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    • 专利摘要:
    A stable, solid pharmaceutical composition containing amlodipine or pharmaceutically acceptable salts thereof and bisoprolol or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable excipients, packaged in a moisture resistant package, and which further comprises less than 0.5% of the compound of formula (3) Weight of the active ingredients, includes.
    公开号:AT14769U1
    申请号:TGM8014/2015U
    申请日:2009-09-30
    公开日:2016-05-15
    发明作者:
    申请人:Egis Gyogyszergyar Nyilvánosan Müködö Részvénytársaság；
    IPC主号:
    专利说明:

    description
    STABLE PHARMACEUTICAL COMBINATION PREPARATION OF THE INVENTION
    The present invention relates to a stable solid pharmaceutical Zusam¬mensetzung, the amlodipine of the formula
    and bisoprolol as active ingredients.
    More particularly, the present invention relates to a composition packaged in a moisture resistant package, the amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, and bisoprolol fumarate of the formula
    further comprising a filler, a disintegrant, a lubricant and an anti-stick agent used in the pharmaceutical industry, further wherein the amount of the compound N- (2 - {[4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- methoxycarbonyl) -6-methyl-1,4-dihydro-2-pyridinyl] -methoxy} -ethyl) -aspartic acid of the formula
    0.5% during preparation and storage of the composition.
    BACKGROUND OF THE INVENTION
    The required blood pressure value for reducing the risk of cardiovascular morbidity and mortality can be achieved by a medicine consisting of a single compound or the optimal combination of two compounds, according to the practice of "evidence-based". Therapy.
    Combination therapy is more effective, in general, lower levels of each compound are required than in the case of monotherapy, therefore, the side effects decrease and patient compliance increases.
    These advantages increase the role of combination therapy of drugs in the treatment of hypertension and complications thereof. Combinations of beta-blockers, diuretics, ACE inhibitors, ARB-s and calcium channel blockers are normally used.
    Recently, these combinations have been used for better patient compliance. and lowering the cost of therapy more and more so-called " fixed combinations " which comprise both active ingredients in a single dosage form.
    The use of fixed combinations is unambiguously recommended by international guidelines.
    Several fixed combinations comprising calcium channel blockers (" calcium channel blockers ") and beta-blockers and preferably used for the treatment of hypertension and angina pectoris have recently been on the market, such as tablets, felodipine and metoprolol or nifedipine and atenolol contain.
    The fixed combination of amlodipine and bisoprolol has not yet been marketed, but several articles and patent applications deal with their combination. International Patent Application No. W02005 / 099699 discloses the combinations of S-amlodipine and beta-blockers including the combination with bisoprolol.
    The application mentions several pharmaceutical solutions for the co-formulation of these ingredients, but says nothing about the main problem of practical applicability, namely the chemical incompatibility of the two active ingredients.
    In the so-called " mono-compositions " containing only one active ingredient, amlodipine is in the form of the besilate salt, and bisoprolol is used as the fumarate salt.
    The formulation of amlodipine besilate and bisoprolol fumarate in a single dosage form seems to be feasible because both bisoprolol fumate and amlodipine besilate are suitable for the preparation of stable pharmaceutical dosage forms.
    According to Indian Patent Application No. 845 / MUM / 2004, amlodipine besilate and bisoprolol fumarate interact. According to our experiments the product is the compound N- (2 - {4- (2-chlorophenyl) -3- (ethoxycarbonyl) -5- (methoxycarbonyl) -6-methyl-1,4-dihydro-2-pyridinyl] - methoxy} -ethyl) aspartic acid of the formula (3). This compound is formed by the chemical reaction of amlodipine base and fumaric acid. The formation of this product is unexpected because US Patent Application No. 6518288 indicates that the salt formed from fumaric acid by amlodipine is stable and does not convert to the compound of formula (3).
    The current requirements of the international pharmaceutical authorities accept only very low levels - a few tenths of a percent - of the breakdown products of pharmaceutical compositions.
    The absorption properties and pharmacokinetic effects of the above-mentioned salts are well known. Patients are accustomed to the use of the compositions containing these salts, and they have become accustomed to the effects.
    There is a need for a stable solid dosage form comprising amlodipine or a pharmaceutically acceptable salt thereof, preferably amlodipine besilate, and bisoprolol frumate. The composition should be a tablet or capsule wherein the level of contaminant resulting from the incompatibility of both agents is also kept low during storage.
