WO2009123304A1 - 水懸濁性を向上させた細粒剤 - Google Patents
水懸濁性を向上させた細粒剤 Download PDFInfo
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- WO2009123304A1 WO2009123304A1 PCT/JP2009/056942 JP2009056942W WO2009123304A1 WO 2009123304 A1 WO2009123304 A1 WO 2009123304A1 JP 2009056942 W JP2009056942 W JP 2009056942W WO 2009123304 A1 WO2009123304 A1 WO 2009123304A1
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- 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
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to a method for improving the suspension of a pharmaceutical fine granule in water and a novel fine granule produced by the method.
- the present invention relates to a method for improving the suspendability of fine granules containing cefcapene hydrochloride as an active ingredient in water and a novel fine granules produced by the method.
- powders are useful dosage forms that can be expected to be absorbed more quickly than tablets and capsules.
- fine granules are widely used because they are easier to take than powdered powders.
- a pharmaceutical product has an unpleasant taste such as a bitter taste, it is often difficult to administer a fine granule, and a technique for overcoming the unpleasant taste by coating the fine granule surface has already been developed (for example, , See Patent Document 1 below).
- Cefcapene hydrochloride pivoxil is a prodrug whose oral absorption is enhanced by converting cefcapene to pivaloyloxymethyl ester.
- An object of the present invention is to provide a method for improving the wettability of a fine granule and improving the suspendability without causing side reactions due to such formulation and without impairing the unpleasant taste improving effect. is there.
- Cefcapene pivoxil hydrochloride is commercially available as "Fromox (registered trademark) pediatric fine granules" in the form of fine granules coated with hydrogenated castor oil.
- the present inventors have found that the suspendability in water can be improved only by newly adding silicon dioxide and a surfactant. Furthermore, the present inventors have confirmed that this technique can be widely applied to fine granules having poor suspendability, and have completed the present invention described below.
- a fine granule, wherein the active ingredient particles contain a main drug fine granule coated with a hydrophobic substance, silicon dioxide and a surfactant; (2) The fine granule according to (1), wherein the active ingredient is cefcapene pivoxil hydrochloride, (3) The fine granule according to (1) or (2), wherein the silicon dioxide is hydrophilic silicon dioxide, (4) The fine granule according to (3), wherein the silicon dioxide is hydrous silicon dioxide, (5) The fine granule according to any one of (1) to (4), wherein the content of silicon dioxide is 0.1 to 5% by weight relative to the total amount of the preparation, (6) The fine granule according to any one of (1) to (5), wherein the surfactant has a melting point of 30 ° C.
- the surfactant is selected from the group consisting of polyoxyethylene (40) monostearate, polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) glycol or The fine granule according to (8), which is two or more types, (10) The fine granule according to (9), wherein the surfactant is polyoxyethylene (160) polyoxypropylene (30) glycol, (11) The fine granule according to any one of (1) to (10) above, wherein the surfactant content is 0.025 to 2% by weight relative to the total amount of the preparation, (12) The fine granule according to any one of (1) to (11), wherein the hydrophobic substance is hydrogenated oil, (13) Fine particles characterized in that the particles containing cefcapene pivoxil hydrochloride contain a main drug fine particle coated with a hydrophobic substance, silicon dioxide, and a surfactant having a melting point of 30 ° C.
- the particle containing cefcapene pivoxil hydrochloride contains a main agent fine particle coated with hydrogenated oil, hydrous silicon dioxide, and a surfactant containing a polyoxyethylene chain having a melting point of 30 ° C. or higher. Fine granules, (15) In the preparation, polyoxyethylene chains having 1 to 20% by weight of cefcapene pivoxil hydrochloride, 1 to 50% by weight of hardened oil, 0.1 to 5% by weight of hydrous silicon dioxide, and a melting point of 30 ° C.
- a surfactant containing (16) The fine granule according to any one of (1) to (15), wherein the main drug fine granule further contains a disintegrant and / or an excipient, (17) A suspension containing the fine granule according to any one of (1) to (16) above, (18) A method for improving the water suspension of the fine granules, comprising adding silicon dioxide and a surfactant to the active ingredient fine granules in which the active ingredient particles are coated with a hydrophobic substance, About.
- the suspendability of fine granules covered with a hydrophobic film in water can be improved, and as a result, fine granules that can be easily suspended and taken in water are provided.
- membrane is not impaired, it can be used suitably especially as a pediatric formulation.
- the generation of related substances that can be generated with the decomposition of the main drug is also controlled.
- Manufacturing process of active pharmaceutical ingredient containing cefcapene pivoxil hydrochloride (1) Manufacturing process of active pharmaceutical ingredient containing cefcapene pivoxil hydrochloride (2) Manufacturing process of suspending agent Carp powder Mixing process of suspending agent Carp powder and fine granules Total amount of related substances produced after 2 weeks in an environment of temperature 40 ° C / humidity 75%
- pharmaceutical compounds used as fine granules are widely used, and examples thereof include the pharmaceutical compounds described in International Publication No. 2005/039538.
- a component having an unpleasant taste such as a bitter taste is preferred.
- poorly water-soluble components are also used.
- cephalosporin antibacterial agent for example, penicillin flucloxacillin sodium, tarampicillin hydrochloride, sultamicillin tosylate and bacampicillin hydrochloride, cephem cefaclor, cefpodoxime proxetil, ceftiam hexetyl , Cefuroxime axetil, cefcapene pivoxil hydrochloride and cefteram pivoxil, or macrolide erythromycin and other antibiotics; quinolone antibacterial agents such as lomefloxacin, norfloxacin, ofloxacin, enoxacin, pipemidic acid; dextrome hydrobromide Antitussive expectorants such as tolphan, isoaminyl citrate and dimemorphan phosphate; antipyretic analgesics and antiphlogistics such as acetaminophen, ketoprofen and tolfenamic acid; diphenhydramine hydrochloride, cephem ce
- cefcapene pivoxil hydrochloride (chemical name: (+)-(6R, 7R) -7-[(Z) -2- (2-amino-4-thiazolyl) -2-pentenamide]- 3-carbamoyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester hydrochloride monohydrate) .
