ES2358403A1 - SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES INCLUDING POLY-EPSYLON-CAPROLACTONE, POLOXAMINE AND ONE OR MULTIPLE ACTIVE SUBSTANCES. (Machine-translation by Google Translate, not legally binding) - Google Patents
SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES INCLUDING POLY-EPSYLON-CAPROLACTONE, POLOXAMINE AND ONE OR MULTIPLE ACTIVE SUBSTANCES. (Machine-translation by Google Translate, not legally binding) Download PDFInfo
- Publication number
- ES2358403A1 ES2358403A1 ES200902039A ES200902039A ES2358403A1 ES 2358403 A1 ES2358403 A1 ES 2358403A1 ES 200902039 A ES200902039 A ES 200902039A ES 200902039 A ES200902039 A ES 200902039A ES 2358403 A1 ES2358403 A1 ES 2358403A1
- Authority
- ES
- Spain
- Prior art keywords
- active substances
- poloxamine
- pcl
- caprolactone
- biologically active
- 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
- 239000013543 active substance Substances 0.000 title claims abstract description 29
- 229920001987 poloxamine Polymers 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000011159 matrix material Substances 0.000 claims abstract description 11
- 239000007787 solid Substances 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 229920001610 polycaprolactone Polymers 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 21
- 239000007943 implant Substances 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 11
- 229920002359 Tetronic® Polymers 0.000 claims description 7
- 239000008188 pellet Substances 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 230000001575 pathological effect Effects 0.000 claims description 2
- 230000035790 physiological processes and functions Effects 0.000 claims description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 claims 1
- 239000010902 straw Substances 0.000 claims 1
- 238000002844 melting Methods 0.000 abstract description 2
- 230000008018 melting Effects 0.000 abstract description 2
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 abstract description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 20
- 229960003405 ciprofloxacin Drugs 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 230000003628 erosive effect Effects 0.000 description 7
- 229920001400 block copolymer Polymers 0.000 description 6
- 229920002366 Tetronic® 1307 Polymers 0.000 description 5
- 238000012377 drug delivery Methods 0.000 description 5
- 210000000988 bone and bone Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 239000012738 dissolution medium Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000004927 fusion Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 239000006069 physical mixture Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229940088623 biologically active substance Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 239000004632 polycaprolactone Substances 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VLGDSNWNOFYURG-UHFFFAOYSA-N 4-propyloxetan-2-one Chemical compound CCCC1CC(=O)O1 VLGDSNWNOFYURG-UHFFFAOYSA-N 0.000 description 1
- 241000272525 Anas platyrhynchos Species 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- 101100000858 Caenorhabditis elegans act-3 gene Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 229920002043 Pluronic® L 35 Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 238000006065 biodegradation reaction Methods 0.000 description 1
- 239000005312 bioglass Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001879 gelation Methods 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K9/4816—Wall or shell material
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Sistema para la administración de sustancias biológicamente activas que comprende poli-\varepsilon-caprolactona, poloxamina y una o varias sustancias activas.Substance Administration System biologically active comprising poly-ε-caprolactone, poloxamine and one or more active substances.
La invención se dirige a un sistema para la administración de sustancias biológicamente activas que comprende poli-\varepsilon-caprolactona, poloxamina y una o varias sustancias activas, un procedimiento para la preparación de dichos sistemas y uso para la fabricación de medicamentos o implantes.The invention is directed to a system for administration of biologically active substances comprising poly-ε-caprolactone, poloxamine and one or more active substances, a procedure for the preparation of said systems and use for the manufacture of medications or implants
El desarrollo de sistemas aptos para el control de la cesión o la liberación de fármacos o sustancias activas encierra un gran interés. En este campo, los sistemas inteligentes y los sistemas biodegradables han sido objeto de una amplia atención. Los sistemas inteligentes, que responden a estímulos externos al organismo o a variables fisio(pato)lógicas, permiten una regulación precisa del momento y la velocidad de liberación del fármaco o la sustancia activa (Alvarez-Lorenzo C, Concheiro A. Intelligent drug delivery systems: polymeric micelles and hydrogels. Mini-Reviews in Medicinal Chemistry 8, 1065-1074, 2008). Los copolímeros bloque poli(óxido de etileno)-poli(óxido de propileno) susceptibles de experimentar procesos de micelización y, a concentraciones suficientemente altas, transiciones de sol a gel se han mostrado muy útiles como componentes de sistemas sensibles a cambios de temperatura (Kabanov AV, Batrakova EV, Alakhov VY. Pluronic (R) block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82, 189-212, 2002). Las dispersiones acuosas de estos polímeros pueden servir para desarrollar sistemas líquidos inyectables que dan lugar a la formación de implantes in situ. La mayor limitación de estos sistemas radica en la reducida capacidad de los implantes formados in situ para soportar el stress mecánico in vivo y en el reducido tiempo de permanencia en el lugar de aplicación.The development of systems suitable for the control of the transfer or release of drugs or active substances is of great interest. In this field, intelligent systems and biodegradable systems have received extensive attention. Intelligent systems, which respond to stimuli external to the organism or to physio (duck) logical variables, allow precise regulation of the moment and speed of release of the drug or active substance (Alvarez-Lorenzo C, Concheiro A. Intelligent drug delivery systems: polymeric micelles and hydrogels. Mini-Reviews in Medicinal Chemistry 8, 1065-1074, 2008). Poly (ethylene oxide) -polis (propylene oxide) block copolymers capable of undergoing micellization processes and, at sufficiently high concentrations, transitions from sun to gel have proved very useful as components of temperature sensitive systems (Kabanov AV, Batrakova EV, Alakhov VY. Pluronic (R) block copolymers as novel polymer therapeutics for drug and gene delivery. Journal of Controlled Release 82, 189-212, 2002). The aqueous dispersions of these polymers can be used to develop injectable liquid systems that give rise to implant formation in situ . The greatest limitation of these systems lies in the reduced capacity of implants formed in situ to withstand mechanical stress in vivo and in the reduced time spent in the place of application.
