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    • 专利摘要:
    BIODEGRADABLE DRUG DELIVERY FOR HYDROPHOBIC COMPOSITIONS Biodegradable drug delivery compositions comprising a triblock copolymer containing a polyester and a polyethylene glycol, and a diblock copolymer containing a polyester and a polyethylene glycol with end cap as well as at least one pharmaceutically active principle or hydrophobic active ingredient, such as medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine are disclosed.
    公开号:BR112014031773B1
    申请号:R112014031773-9
    申请日:2013-06-27
    公开日:2020-10-13
    发明作者:Georges Gaudriault；Christophe Roberge
    申请人:Medincell；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [0001] The present invention relates to biodegradable drug delivery compositions comprising a tri-block copolymer containing a polyester, a polyethylene glycol and a di-block copolymer containing a polyester and a polyethylene glycol with end cap as well as an active ingredient pharmaceutically hydrophobic, among which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine. The ratio of tri-block copolymer to di-block copolymer in this formulation is 1: 3 to 1: 8 or 1: 1 to 1: 9 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2, 3 to 4.1. Methods for producing these biodegradable drug compositions using organic solvents are also disclosed. TECHNICAL STATUS
    [0002] The present invention for drug delivery systems, such as di-block and tri-block copolymers has been used to deliver a variety of drugs and is generally formulated to deliver specific drugs whether they are hydrophobic or hydrophilic drugs. Depending on the solubility of the drug, these drug formulations differ in polymer concentrations, types of polymers used, the molecular weights of the polymers and solvents used in the formulations.
    [0003] In addition, the type of environment in which the drug is administered is an important consideration in formulating a drug delivery system. Thus, there are no drug delivery compositions that are prepared using temperature sensitive polymers, phase sensitive polymers, pH sensitive polymers and photosensitive polymers. See, for example, K. Al-Tahami and J. Singh "Smart Polymers for Peptide and Protein Base Delivery Systems," Recent Patents on Drug Release and Formulation, 1: pages: 65 - 71 Bentham Science Publishers, LTD . 2007.
    [0004] US Patent No. 6,592,899 describes a PLA / PLGA oligomer combined with a block copolymer to increase the solubility of a hydrophobic drug in a hydrophilic environment. More specifically, this polymer composition has a polyester oligomer with a molecular weight between 400 and 10,000 daltons and a biodegradable type AB, type ABA or type BAB block copolymer. The hydrophobic part A is a polyester, while the hydrophilic part B is a polyethylene glycol with a molecular weight between 2,400 and 4,999 daltons. This polymer composition is soluble in an aqueous environment.
    [0005] US Patent 6,541,033 describes a sustained release pharmaceutical composition based on thermosensitive biodegradable hydrogels, consisting of a block copolymer of PLA or PLGA and PEG, for the prolonged administration of biologically active agents, such as leptin . The prolonged release is for a period of a week or more, and preferably up to a month.
    [0006] Hydrogels containing tri-block copolymers are described in US Patent 6,350,812. These hydrogels to retain the weight of the water, at least equal to the weight of the water of the copolymer and the soft hydrogels.
    [0007] US patent 7,875,677 provides micelle forming compositions comprising a hydrophobic drug, a biocompatible block copolymer, which has a hydrophilic protein comprising a polyethylene oxide and a hydrophobic portion having a polyester and a biocompatible water-soluble polymer , in which the water-soluble polymer is present in an amount sufficient to make the composition injectable for micelle formation.
    [0008] It is well known in the art that water-soluble or weakly hydrophobic drugs often result in slow drug absorption that leads to insufficient and variable bioavailability and toxicity of the gastrointestinal mucosa. Thus, the formulation of hydrophobic drugs is a challenge well known in the art.
    [0009] None of the patents, nor the literature cited above, describe drug distribution compositions that are injectable, in situ forming and biodegradable and transform into solid implants when injected into the body and release the hydrophobic active principles from a pharmaceutical point of view. . The biodegradable drug compositions of the present invention comprise tri-block copolymers and di-block copolymers formulated in such a way that the di-block copolymer serves as a reservoir, while the tri-block copolymer acts as a structure in the formulations and increases the life span block copolymer. In addition, the biodegradable drug delivery compositions of the present invention can be long-acting formulations, which reduce the initial violent release of the drug and modulate the rate of release of the hydrophobic drug or drug over time. This phenomenon is illustrated in the flattening of drug release curves. SUMMARY OF THE INVENTION
    [0010] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237 , wherein the ratio of the biodegradable tri-block copolymer of (a) to the biodegradable CA block of copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19 , in said biodegradable drug composition; and (c) at least one pharmaceutically active principle.
    [0011] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formulas: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 and v = x or v ψx; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, wherein the ratio of the biodegradable tri-block copolymer of (a) and a biodegradable di-block copolymer CA and (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 wherein said drug composition is biodegradable; and (c) at least one pharmaceutically active principle.
    [0012] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 and v = x or v ψx; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, wherein the ratio of the biodegradable tri-block copolymer from (a) to the biodegradable di-block copolymer CA and (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 wherein said drug composition is biodegradable; and (c) at least one hydrophobic pharmaceutically active principle.
    [0013] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090e v = x or v ψx; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, wherein the ratio of the biodegradable tri-block copolymer from (a) to the biodegradable di-block copolymer CA and (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 wherein said drug composition is biodegradable; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0014] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av -Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090, v and x being the repeating ester units and w being repeating units of ethylene oxide and v = x or v + x; (b) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, y is the number of ethylene oxide repeat units and z the ester number of repeat units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle.
    [0015] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units varying from 6 to 1090 or from 4 to 1090, vex being repeated units of ester and w being repeat units of ethylene oxide and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, y is the number of ethylene oxide repeat units and z the ester number of repeat units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable di-block copolymer CA and (b) is 1: 3 to 1: 8 or 1: 1: 19 or 3: 2 to 1: 19 or 2: 3 or 4: 1 or 2.3 to 4.1, wherein said drug composition is biodegradable; and (c) at least one pharmaceutically active principle.
    [0016] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090, ie, repeated units of ester and w are repeat units of ethylene oxide and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: where A is a polyester and C is a polyethylene glycol with end cover and y are the number of repeat units ranging from 7 to 371 or from 3 to 237, y is the number of ethylene oxide repeat units ezo number of ester repeat units, wherein the ratio of the biodegradable tri-block copolymer from (a) to the biodegradable CA di-block copolymer from (b) is 1: 3 to 1 : 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or from 2.3 to 4.1, wherein said drug composition is biodegradable; and (c) at least one hydrophobic pharmaceutically active principle.
    [0017] The present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av - Bw - Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units varying from 4 to 090 or 6 to 1090, vex being repeated units of ester and w being repetition units of ethylene oxide and v = x or v ψx; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, y is the number of ethylene oxide repeat units and z the ester number of repeat units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19 or 2: 3 or 4: 1 or from 2.3 to 4.1, wherein said drug composition is biodegradable; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0018] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv - PEGw - PLAx where v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090e v = x or v + x; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, wherein said drug composition is biodegradable and where PEG at the end di bloco is coverage of; and (c) at least one pharmaceutically active principle.
    [0019] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv - PEGw - PLAx where v, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090e v = xor v / x; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable block copolymer from (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1, wherein said drug composition is biodegradable and where the PEG in the block is end-cover and (c) at least one pharmaceutically active principle.
    [0020] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv - PEGw - PLAx where v, w and x are the number of repeating units ranging from 4 to 1090 or from 6 to 1090e v = x or v + x; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable block copolymer from (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1, in which said drug composition is biodegradable and in which the PEG in the block is end-cover; and (c) at least one hydrophobic pharmaceutically active principle.
    [0021] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv-PEGw-PLAx where v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090e v = x or v ψx; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3, or 4: 1 or from 2.3 to 4 , 1, wherein said drug composition is biodegradable and wherein the PEG in the block is of final coverage; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0022] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv - PEGw - PLAx where v, w and x are the number of repeat units ranging from 6 to 1090 or from 4 to 1090 v and v are the repeating ester units and w are ethylene oxide repeating units and x = v or v / x; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, wherein said drug composition is biodegradable and where PEG at the end block cover; and (c) at least one pharmaceutical active ingredient.
    [0023] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv - PEGw - PLAx where v, w and x are the number of repeat units ranging from 6 to 1090 or from 4 to 1090 v and v being the repeating ester units and w being repeating units of ethylene oxide and x = v or v + x; (B) a biodegradable di-block copolymer having the formula: PEGy-PLAz where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 9, or 2: 3, or 4: 1, wherein said composition of biodegradable drugs and in which the PEG in the block is final coverage; and (c) at least one pharmaceutical active ingredient.
    [0024] A composition comprising the release of biodegradable drugs: (a) a biodegradable tri-block copolymer having the formula: PLAv-PEGw-PLAx where v, w and x are the number of repeat units ranging from 6 to 1090 or from 4 to 1090 v and v are the repeating ester units and w are ethylene oxide repeating units and x = v or v + x; (B) a biodegradable di-block copolymer having the formula: PEG y-PLA z where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a ) and the biodegradable block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2, 3 to 4.1, wherein said drug composition is biodegradable and wherein the PEG in the block is end cap; and (c) at least one hydrophobic pharmaceutical active ingredient.
    [0025] A biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: PLA v - PEG w - PLA x where v, w and x are the number of repeat units ranging from 6 to 1090 or from 4 to 1090, v and x being the repeating ester units and w are ethylene oxide repeating units ex = v or v ψx; (B) a biodegradable di-block copolymer having the formula: PEG y-PLA z where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a ) and the biodegradable block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2, 3 to 4.1, wherein said drug composition is biodegradable and wherein the PEG in the block is end cap; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0026] In yet another aspect, a biodegradable drug release composition is provided, which comprises: (a) a biodegradable tri-block copolymer present in an amount from 3% to 45% (weight% / weight%) of the total composition having the formula: PLAv-PEGw-PLAx where v, w and x are the number of repetition units varying from 4 to 1090 or from 6 to 1090 and v = x or v ψx; (B) a biodegradable di-block copolymer present in an amount of 8.0% to 50% (weight% / weight%) of the total composition having the formula: PEGy-PLAz where y and z are the number of repetition units ranging from 7 to 371 or 3 to 237, wherein the ratio of the biodegradable tri-block copolymer from (a) to the biodegradable tri-block copolymer from (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3 : 2 to 1: 19, in which the said biodegradable drug composition and in which the PEG at the end of the block is covered and (c) at least one pharmaceutical active ingredient is present in an amount of 1% to 20% (weight% / weight%) of the total composition or active ingredient, at least one pharmaceutically carrier is present in an amount of 1 to 200 mg / ml.