- the content of the active ingredient is about 1 to 20% by weight, preferably about 2.5 to 17.5% by weight, more preferably about 5 to 15% by weight, based on the total amount of the preparation.
- hydrophobic substance the wax-like substance of international publication 2005/039538 is illustrated, for example.
- a hydrophobic substance a pharmaceutically acceptable substance can be widely used as long as it is solid at room temperature but can be easily softened and melted by heating.
- hardened oil hardened castor oil, hardened soybean oil, hardened rapeseed oil etc.
- higher alcohol stearyl alcohol, cetanol etc.
- higher fatty acid stearic acid, palmitic acid etc.
- vegetable or animal examples thereof include beef fat (beef tallow, carnauba wax), wax, polyethylene glycol (PEG: Macrogol 4000, Macrogol 6000, etc.), and the like.
- those having a melting point in the range of about 40 ° C. to about 100 ° C. are preferred.
- Particularly preferred is hardened oil, and more preferred is hardened castor oil.
- the content of the hydrophobic substance is about 50 to 200% by weight, preferably about 75 to 175% by weight, more preferably about 100 to 150% by weight, based on the active ingredient.
- the amount is about 1 to 50% by weight, preferably about 5 to 40% by weight, more preferably about 10 to 30% by weight, based on the active ingredient fine granules. Further, it is about 1 to 50% by weight, preferably about 2.5 to 25% by weight, more preferably about 5 to 20% by weight, based on the total amount of the preparation.
- the hydrophobic substance has a masking effect when the active ingredient is an ingredient having an unpleasant taste.
- the amount of the hydrophobic substance is larger than the above amount, the granules are difficult to disintegrate in the body, and the elution of the encapsulated component may be lowered. On the other hand, if the amount is less than the above amount, there is a risk that the suppression of leakage in the oral cavity will be insufficient.
- the silicon dioxide is preferably hydrophilic silicon dioxide.
- hydrophilic silicon dioxides hydrous silicon dioxide produced by a wet method (e.g. Carplex (registered trademark, DSL Japan Co., Ltd.)) or light anhydrous silicic acid produced by a dry method (e.g. Aerosil ( Registered trademark, DSL Japan)), and more preferably hydrophilic hydrous silicon dioxide (eg Carplex (registered trademark)).
- hydrophilic hydrous silicon dioxide include Carplex # 67 (specific surface area: about 429 m 2 / g, average particle size: about 6.4 ⁇ m), Carplex # 80 (specific surface area: about 193 m 2 / g).
- Carplex # 1120 (specific surface area: about 109 m 2 / g, average particle size: about 8.1 ⁇ m), Carplex FPS-1 (specific surface area: about 199 m 2 / g, Average particle size: about 2.1 ⁇ m), Carplex FPS-2 (specific surface area: about 242 m 2 / g, average particle size: about 1.8 ⁇ m), Carplex CS-5 (specific surface area: about 154 m 2 / g, (Average particle size: about 2.3 ⁇ m) (all are DSL Japan Co., Ltd.) and the like, preferably Carplex # 67.
- the content of silicon dioxide is about 1 to 20% by weight, preferably about 2.5 to 17.5% by weight, more preferably about 5 to 15% by weight, based on the active ingredient. Further, it is about 0.1 to 5% by weight, preferably about 0.25 to 4.75% by weight, more preferably about 0.3 to 4.5% by weight, based on the total amount of the preparation. If it is more than these amounts, there is a possibility that it will be powdered at the time of administration of the preparation, and if it is less than these contents, the fine granules may not be sufficiently suspended in water.
- the surfactant sodium lauryl sulfate or a nonionic surfactant is used.
- the nonionic surfactant is preferably a surfactant containing a polyoxyethylene chain, specifically, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene (40) monostearate. Polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) glycol. More preferably, the surfactant has a melting point of 30 ° C. or higher, and still more preferably a surfactant containing a polyoxyethylene chain having a melting point of 30 ° C.
- polyoxyethylene (40) monostearate, polyoxy Ethylene hardened castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) glycol Particularly preferred is polyoxyethylene (160) polyoxypropylene (30) glycol.
- polyoxyethylene (160) polyoxypropylene (30) glycol is optimal from the viewpoint of the stability of the active ingredient.
- the stability of the active ingredient can be determined by the generation of the related substance.
- the surfactant content is about 0.1 to 20% by weight, preferably about 0.25 to 15% by weight, more preferably about 0.5 to 10% by weight, based on the active ingredient.
- the amount is about 0.025 to 2% by weight, preferably about 0.05 to 1.75% by weight, more preferably about 0.1 to 1.5% by weight, based on the total amount of the preparation. If it is higher than these contents, the related substances may increase, and if it is lower than these contents, the fine granules may not be sufficiently suspended in water.
- a particularly useful additive for suspending a fine granule is a mixture of silicon dioxide and a surfactant (hereinafter sometimes referred to as “suspending agent carp powder”). If these mixtures are coated on the surface of fine granules and fine granules, the fine granules can be easily suspended in water. In particular, when a fine particle is coated with a hydrophobic substance, when the surface of the hydrophobic substance is coated with a suspending agent, karp powder, the fine granule is easily suspended in water.
- the mixing ratio of silicon dioxide and surfactant is about 0.1 to 2, preferably about 0.5 to 2, when the silicon dioxide is 1.
- the preparation may be powdered. If the ratio is small, the adhesiveness between the fine granules increases and the fine granules may aggregate.
- the content of the mixture of silicon dioxide and surfactant, that is, the suspending agent carp powder is 0.125 to 7% by weight, preferably 0.3 to 6.5% by weight, based on the total amount of the preparation, More preferably, it is 0.4 to 6% by weight. If it is more than these amounts, there is a possibility that it will be powdered by silicon dioxide, and if it is less, sufficient suspendability may not be obtained.
- the preparation of the present invention may further contain the following pharmaceutically acceptable additives.
- the disintegrant include water-swellable substances described in International Publication No. 2005/039538. Hereinafter, it may be referred to as a disintegrant or a water-swellable substance.
- the substance hardly dissolves in water, but swells while absorbing water while maintaining the formulation form to form a matrix structure.