Los sistemas biodegradables, constituidos principalmente por poliésteres y polianhídridos, experimentan una lenta degradación química o enzimática y permiten una liberación de fármacos o sustancias activas muy prolongada en el tiempo (Fair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 32, 762-798, 2007). Aunque sólo están disponibles en un número reducido, los materiales de estas características cuentan ya con interesantes aplicaciones como componentes de implantes y sistemas de liberación de medicamentos o sustancias activas. La poli-\varepsilon-caprolactona (PCL) presenta una excelente biocompatibilidad, pero se degrada in vivo con excesiva lentitud (Ponsart S, Coudane J, Saulnier B, Morgat JL, Vert M. Biodegradation of [3H]poly(e-caprolactone) in the presence of active sludge extracts. Biomacromolecules 2, 373-377, 2001), lo que limita su interés como componente de sistemas de liberación de fármacos y sustancias activas (Peña J, Corrales T, Izquierdo-Barba I, Doadrio AL, Vallet-Regi M. Long term degradation of poly(3-caprolactone) films in biologically related fluids. Polymer Degradation and Stability 91, 1424-1432, 2006).Biodegradable systems, consisting mainly of polyesters and polyanhydrides, undergo a slow chemical or enzymatic degradation and allow a release of drugs or active substances very prolonged over time (Fair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog. Polym. Sci. 32, 762-798, 2007). Although they are only available in a small number, materials of these characteristics already have interesting applications such as implant components and drug delivery systems or active substances. Poly-ε-caprolactone (PCL) exhibits excellent biocompatibility, but degrades in vivo with excessive slowness (Ponsart S, Coudane J, Saulnier B, Morgat JL, Vert M. Biodegradation of [3H] poly (e-caprolactone) in the presence of active sludge extracts, Biomacromolecules 2, 373-377, 2001), which limits its interest as a component of drug delivery systems and active substances (Peña J, Corrales T, Izquierdo-Beard I, Doadrio AL, Vallet -Regi M. Long term degradation of poly (3-caprolactone) films in biologically related fluids. Polymer Degradation and Stability 91, 1424-1432, 2006).
