WO2010052896A1 - Préparation pour administration locale contenant du propionate de fluticasone - Google Patents

Préparation pour administration locale contenant du propionate de fluticasone Download PDF

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WO2010052896A1
WO2010052896A1 PCT/JP2009/005843 JP2009005843W WO2010052896A1 WO 2010052896 A1 WO2010052896 A1 WO 2010052896A1 JP 2009005843 W JP2009005843 W JP 2009005843W WO 2010052896 A1 WO2010052896 A1 WO 2010052896A1
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fluticasone propionate
fine particles
particles
preparation
crystals
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PCT/JP2009/005843
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English (en)
Japanese (ja)
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長尾剛
加賀美和宏
小川泰亮
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日揮株式会社
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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a topical preparation containing fluticasone propionate. More specifically, the present invention relates to a topical administration agent that can exert a high therapeutic effect and sustained action by allowing fluticasone propionate particles to adhere efficiently to the mucosa and staying longer on the mucosa.
  • Fluticasone propionate (Fluticasone® Propionate) is widely used as a corticosteroid that suppresses various inflammations such as allergic rhinitis such as hay fever, vasomotor rhinitis, bronchitis, or bronchial asthma.
  • rhinitis such as allergic rhinitis and vasomotor rhinitis
  • This nasal preparation (for example, “Flunase” (registered trademark), sold by GlaxoSmithKline Co., Ltd.) is considered to have local side effects and has almost no side effects on the whole body. Sneezing associated with rhinitis, runny nose, and nose Especially effective for clogging.
  • the above-mentioned nasal drops containing fluticasone propionate as an active ingredient is an aqueous suspension containing fine particles of fluticasone propionate crystals, which are pulverized into fine particles having an average particle size of about 1 to 10 ⁇ m. It is prepared by suspending uniformly in a medium.
  • cellulose, carmellose sodium, glucose, phenylethyl alcohol, polysorbate 80 and the like are generally used as additives for this nasal preparation as an additive for preparation in order to facilitate atomization.
  • An object of the present invention is to provide a topical preparation containing fluticasone propionate, and more specifically, fluticasone propionate fine particles, which are active ingredients, are retained in the mucosa for a long period of time, resulting in higher therapeutic effect and sustained action. It is in providing the topical administration agent which can achieve.
  • the present inventors diligently studied the relationship between the properties of fluticasone propionate fine particles, mucoadhesiveness and action duration.
  • the fine radiating needle-like crystal lump with a particle size of 5 to 50 ⁇ m obtained by the crystallization method has high adhesion to the mucous membrane, and an aqueous suspension in which the fine particles are dispersed is locally administered.
  • an agent it was found that a higher drug retention was obtained compared to conventional topical administration agents, and higher therapeutic effects and sustained action could be achieved.
  • the present invention has been completed based on the above findings.
  • fluticasone propionate microparticles which are composed of needle-like crystals radially grown around the fluticasone propionate crystal nucleus and having an average particle diameter in the range of 10 to 60 ⁇ m.
  • the fine particles having a fluticasone propionate crystal nucleus having a particle size of 2 to 10 ⁇ m; the fine particles having a needle crystal length of 2 to 30 ⁇ m; an average particle size of 10 to 50 ⁇ m
  • the above microparticles are provided.
  • a method for producing the above fluticasone propionate microparticles the step of adding a suspension containing fluticasone propionate crystal nuclei to a homogeneous solution containing fluticasone propionate in a crystallization solvent; And a method comprising adding water to the resulting suspension and stirring.
  • the present invention provides a topical preparation comprising an aqueous suspension of the above fluticasone propionate microparticles.
  • the fluticasone propionate fine particles of the present invention exhibit high adhesion to mucous membranes, they are characterized by high drug retention compared to conventional topical preparations and excellent action persistence. In addition, the fine particles have excellent solubility in biological components, and can achieve a higher therapeutic effect.
  • the fluticasone propionate microparticles provided by the present invention are needle-shaped crystals that grow radially around the fluticasone propionate crystal nucleus, and are characterized by being fine particles having an average particle size in the range of 10 to 60 ⁇ m (hereinafter referred to as “fine particles”). In the present specification, the fine particles may be referred to as “radiating needle-like crystal lumps”).
  • a fine powder of acicular crystals of fluticasone propionate can be used as the crystal nucleus used for the production of the fine particles of the present invention.
