Title of Invention

"A METHOD OF MAKING A CONTROLLED RELEASE COMPOSITION"

Abstract

A method of making a controlled release composition of microparticle and nanoparticle or an organic ion bioactive agent comprising: combining an organic phase consisting of a solvent and a bioactive agent and a polymer with an aqueous phase consisting of an emulsifying agent and an organic ion, wherein said organic ion is present in an aqueous phase to reduce degradation of said bioactive agent; and recovering said composition.

Full Text

METHOD FOR THE PREPARATION OF CONTROLLED RELEASE FORMULATIONS Fteld of the Invention The present Invention relates to a method of making controlled release compositions; and, specifically to a method of contacting an organic solution containing a bloactive agent and a polymer with an aqueous solution containing an organic ion through an emulsion process to create controlled release compositions. The present Invention further provides methods of using controlled release compositions including a polymer, an organic ton and a bloactive agent BACKGROUND OF THE INVENTION Currently there are numerous controlled release formulations on the market that contain various bioactlve agents, such as GnRH analogs, human growth hormone, risperidone and somatostatin analogs of which octreotide acetate is an example. These controlled release compositions are typically formulated with biodegradable, btocompatlbJe polymers. Such formulations are preferred by healthcare professionals and their patients because they reduce the need for multiple injections. Additionally, sirra one injection treats a patiert time, health care organizations prefer them because they decrease the number of office visits per patient, which works to decrease health care costs. Unfortunately, there are many problems with the current production processes and formulations for controlled release compositions. Many current manufacturing processes are Incapable of producing concentrated product exhibiting a high drug load, thus necessitating a large intramuscular injection volume (2 ml) that Is quite uncomfortable for the patient when administered. Additionally, many methods require time consuming and complex procedures to solubllize bioactive agents prior to encapsulation; and manipulation of solubility for purposes of encapsulation can result in deleterious release profiles, as well as degradation of the bioactive agent Itself. For example, the use of highly water soluble bloactive agents frequently results in an undesirable "burst" of bloactive agent upon contact with an aqueous solution, such as by administration to a patient or introduction to a physiological medium. Such a rapid rise In levels of bioactive agent can be detrimental to a patient and may leave little btoactive agent for later release over the desired treatment time course. Various methods of solving the solubility problem have been attempted but none have been particularly efficient or effective. One such attempt combined a 5 bioactive agent with a surfactant molecule, comprising an anionte head and a hydrophobia tail, to solubilize the btoactive agent In an organic phase prior to encapsulation. Another method combined organic acids with the bioactive agent to produce a water Insoluble addition salt prior to encapsulation. The use of an insoluble additional salt resulted In a lessening of the "burst" effect upon administration; however, this method required additional manufacturing procedures that made production of these compounds expensive and inefficient Another method included encapsulation of the acetate salt of the bioactive agent that resulted In substantial amounts of chemically modified or degraded bioactive agent being released after placement in an aqueous physiological buffer. Chemical degradation was in the form of undesirable acylation of the bioactive agent Methods of producing controlled release compositions that are capable of producing a product with a high drug load, minimum burst effect upon administration and minimum degradation of the bioactive agent are greatiy needed to realize the true benefits of these types of compositions as human or veterinary therapeutics. SUMMARY OF THE INVENTION In accordance with the purposes) of this invention, as embodied and broadly described herein, this Invention, in one aspect, relates to methods of making and using controlled release compositions. In one embodiment, the method includes the steps of combining a bioactive agent and a polymer In an organic phase; combining an organic Ion in an aqueous phase; and contacting the resulting organic and aqueous phases to produce a controlled release composition. In a certain embodiment, the method includes the steps of combining a bioactive agent and a polymer in an organic phase; combining an organic ion in an aqueous phase; and subjecting the resulting organic and aqueous phases to an emulsion process to produce a controlled release composition. In a certain embodiment the method includes contacting an organic phase comprising a polymer and a bioactfve agent with a water phase comprising an organic Ion wherein an effective quantity of an organic ion leaves the aqueous phase and enters the organic phase. In one embodiment, the organic phase comprises a solvent selected from the group consisting of, but not limited to, methylene chloride, ethyl acetate, benzyl alcohol, acetone, acetic add and propylene carbonate. In a particular embodiment, the organic phase further Includes a cosolvent. The cosolvent may be selected from the group consisting of, but not limited to, dimethyl sulfoxide, dimethyl formamide, n-methylpyrrolldinone, PEG200. PEG400, methyl alcohol, ethyl alcohol, Isopropyl alcohol and benzyl alcohol. In another embodiment, the aqueous phase further Includes an emulsifying agent. The emulsifying agent may be selected from the group consisting of, but not limited to, poly(vinyl alcohol), albumin, lecithin, vitamin E- D-aipha-tocopheryl polyethylene glycol (TPGS) and porysorbates. In a particular embodiment, the emulsifying agent may be present at a final concentration ranging from about 0.1 to 10% (w/w). In a certain embodiment, the organic km is at a final concentration ranging from about 0.1 to 1000 mM. In a certain embodiment, the controlled release composition Is selected from the group consisting of, but not limited to, mteroparticles and nanoparticles. In a particular embodiment, the mteroparbcles and nanoparticles are biodegradable. In another embodiment, the polymer may be selected from the group consisting of, but not limited to, poly(lactide)s, poly(glycolide)8l poly(lacHde-co-glycolide)s, poly(lactlc add)s, poly(g!ycolic add)s, poly(lactic acid-co-glycolic acfd)s, polycaprolactone, polycarbonates, polyesteramldes, polyanhydrides, poly(amlno acids), polyorthoeaters, polyacetyls, polycyanoacryiates, polyetheresters, poly(dloxanone)s, poly(alkylene alkylate)s, copolymers of polyethylene glycol and orne ce .: - ,, Express Mali Label No.: US 330070825 US 7 poty(lactide-co-glycollde), biodegradable polyurethanes, blends and copolymers thereof. In another embodiment, the bloactive agent may be selected from the group consisting of, but not limited to, proteins, nucleic acids, pep-tides, small molecule pharmaceutical substances, frnmunogens, metabolic precursors capable of promoting growth and survival of cells and tissues, antineoplastlc agents, hormones, antihistamfnes, cardiovascular agents, anti-ulcer agents, bronchodllators, vasodilators, central nervous system agents, narcotic antagonists and the like. In a certain embodiment, the emulsion process Is selected from the group consisting of oll-ln-water and water-oil-water. In a particular embodiment, the methods of the present Invention may be practiced with any known emulsion process. In a particular embodiment the organic Ion Is selected from the group consisting of entente and cattonte materials. In a particular embodiment, the organic Ion is selected from pamoate, trtfkioromethyl-p-toluate, cholate, 2-napbthatene sulfonate, 2,3-naphthatene dtearboxylate, 1-hydroxy-2-napntnoate, 3-hydroxy-2-naphthoate, 2-naphthoate and sallcyteaHcylate. In another embodiment, degradation Includes acyiatton. In a particular embodiment the acyiatlon reaction Involves nucteophflte attack of an amino group of a bfoacttve agent directed to a carbonyl carbon of a polyester such as pory(d,l-lactide-co-glycollde). It is hypothesized that degradation of the bioactive agent is prevented or reduced in the present compositions by facilitated protonatton of potential nucleophlles (e.g., amlno groups), thus rendering the nucteophiles less apt to participate in acylation reactions with the PLGA polymer backbone or fragments thereof. In another embodiment degradation includes lysis of the polymer. Excessive lysis may lead to rapid loss of polymer molecular weight and premature release of bloactive agent In another embodiment, the molar stolcbtometry of the bloactive agent relative to the organic ion ranges from about 0.5 to 2.0. In a particular embodiment the molar stotehtometry of the bloactive agent relative to the organic Ion ranges from about 1.0 to 1.5. In another certain embodiment, the present Invention provides a controlled release composition Including a polymer and a bloactive agent in the form of a complex with an organic ion. Such a complex may be formed when an organic ion and a bloactive agent form a close physical association. In another embodiment the btoactive agent content may be Increased relative to the btoactive agent content of compositions prepared by the method of the present Invention In the absence of an organic ion. In another embodiment, the present Invention includes a method of combining a bioactlve agent with an organic phase; combining a polymer with the same organic phase; combining an organic ton