KR20010022708A - Injectable biodegradable block copolymer gels for use in drug delivery - Google Patents

Abstract

A system and method for extragastrointestinal administration of drugs contained in a biodegradable polymer matrix to warm-blooded animals, the system comprising a hydrogel depot that is administered in a water-soluble liquid, but releases the drug in a controlled manner in the body of the animal. Form. The copolymer undergoes a gel / sol phase transition at temperatures above the body temperature of the animal to be administered, and when in solution and administered into the body, the temperature is lowered to body temperature to form a hydrogel. Polymers include (i) hydrophobic A copolymers of poly (α-oxyacids); (ii) a hydrophilic B polymer composed of poly (ethylene oxide). The drug is released from the copolymer in a controlled manner, and the polymer is biodegraded into a non-toxic product. Gel / sol transition temperatures and degradation rates can be controlled by appropriate selection of the molecular weight and concentration of the poly (α-oxyacid) and poly (ethylene oxide) polymer block components.

Description

Biodegradable injectable block copolymer gel that can be used for drug transport {INJECTABLE BIODEGRADABLE BLOCK COPOLYMER GELS FOR USE IN DRUG DELIVERY}

There has been considerable research focused on the physicochemical response of stimulus sensitive polymers to changes in temperature, pH, electric field, chemicals, etc. (Langer, Science, 249, 1527-1533 (1990); Ishihara, et al., J. Appl.Polym. Sci., 29, 211-217, (1995); Thomas, et al., J. Am. Chem Soc, 117, 2949-2959, (1995) and Kwon et al., Nature, 354, 291 -392 (1991).

Thermosensitive polymers have been extensively studied to function as drug carriers. N-isopropylacrylamide homopolymer or copolymer (NIPAAm) (Bae et al., Makromo. Chem. Rapid Commun., 8, 481-485 (1987) and Chen, et al., Nature, 373,49-52 (1995) is the same kind. Another form is a triblock copolymer (trademark of Poloxamer) consisting of hydrophobic poly (propylene oxide) with a central block and hydrophilic poly (ethylene oxide) with a side block (Malston, et al., Macromolecules, 25, 5440-). 5445 (1992). Such polymers are generally not biodegradable and their toxicity is a problem. For example, injection of Poloxamer type copolymer into rat peritoneum has been shown to enhance plasma cholesterol and triglycerol (Wout et al., J. Parenteral Sc. & Tech., 46 (6), 192-200 (1992).

Most work on drug delivery systems using polymers has been concentrated on injectable microspheres or biodegradable implant systems that require organic solvents in manufacturing (Youxin, et al., J. Controlled Release, 27, 247-. 257 (1993). Since the implant system has an apparent solid form, it must be inserted by surgery (Churchill et al., U.S. Patent 4,526,938 and 4,745,160). Surgical insertion results in irritation and damage to the tissue.

A.S. Sawhney and J.A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411 (1990) synthesized a triple copolymer of d, l-lactide, glycidide and ε-caprolactone which degrades rapidly in vitro. The hydrophilicity of the material was increased by copolymerization with a polyether surfactant prepolymer (Pulronic F-68). Such prepolymers are block copolymers composed of about 80 wt% hydrophobic poly (propylene oxide) blocks and 20 wt% hydrophilic poly (ethylene oxide) blocks. It is known that polymer surfactants of the Pluronic type, in particular poly (propylene oxide) block portions, are not biodegradable.

Other implantable transport systems are also known, as known from Dunn et al, US Pat. Nos. 4,938,763 and 5,278,202. Such polymers are thermoplastic or thermoset. Thermoplastic solutions require organic solvents such as N-methyl-2-pyrrolidone, methyl ethyl ketone, dimethylformamide, propylene glycol, THF, DMSO, dodecylazacycloheptan-2-one (Azone) and the like. Thermosetting systems are formed in-situ with a curing agent and consist of crosslinkable polymers to be cured. However, a major disadvantage of thermoplastic compositions is the use of organic solvents that are toxic or irritating to human tissue. The thermosetting system has a fairly rapid curing reaction, and injection must be done immediately after adding the curing agent, so the drug should be mixed with the prepolymer solution before the catalyst is added.

