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    • 专利摘要:
    A method and system for transporting a drug encapsulated in a gel depot and a liquid biodegradable polymer matrix for controlled release of the drug through a parenteral route of administration to a warm-blooded animal are described in detail. The system provides an injectable biodegradable block interpolymer drug transport liquid having reversible thermal gel forming properties. The effective amount of the drug trapped in the biodegradable block interpolymer matrix is dispersed or dissolved in the liquid. The interpolymer has a reversible grain formation temperature below the body temperature of the animal after administration and consists of (i) a hydrophobic A block selected from poly (α-hydroxy acid) and poly (ethylene carbonate) and (ii) polyethylene glycol Consists of hydrophilic B blocks, the liquid is stored below the reversible gel forming temperature and administered parenterally to the animal via muscle, peritoneal, subcutaneous or similar routes of administration.
    公开号:KR19990067013A
    申请号:KR1019980702950
    申请日:1996-10-25
    公开日:1999-08-16
    发明作者:차윤식；최영권；배유한
    申请人:젠터 게렌 엠.；마크로메드 인코퍼레이션；
    IPC主号:
    专利说明:

    Thermosensitive Biodegradable Polymers Composed of Poly (ether-ester) Block Interpolymers
    Many peptides or proteins that have recently been effective in a variety of therapies have become commercially available through the development of recombinant DNA and other techniques. However, polypeptides or proteins have a high molecular weight, and due to degradation in the gastrointestinal tract and short half-life in the body, the route for administering them is limited to the intravenous or muscular and subcutaneous routes. In most cases, injections should be done daily for a significant period of time to achieve the expected therapeutic effect. Long-term controlled transport of peptides or proteins is essential for the practical use of such drugs and to exploit these advances in biotechnology. Another problem is the patient's adaptability. It is sometimes difficult for a patient to comply with a prescribed medication regimen if a prescription for a chronic disease or medication has acute side effects. Thus, in increasing the therapeutic effect, bioavailability and patient compliance, it is most desirable to provide a system capable of transporting drugs, peptides or proteins at a controlled rate over a period of time without the aforementioned problems.
    In order to treat various diseases, polymer devices containing drugs have been studied for a long time. An important property of polymer devices is their biodegradability; This means that after all drugs have been released, the polymer is broken down in the body to become a non-toxic substance. In addition, the incorporation of solvents and drugs with the techniques, processes and processes used to make the device should be a medium that is safe for the patient, does not irritate surrounding tissue, and is harmless to peptides and protein drugs. Currently, biodegradable, implantable controlled release devices are made of crystalline polymers of polyglycolic acid or polyratic acid. Due to the hydrophobicity of such polymers, organic solvents such as methylene chloride, chloroform, acetic acid or dimethyl formamide should be used in the collection and preparation of the drug. In most cases the final polymer device is made of a separate solid shape (sphere, slab or rod) that requires surgical implantation and thus can irritate tissue.
    To date, there are no synthetic or natural high molecular materials that can be used for the controlled transport of peptides and proteins because of stringent requirements such as biocompatibility, clean degradation processes and the safety of degradation products. The most widely investigated biodegradable polymers based on available toxicity and clinical data are aliphatic polys such as poly (d, 1- or 1-lactic acid) (PLA) and poly (glycolic acid) (PGA) and hybrid polymers thereof. (α-hydroxy acid). Such polymers are commercially available and are currently used as biodegradable sutures in surgery. The first FDA-approved system for transporting peptides is Lupron Depot ™ , a lactic acid-glycolic acid interpolymer. Lupron Depot ™ consists of a microcapsule for injection that releases leuprolide acetate for a long time (about 30 days) to treat prostate cancer. Based on this use, lactic acid-glycolic acid interpolymers have been selected for early delivery systems with delayed release through parenteral use of biodegradable carriers.
    However, although this has been partly successful, such polymers have problems with their physicochemical properties and methods of making them. Hydrophilic polymers such as polypeptides do not diffuse through the polylactide membrane or matrix. The use of polylactide for the collection of drugs and the manufacture of devices requires organic solvents and solid dosage forms can cause tissue irritation.
    A.S. Sawhney and J.A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411 (1990) synthesized triple polymers of d, 1-lactide, glycolide and ε-caprolactone that can be rapidly degraded in vitro. For example, the triple polymer composition of 60% d, 1-lactide, 30% glycolide and 10% ε-caprolactone had a half-life of about 17 days. Copolymerization with the polyether surfactant prepolymer (Pluronic F-68) increased the hydrophilicity of the material. Such prepolymers are block interpolymers composed of 80w% hydrophobic poly (propylene oxide) and 20w% hydrophilic poly (ethylene oxide). Hybridization with surfactant prepolymers results in strong and partially crystalline materials that are physically stable under water at physiological temperatures (˜37 ° C.). It can be seen that the half-life of such interpolymers is slightly increased compared to that of the base polymer. However, Pluronic type polymeric surfactants, in particular poly (propylene oxide) blocks, are not biodegradable.
    Dunn et al., U.S. Other implantable transport systems, such as those found in Patents 4,938,763 and 5,278,202, have been known for some time. One unique property of such compositions is that they maintain a uniform liquid that can be prepared and injected using a 22/23 Gauge needle. Such polymers are thermoplastic or thermoset. Thermoplastic systems form polymer solutions in a suitable solvent. When the polymer solution is injected into the body and exposed to body fluids or water, the solvent diffuses out of the polymer-drug mixture and the water diffuses into the mixture to agglomerate the polymer containing drug in the polymer matrix as the implant solidifies. The thermoplastic solution should use organic solvents such as N-methyl-2-pyrrolidone, propylene glycol, THF, DMSO, dodecylazacycloheptan-2-one (Azone) and similar materials. Thermosetting systems consist of the synthesis of crosslinkable polymers that are formed and cured using a curing agent. The polymer uses a polyol initiator and a catalyst to make a polyol-attached prepolymer which is further converted to a prepolymer whose end is an acrylic ester. Prior to injection, a curing agent such as benzoyl peroxide or azobisisobutyronitrile is added to the acrylic prepolymer solution. Once injected, the crosslinking reaction proceeds until the polymer has a molecular weight sufficient to solidify. Such polymers are mainly formed by the polymerization or hybrid polymerization of biodegradable hydrophobic polylactide, polyglycolide, polycaprolactone and the like. The decomposition time of the used polymer type is in the range of several weeks to several months. The rate of decomposition can be adjusted by selecting the appropriate polymer. The polymer is non-toxic and adapts well to the body, and the system can be easily manufactured. Such polymer compositions provide a new approach to biodegradable implants because they can be easily injected and avoid surgical procedures. Their biocompatibility and biodegradability are also well established. Once formed, the gel matrix releases the drug in a controlled manner and then degrades, where the degradation product is easy to metabolize and excrete. Such thermosetting and thermoplastic compositions have the advantage that no surgery is required before administration or after release is complete. However, a major disadvantage of thermoplastic compositions is that they use organic solvents, which can be toxic to the body or irritate tissue. Thermosetting systems require a rapid mixing of the prepolymer solution with the drug before the catalyst is added, and the injection should be made immediately after the addition of the curing agent.
    Suitable materials that can be used as injectable or implantable polymeric drug transport media are biodegradable, adaptable to hydrophilic or hydrophobic drugs, are simple to manufacture, stable in solvents such as water, and require further polymerization or other reactions after administration. It should not be.
    The system made in aqueous solution is a block interpolymer consisting of two different polymer blocks, for example, hydrophilic poly (ethylene oxide) blocks and hydrophobic poly (propylene oxide). They are synthesized as poly (ethylene oxide) -poly (propylene oxide) -poly (ethylene oxide) triple blocks and are marketed as Pluronic ™ or Poloxamer ™ . The triblock polymer absorbs water to form a gel, which can be used in topical pharmaceutical cosmetic systems such as topical drug transport systems. It is a surface active block interpolymer which exhibits such gel reversal properties by reversible heat and has drug release properties. However, Pluronic systems are not biodegradable and their gel properties and drug release kinetics should actually be improved.