with an aqueous phase; and contacting the organic phase and aqueous phase through the use of an emulsion process In order to produce an encapsulated form of the btoactive agent AddltkxralaoS^tagesofthetnventtonwIllbesetforthlnDertinthe description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the Invention wHI be realized and attained by means of the elements and combinations particuterry pointed out hi the appended claims. It Is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the Invention as claimed. DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Definitions For the purposes of the present Invention, the following terms shall have the following meanings: For the purposes of the present Invention, the term "biodegradable" refers to polymers that dissolve or degrade in vivo within a period of time that is acceptable in a particular therapeutic situation. Such dissolved or degraded product may include a smaller chemical species. Degradation can result, for example, by enzymatic, chemical and/or physical processes. Biodegradatlon takes typically less than five years and usually less than one year after exposure to a physiological pH and temperature, such as a pH ranging from 8 to 9 and a temperature ranging from 22C to38C. For the purposes of the present Invention, the terms "organic phase* and "discontinuous phase" are interchangeable and refer to the solution of solvent, polymer and bfoactlve agent created In the methods of the present invention that will then be contacted with an aqueous phase through an emulsion process In order to create the controlled release compositions of the present invention. For the purposes of the present invention, the term "degradation" refers to any unwanted modification to the bloactive agent, such as acyiation, or to the polymer, such as lysis. For the purposes of the present Invention, the terms "aqueous phase" and 'continuous phase" are Interchangeable and refer to the solution of water and organic Ion agent created in the methods of the present invention that wfll then be contacted with an organic phase through an emulsion process in order to create the controlled release compositions of the present Invention. For the purposes of the present Invention, the term "combining* refers to any method of putting two or more materials together. Such methods Include, but are not limited to, mixing, blending, commingling, concocting, homogenizing, incorporating, intermingling, fusing, joining, shuffling, stirring, coalescing, integrating, confounding, joining, uniting, and the like. For the purposes of the present invention, ranges may be expressed herein as from "about" or "approximately" one particular value, and/or to "about" or "approximately" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,* It will be understood that the particular value forms another embodiment, it will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint For the purposes of the present Invention, the term "bioactive agent" refers to any agent with biological activity either In vivo or In vitro, where biological activity may be detected as an observable change In overall health or at least one health marker (i.e., symptom) of an individual, as a change in a relevant surrogate biological marker or as a change In the chemical structure or conformation of a physiologically relevant Disclosed are the components used to prepare the controlled release compositions of the present invention. These and other materials are disclosed herein, and It is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective permutation of these compounds may not be explicitly disclosed, each Is specifically contemplated and described herein. For example, if a number of bloactive agents are disclosed and discussed and a number of modifications that can be made to a number of molecules including bloacifve agents are discussed, specifically contemplated Is each and every combination and permutation of bloactive agent and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules 0, E, and F and an example of a combination molecule, A-D Is disclosed, then even if It is not individually recited each Is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B- E, B-F, C-D, C-E and OF are considered disclosed. Likewise, any subset or combination of these Is also disclosed. Thus, for example, the sub-group of A-E, B- F, and C-E would be considered disclosed. This concept applies to aH aspects of this application Including, but not Unfitted to, steps In methods of making and using the present Invention. Bfoactive Agents In one embodiment of the present invention, the btoactive agents are selected from the group consisting of proteins, nucleic adds, carbohydrates, pep-tides or a small molecule pharmaceutical substances. Proteins of use in the present invention Include but are not limited to antibodies, therapeutic proteins, human growth hormone, Insulin, oxytocin, octreotkJe, Gonadotropin-Releaalng Hormone, leuprolide, interferon alpha, interferon beta, interferon gamma, insulin, calcitonln, interieukin-1, interieukin-2, and the like. Nucleic acids of use in the present invention include DMA, RNA, chemically modified DNA and chemically modified RNA, aptamers, antisense, RNA interference, and small RNA Interference. Carbohydrates include heparin, low molecular weight heparin and the like. Peptides include LHRH agonists and synthetic analogs, leuprolide, somatostatin analogs, hormones, octreotide, glucagons-llke peptide, oxytocin and the like. Small molecule pharmaceutical substances include, but are not limited to, antilnfectlves, cytotoxlcs, antihypertensives, antifungal agents, antipsychotics, anttdlabetlc agents, immune stimulants, immune suppressants, antibiotics, antMrals, anticonvulsants, antihistamines, cardiovascular agents, anticoagulants, hormones, antimalarials, analgesics, anesthetics, steroids, nonsterokJal anti-lnfiammatories, antiemetics. In another embodiment, the bioactive agent is an Immunogen. Such Immunogen may be selected from the group consisting of, but not limited to, immunogens for stimulating antibodies against hepatitis, influenza, measles, rubella, tetanus, polio, rabies, and the like. In another embodiment, the bloactive agent Is a substance or metabolic precursor capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells. Such substance or metabolic precursor may be selected from the group consisting of, but not limited to, a nerve growth promoting substance such as a ganglloside, a nerve growth factor, and the like; a hard or soft tissue growth promoting agent such as flbronectin, human growth hormone, a colony stimulating factor, bone morphogente protein, platelet-derived growth factor, Insulin-derived growth factors, transforming growth factor-alpha, transforming growth factor-beta, epidermal growth factor, flbroblest growth factor, interieukin-1, vascular endothelial growth factor, keratinocyte growth factor, dried bone material, and the like. In another embodiment, the btoactive agent is an antineoptastic agent Ina particular embodiment, the antineoplastic agent is selected from the group consisting of, but not limited to, methotrexate, 5-fluorouradl, adriamydn, vinblastin, cteplatin, tumor-epeclflc antibodies conjugated to toxins, tumor necrosis factor, and the like. In other embodiments, the bioactive agent is selected from the group consisting of, but not limited to, antihistamines such as dlphenhydramlne, and the like; cardiovascular agents such as papverfne, streptoklnase and the like; anti-ulcer agents such as Isopropamide iodide, and the like; bronchodllators such as metaprotemal sulfate, amlnophylllne, and the like; vasodilators such as theophylline, nlacln, mlnoxldll, and the like; central nervous system agents such as tranqullizers, B-adrenerglc blocking agents, dopamine, and the like; antipsychotic agents such as risperidone, narcotic antagonists such as naltrexone, naloxone, buprenorphine; and other like substances. In a certain embodiment, the btoactive agent Is capable of providing a local or systemic biological, physiological or therapeutic effect in the biological system in which ft Is applied. For example, the agent may act to control infection or inflammation, enhance ceil growth and tissue regeneration, control tumor growth and enhance bone growth, among other functions. In another embodiment, controlled release compositions may contain combinations of two or more bloactive agents. In a particular embodiment, controlled release compositions contain five or fewer bloactive agents. In another particular embodiment, controlled release compositions contain one bloactive agent. In a particular embodiment, the bloactive agent Is in the form of a complex with an organic ion. In another embodiment, bloactive agents of the present invention may include various salt forms and derivatives Including covalent linkages to hydrophlllc polymers such as polyethylene glycol) and polypropylene glycol). The present invention Includes pharmaceutical equivalents of btoactive agents. Pharmaceutical equivratents demonstrate similar or greater/h v*o activity to the btoactive agent Itself. In a particular example, a pharmaceutical equivalent may have a similar chemical structure to the btoactive agent, contain only the biologically active portion of the btoactive agent or be a synthetic analog of the bioactive agent In a particular embodiment, the bloactive agent has the potential to exhibit at least one positive or negative charge or both positive and negative charge. In a particular embodiment, the btoactive agent Is water soluble. In another particular embodiment, the bloactive agent Is solubllteed in an organic solvent, optionally including a cosolvent The bloactive agent may be soluble in water or In organic solvents or both. It will be appreciated by one skilled In the art that the