A.S. Sawhney et al, Macromolecules, Vol 26, No. 4, 581-589 (1993) have a poly (ethylene glycol) central block and extend into α-oxy acid oligomers such as oligo (d, l-lactic acid) or oligo (glycolic acid) and end up in acrylate groups Was synthesized. Using non-toxic photoinitiators, macromonomers can be rapidly polymerized with visible light. Due to the multifunctionality of the macromonomers, the polymerization results in the formation of crosslinked gels. When the oligo (α-oxy acid) moiety is hydrolyzed by the poly (ethylene glycol) moiety, the gel is decomposed into poly (ethylene glycol), α-oxy acid, oligo (acrylic acid), and this decomposition rate is reduced to any oligo (α). Oxyacids) can be controlled within a day or up to four months, depending on the appropriate choice. In this system, however, an additional component, a photoinitiator, must be used, as well as additional processes such as photocrosslinking reactions. This is further explained in US Pat. No. 5,567,435.

Cha et al., PCT Publication WO97 / 15287 published 1 May 1997, describes a specific block copolymer, which polymer comprises (i) a hydrophilic A polymer block selected from poly (α-oxyacid), poly (ethylene carbonate). ; (ii) consisting of a hydrophilic B polymer block composed of polyethylene glycol. Such copolymers have heat reversal gelling properties, that is, they form aqueous solutions below the body temperature of the animal to which they are administered and become gels when the temperature rises above body temperature.

The optimal material for use as an injectable or implantable polymer drug delivery device must be biodegradable, compatible with hydrophilic or hydrophobic drugs, be made of a simple and stable solvent such as water, and require further polymerization. There should be no or no response after administration.

Object of the present invention

It is an object of the present invention to provide a drug transport system of block copolymers, which is biodegradable, has thermal gelling behavior and has good drug release characteristics.

It is an object of the present invention to provide a method of making a drug delivery device of thermally sensitive, biodegradable copolymer, wherein the polymer matrix must be stored in dry solid form at room temperature or below before it is made into a dosage solution. .

It is a further object of the present invention to provide a drug delivery system for use in the administration of an extranasal of a bioactive substance that does not require any surgical procedure for transplantation.

Another object of the present invention is to provide a method for extra-intestinal administration of a drug in a biodegradable polymer matrix, wherein the matrix forms a gel depot in the human body so that the drug from the depot is adjusted to correspond to the biodegradation rate of the polymer matrix. Released at a rate.

These and other objects of the present invention are accomplished using a hydrogel drug transport system, which comprises a poly (ethylene oxide) B block and a biodegradable poly (α-hydroxy) having both thermal sensitivity and biodegradability. ) A block copolymer is used. Hydrogels have a good balance of hydrophilicity (B block) and hydrophobicity (A block) in order to have thermal inversion. In addition, organic solvents are not used to add bioactive materials to such polymer systems. Therefore, there is no need to remove any organic solvent.

Inventor Byung Moon Jung (US Citizen, US Resident, Address; Utah 84108, SLC, 714 S. arapeen Drive), Bae Yu Han (Korean Citizen, Address: Hyundai Apartment # 103-103, Yeongbong-dong, Gwangju, Republic of Korea, 50-303) (Korean Citizen, Address; Suwon, South Korea, Jangan-gu, Cheoncheon-dong # 300 Zip Code 440-746), and Kim Sung-Wan (US Citizen, Utah, USA; Address: U100, Utah 84100, SLC, Devonshire Drive) developed the invention according to the following specification. Apply for a patent.

The present invention relates to the production of thermosensitive biodegradable block copolymers that can be used for extra-intestinal or subcutaneous administration of bioactive molecules such as peptides and protein drugs, and use them for drug administration. More specifically, the present invention relates to thermosensitive biodegradable polymers comprising bioactive molecules having a block length of the block copolymer and a gel / sol transition temperature that depends on this concentration. The present invention utilizes thermosensitive biodegradable polymers based on poly (ether-ester) block copolymers, which will be described below. Block copolymers with specific molecular weights and composition ranges are found to exist as aqueous solutions at elevated temperatures such as gel / sol transition temperatures, but react with each other to form semi-solid gels when the temperature is lowered below the transition temperature, for example to approximately body temperature. Is based on.

As used herein, the terms have the following meanings;

"Extraintestinal" means any route of administration, excluding digestive and nutrient organs, in particular the intramuscular, intraperitoneal, intraperitoneal, subcutaneous routes, and veins may be included in some sense.

When referring to a drug, biodegradable block copolymer complex contained in a solution, “solution”, “aqueous solution”, etc., are dissolved or homogeneously suspended at the concentration at which such drug / polymer complex functions, and the gel of the block copolymer Refers to a water-based solution maintained at a temperature above the sol transition temperature.