- water-swellable substances include cellulose derivatives such as carboxymethylcellulose calcium, carboxymethylcellulose sodium (CMC-Na), croscarmellose sodium, low substituted hydroxypropylcellulose (L-HPC); partially pregelatinized starch (PCS) And various starches such as carboxymethyl starch-sodium (CMS-Na).
- the content of the disintegrant is about 50 to 250% by weight, preferably about 75 to 200% by weight, more preferably about 100 to 175% by weight, based on the main drug.
- the amount is about 1 to 50% by weight, preferably about 2.5 to 40% by weight, more preferably about 5 to 30% by weight, based on the active ingredient fine granules. Further, it is about 1 to 30% by weight, preferably about 2.5 to 25% by weight, more preferably about 5 to 20% by weight, based on the total amount of the preparation. If the amount of the disintegrant is less than the above, the granules are less likely to disintegrate in the body, and the elution of the encapsulated component may be reduced. On the other hand, if the amount of the disintegrant is larger than the above amount, there is a risk that the suppression of leakage in the oral cavity will be insufficient.
- sweetening agent for example, an agent described in International Publication No. 2005/039538 can be used.
- lactose, sucrose, powdered reduced maltose starch syrup, glucose, xylitol, D-mannitol, mannitol, sorbitol, maltose, erythritol, aspartame, saccharin, sodium saccharin, acesulfame potassium, dipotassium glycyrrhizate, etc. are preferably used.
- the content of the sweetening agent is about 100 to 800% by weight, preferably about 200 to 750% by weight, more preferably about 300 to 700% by weight, based on the main drug. Further, it is about 10 to 80% by weight, preferably about 20 to 75% by weight, more preferably about 30 to 70% by weight, based on the total amount of the preparation.
- a water-soluble binder described in International Publication No. 2005/039538 can be used.
- a binder having a surface active action such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP) and the like are preferable, and hydroxypropylcellulose (HPC) is more preferable.
- the content of the binder is about 5 to 40% by weight, preferably about 7.5 to 35% by weight, more preferably about 10 to 30% by weight, based on the active ingredient. It is about 0.1 to 10% by weight, preferably about 0.5 to 8% by weight, more preferably about 1 to 7.5% by weight, based on sweet fine granules.
- the amount is about 0.1 to 5% by weight, preferably about 0.5 to 4.5% by weight, more preferably about 1 to 4% by weight, based on the total amount of the preparation.
- fragrances eg, strawberry essence
- lubricants eg, magnesium stearate
- excipients eg, talc
- These pharmaceutically acceptable additives can be present inside and / or outside the active ingredient granules.
- some of these pharmaceutically acceptable additives may be prepared as a fine granule separate from the main drug granules and then mixed with the main drug granules.
- a sweetener eg, saccharide or the like
- sweet fine granules containing a sweetener may be prepared.
- cefpapene pivoxil hydrochloride A more preferable embodiment of the present invention when the active ingredient is cefpapene pivoxil hydrochloride is shown below. All amounts are based on the total amount of the preparation. That is, cefcapene hydrochloride is about 1 to 20% by weight, hydrophobic material is about 1 to 50% by weight, silicon dioxide is about 0.1 to 5% by weight, and surfactant is about 0.025 to 2% by weight. (In particular, about 0.125 to 7% by weight as a suspending agent carp powder), about 1 to 50% by weight of a disintegrant, and about 10 to 80% by weight of a sweetener.
- cefcapene pivoxil hydrochloride is about 2.5-17.5 wt%
- hydrophobic material is about 2.5-25 wt%
- silicon dioxide is about 0.25-4.75 wt%
- cefcapene hydrochloride is about 5 to 15% by weight
- hydrophobic substance is about 5 to 25% by weight
- silicon dioxide is about 0.3 to 4.5% by weight
- the surfactant is about 0.1 to 1.5% by weight (particularly 0.4 to 6% by weight as the suspending agent carp powder), about 5 to 20% by weight of disintegrant, and about 30 to 70% by weight of sweetener.
- a particularly preferred embodiment of the present invention when the active ingredient is cefcapene pivoxil hydrochloride is shown below. All amounts are based on the total amount of the preparation. That is, about 1 to 20% by weight of cefcapene pivoxil hydrochloride, about 1 to 50% by weight of hardened oil, about 0.1 to 5% by weight of hydrous silicon dioxide, polyoxyethylene (160) polyoxypropylene (30) About 0.025 to 2% by weight of glycol (especially about 0.125 to 7% by weight as a suspending agent carp powder), about 1 to 50% by weight of low-substituted hydroxypropylcellulose, powdered reduced maltose starch syrup, D-mannitol, xylitol and aspartame are about 10-80% by weight.
- cefcapene hydrochloride is about 2.5 to 17.5% by weight
- hydrogenated oil is about 2.5 to 25% by weight
- hydrous silicon dioxide is about 0.25 to 4.75% by weight
- Polyoxypropylene (30) glycol magnesium stearate is about 0.05 to 1.75% by weight (especially about 0.3 to 6.5% by weight as suspending agent Carp powder)
- low substitution degree Hydroxypropylcellulose is about 5-30% by weight
- powdered reduced maltose starch syrup, D-mannitol, xylitol and aspartame are about 20-75% by weight.
- cefcapene hydrochloride is about 5 to 15% by weight
- hardened oil is about 5 to 20% by weight
- hydrous silicon dioxide is about 0.3 to 4.5% by weight
- polyoxyethylene (160) polyoxypropylene (30) about 0.1 to 1.5% by weight of glycol (especially about 0.4 to 6% by weight as suspending agent kapu powder), about 5 to 20% by weight of low-substituted hydroxypropylcellulose
- Powdered reduced maltose starch syrup, D-mannitol, xylitol and aspartame are about 30-70% by weight.
- the preparation of the present invention is a fine granule, and a fine granule having a particle diameter of 75 ⁇ m to 500 ⁇ m accounts for 85% or more.
- the preparation When taking the preparation of the present invention, the preparation can be put into the mouth as it is and taken with water or the like, but the preparation of the invention can be suspended in water, milk, juice or the like, and the suspension can be taken. .
- the preparation of the present invention has good suspendability in an aqueous liquid and can be sufficiently suspended in a liquid.