La combinación de polímeros con distintas prestaciones en un único sistema de liberación es una aproximación muy útil para ajustar las propiedades físicas y mecánicas y los perfiles de cesión a necesidades específicas. En este sentido, se ha propuesto la combinación de poli-\varepsilon-caprolactona con copolímeros bloque poli(óxido de etileno)-poli(óxido de propileno) para el desarrollo de material quirúrgico biodegradable y moldeable (Patente EP 0 747 072 A3 "Biodegradable moldable surgical material"). También se ha estudiado la incidencia de la incorporación de fosfato tricálcico y biovidrio sobre la velocidad de degradación de implantes de poli-\varepsilon-caprolactona obtenidos por fusión y sobre su funcionalidad en la reparación ósea (Lam CXF, Hutmacher DW, Schantz JT, Woodruff MA, Teoh SH. Evaluation of polycaprolactone scaffold degradation for 6 months in vitro and in vivo. Journal of Biomedical Materials Research Part A 90, 906-919 2009; Chouzouri G, Santos M. In vitro bioactivity and degradation of polycaprolactone composites containing silicate fillers. Acta Biomaterialia 3, 745-756, 2007). La incorporación de polietilenglicol se ha visto como un medio útil para acelerar la liberación de fármacos a partir de matrices de poli-\varepsilon-caprolactona obtenidas por fusión (Sprockel O L, Sen M, Shivanand P, Prapaitrakul W. A melt-extrusion process for manufacturing matriz drug delivery systems. Int. J. Pharm. 155, 191-199, 1997). Finalmente se han preparado copolímeros de poli-\varepsilon-caprolactona y Pluronic, mediante modificación del copolímero bloque con monómeros precursores de poli-\varepsilon-caprolactona con el fin de obtener sistemas de gelificación in situ biodegradables (Liu CB, Gong CY, Pan YF, Zhang YD, Wang JW, Huang MJ, Wang YS, Wang K, Gou ML, Tu MJ, Wei YQ, Qian ZY Synthesis and characterization of a thermosensitive hydrogel based on biodegradable amphiphilic poli-\varepsilon-caprolactona-Pluronic (L35)-poli-\varepsilon-caprolactona block copolymers. Colloids Surf. A 302, 430-438, 2007).The combination of polymers with different benefits in a single release system is a very useful approach to adjust the physical and mechanical properties and the transfer profiles to specific needs. In this regard, the combination of poly-ε-caprolactone with poly (ethylene oxide) -poly (propylene oxide) block copolymers has been proposed for the development of biodegradable and moldable surgical material (EP 0 747 072 A3 "Biodegradable moldable surgical material "). The incidence of the incorporation of tricalcium phosphate and bioglass on the degradation rate of polyvinylcaprolactone implants obtained by fusion and on their functionality in bone repair (Lam CXF, Hutmacher DW, Schantz JT, Woodruff) has also been studied. MA, Teoh SH. Evaluation of polycaprolactone scaffold degradation for 6 months in vitro and in vivo . Journal of Biomedical Materials Research Part A 90, 906-919 2009; Chouzouri G, Santos M. In vitro bioactivity and degradation of polycaprolactone composites containing silicate fillers Biomaterialia Act 3, 745-756, 2007). The incorporation of polyethylene glycol has been seen as a useful means to accelerate the release of drugs from polyvinylcaprolactone matrices obtained by fusion (Sprockel OL, Sen M, Shivanand P, Prapaitrakul W. A melt-extrusion process for manufacturing matrix drug delivery systems Int. J. Pharm. 155, 191-199, 1997). Finally, poly-ε-caprolactone and Pluronic copolymers have been prepared by modifying the block copolymer with polyvare-caprolactone precursor monomers in order to obtain biodegradable in situ gelation systems (Liu CB, Gong CY, Pan YF , Zhang YD, Wang JW, Huang MJ, Wang YS, Wang K, Gou ML, Tu MJ, Wei YQ, Qian ZY Synthesis and characterization of a thermosensitive hydrogel based on biodegradable amphiphilic poly- \ varepsilon-caprolactone-Pluronic (L35) - poly-? -caprolactone block copolymers. Colloids Surf. A 302, 430-438, 2007).
La invención proporciona un nuevo sistema constituido por un material biocompatible, la poli-\varepsilon-caprolactona, y otro citocompatible, poloxamina, que forman una matriz biodegradable de consistencia sólida o semisólida en la que una o varias sustancias biológicamente activas están dispersas a nivel molecular, lo que lo hace adecuado como pelet o como implante para una liberación controlada de dichas sustancias biológicamente activas en el lugar de aplicación sin efectos tóxicos. De forma adicional, los perfiles de cesión de las sustancias biológicamente activas incorporados al sistema de la invención son modulables, mediante la selección de uno de los componentes de la matriz en función de sus características. La matriz de la invención es además sensible a la temperatura.The invention provides a new system. constituted by a biocompatible material, the poly-ε-caprolactone, and another cytocompatible, poloxamine, which form a biodegradable matrix of solid or semi-solid consistency in which one or more biologically active substances are dispersed at the molecular level, which makes it suitable as a pellet or as an implant for a controlled release of said biologically active substances in the place of application without toxic effects. Additionally, the assignment profiles of biologically active substances incorporated into the system of the invention are modular, by means of the selection of one of the components of the matrix based on their features. The matrix of the invention is also sensitive to temperature.
\global\parskip0.950000\baselineskip\ global \ parskip0.950000 \ baselineskip
También se describe un procedimiento de obtención basado en la fusión de los componentes de la matriz, un procedimiento sencillo de pocos pasos, ya que no requiere la modificación previa de ninguno de los componentes, y que es respetuoso con el medioambiente ya que evita el empleo de disolventes orgánicos.A procedure of obtaining based on the fusion of the matrix components, a simple procedure of few steps, since it does not require the previous modification of any of the components, and that is environmentally friendly as it avoids the use of organic solvents
Así, en un primer aspecto la invención se dirige hacia un sistema para la administración de sustancias biológicamente activas que comprende poli-\varepsilon-caprolactona, poloxamina y una o varias sustancias biológicamente activas caracterizado por ser una matriz biodegradable de consistencia sólida o semisólida con aspecto homogéneo.Thus, in a first aspect the invention is directed towards a system for the administration of substances biologically active comprising poly-ε-caprolactone, poloxamine and one or more biologically active substances characterized by being a biodegradable matrix of consistency solid or semi-solid with homogeneous appearance.
