TW201238589A - Stable combination pharmaceutical composition - Google Patents

Abstract

Stable solid pharmaceutical composition containing amlodipine or pharmaceutical acceptable salts thereof and bisoprolol or pharmaceutical acceptable salts thereof as well as pharmaceutically accepted excipients, packaged in a damp-proof package and further comprising less than 0.5% of the compound of the formula based on the weight of the active ingredients.

Description

201238589 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a stable solid pharmaceutical composition comprising amlodipine of the formula

And bisoprolol as an active ingredient. More particularly, the invention relates to a composition encapsulated in a moisture barrier package comprising an amine aflatine or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate and a peso of the formula Lol fumarate

, step package 3 is used in the pharmaceutical industry as a filler, disintegrant, lubricant and (four) agent, in addition, wherein the following formula N · · (2 'ocyl phenyl) · 3 _ (ethoxy, anabase) ("oxygen Amount of compound of several bases·········································

Not more than 0.5% during the preparation and storage of the composition. [Prior Art] The blood pressure value required to reduce the risk of cardiovascular morbidity and mortality can be achieved by the practice of drug-based "evidence based" therapy consisting of a single compound or an optimal combination of two compounds. . Combination therapy is more effective. The amount of each compound required is generally lower than that required under the condition of a single treatment, thus reducing side effects and improving patient compliance. ~ The role of combination therapy is therefore an advantage in the treatment of hypertension and its complications. Combinations of blockers, diuretics, ace inhibitors, ARB-s, calcium channel blockers are typically used, respectively. Recently, these combinations have been increasingly sold in the form of so-called "fixed combinations" comprising two active ingredients in a single dosage form for the purpose of achieving better "patient compliance" and lowering the cost of treatment. The use of fixed links is clearly recommended in accordance with international guidelines. Several fixed combinations of calcium channel blockers ("calcium antagonists") and 0 blockers for the treatment of gray pressure and angina have recently been marketed, such as containing felodipine and metoprolol. (met〇pr〇1〇1) or 201238589 is a bond between nifedipine and atenol (aten〇l〇i). The fixed combination of amlodipine and bisoprolol has not yet been released, but several combinations have been discussed in the literature and patent applications. International Patent Application No. WO2005/G99699 discloses a combination of amlodipine and a zero blocker, including a bisoprolol combination. The Yuan Shenqing case mentioned several pharmaceutical solutions in which these ingredients were formulated, but the main problem of practical application was not mentioned, namely the chemical incompatibility of the two active ingredients. In the so-called "single composition" containing only one active ingredient, the amine amlodipine is in the form of a benzoic acid salt, and the bisoprolol is used in the form of a reverse succinate salt. Because bisoprolol fumarate and amlodipine acid salt are suitable for the preparation of stable pharmaceutical dosage forms, it seems that the combination of amlodipine phenate and bisoprolol fumarate into a single dosage form feasible. According to Indian Patent Application No. 845/MUM/2〇〇4, the amine amlodipine acid salt interacts with bisoprolol fumarate. According to the present inventors, the compound I is a compound of the formula (3) #-{2-{[4-(2-phenylphenyl)-3-(ethoxybutyr-5-(oxiranyl)_6_ Sulfhydryl], 4 dinitrogen 2 _ mouth ratio bite base] methoxy bethyl) aspartic acid. This compound is formed by a 16-gas flat test and a reverse-succinic acid chemical reaction. The U.S. Patent Application No. 65i828s states that the salt formed by amlodipine and the anti-succinic acid is stable and does not convert to the formula (3). The compound, so the formation of this product was unexpected. The current international medical authority's current requirements only accept very low (tens of parts by weight) limits of pharmaceutical composition degradation products. 6 201238589 The absorption characteristics and pharmacokinetic effects of the salt = salt are well known. A person who is accustomed to using a composition containing such a salt and which becomes accustomed to the need to include amlodipine or a pharmaceutically acceptable amlodipine besylate thereof, and a ratio of Dosage form. The composition should be a tablet or a solid, and the amount of contaminants produced by the X·phase of the two active ingredients is also kept low during storage. = Indian Patent Application No. 845/MUM/2004, only when the sexual components are separated into different particles, 'solorepine succinate salt, histamine gas benzoate salt, and Japanese composition. The granules are mixed with other forms such as 5 and filled in a capsule or sachet 7 doses or repeatedly into so-called bilayer tablets. The essence of the solution to the invention is that the method basically prevents separation from being separated from each other. The reaction product of formula (3) is formed during the blending of the particles and especially under = contact. Back to the set There are a number of granulations and homogenizations that are required to increase the amount of tableting that is difficult and specialized in accordance with the Indian patent application. , oh, the number. The preparation of the bilayer needs to contain amlodipine or its medicinal amlodipine besylate) and the ratio of 1 to 1 (preferably the dosage form. The composition should be a tablet or a gelatin-solid stable solid)

