Title of Invention

A METHOD FOR THE MANUFACTURE OF BIODEGRADABLE DELIVERY VEHICLES

Abstract There Is provided a method for the manufacture of biodegradable delivery vehicle made of a biodegradable polymer, a plasticizer and a biologically active substances (BAS) by varying the physiochemical properties as herein described of at least one member of the group consisting of said biodegradable polymer, said plasticizer, and said BAS and combinations thereof, thereby modulating the degradation of said biodegradable vehicle, said method comprising the steps of a. selecting at least one biodegradable polymer as herein described. b. dissolving said polymer in at least one volatile solvent selected from a group consisting of acetone, methyl acetate, ethyl acetate, chlorofonn, dichloromethane, methyl ethyl ketone, hexafluroisopropanol, tetrahydrofuran and hexafluroacetone seqwuihydrate to form a solution. c. adding at least one known plasticizer to said solution of step (b); and d. evaporating said solvent from the solution of step (c) and adding a biologically active substance (BAS) as herein described either before or after the step (b).
Full Text This invention relates to a method for the manufacture of Biodegradable delivery vehicle.
Field of Invention:
Biodegradable vehicles and delivery systems, which can be mixed with one or more physiologically, pharmacologically and biologically active substance(s) (BAS), are provided. The biodegradable vehicle (without any BAS - loading) can be used as a biodegradable filter or spacer to fill in cavities or body tissues in animals, birds and humans.
The biodegradable vehicle can be mixed with one or more BAS. The delivery systems loaded with BAS can be used to control the release of the BAS from the delivery system for a prolonged period of time. The consistency and rheology, hydrophilicity and hydrophobicity, and in vivo degradation rates of the biodegradable vehicles and BAS loaded delivery systems are controlled by modulating the types of polymers or copolymers, molecular weight of polymers and copolymers, copolymer ratios, and ratios of blends of polymers or copolymers with different molecular weights or different hydrophilicity or hydrophobicity, types of plasticizers, concentration of plasticizers, ratios of two or more plasticizers used in combination. The release characteristics of the BAS from the biodegradable delivery system are also controlled by the above-mentioned factors. The present invention also provides methods for preparing these biodegradable vehicles and delivery systems.
Background of the invention:
The term biodegradable polymers refer to those polymers, which are slowly converted to nontoxic degradation products in the body. Examples include homopolymers and copolymers of polylactic acid or polylactide (PLA), polyglycolic acid or polyglycolide, polycaprolactone (PCL), polyanhydrides, polyphosphoesters, polyorthoesters, polyaminoacids, pseudopolyaminoacids, polyhydroxybutyrates, polyhydroxyvalerates, polyphosphazenes, polyalkylcyanoacrylates, polydioxanone, poly (e -decaloactone),
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poly(glycolide-co-trimethylene carbonate), poly(ethylene carbonate), poly(iminocarbonate), poly(l,3-propylene malonate), poly(ethylene-l,4-phenylene-bis-oxyacetate), poly(ester-amides). Some of these polymers and their copolymers have been studied extensively for biomedical applications such as sutures, staples and mesh for wound closure, fracture fixation, bone augmentation and ligament reconstruction in orthopedics, ligation clips and vascular grafts in cardiovascular surgery, and dental repairs (Barrows T. Degradable implant materials: a review of synthetic absorbable polymers and their applications. Clinical materials., 1:233-257,1986). They have also been used to prepare biodegradable drug dehveiy systems capable of releasing the drug or a biologically active substance over the desired length of time.
The advantages of using biodegradable polymers in biodegradable delivery systems of BAS are: ready availability of polymers, polymers used are nontoxic, biocompatibile and biodegradable, facile predictability of biodegradation rates of the polymers, ease of modification of the degradation characteristics of the polymers, regulatory approval of some of the commonly used biodegradable polymers, ease of fabrication of the polymers into various types of devices and the possibility of controlling the release of BAS by polymers over the desired length of time.
Release of BAS from a polymeric delivery system depends on the physicochemical characteristics of the BAS molecule, polymer and other excipients, and the dosage form. The important factors governing BAS release characteristics from the delivery systems prepared witii biodegradable polymers are polymer molecular weight, copolymer ratio, polymer hydrophilicity or lipophilicity, percentage of various polymers in a blend consisting of polymers with varying molecular weights or copolymer ratios, hydrophiUcity or hydrophihcity of the platicizer, percentage of various hydrophilic and hydrophihc plasticizers in a blend of varying types of plasticizers, degree of plasticization, particle size and percentage of BAS-loading, hydrophilicity or lipophilicity of the incorporated BAS, solubility of the BAS ui both the delivery system and in the biological fluids, physical form of the formulation (i.e. liquid, gel or paste), and the method of preparation of the delivery system.
Several types of BAS delivery systems have been prepared from biodegradable polymers. These include microparticles such as microspheres and microcapsules (Schindler A, Jeffcoat R, Kimmel GL, Pitt CG, Wall ME and Zwelinger R, in: Contemporary Topics in Polymer Science, Pearce EM and Schaefgen JR, eds.. Vol. 2, Plenum Publishing Corporation, New York, pp. 251-289,1977; Mason NS, Gupta DVS,
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Keller, DW, Youngquist RS, and Sparks RF. Biomedical applications of microencapsulation, (Lim F, ed.), CRC Press Inc., Florida, pp. 75-84,1984; Harrigan SE, McCarthy DA, Reuning Rand Thies C, Midi Macromol Monograph, 5:91-100,1978.; Sanders LM, Bums R, Bitale K and Hoffinan P., Clinical performance of nafarelin confroUed release injectable: influence of formulation parameters on release kinetics and duration of efficacy., Proceedings of the International Symposium on Controlled Release and Bioactive Materials, 15:62-63,1988; Mathiowitz E, Leong K and Langer R., Macromolecular drug release from bioerodible polyanhydride microspheres, in: Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, Peppas N and Haluska R, eds., pp. 183,1985), films (Jackanicz TM, Nash HA, Wise DL and Gregory JB. Polylactic acid as a biodegradable carrier for contraceptive steroids., Contraception, 8:227-233,1973.; Woodland JHR, YoUes S, Blake AB, Hehich M and Meyer FJ. Long-acting delivery systems for narcotic antagonist. I. J. Med. Chem., 16:897-901,1973), fibers (Eenink MJD, Maassen GCT, Sam AP, Geelen JAA, van Lieshout JBJM, Olijslager J, de Nijs H, and de Jager E. Development of a new long-acting contraceptive subdermal implant releasing 3-ketodesogeatrel., Proceedings of the 15th International Symposium on Controlled Release of Bioactive Materials, Controlled Release Society, Lincotoshire, Illinois, pp.402-403,1988), capsules (Sidman KR, Schwope AD, Steber WD, Rudolph SE, Paulin SB. Biodegradable, implantable sustained release systems based on glutamic acid copolymers. J. Membr. Sci., 7:277-291,1980; Pitt CG, Gratzl MM, Jeffcoat MA, Zweidinger R and Schindler A. Sustained drug delivery systems 11: Factors affecting release rates from poly-s-caprolactone and related biodegradable polyesters., J. Pharm. Sci., 68(12): 1534-1538,1979), discs (Cowsar DR, Dunn RL., Biodegradable and non-biodegradable fibrous delivery systems, in: Long acting Contraceptive Delivery Systems, Zatuchni GI, Goldsmith A, Shelton JD and Sciarra JJ, eds.. Harper & Row, Publishers, Philadelphia, pp. 145-148,1984), wafers (Brem et al., J. Neurosurgery, 74:441-446,1991) and solutions (Dunn et al, U.S. Patents 4,938,763; 5,324,519; 5,324,520; 5,278,201; 5,340,849; 5,368,859; 5,660849; 5,632,727; 5,599,552; 5,487,897). All of these, with the exception of microparticles need to be surgically implanted. This procedure is inconvenient and undesirable. Drug-loaded miaospheres on the other hand, can be easily injected. However, there are several inherent disadvantages of microparticles. These include the need for reconstitution before injection, tlie inability to remove the dose once it is injected, and the relatively complicated manufacturing procedure.
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hydrophilicity of the biodegradable vehicle as well. The plasticizer or blends thereof are also capable of modulating the degradation kinetics, the consistiency, the hydrophilicity and the hydrophobicity of the biodegradable vehicle as well.
In another aspect, the present invention provides a biodegradable delivery system comprising: (a) at least one biodegradable polymer, the polymer selected from polyesters, polyorthoesters, polylactides, polyglycolides, polycaprolactones, polyhydroxybutyrates, polyhydroxyvalerates, polyamides and polyanhydrides; and (b) at least two plasticizers, one of the plasticizers being hydrophilic and the other of the plasticizers being hydrophobic; and (c) at least one biologically active substance.
The method of manufacturing the biodegradable vehicles described in the present invention involves dissolving one or more biodegradable polymers and one or more plasticizers in a volatile solvent or mixture of volatile solvents. The volatile solvent or mixture of volatile solvents is/are then removed using vacuum or evaporated at an elevated temperature, or removed using both vacuum and elevated temperature. The resulting biodegradable vehicles can be free flowing or viscous liquids, gels or pastes. This method is particularly suited when polymers of high molecular weights are used to prepare the vehicles or BAS delivery system, or when a high consistency of the biodegradable vehicle or BAS delivery system, is desired. Alternatively, one or more biodegradable polymers can be directly dissolved in one or more plasticizers by stirring the mixture with or without the use of heat. This method is particularly suited when polymers of low molecular weights are used to prepare the biodegradable vehicles or BAS delivay system, or vdien a low consistency or BAS delivery system is desired.
In order to prepare a BAS-loaded delivery system, the BAS can be loaded into the biodegradable vehicle in any physical form (i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers) at any step during the manufacturing process of biodegradable delivery systems before the volatile solvent is completely removed. The BAS-loaded delivery system can also be manufectured by loading the BAS soon after the biodegradable vehicle is prepared, or blending the BAS to the biodegradable vehicle just prior to the use of the BAS-loaded biodegradable delivery system. Mixing of the BAS with the biodegradable vehicle can be accomphshed by simply stirring the mixture with a stirring device, or by triturating the mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing. When the BAS is blended with the biodegradable vehicle just prior to use, it
