JPH05509088A - Composition containing particulate matrix - 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] Composition containing particulate matrix The present invention provides drug-containing polymeric matrix systems, in particular tailored, sustained Preferably, such systems, preparations thereof, providing pH-independent drug release, and their use in therapy.

Microencapsulation is a well-known encapsulant technique for use in orally administrable drugs. It is the law. Furthermore, the drug can be removed from the drug-portion by a common method known as solvent evaporation. It is also known to incorporate it into remer matrices. formed by solvent evaporation method The matrix has the active substance dispersed throughout its matrix structure. . Thus, they are different from drug microcapsules with a distinct polymeric outer wall. distinguished.

Separate drug-matrix formed by solvent evaporation method resulting in polymer particles The box structure can be either a homogeneous microporous system or a heterogeneous macroporous system. The matrix particles are uniform if they are evenly distributed. macroporous matrix Trix particles are two-phase heterogeneous structures consisting of separate drug and polymer dispersed phases. has. The different refractive indices of these two phases create turbidity in the polymer matrix. to impart an opaque appearance to the matrix particles.

Both drug microencapsulation and matrix formation can be achieved using standard drug delivery methods. It offers many advantages over the Lee system. These are: (a) e.g. The physical properties of the drug can be improved by providing a free-flowing powder preparation. (b) as a means of masking the taste of bitter drugs and concealing unpleasant odors; Providing: (C) Includes providing a means for regulating and sustaining the release of the drug.

GB2166651A (!Elan Corporation ation)) is used in sustained release compositions, produced by solvent evaporation method, Modified release drug powder containing discrete microparticles (''T Armasome (Pharmas) omes).

The microparticles include one active ingredient, at least one non-toxic polymer, and the microparticles. Contains optional excipients uniformly distributed throughout the child matrix. wide range of drugs and Pharmasomes made from polymer or copolymer materials are disclosed. .

Examples include, inter alia, cellulose acetobutylide, ethylcellulose and and Eudragit R5-100. describes microparticles made from copolymer materials. Eudragit R5-1 00 is an acrylate with a small amount of quaternary ammonium group and a counterion of chloride ion. It is a copolymer of lyle and methacrylic acid ester. (Eudragit is Rome (commercial name of Rohm Pharma).

European Patent Application Publication No. 0212641 (Searle) The active ingredient has basic properties and several carboxylic acids and esters. consisting of a pharmaceutically acceptable copolymer (anionic copolymer) having a group of a porous drug-polymer matrix, the matrix having a pH value of 4 or higher; Porous drug-polymer matrices that release the active ingredient in a medium under Ru.

The invention's porous drug-polymer matrix masks the taste of active ingredients. , has been described as having utility in making its release effective under the acidic conditions of the stomach.

Porous matrices such as those described in EPA-0212641 are rocapsules result in significant release of active ingredients only at alkaline pH, and polymer – The active ingredient is transferred to an anionic polymer as the film is insoluble at acidic pH values. It is distinguished from microcapsules manufactured by completely covering them with a material. medicine Agent - The porosity of the polymer matrix increases the release of the active ingredient in acidic media. It is stated that it can be done. Eudragit L-100 and Eudragit S-1 Taste masks made from anionic polymers and copolymers including 00 ing compositions are described. Eudragit L-100 and S-100 are It is a copolymer of tacrylic acid and methyl methacrylate.

JP-A-63-174925 (Hisamitsu Pharmaceutical Company) (Hisamitsu Pharmaceutical Co,) is a solvent evaporation A pharmaceutical product prepared by method 12 and comprising an active agent and an acrylic polymer copolymer. Regarding drug microcapsules.

The microparticles are manufactured from a group of copolymer materials and active ingredients with resistant properties; They are described as having either sustained release or pH-dependent solubility properties.

This time, by mixing polymer materials with different chemical properties, we have realized It provides both taste-masking and sustained and controlled drug release properties. It has been found that microparticulate matrices of drug polymers can be prepared.

