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WO1999036071A1 - Matrices polymeres biodegradables servant a effectuer l'administration prolongee d'anesthesiques - Google Patents

Matrices polymeres biodegradables servant a effectuer l'administration prolongee d'anesthesiques Download PDF

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Publication number
WO1999036071A1
WO1999036071A1 PCT/KR1999/000033 KR9900033W WO9936071A1 WO 1999036071 A1 WO1999036071 A1 WO 1999036071A1 KR 9900033 W KR9900033 W KR 9900033W WO 9936071 A1 WO9936071 A1 WO 9936071A1
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WO
WIPO (PCT)
Prior art keywords
biodegradable polymer
anesthetics
micro
sustained delivery
anesthetic
Prior art date
Application number
PCT/KR1999/000033
Other languages
English (en)
Inventor
Hai Bang Lee
Gil Son Khang
Jin Chul Cho
John Moon Rhee
Original Assignee
Korea Research Institute Of Chemical Technology
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.)
Filing date
Publication date
Application filed by Korea Research Institute Of Chemical Technology filed Critical Korea Research Institute Of Chemical Technology
Priority to EP99900697A priority Critical patent/EP1049469A1/fr
Priority to JP2000539844A priority patent/JP2002509107A/ja
Publication of WO1999036071A1 publication Critical patent/WO1999036071A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics

Definitions

  • the invention herein relates to biodegradable polymer matrices for sustained delivery of anesthetics or more particularly, to the sustained release of an anesthetic preparation in such a manner that anesthetics, widely applicable as pain-killers for the management of various forms of chronic pain, such as pre- and post-operative pain, or the pain associated with many types of cancer, are incorporated into the biodegradable polymer which in turn is formulated into a micro-particles type.
  • anesthetics widely applicable as pain-killers for the management of various forms of chronic pain, such as pre- and post-operative pain, or the pain associated with many types of cancer
  • the biodegradable polymer matrices of the invention herein is capable of 1) providing a localized method in which anesthetic may be administered to the affected or pain sites only, 2) eliminating the toxicity associated with over-dosage, and 3) avoiding various side reactions.
  • a local anesthetics is clinically used which is administered through an injection needle or syringe to a wounded or affected site over a period of a certain time. This required repeated administration where the pain is to be blocked over a period of greater than one day, either as a bolus or through an indwelling catheter connected to an infusion pump.
  • an anesthetic administered by these methods has encountered the following shortcomings, i.e., a) all the targeted and surrounding areas should be anesthetized for the purposes of anesthesia at the affected and pain sites, and b) anesthetic delivered in the form of pulse instead of zero-order kinetics may aggravate adverse reactions due to over-dosage. In all cases, therefore, analgesia rarely lasts for longer than six to twelve hours, more typically six hours. Also, in the case of a pump, the pump tubes and infusion lines are difficult to position and secure, the patient has limited, encumbered mobility and, when the patient is a small child or physically impaired, the applicable scope of the pump is extremely limited.
  • Anesthetics are administered in a variety of ways, including by injections, topical administration, oral administration, and sustained release devices. Injection administration has been widely used for systemic anesthesia. Further, the sustained release devices system can potentially provide for a sustained, controlled, constant localized release for a longer period of time than that which can be achieved by injection or topical administration.
  • sustained release preparations have been intensively studied in the middle of 1980. These preparations typically consist of a polymeric matrix liposome from which drug is released by diffusion and/ or degradation of the polymer matrix. Hence, the release pattern of drug is principally determined by the polymer matrix, as well as by the percent loading, method of manufacture, micro-droplets, and film.
  • a major advantage of sustained release preparations using a biodegradable polymer is that they do not require the surgical removal of the drug depleted device. In fact, such preparations are slowly degraded and absorbed by the patient's body, and ultimately disposed of along with other soluble metabolic waste products.
