EP1324758A1 - Procede de preparation de microspheres contenant une substance soluble dans l'eau - Google Patents
Procede de preparation de microspheres contenant une substance soluble dans l'eauInfo
- Publication number
- EP1324758A1 EP1324758A1 EP01971588A EP01971588A EP1324758A1 EP 1324758 A1 EP1324758 A1 EP 1324758A1 EP 01971588 A EP01971588 A EP 01971588A EP 01971588 A EP01971588 A EP 01971588A EP 1324758 A1 EP1324758 A1 EP 1324758A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- microspheres
- oxaliplatin
- ethyl acetate
- organic phase
- plga
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
Classifications
-
- 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
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- 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
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- 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
- 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
- A61K9/1682—Processes
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Definitions
- the present invention relates to a new process for the preparation by solvent extraction of polymer microspheres of poly (D, L-lactide-co-glycolide) / poly (D, L-lactide) (PLGA / PLA) type encapsulating a soluble therapeutic substance. in water and not soluble in ethyl acetate, as well as the microspheres capable of being obtained by this process.
- microencapsulation of therapeutic substances in microspheres of biodegradable polymer PLGA / PLA is of great interest for the preparation of delayed release formulations.
- Such formulations increase the effectiveness of treatment with cytostatic anticancer agents because they allow, by intraperitoneal (i.p.), intratumoral (i.t.) or intrapleural injection, to increase the local concentration while reducing the systemic toxicity.
- the microspheres must have an average size of 20-100 ⁇ m, preferably 30 to 70 ⁇ m.
- US Patent No. 5,238,714 describes the preparation of microspheres of PLGA polymer encapsulating cisplatin by a process by solvent evaporation. This consists in dispersing particles of cisplatin in methylene chloride, adding to this solution PLGA, in forming an emulsion by mixing, with vigorous stirring, the organic phase to a volume approximately 6 times greater than an aqueous solution of polyvinyl alcohol comprising 0.9 % of NaCl whose pH has been added to less than 4 by addition of HCI, then to evaporate
- microspheres of PLGA encapsulating cisplatin obtained have, according to the operating conditions, a diameter of approximately 100 ⁇ m or 1-5 ⁇ m.
- the process disclosed in the above patent is not suitable for water-soluble therapeutic substances such as oxaliplatin because these substances pass at least partly into the aqueous phase during the evaporation of the organic phase and are not therefore little or not at all encapsulated in the microspheres.
- the microspheres therefore have a low degree of encapsulation which is not acceptable for a delay formulation.
- This, intended to be injected, must indeed release a given quantity of therapeutic substance without having too high a volume.
- this process uses saline and HCl, substances that react with oxaliplatin.
- the problem of the invention is therefore to find a method for preparing microspheres of medium-sized PLGA 20-100 ⁇ m encapsulating a water-soluble therapeutic substance, in particular oxaliplatin, with an acceptable encapsulation rate , for example at least 10%, and continuous release for a period of therapeutic interest.
- the process of the invention makes it possible to obtain PLGA / PLA microspheres of 20 to 100 ⁇ m with an encapsulation rate of water-soluble therapeutic substance of 10 to 45%, an encapsulation yield of at least 80% and a manufacturing yield of at least 80%, with a continuous release of this substance for 5 to 60 days. This corresponds to a release period of therapeutic interest for a cytostatics such as oxaliplatin.
- the invention relates to a process for the preparation by solvent extraction of microspheres of poly (D, L-lactide-co-glycolide) / poly (D, L-) type. lactide) (PLGA / PLA) encapsulating a water-soluble and non-soluble in ethyl acetate therapeutic substance, comprising the following steps:
- Step (a) can be carried out either by adding, with stirring, the polymer to a suspension of particles of the therapeutic substance in ethyl acetate, or by adding, with stirring, particles of the therapeutic substance to a solution of the polymer in ethyl acetate.
- the particle size of the therapeutic substance should be much less than the desired size of the microspheres.
- a size of the particles of therapeutic substance less than 1 ⁇ m is well suited.
- the particles of the therapeutic substance of the desired size can for example be obtained by grinding this substance in a centrifugal ball mill, in the presence or absence of the organic phase.
- the therapeutic substance must be soluble in water and not soluble in ethyl acetate.
