WO2013035423A1 - Pharmaceutical composition containing candesartan cilexetil - Google Patents
Pharmaceutical composition containing candesartan cilexetil Download PDFInfo
- Publication number
- WO2013035423A1 WO2013035423A1 PCT/JP2012/067428 JP2012067428W WO2013035423A1 WO 2013035423 A1 WO2013035423 A1 WO 2013035423A1 JP 2012067428 W JP2012067428 W JP 2012067428W WO 2013035423 A1 WO2013035423 A1 WO 2013035423A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- capsule
- preparation
- candesartan cilexetil
- formulation
- Prior art date
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising candesartan cilexetil as an active ingredient, and the elution rate and stability of the active ingredient are enhanced.
- Candesartan cilexetil is an antihypertensive agent that exhibits angiotensin II (AII) receptor antagonism.
- AII angiotensin II
- Commercially available formulations are tablets for oral administration, but candesartan cilexetil is very poorly soluble in water. (Solubility ⁇ 0.05 ⁇ g / ml)
- this compound is polyvinyl pyrrolidone (PVP), or this compound, PVP and nonionic surfactant are dissolved in ethanol, and then the formed component is granulated using this solution as a binder, and then compressed into tablets. Made up of.
- PVP polyvinyl pyrrolidone
- Patent Document 2 proposes the use of polyethylene glycol 6000 as a stabilizer that suppresses the degradation of the active ingredient over time in solid preparations such as tablets containing candesartan cilexetil (Compound V). ing.
- This technique is not sufficiently considered for improving the dissolution rate.
- the aforementioned solid preparation for oral administration containing candesartan cilexetil in a substantially amorphous form and a solubilizer requires a complicated process including the use of an organic solvent such as ethanol, and is resistant to heat.
- This compound which is unstable and unstable, has not been fully considered for its formulation process and storage stability.
- the dissolution rate is not sufficiently considered.
- the object of the present invention is therefore to provide a new formulation for oral administration of candesartan cilexetil which is improved in these drawbacks, in particular a formulation which is even higher than was possible by the prior art in terms of both dissolution rate and stability. It is to be.
- the pharmaceutical composition of the present invention is provided by uniformly dispersing candesartan cilexetil in a crystalline state in a carrier containing a gelling agent.
- the carrier containing the gelling agent can contain an adjuvant (adjuvant) that can combine functions such as drug elution rate and / or viscosity adjustment of the preparation and / or drug stabilization.
- the pharmaceutical composition of the present invention is a pharmaceutical composition in which candesartan cilexetil in a crystalline state is supported on a hydrogel of a gelling agent used in the pharmaceutical field.
- the pharmaceutical composition of the present invention can be made into solid preparations such as tablets, capsules, granules, powders, oral jelly preparations and the like by conventional formulation techniques.
- a particulate preparation, a capsule preparation, and a multilayer capsule preparation are desirable.
- the particulate preparation is a solid preparation produced by dropping a pharmaceutical composition onto a cooling medium that is not compatible with the pharmaceutical composition and solidifying.
- the capsule preparation is a solid preparation produced by filling a pharmaceutical composition into a capsule or encapsulating with a capsule film, or using the pharmaceutical composition as a capsule film.
- Multi-layer capsule formulation is a solid product produced by dripping and solidifying a pharmaceutical composition at least triple or more concentrically increasing multiple concentric nozzles in a cooling medium incompatible with the solution dripped from the outermost layer. It is a formulation.
- the pharmaceutical composition of the present invention uniformly disperses candesartan cilexetil, it is possible to provide a preparation with high content uniformity.
- the solid preparation prepared using the pharmaceutical composition of the present invention comprises only a step of uniformly dispersing candesartan cilexetil and a preparation step, and can provide a preparation with a very simple manufacturing process.
- the pharmaceutical composition of the present invention can be blended with ingredients classified as antihypertensive agents or hyperlipidemia agents.
- the compounding component can be contained in a pharmaceutical composition containing candesartan cilexetil.
- candesartan cilexetil When it is difficult to mix together, such as when stability is reduced when blended with candesartan cilexetil, or when the blended component is a liquid / semi-solid component, the capsule formulation or multilayer capsule formulation should be used.
- candesartan cilexetil and the blending component can be blended separately in the same preparation. This makes it possible to provide a compounding agent having excellent stability.
- a higher elution rate than that of candesartan cilexetil drug substance can be obtained. This is because the wettability of candesartan cilexetil was greatly improved by uniformly dispersing candesartan cilexetil in a carrier containing a gelling agent. In addition, by uniformly dispersing candesartan cilexetil, variation in elution is reduced and a stable elution rate is obtained.
- Candesartan cilexetil is known to be destabilized by crystal distortion caused by heat, pressure, friction, etc., but candesartan cilexetil is uniformly dispersed in a crystalline state in a carrier containing a gelling agent. Thus, stability in the preparation is ensured, and storage stability is also ensured.
- the example of the particulate formulation manufactured by dripping a pharmaceutical composition on the cooling medium incompatible with a pharmaceutical composition, and solidifying The example of the capsule formulation which used the pharmaceutical composition as the capsule content. The example of the capsule formulation which used the pharmaceutical composition as the capsule membrane
- 10 is a graph obtained by measuring the elution rate of the compositions of Sample 7 to Sample 12 tested in Test Example 2.
- 10 is a graph obtained by measuring the elution rate of the compositions of Sample 13 to Sample 18 tested in Test Example 2. The graph which compared the elution rate of the composition of the prescription 1 thru
- 10 is a graph comparing the dissolution rate of the compositions of Formulations 7 to 11 tested in Test Example 3 with the dissolution rate of the control (candesartan cilexetil drug substance).
- the pharmaceutical composition of the present invention it is convenient to start from the step of preparing a hydrous sol of the gelling agent to be used in advance and supporting candesartan cilexetil in the crystalline state.
- various additives including a plasticizer such as glycerin are also dissolved in water together with the gelling agent to prepare a hydrous sol containing the additive, and candesartan cilexetil is uniformly dispersed therein.
- the hydrous sol loaded with candesartan cilexetil can then be processed into oral dosage formulations such as particulate formulations, capsule formulations, multilayer capsule formulations, capsule coatings and the like.
- Gelling agent is a chemical substance that gels and solidifies liquid. Those used in the pharmaceutical field are selected. Specifically, agar, carrageenan, alginate, pectin, cellulose, gelatin, mannan, glucomannan, gum arabic, tragacanth gum, tamarind gum, modified starch polymer, dextrin, soybean Examples include protein, collagen, ovalbumin, casein, fibrin, elastin, keratin, chitosan, curdlan, gellan gum, xanthan gum, and hyaluronic acid. Gelatin is preferable.
- the carrier containing the gelling agent can use the gelling agent alone or a mixture thereof.
- a plasticizer, a preservative, etc. can be used for the support
- the gelling agent is 0.01 to 10000 parts by weight, preferably 0.1 to 1000 parts by weight, more preferably 1 to 100 parts by weight with respect to 1 part by weight of candesartan cilexetil.
- Candesartan cilexetil is uniformly dispersed in a carrier containing a gelling agent in a crystalline state. At this time, in order to uniformly disperse candesartan cilexetil, it is preferable that the gelling agent is heated, dissolved, and mixed together with a plasticizer, an antiseptic, and the like in advance.
- candesartan cilexetil is dispersed in a carrier, it can be dispersed at an arbitrary ratio with respect to the carrier.
- auxiliary additives other than plasticity and preservatives can be used.
- the auxiliary additive can have functions such as control of drug dissolution rate, viscosity adjustment, and drug stabilization.
- auxiliary additives that can be used include:
- sucrose fatty acid ester polyvinylpyrrolidone, crospovidone, crystalline cellulose, polyethylene glycol, titanium oxide, light anhydrous silicic acid, magnesium stearate, hypromellose, methylcellulose and the like.
- sucrose fatty acid esters include DK esters (SS, F-160, F-140, F-110, F-90, F-70, F-50, F-20W, F-10) (Daiichi Kogyo Seiyaku) Manufactured).
- polyvinylpyrrolidone include Kollidon K25, Kollidon K30, Kollidon K90 (manufactured by BASF Japan) and the like.
- Examples of crospovidone include Kollidon CL-M (manufactured by BASF Japan).
- Examples of the crystalline cellulose include Theolas (manufactured by San-Eigen F.F.I.).
- As polyethylene glycol macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, macrogol 35000 (Sanyo) Chemical Industries).
- Examples of titanium oxide include titanium oxide (manufactured by Sakai Chemical Industry), titanium oxide A-HR (manufactured by Freund Industries), and the like.
- Examples of the light silicic acid anhydride include ADSOLIDER-101 (manufactured by Freund Sangyo).
- magnesium stearate examples include magnesium stearate (manufactured by Saneigen F.F.I, manufactured by NOF Corporation).
- hydroxypropylcellulose examples include TC-5 (manufactured by San-Eigen F.F.I.).
- methyl cellulose examples include METALOSE SM (Shin-Etsu Chemical Co., Ltd.).
- the auxiliary additive can be added in an amount of 0.1 to 100 parts by weight, preferably 20 parts by weight, based on 1 part by weight of candesartan cilexetil.
- the pharmaceutical composition of the present invention in which candesartan cilexetil in a crystalline state is supported on a water-containing gel is prepared by a conventional formulation technique using tablets, capsules, It can be a solid preparation such as a granule, powder, or oral jelly.
- the capsule composition can also be made into a capsule preparation by making the pharmaceutical composition of the present invention into a capsule content or a capsule film.
- the capsule preparation can be produced by a conventional method for producing soft capsules or hard capsules.
- the soft capsule can be produced by any one of a seamless method, a flat plate method, and a rotary die method.
- a hard capsule can be manufactured by the method of filling the content of a capsule of a granule, a liquid, and a paste. Specific examples of the preparation are shown in FIGS.
- the pharmaceutical composition of the present invention is dropped into a cooling medium that is incompatible with the solution dripped from the outermost layer using at least three or more concentrically increasing concentric multiple nozzles, and solidified to form a multilayer capsule formulation Is also possible.
- the multilayer capsule preparation is composed of layers formed by dropping from each nozzle of a multiple nozzle, and is expressed as a first layer, a second layer, a third layer, and the like (hereinafter the same) from the center.
- the multilayer capsule preparation containing the pharmaceutical composition of the present invention is formed by dropping the pharmaceutical composition from any one of the multiple nozzles. Moreover, it can also be set as a compounding formulation by dripping a compounding component from either nozzle at this time. A specific example of the formulation is shown in FIG.
- the gelling agent when the gelling agent is gelatin, it dissolves well in hot water and gels at 35 ° C or lower. Therefore, in order to uniformly disperse the drug, it is necessary to add it before gelation of the gelatin solution.
- a hot gelatin solution in which the drug is dispersed is dropped as a droplet into a cold hydrophobic liquid such as vegetable oil or medium-chain fatty acid triglyceride to cause gelation.
- a hot gelatin solution in which the drug is dispersed is dropped as a droplet into a cold hydrophobic liquid such as vegetable oil or medium-chain fatty acid triglyceride to cause gelation.