    Pluronic TM and Poloxamer TM triple block polymers solidify or gelate when the solution temperature rises above the critical temperature (gel formation temperature). Such polymers form micelles (small spheres in which water is bound) at low concentrations and are then concentrated to form gels continuously at high concentrations and high temperatures (˜30 ° C.).
    As it can be seen in Table 1, Pluronic TM-6 series, including Pluronic TM-6 is made of a gel at 50-60% (w / w) the lowest concentration at room temperature. Pluronic F-88 ™ gels at 40% at 25 ° C. and Pluronic F-108 ™ gels at 30% concentration. Thermal gelling action is described as a micelle dissolver, which expands to form a fake cross-link in the polymer micelle. Gelling mechanisms allow polymer molecules to bind micelles as a function of temperature. As the size of micelles increases with temperature, micelles undergo thermally induced expansion (expansion of micelles) with dissolution of the internal polymer core. This expansion simultaneously changes the shape of the methyl group in the polyoxypropylene chain. This phenomenon is enhanced due to hydrophobic polymer interactions at higher temperatures to form a physically entangled stable network. The network between the polymers gradually increases the viscosity and increases the integrity of the carrier upon heating.
    Physicochemical and Gel-forming Properties of Selected Pluronic TM F-68 F-88 F-98 F-108 F-127 Molecular Weight 8350 10800 13500 15500 11500 PEO: PPO (wt ratio) 80:20 80:20 80:20 80:20 70:30 PPO weight 1750 2250 2750 3250 3850 Melting Point (℃) 50 55 56 57 56 Concentration (%) and temperature (℃) 25 ℃ 20% - - - - + 37 ℃ 20% - - + + + 25 ℃ 30% - - + + + 37 ℃ 30% - + + + + 25 ℃ 40% - + + + + 37 ℃ 40% + + + + + PEO: poly (ethylene oxide) PPO: poly (propylene oxide)-: no gelling +; Gel Formed
    Pluronic F-127 ™ (Poloxamer 407 ™ ) is one of the least toxic block copolymers that gels at 20% concentration at 20 ° C. Pluronic F-127 ™ consists of about 70% ethylene oxide and 30% propylene oxide with an average molecular weight of 11500. A unique feature of this polymer is its gelation by reversible heat; The interpolymer concentrate solution (20-30 wt / wt%) becomes a soft gel at fluid or body temperature at low temperatures (<10 ° C).
    By raising the temperature of the protein and aqueous polymer solution, the protein drug can be included in this type of gel and thus the protein is included in the gel network. Since the solvent is water, the bioactivity of the protein is preserved and the rate of release of the protein from the gel can be controlled.
    Several studies have been conducted on the utility of Pluronic F-127 ™ gels as sustained release depots for injection. Toxicity was evaluated after injection of Pluronic ™ carriers into rabbit muscle (TP Johnson et al., J. Parateral Sci. & Tech., Vol. 39, No. 2, pp83-88 (1985)). It has been reported for the sustained release of urase from Poloxamer ™ (TP Johnson et al., J. Parateral Sci. & Tech., Vol. 44, No. 2, pp58-65 (1990)). It has been reported for the sustained release of IL-2 from Poloxamer 407 ™ gel matrix (TP Johnson et al., Pharmaceutical Research, Vol. 9, No. 3, pp 425-434 (1992)). It has been reported that Pluronic F-127 ™ potentiates anti-tumor immune responses by sustained IL-2 activity in tumor sites (K. Morikawa et al., Cancer Research, 47, 37-41 (1987)). Effective removal of inulin from rat kidneys by glomerular filtration has been reported to have been observed after administration of inulin-Pluronic ™ gels (KF Fults et al., J. Parental Sci. & Tech., Vol. 43, No. 6, 279-285 (1989).
    There is an urgent need for hydrophilic biodegradable materials that can be used to bind water soluble polypeptides in solution. A.S. Sawhney et al., Macromolecules, Vol 26, No. 4, 581-589 (1993) synthesized synthetic macromers extended with poly (ethylene glycol) central blocks and α-hydroxy acid oligomers such as oligo (d, 1-lactic acid) and terminated with acrylate groups. . Using non-toxic photoinitiators, macromers can be rapidly polymerized into visible light. Due to the macrofunctionality of the macromers, crosslinked gels are formed by the polymerization reaction. The gel is decomposed into poly (ethylene glycol), α-hydroxy acid, oligo (acrylic acid) by oligo (α-hydroxy acid) partial hydrolysis, and its degradation rate is from 1 day up to 4 months, and oligo (α-hydroxy Hydroxy acid) can be adjusted by appropriate selection. However, in such systems, photoinitiators can be used as additional components, and additional processes such as light crosslinkers can also be used.
    Okada et al., Japanese Patent 2-78629 (1990) discloses the transesterification of poly (lactic acid) (PLA) or poly (lactic acid) / glycolic acid (PLA / GA) with poly (ethylene glycol) (PEG). Biodegradable block interpolymer materials were synthesized. The molecular weight range of PLA / GA is 400 to 5,000, and 200 to 2,000 for PEG. The mixture is heated to 100 to 250 ° C. for 1 to 20 hours under a nitrogen atmosphere. The product is mixed with water to form a hydrogel. Above room temperature precipitates in water depending on the composition. In other words, the solubility and hydrophobicity in water can be changed by exposing the polymer solution at elevated temperatures. The molecular structure of the product cannot be defined by the description given. However, general experimental conditions are as follows; 30 g of poly (d, 1-lactic acid) (MW 1590) are mixed with 20 g of PEG (MW 570-630) and heated to 250 ° C. under nitrogen for 4,5 hours without using a solvent. The product is immediately dispersed in 300 ml ice water and dissolved. The dispersion can be heated to 50 ° C. to obtain a white polymer precipitate. This process is repeated to purify the polymer and to dry at 50 ° C. under vacuum to give a semi-waxy material. The materials are available in sustained release formulations that can be mixed and injected into various peptide and protein solutions. It can also be freeze-dried to make solid blocks or vacuum dried to make pastes for implantation. It can also be used in combination with other biocompatible materials or microporous materials, such as hydroxyapatite.
    T. Matsuda, ASAIO Journal, M512-M517 (1993), describes the use of biodegradable substances to transport potent peptidic anti-proliferative agents, angiopeptin, to replace diseased vessels with artificial implants or vasculature. It can prevent myocardial endothelial hyperplasmosis. A very viscous block copolymer composed of poly (lactic acid) and poly (ethylene glycol) was used as an in situ coatable drug carrier. The material was supplied by Taki Chemical Co., Ltd., Hyogo, Japan. When a polymer gel consisting of 0.5 g of PLA-PEG and 0.5 mg of angiopeptin was stored in a 37 ° C. buffer, it was observed that prolonged release of angiopeptin from the gel over several weeks in a test tube. No excessive release of early angiopeptin was observed. Based on these results, locally maintained angiopeptin release from biodegradable polymer gels coated on damaged blood vessels in vivo appears to be effective.
    L. Martini et al., J. Chem. Soc., Faraday Trans., 90 (13), 1961-1966 (1994), are very sensitive to the binding of hydrophobic poly (ε-caprolactone) known to be degraded in vivo by the cleavage of hydrolysable chains associated with ester linkages. Low molecular weight ABA type triple interpolymers were synthesized and reported on the nature of the solution of PCL-PEG-PCL block interpolymers. Slowly heating the aqueous block copolymer solution can observe the cloud phenomenon. The clouding point of the 2 wt% aqueous copolymer solution is 65 ° C. for PCL-PEG-PCL (450: 4000: 450) and 55 ° C. for PCL-PEG-PCL (680: 4000: 680). Reversible gel formation in PCL-PEG-PCL cooling solution was observed at 25 ° C., 13% and at a temperature and concentration range of 80 ° C., 30%. Further cooling of the solution to 0 ° C. showed no gel-sol transition. Gel formation of caprolactone and oxyethylene triblock micelle solutions, such as gel formation of micelle solutions of oxyethylene / oxypropylene and oxyethylene / oxybutylene interpolymers, is a process that is almost heatless. In vitro, the degradation rate of PCL-PEG-PCL is very slow. A 20% molar reduction is seen from GPC for 16 weeks.