"Drug transport liquid" or "drug transport liquid with heat gelling properties" means a "solution" suitable for injection into a warm blooded animal that forms a depot at a temperature lower than the body temperature of the warm blooded animal to which it is administered.

"Depot" means a drug transport liquid injected into a warm blooded animal that forms a gel at temperatures below body temperature.

"Gel" refers to a bio-degradable block copolymer and a water-combined semi-solid hydrogel at a gel / sol transition temperature that is at or below body temperature.

"Gel / sol transition temperature", "gel / sol transition" or "gelation temperature" or any other similar term means the temperature at which the block copolymer water soluble composite undergoes phase transition between gel and solution. At temperatures above the gel / sol transition temperature, the water soluble complex is in solution, and below the gel / sol transition temperature the water soluble complex becomes a semi-solid hydrogel. It is possible to make the block copolymer have a wide range of gel / sol transition temperatures, but it is preferred that the temperature just above the body temperature of the subject to which the block copolymer and the aqueous drug solution are to be administered is the gel / sol transition temperature. Since the normal body temperature of a human is about 37 ° C., the gel / sol transition temperature can range from about 30 ° C. to 60 ° C.

"Biodegradable" means that the block copolymer can be broken down into non-toxic components in the body after all of the drugs contained therein are released.

"Drug" refers to any organic compound or substance that has bioactivity and is suitable or used for therapeutic purposes.

"Poly (α-oxy acid) is a poly (αoxy acid) polymer itself or a poly (α-oxy acid) polymer derived from a ring-open polymerization of an α-oxy acid precursor such as lactide, glycolide, lactone or It means a copolymer.

"Poly (ethylene oxide)" or "PEO" and "poly (ethylene glycol)" or "PEG" or "polyoxyethylene" are interchangeable meanings for ethylene glycol or hydrated ethylene oxide polymers. it means.

The basis of the present invention is the use of block copolymers having hydrophobic or "A" block fragments and hydrophilic or "B" block fragments. In general, the block copolymer may be a triple block BAB block copolymer, but may also be a double block BA type copolymer.

Biodegradable hydrophobic or A block fragments include poly (d, l-lactide), poly (l-lactide), poly (d, l-lactide-co-glycolide), poly (l-lactide-co- Glycolide), poly (ε-caprolactone), poly (γ-butyrolactone), poly (δ-barerolactone), poly (ε-caprolactone-co-lactic acid), poly (ε-caprolactone-co -Glycolic acid-co-lactic acid), hydroxybutyl acid, dried acid and their poly (α-oxy acids) derived or selected from binary or terpolymers thereof. The above enumeration is not intended to include or necessarily limit all of the various α-oxyacid complexes and mixtures that may be used to make homopolymer or copolymeric hydrophobic block fragments, and are also within the scope of the present invention. In general, any water-soluble biodegradable copolymer can be used as the hydrophobic A block, including semi-crystalline polymers and amorphous polymers. The average molecular weight of such α-oxyacid polymer blocks is about 500 to 20,000. When made from a double block copolymer, the average molecular weight of the A blocks is about 500 to 15,000, more suitably about 700 to 10,000. When made from a triple block copolymer, the average molecular weight of the A blocks is about 500 to 20,000, more suitably about 700 to 15,000.

The hydrophilic B block fragment is poly (ethylene oxide) (PEO), which has a mean molecular weight of about 500 to 25,000 (polyoxyethylene) or poly (ethylene glycol) (PEG), with a molecular weight of about 1,000 to 10,000. More preferred. The same average molecular weight can be applied to copolymers in the form of double blocks and triple blocks.

synthesis

The copolymer of the present invention is an amphoteric copolymer of double or triple blocks of structure BA or BAB, wherein B is a hydrophilic block and A becomes a hydrophobic biodegradable block.

Diblock copolymers can be synthesized through various methods.

Ring Opening Polymerization

To make biodegradable hydrophobic A blocks, double block copolymers can be synthesized by ring-opening polymerization of ring monomers, such as L-lactide, from one end of a PEO block with or without catalyst.

PEO is preferably a monovalent functional PEO having the formula:

X- (CH ₂ CH ₂ O) -YZ

X is a low cost alkoxy group such as methoxy, ethoxy and the like; Y is a lower alkylene such as methylene, ethylene, propylene and the like; Z is a functional group selected from hydroxy (OH), amino (NH ₂ ), carboxyl (COOH), thiol (SH) and the like.