A, the amount of contaminants produced by the two kinds of viables is not limited, and is kept at a low content during the preparation process or during the composition of the neutrons. The present inventors have surprisingly found that a stable pharmaceutical composition can be prepared under the condition of proper selection of packaging and environment, which satisfies the strictness of the drug if it is satisfactorily packaged. The safety rule requires and ##(2_{[4_(2 gas phenyl)-3-(ethoxycarbonyl)_5_(methoxycarbonyl)_6_fluorenyl., dihydrogen-2_pyridyl The content of ]-methoxy}-ethyl)-aspartic acid in the composition does not exceed 0.5% during preparation (or at least two years) during storage or until storage of the pharmaceutical composition. The present invention relates to a stable solid pharmaceutical composition comprising amlodipine or a pharmaceutically acceptable salt thereof (preferably amlodipine besylate), bisoprolol fumarate, further comprising A pharmaceutically acceptable organic or inorganic filler, disintegrant, lubricant, anti-sticking agent, and the composition is encapsulated in a moisture barrier package. [Embodiment] During the experiment of the present inventors, the inventors have found that the two active ingredients interact even in a simple powder mixture and form a large amount of reaction product. Incompatibility is more pronounced if the two components are placed in a low porosity dosage form (e.g., a tablet whose crystals are in contact with one another over a large area under high pressure). The interaction is strongly dependent on temperature: after storage for one month at different temperatures, the amine gas level and bisoprolol content in the mixture of amine gas benzene sulfonate and bisoprolol fumarate are as follows: 8 201238589 --—^ Table 1 25t/l month 1~·丨|丨_ 40°C/1 巧 nc\°n / 1 /ma Amine gas level--- About 100% 59%__ / U u / 1 1 固月 25% 索索洛豳 about 100% 85% 71% For = medicinal technology, it is obvious that in the case of forming a composition containing: an incompatible component, the ingredients must be used in a suitable form. The knife is away. It is sufficient to coat an active ingredient with a polymeric excipient. The t-coating layer forms a suitable barrier layer between the crystal surfaces of the two active ingredients. The inventor's compounding experiment failed. The active ingredient is heat sensitive. The thermal sensitivity of the -= surface active ingredient not only poses a problem for the aqueous coating process, but also poses a problem for the process using the organic solvent (4) because the solvent is removed and thermally stressed. On the other hand, traces of moisture remain in the composition during the drying process, which also contributes to the interaction of the active ingredients. ^ This month's people have surprisingly found that preventing the incompatibility between the two active ingredients and the thermal degradation of the active ingredient itself is not sufficient to eliminate the use of water or organic solvents with thermal stress. In order to prevent the adverse effects of thermal stress, the composition is prepared by a direct pressing process. If the tablet is stored in a glass container closed by a polyethylene cover in a thief, 65% relative humidity for three months, the degradation product remains below the detection limit. In the same type of lozenge in PVC/PVdC type (polyvinyl chloride/polyvinylidene chloride type) which can be sealed by aluminum foil, it can be formed in 3 generations and relative humidity in 201238589.

Under the condition of two months of storage, the inventors surprisingly found that a very small amount of moisture penetrating the pvc/pvdC type foamed foil (which is known to have a moisture resistance greater than pvc) is sufficient to form an unacceptably large amount of contaminants. It has been shown that it is not sufficient to prevent product from coming into contact with moisture during the manufacturing process, and the environment must remain dry during storage. These experiments indicate that there is a very small amount of absorbed water on the surface of the crystal sufficient to initiate interaction between the components in the solid phase. The reaction causing/depleting substance formation in the composition of the present invention does not occur at all or occurs only in a very limited range. According to the present invention, there is provided a packaged stable solid composition comprising amlodipine and bisoprolol as an active pharmaceutical ingredient, which comprises 〇 5% or less, preferably 0.3% or less, more preferably 〇. 2% or less ( 3) a compound encapsulated in a moisture barrier package and further comprising an amine aflatine or a pharmaceutically acceptable salt thereof (preferably amlodipine besylate), bisoprolol fumarate, a step package 3 pharmaceutically acceptable fillers, disintegrants, lubricants, anti-adhesive agents, adhesives, as appropriate. According to the identification of the present inventors, amlodipine is reacted with fumaric acid. = another salt-forming component (such as an anion of benzenesulfonic acid) does not have any effect during the reaction causing the formation of contaminants... According to the invention, the amine amlodipine may be in the form of a base or a salt (for example amlodipine besylate) Salt) use.