- the amount of hot water for dissolving gelatin is desirably the minimum necessary, but generally, the total amount of glycerin added as a plasticizer is the same amount to 5 times the weight of gelatin.
- a particle preparation made of a gel carrying a drug needs to be dried to reduce the moisture of the gel in order to prevent sticking and microbial growth.
- the drying method is arbitrary, it is better to avoid a high temperature of 40 ° C. or higher.
- a plasticizer is included, it does not become brittle even if it is dried to the same extent as the moisture content of 9 to 12% of the dry gelatin.
- As a simple method for measuring the degree of drying of the gel there is a method for measuring the water activity of the gel.
- Water activity can be considered as 1/100 of the equilibrium relative humidity in the sealed container containing the sample, and is used as a numerical value indicating the amount of free water in the food that microorganisms can use for growth. These measuring instruments are commercially available. In the case of the present invention, the degree of drying of the granular preparation or capsule film is sufficient if the water activity is below 0.8.
- the pharmaceutical composition of this invention can also mix
- Antihypertensive agents include, for example, amlodipine besilate, azelnidipine, alanidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, azelnidipine, Compounds with calcium antagonism such as diltiazem hydrochloride and benidipine hydrochloride, hydrochlorothiazide, trichlormethiazide, benchylhydrochlorothiazide, meticlan, ind
- drugs for hyperlipidemia examples include pravastatin sodium, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, statins such as pitavastatin calcium and rosuvastatin calcium, anion exchange resins such as colestimilan and colestimide, clofibrate Fibrates such as clinofibrate, bezafibrate and fenofibrate, nicotinic acid derivatives such as tocopherol nicotinate, nicomol and niceritrol, cholesterol absorption inhibitors ezetimibe, probucol and ethyl icosapentate.
- statins such as pitavastatin calcium and rosuvastatin calcium
- anion exchange resins such as colestimilan and colestimide
- clofibrate Fibrates such as clinofibrate, bezafibrate and fenofibrate
- nicotinic acid derivatives such as tocopherol nico
- the compounding component can be compounded in a pharmaceutical composition containing candesartan cilexetil.
- the stability decreases, or the compounding component is a liquid / semi-solid component.
- candesartan cilexetil and the blending component can be blended separately as a capsule preparation or a multilayer capsule preparation. A specific example of the formulation is shown in FIG.
- the packaging form is not particularly limited, but a packaging form considering ease of taking is desirable, and a stick shape or the like is preferred.
- Test example 1 First, in order to examine the storage stability of candesartan cilexetil (hereinafter simply referred to as “drug”) in various auxiliary additives, the following severe stability test was conducted. 30 mg of the drug and 0.9 g of various additive components were weighed in a transparent glass container and heated at about 80 ° C. for 30 minutes, and it was visually observed whether or not the drug was dissolved in these components. Next, the liquid was transferred to a glass bottle, sealed, and stored for 2 weeks in an environment of temperature 50 ° C. and humidity 75% RH, and the drug content after storage was quantified by HPLC to calculate the residual rate. The results are shown in Table 1.
- Test example 2 Next, in order to confirm the dissolution property of the drug by the auxiliary additive, a dissolution test using a powdered powder was performed. Samples 1 to 18 were prepared by uniformly mixing 0.95 g of various auxiliary additives shown in Table 2 with 50 mg of the drug. An amount of each sample corresponding to 2 mg of drug was taken, filled into a hard capsule, and a dissolution test was performed. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. A sinker was used. 20 mL was sampled at the specified time and the drug content was measured by HPLC. The results are shown in FIG. 6, FIG. 7, and FIG.
- Test example 3 In order to observe the effect on the drug dissolution of the specimens whose dissolution was improved in Test Example 2, the effect on the drug dissolution by preparing a particulate formulation for formulations 1 to 11 shown in Table 3 was observed.
- An appropriate amount of water was added to the ingredients excluding the drug and mixed, and the mixture was heated at about 70 ° C. to dissolve the gelatin.
- the drug was added and dispersed uniformly to obtain a pharmaceutical composition.
- the pharmaceutical composition is dropped into an incompatible cooling medium, which is a medium-chain fatty acid triglyceride, and the particles obtained by solidification are dried to a water activity of 0.3 to obtain a particulate preparation in the form of a hydrogel. Prepared.
- the dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method.
- the test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm.
- the test was carried out by taking an amount corresponding to 2 mg of drug for each particulate preparation.
- the test was conducted at 10 mg for convenience of collection. 20 mL was sampled at the specified time and the drug content was measured by HPLC. About each result, it converted into the elution rate with respect to the amount of active ingredients, and the elution property was compared.
- Test example 4 In order to examine the storage stability of the particulate preparation prepared in Test Example 3, the following severe stability test was conducted. The particulate preparation was put in a glass bottle and sealed, and stored in an environment of a temperature of 50 ° C. and a humidity of 75% RH, taken out after 2 weeks and 4 weeks, the drug content was quantified by HPLC, and the residual rate was calculated. The results are shown in Table 4.
- Prescription Example 1 The following ingredients except the particulate drug were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to obtain a pharmaceutical composition. The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
- an incompatible cooling medium for example, medium-chain fatty acid triglyceride
- Particulate preparation (compound) The following components excluding the drug and blended components were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug and compounding ingredients were added and dispersed uniformly to obtain a pharmaceutical composition. The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
- an incompatible cooling medium for example, medium-chain fatty acid triglyceride
- Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
- the pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example.
- the capsule preparation was dried to have a water activity of 0.5.
- Capsule formulation (compound)
- the capsule content components excluding the drug and the compounding components were mixed and heated at about 70 ° C. to dissolve. After dissolution, the drug and compounding ingredients were added to produce a pharmaceutical composition.
- the pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example.
- the capsule preparation was dried to have a water activity of 0.5.
- [Prescription Example 17] Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition. The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules to obtain a capsule preparation.
- [Prescription Example 19] Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added, and the uniformly dispersed product was granulated and dried to a water activity of 0.3 to produce a pharmaceutical composition. The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules.
- [Prescription Example 20] Capsule formulation The capsule film components except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition. The capsule contents were filled into the capsule film (pharmaceutical composition) by a conventional method for producing soft capsules to produce a capsule preparation. At this time, the drug content per capsule was, for example, 2 mg. The capsule preparation was dried to have a water activity of 0.5.
- Capsule formulation Capsule film components excluding the drug were mixed and heated at about 70C to dissolve gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition. The capsule contents were simultaneously dropped from the central nozzle and the pharmaceutical composition was simultaneously dropped from the outer nozzle, and a capsule preparation was produced according to a conventional seamless capsule production method. At this time, the capsule preparation was dried to have a water activity of 0.5.
- Multi-layer capsule formulation The ingredients of the third layer excluding the drug were mixed and heated at about 70C to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition. A first layer, a second layer, and a third layer (pharmaceutical composition) were simultaneously dropped from the center, and a multilayer capsule preparation was produced according to a conventional method for producing seamless capsules. At this time, the multilayer capsule preparation was dried so that the water activity was 0.3.
- compositions of Formulation Examples 1 to 9 and Formulation Examples 26 to 30 prepared to contain 0.125 mg to 1 mg of active ingredient per preparation are counted in the number corresponding to the single dose shown in Table 5 and packaged and packaged.
- the packaging form is, for example, packaged in a stick-shaped package.
Abstract
Provided is a pharmaceutical composition containing candesartan cilexetil, in which the stability and elution rate of the drug are increased compared with those achieved in conventional pharmaceutical compositions. A pharmaceutical composition comprising: a hydrogel of a gelling agent; and candesartan cilexetil which is in a crystalline form and is supported on the hydrogel.
Description
本発明は、カンデサルタンシレキセチルを活性成分として含み、活性成分の溶出率と安定性が高められた医薬組成物に関する。
The present invention relates to a pharmaceutical composition comprising candesartan cilexetil as an active ingredient, and the elution rate and stability of the active ingredient are enhanced.
カンデサルタンシレキセチルは、アンジオテンシンＩＩ（ＡＩＩ）受容体拮抗作用を示す高血圧治療薬である。市販されている製剤は、経口投与用の錠剤であるが、カンデサルタンシレキセチルは水に極めて難溶性である。（溶解度０．０５μｇ／ｍｌ未満）
Candesartan cilexetil is an antihypertensive agent that exhibits angiotensin II (AII) receptor antagonism. Commercially available formulations are tablets for oral administration, but candesartan cilexetil is very poorly soluble in water. (Solubility <0.05 μg / ml)
溶出率を高めるため、実質的に非晶質の形態のこの化合物を含んでいる経口投与用固形製剤が提案されている。特表２０１０－５０２６９８（特許文献１）参照。具体的には、この化合物をポリビニルピロリドン（ＰＶＰ）、またはこの化合物とＰＶＰと非イオン界面活性剤をエタノールに溶かし、この溶液を結合液として用いて賦形成分を造粒し、錠剤へ圧縮成形することよりなる。この文献では、実質的に非晶質のカンデサルタンシレキセチルの固体分散体を得る目的で化合物とエチレンオキシドとプロピレンオキシドの共重合体（ポロキサマー）またはポリエチレングリコール６０００の混合物を溶融し、冷却固化して固体分散体とする実験を行っているが、いずれの場合も分散体中の薬剤は結晶質であったことを報告している。
In order to increase the dissolution rate, a solid preparation for oral administration containing this compound in a substantially amorphous form has been proposed. See Special Table 2010-502698 (Patent Document 1). Specifically, this compound is polyvinyl pyrrolidone (PVP), or this compound, PVP and nonionic surfactant are dissolved in ethanol, and then the formed component is granulated using this solution as a binder, and then compressed into tablets. Made up of. In this document, for the purpose of obtaining a solid dispersion of substantially amorphous candesartan cilexetil, a mixture of a compound and a copolymer of ethylene oxide and propylene oxide (poloxamer) or polyethylene glycol 6000 is melted, cooled and solidified. Experiments with solid dispersions were conducted, but in all cases it was reported that the drug in the dispersion was crystalline.
カンデサルタンシレキセチルは単独で固体状態では、温度、湿度、光に対して安定であるが、製剤化において安定性が低下することが知られている。特に製造過程に加えられる圧力、摩擦、熱等により結晶の歪みが生じることがあり、経日的な含量低下が加速される。特許第２６８２３５３号（特許文献２）は、カンデサルタンシレキセチル（化合物Ｖ）を含む錠剤等の固形製剤において、有効成分の経時的分解を抑制する安定剤としてポリエチレングリコール６０００を使用することを提案している。しかしながらこの技術は溶出率の改良については十分に考慮されていない。
It is known that candesartan cilexetil alone is stable to temperature, humidity, and light in the solid state, but its stability is reduced in formulation. In particular, crystal distortion may occur due to pressure, friction, heat, and the like applied to the manufacturing process, and the deterioration of content over time is accelerated. Japanese Patent No. 2682353 (Patent Document 2) proposes the use of polyethylene glycol 6000 as a stabilizer that suppresses the degradation of the active ingredient over time in solid preparations such as tablets containing candesartan cilexetil (Compound V). ing. However, this technique is not sufficiently considered for improving the dissolution rate.
