Sustained-release composition containing hydroxyalkylmethylcellulose

Abstract

To enable a reduction in the overall size of the dosage form and to improve swallowability without compromising its sustained-release properties, an oral dosage form is provided in which the drug is formulated with a reduced amount of excipients. [Solution] The sustained-release composition for oral administration contains particles of a physiologically active ingredient mixed with hydroxyalkylmethylcellulose, the ether substituents being a methyl group, a hydroxyalkyl group, and optionally an alkyl group other than methyl, the hydroxyalkylmethylcellulose having 0.05 to 1.00 MS(hydroxyalkyl), and the hydroxyl group of the anhydroglucose unit being substituted with a methyl group such that [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.30 or less, and the concentration of hydroxyalkylmethylcellulose is 0.1 to 10% based on the dry weight of the active ingredient.

Description

Technical Field

[0001] The present invention relates to a novel sustained-release composition comprising a bioactive ingredient and hydroxyalkyl methylcellulose.

Background Art

[0002] Sustained-release dosage forms have found a wide range of applications in various technical fields such as personal care and agricultural uses, water treatment, and particularly pharmaceutical uses. Sustained-release dosage forms are designed to release a limited amount of an active ingredient in an aqueous environment over a long period of time. Sustained-release pharmaceutical dosage forms are desirable because they provide a way to deliver a continuous dose in a single application without the risk of overdose. Known sustained-release pharmaceutical dosage forms contain a drug or vitamin, and their release is controlled by a polymeric matrix that may contain, for example, one or more water-soluble cellulose ethers. The water-soluble cellulose ether hydrates on the surface of the tablet to form a gel layer. The rapid formation of the gel layer is important to prevent internal wetting and disintegration of the tablet core. Once the gel layer is formed, it controls the ingress of additional water into the tablet. The outer layer must be fully hydrated and dissolve, so the inner layer must replace it and be sufficiently cohesive and continuous to slow the influx of water and control drug diffusion.

[0003] The cellulose ether commonly used to provide sustained release of an active ingredient from an oral dosage form is hydroxypropyl methylcellulose (HPMC). For example, U.S. Patent No. 4,734,285 discloses that the release of an active ingredient can be prolonged by utilizing microparticle-sized HPMC as an excipient for a solid tablet. HPMC is used in commercially available oral pharmaceutical formulations as a component of the polymeric matrix and typically provides sustained release of a drug at a concentration of 30% to 60% by weight of the oral dosage form.

[0004] It is a well-known challenge in pharmaceutical technology that some patients, particularly children, the elderly, or those with dysphagia, have difficulty swallowing conventional oral dosage forms such as capsules or tablets. Especially when drugs administered in such dosage forms are high-dose drugs and are combined with typical amounts of excipients found in commercially available dosage forms, it becomes necessary to either manufacture each dosage form for a very long time or divide the dose into two or more dosage forms that must be swallowed simultaneously. [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, it is desirable to develop oral dosage forms in which the drug is combined with a reduced amount of excipients, in order to enable a reduction in the overall size of the dosage form and to improve swallowability without compromising its sustained-release properties. [Means for solving the problem]

[0006] Surprisingly, it has been found that hydroxyalkylmethylcellulose with a specific substitution pattern, when used as an excipient in a mixture with a bioactive ingredient, can form a stable hydrogel in an aqueous environment at body temperature (i.e., approximately 37°C), resulting in the sustained release of the active ingredient. This is true even when used at concentrations far lower than those of HPMC used in commercially available formulations.

[0007] Therefore, the present invention provides an orally administered sustained-release composition comprising particles of a physiologically active ingredient mixed with hydroxyalkylmethylcellulose, wherein the ether substituent is a methyl group, a hydroxyalkyl group, and optionally an alkyl group other than methyl. Hydroxyalkylmethylcellulose has an MS (hydroxyalkyl) of 0.05 to 1.00, and The hydroxyl group of the anhydroglucose unit is substituted with a methyl group such that [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.30 or less. s23 is the mole fraction of an anhydroglucose unit in which only the two hydroxyl groups at positions 2 and 3 are replaced by methyl groups. s26 is the mole fraction of an anhydroglucose unit in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are replaced by methyl groups, and This invention relates to an orally administered sustained-release composition in which the concentration of hydroxyalkylmethylcellulose is 0.1 to 10% based on the dry weight of the active ingredient.

[0008] Surprisingly, hydroxyalkyl methylcellulose ethers with [s23 / s26-0.2*MS(hydroxyalkyl)] of 0.30 or less were found to be capable of forming hydrogels at low concentrations at body temperature. Therefore, they are particularly useful as excipients for sustained-release dosage forms, meaning they have the ability to regulate the release of the active ingredient from the dosage form over extended periods. For this purpose, these hydroxyalkyl methylcelluloses will hereafter be referred to as "G" (meaning gelling) hydroxyalkyl (hydroxypropyl or hydroxyethyl) methylcellulose (abbreviated as G-HPMC in examples). In contrast, commercially available HPMC grades such as METHOCEL® K4M and METHOCEL® E4M, with [s23 / s26-0.2*MS(hydroxyalkyl)] higher than 0.30, precipitate at low concentrations and do not form hydrogels at body temperature.

[0009] European Patent No. 2627676B1 discloses hydroxyalkylmethylcellulose having MS (hydroxyalkyl) in the range of 0.05 to 1.00 and [s23 / s26-0.2*MS (hydroxyalkyl)] of 0.30 or less. Hydroxyalkylmethylcellulose has been proposed for the manufacture of capsules and coatings for dosage forms. It has not been suggested that hydroxyalkylmethylcellulose can be used as a polymer matrix material in solid dosage forms at very low concentrations compared to the concentration of the active ingredient while maintaining its sustained-release properties. [Brief explanation of the drawing]

[0010] [Figure 1] This graph shows the time-dependent release of acetaminophen (APAP) from the composition of the present invention, which contains a 3% solution of hydrogel-forming hydroxypropyl methylcellulose (G-HPMC) as described herein, when gelatin capsules containing the composition and dried overnight at 50°C are immersed in 900 ml of 0.1N HCl (pH 1.1). [Figure 2] This graph shows the time-dependent release of acetaminophen (APAP) from a composition containing a 3% solution of METHOCEL® K4M HPMC when gelatin capsules containing the composition are immersed in 900 ml of 0.1N HCl (pH 1.1). Release from wet capsules is indicated as -◆-, and release from capsules dried overnight at 50°C is indicated as -■-. [Figure 3] This graph shows the time-dependent release of acetaminophen (APAP) from gelatin capsules containing a composition that includes a 3% solution of METHOCEL® E4M HPMC immersed in 900 ml of 0.1 N HCl (pH 1.1). Release from wet capsules is indicated as -◆-, and release from capsules dried overnight at 50°C is indicated as -■-. [Modes for carrying out the invention]

[0011] In this composition, the G hydroxyalkylmethylcellulose ether used as a sustained-release matrix material contains ether substituents that are methyl groups, hydroxyalkyl groups, and optionally alkyl groups other than methyl groups.