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could be stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers), or gel or paste (where the BAS is dissolved or suspended in the plasticizer or blends of plasticizers). Alternatively, a device, which resembles two syringes or syringe-like devices (e.g. pumps in which materials can be mixed by depressing a trigger-like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle. The BAS is loaded in one syringe or compartment and the biodegradable vehicle is loaded in the other compartment. A removable partition or a valve, which will allow the contents of the two compartments to be mixed uniformly, sq)arates the two compartments. The mixing process is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle. The resulting BAS-loaded biodegradable delivery systems can be free flowing or viscous liquids, gels or pastes In order to prepare a BAS-loaded delivery system just prior to use, the BAS and the biodegradable vehicle can be packaged in two separate containers as a kit. The vehicle and the BAS can then be blended together by (he aforementioned methods.
The biodegradable vehicles or BAS-loaded biodegradable dehvery systems could be sterilized in the final package by an appropriate technique such as irradiation sterilization technique. Alternatively, the biodegradable vehicles or BAS-loaded biodegradable delivery systems can be prepared fi-om pre-sterilized components in an aseptic environment. Sterilization of the solvents and plasticizers used in the manufacturing process could be accompUshed by an appropriate sterihzation technique such as filtration, autoclaving or iiradiation. The polymer and the BAS used to prepare the biodegradable vehicles and the BAS-loaded biodegradable delivery systems could also be sterilized by an appropriate sterilizing technique.
Advantages of the biodegradable vehicles described in the present invention include the ease of manufacturing, injection, implantation, and application, ease of control over the consistency or rheology and hydrophilicity or hydrophobicity of tiie biodegradable vehicle, flexibility of tailoring in vivo degradation kinetics of the vehicles, tailoring the dose of the BAS in the biodegradable dehvery systems by blending the requisite amount of BAS with the biodegradable vehicle, and enhancing stability of the BAS, especially when it is blended with the biodegradable vehicle just prior to its use. A major reason for the enhanced stability of the BAS is that the BAS is not subjected to exposure to solvents, chemicals or the harsh processing conditions especially during the manufacture of the biodegradable vehicle.
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Moreover, if the BAS is stored in an appropriate separate container, it does not come in contact with the biodegradable vehicle unit it is blended with the vehicle.
Advantages of biodegradable delivery systems of the present invention include ease of manufacturing, injection, implantation, and Application, ease of control over the consistency of rheology and hydrophilicty or hydrophobicity of the biodegradable delivery systems, ease of incorporation of BAS into the delivery systems, facile tailoring of the release of BAS from the biodegradable systems, and control of in vivo biodegradation rates of biodegradable delivery systems.
The biodegradable vehicles without blending any BAS may be used as a tissue or cavity fillers or spacers in the body, whereas the biodegradable vehicles loaded with BAS may be used for the treatment of a variety of diseases and pathological conditions.
The final compositions with or without the BAS may be injected, implanted, smeared or applied directly in animals, birds and humans.
In still yet another embodiment, the present invention provides a kit comprising a) a biodegradable vehicle; and b) a BAS. In certain aspects, the BAS is blended with the biodegradable vehicle just prior to use. In certain aspects, the BAS is stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plasticizer or blends or plasticizers). Alternatively, a device, which resembles two syringes o syringes -like device) attached together a removable partition or a valve assembly can also be used to uniformly mix the BAS with the biodegradable vehicle.
Further embodiments and advantages will become more apparent when read with the detailed descriptions and figures that follow.
Brief statement of the invention.
According to this invention there is provided a method for the manufacture of biodegradable delivery vehicle made of a biodegradable polymer, a plasticizer and a biologically active substances (BAS) by varying the physiochemical properties as herein described of at least one member of the group consisting of said biodegradable polymer, said plasticizer, and said BAS and combinations thereof, thereby modulating the degradation of said biodegradable vehicle, said method comprising the steps of
(a) selecting at least one biodegradable polymer as herein described.
(b) dissolving said polymer in at least one volatile solvent selected from a group consisting of acetone, methyl acetate, ethyl acetate, chlorofonn, dichloromethane, methyl ethyl ketone, hexafluroisopropanol, tetrahydrofuran and hexafluroacetone seqvfuihydrate to form a solution.
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(c) adding at least one known plasticizer to said solution of step (b); and
(d) evaporating said solvent from the solution of step (c) and adding a biologically active substance (BAS) as herein described either before or after the step (b).
In this method
(i) the biodegradable polymer is selected from a group consisting homopolymers and copolymers or blends thereof, of polysters, polyphosphosesters, polylactic acid or polyactides, polyglycolic acid or polyglycolides, polycaprolactones, polyalkycyanoacrylates, poiyphospazenes, polyhydroxyburates, polyhydroxyvalerates, poly amino acids, pseudopolyamino acids, polyamides, polyanhydrides, polydioxanone, poly (e -decaloactone), poly (glycolide-co-trimethylene carbonate), poly (ethylene carbonate), poly (imino crbonate), poly (1,3- propylene malonate), poly ( ethylene -1,4- phenylene-bis-oxyacetate), and poly (ester amides).,
(ii) the plasticizer is selected from a group consisting of citrates such a diethyl citrate (DEC), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri -n - citrate, acetyltri - n - hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthal.ate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoetghyl ether, diethylene glycol monoethyl ether, propylene glycol monotertiary butyl ether, dipropylene glycol monomethyl ether, N - methyl - 2 - pyrrolidone, 2-pyrrolidone, isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glyfurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycon laurate, propylene glycol capryiate/caprate, gamma butyrolactone, polyethylene glycols (PEG), vegetable oils obtained from seeds, flowers fruits, leaves stem or any part of a plant or tree such as cotton seed oil, soy bean oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids such PEG-6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG-8 glycerol linoleate, PEG-4 glycerol caprylate/ carpate , PEG-8 glycerol caprylate/carpate, polyglyceryl-3- oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PE~G-32 glyceryl laurate, PEG-32 glyceyl palmitostearate, PEG-32 glceryl stearate, glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate.
(iii) the, when adding at least on biologically active substances to the product of step (d) the said biodegradable vehicle is loaded with at least one biologically active substance soon after preparing the biodegradable vehicle or just prior to using the biodegradable delivery system loaded with the biologically active substances, and
(iv) The biologically active substance is selected form the group consisting of steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS
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agents) narcotic agonists and antagonists, fertility regulating agents, antibodies and antigents, anesthetics, analgestics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, c cavity and infection preventing agents, cardiovascular agents, - angiogenic and antiangiognic agents, anti-inflamatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, live or killed bacteria and viruses, agents or extracts derived from whole or parts of plants, trees, flowers fruits, buds, seeds, leaves, barks stem roots, and animal tissues, growth promoting agents, soft an hard tissues, growth promoting agents, cells, tissues such as bones or agents derived there from , bone growth promoting agents such as calcium phosphates calcium sulfate and hydroxyapatities, whole viable cells and cells lines, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid (RNA) RNA fragments, and biological tissues such as islets of langerhans and pancreas. The biologically active substances can be in the form of a solid, or dissolved or suspended in a plasticizer or mixture of plasticizers.
Detailed description of the invention
In certain embodiments, the present invention relates to compositions of biodegradable vehicle and BAS-loaded delivery systems comprising at least one polymer and at least one plasticizer. The delivery system for the present invention may also comprise.
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of at least one biologically active substance (BAS). It also relates to the method of preparing biodegradable vehicles and dehvery systems loaded with BAS.
According to the present invention, the term polymer includes oMgomer, homopolymer, copolymer and terpolymer. Biodegradable polymers are used in this invention because they form matrices that can control the release of BAS over a desired length of time, can degrade in vivo into non-toxic degradation products, and are available in varying physicochemical properties including varying hydrophilicity and hydrophobicity, varying molecular weights, varying ciystallinily and amorphous states, and varying copolymer ratios.
In the present invention, plasticizers are used in varying ratios to convert a polymer in a sohd state to a biodegradable vehicle or delivery system of varying consistency such as a free flowing or a viscous hquid, a gel or a paste. Plasticizers are chemicals added to polymers to improve their flow, and therefore their processibility (Billmeyer, F., Jr. Textbook of Polymer Science, John Wiley and Sons, New York, 1984, p. 472). This is achieved by lowering their glass transition temperature (a temperature at which a glassy polymer becomes rubbery on heating and a rubbery polymer reverts to a glassy one on cooling), thus achieving a change in properties. A plasticizer can only plasticize a polymer vvhea the molecules of the plasticizer can interact with the molecules of the polymer. Hence, the plasticizers act like lubricants between the polymer chains, facilitating slippage of chain past chain under stress and extending tiie temperature range for segmental rotation to lower temperatures (Martin, A., Physical Pharmacy, Lea and Febiger, Philadelphia, 1993, p. 588). The degree or extent of plasticization of a polymer will depend on the type and amount of plasticizer blended with the polymer. For example, higher the concentration of the plasticizer, greater the extent of plasticization or flexibility of the polymer. If a plasticizer and a polymer are fully compatible with each other, then depending on the concentration of the plasticizer blended with the polymer, it is possible to obtain a polymer matrix of varying consistency or rheology such as a free-flowing or viscous liquid, gel or paste. Moreover, since plasticizers are available with varying physicochemical properties, including varying hydrophilicity and lipophilicity, it is possible to blend an appropriate plasticizer at a desired concentration with a selected compatible polymer such that the resulting biodegradable vehicle or BAS-loaded biodegradable dehvery system has the tailored physicochemical characteristics, including varying hydrophihcity and lipophilicity, and consistency. The present invention also includes formulations wherein two or more plasticizers are used in a combination or blend of varying ratios. The present invention also includes formulations wherein two or more polymers or