    Summary and purpose of the invention
    It is an object of the present invention to provide a block interpolymer drug transport system that is biodegradable and has reversible thermal gelling properties and good drug release properties.
    Another object of the present invention is to provide a method of making a biodegradable thermosensitive peptide or other drug transport system of interpolymers.
    It is an object of the present invention to provide a drug transport system for parenteral administration of hydrophilic drugs and in particular for administration of highly water soluble drugs and protein drugs.
    It is an object of the present invention to provide a drug to be administered parenterally in a biodegradable polymer matrix to form a gel depot in a living body, thereby releasing the drug at a controlled rate, thereby providing a method for biodegradation of the polymer matrix. do.
    These objects will be understood from the following summary, description of various embodiments according to the present invention.
    The terminology used herein has the following meanings;
    "Parenteral" refers to a route of administration other than the food route, particularly the intravenous route, including intramuscular, intraperitoneal, abdominal, and subcutaneous.
    “Solution”, “aqueous solution” and the like are used when the drug and biodegradable block interpolymers in such a solution are combined, so that blocks with drug / polymer complexes dissolved or uniformly dispersed at a functioning concentration can function. Refers to a solution of water maintained below the LCST temperature of the interpolymer.
    "Drug transport liquid" or "drug transport liquid with reversibly heat gelling properties" refers to "solutions" that form depots when the temperature rises above the LCST of the interpolymer and are suitable for injection into warm-blooded animals. .
    "Depot" refers to a drug transport liquid that forms a gel when heated to LCST or above after injection into a warm blooded animal.
    "LCST" or "low critical solution temperature" is the temperature at which the biodegradable block copolymer reversibly heats gelling, i.e. below this temperature, the copolymer is dissolved in water and above this temperature the block copolymer is phase separated. This results in a semi-solid comprising the drug and the block interpolymer.
    "LCST", "gel forming temperature" and "reversible gel forming temperature" or the like may be used interchangeably with LCST.
    The term "gel" used when referring to a semi-solid in which a drug and a biodegradable block interpolymer are combined in LCST or higher refers to a combination of gels, emulsions, dispersions, suspensions or the like.
    "Biodegradable" means that the block interpolymer can be broken down into non-toxic components in vivo after all drugs have been released.
    "Drug" refers to any organic compound or substance that has bioactivity and is used or suitable for therapeutic purposes.
    "Peptide", "polypeptide", "oligopeptide" and "protein" can be used interchangeably when referring to peptides or protein drugs, and unless stated otherwise, a particular molecular weight, molecular sequence or length thereof, bioactivity or treatment There is no restriction on use.
    “Poly (α-hydroxy acid)” refers to lactide, glycolide or lactones derived from ring open polymerization of poly (α-hydroxy acid) polymers or α-hydroxy acid precursors. refers to an interpolymer such as lactone).
    The present invention utilizes block interpolymers having hydrophobic or "A" block fragments and hydrophilic or "B" block fragments. Generally, block interpolymers are triple block, for example ABA or BAB type block interpolymers. However, the block interpolymers are in the form of A (BA) n or B (AB) n where n is an integer or becomes 2-5 using a multi-block interpolymer having repeated BA or AB units.
    Biodegradable hydrophilic or A block fragments include poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly (1-lactide-co- Glycolide), poly (ε-caprolactone), poly (γ-butylarolactone), poly (δ-valerolactone), poly (ε-caprolactone-co-lactic acid), poly (ε-caprolactone- Poly (α-hydroxy acid) derived from co-glycolic acid-co-lactic acid), hydroxybutyl acid, malic acid and di- or tripolymers are suitable. Without wishing to be limited to the above list, various α-hydroxy acid mixtures may be used to make homopolymer or interpolymer hydrophobic block fragments, which are also within the scope of the present invention.
    The average molecular weight of such α-hydroxy acid is about 500 to 10,00 and suitably 500 to 3,000.
    Another biodegradable hydrophobic or A block fragment is a low molecular weight, enzymatically degradable poly (ethylene carbonate). The average molecular weight of such poly (ethylene carbonate) is about 200 to 10,00 and suitably 200 to 3,000.
    The average molecular weight of the hydrophilic B block fragment is about 1000 to 20,00, suitably 1,000 to 5,000 and polyethylene glycol (PEG) is suitable.
    ABA and BAB type hydrophilic / hydrophobic block interpolymers synthesized as detailed herein are reversibly gelled by heat and biodegradable. The BAB type block interpolymer is similar to the Pluronic system described above, except that the hydrophobic poly (α-hydroxy acid) or poly (ethylene carbonate) A blocks are biodegradable and more biocompatible than the hydrophobic PPO blocks of the Pluronic system. .
    As mentioned above, B blocks are formed in a variety of ways, with hydrophilic poly (ethylene glycol) (PEG) being suitable. PEG has been selected as a hydrophilic water soluble block domain due to its unique bioadaptability, non-toxicity, micelle formation ability, and rapid removal from the body.
    Hydrophobic A blocks have been synthesized and used because of their biodegradability and biocompatibility. Degradation of such hydrophilic polymer blocks in vitro and in vivo is known and degradation products can be removed from the body as natural metabolites.
    The molecular weight of the hydrophobic poly (α-hydroxy acid) or poly (ethylene carbonate) A block is controlled to control the molecular weight of the water-soluble B PEG block to maintain solubility in water and gel formation ability. In addition, the molecular weight ratio of the hydrophilic B block to the hydrophobic A block should be such that the block interpolymers have the property to dissolve in water at temperatures below LCST (low critical solution temperature). In general, PEG blocks should be capable of dissolving at least 50% of the block interpolymer in water, and suitably above. Thus, a biodegradable block interpolymer having the property of reversibly forming a gel by heat is made, wherein the hydrophilic B block is composed of about 50 to 85 wt% of the interpolymer, and the hydrophobic A block is 15 to 15 of the interpolymer. It consists of 50wt%.
    The concentration at which the block interpolymer can dissolve at temperatures below LCST is considered to be the concentration at which it can function. Generally speaking, block interpolymers of up to 50 wt% may be used. However, a concentration range of about 3 to 40 wt% is suitable and a concentration of about 10 to 25 wt% is most appropriate. Certain minimum concentrations are required to obtain visible phase transitions of polymers. At low concentrations, phase transitions lead to emulsions rather than gels. At higher concentrations a gel network is formed. The actual concentration at which the emulsion can phase transfer into the gel network depends on the ratio of hydrophobic A blocks to hydrophilic B blocks and the molecular weight of each block. Since both emulsions and gels can function, it is not important to accurately determine the actual physical state. However, it is desirable to make expanded gel networks.
    It is possible to make solution biodegradable polymers and peptide / protein drug mixtures at temperatures below the gel formation temperature of the polymeric material. Once injected into the body as a liquid through muscle, subcutaneous or peritoneum, the drug / polymer formulation is suitably highly expanded gel for phase change since body temperature is above the gel formation temperature of the material.
    Such a system will minimize toxicity and minimize irritation to surrounding tissue due to the biocompatibility of the material and will be fully biodegradable within a predetermined time. Once the gel is made, the drug is released from the polymer matrix by the control of various interpolymer blocks.
    In both ABA and BAB interpolymer formulations, drug and polymer solutions are made and then implanted into the body in solution and gel or solidify when the temperature is elevated due to the reversible gel-forming nature of the drug / polymer. Such compositions may also be made into tablets or capsules for use in the oral cavity.