Furthermore, drug release from drug-polymer microparticle matrices is It depends not only on the properties of the drug and drug, but also on the physical properties of the matrix; was also found to depend on the solvent evaporation conditions during the production of the matrix. . For example, drugs with basic properties and Eudragit L-100 or S-10 A uniform particulate matrix prepared from an anionic polymeric material such as Releases the drug under both acidic and alkaline conditions, and its release at acidic pH was found to be more rapid at alkaline pH than at alkaline pH. In addition, the basic properties made from a neutral polymeric material such as Eudragit R5-100. The release of drug from uniform microparticles depends on the pH of the dissolution medium, in which case the release The rate of release was found to be more rapid at acidic pH values.

Furthermore, this time, surprisingly, it imparts both taste-masking and sustained-release properties. is a drug-polymer matrix whose drug release properties are independent of the pH of the dissolution medium. It was found that it was possible to produce a This type of drug-polymer matrix is It is particularly useful in sustained release compositions for oral administration.

Accordingly, the present invention provides an active agent with basic properties and a pharmaceutically acceptable anionic compound. a neutral polymer or copolymer and a pharmaceutically acceptable neutral polymer or copolymer. It provides a sustained release drug-polymer microparticle matrix consisting of . In a preferred embodiment, the present invention provides said drug-polymer matrix that is homogeneous. provide access. More preferably, the present invention provides a homogeneous and substantially free dissolution medium. The drug-polymer matrix described above imparts drug release properties that are pH independent. offer a souvenir.

Drug release that is independent of the pH of the dissolution medium is particularly important for orally administrable compositions. It is convenient for Rate of drug release in vitro when administered by this route is recognized to be independent of the changes in pH encountered during passage through the gastrointestinal tract. There will be. This is due to the alkalinity in the mouth, which is provided by saliva, to the acidic ring in the stomach. This ranges from the alkaline conditions of the intestines through the boundaries of the intestines. Moreover, surprisingly, the pH - Drugs of the invention that provide independent drug release - Polymer microparticle matrix It was found to enhance radioactivity.

The drug-polymer matrix of the present invention has a drug release rate that is proportional to the square root of time. It has a proportional solubility property. This is a drug-containing matrix that is dispersed or dissolved. lix, suggesting a diffusion-regulated mechanism of drug-release.

The drug-polymer matrix of the present invention is produced by a solvent evaporation process that imparts a fine particle structure. manufactured by Preferably, the microparticles are uniform and enhance the sustained release properties of the matrix. It has a reinforcing, dense, substantially spherical, non-porous structure.

The size of the fine particles of the present invention is preferably 150 μm or less, and more preferably It is 60 μm or less, more preferably 20 μm or less. Small particle size is acceptable Non-gravity that provides a moist mouth-feel ritty) has advantages in tactile formulations for oral administration, as well as in liquid formulations. . Particle size is suitably determined by sieve analysis.

The active agent with basic properties used in the drug-polymer matrix of the invention is , has a basic functional group, such as an amino group, and has ionic interaction ability with polymer materials. This includes drugs that have. Ionic interactions contribute to matrix taste masking and It contributes to release properties and is particularly useful in liquid formulations. A wide range of active agents can be used. Wear. Typical active agents incorporated into the matrices of the present invention include dextrometh dextromethorphan, chlorpheniramine, Nilprochloramine, furthermore, -doephedrin and its pharmaceutically acceptable It is a salt-like drug. The preferred active agent is the cough suppressant dextromethorph. I'm a fan.

The pharmaceutically acceptable polymeric material used in the drug-polymer matrix of the present invention is , consisting of a neutral component and an anionic component. The component itself is a polymer or copolymer. Any limmer material may be used. As used herein, neutral polymers or The term copolymer refers to a polymer having a functional group capable of ionic interaction with a basic drug. refers to polymers or copolymers that are not A preferred neutral component is Eudragit R Acrylic and methacrylic esters sold under the commercial name 3-100 It is a copolymer synthesized from Other suitable neutral ingredients are ethylcellulose It includes cellulose derivatives such as.