  • the average particle size of the fine powder is not particularly limited, but is, for example, about 0.5 to 10 ⁇ m, preferably about 2 to 10 ⁇ m.
  • the upper limit of the particle size is not particularly limited, but is, for example, 50 ⁇ m or less, preferably 20 ⁇ m or less.
  • the above fine powder is generally obtained by pulverizing acicular crystals of fluticasone propionate by an appropriate means and sizing as necessary.
  • the fine powder is pulverized by a means such as a hammer mill or a colloid mill. Things can be used.
  • the fine particles of the present invention include the above-described crystal nuclei and needle-like crystals that have grown radially around the crystal nuclei.
  • the size of the needle crystal is not particularly limited, but generally the length (major axis) is about 2 to 30 ⁇ m, preferably about 5 to 20 ⁇ m, and the width (minor axis) is about 0.5 to 5 ⁇ m, preferably It is about 0.5-2 ⁇ m.
  • the fine particles of the present invention contain needle-like crystals grown radially in at least two directions, preferably in three directions or more, more preferably in multiple directions around the crystal nucleus, for example, substantially spherical or rugby balls. It is a crystal lump having a three-dimensional shape like a mold.
  • the average particle size of the fine particles of the present invention is in the range of about 10 to 60 ⁇ m, preferably in the range of about 10 to 50 ⁇ m.
  • the upper limit of the particle size of the fine particles of the present invention is about 100 ⁇ m or less, preferably about 80 ⁇ m or less.
  • the fine particles of the present invention are prepared by, for example, uniformly dissolving fluticasone propionate in a crystallization solvent, adding a suspension containing fluticasone propionate crystal nuclei to the obtained solution, and further adding water to lower the solubility. It can manufacture by stirring it.
  • a crystallization solvent an organic solvent that can be mixed with water and dissolve fluticasone propionate can be used.
  • ethanol, methanol, acetone, tetrahydrofuran, or the like can be used, but ethanol is preferably used from the viewpoint of the safety of the residual solvent.
  • the concentration of fluticasone propionate in this solution is not particularly limited, but is, for example, about 1 to 3.5 g / L, preferably about 2 to 3.5 g / L, and is preferably close to the saturation concentration.
  • the concentration can be, for example, about 2.0 to 4.0 g / L, preferably about 3.0 to 3.5 g / L.
  • the crystal nuclei having the average particle diameter described above can be used.
  • the crystal nuclei are suspended in a mixture of a crystallization solvent and water or water, and the fluticasone propionate is used. Can be added to the solution.
  • crystal nuclei can be suspended in a mixture of water and ethanol.
  • Water containing can be used.
  • the concentration of crystal nuclei in the suspension is not particularly limited.
  • the concentration may be about 10 to 100 Lg / L, preferably about 30 to 60 g / L, and more preferably about 40 g / L. Yes, but not limited to this concentration.
  • the volume of the crystal nucleus suspension to be added can be, for example, about 1 to 5 parts by volume with respect to 100 parts by volume of the solution containing fluticasone propionate. It can be appropriately selected depending on the concentration.
  • the mass of the crystal nucleus to be added is about 0.1 to 5 parts by mass, preferably about 0.5 to 2 parts by mass, and more preferably about 1 part by mass with respect to 100 parts by mass of fluticasone propionate in the solution.
  • the volume of water to be added is not particularly limited, and a volume capable of forming a supersaturated state by sufficiently reducing the solubility of fluticasone propionate in a solution containing fluticasone propionate may be appropriately selected.
  • the volume of the solution is about 2 to 10 times, preferably about 3 to 5 times the volume of the solution.
  • Water can be added.
  • the speed at which water is added is not particularly limited, it should be added as slowly as possible, and it is not preferable to add all or most of the water at one time. For example, it is preferable to gradually form a supersaturated state by dropping or injecting water over 30 minutes to several hours.
  • needle crystals can be grown radially around the crystal nucleus to produce the fine particles of the present invention, but the fine particle production method of the present invention is not limited to the above specific method. .
  • the obtained fine particles can be collected and dried according to a conventional method.
  • nasal drops can be prepared as a quantitative spray type nasal drop in the form of an aqueous suspension in the same manner as a commercially available fluticasone propionate nasal drop.
  • fluticasone propionate nasal drop can be used for the treatment and / or prevention of rhinitis such as allergic rhinitis and vasomotor rhinitis in the same manner as commercially available fluticasone propionate.