[0012] The hydroxyalkyl groups may be the same or different from each other. Preferably, the hydroxyalkylmethylcellulose contains one or two hydroxyalkyl groups, more preferably one or more species of hydroxy-C 1~3-Includes alkyl groups, such as hydroxypropyl and / or hydroxyethyl. Useful optional alkyl groups include, for example, ethyl or propyl, with ethyl being preferred. Preferred tertiary cellulose ethers are ethyl hydroxypropyl methylcellulose, ethyl hydroxyethyl methylcellulose, or hydroxyethyl hydroxypropyl methylcellulose. Preferred G-hydroxyalkyl methylcelluloses are G-hydroxypropyl methylcellulose (G-HPMC) or G-hydroxyethyl methylcellulose (G-HEMC), with G-hydroxypropyl methylcellulose being particularly preferred.

[0013] An essential characteristic of G hydroxyalkyl methylcellulose ethers is their unique distribution of methyl groups on anhydroglucose units such that [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.30 or less, preferably 0.27 or less, more preferably 0.25 or less, for example 0.23 or less. Typically, [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.07 or more, more typically 0.10 or more, and most typically 0.13 or more. In particular, for hydroxyethyl methylcellulose, the upper limit of [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.30, preferably 0.27. For hydroxypropyl methylcellulose, the upper limit of [s23 / s26-0.2*MS(hydroxyalkyl)] is 0.30, preferably 0.27; more preferably 0.25, and most preferably 0.23. While hydroxyalkylmethylcellulose with an S23 / S26 ratio higher than 0.30 dissolves at room temperature (21-25°C), hydroxyalkylmethylcellulose with this substitution pattern has been found to have a low dissolution temperature, such as below 10°C. Due to its low dissolution temperature, G-hydroxyalkylmethylcellulose does not dissolve at body temperature, and nevertheless, when compounded with pharmaceutical substances, it forms a hydrogel in aqueous liquid at body temperature, likely due to swelling.

[0014] As used herein, the symbol "*" represents the multiplication operator. In the ratio s23 / s26, s23 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups, and s26 is the mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups. With respect to the determination of s23, the term "mole fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups" means that position 6 is not substituted with methyl; for example, they can be unsubstituted hydroxyl groups, or they can be substituted with hydroxyalkyl groups, methylated hydroxyalkyl groups, alkyl groups other than methyl, or alkylated hydroxyalkyl groups. With regard to the determination of s26, the term "molar fraction of anhydroglucose units in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted by methyl groups" means that position 3 is not substituted by methyl; for example, they can be unsubstituted hydroxyl groups, or they can be substituted by hydroxyalkyl groups, methylated hydroxyalkyl groups, alkyl groups other than methyl, or alkylated hydroxyalkyl groups.

[0015] Formula I below shows the numbering of hydroxyl groups in an anhydroglucose unit. Formula I is used for illustrative purposes only and does not represent this G hydroxyalkylmethylcellulose; substitutions by hydroxyalkyl groups are not shown in Formula I. [ka]

[0016] G hydroxyalkyl methylcellulose preferably has a DS (methyl) of 1.2 to 2.2, more preferably 1.25 to 2.10, and most preferably 1.40 to 2.00. The degree of methyl substitution of the cellulose ether, DS (methyl), is the average number of OH groups substituted by methyl groups per anhydroglucose unit. For the determination of DS (methyl), the term "OH group substituted by a methyl group" includes not only the methylated OH groups in the polymer main chain, i.e., those that are directly part of the anhydroglucose unit, but also the methylated OH groups formed after hydroxyalkylation.

[0017] G hydroxyalkyl methylcellulose has an MS (hydroxyalkyl) of 0.05 to 1.00, preferably 0.07 to 0.80, more preferably 0.08 to 0.70, most preferably 0.10 to 0.60, particularly 0.10 to 0.50. The degree of hydroxyalkyl substitution is explained by MS (molar substitution). MS (hydroxyalkyl) is the average number of hydroxyalkyl groups bonded by ether bonds per mole of anhydroglucose unit. During hydroxyalkylation, side chains may be obtained by multiple substitutions.

[0018] The measurement of % methoxyl and % hydroxypropoxyl in hydroxypropyl methylcellulose is carried out according to the United States Pharmacopeia (USP 32). The values obtained are % methoxyl and % hydroxypropoxyl. These are then converted to the degree of substitution (DS) for the methyl substituent and the molar substitution (MS) for the hydroxypropyl substituent. The residual amount of salt is taken into account in the conversion. The DS (methyl) and MS (hydroxyethyl) of hydroxyethyl methylcellulose are carried out by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. 286 (1977) 161 - 190).

[0019] The method for producing hydroxyalkyl methyl cellulose is described in detail in European Patent No. 2627676 B1, which is incorporated herein by reference. Some aspects of the production process of hydroxyalkyl methyl cellulose are described in more general terms below.

[0020] Generally, when cellulose pulp is used or the reaction of cellulose pulp to hydroxyalkyl methyl cellulose proceeds, the partially reacted cellulose pulp is alkalized in one or more reactors containing an aqueous alkaline solution of an alkali metal hydroxide, more preferably sodium hydroxide, in two or more stages, preferably in two or three stages. The aqueous alkaline solution preferably has an alkali metal hydroxide content of 30 to 70 percent, more preferably 35 to 60 percent, and most preferably 48 to 52 percent, based on the total weight of the aqueous alkaline solution.

[0021] In one embodiment, an organic solvent such as dimethyl ether is added to the reactor as a diluent and coolant. Similarly, the headspace of the reactor is optionally purged with an inert gas (such as nitrogen) to control the depolymerization catalyzed by the oxygen of the cellulose ether product.

[0022] Typically, 1.2 to 2.0 molar equivalents of alkali metal hydroxide per mole of anhydroglucose units in cellulose are added in the first stage. The uniform swelling and distribution of the pulp are optionally controlled by mixing and agitation. In the first stage, the rate of addition of the alkali metal hydroxide agent is not very important. It can be added in several portions, for example, divided into 2 to 4 portions, or continuously. The temperature in the first stage of contacting the alkali metal hydroxide with the cellulose pulp is typically maintained at about 45 °C or lower. The first stage of alkalization typically continues for 15 to 60 minutes.

[0023] Methylating agents such as methyl chloride or dimethyl sulfate are also typically added to cellulose pulp after the addition of alkali metal hydroxides. The total amount of methylating agent is generally 2 to 5.3 moles per mole of anhydroglucose units. The methylating agent can be added to cellulose pulp, or to partially reacted cellulose pulp as the reaction of cellulose pulp to hydroxyalkylmethylcellulose proceeds, in a single step, but it is preferably added in two or more steps, more preferably in two or three steps, and most preferably in two steps.

[0024] When a methylating agent is added in a single step, it is generally added in an amount of 3.5 to 5.3 moles of methylating agent per mole of anhydroglucose units, but in any case, it is added in an equimolar amount compared to the total amount of alkali metal hydroxide added before heating the reaction mixture. When a methylating agent is added in a single step, it is preferably added at a rate of 0.25 to 0.5 molar equivalents of methylating agent per mole of anhydroglucose units per minute.