    This can be done by making microspheres comprising peptides or proteins using the ABA or BAB type thermosensitive biodegradable block interpolymers described above. Mix the thermosensitive polymer solution with the peptide / protein solution in cold water and drop it into warm oil drop by drop. When the temperature is raised, the polymer forms a gel, and the drug solidifies or partially precipitates in the gel drops suspended in warm oil and is collected. The solidified droplets become partially cured microspheres, which are washed separately and dried under vacuum. The resulting microspheres are collected in capsules or compressed into tablets to produce sustained release oral formulations for peptide / protein drugs.
    The function is how much of the drug is trapped in the interpolymer.
    In general, the drug is 0.1-10 wt% of the drug polymer composite and suitably about 1-5%.
    In the present invention, a polypeptide can be generally used, and a polypeptide that is stable up to a temperature range of 50 ° C can be used.
    Many labile peptide and protein drugs can utilize the reversible thermal gel formation encapsulation process described herein.
    Pharmaceutically useful polypeptides include, but are not limited to: Oxytocin, vasopressin, salivary cortex hormone, epidermal growth factor. Platelet induced growth factor (PDGF), prolactone, luriberine or progesterone releasing hormone, growth hormone, growth hormone releasing hormone, insulin, somatostatin, glucagon, interleukin-2 (IL-2), Interferon-α, β, γ (IFN-α, β, γ), gastrin, tetragastrin, pentagastrin, urogastrin, secretin, calcitonin , Enkephalins, endorphins, angiotensins, anthyroid releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (G-CSF), granulocyte-colony stimulating factor (GM) -CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), renin, bradykinin, bacitracins, polymyxin (polymixins), colistins, tyrocidin, gramicidines and their synthetic analogs, modifications And the like are pharmaceutically active fragments, and monoclonal antibodies and soluble vaccines.
    Peptide or protein drugs that can be used are limited only in their function.
    In some cases, various additives may be added to the peptide or protein drug aqueous solution to increase the functional or physical stability of the protein. Additives such as polyols (including sugars), amino acids, proteins such as collagen and gelatin, and certain salts can be used. Such additives can be directly incorporated into the reversible thermal gel formation process of the present invention.
    Advanced protein engineering may offer the possibility to increase the inherent stability of the peptide or protein. Such modified or engineered proteins are considered novel materials but do not change the stability for use in the present invention. An example of a typical modification is the PEGylation reaction of a polypeptide. Covalently binding a polymer soluble in water, such as polyethylene glycol, to the polypeptide can significantly improve the safety of the polypeptide drug. Another example of modification is the modification of the identity of the position or amino acid sequence of one or more amino acid residues by additions, deletions and substitutions (eg, deletion of cysteine residues or substitution of alanine or serine) at the ends and middle of the amino acid sequence.
    Any improvement in stability allows for sustained long-term sustained release of therapeutically effective polypeptides or proteins after a single administration of the pharmaceutical composition to the patient.
    In addition to peptides or protein-based drugs, anticancer agents, antibiotics, anti-inflammatory agents, hormones and the like can be used at similar concentrations. Common anticancer agents include adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, 5-fluorouracil (fluorouracil), mettrexate, taxol, taxotere, actinomycin D and the like.
    If desired, the rate of degradation of the block interpolymers can be modified to the extent that the drug is desired to be released for a predetermined time, by introducing a double-, triple-polymer structure into the hydrophobic fragment.
    Different poly (α-hydroxy acids) degrade at different rates. For example, hydrophobic poly (ε-caprolactone) fragments in block interpolymers degrade very slowly. The hydrophobic decomposition main product of poly (ε-caprolactone) is 6-hydroxyhexanoic acid. Studies with tritium-labeled poly (ε-caprolactone) showed that about 70% of the released radioactivity was in the form of tritiated water, indicating substantial metabolism of 6-hydroxyhexanoic acid. Metabolic processes of 6-hydroxyhexanoic acid can be inferred from the metabolic pathways of hexanoic acid and adipic acid. 6-hydroxyhexanoic acid is mainly converted to adipic acid by ω-oxidation in microsomes of the liver or kidney. Adipic acid is then metabolized by β-oxidation in the same way that fatty acids produce mainly carbon dioxide and water.
    Based on the foregoing, it can be expected that the hydrophobic poly (ε-caprolactone) fragments of the PCL-PEG-PCL interpolymers degrade very slowly. For proper use in polymeric drug transport systems, it is desirable to ensure that no polymeric material remains after the drug is completely depleted from the polymer. The rate of degradation of the PCL-PEG-PCL block interpolymer system can be further modified by binding a bi- or tri-polymer structure to the hydrophobic PCL fragment. For example, coupling glycolide or lactide units to PCL fragments to form double- or triple polymeric poly (α-hydroxy acids) can significantly speed up the degradation of such hydrophobic block interpolymer fragments. .
    Other di-, or tri-hydrophobic complexes with different poly (α-hydroxy acids) can be used to derive block fragments with the desired rate of degradation.
    Another variable in creating a thermosensitive drug transport system is the exploitation of the interaction between peptide / protein drugs in contact with a temperature sensitive biodegradable gel. In general, the sustained release period from the thermosensitive gel device is not very long. For example, about 8 hours of release has been observed following subcutaneous injection of Pluronic F-127 ™ (PEO-PPO-PEO) gel preparations that do not degrade. The interaction of the peptide / protein drug with the temperature sensitive biodegradable gel will affect the physical / chemical adaptability and bioactivity of the drug. For example, hydrophobic interactions between drugs and polymers in PCL-PEG-PCL or PLA-PEG-PLA type systems can extend drug release duration. The nature of the drug / polymer complex can also be used to alter the release kinetics and the release duration of the controlled release system. For example, the formation of salts between the carboxy-terminated polyester and the peptide / protein drug can alter the physico-chemical properties of the complex, such as its solubility in organic solvents.
    It is also possible to modify the polymer system by binding ionic groups to control the drug release profile, causing ionic interactions between the drug and the polymer. For example, malic acid or a derivative thereof may be used as a monomer during the synthesis reaction to bind carboxyl functional groups into hydrophobic fragments of thermosensitive polymer systems. Other polycarboxylic acids can also be used. It is known that covalently binding hydrophobic polyethylene glycol to proteins increases the stability of the drug in solution and prevents aggregation. It is also known that certain surfactants also increase the safety of the protein. Modified hydrophilic-hydrophobic block interpolymers containing ionic groups such as carboxyl groups are used not only as release rate modifiers because of certain drug-polymer interactions, but also as stabilizers for labile proteins.
    Another embodiment or method of obtaining a thermosensitive polymer having a desired degradation rate is to bind enzymatically degradable hydrophobic fragments to the block interpolymer system detailed in the present invention. This approach is significant because poly (ether-ester) block interpolymers are unstable in water-soluble environments and difficult to store for many hours. It is desirable to provide a hydrophobic polymeric material that is stable in an in vitro environment but degrades directly by enzymatic activity in vivo. The most suitable material that can be recommended for this purpose is poly (ethylene carbonate). This polymer is flexible at room temperature due to its low glass transition temperature (Tg, 6 ° C.) and is quite hydrophobic. At room temperature eg 37 ° C., no decomposition occurs in water. However, it can be seen that the molecular weight is slightly reduced when the polymer is treated with boiling diluted HCl solution. On the other hand, when the polymer is transplanted into the animal body, degradation occurs quickly. T. Kawaguchi et al., Chem. Pharm. Bull. As described in 31 (4) 1400 (1983), thick slabs made of poly (ethylene carbonate) polymer are completely degraded 2-3 weeks after implantation. Surprisingly, in the case of poly (propylene carbonate), no enzymatic degradation occurs at all, although the structure is similar. Mixing or hybridizing poly (ethylene carbonate) and poly (propylene carbonate) can control the rate of degradation by the enzyme. When hydrolyzed poly (ethylene carbonate), both ends become hydroxyl groups. Using various chemical reactions, such as isocyanate, hydrochloric acid, N-hydroxy succinimide reactions, it is possible to synthesize block or multiblock interpolymers of the ABA or BAB type as detailed herein.