  • sustained release anesthetics such as benzocaine and procaine have been incorporated into polymeric prodrug, as described by M. Kolli et al., Int. J. Pharm., 81, 103-110(1992), but the use of such anesthetics have not been recommended due to poor potency as compared to the target level.
  • morphine preparations for oral administration were commercialized in MST ContinusTM. These preparations contain a hydrophilic granule system within hydrophobic matrix [J. Alvarez-Fueutes et al., Int. J. Pharm., 139, 237-241(1996)].
  • micro-droplets were made available by incorporating morphine into the biodegradable polymer for the sustained release property of drug, but such sustained release preparations were capable of providing the sustained release effects for only a short period of time (about 48 hours), as described by E. Polard et al., Int. J. Pharm., 134, 37- 46, (1996).
  • anesthetics e.g., methoxyflurane, bupivacaine, dibucaine, benzocaine, procaine, morphine, etidocaine, tetracaine, lidocaine, xylocaine, xylazine, and ketamine
  • anesthesia is insufficient
  • b) some adverse reactions such as hypertension, hypotension, nausea, vomiting, pruritus, erythema and headache may occur.
  • the inventor et al. have conducted intensive studies for the application of the method of the sustained release drug using the biodegradable polymer to the sustained release Japanese encephalitis vaccine (Korean Patent Application No. 96-29789, July 23, 1996), and sustained release AZT preparation (Korean Patent Application No. 97- 31100, July 4, 1997).
  • a sustained release preparation was devised by specifying the nature and contents of the particular biodegradable polymer which is more suitable to the fentanyl-based anesthetic.
  • an object of this invention is to provide biodegradable polymer matrices for sustained delivery of anesthetics during anesthetics administration in such a manner that adverse reactions associated with over or under-dosage may be prevented and a complete zero-order release may be obtained without any initial bulk erosion induced by the conventional manufacturing methods.
  • Fig. 1 is a graph showing the sustained release in accordance with the initial drug loading of fentanyl citrate biodegradable polymer micro-droplets
  • Fig. 2 is a graph showing the sustained release in accordance with the initial drug loading of fentanyl citrate biodegradable polymer pellets.
  • Fig. 3 is a graph showing the sustained release in accordance with the initial drug loading of lofentanyl biodegradable polymer film.
  • This invention is characterized by a sustained release anaesthetic preparation where fentanyl-based anesthetic is incorporated into a biodegradable polymer.
  • This invention is explained in more detail as set forth hereunder.
  • This invention is characterized by a novel sustained release anaesthetic preparation with the following advantages, i.e., a) fentanyl-based anesthetic drug is evenly incorporated into the biodegradable polymer, b) it is possible to tailor a system consisting of certain-size micro-particles to deliver the amount of anesthetic according to the severity of affected site without initial bulk erosion, and c) it does not require the surgical removal of the depleted drug since it is slowly degraded in the patient's body.
  • one or more fentanyl-based anesthetic may be selected from the group consisting of fentanyl, benzylfentanyl, alpha-methylfentanyl, p -fluorofentanyl, 3-methylfentanyl, acetyl-alpha-methylfentanyl, alpha-methylacrylfentanyl, alpha-methylthiofentanyl, beta-hydroxyfentanyl, beta-hydroxy-3- methylfentanyl, 3-methylthiofentanyl, thiofentanyl, thenylfentanyl, sufentanil, carfentanil, llofentanil and alfentanil, or the salts, bromides, acetates, citrates and sulfates thereof.
  • the above anesthetics posed difficulty as to the sustained release preparations for long-term therapeutic action due to problems in incorporating anesthetic into the biodegradable polymer.
  • the invention herein has succeeded in overcoming the aforementioned problems by introducing a novel biodegradable polymer as described hereunder.
  • the present invention is characterized in that a specific biodegradable polymer is selected as a novel clathrate for anesthetics as above, and the particle size and molecular weight of micro-droplets thereof are limited so as to attain the zero-order profile for a prolonged period of time. Further, the biodegradable polymer selected from this invention is harmless in the body and can be degraded in the desired period of time.