The composition of the present invention is of great importance in terms of the stability of the pharmaceutical composition. 〃 X and for the preparation of tablets by dry process, such excipients which have suitable compressible and free-flowing properties in addition to the main function are used. 201238589 According to the present invention, all of the compounds of the composition are thief-shaped agents except for the active ingredient. Terms relating to excipients (such as fillers, disintegrants, lubricants, anti-adhesives, and binders) refer to the class of excipients. It also refers to a mixture of suitable excipients and their complexes, and also refers to the use of excipients from the same class in the same composition. This condition is, for example, the use of two different fillers (e.g., lactose and microcrystalline cellulose in the form of a complex) suitable for use in the pharmaceutical industry as a filler in the composition. The above terms with respect to excipients also mean that the composition contains conditions from several classes of excipients of different classes. Such conditions are, for example, the use of a filling mash (for example, a complex of lactose with povidone and copovidon) in addition to a disintegrant; or a slip agent or an anti-adhesive agent. Fillers are used in combination (for example, a composite of microcrystalline cellulose and colloidal cerium oxide). According to the present invention, the use of such composites is equivalent to the common use of different components. Thus, such technical solutions also form part of the present invention. As a filler, the composition of the present invention may contain a filler or a mixture thereof for use in the pharmaceutical industry, preferably containing microcrystalline cellulose, anhydrous acid nitrogen, spray dried lactose or mannitol or a mixture thereof, most Good contains low water grade microcrystalline cellulose. In the course of this month's man-made ingot experiment, the inventors found that the lowest degradation rate was detected using microcrystalline cellulose (preferably using low water grade microcrystalline cellulose; see Table 2). 11 201238589 Table 2 Effect of filler on degradation and interaction rate after storage at 50 ° C for one month (amine gas sulfonate / bisoprolol fumarate / filler at 0.1:0 · 1 : 5 ratio mixture) as follows: Filler microcrystalline cellulose (Vivaour, anhydrous potassium hydrogen phosphate (Emcompress) lactose DC 11 (Tablettose) DC mannitol (Perlitol) Compound of formula (3) 0.06% 0.46% 0.24% 0.09% All contaminants 0.29% 0.77% 0.56% 0.31% The ratio of the filler suitable for the direct pressing process in the bonding agent of the present invention is 6 〇 / ° to 90% 'preferably to 90%, more preferably 80% to 90% In the case of capsule products, no filler is required. To ensure that the active ingredients are evenly distributed in a batch of production batches and thus the capsules are always filled with the required amount of both activities throughout the encapsulation process. Preferably, the ingredient is preferably a suitable filler having a specific surface area to prevent the component from being isolated during the process. The filler having two specific surface areas is, for example, powdered cellulose or microcrystalline cellulose or a capsule. Filled composition It is also preferred from the viewpoint that the relatively low thickening pressure generated by the bonding is gathered together and thereby preventing the substance of the composition from being dispersed during the encapsulation process. ^ For the above reasons, the composition to be filled The weight of the substance is 10 capsules. The optimum amount of filler in 5 is i% to 75%, preferably 12 201238589 to 75% 'more preferably 55% to 65%. According to the present invention, better use is lower. Water graded fillers. In addition to the main functional characteristics, the excipients used to prepare the tablet composition by dry process should also have acceptable compressible and free-flowing properties. In the case of disintegration, a disintegrant is required to ensure that the tablet or capsule disintegrates rapidly due to the action of the digestive juice, thereby quickly and completely dissolving and absorbing the active ingredient. Any disintegrant generally used in the pharmaceutical industry can be used. Used as a disintegrating agent. There are a large number of disintegrants which are especially suitable for direct compression keying processes, and can be selected by those skilled in the art. Therefore, the composition of the present invention may comprise any disintegrating agent generally used in the pharmaceutical industry or Mixture as a disintegrant The disintegrant is preferably crospovidone, sodium hydroxyacetate, croscarmellose, low-substituted (tetra)-based cellulose or a mixture thereof, and is preferably sodium acetoxylate. According to the present invention, the optimum amount of the disintegrant in the composition is from 1% to 1% by weight based on the weight of the tablet or capsule filling material, preferably in the composition of the bond and the encapsulation. It is necessary to use an anti-adhesive