[0025] When the methylating agent is added in two stages, in the first stage, it is generally added in an amount of 2 to 2.5 moles of methylating agent per mole of anhydroglucose units before heating the reaction mixture, but in any case, it is added in an amount at least equimolar to the amount of alkali metal hydroxide added in the first stage of alkali metal hydroxide addition. When the methylating agent is added in two stages, the methylating agent in the first stage is preferably added at a rate of 0.25 to 0.5 molar equivalents of methylating agent per mole of anhydroglucose units per minute. The single-stage or first-stage methylating agent may be premixed with a suspending agent. In this case, the mixture of the suspending agent and the methylating agent preferably contains 20 to 50 weight percent, more preferably 30 to 50 weight percent, of the suspending agent based on the total weight of the methylating agent and the suspending agent. After contacting the cellulose with the alkali metal hydroxide and methylating agent, the reaction temperature is increased to approximately 70–85°C, preferably approximately 75–80°C, over a period of typically 30–80 minutes, more typically 50–70 minutes, and the reaction is then carried out at this temperature for 10–30 minutes.

[0026] When methylating agents are added in two stages, the second-stage methylating agent is generally added to the reaction mixture after the reaction mixture has been heated to a temperature of approximately 70-85°C for 10-30 minutes. The second-stage methylating agent is generally added in an amount of 1.5-3.4 moles per mole of anhydroglucose units, but in any case, it is added in an amount at least equimolar to the amount of alkali metal hydroxide present in the reaction mixture. Therefore, the second-stage methylating agent is added to the reaction mixture before or after the second and optionally third-stage alkali metal hydroxide addition in such a manner that, if present, alkali metal hydroxide does not come into contact with the cellulose pulp in excess. The second-stage methylating agent is preferably added at a rate of 0.25-0.5 molar equivalents of methylating agent per mole of anhydroglucose units per minute. When methylating agents are added in two stages, the molar ratio between the first-stage methylating agent and the second-stage methylating agent is generally 0.68:1-1.33:1.

[0027] When alkali metal hydroxides are added in two stages, typically, 1.0 to 2.9 molar equivalents of alkali metal hydroxide per mole of anhydroglucose units are added in the second stage, either in a single stage or after the first stage of methylation, and simultaneously with or after the second stage of methylation, if present. The molar ratio between the alkali metal hydroxide in the first stage and the alkali metal hydroxide in the second stage is generally 0.6:1 to 1.2:1. It is important that the alkali metal hydroxide used in the second stage is added slowly, i.e., at a rate of less than 0.04 molar equivalents of alkali metal hydroxide per mole of anhydroglucose units per minute, typically less than 0.03 molar equivalents. The alkali metal hydroxide in the second stage is generally added at a temperature of 55 to 80°C, preferably 60 to 80°C.

[0028] Instead of the above procedure in which the methylating agent and alkali metal hydroxide are each added in two stages, a portion of the alkali metal hydroxide is added in the second stage, followed by the addition of the methylating agent in the second stage to the reaction mixture, and then the subsequent addition of the alkali metal hydroxide. That is, the methylating agent is added in the second stage, followed by the third stage addition of the alkali metal hydroxide. In this embodiment of the process, the total amount of alkali metal hydroxide added per mole of anhydroglucose in the second and third stages is generally 1.0 to 2.9 moles per mole of anhydroglucose units, preferably 40 to 60 percent added in the second stage and 60 to 40 percent added in the third stage. Preferably, the alkali metal hydroxide used in the third stage is added slowly, i.e., at a rate of less than 0.04 molar equivalents of alkali metal hydroxide per mole of anhydroglucose units per minute, typically at a rate of less than 0.03 molar equivalents. The third-stage methylating agent and alkali metal hydroxide are generally added at a temperature of 55-80°C, preferably 65-80°C.

[0029] One or more, preferably one or two, hydroxyalkylating agents, such as ethylene oxide and / or propylene oxide, are also added to the cellulose pulp, or, if the reaction of the cellulose pulp to hydroxyalkylmethylcellulose is progressing, to the partially reacted cellulose pulp, before, after, or simultaneously with the alkali metal hydroxide added in the first step. Preferably, only one hydroxyalkylating agent is used. The hydroxyalkylating agent is generally added in an amount of 0.2 to 2.0 moles of hydroxyalkylating agent per mole of anhydroglucose units. The hydroxyalkylating agent is advantageously added before heating the reaction mixture to the reaction temperature, i.e., at a temperature of 30 to 80°C, preferably 45 to 80°C.

[0030] Additional alkylating agents, distinct from methylating agents, may be added to the cellulose pulp before, after, or simultaneously with the alkali metal hydroxide added in the first step. Useful alkylating agents include ethylating agents, such as ethyl chloride. The additional alkylating agent is generally added in an amount of 0.5 to 6 moles per mole of anhydroglucose units. The alkylating agent is advantageously added before heating the reaction mixture to the reaction temperature, i.e., at a temperature of 30 to 80°C, preferably 45 to 80°C.

[0031] To remove salts and other reaction by-products, the hydroxyalkylmethylcellulose is washed. Any solvent in which the salt is soluble may be used, but water is preferred. The hydroxyalkylmethylcellulose may be washed in the reactor, but preferably in a separate washing machine located downstream of the reactor. Before or after washing, the hydroxyalkylmethylcellulose may be stripped by exposure to vapor to reduce the residual organic content.

[0032] Based on the total weight of hydroxyalkylmethylcellulose and volatile substances, the hydroxyalkylmethylcellulose is dried until the water and volatile substance content is reduced to preferably about 0.5 to about 10.0 weight percent water, more preferably about 0.8 to about 5.0 weight percent water and volatile substances. Reducing the water and volatile substance content makes it possible to mill the hydroxyalkylmethylcellulose into particulate form. The hydroxyalkylmethylcellulose is milled into fine particles of the desired size. If necessary, drying and milling may be performed simultaneously.

[0033] The above process generally takes 2.55 seconds. -1 When the shear rate is determined in Haake RS600 in a 1.5 wt% aqueous solution at 20°C, hydroxyalkylmethylcellulose with a viscosity of over 150 mPa·s, preferably 500 to 200,000 mPa·s, more preferably 500 to 100,000 mPa·s, most preferably 1,000 to 80,000, and particularly 1,000 to 60,000 is obtained.