    According to Indian Patent Application No. 845 / MUM / 2004, a combination composition of amlodipine besylate and bisoprolol fumarate can only be prepared when the active ingredients are separated into different granules. The granules are mixed with other Bindemit¬teln and filled in capsules or bags, or pressed into so-called two-ply tablets. The key point of the solution of the Indian invention is the separation of the two ingredients from one another. This substantially prevents the physical contact between the active ingredients which could aid the formation of the reaction product of formula (3) during the mixing of the granules and especially during the tableting with the intensive contact of large surfaces.
    The method according to the Indian patent application has several disadvantages. The individual granulation and homogenization of the active ingredients increases the number of technological steps required. The production of two-ply tablets requires difficult and special devices.
    There is a need for a stable solid dosage form comprising amlodipine or a pharmaceutically acceptable salt thereof, preferably amlodipine besilate, and bisoprolol agarose. The composition should be a tablet or capsule in which even during storage the amount of contaminant resulting from the incompatibility of both agents is kept low and no separate treatment of the active ingredients either during the manufacturing process or in the Require composition.
    SUMMARY OF THE INVENTION
    [0020] We surprisingly found that, in the event of appropriate selection of the package and circumstances, a stable pharmaceutical composition could be produced which, when satisfactorily packaged, meets the requirements of stringent safety regulations relating to pharmaceuticals, and the amount of N - (2 - {[4- (2-chlorophenyl) -3- (ethoxy-carbonyl) -5- (methoxycarbonyl) -6-methyl-1,4-dihydro-2-pyridinyl] -methoxy} -ethyl) -asparaginsäu -re of formula (3) does not exceed 0.5% in composition, during manufacture and also during storage until the expiry date of the pharmaceutical composition, at least two years.
    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, disintegrants, lubricants, antiadherents, and packed in a moisture resistant package is.
    DETAILED DESCRIPTION OF THE INVENTION
    During our experiments, we found that both active substances interact even in a simple powder mixture and the reaction product is formed in a considerable amount. The incompatibility is more pronounced when both ingredients are placed in a low-porous dosage form, e.g. into a tablet wherein their crystals touch each other under high pressure over a large area.
    The interaction strongly depends on the temperature: the amlodipine and bisoprolol content in a mixture of amlodipine besilate and bisoprolol fumarate varies after one month storage at different temperatures as follows: Table 1
    It will be apparent to those skilled in the pharmaceutical art that in the case of preparing a composition containing two incompatible ingredients, these ingredients must be separated by a suitable method. For this purpose, the coating of the one active substance with a polymer adjuvant may be sufficient. The polymer layer of the coating may form a suitable insulating layer between the crystal surfaces of both active ingredients.
    [0026] Our formulation attempts failed. The active compounds are heat-sensitive. On the one hand, the heat sensitivity of the active ingredients causes problems not only for the aqueous coating process, but also for the coating processes using organic solvents, because the elimination of the solvent entails a thermal stress. On the other hand, traces of atmospheric moisture remain in the composition during the drying process, which also aids in the interaction of the active ingredients.
    We have surprisingly found that preventing intolerance between both drugs and self-decomposition of the drugs under heat is insufficient to preclude processes using water or organic solvents, accompanied by heat stress.
    While avoiding negative effects of heat stress, combination tablets were produced by a direct compression process. When tablets were stored in a glass container closed by a Polyethyl¬enverschluss three months at 30 * € and 65% relative humidity, the decay products remained below the detection limit.
    If the same tablets were stored in a thermoformable blister film of PVC / PVdC type (polyvinyl chloride / Polyvinylydenchlorid-type), which was sealed with an aluminum foil, three months at 30 ° C and 65% relative humidity, we found Surprisingly, the minimum humidity that penetrated the PVC / PVdC blister film, which is known to be more moisture resistant than PVC, was sufficient to form an unacceptably high level of contamination.
    It has been found that it is not sufficient to protect the product from humidity during the manufacturing process, but also that during storage the environment must be kept dry.
    These experiments indicate that for the beginning of the interaction between the Inhalts¬stoffen in a solid phase, the presence of an extremely small amount of water that is absorbed on surfaces of crystals, sufficient. In the composition according to the present invention, the reactions causing the formation of the contaminant do not take place at all or only to a very limited extent.
    According to the present invention, there is provided a stable, solid, packaged pharmaceutical composition of amlodipine and bisoprolol as pharmaceutical actives containing less than 0.5%, preferably less than 0.3%, more preferably less than 0.2%, of the compound of U.S. Pat Formula (3) packed in a moistureproof package; it also comprises amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, bisoprolol fumarate, further a pharmaceutically acceptable filler, disintegrants, lubricants, antiadhesives, optionally excipients.
    According to our knowledge, amlodipine reacts with fumaric acid. During the reaction leading to the formation of the contaminant, the other salt forming component (e.g., anion from the benzenesulfonic acid) is not important. Therefore, according to the present invention, amlodipine can be used as the base or in the form of a salt (e.g., amlodipine besilate).
