MXPA00003133A

MXPA00003133A - BIODEGRADABLE LOW MOLECULAR WEIGHT TRIBLOCK POLY(LACTIDE-co-GLYCOLIDE) POLYETHYLENE GLYCOL COPOLYMERS HAVING REVERSE THERMAL GELATION PROPERTIES

Info

Publication number: MXPA00003133A
Application number: MXPA/A/2000/003133A
Authority: MX
Inventors: Ramesh Rathi; Gaylen M Zentner; Byeongmoon Jeong
Original assignee: Macromed Inc
Priority date: 1997-10-03
Filing date: 2000-03-30
Publication date: 2002-02-26

Abstract

A water soluble biodegradable ABA- or BAB- type triblock polymer is disclosed that is made up of a major amount of a hydrophobic polymer made up of a poly(lactide-co-glycolide) copolymer or poly(lactide) polymer as the A-blocks and a minor amount of hydrophilic polyethylene glycol polymer B-block, having an overall weight average molecular weight of between about 2000 and 4990, and that possesses reverse thermal gelation properties. Effective concentrations of the triblock polymer and a drug may be uniformly contained in an aqueous phase to form a drug delivery composition. The release rate of the drug may be adjusted by changing various parameters such as hydrophobic/hydrophilic component content, polymer concentration, molecular weight and polydispersity of the triblock polymer. Because the triblock polymer is amphiphilic, it functions to increase the solubility and/or stability of drugs in the composition, as demonstrated by a phase diagram illustrating the gelation behaviour of aqueous solutions of a PLGA-PEG-PLGA triblock copolymer studied at different concentrations and temperatures.

Description

COPOLYMERS OF THREE BLOCKS OF POLY (LACTIDO-co-GLICOLIDO) LOW WEIGHT MOLECULAR POLYETHYLENGLYCOL BIODEGRADABLE THEY HAVE REVERSE THERMAL GEL FORMATION PROPERTIES The present invention relates to water-soluble, low molecular weight, biodegradable block biodegradable block copolymers having a high weight percentage of hydrophobic block (s) and their use for parenteral, ocular, topical, transdermal, vaginal, buccal, transmucosal, pulmonary, transurethral, rectal, nasal, oral or atrial administration of drugs. This invention is possible through the use of thermosensitive biodegradable three-block polymers based on poly (lactide-co-glycolide) or poly (lactide) and polyethylene glycol blocks, which are described in detail below. The system is based on the discovery that only a selected subset of such block polymers of relatively low molecular weight and relatively high hydrophobic block polymer content exist as clear solutions at a temperature of about 5 ° to 25 ° C in water but, when the temperature is raised to a temperature that corresponds approximately to body temperature (typically 37 ° C in the case of humans), they interact spontaneously to form semi-solid hydrogels (ie, gels) that contain high percentages of water trapped within the body. the gel network, and yet they are substantially insoluble in water.

BACKGROUND OF THE INVENTION AND COMPENDIUM OF THE PREVIOUS TECHNIQUE Recently many peptide / protein drugs, effective for various therapeutic applications, have been marketed through advances in recombinant DNA technology or other technologies. However, as polypeptides or proteins, their high molecular weight, degradation in the gastrointestinal tract, and short half-life in the body limit their routes of administration to parenteral administrations such as, for example, intravenous or intramuscular and subcutaneous injection. Many peptide drugs have limited solubility and / or limited stability in conventional liquid carriers and are therefore difficult to formulate and administer. Likewise, in many cases, numerous administrations are required to obtain the expected therapeutic effect during an extended period of time. The long-term controlled administration of such polypeptides or proteins is essential to provide practical applications of these medications and to employ drugs derived from advanced biotechnology. Another problem is compliance on the part of patients. It is often difficult to get a patient to follow a prescribed dosage regimen, especially when the prescription is for a chronic disorder and the drug has acute side effects. Accordingly, it would be highly desirable to provide a system for the delivery of drugs, polypeptide drugs and protein in particular, at a controlled rate over a sustained period of time without the above mentioned problems in order to optimize the therapeutic efficacy, minimize the side effects and toxicity and therefore increase the effectiveness and compliance by patients. Drug loaded polymeric devices and dosage forms have been investigated for the long-term therapeutic treatment of various diseases. An important property of the polymer is biodegradability, which means that the polymer can decompose or degrade within the body in non-toxic components either concomitantly with the release of drug, or after the release of the entire drug. In addition, techniques, procedures, solvents and other additives used to manufacture the device and load the drug must result in safe dosage forms for the patient, minimize irritation of the surrounding tissues and be a compatible medium for the drug. Nowadays, controlled release devices that can be implanted and are biodegradable are manufactured from solid polymers such as polyglycolic acid, polylactic acid or copolymers of glycolic acid and lactic acid. Due to the hydrophobic properties of these polymers, drug loading and device fabrication using these materials require organic solvents, for example, methylene chloride, chloroform, acetic acid or dimethylformamide. Obviously, due to the toxic nature of some solvents, extensive drying is generally required after this process. In most cases, the final polymeric device is manufactured in a specific solid form (e.g., sphere, plate or rod) that requires implantation frequently accompanied by the trauma of a surgical intervention. Currently, there are few synthetic or natural polymeric materials that can be used for the controlled administration of drugs, including peptide and protein drugs, due to the strict requirements of compliance with regulations, such as biocompatibility, clearly defined degradation pathway, and safety of the degradation products. The most widely researched and advanced biodegradable polymers with regard to the available toxicological and clinical data are the poly (alpha-hydroxy acids) aliphatics, such as poly (D, L- or L-lactic acid) (PLA) and poly (acid) glycolic acid) (PGA) and its copolymers (PLGA). These polymers are commercially available and are currently employed as biological resorption sutures. An FDA-approved system for the controlled release of leuprolide acetate, Lupron Depot®, is also based on PLGA copolymers. Lupron Depot® consists of injectable microspheres, which release leuprolide acetate over a prolonged period (for example, approximately 30 days) for the treatment of prostate cancer. Based on this history of use, PLGA copolymers have been the materials of choice in the initial design of parenteral controlled release drug delivery systems employing a biodegradable carrier. Although some limited successes were obtained, these polymers also present problems associated with their physical-chemical properties and their manufacturing methods. Hydrophilic macromolecules, such as polypeptides, can not easily diffuse through hydrophobic matrices or polylactide membranes. Drug loading and device fabrication using PLA and PLGA often requires toxic organic solvents, and the solid dosage form can mechanically induce tissue irritation. ace. Sa hney and J.A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411 (1990) synthesized terpolymers of D, L-lactic, glycolide and epsilon-caprolactone that degrade rapidly in vitro. For example, a terpolymer composition of 60% glycolide, 30% lactide, and 10% epsilon-caprolactone had a half-life of 17 days. The hydrophilicity of the material was increased by means of copolymerization with a poloxamer surfactant (Pluronic F-68). This poloxamer is a block copolymer comprising about 80% by weight of a relatively hydrophobic poly (oxypropylene) block and 20% by weight of a hydrophilic poly (oxyethylene) block. The copolymerization with the poloxamer resulted in a stronger and partially crystalline material that was mechanically stable at physiological temperatures (e.g., 37 ° C) in water. The half-life of this copolymer was slightly increased compared to the base polymer. However, it is known that poloxamer-type surfactants are not biodegradable. An optimal material for use as an injectable or implantable polymeric drug delivery device must be biodegradable, compatible with hydrophilic or hydrophobic drugs, and allow manufacturing with simple, safe solvents, such as water, and not requiring additional polymerization or other reactions of covalent bond formation after administration. A system that can be a manufacturer in an aqueous solution is a class of block copolymers mentioned above and marketed under the trade name Pluronic®. These copolymers are composed of two different blocks of polymers, ie, hydrophilic poly (oxyethylene) blocks and hydrophobic poly (oxypropylene) blocks to form a triple block of poly (oxyethylene) -poly (oxypropylene) -poly (oxyethylene). The triple block copolymers absorb water to form gels that exhibit a thermally reverse gel forming behavior. However, the Pluronic® system is not biodegradable and the gel properties (water soluble gel) and kinetic characteristics of drug release (very rapid release) from these gels are not useful and require substantial improvement. There is an important need for hydrophilic biodegradable materials that can be used to incorporate water soluble polypeptide drugs in solution. ASSawhney et al., Macromolecules, Vol. 26, No. 4, 581-589 (1993) synthesized macromers that have a central block of polyethylene glycol, extended with oligomers of alpha-hydroxy acids such as for example oligo (D, L- acid). lactic) or oligo (glycolic acid) and terminated with acrylate groups. By using non-toxic photoinitiators, these macromers can be rapidly polymerized with visible light. Due to the multifunctionality of the macromers, the polymerization results in the formation of cross-linked gels. Gels are degraded by hydrolyzing the oligo (alpha-hydroxy acid) regions in polyethylene glycol, alpha-hydroxy acid, and oligo (acrylic acid), and their degradation rates can be designed by the proper choice of oligo (alpha-hydroxy acid) ) of less than 1 day up to 4 months. However, in this system, a photoinitiator, an additional component as well as a photo-crosslinking reaction of additional covalent bond formation is employed. With this approach a highly variable person-to-person performance would be obtained due to differences between people in terms of skin thickness and skin opacity.

