example up to 12 hours regardless of the time or frequency of food intake. This preferred embodiment comprises a composition prepared by the above method which includes a non-enteric coating on the outermost layer.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Maita Gamwanto Nashubuhai United States of America Pennsylvania 19446 Landsdale Valley View Way 2041 (72) Inventor Jawa Ramesh Chandra United States of America Pennsylvania 19067 Yardley Scarlet Oak Road 1428 (72) Inventor One Lian Lee United States Pennsylvania 19002 Maple Glen Terrace Drive 1545 (72) Inventor Grim Wayne Martin United States Pennsylvania 18901 Doylestown Yorkshire Drive 2990 (72) Inventor Richen Poe United States Pennsylvania 19082 Upper Derby Merion Terrace 7200 (56) three Document JP-T Akira 58-501128 (JP, A)

Claims (21)

(57) [Claims] 1. A method for producing a sustained-release pharmacological composition containing seed particles coated with a pharmacologically active compound-containing layer, comprising: (A) simultaneously applying centrifugal force, vertical gravity, and gravity to the seed particles. Forming a fluidized ring of the seed particles by applying positive fluid pressures at the peripheral portions in substantially opposite directions, (B) while keeping the seed particles in the ring-like floating state A step of contacting the particles with a liquid composition containing the pharmacologically active compound and an alkali-soluble substance for a time sufficient to coat the particles, and (C) floating the coated seed particles in a fluidized ring shape. And forming a porous film on the coated seed particles with a porous film-forming solution containing a mixture of an alkali-insoluble and an acid-insoluble component and a water-soluble component and the coated seed particles while maintaining this state. Work to contact for a sufficient time The method, which comprises a. 2. The fluidized ring of the seed particles is filled with a suspension of pharmacologically active particles and an alkali-soluble substance suspended in a dispersion medium containing a lower alkyl alcohol. The method described in. 3. The method of claim 2 wherein the fluid used to form the fluidizing ring comprises an inert gas. 4. The method according to claim 3, wherein the inert gas is maintained at a temperature sufficient to volatilize the dispersion medium.
The method described in the section. 5. The method of claim 4 wherein the temperature of the gas is about 30-75 ° C. 6. The method according to claim 5, wherein the suspension of the pharmacologically active compound and the alkali-soluble substance is sprayed onto the fluidized ring of the seed particles. 7. The method of claim 6 wherein the dispersion is substantially volatilized to form coated particles. 8. The method according to claim 1, wherein the porous film forming solution contains a lower alkylene glycol and a lower alkyl cellulose ether material. 9. The method according to claim 8, wherein the pharmacologically active compound comprises theophylline or a derivative thereof. 10. The method of claim 9 wherein the alkali soluble material comprises shellac. 11. The method of claim 10 wherein said seed particles have an average particle size of about 600-850μ. 12. (A) Fluidization of seed particles by simultaneously applying centrifugal force, gravity in the vertical direction, and positive fluid pressure at the peripheral portion in a direction substantially opposite to the gravity to the seed particles. Forming a ring, (B) filling the ring with an alcoholic suspension of theophylline particles and shellac and sufficient to form the theophylline-coated core particles with the seed particles suspended in the ring. A step of keeping in contact with the suspension for a period of time, and (C) floating the coated core particles in a fluidized ring shape and maintaining this state, to prepare a mixture of an alkali-insoluble and acid-insoluble component and a water-soluble component. The method according to claim 1, comprising a step of bringing a solution containing the coated core particles into contact with each other. 13. A pharmaceutical glaze of from about 52 to about 65% by weight, wherein said theophylline suspension comprises from about 14 to about 17% by weight of shellac in a lower alkyl alcohol, and an average particle size of from about 1 to about.
The method according to claim 12, characterized in that it comprises 20μ of theophylline powder. 14. The coated core particles are coated with an alcoholic solution of a lower alkyl glycol and a lower alkyl cellulose ether material.
The method described in paragraph 13. 15. The method of claim 1 wherein said seed particles are compatible with said active compound and have an average particle size of about 600 to about 850μ.
The method described in the section. 16. The method of claim 15 wherein said seed particles are contacted with said liquid composition in a single coating application. 17. The method of claim 16 wherein said liquid composition comprises about 40 to about 55% by weight of said active compound. 18. A seed particle core, a single layer containing a pharmacologically active substance,
And a porous film-forming coating containing a mixture of an alkali-insoluble and acid-insoluble component and a lower alkylene glycol. 19. An outermost coating formed from a mixture of substances, one of which is acid-insoluble and alkali-insoluble and the other of which is alkali-soluble and acid-insoluble. Composition according to clause 18. 20. The composition according to claim 19, wherein the pharmacologically active substance is theophylline or a derivative thereof. 21. The composition according to claim 18, wherein the seed particles are contained in a pharmacologically active substance.