    The composition according to the present invention is of fundamental importance from the standpoint of stability of the pharmaceutical composition.
    For the formulation of the tablets with dry processes, such adjuvants must be used which have corresponding compaction properties and free-flow characteristics in addition to their main function.
    According to the present invention, all compounds of the composition other than the active ingredients are adjuvants.
    Terms relating to an adjuvant, such as filler, disintegrants, lubricants, antiblocking agents and binders, refer to the categories of excipients. Therefore, they also relate to mixtures of the corresponding auxiliaries and to compositions thereof, as well as to the joint use of auxiliaries of the same category in the same composition. Such a case is e.g. when, as filler, two different fillers which can be used in the pharmaceutical industry are used in the composition, such as lactose and microcrystalline cellulose as a mixture.
    The terms relating to the auxiliaries above also refer to cases in which a composition comprises several adjuvants of different categories. These instances are, for example, when a filler is used in addition to the disintegrant, e.g. Lactose as part of a composition containing povidone and copovidone, or when a lubricant or antiblocking agent is used together with the filler, e.g. as a composite of microcrystalline cellulose with colloidal silica.
    According to the present invention, the use of such compositions is equivalent to the joint use of various components, therefore these technical solutions also form part of the present invention.
    As fillers, the composition according to the present invention may include fillers used in the pharmaceutical industry or mixtures thereof, preferably microcrystalline cellulose, anhydrous calcium hydrogen phosphate, spray dried lactose or mannitol or a mixture thereof, most preferably microcrystalline cellulose of low moisture.
    In the course of our tableting experiments, we found that the lowest degradation rate was observed in the case of using microcrystalline cellulose (microcrystalline low moisture cellulose was preferably used, see Table 2.) The effects of fillers on degradation and the rate of interaction after storage at 50 ° C for one month (mixtures of amlodipine besilate / bisoprolol fumarate / fillers in a proportion: 0.1: 0.1: 5) are as follows:
    Proportions of fillers in the tablets according to the present invention suitable for a direct compression process are 60% -90%, preferably 70% -90%, more preferably 80-90%.
    The use of a filler is not necessary in the case of capsule products. To ensure that the active ingredients are evenly distributed in one production lot, and thereby always filling the required amount of both active ingredients in each capsule during the entire encapsulation process, it is preferred to use an appropriate amount of filler having a high specific surface area which facilitates the separation of the contents Prevents substances during the process.
    Such fillers which have a high specific surface area are e.g. powdered cellulose or microcrystalline cellulose. Microcrystalline cellulose is preferred, also from the standpoint of keeping the composition filled in the capsule together by a relatively low pressure of the thickener due to its mechanically locking bond and accordingly preventing the separation of the substances of the composition during the encapsulation process.
    For these reasons mentioned above, the optimum amount of filler in a capsulated product is 10-75%, preferably 45% 75%, more preferably 55% -65%, based on the weight of the filled substance of the composition.
    The use of low moisture content fillers is more preferred according to the present invention.
    In addition to their major functional features, the excipients used to make the tabletted compositions by a dry process should also have acceptable press properties and free-flow properties.
    A disintegrants must be used both in the case of tableted and encapsulated compositions, which ensures the rapid disintegration of the tablet or capsule due to the effects of the digestive juices; As a result, the dissolution and absorption of the active ingredients take place rapidly and completely. Any disintegrants generally used in the pharmaceutical industry can be used as disintegrants. A wide variety of disintegrants that are particularly suitable for a direct compression tabletting process are available to those skilled in the art.
    In this way, the composition of the present invention may comprise, as a disintegrant, any disintegrating agent generally used in the pharmaceutical industry, or a mixture thereof, preferably cross-povidone, sodium starch glycolate, croscaramelose, low-substituted hydroxypropyl cellulose or a mixture thereof, most preferably sodium starch glycolate. According to the present invention, the optimum amount of disintegrants in the compositions is 1% -10%, preferably 4% -6%, based on the weight of the tablet or filler of the capsule.
    The use of anti-blocking agents and lubricants is necessary both in the tableted and in the encapsulated compositions in which the anti-adhesion agents prevent the unwanted moistening of fillers, which may be hygroscopic, and the bonding of their particles to each other because of their highly hygroscopic nature Prevent properties.
    Therefore, the composition of the present invention may include as anti-sticking agents all kinds of anti-sticking agents generally used in the pharmaceutical industry or a mixture thereof. Preferably, it comprises siloids or colloidal silicas or their mixture. Most preferably, it comprises colloidal silica. The optimum amount of antiblocking agent in the compositions according to the present invention is 0.3% -2%, preferably 0.5% -1%.