Typically α-methoxy ω-hydroxy PEO (X = CH ₃ O, Y = CH ₂ CH ₂ , Z = OH) and α-methoxy ω-amino PEO (X = CH ₃ O, Y = CH ₂ CH ₂ , Z = NH ₂ ).

As mentioned above, the cyclic monomers are D, L-lactide, L-lactide, glycolid, D, L-lactide-co-glycolide), L-lactide-co-glycolide, ε-capro Lactone, γ-butyrolactone, δ-barerolactone, ε-caprolactone-co-lactic acid, ε-caprolactone-co-glycolic acid-co-lactic acid, and the like.

When using a catalyst, typical catalysts are stannous octoate, antimony oxide, tin chloride, aluminum isopropoxide, yttrium isopropoxide, sodium, calcium, t- Butoxide calcium, t-butoxide sodium and the like.

In general, octanoic acid tin salt can be used as a catalyst.

Polycondensation reaction

It is also possible to synthesize a double block copolymer by polycondensation of α-oxyacid monomer at one end of the PEO block. Monomers such as L-lactic acid, D, L-lactic acid and glycolic acid can be used. PEO sources include α-methoxy ω-hydroxy PEO (X = CH ₃ O, Y = CH ₂ CH ₂ , Z = OH) or α-methoxy ω-carboxy PEO (X = CH ₃ O, Y = CH PEO such as ₂ CH ₂ , Z = COOH) is used.

Combination of PEO and Poly (α-oxyacid) Blocks

Alternatively, the monovalent functional biodegradable hydrophobic block can be directly bonded to the monovalent functional PEO in the presence of a binder, in which case the binder can be present as a bond in the copolymer. Diisocyanates such as hexamethylene diisocyanate (HMDI); 2,6-toluene diisocyanate; 1,6-toluene diisocyanate; 2,4-toluene diisocyanate; Diphenyl methane-4,4'-diisocyanate; 3,3'- dimethyl diphenyl netane 4,4'- diisocyanate; (ortho, meta, para) phenylene diisocyanate etc. are mentioned.

It is also possible to bind after activating the functional group with an activating material such as carbonyl diimidazole, succinic anhydride, N-hydroxy succinimide, p-nitrophenyl chloroformate.

The triblock copolymer can be prepared by various methods.

Combination of α-oxyacid A block with PEO block

A hydrophobic A block with a biodegradable difunctional group can be combined with PEO with a monofunctional group to form a BAB copolymer, using a bonding technique for combining the aforementioned B and A blocks to form a double block. For example, diisocyanate (CIICN) binding reagents are used.

Alternatively, the double block copolymer may be bound using terminal functional groups of biodegradable hydrophobic B (eg, poly (α-oxyacid) blocks) according to the following scheme;

BA + AB + DIICN = BA-DIICN-AB

Ring opening polymerization

Ring-opening polymerization of ethylene oxide at both ends of a biodegradable hydrophobic A block such as poly (α-oxy acid) or ring monomers for biodegradable hydrophobic blocks such as L-lactide followed by another of ethylene oxide (PEO The continuous ring-opening polymerization of the ring monomers) may prepare a triple block copolymer.

The double block BA and triple block BAB type hydrophilic / hydrophobic block copolymers synthesized here have heat gelling properties and are biodegradable. Although the BAB type block copolymer has some similarities to the Poloxamer or Pluronic system described above, the hydrophobic poly (α-oxyacid) A block is biodegradable and more biocompatible than the hydrophobic PPO block of the Poloxamer or Pluronic system. It is different.

As described, the B blocks are obtained from hydrophilic poly (ethylene oxide) (PEO) having the appropriate molecular weight. PEO was chosen as a hydrophilic water soluble block domain due to its unique biocompatibility, non-toxicity, micelle-forming ability, and rapid removal from the body.

Hydrophobic A blocks are synthesized and used because of their biodegradability and biocompatibility. In vitro and in vivo degradation of such hydrophobic polymer blocks is well known and degradation products are natural metabolites that can be removed directly from the body.

Compared to the molecular weight of the water soluble B PEG block, the molecular weight of the hydrophobic poly (α-oxy acid) A block is adjusted to retain the desired water soluble and gelling properties. In addition, the weight ratio of the hydrophobic A block to the hydrophilic B block must be adjusted so that the block copolymer can have excellent water solubility at temperatures above the body temperature and the required concentration. Generally, biodegradable block copolymers having gelling properties with heat are made, wherein the hydrophilic B blocks comprise about 20 to up to 90 wt% of the copolymer, and the hydrophobic A blocks comprise about 10 to up to 80 wt%. Suitably the hydrophilic B block is about 25 to 75% of the copolymer and the biodegradable hydrophobic A block is about 25 to 75 wt%.