- the active ingredient particles are coated with the hydrophobic substance by mixing the active ingredient, optionally the pharmaceutically acceptable additive, and the hydrophobic substance, and preparing a granule containing them, followed by heat treatment. Get the main drug granules.
- the heat treatment is performed, for example, according to the method of Japanese Patent Laid-Open No. 4-300821. That is, the coated preparation of the present invention is a pharmaceutical compound, particularly a pharmaceutical compound having an unpleasant taste or / and a property of being easily decomposed by a solvent, a waxy substance, a water-swellable substance, silicon dioxide and a surfactant, if necessary.
- a mixed powder consisting of other additives such as binders, lubricants, sweeteners, colorants, etc. is dry granulated, for example, compressed and then crushed, adjusted to an arbitrary particle size, and then a waxy substance Can be easily manufactured by a manufacturing method characterized by heat treatment so as to cover at least the surface.
- each powder component can be performed according to conventional methods.
- the powder is compressed into slugs and flakes at a pressure of 500 to 1000 kg / cm 2 with a press such as a tableting machine or a roller compressor, and then the particle size is adjusted with a crushing type adjusting machine. Adjust to.
- the granule obtained by this production method referred to as a granule before heat treatment, the same applies hereinafter
- the constituent wax-like substance and water-swellable substance are uniformly dispersed, and a part of the wax-like substance is expanded by compression. Presumed to be extended.
- this elementary granule is subjected to a heat treatment to prepare a hot melt granule (referred to as a granule after the heat treatment, hereinafter the same).
- the heat treatment step is performed for a sufficient time at a temperature sufficient to at least soften the waxy substance.
- a temperature sufficient to at least soften the waxy substance Such temperature and time are usually about 40 ° C. or more and about 10 to about 90 minutes, preferably about 20 to about 60 minutes. That is, the heating temperature only needs to be higher than the temperature at which the wax-like substance can wet the surface at least during this time.
- the heating may be shelf drying, but it is preferable to use a fluidized bed dryer.
- the wax-like substance dispersed in the matrix is melted and coats the powdery substance having an unpleasant taste in a uniform and almost continuous state. Accordingly, the heating temperature varies depending on the melting point of the wax-like substance.
- the waxy substance preferably melts at about 40 to about 90 ° C., particularly preferably about 50 to about 85 ° C.
- coated preparations of the present invention are, for example, pharmaceutical compounds, in particular pharmaceutical compounds with an unpleasant taste, waxy substances, water-swellable substances, silicon dioxide and surfactants, if necessary, binders, lubricants, flavors.
- the mixed powder consisting of other additives such as colorants and colorants is granulated and sized by wet or dry methods, adjusted to an arbitrary particle size, and then heat-treated so that the waxy substance acts as a binder Further, it can be easily produced by a production method characterized by adding about 5 to about 25% by weight of a powdery wax-like substance and performing hot melt coating.
- each powder component can be performed according to conventional methods.
- the powder is granulated by pressing into a slug or flake with a pressure of 50 to 100 MPa using a press such as a tableting machine or roll compressor, and then using a crushing type granulator. Adjust to any particle size.
- Elementary granules obtained by this production method referred to granules before heat treatment; the same shall apply hereinafter
- soot is a uniform dispersion of the constituent waxy substance and water-swellable substance, and a part of the waxy substance by compression. Is presumed to be spreading.
- a powdery wax-like substance is added to prepare a hot melt coating granule (referred to as a granule after being wax-coated while being heated; the same applies hereinafter).
- the heating before and during the addition of the powdery wax-like substance is performed at a temperature sufficient to soften the internally added wax-like substance for a sufficient period of time.
- the heating temperature is usually about 40 ° C. or higher and preferably below the melting point of the internally added wax-like substance. That is, the heating temperature only needs to be equal to or higher than the temperature at which the internally added wax-like substance can wet the granule surface during the process.
- the internally added wax-like substance melted by this treatment acts as a binder for the externally added wax-like substance on the surface of the granule. Accordingly, the heating temperature varies depending on the melting point of the internally added wax-like substance.
- the internally added waxy substance is preferably softened at about 40 to about 90 ° C., particularly preferably at about 50 to about 85 ° C.
- the heating after the addition of the powdery waxy substance is performed for a sufficient time at a temperature sufficient to soften the externally added waxy substance.
- the heating temperature is usually about 40 ° C. or higher and preferably below the melting point of the externally added wax-like substance. Accordingly, the heating temperature varies depending on the melting point of the externally added wax-like substance.
- the externally added wax-like substance preferably softens at about 40 to about 90 ° C., particularly preferably about 50 to about 85 ° C.
- the hot melt coating process when the heating temperature is too high, the internally added wax-like substance and the externally added wax-like substance are completely melted and the coating of the granules with the wax-like substance is complete, so that the granules are not easily disintegrated in the body. , The elution of the encapsulated component is reduced.
- the heating temperature is too low, the internally added waxy substance does not act as a binder for the externally added waxy substance, and the externally added waxy substance does not spread sufficiently on the surface of the granule.
- the coating becomes insufficient, and the suppression of leakage in the oral cavity is insufficient.
- the coating time is preferably about 10 to about 90 minutes, particularly preferably about 20 to about 60 minutes.
- An apparatus suitable for hot melt coating includes a fluidized bed drying apparatus.
- the raw material used here can perform efficient mixing work by carrying out the treatment shown in the table below according to the properties of all the additives described later to obtain fine granules for mixing.
- a hot melt coating granule is obtained by making it flow for a fixed time under a heating state (hot melt coating process).
- the coated preparation containing a sweetener can be granulated.
- sweet granules can be granulated and mixed with the coating formulation.
- the sweetener include lactose, sucrose, powdered reduced maltose starch syrup, glucose, xylitol, mannitol, sorbitol, maltose, erythritol, aspartame, saccharin, saccharin sodium, acesulfame potassium, dipotassium glycyrrhizinate, and the like.
- sweet granules produced by a conventional method can be used.
- it can be obtained by mixing sweeteners, adding an appropriate amount of water and kneading, extruding the kneaded material by extrusion granulation, and drying.