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copolymers with varying copolymer ratios or molecular weights are used in a combination or blend of varying ratios.
Methods of preparing the biodegradable vehicles and delivery systems of the present invention involve dissolving at least one biodegradable polymer in a volatile solvent or a mixture of solvents. At least one plasticizer is added to the resulting polymer solution. The volatile solvent is evaporated using vacuum or removed at an elevated temperature, or evaporated using a combination of both vacuum and elevated temperature. The resulting biodegradable vehicles and dehvery systems could be in the form of either free-flowing or viscous hquids, gels or pastes. This method is particularly suited when polymers of high molecular weights are used to prepare the vehicles or BAS delivery system, or when a high consistency of the biodegradable vehicle or BAS delivery system, is desired. Alternatively, one or more biodegradable polymers can be directly dissolved in one or more plasticizers by stirring the mixture with or without the use of heat. This method is particularly suited when polymers of low molecular weights are used to prepare the biodegradable vehicles or BAS dehvery system, or when a low consistency or BAS dehvery system is desired.
Polymers suitable for preparing the biodegradable delivery systems of the present invention include, but are not limited to, homopolymers and/or copolymers of polyesters, polyorthoesters, polyphosphoesters, polyanhydrides, polyaminoacids, pseudopolyamino acids, polyamides, polyalkylcyanoacrylates, polyphosphazenes, polydioxanone, poly(s-decaloactone), poly(glycolide-co-trimethylene carbonate), poly(ethylene carbonate), poly(iminocarbonate), poly( 1,3-propylene malonate), poly(ethylene-l,4-phenylene-bis-oxyacetate), and poly(ester-amides). In a preferred embodiment, polymers include polylactic acid or polylactide (PLA) and its copolymers, polyglycolic acid or polyglycolide and its copolymers, polycaprolactone (PCL) and its copolymers, polyhydroxybutyrates and their copolymers, and polyhydroxyvalerates and polydioxanone and their copolymers. A mixture of polymers with different molecular weights or different types, or copolymer ratios may be used to tailor physicochemical properties, the degradation characteristics of the biodegradable vehicles and the dehvery systans or the release characteristics of BAS from the biodegradable dehvery systems, or both.
Solvents used to dissolve the polymer for the preparation of biodegradable delivery system of the present invention include, but are not limited to, ketones, ethers, alcohols, amides, and chlorinated solvents. Preferred solvents are acetone, ethyl acetate,
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methyl acetate, methylethylketone, chloroform, methylene chloride, isopropanol, ethyl alcohol, ethyl ether, methylethyl ether, hexafluroisopropanol, tertrahydrofuran, and hexafluroacetone sesquihydrate. A mixture of volatile solvents may also be used to create a suitable mixture, which can dissolve both the polymer and the plasticizer.
Plasticizers used for the preparation of biodegradable delivery system of the present invention include, but are not limited to, citrates such as diethyl citrate (DEC), triethyl citrate (TEC), acetyl diethyl citrate (ATEC), tribulyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri-n-hexyl-citrate, acetyltri-n-hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether (Transcutol®), propylene glycol monotertiaiy butyl ether, dipropylene glycol monomethyl ether, N-methyl-2-pyrrolidone, 2 pyrrolidone (2-Pyrrol®), isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol, glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glycofurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycol laurate, propylene glycol caprylate/caprate, gamma butyrolactone, polyethylene glycols (PEG), vegetable oils obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree such as cotton seed oil, soy bean oil, ahnond oil, sunflower oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids (Gelucires®, Labrafils® and Labrasol®) such as PEG-6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG-8 glycerol linoleate, PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceiyl-3-isostearate, PEG-32 glyceryl laurate (Gelucire 44/1®), PEG-32 glyceryl palmitostearate (Gelucire 50/13®), PEG-32 glyceryl stearate (Gelucire 53/10®), glyceryl behenate, cetyl pahnitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate (Triacetin®). The use of two or more plasticizers in a combination or blend of varying ratios is also encompassed by the present invention.
In order to prepare a BAS-loaded delivery system, the BAS can be loaded in any physical form (i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers) at any step during the manufacturing process of biodegradable delivery systems before the volatile solvent is completely removed. It can also be manufectured by loading the BAS soon after the biodegradable vehicle is prepared, or
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blending the BAS to the biodegradable vehicle just prior to the use of the BAS loaded biodegradable delivery system. Mixing the BAS with the biodegradable vehicle can be accomplished by simply stirring the mixture with a stining device, or by triturating tiie mixture or employing an ointment mill or a suitable device or apparatus or equipment that can be used for blending/mixing. When the BAS is blended with the biodegradable vehicle just prior to use, it could be stored in a separate container in a solid state, liquid state (where the BAS is dissolved or suspended in the plastictzer or blends of plasticizers), or gel or paste where the BAS is dissolved or suspended in the plastidzer or blends of plasticizers). Alternatively, a device, which resembles two syringes or syringe tike devices (e.g. pumps in which materials can be mixed by depressing a trigger like device) attached together with a removable partition or a valve assembly can also be used to uniformly mix the BAS with the bkxiegradable vehicle. The BAS is loaded in one syringe or compartment and the biodegradable vehicle is loaded in the other compartment. A removable partition or a valve, which wilt allow the contents of the two compartments to be mixed uniformly, separates the two compartments. The mixing process is performed in order to dissolve or uniformly suspend the BAS particles in the biodegradable vehicle. The resulting BAS-4oaded biodegradable delivery systems can be free flowing or viscous liquids, gels or pastes, in order to prepare a BAS-loaded delivery system just prior to use, the BAS and the biodegradable vehicle can be packaged in two separate containers as a kit. The vehicle and the BAS can then be blended together by the aforementioned methods.
The different procedures for modulating the degradation kinetics of the biodegradable delivery vehicles is explained in the procedures 1,2 and 3 herein.
The procedure for preparing a biodegradable vehicle first, loading the BAS soon after the biodegradable vehicle is prepared, or blending the BAS to tiie biodegradable vehicle just prior to the use of tfie BAS-loaded biodegradable delivery system is stiown in procedures 1 and 2.
The procedure of loading BAS before removing the volatile solvent or mixture of volatile solverrts to prepare biodegradable delivery systems is shown in procedure 3. However, the method of addition of the BAS is not limited to that shown in these figures, since the BAS can be loaded in any physical fonn (i.e. solid, liquid, gel or paste, where the BAS is dissolved or suspended in the plasticizer or mixtures of plasticizers, volatile solvents or mixture of volatile solvents or mixtures of volatile solvents and plasticizers, at any step during the manufacturing the process, before the volatile solvent is completely removed.
The resulting BAS-loaded biodegradable delivery system can be free flowing or viscous liquids, gels or pastes, wherein the BAS can be dissolved or suspended.
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PROCEDURE 1
BIODEGRADABLE POLYMERS
Polylgctic acid (PLA)
Polylactic-co-glycolic acid (PLGLA)
Polyaminoacids
Polyhydroxybutyric and
Valeric acid copolymers (PHBV)
Poly -e - caprolatone (PCL)
Lactic acid and caprolactone copolymers
+ PLASTICIZER
Citrates Such a dietyl citrate (DEC), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri -n-hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoetghyl ether, diethylene glycol monoethyl ether (Transcutol ®, propylene glycol monotertiary butyl ether dipropylene glycol monomethyl ether, N- methyl-2-pyrrolidone, 2-pyrrolidone (2-Pyrrol ®), isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol glycerol, glyceryl dioieate, ethyl oleate, benzylbenzoate, glyfurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycon laurate, propylene glycol caprylate/caprate, gamma butyrolactone, polyethylene glycots (PEG), , glycerol and PEG esters of acids and fatty acids (Gelucires ©, Labrafils ® and Labrasol ®) such as PEG - 6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG - 8 glycerol linoleate, PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-3-isostearate, PEG-32 glyceryl laurate (Gelucire 44/1 ®, PEG-32 glyceryl palmitostearate (Gelucire 50/13 ®, PEG -32 glycryl stearate (Gelucire 53/10 ®), glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate (Triacetin ®, vegetable oil obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton sees oil, soybean oil, almond oil, sunflower oil, peanut oil, sesamfe oil. The use of two or more plasticizers in a combination or blend of varying ratios and hydrophilicity or hydrohobicity is also encompassed by the present invention.
Stir with or without heat
BIODEGRADABLE FREE FLOWING LIQUID, VISCOUS LIQUID, GEL OR PASTE
(BIODEGRADABLE VEHICLE) + BIOLOGICALLY ACTIVE SUBSTANCE (S) OR BAS
[BAS-LOADED BIODEGRADABLE DELIVERY SYSTEM COULD BE A FREE-FLOWING LIQUID, VISCOUS LIQUID, GEL OR PASTE, WHERE THE BAS IS EITHER DISSOLVED OR SUSPENDED IN THE BIODEGRADABLE DELIVERY SYSTEM]
14
PROCEDURE 2
BIODEGRADABLE POLYMERS VOLATILE SOLVENTS
Polylactic acid (PLA) Acetone
Polylactic -co-glycolic acid (PLGLA) Ethyl acetate
Polyminoacids Chloroform
Polyhydroxybutyric and Methyl acetate
Valeric acid copolymers (PHBV) Methylene chloride
Poly - e-caprolatone (PLC) Methylethyl ketone
Lactic acid and caproiactone copolymers
SOLUTION OF POLYMER IN VOLATILE SOLVENT (S)
+ PLASTICIZER
Citrates such a dietyl citrate (DEC), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri -n-hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoetghyl ether, diethylene glycol monoethyl ether (Transcutol ®, propylene glycol monotertiary butyl ether dipropylene glycol monomethyl ether, N- methyl-2-pyrrolidone, 2-pyrrolidone (2-Pyrrol ®), isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glyfurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycon laurate, propylene glycol caprylate/caprate, gamma butyrolactone, polyethylene glycots (PEG), , glycerol and PEG esterS of acids and fatty acids (Gelucires ®, Labrafils ® and Labrgsol ®) such as PEG - 6 glycerol mpno oleate, PEG-6 glycerol linoleate, PEG - 8 glycerol linoleate, PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, polyglyceryl-S-isostearate, PEG-32 glyceryl laurate (Gelucire 44/1 ®, PEG-32 glyceryl palmitostearate (Gelucire 50/13 ®, PEG -32 glycryl stearate (Gelucire 53/10 ®), glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate (Triacetin ®, vegetable oil obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton sees oil, soybean oil, almond oil, sunflower oil, peanut oil, sesame oil. The use of two or more plasticizers in a combination or blend of varying ratios and hydrophilicity or hydrohobicity is also