  • the biodegradable polymer used as an anesthetic clathrate of said invention includes albumin, collagen, gelatin, fibrinogen, casein, fibrin, hemoglobin, transferrin, chitin, chitosan, hyaluronic acid, heparin, chondroitin, keratinsulfate, alginic acid, starch, dextrin, dextran, polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, polyhyroxybutylic acid, polycaprolactone, polyanhydrides and polyalkylcyanoacrylate.
  • the molecular weight of the biodegradable polymer be 5,000 ⁇ 1,000,000 g/mole. If the molecular weight is less than 5,000, the expected effect of sustained release preparation cannot be obtained due to the extremely short biodegradation period. However, in case of exceeding 1,000,000 in the molecular weight, the biodegradation period will be excessively extended.
  • sustained release anesthetic preparations can be used in the form of slabs, ' beads, pellets, fine powders, micro-droplets, micro-capsules, films, and pastes.
  • the sustained release anesthetic preparation of the present invention may be manufactured in the form of micro-particles based on the biodegradable polymer by a commonly available method, and this 5 manufacturing method is explained in more detail as set forth hereunder.
  • the method of preparing the sustained release anesthetic preparation includes an inter-emulsifying solvent evaporation method (inter-emulsifying solvent evaporation of O/W, W/O, O/O and W/O/W), phase separation method based on the non-solvent addition or solvent separation method, interfacial
  • the inter-emulsifying solvent evaporation method is explained in i 5 more detail as set forth hereunder.
  • the biodegradable polymer is dissolved in an organic solvent to yield a 0.5-30 W/V% solution.
  • one or more solvents may be selected from the group consisting of methylene chloride, acetonitrile, chloroform, dioxane, formamide and 0 acetylamide.
  • anesthetic is added in the amount of 0.01-70% by weight. Thereafter, the mixture is prepared in the form of solution or in the dispersed state by a sonication mixer or homogenizer. If the content of anesthetic is less than 0.01 % by weight, the 5 manifestation of drug will not be made available due to extremely low concentration of anesthetic. However, if the content of anesthetic exceeds 30% by weight, the excessive initial release of drug may produce some adverse reactions, let alone higher production costs.
  • the solution is added to other oil phase where an emulsifier is dissolved in the concentration of 0.01-10 W/V%.
  • the resulting solution is stirred at 10-50 ° C at 300-20,000 rpm for 1-24 hours.
  • One or more emulsifier may be selected from the group consisting of polyvinyl alcohol, sodium dodecyl sulfate and polyethylene oxide, including currently marketed materials such as SpanTM, TweenTM, BrijTM, and PluronicTM. Further, since the stirring rate and time is the most important parameters in modulating the size of micro-particles, the above parameters should be accordingly adjusted if deemed necessary.
  • the micro-particles containing anesthetic within the solution is recovered by an ultracentrifuge and filter. Thereafter, the micro- particles are dried at room temperature and lyophilized to obtain the final micro-particles.
  • the reason for having the size of final micro-particles by 0.1 / m ⁇ 20mm in diameter is as follows: If the size of micro-particles is less than 0.1 /tni, the sustained release profile of drug (e.g., initial burst effect, etc.) cannot be properly controlled, but in case of 20mm or more, there are some drawbacks in human administration.
  • the sustained release profile of drug e.g., initial burst effect, etc.
  • the adjustment of size in the micro-particles may be available by the following parameters: stirring rate in mixing an emulsifying solution derived from the anesthetic and biodegradable polymer, and other oil phase where an emulsifier is dispersed; molecular weight of the biodegradable polymer used; and concentration of the biodegradable polymer on solvent.
  • sustained release anesthetic preparation of the present inventions may be manufactured in the form of pellets based on the biodegradable polymer and some commonly available method, and the manufacturing method thereof is explained in more detail as set forth hereunder.