    The synthesized polymers can be characterized by molecular weight, block length, polymer composition, micelle critical concentration, surface activity, gel formation temperature, water content in the gel, tissue adaptability and degree of biodegradation of the polymer.
    The reversible heat self-gel forming system described herein is very useful as a carrier that increases the viscosity of the protein composition and delays the release of the protein composition into the circulation after extravascular administration. Such polymers are useful for binding proteins and peptide drugs in polymer carriers because they are very sensitive to heat, organic solvents, pH changes, and ionic strength, and tend to lose their biological activity. Thus, such polymers can be used to make sustained release dosage forms where the drug can be dissolved (or dispersed) in a polymer cooling solution to produce a semi-solid gel in which the drug is collected immediately after injection into the body. The polymer / drug mixture can be injected into any part of the body via the intramuscular, subcutaneous or peritoneal route. The rate of drug / protein release and its duration are determined by functions such as solidified gel density, molecular weight of drug / protein and other factors such as hydrophobicity or ionic interactions. The polymer can be broken down into small fragments that are soluble or insoluble in water. Oligomers that can be dissolved in water can be released through various metabolic pathways or directly. Oligomers that are not soluble in water are taken up by macrophages and external body giant cells and are further degraded by lysosomes.
    Due to the properties similar to the surfactants of such block interpolymer systems, the diluted polymer solution forms a milky emulsion when the polymer loses its dissolution in water. Such self-emulsifying systems are of considerable interest because the drugs with weak hydrophobicity can be dissolved and bound to spontaneously formed emulsions (or suspensions) at body temperature by the surface active triple block interpolymers described herein above. Triple block interpolymers are also considered to be degradable non-ionic surfactants that are much better than Pluronic ™ systems that do not degrade. Certain peptides and proteins can be captured or loaded into this system, resulting in a new type of controlled release transport system. The drug is released slowly with the decomposition of the particles. As a result, there is no need for a microencapsulation process which is time consuming and requires a significant amount of organic solvent. The poly (ether-ester) block interpolymers detailed herein are self-gelling or self emulsifying which are temperature-sensitive, injectable outside the blood vessel and capable of releasing captured or bound drugs in a delayed manner. Which has potential for use in the development of biodegradable depot systems.
    As described above, biodegradable poly (ether-ester) block interpolymers have the property of reversibly forming gels by the required heat, wherein the hydrophilic B blocks are suitably composed of about 50 to 85 wt% of the interpolymers. The hydrophobic A block consists of about 15-50 wt% of the interpolymer. In addition, the concentrations at which these interpolymers become soluble below the LCST temperature vary widely. When used for injection, the concentration of the block interpolymer is up to about 50% by weight. In view of the foregoing with regard to the formation of gels and emulsions, the concentration is suitably about 3 to 40% and most preferably the concentration is about 10-25 wt%. Phase transitions of drug / interpolymer composites at temperatures above LCST are required parameters. Within the scope of the guidelines set forth herein, one of ordinary skill in the art would be able to determine the appropriate drug capture amount, polymer composition concentration, degradation rate, gel formation / destruction formation, and the like, without experimentation.
    The present invention relates to the production of thermosensitive biodegradable polymers and their use in parenteral administration of peptides and protein drugs. More specifically, the present invention relates to thermosensitive biodegradable polymers comprising peptides or proteins and processes for making them. The present invention utilizes thermosensitive biodegradable polymers based on poly (ether-ester) block interpolymers, which will be described in detail below. The system is based on the discovery that poly (ether-ester) block interpolymers have a specific molecular weight and composition range that exists in clear solutions in water at room temperature, provided that the temperature rises to body temperature and interacts with each other to give a semi-solid gel, Make an emulsion or suspension.
    In order to explain a suitable embodiment of the present invention, a process for synthesizing an interpolymer of ABA type hydrophobic (A) and hydrophilic (B) blocks will be described. Schemes 1 and 2 can make hydrophilic B blocks using poly (ethylene glycol) (PEG) of various molecular weights.
    In Scheme 1, the process for making a series of triple block interpolymers is described. Polylactide (PLA) or poly (ε-caprolactone) (PCL) can be made in the melting process by ring open polymerization of lactide and ε-caprolactone initiated by reaction with PEG as follows;
    In general experiments, 3 g of lactide (or caprolactone) and octoate tin salt (0.1 wt% / wt% monomer) were added to a reactor equipped with a high-vacuum valve containing an appropriate amount of PEG under dry nitrogen. Next, the air is removed and the reactor is sealed. The polymerization is carried out at 130 ° C. for 30 hours. After cooling to room temperature, the reaction mixture is dissolved in methylene chloride and precipitated in excess diethyl ether. The product is dried under vacuum to constant weight. The resulting interpolymer is characterized using 1 H-NMR (Braker AS 200 FT spectrometer) and subjected to gel permeation chromatography using Ultrastyragel column (Waters) calibrated with polystyrene standards. 1 H-NMR is used to determine total molecular weight and composition. The properties of the ABA block interpolymers obtained by this process are shown in Table 2. The composition of the interpolymers was in close agreement with the values predicted at the feed conditions, indicating that the polymerization was quantitative. Narrow unimodal GPC traces show that homopolymers are not formed and transesterification occurs without reactions such as chain breakdown.
    As a result of the mass polymerization of lactide and caprolactone initiated by poly (ethylene glycol) at 130 ° C. code Supply (PEGwt / wt%) Interpolymer composition Calculation Experimental Value * PELC-1 50 500-1000-500 480-1000-480 PELA-1 77 500-3400-500 510-3400-510 PELA-2 63 1000-3400-1000 1080-3400-1080 PELA-3 53 1500-3400-1500 1530-3400-1530 * Calculated from the 1 H-NMR spectrum PECL: PCL-PEG-PCL triple block interpolymer PELA; PLA-PEG-PLA Triple Block Copolymer
    All of the block interpolymers shown in Table 2 can be dissolved in water at low temperatures and will solidify if the temperature is sufficiently raised. In all cases, phase transitions occur directly in a narrow temperature range. Table 3 shows the transition temperatures of the 5wt / wt% aqueous solution.
    Heat transition temperature of various poly (ether-ester) block copolymer aqueous solutions (5 wt / wt%) code Total PEG (wt / wt%) Transition temperature (℃) PECL-1 50 10 PELA-1 77 50 PELA-2 63 40 PELA-3 53 30 PECL: PCL-PEG-PCL Triple Block Copolymer PELA: PLA-PEG-PLA Triple Block Copolymer
    This kind of physical phenomenon is similar to the temperature sensitivity found in the surface active block interpolymers of poly (ethylene oxide) -poly (propylene oxide) (Pluronics ™ or Poloxamer ™) as mentioned above.
    In the above-described system, it can be seen that both reversible heat gel formation and self-emulation reactions depend on the structure of the polymer. The PCL-PEG multiblock interpolymers formed according to Scheme 2 make a semisolid gel matrix upon heating and the PCL-PEG-PCL triple block interpolymers (PECL-1 shown in Table 2) form emulsions. This different reaction to heat is due to the same basic mechanism but different polymer concentration, temperature and structure.
    Scheme 2 illustrates making a multiblock PEG-PCL interpolymer. Excess hexamethylene diisocyanate (HMDI) and PEG polymers (MW-1000) were reacted at 60 DEG C in benzene to obtain PEG prepolymers having isocyanate (-N = C = O) end groups. PEG prepolymers extended the chain with divalent functional groups polycaprolactone diols (MW-530). The product is a polyethylene glycol-polycaprolactone (PEG-PCL) multiblock interpolymer blocked by a urethane linker.
