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WO2011016435A1 - Procédé de production d’une composition lyophilisée contenant des particules d’acide polylactique - Google Patents

Procédé de production d’une composition lyophilisée contenant des particules d’acide polylactique Download PDF

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Publication number
WO2011016435A1
WO2011016435A1 PCT/JP2010/063055 JP2010063055W WO2011016435A1 WO 2011016435 A1 WO2011016435 A1 WO 2011016435A1 JP 2010063055 W JP2010063055 W JP 2010063055W WO 2011016435 A1 WO2011016435 A1 WO 2011016435A1
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Prior art keywords
polylactic acid
dispersant
solution
aqueous
mannitol
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English (en)
Japanese (ja)
Inventor
敬一 松久
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Senju Pharmaceutical Co Ltd
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Senju Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/12—Powdering or granulating
    • 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
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/007—Methods or devices for eye surgery
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2367/00—Characterised by the use of polyesters obtained by reactions forming a carboxylic ester link in the main chain; Derivatives of such polymers
    • C08J2367/04—Polyesters derived from hydroxy carboxylic acids, e.g. lactones

Definitions

  • the present invention relates to a method for suppressing the generation of aggregates of polylactic acid particles obtained by freeze-drying an aqueous suspension of polylactic acid fine particles.
  • Transparent tissues such as the vitreous body, lens and cornea are gathered in the eye. Cataract surgery removes the nucleus and cortex in the capsular bag, but the lens cortex remaining near the posterior capsule becomes cloudy and is known to cause secondary cataract.
  • vitreous body removal surgery it is required to remove as much as possible the vitreous tissue that has adhered to the retina and the vitreous body that will serve as a scaffold for growth.
  • the vitreous body is a transparent tissue, and complete removal of the vitreous body is not easy.
  • a transparent vitreous body is visualized by injecting a steroid suspension such as a triamcinolone preparation (Kenacort-A: registered trademark) into the vitreous cavity using a syringe during a vitreous removal operation. (See Non-Patent Document 1).
  • a steroid suspension such as a triamcinolone preparation (Kenacort-A: registered trademark)
  • Non-Patent Documents 2 and 3 a method of improving the visibility of the vitreous body by injecting a suspension of particles made of polylactic acid or other high molecular compound having no pharmacological action into the vitreous cavity, and a transparent tissue visualization agent (eye) used therefor A drug for improving the visibility of the transparent tissue of the eye at the time of surgery has been proposed (Patent Document 1).
  • the suspension of fine particles is extremely supplied in the form of a freeze-dried suspension for reasons such as avoiding stability problems such as precipitation separation due to long-term storage in liquid form.
  • some polymer compounds such as polylactic acid, form agglomerates and form coarse particles when the suspension is lyophilized. Since the polymer compound particles are used in the form of being injected into the eye by a syringe, the particles must be of a particle size that can be passed without clogging the injection needle.
  • the particle diameter is disclosed as an average value, the maximum particle diameter is not mentioned, and there is no clear description regarding the preparation conditions for controlling the particle diameter.
  • Patent Document 2 discloses a method for improving the visibility of ocular tissue by adding a divalent or trivalent metal salt to a polylactic acid dispersion. There is no description regarding prevention of the formation of coarse particles.
  • Patent Document 3 discloses a method for producing an injectable implant by forming 20-120 ⁇ m polylactic acid microparticles and freeze-drying in an aqueous carrier containing glycolic acid. In the preparation of pharmaceuticals, taking into account the possibility of chlorinated organic solvent remaining in the formulation, including the steps of dissolving and precipitating in the chlorinated organic solvent, manufacturing pharmaceutical formulations, especially formulations that are injected into the eye It is not preferable as a method.
  • Patent Documents 4 and 5 discuss technical conditions for freeze-drying emulsions and suspensions, but prevent the formation of coarse particles due to particle aggregation during freeze-drying of polylactic acid suspensions. There is no description about what to do.
  • an object of the present invention is to provide a method for producing polylactic acid particles by freeze-drying from an aqueous suspension of polylactic acid microparticles, which can prevent generation of coarse particles in the freeze-drying process. That is.