実質的に非晶質形態のカンデサルタンシレキセチルおよび可溶化剤を含む前述の経口投与用固形製剤は、エタノールのような有機溶媒の使用を含む複雑な工程が必要である上、熱などに対して不安定なこの化合物の製剤化工程および貯蔵時の安定性について十分に考慮されていない。また、カンデサルタンシレキセチルの安定性を改善した前述の固形製剤では、溶出率については十分に考慮されていない。それ故本発明の課題は、これらの欠点が改良されたカンデサルタンシレキセチルの新しい経口投与用製剤、特に溶出率と安定性の両面に関して先行技術によって可能であったよりもさらに高められた製剤を提供することである。
The aforementioned solid preparation for oral administration containing candesartan cilexetil in a substantially amorphous form and a solubilizer requires a complicated process including the use of an organic solvent such as ethanol, and is resistant to heat. This compound, which is unstable and unstable, has not been fully considered for its formulation process and storage stability. Moreover, in the above-mentioned solid preparation with improved stability of candesartan cilexetil, the dissolution rate is not sufficiently considered. The object of the present invention is therefore to provide a new formulation for oral administration of candesartan cilexetil which is improved in these drawbacks, in particular a formulation which is even higher than was possible by the prior art in terms of both dissolution rate and stability. It is to be.
本発明によれば、本発明の医薬組成物はゲル化剤を含む担体にカンデサルタンシレキセチルを結晶状態のまま均一に分散させることにより提供される。ゲル化剤を含む担体には薬物の溶出速度および／または製剤の粘度調節および／または薬物の安定化等の機能を兼ね備えることができる補助剤（アジュバント）を含むことができる。
According to the present invention, the pharmaceutical composition of the present invention is provided by uniformly dispersing candesartan cilexetil in a crystalline state in a carrier containing a gelling agent. The carrier containing the gelling agent can contain an adjuvant (adjuvant) that can combine functions such as drug elution rate and / or viscosity adjustment of the preparation and / or drug stabilization.
従って本発明との医薬組成物は、医薬分野で使用されるゲル化剤の含水ゲルに結晶状態のカンデサルタンシレキセチルを担持させてなる医薬組成物である。
Therefore, the pharmaceutical composition of the present invention is a pharmaceutical composition in which candesartan cilexetil in a crystalline state is supported on a hydrogel of a gelling agent used in the pharmaceutical field.
本発明の医薬組成物は、常法の製剤化技術により錠剤、カプセル剤、顆粒剤、散剤、経口ゼリー剤等の固形製剤とすることができる。特に、粒子状製剤、カプセル製剤、多層カプセル製剤とすることが望ましい。粒子状製剤とは、医薬組成物を医薬組成物と相溶性のない冷却媒体に滴下し、固化することにより製した固形製剤である。カプセル製剤とは、医薬組成物をカプセルに充てん又はカプセル皮膜で被包成形する方法や、医薬組成物をカプセル皮膜として用いる方法により製した固形製剤である。多層カプセル製剤とは、医薬組成物を少なくとも三重以上の順次増大する同心円状の多重ノズルを用い、最外層より滴下される溶液と相溶性のない冷却媒体に滴下し、固化することによって製した固形製剤である。
The pharmaceutical composition of the present invention can be made into solid preparations such as tablets, capsules, granules, powders, oral jelly preparations and the like by conventional formulation techniques. In particular, a particulate preparation, a capsule preparation, and a multilayer capsule preparation are desirable. The particulate preparation is a solid preparation produced by dropping a pharmaceutical composition onto a cooling medium that is not compatible with the pharmaceutical composition and solidifying. The capsule preparation is a solid preparation produced by filling a pharmaceutical composition into a capsule or encapsulating with a capsule film, or using the pharmaceutical composition as a capsule film. Multi-layer capsule formulation is a solid product produced by dripping and solidifying a pharmaceutical composition at least triple or more concentrically increasing multiple concentric nozzles in a cooling medium incompatible with the solution dripped from the outermost layer. It is a formulation.
カンデサルタンシレキセチルを均一に分散させた医薬組成物を粒子状製剤若しくはカプセル製剤、多層カプセル製剤とした場合、製造工程中に圧力、摩擦、熱等の負荷がかからないため、製造工程においても安定性が保たれた製剤を提供することが可能である。また、本発明の医薬組成物はカンデサルタンシレキセチルを均一に分散させているため、含量均一性が高い製剤を提供することができる。さらに、本発明の医薬組成物を用いて調製した固形製剤は、カンデサルタンシレキセチルを均一に分散させる工程と製剤化工程のみからなり、極めて簡単な製造工程で製剤を提供することができる。
When a pharmaceutical composition in which candesartan cilexetil is uniformly dispersed is made into a particulate formulation, capsule formulation or multi-layer capsule formulation, there is no pressure, friction, heat, etc. during the production process, so it is also stable in the production process. Can be provided. In addition, since the pharmaceutical composition of the present invention uniformly disperses candesartan cilexetil, it is possible to provide a preparation with high content uniformity. Furthermore, the solid preparation prepared using the pharmaceutical composition of the present invention comprises only a step of uniformly dispersing candesartan cilexetil and a preparation step, and can provide a preparation with a very simple manufacturing process.
本発明の医薬組成物は血圧降下剤もしくは高脂血症用剤に分類される配合成分を配合することが可能である。配合成分はカンデサルタンシレキセチルを含む医薬組成物中に含有することができる。また、カンデサルタンシレキセチルと一緒に配合すると安定性が低下する場合や、配合成分が液体・半固形成分である場合など、一緒に配合することが難しい場合は、カプセル製剤若しくは多層カプセル製剤などとし、カンデサルタンシレキセチルと配合成分とを同一の製剤中に別々に配合することもできる。これにより安定性に優れた配合剤を提供することが可能となる。
The pharmaceutical composition of the present invention can be blended with ingredients classified as antihypertensive agents or hyperlipidemia agents. The compounding component can be contained in a pharmaceutical composition containing candesartan cilexetil. When it is difficult to mix together, such as when stability is reduced when blended with candesartan cilexetil, or when the blended component is a liquid / semi-solid component, the capsule formulation or multilayer capsule formulation should be used. In addition, candesartan cilexetil and the blending component can be blended separately in the same preparation. This makes it possible to provide a compounding agent having excellent stability.
本発明により、カンデサルタンシレキセチル原体よりも高い溶出率が得られる。これは、ゲル化剤を含む担体にカンデサルタンシレキセチルを均一に分散させることにより、カンデサルタンシレキセチルの濡れ性を大幅に改善させたためである。また、カンデサルタンシレキセチルを均一に分散させたことにより、溶出のバラツキが軽減され、安定した溶出率を有する。
According to the present invention, a higher elution rate than that of candesartan cilexetil drug substance can be obtained. This is because the wettability of candesartan cilexetil was greatly improved by uniformly dispersing candesartan cilexetil in a carrier containing a gelling agent. In addition, by uniformly dispersing candesartan cilexetil, variation in elution is reduced and a stable elution rate is obtained.
カンデサルタンシレキセチルは熱や圧力、摩擦等に起因する結晶の歪みにより不安定化することが知られているが、カンデサルタンシレキセチルをゲル化剤を含む担体に結晶状態のまま均一に分散させることにより製剤中での安定性が確保され、貯蔵安定性も確保される。
Candesartan cilexetil is known to be destabilized by crystal distortion caused by heat, pressure, friction, etc., but candesartan cilexetil is uniformly dispersed in a crystalline state in a carrier containing a gelling agent. Thus, stability in the preparation is ensured, and storage stability is also ensured.
本発明の医薬組成物の製造は、使用するゲル化剤の含水ゾルをあらかじめ調製し、これに結晶状態のカンデサルタンシレキセチルを担持させる工程から出発するのが便利である。その際グリセリンのような可塑剤を含む各種添加剤もゲル化剤と共に水に溶解し、添加剤を含んでいる含水ゾルを調製し、これにカンデサルタンシレキセチルを均一に分散させる。カンデサルタンシレキセチルを担持させた含水ゾルはその後粒子状製剤、カプセル製剤、多層カプセル製剤、カプセル皮膜などの経口投与製剤に加工することができる。
For the production of the pharmaceutical composition of the present invention, it is convenient to start from the step of preparing a hydrous sol of the gelling agent to be used in advance and supporting candesartan cilexetil in the crystalline state. At that time, various additives including a plasticizer such as glycerin are also dissolved in water together with the gelling agent to prepare a hydrous sol containing the additive, and candesartan cilexetil is uniformly dispersed therein. The hydrous sol loaded with candesartan cilexetil can then be processed into oral dosage formulations such as particulate formulations, capsule formulations, multilayer capsule formulations, capsule coatings and the like.
ゲル化剤は液体をゲル化して固化する化学物質である。医薬分野で用いられるものが選ばれるが、具体的には寒天、カラギーナン、アルギン酸塩、ペクチン、セルロース、ゼラチン、マンナン、グルコマンナン、アラビアガム、トラガントガム、タマリンドガム、修飾デンプン系高分子、デキストリン、大豆タンパク質、コラーゲン、卵白アルブミン、カゼイン、フィブリン、エラスチン、ケラチン、キトサン、カードラン、ジェランガム、キサンタンガム、ヒアルロン酸などが挙げられる。好ましくはゼラチンである。
Gelling agent is a chemical substance that gels and solidifies liquid. Those used in the pharmaceutical field are selected. Specifically, agar, carrageenan, alginate, pectin, cellulose, gelatin, mannan, glucomannan, gum arabic, tragacanth gum, tamarind gum, modified starch polymer, dextrin, soybean Examples include protein, collagen, ovalbumin, casein, fibrin, elastin, keratin, chitosan, curdlan, gellan gum, xanthan gum, and hyaluronic acid. Gelatin is preferable.
ゲル化剤を含む担体には上記ゲル化剤を単独で使用するほか、それらの混合物を使用することができる。ゲル化剤を含む担体には可塑剤や防腐剤などを使用することができる。
The carrier containing the gelling agent can use the gelling agent alone or a mixture thereof. A plasticizer, a preservative, etc. can be used for the support | carrier containing a gelatinizer.
ゲル化剤は、カンデサルタンシレキセチル１重量部に対して０．０１～１００００重量部、好ましくは０．１～１０００重量部、より好ましくは１～１００重量部である。
The gelling agent is 0.01 to 10000 parts by weight, preferably 0.1 to 1000 parts by weight, more preferably 1 to 100 parts by weight with respect to 1 part by weight of candesartan cilexetil.
カンデサルタンシレキセチルは結晶状態のままゲル化剤を含む担体に均一に分散させる。このとき、カンデサルタンシレキセチルを均一に分散させるため、予めゲル化剤は可塑剤や防腐剤などと共に加温、溶解、混合しておくことが好ましい。
Candesartan cilexetil is uniformly dispersed in a carrier containing a gelling agent in a crystalline state. At this time, in order to uniformly disperse candesartan cilexetil, it is preferable that the gelling agent is heated, dissolved, and mixed together with a plasticizer, an antiseptic, and the like in advance.
