• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:
    In accordance with the present invention, a liquid polymeric composition comprising a polymer such as a poly (lactide-co-glycolide) copolymer in a mixture of a hydrophilic solvent and a lipophilic solvent can be used for a long time and without "sudden" drug release. Achieve controlled release of hydrophobic bioactive materials in vivo.
    公开号:KR20010041987A
    申请号:KR1020007010314
    申请日:1999-03-18
    公开日:2001-05-25
    发明作者:체른레이티.；징거맨조엘알.
    申请人:폴락 돈나 엘.；머크 앤드 캄파니 인코포레이티드；
    IPC主号:
    专利说明:

    Liquid polymeric compositions for controlled release of bioactive substances
    Biodegradable polymers have been used as parenteral release controlling agents for bioactive compounds. In one solution, the polymer is broken down into microspheres that can be injected through a syringe and the bioactive compound is trapped in the microspheres. This solution has proved impractical, in part because of the difficulty in producing reproducible products sterilized in the manufacturing process and the high cost in the preparation. In another solution, the biodegradable polymer and bioactive material are dissolved in a biocompatible water miscible solvent to provide a liquid composition. When the liquid composition is injected into the body, the solvent diffuses around the aqueous environment and the polymer forms a solid reservoir from which the bioactive material is released.
    European patent application 0537559 relates to polymeric compositions having thermoplastic polymers, rate controlling agents, water soluble bioactive materials and water miscible organic solvents. Upon exposure to an aqueous environment (eg, body fluid), the liquid composition may form a biodegradable microporous solid polymer matrix for controlling release of water-soluble or dispersible bioactive materials for at least about four weeks. Thermoplastic polymers can be polylactide, polyglycolide, polycaprolactone or copolymers thereof, among many listed, and are used at high concentrations (45-50%). The rate controlling agent may be glycerol triacetate (triacetin) among many others on the list, but only ethyl heptanoate is exemplified and the amount of rate controlling agent is 15% or less.
    Furthermore, the following references are mentioned with respect to this patent document.
    U.S. Patent Number inventor No. 4,150,108 Graham No. 4,329,332 Couvreur, etc. No. 4,331,652 Ludwig, etc. No. 4,333,919 Kleber, etc. No. 4,389,330 Tees, etc. No. 4,489,055 Coober etc No. 4,526,938 Churchill, etc. No. 4,530,840 Teeth etc No. 4,542,025 Teeth etc No. 4,563,489 Urist No. 4,675,189 Kent, etc. No. 4,677,191 Tanaka etc. No. 4,683,288 Tanaka etc. No. 4,758,435 Schaaf No. 4,857,335 Spring No. 4,931,287 Bae, etc. No. 5,178,872 Ohtsubo, etc. No. 5,252,701 Jarrett, etc. No. 5,275,820 Chang No. 5,478,564 Vantier, etc. No. 5,540,912 Roorda, etc. No. 5,447,725 Damani, etc. No. 5,599,852 Scopelianos, etc. No. 5,607,686 Totakura, etc. No. 5,609,886 Bantier No. 5,631,015 Bezwada, etc. No. 5,654,010 Herbert and others No. 5,700,485 Johnson, etc. 5,702,717 Verde, etc. No. 5,711,968 Tracy, etc. No. 5,733,566 Lewis No. 4,938,763 Dunn and others No. 5,077,049 Dawn and so on No. 5,278,201 Dawn and so on
    No. 5,278,202 Dawn and so on No. 5,288,496 Louis No. 5,324,519 Dawn and so on No. 5,324,520 Dun etc No. 5,340,849 Dawn and so on No. 5,368,859 Dawn and so on No. 5,401,507 Louis No. 5,419,910 Louis No. 5,427,796 Louis No. 5,487,897 Polson, etc. No. 5,599,552 Dun etc No. 5,632,727 Tipton, etc. No. 5,643,595 Louis No. 5,660,849 Paulson and others No. 5,686,092 Lewis and others 5,702,716 Dun etc No. 5,707,647 Dun etc No. 5,717,030 Dun etc No. 5,725,491 Tipton etc. No. 5,733,950 Dun etc No. 5,736,152 Dun etc No. 5,744,153 Yewey, etc. No. 5,759,563 Yewei and others No. 5,780,044 Yewei and others
    These documents tend to provide compositions that form solids, gels or aggregated masses, for example significant amounts of polymers are contemplated in these documents, similar to European Patent Application No. 0537559.
    Shah et al. Also disclose sustained release formulations of bioactive compounds containing varying concentrations of poly (lactic-co-glycolic) acid copolymers (PLGA) dissolved in excipients such as triacetin. J. Controlled Release, 1993, 27: 139-147; Lambert and Peck, who studied the release of protein from a 20% PLGA solution in N-methylpyrrolidone exposed to an aqueous fluid, see J. Controlled Release, 1995, 33: 189. -195; And solubility parameters of poly (lactide-co-glycolide) copolymers in various solvents and naltrexone (57% PLGA and 38% N-methylpyrrolidone or 35% PLGA from two injectable implants). And Shivley et al., J. Controlled Release, 1995, 33: 237-243, which studied on in vivo release of 5% naltrexone in 60% N-methylpyrrolidone). do.
    Nevertheless, there is a need for long-term sustained release compositions as well as polymeric compositions capable of forming membrane coated or encapsulated liquids.
    In contrast to the preceding compositions, surprisingly, polymeric compositions containing substantially excess water immiscible or lipophilic solvents and substantially fewer polymers than intended in the literature can be prepared in solid, gel or aggregated mass ( It has been found that there is a tendency to remain as a membrane coated (encapsulated) liquid rather than to form "pore-containing" solids, including gels or lumps). The use or amount of lipophilic solvent used in the liquid polymeric formulations of the present invention and the low content of the polymer do not appear to have been considered in the prior art.
    Accordingly, it is an object of the present invention, among other things, to provide a liquid polymeric composition comprising, for example, a bioactive material which has a long lasting sustained release and / or forms a liquid coated or encapsulated. It is to provide a method for preparing or using the composition.
    The present invention provides a liquid polymeric composition; For example, a composition for controlling the release of one or more bioactive materials (eg, one or more hydrophobic biomaterials), such as, for example, may form a membrane encapsulated liquid in situ and / or have a high efficiency (about 70%). Plasma profile showing greater than, for example, at least about 80%, preferably at least about 90%, for example, at least about 100% for at least about 12 months) and / or at least about 50 days or at least about 60 days Or about 2 months or more or about 8 weeks or more, such as about 90 days or more or about 3 months or more or about 12 weeks or about 120 days or about 4 months or more or about 16 weeks or about 150 days or more In a patient or host (eg, animal or human), such as a delayed plasma level for at least about 5 months or at least about 20 weeks or even longer, for example, for about 1 year or more, eg, 1 to 12 months or more. To achieve long-term sustained release Liquid polymeric composition].
    The present invention further provides 1-30% w / v of one or more bioactive materials (eg, hydrophobic bioactive materials); 1-20% w / v of one or more biologically acceptable "polymers" (2) (polymers in which two or more comonomers are polymerized, including "copolymers"), e.g., for bioactive materials The weight ratio of the polymer is 1: 1 or less, eg, 0.5: 1 to 1: 1); And mixtures of one or more hydrophilic solvents with one or more lipophilic solvents (eg, one or more biologically or physiologically or medically or veterinarily acceptable hydrophilic solvents and one or more biologically or physiologically or medically Or veterinary acceptable lipophilic solvent), wherein the volume ratio of the hydrophilic solvent to the lipophilic (or hydrophobic) solvent is about 80:20 to about 0: 100, for example, about 80:20 to about 10:90 Or 5:95, hydrophilic and lipophilic solvents, for example, from about 65:35 to about 35:65 and / or at least about 16.5 weight percent (e.g., about 16.465 weight percent) of the water immiscible or lipophilic solvent ), For example, about 16.5 to about 45 weight percent, for example, about 16.5 to about 30 weight percent or more (eg, about 29 weight percent or more) or one or more about 20 weight percent or about 25 to about 30 weight percent , 35%, 40% or 45%, or 40 weights % Excess (e. G., About 42 to 45% by weight or more) liquid polymeric composition comprising; For example, less than 10% polymer and 1-10% bioactive material or less than about 7% (eg 6.7%) or less than 5% polymer and less than about 10% or 5% bioactive material. It relates to a composition to contain.