Okada et al., Japanese Patent 2-78629 (1990), synthesized biodegradable block copolymer materials by the transesterification of poly (lactic acid) (PLA) or poly (lactic acid) / glycolic acid (PLGA) and polyethylene glycol (PEG) . The range of molecular weights for PLGA was 400 to 5,000 and for PEG from 200 to 2000. The mixture was heated to a temperature of 100 ° C to 250 ° C for 1 to 20 hours under a nitrogen atmosphere. The product was miscible with water and formed a hydrogel; however, it was precipitated in water above room temperature. In other words, the solubility in water and the chain interactions between polymers changed with temperature. This polymer is similar to the polymers described in the Churchill patents discussed below and is used as an aqueous suspension or molded into a solid block for implant. There is no indication in the sense that this polymer presents thermally reversible gel-forming properties for injection as a solution instead of its injection as a colloidal polymer suspension. T. Matsuda, ASAIO Journal, M512-M517 (1993) used a biodegradable polymeric gel to deliver a potent peptidyl antiproliferative agent, angiopeptin, to prevent myointimal hyperplasia that occurs when a diseased vessel is replaced by an artificial or well-treated graft through an intravascular device. A highly viscous block copolymer liquid composed of block segments of poly (lactic acid) and polyethylene glycol (PLA-PEG) was used as a pharmaceutical carrier in situ coating. The materials were supplied by Taki Chemical Co., Ltd., Hyogo, Japan. A prolonged slow release of angiopeptin from the polymer gel, consisting of 0.5 g of PLA-PEG and 0.5 mg of angiopeptin was observed in vitro in a few weeks when the gel was kept in a buffer maintained at a 37 ° C solution. No early release of angiopeptin was observed. Based on these results, the sustained local release of angiopeptin from the biodegradable polymer gel coated in a damaged vessel in vivo was theoretically determined to be effective. L. Martín et al., J. Chem. Soc., Faraday Trans., 90 (13), 1961-1966 (1994) synthesized copolymers of ABA type blocks of very low molecular weight by the incorporation of poly (epsilon). caprolactone) hydrophobic known to be subject to in vivo degradation by hydrolytic chain cleavage involving the ester linkages and reported properties of the PCL-PEG-PCL block copolymer solution. A cloudy was observed when an aqueous solution of the block copolymers was heated slowly. The cloudy spots of aqueous solutions at 2% by weight of the copolymers were 65 ° C and 55 ° C for PCL-PEG-PCL (450: 4000: 450) and PCL-PEG-PCL (680: 4000: 680), respectively. Reversible gel formation upon cooling PCL-PEG-PCL (680: 4000: 680) solutions was observed at critical concentrations and temperatures within a range of 13% at 25 ° C up to 30% at 80 ° C. No lower gel / sol transition was observed upon additional cooling of the solution at 0 ° C. The in vitro degradation rate of PCL-PEG-PCL (680: 4000: 680) It was very slow. Only a 20% decrease in molar mass (from GPC) was observed over a period of 16 weeks. Said slow degradation is insufficient for a practical vehicle for the administration of a drug. Churchill et al., U.S. Patents 4,526,938 and 4,745,160 show copolymers that are either self-dispersible or that can become self-dispersible in aqueous solutions. These copolymers are copolymers of three ABA blocks or of two AB blocks composed of hydrophobic A blocks, for example polylactic (PLA) or poly (lactide-co-glycolide) (PLGA), and hydrophilic blocks B, such as polyethylene glycol (for example). PEG) or polyvinylpyrrolidone. Preferably, so that they are self-dispersible in water without the use of organic solvents, these polymers must contain more than 50% by weight of hydrophilic component (block B) in comparison with the hydrophobic component (block A) or, they are copolymers in which the component hydrophobic (block A) has a weight average molecular weight of less than 5,000. Although polymers having a weight average molecular weight of 1000 are mentioned, there is no direct teaching of such polymers, nor in the sense that ABA type polymers having a molecular weight less than 5,000 are functional. In addition, there is no example of ABA-type polymers other than high molecular weight polymers, which have a hydrophobic content of at least 50% by weight. There is no indication that these block copolymers are soluble in aqueous solutions at any temperature without the use of organic solvents, nor is there any indication that drug / polymers can be administered in the form of a solution. On the contrary, the administration is presented as a colloidal suspension of the polymer or the drug / polymer dispersions are lyophilized in a powder and processed by compression molding to form a solid suitable for use as a depot formulation that can be implanted. Aqueous suspensions or drug / polymer dispersions are two-phase systems where the dispersed polymer phase is suspended in the continuous aqueous phase. Such dispersions are not suitable for use in situations where sterile filtration processes are required to remove bacterial particles or other toxic particles, since such a process would also remove the drug / polymer particles and result in subtherapeutic doses. . ABA-type block copolymers that are water-soluble and heat-forming gels are not included in the Churchill et al. From the above comments it should be noted that thermally reversible gels (eg, Pluronics®) are not inherently useful as systems for delivering drugs. Although there are block copolymers that possess reverse thermal gel-forming properties, these gels do not have the critical characteristics necessary to control the release of a drug in a sustained period and present issues of toxicity or biocompatibility due to their non-biodegradable character . Thus, while the property of reverse thermal gel formation is universally recognized as unique and potentially very useful in the field of drug administration, to date no system has been developed that possesses the necessary properties for a viable system. OBJECTS AND COMPENDIUM OF THE INVENTION It is an object of the present invention to offer biodegradable low molecular weight three block copolymer drug delivery systems, which exhibit a reverse thermal gel formation behavior, ie they exist as a liquid solution at low temperatures, they form gels reversibly at physiologically relevant temperatures, and provide good drug release characteristics. A further object of this invention is to provide a drug delivery system for the parenteral administration of hydrophilic and hydrophobic drugs, peptide and protein drugs, and oligonucleotides. Another object of the present invention is to provide a method for the parenteral administration of drugs in a biodegradable polymer matrix that results in the formation of a gel reservoir within the body from which the drugs are released at a controlled rate. These and other objects are achieved through a biodegradable ABA or BAB-type block copolymer having an average molecular weight of between about 2000 and 4990 consisting of about 51% to 83% by weight of a hydro-phobic A block. which consists of a poly (lactide-co-glycolide) block copolymer (PLGA) or a poly (lactide) polymer (PLA) and from about 17 to 49% by weight of a hydrophilic polymer block B consisting of a polyethylene glycol. Polyethylene glycol (PEG) is sometimes also referred to as poly (ethylene oxide) (PEO) or poly (oxyethylene) and the terms may be used interchangeably for the purposes of this invention. In block A hydrophobic, the lactate content is from about 30 to about 100, preferably between about 30 and 80 mol% and more preferably between about 50 and 80 mol%. The glycolate content is between about 0 and 70, preferably between about 20 and 70 mol% and especially between about 20 and 50 mol%. Additional objects and advantages of this invention will be apparent from the following summary and from the detailed description of the various embodiments of this invention. As used herein, the following terms will have the following meanings: "parenteral" will mean intramuscular, intraperitoneal, intraabdominal, subcutaneous, and as far as practicable, intravenous and intraarterial. "gel formation temperature" refers to the temperature at which the biodegradable block copolymer is subjected to reverse thermal gel formation, ie, the temperature below which the block copolymer is soluble in water and above of which the block copolymer is subjected to a phase transition to increase its viscosity or to form a semi-solid gel. The terms "gel formation temperature" and "reverse thermal gel formation temperature" or the like will be used interchangeably with reference to the gel-forming temperature. The terms "polymer solution", "aqueous solution" and the like, when used with reference to a biodegradable block copolymer contained in said solution, will refer to a water-based solution having said