カンデサルタンシレキセチルを担体に分散させるため、担体に対して任意の比率で分散することが可能である。
Since candesartan cilexetil is dispersed in a carrier, it can be dispersed at an arbitrary ratio with respect to the carrier.
本発明の組成物には可塑性、防腐剤以外の補助添加剤を用いることができる。補助添加剤は、薬物溶出率の制御、粘度の調節、薬物の安定化などの機能を兼ね備えることができる。使用可能な補助添加剤の例は以下のものを含む。
In the composition of the present invention, auxiliary additives other than plasticity and preservatives can be used. The auxiliary additive can have functions such as control of drug dissolution rate, viscosity adjustment, and drug stabilization. Examples of auxiliary additives that can be used include:
ショ糖脂肪酸エステル、ポリビニルピロリドン、クロスポビドン、結晶セルロース、ポリエチレングリコール、酸化チタン、軽質無水ケイ酸、ステアリン酸マグネシウム、ヒプロメロース、メチルセルロースなど。ショ糖脂肪酸エステルとしては、たとえばDKエステル（SS、F-160、F-140、F-110、F-90、F-70、F-50、F-20W、F-10）（第一工業製薬製）などが挙げられる。ポリビニルピロリドンとしては、たとえばコリドンK25、コリドンK30、コリドンK90（BASFジャパン製）などが挙げられる。クロスポビドンとしては、たとえばコリドンCL-M（BASFジャパン製）などが挙げられる。結晶セルロースとしては、たとえばセオラス（三栄源エフ・エフ・アイ製）などが挙げられる。ポリエチレングリコールとしては、マクロゴール２００、マクロゴール３００、マクロゴール４００、マクロゴール６００、マクロゴール１０００、マクロゴール１５００、マクロゴール１５４０、マクロゴール４０００、マクロゴール６０００、マクロゴール２００００、マクロゴール３５０００（三洋化成工業製）などが挙げられる。酸化チタンとしては、たとえば酸化チタン（堺化学工業製）、酸化チタンA-HR（フロイント産業製）などが挙げられる。軽質無水ケイ酸としては、たとえばアドソリダー-１０１（フロイント産業製）などが挙げられる。ステアリン酸マグネシウムとしては、たとえばステアリン酸マグネシウム（三栄源エフ・エフ・アイ製、日本油脂製）などが挙げられる。ヒドロキシプロピルセルロースとしては、たとえばTC-5（三栄源エフ・エフ・アイ製）などが挙げられる。メチルセルロースとしては、たとえばMETOLOSE SM（信越化学工業）などが挙げられる。
Sucrose fatty acid ester, polyvinylpyrrolidone, crospovidone, crystalline cellulose, polyethylene glycol, titanium oxide, light anhydrous silicic acid, magnesium stearate, hypromellose, methylcellulose and the like. Examples of sucrose fatty acid esters include DK esters (SS, F-160, F-140, F-110, F-90, F-70, F-50, F-20W, F-10) (Daiichi Kogyo Seiyaku) Manufactured). Examples of polyvinylpyrrolidone include Kollidon K25, Kollidon K30, Kollidon K90 (manufactured by BASF Japan) and the like. Examples of crospovidone include Kollidon CL-M (manufactured by BASF Japan). Examples of the crystalline cellulose include Theolas (manufactured by San-Eigen F.F.I.). As polyethylene glycol, macrogol 200, macrogol 300, macrogol 400, macrogol 600, macrogol 1000, macrogol 1500, macrogol 1540, macrogol 4000, macrogol 6000, macrogol 20000, macrogol 35000 (Sanyo) Chemical Industries). Examples of titanium oxide include titanium oxide (manufactured by Sakai Chemical Industry), titanium oxide A-HR (manufactured by Freund Industries), and the like. Examples of the light silicic acid anhydride include ADSOLIDER-101 (manufactured by Freund Sangyo). Examples of magnesium stearate include magnesium stearate (manufactured by Saneigen F.F.I, manufactured by NOF Corporation). Examples of hydroxypropylcellulose include TC-5 (manufactured by San-Eigen F.F.I.). Examples of methyl cellulose include METALOSE SM (Shin-Etsu Chemical Co., Ltd.).
添加する場合、補助添加剤は、カンデサルタンシレキセチル１重量部に対して０．１～１００重量部、好ましくは２０重量部まで添加することができる。
When added, the auxiliary additive can be added in an amount of 0.1 to 100 parts by weight, preferably 20 parts by weight, based on 1 part by weight of candesartan cilexetil.
含水ゲルに結晶状態のカンデサルタンシレキセチルを担持させてなる本発明の医薬組成物（以下単に「本発明の医薬組成物」という。）は、常法の製剤化技術により、錠剤、カプセル剤、顆粒剤、散剤、経口ゼリー剤等の固形製剤となることができる。
The pharmaceutical composition of the present invention (hereinafter simply referred to as “the pharmaceutical composition of the present invention”) in which candesartan cilexetil in a crystalline state is supported on a water-containing gel is prepared by a conventional formulation technique using tablets, capsules, It can be a solid preparation such as a granule, powder, or oral jelly.
本発明の医薬組成物を医薬組成物と相溶性のない冷却媒体に滴下し、固化することにより粒子状製剤とすることも可能である。この方法により、粒単位の質量が極めて均一な製剤とすることができる。製剤の具体例を図１に示す。
It is also possible to form a particulate preparation by dripping the pharmaceutical composition of the present invention into a cooling medium incompatible with the pharmaceutical composition and solidifying it. By this method, it is possible to obtain a preparation having an extremely uniform mass per grain. A specific example of the formulation is shown in FIG.
本発明の医薬組成物をカプセル内容物若しくはカプセル皮膜とすることによりカプセル製剤とすることもできる。カプセル製剤は、常法の軟カプセル剤又は硬カプセル剤の製造方法により製造することができる。軟カプセル剤は、シームレス方式、平板方式、ロータリーダイ方式のいずれかにより製造することができる。また硬カプセル剤は、顆粒、液体、ペースト状のカプセル内容物を充てんする手法により製造することができる。製剤の具体例を図２、図３に示す。
The capsule composition can also be made into a capsule preparation by making the pharmaceutical composition of the present invention into a capsule content or a capsule film. The capsule preparation can be produced by a conventional method for producing soft capsules or hard capsules. The soft capsule can be produced by any one of a seamless method, a flat plate method, and a rotary die method. Moreover, a hard capsule can be manufactured by the method of filling the content of a capsule of a granule, a liquid, and a paste. Specific examples of the preparation are shown in FIGS.
本発明の医薬組成物を少なくとも三重以上の順次増大する同心円状の多重ノズルを用い、最外層より滴下される溶液と相溶性のない冷却媒体に滴下し、固化することにより多層カプセル製剤とすることも可能である。多層カプセル製剤は、多重ノズルの各ノズルから滴下されて形成された層により構成され、中心から第１層、第２層、第３層、（以降同様）とあらわされる。本発明の医薬組成物を含む多層カプセル製剤は、医薬組成物を多重ノズルのいずれかのノズルより滴下し形成される。また、この時いずれかのノズルより配合成分を滴下することにより配合製剤とすることもできる。製剤の具体例を図４に示す。
The pharmaceutical composition of the present invention is dropped into a cooling medium that is incompatible with the solution dripped from the outermost layer using at least three or more concentrically increasing concentric multiple nozzles, and solidified to form a multilayer capsule formulation Is also possible. The multilayer capsule preparation is composed of layers formed by dropping from each nozzle of a multiple nozzle, and is expressed as a first layer, a second layer, a third layer, and the like (hereinafter the same) from the center. The multilayer capsule preparation containing the pharmaceutical composition of the present invention is formed by dropping the pharmaceutical composition from any one of the multiple nozzles. Moreover, it can also be set as a compounding formulation by dripping a compounding component from either nozzle at this time. A specific example of the formulation is shown in FIG.
例えばゲル化剤がゼラチンの場合、熱水には良く溶け、３５℃以下でゲル化する。従って薬物を均一に分散させるためにはゼラチン溶液のゲル化前に添加する必要がある。また薬物を担持させたゲルの粒子状製剤を望む場合には、薬物を分散させた熱いゼラチン溶液を植物油や中鎖脂肪酸トリグリセリドのような冷たい疎水性液体中へ液滴として滴下し、ゲル化させて製造することができる。ゼラチンを溶かすための熱水の量は必要最低限であることが望ましいが、一般に可塑剤として添加されるグリセリンと合計してゼラチン重量と同量～５倍が適当である。
For example, when the gelling agent is gelatin, it dissolves well in hot water and gels at 35 ° C or lower. Therefore, in order to uniformly disperse the drug, it is necessary to add it before gelation of the gelatin solution. In addition, when a drug-supported gel particulate formulation is desired, a hot gelatin solution in which the drug is dispersed is dropped as a droplet into a cold hydrophobic liquid such as vegetable oil or medium-chain fatty acid triglyceride to cause gelation. Can be manufactured. The amount of hot water for dissolving gelatin is desirably the minimum necessary, but generally, the total amount of glycerin added as a plasticizer is the same amount to 5 times the weight of gelatin.
薬物を担持させたカプセル皮膜の場合も同じであるが、薬物の担持させたゲルよりなる粒子製剤は、スティッキングや微生物増殖等の防止のため、乾燥してゲルの水分を減らす必要がある。乾燥の方法は任意であるが、４０℃以上の高温は避けた方が良い。可塑剤を含む場合、原料の乾燥ゼラチンの水分９～１２％と同程度まで乾燥しても脆くなることはない。ゲルの乾燥の程度を測定する簡便な方法として、ゲルの水分活性を測定する方法がある。「水分活性」は、試料を入れた密閉容器内の平衡相対湿度の１／１００と考えることができ、微生物が増殖に利用できる食品中の自由水の量を示す数値として利用されており、そのための測定器具が市販されている。本発明の場合、粒状製剤またはカプセル皮膜の乾燥の程度は水分活性が０．８を下廻れば十分である。
The same applies to a capsule film carrying a drug, but a particle preparation made of a gel carrying a drug needs to be dried to reduce the moisture of the gel in order to prevent sticking and microbial growth. Although the drying method is arbitrary, it is better to avoid a high temperature of 40 ° C. or higher. When a plasticizer is included, it does not become brittle even if it is dried to the same extent as the moisture content of 9 to 12% of the dry gelatin. As a simple method for measuring the degree of drying of the gel, there is a method for measuring the water activity of the gel. “Water activity” can be considered as 1/100 of the equilibrium relative humidity in the sealed container containing the sample, and is used as a numerical value indicating the amount of free water in the food that microorganisms can use for growth. These measuring instruments are commercially available. In the case of the present invention, the degree of drying of the granular preparation or capsule film is sufficient if the water activity is below 0.8.
