RS49840B - LIQUID POLYMER MIXTURES FOR CONTROLLED RELEASE OF BIOACTIVE SUBSTANCES - Google Patents

Abstract

A liquid polymer mixture, which includes: a) 1-30% by weight/volume of at least one bioactive substance; b) 1-20% by weight/volume of at least one biologically acceptable polymer; where the weight ratio of polymer to bioactive substance is 1:1 or less, and c) a mixture of at least one hydrophilic and at least one lipophilic solvent, where the volume ratio of hydrophilic and lipophilic solvents is from 80:20 to 0:100 and/or where a lipophilic solvent is present in an amount of at least 16.5% by weight. This application contains 12 more patent claims.

Description

TECHNICAL FIELD

This invention relates to liquid polymer mixtures; for example, such compositions for the controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymer mixture, which can form a thin layer encapsulated liquid, e.g., in situ and/or which can achieve long-term continuous release in a patient Hi host (e.g., animal or human), such that plasma profiles show high efficacy (greater than 70%, such as at least 80%, preferably at least 90 %, e.g., 100% efficacy for more than about 12 months and/or plasma levels are maintained for at least about 50 or about 60 days, or at least about two months or at least about eight weeks, e.g., at least about 90 days, or about three months or about 12 weeks or at least about 120 days or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or longer; for example, from 1 to 12 months.

The present invention further relates to liquid polymer mixtures containing: (1) 1-30% w/v bioactive substance (eg, hydrophobic bioactive substance);

(2) 1-20% w/v of a biologically acceptable "polymer" (including "copolymer", a polymer polymerized from at least two comonomers) (eg, poly(lactide-co-glycolide) copolymer), for example, where the weight ratio of polymer to bioactive substance may be 1 : 1 or less, eg, 0.3 : 1 to 1 : 1; and (3) at least one lipophilic solvent or a mixture of hydrophilic and lipophilic solvents in which the volume ratio of hydrophilic to lipophilic solvents is from 80:20 to 0:100, e.g., 80:20 to 10:90 or 5:95, hydrophilic to lipophilic solvents, e.g., 65:35 to 35:65, and/or where a solvent, which is immiscible with water or U<p>ori Ini solvent present in an amount of at least 16.5% by weight (eg, including 16.465% by weight), thus giving at least 16.5% to 45% by weight, say, at least 16.5% to 30% by weight (eg, at least 29% by weight); or at least more than 40% by weight (for example at least 42-45% by weight); eg, such mixtures in which there is less than 10% polymer and 1 to 10% bioactive substance or about less than 7% (eg, 6.7%) or 5% or less polymer with a bioactive substance content of less than or equal to about 10% or 5%.

This invention further relates to liquid polymer mixtures, which essentially contain the aforementioned, wherein the liquid polymer mixture is able to form a liquid that is encapsulated by a film, e.g., in situ, and/or has a long-term continuous release, where the term "essentially contains" is used in the sense related to that in the patent documents and the term is exclusively used for ingredients, which can prevent the ability of the mixture to form a thin layer encapsulated liquid.

The present invention further relates to methods of making and using such mixtures. For example, a method of making such mixtures, which includes mixing the aforementioned ingredients; eg, dissolving both the polymer and the bioactive substance is desirable (as opposed to suspending, encapsulating, or existing as a solid, the bioactive substance, which if not necessarily excluded by the invention, may be less desirable to dissolve). Or, the use of such mixtures for the production of medicine.

These 1 other areas to which the invention relates will be clarified from the following text. Various documents are cited in the text, which follows, without any admission that any of these documents precedes the invention. All documents referenced herein, as well as all documents referenced in the documents referenced herein, are incorporated herein by reference.

STATE OF THE ART

Biodegradable polymers have been used in parenteral formulations of bioactive compounds with controlled release. In one approach, the polymer is introduced into microspheres, which can be initiated with a syringe, and the bioactive compound is encapsulated within the microspheres. This approach has not proven to be practical partly due to the difficulties in the production process of making sterile and reproducible products and the high cost of production. In another approach, the biodegradable polymer and bioactive material are dissolved in a biocompatible solvent, which is mixed with water to provide a liquid mixture. When the liquid mixture is injected into the body, the solvent is dispersed into the surrounding water environment, and the polymer forms a depot in the form of a solid mass from which the bioactive material is released.

European patent application no. 0537559 refers to polymeric compositions having a thermoplastic polymer, a rate-modifying agent, a water-soluble bioactive material, and a water-miscible organic solvent. Upon exposure to an aqueous environment (eg, body fluids), the liquid mixture is able to form a biodegradable, microporous solid polymeric matrix for the controlled release of water-soluble or dispersible bioactive materials for more than four weeks. The thermoplastic polymer can be, among many listed, polylactide, polyglycolide, polycaprolactone or their copolymers and is used in a high concentration (45 to 50%). The rate modifying agent may be, among many others listed, glycerol triacetate (triacetin); however, it is only exemplified by ethyl heptanoate; and the amount of rate modifying agent is not more than 15%.

Indeed, as far as the patent literature is concerned, references are made

towards;

These documents are aimed at providing mixtures, which

form a solid mass, gel or coagulated mass; eg, a significant amount of polymers are discussed in these documents, close to European patent application no. 0537559.

Mention was also made: Shah et al. (J. Controlled Release, 1993, 27:139-147), regarding formulations for sustained release of bioactive compounds, containing various concentrations of poly(lactide-co-glycolide) acid copolymer (PLGA) dissolved in a vehicle such as triacetin; Lambert and Peck J. Controlled Release. 1995, 33:189-195), as a study of protein release from a 20% solution of PLGA in N-methylpyrrolidone exposed to an aqueous liquid: and Shivlev et al. J. Controlled Release, 1995, 33:237-243). as a study of the solubility parameter of poly(lactide-co-glycolide) copolymer in different solvents and the in vivo release of naltrexone from two injectable implants (5% naltrexone in either 57% PLGA and 38% N-methylpyrrolidone or in 35% PLGA and 60% N-methylpyrrolidone). Cario et al. (J. Controlled Release, 1995, 37:113-121) as a study on the degradation of surfactant - free PLAGA beads: and Sungh U.V. ( Indian J. of Pharmacologv. 1997. 29:168-178 ) as associated with PLGA injectable gel implants for plumbagun delivery.

There is no less need for long-term sustained release compounds, as well as polymer compounds, which can form a thin layer of confined or encapsulated liquid.

OBJECTIVES AND DISCUSSION OF THE ESSENCE OF THE INVENTION

Contrary to the previous mixtures, it was surprisingly found that the polymer mixture, containing significantly higher amounts of water-immiscible or lipophilic solvent and substantially less polymer than that considered in the literature, leads to formulations that tend to remain in the form of a film-bound liquid (encapsulated) rather than in the form of a solid mass, gel or coagulated mass (including porous solids, gels or masses as in the literature). The use or amount of lipophilic solvent and the low amount of polymer used in the liquid polymer formulations of the invention do not appear to have been contemplated by the prior art.

Therefore, the object of the invention may be any or all of: the provision of a liquid polymeric mixture comprising a bioactive substance. for example, such a mixture has a long-term sustained release and/or forms a film-confined liquid or an encapsulated liquid. as well as providing methods for making and/or using such a mixture.