agent and a slip agent, wherein (4) preventing the moisture-absorbing filler from being wet and the particles adhering to each other due to its strong hygroscopic property. The composition may be included in the medicine for use in the medical record. : Type of anti-sticking agent or a mixture thereof as a release agent. Its preferred package: (5). (d) or colloidal dioxygen or a mixture thereof. It best contains gelatin dioxide. The composition of the present invention makes the optimum amount of the anti-adhesive agent ':: preferably 0.5% to 1%. Wang ". It is necessary to use a material-free tool (tool) tool that reduces the adhesion and friction of the adhesive, 2012-03589, in the case of preparing the composition of the ingot and the encapsulation. The lubricant is used to facilitate extrusion in the filling of the tablet or capsule and to prevent the component from sticking to the forming or filling. The composition of the present invention may comprise any type of lubricant or a mixture thereof used in the pharmaceutical industry as a lubricant. It preferably comprises magnesium stearate, stearin, sodium butenoate, glyceryl eugenate or a mixture thereof. Its best includes hardmoon 曰 3夂_. According to the invention, the optimum amount of lubricant in the composition is from 〇 to 3%, preferably from p/〇 to 2〇/〇. The solid dosage form of the invention is preferably a tablet or capsule. + Surprisingly, in the preferred case, the formulation of the tablet does not require a binder for use in the medical industry. Any binder (e.g., polyvinylpyrrolidine, ketone, starch, etc.) can be used as a binder if it is required to be bonded by changing the properties of the tablet (e.g., increasing its hardness). In the case where the solid dosage form of the present invention is a tablet, according to a preferred embodiment of the present invention, the tablet packaged in the moisture-proof protective package contains 2% to 2%%, preferably 2% to H%, most #1% to 6% of the amine gas or its pharmaceutical salt (preferably amlodipine Benzene g-manate); 2% to 2%, preferably 2% to optimal 1 /. To 6. /^ of bisoprolol bromide; further comprising 60% to 90/. 'preferably from 7〇% to 9〇%, more preferably from 8〇% to 9〇〇/❶ of the filler; from 1/〇 to 1〇/0' preferably from 4% to 6% of the disintegrant; m to, Preferably 1% to 2 / 〇, slip agent, 〇 3 % to 2%, preferably 〇 · % to 1% of the anti-adhesive agent; and if necessary, 1% to 10%, the car is good 1 % to 5% binder (based on the weight of the spin). In the case where the solid dosage form of the present invention is a capsule, according to the present invention, 14 201238589 is a preferred embodiment. The capsule encapsulated in the moisture-proof protective package contains 5% to 18% of the capsules of 8% to 18%. % to 15% of the amlodipine or its doctor's salt (preferably amine azepine sulfonate); 5% to 8%, preferably to 15% 'best 1% to 1% pesos Lolf fumarate; further comprising from 1% to 10〇/〇, preferably from 4% to 6% of a disintegrant; from 5% to 3%, preferably from 1% to 2% of a lubricant; .3% to 2%, preferably 5% to 1% of the release agent; and if necessary, from 1G% to 75%' preferably from 45% to (10), more preferably from 55% to 65. /. Filler (based on the weight of the capsule filling material). In the encapsulated dosage form of the present invention, a pharmaceutical composition (e.g., a tablet or capsule) containing the active ingredient is placed in a package that isolates the dosage form from the environment, thereby protecting the dosage form from environmental influences prior to administration. As an example, the following abbreviations are used to refer to different packaging materials: CFF-Cold Formed Foil OPA/AL/PVC Foil (Oriented Polyamide/Aluminum/Polyvinyl Chloride Foil) PVC/PE/PVdC Pig (Polyethylene/Polyethylene) /Polymerized two-air ethylene dilute) PVC/PCTFE foil (polyethylene/polyglycol trifluoroethylene foil) PVdC (polyvinylidene oxide) layer/foil pVC (polyethylene) foil The solid dosage form of the present invention is moisture-proof package It is a so-called cold foam (CFF) or a thermoformed foam which is a closed container or moisture-proof. According to an embodiment of the present invention, the moisture-proof packaging unit may be a container having a closed assembly (for example, a vial having a gas-tight polyethylene or polypropylene cover, a plastic case, a glass container, a polypropylene drug can, etc.), wherein one is placed Or a lozenge or capsule. 