block copolymer dissolved therein at a functional concentration. , and maintained at a temperature below the gel-forming temperature of the block copolymer. The expression "reverse thermal gel formation" refers to the phenomenon whereby a solution of a block copolymer spontaneously increases its viscosity, and in many cases transforms into a semi-solid gel, as the temperature of the solution rises above the gel formation temperature of the copolymer. For the purposes of the invention, the term "gel" includes both the semi-solid gel state and the high viscosity state that exists above the gel-forming temperature. When cooled below the gel formation temperature, the gel reverts spontaneously to form the low viscosity solution again. This cycle between the solution and the gel can be repeated ad infinitum because the sol / gel transition does not involve any change in the chemical composition of the polymer system. All interactions to create the gel are physical in nature and do not involve the formation or breaking of covalent bonds. The terms "drug delivery liquid" or "drug delivery liquid having reverse thermal gel formation properties" refer to a polymer solution containing the drug (the drug per se may be either dissolved or colloidal) suitable for administration to a warm-blooded animal that forms a gel-like drug reservoir when the temperature is raised to the gel-forming temperature of the block copolymer or above said temperature. The term "deposit" refers to a drug delivery liquid after administration to a warm-blooded animal that has formed a gel upon raising the temperature to the gel-forming temperature or above said temperature.

The term "gel" refers to the semisolid phase that occurs spontaneously as the temperature of the "polymer solution" or "drug delivery liquid" rises at the gel-forming temperature of the block copolymer or above said temperature. The term "aqueous polymeric composition" refers to either a drug delivery liquid or a gel comprising a water phase having therein uniformly a drug and the biodegradable block copolymer. At temperatures below the gel-forming temperature, the copolymer can be soluble in the water phase and the composition will be a solution. At temperatures that are at the level of the gel-forming temperature or above, the copolymer will solidify to form a gel with the water phase, and the composition will be a gel or a semi-solid. The term "biodegradable" indicates that the block copolymer can be chemically divided or degraded within the body to form non-toxic components. The rate of degradation may be the same or different than the rate of drug release. The term "drug" will mean here any compound or organic or inorganic substance that has bioactivity and is adapted or used for a therapeutic purpose. Proteins, DNA oligonucleotides and genetic therapies are included in the broad definition of drug. The terms "peptides", "polypeptides", "oligopeptides" and "proteins" will be used interchangeably with reference to peptide or protein drugs and will not be limited to any particular molecular weight, any particular peptide sequence or any particular length, no change of bioactivity or particular therapeutic use unless specifically stated otherwise. The term "poly (lactide-co-glycolide)" or "PLGA" refers to a copolymer derived from the condensation copolymerization of lactic acid and glycolic acid or by the ring-opening polymerization of alpha-hydroxy acid precursors as for example lactide or glycolide. The terms "lactide", "lactate", "glycolide" and "glycolate" are used interchangeably. The term "poly (lactide)" or "PLA" refers to a polymer derived from lactic acid condensation or through lactic ring-opening polymerization. The terms "lactide" and "lactate" are used interchangeably. Accordingly, the present invention is based on the discovery that block copolymers of type ABA or BAB where the A blocks are a poly (lactide-co-glycolide) (PLGA) relatively hydrophobic or a hydrophobic poly (lactide) (PLA) and block B is a relatively hydrophilic polyethylene glycol (PEG), having a hydrophobic content between about 51 and 83% by weight and a molecular weight of copolymer of Global blocks comprised between about 2000 and 4990, exhibit a solubility in water at low temperatures and undergo reversible thermal gel formation at body temperatures of a mammal. In said high hydrophobic content it is unexpected that such block copolymers are soluble in water. It is customarily taught that any polymer having a hydrophobic content of greater than 50% by weight is substantially insoluble in water and can be made appreciably soluble in aqueous systems only when a certain amount of an organic co-solvent has been added, if at all. soluble in aqueous systems. Accordingly, for the present invention the use of ABA or BAB type block copolymers having hydrophobic block segments A PL (G) z_? A and hydrophilic PEG block B segments according to the formula: PL ( G) z-? A - PEG-PL (G) z-? A or PEG-PL (G) z-? A - PEG where z is an integer of 1 or 2. Block copolymers having utility of In accordance with what is disclosed in this invention, they meet the criteria summarized in Table 1, that is, compositional composition within the indicated ranges that result in block copolymers that demonstrate the desired reversible thermal gel formation behavior. For purposes of disclosing molecular weight parameters, all reported molecular weight values are based on measurements made by NMR analytical techniques or GPC (gel permeation chromatography). The weight average molecular weights reported and the average molecular weights reported were determined by GPC and NMR respectively. The reported ratio between lactide / glycolide was calculated from NMR data. A GPC analysis was carried out on a HR-3 Styragel column calibrated with PEG using Rl detection and chloroform as eluent, either in a combination of Phenogel, each mixed, and Phenogel, 500 D columns calibrated with PEG using Rl detection and tetrahydrofuran as eluent. The NMR spectra were taken on CDC13 on a 200 MHz Bruker instrument. Table 1 Total weight average molecular weight: from 2000 to 4990 PEG content: from 17 to 49% by weight Content of PLGA or total PLA: from 51 to 83% by weight Lactate content: 30 to 100% molar Glycolate content: from 0 to 70 mol% Behavior: * soluble in water below the gel formation temperature; * gels above the gel-forming temperature The hydrophobic, biodegradable block segments A are poly (alpha-hydroxy acids) derived or selected from the group consisting of poly (D, L-lactide-co-glycolide), poly ( L-lactide-co-glycolide), poly (D, L-lactide), and poly (L-lactide) which are known as poly (lactide-co-glycolide) and poly (lactide) respectively in the present invention. The calculation from the values for the total molecular weight and the weight percentage of PLGA or PLA is given in Table 1, and considering that the weight average molecular weight of each of the A blocks in a copolymer of three ABA blocks or B blocks in a BAB three block copolymer are essentially the same, the weight average molecular weight of each polymer block A poly (lactide-co-glycolide) or poly (lactide) is between about 600 and 3000 Through similar calculations, the hydrophilic B-block segment is preferably polyethylene glycol (PEG) having an average molecular weight of between about 500 and 2200. The ABA three-block copolymer can be synthesized by ring-opening polymerization or condensation polymerization in accordance with the following reaction schemes: SYNTHESIS BY POLYMERIZATION BY RING OPENING glycolide DL-lactide PEG O CH, -CH) SntOC-CH-ÍCHJj-CHjJ, CH, O i 3 11 H- °, H > ., -. { O- CH, - C), - (O- CK.- H? - (O- C ~ CHJG - (O-C- Hj '.- OH COPOLYMER OF THREE BLOCKS SYNTHETY BY CONDENSATION POLYMERIZATION Step 1: Synthesis of PLGA oligomer CH, O O l * ll II HO-CH-C-OH + HO-CHj-C-CH DL-lactide acid glycolic acid CH, O OR H- (O-CH C), ~ (O-CH3-C), PLGA oligomer Step 2: Synthesis of ABA block copolymer CH, o or H- (O-? H-C), - (O-CH, -C) and -OH H-. { 0-CH, -CH,), .- OH PLGA oligomer H, o or CH. H- (O-CH-C), - (O-CH.-C), - (O-CHj-CH ^ -O- (C-CH-O.