IE47255B1 - Microspheres produced by phase separation techniques - Google Patents
Microspheres produced by phase separation techniquesInfo
- Publication number
- IE47255B1 IE47255B1 IE1708/78A IE170878A IE47255B1 IE 47255 B1 IE47255 B1 IE 47255B1 IE 1708/78 A IE1708/78 A IE 1708/78A IE 170878 A IE170878 A IE 170878A IE 47255 B1 IE47255 B1 IE 47255B1
- Authority
- IE
- Ireland
- Prior art keywords
- polymer
- phase separation
- core material
- solvent
- solution
- Prior art date
Links
- 238000005191 phase separation Methods 0.000 title claims abstract description 36
- 239000004005 microsphere Substances 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims description 42
- 229920000642 polymer Polymers 0.000 claims abstract description 67
- 229940079593 drug Drugs 0.000 claims abstract description 36
- 239000003814 drug Substances 0.000 claims abstract description 36
- 239000011162 core material Substances 0.000 claims abstract description 35
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 25
- 239000006185 dispersion Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims description 50
- 239000003094 microcapsule Substances 0.000 claims description 38
- 230000008569 process Effects 0.000 claims description 27
- 239000002245 particle Substances 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 150000005846 sugar alcohols Polymers 0.000 claims description 4
- 229920000954 Polyglycolide Polymers 0.000 claims description 3
- 229920002988 biodegradable polymer Polymers 0.000 claims description 3
- 239000004621 biodegradable polymer Substances 0.000 claims description 3
- 229920001577 copolymer Polymers 0.000 claims description 3
- 239000008240 homogeneous mixture Substances 0.000 claims description 3
- 229920000747 poly(lactic acid) Polymers 0.000 claims description 3
- 239000004633 polyglycolic acid Substances 0.000 claims description 3
- 239000004626 polylactic acid Substances 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000011859 microparticle Substances 0.000 claims description 2
- 230000002776 aggregation Effects 0.000 abstract description 8
- 238000005054 agglomeration Methods 0.000 abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 44
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 18
- KLBQZWRITKRQQV-UHFFFAOYSA-N Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 12
- 229960002784 thioridazine Drugs 0.000 description 11
- 239000000047 product Substances 0.000 description 10
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 238000007710 freezing Methods 0.000 description 7
- 230000008014 freezing Effects 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- GGNALUCSASGNCK-UHFFFAOYSA-N carbon dioxide;propan-2-ol Chemical compound O=C=O.CC(C)O GGNALUCSASGNCK-UHFFFAOYSA-N 0.000 description 5
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- -1 alkane hydrocarbons Chemical class 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229920001688 coating polymer Polymers 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940088679 drug related substance Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 229940035429 isobutyl alcohol Drugs 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 239000004848 polyfunctional curative Substances 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AJDIZQLSFPQPEY-UHFFFAOYSA-N 1,1,2-Trichlorotrifluoroethane Chemical compound FC(F)(Cl)C(F)(Cl)Cl AJDIZQLSFPQPEY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000005062 Polybutadiene Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 229960000807 dihydroergotamine mesylate Drugs 0.000 description 1
- ADYPXRFPBQGGAH-UMYZUSPBSA-N dihydroergotamine mesylate Chemical compound CS(O)(=O)=O.C([C@H]1C(=O)N2CCC[C@H]2[C@]2(O)O[C@@](C(N21)=O)(C)NC(=O)[C@H]1CN([C@H]2[C@@H](C=3C=CC=C4NC=C(C=34)C2)C1)C)C1=CC=CC=C1 ADYPXRFPBQGGAH-UMYZUSPBSA-N 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000002194 freeze distillation Methods 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- JZQKKSLKJUAGIC-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=C1C=CN2 JZQKKSLKJUAGIC-UHFFFAOYSA-N 0.000 description 1
- 229960002508 pindolol Drugs 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920002857 polybutadiene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000915 polyvinyl chloride Polymers 0.000 description 1
- 239000004800 polyvinyl chloride Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N propane-1,3-diol Chemical compound OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000003128 rodenticide Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229920003051 synthetic elastomer Polymers 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000005061 synthetic rubber Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/26—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests in coated particulate form
- A01N25/28—Microcapsules or nanocapsules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0241—Containing particulates characterized by their shape and/or structure
- A61K8/025—Explicitly spheroidal or spherical shape
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/85—Polyesters
-
- 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
-
- 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
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q13/00—Formulations or additives for perfume preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q15/00—Anti-perspirants or body deodorants
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/08—Simple coacervation, i.e. addition of highly hydrophilic material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/60—Particulates further characterized by their structure or composition
- A61K2800/61—Surface treated
- A61K2800/62—Coated
- A61K2800/624—Coated by macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/60—Particulates further characterized by their structure or composition
- A61K2800/65—Characterized by the composition of the particulate/core
- A61K2800/654—The particulate/core comprising macromolecular material
Abstract
Microspheres of core material and polymer are produced by adding a phase separation agent to a medium comprising a solution of the polymer and a solution or dispersion of the core material at a temperature of -40 to -100 DEG C. Preferably the core material is a drug and the polymer is biodegradable. The low temperature phase separation step prevents uncontrolled agglomeration of the microspheres.