  • fluticasone propionate nasal drops are commercially available, and the use of pharmaceutical additives such as cellulose, carmellose sodium, glucose, phenylethyl alcohol, polysorbate 80, etc.
  • Nasal agents can be prepared.
  • the concentration of fluticasone propionate in the nasal drops of the present invention can be appropriately selected, but is generally about 0.5 to 0.6 mg / mL, and preferably about 0.51 mg / mL as in the case of commercially available preparations. It is desirable to prepare the formulation so that about 50 ⁇ g of fine particles are sprayed per dose (one spray). Furthermore, these fine particles (locally retained type) can be mixed with an appropriate powder and used as a transpulmonary inhaler to be used for the treatment of asthma. In this case, other drugs such as ⁇ stimulants may be added.
  • Example 1 Materials and Methods PLGA (polylactic acid / glycolic acid copolymer: PLGA 5008, Wako Pure Chemical Industries, Ltd.) having a composition ratio (molar ratio) of D, L-lactic acid and glycolic acid as a biodegradable polymer of 50:50 and a weight average molecular weight of 8,000 CVP (carboxyvinyl polymer: Hibiswako 104, manufactured by Wako Pure Chemical Industries, Ltd.) was used as mucoadhesive fine particles. Purified water was used as the water.
  • PLGA polylactic acid / glycolic acid copolymer: PLGA 5008, Wako Pure Chemical Industries, Ltd.
  • CVP carboxyvinyl polymer: Hibiswako 104, manufactured by Wako Pure Chemical Industries, Ltd.
  • FP fluticasone propionate
  • a powder obtained by pulverizing acicular crystals (average particle size of about 1 ⁇ m) is used as a starting material, and FP is quantified by measuring the absorbance with a spectrophotometer. Analysis was performed under the following conditions using measurement or high performance liquid chromatography (HPLC).
  • the fine particle A was prepared using an O / W method. 10 mg of the polymer and 90 mg of the drug were weighed, 6 mL of dichloromethane was added, and the mixture was stirred and dissolved in an ultrasonic water bath to obtain an oil phase. This was put into 18 mL of 0.1% polyvinyl alcohol (PVA) aqueous solution as a dispersion solvent, and stirred to form an O / W emulsion. This O / W emulsion was further poured into 900 mL of a 0.1% PVA aqueous solution and stirred for 5 hours to volatilize dichloromethane and atomize. The obtained particles were washed with water, and the particle suspension was freeze-dried to obtain spherical particles having an average particle size of about 20 to 30 ⁇ m.
  • PVA polyvinyl alcohol
  • Fine Particle B was prepared using a crystallization method. FP crystals were precipitated by dissolving 100 mg of the FP drug substance in 10 mL of acetone, and adding and mixing 40 mL of water over about 1 minute while stirring. The obtained crystals were washed with water, and the particle suspension was freeze-dried to obtain needle-like crystals having a length of about 50 to 100 ⁇ m.
  • Fine particle C was prepared using a crystallization method. 200 mg of FP drug substance was dissolved in 60 mL of ethanol to prepare an almost saturated FP solution. Separately, 20 mg of FP bulk was weighed and suspended in 0.5 mL of a 5% ethanol water mixture to prepare an FP crystal nucleus additive solution. By adding the entire amount of the FP crystal nucleus addition solution into the FP solution, undissolved FP bulk particles were suspended in the FP solution. While stirring this with a stirrer, 240 mL of water was gently added at a rate of 2 mL / min for 120 minutes using an HPLC pump, and the precipitated FP was grown to reach the core FP particles. The obtained crystals were washed with water, and the particle suspension was lyophilized to obtain radial needle crystals having an average particle size of about 30 to 50 ⁇ m.
  • Fine particle D was prepared by a crystallization method under the condition that the precipitation time of fine particle C was shortened and the amount of precipitation was halved.
  • 100 mg of the FP drug substance was dissolved in 30 mL of ethanol to prepare an almost saturated FP solution.
  • 20 mg of FP bulk was weighed and suspended in 0.5 mL of 5% ethanol in water to prepare an FP crystal nucleus additive solution. By adding the entire amount of the FP crystal nucleus addition solution into the FP solution, undissolved FP bulk particles were suspended in the FP solution.