- the present invention provides sweet granules having an increased sweetness than the above-described sweet granules. That is, in order to improve the elution property of the sweetener, the sweet fine granules in the present invention were dissolved or dispersed in water together with a binder having a solubilizing action when the sweetener was granulated. It can be obtained by adding a thing as a binding liquid to the remaining sweetener, kneading, granulating the kneaded product, and drying.
- Unpleasant taste can be further improved by mixing the sweet fine granules with the above-mentioned coated preparation.
- the sweet fine granules in the present invention are granulated by a wet method using a sweetener and a binding solution obtained by dissolving or dispersing the sweetener in water together with a binder.
- a sweetening agent the above-mentioned sweetening agents can be used.
- the binder the water-soluble binders described above can be used.
- a binder having a surface active action such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP) and the like are preferable.
- the suspending agent Carp powder may be added to the main drug fine granules in a plurality of times. For example, in the case of cefcapene hydrochloride, it is preferably added in two portions. More preferably, after adding as a mixture of a fragrance and silicon dioxide (sometimes referred to as “perfume oil karp powder”), it is added as the aforementioned suspending agent carp powder.
- the above-mentioned suspending agent Carp powder may be added after previously mixing the main drug fine particles with other fine particles such as sweet fine particles. The production scheme for the above-mentioned preparation is shown in FIGS.
- Example 1 Manufacture of main drug fine granules and sweet fine granules
- the main drug fine granules were prepared according to the method described in the patent document (WO2005 / 039538), that is, the schemes of FIGS.
- Sweet sweet granules were produced by the method described in the above patent document.
- Example 4-6 and Reference Example 2-3 The property is liquid or waxy.
- the surfactant was treated according to the description in Table 1 above to obtain fine particles for mixing the surfactant.
- the predetermined amount was weighed and mixed with the main drug fine granules and bags, and then the sweet fine granules, perfume carp powder, iron sesquioxide powder and others were mixed into bags to produce the desired fine particles.
- Test Example 1 Evaluation of water suspension The fine granules of the present invention were tested for water suspension immediately after production. In the test, 30 mL of purified water was put in a 50 mL beaker, about 0.5 g of the fine granule of Example was put therein, and the sedimentation property of the fine granule was visually confirmed. The results are shown in Table 5 (immediately after).
- Test Example 2 Stability Evaluation of Suspension in Water The stability over time was evaluated for the fine granules of the present invention in an environment of a temperature of 40 ° C./humidity of 75%. Two weeks later, the suspension in water was tested in the same manner as in the above test example, and the results are shown in Table 5.
- Test Example 3 Stability Evaluation of Active Ingredients
- cefcapene pivoxil hydrochloride it has been reported that the addition of polyethylene glycol accelerates the decomposition into related substances such as trans isomers. For this reason, the generation amount of related substances such as a trans form was traced in the test of Test Example 2 above. After 2 weeks in an environment with a temperature of 40 ° C. and a relative humidity of 75%, add 1 mL of methanol to an equivalent amount of 10 mg (titer) of cefcapene pivoxil hydrochloride, shake and mix, and then a water / methanol mixture (1: 1) approx. 25 mL was added, and the mixture was vigorously permeated for 10 minutes.
- a water / methanol mixture (1: 1) was added to make exactly 50 mL, and this solution was filtered through a membrane filter having a pore size of 0.45 ⁇ m. The filtrate after removing 5 mL or more of the initial flow was used as a sample solution.
- HPLC conditions are as follows. ⁇ Detector: UV absorption photometer (measurement wavelength: 265 nm) Column: A stainless steel tube having an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 ⁇ m of octadecylsilylca silica gel for liquid chromatography. Column temperature: Constant temperature around 20 ° C. Mobile phase A: Dissolve 5.99 g of potassium dihydrogen phosphate in water to make 1100 mL. To this solution, a solution prepared by dissolving 1.89 g of tetra n-pentylammonium bromide in methanol to 1000 mL is added.
- Mobile phase B methanol / water solution (22: 3)
- Mobile phase feeding Mobile phase A / mobile phase B mixture (49: 1) is fed for 20 minutes after sample injection, and the mixing ratio of mobile phase A and mobile phase B is 1: 1 for the next 20 minutes. The liquid is fed while increasing the proportion of mobile phase B until Further, the mobile phase A / mobile phase B mixed solution (1: 1) is fed for the next 10 minutes.
- ⁇ Flow rate 0.8mL per minute -Area measurement range: 2.5 times the retention time of cefcapene pivoxil-Injection volume: 30 ⁇ L
- FIG. 5 shows the total amount of related substances after two weeks.
- a surfactant with a melting point of 30 ° C. or higher such as polyoxyethylene 40 monostearate, polyoxyethylene hydrogenated castor oil 60 and polyoxyethylene (160) polyoxypropylene (30) glycol, As a result, inferior stability was confirmed.
- Examples 7 to 9 were prepared by using a surfactant having a melting point of 30 ° C. or more and mixing a mixture of perfume oil karp powder and surfactant with cefcapene pivoxil hydrochloride fine granules.
- Comparative Example 3 is a preparation to which no surfactant is added, and Comparative Examples 4 and 5 are preparations using a surfactant having a melting point of less than 30 ° C.
- 3 Cefcapene hydrochloride fine grain
- Table 8 shows the results when sodium lauryl sulfate (melting point: 30 ° C. or higher) is used as the surfactant.
- the fine granules of Comparative Examples 1 and 2 and Example 1 were tested in the same manner as described above. Immediately after formulation (week 0), the amount of related substances is in the range of 1.51 to 1.57%, and even if stored for 2 weeks under the conditions of a temperature of 40 ° C. and a relative humidity of 75%, There was also very little in the formulation.
- the preparation of the present invention also reduced the electrostatic adhesion to the container due to static electricity.
- a fine granule which can be easily suspended and taken in water is provided. Since the unpleasant taste masking effect of the active ingredient by the hydrophobic film is not impaired, the fine granule of the present invention is particularly suitably used as a preparation for children.