Description
This invention, relates to microspheres comprising a polymeric material and a solid core material, which are prepared by phase separation techniques.
By the term microspheres is included, both microcapsules, which consist of a particle of core material which is coated by an outer layer of polymeric material, and microprills which are homogeneous mixtures of a core material and a polymer. The term microspheres also TO includes both the individual microcapsules or microprills and approximately spherical aggregates consisting of a number of microcapsules or microprills. Microspheres have ' diameters in the range 1-500 microns, more usually 20-200 microns.
It is known to obtain microcapsules by phase separation techniques in which the core material of the desired particle size is dispersed in a continuous phase comprising a solution of the polymeric coating material, and the polymeric material is deposited on the core material by gradual precipitation of the polymer, for example by addition of an incompatible polymer or a non2 solvent for the polymeric material, or by cooling a hot solution to room temperature. Such processes commonly give rise to uncontrollable aggregation of the encapsulated particles, and do not provide a satisfactory pro5 cedure for obtaining discrete, spherical, microspheres of polymer and core material by phase separation vzhich would be suitable in a broad range of applications.
It has now been found that these problems may be overcome by carrying out phase separation at low temperatures, i.e. from -40 to -100°C.
Accordingly, the present invention provides a process for the production of microspheres comprising a polymer and a core material characterised by the step of adding a phase separation agent to a medium comprising a solution of the polymer and a dispersion or solution of the core material at a temperature of -40 to -100°C.
In order to produce microcapsules, the polymer is dissolved in a solvent in which the core material is insoluble, microparticles of the core material are dis20 persed in the polymer solution, and a phase separation agent is added to the system at a temperature of -40° to -100°C to precipitate the polymer and coat the core material particles.
In order to produce microprills, the polymer and 25 core material are dissolved in a common solvent, and a phase separation agent Is added to the solution at a temperature of -40° to -100°C to precipitate particles consisting of a homogeneous mixture of polymer and core material.
It will be appreciated that it is not critical at what stage of the process the temperature of the system is lowered to -40 to -100°C, so long as phase separation takes place within this temperature range.
The core material of the microspheres prepared by the process of this invention may be agricultural agents such as insecticides, fungicides, herbicides, rodenticides, pesticides, fertilisers, virus particles for crop protection and the like; cosmetic agents such as deodorants, fragrances and the like; food additives such as flavours, oils, fats and the like; and pharmaceutical agents, e.g. drugs. Microspheres comprising drugs as core materials may be useful as long-acting retard forms for oral.or parenteral administration. Pharmaceutical agents, e.g. drugs, are especially preferred core materials and the invention will be further described using drugs as core materials.
The term phase separation agent includes both non-solvents for the polymer and the core material and polymeric materials which are incompatible with the coating polymer and the core material. When the phase separation agent is an incompatible polymer, then a non-solvent must also be added simultaneously or subsequently in order to harden the surface of the microspheres and prevent undue agglomeration.
The addition of the non-solvent, when used as a hardener, will also be at the process temperature of from -40° to -100°C. The term non-solvent in the subsequent description will be applied both to non-solvents used as phase separation agents and to non-solvents used as hardeners where the phase separation agent is an incompatible polymer.
In the preferred embodiments of the invention, the phase separation agent is a non-solvent and no incompatible polymer is used.
The formation of microcapsules according to this invention is based on polymer phase separation phenomena.
When a phase separation agent is initially added to a polymer solution in which solid drug particles are dispersed, the polymer which separates is initially in a liquid phase and is deposited as a coating on the dispersed drug particles. Subsequent addition of non-solvent causes the coating to harden as a capsule wall completely surrounding the drug particle. By varying the process conditions, the coated drug particles may remain as individual capsules or agglomerate in a controlled manner to form larger aggregates of microcapsules. Undesirable massive agglomeration occurs when adhesion and coalescence of the encapsulated particles develop precipitously beyond control. The present low temperature process renders the microspheres sufficiently firm to avoid undesired agglomeration.