  • the supernatant was used as a measurement sample by adding 20 mL of acetonitrile to the intestinal tract to which the drug was attached, extracting the drug, and diluting by adding 10 mL of water. Absorbance at a wavelength of 236 nm was measured with a spectrophotometer to quantify the amount of drug attached. The adhesion rate was evaluated by determining the percentage of the drug amount adhering to the intestinal tract with respect to the added drug amount.
  • the drug solution for administration was adjusted so that the FP particle concentration would be 2.5 to 3 mg / mL based on the detection sensitivity and the amount of nasal fluid that can be applied to the rat. Since the FP particle concentration is 0.51 mg / mL for both the commercial preparations Millicalet and Skylon as controls, the drug substance concentration is increased by adding the FP drug substance to the commercial preparation solution in accordance with this evaluation system. It was.
  • Rat heparin plasma was used as a biological sample, and diluted 25-fold and 4-fold with PBS to prepare 25% and 50% rat plasma.
  • PBS was used as a sample containing no biological component. 1 mL of the sample solution was added to 1 mg of fine particles C, and the mixture was gently stirred in a constant temperature bath at 37 ° C. Immediately after preparation (0 hours), remove the drug particles from 0.20 ⁇ m filtration filter (DISMIC-25CS ADVANTEC) and prepare FP concentration in the filtrate by HPLC. did.
  • Fine particles A Particles A prepared by the O / W method had a spherical shape with an average particle size of about 20-30 ⁇ m and a relatively smooth surface (FIG. 1).
  • Fine particle B FP was crystallized by changing the solubility by adding water to the FP solution completely dissolved in acetone to obtain needle-like crystals of about 50-100 ⁇ m in length (Fig. 1). In this crystallization method, it is considered that crystals grew in one direction to form needle-like crystals. No coating was performed on the particles.
  • Fine particles C In the fine particles C, the granular FP base material, which is the core, was suspended in advance and crystals were grown in multiple directions. FP was dissolved to near saturation using ethanol as a solvent for FP, and after the introduction of the original FP core particles, water was added slowly to grow crystals. The resulting crystal mass was a needle-like crystal mass (radial needle-like crystal mass) having a substantially spherical outer shape and radially extending with an average particle diameter of about 30 to 50 ⁇ m (FIG. 1). Moreover, the surface of this crystal lump was not smooth, but the particle diameter was uniform. A portion of this crystal was coated with CVP to compare its mucoadhesive properties. However, when CVP coating was applied, a portion of the radiating needle-like crystal lump on the particle surface collapsed, resulting in a mixed state with a large amount of needle-like crystals. ( Figure 2).
  • Fine particles D The obtained crystals were a mixture of radiating needle-like crystals with an average particle size of about 30-50 ⁇ m, similar to that of fine particles C, and needle-like crystals with a length of about 50 ⁇ m, similar to fine particles B (Fig. 1). .
  • the dripping instantaneously creates new crystal nuclei near the interface between water and ethanol, which are acicular crystals. It is thought that it became. Since the fine particles D are not homogeneous and contain acicular crystals, the CVP coating was not performed.
  • the CVP coating was applied to the fine particles A that can be easily coated with CVP, which is a mucoadhesive polymer, and the fine particles C, which had the highest particle adhesion rate, and the adhesion due to the presence or absence of coating was compared.
  • the adhesion rate of fine particle A was increased by coating CVP, but no difference was observed in the case of fine particle C due to the presence or absence of CVP. In either case, a high adhesion rate of about 80% was given (Table 2). .
  • Fine particles C showed a high adhesion rate even without coating with CVP, the adhesion in the state of suspension preparations was compared for the commercial preparations Millicalet and Skylon. Fine particles C were suspended in a suspension medium obtained by centrifuging drug particles from a commercially available millicaret to prepare a test preparation. Fine particles C had an adhesion rate as low as 47.3% on average compared to 80% ⁇ when suspended in PBS, but compared to ⁇ 23.9% for Millicalet and 1.621.6% for Skylon, the adhesion rate was about twice as high. Shown (Table 3).
  • the fine particles C have high mucoadhesive properties in the particles themselves, and even when diluted to the concentration of commercial preparations and in viscous suspension media, they have higher mucoadhesive properties than conventional FP drug particles. It was confirmed to show sex.
