CN1842321B - Bioerodible sustained release drug delivery systems - Google Patents

Bioerodible sustained release drug delivery systems Download PDF

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CN1842321B
CN1842321B CN2004800247244A CN200480024724A CN1842321B CN 1842321 B CN1842321 B CN 1842321B CN 2004800247244 A CN2004800247244 A CN 2004800247244A CN 200480024724 A CN200480024724 A CN 200480024724A CN 1842321 B CN1842321 B CN 1842321B
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activating agent
delivery system
inner core
described delivery
fluid
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CN1842321A (en
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P·阿什顿
J·陈
H·郭
D·苏
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Viewpoint Pharmaceutical Usa Ltd
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Control Delivery Systems Inc
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Abstract

The present invention relates to sustained release drug delivery systems, medical devices incorporating said systems, and methods of use and manufacture thereof. The inventive systems feature bioerodible drug delivery devices that include biocompatible solid and biocompatible fluid compositions to achieve desired sustained release drug delivery.

Description

Bioerodible sustained release drug delivery systems
Background of invention
Having researched and developed a large amount of technology and system promotes medicine to send.Main purpose is under the condition that allows abundant control drug delivery rate, to provide the slow release of medicine.Some system has used drug delivery systems so that seek this type control, and other device through temporary transient change activating agent chemical property or pack activating agent with excipient or other reagent and realize slow release.However, still there is demand in the system of passing medicine control that improvement is provided.
Summary of the invention
The present invention relates to the polymer drug delivery systems is the sustained release drug delivery systems of characteristic, comprises biocompatible fluid and biocompatibility solid core composition, and wherein the biocompatibility solid is lower than the dissolubility in biocompatible fluid at physiological fluid.These systems provide required sustained release drug delivery.The present invention also pays close attention to medical treatment device and the method for using thereof of using this type systematic.
Detailed Description Of The Invention
The invention provides polymer delivery system (" polymer system "); Comprise inner core or storage, its contain the activating agent of treating effective dose, impervious, pass through property can ignore not as good as part first overlay and optional that passes through the property activating agent sees through or half see through activating agent second overlay.Can also use extra layer alternatively.
Inner core has biocompatible fluid and biocompatibility solid constituent, and wherein the dissolubility of biocompatibility solid in physiological fluid than in biocompatible fluid is low.Biocompatible fluid can be hydrophilic, hydrophobicity or amphipathic; And can be for polymeric or non-polymeric.This type fluid can also be biocompatibility oil (such as Oleum sesami, saturated vegetable fatty acid triglyceride etc.).In certain embodiments, biocompatibility solid (biological example erosion depolymerization compound) is dissolved in, is suspended in or be scattered in (formation " biocompatibility core composition ") in the biocompatible fluid.In certain embodiments, also at least a activating agent is scattered in, is suspended in or is dissolved in biocompatibility core composition.In certain embodiments, activating agent is dissolved in biocompatible fluid.In certain embodiments, described biocompatible fluid is a liquid reagent, and it is the form that is suitable for injecting when merging with biocompatible fluid.
In certain embodiments; Inner core has biocompatible fluid and biocompatibility solid constituent; Wherein the biocompatible fluid composition is liquid medicine or comprises the liquid that has wherein dissolved medicine, and the biocompatibility solid constituent is dissolved in, is suspended in or be scattered in the liquid medicine and forms biocompatibility core composition.Can other medicines or activating agent be scattered in, be suspended in or be dissolved in the biocompatibility core composition, but not necessarily like this.
First overlay around the inner core be impervious, pass through property and can ignore too late or part is passed through the polymer of property, and can be characteristic with one or more quick holes or a plurality of hole (hole), these holes further allow medicine to be diffused into the system outside from in-core.The rate of release of medicine from this type systematic can receive following controlling factors: activating agent is the size of electric potential gradient from core to physiological fluid on every side of thermodynamic activity in biocompatibility core composition of activity in biofacies visitor property core composition of the permeability of in-core, activating agent, activating agent, activating agent, diffusion hole and/or first or the permeability of extra overlay.In certain embodiments, overlay is bioerodible, and in other embodiments, it is non-bioerodible.
U.S. Pat 5,378,475, US 5; 773,019, US 5,902; 598, US 6,001,386 with US 6; 375,972 and pending trial U.S. Patent application US 10/428,214 and 60/501947 in disclosed the different embodiments of the sustained release drug delivery systems that have one or more polymer-coated layers.As illustrating, but be not the qualification effect, this type device can be used for system as herein described, and the content of the complete disclosure of these lists of references is introduced this paper as a reference.
In preferred embodiments, first overlay comprises at least a polymer (can comprise more than one polymer alternatively), and preferably bioerodible, perhaps, can separate for abiotic erosion.First overlay covers part at least, but is not the surface of whole inner cores, is a quick hole thereby kept this, and activating agent can pass through from inner core through this hole.In certain embodiments, particularly in impervious situation, film can have one or more holes.If the use second layer, it can partly cover or cover basically whole first overlays and inner core so, and its permeability to activating agent allows this activating agent to diffuse into surrounding fluid.
Various polymer can be suitable for forming overlay of the present invention.Preferred polymer obviously is insoluble to physiological fluid.Suitable polymers can comprise natural existence or synthetic polymer.Some typical polymer comprises; But be not limited to polyvinyl acetate, cross-linking polyvinyl alcohol, cross-linked vinyl butyrate, ethylene ethyl acrylate copolymer, polyethylene ethylhexyl acrylate, polrvinyl chloride, polyvinyl acetal class, plastifying ethylene vinyl acetate copolymer, polyvinyl alcohol, ethylene-vinyl chloromethylated copolymer, polyethylene esters, gather vinyl butyrate, polyvinyl formal, polyamide-based, polymethyl methacrylate, polybutyl methacrylate, plastifying polrvinyl chloride, plastifying nylon, plastifying soft nylon, plastifying PETG, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, politef, Vingon, polyacrylonitrile, crospolyvinylpyrrolidone, polytrifluorochloroethylene chlorinated polyethylene, gather (1,4-isopropylidene diphenylene (diephenylene) carbonic ester), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-dimethoxym ethane diethanol (diethyl fumerale) copolymer, silicone rubber, medical grade polydimethylsiloxane class, EPM, siloxanes-carbonate copolymer, ethenylidene chloro-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer, ethenylidene chloro-acrylonitrile copolymer etc.