The homogeneous microprills according to this invention are also formed by phase separation phenomena. When a phase separation agent for both the polymer and the drug is added to a homogeneous solution of polymer and drug, both the polymer and the drug separate out together to form homogeneous microprills. Depending on the process conditions, they may remain as individual spheres or be allowed to agglomerate in a controlled manner to form larger homogeneous microprills.
Depending on the end use of the product, it may be desirable to prepare aggregate microspheres larger than the individual microspheres. For example, for controlled release of drug suitable for parenteral administration, the size of the microspheres should be large enough to provide adequate duration of release yet small enough to not restrict passage through the standard syringe needles employed. Thus, the preferred size would be about 150 microns for a No. 20 gauge needle.
For other applications it may be desirable to allow controlled agglomeration to form microspheres larger or smaller than 150 microns.
The temperature range for the process of this invention is from about -40 to -100°C, preferably -40 to -75°C, more preferably -50 to -70°C. The upper temperature 47235 limit is dictated by the necessity to avoid massive agglomeration. In general, operating at a lower temperature would provide more margin against this undesired agglomeration. The lower temperatures are limited by the freezing point of the solvent, non-solvent or mixture of the two which are utilised.
Natural and synthetic polymers may be used in the process of this invention for the preparation of microspheres. For example, the polymers may include cellulosic polymers, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, natural and synthetic rubbers, polyacrylates, and polystyrene. When the microspheres of this invention are intended for injectable pharmaceutical applications, biodegradable polymers such as polylactic acid, polyglycolic acid, polyhydroxybutyric acid and the like and copolymers thereof may be utilised. The polymer should of course be compatible with the core material to be used.
Multiply encapsulated microcapsules may be prepared by the low temperature phase separation process of this invention by utilising preformed microcapsules or microprills, dispersed in a polymer solution, as the core material. In certain cases it may be necessary to lower the temperature of the polymer solution to -40 to -100°C prior to the introduction of the preformed microspheres to avoid dissolving the preformed microspheres in the polymer solution. This concept is especially useful for reducing the initial release rate, and therefore increasing the duration of release, by depositing an extra layer of polymer as a barrier on preformed microspheres. This technique can be· extended to create multilayered micro5 spheres.
Multiple encapsulation can also be used to produce new microcapsules formed by phase separation of a polymer solution containing a dispersion of one or more kinds of preformed microspheres with or without one or more free drugs in particulate form. For example, two or more drugs can be microencapsulated separately, either because of incompatibility or lack of a common microencapsulation procedure suitable for all the component drugs. These preformed microcapsules may then be mixed together and dispersed in a polymer solution for a subsequent microencapsulation to produce new microcapsules containing the previously encapsulated drug particles. Such compartmentalised microcapsules offer an advantage over a physical mixture in that uniformity is maintained by avoiding any uneven settling of the components upon storage.
Another application for compartmentalised microcapsules would be to segregate one or more reactants for subsequent reaction upon demand. Release for reaction may be effected by pressure rupture, passage of time, exposure to water, air, light, heat or other triggering mechanism.
For the preparation of microcapsules, the solvent selected must dissolve the polymer but not the dispersed core material, e.g. drug particles. This requirement is more easily met at low temperatures since drug solubility is usually decreased at lower temperature. For the preparation of homogeneous microprills, the solvent must dissolve both polymer and drug substance at the very low temperature. For either microcapsules or microprills, the solvent should be relatively volatile, inert to both polymer and drug, having a freezing point sufficiently below the required operating temperature and also be miscible with the nonsolvent at that low temperature.
Mixtures of solvents may be used where appropriate, for example to depress the freezing point of a preferred solvent to enable operation at a temperature below its normal freezing point. Another example is the situation where the drug to be encapsulated has some solubility in the solvent of choice for the polymer; here a second solvent may be added in quantity sufficient to minimise the sol2θ ubility of the drug without significantly affecting the solubility of the polymer. By contrast, when it is desired to form microprills, and a single common solvent for drug and for polymer cannot be found, then a mixed solvent system may be suitable as a common solvent. 47235 For example, where the polymer is a biodegradable polymer such as polylactic acid, polyglycolic acid and copolymers of these, suitable solvents include toluene, xylene, chloroform, methylene chloride, acetone, ethyl acetate, tetrahydrofuran, dioxane, hexafluoroisopropanol, and mixtures thereof.