    The present invention further relates to a liquid polymeric composition consisting essentially of the above mentioned, wherein the liquid polymeric composition is capable of forming a membrane encapsulated liquid, for example in situ, and / or The term "consisting essentially of", which may have sustained release, is used in the sense referred to in the patent literature and excludes terms for ingredients which may interfere with the ability of the composition to form a membrane encapsulated liquid. Thus, for example, agents that have a composition that has one or more opposing properties in situ, such as agents that tend to solidify the composition (eg, curing agents) or agents that tend to form pores May not be required in certain embodiments.
    The present invention provides methods of making such compositions and uses thereof. For example, the preparation method includes the steps of mixing the aforementioned components; For example, preferably dissolving both the polymer and the bioactive material (which is not essentially excluded from the present invention, but may be less preferably dissolved, as opposed to having, suspending and encapsulating the bioactive material as a solid). There is a method for producing such a composition comprising a). Alternatively, there is a method of using such a composition comprising administering a composition of the invention to a patient or host [an animal (eg, a mammal, such as a domestic animal), such as a pet or a domestic animal, or a human]. .
    The present invention further provides a method consisting essentially of one or more steps for preparing or using such a composition, wherein the liquid polymeric composition can, for example, form a membrane encapsulated liquid in situ; Or have sustained sustained release, wherein the term “consisting essentially of” is used in the sense used in the patent literature and excludes terms relating to ingredients that may interfere with the ability of the composition to form a membrane encapsulated liquid. Thus, for example, the step of making the composition have one or more opposite properties in situ, such as adding an agent to solidify the composition (eg, a curing agent) or an agent to form pores, is a particular embodiment. May not be required.
    Bioactive materials can be several biological agents that can provide a biological, physiological or therapeutic effect in an animal or human. The biologically active agent may be one or more known biologically active agents cited herein or recognized in the art. The formulations may also stimulate or inhibit the desired biological or physiological activity in an animal or human, but may also stimulate an immunogen or immunological response without limitation.
    Accordingly, the present invention provides membrane coated or encapsulated liquid implants formed in situ that can act as a delivery system to tissues adjacent to or away from the implant site for drugs, drugs, and other biologically active agents. The biologically active agent is preferably incorporated into a membrane coated or encapsulated liquid and subsequently released into surrounding tissue fluid and appropriate body tissues or organs. The composition can be administered to the implantation site in some suitable way for injecting liquids, such as, for example, syringes, needles, cannulas, catheters and pressure applicators.
    Exemplary biologically active agents or bioactive agents include fipronil, avermectin, ivermectin, eprinomectin, milbamycin, phenylpyrazole, nodulisporic acid, estradiol benzoate, tremblon acetate, norrestis Theron, progesterone, antibiotics (eg macrolide or azalide antibiotics), or nonsteroidal anti-inflammatory drugs (NSAIDs) or combinations thereof.
    Thus, while the object of the present invention is to deliver one or more active ingredients regardless of whether the ingredients are water insoluble or water miscible, the invention is particularly applicable to biologically active substances which are hydrophobic.
    Biologically acceptable polymers may be some biologically acceptable polymers, such as biologically acceptable polymers recognized in the literature cited herein. For example, a biologically acceptable polymer may have one or more or all of the following characteristics: properties that become bioerodible by cellular action, properties that biodegrade by the action of non-living fluid components, exposure to heat Can be substantially dissolved or dispersed in water-miscible carriers or solvents and in a property that softens if present, but returns to its original state when cooled, to form a solution or dispersion. Upon contact with the aqueous fluid, the polymer may assist in the formation of a membrane coated or encapsulated liquid. Kinds of polymers suitable for the composition generally include polymers having the above properties. Examples thereof include polylactide, polyglycolide, polycaprolactone, anhydrous polymer, polyamide, polyurethane, polyesteramide, polyorthoester, polydioxanone, polyacetal, polyketal, polycarbonate, polyorthocarbonate , Polyphosphazene, polyhydroxybutyrate, polyhydroxy valerate, polyalkylene oxalate, polyalkylene succinate, poly (malicaside), poly (amino acid), poly (methyl vinyl ether), poly (anhydrous) Maleic acid), chitin, chitosan and copolymers, terpolymers or combinations or mixtures thereof. Polylactide, polycaprolactone, polyglycolide and copolymers thereof are preferred copolymers and poly (lactide-co-glycolide) copolymers ("PLGA") are very preferred. The construction of the PLGA may be similar to that used in the examples below or in the literature cited herein.
    The solvent may be a solvent that is biologically or physiologically or medically or veterinarily hydrophobic and water miscible, as recognized in the literature cited herein.
    Hydrophilic solvents include propylene glycol, PEG, polyglycols (e.g. polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400), di (ethylene glycol) ethyl ether (transcutol), isopropylidene glycerol (solketal), dimethyl isosorb Beads (arlasolve DMI), propylene carbonate, glycerol, glycofural, pyrrolidone (e.g. N-methyl pyrrolidone and 2-pyrrolidone), isopropylidene glycerol, di (propylene glycol) methyl ether and these It can be selected from a mixture of. Other solvents may also be useful as hydrophilic solvents. For example, hydrophilic solvents include C 2 to C 6 alkanols (e.g. ethanol, propanol, butanol), acetone, alkyl esters (e.g. methyl acetate, ethyl acetate, ethyl lactate), alkyl ketones (e.g. methyl ethyl ketone ), Dialkylamides (e.g. dimethylformamide), dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, cyclic alkyl amides (e.g. caprolactam), decylmethylsulfoxide, oleic acid, propylene carbonate, aromatic amides (e.g. N, N-diethyl-m-toluamide) and 1-dodecylazacycloheptan-2-one. The hydrophilic solvent may be a mixture of solvents.
    The lipophilic or water immiscible or hydrophobic solvent can be selected from triethyl citrate, migliol 812, migliol 840, crodamol GTCC, triacetin or benzyl benzoate, and further lipophilic solvents, for example For example, hydrophobic rate modifiers or plasticizers such as fatty acids, triglycerides, triesters of glycerol, oils such as castor oil, soy milk or other vegetable oils or derivatives thereof such as epoxidized soy milk or hydrogenated castor oil Epoxidized or hydrogenated vegetable oils), sterols, higher alkanols (such as C 6 or higher), glycerin and the like.
    Other solvents include glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, di (ethylene glycol) ethyl ether acetate, di (propylene glycol) methyl ether [Dowanol ) DPM], di (propylene glycol) methyl ether acetate, glycerol formal, glycolfurol, isopropyl myristate, N, N-dimethyl acetamide, PEG 300, propylene glycol and polar, nonpolar solvents such as DMSO can do.
    In certain embodiments, there may be less than 10% polymer and 1-10% active compound, for example, the ratio of PLGA polymer to active compound is 1: 1 or less (e.g., 0.25 75/25 PLGA Dissolved in glycerol formal to give 2.5 mL of solution, in separate flasks 75/25 PLGA dissolved in triacetin to give 2.5 mL of solution 2 solutions mixed and 0.50 g dissolved in mixed PLGA solution Is added to a flask containing the active ingredient of the agent, the amount of traacetin present in the formulation is about 42% by weight, the other formulation contains as little as PLGA contents of 6.7% and 5% and the content of the drug is 10% or See Example 5%).