- water solubility is meant a solubility at room temperature (25 ° C) of at least 3 g / l, preferably at least 5 g / l, and by insolubility in ethyl acetate a solubility at room temperature of less than 10 mg / l, preferably 1 mg / l.
- Therapeutic substances of interest for delayed deliveries are cytostatic anticancer agents.
- An example of such a substance is, for example, oxaliplatin.
- the organic phase prepared during step (a) must be cooled to increase the viscosity of this phase, preferably at a temperature low enough to avoid sedimentation of the therapeutic substance, generating a reduction in the encapsulation yield. (defined as the ratio between the actual encapsulation rate and the theoretical encapsulation rate if all the therapeutic substance used was found in the microspheres).
- this temperature is 6 to -20 ° C, in particular 3 to 0 ° C.
- the temperature of the cold aqueous surfactant solution which regulates the viscosity of the dispersing phase and therefore the size of the microparticles, must be low enough to obtain the desired size range of 20 to 100 ⁇ m and limit the solubilization of the therapeutic substance in this phase.
- this temperature is from 14 to 2 ° C, in particular 6 to 8 ° C.
- step (b) the emulsion in formation is generally maintained at a temperature below 8 ° C, preferably below 5 ° C, by adequate cooling.
- step (c) the emulsion being extracted is kept at low temperature, that is to say at a temperature at least 20 ° C lower than the temperature of the hot water added.
- This low temperature is preferably less than 8 ° C, in particular less than 5 ° C.
- the temperature of the hot water added during step (c) must be high enough to avoid too rapid extraction of the ethyl acetate by the water.
- the solubility of ethyl acetate in water decreases with increasing temperature. This temperature must be lower than the glass transition temperature of the polymer used. Preferably this temperature is from 26 to 40 ° C, in particular 28 to 35 ° C.
- the ratio of the volume of ethyl acetate used for the preparation of the organic phase to the volume of cold aqueous surfactant solution must be sufficiently low so that the proportion of ethyl acetate which leaks to water does not cause microsphere formation by precipitation of the polymer.
- This ratio is preferably 0.10-0.20, in particular 0.12-0.18.
- the volume of ethyl acetate used for the preparation of the organic phase is preferably 8-16 ml, in particular 10-14 ml per g of polymer.
- the volume of water added during step (c) is at least about 10 times that of ethyl acetate, preferably at least 20 times this volume.
- step (c) To control the speed of formation of microspheres, reduce manufacturing waste and therefore increase manufacturing yield (defined as the ratio of the mass of lyophilized microspheres to the sum of the mass of the polymer and that of the therapeutic substance). better to add hot water gradually.
- the volume of water added during step (c) can be divided into n successive additions of 1 / n of this volume, n being between 2 and 10, for periods of 30 s to 5 minutes.
- the surfactant is preferably a nonionic surfactant such as for example a polyvinyl alcohol (PVA).
- PVA polyvinyl alcohol
- the poly (D, L-lactide-co-glycolide) / poly (D, L-lactide) (PLGA / PLA) type polymer denotes here either a copolymer of D, L-lactic and glycolic acids (PLGA), or a mixture of one or more copolymers of D, L-lactic and glycolic acids and / or one or more polymers of D, L-lactic acid (PLA), this mixture generally consisting of 80 to 100% PLGA and 0 to 20% PLA.
- composition of PLGA and in particular the respective percentages of lactic acid units and glycolic acid units, are chosen according to the desired in vivo degradation kinetics of this polymer, which influences the release of the therapeutic substance.
- a PLGA comprising 25 units of D-Iactic acid and 25 units of L-lactic acid per 50 units of glycolic acid (PLGA 25/50) is preferred.
- the molecular weight of PLGA should not be too high so as to allow its solubilization in ethyl acetate.
- this molecular weight is less than 50,000, in particular between 10,000 and 40,000.
- the PLA preferably has a molecular weight of 1000 to 5000, in particular from 1500 to 3000.
- the invention also relates to the new PLGA / PLA microspheres encapsulating a therapeutic substance, in particular oxaliplatin, which can be obtained by the process described above.
- microspheres preferably have an encapsulation rate of the therapeutic substance of at least 10%, in particular from 15 to 40%, and advantageously an average size of 20-100 ⁇ m, in particular of 30-70 ⁇ m.
- microspheres have the advantage of releasing 100% of the therapeutic substance continuously for 5 to 60 days with a 24-hour burst of 15 to 45%. This corresponds to a release period of therapeutic interest for a cytostatics such as oxaliplatin.