Biocompatibility core composition comprises at least and is partially soluble in, is suspended in or be scattered at least a biocompatibility solid in biocompatibility polymerization or non-polymeric fluid or the biocompatibility oil (biological example erosion depolymerization compound).In addition, described biocompatibility solid than dissolving manyly in the physiological fluid closely around, makes that described biocompatibility core becomes fractional precipitation or undergoes phase transition when said device physiological fluid is contacted in described biocompatible fluid or oil.Can inner core be sent as gel.Preferably can it be sent as the granule or the liquid that change into gel when contact with water or the physiological fluid.In certain embodiments, described biocompatibility (for example non-polymeric) fluid can comprise the medicine of free alkali form.
In certain embodiments, the biocompatible fluid in the biocompatibility core composition is hydrophilic (for example PEG, cremophor, polypropylene glycol, a glycerin mono-fatty acid ester etc.), hydrophobic or amphipathic.In certain embodiments, described fluid can be monomer, polymer or its mixture.If use, biocompatibility oil can be Oleum sesami, saturated vegetable fatty acid triglyceride etc. so.
In certain embodiments, can use injectable liquids, it undergoes phase transition and changes in position the gel delivery vector when injection.In certain embodiments, when the contact physiological fluid, at least a polymer in the inner core can be changed in the gel phase of drug diffusion from the liquid phase of drug.Based on the technical description of in-situ gelling in U.S. Pat 4,938,763, US 5,077,049, US 5; 278,202, US 5,324,519 with US 5; In 780,044, all these technology all can be suitable for the present invention, and the content that every piece of open source literature discloses is introduced this paper as a reference.
In certain embodiments, described activating agent polyoxyethylene ether is covalently bound, wherein covalent bond in vivo by cracking to discharge described activating agent.In certain embodiments, described activating agent discharges with continuous fashion.Show shown in the method such as U.S. Pat 5,681,964 and U.S. Provisional Application US60/539306 that forms and use conjugation prodrug (for example PEG-drug conjugate), the full content of these patent documentation description is introduced this paper as a reference.
In certain embodiments, described activating agent is the prodrug of the another kind of activating agent of Pegylation.
In certain embodiments, described activating agent can be included in the chemical compound with following structure 1:
A(-L-) mS n
1
Wherein A is the residue of pharmaceutically active agents A ', and L representes covalent bond or connects base section, and S is for having general formula-(OCH 2CH 2) pThe polyoxyethylene ether of OR, wherein p is that 2-12 and R are C 1-C 4Alkyl.Described biocompatible fluid can comprise the mixture of the chemical compound with p value scope; But in preferred embodiments, p has a kind of chemical compound that single value and compositions only comprise structure 1.Key or connect basic L can be in vivo by cracking with release bioactive agent A '.Activating agent A ' general features is the functional group that the basic L of one or more connections is used to be attached thereto.This type functional group's instance includes, but are not limited to-CO 2H ,-CONH 2,-CHO ,=O ,-OH ,-NH 2With-the SH group.
Can be included, but are not limited to esters, amide-type, carbamates, carbonates, ortho acid esters, cyclic ketones acetal class, thioesters class, thioamide analog, thiocarbamates, thiocarbonic acid esters, xanthic acid esters, disulphide phosphoric acid ester by the instance of cracked key and connecting key in vivo through hydrolysis or through enzyme catalysis.Preferred ester bond, carbonic ester connect base and/or aminoacid coupling part.The connection base of the enzymatic cleavable that is used for polyoxyethylene deriv for example, has been described: U.S. Pat 6,127,355 in many lists of references of following document and wherein citation; Ulbrich etc. " macromolecular chemistry " (Makromol.Chem.) 1986; 187:1131-1144; With " anticarcinogen design " (Anti-CancerDrug Design) 1999 such as Conover; 14:499-506, and this type of special concern connects the application of base.Can also use ester bond (referring to " percutaneous absorptions " such as R.Bronaugh (PercutaneousAbsorption) the 3rd edition, p.58-63, R.L.Bronaugh and H.I.Maibach, eds., Marcel Dekker, New York, 1999).
Generally in the scope of 1-4, but, bigger value belongs to scope of the present invention to the value of m and n.In general, connect base and be bivalence, and m has identical value with n, but can use the Multiple Bonds that is connected with single part S, for example conduct is in ketal or original acid ester key.Perhaps, multiple partial S can be through the basic L of single connection, for example through using (=O) the CH [(OCH such as-C 2CH 2) pOR] 2Or-P (=O) [(OCH 2CH 2) pOR] 2This type partial esterification activating agent A is subsidiary.If m＞1 and/or n＞1, L and S all can be identical or different when occurring at every turn so.
The residue of being represented by A can derive from any activating agent, includes, but are not limited to steroid (preferred corticosteroid), retinoid, NSAIDs, vitamin D3 and vitamin D 3 analogs, antibiotic and antiviral agents.Other suitable activity agent comprises enzyme, peptide class and other macromole O.In certain embodiments of the invention, do not comprise the alltrans tretinoin in the residue of representing by A, and in other embodiments, do not comprise retinoid in the residue of representing by A.
Suitable steroid includes, but are not limited to produce masculine sex character and estrogen sex steroid hormone, androgen receptor antagonists and 5-alpha-reductase inhibitors and corticosteroid.Instantiation includes, but are not limited to alclometasone, clobetasol, fluocinolone acetonide, fluocortolone, diflucortolone, fluticasone, halcinonide, mometasone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone and dexamethasone and various esters and Nai De class.
Suitable retinoid includes, but are not limited to vitamin A, retinal, isotretinoin, acitretin, adapalene, tazarotene and bexarotene.
Suitable NSAID includes, but are not limited to naproxen, suprofen, suprofen, ibuprofen, flurbiprofen, diclofenac, indomethacin, celecoxib and rofecoxib.
Suitable vitamins D3 analog degree of including, but are not limited to ostelin, seocalcitol, calcipotriene, tacalcitol, calcitriol, vitamin D2 and calcifediol.
Suitable antiviral agents includes, but are not limited to trifluridine, GS-504, acyclovir, acyclovir, famciclovir, valaciclovir, ganciclovir and tadenan.Suitable antimicrobial drug includes, but are not limited to metronidazole, clindamycin, erythromycin, vancomycin, ciprofloxacin, ofloxacin, lomefloxacin, bacitracin, neomycin, mupirocin and polymyxin B.Antiviral of the present invention and antibiotic prodrug can be used for suitable therapeutic response property systemic infection.
Connecting basic L can be meant use or not use enzyme catalysis to make compound hydrolysis of the present invention by cracked implication in vivo, otherwise just by cracking, so that generate described activating agent in position.
The instance of suitable connection base includes, but are not limited to-CH 2O-,-OCH 2O-,-C (=O)-O-,-OC (=O)-O-,-C (=O)-(CH 2) 1-4-O-and-C (=O)-(CH 2) 1-4-,-C (=O)-NH-and-C (=S)-NH-.About the description of suitable connection base can be at " prodrug: part and ophthalmic drug delivery " (Prodrugs:Topical and Ocular DrugDelivery); 1992; K.B.Sloan (Ed.), " medicine and pharmacy science " (Drugsand the Pharmaceutical Sciences) find in 53 volumes (Marcel Dekker).Be appreciated that cleavage rate is different and be connected base or key L character and the different of junction point and change with the precision architecture of activating agent and polyoxyethylene ether.The prodrug lysis efficiency that is used for the connection base of any specific embodiments is easy to measured by those skilled in the art; Method is summarized referring to A.Stichcomb, 2003 " drug researches " (Pharm Res.) 20:1113-1118.
Connect base or key L can be present in local hetero atom and be connected with any appropriate on the activating agent, tradable hydrogen is carried with activating agent in described part, such as-OH, SH, NH 2With the COOH group.As an example, can use-C (=O) (OCH 2CH 2) pThe free hydroxyl group of the partially acylated triamcinolone acetonide of OR.
In one embodiment, activating agent contains carboxylic moiety and this carboxylic moiety by general formula HO (OCH 2CH 2) pThe polyoxyethylene ether esterification of OR.Instance includes, but are not limited to structure I as follows, II and III:
Figure S04824724420060316D000061
In alternate embodiment, activating agent contains hydroxyl and this hydroxyl by general formula HO (OCH 2CH 2) pThe carbonyl moiety esterification of the polyoxyethylene ether of OR.Instance includes, but are not limited to structure I V as follows and V:
In certain embodiments, described biocompatible fluid comprises prodrug, and this prodrug contains and general formula-(OCH 2CH 2) pThe medical compounds that the polyoxyethylene ether moiety of OR connects, wherein p=2-12 and R are C 1-C 4Alkyl.In certain embodiments, n is the integer that comprises 2-6.Radicals R can be methyl, ethyl or other organic moiety arbitrarily.
The application of the prodrug key that is connected with activating agent in certain embodiments, can improve activating agent at water or the dissolubility in polymer.For example, the application of Pegylation prodrug can improve activating agent in biocompatible fluid dissolubility and improve injectability of the present invention thus.The application of prodrug key can also reduce the fusing point of solid activator or increase the dissolubility of activating agent in physiological fluid, improves the injectability of this activating agent thus.
Said activating agent is dissolved in, is scattered in or is suspended in the biocompatibility core, thus it can from in-core ooze out and get into around fluid.In certain embodiments, activating agent can break away from from injection mixture after injecting physiological system fast.
In certain embodiments, described biocompatibility solid constituent can for, for example, but be not limited to gather (lactic acid copolymerization-glycolic) acid (PLGA).
In certain embodiments, described inner core is to contain at least 10% activating agent or preferred 50% above activating agent or the more preferably viscous batter of 75% above activating agent.
In certain embodiments, with said polymer system injection or insertion physiological system (for example patient).In injection or when inserting, the delivery system contact can get into polymer system and contact around water or other of inner core physiological fluid closely.In certain embodiments, can select the material of core, so that generate the base that reduces (and allowing control thus) rate of release of activating agent from delivery system.
In preferred embodiments, the rate of release of activating agent from said system mainly receives permeability or the deliquescent restriction of activating agent in substrate.Yet rate of release can receive the control of various other character or factor.For example; But be not limited to, rate of release can receive the control of following character or factor: the dissolubility in the dissolution rate of the permeability of the size of diffusion hole, the second layer of polymer system, the physical property of core (for example permeability or the permeability or the dissolubility in dissolubility and the biofacies visitor property fluid of activating agent in biocompatibility core composition of activating agent in the biocompatibility solid is opposite), core or core composition or the activating agent physiological fluid around polymer system is tight.
In certain embodiments, the rate of release of activating agent mainly receives the restriction of any phase in the following characteristic.For example, in certain embodiments, the rate of release of activating agent can receive the control of the size of diffusion hole, and even mainly receives its restriction.Difference according to the required delivery rate of activating agent; Ground floor can only apply the sub-fraction surface area of inner core; So that the rate of release that makes activating agent is fast (being that diffusion hole is big relatively) more; The most surfaces that maybe can apply inner core is long-pending, so that the rate of release of activating agent slowly (being that diffusion hole is relatively little).
With regard to rate of release faster, it is long-pending that ground floor can apply the core surface of Gao Yueda 10%.In certain embodiments, the core surface that applies about 5-10% with ground floor is long-pending, so that rate of release is very fast.
Some embodiment can obtain ideal slow release, and it is long-pending that condition is that ground floor covers at least 25% core surface, preferred at least 50% surface area, and more preferably at least 75%, and even greater than 85% or 95% surface area.In certain embodiments, particularly be soluble in the situation of polymer core and biofluid,, can realize best slow release so if ground floor covers at least 95% or 99% inner core at activating agent.Therefore, can use first overlay to apply the long-pending arbitrary portion of core surface, be up to, but do not comprise 100%.
In any case first coating all is positioned on the inner core, include, but are not limited to top, bottom or any side of inner core.In addition, it can be positioned at top and side, or bottom and side, or the upper and lower, or opposite side, or top, bottom or lateral combination in any.
Composition to first overlay is selected, so that above-mentioned controlled release is provided.The preferred composition of ground floor can be according to different change the such as rate of release with this type of administering mode factor of activating agent, required activating agent.The character of activating agent is important, because its molecular size at least partly determines it to be released into the speed of the second layer.
In certain embodiments, the rate of release of activating agent from inner core can reduce because of the permeability of second overlay.In certain embodiments, the second layer can freely see through activating agent.In certain embodiments, the second layer as far as activating agent for semipermeable.In certain embodiments, the infiltration coefficient that in the second layer, has of activating agent is less than about 1 * 10 -10Cm/s.In other embodiments, the infiltration coefficient that in the second layer, has is greater than 1 * 10 -10Cm/s, and even greater than 1 * 10 -7Cm/s.In certain embodiments, the infiltration coefficient in the second layer is at least 1 * 10 -5Cm/s, so be at least 1 * 10 -3Cm/sl, or be at least 1 * 10 -2Cm/s.
In certain embodiments, the infiltration coefficient that in first overlay, has of activating agent is less than about 1 * 10 -10Cm/s.In other embodiments, the infiltration coefficient that in first overlay, has is greater than 1 * 10 -10Cm/s, and even greater than 1 * 10 -7Cm/s.In certain embodiments, the infiltration coefficient in first overlay is at least 1 * 10 -5Cm/s, so be at least 1 * 10 -3Cm/sl, or be at least 1 * 10 -2Cm/s.
In certain embodiments, inner core undergoes phase transition (being the biocompatibility solid precipitation), and when polymer system being implanted or inserting in the physiological system, changes into gel.Phase transformation can slow down the speed that activating agent discharges from inner core.For example, if at first the part at least of core is provided and change into gel as liquid, the gel phase of polymer core possibly be lower than the liquid phase that changes into the gel prepolymer permeability to activating agent to the permeability of activating agent so.In certain embodiments, polymer core is low at least by 10% to the permeability of activating agent in gel phase than in liquid phase, and even hangs down 25% at least.In other embodiments, sedimentary biocompatibility solid is lower at least by 50% to the permeability of activating agent than independent biocompatible fluid, and even hangs down 75% at least.
In certain embodiments, the interaction of said core and physiological fluid can change the dissolubility of activating agent in core, and the rate of release of slowing down activating agent thus.For example, core is low at least by 10% before interacting with physiological fluid to the solubilization ratio of activating agent, and even hangs down 25% at least; In other embodiments, if gel phase, gel phase is low at least by 50% to the solubilising of activating agent so, and even hangs down 75% at least.
In certain embodiments, the biocompatibility solid of core and/or biocompatible fluid composition dissolve when contacting with physiological fluid.The dissolved speed of this constituents this moment can influence the rate of release of activating agent.In certain embodiments, when the erosion of core composition was separated or dissolved, the speed that activating agent discharges increased.For example, in certain embodiments, be lower than about 10% core composition and in about 6 hour time limit, can lose and separate or dissolve.This result can increase the rate of release of activating agent about below 10% in this time bar.In certain embodiments, biocompatibility core composition can lose more lentamente and separate or dissolve (for example in about 24 hour time limit, and even in many days, many weeks and even many months time limits, being lower than about 10%).In certain embodiments, (for example in about 6 hours greater than about 10%, in certain embodiments, in about 6 hour time limit even greater than 25%) can take place in this type etch or dissolving more quickly.
In certain embodiments, the dissolubility of activating agent in core influences the speed that this activating agent discharges from polymer system.In certain embodiments, activating agent in core be solvable, moderate is solvable and even slightly soluble or very slightly soluble.Activating agent has surpassed activating agent only slightly soluble or the atomic rate of release that is dissolved under the polymer core situation from the rate of release that this activating agent is dissolved in the polymer core of core.
In certain embodiments, the rate of release of activating agent from inner core can receive the control of activating agent and the ratio (being also referred to as " drug load ") of biocompatibility solid constituent in the core.Through changing drug load, can obtain different release rate properties.Increase drug load and can improve rate of release.With regard to release characteristics more slowly, drug load has and is lower than 10%, and preferably is lower than 5%.With regard to release characteristics faster, drug load can be greater than 10%, and is preferably greater than 20%, and even greater than 50%.
In certain embodiments, activating agent has low solubility in the tight physiological fluid on every side of polymer system of implantation/insertion.In this type embodiment; The speed that activating agent discharges from polymer system can receive the control (be activating agent the dissolubility in the fluid is low more closely around, then its speed of from polymer system, discharging is low more) of the dissolubility of activating agent in this type surrounding fluid.In certain embodiments, activating agent around the dissolubility in the physiological fluid be moderate or be lower than moderate.
In certain embodiments, described activating agent is common medicine (codrug) or its prodrug, wherein said common medicine (codrug) or its prodrug around the dissolubility in the physiological fluid than its constituent at least low 5%.In this type embodiment, the speed that the component that the speed ratio that activating agent discharges from polymer system does not connect discharges from polymer system hangs down 5% at least.In certain embodiments, common medicine (codrug) or its prodrug around the dissolubility in the fluid lower at least by 25% than its component that does not connect, at least low 50% or hang down 75% at least.Therefore, when in common medicine (codrug) (or its prodrug) form, described component being provided, its rate of release is lower than its not connected form.In some embodiment of using common medicine (codrug), common medicine (codrug) separates when the contact physiological fluid, so that from core, produce and discharge one or more therapeutic activity agent.
Therefore, the rate of release of activating agent of the present invention mainly receives the restriction of phase arbitrarily in above-mentioned characteristic or any other factors.For example; But be not limited to, rate of release can receive the control of following characteristic or factor: quick dissolubility in core of the physical characteristic (the for example gel after the phase transformation) of the permeability of the ground floor or the second layer or other characteristic, core in the size in hole and/or position, the polymer system, one or more the dissolution rate, activating agent in the core composition, the activating agent dissolubility in the physiological fluid etc. closely around polymer system.In certain embodiments, the release of activating agent mainly possibly receive the restriction of any one factor, and feasible conduct wherein a kind of result of factor slows down for rate of release.In certain embodiments, liken to the result's of any another kind of factor rate of release as the rate of release of a kind of factor result's activating agent and slow down 10% at least.In certain embodiments, liken to the result's of any another kind of factor rate of release as the rate of release of a kind of factor result's activating agent and to slow down 25% at least, and even slow down 50% or slow down 75% at least at least.
Above-mentioned factor is merely and illustrates.Any other characteristic of those skilled in the art's easy to understand system of the present invention all possibly become activating agent limiting factor in the rate of release from this system.
In one aspect of the method, assemble system of the present invention for the drug delivery systems that can in the extended period, send a kind of medicine and even two or more synergism medicines.In certain embodiments, system of the present invention has the patient of this demand that the activating agent of the treatment effective dose of slow release is provided.In preferred embodiments, described device allowed at least 3 hours, and preferably at least 12 hours, and even 1 day, at least 2 days, so 1 week, send chemical compound at least 1 month or at least 1 year time limit.In certain embodiments, system of the present invention can be applied on support or other device.This type device includes, but are not limited to surgical screw, pseudarthrosis, artificial valve, plate, pacemaker, stitching thread etc.
Definition
Term used herein " activity " refers to biology, treatment or pharmacological activity.
Term used herein " activating agent " is with " at least a activating agent ", " chemical compound " or " at least a chemical compound " synonym and refer at least a medicine or common medicine (codrug) or its prodrug.In certain embodiments, described activating agent can be common medicine (codrug) or its prodrug of at least a low solubility.In certain embodiments, common medicine (codrug) or its prodrug are designed to have low solubility in described core, biofluid or they among both.In certain embodiments, described activating agent is protein, peptide or Pegylation activating agent.In other embodiments, term " activating agent " refers to multiple medicine, protein, peptide class etc.In certain embodiments, described activating agent can be particle form.In certain embodiments, can described activating agent and pharmaceutically acceptable carrier be merged.In certain embodiments, described activating agent is a liquid form.
" effective dose " of the activating agent that aspect Therapeutic Method, relates to refer to as the ingredient administration of required dosage scheme (to mammal; Preferred people) the mitigation symptoms time, improves disease condition or delay the consumption of activating agent in the preparation of disease condition outbreak, described mitigation symptoms, improve disease condition or delay the disease condition outbreak all according to clinically treatment disease or disease or the acceptable standard of cosmetic purpose being confirmed.
Term " ED 50" refer to the drug dose that produces 50% maximum response or effect.
Term used herein " granule (granule) ", " granule (particle) " or " granule (particulate) " can exchange and use and refer to any granule.In some typical embodiments, the diameter that described granule has is in the scope of the about 3mm of about 0.01mm-, preferably in the scope of the about 2mm of about 0.1mm-, and even more preferably in the scope of the about 1.5mm of about 0.3mm-.
Term " EC used herein 50" refer to the drug level that produces 50% maximum response or effect.Term " IC 50" refer to biological activity is suppressed to reach 50% drug dose.
Term " LD 50" refer to lethal drug dose in 50% test subject.
Term " therapeutic index " refers to and is defined as LD 50/ ED 50The Drug therapy index.
" patient " of systematic treating of the present invention or " experimenter " refer to people or inhuman animal.
It is inner that " physiological condition " described organism, promptly intravital condition.Physiological condition comprises acidity and alkaline environment, enzymatic lysis, metabolism and other bioprocess of body cavity and organ, and preferably refers to vertebrates, such as the intravital physiological condition of mammal.
In general, " low solubility " refers to the atomic medium (aqueous solution that for example has the about 8 scope pH of about 5-, and physiological solution particularly, such as blood, blood plasma etc., the gel in other associated media polymer core and other material) that is dissolved in of activating agent.Some activating agent, for example the dissolubility that in said medium, has of low solubility activating agent is lower than about 1mg/ml, is lower than about 100ug/ml, preferably is lower than about 20ug/ml, more preferably less than about 15ug/ml, and even more preferably less than about 10ug/ml.Except as otherwise noted, like listed time-and-motion study among the 1995USP, under 25 ℃ of temperature, be determined at the dissolubility in the water.The present invention pays close attention to soluble compound (greater than about 100mg/ml), moderate soluble compound (the about 10mg/ml of about 100mg/ml-), micro-soluble compound (the about 1mg/ml of about 10mg/ml-), atomic soluble compound (the about 0.1mg/ml of about 1mg/ml-); And particularly dissolubility or insoluble compound (be lower than about 0.1mg/ml, preferably be lower than about 0.01mg/ml) hardly.
" LogP " of activating agent used herein refers to the logarithm of P (partition coefficient), and wherein P is how many activating agents distributes between capryl alcohol and water a measured value.P is defined as chemical compound ratio in concentration with chemical compound the concentration in capryl alcohol of aqueous phase according to formula with it certainly as steady state value:
Partition coefficient P=[organic facies]/[water], wherein [] concentration
LogP=log 10(partition coefficient)=log 10P
The LogP value is that 1 implication is that the concentration of chemical compound in organic facies is higher than 10 times of the concentration of aqueous phase.The LogP value increases by 10 times for increasing the concentration ratio of 1 expression chemical compound in organic facies in the concentration of aqueous phase.
Term " residue " refers to basically the ingredient of the identical activating agent of the activating agent that derived from it when being applied to activating agent, its medium and small difference is to produce the junction point that connects basic L because of one or more atoms are removed.In general, at least one functional group (for the parent drug activating agent) on the change residue is so that accept covalently bound base.This process generally comprises removes tradable hydrogen and/or single hetero atom, thereby has kept the free valency that is used to connect connecting key L.For example; If activating agent comprises the carboxylate functional group; Can form ester bond with the hydroxyl on the polyoxyethylene ether residue through removing the activating agent residue that hydroxyl forms so, described polyoxyethylene ether residue self forms through removing dehydrogenation on the residual hydroxyl of selfpolyoxyethylene ether always.Implication when in this case, term used herein " residue " and this wording are used in reference to peptide and the protein chemistry of peptide upper amino acid residue is similar.
Term " connect base " can exchange use in this article with " connecting key ", refers to the multivalence group of direct key or introducing and the functional group's who is connected activating agent and polyoxyethylene ether atom, it under physiological condition by metabolism so that release bioactive agent A '.In certain embodiments, connect base and be no more than 25 atoms, more preferably be less than the part of the straight chain basically of 10 atoms for having.The preferred base that connects is for discharging in the Topically active agent and being created under the effective dose concentration avirulence during further by metabolism and being the connection base of inert by-product.Direct key between preferred especially residue A and the polyoxyethylene part S.
Term used herein " common medicine (codrug) " refers to the chemical compound that contains the first kind of molecule residue that is connected with second kind of molecule residue, and wherein every kind of residue of independent form (for example in the presence of not combining) is the prodrug of activating agent or activating agent separately.In preferred embodiments, one of first kind and second kind molecule residue or they both be micromolecule.Combination between the said residue can be ions bind or covalent bond, and in covalently bound situation, this combination is directly or indirectly through connecting base.First kind of molecule and second kind of molecule can be identical or different.The typical general formula of common medicine (codrug) can be seen at general formula I, Ia, II, IIa, III, IIIa and IV:
A 1 ＊(-L-A 2 ＊) n(I)
A 1 ＊(-A 2 ＊) n(Ia)
A 1 ＊-L-A 2 ＊?(II)
A 1 ＊-A 2 ＊?(IIa)
A 2 ＊-L-A 1 ＊-L-A 2 ＊(III)
A 2 ＊-A 1-A 2 ＊(IIIa)
A 1 ＊::A 2 ＊(IV)
Wherein separately as giving a definition A 1 *, A 2 *And L:
A 1 *Be first kind of bioactive compound A 1Residue;
A 2 *Be second kind of bioactive compound A 2Residue, with A 1Can be identical or different;
L is selected from direct key and the organic connection base that is connected base of bivalence; And
N is the integer with value of 1-4, preferred 1;
And:: be ionic bond.
Term used herein " prodrug " refers to and second kind of bonded first kind of residue of residue, and wherein one of residue is bioactive.In preferred embodiments, one of first kind and second kind residue or they both be micromolecule.In certain embodiments, one of residue does not have biological activity; In certain embodiments, described prodrug can be active for inanimate object in its prodrug forms.Being combined into covalent bond and can passing through to connect base between the said residue directly or indirectly combines.The prodrug of bioactive compound is included in esters and anhydrides, amide-type and the carbamates that is hydrolyzed into parent compound in the biofluid.Those skilled in the art recognize that " prodrug " part for general no pharmacological activity.Yet, during activation, give the medical function that prodrug has had expection to individuality generally through enzymatic or hydrolytic rupture said prodrug being changed into the active bio part in vivo.Prodrug generally forms through biologically-active moiety is carried out chemical modification.For example, in " prodrug design " (Design ofProdrugs) ed.H.Bundgaard, Elsevier, 1985. " in the selection that is used for suitable prodrug derivant and the routine operation of preparation have been described.
Term used herein " physiological pH " refers under 37.4 ℃ standard physiological temp and is about 7.4 pH.Term used herein " non-physiological pH " refers to the pH that is below or above " physiological pH ", preferably about 4-7.3 or greater than 7.5 be lower than about 12.Term used herein " neutral pH " refers to pH and is about 7.In preferred embodiments, physiology-pH refers to pH 7.4 and non-physiological pH and refers to pH and be about 6-7.Term " acid pH " refers to the pH that is lower than pH 7, preferably is lower than about pH 6, and even is lower than about pH 4.
Term " biological erosion is separated " is generally acknowledged with " biodegradable " synonym and by this area.It comprises in use polymer, compositions and the preparation of degraded, such as as herein described those.The aspect that biodegradable polymer generally is different from non-biodegradable polymer is that the former in use is degraded.In certain embodiments, this type application comprises in the body uses, and such as using in the therapy in vivo, and in some other embodiment, this type application comprises in-vitro application.In general, the degraded that causes because of biodegradability comprises that biodegradable polymer is degraded into its composition subunit, or for example through biochemical process polymer is digested to less non-polymeric subunit.In certain embodiments, biodegradation through enzymatic mediation, having the operation of water and/or other chemical species to degrade down or their both combinations take place.
Term " biocompatibility (biocompatible) " is art-recognized when using in this article with " biocompatibility (biocompatibility) "; And refer to indicant self both to host (for example animal or human) avirulence, again can't be under toxic concentration in the host to produce by-product (for example monomer or oligomeric subunit or other by-product), cause inflammation or stimulation or to bring out immunoreactive speed degraded (if its degraded).Any experimenter's composition has thinks that the compatibility of 100% purity is not necessarily necessary.Therefore; The experimenter forms and can comprise 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% and even lower biocompatibility activating agent, for example comprises polymer as herein described and other material and excipient and remains biocompatibility.
Term used herein " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, compositions or vehicle; Such as liquid or solid filtering agent, diluent, excipient, solvent or coating material, they relate in organ or the part from health and will receive the reagent thing to carry or be transported to another organ or part in the health.Every kind of carrier phenotype is " acceptable ", its implication be with preparation in other compatible and harmless to the patient.
Some instance that can be used as the material of pharmaceutically acceptable carrier comprises: (1) saccharide, such as lactose, dextrose plus saccharose; (2) starch forms sediment such as corn starch and Rhizoma Solani tuber osi; (3) cellulose and derivant thereof are such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) Calculus Bovis from Northwest of China rubber powder; (5) Fructus Hordei Germinatus; (6) gelatin; (7) Pulvis Talci; (8) excipient is such as cocoa butter and suppository wax; (9) oil is such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami.Olive oil, Semen Maydis oil and soybean oil; (10) glycols is such as propylene glycol; (11) polyalcohols is such as glycerol, sorbitol, mannitol and Polyethylene Glycol; (12) esters is such as ethyl oleate and ethyl laurate; (13) agar; (14) buffer agent is such as magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) apirogen water; (17) isotonic saline solution; (18) Ringer's solution; (19) ethanol; (20) PBS; (21) be used for other avirulence compatible material of pharmaceutical preparation.
Term used herein " protection base " or " blocking group " refer to and prevent that possible reactive functional group base from the interim substituent group of unwanted chemical conversion taking place.The instance of this type protection base comprises the silicyl ethers of carboxylic acid esters, alcohols and the acetal and the ketals of aldehydes and ketone respectively.The basic chemical field of protection (Greene, T.W. have been summarized; Wuts, P.G.M. " the protection base in the organic synthesis " (Protective Groups in OrganicSynthesis), the 2nd edition; Wiley:New York, 1991).
Term " residue " refers at chemical compound and directly is connected or is connected with the bivalence coupling part chemical compound part that the back keeps through direct key with another chemical compound.For example, if residue A 1Contain carboxylic moiety, this carboxylic moiety is through amino and second residue A 1Form connecting key and form compd A 1-A 1, comprise amido link, so first residue A 1Be the residue of parent compound, this parent compound comprise except that form the amide groups part-all parent fractions the OH, and another residue comprises except that from all parent fractions the H-of amino.Those skilled in the art think this situation respectively with polypeptide class and protein in aminoacid " residue " or similar with nucleotide and Deoxydization nucleotide " residue " among RNA and the DNA.
Term of the present invention " mainly receives ... restriction " refers to the relevant factor of rate-limiting step in the speed that from system of the present invention, discharges with activating agent.For example; But be not limited to; The rate of release of activating agent mainly receives the restriction of the dissolution rate of activating agent in polymer, and wherein said dissolution rate is the rate-limiting step (the for example described stripping specific activity agent dispersion rate in the physiological fluid around is slow) during activating agent discharges.Similarly; If rate of release (for example rate-limiting step) is the result of medium characteristics (permeability that for example under molecular weight, the gel state activating agent is passed through, the size of diffusion hole), think that so also rate of release " mainly receives " restriction of this class feature, this type substrate etc.
Typical embodiments
In one embodiment, will gather (lactic acid-copolymerization-glycolic) and (PLGA) be dissolved in Polyethylene Glycol (PEG); This solution is remained in the water-bath under 37 ℃.PLGA-PEG solution and bovine albumin mixing and formation semi-solid gel with equivalent.This gel inserted on the bottom have the siloxanes cup (1.5mm ID) of aperture and then with the top seal of organic silica gel with cup.Make the hole of bottom keep opening or coat polymers film so that sustained release.The finished product (being full of the siloxanes cup of albumin-PGA-PEG gel) of finally assembling is put into 0.1m phosphate buffer (pH 7.4) and used HPLC to analyze albuminised burst size under 37 ℃.The albumin rate of release is following:
Provide above-mentioned embodiment only presented for purposes of illustration, but be not used for the qualification effect.Those skilled in the art think should other embodiment of the present invention be regarded as and belong in the above-mentioned general scope of disclosure, and the mode of not estimating with any above-mentioned non-limiting example is abandoned.
Especially all patents of quoting from the above-mentioned disclosure, open source literature and list of references are introduced this paper as a reference.

Claims (33)

1. delivery system comprises:
Inner core comprises: (i) biocompatible fluid composition; (ii) be dissolved in the biocompatibility solid constituent in the biocompatible fluid composition, wherein the biocompatibility solid constituent is PLGA, and wherein when contacting with physiological fluid, biocompatible fluid composition and biocompatibility solid constituent form gel; (iii) at least aly be scattered in, be suspended in or be dissolved in the activating agent in the inner core; With
Cover part at least, but be lower than 100% said inner core, can not see through said activating agent and be insoluble to first polymeric layer of physiological fluid.
2. the described delivery system of claim 1 also comprises the second polymer layer that can see through at least a activating agent.
3. the described delivery system of claim 1, wherein the biocompatible fluid composition of inner core is hydrophilic, hydrophobicity or amphipathic fluid.
4. the described delivery system of claim 3, wherein hydrophilic fluid is Polyethylene Glycol (PEG).
5. the described delivery system of claim 1, wherein the biocompatible fluid composition is a biocompatibility oil.
6. the described delivery system of claim 1, wherein first polymeric layer can not see through at least a activating agent.
7. the described delivery system of claim 1, wherein first polymeric layer covers the inner core at least about 50%.
8. the described delivery system of claim 1 dissolves at least 10% than in the inner core before changing into said gel in the inner core of wherein at least a activating agent in gel form more.
9. the described delivery system of claim 1, the dissolubility in the wherein at least a activating agent physiological fluid around is 10mg/ml-100mg/ml.
10. the described delivery system of claim 1, wherein behind the contact physiological fluid, inner core to the permeability of activating agent than the inner core before taking place to interact with said fluid to the permeability of activating agent at least low 10%.
11. the described delivery system of claim 1, the dissolubility of wherein said activating agent in the biocompatible fluid composition is lower than 100mg/ml, but wherein in said biocompatible fluid composition, during solubilising, can see through inner core when this activating agent.
12. the described delivery system of claim 2, the infiltration coefficient that wherein at least a activating agent has in the second layer is at least about 1 * 10 -5Cm/s, but less than about 1 * 10 -2Cm/s.
13. each described delivery system among the claim 1-12, the rate of release from this system that wherein at least a activating agent has mainly receive the infiltrative restriction of at least a activating agent in inner core.
14. each described delivery system among the claim 1-12, wherein first polymeric layer can not see through basically and be present in enzyme and the protein in the physiological fluid.
15. the described delivery system of claim 1-12, wherein inner core comprises common medicine or the prodrug through the water-splitting that penetrates inner core.
16. delivery system comprises:
Inner core; Comprise (i) biocompatible fluid composition, (ii) be dissolved in the biocompatibility solid constituent in the biocompatible fluid composition, wherein biocompatible fluid is a liquid reagent; And wherein the biocompatibility solid constituent is PLGA; And wherein when contacting with physiological fluid, biocompatible fluid composition and biocompatibility solid constituent form gel and (iii) at least aly are scattered in, are suspended in or be dissolved in the activating agent in the inner core; With
Cover part at least, but be lower than 100% said inner core, can not see through said activating agent and be insoluble to first polymeric layer of physiological fluid.
17. the described delivery system of claim 16 also comprises the second polymer layer that can see through at least a activating agent.
18. the described delivery system of claim 16, wherein the biocompatible fluid composition of inner core is hydrophilic, hydrophobicity or amphipathic fluid.
19. the described delivery system of claim 18, wherein hydrophilic fluid is Polyethylene Glycol (PEG).
20. the described delivery system of claim 16, wherein first polymeric layer can not see through at least a activating agent.
21. the described delivery system of claim 16, wherein first polymeric layer covers the inner core at least about 50%.
22. the described delivery system of claim 16, wherein at least a activating agent in the inner core of gel form than the dissolving of Duoing at least 10% in the inner core that is changing into before the said gel.
23. the described delivery system of claim 16, the dissolubility in the wherein at least a activating agent physiological fluid around is 10mg/ml-100mg/ml.
24. the described delivery system of claim 16, wherein behind the contact physiological fluid, inner core to the permeability of activating agent than the inner core before taking place to interact with said fluid to the permeability of activating agent at least low 10%.
25. the described delivery system of claim 16, the dissolubility of wherein said activating agent in the biocompatible fluid composition is lower than 100mg/ml, but wherein in said biocompatible fluid composition, during solubilising, can see through inner core when this activating agent.
26. the described delivery system of claim 17, the infiltration coefficient that wherein at least a activating agent has in the second polymer layer is at least about 1 * 10 -5Cm/s, but less than about 1 * 10 -2Cm/s.
27. each delivery system among claim 1-12 or the 16-26, wherein at least a activating agent is a prodrug.
28. the delivery system of claim 27, wherein at least a activating agent and polyoxyethylene ether are covalently bound.
29. delivery system comprises:
Each described delivery system among claim 1-12 or the 16-26; With
Can at least a bioactive agent delivery be delivered to the pharmaceutically acceptable carrier at position in the body.
30. the described delivery system of claim 29, wherein at least a activating agent are the prodrug that contains with the covalently bound activating agent of polyoxyethylene ether.
31. the activating agent of effective dose is used for treating the patient's of at least a activating agent of needs claim 1-12 or the application in each described delivery system of 16-26 in preparation.
32. prepare the method for delivery system, comprising:
Inner core is provided, and described inner core comprises: biocompatibility solid constituent and biocompatible fluid composition wherein have the liquid that when contacting with physiological fluid, changes into gel in the part inner core at least; With at least a activating agent that is scattered in the described inner core; And
With described inner core with can not see through at least a activating agent, be insoluble to physiological fluid and cover part at least, but be lower than first polymeric layer merging of 100% said inner core.
33. medical treatment device comprises each described delivery system that is suitable for the patient that this demand is arranged is provided medicine among claim 1-12 or the 16-26.
CN2004800247244A 2003-06-26 2004-06-25 Bioerodible sustained release drug delivery systems Active CN1842321B (en)

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US57530704P 2004-05-28 2004-05-28
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5324280A (en) * 1990-04-02 1994-06-28 Alza Corporation Osmotic dosage system for delivering a formulation comprising liquid carrier and drug
US5378475A (en) * 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
WO2000035419A2 (en) * 1998-12-17 2000-06-22 Alza Corporation Conversion of liquid filled gelatin capsules into controlled release systems by multiple coatings
US6375972B1 (en) * 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof
WO2002049573A2 (en) * 2000-12-18 2002-06-27 Wockhardt Limited Novel in-situ forming controlled release microcarrier delivery system

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5324280A (en) * 1990-04-02 1994-06-28 Alza Corporation Osmotic dosage system for delivering a formulation comprising liquid carrier and drug
US5378475A (en) * 1991-02-21 1995-01-03 University Of Kentucky Research Foundation Sustained release drug delivery devices
WO2000035419A2 (en) * 1998-12-17 2000-06-22 Alza Corporation Conversion of liquid filled gelatin capsules into controlled release systems by multiple coatings
US6375972B1 (en) * 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof
WO2002049573A2 (en) * 2000-12-18 2002-06-27 Wockhardt Limited Novel in-situ forming controlled release microcarrier delivery system

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