The non-solvent used, whether in the phase separation step or in a subsequent hardening step, must be a non-solvent for both the polymer and the drug, at least at the operating jjq temperature.
Additionally, tlie non-solvent should be relatively volatile or easily removed by washing with another volatile non-solvent, chemically inert to both polymer and drug, have a freezing point sufficiently below the required operating temperature and also be miscible with the solvent at that low temperature.
Although both non-polar and polar non-solvents may be used, polar non-solvents are preferred. Examples of non-polar non-solvents include the alkane hydrocarbons (e.g., hexane, heptane, cyclohexane). Examples of polar non-solvents include water, alcohols (e.g., isopropanol, isobutyl alcohol), ethers, polyhydric alcohols (e.g., 1,2-glycols such as propylene glycol; 1,3-glycols such as trimethylene glycol; trihydric alcohols such as glycerol) and ethers and esters of the polyhydric alcohols. Polyhydric alcohols are especially preferred as the non-solvent for producing aggregated microspheres of larger diameters.
Other non-solvents which may be used are the fluorocarbons (e.g.,*Freon-ll, Freon-113 from DuPont). (*Freonis a Trade Hark)· The non-solvent need not be limited to a single component system and mixed non-solvent systems may be used, for example, to depress the freezing point of a non-solvent to allow operation at a very low temperature. Another example is where the drug substance has some solubility in the preferred non-solvent for the polymer. Sufficient amount of another non-solvent may be added to minimise drug solubility, e.g., the addition of a non-polar nonsolvent like heptane to reduce solubility of a drug in isopropanol. A co-non-solvent may also be used to maintain miscibility between the preferred non-solvent and the preferred solvent.
Where the phase separation agent is an incompatible polymer, the polymeric phase separation agent must be incompatible both with the coating polymer and with tlie core material, and miscible with the solvent. Preferably, the polymeric phase separation agent should be miscible with the non-solvent used in the hardening step, so that the nonsolvent will remove traces of the polymeric phase separation agent from the microspheres.
Among the polymeric phase separation agents which may be used are polybutadiene, polydimethylsiloxane and the like.
The following Examples illustrate the invention.
EXAMPLE 1: A solution of 1.0 g poly(D,L-lactic acid) polymer (intrinsic viscosity of 2.32 in hexafluoroisopropanol at • 25°C) in 50 ml of toluene was cooled to about -65°C in a dry ice-isopropanol bath. Micronised thioridazine pamoate (Sandoz, Inc.) (0.5 g) was dispersed in the polymer solution with stirring at 160 rpm. Isopropanoi (150 ml) was added dropwise to the dispersion at the rate of one hour for the first 50 ml and 0.5 hour for the remaining 100 ml. The dry ice bath was removed and the microcapsules were allowed to settle before decanting the supernatant. The product was washed twice with heptane, dried and weighed 1.15 g (77% yield). Microscopic examination (210X) showed that the product was in the form of spherical microcapsules with a diameter of about 25-50 microns.
EXAMPLE 2: The procedure of Example 1 was followed except that 150 ml of isobutyl alcohol (2-methyl-l-propanol) was used in place of isopropanoi as non-solvent. This was followed by the addition of 50 ml heptane in ten minutes to facilitate the capsule wall hardening process. The yield was 1.37 g (91%) of spherical microcapsules with a diameter of 20-30 microns.
EXAMPLE 3; The procedure of Example 1 was followed except that 150 nil of 50:50 (v/v) n-propanol/isopropanol was added in place of isopropanol, at the rate of 40 minutes for the first 50 ml and 35 minutes for the remaining 100 ml. This was followed by the addition of 50 ml heptane. The yield was 1.42 g (95%) of spherical microcapsules with a diameter of 20-40 microns.
EXAMPLE 4: The procedure of Example 1 was followed except that 150 ml of heptane was used instead of isopropanol, and the dispersion was then allowed to warm up to room temperature over four hours with constant stirring. The product weighed 1.22 g (81% yield). Aggregated micro15 spheres of 50-200 micron size were obtained.
EXAMPLE 5: The procedure of Example 1 was followed except that 150 ml of 15:85 (v/v) heptane/isopropanol was used instead of isopropanol. The yield was 1.1 g (73%) of spherical microcapsules with a diameter of 25-35 microns.