15 201238589 ', the container of the valley, the inner key or the capsule can also make the inner moon b enough, in addition to the capsules and tablets. The auxiliaries which block moisture in the internal atmosphere, such as zeolite or terracotta. The auxiliaries for binding moisture can be placed directly into the gel or lozenge, but they can also be placed in a separate container or bag that is permeable to air and placed in dosage form t. The container is also suitable for encapsulating a solid dosage form of the invention wherein the dosage form and the moisture binding compound are placed in two separate parts and air exchange is ensured. In the atmosphere of the package, air, inert gas may be present). According to an embodiment of the present invention, the moisture-proof protective package is a so-called cold, v-foamed a package form in which the foam is cold-formed by the composite pig and covered with an aluminum cover foil. The composite foil can be OPA/AL/PVC (oriented polyamide/aluminum/polyethylene foil). According to an embodiment of the present invention, a dosage form containing an active ingredient (for example, a key or a capsule) is encapsulated in a so-called cold foamed root: another specific example of the present invention: the moisture-proof package is, for example, heat/proof/ A foam made of a composite foil and covered with an aluminum cover foil. According to another embodiment of the present invention, a dosage form containing an active ingredient (for example, is packaged from a deformable moisture-proof composite and used

Foil. - heavy / white (tnplex f0ll)" or PVC / PCTFE According to the best embodiment of the present invention, the dosage form is a tablet, complex / packaged in 201238589 formed by a PA / AL / PVC composite box and used to cover the box Covered cold-formed foam (so-called cold foam/CFF), or encapsulated in a thermoformable moisture-proof composite foil covered with an indicia cover (for example, PVC/PE/pvdc triple foil or PVC/PCTFE foam) 'In the body' or encapsulated in a glass or polypropylene container with a polyethylene or polypropylene hermetic container lid [based on the total weight of the tablet, the tablet contains 1% to 6% of I gas flattening salt , 1% to (4) bisoprolol fumarate, 80% to 9G% microcrystalline cellulose, 4% to (4) sodium methacrylate, i% to 2% magnesium stearate, 〇 5% to 1 % colloidal silica dioxide. According to another excellent embodiment of the present invention, a capsule is provided which is encapsulated in a cold formed foam formed by OPA/AL/PVC composite falling and covered with a queer capping box (so-called In a cold foam/CFF), or a foam encapsulated in a thermoformable moisture-proof composite foil (for example, pVC/pE/pVdc triple foil or PVC/PCTFE poise) covered with an aluminum cover foil. Medium, or encapsulated in a glass or polypropylene container having a polyethylene or polypropylene: airtight lid, filled with a total weight of the capsule, the capsule containing 10% to 15% of amlodipine besylate , 1% to B% bisoprolol fumarate, 55% to 65% microcrystalline cellulose, sodium starch glycolate, 1% to 2% magnesium stearate, 5% 5% to 〖% gum The composition of the present invention contains 〇5% or less, and the content is preferably between 0.01% and 0.5%. (2-{[4-(2-chlorophenyl)-3-() Ethoxycarbonyl)·5-(methoxycarbonyl) 6-f-yl-, 4-dihydro-2-pyridinyl]methoxyindole·ethylaspartic acid. According to a preferred embodiment of the present invention, The θ of the aspartic acid derivative compound is 0 竓 3 竓 or less, more preferably 〇〇 1% to 〇 3%. According to the present invention, 17 201238589, a more preferred embodiment, the amount of the aspartic acid derivative is Q2% or less ^. Those skilled in the art can use the basics of the present invention to injure products containing the compound of formula (7) which are invaluable to measure. Therefore, the scope of protection includes products which are not detectable by using the basic features of the present invention. A compound of the formula (3). In the preparation of the composition of the present invention, the caramine·+, β μ is tested in a known manner or it is pharmaceutically acceptable < (preferably amine adipine benzene) Sulfonic acid 1), bisoprolol fumarate, in addition to the organic 5 '·, 'machine filler, disintegrant, lubricant and optionally the point mixture homogenization' in the industry Adhesive and homogenized, Α.) The resulting homogenate is compressed into a tablet in a known manner, or Β·) filled into a hard gelatin capsule in a known manner, and then the resulting tablet or capsule is encapsulated in a known manner Prevention. J machine If necessary, it can be screened to achieve a uniform particle size of the components prior to homogenization. For the screening, a 250 μm sieve is preferred. Homogenization can be carried out in any apparatus suitable for homogenization, preferably in a drum mixer. The tablet can be compressed in any known manner by using any kind of ☆ preparation of the splicing press bond. Capsules can be prepared in a known manner using any suitable device for the encapsulation process. The tablets or capsules are encapsulated in a suitable foam in a known manner. . . . Preparation of tablets using: 2% to 2% by weight 'better 2% to 1〇0/〇, most 201238589 preferably 1% to 6% of amlodipine base or a pharmaceutically acceptable salt thereof (preferably Amlodipine besylate); 2% to 20%, preferably 2% to 10%, optimally 1% to 6% of bisoprolol fumarate; in addition, 6〇% to 9〇% Preferably, 70% to 90%, most preferably 80% to 90% filler; 1% to 1%, preferably 4% to 6% disintegrant; 0.5% to 3%, preferably 1% to 2% Lubricant; 〇.3% to 2% 'preferably 0.5% to 1% anti-adherent; and if necessary, 1% to 1%, preferably 0. 1% to 5% binder. Capsules are prepared using 5% to 80%, preferably 5% to 18%, optimally 10% to 15% of amlodipine base or a pharmaceutically acceptable salt thereof, by weight of the capsule filling material. Jiawei adipine benzenesulfonate); 5% to 80%, preferably 5% to 15%, optimally 1 〇. /. Up to 15% bisoprolol methacrylate; in addition, 1% to 10%, preferably 4% to 6%, of disintegrant; 〇 5% to 3%, preferably 1% to 2°/. Lubricant; 〇.3% to 2%, preferably 〇5% to 1% anti-adhesive; and, if necessary, 10% to 90%, preferably 45% to 75%, optimal 55% to 65% filling Agent. For the preparation of the tablet or capsule of the present invention, the filler may be microcrystalline cellulose, anhydrous calcium hydrogen phosphate, spray-dried lactose or mannitol, preferably microcrystalline cellulose or a mixture thereof, more preferably Having 16 humidity t microcrystalline cellulose; disintegrating agent may use crospovidone, sodium starch glycolate, croscarmellose cellulose, low substituted hydroxypropyl cellulose or a mixture thereof, preferably glycolic acid Sodium starch; the lubricant may be magnesium stearate, sodium stearyl fumarate, glyceryl eugenate or a mixture thereof, preferably magnesium stearate. Sticky mouth! It is possible to use a sulphate or a colloidal silica, or a mixture thereof, preferably a colloidal cerium oxide as an anti-sticking agent, and if necessary, a polyvinylpyrrolidone or 19 201238589 starch. The bond or capsule is preferably packaged in a cold formed foam (so-called cold foam/CFF) of a 130/m thick 0PA/AL/pvc composite foil covered with a 2 inch thick aluminum cover foil, or The package is enclosed in a foam made of a thermoformable moisture-proof composite foil covered with a 2 inch thick aluminum cover foil, or packaged in a container equipped with a polyethylene or polypropylene gastight container lid. The composition is preferably packaged in a so-called cold foam (CFF). Another specific example of a moisture barrier package is to package a tablet or capsule with a moisture-binding dry compound as described above. These package forms and auxiliaries are described in detail above. According to the optimum process for preparing a solid pharmaceutical dosage form of a tablet, 1% to 6% of amlodipine besylate, 1% to 6% of bisoprolol fumarate, and 8 to 90% of microcrystalline fiber , 4% to 6% sodium starch glycolate, 1% to 2% stearic acid lock homogenization' followed by the addition of 0.5% to 1% colloidal ceria and homogenization, followed by a direct compression process in a known manner Pressing the homogenate into a tablet" The obtained tablet is encapsulated in a cold formed foam (so-called cold foam/CFF) formed of a 0PA/AL/PVC composite foil and covered with an aluminum cover foil, or encapsulated in A foam covered with a thermoformable moisture-proof composite foil (such as PVC/PE/PVdC triple foil or PVC/PCTFE foil) covered with an aluminum cover foil, or encapsulated in a glass with a polyethylene or polypropylene airtight cover or In the polypropylene container, the tablet is preferably encapsulated in a cold-formed foam (so-called cold foam/CFF) formed of a PA/AL/Pvc composite foil covered with an aluminum cover foil. According to the optimum process for preparing the capsule solid pharmaceutical dosage form, 10% to 15% of the amine amlodipine besylate, 10% to 15% of the total weight of the filling material, 20 201238589 sorol rum fumarate, 55% to 65% microcrystalline cellulose, 4% to 6% glycolic acid: sodium powder, 1% to 2% magnesium stearate homogenized, followed by 0.5% ^ 1% colloidal dioxygenation and homogenization, The homogenate is then encapsulated in a hard gelatin capsule in a known manner and packaged in a cold formed foam formed from an OPA/AL/PVC composite pig and covered with an aluminum cover foil (so-called cold foam/CFF) Or encapsulated in a foam made of a thermoformable moisture-proof composite foil (such as PVC/PE/PVdC triple box or PVC/PCTFE pig) covered with aluminum cover foil, or: with polyethylene or polypropylene gas In a glass or polypropylene stirrer of a close container lid, it is preferred to package the tablet in a cold formed foamed enamel formed of an OPA/AL/PVC composite foil covered with an aluminum cover foil. /CFF). An advantage of the present invention is that it enables a simple and low cost direct tableting process, even in the case where the composition of the present invention contains incompatible active ingredients. The content of the compound (3) in the composition of the present invention is not more than 0.5% for at least 2 years. "Patient compliance" is preferred in the case of using a combination composition, and thus such compositions are more advantageous than compositions used as monotherapy. The invention is illustrated in the following examples and the scope of protection is not limited to such embodiments. Example 1 Composition of 1000 tablets: 13.9 g 10.0 g 265.1 g Amlodipine phthalate salt bisoprolol fumarate microcrystalline cellulose 21 201238589 Glycolic acid powder powder 10.0 g Magnesium stearate 4.0 g Colloidal cerium oxide 2.0 g Process: The two active ingredients are sieved using a 25 0 μηι mesh sieve, followed by homogenization with microcrystalline cellulose, sodium starch glycolate and colloidal cerium oxide in a drum mixer. minute. Next, magnesium stearate was added to the mixture, and the resulting