    The reaction process is as follows;
    Example 1
    Synthesis of PECL-1
    3 g of ε-caprolactone and octoate tin salt (0.1 wt% / wt% monomer) were added to a reactor equipped with a high-vacuum valve containing an appropriate amount of PEG under dry nitrogen, followed by venting the reactor Seal it. The polymerization is carried out at 130 ° C. for 30 hours. After cooling to room temperature, the reaction mixture is dissolved in methylene chloride and precipitated in excess diethyl ether. The product is dried under vacuum to constant weight.
    Example 2
    Synthesis of PELA-1,2,3
    3 g of lactide and octoate tin salt (0.1 wt% / wt% monomer) were added to a reactor equipped with a high-vacuum valve containing an appropriate amount of PEG under dry nitrogen, followed by venting the air and sealing the reactor. do. The polymerization is carried out at 130 ° C. for 30 hours. After cooling to room temperature, the reaction mixture is dissolved in methylene chloride and precipitated in excess diethyl ether. The product is dried under vacuum to constant weight.
    Example 3
    Poly (d, 1-lactic acid) (MW = 2,500) (PLA) was synthesized by conventional condensation polymerization of d, 1-lactic acid at elevated temperature under reduced pressure. Polyethylene glycol (MW = 6,000) (PEG) is added to the poly (d, 1-lactic acid) melt. The mixture is heated under reduced pressure of about 50 mm Hg for 20 hours. Continuously providing dry nitrogen bubbles can form PLA-PEG-PLA interpolymers (average molecular weight MW = 2500: 6000: 2500).
    One gram of the triblock interpolymer sample is placed in a glass vial and 10 ml of ice water is added. The polymer dissolves into a tan liquid. The solution is heated to 37 ° C. in a water bath to solidify into a non-flowable gel. After several hours of storage in the refrigerator, the gel becomes fluid again. For example, the polymer undergoes a reversible sol-gel transition. Heating the solution to 60 ° C. separates the polymer from the aqueous phase, forming an opaque precipitate. When cooled in a bath of ice water, the opaque precipitate becomes a clear tan semi-solid gel with a water content of about 50 wt%.
    PLA-PEG-PLA polymers are soluble in water at LCST temperatures, for example, below about 0 ° C. Increasing temperatures above LCST, for example, about 37 ° C, form gels, and when heated to about 60 ° C, deposits form. Indicates that Precipitates formed at 60 ° C. take considerable time to reach solution if they lack solubility or cool to temperatures below LCST. Such polymers, although not completely dissolved in the cooling solution, can be an effective network that can be injected or implanted into the body for drug transport as shown in Example 4.
    Example 4
    0.2 g of the yellowish-brown semi-solid gel obtained in Example 3 was slowly mixed with 0.1 ml of concentrated human calcitonin solution (10 mg / ml) using a spatula. The mixture is placed in 10 ml of phosphate buffered salt (PBS) at 37 ° C. On the surface of the gel a fine polymeric calitonin with 5-20 μm direct particles is formed, which is slowly dispersed in a buffer to form a milky drug / polymer microsphere suspension.
    Dilutions of the polymer gel and calcitonin mixtures mixed in PBS can be directly injected or implanted into the body when microsphere suspensions are made and prepared under sterile conditions.
    When put into the body, calcitonin is slowly released from the polymer gel and diffuses into the surrounding area, and the polymer is biodegraded and removed from the body.
    Example 5
    Malic acid is polymerized with d, 1-ratic acid to make oligomeric polyesters (MW = 3,000) comprising carboxyl groups. Polyethylene glycol (MW 5,000), previously dried at high temperature in vacuo, is added to the carboxylated interpolymer melt and further heated to 180 ° C. under nitrogen atmosphere for 15 h.
    Example 6
    The block interpolymer obtained in Example 5 is dissolved in ice water and mixed with a heat stable platelet-derived growth factor (PDGF-B, isoelectric point 10.2) solution. The mixture was spun at 10,000 rpm in 50 ° C. buffer. Inject into the mixing head of the Homomixer Mark II. The drug is bound to the interpolymer by dispersion and immersion processes. In this process, drug leaching is reduced by ionic interactions and complex formation between the carboxylated interpolymer and the drug. The precipitated interpolymer containing the drug is collected and freeze dried.
    Example 7
    Aliphatic poly (ethylene carbonate) polymers were synthesized according to methods known in the art as follows. Ethylene oxide and carbon dioxide are reacted at 60 ° C. in a pressurized bomb reactor in the presence of a diethyl ammonia-water catalyst. The resulting polymer is dissolved in methylene chloride and purified by reprecipitation in methanol. Refined high molecular weight poly (ethylene carbonate) (PEC) (average molecular weight = 100,000) was refluxed in a 1% HCl solution to reduce the molecular weight with a hydroxyl group such as difunctional diol at both ends of the polymer chain. Poly (ethylene carbonate) (MW = 2,000) is obtained.
    Alternatively, polyethylene glycol (average molecular weight MW = 3,400) is reacted with an excess of hexamethylene diisocyanate (HMDI) in benzene at 60 ° C. to obtain a prepolymer having isocyanate (-N = C═O) ends. The prepolymer extends the chain to bifunctional poly (ethylene carbonate) as described above. The product is a polyethylene glycol-polyethylene carbonate (PEG-PEC) multiblock interpolymer in which the blocks are connected by urethane linkages.
    Example 8
    The multiblock interpolymers synthesized in Example 7 were dissolved in ice cold water. Add insulin zinc (PENTEX), recombinant human insulin, zinc salt to the PEG-PEC multi-block interpolymer solution and mix slowly until the solution is clear. The polymer / insulin salt solution is dropped dropwise into the buffer solution (pH 5.5) above the LCST temperature of the multiblock interpolymer. Solidified multiblock interpolymer / insulin beads are formed, obtained by filtration and freeze dried.
    PEC block fragments are stable for hydrolysis but due to the enzymatic properties, the insulin release form is different from the block copolymers that are unstable for conventional hydrolysis, and the insulin release duration is somewhat extended.
    Example 9
    Methoxy polyethylene glycol chloroformate (average molecular weight MW = 2,000) was reacted with the poly (ethylene carbonate) diol (MW = 2,000) obtained in Example 7 to have reversible thermal gel formation properties with PEG endblocks. Eggplants make BAB type block interpolymers. Such block interpolymers are enzymatically degraded due to hydrophobic PEC central block fragments.
    The resulting polymer is dissolved in ice cold water and mixed with interleukin-2 (IL-2) solution. Due to the pronounced hydrophobicity of the IL-2 protein, it can be stabilized by hydrophobic interactions with surfactant-like interpolymers. The IL-2 polymer can be stored in aqueous solution for a long time due to the enzymatic degradation of the interpolymer, but stable to hydrolysis. After gel formation at body temperature, it can be expected that the release period of the drug is significantly extended as compared to prior art undegradable Pluronic ™ or Poloxamer ™ .
    The foregoing description will enable those skilled in the art to make and use drug-blocked block interpolymers based on the nature of reversibly forming gels by heat. This description is not limited to specific peptides and other drugs may be used or captured in biodegradable block or multiblock interpolymers. Not all block interpolymers can be made. Those skilled in the art will print that various modifications are possible without departing from the scope of the invention and the present invention is limited to the following claims.
    权利要求:
    Claims (50)
    [1" claim-type="Currently amended] In the construction of a biodegradable block interpolymer drug transport system having the property of forming a gel by reversible heat;
    (a) the interpolymer contains an effective amount of the drug;
    (b) biodegradable block interpolymers
    (i) a hydrophobic A block selected from poly (α-hydroxy acid) and poly (ethylene carbonate);
    (ii) a biodegradable block interpolymer drug transport system comprising hydrophilic B blocks composed of polyethylene glycol.
    [2" claim-type="Currently amended] The block interpolymer drug transport system according to claim 1, wherein the hydrophilic polyethylene glycol polymer block has an average molecular weight of 1000 to 20,000 and comprises at least 50% of the weight of the block interpolymer.