  • Another object of the present invention is to provide a method for producing a transparent tissue visualization agent which is a preparation for improving the visibility of transparent tissues of the eye by applying to the transparent tissues of the eye, particularly vitreous body and lens. It is to be.
  • the present inventor added polylactic acid dissolved in a mixture of acetone and ethanol to an aqueous solution containing the dispersant dissolved therein or an aqueous solution containing the dispersant and mannitol dissolved.
  • an aqueous suspension of polylactic acid fine particles having an average particle size of 500 to 1000 nm (maximum particle size of 5 ⁇ m or less) as primary particles (referring to individual particles in an unaggregated state) is obtained.
  • the present invention provides the following.
  • a method for suppressing the formation of coarse particles of polylactic acid during freeze-drying of a polylactic acid microparticle aqueous suspension (a) preparing an aqueous polylactic acid microparticle suspension containing a dispersant and 3.5-10% mannitol, comprising: (i) A polylactic acid solution prepared by dissolving polylactic acid in a water-miscible organic solvent is added to an aqueous dispersant solution containing a dispersing agent after stirring, and then mannitol is added, or (ii) polylactic acid is added.
  • concentration of the dispersing agent in the dispersing agent aqueous solution or the dispersing agent / mannitol aqueous solution is 0.11 to 2.2 W / V%.
  • the method according to 6 above, wherein the mixing ratio of acetone and ethanol in the acetone / ethanol mixed solution is acetone: ethanol 3: 7 to 5: 5 by volume. 8).
  • step (b) the glass vial containing the polylactic acid fine particle aqueous suspension is placed in a freeze dryer chamber, and the cooling rate in the chamber when the polylactic acid fine particle aqueous suspension is frozen.
  • a method of producing polylactic acid particles for visualizing a transparent tissue of the eye (a) preparing an aqueous polylactic acid microparticle suspension containing a dispersant and 3.5-10% mannitol, comprising: (i) A polylactic acid solution prepared by dissolving polylactic acid in a water-miscible organic solvent is added to an aqueous dispersant solution containing a dispersing agent after stirring, and then mannitol is added, or (ii) polylactic acid is added.
  • a production method comprising: 12 12. The production method as described in 11 above, wherein the concentration of the dispersing agent in the aqueous dispersing agent solution or the aqueous solution containing the dispersing agent / mannitol is 0.11 to 2.2 W / V%. 13. 13.
  • the method according to 11 or 12 above, wherein the dispersant is polyvinyl pyrrolidone or polyvinyl alcohol.
  • 14 14 The production method according to any one of 11 to 13 above, wherein the concentration of mannitol in the aqueous polylactic acid microparticle suspension is 5 to 7 W / V%. 15.
  • 15. The method according to any one of 11 to 14 above, wherein the concentration of the polylactic acid in the polylactic acid solution is 1 to 50 W / V%. 16.
  • the water-miscible organic solvent is an acetone / ethanol mixed solution. 17. 16.
  • the production method as described in 16 above, wherein the mixing ratio of acetone and ethanol in the acetone / ethanol mixed solution is acetone: ethanol 3: 7 to 5: 5 by volume. 18.
  • step (b) the glass vial containing the polylactic acid fine particle aqueous suspension is placed in a freeze dryer chamber, and the cooling rate in the chamber when the polylactic acid fine particle aqueous suspension is frozen.
  • 20. The production method according to any one of the above 11 to 19, wherein is adjusted to 0.1 to 1 ° C./min.
  • the present invention having the above structure suppresses the aggregation of the polylactic acid particles during freeze-drying of the polylactic acid fine particle aqueous suspension, and is a coarse aggregate (particularly, the minor axis of the particles is 0.3 mm or more, especially 0.2 mm or more). Generation) can be prevented.
  • the polylactic acid particles when injecting an aqueous suspension of polylactic acid particles into the eye for visualizing a transparent tissue, the polylactic acid particles have a minor axis of 0.3 mm or more, particularly 0.2 mm or more.
