WO2003099262A1 - Procede de production de nanoparticules comprenant l'utilisation simultanee d'energie mecanique faible et d'energie sonique - Google Patents

Procede de production de nanoparticules comprenant l'utilisation simultanee d'energie mecanique faible et d'energie sonique Download PDF

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Publication number
WO2003099262A1
WO2003099262A1 PCT/SI2003/000017 SI0300017W WO03099262A1 WO 2003099262 A1 WO2003099262 A1 WO 2003099262A1 SI 0300017 W SI0300017 W SI 0300017W WO 03099262 A1 WO03099262 A1 WO 03099262A1
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WIPO (PCT)
Prior art keywords
nanoparticles
process according
active substance
encapsulated
acid
Prior art date
Application number
PCT/SI2003/000017
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English (en)
Inventor
Julijana Kristl
Pegi Ahlin
Mateja Cegnar
Franc Vrecer
Janko Kos
Original Assignee
Krka Tovarna Zdravil, D.D., Novo Mesto
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Application filed by Krka Tovarna Zdravil, D.D., Novo Mesto filed Critical Krka Tovarna Zdravil, D.D., Novo Mesto
Priority to AU2003228202A priority Critical patent/AU2003228202A1/en
Priority to EP03725975A priority patent/EP1558224A1/fr
Publication of WO2003099262A1 publication Critical patent/WO2003099262A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes

Definitions

  • the present invention relates to a novel process for the production of nanoparticles.
  • the invention relates to a process for the production of biodegradable nanoparticles made of lactic acid-glycolic acid copolymers, containing one or more active substances by the use of a double emulsion water-in-oil-in-water (W/O/W) process.
  • W/O/W double emulsion water-in-oil-in-water
  • TIMP's tissue inhibitors of metalloproteases
  • plasminogen activator inhibitors plasminogen activator inhibitors
  • cy statins plasminogen activator inhibitors
  • nanoparticles represent a very promising approach since their properties of protecting active substances and of controlled release are considered to be very advantageous.
  • nanoparticles allow the transport of active substances through biological membranes and specific targeting by a potential surface modification (Lamprecht A., Ubrich N., Perez M. H., Lehr C. M., Hoffman M., Maincent P., Biodegradable monodispersed nanoparticles prepared by pressure homogenization-emulsification, Int. J. Pharm. 184 (1999) 97-105).
  • nanoparticles allow parenteral and nonparenteral routes of administration. They can be injected intravenously and, since the protein is incorporated within a polymer matrix and thus protected from circulating enzymes, the plasma half-life of the incorporated protein is prolonged as compared with the injected protein solution. The release of the protein from the nanoparticles is also sustained, which results in a prolonged activity of the protein. Furthermore, by a selection of an appropriate polymer, nanoparticles may facilitate the absorption through biological membranes. An oral intake is possible as well. To this end, the size of nanoparticles is the crucial parameter determining the absorption from the gastrointestinal tract. Smaller nanoparticles are generally absorbed to a larger extent.
  • US 4,177,177 discloses a process for a direct emulsification of a solution of water-insoluble polymers in appropriate organic solvents into an aqueous solution containing at least one emulsifier of nonionic, anionic or cationic type.
  • Ultrasound was used to reduce the size of emulsion droplets, whereby a particle size of less than 0.5 ⁇ m was achieved.
  • Solvent evaporation technique oil-in-water (O/W) process
  • O/W solvent-in-water
  • the aqueous outer phase usually contains surfactants stabilizing the oil-in-water emulsion and preventing agglomeration.
  • the emulsifier used is typically polyvinyl alcohol.
  • the decisive step in the preparation of micro- and nanoparticles is the emulsification that may, in general, be carried out by sonication, high-pressure homogenization or high-shear homogenization. Stirring combined with a subsequent sonication during one hour usually results in nanoparticles of a diameter larger than 1400 nm (Ferdous A. J., Stembridge N. Y., Singh M., Role of monensin PLGA polymer nanoparticles and liposomes as potentiator of ricin A immunotoxins in vitro, J. Control. Rel. 50, 1998: 71-78).
  • the task of the present invention is to overcome the disadvantages of the prior art and to provide a novel process for the production of nanoparticles, which does not have a substantial detrimental effect on the active substances that are to be incorporated.
  • the inventors have found that a combination of different measures, namely stirring and sonication, both at a level at which each single measure as such does not result in a sufficiently intensive emulsification, yields nanoparticles of a small size, wherein the encapsulated active substance exhibits improved biological activity.
  • one aspect the present invention relates to a process for the production of nanoparticles with encapsulated one or more active substances, wherein an emulsification method is used, whereat stirring and sonication are carried out simultaneously, either at an energy level that alone is not sufficient for the formation of nanoparticles and which preserves the biological activity of the encapsulated active substance.
  • stirring and sonication are carried out simultaneously and at moderate conditions.
  • the stirring speed is in the range from 4000 to 15000 rpm, preferably from 5000 to 10000 rpm, and more preferably
  • Sonication is preferably carried out at a frequency from 20 kHz to 70 kHz.
  • Process according to the invention particularly comprises:
  • emulsifying whereat the stirring and the sonication are carried out simultaneously, either at an energy level that alone is not sufficient for the formation of nanoparticles, comprising: a) emulsifying the active substance (preferably a polypeptide or peptide) dissolved in water or in a suitable aqueous solvent therefor (e.g.
  • step I) a primary emulsion with the active substance in the inner aqueous phase
  • step IIa emulsifying the primary emulsion obtained in step Ila) into an aqueous solution of an emulsifier as the continuous phase (preferably with an aqueous polyvinyl alcohol solution) so as to obtain nanoparticles having the active substance encapsulated therein, and
  • step III isolating and drying the nanoparticles in a known manner (drying is preferably carried out by lyophilisation, whereat the active substance is in step Ila) dissolved in a suitable aqueous solvent therefor containing cryoprotectants).
  • a novel conveniently modified technique of emulsification is applied, wherein a high shear homogenization at low rpm and sonication are used simultaneously. Then the obtained primary emulsion is emulsified into the solution of an emulsifier to obtain a double emulsion (W/O/W).
  • the double emulsion is diluted with excessive water to facilitate the removal of the organic solvent and the mixture is stirred to allow the solvent to evaporate, whereby the precipitation of the polymer and thus also the formation of solid nanoparticles with the encapsulated active substance are induced.
  • the particles are isolated by centrifugation or filtration and washed several times with distilled water or suitable aqueous buffers to remove the excessive emulsifier from the surfaces. Then the particles are dried by conventional means, e.g. in vacuum, by streaming nitrogen gas or air, by lyophilisation or spray drying.
  • the organic solvent used in the step of dissolving the biodegradable polymer may be any solvent capable of forming an emulsion with a determined quantity of an aqueous emulsifier solution and which may be removed from the emulsion droplets by the addition of the excessive amount of aqueous emulsifier solution and which is further capable of dissolving biodegradable polymers.
  • the solvent should be immiscible or essentially immiscible with water, but partly soluble in the cited aqueous emulsifier solution.
  • organic solvents examples include chloroform, benzene, dichloromethane, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride, ethyl ether, cyclohexane, n-hexane, toluene, more preferably ethyl acetate, methylene chloride or a mixture of methylene chloride and acetone, most preferably ethyl acetate. It was surprisingly found that the use of ethyl acetate limits the loss of biological activity of proteins such as cystatin, and provides smaller particles as compared to other solvents.
  • this may be due to a greater solubility of ethyl acetate in water, which leads to a faster diffusion of ethyl acetate into the outer aqueous phase, leaving behind insoluble polymer particles with incorporated protein.
  • emulsifier serves for several purposes: it assists in obtaining the correct droplet size distribution of the emulsion, stabilizes the W/O/W emulsion to avoid coalescence of droplets and prevents the precipitated nanoparticles from sticking to each other.
  • anionic surfactants e.g. sodium oleate, sodium stearate, sodium lauryl sulfate etc.
  • nonionic surfactants e.g.
  • polyoxyethylene sorbitan fatty acid esters Teween 80, Tween 60 etc.