[0034] 20℃ and 2.55 seconds -1 The present invention has been found to have high gel strength, possessing a viscosity higher than 150 mPa·s when determined in a 1.5 wt% aqueous solution at a shear rate of 20°C and 2.55 seconds. When an aqueous solution of G hydroxyalkyl methylcellulose is characterized by G' / G'' ≥ 1, i.e., when it forms a gel, the gel strength is measured as the storage modulus G'. -1G-hydroxyalkylmethylcellulose having a viscosity higher than 150 mPa·s when determined in a 1.5 wt% aqueous solution at a shear rate generally has a storage modulus G' of at least 50 Pa, preferably at least 100 Pa, more preferably at least 150, and most preferably at least 200 Pa when measured as a 1.5 wt% aqueous solution at 80°C. Such a storage modulus G' is generally achieved when MS(hydroxyalkyl) is in the range of >0.30 and up to 1.00, more typically up to 0.80, and most typically up to 0.60. When MS(hydroxyalkyl) is in the range of 0.05 to 0.30, the hydroxyalkylmethylcellulose generally has a storage modulus G' of at least 100 Pa, preferably at least 150 Pa, more preferably at least 200 Pa, most preferably at least 250 Pa, and often at least 300 Pa when measured as a 1.5 wt% aqueous solution at 80°C. Under optimized conditions, when measured as a 1.5 wt percent aqueous solution at 80°C, storage capacities of up to 20,000 Pa, typically up to 10,000 Pa, and more typically up to 5,000 Pa can be achieved. As defined above, at 20°C and 2.55 seconds. -1 The gel strength of G-hydroxyalkylmethylcellulose having a viscosity higher than 150 mPa·s, as determined in a 1.5 wt% aqueous solution at a shear rate, is higher than that of comparative cellulose ethers having the corresponding viscosity, type, and percentage of substitution. This makes them highly advantageous as polymer matrix materials for producing solid sustained-release formulations.

[0035] In another embodiment, the viscosity of hydroxyalkylmethylcellulose, when measured as a 2% by weight aqueous solution at 20°C according to ASTM D2363-79 (Reapproved 2006), is typically 2 to 200 mPa·s, preferably 2 to 100 mPa·s, more preferably 2.5 to 50 mPa·s, and particularly 3 to 30 mPa·s. Such low-viscosity hydroxyalkylmethylcellulose is particularly useful for the production of solid dosage forms in which the active ingredient is embedded in the polymer matrix. Such hydroxyalkylmethylcellulose has a lower gelation temperature in aqueous solution than known hydroxyalkylmethylcellulose of the same viscosity and aqueous solution concentration. The gelation temperature depends on the MS(hydroxyalkyl). A 20% by weight aqueous solution of low viscosity G hydroxyalkyl methylcellulose, such as low viscosity G hydroxypropyl methylcellulose or low viscosity G hydroxyethyl methylcellulose, has been found to generally satisfy the following relationship [(gelation temperature [°C] / 1 [°C]) - (150 * MS (hydroxyalkyl)] < 20, preferably < 10, more preferably < 0, and most preferably < -5. Here, the gelation temperature is the temperature in °C where G' / C'' = 1, G' is the storage modulus, and G'' is the loss modulus of the 20% by weight aqueous solution of cellulose ether. When such a 20% by weight aqueous solution of low viscosity cellulose ether of the present invention is heated to induce gelation of the aqueous solution, no precipitate is detected.

[0036] The storage modulus G', loss modulus G'', and gelation temperature at G' / G''=1 of a 20 wt% aqueous solution of cellulose ether are measured in a temperature sweep experiment using an Anton Paar Physica MCR 501 with a Peltier temperature control system under oscillating shear flow. A parallel plate (PP-50) geometry with a 1 mm measurement gap is used. The geometry is covered with a metal ring (65 mm inner diameter, 5 mm width, and 15 mm length) and the outer surface of the solution is coated with paraffin oil. Measurements are performed at a constant frequency of 2 Hz and at a constant strain (deformation amplitude) of 0.5% from 5°C to 75°C, or from -2°C to 75°C if 5°C is already close to the intersection of G' and G''. These measurements are performed with a data acquisition rate of 4 points / min and a heating rate of 1°C / min. The storage modulus G' obtained from the oscillating measurements represents the elastic properties of the solution. The loss modulus G'' obtained from vibration measurements represents the viscosity characteristics of the solution. During the gelation process of the sample, G' exceeds G''. The intersection of G' and G'' represents the gelation temperature. Some cellulose ethers of the present invention may exhibit an intersection of G' and G'' at two points. In such cases, the gelation temperature is the temperature at which G' / G''=1 and the temperature at which G''>G' is 1°C lower than G' / G''=1.

[0037] G-hydroxyalkylmethylcellulose having low viscosity can be adequately prepared by a partial depolymerization process. Partial depolymerization is a well-known technique and is described, for example, in European Patent No. 1,141,029; No. 210,917; No. 1,423,433; and U.S. Patent No. 4,316,982. Alternatively, partial depolymerization can be achieved by the presence of, for example, oxygen or an oxidizing agent during the production of G-hydroxyalkylmethylcellulose. In such a partial depolymerization process, G-hydroxyalkylmethylcellulose having a viscosity of 2 to 200 mPa·s, preferably 2 to 100 mPa·s, more preferably 2.5 to 50 mPa·s, and particularly 3 to 30 mPa·s can be obtained, when determined as a 2% by weight aqueous solution at 20°C according to ASTM D2363-79 (Reapproved 2006).

[0038] G-hydroxyalkylmethylcellulose is useful as an excipient for sustained-release dosage forms, meaning it has the function of regulating the release of the active ingredient from the dosage form over a long period of time. The term “sustained-release” is used herein synonymously with the term “release-controlled.” Sustained release is an approach that makes an active ingredient, such as a bioactive compound, available at a rate and duration designed to achieve the intended effect. G-hydroxypropylmethylcellulose is useful for forming all or part of a polymer matrix in which the active ingredient is embedded. The polymer matrix may additionally contain one or more other polymers that can result in the sustained release of the active ingredient from the dosage form. G-hydroxyalkylmethylcellulose typically constitutes at least 50% by weight, preferably 60–100% by weight, more preferably 70–100% by weight, even more preferably 80–100% by weight, and most preferably 90–100% by weight of the polymer matrix. If one or more other polymers are included in the polymer matrix, they may be selected from cellulose ethers such as methylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, or carboxymethylcellulose, or they may be selected from other polysaccharides such as sodium alginate or calcium alginate.

[0039] G-hydroxyalkylmethylcellulose may be included in sustained-release dosage forms, particularly for the oral administration of drugs or other physiologically active ingredients, and in dosage forms intended for their release into the gastrointestinal tract, to control the absorption rate of the active ingredient in order to achieve a desired plasma profile. The total amount of G-hydroxyalkylmethylcellulose and the active ingredient in the dosage form is preferably at least 50%, more preferably at least 70%, most preferably at least 90%, and preferably up to 100%, more preferably up to 98%, and most preferably up to 95%, based on the dry weight of the dosage form. The dosage forms are designed to provide a constant or near-constant concentration of the active ingredient in plasma with reduced variability through the slow, continuous release of the active ingredient over a long period, such as 4 to 30 hours, preferably 8 to 24 hours, to release all or nearly all of the active ingredient from the dosage form.