  • the polylactic acid particles produced according to the present invention are not spherical, but individually take various irregular shapes, but such irregularly shaped polylactic acid particles are more vitreous and crystalline than the spherical particles. When it comes into contact with a transparent tissue such as the eye, it adheres well to the tissue and does not easily fall out of the tissue due to the flow of intraocular perfusate during surgery. For this reason, irregular-shaped polylactic acid particles are excellent as a transparent tissue visualization agent.
  • polylactic acid used in the study is DL-polylactic acid, D-polylactic acid, L-polylactic acid, and DL-polylactic acid are not distinguished, and appropriate mixtures thereof are also used in the present invention. can do.
  • transparent tissue of the eye refers to a transparent tissue in the ocular tissue such as the vitreous body, the vitreous membrane, the lens and the cornea.
  • transparent tissue visualization agent refers to a preparation in which polylactic acid particles obtained by freeze-drying are dispersed in a dispersion.
  • polylactic acid fine particles means polylactic acid particles having a particle diameter of 5 ⁇ m or less.
  • polylactic acid microparticle aqueous suspension is a liquid containing polylactic acid microparticles in a suspended state
  • the dispersion medium is an aqueous medium, that is, organic in a mixed state. What is water which contains a solvent in part.
  • the term “dispersant aqueous solution” refers to an aqueous solution obtained by adding a dispersant to water and dissolving it
  • the term “dispersant / mannitol aqueous solution” refers to a dispersant and D-mannitol.
  • the water-miscible organic solvent for dissolving polylactic acid is preferably an acetone / ethanol mixed solution.
  • the volume ratio of acetone and ethanol used to prepare this may be appropriate, but it is usually preferably in the range of 3: 7 to 5: 5. Both of these solvents are safer for body tissues than chlorinated organic solvents, and, unlike chlorinated organic solvents, are miscible with water. It is easy to shift from the water phase to the water phase, it is quickly removed by lyophilization, and does not substantially remain in the final lyophilized composition.
  • the concentration of polylactic acid dissolved in a water-miscible organic solvent such as the acetone / ethanol mixture is usually in the range of 1 to 50 W / V%, preferably 2 to 30 W / V%, and 5 to 20 W / V. % Is more preferable.
  • the amount of mannitol is preferably not less than 3.5 times by weight, more preferably not less than 5 times the amount of polylactic acid contained in the aqueous polylactic acid microparticle suspension. Is more preferable. This is because if the amount of mannitol is too small, some of the fine particles may aggregate to form coarse particles during lyophilization. There is no clear upper limit for the content of mannitol, but if it is too much, it takes time for lyophilization, which is not only disadvantageous, but also has a large effect on the osmotic pressure of the liquid when mixed with a dispersion medium during use of the lyophilizate. It becomes difficult to handle.
  • the content of mannitol in the polylactic acid fine particle aqueous suspension is preferably 10 times or less in terms of weight ratio with respect to the amount of polylactic acid contained in the polylactic acid solution added thereto. It is more preferable to set it to double or less.
  • the concentration of mannitol in the dispersant aqueous solution or the dispersant / mannitol aqueous solution is usually 3 It is preferably set to 0.85 to 11 W / V%, more preferably 4.5 to 10 W / V%, and still more preferably 5.5 to 8 W / V%.
  • the dispersant contained in the dispersant aqueous solution or the dispersant / mannitol aqueous solution is a step of adding polylactic acid solution dissolved in a water-miscible organic solvent to the aqueous solution containing the dispersant to precipitate polylactic acid fine particles.
  • it is useful for the suppression of particle growth, and also when maintaining a uniform suspension state of polylactic acid fine particles before lyophilization and preparing a transparent tissue visualization agent by mixing a lyophilized composition with a dispersion medium. This is useful for rapidly suspending polylactic acid particles and maintaining a stable suspended state.
  • a surfactant or a water-soluble polymer having surface activity can be used.
  • a water-soluble polymer that is solid at room temperature and immediately soluble in water is preferably used, and vinyl polymers such as polyvinylpyrrolidone and polyvinyl alcohol are particularly preferably used.
  • the content of the compound in the aqueous dispersant solution or the dispersant / mannitol aqueous solution is preferably 0.11 to 2.2 W / V%, preferably 0.22 to 1.1 W / V V% is more preferable, and 0.44 to 0.66 W / V% is more preferable.
  • the content of the compound in the aqueous dispersant solution or the dispersant / mannitol aqueous solution is preferably 0.55 to 2.2 W / V%, and 0.22 in the case of using polyvinyl alcohol. It is preferably set to 0.55 W / V%.
  • the volume ratio of the dispersant aqueous solution or the dispersant / mannitol aqueous solution to the polylactic acid solution added thereto is usually preferably 95: 5 to 85:15, particularly preferably about 90:10.
  • a polylactic acid solution is added to the aqueous solution at such a ratio and stirred, an aqueous suspension of polylactic acid fine particles having an average primary particle size of 500 to 1000 nm and a maximum particle size of 5 ⁇ m or less can be easily obtained. .
  • the primary particles may be partially agglomerated during the preparation of the aqueous suspension, but there is no problem if the particles applied to the primary suspension are removed by passing the aqueous suspension through a sieve having a diameter of 106 ⁇ m after the preparation.
  • the content of polylactic acid in the aqueous polylactic acid microparticle suspension subjected to freeze-drying is usually 0.05 to 7.5 W / V%, preferably 0.1 to 5.0 W / V%, more preferably 0.5 to 2.5 W / V%.
  • the polylactic acid content in the aqueous polylactic acid microparticle suspension may be adjusted by adjusting the concentration of polylactic acid contained in the acetone / ethanol mixture in advance. You may carry out by adjusting the addition ratio of a solution.
  • the mannitol contained in the polylactic acid fine particle aqueous suspension is useful for preventing aggregation of the polylactic acid particles when the polylactic acid fine particle aqueous suspension is freeze-dried.
  • the concentration of mannitol is preferably 3.5 to 10 W / V%, more preferably 5 to 7 W / V%.
  • the term “average molecular weight” for polylactic acid refers to the weight average molecular weight.
  • the average molecular weight of the polylactic acid used in the present invention is usually 500 or more, preferably 1000 or more, more preferably 3000 or more, particularly preferably 4000 or more, and usually 20000 or less, preferably 15000 or less, more preferably It is 10,000 or less, more preferably 8000 or less, and particularly preferably 6000 or less.
  • the lyophilized composition containing polylactic acid particles produced according to the present invention is mixed with an aqueous dispersion medium and prepared in the form of an aqueous suspension of polylactic acid particles, and used as a transparent tissue visualization agent.
  • an aqueous dispersion medium to be used an aqueous solution having a composition that can be injected into the eye as a medicine can be appropriately used.
  • Various compositions are well known to those skilled in the art as intraocular perfusion / cleaning solutions, and they can be appropriately selected and used as a dispersion medium.
  • pharmaceuticals already sold as intraocular perfusion / cleaning solution may be used as a dispersion medium. Examples of those particularly suitable as such pharmaceuticals include Opegard MA (registered trademark, manufactured by Senju Pharmaceutical Co., Ltd.) and Opegard Neo Kit (registered trademark, manufactured by Senju Pharmaceutical Co., Ltd.).
  • an aqueous suspension of polylactic acid fine particles to be lyophilized includes pharmaceutically acceptable additives such as isotonic agents (salts such as sodium chloride and potassium chloride: saccharides such as glycerin, sorbitol and glucose: Polyhydric alcohols such as glycerin and propylene glycol: boric acid, borax, etc.), buffer (phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, etc.) , Thickener (hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, polyvinyl alcohol, polyethylene glycol, sodium alginate, etc.), stabilizer (sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate) Ascorbic acid, dibutyl hydroxytoluene, magnesium chloride, calcium chloride and the like), pH adjusting agents (hydrochloric acid, sodium hydroxide,
  • these additives may be added in advance to the aqueous dispersion or dispersion / aqueous mannitol solution before the polylactic acid solution is added, and after the preparation of the aqueous polylactic acid microparticle suspension,
  • a part of the aqueous solution may be added in advance to the aqueous dispersant solution or the dispersant / mannitol aqueous solution before the polylactic acid solution is added, and the rest after the preparation of the aqueous solution containing the polylactic acid microparticles. You may add to this.
  • the pH of the aqueous polylactic acid microparticle suspension subjected to freeze-drying is usually adjusted to 4.0 to 8.0, preferably about 5.0 to 7.5.