- the release profile of the therapeutic substance can easily be adjusted by the choice of the encapsulation rate, the size of the particles. and PLGA / PLA polymer.
- a convenient way of influencing the release profile by the choice of the polymer is from a polymer of given composition and mass of which the release profile is known, for example PLGA 25/50 with molecular mass 40,000, is to add to it a variable proportion of another polymer of the same composition and of lower molecular mass, for example PLGA 25/50 of molecular mass 20,000 or 10,000, or of an oligomer of PLA, for example of molecular mass 2000 or 3000.
- microspheres can be sterilized according to conventional methods in the art, for example by gamma irradiation.
- microspheres of the invention encapsulating oxaliplatin have an interesting antitumor activity.
- microspheres of the invention encapsulating an anticancer agent such as oxaliplatin can be administered in a pharmaceutically acceptable vehicle in an i.p., i.t. or intrapleural and thus release the active substance locally close to or in the tumor while decreasing the diffusion of the drug in the systemic circulation.
- the benefit is better drug efficacy and better patient comfort (one injection, fewer side effects).
- the invention therefore also relates to the microspheres defined above for use for use as a medicament, as well as a pharmaceutical formulation for ip, it or intrapleural administration comprising these microspheres in a pharmaceutically acceptable vehicle
- a pharmaceutically acceptable vehicle The description below will be better understood with reference to FIGS. 1A, 1B, 1C, 2 and 3.
- FIGS. 1A, 1 B and 1 C represent photographs by scanning electron microscopy of the microspheres obtained in Example 1 with gold lamination (Fig. 1A), in Example 2 with carbon lamination in normal mode (Fig. 1B) and by backscattering (Fig. 1C),
- Figures 2A and 2B show the oxaliplatin release curves for the microspheres obtained in Examples (1, 2 and 5) and (3 and 4) respectively.
- microspheres were prepared with different copolymers of lactic and glycolic acids D, L: PLGA 25/50 RG 503 with molecular weight 40,000 and PLGA 25/50 RG 502 with molecular weight 10,000 (Bl Chimie, Saint Germain en Laye , France), PLGA 37.5 / 25 with a molecular mass of 22,000 (Phusis, Saint Ismier, France), and an oligomer of lactic acid D, L lactic acid with a molecular mass of 2000, PLA50 (Phusis, Saint Ismier, France )
- the surfactant is a polyvinyl alcohol (PVA), Rhodoviol ® 4/125 88% hydrolyzed (Prolabo, Paris, France), used at 7.5% in water.
- PVA polyvinyl alcohol
- Rhodoviol ® 4/125 88% hydrolyzed Prolabo, Paris, France
- Filtration is carried out on 0.8 ⁇ m filters.
- the oxaliplatinum is ground using a centrifugal ball mill so as to obtain a powder of crystals of this medium-sized substance by volume 1.31 ⁇ m.
- the distribution is bimodal with 80% of the population centered on 0.3 ⁇ m and 20% of this on 9.8 ⁇ m.
- the powder obtained is dispersed and ground in ethyl acetate using an Ultra-Turax disperser-homogenizer (Prolabo, Paris, France), at 11,000 rpm for Examples 1 to 4, and 8000 rpm for Example 5. This grinding allows obtaining a suspension of particles of homogeneous size less than 1 ⁇ m.
- the particle size of the oxaliplatin crystals and the microspheres is analyzed using a laser granulometer (Mastersizer®, Malvern Instruments).
- the microscopic observation of the microspheres is carried out on an optical microscope and a scanning electron microscope, covering them either with gold film or with carbon film, making it possible to visualize platinum by X-ray analysis and by backscatter.
- Example 1 Preparation of microspheres of PLGA 25/50 with a molecular mass of 40,000 with an oxaliplatin encapsulation rate of 14%.
- F3B 102.4 mg of oxaliplatin powder are dispersed in 6 ml of ethyl acetate at 1 ° C for 3 minutes with cooling in a cryostat at 0 ° C.
- 495.5 mg of polymer RG 503 are added and dissolved with magnetic stirring at room temperature for 10 min, then in a cryostat at 0 ° C for 10 min.
- the temperature of the organic phase is 1 ° C.