    [0027] In yet another aspect, a biodegradable drug release composition is provided, which comprises: (a) a biodegradable tri-block copolymer present in an amount of 3% to 45% (weight% / weight%) or 2% 45% (w% / w%) or 1.2% to 30% (weight% / weight%) of the total composition having the formula: PLAv-PEGw-PLAx where v, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 and v = x or v ψ x; (B) a biodegradable di-block copolymer present in an amount of 8.0% to 50% (weight% / weight%) or 1% to 28% (weight% / weight%) of the total composition having the formula: PEGy-PLAz where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer from (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or from 2.3 to 4.1, wherein said drug composition is biodegradable and in which the PEG at the end of the block is covered and (c) at least one pharmaceutically active principle is present in an amount of 1% to 20% (weight% / weight%) of the total composition or active ingredient, at least one vehicle is pharmaceutically present in an amount of 1 to 200 mg / ml.
    [0028] In yet another aspect, a biodegradable drug release composition is provided, which comprises: (a) a biodegradable tri-block copolymer present in an amount of 3.0% to 45% (weight% / weight%) or 2% to 45% (weight% / weight%) or 1.2% to 30% (weight% / weight%) of the total composition having the formula: PLAv-PEGw-PLAx where v, w and x are the number of units repetition ranging from 4 to 1090 or 6 to 1090 and v = x or v + x; (B) a biodegradable di-block copolymer present in an amount of 8.0% to 50% (weight% / weight%) or 1% to 28% (weight% / weight%) of the total composition having the formula: PEGy-PLAz where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer from (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1, wherein said biodegradable drug composition and where the PEG in the block is covered edge and (c) at least one pharmaceutically hydrophobic active ingredient is present in an amount of 1% to 20% (weight% / weight%) of the total composition or active ingredient, at least one pharmaceutically carrier is present in an amount of 1 to 200 mg / ml.
    [0029] In yet another aspect, a biodegradable drug release composition is provided, which comprises: (a) a biodegradable tri-block copolymer present in an amount of 3.0% to 45% (weight% / weight%), or 2.0% to 45% (weight% / weight%) or 1.2% to 30% (weight% / weight%) of the total composition having the formula: PLAv-PEGw-PLAx where v, w and x are the number repetition units ranging from 4 to 1090 or from 6 to 1090 and v = x or v + x; (B) a biodegradable di-block copolymer present in an amount of 8.0% to 50% (weight% / weight%) or 1% to 28% (weight% / weight%) of the total composition having the formula: PEGy-PLAz where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer from (b) is 1: 3 to 1: 8 or 3: 2 to 1: 19 or 1: 1 to 1: 19 or 3: 2, or 4: 1 or from 2.3 to 4.1, where said drug composition is biodegradable and where PEG at the end of the block is capped and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine. is present in an amount of 10% to 40% (weight% / weight%) or 1% to 40% (weight% / weight%) of the total composition or active ingredient, at least one pharmaceutically carrier is present in an amount of 1 200 mg / ml or 0.1 to 200 mg / ml.
    [0030] The biodegradable drug delivery compositions of the present invention may have a lactic acid to ethylene oxide molar ratio in the composition of between 0.5 to 3.5 or from 0.5 to 2.5 or 0.5 to 0.5 to 22.3 for the tri-block copolymer and between 2 to 6 or 0.8 to 13 for the di-block copolymer.
    [0031] In another aspect, the biodegradable drug delivery compositions of the present invention can have a lactic acid to ethylene oxide molar ratio in the composition of between 0.5 to 22.3 per tri-block copolymer and between 0.8 to 13, by the di-block copolymer.
    [0032] In yet another aspect, the biodegradable drug delivery compositions of the present invention may have a lactic acid to ethylene oxide molar ratio in the composition of between 0.5 to 2.5 for the tri-block copolymer and between 3 to 5, for the di-block copolymer.
    [0033] In one aspect, the biodegradable drug release composition is an injectable liquid that when it is inserted into the body of an animal or plant becomes a hardened implant.
    [0034] In yet another aspect, the biodegradable drug release composition can be used as a spatial formulation such that it can be applied on or within the body of an animal or plant. For example, it can be dispensed, during surgery to treat a wound or within a virus treatment plant.
    [0035] In another aspect, the biodegradable drug composition is prepared as small solid particles, which are placed directly on the injured site of the body of an animal or plant.
    [0036] In another aspect, the drug composition is biodegradable in the form of an implant stem.
    [0037] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090 where v = vx or x /; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 at 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 (a) :( b) to form a polymer mixture; and (ii) adding at least one pharmaceutically active principle to said polymer mixture, is yet another aspect of the invention.
    [0038] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090 where v = vx or x and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a) :( b) to form a polymer mixture; and (ii) adding at least one pharmaceutically active principle to said polymer mixture, is yet another aspect of the invention.
    [0039] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090 where v = vx or x /; and (b) a biodegradable di-block copolymer having the formula: C y-Az where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a): (b) to form a mixture of polymers; and (ii) adding a hydrophobic active ingredient to at least one pharmaceutically carrier to said polymer mixture, is yet another aspect of the invention.
    [0040] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090 where v = vx or x and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a): (b) to form a polymer mixture; and (ii) adding at least one hydrophobic pharmaceutically active principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine to said polymer mixture, is yet another aspect of the invention.
    [0041] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1060 where v = vx or x #; and (b) a biodegradable di-block copolymer having the formula: C y-Az where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19 in (a) :( b) to form a polymer mixture; (ii) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0042] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090 or 4 to 1060 or where v = vx or x and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, in a ratio from 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 in (a) :( b) to form a mixture of polymers; (ii) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0043] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1060 where v = x or v ψx; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 in (a ) :( b) to form a polymer mixture; (ii) adding a hydrophobic active principle to at least one pharmaceutically carrier to said polymer mixture; and (iii) evaporating said solvent.
    [0044] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090 or from 4 to 1090 where v = x or v ψx, and (b) a biodegradable di-block copolymer having the formula: C y - A z. where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 to 237, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 in (a) :( b) to form a polymer mixture; (li) adding at least one pharmaceutically hydrophobic active ingredient, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine to said polymer mixture; and (iii) evaporating said solvent.
    [0045] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA-type block copolymer having the formula: Av-Bw-Az where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090or 4 to 1090, ie, repeated units of ester and w constitute units of repeating ethylene oxide where v = vx or x /; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 at 237, y is the number of repeat units of ethylene oxide and z the ester number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19 (a): b) to form a mixture of polymers; (ii) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0046] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090or 4 to 1090, ie vex repeated units of ester and w units repetition of ethylene oxide where v = x or v + x; and (b) a biodegradable di-block copolymer having the formula: C y- A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237, y is the number of repeat units of ethylene oxide and z the ester number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a): b) to form a polymer mixture; (ii) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0047] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090 or from 4 to 1090, vexa ester and repeating oxide units ethylene w being repetition units where v = x or v / x; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 at 237, y is the number of repeat units of ethylene oxide and z the ester number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a): b) to form a polymer mixture; (li) adding a hydrophobic active ingredient to at least one pharmaceutically carrier to said polymer mixture; and (iii) evaporating said solvent.
    [0048] Yet another aspect of the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090 or from 4 to 1090, vex being repeated ester units and w ethylene oxide repeat units where v = x or v + x; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 at 237, y is the number of repeat units of ethylene oxide and z the ester number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3.2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a): (b) to form a polymer mixture; (ii) adding at least one pharmaceutically hydrophobic active ingredient, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine to said polymer mixture; and (iii) evaporating said solvent.
    [0049] In the above methods the organic solvent can be present in an amount of 40% to 74% (weight% / weight%) or 30% to 70% (weight% / weight%) or 26% to 90% (w% / w%) of the total composition. Solvent mixtures can also be used.
    [0050] Other aspects and embodiments are described below, or will easily arise from the following description of preferred embodiments. BRIEF DESCRIPTION OF THE DRAWINGS
    [0051] Fig. 1 is a graph showing the rate of drug in vitro release from formulations based on 40% P6R1 (TB): dP2R4 (DB) in proportions of 1: 0 (- o -) , 1: 2 (- Δ -), 1: 4 (- • -), 1: 6 (- ▼ -) and 1: 9 (- * -) over time in days. This chart shows that TB: DB based formulations are capable of sustaining release for more than 30 days.
    [0052] Fig. 2 is a graph showing the cumulative release curve as a percentage in vitro from candidate formulations of Figure 1 over time (in days). This graph illustrates that the initial release is reduced and the drug release curve is flattened in the combination of tri-block copolymer and di-block copolymer compositions compared to the tri-block copolymer composition alone. It should be noted that the 1: 9 curve is overlapping the 1: 4 curve.
    [0053] Fig. 3 is a graph showing the injectability of formulations based on 40% P6R1 (TB); dP2R4 (DB) in various proportions ranging from 1: 0 tri-block copolymer to di-block copolymer to 0: 1 tri-block copolymer to di-block copolymer. This chart illustrates that all formulations are injectable using a classic injection device.
    [0054] Fig. 4 is a graph showing the in vitro release curve in cumulative percentage of candidate formulations over time (in days) of various compositions according to the invention. The compositions described as numbers 177, 246, 224, 225 and 250 are described in Table 1.
    [0055] Fig. 5 is a graph showing the rate of in vitro release from candidate formulations in micrograms per hour and per gram of formulation (pg / h / gr of formulation) The compositions described as numbers 177, 246, 224, 225 and 250 are described in Table 1.
    [0056] Fig. 6 is a graph showing the concentration in M53 plasma in nanograms per milliliter (ng / ml_) over time in days. Day zero is the day on which the composition was administered subcutaneously. The compositions indicated as numbers 177, 246, 224, 225 and 250 are described in Table 1.
    [0057] Fig. 7 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.2R5 (4 units of ethylene oxide and 24 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0058] Fig. 8 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.2R 4 (4 units of ethylene oxide and 58 units of lactic acid) mixed with various di-block copolymers (see Table 2 for more details).
    [0059] Fig. 9 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.2R22 (4 units of ethylene oxide and 89 units of lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0060] Fig. 10 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.4R4 (9 units of ethylene oxide and 41 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0061] Fig. 11 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.4R7 (9 units of ethylene oxide and 67 units of lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0062] Fig. 12 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.6R1 (13 units of ethylene oxide and 26 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0063] Fig. 13 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P0.6R3 tri-block copolymer (13 units of ethylene oxide and 40 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0064] Fig. 14 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P0.6R4 (13 units of ethylene oxide and 55 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0065] Fig. 15 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P1 R2 tri-block copolymer (22 ethylene oxide units and 47 lactic acid units) mixed with various di-block copolymers (see Table 2 for details).
    [0066] Fig. 16 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P1 R3 (22 ethylene oxide units and 68 lactic acid units) mixed with various di-block copolymers (see Table 2 for details).
    [0067] Fig. 17 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P1 R4 (22 units of ethylene oxide and 88 lactic acid units) mixed with several di-block copolymers (see Table 2 for details).