actual amounts of bioactive agents to utilize in a particular case will vary according to the specific compound being utilized, the particular compositions formulated, the mode of application, and the particular situs and patient being treated. Dosages for a given host can be determined using conventional considerations, for example, by customary comparison of the differential activities of the subject compounds and of a known btoactive agent, for example, by means of an appropriate conventional pharmacological protocol. Physicians and fbrmulators, skilled in the art of determining doses of pharmaceutical compounds, will have no problems determining dose according to standard recommendations. Organic Ion Organic Ions of use In the present invention include anionte and cattonte materials. Antonfc materials Include, but are not limited to, the following organic acids and their salts: pamolc, dodecylsutfurtc, chollc, trifluoromethyl-p-toluic, 2-naphthatene sutfonte, 2,3-naphthatene dicarboxylic, 1-hydroxy-2-naphthoic, 3-hydroxy-2-napnthoic, 2-naphthoic, and sallcylsallcylic. In addition organic forms of surfates, sulfonates, phosphates, and phosphonates are suitable organic Ions. Salt forms of the antonte materials may Include sodium, ammonium, magnesium, calcium and the like. Cationte molecules Include, but are not limited to, those having an ammonium or guanidlnium group or a substituted ammonium group. Organic anionfc agents are used with btoactfve agents that have one or more functional groups having, or capable of adopting, a posftive charge, such as an ammonium or guanldinlum group. Organic cationte agents can be used with btoactive agents that have one or more functional groups having or capable of adopting a negative charge such as a carboxyi, surfate, surronata, phosphate, or phosphorate group. Organic ion agents of use In the present invention may be soluble In water and in the organic phase to the extent required to enhance encapsulation efficiency and drug loading. In a particular embodiment, enhanced encapsulation efficiency and drug loading are achieved via decreased degradation of the bioactive agent In a particular embodiment, the concentration of the organic ion agent in the aqueous phase ranges from about 0.5 to 100 mM. In another particular embodiment, the organic ion ranges from about 5 to 40 mM. Biodegradable MIcropartlcleB In certain embodiments, the controlled release composition is a microparticle. In certain embodiments, a bioactive agent Is associated with a biodegradable polymer In a microparticle form. In a particular embodiment, a microparticle has a diameter less than 1.0 mm and typically between 1.0 and 200.0 microns. MicroparHdes include both mfcrospheres and microcapsules, and may be approximately spherical or have other geometries. Mfcrospheres are typically approximately homogeneous in composition and microcapsules comprise a core of a composition distinct from a surrounding shell. For purposes of this disclosure, the terms mterosphere, microparticle and mfcrocapsule are used Interchangeably. In certain embodiments, mlcroparticies can be made with a variety of biodegradable polymers. Suitable blocompatible, biodegradable polymers include, for example, poly(lacflde)s, poty(gtycollde)s, poly(lactlde-co-Qlvcolide)s, poly(lactte acid)s, poly(giycolic add)s, poly(lactic acld-cc-glycolic acld)s, polycaprolactone, polycarbonates, potyesteramides, por/anhydrides, poly(amino acids), poiyorthoestera, polyacetyis, polycyanoacrytates, polyetherestere, poly(dtoxanone)8, poly(alkvtene alky)ate)s, copolymers of polyethylene glycol and poly(lactide)s or poly(lactlde-co-glycolide)8. biodegradable polyurethanes, blends and copolymers thereof. In a particular embodiment, the microparticle Is made of poly(d,t-!actkJe-co-glycoflde) (PLGA). PLQA degrades when exposed to physiological pH and hydrotyzes to form lactic acid and glycolfc acid, which are normal byproducts of cellular metabolism. The disintegration rate of PLQA polymers will vary depending on the polymer molecular weight, ratio of tectide to glycolide monomers In the polymer chain, and stereoregularity of the monomer subuntts. Mixtures of L and D stereoisomere that disrupt the polymer crystalllnlty will Increase polymer disintegration rates. In addition, mterospheres may contain blends of two or more biodegradable polymers, of different molecular weight and/or monomer ratio. In other alternative embodiments, derivatized biodegradable polymers, including hydrophillc polymers attached to PLQA, can be used to form mfcrospheres. In particular embodiments, the hydrophllic polymer is selected from the group consisting of, but not limited to, polyethylene glycol), polypropylene glycol) and copolymers of polyethylene glycol) and polypropylene glycol). Biodegradable Nanopartlcles In certain embodiments, the controlled release composition Is a nanoparflete. In certain embodiments, the bioactive agent, with or without a hydrophilic polymer attached, Is associated with biodegradable submicron particles for controlled 5 release of the bioactive agent. A nanoparttole has a diameter ranging from 20.0 nanometers to about 2.0 microns and Is typically between 100.0 nanometers and 1.0 micron. Nanopartictes can be created In the same manner as micropartlcles, except that high-speed mixing or homogenization is used to reduce the size of the 10 polymer/bioactive agent emulsions to less than 2.0 microns and typically below 1.0 micron. Alternative methods for nanoparticle production are known in the art and may be employed for the present invention. Production of Controlled Release Compositions In one embodiment an organic phase, containing one or more solvents, a 15 bioactive agent and a polymer Is contacted with an aqueous phase, containing an organic ton. In a particular embodiment, the organic phase additionally includes a cosolvent In another particular embodiment, the aqueous phase additionally Includes an emulsifying agent in another particular embodiment, the organic ion is a salt of an organic acid. In another embodiment, the organic phase Is contacted with the aqueous phase to form an emulsion wherein the emulsion comprises droplets of the organic phase dispersed In the aqueous phase. Solvent Is subsequently removed from the emulsion droplets to form hardened microparticles. In a particular embodiment, the solvent Is removed by evaporation. In another particular embodiment, the solvent is removed by extraction Into an extraction liquid; for example, the extraction liquid may be water. In yet another a particular embodiment, the solvent Is removed by filtration. The hardened microparticles may then be recovered from the aqueous phase and dried. In yet another embodiment, the emulsion Is produced by stirring the organic 30 and aqueous phases. In another embodiment, the emulsion is produced by use of a mixer. In a particular embodiment, the mixer is a static mixer, in a certain embodiment the emulsion is produced by use of turbulent mbdng. In another embodiment the emulsion Is produced without turbulent mixing. The emulsion process may be carried out at any temperature between the boiling point and freezing point of the components. In one embodiment, the temperature ranges from about 0°C to about 100°C and Is typically between 5°C and 758C. In a particular embodiment, the emulsion process Is carried out between about 15°C to about 60°C. The organic phase of the present invention may contain solvents Including, but not limited to, methytene chloride, ethyl acetate, benzyl alcohol, acetone, acetic acid, propytene carbonate and other solvents In which the biodegradable polymer Is soluble. In a particular embodiment, the solvent of the organic phase may be selected from the group consisting of ethyl acetate and methylene chloride. In a particular embodiment, the aqueous phase may Include water and an emulsifler. In a certain embodiment, cosolvents may be added to the organic phase. They are optionally used to promote solubility of the btoactive agent in the organic phase. In a particular embodiment, they are selected from the group consisting of, but not limited to, dimethyl suJfoxkte, dimethyl formamkJe, rHnethylpyrroNdinone, PEGao, PEGwot methyl alcohol, ethyl alcohol, teopropyl alcohol, and benzyl alcohol. In another particular embodiment, the cosolvent may be present between 0 and 90% w/wof the solvent of the organic phase. In another particular embodiment, the cosolvent Is present between 0 and 50% w/w of the solvent of the organic phase. The btoactive agent may be dissolved first in an appropriate volume of the cosolvent which is then added to the solvent of the organic phase, optionally having the biodegradable polymer dissolved therein, so as to form a solution of all the components of the organic phase. A person of ordinary skill can adjust the volumes and order of addition to achieve the desired solution of bloactlve agent and biodegradable polymer. In a certain embodiment, the btoactive agent will be present in the organic phase at a concentration of 1 - 20% w/w. In a particular embodiment, the biodegradable polymer will be present In the organic phase at a concentration of 2-40% w/w. In another particular embodiment, the biodegradable polymer will be present In the organic phase at a concentration of 5-20% w/w. The controlled release compositions of the present inventions are found to show surprising properties. Therefore the compositions are synergistics. Organic tons are dissolved In the aqueous phase. In a certain embodiment, they are dissolved at a concentration of between about 0.1 mM to about 1000 mM. In a particular embodiment, they are dissolved at a concentration of between 1 to 1( mM. The concentration may be adjusted for each particular organic ton agent and bioactive agent to achieve the desired drug loading and encapsulation