EXAMPLE 6: Somewhat larger microcapsules were prepared when propylene glycol/isopropanol was used as the non-solvent.
A solution of 1.0 g poly(D,L-lactic acid) polymer (intrinsic viscosity of 2.32 in hexafluoroisopropanol at 25°C) in 50 ml toluene was cooled to -50 °C (slightly warmer temperature was used to avoid freezing the propylene glycol, f.p. -59°) in a dry ice-isopropanol bath.
Micronised thioradinz pamoate (0.5 g) was dispersed in the polymer solution with stirring at 160 rpm. A solution (100 ml) of 33:67 (v/v) propylene glycol/isopropanol was added dropwise to the dispersion at the rate of one hour for -the first 50 ml and 20 minutes for the remaining 50 ml. This was followed by the addition of 50 ml heptane in 10 minutes. ' The dry ice bath was removed and the microcap- sules were allowed to settle before decanting the supernatant. The product was washed once with 1:1 (v/v) heptane/isopropanol, twice with isopropanol then twice with heptane. After a brief air-drying, microscopic examination showed that the product was well-formed, spherical microcapsules with a diameter of 50-150 but mostly 100-125 microns. However, after drying in the vacuum oven at 50-60°C for four hours, the capsules decreased to about to 75 microns and became crenated. The dried product weighed 1.16 g (77% yield) and contained 14.4% thioridazine pamoate.
EXAMPLE 7: A homogeneous solution of 1.0 g poly(D,L-lactic acid) polymer and 0.5 g thioridazine pamoate in 50 ml of 1:1 (v/v) toluene/chloroform was cooled to -65°C with stirring at 160 rpm. The addition of toluene allowed operation at -65° without freezing the chloroform (f.p. -63°C).
Isopropanol (150 ml) was added dropwise at the rate of 1.5 hours for the first 100 ml and 0.5 hours for the remaining 50 ml. The product was washed twice with heptane, dried and weighed 1.4 g (93% yield). Microscopic examination showed that the resultant homogeneous microprills were 20-50 microns in diameter.
EXAMPLE 8: Larger microprills were prepated when propylene glycol/isopropanol was used as the non-solvent. A homogen15 eous solution of 1.0 g poly(D,L-lactic acid) polymer and 0.5g thioridazine pamoate in 50 ml chloroform was cooled to -50°C with stirring at 160 rpm. A solution (100 ml) of 35:65 (v/v) propylene glycol/isopropanol was added dropwise to above solution at the rate of 70 minutes for the first 50 ml and 20 minutes for the remaining 50 ml. This was followed by the addition of 50 ml heptane in 15 minutes.
After decanting the supernatant, the product was washed once with 1:1 (v/v) heptane/isopropanol, twice with isopropanol then twice with heptane. Upon drying, it 47355 weighed 1.44 g {96% yield). Microscopic examination showed that the resultant homogeneous microprills were 100-125 microns in diameter. The product was found to contain 15.1% weight thioridazine pamoate.
EXAMPLE 9: A solution of 0.22 g poly(D,L-lactic acid) polymer in 50 ml toluene was cooled to about -65°C in a dry iceisopropanol bath. Microcapsules (0.75 g, about 35 microns, previously prepared as in Example 1 to contain 33% thioridazine pamoate) were dispersed in the polymer solution with stirring at 160 rpm. Isopropanol (150 ml) was added dropwise to the dispersion and the rest of the procedure of Example 1 was followed. The yield was 0.73 g (75%). Careful microscopic examination (210X) showed a thin, transparent wall of poly15 (D,L-lactic acid) polymer surrounding each microcapsule.
EXAMPLE 10; The data in this Example showed that the microencapsulated drug thioridazine pamoate has slower release rate than the non-encapsulated thioridazine pamoate. Furthermore, the double-encapsulated thioridazine pamoate microcapsules (25 40 microns) showed significantly reduced initial release rate compared to the single-encapsulated microcapsules (50200 microns). The reason for the shorter release duration of the double-encapsulated material is due to its smaller size.
% Release Non- Encapsulated Single- Encapsulated Drug Example 4 Double- Encapsulated Drug Example 9 Hour Drug 1 48 42 23 4 — 42 37 6 — 44 46 24 100 65 78 30 — 75 100 48 __ 77 __ 72 — 100 — Procedure A sample containing the equivalent of 4.0 mg Mellaril pamoate was placed in a dissolution flask contain- ing 1000 ml of pH 7. 4, 0.2M phosphate buffer. The mixture was maintained at 37 °C with stirring at 500 rpm. Aliquots were with idrawn at various time points and the absorbance was measured at 224 nm with an ultraviolet spectrophotometer. The percent drug released was based on the maximum absorbance measured for each sample.