All resulting double block and triple block copolymers must be able to dissolve in aqueous solutions at functional concentrations. Each copolymer has a minimum required concentration for lowering the temperature to gel at the gel / sol transition temperature. In addition, when the concentration is too high, the aqueous solution is too viscous to be injected outside the intestine. An important concentration variable is that the polymer is within the range in which it can function.

Thus, the concentration at which the block copolymer can be dissolved at the temperature used for extra-intestinal administration is considered a functioning concentration. Generally speaking, in the range of about 5 to 60%, the block copolymer concentration is in a functioning range, and a concentration in the range of about 10 to 50% is appropriate. Certain minimum concentrations are required to obtain apparent phase transitions of the polymer.

Biodegradable polymers and bioactive materials or drug mixtures may be prepared in aqueous solution at temperatures above the gelling temperature of the polymeric material. Once injected into the body in the liquid state via the muscle, subcutaneous, and peritoneal route, the drug / polymer composition undergoes a phase transition, and a moderately expanded gel is formed, because the body temperature is below the gelling temperature of the polymeric material. Because.

Such a system will minimize biotoxicity and mechanical irritation to surrounding tissues due to the biocompatibility of the material and will be fully biodegradable within a specific timeframe. Once gelled, the drug released from the polymer matrix can be adjusted to the appropriate composition of the various copolymer blocks.

The limit on how many drugs can be loaded into a polymer is one factor of functionality. Generally, the drug will be about 1 to 60 wt%, suitably about 5 to 30 wt% of the weight of the drug polymer composite.

The present invention is that any drug is stable in the prepared solution and can be used to transport any drug from which the drug is released from the hydrogel matrix after administration of the solution. The present invention will not be used as a useful material for making a drug list because it will be apparent to those skilled in the art, and the type of drug used to demonstrate the ability of the present invention for a particular drug or drug class and Requires minimal experimentation.

The present invention will be particularly useful for delivering peptide or protein based drugs. Generally, however, the present invention can be used in all therapeutic fields for the transport of a wide range of drugs and bioactive substances, such as therapeutic substances, for example, infection inhibitors, analgesic, analgesic, such as antibiotics and anti-viral agents. Complex, appetite suppressant, anti-diabetic, antihistamine, anti-inflammatory agent, migraine, anti-shake, anti-nausea, anti-neoplastic, anti-parkinsonism, antipruritic, antipsychotic, anticoagulant including choline and urine, choline Central nervous stimulant, including inhibitors, sympathetic palsy, acid derivatives, cardiac vasculature including calcium channel blockers, beta blockers, arrhythmia inhibitors, diuretics, vasodilators including coronary, peripheral, brain, coughing and sensing agents , Decongestant, glycemic agent, hormone, immunosuppressant, muscle relaxant, parasympathetic blocker, parasympathetic stimulant, neuron It comprises a material, a sedative, a stabilizer such as but not limited.

Within the scope referred to herein, those skilled in the art will be able to determine appropriate drug loadings, polymer compositions, concentrations, degradation rates, gelation / destruction formation, and the like, without undue experimentation.

To illustrate embodiments of the present invention, double block BA copolymers and triple block BAB copolymers were synthesized. Double-block BA copolymers composed of PEO / PLLA were synthesized by ring-opening polymerization of L-lactide (LLA) in monomethoxy poly (ethylene oxide) (PEO) according to Scheme 2 below;

In this case, x and y are integers suitable for making a copolymer having the block molecular weight described above.

The triple block BAB copolymer was synthesized by combining the double block BA copolymer according to Scheme 2 according to the following Scheme 3 using hexamethylene diisocyanate (HMDI) as a binder;

In Schemes 2 and 3, the hydrophilic B block can be prepared using various molecular weights of poly (L-lactic acid) (PLLA) and poly (ethylene oxide) (PEO).

Example 1; Synthesis of BA Double Block Copolymer (PEO-PLLA-OH)

According to Scheme 1, methoxy poly (ethylene oxide) (PEO) (MW: 5000) (8 g) is dissolved in 80 ml dried toluene. Residues are removed by azeotropic distillation to bring the final volume to 30 ml. The polymerization of L-lactide (LLA) (4.4 g) and octanoic acid tin salt (8.6 mg) in PEO was then carried out in this solution and refluxed under a dry nitrogen atmosphere for 24 hours. The solution is precipitated in diethyl ether so that the residual solvent is removed in vacuo after filtration. The degree of conversion is over 90%. Double block BA copolymers are made wherein the molecular weights of the A blocks are 720, 1000, 1730, 1960.