  • the suspension is usually preferably freeze-dried in a glass container.
  • a particularly preferred glass container is a glass vial. It is preferable to freeze the suspension in a glass vial gradually.
  • a glass vial into which an aqueous suspension of polylactic acid fine particles is dispensed is placed in a freeze dryer chamber, and the cooling rate in the chamber is 0 when freezing (at the start of ice crystal formation in the suspension). It can be adjusted to 1 to 1 ° C./min. By doing so, the generation of coarse particles can be prevented more reliably.
  • the polylactic acid particles produced according to the present invention are not spherical, but have various irregular shapes, but such irregular shapes are more likely to occur in eyes such as the vitreous body and the lens than the spherical particles.
  • irregular shapes are more likely to occur in eyes such as the vitreous body and the lens than the spherical particles.
  • transparent tissue When in contact with transparent tissue, it adheres well to the tissue and does not easily fall out of the tissue due to the flow of intraocular perfusate during surgery. For this reason, it is excellent as a transparent tissue visualization agent.
  • Example 1 and 2 Comparative Examples 1 to 3
  • Each solution was dissolved so as to be 1.1 times the amount specified in 1-2, and the solution was filtered through a 0.22 ⁇ m aqueous filter to obtain solutions A-1 to A-5, respectively.
  • the solutions A-1 to A-5 and the solution B were mixed at a ratio of 9: 1 as follows. While stirring each solution of A-1 to A-5 in a 200 mL beaker with a stirrer (medium speed 700 to 800 rpm) using a stirrer (diameter 6 mm, length 20 mm), a micropipette tip (Eppendolf ep TIPS Using a tube pump (PERISTALTIC PUMP PST-100 IWAKI) with a silicon tube (outer diameter 6 mm, inner diameter 4 mm) with a standard 2-200 ⁇ L) attached to the discharge side, the B solution was A- Liquids 1 to A-5 were fed to deposit PLA0005 fine particles.
  • the suspensions D-1 to D-5 obtained above were passed through a sieve (caliber 106 ⁇ m) to remove agglomerates.
  • the suspensions D-1 to D-5 after sieving were filled in 1.5 mL glass vials (18 ⁇ , height 33 mm) and freeze-dried under the following conditions. ⁇ E-5 was obtained.
  • Suspensions were prepared by dispersing lyophilized compositions E-1 to E-5 in dispersion medium C having the composition shown in Table 2 so that the polylactic acid content was 1 W / V%.
  • Evaluation method Transfer the entire amount of the suspension prepared above to a 12-well plate (12.5 cm ⁇ 8 cm, inner diameter 22 mm, IWAKI) and observe the size of the particles with a digital microscope (model number: VHX-500, Keyence) did. At that time, the magnification was set so that an almost whole image of one hole could be captured. Photographs were taken, and the number of aggregates having a minor axis of 0.3 and 0.2 mm or more was measured. The results are shown in Table 3 below.
  • Formulation Examples 1-5 Based on Table 4, polyvinyl pyrrolidone (Povidone K-30) or polyvinyl alcohol and D-mannitol were dissolved in purified water to 1.1 times the amounts specified for H-1 to H-4, Filter the solution through a 0.22 ⁇ m aqueous filter to make F-1 to F-4 solutions, respectively. In addition, polyvinyl pyrrolidone (Povidone K-30) is dissolved in purified water to 1.1 times the amount specified for H-5, and the solution is filtered through a 0.22 ⁇ m aqueous filter to obtain F-5 solution. To do.
  • the suspensions H-1 to H-5 obtained above are passed through a sieve (caliber 106 ⁇ m) to remove aggregates.
  • the suspensions H-1 to H-5 after sieving were filled in 1.5 mL glass vials (18 ⁇ , height 33 mm) and lyophilized under the following conditions. Obtain ⁇ I-5.
  • the liquids A-6 to A-9 and the liquid B were mixed at a ratio of 9: 1 as follows. While stirring each solution of A-6 to A-9 in a 200 mL beaker with a stirrer (diameter 6 mm, length 20 mm) with a stirrer (medium speed 700 to 800 rpm), a micropipette tip (Eppendolf ep TIPS Using a tube pump (PERISTALTIC PUMP PST-100 IWAKI) with a silicon tube (outer diameter 6 mm, inner diameter 4 mm) with a standard 2-200 ⁇ L) attached to the discharge side, the B solution was A- Liquids 6 to A-9 were fed to deposit PLA0005 fine particles.
  • the suspensions D-6 to D-9 obtained above were passed through a sieve (caliber 106 ⁇ m) to remove agglomerates.
  • the suspensions D-6 to D-9 after sieving were filled in 1.5 mL glass vials (18 ⁇ , height 33 mm) and lyophilized under the following conditions. To E-9.
  • Suspensions were prepared by dispersing lyophilized compositions E-6 to E-9 in purified water so that the content of polylactic acid was 1 W / V%.
  • Evaluation method The particle size distribution of the suspension prepared above was measured using a laser diffraction particle size distribution analyzer (SALD-2100, Shimadzu Corporation).
  • the production method of the present invention provides a redispersible lyophilized composition containing polylactic acid particles that can suppress aggregation of polylactic acid particles during lyophilization and does not contain coarse particles that clog the injection needle. It can be used to produce a transparent tissue visualization agent suitable for use in ophthalmic surgery such as removal surgery.

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  • Ophthalmology & Optometry (AREA)
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Abstract

La présente invention concerne un procédé permettant d'empêcher la formation de grosses particules dans le processus de lyophilisation d'une suspension aqueuse de fines particules d'acide polylactique, et un procédé de production de particules d'acide polylactique destinées à être utilisées comme un agent permettant de rendre visible le tissu oculaire transparent. Le procédé permettant d'éliminer la formation de grosses particules lorsqu'une suspension aqueuse de fines particules d'acide polylactique est lyophilisée comprend : (a) une étape dans laquelle une suspension aqueuse de fines particules d'acide polylactique contenant un agent dispersant et de 3,5 % à 10 % de mannitol est préparée par (i) ajout, tout en agitant, d'une solution d'acide polylactique dissous dans un solvant organique miscible dans l'eau à une solution aqueuse d'agent dispersant puis ajout de mannitol, ou (ii) ajout, tout en agitant, de la solution d'acide polylactique dissous dans ledit solvant à une solution aqueuse d'agent dispersant/mannitol contenant l'agent dispersant et le mannitol ; et (b) une étape dans laquelle ladite suspension est lyophilisée dans un récipient en verre. Le procédé de production de particules d'acide polylactique destinées à être utilisées comme agent permettant de rendre visible un tissu transparent comprend les étapes (a) et (b).
PCT/JP2010/063055 2009-08-04 2010-08-03 Procédé de production d’une composition lyophilisée contenant des particules d’acide polylactique Ceased WO2011016435A1 (fr)

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JP2009-181970 2009-08-04
JP2009181970A JP2012214524A (ja) 2009-08-04 2009-08-04 ポリ乳酸粒子含有凍結乾燥組成物の製造方法

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KR101732760B1 (ko) 2013-10-10 2017-05-24 주식회사 엘지화학 폴리락트산 입자의 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09110678A (ja) * 1995-10-19 1997-04-28 Tanabe Seiyaku Co Ltd 被覆マイクロスフェア製剤およびその製法
WO2005115411A1 (fr) * 2004-05-31 2005-12-08 Senju Pharmaceutical Co, .Ltd. Agent de visualisation de tissu transparent
WO2008126720A1 (fr) * 2007-04-06 2008-10-23 Senju Pharmaceutical Co., Ltd. Suspension permettant de visualiser des tissus oculaires transparents

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09110678A (ja) * 1995-10-19 1997-04-28 Tanabe Seiyaku Co Ltd 被覆マイクロスフェア製剤およびその製法
WO2005115411A1 (fr) * 2004-05-31 2005-12-08 Senju Pharmaceutical Co, .Ltd. Agent de visualisation de tissu transparent
WO2008126720A1 (fr) * 2007-04-06 2008-10-23 Senju Pharmaceutical Co., Ltd. Suspension permettant de visualiser des tissus oculaires transparents

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