As used herein, the term anionic polymer or copolymer refers to the Has acidic properties that allow the polymer or copolymer to interact with basic drugs. polymers or copolymers capable of ionic interaction with basic drugs, e.g. A polymer or copolymer to which an acidic functional group is added. Appropriate anionicity Ingredients include acrylic and methacrylic acid polymers and their copolymers; and acrylic acid and/or methacrylic acid, and methyl acrylate and methacrylic acid. of acrylic and/or methacrylic esters such as methyl chlorate. Includes copolymers based on combinations. Preferred anionic components are oid Methacrylic acid, commercially available under the commercial names Lugit L and Eudragit S. A copolymer based on a combination of methyl methacrylate. Other suitable anime The active ingredients include cellulose acetophthalade and cellulose acetobutyralide. include.

The combination of neutral and anionic polymeric components forms the pH-independent agent of the present invention. These are the basic characteristics of the emitted particulate matrix. Furthermore, the neutral component is Contributes to the compactness and mechanical strength of the socks. As shown above, the anionic component contributes to the sustained release properties of the matrix through interaction with basic drugs; provides stability to liquid formulations.

The ratio of neutral to anionic components can be varied to achieve the desired sustained release properties of the matrix. can be adapted to Of course, the selection ratio depends on the acid properties of the anionic component. , for example, in polymers or copolymers of anionic components, depending on the number of acidic functional groups available. - By making the ingredients dominant, pH-independent drug It will be appreciated that the balance maintaining drug release is lost. Appropriately, medicine The agent is dextromethorphan and the pharmaceutically acceptable polymer material is Oetragi. If the copolymer has a neutral and anionic component in a weight ratio of 11. It exists.

The ratio of active agent to pharmaceutically acceptable polymeric material is similarly determined by the active agent component. depending on the desired sustained release. Drug release depends on the physical and chemical properties of the matrix. Depends on both characteristics. The sustained release properties of a drug are determined by the combination of the drug and a pharmaceutically acceptable polymer material. It will be enhanced by optimizing the degree of interaction between the anionic components.

Excess drug not bound to the anionic moiety is subjected to binding, especially ionic binding. The drug will be released from the matrix more quickly than the drug in the matrix. In addition, drugs Release is also influenced by the level of densification of the microparticles that make up the matrix. will receive it.

The binding capacity of a polymer or copolymer is conventionally determined by those skilled in the art. It can be easily verified by following the experimental procedure. For example, the equilibrium adsorption isothermal technique drug loading to optimize both drug release characteristics and taste masking effect. can be determined.

The present invention further provides a drug-polymer microparticle matrix of the present invention by a solvent evaporation method. provides a preparation of

The matrix of the present invention is (i) forming a solution of a pharmaceutically acceptable polymeric material in a solvent;

(11) The active agent is dissolved or dispersed in the polymer solution to form a homogeneous mixture. obtain, and (iii) Remove the solvent from the mixture thus formed and remove the external liquid phase (ext By using a substantially spherical matrix Obtain fine particles with trix structure It is manufactured by a solvent evaporation method consisting of:

Preferably, the solvent evaporation method of the invention has a uniform structure, more preferably, A drug-polymer particulate matrix having a dense, non-porous structure is provided.

Suitable solvents for dissolving the pharmaceutically acceptable polymeric material include organic solvents such as ketone solvents, alcohols, hydrocarbon solvents, and mixtures of two or more thereof. Ru. Preferred solvents, especially copolymers sold under the trade name Eutrakit Suitable solvents for use are acetone, ethanol, ethyl acetate, and chloroform. , chloromethane, methanol and isopropanol. active drug Preferably, it is soluble in the polymer solution thus formed. Generally, basic drugs Add the agent directly to the polymer solution. Alternatively, the drug can be added before mixing with the polymer solution. Conveniently, the agent is dissolved in an organic solvent. Uniform mixing of active agents in polymer solutions can be obtained by mixing thoroughly.

Obtaining microparticles with desired physical properties by removing the solvent can be achieved by removing the drug/polymer/solvent. in the presence of a dispersant, unless the mixture is immiscible or partially immiscible. Add part to the liquid phase, emulsify the two-phase mixture thus obtained and evaporate the solvent: as appropriate. This is accomplished by isolating the microparticles by filtration or centrifugation.

Suitable liquids for the external liquid phase are, inter alia, aqueous solutions, organic solvents, mineral oils and vegetable oils. includes. The liquid selected for the external liquid phase is compatible with the selected drug, pharmaceutically acceptable determined by the polymer material used and the organic solvent in which it is dissolved.