    [3" claim-type="Currently amended] 3. The block interpolymer drug transport system according to claim 2, wherein the hydrophilic polyethylene glycol polymer block comprises 50 to 85% of the weight of the block interpolymer and the hydrophobic block consists of 15 to 50% of the weight of the block interpolymer.
    [4" claim-type="Currently amended] 4. The block interpolymer drug transport system according to claim 3, wherein the hydrophobic A polymer block is poly (α-hydroxy acid).
    [5" claim-type="Currently amended] The method of claim 4, wherein the poly (α-hydroxy acid) is selected from poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly ( 1-lactide-co-glycolide), poly (ε-caprolactone), poly (γ-butylarolactone), poly (δ-valerolactone), poly (ε-caprolactone-co-lactic acid), Characterized in that it is selected or derived from poly (α-hydroxy acid), hydroxybutyl acid, malic acid and di- or tripolymers derived from poly (ε-caprolactone-co-glycolic acid-co-lactic acid) Block Interpolymer Drug Transport System.
    [6" claim-type="Currently amended] 6. The block interpolymer drug transport system according to claim 5, wherein the poly (α-hydroxy acid) polymer block has an average molecular weight of about 500 to 10,000.
    [7" claim-type="Currently amended] 7. The block interpolymer drug transport according to claim 6, wherein the average molecular weight of the hydrophobic poly (α-hydroxy acid) polymer A block is about 500 to 3,000 and the average molecular weight of the hydrophilic polyethylene glycol polymer B block is about 1,000 to 5,000. system.
    [8" claim-type="Currently amended] 7. The block interpolymer drug transport system according to claim 6, wherein the block interpolymer is a triple block interpolymer of the type selected from ABA and BAB block fragments.
    [9" claim-type="Currently amended] 9. The hydrophobic A block fragment according to claim 8, wherein the hydrophobic A block fragment comprises poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly (1-lactide) block copolymer drug transport system comprising a poly (α-hydroxy acid) selected from -co-glycolide).
    [10" claim-type="Currently amended] 10. The block interpolymer drug transport system according to claim 8, wherein the hydrophobic A block fragment comprises a poly (α-hydroxy acid) composed of poly (ε-caprolactone).
    [11" claim-type="Currently amended] 4. The block interpolymer drug transport system according to claim 3, wherein the hydrophobic A block fragment is poly (ε-caprolactone) having an average molecular weight of 200 to 10,000.
    [12" claim-type="Currently amended] 12. The block interpolymer drug transport system according to claim 11, wherein the hydrophobic poly (ethylene carbonate) polymer A block has an average molecular weight of about 200 to 3,000 and the hydrophilic polyethylene glycol polymer B block has an average molecular weight of 1,000 to 5,000. .
    [13" claim-type="Currently amended] 12. The block interpolymer drug transport system according to claim 8 or 11, wherein the drug is a polypeptide.
    [14" claim-type="Currently amended] The method of claim 13, wherein the polypeptide is oxytocin, vasopressin, corticosteroids, epidermal growth factor. Platelet induced growth factor (PDGF), prolactone, luriberine or progesterone releasing hormone, growth hormone, growth hormone releasing hormone, insulin, somatostatin, glucagon, interleukin-2 (IL-2), Interferon-α, β, γ (IFN-α, β, γ), gastrin, tetragastrin, pentagastrin, urogastrin, secretin, calcitonin , Enkephalins, endorphins, angiotensins, anthyroid releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (G-CSF), granulocyte-colony stimulating factor (GM) -CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), renin, bradykinin, bacitracins, polymyxin (polymixins), colistins, tyrocidin, gramicidines and their synthetic analogs, modifications And pharmaceutically active fragments, and monoclonal antibodies and soluble block copolymer drug delivery system being selected from the vaccine.
    [15" claim-type="Currently amended] 12. The block interpolymer drug transport system according to claim 8 or 11, wherein the drug is an anticancer agent.
    [16" claim-type="Currently amended] The anticancer agent according to claim 15, wherein the anticancer agent includes adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, daunorubicin, A block interpolymer drug transport system, characterized in that it is selected from 5-fluorouracil, mettrexate, taxol, taxotere, actinomycin D.
    [17" claim-type="Currently amended] In the construction of an injectable biodegradable block interpolymer drug transport liquid having the property of forming a gel by reversible heat;
    (a) the interpolymer contains an effective amount of the drug;
    (b) biodegradable block interpolymers
    (i) a hydrophobic A block selected from poly (α-hydroxy acid) and poly (ethylene carbonate);
    (ii) an injectable biodegradable block interpolymer drug transport liquid, comprising a hydrophilic B block composed of polyethylene glycol.
    [18" claim-type="Currently amended] 18. The injectable drug transport liquid according to claim 17, wherein the liquid contains 3 to 40 wt% of the content of the drug and the polymer.
    [19" claim-type="Currently amended] 19. The injectable drug transport liquid of claim 18, wherein the hydrophilic polyethylene glycol polymer block has an average molecular weight of 1000 to 20,000 and comprises at least 50% of the weight of the block interpolymer.
    [20" claim-type="Currently amended] 20. The liquid for injection drug delivery according to claim 19, wherein the hydrophilic polyethylene glycol polymer block comprises 50 to 85% of the weight of the block interpolymer and the hydrophobic block comprises 15 to 50% of the weight of the block interpolymer.
    [21" claim-type="Currently amended] 21. The injectable drug transport liquid according to claim 20, wherein the hydrophobic A polymer block is poly (α-hydroxy acid).
    [22" claim-type="Currently amended] The method of claim 21, wherein the poly (α-hydroxy acid) is selected from poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly ( 1-lactide-co-glycolide), poly (ε-caprolactone), poly (γ-butylarolactone), poly (δ-valerolactone), poly (ε-caprolactone-co-lactic acid), Characterized in that it is selected or derived from poly (α-hydroxy acid), hydroxybutyl acid, malic acid and di- or tripolymers derived from poly (ε-caprolactone-co-glycolic acid-co-lactic acid) Liquid for transport of drug for injection.
    [23" claim-type="Currently amended] 23. The liquid for injection drug delivery according to claim 22, wherein the poly (α-hydroxy acid) polymer block has an average molecular weight of about 500 to 10,000.
    [24" claim-type="Currently amended] 24. The method of claim 23, wherein the average molecular weight of the hydrophobic poly (α-hydroxy acid) polymer A block is about 500 to 3,000 and the average molecular weight of the hydrophilic polyethylene glycol polymer B block is about 1,000 to 5,000. Liquid.
    [25" claim-type="Currently amended] 24. The injectable drug transport liquid of claim 23, wherein the block interpolymer is a triple block interpolymer of the type selected from ABA and BAB block fragments.
    [26" claim-type="Currently amended] The hydrophobic A block fragment according to claim 25, wherein the hydrophobic A block fragment comprises poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly (1-lactide) -co-glycolide), comprising a poly (α-hydroxy acid) selected for injectable drug transport liquid.
    [27" claim-type="Currently amended] 27. The injectable drug transport liquid according to claim 25, wherein the hydrophobic A block fragment comprises poly ( -Hydroxy acid) composed of poly ( -Caprolactone).
    [28" claim-type="Currently amended] 21. The injectable drug transport liquid according to claim 20, wherein the hydrophobic A block fragment is poly (ε-caprolactone) having an average molecular weight of 200 to 10,000.
    [29" claim-type="Currently amended] 29. The injectable drug transport liquid of claim 28, wherein the hydrophobic poly (ethylene carbonate) polymer A block has an average molecular weight of about 200 to 3,000 and the hydrophilic polyethylene glycol polymer B block has an average molecular weight of 1,000 to 5,000. .
    [30" claim-type="Currently amended] 29. An injectable drug transport liquid according to claim 25 or 28, wherein the drug is a polypeptide.