  • anesthetic is added in an amount of 0.01-70% by weight and then, the mixture is homogeneously blended by a commonly used mixer.
  • the resulting solution is melted for injection at 150-250 ° C via a mould having lmm in diameter using a polymer-processing kneeder or an injector equipped with screw.
  • the injected material is cooled in air and cut by lmm in length to obtain the sustained release local anesthetic in the final form of pellets.
  • it is preferred to set the size of final pellets by 50 /m-10mm in diameter and 50 /ffli-lOmm in length since the pellets are prepared in the same manner as the micro-particles.
  • sustained release anesthetic preparation of the present invention may be manufactured in the form of film based on the biodegradable polymer by a commonly available method, and the manufacturing method thereof is explained in more detail as set forth hereunder.
  • the biodegradable polymer is dissolved in an organic solvent to yield a 0.5-30 W/V% solution.
  • one or more solvents may be selected from the group consisting of methylene chloride, acetonitrile, chloroform, dioxane, formamide and acetylamide.
  • anesthetic is added in the amount of 90-0.01 % by weight. Thereafter, the mixture may be prepared in the form of solution or in the dispersed state by a sonication mixer or homogenizer.
  • the solution is placed into a film machine equipped with Doctor's knife, impregnated in a non-solvent and dried off.
  • the sustained release local anesthetic may be produced in the form of films.
  • sustained release anesthetic preparation of the present invention may be manufactured in the form of pastes based on the biodegradable polymer by a commonly available method, and the manufacturing method thereof is explained in more detail as set forth hereunder.
  • the biodegradable polymer is dissolved in an organic solvent to yield a 0.5-80 W/ V% pastes.
  • organic solvents used for the preparation of micro-droplets and film may be also employed.
  • the anesthetic is added to the biodegradable polymer in the amount of 0.01-70% by weight.
  • a sonication mixer or homogenizer is used in order to homogeneously disperse the drug in the pastes.
  • the pastes may be directly injected to the affected site via syringe.
  • the sustained release local preparations in the form of pastes may be prepared by a generally applicable procedure known to those skilled in the art.
  • a biodegradable period and sustained release pattern of anesthetic may be controlled by the following parameters: molecular weight of the biodegradable polymer used, concentration of the biodegradable polymer on solvent, and concentration of emulsifier when an emulsifying solution derived from the anesthetic and biodegradable polymer is prepared.
  • micro-droplets, fine powder, and micro-capsule may be subcutaneously injected by a proper gauge at the target site of pain relief.
  • the films, slabs and beads may be surgically implanted at the site.
  • the pellets may be injected through a trochar, and the pastes may be administered subcutaneously.
  • PLGA75 0.4g of PLGA75, so produced, was evenly dissolved in 8ml of methylene chloride. Then, 0.05g (initial drug-loading content: 5%, 10%, 20%, and 50%, respectively) of fentanyl citrate(FC) was added to said mixture via an ultrasonicator (40W) for 30 seconds to yield a solution. The solution was rapidly poured into a mineral oil phase where approximately 0.05 W/V% of Span 80 was dissolved and centrifuged at 250 rpm. In order to remove methylene chloride contained in the solution, the resulting solution was stirred at 25 ° C at 250 rpm for 3 hours.
  • FC/PLGA75 micro-particles contained in the solution. These micro-particles, so collected, was washed with hexane, dried and measured by a Coulteur counter.
  • the FC/PLGA75 micro-particles were 45 ⁇ 7 ⁇ m in size.
  • BF/PHB micro-particles were measured by the l-> same Coulteur counter as described in the Example 1.
  • the BF/PHB micro- particles were 270 ⁇ 35 ⁇ m in size.
  • Example 3 1.2g of polycaprolactone (PCL) having the molecular weight of 27,000 was dissolved in 8ml of dioxane. Then, 0.3g of sufentanil (SF) was added to the mixture to produce a solution via an ultrasonicator (40W) to produce a solution.