Suitable dispersants include stearic acid derivatives, such as magnesium stearate and and materials such as aluminum stearate. Dispersants optimize the fine particle structure. Used to optimize. By changing the degree, it affects the particle size, compactness, Alternatively, a substantially non-porous structure can be provided.

Effective emulsification of the external liquid phase and the drug/polymer solution solvent phase is suitably achieved using a high shear mixer. Obtained using a sir. Effective emulsification is achieved when the particle matrix is less than 150 μm. This is a rod-requirement to have an average particle size.

Solvent evaporation can be performed at room temperature for volatile solvents or by heating. Wear. It is desirable to maintain effective mixing throughout the evaporation operation.

Isolation of microparticle matrices and gases is performed by repeatedly washing them with an appropriate solvent to remove any traces of the external liquid phase. It is appropriate to perform this after removal and subsequent drying. .

The properties of the drug-polymer matrix microparticles formed by the method described above are characterized by a number of properties. Influenced by factors.

For example, factors that affect particle size include emulsification rate, amount of dispersant, drug/polymer/ Viscosity and relative amounts of solvent and external liquid phase, mixer and stirrer arrangement, and processing temperature encompasses degrees.

Factors that influence the placement and density of the microparticles include the choice of solvent, its rate of evaporation, and the Includes molecular weight and crystallinity of the remer material and concentration of dispersant.

The invention further provides a drug-polymer microparticle matrix as described above and a pharmaceutically acceptable The present invention provides a pharmaceutical composition comprising a carrier.

Pharmaceutically acceptable carriers include conventional preservatives, binders, fillers, tabletting agents, lubricants, disintegrating agents, etc. Includes additives such as disintegrating agents, suspending agents, buffering agents, flavoring agents and coloring agents. sell.

Pharmaceutical compositions of the invention are preferably formulated for oral administration. composition foaming tablet forms, including chewable tablets, capsules, lozenges, powders and granules. It may be. The matrix of the invention is particularly suitable for compositions in liquid formulations, and also for Suitable for use in compositions of liquid formulations for oral administration.

Oral liquid preparations may be in the form of tablets or elixirs, or Express as a dry product to be reconstituted with water or other suitable liquid vehicle before use Can be done.

The amount of drug-polymer matrix in the pharmaceutical compositions of the present invention is determined by the amount of drug-polymer matrix selected. depending on the agent and dosage level required. Drug in composition-polymer matrix adjust the amount of drug and deliver an effective amount of the selected drug to the patient in need of treatment. Can be done. Pharmaceutical compositions may be in unit dosage form.

In a further aspect, the present invention provides the aforementioned drug-portion for use as an active therapeutic substance. A reamer microparticle matrix is provided.

The present invention provides a drug-polymer microparticle matrix for use as a cough suppressant, Dexj. This will be explained in the following example of compounding and manufacturing a fan, but it is not limited thereto. It's not.

Examples 1 and 2 below and attached Figure 1 provide pH-independent drug release. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to drug-polymer particulate matrices. Examples 3 and 4 below and attached Figures 2 and 3, which are outside the scope of the invention and are included for comparison, p The present invention relates to drug-polymer microparticle matrices that provide H-dependent drug release.

Drug dissolution was performed according to the Hasgett method of the United States Pharmacopoeia. The temperature was measured at 37° C. and 1100 rpm.

dispersed phase Eudragit R3-100: 3.7 5g propan-2-ol/acetone: 100ml (50150v/v) Kistromethorphan hydrobromide: 2.5g continuous phase.

Heavy mineral oil・400ml Magnesium stearate: 12g Add the polymer material to the mixed solvent in a conical flask with a stopper, and add it to the magnetic cooler. for 60 minutes. Add the drug to the polymer solution and apply the magnetic Melt in a colander for 45 minutes. This constituted the dispersed phase. mineral oil Added to an 800ml narrow beaker. Add magnesium stearate to mineral oil Melt in a magnetic cooler for 60 minutes. This forms a continuous phase Ta. The dispersed phase was added to the continuous phase. Blend the mixture in a high-shear mixer for 15 seconds. Processed. The emulsion was stirred with a Karas anchor stirrer during a water bath. Transferred to a 700 ml reaction vessel. By gradually heating the solvent evaporates, i.e. First, by heating to 35℃ for 3 hours and then heating to 60℃ for 3 hours. went. Microparticles were separated from the continuous phase by centrifugation and then washed several times with n-hexane. Washed to completely remove mineral oil. Finally, the matrix particles were heated at 45°C for 6 hours. Allowed to dry for a while. Analysis of the matrix microparticles showed a drug loading of 16.2% by weight. Indicated.