    When implanted, ie injected, the liquid formulations of the present invention form "semi-solid reservoirs with a sheath of polymer" from the overall examination of the host or patient to which the formulation is implanted. Although not necessarily limited to one particular theory, the reservoir is not necessarily a solid or semi-solid (as the term is commonly understood), but rather a membrane-coated or encapsulated liquid (polymer that helps to form the envelope). Over time, the reservoir loses its excipient (solvent) and decomposition of the polymer occurs.
    Although diffuse through the membrane (typically white in a preferred embodiment), no pores are present in the reservoir, and the liquid polymeric formulation is unlikely to form solid or aggregated or gelatinous masses in situ. This belief is that the amount of polymer in the formulations of the present invention is substantially less than that used in the prior art, and the amount of water immiscible or lipophilic solvent present in the formulations of the present invention is substantially less than that used in the prior art. It is based on the fact that the polymer is biodegradable by dispersing more than a rate regulator "or similar solvent (which leaves the core of the reservoir in a liquid state) and the active ingredient is dispersed through the membrane (white thin film in a preferred embodiment). The formulations of the present invention are well suited for delivery lipophilic (hydrophobic) active ingredients.
    These and other aspects are described or are apparent from and included by the following detailed description.
    The present invention provides a liquid polymeric composition; For example, compositions for controlling the release of one or more bioactive substances (eg, one or more hydrophobic bioactive substances), for example, can form a membrane encapsulated liquid in situ and / or have high efficiency. A plasma profile and / or about 50 days or more showing (efficiency of greater than about 70%, eg, at least about 80%, preferably at least about 90%, for example, at least about 100% for at least about 12 months) and / or At least about 60 days or at least about 2 months or at least about 8 weeks, such as at least about 90 days or at least about 3 months or at least about 12 weeks or at least about 120 days or at least about 4 months or at least about 16 weeks or about Patients or hosts (eg, animals, such as delayed plasma levels of at least 150 days or at least about 5 months or at least about 20 weeks or even longer, for example, for about 1 year or more, eg, 1 to 12 months). Or can be sustained sustained release) It relates to liquid polymeric compositions; to.
    The present invention further provides about 1 to 30% w / v of bioactive material 1 (eg hydrophobic bioactive material); About 1 to 20% w / v of a biologically acceptable "polymer" (2) (a polymer in which two or more comonomers are polymerized, including a "copolymer"), eg, a polymer for bioactive materials Weight ratio is less than or equal to 1: 1, eg, 0.3: 1 to 1: 1; And at least one lipophilic solvent or a mixture of a hydrophilic solvent and a lipophilic solvent, wherein the volume ratio of the hydrophilic solvent to the lipophilic solvent is from about 80:20 to about 0: 100, for example from about 80:20 to About 10:90 or 5:95, hydrophilic solvents and lipophilic solvents, for example, from about 65:35 to about 35:65 and / or about 16.5% by weight or more (eg, of water immiscible or lipophilic solvents) , Including about 16.465 weight percent), for example, about 16.5 to about 45 weight percent, for example, about 16.5 to about 30 weight percent or more (eg, about 29 weight percent or more) or greater than 40 weight percent (eg For example, at least about 42-45 weight percent); For example, less than 10% polymer and 1-10% bioactive material or less than about 7% (e.g., 6.7%) or less than 5% polymer and less than about 10% or less than 5% bioactive material. It relates to a composition to contain.
    The present invention further relates to a liquid polymeric composition consisting essentially of the abovementioned, wherein the liquid polymeric composition is capable of forming a membrane encapsulated liquid, for example, in situ and / or The term "consisting essentially of", which may have sustained release, is used in the sense referred to in the patent literature and excludes terms for ingredients which may interfere with the ability of the composition to form a membrane encapsulated liquid.
    The invention still further relates to methods of making such compositions and uses thereof. For example, the preparation method includes the steps of mixing the aforementioned components; For example, preferably dissolving both the polymer and the bioactive material (which is not essentially excluded from the present invention, but may be less preferably dissolved, as opposed to having, suspending and encapsulating the bioactive material as a solid). There is a method for producing such a composition comprising a). Alternatively, there is a method of using such a composition comprising administering a composition of the invention to a patient or host [an animal (eg, a mammal, such as a domestic animal), such as a pet or a domestic animal, or a human]. .
    Other technical fields to which these and the present invention relate are apparent from the following. Various documents are cited in the following documents without approval of the prior art of the present invention. All documents cited herein, as well as all documents referenced in the documents cited herein, are incorporated by reference.
    The following detailed description, given through the examples, is not intended to limit the invention to the particular embodiments described, but may be understood in conjunction with the accompanying drawings, which are incorporated herein by reference.
    1 is 6-amino-3-cyano-1- (2,6-dichloro-4-sulperpentafluorophenyl) -4- (trifluoro) in a dog treated with the formulation of Example 1 Plasma levels of methylthio) pyrazole are shown.
    FIG. 2 shows plasma levels of ivermectin in cattle treated with the three ivermectin formulations of Example 2. FIG.
    3 shows the plasma levels of eprinomectin in swine treated with the eprinomethin formulation of Example 3. FIG.
    The present invention provides a liquid polymeric composition for delivering bioactive substance (s).
    The present invention provides a liquid polymeric composition; For example, a composition for controlling the release of one or more bioactive materials (eg, one or more hydrophobic biomaterials), such as, for example, may form a membrane encapsulated liquid in situ and / or have a high efficiency (about 70%). Plasma profile showing greater than, for example, at least about 80%, preferably at least about 90%, for example, at least about 100% for at least about 12 months) and / or at least about 50 days or at least about 60 days Or about 2 months or more or about 8 weeks or more, such as about 90 days or more or about 3 months or more or about 12 weeks or about 120 days or about 4 months or more or about 16 weeks or about 150 days or more Prolonged in a patient or host (eg, an animal or a human), such as a delayed plasma level of at least about 5 months or at least about 20 weeks or even longer, for example, about 1 year or longer, eg, 1 to 12 months. Capable of sustained release Liquid polymeric composition].
    The present invention provides about 1 to 30% w / v of one or more bioactive materials (1) (eg hydrophobic bioactive materials); About 1-20% w / v of one or more biologically acceptable "polymers" (2) (polymers in which two or more comonomers are polymerized, including "copolymers"), e.g. The weight ratio of polymer to 1: 1 is, for example, 0.5: 1 to 1: 1); And one or more lipophilic solvents or mixtures of one or more hydrophilic solvents with one or more lipophilic solvents (eg, one or more biologically or physiologically or medically or veterinarily acceptable hydrophilic solvents and one or more biologically Or a physiological or medical or veterinary acceptable lipophilic solvent), wherein the volume ratio of the hydrophilic solvent to the lipophilic (hydrophobic) solvent is from about 80:20 to about 0: 100, for example about 80:20 To about 10:90 or about 80:20 to about 5:95, the hydrophilic and lipophilic solvents are, for example, about 65:35 to about 35:65 and / or about 16.5 to a water immiscible or lipophilic solvent. Or greater than or equal to about 1% by weight (eg, including about 16.465%), for example about 16.5 to about 45% or more, for example, about 16.5 to about 30% or more (eg, about 29% or more) or one or more 20 weight percent or about 25 to about 30 weight percent %, 35% by weight, 40% by weight or 45% by weight, or more than 40% by weight (eg, at least about 42-45% by weight); For example, less than 10% polymer and 1-10% bioactive material or less than about 7% (eg 6.7%) or less than 5% polymer and less than about 10% or 5% bioactive material. The composition containing is further provided.