  • PCL polycaprolactone
  • SF sufentanil
  • the final micro- particles was obtained with the SF/PCL micro-particles of 73 ⁇ 20 ⁇ m.
  • the final micro- particles were so obtained.
  • the TF/PL micro-particles were 47 ⁇ 13 ⁇ m in size.
  • Example 5 Monomers of lactic acid and glycolic acid were mixed in the weight ratio of 50:50. Then, the mixture was under thermal polymerization at 165 ° C at 150 rpm for 24 hours to produce a copolymer.
  • the molecular weight of the copolymer (hereinafter referred to as "PLGA50"), so prepared, was 12,000 on gel permeation chromatography. 0.5g of PLGA50 was evenly dissolved in 6ml of dioxane. Then, 0.1 g of beta-hydroxy fentanyl (HF) was added to the mixture. The micro-particles containing the HF was obtained under the same procedure as described in the Example 1. The HF/PLGA50 micro-particles were 87 ⁇ 16 ⁇ m in size.
  • Example 6 Example 6
  • O.lmg of fentanyl was added to 10ml of aqueous solution containing respective concentration of 0.5% glucose, 70% dextran and 0.05% citric acid.
  • the mixture was placed in an oven at 75 ° C for 24 hours in order to evaporate methylene chloride, whereby a AF-contained mass of PLGA 50 was obtained.
  • Such mass was grounded into powder by a mill, and the powder of less than 50 ⁇ m was obtained using a molecular sieve of 50 ⁇ m.
  • Example 10 0.8g of poly anhydrides having the molecular weight of 25,000g/mole was dissolved in 80ml of dioxane. A mixture of 0.02g of lofentanyl(LF) (initial drug-loading content of 5%, 10%, 20% and 50%) and O.OOlg of Span 80 was added to the solution, thus producing the desired solution by using an ultrasonicator (40W) for 30 seconds. Then, the films having the final thickness of 0.7mm were prepared by a cutter equipped with Doctor's knife. The LF drug release of these biodegradable films was measured in PBS solution at 37 ° C, as shown in Fig. 3.
  • LF lofentanyl
  • the sustained release anesthetic preparation according to the examples of the present invention displayed a nearly zero- order release from one day to approximately 2 months, which is an ideal drug of choice for the management of various forms of chronic pain, such as pre- and post-operative pain, or the pain associated with many types of cancer.
  • the sustained release anesthetics have the following advantages as compared to the prior arts: a) by selecting a biodegradable polymer suitable to anesthetic, the toxicity associated with over-dosage and various adverse reactions, e.g., nausea, vomiting, headache, hypertension, hypotension, pruritus, and erythema, may be avoided; b) in accordance with the degree of anesthesia of a patient at the localized site, both anesthetic and biodegradable polymer preparations can be tailored beforehand and then, depending on the patient's drug requirement for the amount of drug may be released via the desired local form or in the desired administration period of time; c) compared to the conventional sustained release preparations, the sustained release preparations of the invention herein may enhance the initial drug-loading content, thus gaining more prolonged anesthetic effects; and, d) by means of a biodegradable polymer used for drug delivery which may be degraded and absorbed in the body, the fentanyl-based
  • sustained release anesthetic preparations according to the invention herein may be applicable to other drugs, thus paving the way to be a wide utilization in the related industry.

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  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Engineering & Computer Science (AREA)
  • Anesthesiology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

L'invention concerne des matrices polymères biodégradables servant à effectuer l'administration prolongée d'anesthésiques et, plus particulièrement, une préparation anesthésique à libération prolongée dans laquelle un anesthésique à base de fentanyl est incorporé dans un polymère biodégradable.