    [31" claim-type="Currently amended] 31. The polypeptide of claim 30, wherein the polypeptide is oxytocin, vasopressin, corticosteroids, epidermal growth factor. Platelet induced growth factor (PDGF), prolactone, luriberine or progesterone releasing hormone, growth hormone, growth hormone releasing hormone, insulin, somatostatin, glucagon, interleukin-2 (IL-2), Interferon-α, β, γ (IFN-α, β, γ), gastrin, tetragastrin, pentagastrin, urogastrin, secretin, calcitonin , Enkephalins, endorphins, angiotensins, anthyroid releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (G-CSF), granulocyte-colony stimulating factor (GM) -CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), renin, bradykinin, bacitracins, polymyxin (polymixins), colistins, tyrocidin, gramicidines and their synthetic analogs, modifications And pharmaceutically active fragments, and monoclonal antibodies and soluble injectable drugs for liquid transport, characterized in that selected from the vaccine.
    [32" claim-type="Currently amended] 29. A liquid for injection drug delivery according to claim 25 or 28, wherein the drug is an anticancer agent.
    [33" claim-type="Currently amended] 33. The anticancer agent according to claim 32, wherein the anticancer agent comprises adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, daunorubicin, Injectable drug transport liquid, characterized in that selected from 5-fluorouracil (fluorouracil), mettrexate, taxol (taxol), taxotere, actinomycin (D).
    [34" claim-type="Currently amended] A method of transporting a drug encapsulated in a gel depot and a liquid biodegradable polymer matrix for controlled release of a drug to a warm-blooded animal via a parenteral route of administration;
    1) An injectable biodegradable block interpolymer drug transport liquid having reversible thermal gel-forming properties, wherein the following components are homogeneously
    (a) the interpolymer contains an effective amount of the drug;
    (b) biodegradable block interpolymers
    (i) a hydrophobic A block selected from poly (α-hydroxy acid) and poly (ethylene carbonate);
    (ii) consists of a hydrophilic B block composed of polyethylene glycol
    2) maintaining a liquid phase at a temperature below the LCST of the block interpolymer; And
    3) Injecting liquid through a parenteral route into a warm-blooded animal, and the drug and biodegradable block polymer form a gel depot when the temperature of the liquid rises due to the body temperature of the animal above the LCST of the interpolymer. Parenterally administering the drug in a biodegradable block interpolymer.
    [35" claim-type="Currently amended] 35. The method of claim 34, wherein the content of drug and polymer in the liquid is 3-40 wt%.
    [36" claim-type="Currently amended] 36. The method of claim 35, wherein the hydrophilic polyethylene glycol polymer block has an average molecular weight of 1000 to 20,000 and comprises at least 50% of the weight of the block interpolymer.
    [37" claim-type="Currently amended] 37. The method of claim 36, wherein the hydrophilic polyethylene glycol polymer block comprises 50-85% of the weight of the block interpolymer and the hydrophobic block consists of 15-50% of the weight of the block interpolymer.
    [38" claim-type="Currently amended] 38. The method of claim 37, wherein the hydrophobic A polymer block is poly (α-hydroxy acid).
    [39" claim-type="Currently amended] The method of claim 38, wherein the poly (α-hydroxy acid) is selected from poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly ( 1-lactide-co-glycolide), poly (ε-caprolactone), poly (γ-butylarolactone), poly (δ-valerolactone), poly (ε-caprolactone-co-lactic acid), Characterized in that it is selected or derived from poly (α-hydroxy acid) derived from poly (ε-caprolactone-co-glycolic acid-co-lactic acid), hydroxybutyl acid, dried acid and di- or tripolymers How to.
    [40" claim-type="Currently amended] 40. The method of claim 39, wherein the poly (α-hydroxy acid) polymer block has an average molecular weight of about 500 to 10,000.
    [41" claim-type="Currently amended] 41. The method of claim 40, wherein the average molecular weight of the hydrophobic poly (α-hydroxy acid) polymer A block is about 500 to 3,000 and the average molecular weight of the hydrophilic polyethylene glycol polymer B block is about 1,000 to 5,000.
    [42" claim-type="Currently amended] 41. The method of claim 40, wherein the block interpolymer is a triple block interpolymer of the type selected from ABA and BAB block fragments.
    [43" claim-type="Currently amended] 41. The hydrophobic A block fragment according to claim 40, wherein the hydrophobic A block fragment comprises poly (d, 1-lactide), poly (1-lactide), poly (d, 1-lactide-co-glycolide), poly (1-lactide) poly (α-hydroxy acid) selected from -co-glycolide).
    [44" claim-type="Currently amended] 43. The method of claim 42, wherein the hydrophobic A block fragment comprises poly (α-hydroxy acid) composed of poly (ε-caprolactone).
    [45" claim-type="Currently amended] 38. The method of claim 37, wherein the hydrophobic A block fragment is poly (ε-caprolactone) having an average molecular weight of 200 to 10,000.
    [46" claim-type="Currently amended] 46. The method of claim 45, wherein the hydrophobic poly (ethylene carbonate) polymer A block has an average molecular weight of about 200 to 3,000 and the hydrophilic polyethylene glycol polymer B block has an average molecular weight of 1,000 to 5,000.
    [47" claim-type="Currently amended] 46. The method of claim 42 or 45, wherein the drug is a polypeptide.
    [48" claim-type="Currently amended] 48. The method of claim 47, wherein the polypeptide is oxytocin, vasopressin, corticosteroids, epidermal growth factor. Platelet induced growth factor (PDGF), prolactone, luriberine or progesterone releasing hormone, growth hormone, growth hormone releasing hormone, insulin, somatostatin, glucagon, interleukin-2 (IL-2), Interferon-α, β, γ (IFN-α, β, γ), gastrin, tetragastrin, pentagastrin, urogastrin, secretin, calcitonin , Enkephalins, endorphins, angiotensins, anthyroid releasing hormone (TRH), tumor necrosis factor (TNF), nerve growth factor (G-CSF), granulocyte-colony stimulating factor (GM) -CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), macrophage-colony stimulating factor (M-CSF), renin, bradykinin, bacitracins, polymyxin (polymixins), colistins, tyrocidin, gramicidines and their synthetic analogs, modifications And pharmaceutically active fragments, and wherein the selected from monoclonal antibodies and soluble vaccines.
    [49" claim-type="Currently amended] 46. The method of claim 42 or 45, wherein the drug is an anticancer agent.
    [50" claim-type="Currently amended] 50. The anticancer agent according to claim 49, wherein the anticancer agent includes adriamycin, mitomycin, bleomycin, cisplatin, carboplatin, doxorubicin, daunorubicin, daunorubicin, 5-fluorouracil, mettrexate, taxol, taxotere, actinomycin D.
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    同族专利:
    公开号 | 公开日
    JP4187789B2|2008-11-26|
    AU7520096A|1997-05-15|
    DE69632593D1|2004-07-01|
    ZA9608944B|1997-07-21|
    AR004522A1|1998-12-16|
    JPH11513985A|1999-11-30|
    EP0863745B1|2004-05-26|
    KR100447244B1|2004-12-31|
    EP0863745A1|1998-09-16|
    US5702717A|1997-12-30|
    WO1997015287A1|1997-05-01|
    EP0863745A4|1999-12-22|
    AT267584T|2004-06-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-10-25|Priority to US08/548,185
    1995-10-25|Priority to US08/548,185
    1995-10-25|Priority to US8/548,185
    1996-10-25|Application filed by 젠터 게렌 엠., 마크로메드 인코퍼레이션
    1999-08-16|Publication of KR19990067013A
    2004-12-31|Application granted
    2004-12-31|Publication of KR100447244B1
    优先权:
    申请号 | 申请日 | 专利标题
    US08/548,185|1995-10-25|
    US08/548,185|US5702717A|1995-10-25|1995-10-25|Thermosensitive biodegradable polymers based on polyblock copolymers|
    US8/548,185|1995-10-25|
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