The present invention provides liquid polymeric compositions; for example, such compositions for the controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymer mixture, which can form a film-encapsulated liquid, e.g., in situ and/or which can achieve long-term sustained release in a patient or host (e.g., animal or human), such that plasma profiles show high efficacy (greater than 70%, such as at least 80%, preferably at least 90%, e.g., 100% efficacy for more than about 12 months and/or plasma levels are maintained for at least about 50 or about 60 days, or at least about two months or at least about eight weeks, e.g., at least about 90 days, or about three months or about 12 weeks or at least about 120 days, or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or more; for example from 1 to 12 months or longer.

The present invention further relates to liquid polymer mixtures containing: (1) 1-30% w/v bioactive substance (eg, hydrophobic bioactive substance); (2) 1-20% w/v of a biologically acceptable "polymer" (including "copolymer", a polymer polymerized from at least two comonomers) (eg, poly(lactide-co-glycolide) copolymer), for example, where the weight ratio of polymer to bioactive substance may be 1:1 or less, eg, 0.5:1 to 1:1; and (3) a mixture of at least one hydrophilic solvent and at least one lipophilic solvent, e.g., at least one biologically or physiologically or medically or veterinary acceptable hydrophilic solvent and at least one biologically or physiologically or medically or veterinary acceptable Hpophilic solvent, wherein the volume ratio of hydrophilic to lipophilic (and hydrophobic) solvents is from 80:20 to 0:100, for example, 80:20 to 10:90 or 5:95, hydrophilic and lipophilic solvents, eg, 65:35 to 35:65, and/or where is a water-immiscible or lipophilic solvent present in an amount of at least 16.5% by weight (eg, including 16.465% by weight), such that at least 16.5% to about 45% by weight, say, at least 16.5% to about 30% by weight (eg, at least about 29% by weight) or at least about 20% or about 25% by weight up to about 30%, 35%, 40% or 45% by weight or at least greater than 40% by weight (eg at least about 42-45% by weight); eg, such mixtures in which there is less than 10% polymer and 1 to 10% bioactive substance or about less than 7%

(eg, 6.7%) or 5% or less polymer with a bioactive substance content of less than or equal to about 10% or 5%.

The present invention further provides liquid polymer mixtures, which are essentially composed of the aforementioned, wherein the liquid polymer mixture is able to form a liquid that is encapsulated in a film, e.g., in situ, and/or has a long-term continuous release, where the term "consisting essentially of" is used in the sense related to that in the patent documents and the term is exclusively used for ingredients, which can prevent the ability of the mixture to form a thin film encapsulated liquid. Thus, for example, an agent that will cause the mixture, e.g., in situ, to have one or more of the opposite properties, e.g., an agent that would cause the mixture to harden, such as a healing agent, or to form pores, may be undesirable in certain embodiments.

The present invention further provides methods of making and using such compositions. For example, a method of making such mixtures, which includes mixing the aforementioned ingredients; eg, preferably dissolving both the polymer and the bioactive substance (as opposed to suspending, encapsulating or solidifying the bioactive substance, which if not necessarily excluded by the invention, may be less desirable to dissolve). Or, using such mixtures to produce medicine.

The invention further provides methods, consisting essentially of at least one step of making or using such mixtures; wherein liquid polymer mixtures, which are capable of forming a film-encapsulated liquid, e.g., in situ, and/or have a long-term continuous release, where the term "consisting essentially of" is used in a sense related to that in the patent documents and the term is used exclusively for ingredients that can prevent the ability of the mixture to form a thin film-encapsulated liquid. Thus, for example, a step that will cause the mixture, e.g., in situ, to have one or more of the opposite properties, e.g., adding an agent that would cause the mixture to harden, such as a curing agent, or to form pores, may be undesirable in certain embodiments.

Bioactive substances can be any biological agent, which is capable of providing a biological, physiological or therapeutic effect in animals or humans. A biologically active agent may be any one or more known biologically active agents recognized in any document cited herein or otherwise recognized in the art. The agent may also stimulate or inhibit a desired biological or physiological activity in animals or humans, including without limitation, stimulation of an immunogenic or immune response.

Therefore, the invention provides an in situ film-bound or encapsulated liquid implant, which is capable of functioning as a system for introducing drugs, medications and other biologically active agents into tissues adjacent to or distant from the implant site. Preferably, the biologically active agent is incorporated into the fluid encapsulated therein and gradually released into contact tissue fluids and into the appropriate body tissue or organ. The mixture may be applied to the implant site by any convenient method of liquid delivery, such as by syringe, needle, cannula, catheter, pressure applicator, and the like.

For example, biologically active agents or bioactive substances include, without limitation, fipronil, avermectin, ivermectin, eprinomectin, milbemycin, phenylpyrazole, nodulisporic acid, estradiol benzoate, tremblon acetate, norethisterone, progesterone, an antibiotic, such as a macrolide or azalide antibiotic, or a non-steroidal anti-inflammatory drug (NSAID) or a combination thereof. Thus, the aim of the invention may be to ensure the intake of at least one active ingredient, regardless of whether the ingredient is insoluble in water or does not mix with water; but, the invention is particularly applicable to hydrophobic biologically active substances.

The bio-acceptable polymer can be any bio-acceptable polymer, such as a bio-acceptable polymer, which is recognized in the documents cited herein. For example, a biologically acceptable polymer may have one or more of the following properties: that it is bioerodible under the influence of cellular activity, biodegradable under the influence of non-living body fluid components, that it softens under the influence of heat but returns to its original state by cooling, and that it can be significantly dissolved or dispersed in carriers or solvents, which are mixed with water to give solutions or dispersions. During contact with an aqueous liquid, the polymer is capable of assisting in the formation of a film-confined or encapsulated liquid. Types of polymers suitable for this composition generally include any with the properties described above. Examples are polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acid), poly(methyl vinyl ether), poly(maleic anhydride), chitin, chitosan and copolymers, terpolymers or their combinations or mixtures. Preferred polymers are polylactides, polycaprolactones, polyglycolides, and copolymers thereof, with poly(lactide-co-glycolide) copolymer ("PLGA") being most preferred. The composition of PLGA may be related to its use in the Examples later or in the documents cited herein.

Solvents can be biological or physiological or medical or veterinary hydrophobic and water-miscible solvents, such as those recognized in the documents cited herein.

The hydrophilic solvent can be selected from propylene glycol, PEG, polyglycol, such as polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, di(ethylene glycol) ethyl ether (Transcutol), isopropylidene glycerol (Solketal), dimethyl isosorbide (Arlasolve DM1), propylene carbonate, glycerol, glycofural, pyrrolidone, such as N-methyl pyrrolidone and 2-pyrrolidone, isopropylidene glycerol, di(propylene glycol) methyl ether and their mixtures. Other solvents may be useful as hydrophilic solvents. For example, the hydrophilic solvent can be a C 2 to C alkanol (eg, ethanol, propanol, butanol), acetone, alkyl esters, such as methyl acetate, ethyl acetate, ethyl lactate, alkyl ketones, such as methyl ethyl ketone, dialkyl amides, such as dimethylformamide, dimethyl sulfoxide, dimethyl sulfone, tetrahydrofuran, cyclic alkyl amides, such as caprolactam, decylmethyl sulfoxide, oleic acid, propylene carbonate, aromatic amides, such as N,N-diethyl-m-toluamide, 1-dodecyl azacycloheptan-2-one. The hydrophilic solvent can be a mixture of solvents.