- Ethyl acetate is extracted by adding for 18 min to the emulsion in a cryostat at 0 ° C increasing volumes of water at 32 ° C, 2 ml for 30 s, 4 ml for 1 min, 8 ml for 1 min 30 s, 16 ml for 5 min.
- the emulsion is then poured into a volume of water of 440 ml at 17.5 ° C, stirred (1000 rpm) for 5 min without cooling, then for 5 min while cooling using a cryostat at 0 ° C.
- microspheres are decanted for a few minutes, then filtered and rinsed with water so as to remove the residual PVA. They are then returned suspended in 1 ml of water, frozen in liquid nitrogen and finally lyophilized.
- Fig. 1A Microscopic observation (see Fig. 1A) shows microspheres loaded with relatively spheroidal oxaliplatin, dense, of variable size and surface appearance, the latter being linked to the load of oxaliplatin.
- Particle size analysis average size 41, 67 ⁇ m, median size 36.57 ⁇ m, standard deviation 30.51 ⁇ m, sizes distributed at 60% between 13.9 and 66.64 ⁇ m. 85% manufacturing efficiency. Encapsulation yield of 81%. Encapsulation rate of 14%.
- oxaliplatin powder 307.9 mg are dispersed in 6 ml of ethyl acetate at 1 ° C for 3 minutes with cooling in a cryostat at 0 ° C.
- 498.5 mg of polymer RG 503 are added and dissolved with magnetic stirring at room temperature for 10 min, then in a cryostat at 0 ° C for 10 min.
- the temperature of the organic phase is 0.3 ° C,
- the emulsion is formed, the ethyl acetate is extracted, filtered, washed and lyophilized the microspheres as described in Example 1.
- Particle size analysis average size 48.49 ⁇ m, median size 38.80 ⁇ m, standard deviation 40.66 ⁇ m, sizes distributed at 60% between 19.26 and 71.96 ⁇ m.
- oxaliplatin powder 176.8 mg are dispersed in 6 ml of ethyl acetate at 1 ° C for 2 minutes with cooling in a cryostat at 0 ° C.
- 508 mg of polymer RG 503 are added and dissolved with magnetic stirring at room temperature for 10 min, then in a cryostat at 0 ° C for 10 min.
- the emulsion is formed, the ethyl acetate is extracted, filtered, washed and lyophilized the microspheres in a similar manner to that described in Example 1, with the main difference that the temperature of the PVA solution is 8 ° C and that of the temperature of the extraction water is 34 ° C.
- microspheres are passed through a 125 ⁇ m mesh screen to remove larger particles. Then they are sterilized by irradiation with gamma rays at 25 kGy.
- Example 4 Preparation of microspheres of 90% PLGA 25/50 of molecular weight 40,000 and 10% of PLA of molecular weight 2000 with an oxaliplatin encapsulation rate of 20%.
- oxaliplatin powder 154.0 mg are dispersed in 6 ml of ethyl acetate at 1 ° C for 2 minutes with cooling in a cryostat at 0 ° C.
- 453 mg of polymer RG 503 and 54.7 mg of PLA50 oligomer are added and dissolved with magnetic stirring at room temperature for 10 min, then in a cryostat at 0 ° C for 10 min.
- the emulsion is formed, the ethyl acetate is extracted, filtered, washed and lyophilized the microspheres in a similar manner to that described in Example 1, with the main difference that the temperature of the PVA solution is 6 ° C.
- microspheres are passed through a 125 ⁇ m mesh screen to remove larger particles. Then they are sterilized by irradiation with gamma rays at 25 kGy.
- Example 5 Preparation of microspheres of 80% of PLGA 25/50 of molecular weight 40,000 and 20% of PGLA 25/50 of molecular weight 10,000 with an oxaliplatin encapsulation rate of 15%
- the emulsion is formed, the ethyl acetate is extracted, filtered, washed and lyophilized the microspheres in a similar manner to that described in Example 1, with the main differences that the temperature of the PVA solution is 12 ° C and the extraction water has a temperature of 30 ° C.
- Microscopic observation shows microspheres charged with spheroid oxaliplatin, dense, of variable sizes, and few empty shells.
- Particle size analysis average size 48.02 ⁇ m, median size 37.82 ⁇ m, standard deviation 43.73 ⁇ m, sizes distributed at 60% between 20.10 and 66.40 ⁇ m. Manufacturing efficiency 90%. Encapsulation yield of 77%. Encapsulation rate of 15%.