EXAMPLE 11: A solution of 0.25 poly(D,L-lactic acid) polymer in 50 ml toluene was cooled to -65°C in a dry ice-isopropanoi bath. Microprills prepared as in Example 8 containing 16% thioridazine pamoate were dispersed in the polymer solution with stirring at 160 rpm. The procedure of Example 1 was followed except that 100 ml of 20:80 (v/v) heptane/isopropanol followed by 50 ml of heptane was used instead of isopropanol. The yield was 0.89 g (89%) of double-encapsulated microprills of 100-150 microns diameter and containing 10.8% thioridazine pamoate.
EXAMPLE 12: A dispersion of 0.6 g bromocriptine (Sandoz, Inc.) in a solution of 1.4 g poly(D,L-lactic acid) polymer in 55 ml of toluene was stirred at 140 rpm with cooling to -70°C in a dry ice-isopropanol bath. The procedure of Example 1 was followed except that 100 ml of 25:75 (v/v) heptane/isopropanol followed by 50 ml of heptane was used instead of isopropanol. The yield was 1.71 g (86%) of spherical microcapsules of 15-40 microns diameter.
Microscopic examination under polarized light of the microcapsules immersed in oil showed that the microcapsules contained drug particles whose iridescence was visible through the capsule wall.
EXAMPLE 13: A dispersion of 1.0 g pindolol (Sandoz, Inc.) (well-pulverized with motar and pestle) in a solution of 1.0 g poly (D,L-lactic acid) polymer in 100 ml of toluene was stirred at 150 rpm with cooling to -70°C in a dry ice18 47355 isopropanoi bath. The procedure of Example 1 was followed except that 50 ml of 5:95 (v/v) heptane/isopropanol followed by 50 ml of heptane was used instead of isopropanoi. The yield was 1.82 g (91%) of spherical microcapsules of 50-75 microns diameter. Microscopic examination under polarized light of the microcapsules immersed in oil showed that tho microcapsules contained drug particles whose iridescence was visible through the capsule wall.
EXAMPLE 14: A dispersion of 1.0 g dihydroergotamine mesylate (Sandoz, Inc.) (well-pulverized with mortar and pestle) in a solution of 1.0 g poly (D,L-lactic acid) polymer in 100 ml of toluene was stirred at 140 rpm with cooling to -70 °C in a dry ice-isopropanol bath. The procedure of Example 1 was followed except that 100 ml of isopropanoi followed by 100 ml of heptane was used instead of isopropanoi alone. The yield was 1.98 g (99%) of spherical microcapsules of 75-150 microns diameter. Microscopic examination under polarized light of the microcapsules immersed in oil showed that the microcapsules contained drug particles whose iridescence was visible through the capsule wall.
Claims (15)
1. A process for the production of microspheres comprising a polymer and a core material characterised by the step of adding a phase separation agent to a medium comprising a solution of the polymer and a dispersion or solution of the core material at a temperature of -40 to -100°C. 15. 20.
2. A process for the production of microcapsules comprising a coating of polymer around a solid particle of core material, characterised by the step of adding a phase separation agent to a medium comprising a dispersion of microparticles of the core material in a solution of the polymer at a temperature of -40 to -100°C.
3. A process for the production of microprills comprising a homogeneous mixture of a polymer and a core material characterised by the step of adding a phase separation agent to a common solution of the polymer and the core material at a temperature of -40 to -100°C.
4. A process as claimed in any one of the preceding claims in which the core material comprises a drug. 5. A process as claimed in any one of the preceding claims in which the core material comprises preformed microspheres.
5. A process as claimed in Claim 4 in which the polymer is a biodegradable polymer.
6. 7. A process as claimed in Claim 6 in which the polymer is polylactic acid, polyglycolic acid, polyhydroxybutyric 25. 5. 15. acid or copolymers thereof.
7. 8. A process as claimed in any one of the preceding claims in which the phase separation agent is a non-solvent for the polymer and the core material.
8. 9. A process as claimed in Claim 8 in which the phase separation agent is a polar non-solvent.
9. 10. A process as claimed in Claim 9 in which aggregated microspheres are produced by the use of a polyhydric alcohol as a polar non-solvent.