    The present invention further provides a liquid polymeric composition consisting essentially of as mentioned above, wherein the liquid polymeric composition is capable of, for example, forming a membrane encapsulated liquid in situ and / or The term “consisting essentially of”, which may have sustained release, is used in the sense referred to in the patent literature and excludes terms for ingredients which may interfere with the ability of the composition to form a membrane encapsulated liquid. Thus, for example, an agent that tends to have one or more opposing properties in situ, such as an agent that tends to solidify the composition (e.g., a hardener) or an agent that forms pores May not be required in certain embodiments.
    The present invention further provides methods of making such compositions and uses thereof as discussed herein.
    Polymers and solvents used in the present invention can be discussed herein.
    The bioactive substance (s) may be some biological agent that can provide a biological, physiological or therapeutic effect in an animal or human. The biologically active agent may be one or more known biologically active agents cited herein or recognized in the art. The formulations may also stimulate or inhibit the desired biological or physiological activity in an animal or human, and may, without limitation, stimulate an immunogenic or immunological response.
    Implants formed in situ may also provide delivery systems for biologically active agents for adjacent or apart body tissues and organs. Biologically active agents that can be used alone or in combination in the compositions and implants can provide local or systemic biological or physiological activity in an animal, including a drug, medicament, or human, and are adjacent to or adjacent to the aqueous reservoir. Some suitable biological, physiological or pharmaceutically active substances that can be released into the fluid are included.
    The biologically active agent may be miscible in the polymer and / or solvent to provide a homogeneous mixture using the polymer or may be insoluble in the polymer and / or solvent for forming the suspension or dispersion using the polymer. It is highly desirable that the bioactive agent be combined with the remaining ingredients of the invention immediately prior to administering the composition to the implantation site. Bioactive agents are not water miscible, for example, it is desirable to be able to dissolve only a small amount in water, or to dissolve in water or into a lipophilic (hydrophobic) solvent. It is also preferred that the bioactive agent does not contain functional groups that interfere with the polymer. Such conditions are readily determined by those skilled in the art simply by partitioning the structure of the bioactive agent and the reactive moiety of the polymer.
    The composition and implants formed in situ contain an effective amount of a biologically active agent to effect a desired biological, physiological, pharmaceutical and / or therapeutic effect, optionally depending on the desired release profile, and / or delayed release time. to provide. It is also desirable to provide a solution or dispersion viscosity in which a biologically active agent is included in an effective amount of the polymer composition.
    Suitable biologically active agents include substances useful for preventing infection at the implant site, such as antiviral substances, antimicrobials, antiparasitic agents, antifungal substances and combinations thereof. The formulation may also be a substance that can act as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like. The delivery system may contain large amounts of biologically active agents, either singly or in combination. Examples of these biologically active agents include, but are not limited to, anti-inflammatory agents such as hydrocortisone, prednisone, fludrotisone, triamcinolone, dexamethasone, betamethasone, and the like. Antimicrobial agents include penicillin, cephalosporins, vancomycin, bacitracin, polymycin, tetracycline, chloramphenicol, erythromycin, streptomycin and the like. Antiparasitic agents include quinacrine, chloroquine and quinine. Antifungal agents include nystatin, gentamicin, myconazole, tolnaftate, undecylenic acid and salts thereof. Antiviral agents include vidarabine, acyclovir, ribaribine, amantadine hydrochloride, iododeoxyuridine, dideoxyuridine, interferon and the like. Antitumor agents include methotrexate, 5-fluorouracil, bleomycin, tumor necrosis factor, tumor specific antibodies associated with toxins, and the like. Analgesics include salicylic acid, salicylate esters and salts, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmethine, jomepilac and the like. Local anesthetics include cocaine, benzocaine, novocaine, lidocaine and the like. Vaccines or antigens, epitopes, and immunogens of human or animal variants include hepatitis, influenza, measles, mumps, rubella, haemophilus, diphtheria, tetanus, rabies, polio, as well as veterinary vaccines. Central nervous system agents include nerve stabilizers, sedatives, antidepressants, hypnotics, B-adrenergic blockers, dopamine, and the like. Growth factors include colony stimulating factor, epidermal growth factor, erythropoietin, fibroblast growth factor, nerve growth factor, human growth hormone, platelet induced growth factor, insulin type growth factor, and the like. Hormones include progesterone, estrogen, testosterone, follicle stimulating hormone, chorionic gonadotropin, insulin, endorphins, and somatotropin. Antihistamines include diphenhydramine, chlorpheneramine, chlorcycline, promethazine, cimetidine, terpenadine, and the like. Cardiovascular preparations include verapamil hydrochloride, digitalis, streptokinase, nitroglycerin paparepin, disopyramid phosphate, isosorbide dinitrate, and the like. Antiulcer preparations include cimetidine hydrochloride, sopropamide iodide, propanetelin bromide and the like. Bronchodilators include metaproternal sulfate, aminophylline, albuterol and the like. Vasodilators include theophylline, niacin, nicotinate esters, amynitrate, minoxydyl, diazooxide, nifedipine and the like.
    Bioactive agents for use in the formulations of the present invention are well known to the practitioner to which the present invention relates. Classes of bioactive agents contemplated by the formulations of the present invention include insecticides, tick repellents, parasitic killers, growth enhancers and oil-soluble nonsteroidal anti-inflammatory agents (NSAIDs). Specific classes of compounds included in these classes include, for example, avermectin, milbmycin, nodulisporic acid and derivatives thereof, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazole and COX-2 Inhibitors.
    Compounds of the avermectin and milbamycin family are potent pesticides and antiparasitic agents against a wide range of internal and external parasites. Compounds belonging to this class are natural products or semisynthetic derivatives thereof. The structures of these two classes of compounds are closely related, both of which share a complex 16-membered macrocyclic lactone ring, while milbamycin does not contain an aglycone substituent at the 13 position of the lactone ring. The natural product avermectin is described in US Pat. No. 4,310,519 to Albers-Schonberg et al., And the 22,23-dihydro avermectin compound is assigned to Chabala et al. Patent 4,199,569. For a general discussion of avermectins, including their use in humans and animals, see "Ivermectin and Abamectin", WC Campbell, ed., Springer-Verlag, New York (1989). do. In addition, bioactive agents, such as avermectin or ivermectin, can be used in combination with other bioactive agents, and U.S. Pat. No. 4,468,390 of Kitano in the formulation of avermectin, ivermectin and bioactive agents US Patent No. 5,824,653 to Beuvry et al., US Patent No. 4,283,400 to von Bittera et al., European Patent Application No. 0 007 812 A1 (June 2, 1980), UK Patent Specification No. 1 390 336 (April 9, 1975), European Patent Application No. 0 002 916 A2, New Zealand Patent No. 237 086 to Ancare, New Zealand Patent No. 176 193 (Bayer) (1975. 11.19).
    Naturally occurring milbamycins are described in U.S. Patent No. 3,950,360 to Aoki et al. And various cited references. "The Merck Index" 12 th ed., S. Budavari, Ed. Whitehouse Station, New Jersey (1996). Semisynthetic derivatives of these classes of compounds are well known in the art and include, for example, US Pat. No. 5,077,308, US Pat. No. 4,859,657, US Pat. No. 4,963,582, US Pat. No. 4,855,317, US Pat. No. 4,871,719. , U.S. Patent 4,874,749, U.S. Patent 4,427,663, U.S. Patent 4,310,519, U.S. Patent 4,199,569, U.S. Patent 5,055,596, U.S. Patent 4,973,711, U.S. Patent 4,978,677, U.S. Patent 4,920,148 It is.
    Nodulisporic acid and derivatives thereof are a class of tick repellents, antiparasitic agents, insecticides and repellents known to the practitioner in the art. These compounds are used to treat or prevent infections in humans and animals. These compounds are described, for example, in US Pat. No. 5,399,582 and WO 96/29073. In addition, the compounds may be administered in combination with other insecticides, parasitic killers and tick repellents. Such combinations include the above-mentioned parasitic agents, including ivermectin, avermectin and emamectin, as well as other agents such as thiabendazole, pevantel or morantel; Phenylpyrazoles such as fipronil; And insect growth regulators such as lufenuron. Such combinations are also contemplated in the present invention.