  • microparticle C Compared to FP particles contained in commercially available preparations, microparticle C was considered to have a very high retention in the nasal mucosa, so it remained over time at the administration site of the test preparation prepared from millicaret or microparticle C. We compared the transition of quantity. The dosage was 25 ⁇ g / mouse for the test preparation prepared from millicaret and 30 ⁇ g / mouse for the test preparation prepared from microparticle C. The results are shown in Figure 3. In the test preparation prepared from millicaret, the drug decreased from the administration site over time, whereas the microparticle C had an almost constant residual amount of about 10% to 12% of the dose from 3 hours to 12 hours after administration. Was showing.
  • the residual amount of the fine particles C at 24 hours after the administration was smaller than the residual amount at 12 hours after the administration, it was considered that the risk of residual and accumulation of these particles was low.
  • the group of test preparations prepared from millicaret 1 of 3 cases was observed at 12 hours after administration, and 2 of 3 cases were below the lower limit of quantification at 24 hours after administration.
  • the lower limit of quantification of 0.2 ⁇ g was substituted, and all time points were expressed as the mean value and SD of 3 cases.
  • the value at 24 hours after administration is not reliable as an absolute value, so in FIG. 3, the period from 12 hours to 24 hours after administration is shown as a broken line.
  • radial particles are small and monodispersed. Therefore, in order to prevent aggregation, an aqueous solution in which polyvinyl alcohol (PVA) was added at 0.5% in the water for precipitation was prepared. This was added using a pump in the same manner as in 1-C above, to obtain FP radial needle crystals. The crystals had a needle-like crystal length distribution of 5 to 30 ⁇ m and an average particle size of about 15 ⁇ m. When suspended in water, it was dispersed in a monodispersed state. To these particles, pulverized mannitol was mixed at a ratio (weight) of 98 to obtain a powder preparation for pulmonary administration.
  • PVA polyvinyl alcohol
  • the fluticasone propionate microparticles of the present invention are characterized by high drug retention compared to conventional topical administration agents and excellent action persistence. Further, the fine particles are excellent in solubility in biological components and can achieve a higher therapeutic effect, so that they are useful as an active ingredient of a locally administered agent.

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Abstract

La présente invention concerne des microparticules de propionate de fluticasone utiles comme principes actifs dans une préparation destinée à l’administration locale qui permet la rétention à long terme des microparticules d’un principe actif dans une muqueuse pendant une longue période de temps pour obtenir un plus grand effet thérapeutique et une plus longue durée d’action, chacune comprenant un noyau cristallin de propionate de fluticasone et des cristaux de propionate de fluticasone en forme d’aiguilles qui se sont développés radialement autour du noyau cristallin et présentant une dimension moyenne des particules allant de 10 à 60 μm.
PCT/JP2009/005843 2008-11-04 2009-11-04 Préparation pour administration locale contenant du propionate de fluticasone WO2010052896A1 (fr)

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JP2008283080A JP2010111592A (ja) 2008-11-04 2008-11-04 プロピオン酸フルチカゾンを含む局所投与剤

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Cited By (6)

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GB2477030A (en) * 2010-01-15 2011-07-20 Lithera Inc Lyophilised forms of fluticasone, salmeterol and combinations thereof
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
WO2014153541A1 (fr) * 2013-03-21 2014-09-25 Eupraxia Pharmaceuticals USA LLC Composition à libération prolongée injectable et son procédé d'utilisation pour traiter une inflammation dans des articulations et la douleur associée à celle-ci
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US11351124B2 (en) 2015-10-27 2022-06-07 Eupraxia Pharmaceuticals Inc. Sustained release of formulations of local anesthetics

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2477030A (en) * 2010-01-15 2011-07-20 Lithera Inc Lyophilised forms of fluticasone, salmeterol and combinations thereof
US9822142B2 (en) 2012-05-08 2017-11-21 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US8765725B2 (en) 2012-05-08 2014-07-01 Aciex Therapeutics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10954263B2 (en) 2012-05-08 2021-03-23 Nicox Ophthalmics, Inc Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US10174071B2 (en) 2012-05-08 2019-01-08 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9815865B2 (en) 2013-01-07 2017-11-14 Nicox Ophthalmics, Inc. Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof
US9987233B2 (en) 2013-03-21 2018-06-05 Eupraxia Pharmaceuticals USA LLC Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith
JP2018052941A (ja) * 2013-03-21 2018-04-05 ユープラシア ファーマシューティカルズ ユーエスエー エルエルシーＥｕｐｒａｘｉａ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｕｓａ Ｌｌｃ 関節の炎症およびそれに関連する疼痛を治療するための注射用持続放出組成物およびその使用方法
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