10. 11. A process as claimed in Claim 8 in which the phase separation agent is a mixture of polar and non-polar nonsolvent.
11. 12. A process as claimed in any one of the preceding claims in which the phase separation agent is added at a temperature of from -40 to -75°C.
12.
13. A process as claimed in Claim 12 in v.’hich the phase separation agent is added at a temperature of from -50 to -70°C. 20.
14. A process for the production of mierospheres substantially as described in any one of the Examples.
15. Mierospheres whenever produced by ? process as claimed in any one of the preceding claims.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US82771077A | 1977-08-25 | 1977-08-25 |
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IE47255B1 true IE47255B1 (en) | 1984-02-08 |
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AT (1) | AT372019B (en) |
AU (1) | AU522215B2 (en) |
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CA (1) | CA1122077A (en) |
CH (2) | CH644768A5 (en) |
DE (1) | DE2836044A1 (en) |
DK (2) | DK361878A (en) |
ES (1) | ES472800A1 (en) |
FI (1) | FI64899C (en) |
FR (1) | FR2400950A1 (en) |
GB (1) | GB2003108B (en) |
IE (1) | IE47255B1 (en) |
IL (1) | IL55418A (en) |
IT (1) | IT1098111B (en) |
NL (1) | NL7808613A (en) |
NZ (1) | NZ188232A (en) |
PH (1) | PH15447A (en) |
PT (1) | PT68473A (en) |
SE (1) | SE431942B (en) |
ZA (1) | ZA784855B (en) |
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JPS6045845B2 (en) * | 1979-10-31 | 1985-10-12 | 田辺製薬株式会社 | Method for producing microcapsules containing pharmaceutical substances |
US4384975A (en) * | 1980-06-13 | 1983-05-24 | Sandoz, Inc. | Process for preparation of microspheres |
PH19942A (en) * | 1980-11-18 | 1986-08-14 | Sintex Inc | Microencapsulation of water soluble polypeptides |
DE3045135A1 (en) * | 1980-11-29 | 1982-06-09 | Sandoz-Patent-GmbH, 7850 Lörrach | BODEGRADABLE POLYMERS CONTAINING PHARMACEUTICAL COMPOSITIONS |
JPS5933214A (en) * | 1982-08-19 | 1984-02-23 | Mitsui Toatsu Chem Inc | Carcinostatic agent formed to microsphere and its preparation |
AT382076B (en) * | 1982-10-15 | 1987-01-12 | Chemie Linz Ag | METHOD FOR THE PRODUCTION OF PRESSURES WITH RETARDED ACTIVE SUBSTANCE RELEASE |
DE3417576A1 (en) * | 1984-05-11 | 1985-11-14 | Lentia GmbH Chem. u. pharm. Erzeugnisse - Industriebedarf, 8000 München | RETARD FORMS OF ALPHA- (2,5-DIMETHOXY-PHENYL) -SS-GLYCINAMIDOAETHANOL AND METHOD FOR THE PRODUCTION THEREOF |
DE3428372A1 (en) * | 1984-08-01 | 1986-02-13 | Hoechst Ag, 6230 Frankfurt | CONTROLLED RELEASE REGULAR PEPTIDES MICROCAPSULES, PRODUCTION METHOD AND INJECTION PREPARATIONS |
CH660302A5 (en) * | 1984-10-17 | 1987-04-15 | Debiopharm Sa | HETEROGENEOUS PHASE MICRO-ENCAPSULATION PROCESS OF WATER-SOLUBLE DRUG SUBSTANCES. |
CH669506A5 (en) * | 1986-01-13 | 1989-03-31 | Hugo Degen | Oscillating and reclining furniture |
DE3712095A1 (en) * | 1987-04-10 | 1988-10-20 | Lentia Gmbh | BINDER-FREE GRANULES WITH DELAYED DELIVERY OF ACTIVE SUBSTANCES |
US4861627A (en) * | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
HU221294B1 (en) * | 1989-07-07 | 2002-09-28 | Novartis Ag | Process for producing retarde compositions containing the active ingredient in a polymeric carrier |
FR2657255B1 (en) * | 1989-12-27 | 1992-04-24 | Sederma Sa | DESCRIPTION OF ORIGINAL COSMETIC PREPARATIONS OF WHICH THE ACTIVE INGREDIENTS ARE TRAPPED IN A POLYMERIC NETWORK GRAFT ON THE SURFACE OF SILICA PARTICLES. |
DE4127757A1 (en) * | 1991-02-06 | 1992-08-13 | Hoechst Ag | NEW PLANT PROTECTIVE FORMULATIONS |
