EP1395626A1 - Copolymeres sequences peg-poe, peg-poe-peg et poe-peg-poe - Google Patents
Copolymeres sequences peg-poe, peg-poe-peg et poe-peg-poeInfo
- Publication number
- EP1395626A1 EP1395626A1 EP02736751A EP02736751A EP1395626A1 EP 1395626 A1 EP1395626 A1 EP 1395626A1 EP 02736751 A EP02736751 A EP 02736751A EP 02736751 A EP02736751 A EP 02736751A EP 1395626 A1 EP1395626 A1 EP 1395626A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- copolymer
- formula
- poe
- active agent
- peg
- 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.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/002—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from unsaturated compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/34—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from hydroxy compounds or their metallic derivatives
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
- C08G2650/38—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing oxygen in addition to the ether group
- C08G2650/42—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type containing oxygen in addition to the ether group containing orthoester groups
Definitions
- This invention relates to poly(ethylene glycol)-poly(ortho ester), poly(ethylene glycol)-poly(ortho ester)-poly(ethylene glycol), and poly(ortho ester)-poly(ethylene glycol)- poly(ortho ester) block copolymers.
- EPR enhanced permeation and retention
- the EPR effect can be used in cancer targeting by using delivery systems containing anticancer drugs that are too large to permeate normal vasculature, but which are small enough to permeate tumor vasculature, and two approaches have been developed.
- a water-soluble polymer is used that contains an anticancer drug chemically bound to the polymer via a hydrolytically labile linkage.
- Such drug-polymer constructs are injected intravenously and accumulate in the tumors, where they are internalized by the cells via endocytosis and released in the lysosomal compartment of the cell via enzymatic cleavage of the labile bond attaching the drug to the polymer.
- an AB or ABA block copolymer is prepared where the B-block is hydrophobic and the A-block is hydrophilic.
- the B-block is hydrophobic and the A-block is hydrophilic.
- Such a material When such a material is placed in water, it will self-assemble into micelles with a hydrophobic core and a hydrophilic shell surrounding the core.
- Such micelles have a diameter of about 100 nm, which is large enough that when they are injected intravenously, the micelles can not leave the normal vasculature, but they are small enough to leave the vasculature within tumors. Further, a 100 nm diameter is too small to be recognized by the reticuloendothelial system, thus enhancing micelle lifetime within the blood stream.
- hydrophilic block is poly(ethylene glycol)
- block copolymer micelles as long- circulating drug delivery vehicles
- US Patents Nos. 5,412,072; 5,449,513; 5,510,103; and 5,693,751 describe block copolymers useful as micellar delivery systems where the hydrophilic block is polyethylene glycol and the hydrophobic blocks are various derivatives of poly(aspartic acid), poly(glutamic acid) and polylysine.
- US Patents Nos. 5,412,072 and 5,693,751 describe an approach where drugs have been chemically attached to the hydrophobic segment; while US Patents Nos. 5,449,513 and 5,510,103 describe an approach where hydrophobic drugs have been physically entrapped within the hydrophobic portion of the micelle. This latter approach is clearly preferable because no chemical modification of the drug is necessary.
- Bioerodible Block Copolymer Matrix for Controlled Drug Delivery In AB, ABA, or BAB block copolymers comprising a hydrophilic A block and a hydrophobic B block, the A and B blocks are incompatible and on a microscopic scale will phase-separate. This phase separation imparts unique and useful thermal properties to the material.
- block copolymers comprised of poly(ethylene glycol) and bioerodible hydrophobic segments such as poly(L-lactic acid), poly(L-lactic- «)-gly colic acid) copolymers and poly( ⁇ -caprolactone), and discussion of their use as drug delivery agents.
- block copolymers comprised of poly(ethylene glycol) and bioerodible hydrophobic segments such as poly(L-lactic acid), poly(L-lactic- «)-gly colic acid) copolymers and poly( ⁇ -caprolactone), and discussion of their use as drug delivery agents.
- Youxin et al. "Synthesis and properties of biodegradable ABA triblock copolymers . . .”,/. Controlled Release, 27, 247-257 (1993),
- this invention is block copolymers of formula X, formula Y, and formula Z:
- R 3 is a bond, -(CH 2 )a-, or -(CH2)b-0-(CH 2 )c-; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
- R 4 is a C ⁇ -4 alkyl; and each A is R 5 , R 6 , or R 7 , where R 5 is:
- p is an integer of 1 to 20;
- R 8 is hydrogen or C ⁇ - 4 alkyl
- R 9 is:
- R 7 is a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups; where A is R 7 in at least 0.1 mol% of the POE units when the POE is of formula I.
- this invention is a micellar pharmaceutical composition for the delivery of a hydrophobic or water-insoluble active agent, comprising the active agent physically entrapped within but not covalently bonded to a drug carrier comprising a block copolymer of formula X, formula Y, or formula Z, or a mixture thereof.
- this invention is a composition for the sustained release of an active agent, comprising the active agent dispersed in a matrix comprising a block copolymer of formula X, formula Y, or formula Z, or a mixture thereof.
- this invention is a process for the preparation of a block copolymer of formula X, formula Y, or formula Z, as described in the "Detailed Description of the Invention".
- Active agent includes any compound or mixture of compounds which produces a beneficial or useful result. Active agents are distinguishable from such components as vehicles, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. Examples of active agents are pharmaceutical, agricultural or cosmetic agents. Stiitable pharmaceutical agents include locally or systemically acting pharmaceutically active agents which may be administered to a subject by topical or intralesional application (including, for example, applying to abraded skin, lacerations, puncture wounds, etc., as well as into surgical incisions) or by injection, such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection.
- topical or intralesional application including, for example, applying to abraded skin, lacerations, puncture wounds, etc., as well as into surgical incisions
- injection such as subcutaneous, intradermal, intramuscular, intraocular, or intra-articular injection.