efficiency. One or more emulsifying agents may be added to the aqueous phase to stabilize the emulsion. Emulsifying agents may be selected from the group consisting of, but not Hmited to, poly(vinyl alcohol), albumin, lecithin, vitamin E TPG and polysorbates. The emulsifying agents are present at a concentration in the aqueous between 0 and 10% (w/w). In a particular embodiment, they are present i a concentration between 0.5 to 5% w/w. Organic antons of the present invention include, but are not limited to, the following organic adds and their salts: pamote, dodecyteulfurte, choHc, trtfluoromethyl-p-tolulc, 2-naphthatene sulfonic, 2,3-naphthatene dicarboxylic, 1-hydroxy-2-naphthoic, 3-hydroxy-2-naphtnote, 2-naphtholc, and salteylsallcyllc or organic derivatives of sulfates, sulfonates, phosphates, and phosphorates. Pharmaceutical Formulations In addition to the compounds formulated for parenteral administration, s as Intravenous or Intramuscular Injection, other alternative methods of administra of the present Invention may also be used, Including but not limited to Intrader administration, pulmonary administration, buccal administration, transdermal transmucosai administration. Transmucosal administration may Include, but is limited to, ophthalmic, vaginal, rectal and intranasal. All such methods administration are well known in the art. In a particular embodiment, the controlled release composition of the pre invention may be administered intranasalfy, such as with nasal solutions or spi aerosols or inhalants. Nasal solutions are usually aqueous solutions designed t administered to the nasal passages In drops or sprays. Nasal solutions are prepare that they are similar in many respects to nasal secretions. Thus, the aqueous r solutions usually are Isotonfc and slightly buffered to maintain a pH of 5.5 to 8.5. Antimicrobial preservatives, similar to those used in ophthalmic preparat and appropriate drug stabilizers, if required, may be included in any of the formula! Preservatives and other additives may be selected from the group consisting of, but not limited to, antimicrobials, anti-oxldants, chelating agents, Inert gases and the like. Various commercial nasal preparations are known and include, for example, antibiotics and antihtetamlnes and are used for asthma prophylaxis. In another embodiment, controlled release compositions of the present invention are applied topically. Such controlled release compositions Include, but are not limited to, lotions, ointments, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Exclpients, Carriers and Diluents Controlled release compositions of the present Invention can be formulated In any exdptent the biological system or entity can tolerate. Examples of such excipients include water, saline, Ringer's solution, dextrose solution, Hank's solution and other aqueous physiologically balanced salt solutions. Nonaqueous vehicles, such as fixed oils, polyethylene glycol and Injectabte organic esters such as ethyl oteate may also be used. Other useful formulations Include suspensions containing viscosity-enhancing agents, such as sodium carboxymetrryteellulose, sorbrtol or dextran. Exdpients can also contain minor amounts of additives, such as substances that enhance (sotonidty and chemical stability. Examples of buffers include phosphate buffer, bicarbonate buffer and Tris buffer, while examples of preservatives include thlmerosol, cresote, formalin and benzyl alcohol. Pharmaceutical carriers for controlled release compositions of the present Invention are known to those skilled in the art Those most typically utilized are likely to be standard carriers for administration to humans including solutions such as sterile water, saline and buffered solutions at physiological pH. The controlled release compositions of the present Invention may be suspended In any aqueous solution or other diluent for Injection In a human or animal patient In need of treatment Aqueous diluent solutions may further include a viscosity enhancer selected from the group consisting of sodium carboxymethylcellulose, sucrose, mannltol, dextrose, trehatose and other blocompatible viscosity enhancing agents. The viscosity may be adjusted to a value between 2 centipoise (cp) and 100 cp, preferably between 4 and 40 cp. In a particular embodiment, a surfactant may be included in the diluent to enhance suspendabillty of the controlled release composition. Surfactants may be selected from the group consisting of, but not limited to, polysorbates and other btocompatibte surfactants. Surfactants are used at a concentration of between 0 and 5 5% (w/w), preferably between 0.1 and 1 % w/w.Attorney Docket No.: 007184-17 Express Mail Label No.: US 330070825 US '" EXAMPLES The following examples are Included to demonstrate particular embodiments of the Invention. It should be appreciated by those of skilI In the art that the techniques disclosed in the examples which follow represent techniques discovered by the Inventors to function well in the practice of the invention, and thus can be considered to constitute particular modes for its practice. However, those of skill In the art should, In fight of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the Invention. Example 1 Conventional Preparation of Octreotlde Acetate Encapsulated In Poty(lactide-co-Qlycollde) (PLGA) Mlcropartlclea Using Co-Solvents According to Previously Uaed Methods. Octreotlde acetate mlcropartlcle formulations were prepared to Investigate the effect of different co-solvents In the organic phase. Formulations A-F were prepared using an oiMn-water emulsion/solvent extraction technique, are summarized In Table 1. PLGA polymer (50:50 lactkte/glycoflde, MW 24,000,180 mg) was dissolved in ethyl acetate (EtOAc, 900 uL), and octreotide acetate (20 mg) dissolved in a co-solvent (Table 1) was added to the polymer solution. The resulting homogeneous organic phase was added to an aqueous phase (2 mL) containing 1% poiy(vlrtyl alcohol) (PVA) and the mixture was vortexed for 15-30 seconds. The emulsion was poured Into a solvent extraction solution (10 mM sodium phosphate, pH 8.0,150 ml) and stirred for four hours to extract EtOAc. Particles were Isolated by filtration, washed with water and air dried overnight. The formulations were characterized by particle size, scanning electron microscopy (SEM), morphology, octreotide core load and In vitro release profiles. Formulation D was repeated using an emulsifying device, such as that disclosed in PCT Application Serial No. PCT/US04/11485, that combined a homogeneous organic phase (2 mL) consisting of octreotide acetate (20 mg), MeOH (100nL), PLGA polymer (50:50 lactlde/glycollde, MW 24,000,180 mg) and EtOAc (1.9 mL) with a 1% PVA aqueous phase (4 mL). The emulsion was then added to a solvent extraction solution and stirred for four hours to extract EtOAc. This process produced formulation D2 (Table 1). The co-solvents Investigated had a small Influence on particle size and core load. Particle sizes were larger with the higher viscosity poly(ethylene glycol) (PEG) co-solvents. In contrast, core toads were similar for the methanol (MeOH) and PEG co-solvents (formulations A-C). The highest core loads were obtained for the MeOH cosolvent with a pH 8 buffered emulsion step (formulation D2) and for the dimethyl sulfoxlde (DMSO) cosolvent (formulation F). In vitro release kinetics were measured In either phosphate buffered saline (PBS, pH 7.2,37°C) or 100 mM sodium acetate (NaOAc, pH 4.0,37°C). An example Is shown in Table 2 (Formulation D2). The PEG co-solvent systems showed the highest initial peptide burst (8-10%), while the remaining formulations had an initial burst In the range of 2-3%. All the formulations released peptide for at least 6 weeks although there was a decrease In the relative release rates for formulations prepared With polar aprotic solvents (formulations E - F) resulting In lower total release of peptide relative to the other formulations. Octreotlde acetate as the free peptide was measured to be 95% Intact by high-pressure liquid chromatography (HPLC) following incubation in the release medium (PBS, pH 7.2,37°C) after 49 days. In contrast, Incubation of octreotlde acetate PLGA mtcroparttcle formulations produced 55% of modified peptide species after 70 days In the release medium (PBS, pH 7.2,37°C, Table 2). HPLC analysis showed that the new peptide entities were more hydrophobia than native octreotide acetate. HPLC/MS analysis revealed masses consistent with acylation of the parent peptide by PLGA polymer. The masses found were consistent with random acylation, for example, peptide plus one or two gtycollc or lactic add monomers In any combination. It may be that acylation products arise from attack on PLGA fragments or the polymer backbone by nucleophilic moieties In octreotlde. At a lower pH these moieties likely would be protonated reducing their nucteophlllclty and consequently the amount of acylated product It was observed that formation of acylated byproducts for octreotlde acetate PLGA mteroparticles Incubated In 100 mM sodium acetate (NaOAc, pH 4.0) buffer was reduced to 1.25% at 49 days, in marked contrast to the results for PBS buffer (55%). Attorney Docket No.: 007184-17 - Express Mall Label No.: US 330070825 US (Table Removed) Attorney Docket No.: 007184-17 Express Mall Label No.: US 330070825 US (Table Removed) Table 2. In vitro release of formulations D2 and AG. NaOAc buffer contains 100 mM (Table Removed) NaOAc (pH 4.0), 0.02% Tween-20 and 0.05% NaN3. PBS Is phosphate buffered saline (pH 7.2) containing 0.02% Tween-20 and 0.05% NaN3. Samples were incubated in a shaking (150 Hz) water bath Incubator at 37C. Peptide and acyiated 5 peptide release values are listed as cumulative percent released. Attorney Docket No.: 007184-17 Express Mall Label No.: US 330070825 US Example 