    [0068] Fig. 18 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P2R2 (45 units of ethylene oxide and 88 units lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0069] Fig. 19 is a graph showing the in vitro release of cumulative acetaminophen percentage over time (in days) from P2 R3 tri-block polymer formulations (45 ethylene oxide units and 157 lactic acid units) mixed with various di-block copolymers (see Table 2 for details).
    [0070] Fig. 20 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P2 R5 tri-block copolymer (45 ethylene oxide units and 216 lactic acid units) mixed with various di-block copolymers (see Table 2 for details).
    [0071] Fig. 21 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P3 R1 tri-block copolymer (68 ethylene oxide units and 66 lactic acid units) mixed with various di-block copolymers (see Table 2 for details).
    [0072] Fig. 22 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P3R2 (68 units of ethylene oxide and 54 units lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0073] Fig. 23 is a graph showing the in vitro cumulative percentage release of acetaminophen over time (in days) from P3R3 tri-block copolymer formulations (68 ethylene oxide units and 218 units lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0074] Fig. 24 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P6R0.9 tri-block copolymer (136 units of ethylene oxide and 125 units of lactic acid) mixed with several di-block copolymers (see Table 2 for details).
    [0075] Fig. 25 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P6R1.6 tri-block copolymer (136 units of ethylene oxide and 218 lactic acid units) mixed with several di-block copolymers (see Table 2 for details).
    [0076] Fig. 26 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P6R2 tri-block copolymer (136 units of ethylene oxide and 272 units lactic acid) mixed with various di-block copolymers (see Table 2 for details).
    [0077] Fig. 27 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P2R4 (45 units of ethylene oxide and 157 units lactic acid) mixed with dP0.4R6 block copolymer (7 units of ethylene oxide and 42 units of lactic acid) in different proportions (see Table 2 for details).
    [0078] Fig. 28 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on P2R4 tri-block copolymer (45 units of ethylene oxide and 157 units lactic acid) mixed with dP0.6R5 di-block copolymer (12 ethylene oxide units and 54 lactic acid units) in different proportions (see Table 2 for details).
    [0079] Fig. 29 is a graph showing the in vitro release of cumulative percentage of acetaminophen over time (in days) from formulations based on tri-block copolymer P2R5 (45 units of ethylene oxide and 216 units lactic acid) mixed with dP0.2R13 di-block copolymer (3 ethylene oxide units and 39 lactic acid units) in different proportions (see Table 2 for details).
    [0080] Fig. 30 is a graph showing the release rate of buprenorphine in vitro over time (in days) from formulations No. 33 (10% BN / 8% P2R2 / 32% dP0.4R10 ), No. 47 (10% BN / 8% P2R2 / 32% dP1 R3) and No. 58 (10% BN / 10% P0.4R8 / 40% dP1 R2).
    [0081] Fig. 31 is a graph showing the plasma concentration of buprenorphine over time (in days) in rats injected with formulations n 0 33 (10% BN / 8% P2R2 Z32% dP0.4R10), No. 47 (10% BN / 8% P2R2 / 32% dP1 R3) and No. 58 (10% BM Z10% P0.4R8 / 40% dP1 R2).
    [0082] Fig. 32 is a graph showing the in vitro release rate of risperidone over time (in days) from tri-block polymer based formulations (P2R5 45 ethylene oxide units and 216 units of lactic acid) mixed with dP0.2R13 polymer di block (3 units of ethylene oxide and 39 units of lactic acid) in different proportions (see Table 2 for details).
    [0083] Fig. 33 is a graph showing the plasma concentration of risperidone and risperidone 9-OH over time (in days) in rats injected with No. 10 formulations (5% RSP / 16% P2R2 / 24% dP2R2 / DMSO), n ° 29 (10% RSP / 24% P1 R4 / 16% dP0.4R5 / DMSO) and n ° 31 (10% RSP / 18% P2R4 / 12% dP0.4R5 / DMSO).
    [0084] Fig. 34 is a graph showing the plasma concentration of ivermectin over time (in days) injected into dogs with No. 7 formulations (5% IVM / 15% P3R3 / 25% dP0.4R5 / DMSO ), No. 9 (5% IVM / 15 P2R4% / 25% dP2R3 / DMSO) and No. 10 (5% IVM / 15% P2R5 / 25% dP2R2 / DMSO).
    [0085] Fig. 35 is a graph showing the rate of in vitro release of medroxyprogesterone acetate (MPA) from candidate formulations in milligrams per gram of formulation per day (mg of MPA / g of formulation / day). formulations described as numbers 33, 34 and 49, as described in Table 6. In vitro release obtained with Depo - SubQ Provera which is shown as a control.
    [0086] Fig. 36 is a graph showing the in vitro release in cumulative percentage of medroxyprogesterone acetate over time (in days) from the formulations described 33, 34 and 49, as described in Table 6. Release in vitro obtained with Depo - SubQ Provera which is shown as a control.
    [0087] Fig. 37 is a graph showing the rate of in vitro release of medroxyprogesterone acetate from candidate formulations in milligrams per gram of formulation per day (mg / g of formulation I day) The formulations described as numbers 2 , 32 and 36 are described in Table 6. In vitro release obtained with Depo - SubQ Provera is shown as a control.
    [0088] Fig. 38 is a graph showing the in vitro release in cumulative percentage of medroxyprogesterone acetate from the formulations described 12, 32 and 36 per day, which are described in Table 6. In vitro release obtained with Depo - SubQ Provera are shown as a control.
    [0089] Fig. 39 is a graph showing the plasma concentration of medroxyprogesterone acetate (MPA) in dogs over time (in days) injected with formulations 33, 34 and 49 as described in Table 6. Each dog received a single dose of 3 mg / kg of MPA.
    [0090] Fig. 40 is a graph showing the plasma concentration of medroxyprogesterone acetate (MPA) in dogs over time (in days) injected with formulations 12, 32 and 36 are described in Table 6. For the formulations 32, 36 and the control group (receiving Depo subQ- Provera), each dog received a single dose of 3 mg / kg MPA. The group that received formulation 12 was administered in doses of 6 mg / kg of MPA.
    [0091] Fig. 41 is a graph showing the percentage of total in vitro release of medroxyprogesterone acetate (MPA) over time (in days) from formulations 7, 10 and 13 described in Table 6.
    [0092] Fig. 42 is a graph showing the percentage of total release in vitro of medroxyprogesterone acetate (MPA) over time (in days) from formulations 32 and 33 described in Table 6.
    [0093] Fig. 43 is a graph showing the percentage of total in vitro release of medroxyprogesterone acetate (MPA) over time (in days) from formulations 25, 27 and 30, described in Table 6.
    [0094] Fig. 44 is a graph showing the total in vitro release of percent progesterone (Pro) over time (in days) from formulations 1, 13 and 7 described in Table 7.
    [0095] Fig. 45 is a graph showing the total in vitro release of percent progesterone (Pro) over time (in days) from formulations 10, 12 and 5 described in Table 7.
    [0096] Fig. 46 is a graph showing the percentage of total in vitro release of Levonorgestrel (Levo) over time (in days) from formulations 7, 8 and 9 described in Table 8.
    [0097] Fig. 47 is a graph showing the percentage of total in vitro release of Levonorgestrel (Levo) over time (in days) from formulations 4, 5 and 6, described in Table 8.
    [0098] Fig. 48 Fig 42 is a graph showing the total percent in vitro release of cyclosporine (CSP) over time (in days) from formulations 19, 20, 21, 22, 23 and 24 described in Table 9.
    [0099] Fig. 49 is a graph showing the percentage of total in vitro release of base bupivacaine (Bupi) over time (in days) from formulations based on formulations of 42, 47, 37, 35 and 34 described in Table 10. DESCRIPTION OF THE PREFERRED EMBODIMENTS
    [0100] As used herein, the term "biodegradable" means that tri-block copolymers and di-block copolymers, which after a period of erosion or degradation in vivo may form smaller non-toxic components.
    [0101] The term "parenteral administration" includes intramuscular, intraperitoneal, intra-abdominal, subcutaneous, intravenous and intra-arterial administration. It also includes intradermal, intravascular, intravitreal, intracerebral, intrathecal, epidural and intraosseous administration.
    [0102] The term "animals" includes all members of the animal kingdom.
    [0103] As used herein, the term "plant" includes all members of the plant kingdom.
    [0104] "Active ingredient" means a drug or medication for the treatment of various medical conditions. Thus, the terms active ingredients, drugs and medicines are used interchangeably. The term drug or active ingredient, as used herein, includes, without limitation, physiologically or pharmacologically active substances that act locally or systemically in the body of an animal or plant. At least one active ingredient is present in the biodegradable drug composition of the present invention.
    [0105] As used herein, "disease" means any disease, in a human, animal or plant caused by infection, diet, or the malfunction of a process.
    [0106] The term "implant" means that the drug delivery compositions are injectable, are in situ forming and are biodegradable and transform into solid implants when injected into the body. In this way, the formulations that are synthesized are liquid such that they can be easily injected through a syringe without excessive force.
    [0107] The term "space formulations" encompasses any formulations, which can be applied on or in the body of the animal or plant, and do not necessarily have to be administered via a syringe.
    [0108] As used herein, "repeating units" are the fundamental recurring units of a polymer.
    [0109] By "final cover polyethylene glycol" (cPEG) refers to PEG in which a hydroxyl end group is reacted and includes, covered PEG ester-covered urethane and as PEG alkoxy-covered PEG compounds. The protecting group is a chemical group that does not contain a chemical function capable of reacting with cyclic esters such as lactide, glycolactide, caprolactone and the esters and mixtures thereof, as or others. The reaction of a PEG polymer with end cap with lactide generates a cPEG - PLA block copolymer.
    [0110] As used herein, polyethylene glycol, abbreviated as PEG throughout the application, is sometimes referred to as poly (ethylene oxide) or poly (oxyethylene) and the terms are used interchangeably in the present invention.
    [0111] The abbreviation for "PLA" refers to poly (lactic acid).
    [0112] The abbreviation for "PLGA" refers to poly (lactic-co-glycolic acid).
    [0113] The abbreviation "T" or "TB" refers to a tri-block copolymer (s), while the abbreviation "D" or "DB" refers to a di-block copolymer (s).
    [0114] The term "di block" as used herein refers, for example, to a covered-end polyester PEG copolymer. "MPEG" refers to methoxy polyethylene glycol.
    [0115] The term "tri-block" refers, for example, to a polyester copolymer - PEG - polyester.
    [0116] As used herein, the term "partial suspension" means that the pharmaceutical active ingredient is in a partially soluble and partially solid form.
    [0117] As used herein, "hydrophobic" when referring to pharmaceutically active principles means that drugs that have poor solubility in aqueous solutions. The International Union of Pure and Applied Chemistry (IUPAC) defines solubility as "the analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent". A substance is said to be soluble if more than 0.1 g of substance is dissolved in 100 ml of distilled water at 250 ° C. If less than 0.1 g is dissolved in 100 ml of distilled water at 250 °. C, the substance is poorly soluble or insoluble at a particular temperature.