-tC-CH, -0), - H THREE-BLOCK COPOLYMER BAB-type three-block polymers can be formed in a similar manner by the appropriate choice of reaction conditions. For example, blocks B (PEG) can be connected to blocks A (PLGA or PLA) by ester or urethane linkages and the like, condensation polymerization and ring-opening polymerization processes can be employed as well as block coupling Hydrophilic monofunctional B at both ends of a hydrophobic block A difunctional in the presence of coupling agents such as for example isocyanates. In addition, coupling reactions can follow the activation of functional groups with activation agents such as for example carbonyldiimidazole, succinic anhydride, N-hydroxysuccinimide and p-nitrophenyl chloroformate and the like. The hydrophilic block B is formed from the appropriate molecular weights of PEG. PEG was chosen as the water soluble hydrophilic block due to its unique biocompatibility, absence of toxicity, hydrophilicity, solubilization and rapid depuration of the patient's body. Hydrophobic A blocks are synthesized and used due to their properties of solubilization, biocompatibility and biodegradation. The in vitro and in vivo degradation of these poly (lactide-co-glycolide) and poly (lactic) hydrophobic blocks is well understood and the degradation products are naturally occurring compounds that are easily metabolized and / or eliminated by the body of the body. patient. Surprisingly, the total weight percentage of hydrophobic poly (lactide-co-glycolide) or poly (lactide) blocks A relative to the total weight percentage of the hydrophilic PEG block B is, for example, between about 51 and 83. % by weight, and more preferably between about 65 and 78% by weight, however the resulting three-block polymer retains the desirable solubility in water and the reverse thermal gel-forming properties. It is an unexpected finding that a block copolymer with such a large proportion of hydrophobic component is soluble in water below normal ambient temperatures such as at refrigerator temperatures (5 ° C). It is believed that the desirable solubility character is possible due to the maintenance of the overall low molecular weight of the entire three-block copolymer between about 2000 and 4990. Thus, water-soluble biodegradable block copolymers possessing thermally reversible gel forming properties. are prepared wherein the hydrophilic block B or the hydrophilic B blocks constitute from about 17 to 49% by weight of the copolymer and the hydrophobic block A or the hydrophobic A blocks constitute from about 51 to 83% by weight of the copolymer. In a preferred embodiment, the A blocks of PLGA or blocks A of PLA may comprise between about 65 and 78 wt.% Of the copolymer and the B blocks of PEG may constitute between about 22 and 35 wt.% Of the copolymer. Further, the preferred overall average molecular weight of the total three-block copolymer will be between about 2800 and 4990. The concentration at which the block copolymers are soluble at temperatures below the gel-forming temperature can be considered as the functional concentration . In general terms, concentrations of block copolymers from 3% by weight and up to about 50% by weight can be used and remain functional. Nevertheless, concentrations within the range of about 5 to 40% by weight are preferred and concentrations within the range of about 10 to 30% by weight are most preferred. To obtain a transition to viable gel phase with the copolymer, a certain minimum concentration, for example 3% by weight, is required. In the lower functional concentration ranges the phase transition can result in a weak gel formation. At higher concentrations, strong gel crosslinking is formed. The mixture of the biodegradable copolymer and peptide / protein drugs, and / or other types of drugs, can be prepared in the form of an aqueous solution of the copolymer below the gel-forming temperature to form a drug delivery liquid where the drug can be used. be either partially or totally dissolved. When the drug is partially dissolved, or when the drug is essentially insoluble, the drug exists in a colloidal state such as, for example, suspension or emulsion. This drug administration liquid is then administered parenterally, typically, transdermally, transmucosally, inhaled, or inserted into a cavity such as for example the ocular, vaginal, transurethral, rectal, nasal, oral, buccal, pulmonary or auricular cavity. to a patient, where he will undergo a reversible thermal gel formation since the body temperature is above the gel formation temperature. This system will cause minimal toxicity and minimal mechanical irritation to the surrounding tissue due to the biocompatibility of the materials and the flexibility of the gel, and will be biologically completely degraded into lactic acid, glycolic acid, and PEG within a specific time interval. The drug release, gel strength, gel formation temperature and degradation rate can be controlled through a suitable design and the preparation of the various blocks of copolymers, that is, through modifications of the weight percentage of blocks A and blocks B, the molar percentages of lactate and glycolate, and the molecular weight and polydispersity of the ABA or BAB three-block copolymers. The drug release can also be controlled by adjusting the polymer concentration in the drug delivery liquid. A dosage form comprising a solution of the block copolymer containing either dissolved drug or drug in the form of a suspension or emulsion is administered to the body. This formulation then spontaneously forms gel due to the reverse thermal gel properties of the block copolymer to form a drug reservoir as the temperature of the formulation is raised to body temperature. The only limitation as to the amount of drug that can be loaded into the formulation is a limitation of functionality, i.e., the drug loading can be increased until the thermal gel-forming properties of the copolymer are adversely affected to a degree unacceptable, or else until the formulation properties are adversely affected to such an extent that the administration of the formulation becomes unacceptably difficult. In general, it is anticipated that in most cases the drug will constitute between about 0.01 and 20% by weight of the formulation with very common ranges between about 0.01 and 10%. These ranges of drug loading are not limiting for the invention. Provided the functionality is maintained, drug loads outside these ranges fall within the scope of the invention. A clear advantage of the compositions of the present invention lies in the ability of the block copolymer to increase the solubility of many pharmaceutical substances. The combination of the hydrophobic block (s) A and the hydrophilic block (s) B makes the copolymer amphiphilic by nature. Regarding this aspect, works very similar to a soap or surfactant in that it has both hydrophilic and hydrophobic properties. It is particularly advantageous in the solubilization of hydrophobic drugs or, in a limited way, water-soluble drugs such as cyclosporine and paclitaxel. What is surprising is the degree of drug solubilization of most, if not all, of the drugs since the main component of the block copolymer is the content of hydrophobic A blocks. However, as already mentioned, even though the hydrophobic polymer block (s) are the main component, the block copolymer is soluble in water and it has been found that there is also an additional increase in solubility of the drug when combined in an aqueous phase of the block copolymer. Another advantage of the composition of the invention is found in the ability of the block copolymer to increase the chemical stability of many pharmaceutical substances. Several mechanisms for the degradation of drugs that cause a chemical instability of a drug have been observed as inhibited when the drug is in the presence of the block copolymer. For example, paclitaxel and cyclosporin A are substantially stabilized in the aqueous polymer composition of the present invention in relation to certain aqueous solutions of these same drugs in the presence of organic cosolvents. This stabilizing effect on paclitaxel and cyclosporin A is only illustrative of the effect that could be achieved with many other pharmaceutical substances. In certain situations, the drug loaded polymer can be administered in the gel state instead of being administered in the form of a solution. The gel formation may be the result of raising the temperature of a drug loaded polymer solution above the gel-forming temperature of the polymer prior to administration, or it may be caused by the raising of the polymer concentration. in the solution above the saturation concentration at the administration temperature, or it can be caused by additives to the polymer solution that cause the solution to become a gel. In any case, the gel formed in this way can be administered parenterally, topically, transdermally, transmucosally, inhaled or inserted in a cavity such as for example ocular cavity, buccal, transurethral, rectal, nasal, oral, pulmonary or atrial cavity. . This invention can be applied to bioactive agents and drugs of all types and offers a particularly effective way of administering polypeptides and proteins. Many labile peptide and protein drugs can be handled in formulation in the block copolymers of the invention and can benefit from the reverse thermal gel formation process described herein. While not specifically limited to the following, examples of pharmaceutically useful polypeptides and proteins may be selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet derived growth factor (PDGF), prolactin, luliberin , luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, somatostatin, glucagon, interleukin -2 (IL-2), interferon-alpha, beta, or gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor ( TNF), nerve growth factor (NGF), granulocyte colony stimulation factor (G-CSF), macrophage colony stimulation factor of granulocyte (GM-CSF), macrophage colony stimulation factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, pyrimidine, gramicidins, cyclosporins, as well as synthetic analogues, modifications and pharmacologically active fragments thereof, enzymes, cytokines, monoclonal antibodies and vaccines. The only limitation to the protein or polypeptide drug that can be employed is functionality. In some cases, the functionality or physical stability of the polypeptides and proteins can also be increased through various additives to the aqueous solutions or suspensions of the protein or polypeptide drug. Additives, such as polyols (including sugars), amino acids, surfactants, polymers, other proteins and some salts can be used. These additives can be easily incorporated into the block copolymers which will then be subjected to the reverse thermal gel formation process of the present invention. Developments in protein engineering may provide the possibility of increasing the inherent stability of peptides or proteins. While such resulting modified or manipulated proteins can be considered as novel entities in terms of regulatory implications, this does not alter their suitability for use in the present invention. One of the typical examples of modification is PEGylation where the stability of the polypeptide drugs can be significantly improved by the covalent conjugation of water soluble polymers such as polyethylene glycol with the polypeptide. Another example is the modification of the amino acid sequence in terms of the identity or location of one or more amino acid residues by terminal and / or internal addition, removal or substitution. Any improvement in stability allows a continuous release of therapeutically effective polypeptide or protein over a prolonged period of time after a single administration of the drug delivery liquid to a patient. In addition to the peptide or protein-based drugs, other drugs of all therapeutic or pharmaceutically useful categories may be used. These drugs are described in well-known literature references such as the Merck Index, the Physicians Desk Reference, and The Pharmacological Basis of Therapeutics. A short list of specific agents is provided for illustrative purposes only and should not be construed as limiting: anticancer agents such as mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D and camptothecin; antipsychotics such as cefoxitin; anthelmintics such as ivermectin; antivirals such as acyclovir; immunosuppressants such as cyclosporin A (cyclic polypeptide-like agent), steroids, and prostaglandins. BRIEF DESCRIPTION OF THE DRAWINGS The above objects, features and advantages as well as other objects, features and advantages of the invention will be apparent from a consideration of the following detailed description presented in combination with the accompanying drawings in which: Figure 1 is a phase diagram illustrating the gel-forming behavior of aqueous solutions of a three-block copolymer of PLGA-PEG-PLGA, studied at different concentrations and temperatures. Figures 2a to 2c are degradation profiles illustrating the in vitro degradation of a three-block copolymer of PLGA-PEG-PLGA incubated at different temperatures and pH levels. Figure 3 is a graph illustrating the continuous release of insulin in a sustained period of time from a thermal gel of three-block PLGA-PEG-PLGA copolymer. Figure 4 is a paclitaxel release profile from a PLGA-PEG-PLGA three-block copolymer thermal gel formulation showing the cumulative controlled release of paclitaxel for about 50 days. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES OF THE INVENTION In order to illustrate preferred embodiments of this invention, synthesis of several low molecular weight ABA block copolymers consisting of 64 to 80% by weight of hydrophobic A blocks (poly (lactide-co-glycolide) "was carried out" PLGA "or poly (lactide)" PLA ", and from 20 to 36% by weight of hydrophilic block B (polyethylene glycol" PEG "). The purpose was the preparation of three-block copolymers PPLGA-PEG-PLGA or PLA- PEG-PLA with weight average molecular weights of about 2000 to 4,990, which consisted of two A blocks each with weight average molecular weights of about 600 to 2000 and a B block with a weight average molecular weight of about 600 to 2200 Each block A consists of about 30 to 100 mole% lactate and 0 to 70 mole% glycolate.Some examples illustrate the preferred embodiments of the invention but are intended to be illustrative only. Example 1 Synthesis of three-block copolymer PLGA-PEG-PLGA by ring-opening copolymerization Following the reaction scheme given above, PEG (Mw = 1000) was dried by azeotropic distillation in a flask with toluene (2 x 75 ml) in a nitrogen atmosphere followed by drying at a temperature of 130 ° C under vacuum (5 mm Hg). Lactide and glycolide monomers (in molar proportions of 3: 1, respectively) were added to the flask followed by the addition of stannous octoate (0.1% by weight) and the reaction mixture was heated to a temperature of 150 ° C under vacuum. (5 mm Hg). The progress of the reaction was followed by GPC (gel permeation chromatography). After an appropriate time, the reaction was suspended and the flask was cooled to room temperature. The residue was dissolved in cold water and heated to a temperature of 70-80 ° C to precipitate the formed polymer. The supernatant was decanted and the polymer residue was dissolved again in cold water and heated to induce precipitation. This dissolution process followed by precipitation was repeated three times. Finally, the polymer was dissolved in a minimum amount of water and lyophilized. The resulting PLGA-PEG-PLGA copolymer had a weight average molecular weight (Mw) of 3737, an average molecular weight index (Mn) of 2928, and an Mw / Mn ratio of 1.3. This copolymer exhibited reverse thermal gel formation properties as will be described in greater detail in Example 4. Example 2 Following the basic procedure presented in Example 1, other three-block copolymers were synthesized using the same PEG (Mw = 1000) but varying the content of lactide and / or glycolide. The properties of these three block copolymers appear in the following table: Example of ABA block copolymers with reverse thermal gel formation properties GPC% by weight of LA: GA molecular weight formation A blocks (weight average thermal gel proportion) molar) reverse 2052 67 75:25 yes 2800 64 30:70 yes 3672 73 75:25 yes 4000 75 100: 0 yes 4133 76 75:25 yes 4323 77 50:50 yes 4920 80 75:25 yes 4990 80 40:60 yes It will be noted that all the polymers listed in the table above had properties of reverse thermal gel formation even though the content of lactide (LA) presented variations of 30 to 100 mol% and the content of glycolide (GA) presented variations of 0 to 70% molar. Therefore, both triple PLGA-PEG-PLGA blocks and triple PLA-PEG-PLA blocks are presented in this example. Example 3 Synthesis of three-block copolymer PLGA-PEG-PLGA by condensation copolymer In a three-necked flask, equipped with a nitrogen inlet, thermometer and distillation head for water removal, DL-lactic acid and glycolic acid were placed (molar ratio 3: 1, respectively). The reaction mixture was heated to a temperature of 160 ° C under a nitrogen atmosphere with stirring at atmospheric temperature for three hours and then under reduced pressure (5 mm Hg). The progress of the reaction was followed by GPC. The reaction was stopped at the appropriate time and the polymer formed was purified by precipitation from a dichloromethane solution in a large excess of methanol. The residue was triturated with methanol and dried in vacuum (0.05 mm Hg) at a temperature of 23 ° C. The PLGA oligomer was characterized by GPC, IR and NMR. The resulting PLGA oligomer had a weight average molecular weight (Mw) of 9900, a number average molecular weight (Mn) of 5500 and a Mw / Mn ratio of 1.8. The PLGA was mixed with PEG (Mw = 1000) and heated in a flask at a temperature of 160 ° C under a nitrogen atmosphere. The progress of the reaction was followed by GPC. After an appropriate time, the reaction was stopped and the flask was cooled to room temperature. The residue was dissolved in cold water and then heated to a temperature of 70-80 ° C to precipitate the copolymer. The supernatant was decanted and the residue was dissolved again in cold water and heated to precipitate the polymer. This process of dissolution and precipitation was repeated three times. Finally, the polymer was dissolved in a minimum amount of water and lyophilized. The resulting PLGA-PEG-PLGA block copolymer had a weight average molecular weight (Mw) of 4043, a number average molecular weight (Mn) of 2905 and a Mw / Mn ratio of 1.4. The weight average molecular weights and number average molecular weights were determined by GPC and