mixture was further homogenized for 2 minutes. The homogenate was pressed into a tablet having a weight of 305 mg by a tablet press. The tablet was packaged in a cold formed foam formed of a 130 μη thick OPA/AL/PVC composite foil and covered with a 20 μη thick aluminum cover foil. The contaminant test results of the tablet prepared according to Example 1 on the day of manufacture and after storage for 3 months at 40 ° C / 75% relative humidity are as follows: Contaminants are 3 months after the day of preparation (40 ° C / 75%) Relative humidity) After 6 months (40 ° C / 75% relative humidity) ΛΚ2-{[4-(2-Phenylphenyl}-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-A --1,4-dihydro-2-° ratio thiol]·methoxy]-ethyl)-aspartic acid < 0.02% 0.15% 0.26% 22 201238589 Other qualities of the product of Example 1 are as follows : 3 months after preparation (40 ° C / 75% relative humidity) Disintegration time: 1 ' 1 ' Dissolution of active ingredient (15 minutes) Amlodipine besylate: 103.1% 97.9% Bisoprolol Butylene salt: 102.6% 98.9% Breaking strength 104 N 113 N Friction loss: 0% 0% Humidity (Karl-Fisher): 3.3% 3.5% Example 2 Composition of 1000 capsules: Amlodipine besylate 6.95 g Bisoprolol fumarate 5.0g Microcrystalline cellulose 30.05 g Sodium starch glycolate 2.0 g Stearic acid town 2.0 g Colloidal 矽 1.0 g Process: Use 25 0 μπι Sieve sieves two active ingredients Then the microcrystalline cellulose, starch sodium glycolate and colloidal silicon dioxide in a drum-type homogenizing mixer 10 min. Next, magnesium stearate was added to the powder mixture, and the resulting mixture was further homogenized for 2 minutes. The homogenate was filled in a capsule having 47 mg of filler using a tablet press. The capsules were packaged in a cold formed foam formed from a 130 μη thick OPA/AL/PVC composite foil 23 201238589 and covered with a 20 μχ thick aluminum cover. The results of the contaminant inspection of the capsules prepared and packaged according to Example 2 on the day of manufacture and after storage for 3 months at 40 C/75% relative humidity are as follows: Contaminants are 3 months after the day of preparation (4 ° C/75 % Relative Humidity) After 6 months (4 °C / 75% relative humidity) ΛΚ2-{[4-(2-Phenylphenyl}-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6 -Methyl-1,4-dihydro-2-pyridyl]-methoxy}-ethyl)-aspartic acid <0.02% 0.11% 0.23% Reference Example: Composition of 1000 tablets: Amine Aflatoxin 13.9g 10.0 g 189.0 g 40.1 g Bisoprolol fumarate acid-filled sputum 2Η2〇 (Emeompress) Cornstarch (STA RX-1500) Povidone K-25 14.0 g Crosslinking Povidone lo.og 2.0 Magnesium stearate colloidal cerium oxide 1.0 g Process: Screening of two active ingredients using a 250 μπι sieve, followed by

Emc〇mpres, corn starch, povidone, cross-linked polyethylene-ketone and cerium oxide were homogenized in a drum mixer for 10 minutes. " In addition, the hard fat magnesium was added to the powder mixture, and the resulting mixture was further homogenized. 2 八 24 24 24 24 24 24 24 24 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 2012 The tablet was packaged in a 250 μm thick PVC foil thermoformed foam and a coating of 60 g/m2 PVdC and the foam was covered with a 2 μm thick aluminum cover foil. The results of the contaminant inspection of the tablets prepared and packaged according to the Reference Example on the day of manufacture and after storage for 3 months at 40 ° C / 75% relative humidity are as follows: Contaminants are 3 months after the preparation date (40 ° C / 75% relative humidity) ΛΚ2-{[4-(2-Phenylphenyl}_3_(ethoxycarbonyl)_5-(methyl hydrazinocarbonyl)-6-fluorenyl-1,4-dihydro-2-pyridinyl ]_methoxy bethyl)_aspartic acid -------- < 0.02% 0.47% L------- A tablet of the reference example is stored; a 】 word deposit 3 After a month, it was subjected to a fairly high degree of smear, partly due to the chemical nature of the excipients used (thirst and chemical incompatibility), which was attributed to insufficient moisture barrier properties of the packaging system. [Simple description of the diagram] None [Key component symbol description] None 25

Claims (1)

201238589 VII. A patent scope: ι_ A stable solid pharmaceutical composition containing amoxidipine or its pharmaceutically acceptable salt and bisoprolol (b_1〇1) or pharmaceutically acceptable Accepted salts and pharmaceutically acceptable excipients, "The solid (4) system is encapsulated in a moisture barrier package = and the step comprises: 5% or less by weight of the active ingredients: compound 2. As in the scope of the patent application, the group consists of the ancient π β side music composition, which is characterized by this, and the product 3 has amlodipine benzene sulfonate salt.卞 医 医 医 医 胺 · · · · · · · · · · · · · · · · · · · · · · · · · · The pharmaceutical composition according to Item 1, characterized in that the butylene disulfonium salt is pharmaceutically acceptable, characterized in that it is characterized in that the present invention is in the range of i. The formula containing Q.3% or less, Q 3 ) compound 5. The pharmaceutical plant composition of claim 1 contains less than 2% of the formula, V 3 ) compound 26 201238589 6. If the patent application scope Item 1 & The solid pharmaceutical composition of the packaged product, characterized in that the composition is encapsulated in a cold-formed foam formed by a * OPA/AL/PVC composite fl covered with 33 lids (so-called Cold foam is called). The packaged solid medicinal composition of claim 1 is characterized in that the composition is encapsulated in a foam which is covered by a thermoformed moisture-proof composite and covered with a cover foil. / 8· The encapsulated solid pharmaceutical composition of the item i of the scope of the patent application is characterized in that the composition is a ten-key in a container of polyethylene or polypropylene, and is equipped with a gas-tight container lid. In a glass or polypropylene container. 9. If you apply for a patent scope! The solid pharmaceutical composition of any one of items to item 8, which is a tablet or capsule. 10. The solid pharmaceutical composition form of claim 9 wherein the pot is a tablet packaged in a moisture-proof package, characterized in that the bond comprises 2% to 20% by weight of the (4), preferably 2 From about 1% to about 6%, more preferably from 1% to 6%, amlodipine or a pharmaceutically acceptable acid addition salt thereof, preferably amlodipine phenic acid salt; 2% to 2% by weight; 2% to 〇%, more preferably % to 6% bisoprolol fumarate; further comprising 6% to 9%, preferably to 90%. 'More preferably from 8 % to 9 % by weight; from 1% to 1% by weight, preferably from % to 6% of disintegrant; from 5% to 3%, preferably from 1% to 2% of lubricant; 3% to, preferably & 5% to 1% of the release agent; if necessary, from 1% to 10%, preferably from 1% to 5% of the binder. U. The solid pharmaceutical composition of claim 1 is a tablet which is encapsulated in a cold formed foam formed by a combination of 0PA/AL/PVc covered with an aluminum cover foil (so-called cold) Foam/CFF), or package 27 201238589 in a foam covered by a thermoformable moisture-proof composite foil and covered with an aluminum cover foil, or encapsulated in a glass equipped with a polyethylene or polypropylene hermetic container lid Or in a polypropylene dish, 'based on the weight of the tablet', the blowing agent comprises 1% to 6% of amlodipine besylate, 1% to 6% of bisoprolol fumarate' 8 % Up to 90% microcrystalline cellulose, 4% to 6% sodium starch glycolate, 1% to 2% magnesium stearate, 0.5% to 1% colloidal cerium oxide. 1 2 · As in the solid pharmaceutical dosage form of claim 1, the capsule is encapsulated in a cold-formed foam formed of 〇PA/AL/pvc composite/animal covered with aluminum cover foil (so-called In a cold foam/CFF), or in a foam covered by a thermoformable moisture-proof composite foil and covered with an aluminum cover foil, or encapsulated in a glass equipped with a polyethylene or polypropylene gas-tight container lid or In a polypropylene container, the weight of the filling material of the capsule is ten, and the capsule contains 10°/. Up to 15% amlodipine besylate, 10% to 15% bisoprolol butyric acid progress contains 55% to 65% microcrystalline fiber: 4% to 6% sodium starch glycolate, 1% To 23⁄4 magnesium stearate, 〇.5% to 1% colloidal cerium oxide.卞I3. A method of preparing a stable solid encapsulating dosage form comprising amlodipine and bisoprolol, characterized in that the amlodipine base or a pharmaceutically acceptable salt thereof, the bisoprolol base or a pharmaceutically thereof thereof Acceptable salts, disintegrants, lubricants and, if necessary, other agents used in the pharmaceutical industry: nucleation, followed by the addition of a release agent, continued homogenization, followed by a) the homogenization using a direct compression process Pressing into tablets, or b.) filling into hard gelatin capsules in a known manner, and then encapsulating the resulting key or capsules in a known manner in a moisture barrier 28 201238589 14. Preparation as claimed in claim 13 A method of tableting, characterized in that it is used in an amount of from 2% to 20%, preferably from 2% to 10%, more preferably from 1% to 6%, by weight of the tablet, or a pharmaceutically acceptable amount thereof. The acid addition salt is preferably an amlodipine besylate; from 2% to 2%, preferably from 2% to 1%, more preferably from 1% to 6%, of bisoprolol fumarate; Further using 6〇% to 90%' preferably 70% to 90%, more preferably 80% to 90% filler; 1% to 1%, preferably 4% to 6% disintegrant; 〇.5 % to 3%, preferably 1% to 2% lubricant; 0.3% to 2%, preferably 0.5% to ι〇/〇 anti-adherent; if necessary, 1% to 1%, preferably 0.5% to 1Q /. Adhesive. 15. The method of preparing a capsule according to claim 13, wherein the weight of the filling material of the capsule is 5% to 8%, preferably 5/ί» to 18/ί», Preferably, from 1% to 15% of amlodipine or a pharmaceutically acceptable acid addition salt thereof is preferably amlodipine besylate; from 5% to 80%, preferably from 5% to 15%, more preferably 10% to 15% bisoprolol fumarate; further use 1% to 10%, preferably 4% to 6% disintegrant; 〇 5% to 3%, preferably 1% to 2% Lubricant; 〇.3% to 2%, preferably 〇5% to 1% anti-adherent; and if necessary, 10% to 75%, preferably 45% to 75%, more preferably 55% to 65% filler . Eight, schema ·' No 29