    [0118] The LA / EO ratio refers to the molar ratio of lactic acid units to ethylene oxide units that is present in the biodegradable drug release composition. It is determined experimentally by NMR. The LA / EO molar ratio of the combined tri-block copolymer can vary from 0.5 to 3.5. In another aspect, the LA / EO molar ratio in the tri-block can vary from 0.5 to 2.5 in the biodegradable drug release composition described herein. In yet another aspect, the proportion of ethylene oxide in the LA tri-block can vary from 0.5 to 22.3.
    [0119] The LA / EO molar ratio in the di-block can vary from 2 to 6. In another aspect, the proportion of ethylene oxide in the LA-di-block can vary from 3 to 5 in the biodegradable drug release composition. In another aspect, the LA / EO molar ratio in the di-block can vary between 0.8 to 13.
    [0120] The degree of polymerization or DP is the number of repetition units of a medium chain polymer at time t in a polymerization reaction. For example, the degree of polymerization for PEG is about 45 to 170 or it can be 4 - 273 or 3 - 45 or 0.55 cases to 68, while for PLA it can vary from about 84 - 327 or it can be 24 - 682 or 7 for 327 or 39.9 to 170.
    [0121] The present invention thus relates to a drug composition comprising a biodegradable tri-block copolymer and a di-block copolymer. The biodegradable tri-block copolymer has the formula: Av-Bw-Ax, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units varying, for example, 4 - 1090 or from 6 - 1090 ev = xor v / x. w is the degree of polymerization (number of repetition units) for PEG. The degree of polymerization for DP - PEG is calculated by dividing the molecular weight of PEG by the molecular weight of the EO unit (44 Da), v + x is equal to the degree of polymerization (number of repeat units) of the PLA. DP-PLA is calculated by multiplying the DP - PEG by the LA I EO ratio.
    [0122] However, the number of repeat units of v, w and x in the composition of tri-block copolymers may vary due to the target release time of the active ingredient and the type of active ingredient itself. Therefore, the number of repetition units in the tri-block of v, w and x can vary from 4 - 1090 or 6 - 1090 or 8 - 1090, from 10 to 850, 20 - 700, 30 - 650 and v = x or v + x. For example, w can be 273, while x + y can be 682 and v = xouv / xwou can be 136 and x + y can be 273 and v = x or v + xw or can be 45.5 and x + y can be be 546 or 273 can be wex + y can be 136.
    [0123] The size of the PEG in the tri-block can vary from 94 Da to 12,000 Da.
    [0124] The polyester in the tri-blocks can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester, which is used is polylactic acid.
    [0125] The tri-block copolymer is then combined with a biodegradable di-block copolymer having the formula: Cy - Az, where A is a polyester and C is a final polyethylene glycol cover and y and are the number of repeat units ranging from 7- 371 or 3 - 327 or 3 to 237. This association has a tri-block copolymer ratio of di-block copolymer ranging from 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19, or 2: 3 or 4: 1 or 2.3 - 4.1.
    [0126] Examples of coated end polyethylene glycol include PEG-covered alkoxy such as methoxy PEG or ethoxy PEG, PEG urethane coating, PEG'S ester coating, PEG amine coating and PEG'S amide coating. This PEG end coverage list is not exhaustive, and a person skilled in the art will recognize additional protected PEG ends, which are not listed.
    [0127] However, the number of repetition units (degree of polymerization (DP)) of y and z in the di-block composition may also vary. Thus, y can, for example, be in the range of 7 - 43 or 3 - 45 or 0.55 to 68 and z can range from 32 - 123 or 7 - 327 or 39.9 to 170. For example, it can be 25 y and z can be 23, y can be 34.5 ez can be 123 or y can be 45 ez can be 32 he degree of polymerization for DP - PEG is calculated by dividing the molecular weight of the PEG of the capped PEG by the molecular weight of the unit EO (44 Da). DP - PLA is calculated by multiplying DP - PEG by the LA / EO ratio.
    [0128] The polyester in the block can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly (lactic - co - glycolic acid) (PLGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester, which is used is polylactic acid. In another embodiment, the polyester is poly (lactic acid - co - glycolic acid).
    [0129] In another aspect, the present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev , w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090, v and x are repeated units of ester and w are ethylene oxide repetition units and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237 , y is the number of ethylene oxide repeating units and z the number of repeating ester units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 9 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle.
    [0130] In another aspect, the present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev , w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090, v and x being repeated units of ester and w are repeating units of ethylene oxide and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: Cy - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237 , y is the number of ethylene oxide repeating units and z the number of repeating ester units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 or 2: 3 or 4: 1 or 2.3 to 4.1, wherein said drug composition is biodegradable; and (c) at least one hydrophobic pharmaceutically active principle.
    [0131] In another aspect, the present invention provides a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev , w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090, v and x are repeated units of ester and w are repeating units of ethylene oxide and v = x or v + x; (B) a biodegradable di-block copolymer having the formula: Cy - Az where A is a polyester and C is a polyethylene glycol with an end cover and y and are the number of repeat units ranging from 7 to 371 or from 3 to 237, y is the number of ethylene oxide repeat units and z the number of repeat ester units, where the proportion of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 or 2: 3 or 4: 1 or 2.3 to 4.1, wherein said drug composition is biodegradable; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0132] In another aspect, the present invention provides a biodegradable drug release composition comprising a biodegradable tri-block copolymer having the formula: PLAv-PEGw-PLAx, where v, w and x are the number of repeat units ranging from 4 at 1090 or from 6 to 1090 and v = xouv / x; a biodegradable di-block copolymer having the formula: mPEG y -PLA z, where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 327, where the proportion of the biodegradable tri-block copolymer and the di-copolymer biodegradable block is 1: 6 in said biodegradable drug composition; and active ingredient, at least one pharmaceutically carrier.
    [0133] In another aspect, the present invention provides a biodegradable drug release composition comprising a biodegradable tri-block copolymer having the formula: PLA v -PEG w -PLA x, where v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090 and v = x or v + x; a biodegradable di-block copolymer having the formula: mPEG y -PLA z, where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 327, where the proportion of the biodegradable tri-block copolymer and the di-copolymer biodegradable block is 1: 6 in said biodegradable drug composition; and hydrophobic active ingredient such as at least one pharmacist.
    [0134] In another aspect, the present invention provides a biodegradable drug release composition comprising a biodegradable tri-block copolymer having the formula: PLA v -PEG w -PLA x, where v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090 and v = xouv / x; a biodegradable di-block copolymer having the formula: mPEG y -PLA z, where y and z are the number of repeating units ranging from 7 to 371 or from 3 to 327, where the proportion of the biodegradable tri-block copolymer and the di-copolymer biodegradable block is 1: 6 or 2: 3 or 3: 2 or 4: 1 or 2.3 to 4.1 where said biodegradable drug composition; and at least one pharmaceutically active hydrophobic principle, one of which is levonorgestrel medroxyprogesterone acetate, cyclosporins, progesterone or bupivacaine.
    [0135] In another aspect, a biodegradable drug release composition comprising: (a) a biodegradable tri-block copolymer having the formula: PLAv-PEGw-PLAx where, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090 ev = xor v / x; (B) a biodegradable di-block copolymer having the formula: mPEGy-PLAz where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer of (b) is 1: 4 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle.
    [0136] In another aspect comprising a biodegradable drug release composition: (a) a biodegradable tri-block copolymer having the formula: PLAv-PEGw-PLAx where v, w and x are the number of repeat units ranging from 4 to 1090 or from 6 to 1090 and v = x or v / x; (B) a biodegradable di-block copolymer having the formula: mPEG y - PLA z where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a ) and the biodegradable di-block copolymer of (b) is 1: 4 in said biodegradable drug composition; and (c) at least one hydrophobic pharmaceutically active principle.
    [0137] In another aspect comprising a biodegradable drug release composition: (a) a biodegradable tri-block copolymer having the formula: PLA v-PEG w-PLAx where v, w and x are the number of repeat units ranging from 4 at 1090 or from 6 to 1090 and v = x or v x; (B) a biodegradable di-block copolymer having the formula: mPEGy-PLA z where y and z are the number of repeat units ranging from 7 to 371 or from 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer of (b) is 1: 4 or 2: 3 or 3: 2 or 4: 1 or 2.3 to 4.1 wherein said biodegradable drug composition; and (c) at least one pharmaceutically active hydrophobic principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0138] The ratio of the biodegradable tri-block copolymer of (a) and the biodegradable CA di-block copolymer of (b) is 1: 3 to 1: 8 or 1: 1 to 1:19 or 3: 2 to 1: 19: wherein said drug composition is biodegradable. In one embodiment the ratio of the biodegradable tri-block copolymer and the biodegradable CA di-block copolymer is selected from the group of 1: 3, 1: 4, 1: 5, 1: 6, 1: 7 and 1: 8 or 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9, 1: 10, 1: 11, 1: 12, 1: 13, 1: 14, 1: 15, 1: 16, 1: 17, 1: 18 and 1: 19. It can also be 3: 2 or 2: 3, or 4: 1. In another aspect, the tri-block ratio with respect to the block is 1: 6.
    [0139] The length of the polyester chain is defined by the molar ratio of its polyester and ethylene oxide, which is between 0.5 to 3.5 or 0.5 to 2.5 or 0.5 to 22.3 for the tri-block copolymer e3a5 or 2a6 or 0.8 to 13, for the copolymer.di block. So, for example, if polylactic acid is used the chain length is defined by the molar ratio of lactic acid / ethylene oxide. Likewise, if polyglycolic acid is used, the length of the chain is defined by the polyglycolic acid / molar ethylene oxide ratio or the ethylene oxide / molar ratio or the polycaprolactone / polyhydroxyalkanoate ethylene oxide molar ratio. If poly (lactic-co-glycolic) acid is used the chain length is defined by the ratio of LA + G / EO.
    [0140] The mass of the polyethylene glycol with end cover can vary from 164 Da to 2000 Da or between 100 Da to 2 kDa. It can vary at the bottom of the 100 to 300 Da range or in the 1 to 2 kDa kDa range.
    [0141] The size of the polyethylene glycol chain ranges from 200 Da to 12 kDa in the biodegradable drug release composition or can vary from 400 Da to 12 kDa or 194 Da to 12 kDa.
    [0142] The polymers are present in an amount of 20% to 50% (weight% / weight%) of the total weight of the composition. In another aspect, the total weight of the polymers present in the biodegradable drug composition is 30% to 50% (weight% / weight%) of the total weight of the composition. In yet another aspect, polymers are present in the composition of the biodegradable drug at 40% to 50% (weight% / weight%) of the total weight of the composition. In yet another aspect, the polymers are present in an amount of 5% to 40% (weight% / weight%) of the total composition, or from 5% to 50% (weight% / weight%) of the total composition. In yet another aspect, the polymers are present in the biodegradable drug composition at 2.5% to 40% (weight% / weight%), or 2.5% to 50% (weight% / weight%) of the total weight of the composition .