  • polyoxyethylene castor oil derivatives polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin etc., more preferably polyvinyl alcohol.
  • emulsifiers may be used either alone or in a combination.
  • polymer materials for encapsulating the active substance various different polymer materials may be used such as lactic acid-glycolic acid polyesters, polylactic acid, poly- ⁇ -hydroxybutyric acid, polyhydroxyvaleric acid, polycaprolactone, polyesteramides, polycyanoacrylates, poly(amino acids), polycarbonates, polyanhydrides, biodegradable polymers, whereat lactid acid-glycolic acid polyester is specifically preferred.
  • the weight ratio of (poly)lactic acid/(poly)glycolic acid is preferably from about 99/1 to 36/65, more preferably 95/5 to 50/50, with the exact composition of the polymer being selected by a person skilled in the art based upon his general knowledge and depending on the desired release kinetics.
  • Lactic acid- glycolic acid copolymer i.e. poly(lactic-co-glycolic acid), PLGA
  • PLGA lactic acid- glycolic acid copolymer
  • the polymer matrix perfectly protects the proteins and peptides against destructive environmental conditions, especially when administered orally.
  • the release kinetics of the encapsulated active substances can be controlled as well by varying the molecular weight and the monomer ratio of PLGA.
  • any medicinal active ingredient may be used, in particular substances having a short half- life in the body such as proteins and or peptides.
  • biologically active macromolecules such as interferons, interleukins, colony stimulating factors, tumour necrosis factors, other immunomodulators, growth factors, transforming growth factors, erythropoietin, albumin, blood proteins, hormones, vaccines, viruses, toxins, antibodies, antibody fragments, enzymes, enzyme inhibitors including cystatin.
  • agents for controlling the stability may be included in addition to the active substance, such as agents for controlling the stability and, if desired, agents for controlling the solubility of the biologically active substance.
  • agents for controlling the stability may be pH controlling agents, preservatives and stabilizers, and cryoprotectants that may include glycols, albumin, gelatin, amino acids, ethylenediamine tetraacetic acid, dimethyl sulfoxide, citric acid, dextrin, saccharose, fructose, mannose, trehalose, other sugars and all combinations thereof.
  • Another object of the present invention are nanoparticles obtained according to the process of the present invention and having a preferable particle size from about 100 to about 800 nm. These nanoparticles surprisingly convey an increased biological activity and stability to the active substances encapsulated therein.
  • the present invention is essentially based on the finding that the rotation of the homogenizer with high speed (15000 rpm or more), which is normally required for the production of nanoparticles, can be substituted by a lower speed if the system is simultaneously subjected to the action of ultrasound with low energy, whereat the biological activity and bioavailability of the encapsulated active substance is improved as compared to nanoparticles produced by common techniques of stirring or sonication alone or of a successive combination thereof.
  • Nanoparticles according to the invention are suitable for the production of a drug for parenteral, nasal, pulmonal, peroral, oral, transdermal or rectal administration of the active substance.
  • Fig. 1 shows the size of nanoparticles obtained by the process according to the invention as compared to prior art nanoparticles
  • Fig. 2 shows cystatin activity under different experimental conditions
  • Fig. 3 shows cystatin activity during storage when it is encapsulated in nanoparticles (3 a) obtained according to the present invention, as compared to the cystatin solution (3b).
  • lactic acid-glycolic acid copolymer i.e. poly(lactic-co-glycolic acid), PLGA
  • nanoparticles without incorporated protein
  • a polymer solution was prepared in a test tube by dissolving 50 mg of PLGA (Resomer RG 503H, Boehringer Ingelheim) in 1 ml of ethyl acetate. Then 200 ⁇ l of water were added to the polymer solution and the mixture was homogeneously emulsified by a rotor-stator homogenizer (Omni Labtek, Omni International, USA) for two minutes. On two different samples two different rotation speeds, 15000 and 12500 rpm, respectively, were applied.
  • PLGA Resomer RG 503H, Boehringer Ingelheim
  • the dispersion was ultracentrifuged at 15000 rpm for 15 minutes using Ultracentrifuge Sorvall RC 5C plus, Rotor SS 34, USA. After separation, the nanoparticles were washed three times with distilled water (20 ml) and collected by centrifugation at conditions mentioned before.
  • Example lb The obtained particles had a size ranging from 600 nm to 700 nm with the minimum particle size in the formulation prepared with the highest rotation speed.
  • Example lb
  • Cystatin a cysteine proteinase inhibitor
  • BANA ⁇ -N-benzoyl-DL-arginine- ⁇ -naphtylamide
  • Example la The influence of different homogenization conditions on cystatin activity was observed on an aqueous cystatin solution.
  • Example la In order to enable the production of nanoparticles also at lower rotation speeds, the same procedure as in Example la was performed with the exception that, simultaneously with homogenization (10000, 7500 and 5000 rpm), ultrasound was used as well.
  • the formed nanoparticles had a particle size of 320, 350 and 360 nm, respectively.
  • Example lb The same procedure as in the Example lb was performed, with exception that, simultaneously with homogenization at 5000 rpm, ultrasound was used. The loss of biological activity of cystatin was only 20 %. This indicates that this process is a good compromise between retaining a high level of protein activity and the formation of nanoparticles with the desired particle size.
  • Nanoparticles were produced by the process according to the present invention.
  • the same process as in Example la was carried out with the exception that instead of 200 ⁇ l of water there were used 200 ⁇ l of a solution of cystatin in water and that instead of homogenization at a high speed there was used homogenization at 5000 rpm with a simultaneous application of ultrasound.
  • Example la The resulting nanoparticles were washed, centrifuged and collected as in Example la and finally they were dispersed in 5 ml of 0.12 M phosphate buffer (PBS) with pH 7.2-7.4 and incubated for 19 days at 37 °C under stirring on a magnetic stirrer (2 rpm).
  • PBS phosphate buffer
  • the nanoparticles with incorporated cystatin were prepared according to the present invention with the exception that cystatin was dissolved in a solution of 2 % albumin, 300 mM trehalose, 300 mM mannose, 300 mM fructose and 100 mM saccharose (cryoprotectant).
  • the particles were centrifuged for 15 min at 7000 rpm using ultracentrifuge Sorvall RC 5C plus, Rotor SS 34, USA. The sediment was resuspended in water by means of ultrasound and dried by lyophilisation.
  • the activity of cystatin in the dispersion of nanoparticles after lyophilisation was 90 % of that before lyophilisation. If the nanoparticles with cystatin were prepared as in lb and lyophilized, the activity of cystatin was only 17 % of that before lyophilisation.
  • Example 3 a In order to compare the stability of the protein released from nanoparticles with an ordinary protein solution, a control sample was prepared and treated under the same conditions as the dispersion of nanoparticles in Example 3 a.
  • control sample was prepared by dissolving an appropriate amount of cystatin in 5 ml of PBS (approximately the same concentration with regard to the protein in the released medium of the previous Example 3 a).
  • Example 3 a The same procedure as in Example 3 a was performed and the stability of incubated protein for different time intervals was obtained.