PCT/KR1999/000033 1998-01-19 1999-01-19 Matrices polymeres biodegradables servant a effectuer l'administration prolongee d'anesthesiques WO1999036071A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP99900697A EP1049469A1 (fr) 1998-01-19 1999-01-19 Matrices polymeres biodegradables servant a effectuer l'administration prolongee d'anesthesiques
JP2000539844A JP2002509107A (ja) 1998-01-19 1999-01-19 麻酔剤の徐放性製剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1998/1442 1998-01-19
KR1019980001442A KR100289471B1 (ko) 1998-01-19 1998-01-19 휀타닐계마취제의이식형서방성제제

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WO1999036071A1 true WO1999036071A1 (fr) 1999-07-22

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EP (1) EP1049469A1 (fr)
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EP1341522B1 (fr) * 2000-12-13 2005-11-16 Merckle Gmbh Microparticules presentant un meilleur profil de liberation et procede de fabrication
WO2006120382A1 (fr) * 2005-05-06 2006-11-16 Cranfield University Recepteur synthetique
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US7910132B2 (en) * 1998-09-24 2011-03-22 Orexo Ab Pharmaceutical composition for the treatment of acute disorders
EP2394663A1 (fr) * 2010-05-31 2011-12-14 Laboratorios Farmaceuticos Rovi, S.A. Compositions pour implants biodégradables in situ injectables
US8096972B2 (en) 2000-08-30 2012-01-17 Johns Hopkins University Devices for intraocular drug delivery
US8343545B2 (en) 2004-01-21 2013-01-01 University College London Method of producing microparticles
US9308355B2 (en) 2012-06-01 2016-04-12 Surmodies, Inc. Apparatus and methods for coating medical devices
US9827401B2 (en) 2012-06-01 2017-11-28 Surmodics, Inc. Apparatus and methods for coating medical devices
US10285936B2 (en) 2010-05-31 2019-05-14 Laboratorios Farmacéuticos Rovi, S.A. Injectable composition with aromatase inhibitor
US10335366B2 (en) 2010-05-31 2019-07-02 Laboratorios Farmacéuticos Rovi, S.A. Risperidone or paliperidone implant formulation
US10350159B2 (en) 2010-05-31 2019-07-16 Laboratories Farmacéuticos Rovi, S.A. Paliperidone implant formulation
US10449152B2 (en) 2014-09-26 2019-10-22 Covidien Lp Drug loaded microspheres for post-operative chronic pain
US10463607B2 (en) 2010-05-31 2019-11-05 Laboratorios Farmaceutics Rofi S.A. Antipsychotic Injectable Depot Composition
WO2020092698A1 (fr) * 2018-11-01 2020-05-07 New Jersey Institute Of Technology Formulations injectables d'agents anesthésiques contre toute douleur pathologique
US10722586B2 (en) 2014-11-10 2020-07-28 Universidade Federal De Pelotas Filmogenic compositions for topical anaesthetic bioadhesives—tabs, for controlled release of active principles and topical anaesthetic bioadhesives
US10881605B2 (en) 2010-05-31 2021-01-05 Laboratorios Farmaceuticos Rovi, S.A. Methods for the preparation of injectable depot compositions
US11202754B2 (en) 2017-10-06 2021-12-21 Foundry Therapeutics, Inc. Implantable depots for the controlled release of therapeutic agents
US11628466B2 (en) 2018-11-29 2023-04-18 Surmodics, Inc. Apparatus and methods for coating medical devices
US11819590B2 (en) 2019-05-13 2023-11-21 Surmodics, Inc. Apparatus and methods for coating medical devices
US11964076B2 (en) 2015-03-31 2024-04-23 Foundry Therapeutics, Inc. Multi-layered polymer film for sustained release of agents
US12226485B2 (en) 2018-06-12 2025-02-18 Laboratorios Farmacéuticos Rovi, S.A. Injectable composition
US12290616B2 (en) 2015-03-31 2025-05-06 Foundry Therapeutics, Inc. Multi-layered polymer film for sustained release of agents

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KR100289471B1 (ko) 2001-09-17
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JP2002509107A (ja) 2002-03-26

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