本発明の医薬組成物は、血圧降下剤もしくは高脂血症用剤に分類される１種又は２種以上の配合成分をも配合することができる。
血圧降下剤には、例えば、アムロジピンベシル酸塩、アゼルニジピン、アラニジピン、エホニジピン塩酸塩、シルニジピン、ニカルジピン塩酸塩、ニソルジピン、ニトレンジピン、ニフェジピン、ニルバジピン、塩酸バルニジピン、フェロジピン、ベニジピン塩酸塩、マニジピン塩酸塩、アゼルニジピン、ジルチアゼム塩酸塩、ベニジピン塩酸塩などのカルシウム拮抗作用を有する化合物や、ヒドロクロロチアジド、トリクロルメチアジド、ベンチルヒドロクロロチアジド、メチクラン、インダパミド、クロルタリドン、メフルシド、フロセミド、ピレタニド、ブメタニド、スピロノラクトン、トリアムテレン、カンレノ酸カリウムなどの利尿作用を有する化合物、カプトプリル、エナラプリルマレイン酸塩、アラセプリル、デラプリル塩酸塩、シラザプリル、リシノプリル、ベナゼプリル塩酸塩、イミダプリル塩酸塩、テモカプリル塩酸塩、キナプリル塩酸塩、トランドラプリル、ペリンドプリルエルブミンなどのアンジオテンシン転換酵素阻害作用を有する化合物や、プロプラノロール塩酸塩、ナドロール、ピンドロール、ニプラジロール、チリソロール塩酸塩、インデノロール塩酸塩、カルテオロール塩酸塩、ピンドロール、塩酸ブニトロロール、硫酸ペンブトロール、ボピンドロールマロン酸塩、アテノロール、ビソプロロールフマル酸塩、ベタキソロール塩酸塩、メトプロロール酒石酸塩、塩酸ベバントロール、アセブトロール塩酸塩、セリプロロール塩酸塩などのβ受容体遮断作用を有する化合物などが挙げられる。
高脂血症用剤には、例えば、プラバスタチンナトリウム、シンバスタチン、フルバスタチンナトリウム、アトルバスタチンカルシウム水和物、ピタバスタチンカルシウム、ロスバスタチンカルシウム、などのスタチン系化合物、コレスチミラン、コレスチミドなどの陰イオン交換樹脂、クロフィブラート、クリノフィブラート、ベザフィブラート、フェノフィブラート、などのフィブラート系化合物、ニコチン酸トコフェロール、ニコモール、ニセリトロール、などのニコチン酸誘導体、コレステロール吸収阻害薬のエゼチミブ、プロブコール、イコサペント酸エチルなどが挙げられる。 The pharmaceutical composition of this invention can also mix | blend the 1 type, or 2 or more types of mixing | blending component classified into an antihypertensive agent or a hyperlipidemia agent.
Antihypertensive agents include, for example, amlodipine besilate, azelnidipine, alanidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, azelnidipine, Compounds with calcium antagonism such as diltiazem hydrochloride and benidipine hydrochloride, hydrochlorothiazide, trichlormethiazide, benchylhydrochlorothiazide, meticlan, indapamide, chlorthalidone, mefluside, furosemide, piretanide, bumetanide, spironolactone, triamterene, potassium canrenoate, etc. Compounds with diuretic action, captopril, enalapril maleate, aracepril, delapril hydrochloride , Cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril erbumine and other compounds having angiotensin converting enzyme inhibitory activity, propranolol hydrochloride, nadolol, pindolol, nipradilol, Chirisolol hydrochloride, indenolol hydrochloride, carteolol hydrochloride, pindolol, bunitrolol hydrochloride, penbutolol sulfate, bopindolol malonate, atenolol, bisoprolol fumarate, betaxolol hydrochloride, metoprolol tartrate, bevantolol hydrochloride, acebutolol hydrochloride, Examples thereof include compounds having a β receptor blocking action such as seriprolol hydrochloride.
Examples of drugs for hyperlipidemia include pravastatin sodium, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, statins such as pitavastatin calcium and rosuvastatin calcium, anion exchange resins such as colestimilan and colestimide, clofibrate Fibrates such as clinofibrate, bezafibrate and fenofibrate, nicotinic acid derivatives such as tocopherol nicotinate, nicomol and niceritrol, cholesterol absorption inhibitors ezetimibe, probucol and ethyl icosapentate.
血圧降下剤には、例えば、アムロジピンベシル酸塩、アゼルニジピン、アラニジピン、エホニジピン塩酸塩、シルニジピン、ニカルジピン塩酸塩、ニソルジピン、ニトレンジピン、ニフェジピン、ニルバジピン、塩酸バルニジピン、フェロジピン、ベニジピン塩酸塩、マニジピン塩酸塩、アゼルニジピン、ジルチアゼム塩酸塩、ベニジピン塩酸塩などのカルシウム拮抗作用を有する化合物や、ヒドロクロロチアジド、トリクロルメチアジド、ベンチルヒドロクロロチアジド、メチクラン、インダパミド、クロルタリドン、メフルシド、フロセミド、ピレタニド、ブメタニド、スピロノラクトン、トリアムテレン、カンレノ酸カリウムなどの利尿作用を有する化合物、カプトプリル、エナラプリルマレイン酸塩、アラセプリル、デラプリル塩酸塩、シラザプリル、リシノプリル、ベナゼプリル塩酸塩、イミダプリル塩酸塩、テモカプリル塩酸塩、キナプリル塩酸塩、トランドラプリル、ペリンドプリルエルブミンなどのアンジオテンシン転換酵素阻害作用を有する化合物や、プロプラノロール塩酸塩、ナドロール、ピンドロール、ニプラジロール、チリソロール塩酸塩、インデノロール塩酸塩、カルテオロール塩酸塩、ピンドロール、塩酸ブニトロロール、硫酸ペンブトロール、ボピンドロールマロン酸塩、アテノロール、ビソプロロールフマル酸塩、ベタキソロール塩酸塩、メトプロロール酒石酸塩、塩酸ベバントロール、アセブトロール塩酸塩、セリプロロール塩酸塩などのβ受容体遮断作用を有する化合物などが挙げられる。
高脂血症用剤には、例えば、プラバスタチンナトリウム、シンバスタチン、フルバスタチンナトリウム、アトルバスタチンカルシウム水和物、ピタバスタチンカルシウム、ロスバスタチンカルシウム、などのスタチン系化合物、コレスチミラン、コレスチミドなどの陰イオン交換樹脂、クロフィブラート、クリノフィブラート、ベザフィブラート、フェノフィブラート、などのフィブラート系化合物、ニコチン酸トコフェロール、ニコモール、ニセリトロール、などのニコチン酸誘導体、コレステロール吸収阻害薬のエゼチミブ、プロブコール、イコサペント酸エチルなどが挙げられる。 The pharmaceutical composition of this invention can also mix | blend the 1 type, or 2 or more types of mixing | blending component classified into an antihypertensive agent or a hyperlipidemia agent.
Antihypertensive agents include, for example, amlodipine besilate, azelnidipine, alanidipine, efonidipine hydrochloride, cilnidipine, nicardipine hydrochloride, nisoldipine, nitrendipine, nifedipine, nilvadipine, varnidipine hydrochloride, felodipine, benidipine hydrochloride, manidipine hydrochloride, azelnidipine, Compounds with calcium antagonism such as diltiazem hydrochloride and benidipine hydrochloride, hydrochlorothiazide, trichlormethiazide, benchylhydrochlorothiazide, meticlan, indapamide, chlorthalidone, mefluside, furosemide, piretanide, bumetanide, spironolactone, triamterene, potassium canrenoate, etc. Compounds with diuretic action, captopril, enalapril maleate, aracepril, delapril hydrochloride , Cilazapril, lisinopril, benazepril hydrochloride, imidapril hydrochloride, temocapril hydrochloride, quinapril hydrochloride, trandolapril, perindopril erbumine and other compounds having angiotensin converting enzyme inhibitory activity, propranolol hydrochloride, nadolol, pindolol, nipradilol, Chirisolol hydrochloride, indenolol hydrochloride, carteolol hydrochloride, pindolol, bunitrolol hydrochloride, penbutolol sulfate, bopindolol malonate, atenolol, bisoprolol fumarate, betaxolol hydrochloride, metoprolol tartrate, bevantolol hydrochloride, acebutolol hydrochloride, Examples thereof include compounds having a β receptor blocking action such as seriprolol hydrochloride.
Examples of drugs for hyperlipidemia include pravastatin sodium, simvastatin, fluvastatin sodium, atorvastatin calcium hydrate, statins such as pitavastatin calcium and rosuvastatin calcium, anion exchange resins such as colestimilan and colestimide, clofibrate Fibrates such as clinofibrate, bezafibrate and fenofibrate, nicotinic acid derivatives such as tocopherol nicotinate, nicomol and niceritrol, cholesterol absorption inhibitors ezetimibe, probucol and ethyl icosapentate.
配合成分はカンデサルタンシレキセチルを含む医薬組成物に配合することも可能であり、また、カンデサルタンシレキセチルと一緒に配合すると安定性が低下する場合や、配合成分が液体・半固形成分である場合など、一緒に配合することが難しい場合は、カプセル製剤又は多層カプセル製剤などとしカンデサルタンシレキセチルと配合成分とを別々に配合することもできる。製剤の具体例を図５に示す。
The compounding component can be compounded in a pharmaceutical composition containing candesartan cilexetil. In addition, when the compounding component is combined with candesartan cilexetil, the stability decreases, or the compounding component is a liquid / semi-solid component. When it is difficult to blend together, for example, candesartan cilexetil and the blending component can be blended separately as a capsule preparation or a multilayer capsule preparation. A specific example of the formulation is shown in FIG.
現在国内では、１錠あたりのカンデサルタンシレキセチル含有量が２、４、８、１２ｍｇの４規格の製剤が販売されている。しかしながら、同一製剤に対して複数の規格が存在する場合、投与の際に製剤の取り違いが起こりやすく薬物の過少投与または過量投与の危険がある。このような危険を回避するため、医薬組成物の薬物濃度を一定とした１種類の製剤のみを用意し、製剤の個数によって各規格に対応することが好ましい。
Currently, 4 standard preparations with candesartan cilexetil content of 2, 4, 8, 12 mg per tablet are sold in Japan. However, when there are a plurality of standards for the same preparation, there is a risk of underdose or overdose of the drug because the preparation is likely to be mixed during administration. In order to avoid such a risk, it is preferable to prepare only one type of preparation with a constant drug concentration of the pharmaceutical composition, and to support each standard depending on the number of preparations.
また、本発明の医薬組成物を用いて調製した固形製剤を１回投与量ごと分包包装することも可能である。カンデサルタンシレキセチルは２ｍｇ～１２ｍｇの間で細かい投与量の調節が行われているため、患者の１回投与量を分包化した製剤を提供することは服用量の間違いの防止や、服用しやすさの観点からも利点となる。包装形態については特に限定されないが、服用しやすさを考慮した包装形態が望ましく、スティック形状などが好ましい。
It is also possible to package and package a solid preparation prepared using the pharmaceutical composition of the present invention for each single dose. Since candesartan cilexetil is finely adjusted between 2 mg and 12 mg, providing a preparation that divides the single dose of the patient prevents mistakes in dosage and This is also an advantage from the viewpoint of ease. The packaging form is not particularly limited, but a packaging form considering ease of taking is desirable, and a stick shape or the like is preferred.