    In general, all classes of such pesticides can be used in the present invention. Examples of one of these classes include substituted pyridylmethyl derivatives such as imidacloprid. Formulations of this class are described, for example, in US Pat. No. 4,742,060 or European Patent Publication No. 892,060.
    Pyrazoles such as phenylpyrazole and N-arylpyrazole are another class of pesticides that have good insecticidal activity against all insect pests, including blood-sucking fests (eg mites, fleas) that are parasitic in animals. This class of agents kills insects by acting on the γ-butyric acid receptor of invertebrates. Such formulations are described, for example, in US Pat. No. 5,567,429, US Pat. No. 5,122,530, EP 295,117, and EP 846686 A1 (or US Patent Application No. 309,229 (1997. 11. 17, 1997). European Patent No. 9625045 (Nov. 30, 1996) of Banks, which is believed to be the same. It is within the skill of the practitioner to determine each compound that can be used in the formulation of the invention.
    Insect growth regulators are another class of insecticides or tick repellents that are also provided in the formulations of the present invention. Compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. All of these compounds act by interfering with the development or growth of insect pests. Insect growth regulators are described, for example, in US Pat. No. 3,748,356, US Pat. No. 3,818,047, US Pat. No. 4,225,598, US Pat. No. 4,798,837, and US Pat. No. 4,751,225, and European Patent Publication No. 179,022 or UK Patents. US 2,140,010. It is also within the skill of the practitioner to determine each compound that can be used in the formulation of the invention.
    Estrogens, progestins and androgens are associated with a class of chemical compounds that are also well known to practitioners in the art. In fact, estrogens and progestins are one of the most widely described drugs and are used alone or in combination as contraceptive or hormone replacement therapy in postmenopausal women, for example. Estrogens and progestins are either naturally occurring or made synthetically. Compounds of this class also include estrogen or progesterone receptor antagonists. Antiestrogens such as tamoxyphene and clomiphene are used to treat breast cancer and infertility. Antiprogesterone is used not only as a contraceptive and anticancer agent, but also to induce labor or to give birth artificially quickly.
    Androgens and antiandrogens are structurally related to estrogens and progestins when they are also biosynthesized from cholesterol. These compounds are based on testosterone. Androgens are used for hypogonadism and promote muscle development. Antiandrogens are used, for example, to manage prostate hyperplasia and baldness of carcinomas, acne and male patterns, and to suppress sexual impulses of sex offenders. Estrogens, progestins and androgens are described, for example, in "Goodman &Gilman's The Pharmacological Basis of Therapeutics" 9 th ed., JG Handman and L, Elimbird, eds., Ch. 57 to 60, pp. 1411-1485, McGraw Hill, New York (1996) or "Principles of Medicinal Chemistry," 2 nd ed., WO Foye, ed., Ch. 21, pp. 495-559, Lea & Febiger, Philadelphia (1981).
    Estrogens, progestins and androgens are also used in animal farming as growth inhibitors for food animals. It is known in the art that these classes of compounds act as growth promoting steroids in animals (eg cattle, sheep, pigs, poultry, rabbits, etc.). Delivery systems that promote the growth of animals are described, for example, in U.S. Patent 5,401,507, U.S. Patent 5,288,469, U.S. Patent 4,758,435, U.S. Patent 4,686,092, U.S. Patent 5,072,716, and U.S. Patent 5,419,910 It is described.
    NSAIDs are well known in the art. Classes of compounds belonging to this group include salicylic acid derivatives, p-aminophenol derivatives, indole and indene acetic acid, heteroaryl acetic acid, arylpropionic acid, anthranilic acid (phenamate), enolic acid and alkanones. NSAIDs exert their activity by interfering with prostaglandin biosynthesis by inhibiting cyclooxygenase irreversibly or by heating. Also included are COX-2 inhibitors that act by inhibiting COX-2 receptors. Compounds of this group have non-allergic, antipyretic and nonsteroidal anti-inflammatory properties. Compounds belonging to this class are described, for example, in Chapter 27 of Goodman and Gilman on pages 617 to 658 or Ch. 22 of Foye on pages 561 to 590, US Patent 3,896,145, US Patent 3,337,570, US Patent 3,904,682, US Patent 4,009,197, US Patent 4,223,299, US Patent 2,562,830, as well as the Merck It is listed in the specific formulations listed in the list of The Merck Index.
    Macrolides are a class of antibiotics that contain a multi-membered lactone ring that is bound to one or more deoxy sugars. Macrolides are generally bacteriostatic, but appear to sterilize at high concentrations for highly sensitive organisms. Macrolides are most effective against γ-positional moleworm and bacillus, although they have some activity against some γ-negative organisms. Macrolide exerts their bacteriostatic activity by inhibiting bacterial protein synthesis by reversibly binding to 50 S ribosomal subunits. See, "Goodman & Gilman's the Pharmacological Basis of Therapeutics," 9th ed., JG Hadman & LE Limbird. , eds., ch. 47, pp. 1135-1140, McGraw-Hill, New-York (1996).
    As a class, macrolides are colorless and generally crystalline. The compounds are generally stable in pure neutral solutions, but their stability in acid or base solutions is only limited. This is due to glycosidic bond hydrolysis in acids and lactone ring saponification in bases. See, "Principles of Medicinal Chemistry," 2nd ed., W. F. Foye, ed., Ch. 31, pp. 782-785, Lea & Febiger, Philadelphia (1981). Thus, there is a need for pharmaceutical or veterinary compositions for parenteral use (eg, intravenous, intramuscular, subcutaneous, administration of macrolide antibiotics).
    The bioactive agent of the present invention may be a macrolide in which macrolides are dissolved in many organic solvents but only slightly in water. Solutions of macrolides in organic solvent systems are used in human and veterinary practice for administration via intramuscular and subcutaneous routes.
    Macrolides as a class include erythromycin and derivatives thereof, as well as other derivatives such as azalides. Erythromycin (Mw 733.94 Dalton) is the common name for macrolide antibiotics produced by the growth of strains of Streptomyces erythreous. The mixture of three erythromycin A, B and C consists mostly of erythromycin A. Its chemical name is (3R * , 4S * , 5S * , 6R * , 7R * , 9R * , 11R * , 12R * , 13S * , 14R * )-4-[(2,6-dideoxy-3-C- Methyl-3-O-methyl-α-L-ribo-hexopyranosyl) -oxy] -14-ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexa Methyl-6-[[3,4,6-trideoxy-3- (dimethylamino) -β-D-xyllo-hexapyranosyl] oxy] oxacyclotetradecane-2,10-dione, (C 37 H 67 NO 13 ).
    Erythromycin has a wide and necessary bacteriostatic action against many γ-positive and some γ-negative bacteria, as well as other organisms including mycoplasma, spirokite, chlamydia and lycheechia. In humans, it has been found to be useful for treating various infections. It has been found to be widely used in veterinary medicine for the treatment of infectious diseases (eg pneumonia, mastitis, uterus, rhinitis and bronchitis in cattle, pigs, sheep).