- anti-infectives including antibiotics, antivirals, fungicides, scabicides or pediculicides
- antiseptics e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, mafenide acetate, methylbenzethonium chloride, nitrofurazone, nitromersol and the like
- steroids e.g., estrogens, progestins, androgens, adrenocorticoids, glucocorticoids, and the like
- therapeutic polypeptides e.g., insulin, erythro oietin, morphogenic proteins such as bone morphogenic protein, and the like
- analgesics and anti-inflammatory agents e.g., aspirin, ibuprofen, naproxen, ketorolac, COX-1 inhibitors, COX-2 inhibitors, and the like; and the anti-inflammatory steroids
- cancer chemotherapeutic including antibiotics, antivir
- the present invention may also be applied to other locally acting active agents, such as astringents, antiperspirants, irritants, rubefacients, vesicants, sclerosing agents, caustics, escharotics, keratolytic agents, sunscreens and a variety of dermatologies including hypopigmenting and antipruritic agents.
- active agents further includes biocides such as fungicides, pesticides, and herbicides, plant growth promoters or inhibitors, preservatives, disinfectants, air purifiers and nutrients.
- Alkyl denotes a linear saturated hydrocarbyl having from one to the number of carbon atoms designated, or a branched or cyclic saturated hydrocarbyl having from three to the number of carbon atoms designated (e.g., C1-C4 alkyl).
- alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and the like.
- Bioerodible refers to the degradation, disassembly or digestion of the polymer by action of a biological environment, including the action of living organisms, and most notably at physiological pH and temperature.
- a principal mechanism for bioerosion of the copolymers of the present invention is hydrolysis of linkages between and within the poly(ortho ester) blocks of the copolymer.
- Controlled release means a mode of active agent delivery that occurs when the active agent is released from the vehicle or carrier at an ascertainable and controllable rate over a period of time, rather than dispersed immediately upon ingestion or application.
- Controlled or sustained release may extend for hours, days or months, and may vary as a function of numerous factors.
- an important determinant of the rate of delivery is the rate of hydrolysis of the linkages between and within the copolymer. TThe rate of hydrolysis in turn may be controlled by the composition of the copolymer and the number of hydrolysable bonds in the copolymer.
- Delivery vehicle denotes a composition which has the functions including transporting an active agent to a site of interest, controlling the rate of access to, or release of, the active agent by sequestration or other means, and facilitating the application of the agent to the region where its activity is needed.
- Microx means the physical structure of the copolymer. Solid matrices essentially retain the active agent in a manner preventing release of the agent until the copolymer erodes or decomposes.
- PEG means polyethylene glycol, H-[OCH 2 CH2]f-OH, with a numerical suffix indicating the nominal number average molecular weight, M n . Unless the context requires otherwise, "PEG” also includes polyethylene glycol mono(C ⁇ -C4 alkyl) ethers, R- [OCH 2 CH 2 ]f-OH, where R is C ⁇ -C 4 alkyl, sometimes referred to as "RPEG",
- POE means a poly(ortho ester).
- Sequestration means the confinement or retention of an active agent within the internal spaces of a copolymer matrix. Sequestration of an active agent within the matrix may limit the toxic effect of the agent, prolong the time of action of the agent in a controlled manner, permit the release of the agent in a precisely defined location in an organism, or protect an unstable agent against the action of the environment.
- a “therapeutically effective amount” means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
- Treating" or “treatment” of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
- a "disease” includes pain and/ or inflammation.
- a "unit” denotes an individual segment of a poly(ortho ester) chain, which consists of the residue of a diketene acetal molecule and the residue of a polyol.
- ⁇ -hydroxy acid containing unit denotes a unit where A is R 5 , i.e. in which the polyol is prepared from an ⁇ -hydroxy acid or cyclic diester thereof and a diol of the formula HO-R 5 -OH.
- the fraction of the poly(ortho ester) that is ⁇ -hydroxy acid containing units affects the rate of hydrolysis (or bioerodibility) of the poly(ortho ester), and in turn, the release rate of the active agent.
- Vehicle and carrier mean an ingredient that is included in a composition such as a pharmaceutical or cosmetic preparation for reasons other than a therapeutic or other biological effect.
- Functions served by vehicles and carriers include transporting an active agent to a site of interest, controlling the rate of access to, or release of, the active agent by sequestration or other means, and facilitating the application of the agent to the region where its activity is needed.
- the copolymers of this invention may serve as vehicles for the sustained release of active agents.
- this invention provides block copolymers of formula X, formula Y, and formula Z * .
- R 1 [OCH 2 CH 2 ] f — [POE] g — H (X)
- R 1 is C ⁇ -4 alkyl
- R 2 is C ⁇ -4 alkyl
- f and h are independently an integer from 2 to 1000
- g and j are independently an integer from 2 to 200
- POE is a poly(ortho ester) of formula I or formula II:
- R 3 is a bond, -(CH2) a -, or -(CH2)b-0-(CH2)c-; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
- R 4 is a C ⁇ -4 alkyl
- A is R 5 , R 6 , or R 7 , where
- R 5 is:
- R 8 is hydrogen or Ci-4 alkyl
- R 9 is:
- R 7 is a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups; where A is R 7 in at least 0.1 mol% of the POE units when the poly(ortho ester) is of formula I.
- the copolymers are AB (formula X), ABA (formula Y), and BAB (formula Z) block copolymers in which the A blocks are hydrophilic poly(ethylene glycol) and the B blocks are hydrophobic poly(ortho ester).
- the poly(ortho ester) blocks are composed of alternating residues of a diketene acetal and a diol.
- the properties of the copolymers are determined by the type of the copolymer, whether AB diblock, ABA triblock, or BAB triblock, the length of the PEG and POE blocks, and the diol(s) used in the POE blocks (in particular, the proportion of diol of the general formula HO-R 5 -OH used in the POE blocks).
- Preferred polymers are those in which one or more of the following are true:
- f and h are independently an integer from 10 to 500, especially from 50 to 250, for example 100, for micellar delivery; and f and h are independently an integer from 50 to 1000, especially from 100 to 1000, for example from 250 to 1000, for bioerodible matrices; and f and h are preferably the same if both are present;
- g and j are independently an integer from 5 to 100, especially 10 to 50, for example 15, for micellar delivery; and g and j are independently an integer from 10 to 200, especially from 20 to 200, for example from 50 to 200, for bioerodible matrices; and g and j are preferably the same if both are present;
- R 4 is ethyl
- R 1 and R 2 are methyl
- R 6 is 1,4-cyclohexanedimethanol
- block copolymer having any one of these preferences listed above is preferred over a block copolymer not having that preference, the block copolymers will be more preferred the greater the number of preferences met.
- the number of repeating units within the blocks, f, g, h, and j necessarily represent averages of distributions rather than exact numbers; and in particular, when f and h or g and j are described as being the same, this indicates that the average values of f and h, or of g and j, should be approximately the same.
- the lengths of other polymeric chains, such as the poly(ethylene glycol) of R 9 ; of the long chain diol of R 9 ; and of the poly ( ⁇ -hydroxy acid) group within R 5 necessarily represent averages of distributions rather than exact numbers.
- Polyethylene glycols, and polyethylene glycol lower alkyl ethers of various chain lengths (molecular weights) are available from a number of sources, including Aldrich Chemical Company, Inc., Milwaukee, WI, and Shearwater Polymers, Huntsville, AL.
- Aldrich Chemical Company, Inc. Milwaukee, WI
- Shearwater Polymers Huntsville, AL.
- L is hydrogen or a C1-3 alkyl
- a typical method is the condensation of a bis(diol) of formula V (i.e. entaerythritol) or formula VI:
- the diketene acetals may also be prepared by the isomerization of divinyl acetals.
- 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane may be prepared by the isomerization of 3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using »-butyIlithium in etiiylenediamine.
- the isomerization of the double bond is described in Corey et al., /. Org. Chem., 38, 3224 (1973).
- the divinyl acetals may be prepared by the condensation of the bis (diol) of formula V or formula VI with two equivalents of a vinylic aldehyde, such as acrolein or crotonaldehyde, or their dialkyl acetals, such as acrolein dimethyl acetal, and such condensation reactions are well known.
- 2,2'-divinyl-4,4'-bi(l,3- dioxolanyl) is prepared from the reaction of erythritol with acrolein in benzene/ j fj-toluenesulfonic acid, and is subsequently isomerized to 2,2'-diethylidene-4,4'-bi(l,3- dioxolanyl) with tris(triphenylphosphine)ruthenium (II) chloride.
- the bis(diol) of formula VI where R 3 is a bond is erythritol.
- the bis(diol) of formula VI where R 3 is -(CH2)a- may be prepared by the oxidation of an ⁇ , ⁇ -diene, such as 1,3- butadiene, 1,4-pentadiene, or 1,5-hexadiene, with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis(diol).
- the bis(diol) of formula VI where R 3 is -(CH2)b-0-(CH2) c - may be prepared by the reaction of an ⁇ -hydroxy- ⁇ -olefin, such as allyl alcohol, with an ⁇ -haloalkyloxirane, such as epichlorohydrin, to form an ⁇ -epoxy- ⁇ -olefin with the backbone interrupted by an oxygen atom, such as 2-allyloxymethyloxirane, which is then oxidized with an oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or by other methods known in the art, to give the bis (diol).
- an oxidizing reagent such as osmium tetroxide/hydrogen peroxide
- the diols of the formulae HO-R 5 -OH, HO-R 6 -OH, and HO-R 7 -OH are prepared according to methods known in the art, and as described, for example, in US Patents Nos. 4,549,010 and 5,968,543. Some of the diols are commercially available.
- the diol of the formula HO-R 5 -OH that comprises a polyester moiety may be prepared by reacting a diol of the formula HO-R 9 -OH with between 0.5 and 10 molar equivalents of a cyclic diester of an ⁇ -hydroxy acid, such as lactide or glycolide, and allowing the reaction to proceed at 100 - 200 °C for about 12 hours to about 48 hours.
- organic solvents such as dimethylacetamide, dimethylsulfoxide, dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, and methylbutyl ether may be used.
- Diols of the formula HO-R 7 -OH include diols where R 7 is of the form R'CONR"R' (amide), R'CONR"COR' (imide), R'NR"CONR"R' (urea), and R'OCONR"R' (urethane), where each R' is independently an aliphatic, aromatic, or aromatic/aliphatic straight or branched chain hydrocarbyl, especially a straight or branched chain alkyl of 2 to 22 carbon atoms, especially 2 to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and each R" is hydrogen or Ci- ⁇ alkyl, especially hydrogen or methyl, more especially hydrogen.
- Some representative diols of the formula HO-R 7 -OH include _V,JV-bis-(2-hydroxyethyl)- terephthalamide, iV,N'-bis-(2-hydroxyethyl)pyromellitic diimide, l,l'-methylene-di-(p- phenylene)-bis-[3-(2-hydroxyethyl)urea], N,N'-bis-(2-hydroxyethyl)oxamide, l,3-bis(2-hydroxyethyl)urea, 3-hydroxy-JV-(2-hydroxyethyl)propionamide, 4-hydroxy-
- N-(3-hydroxypropyl)butyramide, and bis(2-hydroxyethyl)ethylenedicarbamate are known to the art in reported syntheses and may are commercially available.
- Representative diols of the formula HO-(CH2) n -NHCO-(CH2)m-OH where n is an integer of 2 to 6 and m is an integer of 2 to 5 are made by the reaction of 2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 5-aminopentanol, or 6-aminohexanol with ⁇ - propiolactone, ⁇ -butyrolactone, ⁇ -valerolactone, or ⁇ -caprolactone.
- diols of the formula HO-(CH2) n -NHCOO-(CH2) m -OH where n and m are each integers of 2 to 6 are made by the reaction of the same aminoalcohols just mentioned with cyclic carbonates of the formula
- Bis-amide diols of the formula HO-A-NHCO-B-CONH-A-OH are prepared by the reaction of a diacid, optionally in activated form, such as the diacyldihalide, with two equivalents of a hydroxy-amine.
- Other methods of preparation of the diols of the formula HO-R 3 -OH are known in the art.
- the diblock copolymers of formula X are prepared in a two-step synthesis.
- a diol of the formula HO-R 5 -OH, HO-R 6 -OH, HO-R 7 -OH, or a mixture thereof is reacted with the solution of the first step (containing the intermediate of formula VII or VIII and the excess diketene acetal) to extend the POE block, thereby forming the diblock copolymer of formula I.
- the quantities of the RPEG, the diketene acetal, and the diol are chosen so that the molar amount of diketene acetal is equal to the sum of the molar amounts of the RPEG and the diol.
- the value of fin the PEG block i.e. the length of the PEG block, is determined by the RPEG chosen.
- the value of g in the POE block i.e. the length of the POE block, is determined by the molar quantity of diol relative to the molar quantity of RPEG: the greater the molar quantity of diol (assuming that the diketene acetal is present in at least an equimolar quantity), the longer is the POE block.
- the triblock copolymers of formula Y are also formed in a two-step synthesis.
- an excess of the diketene acetal of formula III or formula TV is reacted with a diol of the formula HO-R ⁇ OH, HO-R 2 -OH, or HO-R 3 -OH, or a mixture thereof, to form a POE block which is terminated at each end with a diketene acetal unit, giving an intermediate of formula IX or formula X:
- the quantities of the diketene acetal and the diol are chosen so that the molar amount of diketene acetal is slightly greater than the molar amount of the diol.
- the molar ratio of PEG/RPEG to POE block should be approximately 2:1, but an excess of PEG/RPEG may be used, as it may be easily separated from the polymer after completion of the reaction.
- the values of f and h for the PEG blocks are determined by the PEG/RPEG chosen.
- f and h are the same, when a single PEG/RPEG is used; but if two or more PEGs/RPEGs of different lengths are used, then mixtures of copolymers containing varying PEG block lengths can be obtained, and these mixtures may be separated if desired, by such molecular weight fractionation techniques as gel permeation chromatography.
- the value of g for the POE block is determined primarily by the ratio of the diketene acetal to the diol used to form the POE.
- the triblock copolymers of formula Z are also formed in a two-step synthesis.
- a PEG of the formula H-[OCH 2 CH2]h-OH is reacted with an excess of a diketene acetal of formula III or formula TV to form an intermediate of formula XI or formula XII:
- a diol of the formula HO-R 5 -OH, HO-R 6 -OH, or HO-R 7 -OH, or a mixture thereof is reacted with the solution of the first step (containing the intermediate of formula XI or formula XII and the excess diketene acetal) to extend the POE blocks, thereby forming the triblock copolymer of formula Z.
- the quantities of the PEG, the diketene acetal, and the diol are chosen so that the molar amount of diketene acetal is equal to the sum of the molar amounts of the PEG and the diol.
- the value of h for the PEG block is determined by the PEG chosen.
- the values of g and j for the POE blocks are determined by the molar quantity of diol relative to the molar quantity of PEG: the greater the molar quantity of diol (assuming that the diketene acetal is present in at least an equimolar quantity), the longer are the POE blocks.
- the POE blocks will be of equal lengths, on average.
- POE blocks terminated with diketene acetal units are prepared, and reacted with 0.5 molar equivalent of PEG to terminate each end of the PEG with the POE blocks.
- the copolymer may be reacted with a hydroxy-containing compound, such as a C 1 -C 4 alcohol, to terminate the copolymer with alkoxy units; and such alkoxy- terminated copolymers are included within the scope of the invention.
- a hydroxy-containing compound such as a C 1 -C 4 alcohol
- the hydroxy- containing compound especially a C1-C4 alcohol, may be employed in excess and the unreacted excess easily separated during purification of the polymer
- Suitable reaction conditions for the formation of the copolymers are those conditions well known for the formation of poly(ortho esters), such as are described in US Patent No.
- reaction takes place in a polar aprotic solvent, such as those solvents mentioned previously for the preparation of the ⁇ -hydroxy acid containing diols, and ethers, especially tetrahydrofuran.
- a catalyst may be used if desired or necessary, and may be selected from those catalysts known to the art for the formation of orthoesters.
- Suitable such catalysts include iodine/pyridine, strong acids such as ⁇ -toluenesulfonic acid; Lewis acids, such as boron trichloride etherate, boron trifiuoride etherate, tin oxychloride, phosphorus oxychloride, zinc chloride, phosphorus pentafluoride, antimony pentafiuoride, stannic chloride, and the like; and Br ⁇ nsted acids, such as polyphosphoric acid, polystyrenesulfonic acid, and the like.
- a particularly suitable catalyst is j fr-toluenesulfonic acid.
- a typical amount of catalyst used is about 0.2% by weight relative to the diketene acetal, though quantities between 0.005% and 2% may be used.
- Suitable reaction temperatures are from room temperature to the boiling point of the solvent used, for example, between 20 C and 70°C; and suitable reaction times are between a few minutes and 48 hours, typically between 15 minutes and 24 hours.
- the copolymer can be isolated by precipitation in a non-polar aprotic solvent such as hexane.
- a non-polar aprotic solvent such as hexane.
- the reaction mixture containing the copolymer (which may be cooled before the addition) is added slowly to about ten volumes of the rapidly stirred solvent at room temperature.
- the precipitated block copolymer may be collected by filtration, decantation, or other suitable method, washed to remove unreacted monomers or other contaminants, and dried, typically in a vacuum oven at a temperature below its melting point.
- the bioerodibility of a block copolymer of this invention is determined by two factors: first, the extent to which the copolymer will dissolve/become suspended intact in an aqueous medium, the solubility of the copolymer; and second, the extent to which the copolymer, or, to be more precise, the POE block(s), will degrade in the environment to which it is exposed.
- the speed of degradation of the POE block(s) of the copolymer in an aqueous environment is determined by the hydrophilicity of tiie copolymer and by the proportion of ⁇ -hydroxy acid ester groups, if present, in the block(s), with greater bioerodibility being achieved by inclusion of a greater proportion of diols of the formula HO-R ⁇ OH in the diol mixture used to form the POE block(s).
- block copolymers of this invention will find utility in any of the uses for which biodegradable polymers are useful, including such uses as vehicles for the sustained release of active agents, ortiiopedic implants, degradable sutures, and the like, they will also find particular utility in applications where their nature as block copolymers having both hydrophobic and hydrophilic blocks confers a special benefit, and these uses will be addressed in greater detail, since a person of ordinary skill in the art will be well acquainted with the uses of biodegradable polymers and will have no difficulty, having regard to the skill of the art and this disclosure, in adapting the block copolymers of this invention to such uses.
- Micellar System for Targeting of Tissues with EPR Tumors and Inflamed Tissues
- Polymers useful as micellar delivery systems can be prepared by forming diblock, AB, or triblock, ABA or BAB, copolymers comprising a hydrophilic poly(ethylene glycol) A block and a hydrophobic poly(ortho ester) B block.
- block copolymers When such block copolymers are placed in water, in which the polyethylene glycol) block is soluble and the poly(ortho ester) block is insoluble, the block copolymer chains will spontaneously self-aggregate to form micellar structures.
- the hydrodynamic diameter of such micelles which may be determined by methods such as dynamic light scattering, will be in the order of 10-30 nm. As may be determined by methods such as static light scattering, such micelles will contain several hundred polymer chains.
- the micelles will undergo a secondary, reversible association, giving particles of an average diameter of about 100 nm. While such micelles are too large to be excreted by the kidneys, individual block copolymers are not. Further, since the poly(ortho ester) segments can be made to be biodegradable, facile renal excretion will take place.
- the major utility of such micellar systems resides in their ability to entrap and solubilize hydrophobic drugs in the hydrophobic core. Such entrapment is easily carried out in a number of ways.
- the drug can be added to the aqueous solution containing micelles and incorporated by simple stirring, by heating to moderate temperatures, or by ultrasonication.
- the micelles are efficient carriers for a variety of hydrophobic or insoluble active agents, and are particularly suitable as carriers for anticancer agents, which will accumulate in the tumor by an endocytotic process.
- hydrophobic drugs require a highly hydrophobic core.
- AB, ABA, or BAB block copolymers where the hydrophobic B block forms a biodegradable, highly hydrophobic poly(ortho ester) core will allow preparation of systems with significantly enhanced entrapment efficiency relative to other biodegradable segments such as poly(L-lactic- «>-glycolic acid) copolymers.
- anticancer agents that are particularly suitable for micellar tumor targeting are those with low water solubility or high aromatic content, such as the anthiacycline antibiotics (e.g. doxorubicin, daunorubicin, and epirubicin), mitomycin C, paclitaxel and its analogs (e.g. docetaxol), platinum analogs (e.g. cisplatin and carboplatin), and the like.
- anthiacycline antibiotics e.g. doxorubicin, daunorubicin, and epirubicin
- mitomycin C paclitaxel and its analogs (e.g. docetaxol)
- platinum analogs e.g. cisplatin and carboplatin
- Other agents may include anticancer proteins, such as neocarzinostatin, L-asparaginase, and the like, and photosensitizers used in photodynamic therapy.
- anti-inflammatory agents that can form micellar complexes are suitable for this use
- anti-inflammatory agents that are particularly suitable for micellar targeting are those with low water solubility or high aromatic content, such as the anti-inflammatory steroids (e.g., cortisone, hydrocortisone, dexamethasone, prednisone, prednisolone, beclomethasone, betamethasone, flunisolide, fluocinolone acetonide, fluocinonide, triamcinolone, and the like) and the non-ionized NSAlDs (e.g., naproxen, nabumetone, ketoprofen, mefenamic acid, fenbufen, piroxicam, meloxicam, celecoxib, rofecoxib, and the like).
- the anti-inflammatory steroids e.g., cortisone, hydrocortisone, dexamethasone, prednisone, prednisolone, be
- phase separation will occur where domains of the B block form within the continuous A-phase or vice versa.
- phase- separated material will have unique and useful thermal properties.
- PEG/POE AB, ABA, or BAB block copolymers have relatively sharp melting points.
- poly(ortho esters) containing short segments of poly(ethylene glycol) that have low softening temperatures have very poor mechanical properties, the copolymers of this invention, even those having very low melting temperatures, will retain mechanical properties suitable for use as implants.
- the active agent must be incorporated into a matrix of the copolymer or encapsulated within a capsule (or a
- micro capsule or “nanocapsule”, as those terms are sometimes used) of the copolymer.
- Methods for the preparation of sustained-release dosage forms using biodegradable polymers are well known in the art, as discussed in the references cited in the BACKGROUND OF THE INVENTION section of this application, and in other references familiar to those of ordinary skill in the art; so that a person of ordinary skill in the art would have no difficulty, having regard to that skill and this disclosure, in preparing sustained-release formulations using the copolymer of this invention.
- Suitable active agents include therapeutic agents such as pharmaceutical or pharmacological active agents, e.g. drugs and medicaments, as well as prophylactic agents, diagnostic agents, and other chemicals or materials useful in preventing or treating disease.
- compositions of this invention are particularly useful for the therapeutic treatment of humans and other mammals, but may also be used for other animals.
- sustained-release compositions of this invention may also be used for the release of cosmetic and agricultural agents, or for the release of biocides, such as fungicides or other pesticides, into an environment where prolonged release of the active agent is desired.
- the copolymer is first mixed with the active agent.
- High homogeneity may be achieved by mixing the polymer in its heat softened state with the active agent, followed by lowering the temperature to harden the composition.
- the copolymer can be dissolved in an appropriate casting solvent, such as tetrahydrofuran, methylene chloride, chloroform, or ethyl acetate, and the active agent can then be dispersed or dissolved in the copolymer solution, followed by evaporating the solvent to achieve the finished composition.
- Another method is grinding a solid copolymer material into powder which is then mixed with a powdered active agent.
- the active agent may also be incorporated into the mixture of monomers before polymerization provided that it is stable under the polymerization conditions and does not interfere with the polymerization reaction. If the active agent is one that is unstable at elevated temperatures (e.g. above 40 °C), or in the presence of organic solvents or organic solvent/water mixtures, such as a protein, then special preparation techniques may be required to minimize the exposure of the active agent to damaging conditions. Such techniques are disclosed in, for example, US Patents Nos. 5,620,697, which discloses "ultrasonic melting to form matrix-type pharmaceutical compositions, and 5,518,730, which discloses melt-spinning, both of which techniques are designed to minimize the exposure of the polymer and active to elevated temperatures. Other methods are disclosed in the documents cited elsewhere in this application.
- bioerodible copolymers that have physical properties tailored for this incorporation.
- the copolymer may be chosen so that it is semi-solid and has an ointment-like consistency, rather than being fully solid.
- a copolymer may be chosen that has a very high viscosity at normal body temperature of 37 °C so that little if any deformation takes place at that temperature.
- the viscosity of the copolymer may decrease substantially at temperatures no higher than 45 °C, or preferably by 40 °C, so that injection of the material may be possible at a temperature at which the active agent retains its activity.
- the copolymer composition may be injection molded, extruded or compressed into a thin film or made into devices of various geometric shapes or forms such as flat, square, round, cylindrical, tubular, disc, ring and the like.
- Rod- or pellet-shaped devices may be implanted through a trocar, such as is known for Norplant ® implants, and these or other shapes may be implanted by minor surgical procedures.
- a device may be implanted following a major surgical procedure such as tumor removal in the surgical treatment of cancer.
- the implantation of polymer wafers containing anticancer agents is described, for example, in US Patents Nos. 5,626,862 and 5,651,986, and references cited therein; and the copolymers of this invention will find utility in such applications.
- the polymer composition may also be injected by syringe subcutaneously or intramuscularly as particles of 0.1 ⁇ m to 1000 ⁇ m, preferably 0.5 ⁇ m to 200 ⁇ m, and more preferably 1 ⁇ m to 150 ⁇ m suspended in a pharmaceutically acceptable injection base.
- Liquid vehicles useful for suspending the drug- copolymer composition for injection include isotonic saline solution or oils (such as corn oil, cottonseed oil, peanut oil and sesame oil) which, if desired, may contain other adjuvants.
- oils such as corn oil, cottonseed oil, peanut oil and sesame oil
- Another injectable dosage form may be prepared from an active agent mixed in with a copolymer of the present invention which has an ointment-like consistency. Such a dosage form may be administered by injection with or without a solvent.
- the copolymer composition administered by either injection or implantation undergoes bioerosion in the body into non-toxic and non-reactive materials.
- the active agent may be released at a desired rate.
- Implants prepared from the present copolymers in which the copolymer constitutes the matrix containing an active agent also have the advantage that they do not require removal because of the bioerodibility of the copolymer.
- particles with cores of the pure active agent coated with various thicknesses of the present copolymer may be preferred for sustained delivery of the active agent.
- Coating or encapsulation of discrete particles of the active agent may be accomplished by conventional methods which are all well-known to the person skilled in the art. For example, finely divided drug particles may be suspended in a solvent system (in which the drug is not soluble) containing the dissolved copolymer and other excipients, followed by spray drying. Alternatively, the drug particles may be placed in a rotating pan or a fluid-bed dryer and the copolymer dissolved in a carrier solvent is sprayed onto the drug particles until a suitable coating quantity is deposited on the particles to give a desired thickness. The coating may also be achieved by suspending the drug particles in a solvent system containing the dissolved copolymer followed by adding to the suspension a non- solvent causing the copolymer to precipitate and form a coating over the drug particles.
- the agent for the sustained release compositions, because the active agent will be released over a controlled period of time, the agent usually is present in an amount which is greater than the conventional single dose.
- the relative proportions of the active agent and the copolymer can vary over a wide range (e.g., 0.1 to 50 weight percent) depending on the therapeutic agent and the desired effect.
- Sustained compositions of cosmetic and agricultural agents may also be prepared by any one of the methods as described above, using the copolymers of the present invention.
- the solid copolymers are also useful for a variety of orthopedic applications. For example, they can be used as fracture fixation devices for repair of osteochondral defects, ligament and tendon reconstructions and bone substitutes.
- the fact that the present copolymers permit simultaneous selection of both a desired level of their mechanophysical state and a desired rate of bioerodibility also renders them attractive as grafts or scaffolds on which cells can be cultured in vitro prior to implantation to regenerate tissues.
- Tissues which can be regenerated using this approach include but are not limited to bone, tendon, cartilage, ligaments, liver, intestine, ureter and skin tissues.
- the copolymers may be used to regenerate skin for patients with burns or skin ulcers. Cartilages may be repaired by first isolating chondrocytes from a patient (or a donor), allowing them to proliferate on the scaffolds prepared from the present copolymer and re-implanting the cells in the patient.
- the copolymer scaffolds or implants may further contain other biologically active substances or synthetic inorganic materials such as reinforcing filler material for enhancing the mechanical properties of the scaffolds or implants (e.g. calcium sodium metaphosphate fibers), antibiotics, or bone growth factors to induce and/ or promote ortiiopedic restoration and tissue regeneration.
- the compositions are also stable. The release rates of the active agent are not affected by irradiation for sterilization.
- compositions of this invention include: (1) compositions containing local anesthetics, optionally in combination with glucocorticosteroids such as dexamethasone, cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone, flunisolide, fluocinolone acetonide, fluocinonide, triamcinolone, and the like, for the prolonged relief of local pain or a prolonged nerve blockade.
- glucocorticosteroids such as dexamethasone, cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone, flunisolide, fluocinolone acetonide, fluocinonide, triamcinolone, and the like, for the prolonged relief of local pain or a prolonged nerve blockade.
- compositions containing cancer chemotherapeutic agents such as those listed above under “Active Agents”, for deposition by syringe or by injection into tumors or operative sites from which a tumor has been ablated, for tumor control or treatment and/ or the suppression of regrowth of the tumor from residual tumor cells after ablation of the tumor;
- compositions containing progestogens such as flurogestone, medroxyprogesterone, norgestrel, norgestimate, norethindrone, and the like, for estrus synchronization or contraception;
- compositions containing therapeutic polypeptides such as insulin, luteinizing hormone releasing factor antagonists, and the like, for the controlled delivery of these polypeptides, avoiding the need for daily or other frequent injection;
- compositions containing anti-inflammatory agents such as the NSAIDs, e.g., ibuprofen, naproxen, COX-1 or COX-2 inhibitors, and the like, or tmti-inflammatory steroids, for deposition by injection into inflamed tissue or intra-articular injection;
- compositions containing antibiotics for the prevention or treatment of infection, especially for deposition into surgical sites to suppress post-operative infection, or into or on wounds, for the suppression of infection (e.g. from foreign bodies in the wound);
- compositions containing morphogenic proteins such as bone morphogenic protein
- compositions containing DNA or other polynucleotides, such as antisense oligonucleotides are derived from various sources.
- Local anesthetics induce a temporary nerve conduction block and provide pain relief which lasts from a few minutes to a few hours. They are frequently used to prevent pain in surgical procedures, dental manipulations or injuries.
- the synthetic local anesthetics may be divided into two groups: the slightly soluble compounds and the soluble compounds.
- the soluble local anesthetics can be applied topically and by injection, and the slightly soluble local anesthetics are used only for surface application.
- the local anesthetics conventionally administered by injection can also be divided into two groups, esters and non-esters.
- the esters include (1) benzoic acid esters (piperocaine, meprylcaine and isobucaine); (2) ⁇ -aminobenzoic acid esters (procaine, tetracaine, butethamine, propoxycaine, chloroprocaine); (3) r ⁇ -aminobenzoic acid esters (metabutethamine, primacaine); and (4) j -ethoxybenzoic acid esters (parethoxycaine).
- the non-esters are largely anilides (amides), and include bupivacaine, lidocaine, mepivacaine, pyrrocaine and prilocaine.
- the semi-solid injectable form of a local anesthetic of the present invention is prepared by incorporating the local anesthetic into the delivery vehicle in a manner as described above.
- the concentration of the local anesthetic may vary from 1 - 60 wt.%, preferably 5 - 30 wt.%, e.g., about 10 wt.%.
- the semi-solid composition is then filled into a syringe with a 18-25 gauge needle, and injected into sites that are painful or to be subjected to surgical procedures.
- the semi-solid injectable composition of the present invention can be used for controlled delivery of both slightly soluble and soluble local anesthetics.
- the present injectable delivery system can maintain localization of the anesthetic at the nerve for an extended period of time which will greatly prolong the effect of the anesthetic.
- a number of authors, including in US Patent No. 6,046,187 and related patents, have suggested that the co-administration of a glucocorticosteroid may prolong or otherwise enhance the effect of local anesthetics, especially contr oiled-release local anesthetics; and formulations containing a local anesthetic and a glucocorticosteroid, and their uses for controlled release local anesthesia, are within the scope of this invention.
- Preparation 1 Preparation of a diketene acetal of formula TV, 3,9-di(ethylidene)- 2,4,8,10-tetraoxaspiro[5.5]undecane, DETOSU
- diblock copolymers were prepared from the starting materials given in the table below:
- M-PEG polyfethylene glycol
- CDM 1,4-cyclohexanedimethanol
- TEG 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethanol
- TEG-G1 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethyl hydroxyacetate
- 1,4-Cyclohexanedimethanol (11.52 g, 79.9 mmol), 0.638 g (4.25 mmol) 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethanol and 0.226 g (0.85 mmol) 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethyl hydroxyacetate in 40 mL tetrahydrofuran were added to the flask, followed by another 0.05 mL of the ⁇ -toluenesulfonic acid solution.
- reaction mixture was stirred for about 30 min, and then added dropwise to about 1 L of hexane with vigorous stirring, precipitating the diblock copolymer product, which was separated by filtration and dried in a vacuum oven, giving a triblock POE-PEG-POE copolymer of 33,370 weight average molecular weight.
- DETOSU 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane
- PEG poly(ethylene glycol), with weight average molecular weight in parentheses
- CDM 1,4-cyclohexanedimethanol
- TEG 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethanol
- TEG-Gl 2- ⁇ 2-[2-(2-hydroxyethoxy)ethoxy]ethoxy ⁇ ethyl hydroxyacetate
- copolymers of formula X, Y, and Z are similarly prepared.
- the copolymer of Example 1 100 mg, is dissolved in 2 mL acetone, and 20 mL phosphate-buffered saline, pH 7.4, is added. No precipitation of the copolymer is observed. The solution is placed under aspirator vacuum at room temperature to remove the acetone, and the copolymer remains in solution.
- copolymers of formulae X, Y, and Z show similar solubility.
- the copolymer of Example 1 100 mg, is dissolved in 2 mL acetone, and the solution added to a solution of 7.7 mg hydrocortisone in 2 mL acetone.
- the combined acetone solutions are added to 5 mL phosphate-buffered saline, pH 7.4, the acetone removed under vacuum, and the aqueous solution filtered through a 0.45 ⁇ m filter.
- the aqueous solution is found to have a hydrocortisone concentration greater than the water solubility of hydrocortisone of 0.28 mg/mL, indicating micellar encapsulation and solubilization of the hydrocortisone by the copolymer.
- Other copolymers of formula X, Y, and Z show similar solubilization of hydrophobic/water-insoluble active agents.
- the copolymer of Example 1 is pressed at 48 °C and 1000 mPa into a slab 0.6 mm thick, and the slab then cut into wafers approximately 6 mm X 6 mm. The wafers are weighed, and then placed into phosphate-buffered saline, pH 7.4, at 37°C; and the weight loss of the wafers measured as a function of time.
- the copolymer is bioerodible as shown by loss in weight over time.
- copolymers of formulae X, Y, and Z show similar bioerodibility.
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Abstract
Cette invention porte sur des copolymères séquencés PEG-POE, PEG-POE-PEG et POE-PEG-POE comportant à la fois une séquence hydrophile et une séquence hydrophobe. Ils forment des micelles dans une solution aqueuse, ce qui permet de les utiliser pour encapsuler ou solubiliser des matériaux hydrophobes ou non solubles dans l'eau. Ces copolymères forment également des matrices bioérodables permettant la libération continue d'agents actifs, spécialement lorsque la ou les séquences POE contiennent au moins une unité renfermant un acide α-hydroxy.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US854150 | 1997-05-09 | ||
US85415001A | 2001-05-11 | 2001-05-11 | |
US139114 | 2002-05-02 | ||
US10/139,114 US20030152630A1 (en) | 2001-05-11 | 2002-05-02 | PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers |
PCT/US2002/014945 WO2002092661A1 (fr) | 2001-05-11 | 2002-05-09 | Copolymeres sequences peg-poe, peg-poe-peg et poe-peg-poe |
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EP1395626A1 true EP1395626A1 (fr) | 2004-03-10 |
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EP02736751A Withdrawn EP1395626A1 (fr) | 2001-05-11 | 2002-05-09 | Copolymeres sequences peg-poe, peg-poe-peg et poe-peg-poe |
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WO (1) | WO2002092661A1 (fr) |
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US7045589B2 (en) | 2002-11-15 | 2006-05-16 | A.P. Pharma, Inc. | Bioerodible poly(ortho esters) from dioxane-based di(ketene acetals), and block copolymers containing them |
JPWO2005018607A1 (ja) * | 2003-08-20 | 2007-11-01 | 味の素株式会社 | 溶解性を改善した医薬品製剤 |
US20060275230A1 (en) | 2004-12-10 | 2006-12-07 | Frank Kochinke | Compositions and methods for treating conditions of the nail unit |
JP2008523101A (ja) | 2004-12-10 | 2008-07-03 | タリマ セラピューティクス, インコーポレイテッド | 爪ユニットの状態を治療するための組成物および方法 |
US20060235161A1 (en) * | 2005-03-31 | 2006-10-19 | Jorge Heller | PEG-polyacetal and PEG-polyacetal-POE graft copolymers and pharmaceutical compositions |
CN101309713A (zh) | 2005-11-17 | 2008-11-19 | 周吉尼克斯股份有限公司 | 用无针注射递送粘稠制剂 |
EP2044142A2 (fr) | 2006-06-29 | 2009-04-08 | Medtronic, Inc. | Polymères de poly(orthoester) et leurs procédés de préparation et d'utilisation |
US8268347B1 (en) | 2006-10-24 | 2012-09-18 | Aradigm Corporation | Dual action, inhaled formulations providing both an immediate and sustained release profile |
US8475823B2 (en) | 2008-04-18 | 2013-07-02 | Medtronic, Inc. | Baclofen formulation in a polyorthoester carrier |
US8956642B2 (en) | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
ES2527448T3 (es) | 2008-04-28 | 2015-01-23 | Zogenix, Inc. | Nuevas formulaciones para el tratamiento de la migraña |
CA2904703A1 (fr) | 2013-03-14 | 2014-10-02 | Hallux, Inc. | Procede de traitement d'infections, maladies ou troubles d'unite d'ongle |
CN111925516B (zh) * | 2020-08-19 | 2023-04-07 | 长治医学院 | 一种两亲性聚美法仑前药胶束及其制备方法 |
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US4304767A (en) * | 1980-05-15 | 1981-12-08 | Sri International | Polymers of di- (and higher functionality) ketene acetals and polyols |
GB8416234D0 (en) * | 1984-06-26 | 1984-08-01 | Ici Plc | Biodegradable amphipathic copolymers |
US4549010A (en) * | 1984-06-27 | 1985-10-22 | Merck & Co., Inc. | Bioerodible poly(ortho ester) thermoplastic elastomer from diketene diacetal |
US5939453A (en) * | 1998-06-04 | 1999-08-17 | Advanced Polymer Systems, Inc. | PEG-POE, PEG-POE-PEG, and POE-PEG-POE block copolymers |
CA2445638C (fr) * | 2000-05-11 | 2010-02-09 | Advanced Polymer Systems, Inc. | Vecteur d'administration semi-solide et compositions pharmaceutiques associees |
-
2002
- 2002-05-09 WO PCT/US2002/014945 patent/WO2002092661A1/fr not_active Application Discontinuation
- 2002-05-09 EP EP02736751A patent/EP1395626A1/fr not_active Withdrawn
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