[0040] Sustained-release dosage forms, such as tablets and capsules, in which the polymer matrix is ​​partially or completely formed from G-hydroxyalkylmethylcellulose, have been found to remain undamaged for extended periods, such as at least 4 hours, preferably at least 6 hours, and at least 8 hours under optimized conditions. While we do not wish to be bound by theory, it is thought that G-hydroxyalkylmethylcellulose hydrates and forms a highly expanded layer on the outer surface of the dosage form upon contact with aqueous liquids at body temperature. This highly expanded layer minimizes the release of active ingredients caused by corrosion of the dosage form. Because the tablet or capsule contents do not disperse (i.e., do not separate to any significant degree), the release of active ingredients is controlled by slow diffusion from the expanded layer formed by the hydration of G-hydroxyalkylmethylcellulose on the outer surface of the dosage form. The highly expanded layer reduces the intrusion of water into the sustained-release dosage form, and because the amount of water in the region of the dosage form where water diffuses and dissolves the active ingredients is reduced, the release of active ingredients, especially water-soluble active ingredients, into the aqueous environment is slowed.

[0041] While the concentration of G-hydroxyalkylmethylcellulose in the composition can vary between a wide range of limits, it has been found that even when very low amounts of G-hydroxyalkylmethylcellulose are included as all or part of the polymer matrix, essentially identical release rates of the active ingredient can be achieved. Therefore, it has been found that when G-hydroxyalkylmethylcellulose is included in the dosage form as a mono-matrix polymer at a concentration of 0.1-10%, preferably 0.2-5.0%, more preferably 0.5-4.0%, more preferably 0.75-2.0%, and even more preferably 1-1.8% based on the dry weight of the active ingredient, an acceptable release rate of the active ingredient can be achieved compared to commercially available sustained-release dosage forms that typically contain about 30% by weight of HPMC. In one embodiment, G-hydroxyalkylmethylcellulose is included in the dosage form as a mono-matrix polymer at a concentration of about 1.5% based on the dry weight of the active ingredient. The resulting sustained-release dosage form, such as a tablet or capsule, is smaller in size and therefore easier to ingest. It has been found that a satisfactory release rate can be obtained without adding any other excipients to the dosage form, although a surfactant may optionally be added as an antifoaming agent during the manufacturing process.

[0042] In one embodiment, the composition includes an additive that reacts with gastric juice upon ingestion to produce a gas such as CO2. The generated gas is trapped in the hydrogel and, as a result, floats on the surface of the stomach contents, resulting in a prolonged gastric retention time. This prolonged gastric retention time improves the bioavailability of the active ingredient, increases the release period, and improves the solubility of the active ingredient, which does not readily dissolve in the high-pH environment of the intestines. Examples of additives that produce gas upon contact with gastric juice include alkali metal and alkaline earth metal salts, such as CaCO3 and Na2CO3. The concentration of the additive may be in the range of 1 to 5% by weight of the composition, preferably 1.5 to 3% by weight, for example, 2% by weight.

[0043] This composition can be appropriately prepared by optionally adding a surfactant as a processing aid to the solution to provide a solution of G hydroxyalkylmethylcellulose in a liquid diluent. The active ingredient in powder or crystalline form and optionally one or more solid excipients (collectively referred to as "solids" herein) may then be mixed with G hydroxyalkylmethylcellulose such that the weight ratio of the G hydroxyalkylmethylcellulose solution to the active ingredient is in the range of 0.1:1 to 0.85:1. The liquid diluent is preferably an aqueous liquid containing 50 to 100% water, and can be selected from, for example, pure water or water containing a surfactant that acts as an antifoaming aid during the preparation of the composition. The weight ratio of liquid diluent to solid is preferably in the range of 0.1:1 to 0.75:1, 0.1:1 to 0.70:1, 0.1:1 to 0.65:1, 0.1:1 to 0.60:1, 0.1:1 to 0.60:1, 0.1:1 to 0.55:1, 0.1:1 to 0.50:1, 0.1:1 to 0.45:1, or 0.1:1 to 0.40:1.

[0044] The addition of surfactants helps to homogenize low concentrations of liquid diluents, and possibly through defoaming and emulsification, to produce a smooth, highly viscous semi-solid paste. The surfactant may be selected from conventional defoamers selected from the group consisting of anionic surfactants having anionic functional groups, such as sulfates, sulfonates, phosphates and carboxylates, such as alkyl sulfates, such as ammonium lauryl sulfate, sodium lauryl sulfate (sodium dodecyl sulfate, SLS or SDS) and alkyl ether sulfates, such as sodium laureth sulfate (sodium lauryl ether sulfate or SLES) and sodium myreth sulfate; cationic surfactants having cationic functional groups, such as cetrimonium bromide (CTAB), cetylpyridinium chloride (CPC), benzalkonium chloride (BAC), benzethonium chloride (BZT), dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB); zwitterionic surfactants, such as cocamidopropyl betaine; and nonionic surfactants, such as siloxane surfactants such as modified polydimethylsiloxane-based defoamers, ethoxylates, fatty acid esters of glycerol, sorbitol and saccharose. The concentration of the surfactant may be in the range of 0.1 to 1.5% by weight of the composition.

[0045] In one embodiment of the present invention, the composition comprising G hydroxyalkylmethylcellulose mixed with an active ingredient is in the form of a dry powder. As is evident from Figure 1 attached herein, the dry composition results in the slow release of the active ingredient over time under the conditions described in the following examples. The dry powder may be prepared in a manner known in the art by drying the mixture of the G hydroxyalkylmethylcellulose solution and the active ingredient at a temperature of 40 to 100°C until the mixture has a water content of less than 10% by weight, preferably less than 5% by weight, more preferably 3% by weight, and particularly less than 2% by weight, for example less than 1% by weight, and then milling or grinding the mixture until it becomes granules of a desired particle size. The dry powder will typically contain granules containing the active ingredient partially or completely embedded in the G hydroxyalkylmethylcellulose, which promotes the sustained release of the active ingredient as described above.

[0046] In one embodiment, the present invention relates to a unit dosage form comprising the composition. The unit dosage form is intended for oral administration and may be in the form of a tablet containing compressed granules of the dry composition. Alternatively, the unit dosage form may be in the form of a tablet, granule, or pellet prepared by extruding a semi-solid paste prepared as described above, cutting the extruded object into appropriate diameters, and subsequently drying. The tablet may optionally contain one or more other excipients, except that a surfactant may optionally be included as shown above, except that G-hydroxyalkylmethylcellulose is preferably the only excipient contained in the dosage form. The unit dosage form may preferably be in the form of dry granules containing a mixture of G-hydroxyalkylmethylcellulose and the active ingredient, and may also be a capsule containing the dry composition.

[0047] Each unit dosage form contains one or more physiologically active ingredients, preferably one or more drugs, one or more diagnostic agents, or one or more physiologically active ingredients useful for cosmetic or nutritional purposes. The term "drug" means a compound that has beneficial prophylactic and / or therapeutic properties when administered to an individual, typically a mammal, especially a human individual. This dosage form is considered particularly suitable for administering high-dose drugs, i.e., drugs administered in unit doses of 500 mg or more, because it is possible to provide a unit dose containing the required amount of the active ingredient in a more easily absorbed form. Examples of high-dose drugs are metformin, metformin hydrochloride, acetaminophen (paracetamol), or acetylsalicylic acid. Thus, each unit dosage form may typically contain 500 to 1000 mg of the active ingredient.