    Other derivatives of erythromycin include carbomycin, clarithromycin, probemycin, luchomycin, midecamycin, mikamycin, miokamycin, oleandomycin, pristinamycin, rokitamycin, rosaramycin, leucine Tromycin, spiramycin, tyrosine, troleandomycin and virginiamycin. By using erythromymic acid, many of these derivatives exist as component mixtures. For example, carbomycin is a mixture of carbomycin A and carbomycin B. Lucomycin is present as a mixture of components A 1 , A 2 , A 3 , A 9 , B 1 -B 4 , U and V in various ratios. Component A 3 is also known as probemycin and lucomycin V is also known as myocomycin. The main components of midecamycin are midecamycin A and the minor ingredients are midecamycin A 2 , A 3 and A 4 . In addition, mikamycin is a mixture of a number of components mikamycin A and B. Mikamycin A is also known as Virginiamycin M 1 . Pristinamycin is the same pristine mycin I A , I B and I C as Virginiamycin B 2 , B 13 and B 2, respectively, and the same pristine mycin to Virginia mycin M 1 and 26,27-dihydroviramycin M 1 It consists of II A and II B. Spyramicin consists of three components, spiromycin I, II and III. Virginiamycin is composed of Virginiamycin S 1 and Virginiamycin M 1 . All these components can be used in the present invention. Sources of these macrolides are well known to physicians and are described in "The Merck Index", 12th ed., S. Budarari, ed., Merck & Co., Inc., Whitehouse Station, NJ (1996 )].
    Azalides are semisynthetic macrolide antibiotics related to erythromycin A and exhibit similar solubility properties. The structure of azithromycin is known. Useful azalide components are described in EP 508699, incorporated herein by reference. Corresponding basic and acid addition salts and ester derivatives of macrolide compounds are also contemplated for use in the present invention. These salts are formed from the corresponding organic or inorganic acid or base. These derivatives include conventional hydrochlorides, phosphates and acetates, propionate and butyrate esters. These derivatives have different names. For example, the phosphate salt of oleandomycin is matromycin, and the triacetyl derivative is troleandomycin. Lokitamycin is leucomycin V 4-B-butanoate, 3B-propionate.
    Other antibiotics can also be used as bioactive agents when practicing the present invention.
    Bioactive agents can be, for example, peptides or proteins. Biologically active agents can also promote the growth and survival of cells and tissues or substances or metabolic precursors thereof that can increase the activity of functionalizing cells (eg, blood cells, nerves, muscle, bone marrow, bone cells and tissues, etc.). Can be. For example, the biologically active agent can be a nerve growth promoter, such as gangliosides, phosphatidylserine, nerve growth factor, brain induced neurotrophic factor, fibroblast growth factor, and the like. To promote tissue growth, the biologically active agent can be a hard or soft tissue promoting substance or a combination thereof. Suitable tissue growth promoting agents include, for example, fibronectin (FN), endothelial cell growth factor (ECGF), chalky adjunct extract (CAE), human growth hormone (HGH), fascia membrane ligament cell growth factor, fibroblast growth factor (FGF), animal growth hormone, platelet-induced growth factor (PDGF), epidermal growth factor (EGF), protein growth factor interleukin-1 (IL-1), transforming growth factor (TGF. Β-2), insulin type growth factor II (ILGF-II), human α thrombin (HAT), bone induction factor (OIF), bone morphogenesis proteins (BMF) or proteins derived therefrom, mineral-loss bone matrices and their release factors. In addition, the preparation may be a bone growth promoting substance such as hydroxyapatite, tricalcium phosphate, diphosphoric acid, polyphosphoric acid, antiestrogens, sodium fluoride preparations, materials having a phosphate ratio to calcium similar to natural bone. The bone growth promoting substance may be, for example, in the form of bone fragments, bone crystals or small fractions of bone and / or teeth, synthetic hydroxyapatite or other suitable form. The formulation may further treat metabolic bone diseases such as abnormal calcium and phosphate metabolism, for example by inhibiting bone resorption, promoting bone mineral deposition, or inhibiting calcium deposition, for example, Benedict ( US Patent No. 4,939,131 to Benedict et al., US Patent No. 4,942,157 to Gall et al., US Patent No. 4,894,373 to Young et al., USA to Walsdorf et al. Patent 4,904,478, US Patent 4,911,931 to Baylink, US Patent 4,916,241 to Hayward, and US Patent 4,921,697 to Peterlik, et al. U.S. Patent 4,902,296 to Borlander et al., U.S. Patent 4,294,753 to Uryst, U.S. Patent 4,455,256 to Ulyst, U.S. Patent 4,526,909 to Ulyst, U.S. Patent No. 4,563,489 to Uyrst, U.S. Patent No. 4,596,574 to Ulyst, U.S. Patent No. 4,619,989 to Ulyst, U.S. Patent No. 4,761,471 to Ulyst, U.S. Patent Patent 4,789,732, U.S. Patent No. 4,795,804 to Uryst, and U.S. Patent No. 4,857,456 to Uryst are incorporated herein by reference.
    In addition, the biologically active agent or bioactive agent may be an anti-neoplastic agent, an anti-tumor agent or an anticancer agent.
    Biologically active agents can be, for example, in the form of uncharged molecules, molecular complexes, salts, ethers, esters, amides, or can include other forms of compositions that provide effective biological or physiological activity.
    For biologically active agents useful in practicing the present invention, the US patent and PCT application of Williams and Chern, filed September 14, 1998 ("Long Acting Injectabel Formulations Containing Hydrogenated Castor Oil") , US Patent No. 09/15277 and PCT Application No. US98 / 190 and US Application Serial No. 60 / 067,374, which are incorporated herein by reference.
    From the above, the bioactive agent can vary. Suitable amounts for use in the formulations according to the invention can be determined by those skilled in the art without undue experimentation from the knowledge in the art, and include herein considered factors that are commonly considered by those skilled in the medical, veterinary or pharmaceutical arts, For example, the species, age, weight, general health, sex of the host, patient, animal or human, treated state, LD 50 and other properties of the bioactive substance (s) are investigated.
    Thus, administration of the compositions of the present invention is ultimately accomplished according to the wisdom and findings of the attending health care professional (e.g. doctor or veterinarian, optionally a dentist) of a patient, host, animal or human. The choice of a particular composition depends on the adverse condition or condition to be treated, which is selected by the attending health care professional. It can be applied to tissue by syringe or other method for applying liquid. The amount and concentration of the composition administered to the patient, host, animal or human is generally sufficient to achieve the intended task. To administer the bioactive agent, the amount and release rate are accompanied by the manufacturer's recommendation of the bioactive agent. In general, the concentration of bioactive agent in the liquid polymer formulation can be from 0.01 to 400 mg per gram of the mixture.
    In certain embodiments, the invention provides a hydrophobic bioactive material (a) of 1-30% w / v, a poly (lactide-co-glycolide) copolymer (b) and a hydrophilic solvent of 1-20% w / v. And a mixture (c) of a hydrophilic solvent with a lipophilic solvent having a volume ratio of about 80:20 to about 5:95 of a lipophilic solvent, to provide a liquid polymer composition for controlling hydrophobic bioactive substance release.
    In certain preferred embodiments, the bioactive material (eg, one or more hydrophobic bioactive material) is present at a concentration of 1-10% w / v, more preferably 5-10% w / v.
    In another preferred embodiment, the polymer [eg poly (lactide-co-glycolide)] copolymer is present at a concentration of 1 to 10% w / v, more preferably 1 to 5% w / v.
    In another preferred embodiment, the weight ratio of the polymer (eg poly (lactide-co-glycolide) copolymer) to the bioactive material (eg one or more hydrophobic bioactive materials) is 1: 1 or less, more preferably Is from 0.5: 1 to 1: 1.
    In a more preferred embodiment, the volume ratio of hydrophilic and lipophilic solvent is about 65:35 to about 35:65
    In another aspect of the invention, a hydrophobic bioactive material comprising a hydrophobic bioactive material (a), a poly (lactide-co-glycolide) (b) and a mixture of glycerol formal and triacetin (c) It provides a liquid polymer composition for controlling the release of.
    In another aspect of the invention, there is provided a method of controlling release of one or more bioactive materials (eg, one or more hydrophobic bioactive materials), comprising injecting an animal with a liquid polymer composition described herein.