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Abstract
Description
塩酸セフカペンピボキシルは、セフカペンをピバロイルオキシメチルエステル化することで経口吸収性を高めたプロドラッグである。グラム陽性菌からグラム陰性菌まで幅広い抗菌スペクトラムを有しているが、細粒剤にすると服用時の苦味が問題となっている。そこで、その素粒剤表面に熱溶融コーティング法で硬化ヒマシ油を施すことにより、不快味を改善する方法が公開されている(後記特許文献2参照)。
また、ある種の医薬は添加剤と混合して製剤化する際に副反応を生じ、類縁体を生成することが知られている。本発明の目的は、このような製剤化による副反応を起こさず、また不快味改善効果を損なうことなく、細粒剤の水濡れ性を向上させ懸濁性を改良する方法を提供することにある。
(1)有効成分の粒子が、疎水性物質で被覆された主薬細粒、二酸化ケイ素および界面活性剤を含有することを特徴とする細粒剤、
(2)当該有効成分が、塩酸セフカペンピボキシルである上記(1)に記載の細粒剤、
(3)二酸化ケイ素が、親水性の二酸化ケイ素である、上記(1)又は(2)に記載の細粒剤、
(4)二酸化ケイ素が、含水二酸化ケイ素である、上記(3)に記載の細粒剤、
(5)二酸化ケイ素の含量が、製剤全量に対して、0.1~5重量%である、上記(1)から(4)のいずれかに記載の細粒剤、
(6)当該界面活性剤の融点が、30℃以上である、上記(1)から(5)のいずれかに記載の細粒剤、
(7)当該界面活性剤が、ノニオン性界面活性剤である、上記(1)から(6)のいずれかに記載の細粒剤、
(8)当該界面活性剤が、ポリオキシエチレン鎖を含む界面活性剤である、上記(1)から(7)のいずれかに記載の細粒剤、
(9)当該界面活性剤が、ポリオキシエチレン(40)モノステアレート、ポリオキシエチレン硬化ヒマシ油60およびポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールよりなる群から選択される1種または2種以上である、上記(8)記載の細粒剤、
(10)当該界面活性剤が、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールである上記(9)記載の細粒剤、
(11)界面活性剤の含量が、製剤全量に対して、0.025~2重量%である、上記(1)から(10)のいずれかに記載の細粒剤、
(12)当該疎水性物質が、硬化油である、上記(1)から(11)のいずれかに記載の細粒剤、
(13)塩酸セフカペンピボキシルを含有する粒子が、疎水性物質で被覆された主薬細粒、二酸化ケイ素および融点が30℃以上の界面活性剤を含有することを特徴とする細粒剤、
(14)塩酸セフカペンピボキシルを含有する粒子が、硬化油で被覆された主薬細粒、含水二酸化ケイ素および融点が30℃以上のポリオキシエチレン鎖を含む界面活性剤を含有することを特徴とする細粒剤、
(15)製剤中に、塩酸セフカペンピボキシルを1~20重量%、硬化油を1~50重量%、含水二酸化ケイ素を0.1~5重量%、融点が30℃以上のポリオキシエチレン鎖を含む界面活性剤を0.025~2重量%を含有する、上記(13)または(14)に記載の細粒剤、
(16)主薬細粒がさらに、崩壊剤および/または賦形剤を含有する、上記(1)から(15)のいずれかに記載の細粒剤、
(17)上記(1)から(16)のいずれかに記載の細粒剤を含有した懸濁剤、
(18)有効成分の粒子が疎水性物質で被覆された主薬細粒に、二酸化ケイ素および界面活性剤を添加することを特徴とする、該細粒剤の水懸濁性を向上する方法、
に関する。
有効成分の含量は、製剤全量に対して、約1~20重量%、好ましくは約2.5~17.5重量%、さらに好ましくは約5~15重量%である。
疎水性物質の含量は、主薬に対して、約50~200重量%、好ましくは約75~175重量%、さらに好ましくは約100~150重量%である。主薬細粒に対して、約1~50重量%、好ましくは約5~40重量%、さらに好ましくは約10~30重量%である。また製剤全量に対して、約1~50重量%、好ましくは約2.5~25重量%、さらに好ましくは約5~20重量%である。疎水性物質は、有効成分が不快味を有する成分である場合に、マスキング効果がある。疎水性物質が上記量よりも多いと、体内で顆粒が崩壊しにくくなり内包成分の溶出性が低下する可能性がある。逆に、上記量よりも少ないと口腔内での漏出の抑制が不充分となる恐れがある。
二酸化ケイ素の含量は、主薬に対して、約1~20重量%、好ましくは約2.5~17.5重量%、さらに好ましくは約5~15重量%である。また、製剤全量に対して、約0.1~5重量%、好ましくは約0.25~4.75重量%、さらに好ましくは約0.3~4.5重量%である。これら量よりも多ければ、製剤投与時に粉立ちする可能性があり、これら含量よりも少なければ、細粒剤が水中で十分に懸濁しない恐れがある。
また、二酸化ケイ素と界面活性剤の混合物、すなわち懸濁化剤カープ散としての含有量は、製剤全量に対して、0.125~7重量%、好ましくは0.3~6.5重量%、さらに好ましくは0.4~6重量%である。これらの量よりも多ければ、二酸化ケイ素によって粉立ちする可能性があり、少なければ、十分な懸濁性を得ることができない恐れがある。
崩壊剤としては、例えば、国際公開第2005/039538号に記載の水膨潤性物質が例示される。以下、崩壊剤あるいは水膨潤性物質ということがある。当該物質は、水にはほとんど溶解しないが、製剤形を保ちながら吸水しつつ膨張しマトリックス構造を形成するものである。水膨潤性物質の例としては、カルボキシメチルセルロースカルシウム、カルボキシメチルセルロースナトリウム(CMC-Na)、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース(L-HPC)などのセルロース誘導体;部分アルファ化スターチ(PCS)、カルボキシメチルスターチ-ナトリウム(CMS-Na)などの各種デンプン類を挙げることができる。
崩壊剤の含量は、主薬に対して、約50~250重量%、好ましくは約75~200重量%、さらに好ましくは約100~175重量%である。主薬細粒に対して、約1~50重量%、好ましくは約2.5~40重量%、さらに好ましくは約5~30重量%である。また製剤全量に対して、約1~30重量%、好ましくは約2.5~25重量%、さらに好ましくは約5~20重量%である。崩壊剤の量が上記よりも少ないと、体内で顆粒が崩壊しにくくなり内包成分の溶出性が低下する可能性がある。逆に、崩壊剤が上記量よりも多いと、口腔内での漏出の抑制が不充分となる恐れがある。