A lipophilic or hydrophobic or water-immiscible solvent may be selected from triethyl citrate, Miglvol 812, Miglyol 840, Crodamol GTCC, triacetin or benzyl benzoate; and additional lipophilic solvents may be used, e.g., hydrophobic rate-modifying agents or plasticizers, such as fatty acids, triglycerides, glycerol triesters, oils, such as castor, soybean oil, or other vegetable oils or derivatives thereof, such as epoxidized or hydrogenated vegetable oils, such as epoxidized soybean oil or hydrogenated castor oil, sterols, higher alkanols (e.g., Csili higher), glycerin and the like. The lipophilic solvent can be a mixture of solvents.

Other solvents may 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, glycofurol, isopropyl myristate, N,N-dimethyl acetamide, PEG 300, propylene glycol and polar aprotic solvents such as DMSO.

In certain embodiments there may be less than 10% polymer and 1 to 10% active compound; e.g., the ratio of PLGA polymer to active compound is less than or equal to 1:1 (See, e.g., Examples, where, e.g., 0.2575/25PLGA is dissolved in glycerol formal for 2.5 ml of solution; in a separate vessel, 75/25 PLGA is dissolved in triacetin for 2.5 ml of solution; the two solutions are mixed and added to a flask containing 0.50 g of active ingredient, which was dissolved in the mixed PLGA solutions; the amount of triacetin, which is present in the formulation, should be 42% by weight; other formulations contain only 6.7% and 5% of the drug content of 10%.)

When implanted, e.g., during injection, the patent liquid formulation forms what has been concluded from numerous studies of patient hosts in which the formulation has been implanted, a "semi-solid depot with the skin containing the polymer". A depot, however, without wishing to be bound by any particular theory, is not necessarily solid or semi-solid (as those terms are commonly understood); but rather, a film-covered or encapsulated liquid (the polymer helps form the skin). Over time, the depot loses its solvent vehicle(s) and polymer degradation occurs.

While diffusion through the film (typically whitish in color in preferred embodiments) is ongoing, there are believed to be no pores in the depot; and similarly that the liquid polymer formulation does not form in situ, a solid mass or a coagulated mass or a gelatinous mass. These beliefs are based on the fact that the amount of polymer in the patent formulation is substantially less than that used by the prior art; the amount of water-immiscible lipophilic solvent present in the patent formulation is substantially greater than any "rate modifying agent" or similar solvent used in the prior art (allowing the depot core to remain liquid); and as the active ingredient diffuses through the film (a very, very thin film, usually whitish in preferred embodiments), the polymer biodegrades. The patented formulation is well suited for the introduction of lipophilic (hydrophobic) active ingredients.

These and other accomplishments are set forth or arise from, as they are included in, the Detailed Description that follows.

BRIEF DESCRIPTION OF THE PICTURES

The following detailed description, which is given by way of example, but is not intended to limit the invention to the specific embodiments described, may be understood in connection with the accompanying Figures, incorporated by reference, in which: Figure 1 shows plasma levels of 6-amino-3-cyano-1-(2,6-dichloro-4-sulfurpentafluorophenyl)-4-(trifluoromethylthio)pyrazole in dogs treated with the formulation of Example 1;

Figure 2 shows the plasma levels of ivermectin in cattle treated with the three ivermectin formulations of Example 2;

Figure 3 shows the plasma levels of eprinomectin in pigs treated with the eprinomectin formulations of Example 3.

DETAILED DESCRIPTION

The present invention provides liquid polymeric compositions for the delivery of bioactive substance(s).

The present invention provides liquid polymeric compositions; for example, such compositions for the controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance, such as a liquid polymer mixture, which can form a film-encapsulated liquid, e.g., in situ and/or which can achieve long-term continuous release in a patient or host (e.g., animal or human) such as plasma profiles, which show high efficiency (greater than 70%, such as at least 80%, preferably at least 90%, e.g., 100% efficacy for more than 12 months and/or plasma levels continuous for at least about 50 or about 60 days or at least about two months or at least about eight weeks, e.g., at least about 90 days or about three months or about 12 weeks or at least about 120 days or about four months or about 16 weeks, or at least about 150 days or about five months or about 20 weeks, or even longer, e.g., up to about a year or longer; from 1 to 12 months or longer.

The present invention further provides a liquid polymer composition comprising; (1) 1-30% wt/vol wt/vol) of at least one bioactive substance (eg, hydrophobic bioactive substance); (2) 1-20% w/v of at least one biologically acceptable "polymer" (including "copolymer", a polymer polymerized from at least two comonomers) (eg, poly(actide-co-glycolide) copolymer), say, where the weight ratio of polymer to bioactive substance may be 1 : 1 or less, eg, 0.5 : 1 to 1 : 1; and (3) at least one lyophilic solvent or a mixture of at least one hydrophilic solvent and at least one lipophilic solvent, e.g., at least one biological or physiological or medical or veterinary acceptable hydrophilic solvent and at least one biological or physiological or medical or veterinary acceptable lipophilic solvent where the volume ratio of hydrophilic to lipophilic (or hydrophobic) solvent is from 80 : 20 to about 0 : 100, say, 80:20 to about 10:90 or 80:20 to 5:95, of hydrophilic and lipophilic solvents, eg, 65:35 to 35; 65, and/or wherein the lipophilic, water-immiscible solvent is present in an amount of at least 16.5% by weight (e.g., including 16.465% by weight), such as at least 16.5% to about 45% by weight, say, at least 16.5% to about 30% by weight (e.g., at least about 29% by weight), or at least about 20% or about 25% by weight to about 30%, 35%, 40% or 45% by weight, or at least more than 40% by weight (say at least about 42-45% by weight); eg, such mixtures in which there is less than 10% polymer and 1 to 10% bioactive substance or about less than 7% (eg, 6.7%) or 5% or less polymer, with a bioactive substance content of less than or equal to about 10% or 5%.

The present invention further provides a liquid polymer mixture consisting essentially of the aforementioned, wherein the liquid polymer mixture is capable of forming a film-encapsulated liquid, e.g., in situ, and/or has a long-term continuous release, where the term "consisting essentially of" is used in the sense attributed in the patent documents and the term is exclusively used for ingredients, which can stop the ability of the mixture to form a thin film-encapsulated liquid. Thus, for example, an agent intended to cause the mixture, e.g., in situ, to have one or more of the opposite properties, e.g., an agent intended to cause the mixture to harden, such as a curing agent, or to form pores, may be undesirable in certain embodiments.

The present invention further provides methods for making and using such compositions, as discussed herein.

Polymers and solvents used in the invention may be as discussed herein.

Bioactive substance(s) can be any biological agent, which is capable of producing a biological, physiological or therapeutic effect in an animal or Human. The biologically active agent may be any one or more of the known biologically active agents recognized in any document cited herein or otherwise recognized in the art. The agent may also stimulate or inhibit a desired biological or physiological activity in an animal or human, including without limitation, stimulation of an immunogenic or immune response.

In situ formed implants can also provide a delivery system for biologically active agents into adjacent or distant body tissues and organs. Biologically active agents, which may be used alone or in combination in these mixtures and implants, include medicaments, drugs or any suitable biologically-, physiologically- or pharmacologically-active substance, which is capable of providing local or systemic biological or physiological activity in an animal, including man and which is capable of being released from the depot into the adjacent or surrounding aqueous fluid.