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  • Bioinformatics & Cheminformatics (AREA)
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Abstract

L'invention concerne un nouveau procédé permettant de produire des nanoparticules, et plus spécifiquement un procédé consistant à préparer des nanoparticules biodégradables à base de copolymères acide lactique-acide glycolique au moyen d'un processus de double émulsion eau dans l'huile dans l'eau (H/L/H) dans des conditions de faible énergie, comprenant l'application simultanée d'une agitation et d'une sonification. Les nanoparticules obtenues contiennent une ou plusieurs substances actives, et permettent de conserver l'activité biologique de la substance active encapsulée.
PCT/SI2003/000017 2002-05-28 2003-05-27 Procede de production de nanoparticules comprenant l'utilisation simultanee d'energie mecanique faible et d'energie sonique WO2003099262A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003228202A AU2003228202A1 (en) 2002-05-28 2003-05-27 Process for the production of nanoparticles, wherein low mechanical and sonic energies are used simultaneously
EP03725975A EP1558224A1 (fr) 2002-05-28 2003-05-27 Procede de production de nanoparticules comprenant l'utilisation simultanee d'energie mecanique faible et d'energie sonique

Applications Claiming Priority (2)

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SI200200136A SI21222A (sl) 2002-05-28 2002-05-28 Postopek za pripravo nanodelcev
SIP-200200136 2002-05-28

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006109317A1 (fr) * 2005-04-11 2006-10-19 Lifecare Innovations Pvt. Ltd. Procédé de synthèse de nanoparticules de poly(dl-lactide-co-glycolide) comportant en leur sein des médicaments antituberculeux encapsulés
CN1306955C (zh) * 2004-09-17 2007-03-28 中国人民解放军第二军医大学 阿魏酸钠白蛋白纳米粒制剂及其制备方法
NO20190306A1 (no) * 2005-08-31 2008-05-13 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
NO20191301A1 (no) * 2005-08-31 2008-05-13 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
WO2009105792A1 (fr) * 2008-02-18 2009-08-27 Csir Vecteurs de nanoparticules pour l’administration de médicaments et procédé pour leur production
WO2010000050A1 (fr) * 2008-06-30 2010-01-07 Instituto Nacional De Tecnologia - Int Compositions pharmaceutiques de nanoparticules contenant des substances actives
US20110207685A1 (en) * 2008-08-06 2011-08-25 David Bonnafous Oral Formulations of Chemotherapeutic Agents
EP4011386A1 (fr) 2017-01-31 2022-06-15 Veru Inc. Compositions et méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (gnrh)
CN115634204A (zh) * 2022-09-07 2023-01-24 依诺科技(香港)有限公司 载s-炔丙基半胱氨酸的微球制剂及其制备方法

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EP0269921A1 (fr) * 1986-11-12 1988-06-08 Sanraku Incorporated Microsphères d'acide polylactique et procédé pour leur fabrication
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WO2001051032A2 (fr) * 2000-01-14 2001-07-19 Brown University Research Foundation Particules lyophilisees microfines

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EP0269921A1 (fr) * 1986-11-12 1988-06-08 Sanraku Incorporated Microsphères d'acide polylactique et procédé pour leur fabrication
WO2000071079A2 (fr) * 1999-05-21 2000-11-30 American Bioscience, Inc. Agents a stabilisation proteinique actifs pharmacologiquement; procedes de fabrication et methodes d'utilisation
WO2001051032A2 (fr) * 2000-01-14 2001-07-19 Brown University Research Foundation Particules lyophilisees microfines

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Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1306955C (zh) * 2004-09-17 2007-03-28 中国人民解放军第二军医大学 阿魏酸钠白蛋白纳米粒制剂及其制备方法
CN101160119B (zh) * 2005-04-11 2013-07-17 莱富凯尔创新私人有限公司 在其中包封有抗结核药物的聚dl-丙交酯-共-乙交酯纳米微粒的制备方法
WO2006109317A1 (fr) * 2005-04-11 2006-10-19 Lifecare Innovations Pvt. Ltd. Procédé de synthèse de nanoparticules de poly(dl-lactide-co-glycolide) comportant en leur sein des médicaments antituberculeux encapsulés
EP3311805A1 (fr) * 2005-08-31 2018-04-25 Abraxis BioScience, LLC Compositions comprenant des agents pharmaceutiques peu solubles dans l'eau et des agents antimicrobiens
US9308180B2 (en) 2005-08-31 2016-04-12 Abraxis Bioscience, Llc Compositions and methods for preparation of poorly water soluble drugs with increased stability
NO345390B1 (no) * 2005-08-31 2021-01-11 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
EP3659589A1 (fr) * 2005-08-31 2020-06-03 Abraxis BioScience, LLC Compositions comprenant des agents pharmaceutiques peu solubles dans l'eau et des agents antimicrobiens
NO344525B1 (no) * 2005-08-31 2020-01-27 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
EP2399573B1 (fr) * 2005-08-31 2019-01-02 Abraxis BioScience, LLC Compositions comprenant des agents pharmaceutiques peu solubles dans l'eau
EP1931321B1 (fr) * 2005-08-31 2018-12-26 Abraxis BioScience, LLC Compositions comprenant des agents pharmaceutiques peu solubles dans l'eau et des agents antimicrobiens
NO20191301A1 (no) * 2005-08-31 2008-05-13 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
NO20190306A1 (no) * 2005-08-31 2008-05-13 Abraxis Bioscience Llc Preparater omfattende dårlig vannløselige farmasøytiske midler og antimikrobielle midler
AU2008351331B2 (en) * 2008-02-18 2014-07-17 Csir Nanoparticle carriers for drug administration and process for producing same
AP2966A (en) * 2008-02-18 2014-09-30 Csir Nanoparticle carriers for drug administration and process for producing same
WO2009105792A1 (fr) * 2008-02-18 2009-08-27 Csir Vecteurs de nanoparticules pour l’administration de médicaments et procédé pour leur production
US8518450B2 (en) 2008-02-18 2013-08-27 Csir Nanoparticle carriers for drug administration and process for producing same
GB2469965B (en) * 2008-02-18 2012-06-20 Csir Nanoparticle carriers for drug administration and process for producing same
GB2469965A (en) * 2008-02-18 2010-11-03 Csir Nanoparticle carriers for drug administration and process for producing same
US20110118364A1 (en) * 2008-06-30 2011-05-19 Lins Dantas Fabio Moyses Pharmaceutical compositions of nanoparticles containing active ingredients
WO2010000050A1 (fr) * 2008-06-30 2010-01-07 Instituto Nacional De Tecnologia - Int Compositions pharmaceutiques de nanoparticules contenant des substances actives
US20110207685A1 (en) * 2008-08-06 2011-08-25 David Bonnafous Oral Formulations of Chemotherapeutic Agents
EP4011386A1 (fr) 2017-01-31 2022-06-15 Veru Inc. Compositions et méthodes pour la libération à long terme d'antagonistes de l'hormone de libération des gonadotropines (gnrh)
CN115634204A (zh) * 2022-09-07 2023-01-24 依诺科技(香港)有限公司 载s-炔丙基半胱氨酸的微球制剂及其制备方法

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EP1558224A1 (fr) 2005-08-03
SI21222A (sl) 2003-12-31

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