- Example 1 to 5 100 mg of microspheres obtained in Example 1 to 5 are suspended in 1 I of phosphate buffer of pH 7.4 with stirring at 100 rpm. Aliquots of the dissolution medium are removed periodically and their platinum content is assayed using the ICP-MS (Inductively Coupled Plasma Mass Spectrometry) technique, while adding phosphate buffer to the dissolution medium so as to keep the volume of the dissolution medium constant.
- ICP-MS Inductively Coupled Plasma Mass Spectrometry
- the initial burst is greater and the first release plateau of shorter duration. This is expected because it is known in the art that sterilization by irradiation with gamma rays has the effect of increasing the initial burst and reducing the duration of the first release plateau.
- Example 7 In vivo evaluation of the antitumor activity and of the toxicity of the microspheres of the invention.
- IGROV-1 viable cells were inoculated ip into Nude mice. On day 15 after the inoculation of tumor cells, the mice received the test substances by ip administration.
- mice received a single ip administration of microspheres F3B (Example 1) or F3A (Example 2) at doses corresponding to 15 to 70 mg oxaliplatin base / kg.
- Free oxaliplatin was administered ip at doses of 6 and 15 mg base / kg.
- a group of mice received 3 injections of free oxaliplatin at 6 mg base / kg per injection every 4 days (q4dx3 administration scheme).
- Another group received a single ip injection of free oxaliplatin at 15 mg / kg.
- the group control received only 5% glucose solution or empty microspheres.
- Each group consisted of 5 mice. Isoflurane has been used to anesthetize animals before implantation of the tumor or sacrifice of the animals.
- the microspheres F3A and F3B were administered in a single injection it of 15 or 30 mg oxalipiatine / kg.
- Free oxaliplatin was administered as a single intravenous (iv) or it injection at doses of 15 and 30 mg base / kg respectively.
- a group of mice received 3 iv injections of free oxaliplatin at 6 mg base / kg by injection every 4 days (q4dx3 administration scheme).
- the volume of test substances administered to PC-3 tumors was equivalent to the tumor volume (1 ⁇ l of treatment for 1 mm 3 of tumor).
- mice carrying progressive tumors were sacrificed. The mice were weighed and examined twice a week, the weight of the sick animals was compared with the weight of three healthy mice (without tumor, without treatment, from the same batch). The animals were followed for 98 days.
- Intraperitoneal administration As described in the biological evaluations, the oxaliplatin microspheres were tested on IGROV-1 tumor models intraperitoneally and on PC-3 tumor models intratumoral. Within the framework of the intraperitoneal tumor were inoculated on day 0. The treatment was done 15 days after the inoculation of the tumor cells with microspheres F3A and F3B in comparison with free oxaliplatin administered either 3 times every four days or as a single dose. The administration was made at variable doses and the result is shown in Table 1. As can be seen in Table 1, significant antitumor activity has been demonstrated for the F3B microspheres at a dose of 15 mg base / kg per oxaliplatin. Free oxaliplatin at a dose of 15 mg did not show significant anti-tumor activity.
- Free oxaliplatin injected intratumorally at a dose of 30 mg oxaliplatin base / kg, demonstrated significant antitumor activity (T / C% ⁇ 42%) but also an acute toxicity (2 mice out of 5 died 4 to 7 days after treatment).
- the F3B and F3A microspheres (at doses of 30 and 15 mg base / kg) showed significant antitumor activity (T / C% ⁇ 42%) without acute toxicity.
- the antitumor activity was observed later with oxaliplatin encapsulated in microspheres compared to that observed with free oxaliplatin in it at doses of 30 mg base / kg but the inhibition of tumor growth was identical.
- the encapsulation of oxaliplatin in microspheres increases the tolerance of oxaliplatin. Tolerance depends on the rate of release and the load of oxaliplatin in the microspheres.