    In addition to the foregoing, the following terms used herein are unless otherwise stated:
    "Polymer" includes "copolymer"; "Copolymer" is a polymer that polymerized two or more monomers; Thus, a "copolymer" may include a "terpolymer" or a polymer of two or more monomers.
    By "hydrophobic bioactive material" is meant a compound useful for human or animal health with a water solubility of less than 2%, preferably less than 1% at room temperature. Examples of hydrophobic bioactive materials suitable for the present invention include avermectins (eg ivermectin, eprinomectin, etc.), milbemacin, phenylpyrazole, nodulisporic acid and US Pat. No. 5,399,582. And derivatives described in WO 96/29073, estradiol benzoate, trenbolone acetate, progesterone, noretysterone, water-insoluble NSAID, and the like.
    "Poly (lactide-co-glycolide)" means a copolymer of lactic acid and glycolic acid having a ratio of lactide: glycolide 95: 5 to 50:50, preferably 75:25 to 65:35. The lactic acid can be d, l or dl. The copolymer may be a single copolymer of a mixture of copolymers within the parameters defined above.
    A "hydrophilic solvent" is a water affinity solvent, preferably a solvent which forms a single phase solution when mixed with water in a ratio of 1: 9 to 9: 1. Examples of hydrophilic solvents suitable for the present invention include, but are not limited to, glycerol formal, glycofural, N-methyl pyrrolidone, 2-pyrrolidone, isopropylidene glycerol, di (propylene glycol) methyl ether and mixtures thereof It is not limited.
    A "lipophilic solvent" is a water immiscible solvent, preferably a solvent having a solubility of less than 10% at room temperature. Examples of lipophilic solvents suitable for the present invention include, but are not limited to, triacetin, benzyl benzoate and mixtures thereof.
    The liquid composition of the present invention can provide a sustained release drug once injected, without sudden drug release over existing liquid injectable formulations. Without wishing to be bound by theory, when injected, the liquid formulation of the present invention initially forms a reservoir having a sheath made of a polymer surrounding the liquid core (which may appear to be “semi-solid”), while a portion of the hydrophilic solvent is in combination with the formulation. Diffusion from reservoirs carrying bioactive compounds dissolved together. Initial drug release from the ileum is largely due to infiltration through the skin. The permeability of the skin and the initial drug delivery rate are controlled by the ratio of hydrophilic and lipophilic solvents in the liquid excipient. Over time, the reservoir is reduced in its liquid excipient, and degradation of the polymer gradually becomes a significant drug release mechanism. Thus, proper control of the liquid formulation composition results in overlapping penetration-controlled and corrosion-controlled drug delivery, resulting in flattening and extending the drug release profile over long periods of time. Thus, the reservoir is biodegradable without the need to form a solid or other physical form associated with a composition of the prior art that need not be limited to one particular theory.
    The presence of a lipophilic solvent in the liquid composition of the present invention reduces the initial delivery of the bioactive compound, thus eliminating the abrupt drug release customary for existing liquid injectable formulations, where most of the hydrophilic excipients are used. The presence of the hydrophilic solvent promotes the formation of the polymer shell while preventing the precipitation of the bioactive compound, thus increasing the level of drug delivery possible than if only lipophilic excipients were used. In the present invention, the preferred hydrophilic: lipophilic solvent ratio is 80:20 to 20:80, most preferably 65:35 to 35:65.
    Other factors that significantly affect the performance of this liquid formulation include polymers (e.g. PLGA polymer concentration) (1), relative ratios of bioactive compounds and polymers (2), comonomers (e.g. lactide: glycolide ratio in polymers). (3) and the molecular weight (4) of the polymer. Factors (3) and (4) are well known in the art (see references cited herein). However, the present invention differs considerably from the techniques present, in particular embodiments (1) and (2).
    Liquid formulations of the present invention may contain up to 20% polymer, preferably 10% polymer, such as PLGA polymer, in order to maintain a relatively acceptable drug delivery rate at the same time to secure a reasonably long drug delivery period (3 months or more). It contains below. Thus, the concentration of polymer (eg PLGA) in the formulation is high, in contrast to known formulations, and a substantially high proportion of polymer (eg PLGA) is described. The concentration of bioactive material in the liquid formulation may be 1-30%. Preferably, the ratio of polymer (PLGA polymer) to bioactive compound is less than or equal to 1: 1 and substantially less than or equally defined. Within the ranges described herein, high polymer concentrations reduce drug delivery rates and increasing polymer: live compound ratios also reduce delivery rates.
    Liquid compositions of the present invention can be prepared by dissolving all of the solid components in excipients under normal manufacturing conditions used in sterile injectable products. The compositions may contain additional inert materials commonly used in parenteral formulations, including but not limited to antibacterial agents, antioxidants, and the like.
    The liquid compositions of the present invention are administered to warm blooded animals such as humans, cattle, sheep, pigs, dogs, horses, cats (e.g., mammals such as humans, companions and feedstock animals) by intramuscular or subcutaneous injection. The formulations will generally be prepared to contain 1-30%, preferably 1-10%, of the bioactive compound. For example, a preferred dosage volume of about 1 mL for treating 50 kg cows contains 50-100 mg or about 5-10% w / v of avermectin compound per mL volume. However, depending on the activity of the compound and the animal to be treated, a low concentration of bioactive compound by 1% may be used.
    The following examples are provided to illustrate the invention and should not be construed as limiting the invention in any way.
    Example 1
    Preparation of long-acting injectable preparations containing 6-amino-3-cyano-1- (2,6-dichloro-4-sulperpentafluorophenyl) -4- (trifluoromethylthio) pyrazole
    Poly (DL-lactide / glycolide) 75/25 (PLGA, 0.25 g) is dissolved in sufficient glycerol formal to give 2.5 mL of solution. In a separate flask, poly (DL-lactide / glycolide) 75/25 (0.25 g) is dissolved in sufficient triacetin to give 2.5 mL of solution. The two PLGA solutions are mixed well and added to the flask containing the active ingredient (0.50 g). The contents of the flask are mixed until the active ingredient is dissolved, then the resulting solution is sealed by aseptic filtration into the vial.
    Example 2
    Preparation of long-acting injectable preparations containing ivermectin
    The general procedure of Example 1 provides the following ivermectin preparations:
    number Content of Pharmaceuticals% w / v Content of PLGA% x / v Solvent Ratio TA / GF * Polymer Type One 10 10 20/80 7525 2 10 10 35/65 7525 3 10 6.7 50/50 7525 4 10 5 50/50 7525 5 10 5 50/50 5050
    * TA = triacetin; GF = Glycerol Formal
    For comparison purposes, ie for the purpose of illustrating how much solvent was used in the present invention as compared to compositions in the prior art; In the formulation (1) of this example, the triacetin, lipophilic solvent is present at about 16.45% by weight. In formulation (2) of this example, triacetin, lipophilic solvent is present at about 29% by weight. In formulation (3) of this example, triacetin, lipophilic solvent is present at about 42% by weight. In the formulation (4) of this example, the triacetin, lipophilic solvent is present at about 43% by weight.
    Example 3
    Preparation of Long-acting Injectable Formulations Containing Eprinomectin
    The general procedure of Example 1 provides the following eprinomectin formulations:
    number Content of Pharmaceuticals% w / v Content of PLGA% x / v Solvent Ratio TA / GF * Polymer Type One 10 10 50/50 7525 2 5 5 50/50 6535
    In the formulation (2) of this Example for comparison purposes, ie for explaining the purpose of explaining how much solvent was used in the present invention as compared to the compositions of the prior art, the triacetin, lipophilic solvent is about 45 weight Exists in% And, in the formulations according to the invention, it is noted that the lipophilic solvent can be 100% of the volume of the solvent present as discussed in the above-mentioned specification.