En otro aspecto, la invención se dirige a un procedimiento de obtención de un sistema como se ha definido anteriormente, que comprende: a) preparación de una mezcla física de poli-\varepsilon-caprolactona (PCL), poloxamina y una o varias sustancias biológicamente activas; b) aplicación de calor para fundir la mezcla; y c) enfriamiento.In another aspect, the invention is directed to a procedure to obtain a system as defined above, which comprises: a) preparation of a physical mixture of poly-? -caprolactone (PCL), poloxamine and one or more biologically active substances; b) application of heat to melt the mixture; and c) cooling.
En otro aspecto la invención se dirige hacia el uso del sistema como se ha definido anteriormente para la preparación de un medicamento o implante para el tratamiento de estados patológicos o fisiológicos en humanos o animales.In another aspect the invention is directed towards the use of the system as defined above for the preparation of a medicine or implant for the treatment of pathological or physiological states in humans or animals.
En un aspecto adicional, la invención se dirige a una composición farmacéutica que comprende el sistema previamente descrito.In a further aspect, the invention is directed to a pharmaceutical composition comprising the system previously described
La invención se refiere a un sistema para la administración de sustancias biológicamente activas, como se ha definido previamente. Este sistema tiene un tamaño preferentemente comprendido entre 0.5 mm y 50 mm. En una realización particular, el sistema de la invención se puede obtener como pelet o como implante para una liberación controlada en el lugar de aplicación sin efectos tóxicos.The invention relates to a system for administration of biologically active substances, as has been previously defined. This system is preferably sized between 0.5 mm and 50 mm. In a particular embodiment, the system of the invention can be obtained as a pellet or as an implant for controlled release at the place of application without effect Toxic
La presente invención se refiere también a un procedimiento para preparar un sistema como el descrito anteriormente, que comprende las siguientes etapas: a) preparación de una mezcla física de poli-\varepsilon-caprolactona (PCL), poloxamina y una o varias sustancias biológicamente activas; b) aplicación de calor para fundir la mezcla; y c) enfriamiento. Este procedimiento no requiere la incorporación de disolventes en ninguna de sus etapas.The present invention also relates to a procedure to prepare a system like the one described previously, which comprises the following stages: a) preparation of a physical mixture of poly-? -caprolactone (PCL), poloxamine and one or more biologically active substances; b) application of heat to melt the mixture; and c) cooling. This procedure does not require the incorporation of solvents in None of its stages.
En una realización particular, la proporción de poli-\varepsilon-caprolactona (PCL) en la mezcla PCL:poloxamina está comprendida entre el 1% y el 99%. En una realización aún más particular, la proporción de PCL está comprendida entre el 25% y el 75%.In a particular embodiment, the proportion of poly-? -caprolactone (PCL) in the PCL mixture: poloxamine is between 1% and 99% In an even more particular embodiment, the proportion of PCL It is between 25% and 75%.
Las poloxaminas son copolímeros de bloque de
cuatro brazos de poli(óxido de etileno)-poli(óxido
de propileno) (EO-PO) unidos a un grupo central de
etilenodiamina, que tienen la capacidad de dar lugar a soluciones
micelares en medio acuoso. Las poloxaminas de la invención tienen un
peso molecular de entre 1000 y 25000 Daltons. Los autores de la
presente invención demuestran que la selección de la poloxamina
permite modular las propiedades mecánicas del sistema de la
invención como se ha definido anteriormente, y adicionalmente,
permite modular los perfiles de cesión de las sustancias
biológicamente activas incorporadas al sistema. De este modo, se
pueden obtener sistemas según la invención con perfiles de cesión
ajustados a necesidades específicas seleccionando poloxaminas de
distintas caracterís-
ticas estructurales e incorporándolas
en diferentes proporciones para modular la velocidad de erosión de
la matriz.Poloxamines are four-arm block copolymers of poly (ethylene oxide) -poly (propylene oxide) (EO-PO) bonded to a central group of ethylenediamine, which have the ability to give rise to micellar solutions in aqueous medium. The poloxamines of the invention have a molecular weight of between 1000 and 25000 Daltons. The authors of the present invention demonstrate that the selection of the poloxamine allows modulating the mechanical properties of the system of the invention as defined above, and additionally, allows modulating the transfer profiles of the biologically active substances incorporated into the system. Thus, systems according to the invention can be obtained with assignment profiles adjusted to specific needs by selecting poloxamines of different characteristics.
Structural techniques and incorporating them in different proportions to modulate the erosion rate of the matrix.
En una realización particular de la invención, las poloxaminas se seleccionan entre los Tetronic 304, 701, 901, 904, 908, 1107, 1301, 1304, 1307, 90R4 y 150R1, cuyas propiedades se recogen en la siguiente tabla.In a particular embodiment of the invention, poloxamines are selected from Tetronic 304, 701, 901, 904, 908, 1107, 1301, 1304, 1307, 90R4 and 150R1, whose properties are collected in the following table.
El término "sustancia biológicamente activa" se refiere a cualquier sustancia que se utiliza en el tratamiento, cura, prevención o diagnóstico de una enfermedad o que se utiliza para mejorar el bienestar físico y mental de seres humanos y animales, así como aquel compuesto que se destina a destruir, impedir la acción, contrarrestar o neutralizar, cualquier organismo nocivo. Cuando una o varias sustancias biológicamente activas se incorporan al sistema de la invención éstas se encuentran dispersas a nivel molecular o particular. El sistema es adecuado para incorporar sustancias biológicamente activas independientemente de las características de solubilidad de las mismas. Sin embargo, debido a las características de los componentes del sistema, éste es especialmente adecuado para incorporar sustancias biológicamente activas de baja hidrosolubilidad.The term "biologically substance active "refers to any substance that is used in the treatment, cure, prevention or diagnosis of a disease or that It is used to improve the physical and mental well-being of beings humans and animals, as well as that compound that is intended for destroy, prevent action, counteract or neutralize, any harmful organism. When one or more substances biologically active are incorporated into the system of the invention these are found dispersed at the molecular or particular level. The system is adequate to incorporate biologically active substances independently of the solubility characteristics thereof. But nevertheless, Due to the characteristics of the system components, this is especially suitable for incorporating substances biologically active low water solubility.
\global\parskip1.000000\baselineskip\ global \ parskip1.000000 \ baselineskip
En una realización particular, las sustancias biológicamente activas se seleccionan entre hormonas, antiinflamatorios, antineoplásicos, agentes antimicrobianos y sustancias morfogénicas para reparación de defectos óseos. En una realización más particular, el agente antimicrobiano está destinado al tratamiento localizado de infecciones en tejidos blandos o huesos.In a particular embodiment, the substances biologically active are selected from hormones, anti-inflammatory, antineoplastic, antimicrobial agents and morphogenic substances for bone defect repair. In a more particular embodiment, the antimicrobial agent is intended to localized treatment of soft tissue infections or bones.
En una realización particular de la invención, la proporción de sustancia biológicamente activa está comprendida entre el 1% y el 50% en peso de la mezcla PCL:poloxamina.In a particular embodiment of the invention, the proportion of biologically active substance is comprised between 1% and 50% by weight of the PCL: poloxamine mixture.
La preparación de la mezcla física entre la PCL, la poloxamina y una o varias sustancias biológicamente activas, según la etapa a) del procedimiento, se puede realizar empleando técnicas habituales de mezclado, como por ejemplo una mezcladora de paletas una mezcladora planetaria o una mezcladora tipo túrbula.The preparation of the physical mixture between the PCL, poloxamine and one or more biologically active substances, according to step a) of the procedure, it can be performed using usual mixing techniques, such as a mixer paddles a planetary mixer or a turbo mixer.
La aplicación de calor para fundir la mezcla, según la etapa b) del procedimiento de la invención, se puede llevar a cabo, por ejemplo, con un baño termostatizado de manta o de fluido al que se acopla un sistema de agitación. En esta etapa, las sustancias biológicamente activas se pueden encontrar disueltas o en suspensión.The application of heat to melt the mixture, according to step b) of the process of the invention, it can be carried carried out, for example, with a thermostatized bath of blanket or fluid to which a stirring system is coupled. At this stage, the biologically active substances can be found dissolved or in suspension.
La mezcla de la etapa b) se enfría para obtener el sistema de la invención anteriormente descrito con consistencia sólida o semisólida y aspecto homogéneo. Adicionalmente, si este líquido se deja enfriar en moldes se obtiene el sistema con tamaños predefinidos según el molde. En otra realización particular, los procesos de fusión y moldeo también se llevan a cabo en una sola etapa utilizando un sistema de extrusión en caliente (hot melt).The mixture of step b) is cooled to obtain the system of the invention described above with consistency solid or semi-solid and homogeneous appearance. Additionally, if this liquid is allowed to cool in molds the system is obtained with sizes predefined according to the mold. In another particular embodiment, the melting and molding processes are also carried out in a single stage using a hot melt extrusion system.
En una realización particular, la invención se refiere a una etapa adicional al procedimiento descrito, que comprende la formación de implantes o pelets: el sistema enfriado se puede dividir en porciones por corte y también es posible obtener pelets por pulverización.In a particular embodiment, the invention is refers to an additional step to the described procedure, which It includes the formation of implants or pellets: the cooled system is it can be divided into portions by cut and it is also possible to obtain spray pellets.
Los sistemas obtenidos, en forma de pelets o con otra morfología adecuada para su implantación, son adecuados para administrar sustancias biológicamente activas por distintas vías con el fin de proporcionar una liberación sostenida, de velocidad ajustable a requerimientos específicos.The systems obtained, in the form of pellets or with other morphology suitable for implantation, are suitable for administer biologically active substances by different routes with in order to provide a sustained, speed release Adjustable to specific requirements.
En consecuencia, un aspecto adicional de la invención se refiere al uso de un sistema como se ha definido anteriormente en la preparación de un medicamento o implante.Consequently, an additional aspect of the invention refers to the use of a system as defined previously in the preparation of a medicine or implant.
En una realización preferida, la invención se dirige al uso de un sistema como el definido anteriormente en la preparación de un implante. En una realización más preferida, dicho implante es capaz de liberar una sustancia biológicamente activa para la reparación de defectos óseos.In a preferred embodiment, the invention is directs the use of a system as defined above in the Implant preparation. In a more preferred embodiment, said implant is able to release a biologically active substance for the repair of bone defects.
En otro aspecto, la invención se dirige a una composición farmacéutica que comprende el sistema previamente descrito.In another aspect, the invention is directed to a pharmaceutical composition comprising the system previously described
Figura 1. Perfiles de cesión de ciprofloxacino en medio tampón fosfato pH7.4 a partir de matrices de 1 gramo preparadas a partir de mezclas PCL:Tetronic 1107 75:25 y 25:75 peso/peso y 10 mg de ciprofloxacino.Figure 1. Ciprofloxacin assignment profiles in pH7.4 phosphate buffer medium from 1 gram matrices prepared from PCL mixtures: Tetronic 1107 75:25 and 25:75 weight / weight and 10 mg of ciprofloxacin.
Figura 2. Perfiles de erosión en medio tampón fosfato pH7.4 de matrices de PCL:Tetronic 1107 75:25 y 25:75 peso/peso.Figure 2. Erosion profiles in half buffer pH7.4 phosphate of PCL matrices: Tetronic 1107 75:25 and 25:75 weight / weight
Figura 3. Perfiles de cesión de ciprofloxacino en medio tampón fosfato pH7.4 a partir de matrices de 1 gramo preparadas a partir de mezclas PCL:Tetronic 1307 75:25 y 25:75 peso/peso y 10 mg de ciprofloxacino.Figure 3. Ciprofloxacin assignment profiles in pH7.4 phosphate buffer medium from 1 gram matrices prepared from PCL mixtures: Tetronic 1307 75:25 and 25:75 weight / weight and 10 mg of ciprofloxacin.
Figura 4. Perfiles de erosión en medio tampón fosfato pH7.4 de matrices de PCL:Tetronic 1307 75:25 y 25:75 peso/peso.Figure 4. Erosion profiles in half buffer Phosphate pH7.4 of PCL matrices: Tetronic 1307 75:25 and 25:75 weight / weight
A continuación, para una mejor comprensión de la invención se proporcionan los siguientes ejemplos, sin que éstos supongan una limitación a la invención.Next, for a better understanding of the invention the following examples are provided, without these suppose a limitation on the invention.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Se prepararon mezclas de PCL y Tetronic 1107 en proporciones 75:25 p/p y 25:75 p/p y se incorporó ciprofloxacino al 1% en relación al peso de mezcla PCL:Tetronic 1107. Se fundió la mezcla en un baño de aceite a 150ºC aplicando agitación magnética. A continuación, la mezcla se vertió en moldes refrigerados a 0ºC.Mixtures of PCL and Tetronic 1107 were prepared in proportions 75:25 p / p and 25:75 p / p and ciprofloxacin was incorporated into the 1% in relation to the PCL mix weight: Tetronic 1107. The Mix in an oil bath at 150 ° C by applying magnetic stirring. TO Then, the mixture was poured into molds cooled to 0 ° C.
Para realizar el ensayo de cesión, matrices de 1 gramo se llevaron a tubos de ensayo y se pusieron en contacto con 10 ml de tampón fosfato de pH 7.4 a 37ºC, exponiendo 1.57 cm^{2} al medio de disolución. Los tubos se sometieron a agitación oscilante (50 osc/min). A tiempos preestablecidos se tomaron alícuotas de 1 ml del medio de disolución y se determinó espectrofotométricamente la cantidad de ciprofloxacino cedido. El medio extraído se reemplazó con un volumen igual de tampón. Como control se utilizó una matriz de PCL sin poloxamina preparada por el mismo procedimiento. Los perfiles de cesión obtenidos se muestran en la figura 1.To perform the assignment essay, matrices of 1 gram were taken to test tubes and contacted 10 ml of pH 7.4 phosphate buffer at 37 ° C, exposing 1.57 cm 2 to dissolution medium The tubes were subjected to oscillating agitation (50 osc / min). At pre-established times, 1 ml aliquots were taken of the dissolution medium and the spectrophotometrically determined amount of ciprofloxacin transferred. The extracted medium was replaced with an equal volume of buffer. As a control a matrix was used of PCL without poloxamine prepared by the same procedure. The Assignment profiles obtained are shown in Figure 1.
La velocidad de erosión de las matrices se evaluó registrando la evolución de su peso en el transcurso del tiempo. En la Figura 2 se muestran los perfiles obtenidos.The erosion rate of the matrices is evaluated by recording the evolution of its weight over the course of weather. The profiles obtained are shown in Figure 2.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Se prepararon mezclas de PCL y Tetronic 1307 en proporciones 75:25 p/p y 25:75 p/p y se incorporó ciprofloxacino al 1% en relación al peso de mezcla PCL:Tetronic 1307. Se fundió la mezcla en un baño de aceite a 150ºC aplicando agitación magnética. A continuación, la mezcla se vertió en moldes refrigerados a 0ºC.Mixtures of PCL and Tetronic 1307 were prepared in proportions 75:25 p / p and 25:75 p / p and ciprofloxacin was incorporated into the 1% in relation to the PCL mix weight: Tetronic 1307. The Mix in an oil bath at 150 ° C by applying magnetic stirring. TO Then, the mixture was poured into molds cooled to 0 ° C.
Para realizar el ensayo de cesión, matrices de 1 gramo se llevaron a tubos de ensayo y se pusieron en contacto con 10 ml de tampón fosfato de pH 7.4 a 37ºC, exponiendo 1.57 cm^{2} al medio de disolución. Los tubos se sometieron a agitación oscilante (50 osc/min). A tiempos preestablecidos se tomaron alícuotas de 1 ml del medio de disolución y se determinó espectrofotométricamente la cantidad de ciprofloxacino cedido. El medio extraído se reemplazó con un volumen igual de tampón. Como control se utilizó una matriz de PCL sin poloxamina preparada por el mismo procedimiento. Los perfiles obtenidos se muestran en la figura 3.To perform the assignment essay, matrices of 1 gram were taken to test tubes and contacted 10 ml of pH 7.4 phosphate buffer at 37 ° C, exposing 1.57 cm 2 to dissolution medium The tubes were subjected to oscillating agitation (50 osc / min). At pre-established times, 1 ml aliquots were taken of the dissolution medium and the spectrophotometrically determined amount of ciprofloxacin transferred. The extracted medium was replaced with an equal volume of buffer. As a control a matrix was used of PCL without poloxamine prepared by the same procedure. The Profiles obtained are shown in Figure 3.
La velocidad de erosión de las matrices se evaluó registrando la evolución de su peso en el transcurso del tiempo. En la Figura 4 se muestran los perfiles obtenidos.The erosion rate of the matrices is evaluated by recording the evolution of its weight over the course of weather. The profiles obtained are shown in Figure 4.
Claims (11)
loxamina está comprendida entre el 1% y el 99%7. Method according to claims 4 to 6, characterized in that the proportion of PCL in the PCL mixture:
loxamine is between 1% and 99%
mina está comprendida preferentemente entre el 25% y el 75%.Method according to claim 7, characterized in that the proportion of PCL in the PCL mixture: poloxa-
mine is preferably between 25% and 75%.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200902039A ES2358403B2 (en) | 2009-10-26 | 2009-10-26 | SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES THAT INCLUDES POLY-EPSILON-CAPROLACTONE, POLOXAMINE AND ONE OR VARIOUS ACTIVE SUBSTANCES. |
PCT/ES2010/070683 WO2011051525A1 (en) | 2009-10-26 | 2010-10-25 | System for administering biologically active substances, which comprises poly-ε-caprolactone, poloxamine and one or more active substances |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200902039A ES2358403B2 (en) | 2009-10-26 | 2009-10-26 | SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES THAT INCLUDES POLY-EPSILON-CAPROLACTONE, POLOXAMINE AND ONE OR VARIOUS ACTIVE SUBSTANCES. |
Publications (2)
Publication Number | Publication Date |
---|---|
ES2358403A1 true ES2358403A1 (en) | 2011-05-10 |
ES2358403B2 ES2358403B2 (en) | 2011-12-13 |
Family
ID=43897032
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES200902039A Active ES2358403B2 (en) | 2009-10-26 | 2009-10-26 | SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES THAT INCLUDES POLY-EPSILON-CAPROLACTONE, POLOXAMINE AND ONE OR VARIOUS ACTIVE SUBSTANCES. |
Country Status (2)
Country | Link |
---|---|
ES (1) | ES2358403B2 (en) |
WO (1) | WO2011051525A1 (en) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2232287A1 (en) * | 2003-07-04 | 2005-05-16 | Universidad De Santiago De Compostela | Nanoparticles of polyoxyethylenated derivatives |
US20070053870A1 (en) * | 2005-09-08 | 2007-03-08 | Gwangju Institute Of Science And Technology | Polysaccharide-functionalized nanoparticle, drug delivery system for controlled release comprising the same and preparation method thereof |
US20070092575A1 (en) * | 2005-05-10 | 2007-04-26 | Naomi Balaban | Compositions for administering RNAIII-inhibiting peptides |
US20080139694A1 (en) * | 2006-12-12 | 2008-06-12 | Anthony Ratcliffe | Composite material for tissue repair |
JP2009137922A (en) * | 2007-11-16 | 2009-06-25 | Kaneka Corp | Pharmaceutical preparation for delivering rifamycin derivative to damaged tissue |
-
2009
- 2009-10-26 ES ES200902039A patent/ES2358403B2/en active Active
-
2010
- 2010-10-25 WO PCT/ES2010/070683 patent/WO2011051525A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2232287A1 (en) * | 2003-07-04 | 2005-05-16 | Universidad De Santiago De Compostela | Nanoparticles of polyoxyethylenated derivatives |
US20070092575A1 (en) * | 2005-05-10 | 2007-04-26 | Naomi Balaban | Compositions for administering RNAIII-inhibiting peptides |
US20070053870A1 (en) * | 2005-09-08 | 2007-03-08 | Gwangju Institute Of Science And Technology | Polysaccharide-functionalized nanoparticle, drug delivery system for controlled release comprising the same and preparation method thereof |
US20080139694A1 (en) * | 2006-12-12 | 2008-06-12 | Anthony Ratcliffe | Composite material for tissue repair |
JP2009137922A (en) * | 2007-11-16 | 2009-06-25 | Kaneka Corp | Pharmaceutical preparation for delivering rifamycin derivative to damaged tissue |
Also Published As
Publication number | Publication date |
---|---|
ES2358403B2 (en) | 2011-12-13 |
WO2011051525A1 (en) | 2011-05-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1404294B1 (en) | Biodegradable polymer composition | |
Singh et al. | In situ gelling pH-and temperature-sensitive biodegradable block copolymer hydrogels for drug delivery | |
Yu et al. | Injectable hydrogels as unique biomedical materials | |
Kim et al. | Stimuli-responsive injectable in situ-forming hydrogels for regenerative medicines | |
US20120063997A1 (en) | Delivery system with scaffolds | |
Wan et al. | Investigating a new drug delivery nano composite membrane system based on PVA/PCL and PVA/HA (PEG) for the controlled release of biopharmaceuticals for bone infections | |
EP3030273A1 (en) | Composition and delivery system | |
Hu et al. | A multi-functionalized calcitriol sustainable delivery system for promoting osteoporotic bone regeneration both in vitro and in vivo | |
ES2952975T3 (en) | Tissue framework and framework composition | |
Joshi et al. | Polylactic coglycolic acid (PLGA)-based green materials for drug delivery | |
JP2022068212A (en) | Scaffold material, methods, and uses | |
Küçüktürkmen et al. | Development of zoledronic acid containing biomaterials for enhanced guided bone regeneration | |
ES2358403B2 (en) | SYSTEM FOR THE ADMINISTRATION OF BIOLOGICALLY ACTIVE SUBSTANCES THAT INCLUDES POLY-EPSILON-CAPROLACTONE, POLOXAMINE AND ONE OR VARIOUS ACTIVE SUBSTANCES. | |
Zegre et al. | Research progress on biodegradable polymeric platforms for targeting antibiotics to the bone | |
US11497810B2 (en) | System for administering biologically active substances produced by foaming techniques using compressed gases or supercritical fluids | |
Joshi et al. | 1Department of Pharmaceutical Sciences, Mohanlal Sukhadia University, Udaipur, India, 2Smriti College of Pharmaceutical Education, Indore, India, 3Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS (Deemed to be University), Mumbai, India | |
Hosseini et al. | A Review on Synthesis, Characterization and Applications of Polycaprolactone as a Novel Drug Delivery System and Tissue Engineering |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FG2A | Definitive protection |
Ref document number: 2358403 Country of ref document: ES Kind code of ref document: B2 Effective date: 20111213 |