    [0143] Thus, the tri-block copolymer is present in an amount of 3.0% to 45% (weight% / weight%) of the total weight of the composition. In another aspect, the tri-block copolymer is present in an amount of 6% to 10% (weight% / weight%) of the total weight of the composition. In yet another aspect, the tri-block copolymer is present in an amount of 20% to 40% (weight% / weight%) of the total weight of the composition. In yet another aspect, the tri-block copolymer is present in an amount of 1.2% to 30% (weight% / weight%) of the total weight of the composition, or 1.2% to 45% (weight% / weight%) of the total weight of the composition.
    [0144] In another embodiment the tri-block copolymer is present in 3.3% to 4.0% (weight% / weight%) or 3.5% (weight%) or 4.0% (weight%) or 1.9% to 4.0% (weight% / weight%) of the total weight of the composition.
    [0145] Likewise the di-block copolymer may be present in the biodegradable drug composition in an amount of 8% to 50% (weight% / weight%) of the total weight of the composition. In another aspect, the di-block copolymer is present in an amount of 10% to 20% (weight% / weight%) of the total weight of the composition. In yet another aspect, the di-block copolymer is present in an amount of 20% to 40% (weight% / weight%) of the total weight of the composition. In yet another aspect, the di-block copolymer is present in an amount of 1% to 28% (weight% / weight%) of the total weight of the composition or 1% to 50% (weight% / weight%) of the total weight of the composition .
    [0146] In yet another embodiment of the di-block it is present in an amount of 2.48% to 5.02% (weight% / weight%), or 2.3% to 5.4% (weight% / weight% ), or 2.5% to 5.1% (weight% / weight%) or 2.3% (weight%) or 2.3% to 5.8% (weight% / weight%), of the total weight of the composition.
    [0147] The at least one pharmaceutically active principle is retained in the tri-block: biodegradable drug release composition di-block. Representative drugs and biologically active agents to be used in the invention include, without limitation, drugs, protein peptide drugs, desensitizing agents, antigens, vaccine antigens, vaccines, anti-infectives, antibiotics, antimicrobials, antiallergenics, anti-diabetics , anti-steroidal inflammatory agents, decongestants, myotics, anticholinergics, sympathomimetics, sedatives, hypnotics, psychic stimulants, tranquilizers, androgenic steroids, estrogens, progestational agents, medroxyprogesterone acetate, humoral agents, prostaglandins, analgesics, corticosteroids, antispasmodics, antispasmodics -histamines, cardioactive agents, non-steroidal anti-inflammatory agents, anti-parkinsonian agents, antihypertensive agents, adrenergic agents, beta-nutritional blocking agents, gonadotropin-releasing hormone agonists, insecticides, anthelmintic agents and alkaloids from benzophenanthridine.
    [0148] Thus, drug combinations can also be used in the biodegradable drug release composition of the present invention. For example, if it is necessary to treat lupus erythematosus, corticosteroid and non-steroidal anti-inflammatory agents can be administered together in the present invention.
    [0149] In one embodiment the pharmaceutical active ingredient is a hydrophobic drug having low solubility or is insoluble in aqueous solutions. Hydrophpbioc drugs are described here and include, for example, amphotericin, anthralin, beciomethasone, betamethasone, camptothecin, curcumin, dexamethasone, genistein, indomethacin, lidocaine, taxol, tetracycline, tretinoin, therapeutic proteins that are insoluble in water and the like. In one embodiment the active ingredient is pharmaceutically medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine.
    [0150] Veterinary medicines, such as medicines for the treatment of worms or vaccines for animals are also part of the present invention. Hydrophobic veterinary drugs can also be formulated in biodegradable drug compositions as described herein.
    [0151] Viral medications for plants, such as the Potyviridae, Geminiviridae, of the genus Tospovirus Bunyaviridiae and Banana streak virus are also encompassed by the present invention. Also medicaments for tobacco mosaic virus, turnip turnip, yellow dwarf barley, local watermelon ring and cucumber mosaic virus can be used in the biodegradable drug release composition of the present invention. Hydrophobic viral drugs for plants can also be formulated into biodegradable drug compositions, as described herein.
    [0152] For those skilled in the art, other drugs or biologically active agents that can be released in an aqueous environment can be used in the described delivery system. In addition, various forms of drugs or biologically active agents can be used. These include, without limitation of forms, such as uncharged molecules, molecular complexes, salts, ethers, esters, amides, etc., which are biologically activated when injected into the animal or plant or used as a spatial formulation such that it can be applied on or inside the body of an animal or plant or as a stem implant.
    [0153] The pharmaceutically effective amount of a hydrophobic active ingredient or active ingredient may vary according to the active ingredient, the extent of the plant or animal's medical condition and the time required to provide the hydrophobic active ingredient or active ingredient. There is no critical upper limit on the amount of active ingredient or hydrophobic active ingredient incorporated in the polymer solution except that of a solution or dispersion acceptable viscosity for injection through a syringe needle and that it can effectively treat the medical condition without subjecting the animal or plant to overdose. The lower limit of the hydrophobic active ingredient or active ingredient incorporated in the delivery system is simply dependent on the activity of the active ingredient or hydrophobic active ingredient and the time period required for treatment.
    [0154] For example, some hydrophobic active ingredients or active ingredients may be present in the 10 to 200 mg / ml biodegradable drug release composition. In another aspect, the drugs must be present in the amount of 10 to 40 g / ml. . In another aspect, the drugs must be present in the amount of 10 to 500 mg / ml. For a small molecule, for example, the active ingredient can be loaded as high as 100 to 200 mg per ml.
    [0155] Generally the pharmaceutical active ingredient is present in an amount of 1% to 20% (weight% / weight%) of the total weight of the composition. In another aspect, the active ingredient is present in 1% to 4% (weight% / weight%) of the total weight of the composition. In another aspect, the active ingredient is present in 2% to 4% (weight% / weight%) of the total weight of the composition. In yet another aspect, the active ingredient, which is a small molecule, is present in an amount of 10% to 20% (weight% / weight%) of the total weight of the composition. In another aspect, the active ingredient is present in an amount of 10% to 40% (weight% / weight%) of the total composition. In another embodiment of the active hydrophobic pharmaceutically active principle it is present in the amounts of 1% to 40% (weight% / weight%).
    [0156] As examples, medroxyprogesterone acetate can be present in an amount of 10% to 40% (weight% / weight%) of the total weight of the biodegradable drug delivery compositions; progesterone can be present in an amount of 20% to 40% (weight% / weight%) of the total weight of the biodegradable drug delivery compositions; cyclosporine can be present in an amount of 5% to 21.1% (weight% / weight%) of the total weight of the biodegradable drug delivery compositions; levonorgestrel can be present in an amount of 10% to 20% (weight% / weight%) of the total weight of the biodegradable drug delivery compositions; and bupivacaine can be present in an amount of 1% to 15% (weight% / weight%) of the total weight of the biodegradable drug delivery compositions.
    [0157] In the biodegradable drug release composition of the present invention, the pharmaceutically effective amount can be gradually released over an extended period of time. This slow release can be continuous or discontinuous, linear or non-linear and can vary according to the composition of the tri-block copolymer and di-block copolymer. Thus, the higher the lactic acid content of the tri-block and di-block copolymers compared to the polyethylene glycol content, as well as the amount of tri-block and di-block copolymers present in the biodegradable drug composition the more the release of the active principle or hydrophobic active ingredient or drug. In other words, the higher the LA / EO molar ratio and the higher weight percentage of the tri-block and di-block copolymers, the longer it will take for the hydrophobic active ingredient or active ingredient to be released from the drug composition.
    [0158] The active ingredient or hydrophobic active ingredient can be released for a period of between 7 days to 1 year or more, depending on the type of treatment required, and the biodegradable drug release composition used. In one aspect, the biodegradable drug delivery composition can release the active ingredient or hydrophobic active ingredient for at least 7 days. In another aspect, the biodegradable drug delivery composition can release the active ingredient or hydrophobic active ingredient for at least 30 days. In one aspect, the biodegradable drug delivery composition can release the active ingredient or hydrophobic active ingredient for at least 90 days. In yet another aspect, the biodegradable drug delivery composition can release a hydrophobic active ingredient or active ingredient of 1 year or more.
    [0159] The biodegradable drug release composition can be an injectable liquid or a partial suspension at room temperature and be injected through a syringe without excessive force. But these biodegradable drug delivery compositions are also in situ forming and biodegradable and turning into solid implants when injected into the animal or plant. Alternatively, the biodegradable drug composition is produced as a solid, prepared as small particles and used as a powder, which is sprinkled on the injured site. In another aspect, the drug delivery composition is an implant stem, which can be implanted under the skin or in any other compartment of the body. In another aspect, the drug release composition can be prepared and applied as a film. In yet another aspect, the biodegradable drug release composition can be used as a spatial formulation such that it can be applied on or within the body of an animal or plant. It can be applied to any part of the body, including the eye. In another aspect, the biodegradable drug composition can be produced as a partial suspension, the drug being in the state of being partially soluble and partially solid.
    [0160] The biodegradable drug delivery composition can further comprise an acceptable carrier, adjuvant or pharmaceutically acceptable carrier. An acceptable vehicle can be saline, buffered saline and the like. It can be added to the biodegradable drug release composition after its formulation with the drug and di-block copolymer and tri-block copolymer.
    [0161] The adjuvant can be formulated simultaneously, when mixing the drug. In this regard, the adjuvants that can be used are alum, aluminum phosphate, calcium phosphate, MPL ™, CpG motifs, modified toxins, saponins, endogenous stimulating adjuvants such as cytokines, complete and incomplete Freund's adjuvants, type adjuvants ISCOM, muramyl peptides and their resins.
    [0162] The vehicle can be any diluent, additional solvent, filler or a binder, which can change the distribution of the active principle when necessary in the biodegradable drug release composition. Examples include small amounts of triglycerides, such as triacetin or tripropionin. The amount that can be used in the present biodegradable drugs to release the compositions of the present invention can vary from 12% to 20% (weight% / weight%). In one aspect, a triacetin can be added to the formulation at 17.0% (weight% / weight%). In another aspect, tripropionin (abbreviated here as triPro) can be added by 16% (weight% / weight%). In yet another aspect, benzyl alcohol can be added in 15% to 35% (weight% / weight%).
    [0163] A method for preparing the biodegradable drug delivery composition of the invention is also encompassed by the invention. This method comprises: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: A v - B w - A x, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237 in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 from tri-block to di-block, to form a mixture of polymers; and adding at least one pharmaceutically active principle to said polymer mixture.
    [0164] A method for preparing the biodegradable drug delivery composition of the invention is also encompassed by the invention. This method comprises: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: A v -B w -A x, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6-090; and (b) a biodegradable di-block copolymer having the formula: C y -A Zi where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3- 237 in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19 or 2: 3, or 4: 1 di-block tri-block, to form a polymer mixture; and adding a hydrophobic active ingredient to at least one pharmaceutically carrier to said polymer mixture.