The fine particles were subjected to annealing (using a British standard test tube) to obtain various particle size ranges. and examined by scanning electron microscopy. Test imaging and SEM In both cases, the particle size ranges from 0 to 150 μm, with the predominant particle size fraction being 0 to 508 m. It was shown that

Attached Figure 1 shows dextromethorphan/Eudragi prepared according to the procedure described above. Graph showing drug release from Noto S-100/R8-100 matrix particles. be. The graph shows that drug release is independent of the pH of the dissolution medium and is substantially uniform. This shows that the drug release is maintained over 12 hours.

Example 2 Dextromethorphan/Eudragit S-100/R5-100 matrix Manufacture of liquid formulation composition containing fine particles A liquid formulation was prepared by suspending the microparticles obtained from Example 1 in a liquid vehicle. (247 mg/10 ml vehicle). The vehicle composition is as follows: It was a cage.

Ingredients Weight% Sorbitol solution 57.2 1.2-Propylene glycol 2,5 Sodium citrate 0.2 Citric acid 0.2 Keltrol 0.7 soluhinic acid o1 Sodium benzoate 1) Rum 0.1 Distilled water 39 A particle size fraction of 0 to 50 μm was used.

The weight of microparticles required for the production of suspensions is 4 The amount was such that 0 mg was obtained. Panel tests showed that the fine particle suspension had a good feel in the mouth. (mouth-feel) and is unique to dextromethorphan hydrobromide. It was shown that there was no bitter taste. The formulation was evaluated 18 weeks after manufacture and its taste-mass It was found that the king was retained and the potential for drug release was maintained.

The general operation of Example 1 was repeated using only Eudragit S-100 as the polymer material. I repeated. The compositions of the dispersed phase and continuous phase were as follows.

Dispersed phase・ Eudraxotho S-100: 7.5g propan-2-ol/7setone: 1 00ml (50150v/v) Dextromethorphan hydrobromide: 2.5 g continuous phase Heavy mineral oil: 400ml Magnesium stearate, 12g Scanning electron microscopy and test sieving were carried out in the particle size range of 0 to 150 μm, with 0 to 5 It was shown that 0 μm is the resulting particle size fraction.

Attached FIG. 2 is a graph showing drug release from the microparticles of Example 3. The graph is Drug release from anionic copolymer microparticles depends on 11H in the dissolution medium; shows that release is faster and more complete at alkaline pH. .

The general procedure of Example 1 was repeated using only Eudragit R5-100 as the polymer material. I repeated. The compositions of the dispersed phase and continuous phase were as follows.

Dispersed phase・ Eudragit R5-100: 30g methanol 70ml Dextromethorphan hydrobromide: 4.5g continuous phase Heavy mineral oil・300ml Magnesium stearate: 4.0g Scanning electron microscopy and test noping in the particle size range of 0-400 μm, 180 μm It was shown that ~355 μm was the predominant fraction.

Attached FIG. 3 is a graph showing drug release from microparticles of Example 4. The graph is Drug release from neutral copolymer microparticles depends on the pH of the dissolution medium; It has been shown to be faster and more complete at neutral pH.