The biologically active agent can be mixed with the polymer and/or solvent to obtain a homogeneous mixture with the polymer, or it can be insoluble in the polymer and/or solvent to obtain a suspension or dispersion with the polymer. It is highly desirable that the biologically active agent is combined with the rest of the ingredients of the patent mixture practically immediately before applying the mixture to the implant site. Also, it is preferred that the bioactive agent is immiscible with water, eg, preferably only slightly soluble in water or has low water solubility or is capable of being dissolved in a lipophilic (hydrophobic) solvent. It is further assumed that the bioactive agent will not have functional groups that will interfere with the polymer. These conditions are easily determined by experts simply by comparing the structure of the bioactive agent and the reactive parts of the polymer.

The mixture and in situ formed implant contain a biologically active agent in an amount effective to provide the desired biological, physiological, pharmacological and/or therapeutic effect, optionally matched to the desired release profile and/or release time. Furthermore, it is preferable that the biologically active agent included in the polymer mixture in an amount effective to ensure an acceptable viscosity of the solution or dispersion.

Suitable biologically active agents include substances useful in preventing infections at the implant site, such as, for example, antiviral, antibacterial, antiparasitic, antifungal substances and combinations thereof. The agent, furthermore, can be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant and the like. The delivery system can have a large number of biologically active agents, either individually 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. Anti-bacterial agents, such as penicillins, cephalosporins, vancomycin, bacitracin, polymycins, tetracyclines, chloramphenicol, erythromycin, streptomycin and the like. Antiparasitic agents, such as quinacrine, chloroquine, quinine, and the like. Antifungal agents, such as nystatin, gentamicin, miconazole, tolnaftate, undecyclic acid and its salts and the like. Antiviral agents, such as vidarabine, acyclovir, ribarivine, amantadine, hydrochloride, iododeoxyuridine, dideoxyuridine, interferons and the like. Antineoplastic agents, such as methotrexate, 5-fluorouracil, biomycin, tumor necrosis factor, tumor specific antibodies conjugated with toxins, and the like. Analgesic agents, such as salicylic acid, salicylate esters and salts, acetaminophen, ibuprofen, morphine, phenylbutazone, indomethacin, sulindac, tolmetin, zomepirac and the like. Local anesthetics, such as cocaine, benzocaine, novocaine, lidocaine and the like. Vaccines, or antigens, epitopes, immunogens of human or animal pathogens, such as hepatitis, influenza, measles, mumps, rubella, hemophilus, diphtheria, tetanus, rabies, polio, as well as veterinary vaccines and the like. Central nervous system agents, such as tranquilizers, sedatives, anti-depressants, hypnotics, B-adrenergic blocking agents, dopamine and the like. Growth factors, such as colony stimulating factor, epidermal growth factor, erythropoietin, fibroblast growth factor, neural growth factor, human growth hormone, platelet-derived growth factor, insulin-like growth factor and the like. Hormones, such as progesterone, estrogen, testosterone, follicle-stimulating hormone, chorionic gonadotrophin, insulin, endorphins, somatotropins and the like. Antihistamines, such as diphenhydramine, chlorpheniramine, chlorcyclizine, promethazine, cimetidine, terfenadine, and the like. Cardiovascular agents, such as verapamil hydrochloride, digitalis, streptokinase, nitroglycerin paparafine, disopyramide phosphate, isosorbide dinitrate, and the like. Anti-ulcer agents such as cimetidine hydrochloride, sopropamide iodide, propantheline bromide and the like. Bronchodilators, such as metaproternal sulfate, aminophylline, albuterol, and the like. Vasodilators, such as theophylline, niacin, nicotinate esters, amyl nitrate, minoxidil, diazoxide, nifedipine and the like.

The bioactive agents used in the patent formulations may be well known to those skilled in the art to whom this invention relates. The classes of bioactive agents contemplated by the patent formulations include insecticides, acaricides, parasiticides, growth promoters, and oil-soluble, non-steroidal anti-inflammatory drugs (NSAIDs). Specific classes of compounds belonging to these classes include, for example, avermectins, milbemycins, nodulisporic acid and its derivatives, estrogens, progestins, androgens, substituted pyridylmethyl derivatives, phenylpyrazoles, and COX-2 inhibitors.

The avermectin and milbemycin series of compounds are potent anthelmintic and antiparasitic agents against a wide range of internal and external parasites. The compounds belonging to these series are either natural products or their semi-synthetic derivatives. The structures of these two series of compounds are closely related and both share a 16-membered macrocyclic lactone ring complex; however, milbemycin does not have an aglycone substituent at the 13-position of the lactone ring. Avermectin natural products are exhibited in the U.S. Patent 4,310,519 to Albers-Schonberg et al., and 22,23-dihydro avermectin compounds are disclosed in Chabala et al., U.S. Pat. Patent 4,199,569. For a general discussion of avermectins, including consideration of their use in humans and animals, see "Ivermectin and Abamectin," W.C. Campbell, published by Springer-Verlag, New York (1989). In addition, bioactive agents such as avermectins or ivermectin can be used in combination with other bioactive agents; and for avermectin, ivermectin and combinations of bioactive agents, references are Kitano, U.S. Patent No. 4,468,390, Beuver et al., U.S. Pat. Patent No. 5,824,653, von Bittera et al., U.S. Pat. Patent No. 4, 283, 400, European Patent Application 0 007 812 Al, published June 2, 1980, U.K. Patent Specification 1 390 336, published April 9, 1975, European Patent Application 0 002 916 A2, Ancare New Zealand Patent No. 237 086, Bayer New Zealand Patent 176193, issued November 19, 1975, intcralia.

The naturally occurring milbemycins are described in Aoka et al., U.S. Patent 3,950,360, as well as in various references cited in 'The Merck Index" 12th ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, New Jersey (1996). Synthetic derivatives of these classes of compounds are well known in the art and are described, for example, in U.S. Patent 5,077,308, U.S. Patent 4,859,657, U.S. Patent 4,855,319, U.S. Patent 4,427,669, U.S. Patent 4,199,569 Patent 5,055,596, U.S. U.S. Patent 4,973,711 Patent 4,978,677 and U.S. Pat. Patent 4,920,148.

Nodulisporic acid and its derivatives are a class of acaricidal, antiparasitic, insecticidal and anthelmintic agents known to those skilled in the art. These compounds are used to treat or prevent infections in humans and animals. These compounds are described, for example, in U.S. Pat. Patent 5,399,582 and WO 96/29073. Additionally, the compounds can be used in combination with other insecticides, parasiticides and acaricides. Such combinations include anthelmintic agents, such as those previously discussed, which include ivermectin, avermectin, and emamectin, as well as other agents, such as thiabendazole, febantel, or morantel; phenylpyrazoles, such as fipronil; and insect growth regulators, such as lufenuron. Such combinations are also contemplated by the present invention.

In general, all classes of such insecticides can be used in the present invention. One example of this class includes substituted pyridylmethyl derivatives, such as imidacloprid. Agents of this class are described, for example, in U.S. Pat. Patent 4,742,060 or in EP 892,060.

Pyrazoles such as phenylpyrazoles and N-arylpyrazoles are another group of insecticides, which possess excellent insecticidal activity against all insect pests, including blood-sucking vermin such as ticks, fleas, etc., which are parasites of animals. This group of agents kills insects by acting on the gamma-butyric acid receptor of invertebrates. Such agents are described, for example, in U.S. Pat. Patent No. 5,567,429, U.S. Patent No. 5,122,530, EP 295,117 and EP 846686 Al (or Banks GB 9625045, filed Nov. 30, 1996, also believed to be identical to USSN 309,229, filed Nov. 17, 1997). It would be well within the skill level of the practitioner to decide which individual compounds can be used in patent formulations.

Insect growth regulators are another class of insecticides or acaricides, which have also secured patent formulations. The compounds belonging to this group are well known to the practitioner and represent a wide range of different chemical classes. All these compounds act by interfering with the development or growth of the insect pest. Insect growth regulators are described, for example, in U.S. Pat. U.S. Patent 3,748,356 U.S. Patent 3,818,047 U.S. Patent 4,225,598 Patent 4,798,837 and U.S. Pat. Patent 4,751,225, as well as in EP 179,022 or U.K. 2,140,010. Again, it would be well within the skill level of the practitioner to decide which individual compounds can be used in patent formulations.

Estrogens, progestins and androgens refer to groups of chemical compounds which are also well known to those skilled in the art. In fact, estrogens and progestins are among the most commonly prescribed drugs, and are used, for example, alone or in combination for contraception or hormone replacement therapy in postmenopausal women. Estrogens and progestins occur naturally or can be made synthetically. This class of compounds also includes estrogen or progesterone receptor antagonists. Anti-estrogens such as tamoxifen and clomiphene are used to treat breast cancer and infertility. Antiprogestives are used as contraceptives and anticancer drugs, as well as for induction of labor or termination of pregnancy.

Androgens and antiandrogens are structurally related to estrogens and progestins since they, too, are biosynthesized from cholesterol. These compounds are based on testosterone. Androgens are used in hypogonadism and help muscle development. Antiandrogens are used, for example, in the treatment of prostate hyperplasia and cancer, acne, male pattern baldness, as well as to inhibit the sex drive in people who are sex offenders. Estrogens, progestins and androgens are described, for example, in "Goodman & Gilman's The Pharmacological Basis of Therapeutics", 9* ed., J.G. Handman and L. Elimbird, eds., Ch. 57 to 60, pp. 1411-1485, McGraw Hill, New York

(1996) or in "Principles of Medicinal Chemistry", 2* ed., VV.O. Foye, ed., Ch. 21, pp. 495-559, Lea & Febiger, Philadelphia (1981).

Estrogens, progestins and androgens are also used in animal husbandry as growth promoters for feed animals. Compounds of these classes are known in the art to act as growth promoting steroids in animals such as cattle, sheep, pigs, poultry, rabbits, etc. Animal growth promotion delivery systems are described, for example, in U.S. Pat. U.S. Patent 5,401,507 U.S. Patent 5,288,469 U.S. Patent 4,758,435

U.S. Patent 4,686,092 5,072,716 and U.S. Pat. Patent 5,419,910.

NSAIDs are well known in the art. The class of compounds belonging to this group includes salicylic acid derivatives, para-aminophenol derivatives, indole and indene acetic acids, heteroaryl acetic acids, arylpropionic acids, anthranilic acids (phenamates), enolic acids and alkanones. NSAIDs exert their activity by interfering with the biosynthesis of prostaglandins, by irreversibly or reversibly inhibiting cyclooxygenase. Also included are C0X-2 inhibitors, which act by inhibiting the C0X-2 receptor. The compounds of this group have analgesic, antipyretic and non-steroidal anti-inflammatory properties. Compounds belonging to these classes are described, for example, in Chapter 27 of Goodman and Gilman, pages 617 to 658 or in Chapter 22 of Foye, pages 561 to 590, as well as in U.S. Pat. Patent 3,896,145; U.S. Patent 3,337,570; U.S. Patent 3,904,682; U.S. Patent 4,009,197; U.S. Patent 4,223,299 and U.S. Pat. Patent 2,562,830, as are specific agents listed in the Merck Index.

Macrolides are a class of antibiotics that contain a multi-membered lactone ring to which one or more deoxy sugars are attached. Macrolides are generally bacteriostatic, but have been shown to be bactericidal at high concentrations against highly sensitive organisms. Macrolides are most effective against gram-positive cocci and bacilli, although they also have some activity against some gram-negative organisms. Macrolides exert their bacteriostatic activity by inhibiting bacterial protein synthesis by reversibly binding to the 50 S ribosomal subunit.

("Goodman & Gillman's the Pharmacological Basis of Therapeutics", 9th ed., J.G. Hadman & L.E. Limbird, eds., ch. 47, pp. 1135-1140, McGraw-Hill, New York (1996)).

Macrolides, as a class, are colorless and usually crystalline. The compounds are generally stable in near-neutral solution, but have only limited stability in acidic or basic solutions. The reason for this is that the glycosidic bonds are hydrolyzed in acid, and the lactone ring is saponified in basic ("Principles of Medicinal Chemistry", 2<nd>ed., VV.F. Foye, ed., ch. 31, pp. 782-785, Lea & Febiger, Philadelphia (1981)). Therefore, there is a need for pharmaceutical or veterinary compositions for parenteral, eg, intravenous, intramuscular, subcutaneous, administration of macrolide antibiotics.

The bioactive agent of the present invention may be a macrolide, since macrolides are soluble in many organic solvents and only slightly soluble in water. Macrolide solutions in organic solvent systems are used in human and veterinary practice for intramuscular or subcutaneous administration.

Macrolides as a class include erythromycin and its derivatives, as well as other derivatives such as azalides. Erythromycin (MW. 733.94 daltons) is the common name for a macrolide antibiotic produced by the strain Sireptomyces erythreous. It is a mixture of three erythromycins, A, B and C, which mostly consists of erythromycin A. Its chemical name is (3R<*>. 4S*, 5S*,6R<*>.7R<*>, 9R<*>, 11R<*>, 12R* 13S* 14R<*>)-4-[(2,6-dideoxy-3-C-methyl-3-0-methyl-a-L-ribo-hexopyranosyl)-oxy]- 14-Ethyl-7,12,13-trihydroxy-3,5,7,9,11,13-hexamethyl-6[[3,4,6-trideoxy-3-(dimethylamino)-P-D-xylo-hexapyranosyl]oxy]oxacyclotetradecane-2,10-dione, (C37H67NO13).

Erythromycin has broad and substantial bacteriostatic activity against many Gram-positive and some Gram-negative bacteria, as well as other organisms, including mycoplasmas, spirochetes, chlamydia, and rickettsiae. In humans, it finds useful application in the treatment of a wide range of infections. It is widely used in veterinary practice in the treatment of infectious diseases, such as pneumonia, mastitis, metritis, rhinitis and bronchitis in cattle, pigs and sheep.