encompassed by the present invention.
SOLUTION OF POLYMER + PLASTICIZER IN VOLATILE SOLVENT (S) HEAT AND/OR APPLY VACCUM TO EVAPORATE THE VOLATILE SOLVENT BIODEGRADABLE FREE - FLOWING LIQUID, VISCOUS LIQUID, GEL OR PASTE (BIODEGRADABLE VEHICLE) BIOLOGICALLY ACTIVE SUBSTANCE (S) OR BAS
BAS -LOADED BIODEGRADABLE DELIVERY SYSTEM
[BAS-LOADED BIODEGRADABLE DELIVERY SYSTEM COULD BE A FREE-FLOWING LIQUID, VISCOUS LIQUID, GEL OR PASTE, WHERE THE BAS IS EITHER DISSOLVED OR SUSPENDED IN THE BIODEGRADABLE DELIVERY SYSTEM]
15
PROCEDURE 3
BIODEGRADABLE POLYMERS VOLATILE SOLVENTS
Polylactic acid (PLA) Acetone
Polylactic -co-glycolic acid (PLGLA) Ethyl acetate
Polyminoacids Chloroform
Polyhydroxybutyric and Methyl acetate
Valeric acid copolymers (PHBV) Methylene chloride
Poly - e-caprolatone (PLC) Methylethyl ketone
Lactic acid and caprolactone copolymers
SOLUTION OF POLYMER IN VOLATILE SOLVENT (S)
+ PLASTICIZER
Citrates such a dietyl citrate (DEC), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl bitrate (TBC), acetyl tributyl citrate (ATBC), butyryltri -n-hexyl citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoetghyl ether, diethylene glycol monoethyl ether (Transcutol ®, propylene glycol monotertiary butyl ether dipropylene glycol monomethyl ether, N- methyl-2-pyrrolidone, 2-pyrrolidone (2-Pyrrol ®), isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glyfurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycon laurate, propylene glycol caprylate/caprate, gamma butyrolactone, polyethylene glycots (PEG), , glycerol and PEG esters of acids and fatty acids (Gelucires ®, Labrafils ® and Labrasol ®) such as PEG - 6 glycerol mono oleate, PEG-6 glycerol linoleate, PEG - 8 glycerol linoleate, PEG-4 glyceryl caprylate/caprate, PEG-8 glyceryl caprylate/caprate, polyglyceryl-3-oleate, polyglyceryl-6-dioleate, potyglyceryl-3-isostearate, PEG-32 glyceryl laurate (Gelucire 44/1 ®, PEG-32 glyceryl palmitostearate (Gelucire 50/13 ®, PEG -32 glycryl stearate (Gelucire 53/10 ®), glyceryl behenate, cetyl palmitate, glyceryl di and tri stearate, glyceryl palmitostearate, and glyceryl triacetate (Triacetin ®, vegetable oil obtained from seeds, flowers, fruits, leaves, stem or any part of a plant or tree including cotton sees oil, soybean oil, almond oil, sunflower oil, peanut oil, sesame oil. The use of two or more plasticizers in a combination or blend of varying ratios and hydrophilicity or hydrohobicity is also
encompassed by the present invention.
SOLUTION OF POLYMER + PLASTICIZER IN VOLATILE SOLVENT (S)
+ BIOLOGICALLY ACTIVE SUBSTANCE (S) OR BAS
HEAT AND/OR APPLY VACCUM TO EVAPORATE THE VOLATILE SOLVENT
BAS -LOADED BIODEGRADABLE DELIVERY SYSTEM
[BAS-LOADED BIODEGRADABLE DELIVERY SYSTEM COULD BE A FREE-FLOWING LIQUID, VISCOUS LIQUID, GEL OR PASTE, WHERE THE BAS IS EITHER DISSOLVED OR SUSPENDED IN THE BIODEGRADABLE DELIVERY SYSTEM]
16
Examples of BAS include, but are not limited to, steroids, hormones, antipsychotic agents, agents that act on the central nervous system (CNS - agents), narcotic agonists and antagonists, fertility regulating agents, antibodies and antigens, anesthetics, analgesics, antibiotics, antiviral agents, antineoplastic agents, antifungal agents, cavity and infection preventing agents, cardiovascular agents, angiogenic and antiangiogenic agents, anti-inflammatoiy agents, immunomodulators, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, live or killed bacteria and viruses, agents or extracts derived from whole or parts of plants, trees, flowers, fruits, buds, seeds, leaves, barks, stem, roots, and animal tissues, growth promoting agents, soft and hard tissues, growth factors, human growth factor, human growth hormone, FGF, erythropoietin, Nupagen, granulocyte colony-stimulating factor (G-CSF), cells, tissues such as bones or agents derived there from, bone growth promoting agents such as calcium phosphates, calcium sulfate and hydroxyapatites, whole viable cells and cell-lines, genes, nucleic acid, antisense, deoxyribonucleic acid (DNA), DNA fragments, ribonucleic acid (RNA), RNA fragments, and biological tissues such as islets of langerhans and pancreas, insulin, vitamin and mineral supplements, iron, chelating agents, coagulants, anticoagulants, and the like.
In certain aspects, the bioactive agents include anticancer agents such as taxol, carmustine, interleukin 2, interferon, growth hormones such as human growth hormone, somatotropin hormone, antipsychotic agents such as risperidone, antibiotics such as gentamicin, tetracycline, oxytetracycline, topical anesthetic agents such as benzocaine, chloroprocaine, cocaine, procaine, propoxycaine tetracaine, depravaine, bupivacaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, propofol and ropivacaine, analgesic agents such as morphine, oxycodone, fentanyl, sufentanyl, butorphanol, narcotic antagonists such as naltrexone, nalorphine, naloxone, nalmefene, growth promotic agents such as TGF alpha and TGF beta, bone morphogenic peptides and proteins and calciimi salts such as calcium sulfate, calcium phosphate, and anti-inflammatory agents such as dichlofenac. In one preferred aspect, the present invention provides a biodegradable vehicle comprising oxytetiracycline for veterinary use.
In certain other embodiments, the biologically active agents include, but are not limited to, steroids such as protaglandins, estrogens, androgens, and progestins; ophthalmics such as lubricants and anti-glaucoma; antibiotics such as quinolones; saliva subsitiutes, sedative/hypnotics such as benzodiazepines and barbituates; wound care such as growth factors (EPO, FGF, G-CSF); antiparasitics (worms, malarial); anticonvulsants, muscle relaxants, nucleoside analogs, osteoporosis preparations (supplement bone growth),
17
antiparkmsoman agents, antibiotics such as cephalosporins, aminoglycosides and sulfonamides, oxytocic agents and prostaglandins.
Those of skill in the art will know of other biological agents useful in the practice of the present invention.
The physical form (i.e. liquids, gels or pastes), consistency or rtieology, hydrophihcity or hydrophobicity, in vivo duration of stay of the biodegradable vehicles or delivery systems, in vivo biodegradation rate of biodegradable vehicles or delivery systems, and BAS release characteristics from BAS-loaded biodegradable delivery systems depend on a number of factors. These include: type of polymer or copolymer, hydrophihcity or lipophilicity of polymer or copolymer, concentration of polymer or copolymer, molecular weight of polymer or copolymer, copolymer ratios, combination of polymers or copolymers with different molecular weights, combination of copolymer with varying copolymer ratios, combination of different types of polymer with varying ciystallinity, hydrophihcity or hydrophobicity, type of plasticizer, hydrophilicily or lipophilicity of plasticizer, concentration of plasticizer (polymer or copolymer to plasticizer/plasticizers ratios), combination of plasticizers, type of BAS, loading of BAS, hydrophihcity or lipophihcity of BAS, molecular weight of BAS. In addition, the physicochemical interactions between the polymer, plasticizer and BAS also affect the above-mentioned properties of biodegradable vehicles and delivery systems.
For example, using the present invention, it is possible to tailor the release of a BAS (with specific physicochemical properties and the desired in vivo concentration), for the desired length time. This is achieved by blending an appropriately selected polymer or polymers with an appropriately selected plasticizer or mixtures of plasticizers. Besides controlling the release characteristics of the BAS from the dehvery system described in the present invention, a blend of the appropriate polymer or polymers and plasticizer also controls the consistency or rheology of the delivery system.
It is also possible to extend the in vivo duration of stay of the biodegradable vehicle or delivery system by selecting a higher molecular weight or highly hydrophobic polymer, since polymers with higher molecular weights or high hrdrophobicity generally degrade slowly in the body. Furthermore, it is possible to modify the degradation kinetics of the biodegradable vehicle or dehvety system, or obtain pulsatile or intermittently fluctuating delivery of the BAS from the BAS-loaded dehvery systems by combining polymers of different molecular weights (e.g. low, intermediate and high molecular weights or low and high molecular weights or low and medium molecular weights or medium and high
18
molecular weights), whereby the low molecular weight polymer in the biodegradable vehicle may degrade at a much fester rate than the rest of the polymer in the blend. Alternatively, using blends of copolymers of different copolymer ratios of varying hydrophilicity and hydrophobicity (e.g. different copolymer ratio of lactide-glycolide or lactide-caprolactone) or using blends of two different polymers or copolymers with different crystallinity (e.g. blends of polyacaprolactone and polylactic acid or polycaprolactone and poly-lactic-co-glycolic acid/polylactide-co-glycohde (PLGA)) can also result in a biodegradable vehicle or biodegradable delivery system with varying degradation kinetics where the more hydrophilic or amorphous polymer may degrade at a much faster rate than the rest of the polymers in the blend.
The biodegradable vehicle without any BAS may be used as a biodegradable tissue or cavity filler or spacer in the body, whereas, BAS-loaded biodegradable delivery system may be used for the treatment of a variety of diseases and pathological conditions. The final composition with or without the BAS may be injected, implanted, smeared or applied in animals, birds or humans.
For example, the biodegradable dehvery system loaded with an antitumor agent or antiangiogenic agent can be directly injected into or adjacent to solid tumors such as brain tumor, breast tumors, melanomas, etc. It can also be injected, implanted or smeared at a site fi"om where a solid tumor has been surgically removed, thus affording site-specific delivery for disease states that are otherwise very difficult, (if not impossible) to treat using the conventional methods of treatment. For localized BAS delivery and treatment, BAS-loaded biodegradable vehicle can also be used in surgeries where appropriate quantities of an antibiotic, an anti-inflammatory agent, a local anesthetic or analgesic, or combinations thereof can be loaded in the biodegradable vehicle by the surgeon in an operating room, and the resulting mixture can then be injected, implanted, smeared or applied at the site of surgery to minimize the chances of localized infections or inflammation and reduce pain respectively, due to surgery. In the case of orthopedic surgery, currently, the majority of the orthopedic surgeons prepare beads in the operating room with a non-biodegradable polymer, polymethylmethacrylate (PMMA). These beads are loaded with an appropriate dose of an antibiotic. These beads are then placed in the cavity at the site of surgery to prevent infections such as osteomyelitis. However, the non-degradable polymer beads have to be eventually removed before closing the wound with a suture, and the patients are then given an intravenous dose of an antibiotic or treated with an oral antibiotic. This procedure can easily be corrected with the use of an antibiotic loaded biodegradable vehicle that can be injected,