以下に試験例および実施例により、本発明を例証する。これらにおいて、特記しない限り、部および％は重量基準による。
Hereinafter, the present invention is illustrated by test examples and examples. In these, unless otherwise indicated, parts and percentages are based on weight.
試験例１
最初に各種補助添加剤中のカンデサルタンシレキセチル（以下単に「薬物」という。）の貯蔵安定性を調べるため、以下の苛酷安定性試験を行った。
薬物３０ｍｇと、各種添加成分０．９ｇとをそれぞれ透明ガラス容器に秤取し、約８０℃で３０分間加温し、薬物がこれらの成分に溶解するか否かを目視により観察した。次に液体をガラス瓶に移して密栓し、温度５０℃湿度７５％ＲＨの環境で２週間保管し、保管後の薬物含量をＨＰＬＣにより定量し、残存率を算出した。結果を表１に示す。 Test example 1
First, in order to examine the storage stability of candesartan cilexetil (hereinafter simply referred to as “drug”) in various auxiliary additives, the following severe stability test was conducted.
30 mg of the drug and 0.9 g of various additive components were weighed in a transparent glass container and heated at about 80 ° C. for 30 minutes, and it was visually observed whether or not the drug was dissolved in these components. Next, the liquid was transferred to a glass bottle, sealed, and stored for 2 weeks in an environment of temperature 50 ° C. and humidity 75% RH, and the drug content after storage was quantified by HPLC to calculate the residual rate. The results are shown in Table 1.
最初に各種補助添加剤中のカンデサルタンシレキセチル（以下単に「薬物」という。）の貯蔵安定性を調べるため、以下の苛酷安定性試験を行った。
薬物３０ｍｇと、各種添加成分０．９ｇとをそれぞれ透明ガラス容器に秤取し、約８０℃で３０分間加温し、薬物がこれらの成分に溶解するか否かを目視により観察した。次に液体をガラス瓶に移して密栓し、温度５０℃湿度７５％ＲＨの環境で２週間保管し、保管後の薬物含量をＨＰＬＣにより定量し、残存率を算出した。結果を表１に示す。 Test example 1
First, in order to examine the storage stability of candesartan cilexetil (hereinafter simply referred to as “drug”) in various auxiliary additives, the following severe stability test was conducted.
30 mg of the drug and 0.9 g of various additive components were weighed in a transparent glass container and heated at about 80 ° C. for 30 minutes, and it was visually observed whether or not the drug was dissolved in these components. Next, the liquid was transferred to a glass bottle, sealed, and stored for 2 weeks in an environment of temperature 50 ° C. and humidity 75% RH, and the drug content after storage was quantified by HPLC to calculate the residual rate. The results are shown in Table 1.
試験例２
次に補助添加剤による薬物の溶出性を確認するため、倍散末による溶出試験を行った。薬物５０ｍｇに対し、表２に示す各種補助添加剤０．９５ｇを均一になるよう混合し検体１～検体１８とした。薬物２ｍｇに対応する量の各検体をとり、硬カプセルに充てんし、溶出試験を行った。溶出試験は日本薬局方・一般試験法・溶出試験法のパドル法により試験を行い、試験液には1.0％ポリソルベート20溶液、900mLを用い、回転数は50回転／分とした。なお、シンカーを用いた。規定の時間に20mLをサンプリングし、薬物含量をHPLCにより測定した。結果を図６、図７、図８に示す。 Test example 2
Next, in order to confirm the dissolution property of the drug by the auxiliary additive, a dissolution test using a powdered powder was performed. Samples 1 to 18 were prepared by uniformly mixing 0.95 g of various auxiliary additives shown in Table 2 with 50 mg of the drug. An amount of each sample corresponding to 2 mg of drug was taken, filled into a hard capsule, and a dissolution test was performed. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. A sinker was used. 20 mL was sampled at the specified time and the drug content was measured by HPLC. The results are shown in FIG. 6, FIG. 7, and FIG.
次に補助添加剤による薬物の溶出性を確認するため、倍散末による溶出試験を行った。薬物５０ｍｇに対し、表２に示す各種補助添加剤０．９５ｇを均一になるよう混合し検体１～検体１８とした。薬物２ｍｇに対応する量の各検体をとり、硬カプセルに充てんし、溶出試験を行った。溶出試験は日本薬局方・一般試験法・溶出試験法のパドル法により試験を行い、試験液には1.0％ポリソルベート20溶液、900mLを用い、回転数は50回転／分とした。なお、シンカーを用いた。規定の時間に20mLをサンプリングし、薬物含量をHPLCにより測定した。結果を図６、図７、図８に示す。 Test example 2
Next, in order to confirm the dissolution property of the drug by the auxiliary additive, a dissolution test using a powdered powder was performed. Samples 1 to 18 were prepared by uniformly mixing 0.95 g of various auxiliary additives shown in Table 2 with 50 mg of the drug. An amount of each sample corresponding to 2 mg of drug was taken, filled into a hard capsule, and a dissolution test was performed. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. A sinker was used. 20 mL was sampled at the specified time and the drug content was measured by HPLC. The results are shown in FIG. 6, FIG. 7, and FIG.
以上の結果から、各種補助添加剤により薬物の溶解性の制御が可能であることが確かめられた。
From the above results, it was confirmed that the solubility of the drug can be controlled by various auxiliary additives.
試験例３
試験例２により溶出性の向上が見られた検体につき、薬物の溶出性に与える影響を観察するため、表３に示す処方１～１１について、粒子状製剤を調製し薬物の溶出性に与える影響を観察した。
薬物を除く成分に適量の水を加えて混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一になるよう分散させ、医薬組成物とした。医薬組成物をこの場合は中鎖脂肪酸トリグリセリドである相溶性のない冷却媒体に滴下し、固化させて得た粒子を水分活性０．３になるまで乾燥し、含水ゲルの形の粒子状製剤を調製した。溶出試験は日本薬局方・一般試験法・溶出試験法のパドル法により試験を行い、試験液には1.0％ポリソルベート20溶液、900mLを用い、回転数は50回転／分とした。各粒子状製剤につき薬物２ｍｇに相当する量をとり試験を行った。なお、対照については採取量の都合上10mgで試験を行った。規定の時間に20mLをサンプリングし、薬物含量をHPLCにより測定した。それぞれの結果については、有効成分量に対する溶出率に換算し溶出性を比較した。 Test example 3
In order to observe the effect on the drug dissolution of the specimens whose dissolution was improved in Test Example 2, the effect on the drug dissolution by preparing a particulate formulation for formulations 1 to 11 shown in Table 3 Was observed.
An appropriate amount of water was added to the ingredients excluding the drug and mixed, and the mixture was heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to obtain a pharmaceutical composition. In this case, the pharmaceutical composition is dropped into an incompatible cooling medium, which is a medium-chain fatty acid triglyceride, and the particles obtained by solidification are dried to a water activity of 0.3 to obtain a particulate preparation in the form of a hydrogel. Prepared. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. The test was carried out by taking an amount corresponding to 2 mg of drug for each particulate preparation. For the control, the test was conducted at 10 mg for convenience of collection. 20 mL was sampled at the specified time and the drug content was measured by HPLC. About each result, it converted into the elution rate with respect to the amount of active ingredients, and the elution property was compared.
試験例２により溶出性の向上が見られた検体につき、薬物の溶出性に与える影響を観察するため、表３に示す処方１～１１について、粒子状製剤を調製し薬物の溶出性に与える影響を観察した。
薬物を除く成分に適量の水を加えて混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一になるよう分散させ、医薬組成物とした。医薬組成物をこの場合は中鎖脂肪酸トリグリセリドである相溶性のない冷却媒体に滴下し、固化させて得た粒子を水分活性０．３になるまで乾燥し、含水ゲルの形の粒子状製剤を調製した。溶出試験は日本薬局方・一般試験法・溶出試験法のパドル法により試験を行い、試験液には1.0％ポリソルベート20溶液、900mLを用い、回転数は50回転／分とした。各粒子状製剤につき薬物２ｍｇに相当する量をとり試験を行った。なお、対照については採取量の都合上10mgで試験を行った。規定の時間に20mLをサンプリングし、薬物含量をHPLCにより測定した。それぞれの結果については、有効成分量に対する溶出率に換算し溶出性を比較した。 Test example 3
In order to observe the effect on the drug dissolution of the specimens whose dissolution was improved in Test Example 2, the effect on the drug dissolution by preparing a particulate formulation for formulations 1 to 11 shown in Table 3 Was observed.
An appropriate amount of water was added to the ingredients excluding the drug and mixed, and the mixture was heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to obtain a pharmaceutical composition. In this case, the pharmaceutical composition is dropped into an incompatible cooling medium, which is a medium-chain fatty acid triglyceride, and the particles obtained by solidification are dried to a water activity of 0.3 to obtain a particulate preparation in the form of a hydrogel. Prepared. The dissolution test was conducted by the Japanese Pharmacopoeia, General Test, and dissolution test paddle method. The test solution was 20% 1.0% polysorbate solution, 900 mL, and the rotation speed was 50 rpm. The test was carried out by taking an amount corresponding to 2 mg of drug for each particulate preparation. For the control, the test was conducted at 10 mg for convenience of collection. 20 mL was sampled at the specified time and the drug content was measured by HPLC. About each result, it converted into the elution rate with respect to the amount of active ingredients, and the elution property was compared.
結果を図９、図１０に示す。処方例１～処方例１１は対照と比べて、溶出率曲線のＡＵＣにおいて少なくとも２倍に増加した。
The results are shown in FIGS. Formulation Examples 1 to 11 increased at least 2-fold in the AUC of the dissolution rate curve compared to the control.
試験例４
試験例３で調製した粒子状製剤の貯蔵安定性を調べるため、以下の苛酷安定性試験を行った。
粒子状製剤をガラス瓶に入れて密栓し、温度５０℃湿度７５％ＲＨの環境で保管し、２週間、４週間後に取り出し薬物含量をＨＰＬＣにより定量し、残存率を算出した。結果を表４に示す。 Test example 4
In order to examine the storage stability of the particulate preparation prepared in Test Example 3, the following severe stability test was conducted.
The particulate preparation was put in a glass bottle and sealed, and stored in an environment of a temperature of 50 ° C. and a humidity of 75% RH, taken out after 2 weeks and 4 weeks, the drug content was quantified by HPLC, and the residual rate was calculated. The results are shown in Table 4.
試験例３で調製した粒子状製剤の貯蔵安定性を調べるため、以下の苛酷安定性試験を行った。
粒子状製剤をガラス瓶に入れて密栓し、温度５０℃湿度７５％ＲＨの環境で保管し、２週間、４週間後に取り出し薬物含量をＨＰＬＣにより定量し、残存率を算出した。結果を表４に示す。 Test example 4
In order to examine the storage stability of the particulate preparation prepared in Test Example 3, the following severe stability test was conducted.
The particulate preparation was put in a glass bottle and sealed, and stored in an environment of a temperature of 50 ° C. and a humidity of 75% RH, taken out after 2 weeks and 4 weeks, the drug content was quantified by HPLC, and the residual rate was calculated. The results are shown in Table 4.
以下に限定の意図しない実施例により本発明を説明する。なお処方例中の各種成分の数値は重量部を意味する。
The present invention will be described below with reference to non-limiting examples. In addition, the numerical value of the various components in a formulation example means a weight part.