US6204308B1 (en) | 1999-03-01 | 2001-03-20 | Novartis Ag | Organic compounds |
AU2001258127B2 (en) | 2000-05-12 | 2005-11-10 | Matregen Corp. | Method of producing structures using centrifugal forces |
US6969480B2 (en) | 2000-05-12 | 2005-11-29 | Matregen Corp. | Method of producing structures using centrifugal forces |
US6824822B2 (en) * | 2001-08-31 | 2004-11-30 | Alkermes Controlled Therapeutics Inc. Ii | Residual solvent extraction method and microparticles produced thereby |
EP2219775A4 (en) * | 2007-12-11 | 2012-10-03 | Univ Nanyang Tech | Hollow multi-layered microspheres for delivery of hydrophilic active compounds |
CN104109250B (en) | 2008-05-21 | 2017-04-12 | 东丽株式会社 | Method For Producing Polymer Fine Particle |
CN103828801B (en) * | 2014-01-15 | 2016-01-27 | 福建农林大学 | Pleocidin/emamectin-benzoate microballoon and preparation method thereof |
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IT631615A (en) * | 1960-02-26 | |||
US3427250A (en) * | 1963-03-25 | 1969-02-11 | Polaroid Corp | Microscopic capsules and process for their preparation |
US3531418A (en) * | 1965-08-18 | 1970-09-29 | Ncr Co | En masse encapsulation process |
FR1497584A (en) * | 1966-08-11 | 1967-10-13 | Roussel Uclaf | Microcapsule manufacturing process |
US3703474A (en) * | 1967-08-21 | 1972-11-21 | Ncr Co | Encapsulation process |
US3773919A (en) * | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
JPS51125675A (en) * | 1975-02-13 | 1976-11-02 | Asahi Chem Ind Co Ltd | A porous capsule structvre and a process for manufacturing turing it |
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- 1978-08-21 NL NL7808613A patent/NL7808613A/en active Search and Examination
- 1978-08-22 GB GB7834199A patent/GB2003108B/en not_active Expired
- 1978-08-23 NZ NZ188232A patent/NZ188232A/en unknown
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- 1978-08-23 ES ES472800A patent/ES472800A1/en not_active Expired
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- 1978-08-23 IE IE1708/78A patent/IE47255B1/en unknown
- 1978-08-23 AT AT0612478A patent/AT372019B/en not_active IP Right Cessation
- 1978-08-24 PT PT68473A patent/PT68473A/en unknown
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- 1978-08-25 PH PH21539A patent/PH15447A/en unknown
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1989
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IL55418A (en) | 1981-07-31 |
BE869915A (en) | 1979-02-23 |
IE781708L (en) | 1979-02-25 |
DE2836044C2 (en) | 1988-06-23 |
IL55418A0 (en) | 1978-10-31 |
DK618189D0 (en) | 1989-12-07 |
DK361878A (en) | 1979-02-26 |
GB2003108A (en) | 1979-03-07 |
JPS5455717A (en) | 1979-05-04 |
AU522215B2 (en) | 1982-05-20 |
SE7808759L (en) | 1979-02-26 |
CH644768A5 (en) | 1984-08-31 |
SE431942B (en) | 1984-03-12 |
GB2003108B (en) | 1982-03-24 |
AT372019B (en) | 1983-08-25 |
FR2400950A1 (en) | 1979-03-23 |
IT1098111B (en) | 1985-09-07 |
AU3923678A (en) | 1980-02-28 |
JPS645005B2 (en) | 1989-01-27 |
DE2836044A1 (en) | 1979-03-01 |
DK618189A (en) | 1989-12-07 |
NL7808613A (en) | 1979-02-27 |
ZA784855B (en) | 1980-04-30 |
PH15447A (en) | 1983-01-18 |
CA1122077A (en) | 1982-04-20 |
NZ188232A (en) | 1980-12-19 |
ATA612478A (en) | 1983-01-15 |
FR2400950B1 (en) | 1983-10-07 |
IT7826961A0 (en) | 1978-08-23 |
FI782501A (en) | 1979-02-26 |
FI64899B (en) | 1983-10-31 |
ES472800A1 (en) | 1979-10-16 |
PT68473A (en) | 1978-09-01 |
CH649217A5 (en) | 1985-05-15 |
FI64899C (en) | 1984-02-10 |
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