Other erythromycin derivatives include carbomycin, clarithromycin, josamycin, leukomycins, midekamycins, mycamycin, myocamycin, oleandomycin, pristinamycin, rokitamycin, rosaramycin, roxithromycin, spiramycin, tylosin, troleandomycin, and virginiamycin. As with erythromycin, many of these derivatives exist as mixtures of components. For example, carbomycin is a mixture of carbomycin A and carbomycin B. Leukomycin exists as a mixture of components Ai, A2, A3, A9, B1-B4, U, and V in various ratios. Component A3 is also known as josamycin, and leukomycin V is also known as myocomycin. The main component of midekamycin is midekamycin A, and the minor components are midekamycin A2, A3 and A4. Similarly, mycamycin is a mixture of several components, mycamycin A and B. Mycamycin A is also known as virginiamycin M1. Pristinamycin is composed of pristinamycin IA, Ibi Ic, which are identical to virginiamycins, individually, B2, B13 and B2, and pristinamycin IIAi Hb, which are identical to virginiamycin M1 and 26,27-dihydrovirginiamycin M1. Spiramycin consists of three components, spiromycin I, II and III. Virginiamycin is composed of virginiamycin Sii virginiamycin Mi. All of these components can be used in the present invention. The sources of these macrolides are well known to the practitioner and are described in the literature in references such as "The Merck Index", 12th ed., S. Budarari, ed., Merck & Co., INE, Whitehouse Station, NJ (1996).

Azalides are semi-synthetic macrolide antibiotics, related to erythromycin A and showing similar solubility properties. The structure of azithromycin is known. Useful azalide compounds are disclosed in EP 508699, incorporated herein by reference. Suitable base and acid addition salts and ester derivatives of macrolide compounds are also contemplated for use in the present invention. These salts are formed from suitable organic or inorganic acids or bases. These derivatives include the usual hydrochloride and phosphate salts, as well as acetate, propionate and butyrate esters. These derivatives may have different names. For example, the phosphate salt of oleandomycin is matromycin, and the triacetyl derivative is troleandomycin. Rokitamycin is leukomycin V 4-B-butanoate, 3B-propionate.

Other antibiotics may also be used as the bioactive agent in the practice of the present invention.

The bioactive agent can be, for example, a peptide or a protein. A biologically active agent can also be a substance or its metabolic precursor, which is capable of stimulating the growth and survival of cells and tissues or increasing the functioning of cells, such as blood cells, neurons, muscles, bone marrow, bone cells and tissues, and the like. For example, the biologically active agent may be a substance that promotes nerve growth, such as ganglioside, phosphatidylserine, nerve growth factor, brain-derived neurotrophic factor, fibroblast growth factor, and the like. To promote tissue growth, the biologically active agent can be either a hard or soft tissue promoter substance or a combination thereof. Suitable tissue growth promoting agents include, for example, fibronectin (FN), endothelial growth factor (ECGF), cementum connective extracts (CAE), human growth hormone (HGH), periodontal ligament cell growth factor, fibroblast growth factor (FGF), animal growth hormones, platelet-derived growth factor (PDGF), epidermal growth factor (EGF), interleukin-1 protein growth factor (IL-1), transforming growth factor (TGF.beta.-2'). insulin-like growth factor II (ILGF-II), human alpha thrombin (HAT), osteoinductive factor (OIF), bone morphogenetic protein (BMP) or proteins derived from them, demineralized bone matrix and their releasing factors. Further, the agent can be a substance that promotes bone growth, such as hydroxyapatite, tricalcium phosphate, di- or polyphosphoric acid, anti-estrogen, sodium fluoride preparations, substances that have a phosphate-to-calcium ratio similar to that of natural bone, and the like. The bone growth promoting substance may be in the form of, for example, bone chips, bone crystals or mineral fractions of bones and/or teeth, synthetic hydroxyapatite or other suitable form. The agent can further be used to treat metabolic bone disorders, such as abnormal calcium and phosphate metabolism, by, for example, inhibiting bone resorption, promoting bone mineralization, or inhibiting calcification. See, for example, U.S. Pat. No. 4,939,131 Benedict et al., U.S. Pat. Pat No. 4,942,157 Galli et al., U.S. Pat. Pat No. 4,894,373 to Young, U.S. Pat. No. 4,904,478 to Walsdorf et al. and U.S. Pat. Pat No. 4,911,931 to Baylink, U.S. Pat. Pat No. 4,916,241 Hayward et al., U.S. Pat. Pat No. 4,921,697 to Peterlik et al., U.S. Pat. Pat No. 4,902,296 Bolander et al., U.S. Pat. Pat No. 4,294,753 to Urist, U.S. Pat. Pat No. 4,455,256 to Urist, U.S. Pat. Pat No. 4,526,909 to Urist, U.S. Pat. Pat No. 4,563,489 to Urist, U.S. Pat. Pat No. 4,596,574 to Urist, U.S. Pat. Pat No. 4,619,989 to Urist, U.S. Pat. Pat No. 4,761,471 to Urist, U.S. Pat. Pat No. 4,789,732 to Urist, U.S. Pat. Pat No. 4,795,804 to Urist, U.S. Pat. Pat No. 4,857,456 Urist, disclosures, which are incorporated herein by reference.

Still further, the biologically active agent or bioactive agent may be an antineoplastic, antitumor or anticancer agent.

A biologically active agent can be included in the mixture in the form of, for example, an uncharged molecule, molecular complex, salt, ether, ester, amide, or other form to provide effective biological and physiological activity.

With respect to biologically active agents useful in the practice of the present invention, the following references are also made to U.S. Pat. and Williams and Chera's PCT applications, "Long Acting Injectable Formulations Containing Hydrogenated Castor Oil," filed Sep. 14, 1998, US Serial No. 09/15277 and PCT Application No. US98/190, and having priority over U.S. Pat. application Serial No. 60/067,374, incorporated herein by reference.

It follows from the above that the bioactive agent can be changed. The amount suitable for use in a formulation in accordance with the invention can be determined by one skilled in the art, without undue experimentation, from the knowledge of the art and this disclosure, taking into account factors commonly considered by those skilled in the medical, veterinary or pharmaceutical professions, such as the species used, age, weight, general health and sex of the host or patient or animal or human and the condition being treated and the LD50 and other properties of the bioactive substance(s).

The application of the composition of the invention will, therefore, finally be carried out in accordance with the method and protocol for the health care of the patient or host or animal or human following a professional, such as a doctor or veterinarian or, if more appropriate, a dentist. The choice of a particular mixture depends on the disease state or the condition to be treated, a choice that will be made following professional health care. Application by syringe or other means of applying liquid to or into tissue may be used. The amounts and concentrations of the composition administered to the patient, host, animal or human will generally be sufficient to accomplish the intended task. The quantities and rates of release, in the application of the bioactive agent, should follow the recommendations of the manufacturer of the bioactive agent. In general, the concentration of the bioactive agent in the liquid polymer formulation can be from 0.01 mg per g of the mixture to 400 mg per g of the mixture.

In certain embodiments, the present invention provides a liquid polymeric composition for the controlled release of hydrophobic bioactive substances, comprising;

(a) 1 to 30% w/v hydrophobic bioactive substance; (b) 1 to 20% w/v poly(lactide-co-glycolide) copolymer; (c) a mixture of hydrophilic and lipophilic solvents in which the volume ratio of hydrophilic to lipophilic solvents is from about 80:20 to about 5:95 and/or where the lipophilic solvent is present in an amount of at least 16.5% by weight.

In a certain preferred embodiment, the bioactive substance, eg, at least one hydrophobic bioactive substance, is present at a concentration of 1 to 10% w/v; preferably 5 to 10% wt/vol.