2 Production of Water Insoluble Organic Acid Salts (Complexes) of Octreotlde and Encapsulation In PLGA Mlcropartides According to Previously Used Methods. Organic ion agents were Investigated where the organic Ion was Initially complexed with octreotkte acetate to form a water insoluble salt fotlowed by encapsulation in PLOA micropartides. Sodium Dodecvlsulfate (SDSV An octreotkJe-SDS complex was prepared by dissolving octreotide acetate (100 mg) In H2O (500 \iL). SDS (1.5 equlv, 43.2 mg) dissolved In HzO (500 jit) was added drop wise to the octreotide acetate solution with vortexkig at room temperature. A precipitate Immediately formed. The sample was centrifuged at 10,000 rpm for 1 minute and the supernatant removed by pipette. The precipitate was washed with cold water and lyophlllzed providing an octreotide-SDS complex (95.3 mg). RP-HPLC analysis showed a pronounced broadening of the octreotide peak Indicating formation of the octreotide/SDS complex. Formulations G-l were prepared using an oil-in-water emulsion/solvent extraction technique. PLGA polymer (MW 24,000,180 mg) was dissolved in EtOAc (900 nL). OctreotkWSDSoxTtp^wa8dte8oh^lnMeOH(100^L)arxladdedtD the polymer solution. This resulted in a heterogeneous organic phase. In the case of formulation I (Tabte 3) an additional aliquot of MeOH (100 uL) was added to produce a homogeneous organic phase. The resulting organic phase was added to an aqueous phase (2 ml_) containing 1% PVA and the mixture was vortexed for 15 - 30 seconds. The emulsion was poured into a solvent extraction solution (10 mM sodium phosphate, pH 8.0,150 ml) and stirred for four hours to extract EtOAc. Particles were Isolated by filtration, washed with water and air dried overnight. The formulations were characterized by particle size, SEM morphology, octreotide core load and In vitro release profiles. The measured core load for formulations G-l prepared from the octreotide-SDS complex were relatively low, between 0.6-2.6% (Table 3). Ateo the median particle size was reduced by approximately 40% relative to formulations (A-F) prepared with octreotide acetate. The In vitro release profiles of formulations G-l in PBS were quite similar,, Each had an Initial burst of approximately 20% followed by three weeks of 1.5% release/week. After three weeks the rate of release Increased to approximately 7.0 % release/week, culminating In approximately 80% total peptide release at 9 weeks. The In vitro PBS release assay with these formulations resulted in the release of similar amounts of acylated (40-55%) and total peptide compared to octreotide acetate (formulations A-F). Table 3. Octreotlde-SDS Complex in the Organic Phase. (Table Removed) Benzole Add. Formulations (J-M) were prepared using one to ten equtvalerrts of benzote acM oKllssorved hi to PLGA polymer (MW 24,000,180 mg) and benzote acid (2.4-24 mg) were dissolved in EtOAc (900 |iL). Octreotide acetate was dissolved in MeOH (100 uL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was added to an aqueous phase (2 ml) containing 1% PVA and the mixture was vortexed for 15 - 30 seconds. The emulsion was poured Into a solvent extraction solution (10 mM sodium phosphate, pH 8.0,150 mL) and stirred for four hours to extract EtOAc. Particles were isolated by filtration, washed with water and air dried overnight The core loads measured between 0.88-1.67% over the range of 1-10 added equivalents of benzole acid per equivalent of octreotide acetate (Table 4). PamoicAcid. An octreotide-pamoate complex was prepared by dissolving pamote add (19.4 mg, 0.05 mmol) In 0.2 N NaOH (500 jiL) to provide the sodium pamoate salt. Octreotide acetate (100 mg, 0.10 mmol) was dissolved In defonlzed water (100 nL) and added drop wise with gentle vortexlng to the sodium pamoate salt solution. This produced a flocculent light yellow precipitate. The precipitate was pelleted by centrif ugatton, and the supernatant removed by pipette. The pellet was washed with water (1.0 ml_), re-suspended In water and lyophlllzed to a light yellow powder (113 mg). The octreotide/pamoate ratio of this preparation was 1.71 as measured by RP-HPLC. A second octreotide-pamoate complex was prepared by dissolving pamoic acid (19.4 mg, 0.05 mmol) In 0.4 N NaOH (250 nL) and dtoxane (250 uL) to provide a solution of sodium pamoate in dloxane/water (1:1). Octreotide acetate (50 mg, 0.05 mmol) was dissolved in dloxane/water (1:1,200 \il). The octreotide acetate solution was added drop wise to the sodium pamoate with mixing to provide a light yellow, homogenous solution. This material was lyophlllzed to dryness providing a light yellow powder (65 mg). The octreotide/pamoate ratio of this preparation was 1.02 as measured by RP-HPLC. These two preparations were used to prepare new PLGA mlcroparticle formulations. Table 4. Benzole add and Octreotide Acetate In Organic Phase. (Table Removed) Mlcroparticle formulations (Table 5, Q-W) were prepared by an oll-in-water emulsion/ solvent extraction method. PLGA polymer (MW 24,000,180 mg) was Attorney Docket No.: 007184-17 Express Mall Label No.: US 330070825 US dissolved In EtOAc (1000 μL). Octreotide pamoate (20 or 40 mg) was dissived in-benzyl alcohol (BnOH, 1000 )iL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% FVA aqueous phase In a ratio of1:2 to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened mlcropartfcles were collected by filtration, washed with water, air dried and stored at 4°C. Formulation characterization (Table 5) revealed that the initial octreotide/pamoate ratio of 1.7 had little effect on the encapsulation efficiency and core load relative to the formulations prepared with the octreotide/pamoate ratio of 1.02. In contrast, changing the co-solvent to benzyl alcohol increased the encapsulation efficiency by approximately 60% relative to methanof (e.g. Formulation S compared to T). The in vitro release profiles of these formulations In PBS demonstrated total peptlde released (79-92%, Table 5 Q-T) is comparable to PLGA octreotkJe acetate mteropartfctes made by conventional methods (formulations D, F Table 1) white the amount of acyteted peptkie released (28-40%, Table 5 Q-T) Is decreased slightly relative to conventional formulations (44-55%, Table 1, A-D). Formulations prepared using the octreotide/pamoate ratio of 1:1 did not show as strong a dependence of encapsulation efficiency and core toad on the nature of the co-solvent as the 1.7 ratio formulations above. The differences in solubility tor the complexes with different octreotide/pamoate ratios in the co-solvent is proposed as an explanation for this observation. The higher octreotide/pamoate ratio material had an Increased solubility in benzyl alcohol relative to methanol resulting in higher encapsulation efficiency. In contrast, it was found that there was no significant difference in solubility In methanol versus benzyl alcohol for the 1:1 octreotide/pamoate complex. This resulted In similar encapsulation efficiencies and core toads Independent of the co-solvents. The In vitro release profiles of these 1:1 formulations (U-W) reveal similar trends as discussed above, namely, that the total percent of peptlde released (85 -110%, Table 5 U-W) is again comparable to conventional formulations (Example 1) Attorney Docket No.: 007184-17 Express Mail Label No.: US 330070825 US (ca. 85%, Table 2)'while the amount of acytated product released (35-44% Table 5-U-W) Is decreased somewhat relative to conventional formulations (44-55%, Table 1, A-D2). Analysis of the final octreotide/pamoate molar ratio showed a wide variation among the formulations tested (Table 5) with a range from 2.1:1 (formulation W) to over 200:1 (formulation R). In all cases the ratio Is more than twice the octreotide/pamoate ratio of the starting peptide salt complex. Thus the use of a preformed pamoate salt of the peptide octreotide yielded highly variable octreotide/pamoate molar ratios In the final sustained release formulation. Attorney Docket No.: 007184-17 Express Mail Label No.: US 330070825 US Table 5. OctreotkJe-Pamoate Mteroparticles Prepared Using Pre-Formed Complex. Examples Octreotlde Acatate Encapsulation In PLGA Mlcrospheres Using Organic Add Salts In the Aqueous Emulsion Phase According to the Present Invention. Surprisingly it was discovered that the use of an organic acid salt In the aqueous phase of the emulslfication process allowed use of a water soluble peptWe and eliminated the need to prepare complexed species in an Independent step prior to preparing the formulation. The present Invention provided added benefits such as increased drug coreload, consistent octreotlde/organic ion ratio, and decreased peptWe degradation during In vitro release. Microparticte formulations were prepared by an oll-in-water emulsion/solvent extraction method. PLGA polymer (MW 24,000,140 -180 mg) was dissolved In EtOAc (1000 μL). Octreotlde acetate (20 -60 mg) was dissolved In BnOH (1000 nL) and added to the polymer solution yielding a homogenous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10-50 mM dlsodium pamoate to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (150 mL) and stirred forfour hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4°C. This resulted In a final octreotide/pamoate ratio of approximately 1-1.5 in the microparticle formulation measured by RP-HPLC (Table6). The effects of various experimental parameters on core load were Investigated including organic to aqueous phase ratio, nature of co-solvent, and volume of co-solvent BnOH was found to be a more suitable co-solvent than MeOH. It was possible to use BnOH in larger volumes than MeOH, as MeOH induced polymer precipitation in the organic phase. BnOH also led to a small Increase in core load versus MeOH (Formulation Y, AB, Table 6). However, the use of BnOH without the organic ton in the aqueous phase did not