〔処方例１〕
粒子状製剤
薬物を除く下記の成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させ、医薬組成物とした。
医薬組成物を相溶性のない冷却媒体（例えば、中鎖脂肪酸トリグリセリド）に滴下し、水分活性が0.3となるよう乾燥して粒子状製剤を製造した。この時、１粒当たりの薬物含量が例えば０．１２５～１ｍｇになるように製造した。
[Prescription Example 1]
The following ingredients except the particulate drug were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to obtain a pharmaceutical composition.
The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
粒子状製剤
薬物を除く下記の成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させ、医薬組成物とした。
医薬組成物を相溶性のない冷却媒体（例えば、中鎖脂肪酸トリグリセリド）に滴下し、水分活性が0.3となるよう乾燥して粒子状製剤を製造した。この時、１粒当たりの薬物含量が例えば０．１２５～１ｍｇになるように製造した。
The following ingredients except the particulate drug were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to obtain a pharmaceutical composition.
The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
〔処方例２〕
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
[Prescription Example 2]
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
〔処方例３〕
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
[Prescription Example 3]
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
〔処方例４〕
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
[Prescription Example 4]
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
〔処方例５〕
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
[Prescription Example 5]
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
粒子状製剤
処方例１に準じ粒子状製剤を製造した。
Particulate preparation A particulate preparation was produced according to Formulation Example 1.
〔処方例６〕
粒子状製剤（配合剤）
薬物及び配合成分を除く下記の成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物及び配合成分を加え、均一に分散させることにより医薬組成物とした。
医薬組成物を相溶性のない冷却媒体（例えば、中鎖脂肪酸トリグリセリド）に滴下し、水分活性が0.3となるよう乾燥して粒子状製剤を製造した。この時、１粒当たりの薬物含量が例えば０．１２５～１ｍｇになるように製造した。
[Prescription Example 6]
Particulate preparation (compound)
The following components excluding the drug and blended components were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug and compounding ingredients were added and dispersed uniformly to obtain a pharmaceutical composition.
The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
粒子状製剤（配合剤）
薬物及び配合成分を除く下記の成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物及び配合成分を加え、均一に分散させることにより医薬組成物とした。
医薬組成物を相溶性のない冷却媒体（例えば、中鎖脂肪酸トリグリセリド）に滴下し、水分活性が0.3となるよう乾燥して粒子状製剤を製造した。この時、１粒当たりの薬物含量が例えば０．１２５～１ｍｇになるように製造した。
Particulate preparation (compound)
The following components excluding the drug and blended components were mixed and heated at about 70 ° C. to dissolve the gelatin. After dissolution, the drug and compounding ingredients were added and dispersed uniformly to obtain a pharmaceutical composition.
The pharmaceutical composition was added dropwise to an incompatible cooling medium (for example, medium-chain fatty acid triglyceride) and dried to have a water activity of 0.3 to produce a particulate preparation. At this time, it was manufactured so that the drug content per grain was, for example, 0.125 to 1 mg.
〔処方例７〕
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
[Prescription Example 7]
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
〔処方例８〕
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
[Prescription Example 8]
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
〔処方例９〕
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
[Prescription Example 9]
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
粒子状製剤（配合剤）
処方例６に準じ粒子状製剤を製造した。
Particulate preparation (compound)
A particulate preparation was produced according to Formulation Example 6.
〔処方例１０〕
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
医薬組成物を常法の軟カプセル剤の製造方法によりカプセル皮膜に充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で充てんした。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
[Prescription Example 10]
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example. The capsule preparation was dried to have a water activity of 0.5.
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
医薬組成物を常法の軟カプセル剤の製造方法によりカプセル皮膜に充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で充てんした。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example. The capsule preparation was dried to have a water activity of 0.5.
〔処方例１１〕
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
[Prescription Example 11]
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
〔処方例１２〕
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
[Prescription Example 12]
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
〔処方例１３〕
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
[Prescription Example 13]
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
カプセル製剤
処方例１０に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 10.
〔処方例１４〕
カプセル製剤（配合剤）
薬物及び配合成分を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物及び配合成分を加え、医薬組成物を製造した。
医薬組成物を常法の軟カプセル剤の製造方法によりカプセル皮膜に充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で充てんした。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
[Prescription Example 14]
Capsule formulation (compound)
The capsule content components excluding the drug and the compounding components were mixed and heated at about 70 ° C. to dissolve. After dissolution, the drug and compounding ingredients were added to produce a pharmaceutical composition.
The pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example. The capsule preparation was dried to have a water activity of 0.5.
カプセル製剤（配合剤）
薬物及び配合成分を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物及び配合成分を加え、医薬組成物を製造した。
医薬組成物を常法の軟カプセル剤の製造方法によりカプセル皮膜に充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で充てんした。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
Capsule formulation (compound)
The capsule content components excluding the drug and the compounding components were mixed and heated at about 70 ° C. to dissolve. After dissolution, the drug and compounding ingredients were added to produce a pharmaceutical composition.
The pharmaceutical composition was filled into a capsule film by a conventional method for producing soft capsules to produce a capsule preparation. At this time, it was filled in such an amount that the drug content per capsule was 2 mg, for example. The capsule preparation was dried to have a water activity of 0.5.
〔処方例１５〕
カプセル製剤（配合剤）
処方例１４に準じカプセル製剤を製造した。
[Prescription Example 15]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 14.
カプセル製剤（配合剤）
処方例１４に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 14.
〔処方例１６〕
カプセル製剤（配合剤）
処方例１４に準じカプセル製剤を製造した。
[Prescription Example 16]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 14.
カプセル製剤（配合剤）
処方例１４に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 14.
〔処方例１７〕
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
医薬組成物を常法の硬カプセル剤の製造方法により１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で硬カプセルに充てんしカプセル製剤とした。
[Prescription Example 17]
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules to obtain a capsule preparation.
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
医薬組成物を常法の硬カプセル剤の製造方法により１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で硬カプセルに充てんしカプセル製剤とした。
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules to obtain a capsule preparation.
〔処方例１８〕
カプセル製剤
処方例１７に準じカプセル製剤を製造した。
[Prescription Example 18]
Capsule preparation A capsule preparation was produced according to Formulation Example 17.
カプセル製剤
処方例１７に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 17.
〔処方例１９〕
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させたものを顆粒状とし、水分活性が0.3となるよう乾燥させることにより医薬組成物を製造した。
医薬組成物を常法の硬カプセル剤の製造方法により１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で硬カプセルに充てんした。
[Prescription Example 19]
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added, and the uniformly dispersed product was granulated and dried to a water activity of 0.3 to produce a pharmaceutical composition.
The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules.
カプセル製剤
薬物を除くカプセル内容物成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させたものを顆粒状とし、水分活性が0.3となるよう乾燥させることにより医薬組成物を製造した。
医薬組成物を常法の硬カプセル剤の製造方法により１カプセル当たりの薬物含量が例えば２ｍｇになるような分量で硬カプセルに充てんした。
Capsule formulation The capsule contents except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added, and the uniformly dispersed product was granulated and dried to a water activity of 0.3 to produce a pharmaceutical composition.
The pharmaceutical composition was filled into hard capsules in an amount such that the drug content per capsule was 2 mg, for example, by a conventional method for producing hard capsules.
〔処方例２０〕
カプセル製剤
薬物を除くカプセル皮膜成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
常法の軟カプセル剤の製造方法によりカプセル皮膜（医薬組成物）にカプセル内容物を充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるように製造した。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
[Prescription Example 20]
Capsule formulation The capsule film components except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The capsule contents were filled into the capsule film (pharmaceutical composition) by a conventional method for producing soft capsules to produce a capsule preparation. At this time, the drug content per capsule was, for example, 2 mg. The capsule preparation was dried to have a water activity of 0.5.
カプセル製剤
薬物を除くカプセル皮膜成分を混合し、約７０℃で加温して溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
常法の軟カプセル剤の製造方法によりカプセル皮膜（医薬組成物）にカプセル内容物を充てんしカプセル製剤を製造した。この時１カプセル当たりの薬物含量が例えば２ｍｇになるように製造した。また、カプセル製剤は水分活性が0.5となるよう乾燥した。
Capsule formulation The capsule film components except the drug were mixed and dissolved by heating at about 70C. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The capsule contents were filled into the capsule film (pharmaceutical composition) by a conventional method for producing soft capsules to produce a capsule preparation. At this time, the drug content per capsule was, for example, 2 mg. The capsule preparation was dried to have a water activity of 0.5.
〔処方例２１〕
カプセル製剤
処方例２０に準じカプセル製剤を製造した。
[Prescription Example 21]
Capsule preparation A capsule preparation was produced according to Formulation Example 20.
カプセル製剤
処方例２０に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 20.
〔処方例２２〕
カプセル製剤
処方例２０に準じカプセル製剤を製造した。
[Prescription Example 22]
Capsule preparation A capsule preparation was produced according to Formulation Example 20.
カプセル製剤
処方例２０に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 20.
〔処方例２３〕
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
[Prescription Example 23]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
〔処方例２４〕
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
[Prescription Example 24]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
〔処方例２５〕
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
[Prescription Example 25]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
カプセル製剤（配合剤）
処方例２０に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 20.
〔処方例２６〕
カプセル製剤
薬物を除くカプセル皮膜成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
中心ノズルからカプセル内容物、外側ノズルから医薬組成物を同時に滴下し、常法のシームレスカプセルの製造方法に従ってカプセル製剤を製造した。この時、カプセル製剤は水分活性が0.5となるよう乾燥した。
[Prescription Example 26]
Capsule formulation Capsule film components excluding the drug were mixed and heated at about 70C to dissolve gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The capsule contents were simultaneously dropped from the central nozzle and the pharmaceutical composition was simultaneously dropped from the outer nozzle, and a capsule preparation was produced according to a conventional seamless capsule production method. At this time, the capsule preparation was dried to have a water activity of 0.5.
カプセル製剤
薬物を除くカプセル皮膜成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
中心ノズルからカプセル内容物、外側ノズルから医薬組成物を同時に滴下し、常法のシームレスカプセルの製造方法に従ってカプセル製剤を製造した。この時、カプセル製剤は水分活性が0.5となるよう乾燥した。
Capsule formulation Capsule film components excluding the drug were mixed and heated at about 70C to dissolve gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
The capsule contents were simultaneously dropped from the central nozzle and the pharmaceutical composition was simultaneously dropped from the outer nozzle, and a capsule preparation was produced according to a conventional seamless capsule production method. At this time, the capsule preparation was dried to have a water activity of 0.5.
〔処方例２７〕
カプセル製剤
処方例２６に準じカプセル製剤を製造した。
[Prescription Example 27]
Capsule preparation A capsule preparation was produced according to Formulation Example 26.
カプセル製剤
処方例２６に準じカプセル製剤を製造した。
Capsule preparation A capsule preparation was produced according to Formulation Example 26.
〔処方例２８〕
カプセル製剤（配合剤）
処方例２６に準じカプセル製剤を製造した。
[Prescription Example 28]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 26.