[0048] Several embodiments of the present invention are described in detail in the following examples.

[0049] Unless otherwise specified, all parts and percentages are given by weight. In this embodiment, the following test procedure is used.

[0050] The measurement of % methoxyl and % hydroxypropoxy in hydroxypropyl methylcellulose is performed according to the United States Pharmacopeia (USP 32). The obtained values ​​are % methoxyl and % hydroxypropoxy. These are then converted to degrees of substitution (DS) for methyl substituents and molar substitution (MS) for hydroxypropyl substituents. The residual amount of salt was taken into consideration in the conversion.

[0051] The DS (methyl) and MS (hydroxyethyl) groups of hydroxyethyl methylcellulose are determined by Zeisel cleavage with hydrogen iodide followed by gas chromatography. (G. Bartelmus and R. Ketterer, Z. Anal. Chem. 286 (1977) 161-190).

[0052] Decisions for s23 / s26 The determination of ether substituents in cellulose ethers is generally known, for example, as described by Bengt Lindberg, Ulf Lindquist, and Olle Stenberg in Carbohydrate Research, 176 (1988) 137-144, Elsevier Science Publishers BV, Amsterdam, DISTRIBUTION OF SUBSTITUENTS IN O-ETHYL-O-(2-HYDROXYETHYL)CELLULOSE.

[0053] Specifically, the decisions in s23 / s26 are carried out as follows: Dissolve 10-12 mg of cellulose ether in 4.0 mL of dry analytical-grade dimethyl sulfoxide (DMSO) (Merck, Darmstadt, Germany, stored on 0.3 nm molecular sieve beads) at approximately 90°C under stirring, then allow to cool again to room temperature. To ensure complete solubilization, leave the solution stirred at room temperature overnight. All reactions, including the solubilization of cellulose ether, are carried out in a 4 mL screw-cap vial under a dry nitrogen atmosphere. After solubilization, transfer the dissolved cellulose ether to a 22 mL screw-cap vial. Add reagent sodium hydroxide and ethyl iodide in a molar excess of 30 times per hydroxyl group of anhydroglucose units. Powdered sodium hydroxide (freshly ground with a mortar and pestle, analytical grade, Merck, Darmstadt, Germany) and ethyl iodide (analytical grade, silver-stabilized, Merck-Schuchardt, Hohenbrunn, Germany) are added, and the solution is vigorously stirred in a dark room under nitrogen at ambient temperature for 3 days. Repeat the perethylation by adding three times the amount of reagent sodium hydroxide and ethyl iodide compared to the first reagent addition and stirring further at room temperature for a further 2 days. To ensure good mixing during the reaction, the reaction mixture can be optionally diluted with up to 1.5 mL of DMSO. Pour 5 mL of 5% sodium thiosulfate aqueous solution into the reaction mixture, and then extract the resulting solution three times with 4 mL of dichloromethane. Wash the combined extract three times with 2 mL of water. Dry the organic phase with anhydrous sodium sulfate (approximately 1 g). After filtration, remove the solvent in a gentle nitrogen stream, and then store the sample at 4°C until further sample preparation.

[0054] Hydrolysis of approximately 5 mg of perethylated sample is carried out under nitrogen in a 2 mL screw-cap vial containing 1 mL of 90% hydrated formic acid, with stirring at 100°C for 1 hour. The acid is removed in a nitrogen stream at 35-40°C, and the hydrolysis is repeated with stirring and in an inert nitrogen atmosphere at 120°C for 3 hours using 1 mL of 2 M hydrated trifluoroacetic acid. After completion, the acid is removed in a nitrogen stream at ambient temperature using approximately 1 mL of toluene for co-distillation, and the mixture is allowed to dry.

[0055] The hydrolysis residue is reduced with 0.5 mL of 0.5 M sodium borode deuterated solution in a freshly prepared 2 N aqueous ammonia solution for 3 hours at room temperature under stirring. Excess reagent is destroyed by adding approximately 200 μL of concentrated acetic acid droplets. The resulting solution is evaporated to dryness in a nitrogen stream at approximately 35-40°C, and then dried in vacuum at room temperature for 15 minutes. The viscous residue is dissolved in 0.5 mL of 15% acetic acid in methanol and evaporated to dryness at room temperature. This is repeated 5 times, and then 4 times using pure methanol. After the final evaporation, the sample is vacuum-dried overnight at room temperature.

[0056] The reduction residue is acetylated at 90°C for 3 hours using 600 μL of acetic anhydride and 150 μL of pyridine. After cooling, the sample vial is filled with toluene and evaporated to dryness in a nitrogen stream at room temperature. The residue is dissolved in 4 mL of dichloromethane, poured into 2 mL of water, and extracted with 2 mL of dichloromethane. The extraction is repeated three times. The combined extracts are washed three times with 4 mL of water and dried using anhydrous sodium sulfate. The dried dichloromethane extract is then subjected to GC analysis. Depending on the sensitivity of the GC system, further dilution of the extract may be necessary.

[0057] Gas-liquid (GLC) chromatography analysis is performed using a Hewlett Packard 5890A and 5890A Series II gas chromatograph equipped with a J&W DB5 capillary column, 30 m, 0.25 mm inner diameter, and 0.25 μm phase thickness, operated with a 1.5 bar helium carrier gas. The gas chromatograph is programmed with a temperature profile that maintains a constant temperature of 60°C for 1 minute, then heats to 200°C at a rate of 20°C / min, further heats to 250°C at a rate of 4°C / min, further heats to 310°C at a rate of 20°C / min, and then maintains a constant temperature for another 10 minutes. The injector temperature is set to 280°C, and the flame ionization detector (FID) temperature is set to 300°C. 1 μL of sample is injected in splitless mode with a valve time of 0.5 minutes. Data is acquired and processed using a LabSystems Atlas workstation.

[0058] Quantitative monomer composition data can be obtained from peak areas measured by GLC using FID detection. The molar response of the monomer is calculated in accordance with the modified concept of effective carbon number (ECN), as shown in the table below. The concept of effective carbon number (ECN) is described by Ackman (RGAckman, J. Gas Chromatogr., 2(1964)173-179 and R. Addison, RGAckman, J. Gas Chromatogr., 6(1968)135-138) and applied by Sweet et al. (DPSweet, RHShapiro, P. Albersheim, Carbohyd. Res., 40(1975)217-225) to the quantitative analysis of partially alkylated alditol acetates.