    The use of so-called lubricants which reduce the caking and friction characteristics is necessary in the case of the preparation of both tabletted and encapsulated compositions in order to force the tablets or filler of the capsules out of the mold (tool) facilitate and to prevent the caking of Kom¬ponenten to the forming or filling tools.
    As lubricants, the compositions according to the present invention may comprise all kinds of lubricants used in the pharmaceutical industry or a mixture thereof. Preferably, they include magnesium stearate, sodium stearoyl fumarate, glyceryl behenate, or a mixture thereof. Most preferably, they comprise magnesium stearate. According to the present invention, the optimum amount of lubricants in the compositions is 0.5% -3%, preferably 1% -2%.
    The solid dosage form according to the present invention is preferably a tablet or a capsule.
    Unexpectedly, in a preferred case, no binders used in the pharmaceutical industry for the formulation of the tablets are necessary. If this becomes necessary due to a change in the properties of the tablets, e.g. because their hardness has increased, any binder, e.g. Polyvinylpyrrolidone, starch, etc. verwen¬ as a binder.
    If the solid dosage form of the present invention is a tablet, according to the preferred embodiment of the present invention, the tablets packaged in a moisture-resistant protective package comprise 2% -20%, preferably 2% -10%, most preferably 1% -6 % Amlodipine base or a pharmaceutical salt thereof, preferably amlodipine besylate, 2% -20%, preferably 2% -10%, most preferably 1% -6% bisoprolol fumarate, further 60% -90%, preferably 70% -90%, even more preferably 80% -90% filler, 1% -10%, preferably 4% -6% disintegrant, 0.5% -3%, preferably 1% -2% lubricant, 0.3% -2%, preferably 0 , 5% 1% non-stick agent and if necessary 1% -10%, preferably 0.1% -5% binder, calculated on the basis of the weight of the tablets.
    If the solid dosage form of the present invention is a capsule, the capsules packaged in a moisture-proofing protective package according to the preferred embodiment of the present invention comprise 5% -80%, preferably 5% -18%, most preferably 10% -15% amlodipine base or a pharmaceutical salt thereof, preferably amlodipine besylate, 5% -80%, preferably 5% -15%, most preferably 1% -10% bisoprolol fumarate, further 1% -10%, preferably 4% -6% disintegrant, 0, 5% -3%, preferably 1% -2% lubricant, 0.3% -2%, preferably 0.5% -1% non-stick agent and if necessary 10% -75%, preferably 45% -75%, more preferably 55% -65% filler, calculated on the basis of the weight of the filling substance of the capsules.
    In the packaged dosage forms according to the present invention, the pharmaceutical composition containing the active ingredients, e.g. Tablets or capsules, in a package that isolates the dosage forms from the environment, so that the dosage forms are protected in this way from the effects of the environment until they are administered.
    As examples, various packaging materials are mentioned with the following abbreviations: CFF cold forming film OPA / AL / PVC film (oriented polyamide / aluminum / polyvinyl chloride film.) PVC / PE / PVdC Film (polyvinyl chloride / polyethylene / polyvinyl chloride film). PVC / PCTFE film (polyvinyl chloride / polychlorotrifluoroethylene film). PVdC (polyvinyl chloride) layer / film PVC (polyvinyl chloride) film [0068 The moisture resistant package of the solid dosage form of the present invention is a hermetically sealed container or a moisture-resistant, so-called cold blister (CFF) or thermoformed blister.
    According to one embodiment of the present invention, the moisture-resistant packing unit may be a container having a closure component (eg vial, plastic box, a glass container with an airtight Polyethylen- or Polypropy¬lenverschluss, polypropylene Sergeant, etc.), in which one or more tablets or capsules are placed.
    Containers containing tablets or capsules may, if necessary, except Kap¬seln and tablets contain such auxiliaries, which are able to bind humidity of the Innenat¬mosphäre the container; such compounds for binding the humidity are e.g. Zeolites or silica gel. Moisture binding aids can be placed directly under the capsules or tablets, but they can also be placed in a separate container or wrapper that is permeable to air and placed in the middle of the dosage forms. Such containers are also suitable for packaging the solid dosage forms according to the present invention in which the dosage form and the compound for binding humidity are in two separate parts and air exchange is ensured.
    In the atmosphere of the package may be air, noble gases or, if appropriate, vacuum.