provide high core loads or encapsulation efficiencies (Al, Table 6). It was also found that increasing the aqueous to organic phase ratio Increased the encapsulation efficiency slightly when BnOH was used as the co-80»vent(Formulatk)n8AE,AF, Table 6). In all cases the molar ratio of octreotide to pamoate was tightly grouped between 1.0 and 1.5, In contrast to the formulations of Example 2 (Table 5) where the use of a preformed octreotide/pamoate complex led to wide variations of the final octreotide/pamoate ratio from 2.1 to over 200. Significantly, product with predictable and elevated drug core loads ranging from 5-17.5% could be formed with the method of the present invention, (formulations AD, AQ, AH, Table 6), in contrast to the prior art methods of Examples 1 and 2 where the maximum drug core load achieved was about 8% (Table 5 - S) with averages ranging from 2-6% (Tables 1-5). In addition, the compositions of the present invention have consistent stolchiometry for the molar ratio of bioactfve agent to organic Ion (Table 6). This Is In contrast to the compositions made using previous methods (Table 5). Furthermore, the relative production of acylated peptide is lower for mfcroparticles made with the organic ion in the aqueous phase (Table 2, Table 6) than for microparticles made with the use of preformed octreotide-pamoate (Table 5) or octreotide acetate (Table 2). (Table Removed) The effect of organic add concentration in the aqueous phase was explored to determine the optimal manufacturing parameters. PLGA polymer (MW 24,000, 160 mg) was dissolved In EtOAc (1000 jit). Octreotide acetate (40 mg) was dissolved in BnOH (1000 fiL) and added to the polymer solution yielding a homogenous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 20 or 50 mM sodium pamoate to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened mlcropartfcles were collected by filtration, washed with water, air dried and stored at 4°C. Formulations AJ - AL show that 20 or 50 mM disodlum pamoate had no effect on core load relative to 10 mM dlsodium pamoate (Table 7). However, the dlsodium pamoate concentration In the aqueous phase did have a measurable effect on the 'day one" in vitro PBS release. The formulation prepared using 50 mM disodlum pamoate resulted In a 15% burst (Formulation AL, Table 7) as compared to less than 4% burst for formulations prepared with 20 mM organic ion (Formulations AJ, AK, Table 7). This suggests that excess organic Ion In the aqueous phase Is deleterious to the in vitro release performance of the formulations. (Table Removed) Alternative organic ions In addition to pamoate were investigated to explore the general utility of the present Invention. Microparticle formulations were prepared by an oiWn-water emulsion/solvent extraction method. PLGA polymer (MW 24,000, 160 mg) was dissolved In EtOAc (1000 |iL). Octreotide acetate (40 mg) was dissolved in BnOH (1000 nL) and added to the polymer solution yielding a homogenous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10-20 mM organic acid as Its sodium salt to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (150 ml) and stirred for four hours to extract EtOAc. Hardened mteropartlcles were collected by filtration, washed with water, air dried and stored at 4°C. This resulted In mlcroparticle formulations with octreotide core loads between 6.8 and 15.3% as measured by RP-HPLC (Table 8). The effects of the tested organic ions on core toad are revealing. Formulations AM - AP show no increase in the measured core load relative to control containing sodium pamoate (Formulations AT, All, AY, Table 8). In contrast formulations AQ-AS, AV-AX and AZ-BB, which employed organic adds ranging from cholte add to blcyllc aromatics, provided peptide core loads comparable to pamolc add (Table 8). These results imply that organic adds with appropriate phystochemical properties can be substituted for pamolc add to produce comparable mlcropartide formulations. (Table Removed) Encapsulation of Additional Peptldes In PLGA Mterospheros Using Organic Acid Salts in the Aqueous Emulsion Phase According to the Present Invention. Oxytocin acetate and leuprolkte acetate were formulated in PLGA mteropartictes according to the present invention as described in the examples below. The results of these investigations demonstrate the utility of the present Invention in relation to increased core load and encapsulation efficiency (Formulations Bl vs BJ-BK and BLvs BM) relative to conventional methodology (Table 9). Formulation Bl (Leuprolide) - Conventional encapsulation method PLGA polymer (MW 24,000,160 mg) was dissolved in CHaCfe (1000 uL). Leuprolide acetate (40 mg) was dissolved in BnOH (1000 pL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened mteroparbcles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation Bi (140 mg, 70.0% yield) with a median particle size 50.1 urn. The core load (1.09%), encapsulation efficiency (9.95%) end /n vftro burst (1.63%) were determined by RP-HPLC assay. Formulation BJ (LeuproHde) - Organic Ion assisted encapsulation method PLGA polymer (MW 24,000,160 mg) was dissolved In CH2CI2 (1000 nL). Leuprolide acetate (40 mg) was dissolved in BnOH (1000 id.) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (100 mL) and stirred for 10 minutes. A secondary extraction solution consisting of 2% Isopropanol (200 mL) was added and stirred for an additional four hours. Hardened mlcropartlcles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BJ (157 mg, 78.5% yield) with a median parade size 54.0 urn. The core load (9.4%), encapsulation efficiency (47.0%) and In vitro burst (5.31%) were determined by RP-HPLC assay. Formulation BK (LeuproBde) - Organic ion assisted method A microparticle formulation was prepared by an oil-in-water emulsion/solvent extraction method. PLOA polymer (MW 24,000,160 mg) was dissolved In CH2Cl2 (1000 til). Leuprolide acetate (40 mg) was dissolved in BnOH (1000 \iL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 50 mM disodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (100 ml) and stirred for 10 minutes. A secondary extraction solution consisting of 2% Isopropanol (200 mL) was added and stirred for an additional four hours. Hardened micropartlcles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BK (120 mg, 60.0% yield) with a median particle size 43.1 urn. The core load (10.6%), encapsulation efficiency (53.0%) and In vitro burst (21.1%) were determined by RP-HPLC assay. Formulation BL (Oxytodn) - Conventional encapsulation method PLGA polymer (MW 13,000,180 mg) was dissolved in EtOAc (900 μL). Oxytocin acetate (20 mg) was dissolved In MeOH (100 uL) and added to the polymer solution yielding a milky suspension as the organic phase. The resulting organic phase was combined with a 1 % PVA aqueous phase containing 5% EtOAc to provide an emulsion. The emulsion was collected directly into a 10 mM sodium phosphate (pH 8,0°C, 150 ml) solvent extraction solution and stirred for four hours white warming to room temperature to extract EtOAc. Hardened micropartlcles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BL (143 mg, 71.5% yield) with a median particle size 44.0 urn. The core load (1.67%), encapsulation efficiency (16.7%) and In vitro burst (46.3%) were determined by RP-HPLC assay. Formulation BM (Oxytocln) - Organic ton assisted encapsulation method PLGA polymer (MW 24,000,180 mg) was dissolved In EtOAc (1800 uL). Oxytocin acetate (40 mg) was dissolved In MeOH (200 fiL) and added to the polymer solution yielding a milky suspension as the organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (150 mL) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BM (158 mg, 79.0% yield) with a median particle size 144 urn. The core load (8.9%), encapsulation efficiency (44.5%) and In vitro burst (21.1%) were determined by RP-HPLC assay. Table 9 shows that the core toad and encapsulation efficiency of two different peptides were increased by the presence of an organic ion. Table 9. Peptide-pamoate complex micropartfcles by an In situ process. (Table Removed) Example 5 Insulin Encapsulation In PLOA MIcroparHctes Using Organic Add Salts In the Aqueous Emulsion Phase. Sodium Dodecvteulfate Mlcropartfcte formulations were prepared using an olMn-water emulsion/solvent extraction method. The organic phase consisted of PLGA polymer (MW 11,800,150 mg) and PEGyteted-lnsulln (50 mg) dissolved in CHjCb (2 mL). The aqueous phase consisted of 1% PVA and 14 mM SDS. The homogeneous organic and aqueous phases were combined in a ratio of 1:5 to produce an organic In aqueous phase emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (100 ml) and stirred for 10 minutes before adding 100 mL 2% IPA. The solvent extraction solution was then stirred for an additional 3 hours to extract CH^fe. Hardened mlcroparUcles were collected by filtration, washed with water, air dried and stored at -20°C. The resulting mlcroparticle had a core load of 21% (encapsulation efficiency 84%). These micropartictes were characterized by a large in vitro burst of 50% at 24 h in PBS at 37°C. Dlsodlum Pamoate Microparticle formulations were prepared using an oiHn-water emulsion/solvent extraction method. The organic phase consisted of PLGA polymer (MW 11,800,75 mg) and PEGytated-lnsulin (25 mg) dissolved in CH2CI2 (1 ml). The aqueous phase consisted of 1% PVA and 10 mM dlsodlum pamoate. The homogeneous organic and aqueous phases were combined in a ratio of 1:5 to produce an organic in aqueous phase emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (50 ml) and stirred for 10 minutes before adding water (100 ml). The solvent extraction solution was then stirred for an additional 3 hours to extract CH2CI2. Hardened mlcroparticles were collected by filtration, washed with water, air dried and stored at -20°C. The resulting mlcroparticles had a core load of 18% (encapsulation efficiency 78%) and a final PEGylated-lnsulln/pamoate ratio of 1:2. In contrast to the mlcroparticles made with SDS, these mlcroparticles had a low In vitro burst of 5% in PBS at 37°C. Example 6 Evaluation of the Pharmacokinetics of Octraotlde In PLGA Mlcroparticles after Administration to Sprague Dawley Rate. Blood serum levels were measured for octreotlde released from PLGA microparttcte formulations injected subcutaneously In rats. Animals (n=6/group) were treated once by subcutaneous injection of a single dose level (-8-10 mg/kg) of six different octreotlde PLGA micropartJde formulations. At hours 1 and 8, and on days 1,4,7,11,14,20,28,42 and 54, serum samples were obtained from each animal to evaluate the octreotide pharmacokinetics. Serum concentrations were measured by a commercially available extraction-free radtolmmunoassay kit (#8-2211) (Peninsula Labs). The Limit of Quantitation (LOQ) of the assay was 0.1 ng/mL. The mean octreotide serum concentrations for each time point are reported in Table 10. The preparation of the octreotlde PLGA formulations tested is described below. (Table Removed) Preparation and characterization of octraotide formulations used In the animal study. Formulation BC PLGA polymer (MW 24,000,720 mg) was dissolved in EtOAc (4000 pL). Octreotide acetate (80 mg) was dissolved In BnOH (4000 \iL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (600 ml) and stirred for four hours to extract EtOAc. Hardened mteropartteles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BC (754 mg, 94% yield) with a median particle size 55.0 urn. The core load (8.5%), encapsulation efficiency (85.0%) and In vitro burst (7.4%) were determined by RP-HPLC assay. Attorney Docket No.: 007184-17 Express Mail Label No.: US 330070825 US Formulation BD PLGA polymer (MW 24,000,680 mg) was dissolved In EtOAc (4000 >iL). Octreotide acetate (120 mg) was dissolved in BnOH (4000 jiL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (600 ml) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BD (694 mg, 94% yield) with a median particle size 58.7 urn. The core load (11.8%), encapsulation efficiency (78.7%) and In vitro burst (4.1%) were determined by RP-HPLC assay. Formulation BE PLGA polymer (MW 24,000,680 mg) was dissolved In EtOAc (4000 μL). Octreotide acetate (120 mg) was dissolved In BnOH (4000 pL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM dlsodium pamoate to provide an emulsion. The emulsion was collected directly into a 0.3% PVA solvent extraction solution (600 mL) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4«C. This provided formulation BE (727 mg, 91% yield) with a median particle size 52.2 μm,. The core load (11.6%), encapsulation efficiency (77.3%) and In vitro burst (2.75%) were determined by RP-HPLC assay. Formulation BF PLGA polymer (MW 24,000,640 mg) was dissolved in EtOAc (4000 uL). Octreotide acetate (160 mg) was dissolved hi BnOH (4000 \>L) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM dlsodium pamoate to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (600 mL) and stirred for four hours to extract EtOAc. Hardened microparticles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BF (766 mg, 95.8% yield) with a median particle size 47.7 μm. The core load (14.7%), encapsulation efficiency (73.5%) and in vitro burst (5.5%) were determined by RP-HPLC assay. Formulation BO PL6A polymer (MW 28,000,640 mg) was dissolved in EtOAc (4000 nL). Octreotide acetate (160 mg) was dissolved In BnOH (4000 (iL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected directly Into a 0.3% PVA solvent extraction solution (600 mL) and stirred for four hours to extract EtOAc. Hardened mteroparUcles were collected by filtration, washed with water, air dried and stored at 4°C. This provided formulation BG (715 mg, 89.3% yield) with a median particle size 48.7|im. The core load (11.9%), encapsulation efficiency (59.5%) and In vitro burst (2.3%) were determined by RP-HPLC assay. Formulation BH PLGA polymer (MW 14,000,560 mg) was dissolved in EtOAc (4000 uL). Octreotide acetate (240 mg) was dissolved In BnOH (4000 uL) and added to the polymer solution yielding a homogeneous organic phase. The resulting organic phase was combined with a 1% PVA aqueous phase containing 10 mM disodium pamoate to provide an emulsion. The emulsion was collected dtrectty Into a 0.3% PVA solvent extraction solution (600 mL) and stirred for four hours to extract EtOAc. Hardened mlcropartictes were collected by filtration, washed with water, ah- dried and stored at 4°C. This provided formulation BH (680 mg, 85.0% yield) with a median particle size 40.6 pm. The core load (17.4%), encapsulation efficiency (58.0%) and in vitro burst (6.8%) were determined by RP-HPLC assay. In all cases, release of the bloactive agent In vivo occurred for at least 42 days and in some cases for as many as 54 days. All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation In light of the present disclosure. While the compositions and methods of this invention have been described In terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions, and methods and in the steps or In the sequence of steps oftrie methods described herein without departing from the concept, spirit and scope of the Invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. Ail such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the Invention as defined by the appended claims. WE CLAIM: 1. A method of making a controlled release composition of microparticle and nanoparticle or an organic ion bioactive agent comprising: combining an organic phase consisting of a solvent and a bioactive agent and a polymer with an aqueous phase consisting of an emulsifying agent and an organic ion, wherein said organic ion is present in an aqueous phase to reduce degradation of said bioactive agent; and recovering said composition. 2. The method as claimed in claim 1, wherein the solvent is selected from the group comprising dimethyl sulfoxide, dimethyl formamide, n-methylpyrrolidinone. PEG200, PEG400, methyl alcohol, ethyl alcohol, isopropyl alcohol and benzyl alcohol. 3. The method as claimed in claim 1, wherein the emulsifying agent is selected from the group comprising poly (vinyl alcohol), albumin, lecithin vitamin E-TPGS and polysorbate. 4. The method as claimed in claim 1 and 3, wherein the emulsifying agent is at a final concentration ranging from about 0.1 to 10% (w/w). 5. The method as claimed in claim 1, wherein the organic phase comprises a solvent selected from the group comprising methylene chloride, ethyl acetate, benzyl alcohol, acetone, acetic acid and propylene carbonate. 6. The method as claimed in claim 1, wherein the organic ion is at a final concentration ranging from about 0.1 to 1000 raM. 7. The method as claimed in claim 1, wherein the microparticle and nanoparticle are biodegradable. The method as claimed in claim 1, wherein the polymer is selected from the group comprising poly (lactide) , poly (glycolide), poly (lactide-co-glycolide), poly (lactic acid), poly (glycolic acid), poly (lactic acid-co-glycolic acid), polycaprolactone, polycarbonate, polyesteramide, polyanhydride, poly (amino acid), polyorthoester. polyacetyl, polycyanoacrylate, polyetherester, poly (dioxanone) , poly (alkylene alkylate) , copolymer of polyethylene glycol and polyorthoester, biodegradable polyurethane, blend and copolymer thereof. 9. The method as claimed in claim 1, wherein the bioactive agent is any of protein, nucleic acid, carbohydrate, peptide, LHRH agonist and synthetic analogs thereof, leuprolide, oxytocin, somatostatin and synthetic analog thereof, small molecule pharmaceutical substance, immunogen, metabolic precursor capable of promoting growth and survival of cells and tissues, antineoplastic agent, hormone, antihistamine, cardiovascular agent, anti-ulcer agent, bronchodilator, vasodilator, central nervous system agent and narcotic antagonist. 10. The method as claimed in claim 9, wherein the protein or the peptide is selected from the group comprising octreotide, oxytocin, insulin, leuprolide and synthetic variations thereof. 11. The method as claimed in claim 1 wherein the organic phase and aqueous phase are combined using an emulsion process. 12. The method as claimed in claim 11, wherein the emulsion process is any of oil-in-water and water-oil-water. 13. The method as claimed in claim 1, wherein the organic ion is selected from the group comprising carboxylate, sulfate, phosphate, pamoate, dodecylsulfate, trifluoromethyl-p-toluate, dictate, 2-naphthalene sulfonate, 2, 3-naphthalene dicarboxylate, 1-hydroxy-2-naphthoate, 3-hydroxy-2-naphthoate, 2-naphthoate, and salicylsalicylate. 14. A controlled release composition made by the method of claim 1. 15. A process for the production of a microparticle or organic ion bioactive agent as claimed in claim 1 comprising the steps of: a) combining a biodegradable polymer and an organic phase; b) combining a bioactive agent and the organic phase; c) combining an organic ion and an aqueous phase; d) contacting the organic and aqueous phases through the use of an emulsion process; and e) recovering the microparticles. 16. The microparticle or organic ion bioactive agent obtained according to claim 15. 17. An improved process for the production of a microparticle comprising a bioactive agent in a polymer via an emulsion process, wherein the improvement consists of providing an organic ion in an aqueous phase to reduce degradation of the bioactive agent. 18. A method for making a controlled release composition comprising and/or a process for the production of a microparticle comprising and/or a controlled release composition and/or a improved process for the production of a microparticle comprising substantially as herein described with reference to the given examples.