[0059] [Table 1]

[0060] To correct for the various molar responses of monomers, the peak area is multiplied by the molar response factor MRF monomer, which is defined as the response to the 2,3,6-Me monomer. The 2,3,6-Me monomer is selected as a reference because it is present in all samples analyzed in the s23 / s26 determination. MRF monomer = ECN2,3,6-Me / ECN monomer

[0061] The mole fraction of a monomer is given by the following formula: s23=[(23-Me+23-Me-6-HAMe+23-Me-6-HA+23-Me-6-HAHAMe+23-Me-6-HAHA]; and s26=[(26-Me+26-Me-3-HAMe+26-Me-3-HA+26-Me-3-HAHAMe+26-Me-3-HAHA] It is calculated by dividing the corrected peak area by all the corrected peak areas. Here, s23 is the sum of the mole fractions of anhydroglucose units that satisfy the following conditions: a) The two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups, and the group at position 6 is left unsubstituted (=23-Me); b) The two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups, and position 6 is substituted with a methylated hydroxyalkyl group (=23-Me-6-HAMe), or with a methylated side chain containing two hydroxyalkyl groups (=23-Me-6-HAHAMe); and c) The two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are substituted with methyl groups, and position 6 is substituted with a hydroxyalkyl group (=23-Me-6-HA) or with a side chain containing two hydroxyalkyl groups (=23-Me-6-HAHA). s26 is the sum of the mole fractions of anhydroglucose units that satisfy the following conditions: a) The two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups, and the group at position 3 is left unsubstituted (=26-Me); b) The two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups, and position 3 is substituted with a methylated hydroxyalkyl group (=26-Me-3-HAMe), or with a methylated side chain containing two hydroxyalkyl groups (=26-Me-3-HAHAMe); and c) The two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are substituted with methyl groups, and position 3 is substituted with a hydroxyalkyl group (=26-Me-3-HA) or with a side chain containing two hydroxyalkyl groups (=26-Me-3-HAHA).

[0062] The results of determining the substituents of HAMC are listed in Table 4 below. In the case of hydroxyalkyl (HA) in HPMC, hydroxypropyl (HP) and methylated hydroxyalkyl (HAMe) are methylated hydroxypropyl (HPMe).

[0063] Production of a 2% pure aqueous solution of G-HPMC To obtain a 2% aqueous solution of G-HPMC, 3 g of G-HPMC, which had been milled, ground, and dried (taking into account the water content of methylcellulose), was added to 147 g of tap water (temperature 20-25°C) at room temperature, while stirring at 750 rpm using an overhead laboratory stirrer equipped with a 3-wing (wing = 2 cm) blade stirrer. The solution was then cooled to approximately 1.5°C. After reaching 1.5°C, the solution was stirred at 750 rpm for 180 minutes. Before use or analysis, the solution was stirred at 100 rpm in an ice bath for 15 minutes.

[0064] Determination of the viscosity of G-HPMC Using an Anton Paar Physica MCR 501 rheometer and cup and bobber fittings (CC-27), the temperature was set to 5°C for 10 seconds. -1 At the shear rate, the constant shear-flow viscosity η (20°C, 10 seconds) of a 2 wt% G-HPM aqueous solution was measured. -1, 2 wt% MC) was measured.

[0065] Determination of storage modulus G', loss modulus G'', gelation temperature t, and gel strength. To characterize the temperature-dependent properties of precipitation or gelation of 1.5 wt% aqueous cellulose ether solutions, an Anton Paar Physica MCR 501 rheometer (Ostfildern, Germany) with a cup and bob setup (CC-27) and a Peltier temperature control system is used in a vibrating shear flow. These solutions are prepared by the same dissolution procedure as described for viscosity measurements. Measurements are performed at a heating rate of 1°C / min, a data acquisition rate of 4 points / min, a constant vibration frequency of 2 Hz, and a constant strain (deformation amplitude) of 0.5% from 10°C to 85°C. The storage modulus G' obtained from the vibration measurements represents the elastic properties of the solution. The loss modulus G'' obtained from the vibration measurements represents the viscous properties of the solution. At low temperatures, the loss modulus G'' is higher than the storage modulus G', and both values ​​decrease slightly as the temperature increases. If precipitation occurs at high temperatures, the storage modulus decreases. This precipitation temperature is analyzed from a plot of log storage modulus G' versus temperature as the intersection of two tangents. The first tangent corresponds to the decrease in storage modulus with increasing temperature, and the second tangent corresponds to the decrease in storage modulus over a temperature range of 1–3°C. As the temperature increases further, the storage modulus value increases, and an intersection between the storage modulus and the loss modulus is obtained. The intersection of G' and G'' is determined to be the gelation temperature. Some cellulose ethers of the present invention may exhibit an intersection of G' and G'' at two points. In such cases, the gelation temperature is the temperature at which G' / G''=1, and the temperature at which G''>G' at a temperature 1°C lower than G' / G''=1. [Examples]

[0066] Example 1: Preparation of G-HPMC HPMC was produced by the following procedure: Finely milled wood cellulose pulp was loaded into a jacketed stirred reactor. The reactor was degassed to remove oxygen, purged with nitrogen, and then degassed again. The reaction was carried out in two stages. In the first stage, a 50 wt% aqueous sodium hydroxide solution was sprayed onto the cellulose at a rate of 1.2 moles of sodium hydroxide per mole of anhydroglucose units in the cellulose, and the temperature was adjusted to 40°C. After stirring the mixture of aqueous sodium hydroxide solution and cellulose at 40°C for about 30 minutes, 1.5 moles of dimethyl ether, 3.5 moles of methylene chloride, and 0.33 moles of propylene oxide per mole of anhydroglucose units were added to the reactor. The contents of the reactor were then heated to 80°C for 60 minutes. After reaching 80°C, the first stage reaction was allowed to proceed for 20 minutes.

[0067] Next, a 50% by weight aqueous sodium hydroxide solution was added over 90 minutes at a rate of 1.0 mole of sodium hydroxide per mole of anhydroglucose units. The addition rate was 0.011 moles of sodium hydroxide per mole of anhydroglucose units per minute. After the second stage of addition was completed, the contents of the reactor were maintained at a temperature of 80°C for 120 minutes.

[0068] After the reaction, the reactor was opened and cooled to approximately 50°C. The contents of the reactor were removed and transferred to a tank containing hot water. The crude HPMC was then neutralized with formic acid, washed with hot water until the chlorides were removed (evaluated by an AgNO3 coagulation test), cooled to room temperature, and dried at 55°C in a cleaned dryer. The material was then milled.

[0069] The resulting G-HPMC has 1.50 DS (methyl) and 0.14 MS (hydroxyalkyl), which corresponds to a methoxyl content of 24.3% and a hydroxypropoxyl content of 5.5%. The G-HPMC was incubated at 20°C for 10 seconds. -1 When measured as a 2 wt% solution at a shear rate, it had a viscosity of 4890 MPa·sec and a ratio of 0.18 s23 / s26.