    Example 4
    Long-term functionality containing 6-amino-3-cyano-1- (2,6-dichloro-4-sulperpentafluorophenyl) -4- (trifluoromethylthio) pyrazole against fleas in dogs Activity of the preparation for injection
    Three beagle dogs are treated using the formulation of Example 1 at a single subcutaneous dose of 10 mg / kg. Dogs are fasted for at least 6 hours before treatment and at least 6 hours after treatment. On day 1 (day 0 = day of drug administration), animals are infested with approximately 100 fleas. Animals are combed and the flea counted, then removed after approximately 48 hours of invasion. Animals are invaded on Day 12 and Day 26, combed, and counted fleas, then removed after approximately 48 hours of invasion. Repeat the invasion / calculation for approximately one month.
    Blood samples are taken from animals at 1 hour, 2 hours, 3 hours and 6 hours after treatment on day 0, at 24 hours after treatment on day 1, and if vomiting is observed. If flea calculations are measured, blood samples are also collected. Animals are observed every hour for 6 hours after treatment during vomiting. Efficiency close to 100% has been demonstrated for more than 12 months without the occurrence of vomiting in treated animals. The plasma level profile of individual dogs is shown in FIG. 1.
    Example 5
    Plasma level profile of long-acting ivermectin preparations in cattle
    Plasma levels of ivermectin are measured in healthy cattle using the ivermectin preparations (1), (2) and (3) of Example 2. Each formulation is administered to a group of 5 cows (typically 125-250 kg body weight) as a single subcutaneous injection dose of 1 mg / kg. Blood samples treated with 10 mL of heparin are collected from each treated animal on days 1-7 (daily), 10, 14 and weekly after 15 days of treatment. The plasma level profile (average of five animals in each group) is shown in FIG. 2.
    Example 6
    Plasma Level Profiles of Long-acting Eprinomectin Formulations in Swine
    Plasma levels of eprinomectin are measured in pigs using the eprinomectin preparation (2) of Example 3. Administration of 1.5 mg / kg of 3 pigs [inoculated with infectious eggs of 2,000 Trichoris suis on day 50 and orally inoculated with 15,000 infectious larvae of exopagostonium species on day 0] Subcutaneously, using the formulation (2) of Example 3 in the amount. On day 3, day 7 and weekly after treatment, 10 mL of blood samples are collected from each animal. Plasma level profiles are shown in FIG. 3 (using a selective formulation of drug / PLGA in 100 glycerol formals).
    Thus, describing preferred embodiments of the present invention in detail does not limit the invention defined by the appended claims to the specific items set forth in the specification, since many obvious variations thereof are possible without departing from the spirit or scope of the invention. It should be understood that.
    权利要求:
    Claims (14)
    [1" claim-type="Currently amended] 1-30% hydrophobic bioactive material (a);
    1 to 20% poly (lactide-co-glycolide) copolymer (b), wherein the weight ratio of poly (lactide-co-glycolide) copolymer to hydrophobic bioactive material is 1: 1 or less; And
    Liquid polymeric composition for controlling release of hydrophobic bioactive material, comprising a mixture of a hydrophilic solvent with a lipophilic solvent (c), wherein the volume ratio of the hydrophilic solvent to the lipophilic solvent is about 80:20 to about 5:95 .
    [2" claim-type="Currently amended] The composition of claim 1, wherein the bioactive material is present in an amount of about 1-10%.
    [3" claim-type="Currently amended] The composition of claim 1, wherein the poly (lactide-co-glycolide) copolymer is present in an amount of about 1-10%.
    [4" claim-type="Currently amended] The composition of claim 1 wherein the ratio of hydrophilic solvent to lipophilic solvent is about 65:35 to about 35:65.
    [5" claim-type="Currently amended] The method of claim 1,
    1 to 10% hydrophobic bioactive material (a);
    1 to 10% of poly (lactide-co-glycolide) copolymer (b), wherein the weight ratio of poly (lactide-co-glycolide) copolymer to hydrophobic bioactive material is 1: 1 or less; And
    A composition comprising a mixture of a hydrophilic solvent and a lipophilic solvent (c), wherein the volume ratio of the hydrophilic solvent and the lipophilic solvent is about 65:35 to about 35:65.
    [6" claim-type="Currently amended] The method of claim 1,
    5 to 10% hydrophobic bioactive material (a);
    5-10% poly (lactide-co-glycolide) copolymer (wherein the weight ratio of poly (lactide-co-glycolide) copolymer to hydrophobic bioactive material is 1: 1 or less); and
    A composition comprising a mixture of a hydrophilic solvent and a lipophilic solvent (c), wherein the volume ratio of the hydrophilic solvent and the lipophilic solvent is about 65:35 to about 35:65.
    [7" claim-type="Currently amended] The bioactive agent according to claim 1, wherein the bioactive materials are fipronil, avermectin, ivermectin, eprinomectin, milbymine, nodulisporic acid and derivatives thereof, estradiol benzoate, trenbolone acetate, progesterone and noretis. Composition selected from therons.
    [8" claim-type="Currently amended] The composition of claim 1 wherein the ratio of lactide: glycolide of the poly (lactide-co-glycolide) copolymer is from about 95: 5 to about 50:50.
    [9" claim-type="Currently amended] The composition of claim 1 wherein the ratio of lactide: glycolide of the poly (lactide-co-glycolide) copolymer is from about 75:25 to about 65:35.
    [10" claim-type="Currently amended] The composition of claim 1 wherein the hydrophilic solvent is selected from glycerol formal, glycofural, N-methyl pyrrolidone, 2-pyrrolidone, isopropylidene glycerol, di (propylene glycol) methyl ether and mixtures thereof.
    [11" claim-type="Currently amended] The method of claim 1,
    5 to 10% hydrophobic bioactive material (a);
    5-10% poly (lactide-co-glycolide) copolymer (b), wherein the ratio of lactide: glycolide of the poly (lactide-co-glycolide) copolymer is about 75:25 to about 65:35 and the weight ratio of poly (lactide-co-glycolide) copolymer to hydrophobic bioactive material is 1: 1 or less; And
    A composition comprising a mixture of glycerol formal and triacetin (c), wherein the volume ratio of glycerol formal and triacetin is about 65:35 to about 35:65.
    [12" claim-type="Currently amended] A method of controlling the release of hydrophobic bioactive material in an animal, including a human, comprising injecting the liquid polymeric composition according to claim 1 into an animal, including a human.
    [13" claim-type="Currently amended] About 1 to 30% of one or more bioactive materials (1);
    About 1 to 20% of one or more biologically acceptable polymers 2, wherein the weight ratio of polymer to bioactive material is no greater than 1: 1; And
    One or more lipophilic solvents, or mixtures of one or more hydrophilic solvents with one or more lipophilic solvents, wherein the volume ratio of the hydrophilic solvent and the lipophilic solvent is about 80:20 to about 0: 100 and / or lipophilic solvent Is present in an amount of at least about 16.5% by weight).
    [14" claim-type="Currently amended] A method of controlling the release of hydrophobic bioactive material in an animal, including a human, comprising injecting the liquid polymeric composition of claim 13 into an animal, including a human.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-03-19|Priority to US7957498P
    1998-03-19|Priority to US60/079,574
    1998-07-21|Priority to GB9815801A
    1998-07-21|Priority to GB9815801.7
    1999-03-18|Application filed by 폴락 돈나 엘., 머크 앤드 캄파니 인코포레이티드
    2001-05-25|Publication of KR20010041987A
    2007-02-16|Application granted
    2007-02-16|Publication of KR100684055B1
    优先权:
    申请号 | 申请日 | 专利标题
    US7957498P| true| 1998-03-19|1998-03-19|
    US60/079,574|1998-03-19|
    GB9815801A|GB9815801D0|1998-07-21|1998-07-21|Liquid polymeric compositions for controlled released bioactive substances|
    GB9815801.7|1998-07-21|
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