Documents:

706-DELNP-2006-Abstract-(07-01-2009).pdf

706-DELNP-2006-Abstract.pdf

706-DELNP-2006-Claims-(07-01-2009).pdf

706-delnp-2006-claims.pdf

706-delnp-2006-correpsondence-others 1.pdf

706-DELNP-2006-Correspondence-Others-(07-01-2009).pdf

706-delnp-2006-correspondence-others.pdf

706-delnp-2006-description (complete).pdf

706-DELNP-2006-Form-1-(07-01-2009).pdf

706-delnp-2006-form-1.pdf

706-delnp-2006-form-18.pdf

706-DELNP-2006-Form-2-(07-01-2009).pdf

706-delnp-2006-form-2.pdf

706-DELNP-2006-Form-26-(07-01-2009).pdf

706-delnp-2006-form-26.pdf

706-delnp-2006-form-3.pdf

706-delnp-2006-form-5.pdf

706-delnp-2006-pct-101.pdf

706-delnp-2006-pct-105.pdf

706-delnp-2006-pct-210.pdf

706-delnp-2006-pct-220.pdf

706-delnp-2006-pct-237.pdf

706-delnp-2006-pct-301.pdf

706-delnp-2006-pct-304.pdf

706-delnp-2006-pct-306.pdf

706-delnp-2006-pct-308.pdf