19

implanted, smeared or applied near or at the site of surgery. High concentrations of the antibiotic at the site of surgery can prevent infections. Moreover, the BAS delivery system need not be removed from the site of administration because of the biodegradable nature of the system. The biodegradable vehicle loaded with bone growth promoting agents such as calcium sulfate, calciimi phosphate or hydroxyapatite can be injected, implanted, applied or smeared at an appropriate site, where it is needed following bone, disc or spine surgery. BAS such as low molecular weight heparin can also be incorporated into the biodegradable vehicle and the resulting mixture can be used to treat conditions such as deep venous thrombosis (DVT) in trauma or surgical patients.
The system could be loaded with a contraceptive agent, antipsychotic agent, anticonvulsants, antimalarial, antihypertensive agent, antibiotics, antiviral agents, biologically active protein and peptides, vaccines, live or killed bacteria and viruses, genes, DNA or DNA fragments, RNA or RNA fragments, and injected, implanted, smeared or applied in the body to provide a controlled release of the agents for the desired length of time. Biodegradable deMveiy system loaded with BAS such as antiinflammatory agents, analgesics and anesthetics could be injected directly into joints or sites in the body from where the pain is emanating, thus providing rehef from the excruciating pain and making the joints more mobile. Antigens may also be incorporated into the delivery system and injected, implanted or apphed in animals or humans to induce the production of specific antibodies. Bones (fragments or powder), morphogenic proteins such as growth promoting agents of biological tissues and organs and wound-healing factors, can also be incorporated into the biodegradable vehicle, and the resulting mixture is injected, implanted or appHed at the site of administration. Live cells and/or whole or a part of a tissue or tissues and organs can also be blended with the biodegradable vehicle and injected, implanted or apphed at the site of administration. For pulsatile or intermittent delivery of BAS such as vaccines, the biodegradable vehicle can be prepared with blends of varying molecular weights of polymers or copolymers, or with blends of copolymers of varying copolymer ratios (e.g. 50/50 PLGA and 85/15 PLGA or 100% PL A and 25/75 PLGA) or blends of different types of biodegradable polymers with varying hydrophobicity or lipophilicity or crystallinity (e.g. 1:1 of PLA:PCL or 1:3 of PLA:PCL or 1:1 of 50/50 PLGA:PCL).
The formulation, which is sterile, is suitable for various topical or parenteral routes, such as intramuscular, subcutaneous, intra-articular, by suppository (e.g. per-rectum or vaginal application), intradermal. In certain aspects, the biological active agents and biodegradable delivery systems are delivered or administered topically. Additionally, the
20

agents can be delivered parenterally. Topical administration is preferred in treatment of lesions of the skin as in psoriasis, where such direct Application is practical and clinically indicated.
An effective quantity of the compound of interest is employed in treatment. The dosage of compounds used in accordance with the invention varies depending on the compound and the condition being treated. For example, the age, weight, and clinical condition of the recipient patient; and the experience and judgment of the clinician or practitioner administering the therapy are among the factors affecting the selected dosage. Other factors include: the route of administration, the patient, the patient's medical history, the severity of the disease process, and the potency of the particular compound. The dose should be sufficient to ameliorate symptoms or signs of the disease treated without producing unacceptable toxicity to the patient. In general, an effective amount of the compound is that which provides either subjective relief of symptoms or an objective identifiable improvement as noted by the clinician or other qualified observer.
This invention will be understood with greater particularity by reviewing the following examples; with reference to figures 1 to 13 of the accompanying drawings wherein
Figure 1 describes the effect of varying polymer to plasticizer ratios on cumulative amount of levonorgestrel released from biodegradable delivery systems.
Figure 2 describes the effect of varying the polymer inherent viscosity on cumulative amount of levonorgestrel released from biodegradable delivery systems.
Figure 3 describes the effect of varying copolymer ratios on cumulative amount of levonorgestrel released from biodegradable delivery systems.
Figure 4 describes the effect of varying drug loading on oxytetracycline base released from biodegradable delivery systems.
Figure 5 describes the effect of varying plasticizer to polymers ratios on oxytetracycline base released from biodegradable delivery systems..
Figure 6 describes the effect of varying plasticizer to polymer ratios on oxytetracycline base released from biodegradable delivery systems.
Figure 7 describes the effect of varying hydrophilicity of plasticizers on oxytetracycline base released from biodegradable delivery systems.
Figure 8 describes the effect of varying polymer to plasticizer ratios and plasticizers compositions on oxytetracycline base released from biodegradable delivery systems.
21

Figure 9 describes the effect of varying polymer molecular weights on oxytetracycline base released from biodegradable delivery systems.
Figure 10 describes the effect of varying drug solubility on naltrexone released from biodegradable delivery systems.
Figure 11 describes the effect of varying solubility of drug on oxytetracycline released from biodegradable delivery systems.
Figure 12 describes the effect of varying polymer molecular weights on oxytetracycline base released from biodegradable delivery systems
Figure 13 describes the effect of varying polymer weights on in vivo release of oxytetracycline base released from biodegradable delivery systems
EXAMPLE
EXAMPLE 1
Preparation of a biodegradable vehicle:
A polymer (50% w/w of 50/50 lactic-co-glycolide copolymer) was dissolved in minimum quantity of acetone. Triethyl citrate (TEC) at a concentration of 50% w/w was added to the polymer solution and was stirred to yield a uniform mixture. Acetone was evaporated from the mixture by heating at 60 - 75 °C with constant stirring. The resulting formulation obtained was a matrix with a gel-like consistency.
EXAMPLE 2
Example 1 was repeated using 10% w/w of 50/50 lactide-co-glycolide copolymer and 90% w/w TEC. The resulting formulation obtained was a matrix with a liquid like consistency.
EXAMPLE 3.
Example 1 was a repeated using 20% w/w of 50/50 lactide -co-glycolide copolymer and 80% w/w TEC. The resulting formulation obtained was a matrix with a viscous liquid like consistency.
22

Example 1 was repeated, using 30% w/w of 50/50 lactide-co-glycolide copolymer and 70% w/w TEC was used. The resulting formulation obtained was a matrix with a viscous liquid-like consistency.
EXAMPLE 5
Example 1 was repeated, using 40% w/w of 50/50 lactide-co-glycolide copolymer and 60% w/w TEC was used. The resulting formulation obtained was a matrix with a viscous liquid-like consistency.
EXAMPLE 6
Example 1 was repeated, using 60% w/w of 50/50 lactide-co-glycolide copolymer and 40% w/w TEC was used. The resulting formulation obtained was a matrix with a gel-like consistency.
EXAMPLE?
Example 1 was repeated, using 70% w/w of 50/50 lactide-co-glycohde copolymer and 30% w/w TEC was used. The resulting formulation obtained was a matrix with a gel-like consistency.
EXAMPLE 8
Example 1 was repeated, using 80% w/w of 50/50 lactide-co-glycolide copolymer and 20% w/w TEC was used. The resulting formulation obtained was a matrix with thick sticky paste.
EXAMPLE 9
Example 1 was repeated with the following polymers and plasticizers as shown in Table 1 below:
23