- JIQ 0 / o ratio of the median survival time of the treated animals divided by the median survival time of the untreated control group x 100
- T / C% ratio of the median average survival time of the treated animals divided by the median of average survival time of the untreated control group x
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH194100 | 2000-10-03 | ||
CH19412000 | 2000-10-03 | ||
PCT/CH2001/000596 WO2002028386A1 (fr) | 2000-10-03 | 2001-10-03 | Procede de preparation de microspheres contenant une substance soluble dans l'eau |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1324758A1 true EP1324758A1 (fr) | 2003-07-09 |
EP1324758B1 EP1324758B1 (fr) | 2005-01-12 |
Family
ID=4566851
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01971588A Expired - Lifetime EP1324758B1 (fr) | 2000-10-03 | 2001-10-03 | Microspheres de polymere de type plga/pla encapsulant des substances solubles dans l'eau, et leur procede de preparation |
Country Status (5)
Country | Link |
---|---|
US (1) | US20040126431A1 (fr) |
EP (1) | EP1324758B1 (fr) |
AU (1) | AU2001291583A1 (fr) |
DE (1) | DE60108405D1 (fr) |
WO (1) | WO2002028386A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7829113B2 (en) | 2005-03-10 | 2010-11-09 | Mebiopharm Co., Ltd. | Liposome compositions |
Families Citing this family (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002058672A2 (fr) * | 2001-01-26 | 2002-08-01 | Debio Recherche Pharmaceutique S.A. | Microparticules de polymere biodegradable encapsulant une substance biologiquement active et formulations pharmaceutiques a liberation prolongee contenant lesdites particules |
FR2869801B1 (fr) * | 2004-05-05 | 2008-09-12 | Ethypharm Sa | Procede de preparation de compositions a liberation prolongee et utilisation de ces compositions pour le traitement des affections chroniques du systeme nerveux central (snc) |
US20070253994A1 (en) * | 2006-04-28 | 2007-11-01 | Medtronic, Inc. | Intraspinal Drug Delivery Methods and Devices To Alleviate Chronic Pelvic Pain |
US8940315B2 (en) * | 2008-04-18 | 2015-01-27 | Medtronic, Inc. | Benzodiazepine formulation in a polyorthoester carrier |
US8956642B2 (en) * | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
CN102209531B (zh) * | 2008-11-14 | 2014-08-27 | 梨花女子大学校产学协力团 | 高分子微球的制造方法和通过该方法制造的高分子微球 |
GB201016436D0 (en) | 2010-09-30 | 2010-11-17 | Q Chip Ltd | Method of making solid beads |
GB201016433D0 (en) | 2010-09-30 | 2010-11-17 | Q Chip Ltd | Apparatus and method for making solid beads |
CN105943506B (zh) * | 2016-06-22 | 2019-01-11 | 山东省药学科学院 | 一种可吸收自致孔注射用微球及其制备方法 |
CN107596376A (zh) * | 2017-09-27 | 2018-01-19 | 同济大学 | 复合型药物及其制备方法与应用 |
CN114634634A (zh) * | 2022-03-22 | 2022-06-17 | 陈凌卉 | 一种生物功能复合多孔聚酯微球及其制备方法 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4389330A (en) * | 1980-10-06 | 1983-06-21 | Stolle Research And Development Corporation | Microencapsulation process |
US5238714A (en) * | 1990-10-02 | 1993-08-24 | Board Of Regents, The University Of Texas System | Efficient microcapsule preparation and method of use |
AU5416394A (en) * | 1992-11-24 | 1994-06-22 | Debiopharm S.A. | Cisplatinum/oxaliplatinum combination |
CA2263455C (fr) * | 1996-08-23 | 2002-10-29 | Sequus Pharmaceuticals, Inc. | Liposomes contenant un compose cisplatine |
-
2001
- 2001-10-03 DE DE60108405T patent/DE60108405D1/de not_active Expired - Lifetime
- 2001-10-03 WO PCT/CH2001/000596 patent/WO2002028386A1/fr not_active Application Discontinuation
- 2001-10-03 US US10/398,024 patent/US20040126431A1/en not_active Abandoned
- 2001-10-03 AU AU2001291583A patent/AU2001291583A1/en not_active Abandoned
- 2001-10-03 EP EP01971588A patent/EP1324758B1/fr not_active Expired - Lifetime
Non-Patent Citations (1)
Title |
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See references of WO0228386A1 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7829113B2 (en) | 2005-03-10 | 2010-11-09 | Mebiopharm Co., Ltd. | Liposome compositions |
Also Published As
Publication number | Publication date |
---|---|
WO2002028386A1 (fr) | 2002-04-11 |
DE60108405D1 (de) | 2005-02-17 |
US20040126431A1 (en) | 2004-07-01 |
AU2001291583A1 (en) | 2002-04-15 |
EP1324758B1 (fr) | 2005-01-12 |
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