    [0165] A method for preparing the biodegradable drug release composition of the invention is also encompassed by the invention. This method comprises: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 for a ratio of 237 in del: 3: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 of tri-block to di block, to form a mixture of polymers; and adding at least one hydrophobic pharmaceutically active principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine to said polymer mixture.
    [0166] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090, v and x are repeated units of ester and W is repeat units of ethylene oxide where v = x or v + x; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 237, y is the number of repeat units of ethylene oxide and z the number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 (a) :( b) to form a mixture of polymers; and (ii) adding at least one pharmaceutically active principle to said polymer mixture, is yet another aspect of the invention.
    [0167] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 4 to 1090 or 6 to 1090, v and x being repeated units of ester and w are repeating units of ethylene oxide where v = x or v ψx; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 237, y is the number of repeat units of ethylene oxide and z the number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 , or 2: 3, or 4: 1 or 2.3 - 4.1 (a): (b) to form a polymer mixture; and (ii) adding a hydrophobic active ingredient to at least one pharmaceutically carrier to said polymer mixture, is yet another aspect of the invention.
    [0168] A method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax in that A is a polyester and B is polyethylene glycol ev, w and x are the number of repeat units ranging from 4 to 1090 or 6 to 1090, v and x are repeated units of ester and w are repeat units of ethylene oxide where v = x or v + x; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 237, y is the number of repeat units of ethylene oxide and z the number of repeat units, in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19 , or 2: 3, or 4: 1 or 2.3 to 4.1 (a): (b) to form a polymer mixture; and (ii) adding at least one pharmaceutically active principle, one of which is medroxyprogesterone acetate, levonorgestrel, cyclosporine, progesterone or bupivacaine to said polymer mixture, is yet another aspect of the invention.
    [0169] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA-type block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 where v = vx or xe (b ) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 137 in one 1: 3 to 1: 8 or 1: 1 to 1: 3 or 19: 2 to 1: 19 ratio of (a): (b) to form a polymer mixture; (ii) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0170] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable tri-block copolymer of the ABA type has the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 where v = vx or x /; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 for 137 in a ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2,3-4,1 (a): (b) to form a mixture of polymers; (ii) adding a hydrophobic active principle to at least one pharmaceutically carrier to said polymer mixture; and (iii) evaporating said solvent.
    [0171] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in a organic solvent (a) a biodegradable ABA-type block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or from 6 to 1090 where v = vx or xe (b ) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 to 137 in one ratio of 1: 3 to 1: 8 or 1: 1 to 1: 19 or 3: 2 to 1: 19, or 2: 3, or 4: 1 or 2.3 to 4.1 (a) :( b) to form a mixture of polymers; (li) adding at least one pharmaceutically hydrophobic active ingredient, one of which is levonorgestrel medroxyprogesterone acetate, cyclosporine, progesterone or bupivacaine to said polymer mixture; and (iii) evaporating said solvent.
    [0172] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in a organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090, with x and v repeating ester units and w are ethylene oxide units repetition where v = vx or x ψ; and (b) a biodegradable di-block copolymer having the formula: C y - A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeating units ranging from 7 to 371 or 3 at 237, y is the number of repeating units of ethylene oxide and z the number of repeating ester units, in a ratio of 1: 4 (a) :( b) to form a polymer mixture; (li) adding at least one pharmaceutically active principle to said polymer mixture; and (iii) evaporating said solvent.
    [0173] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repeating units ranging from 6 to 1090, with x and v repeating ester units and w are ethylene oxide units repetition where v = vx or x +; and (b) a biodegradable di-block copolymer having the formula: C y- A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237, y is the number of repeating units of ethylene oxide and z the number of repeating ester units, in a ratio of 1: 4 (a) :( b) to form a polymer mixture; (li) adding at least one pharmaceutically carrier to the hydrophobic active ingredient to said polymer mixture; and (iii) evaporating said solvent.
    [0174] Yet another aspect, the present invention provides a method for preparing the biodegradable drug release composition of the present invention, said method comprising: - (i) dissolving in an organic solvent (a) a block copolymer of the ABA type biodegradable having the formula .: Av-Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 6 to 1090, with x and v repeat units of ester and w are oxide units repeating ethylene where v = vx or x +; and (b) a biodegradable di-block copolymer having the formula: C y- A z where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 to 237, y is the number of repeating units of ethylene oxide and z the number of repeating ester units, in a ratio of 1: 4 or 2: 3 or 3: 2 or 4: 1 (a) :( b) for forming a mixture of polymers; (li) adding at least one hydrophobic pharmaceutical active ingredient, one of which is levonorgestrel medroxyprogesterone acetate, cyclosporine, progesterone or bupivacaine to said polymer mixture; and (iii) evaporating said solvent.
    [0175] Another embodiment provides a method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in an organic solvent (a) a biodegradable block copolymer of the ABA type has the formula: Av -Bw-Ax, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237 in a 1: 6 di-block-to-block ratio to form a polymer mixture; adding at least one pharmaceutically active principle to said polymer mixture; and evaporating said solvent. In this non-solvent aspect it is present in the biodegradable drug release composition.
    [0176] Another embodiment provides a method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in an organic solvent (a) a biodegradable block copolymer of the ABA type has the formula: Av -Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237 in a 1: 6 di-block-to-block ratio to form a polymer mixture; adding a hydrophobic active ingredient to at least one pharmaceutically carrier to said polymer mixture; and evaporating said solvent. In this non-solvent aspect it is present in the biodegradable drug release composition.
    [0177] Another embodiment provides a method for preparing the biodegradable drug release composition of the invention, comprising said method: (i) dissolving in an organic solvent (a) a biodegradable block copolymer of the ABA type has the formula: Av -Bw-Ax where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090; and (b) a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol with end cover y and z are the number of repeat units ranging from 7 to 371 or 3 at 237 in a ratio of 1: 2 or 6: 3 or 3: 2 or 4: 1 or 2.3 to 4.1 tri-block di-block, to form a polymer mixture; adding at least one pharmaceutically hydrophobic active ingredient, one of which is levonorgestrel medroxyprogesterone acetate, cyclosporine, progesterone or bupivacaine to said polymer mixture; and evaporating said solvent. In this respect, no solvent is present in the biodegradable drug release composition.
    [0178] The organic solvent that can be used in the method here decribed is selected from the group of: benzyl alcohol, benzyl benzoate, diethylene glycol dimethyl ether (diglyme), diethylene glycol monoethyl ether (DEGMEE), dimethyl isosorbide (DMI ), dimethyl sulfoxide (DMSO), ethyl acetate, ethyl benzoate, ethyl lactate, ethylene glycol monoethyl ether acetate, glycerol formal, methyl ethyl ketone, methyl isobutyl ketone, N-ethyl-2-pyrrolidone , N-methyl-2-pyrrolidone (NP), pyrrolidone -2, tetraglycol, triacetin, tributyrin, tripropionin (triPro), or triethylene glycol dimethyl ether (triglyme) and mixtures thereof.
    [0179] The organic solvent is present in an amount of 40% to 74% (weight% / weight%) of the total composition. In another aspect, the organic solvent used in the preparation of the biodegradable drug release composition is present in an amount of 50% to 60% (weight% / weight%) of the total composition. In yet another aspect, the solvent used in the preparation of the biodegradable drug release composition is present in an amount of 60% to 70% (weight% / weight%) of the total composition. In yet another aspect, the solvent used in the preparation of the biodegradable drug delivery system is present in the amount of 30 %% and 70% (weight% / weight%) of the total composition. In another embodiment, the organic solvent is present in the amount of 30% to 90% (weight% / weight%) of the total composition.
    [0180] As examples, when medroxyprogesterone acetate is the active ingredient of 30% to 70% (weight% / weight%) of the total solvent composition is used; Progesterone is the active ingredient of 40% to 80% (weight% / weight%) of the total solvent composition used; when cyclosporine is the active ingredient from 55% to 72.9% (% w / w%) of the total solvent composition is used; levonorestrel when the active ingredient is 70% to 90% (weight% / weight%) of the total solvent composition is used; and when the base is the active ingredient bupivacaine from 62.5% to 80% (weight% / weight%) of the total solvent composition is used.
    [0181] Some mPEG - OH are contaminated with a small amount of HO - PEG - OH. Following the methods of the present invention and using contaminated MPEG-OH the final product would be mPEG-PLA contaminated with a small amount of PLA - PEG - PLA, which is covered by the present invention. This contamination is less than 2%.
    [0182] Another aspect of the present invention is the use of di-block and tri-block for the manufacture of a biodegradable drug composition. In this regard, the biodegradable tri-block copolymer has the formula: Av-Bw-Ax, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090 ev = xouvx. The polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester used is poly (lactic) acid.
    [0183] The tri-block copolymer is then combined with a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol coating end and y are the number of repetition units varying 7 to 371 or 3 to 237. The polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly (lactic-co-glycolic acid (PLGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester used is poly (lactic) acid.
    [0184] The pharmaceutically active principle is then combined with the tri-block and di-block.
    [0185] In yet another aspect of the present invention is the use of di-block and tri-block for the manufacture of a biodegradable drug composition. In this regard, the biodegradable tri-block copolymer has the formula: Av-Bw-Ax, where A is a polyester and B is polyethylene glycol ev, w and x are the number of repetition units ranging from 4 to 1090 or 6 to 1090 ev = xouv ^ x. The polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA) or polyhydroxyalkanoate (PHA). In one embodiment, the polyester used is poly (lactic) acid.
    [0186] The tri-block copolymer is then combined with a biodegradable di-block copolymer having the formula: C y - A z, where A is a polyester and C is a polyethylene glycol cover end and y and are the number of repetition units varying 7 to 371 or 3 to 237. Polyester can be polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), poly (lactic-co-glycolic acid (PLGA) or polyhydroxyalkanoate (PHA) In one embodiment the polyester that is used is poly (lactic) acid.
    [0187] The hydrophobic pharmaceutically active principle is then combined with the tri-block and di-block and can be levonorgestrel medroxyprogesterone acetate, cyclosporine, progesterone or bupivacaine base.
    [0188] The proportion of the biodegradable tri-block copolymer of (a) and that of the biodegradable CA-block copolymer of (b) is 1: 3 to 1: 8 in said biodegradable drug composition. In one embodiment the ratio of the biodegradable tri-block copolymer and the biodegradable CA di-block copolymer is selected from the group of 1: 3, 1: 4, 1; 5, 1: 6, 1: 7 and 1: 8 or 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 6, 1: 7, 1: 8, 1: 9 , 1: 10, 1: 11, 1: 12, 1: 13, 1: 14, 1: 15, 1: 16, 1: 17, 1: 18 and 1: 19. In another aspect, the proportion of the tri-block the block is 1: 6. It can also be 3: 2 or 2: 3, or 4: 1 or 2.3 to 4.1.
    [0189] The length of the polyester chain is defined by its molar ratio of polyester and ethylene oxide, which is between 0.5 to 3.5 or 0.5 to 2.5 or 0.5 to 22.3 for the tri-block and 3 to 5 or 2 to 6 or 0.8 to 13, for the di-block.
    [0190] The mass of the polyethylene glycol with end cover can vary from 100 Da to 2 kDa or 164 Da to 2 kDa. It can vary between the 100 and 300 Da range or in the 1 to 2 kDa kDa range.
    [0191] The size of the polyethylene glycol chain ranges from 200 Da to 2 kDa in the biodegradable drug release composition or can vary from 400 Da to 12 kDa or 194 Da to 12 kDa.
    [0192] A number of embodiments and / or aspects of the invention have been described herein. However, it will be understood that various modifications can be made without departing from the spirit and scope of the invention. EXAMPLES
    [0193] Example 1 - Polymer Synthesis
    [0194] Copolymers were synthesized according to the method described in US Patent No. 6,350,812, incorporated herein by reference, with minor modifications. Typically, the required amount of PEG (given by the tri-block copolymer) or methoxy - PEG (given by the di-block copolymer) was heated to 65 ° C and dried under vacuum for 2 hours in a reactor vessel. DL-lactide (corresponding to the target LA / EO molar ratio) and zinc lactate (1/1000 of the amount of lactide) were added. The reaction mixture was first dehydrated three times in a vacuum of N2 short cycles. The reaction mixture was heated to 140 ° C and quickly degassed under vacuum. The reaction was carried out for four days at 140 ° C under constant nitrogen flow (0.2 bar). The reaction was cooled to room temperature and its content was dissolved in acetone and then subjected to ethanol precipitation. The product obtained was subsequently dried under reduced pressure. The final product was characterized by 1 H-NMR for the lactate content. The PLA - PEG - PLA tri - block polymers described here were marked PxRy where x represents the size of the PEG chain in kDa and y is the molar ratio LA / EO. The mPEG-PLA block polymers described herein were labeled dPxRy where x represents the size of the PEG chain in kDa and y is the LA / EO molar ratio.
    [0195] Example 2 Preparation of the Specific Formulation for M53 Peptide
    [0196] The formulations described here were based on the organic solution of polymers containing as the drug, the M53 peptide, a GLP-1 analog. Typically, 0.4 grams of polymers, which corresponds to a mixture of a di-block copolymer and a tri-block copolymer in relation to defined mass, were dissolved in 0.57 grams of a biocompatible solvent at room temperature overnight with stirring. constant magnetic. The solvent was either a single solvent or a combination of solvents. The next day, 20 mg of drug was added to the polymer solution and stirred until complete dissolution. When the drug was not soluble in the solvent, a suspension of the drug in a polymer solution was obtained. Alternatively, the drug was dissolved or suspended in the solvent and the biocompatible polymer (s) added subsequently. The formulations were loaded into a syringe before use.
    [0197] Example 3 - The formulations that were prepared following Examples 1 and 2 were prepared several formulations, which are shown in Table 1 for peptide 53. TABLE 1


    [0198] Example 4 - Preparation of acetaminophen formulations
    [0199] The formulations described here were based on the organic polymer solution prepared as in Example 1, containing acetaminophen as the drug. Typically, 0.4 grams of polymers, which corresponds to a mixture of a di-block copolymer and a tri-block copolymer in relation to defined mass, were dissolved in 0.55 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 50 mg of acetaminophen was added to the polymer solution and stirred until complete dissolution. The formulations were loaded into a syringe before use. The composition of the various formulations is shown in Table 2 below, where the solvent used is DMSO.
    [0200] Figures 7 to 26 illustrate the results of these formulations show that all possible combinations of 15 tri-block copolymers with 20 di-block copolymers. TABLE 2











    [0201] Example 5 - Preparation of buprenorphine formulations
    [0202] The formulations described here were based on the organic polymer solution prepared as in Example 1, containing buprenorphine as the drug. Typically, 0.4 grams of polymers, which corresponds to a mixture of a di-block copolymer and a tri-block copolymer in relation to defined mass, were dissolved in 0.5 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 100 mg of buprenorphine was added to the polymer solution and stirred until complete dissolution. The formulations were loaded into a syringe before use.
    [0203] Three different formulations were selected for in vivo experiments. The composition of these formulations is shown in Table 3 below. The formulations were injected subcutaneously into the interscapular space of male rats (200-250 gr) at a final dose of 100 mg / kg of buprenorphine. Blood samples were taken periodically and analyzed for buprenorphine concentrations by LC / MS / MS.
    [0204] The formulations are shown in Table 3 below. TABLE 3




    [0205] The results of these formulations are illustrated in Figures 30 and 31.
    [0206] Example 6 - Preparation of risperidone formulations
    [0207] The formulations described here were based on the organic polymer solution prepared as in Example 1, containing risperidone as the drug. Typically, 0.4 grams of polymers, which corresponds to a mixture of a di-block copolymer and a tri-block copolymer in relation to defined mass, were dissolved in 0.5 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The following day, 100 mg of risperidone was added to the polymer solution and stirred. The formulations were loaded into a syringe before use.
    [0208] Three different formulations were selected for in vivo experiments. The composition of these formulations is shown in Table 4 below. The formulations were injected subcutaneously into the interscapular space of male rats (300 gr) in a final dose of 21 mg / kg of risperidone. Blood samples were taken periodically and analyzed for risperidone and 9-OH risperidone concentrations by LC / MS / MS. The formulations are shown in Table 4 below. TABLE 4


    [0209] The results of these formulations are illustrated in Figures 32 and 33.
    [0210] Example 7 - Preparation of ivermectin formulations
    [0211] The formulations described here were based on the organic polymer solution prepared as in Example 1, containing ivermectin as the drug. Typically, 0.4 grams of polymers, which corresponds to a mixture of a di-block copolymer and a tri-block copolymer in relation to defined mass, were dissolved in 0.55 grams of dimethyl sulfoxide at room temperature overnight with stirring. constant magnetic. The next day, 50 mg of ivermectin was added to the polymer solution and stirred until complete dissolution. Three different formulations were selected for in vivo experiments. The composition of these formulations is shown in Table 5 below. The formulations were injected subcutaneously into the interscapular space of male dogs (10 to 17 kg) at a final dose of 0.6 mg / kg of ivermectin. Blood samples were removed periodically and analyzed for ivermectin concentration by LC / MS / MS.
    [0212] The formulations are shown in Table 5. TABLE 5

    [0213] The results are illustrated in Figure 34.
    [0214] Example 8 Preparation of medroxyprogesterone acetate formulations
    [0215] The formulations as described herein are based on organic polymer solutions, as described in Example 1, containing medroxyprogesterone acetate as the drug. Typically 0.4 grams of polymers that correspond to a mixture of di-block and tri-block copolymer in a defined mass ratio were dissolved in 0.3 grams of DMSO or a combination of DMSO and benzyl alcohol at room temperature overnight with magnetic stirring constant. The next day, the polymeric solution was filtered through a 0.22 pm filter and 0.3 grams of medroxyprogesterone acetate was added to the filtered polymer solution and stirred until a homogeneous suspension of the drug was obtained. The formulations were loaded into a syringe before use. The compositions are shown in Table 6 below. The formulations were injected subcutaneously into the interscapular space of bitches (11.4 to 14.1 kg). Blood samples were taken periodically and analyzed for concentration of medroxyprogesterone acetate by LC / MS / MS with a lower limit of quantification of 0.25 ng / ml. The results are shown in Figure 35.
    [0216] The formulations are shown in Table 6. TABLE 6








    [0217] Example 9 - Preparation of progesterone formulations
    [0218] The formulations as described herein are based on organic polymer solutions, as described in Example 1, containing as the drug progesterone. Typically 0.1 grams of polymers which correspond to a mixture of di-block and tri-block copolymer in a defined mass ratio were dissolved in 0.6 grams of DMSO at room temperature overnight with constant magnetic stirring. The next day, the polymeric solution was filtered through a 0.22 µm filter and 0.3 grams of progesterone was added to the polymer solution and the filtrate was stirred until a homogeneous suspension of the drug was obtained. The formulations were loaded into a syringe before use. The compositions are shown in Table 7 below. TABLE 7 DRUG: PROGESTERONE


    [0219] Example 10 - Preparation of levonorgestrel formulations
    [0220] The formulations as described herein are based on organic polymer solutions, as described in Example 1, containing as the drug levonorgestrel. Typically 0.1 grams of polymers that correspond to a mixture of di-block and tri-block copolymer in a defined mass ratio were dissolved in 0.7 grams of DMSO at room temperature overnight with constant magnetic stirring. The next day, the polymeric solution was filtered through a 0.22 pm filter and 0.2 grams [of levonorgestrel was added to the filtered polymer solution and stirred until a homogeneous suspension of the drug was obtained. The formulations were loaded into a syringe before use. The compositions are shown in Table 8 below. TABLE 8 DRUG: LEVONORGESTREL

    [0221] Example 10 - Preparation of A cyclosporine formulations
    [0222] The formulations as described herein are based on organic polymer solutions, as described in Example 1, containing as the drug cyclosporine. Typically 0.15grams of polymers that correspond to a mixture of di-block and tri-block copolymer in a defined mass ratio were dissolved in 0.65 grams of DMSO at room temperature overnight with constant magnetic stirring. The next day, the polymeric solution was filtered through a 0.22 pm filter and 0.2 grams of cyclosporine was added to the filtered polymer solution and stirred until a homogeneous suspension of the drug was obtained. The formulations were loaded into a syringe before use. The compositions are shown in Table 9 below. TABLE 9 DRUG: CYCLOSPORINE


    [0223] Example 11 - Preparation of Bupivacaine formulations
    [0224] The formulations as described herein are based on organic polymer solutions, as described in Example 1, containing Bupivacaine-based drugs. Typically 0.1 grams of polymers that correspond to a mixture of di-block and tri-block copolymer in a defined mass ratio were dissolved in 0.75 grams of DMSO at room temperature overnight with constant magnetic stirring. The next day, the polymeric solution was filtered through a 0.22 pm filter and 0.15 grams of Bupivacaine base was added to the polymer solution and the filtrate was stirred until a homogeneous suspension of the drug was obtained. The formulations were loaded into a syringe before use. The compositions are shown in table 10 below. TABLE 10 DRUG: FORMULATIONS OF BUPIVACAINE (BUPI)



    [0225] Example 12 - Injectability of different compositions
    [0226] Several formulations have been tested for injectability using formulations with different proportions of tri-block (TB) and di-block (DB). Different DMSO solutions were prepared based on a mixture of the tri-block copolymer P6R1 (TB) and the di-block copolymer dP2R4 (DB).
    [0227] A polymer mass / formulation of 50% weight% / weight% was used in these viscosity experiments. The weight% / weight% of tri-block di block, which was used in this experiment were as follows: 50 by weight. %: 0 by weight. %, 45 by weight. %: 5 by weight. %, 20 by weight. %: 5 by weight. %, 35 by weight. %: 15 by weight. %, 15 by weight. %: 10 by weight. %, 25 by weight. %: 25 by weight. %, 10 by weight. %: 15 by weight. %, 15 by weight. %: 35 by weight. %, 5 by weight. %: 20 by weight. %, 5 by weight. %: 45% by weight, and 0% by weight. %: 50 by weight. %.
    [0228] The injectability results are shown in Figure 3.
    [0229] Example 13 - In vitro release test
    [0230] From 100 to 500 mg of formulation was added to 20 ml to 50 ml of physiological buffer. The physiological buffer that was used was KRT containing 50 ml of Krebs / Ringer I Tris (KRT) buffer pH 7.4, which is 143 mM sodium chloride, 5.1 mM potassium chloride, calcium chloride 2.7 mM, 1.34 mM magnesium sulfate, 25 mM Tris - Cl pH 7.4 and 0.1% sodium azide. After injection, the solvent diffuses away from the formulation and the remaining polymer forms a solid biodegradable implant into the aqueous medium.
    [0231] In order to maintain immersion conditions, for the release of the drug, the release medium was kept under constant agitation at 180 rpm (010 Unimax apparatus, Heidolph) at 37 ° C. At predetermined time intervals, media are collected and analyzed by HPLC. The amount of the M53 peptide GLP-1 analogue released from the formulation was calculated from a calibration curve. The concentration of M53 varied between 0 and 5 mg / ml or that varied between 0 and 200 pg / ml.
    [0232] Results are shown in Figure 4 and Figure 5. Figure 5 illustrates the release speed of formulations 177, 224, 225, 246 and 250, as shown in Table 1, while Figure 4 shows the cumulative release of the drug from the formulations indicated.
    [0233] When the GPL- analog was incorporated into the polymer solution, it was encapsulated inside the polymer matrix, as it solidified. The drug was then released, either by diffusion into the matrix or by biodegradation of the matrix.
    [0234] Example 14 - Pharmacokinetic study
    [0235] Several formulations were tested in a pharmacokinetic study in rats. Compositions containing 1 mg of the drug per animal of formulations 177, 224, 225, 246 and 250, as indicated in Table 1 were administered subcutaneously to the rats. Blood samples were collected in EDTA tubes at different time points, centrifuged and the plasma at each time point was retained. Plasma samples were analyzed by LC / MS / MS and quantified by the drug content present. The results are presented as ng / ml of plasma measured over time.
    [0236] The results of a pharmacokinetic study are shown in Figure 6. As shown in this Figure, three of the five formulations are able to maintain a plasma concentration higher than 0.1 ng / ml for more than 28 days, while still promoting a moderate initial drug release burst below 30 ng / ml.
    [0237] Example 15 - Blood glucose levels
    [0238] Blood glucose levels with patients suffering from type 2 diabetes are taken before treatment. A control group with no treatment is used for this study. Patients of both sexes are used in this study, as long as they have type 2 diabetes and are between the ages of 35 and 60.
    [0239] A GPL-1 analogue is formulated according to Examples 1 and 2 and has the chemical characteristics of number 230 in Table 1. The injectable liquid that is obtained is then injected into several patients, at a dosage of 8 mg / ml. The control group is given as PBS.
    [0240] The amount of blood sugar and fructosamine levels is then measured for a period of 30 days, twice a week, before meals and 2 hours after meals. Blood glucose values after treatment are measured and results are averaged. The values are shown in Table 11: TABLE 11


    [0241] Normal results for glucose levels before meals range from 80 to 120 mmol / L. Normal results for glucose levels after meals should be 160 mmol / L or less. Normal fructosamine levels were 265. Between 265 and 280 indicates excellent blood glucose control; 280 and 500 indicates good blood glucose control; between 320 and 340 indicates that blood glucose control is fair; and more than 350 indicates poor glycemic control.
    [0242] Patient 4 was administered placebo.
    [0243] These results show that when administered the biodegradable drug delivery compositions of the present invention are effective for the treatment of type 2 diabetes.
    [0244] Although the invention has been described in terms of several preferred embodiments, those skilled in the art will appreciate that various modifications, substitutions, omissions and changes can be made without departing from the scope of the invention. Therefore, it is intended that the scope of the present invention is limited by the scope of the claims, including their equivalents.
    权利要求:
    Claims (9)
    [0001]
    1. Biodegradable drug release composition characterized by the fact that it comprises: (a) a biodegradable tri-block copolymer having the formula: poly (lactic acid) v.poly (ethylene glycol) w-poly (lactic acid) x where v, wex are the number of repeat units ranging from 4 to 1090 or 6 to 1090 and v = xouv / x; and (b) a biodegradable di-block copolymer having the formula: poly (ethylene glycol) y- (polylactic acid) z where y and z are the number of repeat units ranging from 7 to 371 or 3 to 237, where the proportion of the biodegradable tri-block copolymer from (a) and the biodegradable di-block copolymer from (b) is 3: 2 to 1: 19 in said biodegradable drug composition; and (c) at least one pharmaceutically hydrophobic active ingredient, wherein said at least one pharmaceutically hydrophobic active ingredient is levonorgestrel, cyclosporine, progesterone, bupivacaine base or medroxyprogesterone acetate.
    [0002]
    2. Biodegradable drug release composition according to claim 1, characterized by the fact that said at least one hydrophobic active ingredient is a partial suspension.
    [0003]
    3. Biodegradable drug release composition according to either of Claims 1 or 2, characterized by the fact that it comprises: (a) a biodegradable tri-block copolymer present in an amount of 3.0% to 45% (weight% / weight %) or from 2% to 45% (weight% / weight%) of the total composition; (b) a biodegradable di-block copolymer present in an amount of 8.0% to 50% (weight% / weight%) of the total composition; and at least one pharmaceutically hydrophobic active ingredient is present in an amount of 1% to 20% (weight% / weight%) or 1% to 40% (weight% / weight%) of the total composition.
    [0004]
    4. Biodegradable drug release composition according to any one of the preceding claims, characterized in that the molar ratio of lactic acid to ethylene oxide in said composition is between 0.5 to 3.5 or between 0.5 to 2.5 or between 0.5 to 22.3 per tri-block copolymer and between 2 to 6, or between 0.8 to 13 or between 3 to 5, for di-block copolymer.
    [0005]
    5. Biodegradable drug release composition, according to any of the preceding claims, characterized by the fact that said compositions are an injectable liquid that, when inserted into the body of an animal or plant, becomes a hardened implant.
    [0006]
    6. Method for preparing a biodegradable drug release composition, characterized by the fact that it comprises: (i) dissolving in an organic solvent (a) a biodegradable ABA block copolymer having the formula: poly (lactic acid) v-poly (ethylene glycol) w-poly (lactic acid) x where v, w and ex are the number of repeat units from 6 to 1090 or 4 to 1090, where v = x or v + x; and (b) a biodegradable di-block copolymer having the formula: poly (ethylene glycol) methoxy y- (polylactic acid) z where y and z are the number of repetition units ranging from 7 to 371 or 3 to 237, in a ratio of 3.2 to 1:19 (a) (b) to form a mixture of polymers; and (ii) adding at least one pharmaceutically hydrophobic active ingredient to said polymer mixture, wherein said at least one pharmaceutically hydrophobic active ingredient is levonorgestrel, cyclosporine, progesterone, bupivacaine or medroxyprogesterone acetate.
    [0007]
    7. Method for the preparation of biodegradable drug delivery compositions, according to claim 6, characterized by the fact that it comprises (iii) evaporation of said solvent.
    [0008]
    8. Method according to claim 7, characterized by the fact that at least one hydrophobic active principle is a partial suspension.
    [0009]
    Method according to any one of claims 6 to 8, characterized in that the organic solvent is present in an amount of 40% to 74% (weight% / weight%) or 30 ° / o to 70 ° / o ( weight% / weight%) or 26% to 90% (weight% / weight%) of the total composition.
    类似技术:
    公开号 | 公开日 | 专利标题
    BR112014031773B1|2020-10-13|hydrophobic biodegradable drug release composition
    US20210154301A1|2021-05-27|Biodegradable drug delivery compositions
    BR112020001031A2|2020-07-14|mixtures of biodegradable drug release compositions to modulate the drug release kinetics of at least one active ingredient
    同族专利:
    公开号 | 公开日
    TN2014000520A1|2016-03-30|
    AU2013282891A2|2015-02-05|
    UA113549C2|2017-02-10|
    US20210008216A1|2021-01-14|
    CN104582733A|2015-04-29|
    KR102189442B1|2020-12-11|
    EP2866837A1|2015-05-06|
    CO7160098A2|2015-01-15|
    MX353280B|2018-01-05|
    BR112014031773A2|2017-06-27|
    HK1208374A1|2016-03-04|
    US20200085958A1|2020-03-19|
    CR20140581A|2015-02-06|
    US20150150987A1|2015-06-04|
    MX2014015902A|2015-07-17|
    AU2013282891A1|2015-01-22|
    JP2015522001A|2015-08-03|
    CU24287B1|2017-12-08|
    CN104582733B|2017-07-04|
    CU20140148A7|2015-03-30|
    SG11201408658PA|2015-02-27|
    MA37809B1|2018-12-31|
    WO2014001904A1|2014-01-03|
    IL236472D0|2015-02-26|
    CL2014003531A1|2015-08-28|
    MA37809A1|2017-07-31|
    EA201492172A1|2015-09-30|
    JP6134788B2|2017-05-24|
    KR20150027265A|2015-03-11|
    AU2013282891B2|2018-04-12|
    CA2877083C|2020-10-06|
    IL236472A|2020-02-27|
    US20190160171A1|2019-05-30|
    CA2877083A1|2014-01-02|
    ZA201409291B|2017-05-31|
    EA031522B1|2019-01-31|
    WO2014001905A1|2014-01-03|
    IN2014DN11063A|2015-09-25|
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    法律状态:
    2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law|
    2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-03-20| B06I| Technical and formal requirements: publication cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |
    2019-04-16| B07E| Notice of approval relating to section 229 industrial property law|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |
    2019-07-02| B06T| Formal requirements before examination|
    2019-11-26| B07A| Technical examination (opinion): publication of technical examination (opinion)|
    2020-03-31| B09A| Decision: intention to grant|
    2020-10-13| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/06/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261665192P| true| 2012-06-27|2012-06-27|
    US61/665.192|2012-06-27|
    PCT/IB2013/001547|WO2014001904A1|2012-06-27|2013-06-27|Biodegradable drug delivery for hydrophobic compositions|
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