Time (hr) -9-p)12. L 0123 ζ 5 6 7 8 9 10 TT 12 hours (hr) 0 1 2 3 L 5 6 7 13 9 1011 12 hours (hr) Summary book Mixtures of active agents with basic properties and pharmaceutically acceptable polymers or copolymers. A sustained release drug-polymer microparticle matrix comprising a compound.

international search report international search report G89101140

Claims (26)

[Claims] 1. an active agent with basic properties and a pharmaceutically acceptable anionic polymer or consisting of a copolymer and a pharmaceutically acceptable neutral polymer or copolymer A sustained release drug-polymer microparticle matrix characterized by: 2. The sustained release drug-polymer microparticle matrix according to claim 1, wherein the microparticles have a uniform structure. Ricks. 3. 3. The fine particles according to claim 1 or 2, wherein the fine particles have a dense, substantially spherical, non-porous structure. Sustained release drug - polymer microparticle matrix. 4. Sustained release according to claim 1, 2 or 3, wherein the fine particles have a size of 150 μm or less. Drug-polymer microparticle matrix. 5. The sustained release drug-polymer according to claim 4, wherein the particle size is 60 μm or less. Particulate matrix. 6. Claims 1 to 5, wherein drug release is substantially independent of the pH of the dissolution medium. Any one of the sustained release drug-polymer microparticle matrix. 7. If the active agent is dextromethorphan, chlorpheniramine, or phenylpropyl Noramine or pseudoephedrine or a pharmaceutically acceptable salt thereof A sustained release drug-polymer microparticle matrix according to any one of claims 1 to 6. 8. Neutral polymer or copolymer is ethyl cellulose, acrylic ester or methacrylic acid ester. Drug-polymer microparticle matrix. 9. Neutral polymers or copolymers combine acrylates and methacrylates. 9. The sustained release drug-polymer microparticle matrix according to claim 8, which is a copolymer of C. vinegar. 10. Anionic polymers or copolymers include acrylic acid and methacrylic acid. Polymers or their copolymers, acrylic acid and/or methacrylic acid Copolymers of lyric and/or methacrylic esters, cellulose Claims 1 to 9 consisting of acetophthalate or cellulose acetobutyrate. Any one of the sustained release drug-polymer microparticle matrix. 11. The anionic polymer or copolymer is methacrylic acid and methacrylate. The sustained release drug-polymer microparticle matrix according to claim 10, which is a copolymer of vinegar. 12. Dextromethorphan or its pharmaceutically acceptable salt and acrylic acid ester Copolymers of stell and methacrylic acid esters and methacrylic acid and methacrylic acid esters. Sustained-release drug characterized by comprising a copolymer of methyl sulfate - Polymer fine particles Child matrix. 13. A sustained release drug-polymer microparticle matrix substantially as described in Example 1 above. Kusu. 14. (i) forming a solution of a pharmaceutically acceptable polymeric material in a solvent; (ii) dissolving or dispersing the active agent in the polymer solution to obtain a homogeneous mixture; (iii) removing the solvent from the mixture thus formed and using an external liquid phase; A claim characterized in that microparticles having a substantially spherical matrix structure are obtained by Producing a sustained release drug-polymer microparticle matrix according to any one of Items 1 to 13 Solvent removal method for manufacturing. 15. 15. The method of claim 14, wherein the external liquid phase contains a dispersant. 16. Pharmaceutically acceptable solvents for polymer materials include organic ketones, alcohols, or a hydrocarbon solvent or a mixture thereof. . 17. Solvent: acetone, ethanol, ethyl acetate, chloroform, dichloromethane Claim 16 consisting of alcohol, methanol or isopropanol or a mixture thereof. Method described. 18. Claims 14 to 17, wherein the external liquid phase consists of an organic solvent, mineral oil or vegetable oil. Any one method. 19. Any one of claims 15 to 18, wherein the dispersant is a stearic acid derivative. the method of. 20. Any one of claims 1 to 13 substantially as described in Example 1 above. A method for preparing sustained release drug-polymer microparticle matrices. 21. A drug-polymer microparticle matrix according to any one of claims 1 to 13. and a pharmaceutically acceptable carrier. 22. A pharmaceutical composition substantially as described in Example 2 above. 23. An agent according to any one of claims 1 to 13 in a pharmaceutically acceptable liquid carrier. - a medicament for oral administration as a liquid consisting of a suspension of a polymer microparticle matrix; Composition. 24. A drug-polymer microparticle matrix according to any one of claims 1 to 13. Claim 21, 22 or 2, characterized in that the 3. The method for producing the pharmaceutical composition according to 3. 25. A method of making a pharmaceutical composition substantially as described in Example 2 above. 26. A drug according to any one of claims 1 to 13 for use as an active therapeutic substance. - Polymer microparticle matrix.