In another preferred embodiment, the polymer, eg, poly(lactide-co-glycolide) copolymer, is present at a concentration of 1 to 10% w/v; preferably 1 to 5% wt/vol.

In another preferred embodiment, the weight ratio of the polymer, e.g., poly(lactide-co-glycolide) copolymer to the bioactive substance, e.g., at least one hydrophobic bioactive substance, is 1:1 or less; preferably 0.5 : 1 to 1 : 1.

In yet another preferred embodiment, the volume ratio of hydrophilic and lipophilic solvents is from 65:35 to 35:65.

Another aspect of the present invention provides a liquid polymeric composition for the controlled release of hydrophobic bioactive substances, comprising: (a) a hydrophobic bioactive substance; (b) poly(lactide-co-glycolide);

(c) mixture of glycerol formal and triacetin.

Another aspect of the present invention provides the use of a liquid polymer mixture described herein in the manufacture of a medicament for the controlled release of at least one bioactive substance, e.g., at least one hydrophobic bioactive substance.

In addition to the foregoing, as the following terms are used herein, they are subject to the following definitions unless otherwise indicated: "Polymer" includes "copolymers"; "copolymer" is a polymer formed by polymerization of at least two monomers; and therefore, a "copolymer" may include a "terpolymer" or a polymer of two, three, or more monomers.

"Hydrophobic bioactive substance" means compounds useful for human or animal health, which have a solubility in water <2%,

preferably <1%, at room temperature. Examples of hydrophobic bioactive substances suitable for this invention include, but are not limited to, avermectins (eg, ivermectin, eprinomectin, etc.), milbemycins, phenylpyrazoles, nodulisporic acid and derivatives, such as those disclosed in US Patent 5,399,582 and WO96/29073, estradiol benzoate, trenbolone acetate, progesterone, norethisterone, water-insoluble NSAIDs, etc.

"Poly(lactide-co-glycolide)" means a copolymer of lactic and glycolic acid, having a lactide : glycolide ratio of 95 : 05 to 50 : 50, preferably 75 : 25 to 65 : 35. The lactic acid may be d- or 1- or dl-. The copolymer may be a single copolymer of a blend of copolymers within the parameters defined above.

"Hydrophilic solvent" means solvents, which are miscible with water, preferably those which when mixed with water in a ratio of 1:9 to 9:1 form a single-phase solution. Examples of hydrophilic solvents suitable for this 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.

"Lipophilic solvent" means solvents, which are immiscible with water, preferably having a solubility in water 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.

Once injected, the liquid composition of the present invention is able to provide sustained drug release without the burst of drug release typical of existing liquid injectable formulations. Without being bound by theory, it is assumed that during the injection of a liquid formulation of the present invention, skin depots are initially formed, which are made of polymer, surrounding a liquid core (which may appear to be "semi-solid"), while a certain hydrophilic solvent passes through the depot carrying with it the dissolved bioactive compound. The initial release of the drug from the depot is mainly through the skin. Skin permeability and the rate of initial drug uptake are controlled by the proportion of hydrophilic and lipophilic solvents in the liquid vehicle, at given polymer and drug concentrations. Over time, the depot loses its liquid vehicle, and the significant mechanism of drug release gradually becomes degradation of the polymer. Proper tuning of the liquid formulation thus allows overlapping of permeation-controlled drug uptake and erosion-controlled drug uptake and leads to a uniform and sustained drug release profile over a long period of time. And so, the depot biodegrades, not necessarily wanting to be tied to any particular theory, and not necessarily forming a solid mass of them in another physical form, which is in accordance with the mixtures of previous techniques.

The presence of a lipophilic solvent in the liquid composition of the present invention reduces the initial uptake of the bioactive compound, thereby eliminating the burst of drug release typical of existing injectable formulations where a large portion of the hydrophilic vehicle is used. The presence of a hydrophilic solvent facilitates formation of the skin polymer while preventing deposition of the bioactive compound allowing much higher levels of drug uptake than is possible when lipophilic vehicles alone are used. In the present invention, a preferred hydrophilic:lipophilic solvent ratio is between 80:20 to 20:80, most preferably between 65:35 to 35:65.

Other factors that may affect the performance of this liquid formulation include: (1) the polymer, eg, the concentration of the PLGA polymer, (2) the relative ratio of the bioactive compound to the polymer, (3) the copolymer, eg, the ratio of lactide:glycolide in the polymer, and (4) the molecular weight of the polymer. Factors (3) and (4) were well known in the art (see documents cited herein). This invention, however, differs significantly from the existing techniques, especially in aspects (1) and (2).

The liquid formulation of the present invention contains no more than 20% polymer, eg, PLGA polymer, preferably less than 10% polymer, in order to maintain a relatively constant rate of drug uptake and at the same time ensure a reasonably long duration of drug uptake (longer than 3 months). The concentration of polymer, eg, PLGA in this formulation is therefore in sharp contrast to known formulations which prescribe a significantly higher ratio of polymer, such as PLGA polymer. The concentration of the bioactive substance in the liquid formulation can be from 1% to 30%. Preferably, the ratio of polymer, eg, PLGA polymer to bioactive compound is less than or equal to 1:1; ratio, which is also significantly lower than the one usually prescribed. Within the range described here, higher polymer concentrations decrease the rate of drug uptake, and increasing polymer:bioactive compound ratios also decrease the rate of uptake.

Liquid formulations may be prepared by dissolving all solid ingredients in a vehicle under normal manufacturing conditions used for sterile injectable products. This mixture may have additional inert substances commonly used in parenteral formulations including, but not limited to, antimicrobial agents, antioxidants, and the like.

The instant liquid compositions are administered to a warm-blooded animal, such as man, cattle, sheep, swine, dog, horse, cat, and the like (eg, mammals, such as humans and pets and food animals) by intramuscular or subcutaneous injection. Formulations are generally prepared to contain from 1 to 30%, preferably from 1 to 10%, of the bioactive compound. For example, at a preferred dosage volume of about 1 ml for treating cattle of 50 kg body weight, the formulation contains from 50 to 100 mg of avermectin compound per ml of solution or about 5 to 10% w/v. However, depending on the activity of the compound and the animal being treated, concentrations as low as 1% of the bioactive compound are also useful.

The following examples are provided to illustrate the invention and are not intended to limit the invention in any way.

EXAMPLE 1

Development of a long-acting injectable formulation containing 6-amino-3-cyano-1-(2,6-dichloro-4-sulfurpentafluorophenyl)-4-(trifluoromethylthio)pyrazole

Poly(DL-lactide/glycolide) 75/25 (PLGA, 0.25 g) was dissolved in enough glycerol formal to provide a 2.5 ml solution. In a separate vessel, poly(DL-lactide/glycolide) 75/25 (0.25 g) was dissolved in enough triacetin to make 2.5 ml of solution. The two PLGA solutions were mixed well and added to the vessel containing the active ingredient (0.50 g). The contents of the vessel were mixed until the active ingredient was dissolved, and the resulting solution was sterile filtered into a vial and sealed.