NMR, respectively. The ratio between lactide and glycolide was calculated from NMR data. A GPC analysis was carried out on an HR-3 Styragel column calibrated with PEG using detection of Rl and chloroform as the eluent. NMR spectra were taken on CDC13 on a Bruker 200 MHZ instrument. The peak assignments according to NMR confirmed the structure of three ABA blocks. Example 4 The gel-forming behavior of aqueous solutions of the ABA three-block copolymer of Example 1 was studied in different concentrations. Polymer solutions of 9 to 30% by weight were prepared in water and the change in viscosity was observed at temperatures within a range between 10 ° C and 60 ° C. Gel formation was defined as the physical state in which the polymer solution did not flow easily when a vial of polymer solution was inverted. The phase diagram (Figure 1) of the polymer of Example 1) was generated as a function of the temperature and concentration of the three-block copolymer. The novel behavior of reverse thermal gel formation was clearly apparent, and was observed as the three-block copolymer solutions were heated. Gel formation at physiologically relevant temperatures (e.g., 37 ° C) was especially prevalent and formed the basis of the substantial utility of the systems for medical and drug administration purposes. Example 5 The in vitro degradation of the PLGA-PEG-PLGA three block copolymer of Example 1 was determined for a 23% by weight solution or gel (1 ml) of copolymer incubated at different temperatures (-10 ° C, 5 ° C , 23 ° C, and 37 ° C) and different initial pH values (3.0, 5.0 and 7.4) over a period of 30 weeks. The degradation and biodegradation of this three block copolymer was caused by hydrolysis and resulted in lactic acid, glycolic acid and PEG as the final products of the degradation. Samples were taken (50 μl) weekly. The samples were lyophilized, dissolved in chloroform, and the molecular weights of the polymer residues were determined by GPC according to what was previously described. The degradation of the polymer was substantially independent of the initial pH within a pH range of 3.0 to 7.4, which can be attributed to the acidification of the medium as the polymer was hydrolyzed to form lactic acid and glycolic acid. The behavior of thermal gel formation was also independent of the pH in the same pH range. The degradation was faster at higher temperatures. The degradation profiles that were generated are shown in figures 2a, 2b and 2 c.

Example 6 The in vivo biodegradation of the polymer of example 1 was determined over a period of four weeks. A sample of 0.40 to 0.45 ml of a cold aqueous solution containing 23% by weight of a three-block copolymer was injected subcutaneously into rats. Upon reaching body temperature, above the gel-forming temperature of the polymer, a mass of gel was immediately formed that was visibly apparent. Samples were surgically recovered as a function of time and indicated that the gel became progressively smaller over a period of two weeks. Between two weeks and four weeks, the physical state of the injected three-block copolymer changed from a gel to a mixture of a gel in a viscous liquid, and finally to a viscous liquid containing no gel that was gradually fully resorbed. At the end of the four-week period, no formulation was visible at the injection site. Microscopically, small pockets of viscous liquid could be observed that were also fully absorbed over the course of the next two weeks. Example 7 Paclitaxel and cyclosporin A are hydrophobic drugs highly insoluble in water (solubilities of about 4 μg / ml). However, these drugs showed significantly higher solubilities when dissolved in aqueous solutions of three-block PLGA-PEG-PLGA copolymers. For example, in a 20% by weight aqueous copolymer solution (polymer of example 3), paclitaxel was soluble up to 5 mg / ml and cyclosporin A was soluble up to 2 mg / ml. Paclitaxel and cyclosporin A were highly unstable in solutions of aqueous cosolvents (for example, in water / acetonitrile solutions). Paclitaxel contained either in 20% by weight aqueous triple PLGA block copolymer solutions (ie, below the gel forming temperature of the copolymer) or gels (ie, above the gel formation temperature of the copolymer) was intact to more than 85% after 120 days of storage (5 ° C and 37 ° C), while cyclosporin A was stable for 100 days (5 ° C). Example 8 A 28% by weight aqueous solution of the PLGA-PEG-PLGA three-block copolymer of Example 1 was prepared. Insulin (without zinc), a parenterally administered protein with proven beneficial effects in the treatment of diabetes mellitus in this aqueous solution of three block copolymer to a final concentration of 5mg / ml. Approximately 2 ml of this composition was placed in a balanced watch glass at a temperature of 37 ° C. The composition formed a gel immediately and adhered on the watch glass, inside which it was placed directly in a 10 mM phosphate buffered saline solution, pH 7.4, 37 ° C, and the kinetic characteristics of insulin release were monitored. from the gel by reverse phase HPLC using UV detection and gradient elution (mobile phase TFA / acetonitrile / water). The data have been summarized graphically in Figure 3. Insulin was released continuously for approximately one week. The utility of the three block copolymer thermal gel in the controlled administration of proteins and peptides over a substantial period was clearly established and illustrated through this example. Example 9 To a 23 wt.% Aqueous solution of PLGA-PEG-PLGA three-block copolymer of Example 1 a sufficient amount of paclitaxel was added to provide approximately 2.0 mg / ml of drug. A 2 ml sample of this solution was placed on a watch glass and equilibrated at a temperature of 37 ° C. Since the temperature was higher than the gel forming temperature of the copolymer, a gel formed on the watch glass. The watch glass was placed in a 200 ml lab vessel containing release medium consisting of 150 ml of PBS (pH 7.4) containing 2.4% by weight of Tween-80 and 4% by weight of Cremophor EL equilibrated at 37 ° C. The solution was stirred in the beaker. The upper part of the beaker was sealed to avoid evaporation. The total set was placed in an incubator at a temperature of 37 ° C. The triplicate release study was carried out. At different time periods a 5 ml aliquot of the release medium was taken and analyzed for paclitaxel. The PBS solution was replaced with fresh PBS after each aliquot removal. Samples were collected 1, 2, 4, 8, 18, and 24 hours and then at 24 hour intervals, and analyzed by HPLC. The paclitaxel release profile of the gel is shown in Figure 4. The gel formulation provided excellent control over the release of paclitaxel for approximately 50 days. EXAMPLE 10 Copolymers of three blocks of BAB were synthesized using the same block B of PEG at both ends (Mw = 550) but varying the content of poly (lactide) and / or poly (glycolide). PEG and PLGA were coupled to each other via ester, urethane, or a combination of ester and urethane linkages. The properties of these three block copolymers appear in the following table: Example of BAB block copolymers with reverse thermal gel formation properties GPC% by weight of PLA: PGA molecular weight formation bl <; oques A (ratio gel average temperature in molar weight) reverse 4140 70 78:22 yes 4270 72 78:22 yes 4580 73 78:22 yes 4510 73 72:28 yes All copolymers of three blocks of PEG-PLGA-PEG presented in the previous table they possessed thermal reverse gel formation properties. The sol / gel transition temperatures for the polymers of three previous blocks were 36, 34, 30 and 26 ° C, respectively. The above description will allow one skilled in the art to make copolymers of three blocks of type ABA (for example, PLGA-PEG-PLGA and PLA-PEG-PLA) or BAB (for example, PEG-PLGA-PEG and PEG-PLA). -PEG) which form aqueous solutions having reverse thermal gel formation properties and use thereof in the field of drug administration. Even when the controlled administration of a conventional drug (paclitaxel) and a protein (insulin) drug are illustrated in the examples to show the functionality of the hydrogels formed from aqueous solutions of three-block copolymers, these descriptions do not have the purpose to represent an exhive statement of all the drugs that can be used and loaded into the biodegradable block copolymers. Certainly numerous other drugs of various classes of therapeutic agents are suitable for administration from aqueous compositions of three-block copolymers in accordance with that described in this description of the invention. Nor are all block copolymers which can be prepared and which demonstrate the critical reverse thermal gel formation property specifically shown. However, it will be immediately apparent to one skilled in the art that various modifications can be made without departing from the scope of the invention which is limited only by the following claims and their functional equivalents.