甘味剤の含量は、主薬に対して、約100~800重量%、好ましくは約200~750重量%、さらに好ましくは約300~700重量%である。また、製剤全量に対して、約10~80重量%、好ましくは約20~75重量%、さらに好ましくは約30~70重量%である。
結合剤の含量は、主薬に対して、約5~40重量%、好ましくは約7.5~35重量%、さらに好ましくは約10~30重量%である。甘味細粒に対して、約0.1~10重量%、好ましくは約0.5~8重量%、さらに好ましくは約1~7.5重量%である。また製剤全量に対して、約0.1~5重量%、好ましくは約0.5~4.5重量%、さらに好ましくは約1~4重量%である。
有効成分、所望により前記の製薬上許容される添加物、および疎水性物質を混合し、それらを含む素粒剤を調製した後、加熱処理することにより、有効成分の粒子が疎水性物質で被覆された主薬細粒を得る。該加熱処理は、例えば、特開平4-300821号の方法に準じて行われる。すなわち、本発明の被覆製剤は医薬化合物、特に不快な味または/および溶剤で容易に分解する性質を有する医薬化合物、ワックス状物質、水膨潤性物質、二酸化ケイ素および界面活性剤、必要とあれば結合剤、滑沢剤、甘味剤、着色剤などのその他添加剤からなる混合粉末を、乾式造粒し、例えば、圧縮成形した後破砕して、任意の粒子径に調整し、ついでワックス状物質が少なくとも表面を覆うように加熱処理することを特徴とする製造方法により容易に製造し得る。
まず、医薬化合物、特に不快味を有する医薬化合物約40重量%以下、ワックス状物質約5~約25重量%及び水膨潤性物質約5~約35重量%、必要とあれば、結合剤、滑沢剤、甘味剤、着色剤等のその他添加剤を混合する。この混合粉末を、圧縮してフレーク状に成形後、破砕する。その後、ふるい機で分級し、任意の粒子径に調整することにより、素粒剤を得る。(造粒工程)
また、口腔内において不快味を改善するために、甘味剤を含む該被覆製剤を造粒することができる。又は、甘味細粒を造粒して該被覆製剤と混合することができる。甘味剤としては、例えば、乳糖、白糖、粉末還元麦芽糖水あめ、ブドウ糖、キシリトール、マンニトール、ソルビトール、マルトース、エリスリトール、アスパルテーム、サッカリン、サッカリンナトリウム、アセスルファムカリウム又はグリチルリチン酸二カリウム等が用いられる。
界面活性剤を粉砕した後、倍散篩過機(シオノギエンジニアリングサービス株式会社製)で篩過する。その後、篩過した界面活性剤と二酸化ケイ素を混合し、攪拌造粒機(ハイスピードミキサー、深江パウテック(株)製)内で溶融後、再度倍散篩過機で篩過する。以下、当該混合物を「懸濁化剤カープ散」という場合もある。
上記の通り主薬細粒を製造した後、前述の懸濁化剤カープ散が添加される。懸濁化剤カープ散は、主薬細粒に対して、複数回に分けて添加してもよい。例えば、塩酸セフカペンの場合、好ましくは、2回に分けて添加する。より好ましくは、香料と二酸化ケイ素との混合物(「香油カープ散」という場合がある)として添加した後、前述の懸濁化剤カープ散として添加される。また主薬細粒をあらかじめ、甘味細粒等の別の細粒と混合した後、前述の懸濁化剤カープ散を添加してもよい。なお上述の製剤の製造スキームは、図1~4で示す。
(1)主薬細粒および甘味細粒の製造
主薬細粒は、下表2に示す成分を特許文献(WO2005/039538)記載の方法、すなわち図1、2のスキームに従い、製造した。また、甘味細粒は、上記特許文献記載の方法で製造した。
性状が粉体のラウリル硫酸ナトリウムを先の表1に従って処理した。具体的には、ZM200型超遠心粉砕機を用いて、50%平均粒子径が50μm以下となるようにラウリル硫酸ナトリウムを粉砕し(スクリーン:1mm、回転数:低速)、混合用細粒とした。次いで下表3に示すとおり、ラウリル硫酸ナトリウムの該混合用細粒と含水二酸化ケイ素から懸濁化剤カープ散を製造し、所定量の懸濁化剤カープ散を秤量して主薬細粒と袋混合した後、甘味細粒と香油カープ散および三二酸化鉄五倍散その他を袋混合して目的の細粒を製造した。
性状が液体またはろう状である。界面活性剤を先の表1の記載に従って処理し界面活性剤混合用細粒とした。次いで下表4に従い、その所定量を秤量して主薬細粒と袋混合した後、甘味細粒と香油カープ散および三二酸化鉄五倍散その他を袋混合して目的の細粒を製造した。
本発明の細粒剤について、製造直後に水への懸濁性を試験した。試験は、50mLビーカーに精製水を30mL入れて、その中に実施例細粒剤約0.5gを投入し、当該細粒剤の沈降性を目視で確認した。結果を表5に示す(直後)。
本発明の細粒剤について、温度40℃/湿度75%の環境下において経時安定性評価を実施した。2週間後に上記試験例と同様の方法で水への懸濁性を試験し、結果を表5に示す。
塩酸セフカペンピボキシルの場合、ポリエチレングリコール類の添加によりトランス体等、類縁物質への分解が促進されることが報告されている。このため、上記試験例2の試験でトランス体等、類縁物質の発生量を追跡した。
温度40℃、相対湿度75%の環境下で2週間経過後、塩酸セフカペンピボキシル10mg(力価)相当量にメタノール1mLを加えて振り混ぜた後,水/メタノール混液(1:1)約25mLを加えて10分間激しく浸透し、さらに水/メタノール混液(1:1)を加え,正確に50mLとし、この液を孔径0.45μmのメンブランフィルターでろ過した。初流5mL以上を除去した後のろ液を試料溶液とした。
・検出器:紫外吸光光度計(測定波長:265nm)
・カラム:内径4.6mm、長さ15cmのステンレス管に5μmの液体クロマトグラフィー用オクタデシルシリルカシリカゲルを充填する。
・カラム温度:20℃付近の一定温度
・移動相A:リン酸二水素カリウム5.99gを水に溶かし、1100mLとする。この液に、臭化テトラn-ペンチルアンモニウム1.89gをメタノールに溶かして1000mLとした液を加える。
・移動相B:メタノール/水溶液(22:3)
・移動相の送液:試料注入後20分間は移動相A/移動相B混液(49:1)を送液し、次の20分間は移動相Aと移動相Bの混合比が1:1になるまで,移動相Bの割合を増加させながら送液する。更に、次の10分間は移動相A/移動相B混液(1:1)を送液する。
・流量:毎分0.8mL
・面積測定範囲:セフカペンピボキシルの保持時間の約2.5倍の範囲
・注入量:30μL
2週間経過後の類縁物質の総量値を図5に示す。ポリオキシエチレン40モノステアレート、ポリオキシエチレン硬化ヒマシ油60やポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールのような融点が30℃以上の界面活性剤を用いた場合は、対照と比して遜色のない安定性が確認された。