Poly (ethylene oxide-DL-lactic acid) (PEO-PDLLA); Poly (ethylene oxide- (DL-lactic acid-co-glycolic acid) PEO-P (DLLA / GA); poly (ethylene oxide-DL-lactic acid-co-ε-caprolactone) PEO-P (DLLA / CL) Other double block copolymers containing were also synthesized.

Example 2; Synthesis of Double Block Copolymer PEO-P (DLLA / GA)

To 200 ml of dried toluene was added monomethoxy PEO (10 g). The residue is removed by azeotropic distillation, in which case all toluene is removed by distillation. DL-lactide (2.5 g) and glycoride (3 g) and octanoic acid tin salt (10.87 mg) were added to PEO / toluene and heated to 160 ° C. in an oil bath for 24 hours under dry nitrogen. The reaction mixture was dissolved in methylene chloride, precipitated in diethyl ether, and the residual solvent was removed using vacuum after filtration. The degree of conversion was over 90%.

Example 3; BAB triple block copolymer (PEO-PLLA-PEO) synthesis

BA double block (PEO-PLLA-OH), MW: 500-2560, was added to 200 ml dried toluene. The residue was removed by azeotropic distillation to bring the final volume to 70 ml. HMDI (55.59 mg) and octanoic acid tin salt (5.356 mg) were added to the solution, stirred at 60 ° C. for 12 h and then gently refluxed for 6 h under dry nitrogen. The resulting triblock copolymer is purified by fractional precipitation of the copolymer from methylene chloride using diethyl ether. The binding reaction was monitored via GPC. After fractional precipitation, the yield of the triple block copolymer is 50%. The copolymer was interpolated in a refrigerator under nitrogen gas. In the same manner, other triblock copolymers were also synthesized.

The resulting triblock copolymer consists of two B (PEO) blocks each having a molecular weight of 5000 and a central A (PLLA) block having 2040, 3000 and 5000 of each molecular weight.

Example 4; Gel / sol transition temperatures of various BA and BAB copolymers at a given concentration (wt / wt%)

All block copolymers of Table 1 can be dissolved in water at the concentrations specified above the gel / sol transition temperatures shown in Table 1. First, the polymer is dissolved in distilled water at a given temperature and the specified concentration and placed in a fully sealed 4 ml vial. The vial was cooled to a temperature below the gelling temperature and stored at 4 ° C. for 12 hours. Gel / sol transition temperature is defined as the temperature at which the gel melts. The gel is allowed to equilibrate for 20 minutes at the given temperature in the bath. Gel melting was observed by increasing the temperature by 2 ℃ step by step. Gel is defined as the flow does not occur within 1 minute after rotating 90 ℃ in the bath. All gels are thermally sensitive and gel / sol transitions occur over a narrow temperature range. The transition temperatures and concentrations shown in Table 1 are estimated from gel / sol transition curves based on temperature and concentration, but the gel / sol transition temperature is the molecular weight of A, B blocks, the relative amounts of A and B in the copolymer, The effect of concentration can be fully explained.

Double-block BA (PEO-PLAA) and triple-block PEO-PLLA-PEO copolymer aqueous solutions form micelles at low concentrations but gel at a certain concentration. Micellar packing is also regarded as the gelling mechanism of these block copolymers. In contrast to Poloxamer or Pluronic type copolymers, the copolymers described above form gels at low temperatures and become sol at high temperatures. This means that these copolymers do not exhibit inverted thermogelation reactions, and become solid or gel when the temperature is lowered at high temperatures according to a rather common route. By changing the biodegradable block length, the sol / gel transition temperatures shown in Table 1 can be easily controlled. By reducing the PLLA block length, it is possible to change the gel / sol transition temperature towards higher concentrations. Selected block copolymers, such as 25% PEO-PLLA (5000: 1730) or 22% PEO-PLLA-PEO (5000: 2040: 5000) aqueous solution, are gelled at body temperature (37 ° C.) and at a given concentration At the temperature, it becomes a sol state.

Such copolymers incorporating suitable bioactive materials can be dissolved in water at temperatures above body temperature (eg 45 ° C.). Due to the phase transition with temperature, the sol state becomes gel after subcutaneous injection into the body. Since they become gel in the body, these copolymers can act as a sustained release matrix.

Based on the thermal sensitivity and biodegradability of such copolymers, injectable systems that do not use solvents (organic solvents) can be used as carriers to control and release the drug. Such a system has many advantages over conventional drug delivery systems. First, preparation is simple and no organic solvent is used. If desired, the designed matrix may also be stored in a dry solid state at room temperature or below prior to administration. It also does not require surgical procedures for transplantation. Since the system is biodegradable, it has the typical advantages of hydrogels, such as very little or no tissue irritation and improved biocompatibility.

Based on the above description, those skilled in the art will be able to make and use block copolymers loaded with drugs based on thermogelling properties. This description is not limited to the particular drug loaded onto the biodegradable block copolymer. It is also not limited to all copolymers prepared and presented here. Those skilled in the art will recognize that various changes can be made without departing from the scope of the invention as defined by the following claims and their equivalents.

Claims (33)

In a water-soluble injectable drug delivery system of biodegradable block copolymers having thermal gelling properties, such systems are in solution at temperatures above the thermal gelling temperature and hydrogel at or below the thermal gelling temperature. silver (a) an effective amount of drug contained therein; (b) (i) hydrophobic A polymer consisting of poly (α-oxyacid); (ii) an injectable aqueous drug delivery system of biodegradable block copolymers, characterized in that it is an aqueous carrier composed of an effective concentration of a biodegradable block copolymer composed of a hydrophilic B polymer composed of poly (ethylene oxide). The method of claim 1, wherein the hydrophobic A polymer is poly (d, l-lactide), poly (l-lactide), poly (d, l-lactide-co-glycolide), poly (l-lactide- co-glycolide), poly (ε-caprolactone), poly (γ-butyrolactone), poly (δ-barerolactone), poly (ε-caprolactone-co-lactic acid), poly (ε-caprolactone -co-glycolic acid-co-lactic acid), hydroxybutyl acid, dried acid and their dual or terpolymers, injectable, water-soluble drug delivery systems of biodegradable block copolymers. 3. The injectable aqueous drug delivery system of claim 2, wherein the effective concentration of the biodegradable block copolymer in the water soluble carrier is about 5 to 60 wt%. 4. The water-soluble injectable of the biodegradable block copolymer according to claim 3, wherein the content of the hydrophobic A block in the biodegradable block copolymer is about 10 to 80 wt%, and the content of the hydrophilic B block is about 20 to 90 wt%. Drug delivery system. 5. The injectable aqueous drug delivery system of claim 4, wherein the double block copolymer has a gel-sol transition temperature between about 30 ° C and 60 ° C. 5. The water-soluble injectable drug delivery system of claim 4, wherein the block copolymer is a BA type double block copolymer. 7. The water-soluble injectable drug delivery system of claim 6, wherein the average molecular weight of the A block polymer is about 500 to 15,000 and the average molecular weight of the B block polymer is about 500 to 25,000. 8. The water-soluble drug delivery system for injection of biodegradable block copolymers according to claim 7, wherein the average molecular weight of the A block polymer is about 700 to 10,000 and the average molecular weight of the B block polymer is about 1,000 to 10,000. 5. The injectable aqueous drug delivery system of claim 4, wherein the block copolymer is a BAB type triple block copolymer. 4. The injectable aqueous drug delivery system of claim 3, wherein the average molecular weight of the A block polymer is about 500 to 20,000 and the average molecular weight of the B block polymer is about 500 to 25,000. The water-soluble injectable drug delivery system of claim 10, wherein the average molecular weight of the A block polymer is about 700 to 10,000 and the average molecular weight of the B block polymer is about 1,000 to 10,000. 10. The water-soluble injectable drug delivery system according to claim 6 or 9, wherein the effective amount of drug to be included in the block copolymer is about 1 to 60 wt% based on the weight of the drug copolymer complex. 