カプセル製剤（配合剤）
処方例２６に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 26.
〔処方例２９〕
カプセル製剤（配合剤）
処方例２６に準じカプセル製剤を製造した。
[Prescription Example 29]
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 26.
カプセル製剤（配合剤）
処方例２６に準じカプセル製剤を製造した。
Capsule formulation (compound)
A capsule preparation was produced according to Formulation Example 26.
〔処方例３０〕
多層カプセル製剤
薬物を除く第３層成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
中心から第１層、第２層、第３層（医薬組成物）を同時に滴下し、常法のシームレスカプセルの製造方法に従って多層カプセル製剤を製造した。この時、多層カプセル製剤は水分活性が0.3となるよう乾燥した。
[Prescription Example 30]
Multi-layer capsule formulation The ingredients of the third layer excluding the drug were mixed and heated at about 70C to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
A first layer, a second layer, and a third layer (pharmaceutical composition) were simultaneously dropped from the center, and a multilayer capsule preparation was produced according to a conventional method for producing seamless capsules. At this time, the multilayer capsule preparation was dried so that the water activity was 0.3.
多層カプセル製剤
薬物を除く第３層成分を混合し、約７０℃で加温してゼラチンを溶解させた。溶解後薬物を加え、均一に分散させることにより医薬組成物を製造した。
中心から第１層、第２層、第３層（医薬組成物）を同時に滴下し、常法のシームレスカプセルの製造方法に従って多層カプセル製剤を製造した。この時、多層カプセル製剤は水分活性が0.3となるよう乾燥した。
Multi-layer capsule formulation The ingredients of the third layer excluding the drug were mixed and heated at about 70C to dissolve the gelatin. After dissolution, the drug was added and dispersed uniformly to produce a pharmaceutical composition.
A first layer, a second layer, and a third layer (pharmaceutical composition) were simultaneously dropped from the center, and a multilayer capsule preparation was produced according to a conventional method for producing seamless capsules. At this time, the multilayer capsule preparation was dried so that the water activity was 0.3.
１製剤当り有効成分０．１２５ｍｇ～１ｍｇを含むよう調製した処方例１～９及び処方例２６～３０の製剤は、表５に示す１回投与量に対応した個数に計数し、分包包装する。包装形態は例えばスティック形状の分包に包装する。
The preparations of Formulation Examples 1 to 9 and Formulation Examples 26 to 30 prepared to contain 0.125 mg to 1 mg of active ingredient per preparation are counted in the number corresponding to the single dose shown in Table 5 and packaged and packaged. . The packaging form is, for example, packaged in a stick-shaped package.
Claims (9)
- ゲル化剤の含水ゲルに結晶状態のカンデサルタンシレキセチルを担持させてなる医薬組成物。 A pharmaceutical composition obtained by supporting candesartan cilexetil in a crystalline state on a water-containing gel as a gelling agent.
- ゲル化剤は、ゼラチン、ヒドロキシプロピルスターチ、カラギーナン、デキストリン、寒天、またはそれらの混合物から選ばれる請求項１の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the gelling agent is selected from gelatin, hydroxypropyl starch, carrageenan, dextrin, agar, or a mixture thereof.
- 含水ゲルが可塑剤を含んでいる請求項１または２の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, wherein the hydrogel contains a plasticizer.
- ゲル化剤がゼラチンであり、可塑剤がグリセリンおよび／またはＤ－ソルビトールである請求項３の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the gelling agent is gelatin and the plasticizer is glycerin and / or D-sorbitol.
- カンデサルタンシレキセチルを担持させた含水ゲルは、含水ゲル中のカンデサルタンシレキセチルの貯蔵安定性および／または溶出性を向上させるための補助添加剤をさらに含んでいる請求項１ないし４のいずれかの医薬組成物。 The hydrogel carrying candesartan cilexetil further comprises an auxiliary additive for improving the storage stability and / or dissolution property of candesartan cilexetil in the hydrogel. Pharmaceutical composition.
- 補助添加剤は、ポリビニルピロリドン、ポリエチレングリコールまたはヒドロキシプロピルセルロースから選ばれる請求項５の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the auxiliary additive is selected from polyvinylpyrrolidone, polyethylene glycol or hydroxypropylcellulose.
- 粒子状製剤、カプセル製剤の内容物もしくはカプセル皮膜、または多層カプセル製剤の最外層の形にある請求項１ないし６のいずれかの医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, which is in the form of a particulate preparation, the contents of a capsule preparation or a capsule film, or the outermost layer of a multilayer capsule preparation.
- 血圧降下剤または高脂血症用剤が請求項７の医薬組成物と同じ製剤に含まれている固形製剤。 A solid preparation containing a hypotensive agent or a hyperlipidemia agent in the same preparation as the pharmaceutical composition of claim 7.
- 請求項７の医薬組成物または請求項８の固形製剤が投与量ごとに分包包装されてなる医薬品。 A pharmaceutical product comprising the pharmaceutical composition of claim 7 or the solid preparation of claim 8 packaged and packaged for each dose.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2013532485A JP5991978B2 (en) | 2011-09-09 | 2012-07-09 | Pharmaceutical composition containing candesartan cilexetil |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2011196631 | 2011-09-09 | ||
| JP2011-196631 | 2011-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013035423A1 true WO2013035423A1 (en) | 2013-03-14 |
Family
ID=47831875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2012/067428 WO2013035423A1 (en) | 2011-09-09 | 2012-07-09 | Pharmaceutical composition containing candesartan cilexetil |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP5991978B2 (en) |
| WO (1) | WO2013035423A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6103111B1 (en) * | 2016-05-24 | 2017-03-29 | 三生医薬株式会社 | Oral pharmaceutical composition and method for producing particulate preparation comprising the composition |
| CN111000821A (en) * | 2019-12-30 | 2020-04-14 | 河南新孚望新材料科技有限公司 | Hydroxypropyl starch empty capsule and preparation method thereof |
| CN111743869A (en) * | 2019-03-29 | 2020-10-09 | 南京济群医药科技股份有限公司 | Pitavastatin calcium tablet and preparation method thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006514688A (en) * | 2002-09-11 | 2006-05-11 | エラン ファーマ インターナショナル，リミティド | Gel-stabilized nanoparticle active substance composition |
| JP2008150306A (en) * | 2006-12-15 | 2008-07-03 | Air Water Inc | Gelatin molded product and method for producing the same |
| JP2008526732A (en) * | 2004-12-30 | 2008-07-24 | ハンミ ファーム． シーオー．， エルティーディー． | Combination preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and antihypertensive agent, and method for producing the same |
| JP2009007262A (en) * | 2007-06-26 | 2009-01-15 | Toyo Capsule Kk | Bisphosphonate formulation |
-
2012
- 2012-07-09 WO PCT/JP2012/067428 patent/WO2013035423A1/en active Application Filing
- 2012-07-09 JP JP2013532485A patent/JP5991978B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006514688A (en) * | 2002-09-11 | 2006-05-11 | エラン ファーマ インターナショナル，リミティド | Gel-stabilized nanoparticle active substance composition |
| JP2008526732A (en) * | 2004-12-30 | 2008-07-24 | ハンミ ファーム． シーオー．， エルティーディー． | Combination preparation of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor and antihypertensive agent, and method for producing the same |
| JP2008150306A (en) * | 2006-12-15 | 2008-07-03 | Air Water Inc | Gelatin molded product and method for producing the same |
| JP2009007262A (en) * | 2007-06-26 | 2009-01-15 | Toyo Capsule Kk | Bisphosphonate formulation |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6103111B1 (en) * | 2016-05-24 | 2017-03-29 | 三生医薬株式会社 | Oral pharmaceutical composition and method for producing particulate preparation comprising the composition |
| WO2017204210A1 (en) | 2016-05-24 | 2017-11-30 | 三生医薬株式会社 | Oral pharmaceutical composition and method for producing particulate formulation comprising composition |
| JP2017210415A (en) * | 2016-05-24 | 2017-11-30 | 三生医薬株式会社 | Oral pharmaceutical composition and method for producing particulate formulation comprising composition the same |
| EP4279137A2 (en) | 2016-05-24 | 2023-11-22 | Sunsho Pharmaceutical Co., Ltd. | Oral pharmaceutical composition and method for producing particulate formulation comprising composition |
| CN111743869A (en) * | 2019-03-29 | 2020-10-09 | 南京济群医药科技股份有限公司 | Pitavastatin calcium tablet and preparation method thereof |
| CN111000821A (en) * | 2019-12-30 | 2020-04-14 | 河南新孚望新材料科技有限公司 | Hydroxypropyl starch empty capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JPWO2013035423A1 (en) | 2015-03-23 |
| JP5991978B2 (en) | 2016-09-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105873566B (en) | The purposes of compressed tablets containing Δ 9- tetrahydrocannabinol, its manufacturing method and such tablet in oral medication | |
| CA2804635A1 (en) | Formulations of rifaximin and uses thereof | |
| JP2022082823A (en) | Pharmaceutical product | |
| TWI708603B (en) | Pharmaceutical composition containing arylalkylamine compound | |
| JP2024033014A (en) | pharmaceutical composition | |
| JP2016044170A (en) | Olmesartan prodrug formulation | |
| JP5991978B2 (en) | Pharmaceutical composition containing candesartan cilexetil | |
| TWI715291B (en) | Pharmaceutical composition including parp inhibitor | |
| AU2013365715B2 (en) | A pharmaceutical composition containing candesartan cilexetil and amlodipine | |
| TW201034688A (en) | Solid coated preparation | |
| AU2013346363B2 (en) | Solid dosage form comprising micronized cytisine | |
| EA023996B1 (en) | Homogenous pharmaceutical oral dosage forms comprising lercanidipine and enalapril or their pharmaceutically acceptable salts with an organic acid | |
| TWI535463B (en) | Coating agent for pharmaceutical solid preparation, film coating preparation for medicine and coated pharmaceutical solid preparation | |
| EA023340B1 (en) | Ropinirole composition | |
| JP6126780B2 (en) | Solid formulation containing loxoprofen sodium and tranexamic acid | |
| ES2732711T3 (en) | Solid stable pharmaceutical composition of citisine and process for the preparation thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| WO2017093890A1 (en) | Clobazam tablet formulation and process for its preparation | |
| ES2444591T3 (en) | Medication with the active substance hydromorphone with improved storage stability | |
| JP6112765B2 (en) | Solid preparation containing loxoprofen sodium and dl-methylephedrine hydrochloride | |
| CZ309631B6 (en) | A pharmaceutical composition for solid dosage forms | |
| JP2024007837A (en) | Pharmaceutical composition including lacosamide and use thereof | |
| WO2020216450A1 (en) | Pharmaceutical composition comprising amorphous sunitinib | |
| WO2021191268A1 (en) | A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a process for its preparation | |
| JP2020075874A (en) | Film-form pharmaceutical composition containing lubiprostone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12829892 Country of ref document: EP Kind code of ref document: A1 |
|
| ENP | Entry into the national phase |
Ref document number: 2013532485 Country of ref document: JP Kind code of ref document: A |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 12829892 Country of ref document: EP Kind code of ref document: A1 |