EXAMPLE 2

Development of a long-acting injectable formulation containing ivermectin

The general procedure of Example 1 was followed to provide the following ivermectin formulations:

For the sake of comparison, ie, to show just how much more solvent is used in this invention compared to prior art mixtures: In Preparation 1 in this example, triacetin, a lipophilic solvent, is present at 16.45% by weight. In formulation 2 in this example, triacetin, a lipophilic solvent, is present at about 29% by weight. In formulation 3 in this example, triacetin, a lipophilic solvent, is present at about 42% by weight. In formulation 4 in this example, triacetin, a lipophilic solvent, is present at about 43% by weight.

EXAMPLE 3

Development of a long-acting injectable formulation incorporating eprinomectin

The general procedure of Example 1 was followed to provide the following eprinomectin formulations:

For the sake of comparison, ie, to show just how much more solvent is used in this invention compared to prior art mixtures: In preparation 2 in this example, triacetin, a lipophilic solvent, is present at about 45% by weight. And it is indicated that the lipophilic solvent, in the preparations according to the present invention, may be 100% by volume of the solvent present, as discussed in the foregoing general description.

EXAMPLE 4 Activity of a long-acting injectable formulation containing 6-amino-3-cyano-1-(2,6-dichloro-4-sulfurpentafluorophenyl)-4-(trifluoromethylthio)pyrazole against fleas in dogs

Three short-legged dogs were treated with the formulation from Example 1 in the form of a single subcutaneous dose of 10 mg/kg. The dogs were fasted for at least 6 hours before and 6 hours after the treatment. On day 1 (day 0 = day of drug administration) the animals are exposed to being swarmed by about 100 fleas. Animals were combed and fleas were counted and removed approximately 48 hours after infestation. Animals were exposed to fleas on days 12 and 26, then combed and fleas counted and removed approximately 48 hours after infestation. Infestation/counting was repeated approximately monthly.

Blood samples were collected from animals on Day 0 at 1, 2, 3 and 6 hours after treatment, on Day 1 at 24 hours after treatment and if vomiting was observed. Blood samples were also collected after determining the number of fleas. Animals were observed for vomiting every hour for 6 hours per treatment. Almost 100% efficacy has been demonstrated for >12 months without any occurrence of emesis in treated animals. Plasma level profiles for individual dogs are shown in Figure 1.

EXAMPLE 5

Plasma level profiles of long-acting ivermectin formulations in cattle

Plasma levels of ivermectin were determined in healthy cattle treated with ivermectin formulations 1, 2 and 3 of Example 2. Each formulation was administered to a group of five cattle (generally weighing 125 to 250 kg) as a single subcutaneous injection dose of 1 mg/kg. From each treated animal, ten ml samples of heparinized blood were collected on Days 1-7 (daily), 10, 14 and weekly, then for 15 weeks. Plasma level profiles (mean of five animals in each group) are shown in Figure 2.

EXAMPLE 6

Plasma level profiles of long-acting eprinomectin formulations in the pig

Plasma eprinomectin levels were determined in a pig treated with eprinornectin formulation 2 from Example 3. Three pigs

(inoculated with 2,000 infective eggs of Trichurissuis on day -50 and orally with 15,000 infective larvae of Oesophagostomum sp. on day 0) received by subcutaneous injection formulation 2 of Example 3 at a dose of 1.5 mg/kg. Ten ml blood samples were collected from each animal on days 3, 7 and weekly thereafter. The plasma level profile is shown in Figure 3 (with alternating drug/PLGA formulation in 100 glycerol formal).

Claims (13)

1. Liquid polymer mixture, which includes: a) 1-30% by weight/volume of at least one bioactive substance; b) 1-20% by weight/volume of at least one biologically acceptable polymer; where the weight ratio of polymer to bioactive substance is 1:1 or less, and c) a mixture of at least one hydrophilic and at least one lipophilic solvent, where the volume ratio of hydrophilic and lipophilic solvents is from 80:20 to 0:100 and/or where the lipophilic solvent is present in an amount of at least 16.5% by weight. 2. A liquid polymer mixture, as in claim 1, for the controlled release of hydrophobic bioactive substances, which includes: a) 1 to 30% of the weight/volume of the hydrophobic bioactive substance; b) 1 to 20% by weight/volume of poly(lactide-co-glycolide) copolymer; where the weight ratio of poly(lacid-co-glycolide) copolymer to hydrophobic bioactive substance is 1:1 or less; and c) a mixture of hydrophilic and lipophilic solvents wherein the volume ratio of hydrophilic to lipophilic solvents is from about 80:20 to about 5:95 and/or where the lipophilic solvent is present in an amount of at least 16.5% by weight. 3. A mixture, as in claim 1, characterized in that said bioactive substance is present from 1 to 10% by weight/volume. 4. A mixture, as in claim 1, characterized in that said poly(lactide-co-glycolide) copolymer is present from 1 to 10% w/v. 5. A mixture, as in patent claim 1, characterized by the fact that the ratio of the mentioned hydrophilic and lipophilic solvents is from 65:35 to 35:65. 6. A mixture, as in claim 1, characterized by including: a) 1 to 10% by weight/volume of hydrophobic bioactive substance; b) 1 to 10% by weight/volume of poly(lactide-co-glycolide) copolymer, where the weight ratio of poly(lactide-co-glycolide) copolymer to hydrophobic bioactive substance is 1:1 or less; c) a mixture of hydrophilic and lipophilic solvents where the volume ratio of hydrophilic and lipophilic solvents is from 65:35 to 35:65. 7. A mixture, as in claim 1, characterized by including: a) 5 to 10% by weight/volume of hydrophobic bioactive substance; b) 5 to 10% by weight/volume of poly(lactide-co-glycolide) copolymer, where the weight ratio of poly(lactide-co-glycolide) copolymer to hydrophobic bioactive substance is 1:1 or less; c) a mixture of hydrophilic and lipophilic solvents where the volume ratio of hydrophilic and lipophilic solvents is from 65:35 to 35:65. 8. A mixture, as in patent claim 1, indicated by the fact that said bioactive substance is selected from fipronil, avermectin, ivermectin, eprinomectin, milbemycin, nodulisporic acid and their derivatives, estradiol benzoate, trenbolone acetate, progesterone and norethisterone. 9. A mixture, as in claim 1, characterized in that the ratio of lactide:glycolide in the poly(lactide-co-glycolide) copolymer is from 95:5 to 50:50. 10. A mixture, as in claim 1, characterized in that the ratio of lactide:glycolide in the poly(lactide-co-glycolide) copolymer is from 75:25 to 65:35. 11. The mixture, as in claim 1, indicated by the said hydrophilic solvent being selected from glycerol formal, glycofural, N-methyl pyrrolidone, 2-pyrrolidone, isopropylidene glycerol, di(propylene glycol) methyl ether and their mixtures. 12. A mixture, as in claim 1, characterized by including: a) 5 to 10% by weight/volume of hydrophobic bioactive substance; b) 5 to 10% by weight/volume of poly(lactide-co-glycolide) copolymer, where the ratio of lactide:glycolide poly(lactide-co-glycolide) copolymer is from 75:25 to 65:35, and the weight ratio of poly(lactide-co-glycolide) copolymer to the hydrophobic bioactive substance is 1:1 or less; c) A mixture of glycerol formal and triacetin, where the volume ratio of glycerol formal and triacetin is from 65 : 35 to 35 : 65. 13. The use of a liquid polymer mixture according to claim 1 and claim 2, characterized by the fact that it is used for the production of a drug with a controlled release of a hydrophobic bioactive substance.