TABLE 1


TYPEOFPOLXMlR PLASTICIZER SOLVENT DESCRIPTION OF THE FORMULATION
DL-POLYLACTTC ACE) (DL-PLA; I.V. = 0.58) GLYCERYL TRIACETATE (TRIACETIN) ACETONE GEL, SLIGHTLY CLOUDY
DL-POLYLACTIC ACID (DL-PLA; LV. = 0.58) TRIETHYL CITRATE (TEC) ACETONE GEL, TRANSPARENT
DL-POLYLACTIC ACED (DL-PLA; LV. =0.58) ACETYL TRIETHYL CITRATE (ATEC) ACETONE GEL, SLIGHTLY CLOUDY
DL-POLYLACnC ACID (DL-PLA; I.V. = 0.58) DIMETHYL PHTHALATE (DMP) ACETONE GEL, LESS VISCOUS, TRANSPARENT
DL-POLYLACTIC ACID (DL-PLA; I.V. = 0.58) DIETHYL PHTHALATE (DEP) ACETONE GEL, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) GLYCERYL TRIACETATE (TRIACETIN) ACETONE GEL, LESS VISCOUS, SLIGHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. =0.58) TRIETHYL CITRATE (TEC) ACETONE GEL, SLIGHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) ACETYL TRIETHYL CITRATE (ATEC) ACETONE GEL, SLIGHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. =0.58) TRIETHYL CITRATE (TEC) ACETONE GEL, SLIGHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. =0.58) DIMETHYL PHTHALATE (DMP) ACETONE GEL, LESS VISCOUS, RANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V, = 0.58) DIETHYL PHTHALATE (DEP) ACETONE GEL, SLICJHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) N-METHYL PYRROLIDONE (NMP) ACETONE VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. =0.15) GLYCERYL TRIACETATE (TRIACETIN) ACETONE VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V.= 0.15) TRIETHYL CITRATE (TEC) ACETONE VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. =0.15) ACETYL TRIETHYL CITRATE (ATEC) ACETONE VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACE) (DL-PLGA; I.V. = 0.15) TRIETHYL CITRATE (TEC) ACETONE VISCOUS LIQUID, TRANSPARENT
EXAMPLE 10
Several polymers were separately dissolved in several volatile solvents. Several plasticizers were separately added to the polymer-solutions, such that the ratio of polymer to plasticizer in the final formulations ranged from 1:19 to 4:1. Several drugs were separately added to the polymer-plasticizer-solvent blends. The solvents were then evaporated at an elevated temperature to obtain drug-loaded formulations. The drug content in the final formulations constituted up to 50% w/w.
For several formulations, blank formulations of polymers and plasticizers blends were first obtained. The drugs were then separately added to the blank formulations to obtain drug-loaded formulations. Table 2 lists examples of polymers, plasticizers, solvents, polymer to plasticizer ratio and concentration of drugs in the formulations.
24

TABLE 2

1 POLYMER CONCEN-
1 TYPE OF PLASTICIZERS SOLVENTS TO DRUGS TRATION
POLYMERS PLASTICIZER RATIOS OF DRUGS
(% w/w)
IN
POLYMER


MATRICE
S
POLYCAPROLAC- DEETHYLENE METHYLENE 1:1 TESTOSTERONE
TONE GLYCOL CHLORIDE
MONOETHYL ETHER 1:2 PROGESTERONE 0.5%-50%
POLYLACTICAC© (TRANSCUTOL®), CHLOROFORM 1:3 LEVONORGESTREL w/w
POLYLACTIC-CO- PEG-8-GLYCERYL ACETONE
GLYCOLICACID CAPRYLATE/CAPRA
TE ETHYL ACETATE 1:4 THEOPHYLLINE
COPOLYMERS OF (LABRASOL®) 1:9 PROPRANOLOL
LACTIC ACID AND
CAPROLACTONE TRIETHYL CITRATE (TEC),
ACETYL TRIETHYL CITRATE (ATEC)
GLYCERYL TRIACETATE (TRIACETIN*)
POLYETHYLENE GLYCOLS (PEG)
N-METHYL
PYRROLIDONE
(NMP) 1:19
2:1 2:3 3:2 3:1 4:1 ATENOLOL
METOPROLOL CHLORPROAMAZINE
CLONIDINE
INSULIN
OXYTETRACYCLINE
NALTREXONE
EXAMPLE 11
Effect of varying polymer-to-plasticizer ratios on the physical state of
formiilations and drug release characteristics
Several samples of polylactic-co-glycolic acid (inherent viscosoty - 0.59) were weighed and separately dissolved in acetone. Varying ratios of N-methyl pyrrolidone (NMP) were separately added to the polymer-solutions, such that the ratio of polymer to plasticizer in the formulations ranged from 20:80 to 80:20. Acetone was then evaporated by heating the solutions at 70-80°C. Levonorgestrel (2% w/w) was added to the resulting formulations. Table 3 describes the physical state of the formulations containing varying polymer-to-plasticizer ratios. Drug release characteristics from the formulations depicted in Table 3 are shown in Figure. 1

25



TABLE3 Physical state of formulations prepared with varying polymer-to-plasticizer ratios

Polymer*-to-NMP Ratio Physical State of the Formulation Physical State of Drug in die Fonniilation
20:80 Very flowable liquid Dissolved
40:60 Viscous liquid Dissolved initially; however precipitated partially after 48 hrs
50:50 Flowable gel Suspended
60 :40 Flowable gel Suspended
80:20 Thick paste Suspended
* 50/50 Polylactide-co-glycolide (IV=0.59 dL/g) Drug loading = 2% w/w
EXAMPLE 12
Effect of varying polymer inherent viscosities on the physical state of the
formulations and drug release characteristics
Several samples of polylactic-co-glycolic acid (PLGA) with vaiying itiherent viscosities ranging from 0.15-1.07) were weighed and separately dissolved in acetone. An appropriate quantity of N-methyl pyrrohdone (NMP) was added to the polymer-solutions such that the ratio of polymer to plasticizer in the formulations was 33% PLGA and 67% NMP, Acetone was then evaporated by heating the solutions at 70-80°C. Levonorgestrel (2% w/w) was added to the resulting formulations. Table 4 describes the physical state of the formulations containing varying polymer inherent viscosities. Drug release characteristics from the formulations depicted in Table 4 are shovra in Figure .2

26



TABLE4 Physical state of formulations prepared with polymer of varying inherent viscosities

Polymer Inherent Viscosity (dL/g) Physical State of the Formulation* Physical State of Drug in the Fonnnlatio*
0.15 Very flowable liquid Dissolved
0.26 Flowable hquid Dissolved
0.42 Flowabie liquid Dissolved
0.59 Viscous liquid Dissolved
0.74 Flowable gel Dissolved
1.07 Viscous gei Dissolved
?33% w/w of 50/50 Polylactide-co-glycoUde and 67% w/w NMP Drug loading = 2% w/w
EXAMPLE 13
Effect of varying copolymer ratios on physical state of formulations and drug
release characteristics
Samples of pure polylactic acid and polylactic-co-glycohc acid (PLGA) with varying copolymer ratios ranging from 50/50 to S5/15 were weired and separately dissolved in acetone. An appropriate quantity of N-methyl pyrrolidone (NMP) was added to the polymer-soktions such that the ratio of polymer to plasticizer in the formulations was 33% PLGA and 67% NMP. Acetone was then evaporated by heatmg the solutions at 70-80°C. Levonorgestrel (2% w/w) mts added to the resulting fonnul^ons. Table 5 describes the physical state of the formulations prepared from varying copolymer ratios. Drug release characteristics from the formulations depicted in Table 5 are shown in Figuret^.I^
27

TABLE5 Physical state of formulations prepared vnth polymers of varying copolymer
ratios.

Ratio of Lactide to
Glycolide in
Polymer Physical State of the Formulation* Physical State of Drug in the Formulation*
50/50 Yellowish, viscous liquid Dissolved
65/35 Yellowish, viscous liquid Dissolved
75/25 Pale yellow, highly viscous liquid Dissolved
85/15 Straw colored, slightly
translucent, highly
viscous liquid Dissolved
100/0 Clear, highly viscous liquid Dissolved
* 33% w/w of Polylactide-co-glycolide and 67% w/w NMP Drug loading = 2% w/w
EXAMPLE 14
Effect of varying drug loadings on drug release
A polymer (25% w/w of 50/50 lactide-co-glycohde copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone. Pure polyethylene glycol 400 (PEG 400) was added to the polymer solution. The solution was stirred to yield a uniform mixture. Acetone was evaporated from die mixture by heating at 60-7 5 °C with constant stirring. The blank formulation was kept in a vacuum oven at 60-7 5 °C overnight to ensure complete removal of acetone. The resulting formulation obtained was a matrix with a viscous liquid like consistency. Three different concentrations of oxytetracyclme base (either 10,20 or 30% w/w) were added to the blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure j» shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. Increasing the percentage of drug in the formulations from 10 to 30% w/w increased the cumulative amount of drug released at the end of 360 hours. This increase occurred because, at higher drug-loadings, more drug is available on the surface of the formulations for release. Moreover, a higher
28

drug concentration gradient between the formulation and the dissolution medium is expected at 30% w/w drug-loading compared to the one at 10% w/w drug loading. EXAMPLE 15
Effect of plasticizer compositions on drug release A polymer (25% w/w of 50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone. Either pure triethyl citi:ate (TEC), or polyethylene glycol 400 (PEG 400), or blends of PEG 400 and TEC (either 50/50% or 75/25,% blends of PEG 400/TEC) was added to the polymer solution. The resultiug solutions were stirred to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75 °C overnight to ensure complete removal of acetone. The resulting formulations obtained were matrices with a viscous liquid like consistent'. Oxytetracycline base (20% w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure^shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. Increasing the percentage of PEG 400 in tiie formulations prepared from 0% PEG 400 and 100% TEC to 100% PEG 400 and 0% TEC resulted in faster drug release. This is because PEG 400 is very hydrophilic and is completely miscible in water, whereas, the aqueous solubility of TEC is approximately 6%. EXAMPLE 16
Effect of varying ratios of polymer and plasticizer on drug release Three different concentrations (10,20 or 25% w/w) of a polymer (50/50 lactide-co-glycolide copolymer, ioherent viscosity of 0.59) were dissolved in a minimum quantity of acetone. Pure PEG 400 (90,80 or 75% w/w) was added to the polymer solutions. The solutions were stirred to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-7 5 °C overnight to ensure complete removal of acetone. The resulting formulations obtained were matrices with varying viscosities or consistency. The formulation with 25% polymer was considerably more viscous than the one with 10% polymer. Oxytetracycline base (20% w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure 6 shows the cumulative amount of oxytetracycline