Claims

CLAIMS A three-block polymer of type ABA or biodegradable BAB, said three-block polymer ABA has the formula: PL (G) z-? A-PEG-PL (G) z_? A and said three-block polymer BAB has the formula: PEG - PL (G) z-? A - PEG where z is an integer that represents 1 or 2, where block A is represented by PL (G) z-? A such that when z is 2 block A is a poly (lactide-co-glycolide) or PLGA copolymer, and when z is 1 block A is a poly (lactide) polymer or PLA and where block B is represented by PEG which is a hydrophilic polyethylene glycol polymer, said block copolymer has a weight average molecular weight of between about 2000 and 4990 and possesses reverse thermal gel-forming properties.
A three-block polymer according to claim 1, wherein the block A PL (G) z-? A comprises from about 51 to 83% by weight of said polymer and the PEG block B comprises from about 17 to 49% by weight of said polymer.
A polymer of three blocks according to claim 2 wherein the polymer is of type BAB.
A polymer of three blocks according to claim 2 wherein the polymer is of the ABA type.
A three block polymer according to claim 4 wherein z is 1 such that block A is a PLA polymer.
A three block polymer according to claim 4 wherein z is 2 such that block A is a PLGA copolymer.
A three-block polymer according to claim 6 wherein the block A is a PLGA copolymer comprising between about 80 and 20 mol% lactide and between about 20 and 80 mol% glycolide.
A three block polymer according to claim 7 wherein the block A PLGA comprises between about 65 and 78 wt% and said block B PEG comprises between about 22 and 35 wt% of said three block copolymer.
A three block polymer according to claim 7 wherein each A PLGA block has a weight average molecular weight of between about 600 and 3000 and each B PEG block has a weight average molecular weight of between about 500 and 2200..
An aqueous, biodegradable, polymeric drug delivery composition having reverse thermal gel-forming properties, comprising an aqueous phase having uniformly: (a) an effective amount of a drug; and (b) a biodegradable three-block ABA or BAB polymer, said triple ABA block has the formula: PL (G) z-? A-PEG-PL (G) z-? A and said triple block BAB has the formula: PEG - PL (G) z-? A - PEG where z is an integer that represents 1 or 2, where block A is represented by PL (G) z-? A such that when z is 2 block A is a poly (lactide-co-glycolide) or PLGA copolymer, and when z is 1 block A is a poly (lactide) polymer or PLA and where block B is represented by PEG which is a polymer of hydrophilic polyethylene glycol, said three block polymer has a weight average molecular weight of between about 2000 and 4,990.
An aqueous polymer composition according to claim 10 wherein the three block polymer content of said composition is between about 3 and 50% by weight.
An aqueous polymer composition according to claim 11 wherein, in the three-block polymer, the block A PL (G) z-? A comprises from about 51 to 83% by weight of said polymer - and the block B PEG comprises from about 17 to 49% by weight of said polymer. .
An aqueous polymer composition according to claim 12 wherein the three block polymer is of a BAB type. .
An aqueous polymer composition according to claim 12 wherein the polymer is of the ABA type. .
An aqueous polymer composition according to claim 14 wherein, in the three-block polymer, z represents 1 such that block A is a PLA polymer. .
An aqueous polymer composition according to claim 14 wherein, in the three-block polymer, z represents 2 such that block A is a PLGA copolymer. .
An aqueous polymer composition according to claim 16 wherein, in the three-block polymer, block A is a PLGA copolymer comprising between about 80 and 20 mol% lactide and between about 20 and 80 mol% glycolide.
An aqueous polymer composition according to claim 17 wherein, in the three-block polymer, block A PLGA represents between about 65 and 78% by weight and said block B PEG represents between about 22 and 35% by weight of said polymer of three blocks. .
An aqueous polymer composition according to claim 17 wherein, in the three block polymer, each A PLGA block has a weight average molecular weight of between about 600 and 3000 and each B PEG block has a weight average molecular weight of between approximately 500 and 2200..
An aqueous polymer composition according to claim 17 wherein said drug is a polypeptide or a protein. .
An aqueous polymeric composition according to claim 20 wherein said polypeptide or protein is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet derived growth factor (PDGF), prolactin, luliberin , luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone releasing factor, insulin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-alpha, beta, or gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (NGF), granulocyte colony stimulation factor (G-CSF), granulocyte macrophage colony stimulation factor ( GM-CSF), macrophage colony stimulation factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins, cyclosporins, as well as synthetic analogues, modifications and pharmacologically active fragments thereof, enzymes, cytokines, monoclonal antibodies and vaccines.
22. An aqueous polymer composition according to claim 21 wherein the drug content of said composition is between about 0.01 and 20% by weight.
23. An aqueous polymer composition according to claim 17 wherein said drug is an anticancer or cell antiproliferative agent.
24. An aqueous polymer composition according to claim 23 wherein said drug is an anticancer agent selected from the group consisting of mitomycin, bleomycin, BCNI, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D, and camptothecin.
25. An aqueous polymer composition according to claim 24 wherein the drug content of said composition is between about 0.01 and 20% by weight.
26. A method for administering a drug to a warm-blooded animal in a controlled release form, comprising: (1) administering an aqueous biodegradable polymeric drug delivery composition having reverse thermal gel-forming properties consisting of of an aqueous phase having uniformly: (a) an effective amount of a drug; and (b) a biodegradable three-block ABA or BAB polymer, said triple ABA block has the formula: PL (G) z-? A-PEG-PL (G) z-? A and said triple block BAB has the formula: PEG - PL (G) z-? A - PEG where z is an integer representing 1 or 2, where block A is represented by PL (G) z-? A such that when z is 2 , block A is a copolymer of poly (lactide-co-glycolide) or PLGA, and when z is 1 block A is a polymer of poly (lactide) or PLA and where block B is represented by PEG which is a hydrophilic polyethylene glycol polymer, said block copolymer has a weight average molecular weight of between about 2000 and 4990, (2) keeping said composition in a liquid state at a temperature lower than the gel forming temperature of said three-polymer blocks; Y (3) administering said composition in liquid form to said warm-blooded animal with the subsequent formation of a gel as the temperature of said composition rises due to the body temperature of said animal above the gel-forming temperature of said animal. polymer of three blocks. .
A method according to claim 26 wherein said administration is through parenteral, ocular, topical, by inhalation, transdermal, vaginal, buccal, transmucosal, transurethral, rectal, nasal, oral, pulmonary or atrial means. .
A method according to claim 27 wherein the content of three block polymer of said composition is between about 3 and 50% by weight.
A method according to claim 28 wherein, in the three-block polymer, the block A PL (G) Z-? A forms from about 51 to 83% by weight of said polymer and the block B PEG forms from about 17 to 49% by weight of said polymer.
30. A method according to claim 29 wherein the three block polymer is a BAB type polymer.
31. A method according to claim 29 wherein the three-block polymer is a polymer of type ABA.
32. A method according to claim 31 wherein in the three-block polymer, z is 1 such that block A is a PLA polymer.
33. A method according to claim 31 wherein in the three block polymer, z is 2 such that block A is a PLGA copolymer.
34. A method according to claim 33 wherein in the block polymer, block A is a PLGA copolymer comprising from about 80 to 20 mole% lactide and from about 20 to 80 mole% glycolide.
35. A method according to claim 34 wherein in the three-block polymer the block A PLGA forms between about 65 and 78% by weight and said block B PEG forms between about 22 and 35% by weight of said three block polymer . 6.
A method according to claim 35 wherein in the three block polymer, each A PLGA block has a weight average molecular weight of between about 600 and 3000 and wherein each B PEG block has a weight average molecular weight between approximately 500 and 2200..
A method according to claim 34 wherein said administered drug is a poptide or a protein. .
A method according to claim 37 wherein said poptide or protein is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet-derived growth factor. (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone release factor, insulin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-alpha, beta, or gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), factor of tumor necrosis (TNF), nerve growth factor (NGF), granule cell colony stimulation factor (G-CSF), granulocyte macrophage colony stimulation factor (GM-CSF), macrophage colony stimulation factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, tirocidin, gramicidins, cyclosporins, as well as analogues synthetics, modifications and pharmacologically active fragments thereof, enzymes, cytokines, monoclonal antibodies and vaccines. .
A method according to claim 37 wherein the drug content of said composition is between about 0.01 and 20% by weight. .
A method according to claim 43 wherein said administered drug is an anticancer or cell antiproliferative agent. .
A method according to claim 40 wherein said drug is an anticancer agent selected from the group consisting of mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D and camptothecin.
A method according to claim 40 wherein the drug content of said composition is between about 0.01 and 20% by weight.
A method for increasing the solubility of a drug comprising the uniform mixing of an effective amount of said drug in an aqueous biodegradable polymeric pharmaceutical delivery composition having thermal to reverse properties of gel formation, said aqueous composition is comprised of a phase aqueous having uniformly a three-block polymer of type ABA or biodegradable BAB, said three-block polymer ABA has the formula: PL (G) z-? A-PEG-PL (G) z-? A and said polymer of three blocks BAB has the formula: PEG - PL (G) z-? A - PEG where z is an integer representing 1 or 2, where block A is represented by PL (G) z-? A of such that when z is 2, block A is a copolymer of poly (lactide-co-glycolide) or PLGA, and when z is 1 block A is a polymer of poly (lactide) or PLA and where block B is represented by PEG which is a polyethylene glycol hydro polymer phylic, said three-block polymer has a weight average molecular weight of between about 2000 and 4990..
A method according to claim 43 wherein the content of three block polymer of said composition is between about 3 and 50% by weight. .
A method according to claim 44 wherein in the three-block polymer, the block A PL (G) z-? A forms from about 51 to 83% by weight of said polymer and the block B PEG forms from about 17 to 49 % by weight of said polymer. .
A method according to claim 45 wherein the three block polymer is a BAB type polymer. .
A method according to claim 45 wherein the three-block polymer is a polymer of type ABA. .
A method according to claim 47 wherein in the three block polymer, z is 1 such that block A is a PLA polymer. .
A method according to claim 47 wherein in the three block polymer, z is 2 such that block A is a PLGA copolymer. .
A method according to claim 49 wherein in the block polymer the block A is a copolymer of PLGA comprising between about 80 and 20 mol% of the acid and between about 20 and 80 mol% of glycolide. .
A method according to claim 50 wherein in the three block polymer, block A PLGA forms between approximately 65 and 78% by weight and said block B PEG forms between approximately 22 and 35% by weight of said three block polymer.
A method according to claim 51 wherein, in the three block polymer, each A PLGA block has a weight average molecular weight of between about 600 and 3000 and each B PEG block has a weight average molecular weight of between about 500 and 2200.
53. A method according to claim 50 wherein said drug is a polypeptide or a protein. 5 .
A method according to claim 53 wherein said polypeptide or protein is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet derived growth factor (PDGF), prolactin, luliberin, hormone of luteinizing hormone (LHRH) release, LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone release factor, insulin, somatostatin, glucagon, interleukin-2 (IL -2), interferon-alpha, beta, or gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), tumor necrosis factor (TNF), factor nerve growth (NGF), granulocyte colony stimulation factor (G-CSF), granulocyte macrophage colony stimulation factor (GM-CSF), stimulation factor ulation of macrophage colonies (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins , tyrocidin, gramicidins, cyclosporins, as well as synthetic analogues, modifications and pharmacologically active fragments thereof, enzymes, cytokines, monoclonal antibodies and vaccines.
55. A method according to claim 53 wherein the drug content of said composition is between about 0.01 and 20% by weight.
56. A method according to claim 50 wherein said administered drug is an anticancer or cell antiproliferative agent.
57. A method according to claim 56 wherein said drug is an anticancer agent selected from the group consisting of mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D and camptothecin.
58. A method according to claim 56 wherein the drug content of said composition is between about 0.01 and 20% by weight.
59. A method for increasing the solubility of a drug comprising the uniform mixing of an effective amount of said drug in an aqueous biodegradable polymeric pharmaceutical delivery composition having thermal to reverse properties of gel formation, said aqueous composition being comprised of an aqueous phase having uniformly a three-block polymer of ABA or biodegradable BAB type, said ABA three block polymer has the formula: PL (G) z-? A-PEG-PL (G) z-? A and said three-block polymer BAB has the formula: PEG-PL (G) z-? A-PEG where z is an integer representing 1 or 2, where block A is represented by PL (G) z-? A such that when z is 2, block A is a copolymer of poly (lactide-co-glycolide) or PLGA, and when z is 1 block A is a polymer of poly (lactide) or PLA and where the Block B is represented by PEG which is a polyethylene glycol polymer hydrophilic, said three block polymer has a weight average molecular weight between about 2000 and 4990.
60. A method according to claim 59 wherein the three block polymer content of said composition is between about 3 and 50 % in weigh.
61. A method according to claim 60 wherein in the three block polymer, block A PL (G) z-? A comprises from about 51 to 83% by weight of said polymer and block B PEG forms from about 17 to 49% by weight of said polymer.
62. A method according to claim 61 wherein the three block polymer is a BAB type polymer.
63. A method according to claim 61 wherein the three block polymer is an ABA type polymer.
64. A method according to claim 63 wherein in the three block polymer, z is 1 such that block A is a PLA polymer.
65. A method according to claim 63 wherein in the three block polymer, z is 2 such that block A is a PLGA copolymer.
66. A method according to claim 65 wherein in the block polymer the block A is a PLGA copolymer comprising between about 80 and 20 mol% of the acid and between about 20 and 80 mol% glycolide.
67. A method according to claim 66 wherein in the three block polymer, block A PLGA forms between about 65 and 78% by weight and said block B PEG forms between about 22 and 35% by weight of said three block polymer. blocks.
68. A method according to claim 67 wherein, in the three block polymer, each A PLGA block has a weight average molecular weight of between about 600 and 3000 and each B PEG block has a weight average molecular weight of between approximately 500 and 2200. .
A method according to claim 66 wherein said drug is a polypeptide or a protein. .
A method according to claim 69 wherein said polypeptide or protein is a member selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, platelet derived growth factor (PDGF), prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRH antagonists, growth hormone (human, porcine, bovine, etc.), growth hormone release factor, insulin, somatostatin, glucagon, interleukin-2 (IL-2), interferon-alpha, beta, or gamma, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropin releasing hormone (TRH), factor of tumor necrosis (TNF), nerve growth factor (NGF), granule cell colony stimulation factor (G-CSF), granulocyte macrophage colony stimulation factor (GM-CSF), macrophage colony stimulation factor (M-CSF), heparinase, bone morphogenic protein (BMP), hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin, bradykinin, bacitracins, polymyxins, colistins, tirocidin, gramicidins, cyclosporins, as well as analogues synthetics, modifications and pharmacologically active fragments thereof, enzymes, cytokines, monoclonal antibodies and vaccines.
71. A method according to claim 69 wherein the drug content of said composition is between about 0.01 and 20% by weight.
72. A method according to claim 66 wherein said administered drug is an anticancer or cell antiproliferative agent.
73. A method according to claim 72 wherein said drug is an anticancer agent selected from the group consisting of mitomycin, bleomycin, BCNU, carboplatin, doxorubicin, daunorubicin, methotrexate, paclitaxel, taxotere, actinomycin D and camptothecin.
74. A method according to claim 72 wherein the drug content of said composition is between about 0.01 and 20% by weight.