    According to one embodiment of the present invention, the moisture-resistant protective package is a so-called cold blister. The cold blister is a packing form in which the blister is cold-formed from a composite film and covered with an aluminum cover sheet. Such a composite film may be OPA / AL / PVC (oriented polyamide / aluminum / polyvinylchloride film). According to one embodiment of the present invention, the dosage forms containing the active ingredients, e.g. Tablets or capsules packed in a so-called cold blister.
    According to another embodiment of the present invention, the moisture-resistant packaging is e.g. a blister made of a thermoformable, moisture-resistant composite film covered with an aluminum cover film.
    According to another embodiment of the present invention, the dosage form containing the active ingredients, e.g. Tablets or capsules, packaged in a blister made from a thermoformable, moisture resistant composition which is covered with an aluminum cover sheet. Such a moisture-resistant composite film may e.g. PVC / PE / PVdC, a so-called " triplex film " or PVC / PCTFE film.
    According to the most preferred embodiment of the present invention, the dosage form is a tablet packaged in a cold formed blister of OPA / AL / PVC composite film and covered with an aluminum cover sheet (so called cold blister / CFF /) or blister thermoformable, moisture resistant composite film (e.g., PVC / PVDC triplex film or PVC / PCTFE film) covered with an aluminum cover film, or packed in a glass or polypropylene container having an airtight polyethylene or polypropylene container closure, which tablet 1 % -6% amlodipine besylate, 1% -6% bisoprolol fumarate, 80% -90% microcrystalline cellulose, 4% -6% sodium starch glycolate, 1% -2% magnesium stearate, 0.5% -1% colloidal silica, based on the total weight of the Tablet¬te, includes.
    According to another very preferred embodiment of the present invention, a capsule is prepared which is packaged in a cold formed blister of OPA / AL / PVC composite film and covered with an aluminum cover sheet (so called cold blister / CFF /) or in a thermoformable, moisture resistant blister Composite film (eg PVC / PE / PVdC triplex film or PVC / PCTFE film) covered with an aluminum cover film, or packed in a glass or polypropylene container with an airtight closure made of polyethylene or polypropylene, which capsule contains 10% -15% amlodipine besilate , 10% -15% bisoprolol fumarate, 55% -65% microcrystalline cellulose, 4% -6% sodium starch glycolate, 1% -2% magnesium stearate, 0.5% -1% colloidal silica, based on the total weight of the filler of the capsule ,
    The composition according to the present invention contains less than 0.5%, preferably an amount between 0.01% and 0.5% of N- (2 - {[4- (2-chlorophenyl) -3- (ethoxycar -bonyl) -5- (methoxycarbonyl) -6-methyl-1,4-dihydro-2-pyridinyl] -methoxy} -ethyl) -aspartic acid. According to a preferred embodiment of the present invention, the amount of the aspartic acid derivative compound is less than 0, 3%, more preferred is an amount between 0.01% and 0.3%. According to a more preferred embodiment of the present invention, the amount of aspartic acid derivative compound is less than 0.2%, more preferably 0.01% -0.2%. A person skilled in the art can use the essential features of the present invention to produce a product which contains the compound of the formula (3) only in a non-detectable amount. Therefore, the scope of the present invention includes those products in which the essential features of the present invention are realized and the product contains an undetectable amount of the compound of the formula (3).
    In the course of the preparation of the compositions according to the present invention, amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, bisoprolol fumarate, further organic or inorganic fillers, disintegrants, lubricants and optionally binders used in the pharmaceutical industry homogenizing the known type, then adding and homogenizing an adhesive A) the resulting homogenate is compressed in a known manner into tablets, or B) filled into hard gelatin capsules in a known manner, then the obtained
    Tablets or capsules are packed in a moisture resistant package in a known manner.
    If necessary, sieving can be done prior to homogenization to achieve uniform grain size of the components. For sieving, preferably a 250 μm sieve can be used. The homogenization can be carried out in any device suitable for homogenization, preferably in a drum mixer. Tablets can be pressed in a known manner using any kind of apparatus for the preparation of directly pressed tablets. Capsules can be prepared in a known manner with the aid of any suitable device for the encapsulation process.
    Tablets or capsules are packed in suitable blisters or containers in known manner.
    Tablets are made by using 2% -20%, preferably 2% -10%, most preferably 1% -6% amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besylate, 2% -20%, preferably 2% % -10%, most preferably 1% -6% bisoprolol fumarate, further 60% -90%, preferably 70% -90%, most preferably 80% -90% filler, 1% -10%, preferably 4% -6 % Disintegrant, 0.5-3%, preferably 1% -2% lubricant, 0.3-2%, preferably 0.5% -1% anti-adhesive and if necessary 1% -10%, preferably 0.1-5% Binders made.