*2:融点が30℃以上の界面活性剤
*3:塩酸セフカペンピボキシル細粒
Claims (14)
- 塩酸セフカペンピボキシルの粒子が、疎水性物質で被覆された塩酸セフカペンピボキシル細粒、二酸化ケイ素、および融点が30℃以上である界面活性剤を含有することを特徴とする細粒剤。
- 二酸化ケイ素が、親水性の二酸化ケイ素である、請求項1に記載の細粒剤。
- 二酸化ケイ素が、含水二酸化ケイ素である、請求項2に記載の細粒剤。
- 二酸化ケイ素の含量が、製剤全量に対して、0.1~5重量%である、請求項1~3のいずれかに記載の細粒剤。
- 当該界面活性剤が、ノニオン性界面活性剤である請求項1~4のいずれかに記載の細粒剤。
- 当該界面活性剤が、ポリオキシエチレン鎖を含む界面活性剤である請求項1~5のいずれかに記載の細粒剤。
- 当該界面活性剤が、ポリオキシエチレン(40)モノステアレート、ポリオキシエチレン硬化ヒマシ油60およびポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールよりなる群から選択される1種または2種以上である請求項6記載の細粒剤。
- 当該界面活性剤が、ポリオキシエチレン(160)ポリオキシプロピレン(30)グリコールである請求項7記載の細粒剤。
- 界面活性剤の含量が、製剤全量に対して、0.025~2重量%である、請求項1~8のいずれかに記載の細粒剤。
- 当該疎水性物質が、硬化油である請求項1~9のいずれかに記載の細粒剤。
- 製剤中に、塩酸セフカペンピボキシルを1~20重量%、硬化油を1~50重量%、含水二酸化ケイ素を0.1~5重量%、融点が30℃以上のポリオキシエチレン鎖を含む界面活性剤を0.025~2重量%を含有する、請求項10記載の細粒剤。
- 塩酸セフカペンピボキシルの細粒がさらに崩壊剤および/または賦形剤を含有する、請求項1~11のいずれかに記載の細粒剤。
- 請求項1~12のいずれかに記載の細粒剤を含有した懸濁剤。
- 塩酸セフカペンピボキシルの粒子が、疎水性物質で被覆された塩酸セフカペンピボキシル細粒に、二酸化ケイ素および融点が30℃以上の界面活性剤を添加することを特徴とする、塩酸セフカペンピボキシル細粒剤の水懸濁性を向上する方法。
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RU2010145148/15A RU2488396C2 (ru) | 2008-04-04 | 2009-04-03 | Тонкие гранулы, имеющие улучшенные характеристики в водной суспензии |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101756906B (zh) * | 2009-11-02 | 2011-11-16 | 严洁 | 盐酸头孢卡品酯颗粒的药物组合物及其制备方法 |
WO2015152190A1 (ja) * | 2014-03-31 | 2015-10-08 | 富山化学工業株式会社 | セファロスポリンエステルを含む粒状固形製剤およびその製造方法 |
CN110974803A (zh) * | 2019-12-31 | 2020-04-10 | 山东罗欣药业集团股份有限公司 | 一种盐酸头孢卡品酯颗粒剂及其制备方法 |
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JP6192919B2 (ja) | 2012-11-02 | 2017-09-06 | Ntn株式会社 | インホイールモータ駆動装置 |
CN113423570B (zh) * | 2019-02-22 | 2024-05-14 | 大金工业株式会社 | 层压体 |
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- 2009-04-03 RU RU2010145148/15A patent/RU2488396C2/ru not_active IP Right Cessation
- 2009-04-03 KR KR1020107024757A patent/KR101343283B1/ko active IP Right Grant
- 2009-04-03 CN CN2009801207603A patent/CN102056610B/zh active Active
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CN101756906B (zh) * | 2009-11-02 | 2011-11-16 | 严洁 | 盐酸头孢卡品酯颗粒的药物组合物及其制备方法 |
WO2015152190A1 (ja) * | 2014-03-31 | 2015-10-08 | 富山化学工業株式会社 | セファロスポリンエステルを含む粒状固形製剤およびその製造方法 |
JPWO2015152190A1 (ja) * | 2014-03-31 | 2017-04-13 | 富山化学工業株式会社 | セファロスポリンエステルを含む粒状固形製剤およびその製造方法 |
CN110974803A (zh) * | 2019-12-31 | 2020-04-10 | 山东罗欣药业集团股份有限公司 | 一种盐酸头孢卡品酯颗粒剂及其制备方法 |
CN110974803B (zh) * | 2019-12-31 | 2022-03-11 | 山东罗欣药业集团股份有限公司 | 一种盐酸头孢卡品酯颗粒剂及其制备方法 |
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CN102056610A (zh) | 2011-05-11 |
JP2011153075A (ja) | 2011-08-11 |
CN102056610B (zh) | 2013-07-17 |
KR101343283B1 (ko) | 2013-12-18 |
KR20110003357A (ko) | 2011-01-11 |
RU2488396C2 (ru) | 2013-07-27 |
RU2010145148A (ru) | 2012-05-20 |
TWI426913B (zh) | 2014-02-21 |
TW201004625A (en) | 2010-02-01 |
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