[0070] Example 2: Release of acetaminophen from a dry gelatin capsule containing G-HPMC A 3% by weight aqueous solution of G-HPMC prepared as described in Example 1 was prepared, and a modified polydimethylsiloxane-based defoamer (available from BASF under the trade name Foamstar SI2210) was added to the solution. 3.5 g of acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 1.5 g of the G-HPMC solution until a white, homogeneous, and highly viscous paste was obtained. The Foamstar SI2210 content in the paste was 0.115 g. The mixture was filled into a syringe and injected into gelatin capsules (size 000), which were then closed and sealed. The mixture was carefully dried overnight at 50°C.

[0071] The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and shaken at 150 rpm for 22 hours. Drug release was measured at a wavelength of 243 nm with a path length of 0.1 mm.

[0072] Figure 1 shows the release of APAP from the dried capsule. From this figure, it is clear that approximately 90% of the drug was released after 21 hours (indicated as -●- in the figure).

[0073] Example 3: Release of acetaminophen from gelatin capsules containing K4M HPMC A 2 wt% aqueous solution of METHOCEL® K4M HPMC (available from DuPont) was prepared, and a modified polydimethylsiloxane-based defoamer (trade name Foamstar SI2210, available from BASF) was added to the solution. 9.75 g of acetaminophen (abbreviated herein as APAP) was thoroughly mixed with 5.25 g of METHOCEL® K4M HPMC solution until a white, homogeneous, and highly viscous paste was obtained. The Foamstar SI2210 content in the paste was 0.115 g. The mixture was filled into a syringe and injected into gelatin capsules (size 000), which were then sealed. The filled capsules were immediately placed in 900 ml of 0.1N HCl (pH 1.1) at 37°C and shaken at 150 rpm for 50 hours. 250 μl samples were taken at intervals and analyzed for APAP content.

[0074] Figure 2 shows the release of APAP from the capsule. From this figure, it is clear that approximately 90% of APAP was released from the capsule within 6 hours (indicated as -◆- in the figure).

[0075] Approximately 1 g of the mixture was filled into gelatin capsules (size 000) and then sealed. The mixture was dried overnight at 50°C. The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and shaken at 150 rpm for 22 hours. Drug release was measured at a wavelength of 243 nm with a path length of 0.1 mm.

[0076] Figure 2 shows the release of APAP from the capsule. From this figure, it is clear that approximately 90% of the drug was released after 1 hour (indicated as -■- in the figure). Therefore, the release rate from dry capsules is faster than that from wet capsules.

[0077] Therefore, neither wet nor dry capsules containing METHOCEL® K4M HPMC as the matrix polymer provided sustained release of the active ingredient.

[0078] Example 4: Release of acetaminophen from gelatin capsules containing E4M HPMC A 2 wt% aqueous solution of METHOCEL® E4M HPMC (available from DuPont) was prepared, and 9.75 g of acetaminophen (hereinafter abbreviated as APAP) was thoroughly mixed with 5.25 g of METHOCEL® E4M HPMC solution until a white, homogeneous, and highly viscous paste was obtained. The mixture was filled into a syringe and injected into gelatin capsules (size 000), which were then sealed. The filled capsules were immediately placed in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and shaken at 150 rpm for 50 hours. 250 μl samples were taken at intervals and analyzed for APAP content.

[0079] Figure 3 shows the release of APAP from the capsule. From this figure, it is clear that approximately 85% of APAP was released from the capsule within 3 hours, and approximately 90% was released within 6 hours (indicated as -◆- in the figure).

[0080] Approximately 1 g of the mixture was filled into gelatin capsules (size 000) and then sealed. The mixture was dried overnight at 50°C. The dried capsules were placed in 900 ml of 0.1 N HCl (pH 1.1) at 37°C and shaken at 150 rpm for 22 hours. Drug release was measured at a wavelength of 243 nm with a path length of 0.1 mm.

[0081] Figure 3 shows the release of APAP from the capsule. From this figure, it is clear that approximately 90% of the drug was released after 1 hour (indicated as -■- in the figure). Therefore, the release rate from dry capsules is faster than that from wet capsules.

[0082] Therefore, neither wet nor dry capsules containing E4M HPMC as the matrix polymer provided sustained release of the active ingredient.

Claims

1. An orally administered sustained-release composition comprising particles of a physiologically active ingredient mixed with hydroxyalkylmethylcellulose, wherein the ether substituent is a methyl group, a hydroxyalkyl group, and optionally an alkyl group other than methyl. The hydroxyalkylmethylcellulose has 0.05 to 1.00 MS (hydroxyalkyl), and The hydroxyl group of the anhydroglucose unit is substituted with a methyl group such that [s23 / s26-0.2*MS (hydroxyalkyl)] is 0.30 or less. s23 is the mole fraction of an anhydroglucose unit in which only the two hydroxyl groups at positions 2 and 3 of the anhydroglucose unit are replaced by methyl groups. S26 is the mole fraction of an anhydroglucose unit in which only the two hydroxyl groups at positions 2 and 6 of the anhydroglucose unit are replaced by methyl groups, and A sustained-release composition wherein the concentration of hydroxyalkylmethylcellulose is 0.1 to 10% based on the dry weight of the active ingredient.

2. The composition according to claim 1, wherein the concentration of the hydroxyalkylmethylcellulose is 0.2 to 5%, preferably 0.5 to 4%, more preferably 0.75 to 2%, and even more preferably 1 to 1.8%, based on the dry weight of the active ingredient.

3. The composition according to claim 1, wherein the concentration of the hydroxyalkylmethylcellulose is about 1.5% based on the dry weight of the active ingredient.

4. The composition according to any one of claims 1 to 3, wherein the hydroxyalkyl methylcellulose is hydroxypropyl methylcellulose and [s23 / s26-0.2*MS (hydroxyalkyl)] is 0.27 or less.

5. The composition according to any one of claims 1 to 3, wherein the hydroxyalkyl methylcellulose is hydroxyethyl methylcellulose and [s23 / s26-0.2*MS (hydroxyalkyl)] is 0.30 or less.

6. The composition according to any one of claims 1 to 5, wherein the hydroxyalkylmethylcellulose has 1.2 to 2.2 DS(methyl) groups.

7. The composition according to any one of claims 1 to 6, wherein the hydroxyalkylmethylcellulose constitutes at least 50% by weight, preferably 60 to 100% by weight, of the polymer matrix in which the particles of the active ingredient are embedded.

8. The composition according to any one of claims 1 to 7, further comprising a surfactant.

9. The composition according to any one of claims 1 to 8, wherein the concentration of the surfactant is in the range of 0.1 to 1.5% by weight of the composition.

10. The composition according to any one of claims 1 to 9, further comprising an additive capable of reacting with gastric juice to generate gas.

11. The composition according to claim 10, wherein the additive is selected from alkali metal or alkaline earth metal carbonates, for example, CaCO3 or Na2CO3.

12. The composition according to any one of claims 1 to 11, in the form of a dried powder.

13. A unit dosage form comprising the composition according to any one of claims 1 to 12.

14. The unit dosage form according to claim 13, comprising 500 to 1000 mg of the active ingredient.

15. The unit dosage form according to claim 14, wherein the active ingredient is selected from the group consisting of metformin, metformin hydrochloride, acetaminophen, and acetylsalicylic acid.

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