    Capsules are made by using 5% -80%, preferably 5% -18%, most preferably 10% -15% amlodipine base or a pharmaceutically acceptable salt thereof, preferably amlodipine besilate, 5% -80%, preferably 5% -15% %, most preferably 10% -15% bisoprolol fumarate, further 1% -10%, preferably 4% -6% disintegrant, 0.5-3%, preferably 1% -2% lubricant, 0.3-2% , preferably 0.5% -1% of non-stick agent and if necessary 10% -90%, preferably 45% -75%, most preferably 55% -65% filler, based on the weight of the filling substance of the capsules.
    Microcrystalline cellulose, anhydrous calcium hydrogen phosphate, spray dried lactose or mannitol, preferably microcrystalline cellulose or a mixture thereof, more preferably microcrystalline low moisture cellulose can be used as a filler, cross povidone, sodium starch glycolate, croscaramellose, low substituted hydroxypropyl cellulose or a mixture thereof, preferably sodium starch glycolate , can be used as a disintegrating agent, magnesium stearate, sodium stearyl fumarate, glyceryl behanate or a mixture thereof, preferably magnesium stearate, can be used as a lubricant for the preparation of tablets or capsules according to the present invention. siloide or colloidal silica or a mixture thereof, preferably colloidal silica is used as an anti-sticking agent and if necessary, polyvinylpyrrolidone or starch is used as the binder.
    Tablets or capsules are preferably packaged in a cold formed blister of 130Å thick OPA / AL / PVC composite film covered with an aluminum cover sheet of 20pm thickness (so called cold blister / CFF /) or thermoformable, moisture resistant sheet Laminated film covered with an aluminum cover sheet of 20 pm thickness, prepared blisters, or in containers which are equipped with an airtight container closure made of polyethylene or polypropylene, packed. Most preferably, the composition is packaged in a so-called cold blister (CFF).
    Another embodiment of moisture resistant package, as mentioned above, is to package the tablets or capsules together with drying compounds that bind the humidity. These packaging forms and tools are described above in detail.
    According to the most preferred method for preparing a solid pharma¬zeutischen dosage form of tablets are 1% -6% amlodipine besilate, 1% -6% Bisopro¬lolfumarat, 80% -90% microcrystalline cellulose, 4% -6% sodium starch glycolate , 1% -2% Magne¬siumstearat homogenized, then 0.5% -1% colloidal silica is added and homogeni¬siert, then the homogenate is pressed by a direct pressing method in a known manner in Tab¬letten, the tablets obtained are in a cold-formed OPA / AL / PVC composite film blisters packed and covered with aluminum cover film (so-called cold blister / CFF /), or covered in a thermoformable, moisture-resistant composite film blister, eg PVC / PE / PVdC triplex film or PVC / PCTFE film with an aluminum cover film, packaged or packaged in a glass or polypropylene container having an airtight closure of polyethylene or polypropylene, the tablets preferably being placed in a cal Molded blisters made of OPA / AL / PVC composite film, covered with an aluminum cover film (so-called cold blister / CFF /) are packed.
    10% -15% amlodipine besylate, 10% -15% bisoprolol fumarate, 55% -65% microcrystalline cellulose, 4% -6% sodium starch glycolate, 1%, according to the most preferred method for the preparation of a solid pharma¬zeutischen dosage form of capsules % -2% magnesium stearate, based on the total weight of the filler, homogenized, then 0.5% -1% colloidal silica is added and homogenized, then the homogenate is encapsulated in hard gelatin capsule in a known manner and placed in a cold formed blister of OPA / AL / PVC Composite film packaged and covered with an aluminum cover film (so-called cold blister / CFF /), or in a blister of thermoformable, moisture-resistant composite film, eg PVC / PE / PVdC Triplexfolie or PVC / PCTFE film which is covered with aluminum cover film , packaged or packaged in a glass or polypropylene container having an airtight Behälter¬terverschluss made of polyethylene or polypropylene, preferably the Kap¬s in a cold-formed blister made of OPA / AL / PVC composite film, covered with an Alumi¬niumdeckfolie, packed (so-called cold blister / CFF /).
    The advantage of the present invention is that it makes possible the use of the simple and cheap direct tabletting process, even in the case where the composition according to the present invention contains incompatible active ingredients. The content of Compound (3) in the composition of the present invention does not exceed 0.5% for at least 2 years.
    In the case of using the combination composition, the " patient compliance " better, therefore, these compositions are more advantageous than compositions used as monotherapy.