13. The injectable aqueous drug delivery system of claim 12, wherein the amount of effective drug to be included in the block copolymer is about 5 to 30 wt% by weight of the drug copolymer complex. In biodegradable block copolymers, (i) hydrophobic A block polymers composed of poly (α-oxyacids); (ii) a hydrophilic B block polymer composed of poly (ethylene oxide), wherein the amount of hydrophobic A block copolymer in the block copolymer is about 10 to 80 wt%, and the amount of hydrophilic B block copolymer is about 20 to 90 wt% Biodegradable block copolymers characterized in that the. 15. The biodegradable block copolymer according to claim 14, wherein the block copolymer has a property of being heat sensitive in a water soluble carrier, i.e., at a low temperature, in a gel state, and then transitioning to a sol state at a higher temperature. . The method of claim 15, wherein the hydrophobic A polymer is poly (d, l-lactide), poly (l-lactide), poly (d, l-lactide-co-glycolide), poly (l-lactide- co-glycolide), poly (ε-caprolactone), poly (γ-butyrolactone), poly (δ-barerolactone), poly (ε-caprolactone-co-lactic acid), poly (ε-caprolactone -co-glycolic acid-co-lactic acid), hydroxybutyl acid, dried acid and their bi- or tri-polymers thereof. The biodegradable block copolymer according to claim 16, wherein the block copolymer is a BA type double block copolymer. 18. The biodegradable block copolymer of claim 17, wherein the average molecular weight of the A block polymer is about 500 to 15,000 and the average molecular weight of the B block polymer is about 500 to 25,000. 19. The water-soluble injectable drug delivery system of claim 18, wherein the average molecular weight of the A block polymer is about 700 to 10,000 and the average molecular weight of the B block polymer is about 1,000 to 10,000. 17. The biodegradable block copolymer according to claim 16, wherein the block copolymer is a BAB type triple block copolymer. 21. The biodegradable block copolymer of claim 20, wherein the average molecular weight of the A block polymer is about 500 to 20,000 and the average molecular weight of the B block polymer is about 500 to 25,000. 22. The biodegradable block copolymer of claim 21, wherein the average molecular weight of the A block polymer is about 700 to 10,000 and the average molecular weight of the B block polymer is about 1,000 to 10,000. 21. The biodegradable block copolymer according to claim 17 or 20, wherein the block copolymer further comprises an effective amount of drug to be contained therein. 24. The biodegradable block copolymer of claim 23, wherein the amount of effective drug to be included in the block copolymer is about 1 to 60 wt% by weight of the drug copolymer composite. The biodegradable block copolymer of claim 24, wherein the amount of effective drug to be included in the block copolymer is about 5 to 30 wt% of the weight of the drug copolymer composite. A method of delivering a drug contained in a liquid biodegradable polymer matrix to a warm blooded animal via an extra-intestinal route, wherein the matrix is a gel depot in the body of the animal for controlled controlled release of the drug contained therein. Has the property to be right, (1) to produce a water-soluble injectable drug transport system of biodegradable block copolymers having thermogelling properties, wherein the system is in solution at temperatures above the thermogelling temperature and hydrogel at or below the thermogelling temperature. And the configuration of the system (a) an effective amount of drug contained therein; (b) (i) hydrophobic A polymer consisting of poly (α-oxyacid); (ii) a hydrophilic B polymer composed of poly (ethylene oxide); (2) the composition remains in the liquid at a temperature between the gel / sol transition temperatures of the block copolymer in the water soluble carrier; (3) When the liquid is administered through the extra-intestinal route to a warm-blooded animal, the biodegradable block polymer containing the drug forms a gel depot because the body temperature of the animal is lower than the gel / sol transition temperature. How to. The method of claim 26, wherein the hydrophobic A polymer is poly (d, l-lactide), poly (l-lactide), poly (d, l-lactide-co-glycolide), poly (l-lactide- co-glycolide), poly (ε-caprolactone), poly (γ-butyrolactone), poly (δ-barerolactone), poly (ε-caprolactone-co-lactic acid), poly (ε-caprolactone -co-glycolic acid-co-lactic acid), hydroxybutyl acid, dried acid and their di- or tri-polymers thereof. The method of claim 27, wherein the effective concentration of the block copolymer in the water soluble carrier is about 5 to 60 wt%. The method of claim 28, wherein the content of hydrophobic A blocks in the biodegradable block copolymer is about 10 to 80 wt% and the content of hydrophilic B blocks is about 20 to 90 wt%. 30. The method of claim 29, wherein the block copolymer is a BA type diblock copolymer. 30. The method of claim 29, wherein the average molecular weight of the A block polymer is about 500 to 15,000 and the average molecular weight of the B block polymer is about 500 to 25,000. 32. The method of claim 31, wherein the average molecular weight of the A block polymer is about 700 to 10,000 and the average molecular weight of the B block polymer is about 1,000 to 10,000. 30. The method of claim 29, wherein the block copolymer is a BAB type triple block copolymer.