29

released from formulations prepared with the above-mentioned compositions. It is evident from the figure that decreasing the percentage of polymer in ihe formulations from 25% to 10% dramatically increased the drug release. This is because a decrease in polymer concentration from 25% to 10% and a corresponding increase in the plastidzer concentration from 75% to 90% resulted in a decrease in the glass transition temperature, viscosity and an increase in polymer chain mobility of the formulations. Hence, the formulation with 10% polymer offered considerably less resistance for drug diffusion through the matrix compared to the one prepared with 25% polymer.
EXAMPLE 17
Effect of varying plasticizer hydrophihcity on drug release
A polymer (25% w/w of 50/50 lactide-co-glycohde copolymer, inherent viscosity of 0.59) was dissolved in a minimum quantity of acetone. Either pure polyethylene glycol 400, triethyl citrate (TEC) or acetyl triethyl citrate (ATEC) was added to the polymer solution. The resulting solutions were stirred to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone. The resulting formulations obtained were matrices with a viscous hquid like consistency. Oxytetiacycline base (20% w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performe^d at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure ^9 shows the cumulative amount of oxytetiacycline released from formulations prepared with the above-mentioned compositions. It is evident from the figure that drug release was fastest from formulations prepared with PEG 400, and slowest from those prepared with ATEC. Intermediate drug release was observed from formulations prepared from TEC. This is because PEG 400 is completely miscible with water, whereas, the solubility of TEC in water is approximately 6% and ATEC is almost insoluble in water with an aqueous solubility of less than 0.1%.
EXAMPLE 18
Effect of varying polymer to plasticizer ratios and plasticizer compositions on
drug release
Blank formulations were prepared by dissolving either 16.67% w/w or 25% w/w of 50/50 polylactide-co-glycolide copolymer (inherent viscosity of 0.59) and either 50/50% or 75/25% blends of PEG 400 and TEC in a minimum quantity of acetorW. TUl resulting solutions were stirred to yield uniform mixtures. Acetone was evaporatid from the
30

mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensure complete removal of acetone. The resulting formulations obtained were matrices with a viscous liquid like consistency. Oxytetracycline base (20% w/w) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure 8 shows the cumulative amount of oxytetracycline released from formulations prepared with the above-mentioned compositions. It is evident from the figure that faster drug release was observed from formulations prepared with a 16.67% polymer and 83.3% of plasticizer blends of vaiying compositions (polymer to plasticizer ratio of 1:5) compared to those prepared from formulations with polymer to plasticizer ratios of 1:3 (25% polymer and 75% plasticizer). This is because increasing the polymer concentration in the formulations from 16.67% to 25% increased the viscosity of the formulations and decreased the drug diffusion from the formulations. Moreover, a comparison of drug released from formulations witii similar polymer to plasticizer ratios but varying plasticizer compositions revealed that dnig release was considerably faster from formulations prepared with blends of 75% PEG 400 and 25% TEC compared to those prepared from 50/50% blend of PEG 400/TEC. This is because the PEG 400 is completely miscible in water, whereas, the aqueous solubiUty of TEC in water is approximately 6%. EXAMPLE 19
Effect of varying polymer inherent viscosities on drug release Four different inherent viscosities (i.v. = 0.15,0.26,0.59 and 0.76) of a polymer (50/50 lactide-co-glycolide copolymer) were dissolved in a minimum quantity of acetone. Pure PEG 400 was added to the polymer solutions. The solutions were stirred to yield uniform mixtures. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75°C overnight to ensxure complete removal of acetone. The resulting formulations obtained were matiices with varying viscosities or consistency. The formulation prepared with the polymer of inherent viscosity of 0.76 was considerably more viscous than the one prepared with the polymer of inherent viscosity of 0.15. Ojtytetiacycline base (20% w/W) was added to each blank formulation and mixed thoroughly to ensure uniform distribution of the drug in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer contaming sodium sulfite as an antioxidant. Figure 9. shows the cumulative amount of oxytetracline released from formulations prepared with the above-

31

mentioned compositions. It is evident from the figure that decreasing the inherent viscosity of polymer from 0.76 to 0.15 dramatically inaeased the drug release. This is because a decrease in polymer inherent viscosity resulted in a dramatic decrease in the viscosity of the. formulation and a corresponding decease in resistance to drug diffusion from the matrix.
EXAMPLE 20
Effect of varying drug solubility on drug release
Blank formulations were prq)ared by dissolving 25% of a polymer (50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.64) and pure PEG 400 or 50/50% blends of PEG 400 and TEC in a minimum quantity of acetone. The solutions were stirred to yield a uniform mixture. Acetone was evaporated from the mixtures by heating at 60-75°C with constant stirring. The blank formulations were kept in a vacuum oven at 60-75 °C ovemi^t to ensure complete removal of acetone. The resulting formulations obtained were a matrix with viscous liquid-like consistency. Either hydrated naltrexone base (20% w/w) or naltrexone hydrochloride (20% w/w) was added to the blank formulations and mixed thoroughly to ensure unifonn distribution of the drugs in the formulations. Drug release from the drug-loaded formulations was performed at 37°C in isotonic phosphate buffer. Figure 10 shows the ciunulative amount of either hydrated naltrexone base or naltrexone hydrochloride released from formulations prepared with the above-mentioned compositions. The release of naltrexone hydrochloride is considerably faster from formulations prepared with both pure PEG 400 and 50/50% blends of PEG 400 and TEC than the release of the hydrated natrexone base from similar formulations. This is because the solubility of the naltrexone hydrochloride in the dissolution buffer is much greater than that of the hydrated naltrexone base.
A similar drug release study was performed with formulations containing either 20% oxytetracycline hydrochloride or 20% oxytetracycline base. The blank formulations were prepared by dissolving 25% of a polymer (50/50 lactide-co-glycolide copolymer, inherent viscosity of 0.59) and 75% of pure PEG 400 in a minimum quantity of acetone. The solutions were stirred to yield a xmiform mixture. Acetone was evaporated from the mixtures by heating at 60-7 5 °C with constant stirring. The blank formulations were kept in a vacuum oven at 60-7 5 °C overnight to ensure complete removal of acetone. The resulting formulations obtained were a matrix with viscous liquid-like consistency. Either 20% oxytetracycline hydrochloride or 20% oxytetracycline base was added to the resulting formulations and mixed thoroughly to ensure uniform drug distribution. Drug release from the drug-loaded foraiulations was performed at 37°C in isotonic phosphate buffer containing sodium sulfite as an antioxidant. Figure l1 shows the cumulative amount of oxytetracycline

32

released from formulations prepared with the above-mentioned compositions. It is evident from the figure that the release of oxytetracycline hydrochloride is considerably faster than the release of oxytetracycline base from similar formulations. This is because of the greater aqueous solubility of the hydrochloride salt than the base.
EXAMPLE 21
Biodegradable delivery systems could be prepared by the procedures shown in Examples 1-20. Instead of adding a single biologically active agent, a combination of two or more biologically active agents could be incorporated together in the said delivery system. Examples of some of the combinations of the biologically active agents include levonorgestrel and ethinyl estradiol, trimethoprim and sulfamethoxazole, trimetrexate and leucovorin, isoniazid, rifampin and ethambutol, dapsone and rifampicin, erythromycin and rifampicin, clotrimazole and nystatin, amphotericin B and flucytosine, hydrochlorothiazide and amiloride, hydrochlorothiazide and spironolactone, hydrochlorothiazide and captopril, polythiazide and reserpine. Moreover, instead of adding a single plasticizer, a combination of two or more plasticizers could be added to obtain a formulation with the desired consistency and hydrophilicity or hydrophobicity. An example of a combination of plasticizer is acetyl triacetyl citrate (ATEC), n-methyl pyrrolidone (NMP) and a vegetable oil such as sesame oil, olive oil, safflower oil, sunflower oil, cottonseed oil or ahnond oil.
EXAMPLE 22
Biodegradable vehicle could be prepared by the procedures shown in Examples 1 -20. The vehicle could be loaded with BAS in a pharmacy or in an operating room by the health practitioner (a pharmacist, surgeon, nurse), just prior to administration to the patient, with an appropriate quantity of an antitumor agent and inected directiy into a solid tumor or at a site from where a solid tumor has been surgically removed. Alternatively, biodegradable vehicle loaded with an antitumor agent can also be injected into the tumor, or injected, implanted, smeared or applied at the site from where the tumor is removed by the surgeon.
EXAMPLE 23
A similar treatment described in Example 22 can be offered to patients with brain tumors where the biodegradable vehicle prepared by the methods shown in Examples 1-20 and loaded with an appropriate quantity of an antitumor agent The BAS-loaded delivery system can be injected, implanted or applied directly at the site in the brain from where the tumor has been removed.
33

EXAMPLE 24
The biodegradable vehicle prepared as shown in examples 1-20 and loaded with a BAS such as an antibiotic an anti-inflammatory agent, a local anesthetic or analgesic, or combinations thereof can also be used in surgeries where appropriate quantities of the BAS, can be mixed with the biodegradable vehicle by the surgeon in an operating room, and the resulting mixture can then be injected, implanted, smeared or applied at the site of sm-gery to minimize the chances of localized infections or inflammation and reduce pain respectively, due to surgery. Altanatively, an antibiotic loaded biodegradable vehicle can also be injected, implanted, smeared or applied at the site of surgery by the surgeon at the site of surgery.
EXAMPLE 25
In the case of orthopedic surgery, a biodegradable vehicle prepared by the method shown in examples 1-20 and loaded with an antibiotic can be injected, implanted, applied or smeared near or at the site of surgery. High concentrations of the antibiotic at the site of surgery can prevent infections. Moreover, the BAS delivery system need not be removed from the site of administration because of the biodegradable nature of the system.
EXAMPLE 26
The biodegradable vehicle prepared with the methods described in examples 1-20 and loaded with bone (fragments or powdered) or bone growth promoting agents such as calcium sulfate, calcium phosphates or hydroxyapatite can be injected, implanted, applied or smeared at an appropriate site where it is needed following orthopedic surgery.
EXAMPLE 27
The biodegradable vehicle prepared with the methods described in examples 1-20 and loaded with a low molecular weight heparin can also be used to freat conditions such as deep venous thrombosis (DVT) in traiuna or surgical patients.
EXAMPLE 28
For pulsatile or intermittent delivery of BAS such as vaccines, live or killed viruses or bacteria, the biodegradable vehicle prepared with the methods described in examples 1-20 can be prepared with blends of varying molecular weights of polymers or copolymers, or with blends of copolymers of varying copolymer ratios such as 50/50 PLGA and 85/15 PLGA or 100% polylactic acid (PLA) and 25/75 PLGA, or blends of different types of biodegradable polymers with varying hydrophobicity or lipophilicity or crystallinity such as 1:1 of PLArPCL or 1:3 of PLA:PCL or 1:1 of 50/50 PLGA:PCL.
EXAMPLE 29
34