    The present invention is demonstrated in the Examples below, without limiting the scope to the Examples. EXAMPLE 1 Composition for 1000 tablets:
    Amlodipine besylate 13.9g
    Bisoprolol fumarate 10.0g
    Microcrystalline cellulose 265.1 g Sodium starch glycolate 10.0 g
    Magnesium stearate 4.0 g
    Colloidal silica 2.0 g METHOD: Both active ingredients are sieved with the aid of a sieve of 250 μm mesh size, then homogenized for ten minutes with microcrystalline cellulose, sodium starch glycolate and colloidal silica in a tumbler mixer. Then the magnesium stearate is added to the mixture, and the resulting mixture is homogenized for a further two minutes.
    The homogenate is pressed with a tableting machine into tablets having 305 mg weight.
    The tablets are packed in a cold-formed blister of OPA / AL7PVC composite film of 130 pm thickness and covered with an aluminum cover sheet of 20 pm thickness.
    The results of testing the tablets prepared according to Example 1 for impurities at the date of manufacture and after 3 months storage at 40 ° / 75% relative humidity are as follows:
    Further quality data of the product of Example 1 are as follows:
    EXAMPLE 2 Composition of 1000 Capsules:
    Amlodipine besylate 6.95 g
    Bisoprolol fumarate 5.0 g
    Microcrystalline cellulose 30.05 g
    Sodium starch glycolate 2.0 g
    Magnesium stearate 2.0 g
    Colloidal Slicon 1.0 g Method: Both active ingredients are sieved with the aid of a sieve of 250 μm mesh size, homogenized for ten minutes with microcrystalline cellulose, sodium starch glycolate and colloidal silica in a tumbler mixer. Then the magnesium stearate is added to the powder mixture and the resulting mixture is homogenized for another two minutes. Homo-genisate is filled into capsules containing 47 mg of filler using a tablet machine.
    The capsules are packed in a cold-formed blister made of OPA / AI_ / PVC composite film with 130 pm thickness and covered with an aluminum cover sheet of 20 pm thickness.
    The results of testing the capsules prepared and packaged according to Example 2 for impurities at the date of manufacture and after 3 months storage at 40 ° C / 75% relative humidity are as follows:
    COMPARATIVE EXAMPLE: Composition for 1000 tablets:
    Amlodipine besylate 13.9g
    Bisoprolol fumarate 10.0g
    Potassium hydrogen phosphate x 2 H 2 O (Emcompress) 189.0 g
    Corn starch (STA RX-1500) 40.1 g
    Povidone K-25 14.0g
    Crosspovidone 10.0g
    Magnesium stearate 2.0 g
    Colloidal silica 1.0 g METHOD: Both active ingredients are sieved with the aid of a sieve of 250 μm mesh size, then homogenized with Emcompres, maize starch, povidone, crospovidone and colloidal silica in a tumbler mixer for ten minutes. Then, the magnesium stearate is added to the powder mixture, and the resulting mixture is homogenized for another two minutes.
    The homogenate is pressed with a tableting machine into tablets weighing 280 mg.
    The tablets are packaged in a thermoformed blister of PVC film 250 μm thick and a coating layer of PVG 60 g / m2, and the blister is covered with an aluminum cover sheet 20 μm thick.
    The results of the test for impurities of the tablets prepared and packaged according to the comparative example on the date of manufacture and after storage for 3 months at 40 ° C./75% relative atmospheric humidity are as follows:
    Impurities of the tablets according to the comparative example are considerably higher after 3 months storage, which results partly from the chemical characteristics of the auxiliaries used (moisture and chemical incompatibility) and partly from the characteristics of the inadequate moisture resistance of the packaging system.
    权利要求:
    Claims (12)
    [1]
    Claims 1. Kit-of-parts comprising a moisture-proof package in which a stable, solid pharmaceutical composition is packaged, the amlodipine or pharmaceutically acceptable salts thereof and bisoprolol or pharmaceutically acceptable salts thereof, wherein at least one of amlodipine or bisoprolol in the form of a Fumarate or maleate salt, and pharmaceutically acceptable excipients, and wherein the pharmaceutically acceptable excipients include fillers, disintegrants, antiadherents and lubricants, and optionally binders, and that the amlodipine or pharmaceutically acceptable salt thereof and the bisoprolol or pharmaceutically acceptable salts thereof are undivided in composition.
    [2]
    2. Kit-of-parts according to claim 1, characterized in that the filler is selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate, spray-dried lactose or mannitol or a mixture thereof; the disintegrant is selected from cross-povidone, sodium starch glycolate, croscaramellose, low substituted hydroxypropyl cellulose or a mixture thereof, preferably sodium starch glycolate; the anti-adhesive agent is selected from silica or colloidal silica or a mixture thereof, preferably colloidal silica; the lubricant is selected from magnesium stearate, Natriumstearylfumarat, Glycerylbehanat or a mixture thereof, preferably Magne¬siumstearat; and the optional binder is selected from polyvinylpyrrolidone or starch.
    [3]
    Kit of parts according to claim 1, characterized in that the composition contains amlodipine besilate as pharmaceutically acceptable amlodipine salts.
    [4]
    Kit of parts according to claim 1, characterized in that the composition contains bisoprolol fumarate as pharmaceutically acceptable bisoprolol salts.
    [5]
    5. Kit-of-parts according to claim 1, characterized in that the composition in a cold-formed blister (so-called cold blister / CFF /) of OPA / AL / PVC composite film, covered with an aluminum cover film, is packaged.
    [6]
    6. Kit-of-parts according to claim 1, characterized in that the composition is packaged in a blister of thermoformed moisture-proof composite film and covered with ei¬ner aluminum cover film.
    [7]
    7. Kit-of-parts according to claim 1, characterized in that the composition is packaged in a glass or polypropylene container, which is provided with an airtight Behälterver¬schluss of polyethylene or polypropylene.
    [8]
    8. Kit-of-parts according to any one of claims 1-7, characterized in that the solid pharmaceutical composition is designed as a dosage form in the form of a tablet or ei¬ner capsule.
    [9]
    9. kit-of-parts according to claim 8, characterized in that the packed in a moisture-tight packaging dosage form of the solid pharmaceutical Zusam¬mensetzung 2% -20%, preferably 2% -10%, more preferably 1-6% amlodipine base or a pharmaceutically acceptable acid addition salt thereof, preferably amlodipine besilate, 2% -20%, preferably 2% -10%, more preferably 1% -6% bisoprolol fumarate, further comprising 60% -90%, preferably 70% -90%, more preferably 80% -90% filler, 1% -10%, preferably 4% -6% disintegrant, 0.5% -3%, preferably 1% -2% lubricant, 0.3% -2%, preferably 0.5-1% of antiblocking agent, if necessary 1-10%, preferably 0.1% -5% of binder, based on the weight of the dosage form.
    [10]
    Kit of parts according to claim 1, characterized in that the dosage form of the composition is a tablet packaged in a cold-formed blister (so-called cold blister / CFF /) of OPA / AL / PVC composite foil covered with an aluminum cover foil or packaged in a blister of thermoformable moisture-resistant composite film and covered with an aluminum cover film or packed in a glass or polypropylene container with an airtight container closure made of polyethylene or polypropylene, comprising 1% -6% amlodipine besylate, 1% 6% bisoprolol fumarate, 80% -90% microcrystalline cellulose, 4% -6% sodium starch glycolate, 1% -2% magnesium stearate, 0.5% -1% colloidal silica, based on the weight of the tablet.
    [11]
    The kit-of-parts according to claim 1, characterized in that the dosage form of the composition is a capsule packaged in a cold-formed blister (so-called cold blister / CFF /) of OPA / AL / PVC composite foil covered with an aluminum cover foil or in a blister of thermoformable, moisture-resistant composite film and covered with an aluminum cover film, or is packed in a glass or polypropylene container with an airtight container closure made of polyethylene or polypropylene, comprising 10% -15% amlodipine besylate, 10 % - 15% bisoprolol fumarate, further 55% -65% microcrystalline cellulose, 4% -6% sodium starch glycolate, 1% -2% magnesium stearate, 0.5% -1% colloidal silica, based on the weight of the filling substance of the capsule.
    [12]
    A process for producing a stable solid packaged dosage form containing amlodipine and bisoprolol, characterized in that the amlodipine base or a pharmaceutically acceptable salt thereof, the bisoprolol base or a pharmaceutically acceptable salt thereof, wherein at least one of amlodipine or bisoprolol is in the form of a fumarate or maleate salt Disintegrating agent, a lubricant and, if necessary, other adjuvants used in the pharmaceutical industry are homogenized, then an antiblocking agent is added, the homogenization is continued, then a) the homogenate is pressed into tablets using a direct pressing method or b) in a known manner is filled into hard gelatin capsules, then the tablets or capsules obtained are packaged in moisture-proof protective Verpackun¬gen in a known manner. No drawings for this
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    法律状态:
    2019-11-15| MK07| Expiry|Effective date: 20190930 |
    优先权:
    申请号 | 申请日 | 专利标题
    HU0800591A|HU230877B1|2008-09-30|2008-09-30|Stable pharmaceutical combination|
    ATA9359/2009A|AT510866A3|2008-09-30|2009-09-30|STABLE PHARMACEUTICAL COMBINATION PREPARATION|
    PCT/HU2009/000085|WO2010038091A2|2008-09-30|2009-09-30|Stable combination pharmaceutical composition|
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