The polymer (50/50 lactide-co-glycolide copolymer) was dissolved directly in various plasticizers with stirring with or without the use of heat. Specific examples of formulations prepared using this method are listed in Table 6 below. The resulting formulations obtained were a matrix with a viscous liquid or gel-like consistency.
Table 6: Description of formulations prepared by directly mixing the polymer with the plasticizer with or without the use heat

TYPE OF POLYMER PLASTICIZER DESCRIPTION OF THE FORMULATION
DL-POLYLACTIC ACID (DL-PLA; LV. = 0.58) TRBETHYL CITRATE (TEC) GEL, TRANSPARENT
DL-POLYLACTIC ACID (DL-PLA; I.V. = 0.58) ACETYL TRIETHYL CITRATE (ATEC) GEL, SLIGHTLY CLOUDY
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) 2-PYRROLIDONE LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; iV. =0.58) TRIETHYL CITRATE AND
POLYETHYLENE GLYCOL 400
(TEC + PEG 400) GEL
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) ACETYL TRIETHYL CITRATE AND
POLYETHYLENE GLYCOL 400
(ATEC+ PEG 400) GEL
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. = 0.58) TRIETHYL CITRATE (TEC) GEL, SLIGHTLY YELLOW
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. = 0.58) N-METHYL PYRROLIDONE
(NMP) LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. =0.15) TRIETHYL CITRATE (TEC) VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. =0.15) ACETYL TRIETHYL CITRATE (ATEC) VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I. V. =0.15) TRIETHYL CITRATE (TEC) VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; I.V. =0.15) POLYETHYLENE GLYCOL 400 (PEG-400) VISCOUS LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. = 0.15) ACETYL TRIETHYL CITRATE AND
N-METHYL PYRROLIDONE (NMP)
(ATEC + NMP) LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC ACID (DL-PLGA; LV. =0.15) TRIETHYL CITRATE CITRATE AND
N-METHYL PYRROLIDONE (NMP)
(TEC + NMP) LIQUID, TRANSPARENT
DL-POLYLACTIC-CO-GLYCOLIC AC© (DL-PLGA; I.V. = 0.15) TRIETHYL CITRATE CITRATE AND 2-PYRROLIDONE LIQUID, TRANSPARENT
EXAMPLE 30
A biodegradable dehvery system loaded with OTC was prepared with

combination of two (Figure 12) and three different molecular weights (Figure 13) of PLGA
by the method described in Example 14. It is evident from the Figure 15 that by replacing
33.3% of the higher molecular weight polymer (inherent viscosity of 0.25), with a lower
molecular weight of polymer (inherent viscosity of 0.16), a shght increase in drug release was
achieved. By using the right composition of blends of different molecular weights of
35

polymer, the desired controlled release of the OTC was achieved in vivo in quail, as seen in Figure 13.
All publications, patents and patent publications mentioned in this specification are herein incorporated by reference into the specification in their entirety for all purposes. Although the invention has been described with reference to preferred embodiments and examples thereof, the scope of the present invention is not limited only to those described embodiments. As will be apparent to persons skilled in the art, modifications and adaptations to the above-described invention can be made without dq)arting from the spirit and scope of the invention, which is defined and circumscribed by the appended claims.
The foregoing is offered primarily for purposes of illustration. It will be readily apparent to those of ordinary skill in the art that the operating conditions, materials, procedural steps and other parameters of the invention described herein may be fiirther modified or substituted in various ways without departing fi-om the spirit and scope of the invention. For example, the invention has been described with human patients as the usual recipient, but veterinary use is also contemplated. Thus, the preceding description of the invention should not be viewed as limiting but as merely exemplary.
36

I claim:
1. A method for the manufacture of biodegradable delivery vehicle made of a biodegradable
polymer, a plasticizer and a biologically active substances (BAS) by varying the
physiochemical properties as herein described of at least one member of the group
consisting of said biodegradable polymer, said plasticizer, and said BAS and combinations
thereof, thereby modulating the degradation of said biodegradable vehicle, said method
coinprising the steps of
a. selecting at least one biodegradable polymer as herein described.
b. dissolving said polymer in at least one volatile solvent selected from a group consisting
of acetone, methyl acetate, ethyl acetate, chloroform, dichloromethane, methyl ethyl
ketone, hexafluroisopropanol, tetrahydrofuran and hexafluroacetone sequithydrate to
form a solution.
c. adding at least one known plasticizer to said solution of step (b); and
d. evaporating said solvent from the solution of step (c) and adding a biologically active
substances (BAS) as herein described either before or after the step (b).
2. A method as claimed in Claim 1 wherein said biodegradable polymer is selected from a group consisting homopolymers and copolymers or blends thereof, of polysters, polyphosphosesters, polylactic acid or polyactides, polyglycolic acid or polyglycolides, polycaprolactones, polyalkycyanoacrylates, polyphospazenes, polyhydroxyburates, polynydroxyvalerates, poly amino acids, pseudopolyamino acids, polyamides, polyanhydrides, polydioxanone, poly (e - decloactone), poly (glycolide -co - trimethylene carbonate), poly (ethylene carbonate) , poly (imino carbonate), poly (1,3- propylene malonate), poly (ethylene -1,4- phenylene - bis - oxyacetate), and poly (ester amides).
3. A method as claimed in claim 1 wherein said plasticizer is selected from a group consisting of citrates such a dietyl citrate (DEC) , triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), butyryltri -n-citrate, acetyltri -n- hexy citrate, phthalates such as dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthaiate (DBP), dioctyl phthalate, glycol ethers such as ethylene glycol diethyl ether, propylene glycol monomethyl ether, ethylene glycol monoetghyl ether, diethylene glycol monoethyl ether, propylene glycol monotertiary butyl ether dipropylene glycol monomethyl ether, N- methyl-2-pyrrolidone, 2-pyrrolidone, isopropyl myristate, isopropyl palmitate, dimethylacetamide, propylene glycol glycerol, glyceryl dioleate, ethyl oleate, benzylbenzoate, glyfurol, sorbitol, sucrose acetate isobutyrate, sebacates such as dibutyl sebacate, dipropylene glycol methyl ether acetate (DPM acetate), propylene carbonate, propylene glycon laurate, propylene glycol caprylate/caprate, gamma butyrolactone, polyethylene
37

glycols (PEG), vegetable oils obtained from seeds, flowers fruits leaves stem or any part of a plant or tree such as cotton seed oil, soy bean oil, peanut oil, sesame oil, glycerol and PEG esters of acids and fatty acids such as glycerol mono oleate, glycerol linoleate, glycerol caprylate /carpate, gfycerol caprylate/carpate, polyglyceryl-3-oleate, poiyglyceryl-6-dioleate, polyglyceryl-3-isostearate, glyceryl laurate, glyceryl palmitostearate, glceryl stearate, glyceryl behenate, cetyl palmitat, glyceryl di and tri stearate, glyceryl palmitostearate and glyceryl triacetate.
4. A method as claimed in claim 1 wherein when adding at least on biologically active substances to the product of step (b), the said biodegradable vehicle is loaded with at least one biologically active substances soon after preparing the biodegradable vehicle or just prior to using the biodegradable delivery system loaded with the biologically active substances.
5. A method as claimed in claim 1 to 4 wherein said biologically active substance is selected from the group consisting o steroids, hormones, antipsychotic agents, agents the act on the central nervous system (CNS - agents) narcotic agonists and antagonists, fertility regulating agents, antibodies and antigents, anesthetics, analgestics, antibiotics, antiviral agents, antineoplastic agents, cavity and infection preventing agents, cardiovascular agents, angiogenic and antiangiognic agents, anti-inflammatory agents, vasodilators, brochiodilators, alkaloids, peptides and proteins, vaccines, live or killed bacteria and viruses, trees, flowers fruits, buds, seeds, leaves, barks stem roots, and animal tissues,
soft and hard tissues, growth promoting agents, tissues such as bones or agents derived therefrom, bone growth promoting agents such as calcium phosphates calcium sulfate and hydroxyapatities, deoxyribonucleic acid (DNA), DNA fragments, ribunucleic acid (RNA) RNA fragments, and biological tissues such as islets of langerhans and pancreas. The biologically active substances can be in the form of a solid, or dissolved or suspended in a plasticizer or mixture of plasticizers.
6. A method for modulating the degradation o a biodegradable delivery vehicle substantially as
herein described with reference to the example.
There Is provided a method for the manufacture of biodegradable delivery vehicle made of a biodegradable polymer, a plasticizer and a biologically active substances (BAS) by varying the physiochemical properties as herein described of at least one member of the group consisting of said biodegradable polymer, said plasticizer, and said BAS and combinations thereof, thereby modulating the degradation of said biodegradable vehicle, said method comprising the steps of
a. selecting at least one biodegradable polymer as herein described.
b. dissolving said polymer in at least one volatile solvent selected from a group
consisting of acetone, methyl acetate, ethyl acetate, chlorofonn,
dichloromethane, methyl ethyl ketone, hexafluroisopropanol, tetrahydrofuran and
hexafluroacetone seqwuihydrate to form a solution.
c. adding at least one known plasticizer to said solution of step (b); and
d. evaporating said solvent from the solution of step (c) and adding a biologically
active substance (BAS) as herein described either before or after the step (b).


Documents:


Patent Number 208408
Indian Patent Application Number IN/PCT/2002/01562/KOL
PG Journal Number 30/2007
Publication Date 27-Jul-2007
Grant Date 26-Jul-2007
Date of Filing 23-Dec-2002
Name of Patentee SHUKLA ATUL J.
Applicant Address 837 WALNUT BEND ROAD, CORDIVA, TN 38018,
Inventors:
# Inventor's Name Inventor's Address
1 SHUKLA ATUL J. 837 WALNUT BEND ROAD, CORDIVA, TN 38018,
PCT International Classification Number A 61 F 2/00, 13/00
PCT International Application Number PCT/US01/06138
PCT International Filing date 2001-02-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA