WO2009148583A2

WO2009148583A2 - Method for improvement of octreotide bioavailability

Info

Publication number: WO2009148583A2
Application number: PCT/US2009/003366
Authority: WO
Inventors: Richard L. Norton
Original assignee: Qlt Usa, Inc.
Priority date: 2008-06-03
Filing date: 2009-06-03
Publication date: 2009-12-10
Also published as: WO2009148583A3

Abstract

The invention provides a an octreotide sustained release delivery system for treatment of diseases ameliorated by octreotide compounds. The sustained release delivery system of the invention includes a flowable composition containing octreotide. Injection of the delivery system results in a biocompatible implant containing the octreotide. The flowable composition includes a poly(lactide-glycolide) copolymer compositions adapted for use in controlled release delivery systems, and exhibits favorable release kinetics for octreotide when implanted in patients.

Description

METHOD FOR IMPROVEMENT OF OCTREOTIDE BIOAVAILABILITY

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Serial No. 61/058,491, filed June 3, 2008, which is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Developing treatments for malconditions relating to somatostatin and somatotropin are of significant importance because of the serious impact of impaired vision and blindness. One malcondition relating to somatostatin is diabetic retinopathy. Diabetic retinopathy is the leading cause of blindness in patients between the ages of 25 and 74 years. It is estimated that diabetic retinopathy will be responsible for 12,000 to 24,000 new cases of blindness in the United States each year. Studies have shown that octreotide has efficacy in treating diabetic retinopathy. The Sandostatin^® product has been developed for treatment of diseases related to endogenous somatostatin and/or somatotropin, such as diabetic retinopathy. One form is the Sandostatin LAR^® depot, which is a sustained release composition of microparticles containing octreotide. Another is an injectable aqueous solution of octreotide, trade-named Sandostatin " injection.

Effective treatment of diabetic retinopathy using Sandostatin injection requires multiple daily subcutaneous injections with total daily doses between 200 and 5,000 micrograms (Grant, et al., Diabetes Care (2000) 23 (4), 504-509). However, its use in this manner is plagued by such problems as large injection volumes, significant variation in blood level, lack of sustained blood level, multiple daily injection regimen, and short duration of action. Sandostatin^® LAR is an octreotide sustained release microsphere-based product that provides a 1 -month release profile. A major limitation of this microsphere-based product is the relatively low octreotide bioavailability that it provides. Consequently, there is a need for a product that provides higher and more consistent levels of octreotide to treat diabetic retinopathy while minimizing these side effects. Furthermore, a product providing an increased bioavailability of octreotide and other somatostatin analogues is also desired. In particular, there is a need to develop sustained release formulations of octreotide that does not suffer from low bioavailability, poor release kinetics, injection site toxicity, relatively large volume injections and inconveniently short duration of release. Therefore there is also a need for a controlled or sustained release formulation that provides a substantially constant, zero-order rate of release of the bioactive agent over a period of time, or at least a more constant rate of release compared to formulations currently known in the art, while also avoiding an initial burst effect.

SUMMARY The present invention is directed to an octreotide sustained release delivery system capable of delivering octreotide for a duration of about one month to about 6 months, and in some embodiment, about 90 days. The octreotide sustained release delivery system includes a flowable composition and a gel or solid implant for the sustained release of octreotide. The implant is produced from the flowable composition. In certain preferred embodiments, the octreotide sustained release delivery system provides in situ 1 -month and 3- month release profiles characterized by an exceptionally high bioavailability and minimal risk of permanent tissue damage and essentially no risk of muscle necrosis. Several direct comparisons between the octreotide sustained release delivery system of the invention and Sandostatin LAR^® product have been conducted in the preclinical and clinical settings. The octreotide sustained release delivery system of the invention provides significantly higher bioavailability of octreotide as compared to Sandostatin LAR^® product. In addition, the sustained release delivery system of the invention provides blood levels in the therapeutic range immediately after injection, whereas Sandostatin LAR^® product has exhibited the characteristic lag phase prior to the release of octreotide. Finally, the sustained release delivery system of the invention causes little or no tissue necrosis while the Sandostatin LAR^® product causes significant tissue necrosis.

The present invention is directed to an octreotide sustained release delivery system. This delivery system includes a flowable composition and a controlled, sustained release implant. The flowable composition of the invention includes a biodegradable thermoplastic polymer, a biocompatible, polar, aprotic organic liquid and octreotide. The flowable composition of the invention may be transformed into the implant of the invention by contact with water, body fluid or other aqueous medium. In one embodiment, the flowable composition is injected into the body whereupon it transforms in situ into the solid or gel implant of the invention.

The thermoplastic polymer of the flowable composition and implant is at least substantially insoluble in an aqueous medium or body fluid, preferably, essentially completely insoluble in those media. The thermoplastic polymer may be a homopolymer, a copolymer or a terpolymer of repeating monomeric units linked by such groups as ester groups, anhydride groups, carbonate groups, amide groups, urethane groups, urea groups, ether groups, esteramide groups, acetal groups, ketal groups, orthocarbonate groups and any other organic functional group that can be hydrolyzed by enzymatic or hydrolytic reaction (i.e., is biodegradable by hydrolytic action). The preferred thermoplastic polymer, polyester, may be composed of units of one or more hydroxycarboxylic acid residues or diol and dicarboxylic acid residues, wherein the distribution of differing residues may be random, block, paired or sequential.

When the biodegradable thermoplastic polymer is a polyester, the preferable polyesters include a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof, optionally incorporating a third mono-alcohol or polyol component. More preferably, the biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymer thereof, a terpolymer thereof, or a combination thereof, optionally incorporating a third mono-alcohol or polyol component. More preferably, the suitable biodegradable thermoplastic polyester is 50/50 poly (lactide-co-glycolide) (hereinafter PLG) having a carboxy terminal group or is a 75/25 or a 85/15 PLG with a carboxy terminal group or such a PLG formulated with one or more mono-alcohol or polyol units. When a mono- alcohol or polyol is incorporated into the polyester, the mono-alcohol or polyol constitutes a third covalent component of the polymer chain. When a mono- alcohol is incorporated, the carboxy terminus of the polyester is esterified with the mono-alcohol. When a polyol is incorporated, it chain extends and optionally branches the polyester. The polyol functions as a polyester polymerization point with the polyester chains extending from multiple hydroxyl moieties of the polyol, and those hydroxyl moieties are esterified by a carboxyl group of the polyester chain. For an embodiment employing a diol, the polyester is linear with polyester chains extending from both esterified hydroxy groups. For an embodiment employing a triol or higher polyol, the polyester may be linear or may be branched with polyester chains extending from the esterified hydroxy groups. Examples of polyols include aliphatic and aromatic diols, saccharides such as glucose, lactose, maltose, sorbitol, triols such as glycerol, fatty alcohols and the like, tetraols, pentaols, hexaols and the like. The biodegradable thermoplastic polymer can be present in any suitable amount, provided the biodegradable thermoplastic polymer is at least substantially insoluble in aqueous medium or body fluid. The biodegradable thermoplastic polymer is present in about 10 wt. % to about 95 wt.% of the flowable composition, preferably present in about 20 wt.% to about 70 wt.% of the flowable composition or more preferably is present in about 30 wt.% to about 60 wt.% of the flowable composition. Preferably, the biodegradable thermoplastic polymer has an average molecular weight of about 10,000 to about 45,000 or more preferably about 15,000 to about 35,000.

The flowable composition of the invention also includes a biocompatible, polar aprotic organic liquid. The biocompatible polar aprotic liquid can be an amide, an ester, a carbonate, a ketone, an ether, a sulfonyl or any other organic compound that is liquid at ambient temperature, is polar, and is aprotic. The biocompatible polar aprotic organic liquid may be only very slightly soluble to completely soluble in all proportions in body fluid. While the organic liquid generally will have similar solubility profiles in aqueous medium and body fluid, body fluid is typically more lipophilic than aqueous medium. Consequently, some organic liquids that are insoluble in aqueous medium will be at least slightly soluble in body fluid. These examples of organic liquid are included within the definition of organic liquids according to the invention. Preferably, the biocompatible polar aprotic liquid is N-methyl-2- pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, or any combination thereof. More preferably, the biocompatible polar aprotic liquid is N-methyl-2-pyrrolidone. Preferably, the polar aprotic organic liquid is present in about 30 wt.% to about 80 wt.% of the composition or is present in about 40 wt.% to about 60 wt.% of the composition.

The flowable composition of the invention also includes octreotide compounds (hereinafter octreotide) which are oligopeptides having somatostatin- like properties. The octreotide is present in at least about a 0.1 wt. % concentration in the flowable composition with the upper limit being the limit of dispersibility of the peptide within the flowable composition. Preferably, the concentration is about 0.5 wt.% to about 20 wt.% of the flowable composition or more preferably about 1 wt.% to about 15 wt.% of the flowable composition. Preferably, the flowable composition of the invention is formulated as an injectable delivery system. The flowable composition preferably has a volume of about 0.20 mL to about 2.0 mL or preferably about 0.30 mL to about 1.0 mL. The injectable composition is preferably formulated for administration about once per month, about once per three months, or about once per four months, to about once per six months. Preferably, the flowable composition is a liquid or a gel composition, suitable for injection into a patient.

Excipients, release modifiers, plasticizers, pore forming agents, gelation liquids, non-active extenders, and other ingredients may also be included within the octreotide sustained release delivery system of the invention. Upon administration of the flowable composition, some of these additional ingredients, such as gelation liquids and release modifiers will remain with the implant, while others, such as pore forming agents will separately disperse and/or diffuse along with the organic liquid.

The present invention also is directed to a method for forming a flowable composition. The method includes mixing, in any order, a biodegradable thermoplastic polymer, a biocompatible polar aprotic liquid, and octreotide. These ingredients, their properties, and preferred amounts are as disclosed above. The mixing is performed for a sufficient period of time effective to form the flowable composition for use as a controlled release implant. Preferably, the biocompatible thermoplastic polymer and the biocompatible polar aprotic organic liquid are mixed together to form a mixture and the mixture is then combined with the octreotide to form the flowable composition. Preferably, the flowable composition is a solution or dispersion, especially preferably a solution, of the octreotide and biodegradable thermoplastic polymer in the organic liquid. The flowable composition preferably includes an effective amount of a biodegradable thermoplastic polymer, an effective amount of a biocompatible polar aprotic organic liquid and an effective amount of octreotide. These ingredients, the preferred ingredients, their properties, and preferred amounts are as disclosed above.

The present invention also is directed to a method of forming a biodegradable implant in situ, in a living patient. The method includes injecting the flowable composition of the present invention within the body of a patient and allowing the biocompatible polar aprotic organic liquid to dissipate to produce a solid or gel biodegradable implant. Preferably, the biodegradable solid or gel implant releases an effective amount of octreotide by diffusion, erosion, or a combination of diffusion and erosion as the solid or gel implant biodegrades in the patient.

The present invention is also directed to the use of the controlled release formulation in the manufacture of a medicament. In some embodiments, the controlled release formulation includes a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, and wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups; a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2- pyrrolidone, N-methyl-2-pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethyleneglycol or a combination thereof; and octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the composition; wherein the composition is formulated to persist in a mammal for about 80 to about 100 days. In some embodiments, the controlled release formulation is used in the manufacture of a medicament for treatment of a patient having a malcondition associated with somatotropin hypersecretion, gastrointestinal syndrome, with an imbalance, hyper or hypo activity of an insulin, glucagon or somatotropin pathway, or with a somatotropin or somatostatin receptor function. In some embodiments, the controlled release formulation is used in the manufacture of a medicament for treatment of a patient having any somatostatin-responsive disease or medical condition, including non-ocular and ocular diseases. The controlled release formulation is particularly useful in the manufacture of a medicament for the treatment of proliferative ocular diseases, and most particularly, for the treatment of neo vascular diseases of the eye. Examples of such diseases include, but are not limited to, retinal or choroidal neovascularizaton, which occur in diabetic retinopathy and age-related macular degeneration, respectively. In some embodiments, the controlled release formulation is used in the manufacture of a medicament for treatment of malconditions associated with diabetes, cardiovascular failure or abnormal performance, angiopathy, carcinoid syndrome, somatotropin or somatostatin receptor associated cancer.

The present invention also is directed to a method of treating or preventing mammalian diseases that are ameliorated, cured or prevented by octreotide. The method includes administering, to a patient (preferably a human patient) in need of such treatment or prevention, an effective amount of a flowable composition of the present invention. Specifically, the diseases can be those that have an etiology associated with growth hormone related problems, including those concerning imbalance or malconditions associated with insulin, glucagon and/or somatotropin or somatostatin pathways. In particular, the diseases are those associated with diabetes including but not limited to cardioconditions, ocular conditions, nephritic conditions. Especially, these diseases include those concerning ocular conditions such as diabetic retinopathy and proliferative eye disease.

The present invention also is directed to a kit. The kit includes a first container and a second container. The first container includes a composition of the biodegradable thermoplastic polymer and the biocompatible polar aprotic organic liquid. The second container includes octreotide. These ingredients, their properties, and preferred amounts are as disclosed above. Preferably, the first container is a syringe and the second container is a syringe. In addition, the octreotide is preferably lyophilized. The kit can preferably include instructions. Preferably, the first container can be connected to the second container. More preferably, the first container and the second container are each configured to be directly connected to each other.

The present invention also is directed to a solid or gel implant. The solid or gel implant is composed of at least the biocompatible thermoplastic polymer and octreotide and is substantially insoluble in body fluid. While octreotide itself has at least some solubility in body fluid, its isolation within the substantially insoluble implant allows for its slow, sustained release into the body.

The solid implant has a solid matrix or a solid microporous matrix while the gel implant has a gelatinous matrix. The matrix can be a core surrounded by a skin. When microporous, the core preferably contains pores of diameters from about 1 to about 1000 microns. When microporous, the skin preferably contains pores of smaller diameters than those of the core pores. In addition, the skin pores are preferably of a size such that the skin is functionally non-porous in comparison with the core. The solid or gel implant can optionally include one or more biocompatible organic substances which may function as an excipient as described above, or which may function as a plasticizer, a sustained release profile modifier, emulsifier and/or isolation carrier for octreotide.

The biocompatible organic liquid may also serve as an organic substance of the implant and/or may provide an additional function such as a plasticizer, a modifier, an emulsifier or an isolation carrier. There may be two or more organic liquids present in the flowable composition such that the primary organic liquid acts as a mixing, solubilizing or dispersing agent, and the supplemental organic liquid or liquids provide additional functions within the flowable composition and the implant. Alternatively, there may be one organic liquid which at least may act as a mixing, solubilizing or dispersing agent for the other components, and may provide additional functions as well. As second or additional components, additional kinds of biodegradable organic liquids typically are combined with the flowable composition and may remain with the implant as the administered flowable composition coagulates.

When serving as a plasticizer, the biocompatible organic substance provides such properties as flexibility, softness, moldability and drug release variation to the implant. When serving as a modifier, the biocompatible organic substance also provides the property of octreotide release variation to the implant. Typically, the plasticizer increases the rate of octreotide release while the modifier slows the rate of octreotide release. Also, there can be structural overlap between these two kinds of organic substances functioning as plasticizers and rate modifiers.

When serving as an emulsifier, the biocompatible organic substance at least in part enables a uniform mixture of the octreotide within the flowable composition and within the implant.

When serving as an isolation carrier, the biocompatible organic substance will function to encapsulate, isolate or otherwise surround molecules or nanoparticles of the octreotide so as to prevent its burst at least in part, and to isolate the octreotide from degradation by other components of the flowable composition and implant.

The amount of biocompatible organic substance optionally remaining in the solid or gel implant is preferably minor, such as from about 0 wt.% (or an almost negligible amount) to about 20 wt.% of the composition. In addition, the amount of biocompatible organic substance optionally present in the solid or gel implant preferably decreases over time.

Accordingly, the invention provides a controlled release formulation comprising:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, and wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups; (b) a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2-pyrrolidone, ./V-methyl-2- pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethylene glycol or a combination thereof; and

(c) octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the composition; wherein the composition is formulated to persist in a mammal for about 80 to about 100 days. The formulation can have a substantially linear cumulative release profile. In some embodiments, the composition does not release degraded octreotide components. The PLG copolymer can be a low burst PLG copolymer. The PLG copolymer can be a PLG(p) copolymer. The PLG copolymer can be a PLGH copolymer. The PLGH copolymer can be a low burst PLGH. The PLGH copolymer can be a PLGH(p) copolymer. The formulation can be a low burst formulation.

The PLG oligomer can include at least about 50 mole% lactide residues and can have a weight average molecular weight of about 5-10 kDa. The PLG oligomer can be at least about a 65 mole% of lactide residues. The oligomer can comprise 100 mole% of lactide residues. The PLG oligomer can have a weight average molecular weight of about 7-8 kDa. The hydroxy carboxylic acid or acids can be in the form of dimers, and the polyester can be a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof. The biodegradable thermoplastic polyester can be a 50/50, 55/45, 75/25,

85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) having a carboxy terminal group, or can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide- co-glycolide) without a carboxy terminal group, and optionally the polyester without a terminal carboxyl group can be extended with a diol. The biodegradable thermoplastic polyester can be present in about 30 wt.% to about 70 wt.% of the composition, and optionally the biodegradable thermoplastic polyester has an average molecular weight of from about 15,000 to about 45,000 Daltons, preferably about 20,000 to about 40,000 Daltons. The biocompatible polar aprotic liquid can be N-methyl-2-pyrrolidone. The biocompatible polar aprotic liquid can be present about 30 wt.% to about 70 wt.% of the formulation. The octreotide can be present in about 5 wt.% to about 12 wt.% of the formulation.

The formulation can be an injectable subcutaneous formulation, and optionally can have a volume of about 0.20 mL to about 2 mL, or preferably has a volume of about 0.30 mL to about 1 mL. The octreotide can be in the form of a salt and the salt gegenion is derived from a pharmaceutically acceptable organic or inorganic acid, or preferably the gegenion is a polycarboxylic acid. The formulation can have the property of production of minimal tissue necrosis when injected subcutaneously.

The invention also provides a method for preparing the formulation for use as a controlled release implant, comprising the step of mixing, in any order:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in aqueous medium or body fluid, wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups;

(b) a biocompatible polar aprotic liquid; and

(c) octreotide; wherein the mixing is performed for a sufficient period of time effective to form the flowable composition for use as a controlled release implant. The biocompatible thermoplastic polymer and the biocompatible polar aprotic liquid can be mixed together to form a mixture and the mixture can then be mixed with the octreotide to form the formulation. The invention also provides a biodegradable implant formed in situ, in a patient, by the steps comprising:

(a) injecting a formulation of claim 1 into the body of the patient; and

(b) allowing the biocompatible polar aprotic liquid to dissipate to produce a solid or gel biodegradable implant; wherein the formulation comprises an effective amount of the biodegradable thermoplastic polymer; an effective amount of the biocompatible polar aprotic liquid; and an effective amount of octreotide, and wherein the solid implant releases an effective amount of octreotide over time as the solid implant biodegrades in the patient and optionally the patient is a human. The solid biodegradable implant can release an effective amount of octreotide by diffusion, erosion, or a combination of diffusion and erosion as the implant biodegrades in the patient.

The invention also provides a kit comprising: (a) a first container comprising a composition comprising a biodegradable thermoplastic polymer that is at least substantially insoluble in or body fluid and a biocompatible polar aprotic liquid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, and wherein the biocompatible polar aprotic liquid is 2- pyrrolidone, N-methyl-2-pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethylene glycol or a combination thereof; and

(b) a second container comprising octreotide, and wherein optionally the first container is a syringe, and optionally the second container is a syringe, and optionally the octreotide is lyophilized, and optionally the kit further comprises instructions, and optionally the first container can be connected to the second container, or optionally the first container and the second container are each configured to be directly connected to each other. Any composition for formulation of the invention can also optionally include citric acid.

The invention also provides an implant comprising: (a) a biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium or body fluid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups; (b) a biocompatible organic liquid that is very slightly soluble to completely soluble in all proportions in body fluid and at least partially dissolves at least a portion of the thermoplastic polyester, and optionally the amount of biocompatible organic liquid is less than about 5 wt.% of the total weight of the implant, and optionally the amount of biocompatible organic liquid decreases over time; and

(c) octreotide, or a salt thereof; wherein the implant has a solid or gel monolithic structure, and a microporous solid matrix or gelatinous matrix, the matrix being a core surrounded by a skin; and wherein the core contains pores of diameters from about 1 to about 1000 microns, and optionally the skin contains pores of smaller diameters than those of the core pores, and optionally the skin pores are of a size such that the skin is functionally non-porous in comparison with the core.

The invention further comprises a method for treatment of a patient having a malcondition associated with somatotropin hypersecretion, gastrointestinal syndrome, with an imbalance, hyper or hypo activity of an insulin, glucagon or somatotropin pathway, or with a somatotropin or somatostatin receptor function, comprising administering to the patient an effective amount of a flowable composition or formulation of the invention, or preferably the malcondition is associated with diabetes, cardiovascular failure or abnormal performance, angiopathy, carcinoid syndrome, somatotropin or somatostatin receptor associated cancer, and more preferably the malcondition is a proliferative eye disease, a neovascular proliferative eye disease or a diabetic eye disease.

The invention also provides a method for treatment of a patient having diabetic retinopathy comprising administering to the patient an effective amount of octreotide in combination with an at least substantially water-insoluble biodegradable thermoplastic polymer and a biocompatible, polar, aprotic organic liquid. The invention further provides method for treatment of a patient having carcinoid syndrome comprising administering to the patient an effective amount of octreotide in combination with an at least substantially water-insoluble biodegradable thermoplastic polymer and a biocompatible, polar, aprotic organic liquid. In some embodiments the method further includes a combination therapy with another known pharmaceutical compound designated for treatment of the malcondition.

Also provided is a method of preparing the controlled release formulation described herein by combining a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups and a PLG copolymer to provide a constant release copolymer, then forming the controlled release formulation by combining the constant release copolymer with an organic solvent having at least a very slight solubility in body fluids with octreotide. The invention provides a method of administering octreotide to a patient over a prolonged period of time, wherein a substantially constant rate of release of the bioactive agent is achieved, comprising administering to the patient a controlled release formulation of the invention. The formulation can be administered as a depot. The depot can be emplaced subcutaneously. The patient can be a patient that suffers from a malcondition wherein the octreotide can treat, arrest, or palliate the malcondition. The malcondition can be acromegaly.

The invention also provides a controlled release formulation comprising: (a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer comprises a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein at least one of the polymers is a polymer of formula I:

(I) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms; R^b is hydrogen or methyl with the proviso that both R^b groups are identical; R^c is hydrogen or methyl with the proviso that both R^c groups are identical; each L/G independently comprises a lactide/glycolide copolymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 200 kD; (b) a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2-pyrrolidone, N-methyl-2- pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethyleneglycol or a combination thereof; and

(c) octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the formulation; wherein the formulation is formulated to persist in a mammal for about 80 to about 100 days. The invention further provides a controlled release formulation comprising:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer comprises a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein at least one of the polymers is a polymer of formula II:

(H) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms; R^b is hydrogen or methyl; R^c is hydrogen or methyl; each Lt/Gt independently comprises a lactate/glycolate copolymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 50 kD;

(b) a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2-pyrrolidone, 7V-methyl-2- pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethyleneglycol or a combination thereof; and

(c) octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the formulation; wherein the formulation is formulated to persist in a mammal for about

80 to about 100 days.

The invention also provides a controlled release formulation comprising: (a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer comprises a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein at least one of the polymers is a polymer of formula III:

(III) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms; R^b is methyl; each L comprises a polylactide or poly-lactate polymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 200 kD;

(b) a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2-pyrrolidone, N-methyl-2- pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetin, a polyethyleneglycol or a combination thereof; and

80 to about 100 days. The L/G can include a lactide/glycolide copolymer segment with a lactide/glycolide ratio of about 45/55 to about 99/1. The L/G can include a lactide/glycolide copolymer segment with a lactide/glycolide ratio of about 70/30 to about 90/10. The polymer can have a weight average molecular weight of about 8 kD to about 100 kD, or about 10 kD to about 50 kD, or about 15 kD to about 45 kD. R^a can be a linear unsubstituted carbon chain. R^a can be a linear unsubstituted carbon chain of about 4 to about 8 carbon atoms. R^a can be a linear unsubstituted carbon chain of about 6 carbon atoms.

The polydispersity of the polymer can be about 1.2 to about 2.0, or about 1.4 to about 1.7. The inherent viscosity of the polymer can be about 0.20 dL/gm to about 0.60 dL/gm, or about 0.25 dL/gm to about 0.40 dL/gm. The biodegradable thermoplastic polyester can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) having a carboxy terminal group, or can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co- glycolide) without a carboxy terminal group, and optionally the polyester without a terminal carboxyl group is extended with a diol.

The biodegradable thermoplastic polyester can be present in about 30 wt.% to about 70 wt.% of the composition, and optionally the biodegradable thermoplastic polyester has an average molecular weight of from about 15,000 to about 45,000 Daltons, preferably about 20,000 to about 40,000 Daltons.

The biocompatible polar aprotic liquid can be iV-methyl-2-pyrrolidone. The biocompatible polar aprotic liquid can be present in about 30 wt.% to about 70 wt.% of the formulation. The octreotide can be present in about 5 wt.% to about 12 wt.% of the formulation. The formulation can be an injectable subcutaneous formulation, which optionally has a volume of about 0.20 mL to about 2 mL, or preferably has a volume of about 0.30 mL to about 1 mL. The octreotide can be in the form of a salt and the salt gegenion can be derived from a pharmaceutically acceptable organic or inorganic acid, or preferably the gegenion is a polycarboxylic acid. The formulation can have the property of production of minimal tissue necrosis when injected subcutaneously.

The biodegradable thermoplastic polymer can be a biocompatible, non- hydrolyzed PLG low-burst copolymer material for a controlled release formulation having a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4-2.0, and from which a copolymer fraction characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5 has been removed; and the low-burst copolymer material comprises copolymer molecular chains wherein a predominant proportion of the molecular chains comprise predominantly lactate or lactide residues in at least one end domain of each molecular chain and predominantly glycolate or glycolide resides in an internal domain of each molecular chain.

The invention also provides the low-burst copolymer material prepared, without a step of hydrolysis of a higher molecular weight PLG copolymer material, from a starting PLG copolymer material by dissolving the starting PLG copolymer in a solvent, precipitating the low-burst copolymer material with a non-solvent, and collecting the PLG low-burst copolymer material; wherein the removed copolymer fraction is about 2% to about 20% by weight of the sum of the weights of the removed copolymer fraction and the PLG low-burst copolymer material; and wherein the solvent and the non-solvent are miscible. The PLG low-burst copolymer material can have a weight average molecular weight of about 15 kDa to about 50 kDa, and a polydispersity index of about 1.4-1.8; and wherein the content of unreacted lactide and glycolide can be less than about 1.0 weight % and 0.1 weight % respectively. The removed copolymer fraction can be about 3% to about 15% by weight, or about 5% to about 10% by weight, of the sum of the weights of the removed copolymer fraction and the PLG low-burst copolymer material. The starting PLG copolymer material can be prepared by a ring-opening polymerization reaction of lactide and glycolide, and the ring-opening polymerization reaction of lactide and glycolide can be optionally catalyzed by a tin salt. The solvent can be dichloromethane or chloroform and the non-solvent can be methanol or ethanol.

The invention can further include a controlled release formulation comprising a flowable delivery system comprising the PLG low-burst copolymer material, an organic solvent, and octreotide. The invention can further include a method of treatment of a condition in a patient, comprising providing the patient with a therapeutically effective amount of a flowable delivery system comprising a PLG low-burst copolymer material, an organic solvent, and octreotide. The condition can be acromegaly. The condition can also be an ocular condition and the formulation can be disposed intraocularly or in proximity to the eye.

BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention may be best understood by referring to the following description and accompanying drawings. The description and accompanying drawings may highlight a certain specific example, or a certain aspect of the invention; however, one skilled in the art will understand that portions of the highlighted example or aspect may be used in combination with other examples or aspects of the invention.

Figure 1 illustrates octreotide release in a rat study. The octreotide products used had 12% octreotide-citric acid, by weight, and varying polymer contents, as indicated in the figure.

Figure 2 illustrates plasma octreotide levels in a rat study, from zero to 100 days post-dosing with formulations that included 12%, 13.5%, and 15% octreotide drug powder (ODP).

Figure 3 illustrates plasma octreotide and serum IGF-I levels from zero to 100 days post-dosing in rabbits that received a 90 mg dose of octreotide from a 12% ODP in 50% w/w 85/15 PLGH, 50% NMP delivery system. Figure 4 illustrates plasma octreotide levels in a rabbit study using 60 mg

ATRIGEL^®/octreotide formulations, compared to a Sandostatin LAR 20 mg formulation.

Figure 5 illustrates the results of implant retrieval studies in rats to assess the effect of increasing the lactide to glycolide ratio in the polymer and increasing the polymer molecular weight while maintaining the drug loading at the level used for ATRIGEL^®/Octreotide 90 mg 3 -month Depot.

Figure 6 illustrates plasma octreotide levels in a pharmacokinetics and pharmacodynamics study in rabbits that evaluated three ATRIGEL^®/Octreotide 60 mg formulations (60 mg octreotide dose) with ATRIGEL^®/Octreotide 90 mg 3-month Depot (90 mg octreotide dose) and an ATRIGEL^® Delivery System only injection as controls.

Figure 7 illustrates the serum IGF-I levels of rabbits from 7 days prior to injection through 90 days post dosing. Figure 8 illustrates the mean octreotide plasma levels for a 45 mg formulations tested over the first 24 hours of the study in Example 1 , Part III.

Figure 9 illustrates the mean octreotide plasma levels for a 45 mg formulations tested over the first 21 days of the study in Example 1 , Part III. Figure 10 illustrates the mean octreotide plasma levels for 45 mg formulations tested over the entire study in Example 1 , Part III.

Figure 1 1 illustrates the IGF-I data for the three 45 mg test articles of Example 1, Part III.

Figure 12 illustrates a cumulative release profile for octreotide from a depot of a controlled release formulation emplaced in rats, the formulations including a control containing as a copolymer only a purified PLGH(p), and four test systems each containing a copolymer system including the purified PLGH(p) and a PLG oligomer such as a PLA or 65/35 PLG oligomer (study QRS R214 06).

DEFINITIONS

The words and phrases presented in this patent application have their ordinary meanings to one of skill in the art unless otherwise indicated. Such ordinary meanings can be obtained by reference to their use in the art and by reference to general and scientific dictionaries such as Webster's New World Dictionary, Simon & Schuster, publishers, New York, N. Y., 1995; The American Heritage Dictionary of the English Language, Houghton Mifflin, Boston MA, 1981 ; Hawley's Condensed Chemical Dictionary 14^th edition, I. Sax, editor, Wiley Europe, 2002. The following explanations of certain terms are meant to be illustrative rather than exhaustive. These terms have their ordinary meanings given by usage in the art and in addition include the following explanations.

The term "and/or" means any one of the items, any combination of the items, or all of the items with which this term is associated. As used herein, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a formulation " includes a plurality of such formulations, so that a formulation of compound X includes formulations of compound X. The term "amino acid," means the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, GIu, GIn, GIy, His, HyI, Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Tip, Tyr, and VaI) in D or L form, as well as unnatural amino acids (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g. acetyl or benzyloxycarbonyl), as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (C1-C6) alkyl, phenyl or benzyl ester or amide; or as an α-methylbenzyl amide). Other suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, Greene, T. W.; Wutz, P. G. M. "Protecting Groups In Organic Synthesis" second edition, 1991, New York, John Wiley & sons, Inc., and references cited therein).

The term "biocompatible" means that the material, substance, compound, molecule, polymer or system to which it applies will not cause severe toxicity, severe adverse biological reaction, or lethality in an animal to which it is administered at reasonable doses and rates.

The term "biodegradable" means that the material, substance, compound, molecule, polymer or system is cleaved, oxidized, hydrolyzed or otherwise broken down by hydrolytic, enzymatic or another mammalian biological process for metabolism to chemical units that can be assimilated or eliminated by the mammalian body.

The term "bioerodable" means that the material, substance, compound, molecule, polymer or system is biodegraded or mechanically removed by a mammalian biological process so that new surface is exposed.

As used herein, the term "flowable" refers to the ability of the "flowable" composition to be transported under pressure into the body of a patient. For example, the flowable composition can have a low viscosity like water, and be injected with the use of a syringe, beneath the skin of a patient. The flowable composition can alternatively have a high viscosity as in a gel and can be placed into a patient through a high pressure transport device such as a high pressure syringe, cannula, needle and the like. The ability of the composition to be injected into a patient will typically depend upon the viscosity of the composition. The composition will therefore have a suitable viscosity ranging from low like water to high like a gel, such that the composition can be forced through the transport device (e.g., syringe) into the body of a patient.

A solid implant, of the monolithic or of the microparticulate type, also displays a burst effect due to the presence of bioactive agent on and near the surface of the implant, and due to the presence of easily leached bioactive agent within the micro-channels and mesopores that form within the implant as a result of its initial interaction with body fluid.

The term "low-burst" as used herein, such as a "low-burst copolymer material," refers to a phenomenon wherein this burst effect is minimized or reduced relative to that observed from a comparable art copolymer composition, while maintaining a desirable long-term release profile. As used herein, a "gel" is a substance having a gelatinous, jelly-like, or colloidal properties. Concise Chemical and Technical Dictionary, 4th Enlarged Ed., Chemical Publishing Co., Inc., p. 567, NY, NY (1986).

The term "heteroaromatic" refers to any aromatic compound or moiety containing carbon and one or more nitrogen and/or oxygen and/or sulfur atoms in the nucleus of the heteroaromatic structure. A heteroaromatic compound exhibits aromaticity such as that displayed by a pyridine, pyrimidine, pyrazine, indole thiazole, pyrrole, oxazole or similar compounds.

The term "heterocyclic" refers to any cyclic organic compound containing one or more nitrogen and/or oxygen and/or sulfur atoms in its cyclic structure. A heterocyclic compound may be saturated or unsaturated but is not aromatic.

As used herein, a "liquid" is a substance that undergoes continuous deformation under a shearing stress. Concise Chemical and Technical Dictionary. 4th Enlarged Ed., Chemical Publishing Co., Inc., p. 707, NY, NY (1986).

The compound "octreotide" is a known oligopeptide of the peptide sequence Phe-Cys-Phe-Trp-Lys-Thr-Cys. Octreotide typically includes a disulfide link between the cysteines, and the phenylalanine (Phe) and the tryptophan (Trp) are in the D configuration although their L configurations may also be included. The chemical structure of natural octreotide is illustrated below:

Octreotide Other stereochemical isomers of octreotide are included within the scope of this invention.

The term "peptide" describes a sequence of 2 to about 50 amino acids (e.g. as defined hereinabove) or peptidyl residues. The sequence may be linear or cyclic. For example, a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence. Preferably a peptide comprises 3 to 30, or 5 to 20 amino acids. Peptide derivatives can be prepared as disclosed in U.S. Patent Numbers 4,612,302; 4,853,371 ; and 4,684,620, or by techniques known to those of skill in the art. Peptide sequences specifically recited herein are written with the amino terminus on the left and the carboxy terminus on the right.

The term "polymer" means a molecule of one or more repeating monomeric residue units covalently bonded together by one or more repeating chemical functional groups. The polymer can be a macromolecular organic compound that is largely, but not necessarily exclusively, formed of repeating units covalently bonded in a chain, which may be linear or branched. The term "polymer" includes all polymeric forms such as linear, branched, star, random, block, graft and the like. It includes homopolymers formed from a single monomer, copolymer formed from two or more monomers, terpolymers formed from three or more polymers and polymers formed from more than three monomers. Differing forms of a polymer may also have more than one repeating, covalently bonded functional group. A "repeating unit" is a structural moiety of the macromolecule which is found more than once within the macromolecular structure. Typically, a polymer is composed of a large number of only a few types of repeating units that are joined together by covalent chemical bonds to form a linear backbone, from which substituents may or may not depend in a branching manner. The repeating units can be identical to each other but are not necessarily so. Therefore a structure of the type -A-A-A-A- wherein A is a repeating unit is a polymer, also known as a homopolymer, and a structure of the type -A-B-A-B- or -A-A-A-B-A-A-A-B- wherein A and B are repeating units, is also a polymer, and is sometimes termed a copolymer. A structure of the type -A-A-A-C-A-A-A or A-B-A-C-A-B-A wherein A and B are repeating units but C is not a repeating unit (i.e., C is only found once within the macromolecular structure) is also a polymer under the definition herein. When C is flanked on both sides by repeating units, C is referred to as a "core" or a "core unit." In some embodiments, a short polymer, formed of up to about 10 repeating units, can be referred to as an "oligomer." There is theoretically no upper limit to the number of repeating units in a polymer, but practically speaking the upper limit for the number of repeating units in a single polymer molecule may be approximately one million. However, in the polymers of the present invention the number of repeating units is typically in the hundreds.

The term polyester refers to polymers containing monomeric repeats, at least in part, of the linking group: -OC(=O)- or -C(=O)O-.

The term polyanhydride refers to polymers containing monomeric repeats, at least in part, of the linking group -C(=O)-O-C(=O)-. The term polycarbonate refers to polymers containing monomeric repeats, at least in part, of the linking group -OC(=O)O-.

The term polyurethane refers to polymers containing monomeric repeats, at least in part, of the linking group -NHC(=O)O-.

The term polyurea refers to polymers containing monomeric repeats, at least in part, of the linking group -NHC(=O)NH-.

The term polyamide refers to polymers containing monomeric repeats, at least in part, of the linking group -C(=O)NH-.

The term polyether refers to polymers containing monomeric repeats, at least in part, of the linking group -O-. The term polyacetal refers to polymers containing monomeric repeats, at least in part, of the linking group -CHR-O-CHR-.

The term polyketal refers to polymers containing monomeric repeats, at least in part, of the linking group -CR₂-O-CR₂-. The term "saccharide" refers to any sugar or other carbohydrate, especially a simple sugar or carbohydrate. Saccharides are an essential structural component of living cells and source of energy for animals. The term includes simple sugars with small molecules as well as macromolecular substances. Saccharides are classified according to the number of monosaccharide groups they contain.

The term "skin" and the term "core" of a skin and core matrix mean that a cross section of the matrix will present a discernable delineation between an outer surface and the inner portion of the matrix. The outer surface is the skin and the inner portion is the core. The term "thermoplastic" as applied to a polymer means that the polymer repeatedly will melt upon heating and will solidify upon cooling. It signifies that no or only a slight degree of cross-linking between polymer molecules is present. It is to be contrasted with the term "thermoset" which indicates that the polymer will set or substantially cross-link upon heating or upon application of a similar reactive process and will then no longer undergo melt-solidification cycles upon heating and cooling.

A "copolymer" is a variety of polymer wherein non-identical repeating units are present. A copolymer may be regular or random in the sequence defined by the more than one type of repeating unit. Some types of copolymers are random copolymers, graft copolymers and block copolymers.

A "copolymer" or a "PLG copolymer" as the terms are used herein can refer to a poly(lactide-glycolide) polymer formed of monomeric lactide (or lactate) and glycolide (or glycolate) units in a defined molar proportion. The molar proportion can range from 100 mole% lactide to 100 mole% glycolide but typically ranges from about 50-99 mole% lactide. Thus, a pure poly(lactide), i.e., 100 mole% lactide, also known as PLA, is a PLG copolymer within the meaning herein. Copolymers composed of both lactide and glycolide units can be described in terms of their molar compositions; i.e., a 65/35 PLG is understood to consist of 65 mole% lactide units and 35 mole% glycolide units. A "polymer segment" or a "copolymer segment" as used herein refers to a portion or moiety of a larger molecule wherein that segment is a section of a polymer or a copolymer respectively that is bonded to other portions or moieties to make up the larger molecule. When the polymer segment or a copolymer segment is attached to the larger molecule at only one end of the segment, the end of attachment is the "proximal end" and the other, free end is the "distal end."

A "core" or a "core unit" as used herein refers to a portion or moiety of a polymer that is not itself a copolymer segment, but is incorporated within the polymer chain and has at least one polymer or copolymer segment bonded to it. A core may have two or more polymer or copolymer segments bonded to it. A core may be formed from a molecule that is incorporated into the polymer chain that grows from it during the polymerization reaction.

A copolymer can include neutral poly(lactide-glycolide) molecular chains that terminate in alcohol or ester groups. A copolymer can also include ionic poly(lactide-glycolide) molecular chains that terminate in carboxylic acid groups (known as PLGH copolymers). PLG copolymers as the term is used herein include compositions referred to in the art as poly(lactate-glycolate), poly(lactate(co)glycolate), poly(lactide-glycolide), poly(lactide(co)glycolide), and the like, with the understanding that additional moieties may be included, such as core or initiator groups (for example, diols, hydroxyacids, and the like), capping groups (for example, esters of terminal carboxyl groups, and the like) and other pendant groups or chain extension groups covalently linked to or within the polyester backbone, including groups that cross-link the substantially linear polyester molecular chains.

General methods of preparation of these various types of PLG copolymer are well known in the art. For example a neutral PLG can be synthesized by catalyzed polymerization of lactide and glycolide reagents (cyclic dimers) from a core diol, such as hexane-l,6-diol, wherein ester bonds are formed between the end of the growing chains and the newly added lactide/glycolide units resulting in polymer chains wherein both ends have terminal hydroxyl groups, thus providing a neutral PLG. Alternatively, an ionic or acidic PLG (a "PLGH") can be prepared by polymerization of lactide/glycolide reagents initiated by lactic acid, wherein one end of the PLG chain that is formed bears an ionizable carboxylic acid group. An acidic PLGH can be capped with an alcohol to provide a neutral PLG copolymer. For example, an ester group can be formed from the free carboxylic end group and the alcohol.

The terms "burst effect" and "initial burst effect" are used herein to refer to a higher than average rate of diffusion of a bioactive agent out of a controlled release formulation that can occur immediately following emplacement of a liquid delivery system, for example, within 1-2 days following emplacement. The phrase "higher than average" means that during this initial time period following emplacement of the controlled release formulation with body tissues, the rate of release of the agent is higher than is seen on the average over the entire period of time that the implant continues to release the agent within the body tissues. Thus a burst effect represents a surge of the octreotide, which can in some instances amount to 25-30% of the total agent contained in a depot, immediately after emplacement, which then tapers off to the lower rate of release that occurs throughout the total time period that the depot persists within the body tissues. A "low burst copolymer" is a copolymer that, when incorporated into a controlled release formulation, for example of the Atrigel^® type, provides for a low initial burst effect and reduces or avoids the undesired effects on the patient of a transient but high level of the octreotide immediately following emplacement of the depot.

One type of low burst copolymer, referred to herein as a "PLG(p) copolymer" (for PLG(purified)), is a PLG copolymer adapted for use in a controlled release formulation characterized by a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index (PDI) of about 1.4-2.0, and having separated therefrom a copolymer fraction characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5. As is disclosed in U.S. Ser. No. 60/901 ,435, this PLG low-burst copolymer material can be prepared by dissolving an initial PLG copolymer material, which is not a product of hydrolysis of a higher molecular weight PLG copolymer material, in a solvent, then precipitating the low-burst copolymer material with a non-solvent. A PLG(p) copolymer can be a component of a constant release copolymer as disclosed herein. An "oligomer" or a "PLG oligomer" as the terms are used herein can refer to a PLG copolymer as the term is defined above wherein the average molecular weight is about 5-10 kDa, preferably about 7-8 kDa. A "hydrophobic" PLG oligomer is an oligomer wherein the mole% of lactide units is greater than about 50%, i.e., the oligomer includes more lactide units than glycolide units. The proportion of lactide units can be greater than 65 mole%, or can be up to and including 100 mole%. Thus, a poly-lactide or poly-lactic acid (PLA) oligomer is a PLG oligomer within the meaning herein. Lactide units, which have a side chain methyl group, are known to be more hydrophobic than are glycolide units, which lack the methyl group. A PLG oligomer that substantially lacks "free carboxylic acid groups" is a neutral PLG copolymer within the meaning herein, including only non-ionizable end groups such as hydroxyl groups or ester groups ("capped" carboxylic acids) and also lacking or substantially lacking any pendant free carboxylic acid groups. A "substantially constant rate of release" as used herein means that the release per unit time ("rate of release") of a bioactive agent (e.g., octreotide) from a depot of a controlled release formulation into the body of a patient is relatively constant over the period of time during which the formulation is adapted to release the agent. Thus, if the formulation is a "30-day" formulation, i.e., is adapted to release the agent over a period of time of about 30 days before the depot is completely biodegraded, a "substantially constant" rate of release means that every unit of time during that period, such as every day during that period, the amount of bioactive agent released into the patient's body is approximately a constant amount. This is known in the art as "zero order release", i.e., if plotting the instantaneous rate of release of a bioactive agent vs. time, an equation of the type y=kx° describes the curve. If cumulative release versus time is plotted, a straight line having a slope corresponding to a linear cumulative release rate results. The later times in the period correspond to times when the depot is nearing complete dissolution in the body tissues. Once the depot is completely dissolved or biodegraded, release of the octreotide is likewise complete.

A "liquid delivery system" or a "flowable delivery system" refers to a combination of polymer, octreotide, and an organic solvent, such as in the Atrigel system. After injection of the flowable material containing the polymer, octreotide, and solvent, into tissue as a single bolus, the solvent disperses into the tissue while body fluid diffuses into the injected bolus, thereby causing coagulation of the polymer into a solid or semi-solid mass. This mass (or "bolus") then undergoes biodegradation over time, releasing the octreotide. The organic solvent has at least a very slight solubility in body fluids, such that it can diffuse into the body fluids and vice versa. In some embodiments, the organic solvent can be soluble in body fluids. Solvents that can be used with the polymers disclosed herein for a liquid or flowable delivery system include N-methyl-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, polyethylene glycol 200, polyethylene glycol 300, or methoxypolyethylene glycol 350.

When the "molecular weight" or the "average molecular weight" of a copolymer or an oligomer is referred to, it is a weight average molecular weight, as is well known in the art. If the average molecular weight being referred to is the number-average molecular weight, it will be explicitly stated in this specification. When the individual molecular weights of the component individual molecules (molecular chains) are referred to, the term "individual molecular weight" is recited. Weight average molecular weights are determined by the use of gel permeation chromatography (GPC) with reference to polystyrene standards, as is well known in the art.

The term "polydispersity index" as used herein is defined as the weight- average molecular weight of a sample of a polymer material divided by the number-average molecular weight of the sample of polymer material. The polydispersity index is well-known to relate to the distribution of molecular weights in a polymer. The higher the value of the polydispersity index, the broader the spread of individual molecular weights of the polymer molecular chains making up the polymer material. The lower the value of the polydispersity index, the more uniform and tightly grouped are the individual molecular weights of the individual polymer molecules making up the polymer material in question. In the unlikely event that every polymer molecule in the polymer material were identical, the weight-average molecular weight and the number-average molecular weight would be identical, and thus the polydispersity index ("PDI") would be unity in such case. The terms "lactate" and "glycolate" as used herein, depending upon context, refer to either the hydroxyacids, lactic acid and glycolic acid respectively or their salts (lactates and glycolates) which are used as reagents in preparation of copolymers, or refer to those moieties as residues incorporated via ester bonds into the inventive polyester molecular chains. When a copolymer is formed by polymerization of lactic acid (lactate) and glycolic acid (glycolate), each molecular chain consists of individual lactate and glycolate monomeric units incorporated into the copolymer molecular chain by ester bonds.

The terms "lactide" and "glycolide" as used herein, depending upon context, refer to either the cyclic dimeric esters of lactate and glycolate respectively when referring to reagents used in preparation of copolymers, or refer to those segments as incorporated ring-opened dimers in the formed polymer molecular chains. Thus, a statement about polymerization of lactide and glycolide refers to a polymerization reaction of the cyclic dimeric esters, whereas a statement about a lactide or glycolide residue within a copolymer molecular chain refers to that grouping of atoms, ring-opened, and incorporated into the copolymer chain.

When a copolymer is formed by polymerization of lactide and glycolide, each incorporated lactide or glycolide residue includes a pair of lactate or glycolate monomeric units, respectively. It is understood that when a lactide and glycolide residue in a copolymer molecular chain is referred to, the terms refers to dimeric units, i.e., two lactate ("L-L"), or two glycolate ("G-G"), residues in the molecular chain, respectively, such as is believed to result from the polymerization of lactide and glycolide. When a lactate (L) or a glycolate (G) residue in a copolymer molecular chain is referred to, the terms mean single lactate (L) or glycolate (G) residues in the molecular chain, respectively, which can be within a lactide (L-L) or a glycolide (G-G) residue if the given lactate or glycolate is adjacent to another lactate or glycolate residue, respectively, regardless of the method used to prepare the copolymer molecular chain. As in most polymeric systems, this arrangement of residues is not all or none, but instead, the arrangement is a predominance. Thus, for the lactide and glycolide copolymers, a predominance of L-L and G-G residues will be present with some L and G (single) residues also present. The driving force underlying this characterization is the polymerization process. During polymerization, growing polymer chains are broken and reformed. Various scissions may split dimer residues and recombine single residues. For the lactate and glycolate copolymers, L and G (single) residues will be present on a statistical basis. This kind of polymer (formed from single L and/or G residues) will have relatively few sequences including repeats of dimer residues because of entropy factors. It is understood that when the terms "lactic acid," "lactate," or "lactide" are used herein, that any and all chiral forms of the compounds are included within the terms. Thus, "lactic acid" includes D-lactic acid, L-lactic acid, DL- lactic acid, or any combination thereof; "lactide" includes DD-lactide, DL- lactide, LD-lactide, LL-lactide, or any combination thereof.

A substantially linear molecular chain as is formed by a polymerization process, such as a copolymer molecule that is within a copolymer material of the invention, has two ends, each end with a nearby "end domain," and an "internal domain" between the end domains. The terms are not exact, but rather describe general regions of a copolymer molecular chain, wherein each end domain is the approximately 10-20% of the total length of the chain terminating at each of the two chain ends, and the internal domain being the remaining approximately 60- 80% of the chain that lies between the end domains.

A "titratable carboxylic acid group" as used herein refers to a carboxylic acid group in free form, that is, not bound as an ester or other derivative, wherein the carboxylic acid group can bear a free proton which may dissociate (ionize) in aqueous solution to form a carboxylate anion and a proton (acid). Therefore, an organic polymer with no titratable carboxylic acid groups is not an acidic polymer, and all carboxylate moieties within the polymer are bonded into esters, amides, or other non-acidic derivatives.

"Alkanediol" as used herein refers to a saturated, branched or straight chain or cyclic alkane diradical of about 4 to about 8 carbon atoms, having two monovalent radical centers derived by the removal of two hydrogen atoms from different carbon atoms of the parent alkane, wherein each monovalent radical center bears a hydroxyl group. Thus, an alkanediol is a dihydroxyalkane. Alkane diradicals include, but are not limited to: 1 ,4-butylene(-CH₂CH₂CH₂CH₂-), 2,3- butylene (CH₃CHCHCH₃), 1 ,6-hexylene

(-CH₂CH₂CH₂CH₂CH₂CH₂-), 1 ,4-cyclohexanedimethyl (-CH₂-cyclohexyl-CH₂-), and the like. Typical alkanediols of the invention therefore include, but are not limited to, 1 ,4-butanediol (HOCH₂CH₂CH₂CH₂OH), 2,3-butanediol (CH₃CH(OH)CH(OH)CH₃), 1,6-hexanediol (HOCH₂CH₂CH₂CH₂CH₂CH₂OH), cyclohexane-l^-dimethanol, and the like. An alkanediol may be optionally substituted with other functional groups on the carbon atoms that form the alkane moiety, including but not limited to groups such as alkoxy, hydroxy, halo, cyano, carboxy, alkylcarboxy, carboxamido, alkyl or dialkyl carboxamido, alkyl or aryl thio, amino, alkyl or dialkyl amino, aryl, or heteroaryl.

An "α,ω-diol" refers to an alkanediol wherein the two hydroxyl groups are disposed respectively on the two terminal carbon atoms of an alkane chain. Typical α,ω-diols are 1,4-butanediol and 1 ,6-hexanediol. An α,ω-diol comprises two primary hydroxyl groups.

As used herein, the term "inherent viscosity" refers to the standard polymer parameter defined as the natural logarithm of the relative viscosity of a polymer solution divided by the concentration of the polymer in the solution. The relative viscosity is the ratio of the viscosity of the polymer solution to the viscosity of the solvent alone.

A "number average molecular weight" refers to the standard polymer parameter defined as the total weight of a sample divided by the total number of polymer molecules in the sample:

A "weight average molecular weight" refers to the standard polymer parameter defined as:

where JV, is the number of molecules of molecular weight M₁. The term "organic solvent" refers to an organic liquid that can dissolve a copolymer material to provide a homogeneous solution. The term "non-solvent" refers to a precipitation solvent, a usually organic liquid, that is not a solvent for the copolymer. It is in this context that the term "non-solvent" is used herein. Two liquids, such as a solvent and a non-solvent, are "miscible" when they combine with each other in all proportions without phase separation. Solvents may be "soluble" in each other but not "miscible" when they can combine without phase separation in some, but not in all, relative proportions. A solvent is "at least very slightly soluble in body fluids" when a measurable or significant quantity of the solvent is found to dissolve in aqueous liquid compositions with properties of, or similar to, human body fluids. Typically the organic solvent used herein is of sufficient solubility in body fluids to diffuse from an injected bolus into surrounding tissue such that the copolymers of the bolus can precipitate and form a skin or membrane surrounding the bolus to provide a solid or semi-solid depot.

DETAILED DESCRIPTION The present invention is directed to an octreotide sustained release delivery system. The sustained release delivery system includes a flowable composition of the invention and/or a gel or solid implant of the invention. The delivery system can provide an in situ sustained release of octreotide. The flowable composition can accomplish the sustained release through its use to produce the implant of the invention. The implant can have a low implant volume and can provide a long term delivery of octreotide. The flowable composition enables subcutaneous formation of the implant in situ and causes little or no tissue necrosis. The in situ implant of the invention exhibits surprising results relative to the sustained release Sandostatin LAR^® implant in that the implant of the invention delivers higher and longer lasting blood levels of the octreotide compared with the Sandostatin LAR ^κ implant. It also exhibits a surprisingly low tissue irritation relative to Sandostatin LAR^® implant. The flowable composition of the invention is a combination of a biodegradable, at least substantially water-insoluble thermoplastic polymer, a biocompatible polar aprotic organic liquid and octreotide. The polar, aprotic organic liquid has a solubility in body fluid ranging from practically insoluble to completely soluble in all proportions. Preferably, the thermoplastic polymer is a thermoplastic polyester of one or more hydroxycarboxylic acids or one or more diols and dicarboxylic acids. Especially preferably, the thermoplastic polymer is a polyester of one or more hydroxylcarboxyl dimers such as lactide, glycolide, dicaprolactone and the like.

Specific and preferred biodegradable thermoplastic polymers and polar aprotic solvents; concentrations of thermoplastic polymers, polar aprotic organic liquids, octreotide, and molecular weights of the thermoplastic polymer; and weight or mole ranges of components of the solid implant described herein are exemplary. They do not exclude other biodegradable thermoplastic polymers and polar aprotic organic liquids; other concentrations of thermoplastic polymers, polar aprotic liquids, octreotide, or molecular weights of the thermoplastic polymer; and components within the solid implant.

The present invention is directed to a flowable composition suitable for use in providing a controlled sustained release implant, a method for forming the flowable composition, a method for using the flowable composition, the biodegradable sustained release solid or gel implant that is formed from the flowable composition, a method of forming the biodegradable implant in situ, a method for treating disease through use of the biodegradable implant and a kit that includes the flowable composition. The flowable composition may preferably be used to provide a biodegradable or bioerodible microporous in situ formed implant in animals. The flowable composition is composed of a biodegradable thermoplastic polymer in combination with a biocompatible polar aprotic organic liquid and octreotide. The biodegradable thermoplastic polymer is substantially insoluble in aqueous medium and/or in body fluid, biocompatible, and biodegradable and/or bioerodible within the body of a patient. The flowable composition may be administered as a liquid or gel to tissue and forms an implant in situ.

Alternatively, the implant may be formed ex vivo by combining the flowable composition with an aqueous medium. In this embodiment, the preformed implant may be surgically administered to the patient. In either embodiment, the thermoplastic polymer coagulates or solidifies to form the solid or gel implant upon the dissipation, dispersement or leaching of the organic liquid from the flowable composition when the flowable composition contacts a body fluid, an aqueous medium or water.

The coagulation or solidification entangles and entraps the other components of the flowable composition such as octreotide, excipients, organic substances and the like so that they become dispersed within the gelled or solidified implant matrix. The flowable composition is biocompatible and the polymer matrix of the implant does not cause substantial tissue irritation or necrosis at the implant site. The implant delivers a sustained level of octreotide to the patient. Preferably, the flowable composition can be a liquid or a gel, suitable for injection in a patient (e.g., human).

The present invention surprisingly improves the bioavailability of a sustained release formulation of octreotide. According to the invention, the sustained release of octreotide has the ability to inhibit any abnormal cellular proliferation, which includes neovascularization, fibrosis, lymphoid proliferation, acromegaly and/or neoplastic growth such as carcinoid syndrome, occurring in any tissue, but particularly in ocular tissues. In the case of ocular tissues, maximal efficacy enables relatively high bioavailability of octreotide, because: (1) the blood-retinal barrier limits penetration into the ocular tissues; and (2) activation of somatostatin receptors in retinochoroidal tissues may require higher doses, and more sustained levels of octreotide.

In addition, the present invention provides: (a) relatively low volume injections; (b) improved local tissue tolerance at the injection site; (c) an opportunity to use a subcutaneous, or an intraocular, injection rather than an intramuscular injection; and (d) less frequent injections compared to other products.

The basis for the large differences in bioavailability and pharmacokinetics of the invention, compared with the Sandostatin LAR^® product, is not completely understood. However, it can be noted that the Sandostatin LAR^® product is injected intramuscularly and it elicits a severe tissue reaction characterized by myonecrosis and intense acute inflammation. Gross and microscopic examination of intramuscular injection sites taken from a variety of animal species reveals extensive neutrophilic infiltration surrounding the Sandostatin LAR^® product depots. A review of the summary basis of approval for the Sandostatin LAR^® product does not mention this phenomenon. However, in multiple experiments conducted in rats, rabbits and dogs, these changes have been observed in every sample examined. In addition, oncologists and endocrinologists who chronically administer IM injections of the Sandostatin LAR^® product to patients, have observed that this product produces severe tissue reactions leading to chronic scarring in the gluteal muscle tissues. Thus, the data indicate that chronic administration of the Sandostatin LAR^® product to produce a Sandostatin^® LAR depot is associated with adverse injection site reactions, which are not desirable in patients, and is especially not desirable in patients with diabetes or in elderly patients suffering from adult macular degeneration (AMD).

The severe tissue reaction surrounding the Sandostatin^® depot not only produces pain and scarring, it may also contribute to the poor pharmacokinetics, which include a 7-10 day lag phase and a very low bioavailability. By comparison, the octreotide sustained release delivery system of the invention may be injected into the subcutaneous tissue. At the same dose of octreotide, experiments conducted in animals and humans have repeatedly indicated that the flowable composition of the invention provides much higher bioavailability as compared to the Sandostatin LAR^® product, causes no tissue reaction and has no lag phase.

According to the present invention, the octreotide sustained release delivery system provides several advantages that increase the efficacy, safety, and convenience of octreotide used to treat any somatostatin-responsive disease or medical condition. This includes non-ocular and ocular diseases. The invention is particularly useful for the treatment of proliferative ocular diseases, and most particularly, for the treatment of neovascular diseases of the eye. Examples of such diseases include, but are not limited to, retinal or choroidal neovascularizaton, which occur in diabetic retinopathy and age-related macular degeneration, respectively.

By comparison to formulations derived from other sustained release drug delivery technologies, the octreotide sustained release delivery system will provide: (a) superior release kinetics with minimal burst; (b) increased duration of drug release with less frequent injections; (c) markedly improved bioavailability; (d) improved local tissue tolerance due to a small injection volume, and (e) the ability to use of a subcutaneous injection rather than intramuscular injection. Taken together, these features make a highly beneficial octreotide sustained release delivery system.

Biodefiradable Thermoplastic Polymers

The flowable composition of the invention is produced by combining a solid, biodegradable thermoplastic polymer and octreotide and a biocompatible polar aprotic organic liquid. The flowable composition can be administered by a syringe and needle to a patient in need of treatment. Any suitable biodegradable thermoplastic polymer can be employed, provided that the biodegradable thermoplastic polymer is at least substantially insoluble in body fluid.

The biocompatible, biodegradable, thermoplastic polymer used according to the invention can be made from a variety of monomers which form polymer chains or monomeric units joined together by linking groups. The thermoplastic polymer is composed of a polymer chain or backbone containing monomeric units joined by such linking groups as ester, amide, urethane, anhydride, carbonate, urea, esteramide, acetal, ketal, and orthocarbonate groups as well as any other organic functional group that can be hydrolyzed by enzymatic or hydrolytic reaction (i.e., is biodegradable by this hydrolytic action). The thermoplastic polymer is usually formed by reaction of starting monomers containing the reactant groups that will form the backbone linking groups. For example, alcohols and carboxylic acids will form ester linking groups. Isocyanates and amines or alcohols will respectively form urea or urethane linking groups.

Any aliphatic, aromatic or arylalkyl starting monomer having the specified functional groups can be used according to the invention to make the thermoplastic polymers of the invention, provided that the polymers and their degradation products are biocompatible. The monomer or monomers used in forming the thermoplastic polymer may be of a single or multiple identity. The resultant thermoplastic polymer will be a homopolymer formed from one monomer, or one set of monomers such as when a diol and diacid are used, or a copolymer, terpolymer, or multi-polymer formed from two or more, or three or more, or more than three monomers or sets of monomers. The biocompatiblity specifications of such starting monomers are known in the art.

The thermoplastic polymers useful according to the invention are substantially insoluble in aqueous media and body fluids, preferably essentially completely insoluble in such media and fluids. They are also capable of dissolving or dispersing in selected organic liquids having a water solubility ranging from completely soluble in all proportions to water insoluble. The thermoplastic polymers also are biocompatible.

When used in the flowable composition of the invention, the thermoplastic polymer in combination with the organic liquid provides a viscosity of the flowable composition that varies from low viscosity, similar to that of water, to a high viscosity, similar to that of a paste, depending on the molecular weight and concentration of the thermoplastic polymer. Typically, the polymeric composition includes about 10 wt. % to about 95 wt. %, more preferably about 20 wt. % to about 70 wt. %, most preferably about 30 wt.% to about 65 wt.%, of a thermoplastic polymer.

According to the present invention, the biodegradable, biocompatible thermoplastic polymer can be a linear polymer, it can be a branched polymer, or it can be a combination thereof. Any option is available according to the present invention. To provide a branched thermoplastic polymer, some fraction of one of the starting monomers may be at least trifunctional, and preferably multifunctional. This multifunctional character provides at least some branching of the resulting polymer chain. For example, when the polymer chosen contains ester linking groups along its polymer backbone, the starting monomers normally will be hydroxycarboxylic acids, cyclic dimers of hydroxycarboxylic acids, cyclic trimers of hydroxycarboxylic acids, diols or dicarboxylic acids. Thus, to provide a branched thermoplastic polymer, some fraction of a starting monomer that is at least multifunctional, such as a triol or a tricarboxylic acid is included within the combination of monomers being polymerized to form the thermoplastic polymer used according to the invention. In addition, the polymers of the present invention may incorporate more than one multifunctional unit per polymer molecule, and typically many multifunctional units depending on the stoichiometry of the polymerization reaction. The polymers of the present invention may also optionally incorporate at least one multifunctional unit per polymer molecule. A so-called star or branched polymer is formed when one multifunctional unit is incorporated in a polymer molecule. According to the invention, the preferred thermoplastic polyester may be formed from such monomers as hydroxycarboxylic acids or dimers therefor. Alternatively, a thermoplastic polyester may be formed from a dicarboxylic acid and a diol. A branching monomer such as a dihydroxycarboxylic acid would be included with the first kind of starting monomer, or a triol and/or a tricarboxylic acid would be included with the second kind of starting monomer if a branched polyester were desired. Similarly, a triol, tetraol, pentaol, or hexaol such as sorbitol or glucose can be included with the first kind of starting monomer if a branched or star polyester were desired. The same rationale would apply to polyamides. A triamine and/or triacid would be included with starting monomers of a diamine and dicarboxylic acid. An amino dicarboxylic acid, diamino carboxylic acid or a triamine would be included with the second kind of starting monomer, amino acid. Any aliphatic, aromatic or arylalkyl starting monomer having the specified functional groups can be used to make the branched thermoplastic polymers of the invention, provided that the polymers and their degradation products are biocompatible. The biocompatiblity specifications of such starting monomers are known in the art.

The monomers used to make the biocompatible thermoplastic polymers of the present invention will produce polymers or copolymers that are thermoplastic, biocompatible and biodegradable. Examples of thermoplastic, biocompatible, biodegradable polymers suitable for use as the biocompatible thermoplastic branched polymers of the present invention include polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids), and copolymers, terpolymers, or combinations or mixtures of the above materials. Suitable examples of such biocompatible, biodegradable, thermoplastic polymers are disclosed, e.g., in U.S. Patent Nos. 4,938,763; 5,278,201 ; 5,324,519; 5,702,716; 5,744,153; 5,990,194; 6,461,63 land 6,565,874.

The polymer composition of the invention can also include polymer blends of the polymers of the present invention with other biocompatible polymers, so long as they do not interfere undesirably with the biodegradable characteristics of the composition. Blends of the polymer of the invention with such other polymers may offer even greater flexibility in designing the precise release profile desired for targeted drug delivery or the precise rate of biodegradability desired for implants such as ocular implants. The preferred biocompatible thermoplastic polymers or copolymers of the present invention are those which have a lower degree of crystallization and are more hydrophobic. These polymers and copolymers are more soluble in the biocompatible organic liquids than highly crystalline polymers such as polyglycolide, which has a high degree of hydrogen-bonding. Preferred materials with the desired solubility parameters are polylactides, polycaprolactones, and copolymers of these with glycolide so as to provide more amorphous regions to enhance solubility. Generally, the biocompatible, biodegradable thermoplastic polymer is substantially soluble in the organic liquid so that solutions, dispersions or mixtures up to 50-60 wt % solids can be made. Preferably, the polymers used according to the invention are essentially completely soluble in the organic liquid so that solutions, dispersions or mixtures up to 85-98 wt % solids can be made. The polymers also are at least substantially insoluble in water so that less than 0.1 g of polymer per mL of water will dissolve or disperse in water. Preferably, the polymers used according to the invention are essentially completely insoluble in water so that less than 0.001 g of polymer per mL of water will dissolve or disperse in water. At this preferred level, the flowable composition with a completely water miscible organic liquid will almost immediately transform to the solid implant. Optionally, the delivery system may also contain a combination of a non- polymeric material and an amount of a thermoplastic polymer. The combination of non-polymeric material and thermoplastic polymer may be adjusted and designed to provide a more coherent octreotide sustained release delivery system. Non-polymeric materials useful in the present invention are those that are biocompatible, substantially insoluble in water and body fluids, and biodegradable and/or bioerodible within the body of an animal. The non- polymeric material is capable of being at least partially solubilized in an organic liquid. In the flowable composition of the invention containing some organic liquid or other additive, the non-polymeric materials are also capable of coagulating or solidifying to form a solid or gel implant upon the dissipation, dispersement or leaching of the organic liquid component from the flowable composition upon contact of the flowable composition with a body fluid. The matrix of all embodiments of the implant including a non-polymeric material will have a consistency ranging from gelatinous to impressionable and moldable, to a hard, dense solid.

Non-polymeric materials that can be used in the delivery system generally include any having the foregoing characteristics. Examples of useful non-polymeric materials include sterols such as cholesterol, stigmasterol, beta- sistosterol, and estradiol; cholestery esters such as cholesteryl stearate, Ci₈-C₃₆ mono-,di-, and tricylglycerides such as glyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glyceryl tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate, and sorbitan tristearate; Ci₈-C₃₆ fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol; esters of fatty alcohols and fatty acids such as cetyl palmitate and cetearyl palmitate; anhydrides of fatty acids such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol, and lysoderivatives thereof; sphingosine and derivatives thereof; spingomyelins such as stearyl, palmitoyl, and tricosanyl sphingomyelins; ceramides such as stearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures thereof. Preferred non-polymeric materials include cholesterol, glyceryl monostearate, glyceryl tristearate, stearic acid, stearic anhydride, glyceryl monooleate, glyeryl monolinoleate, and acetylated monoglyerides.

The polymeric and non-polymeric materials may be selected and/or combined to control the rate of biodegradation, bioerosion and/or bioabsorption within the implant site. Generally, the implant matrix will breakdown over a period from about 1 week to about 12 months, preferably over a period of about 1 week to about 4 months.

Thermoplastic Polymer Molecular Weight

The molecular weight of the polymer used in the present invention can affect the rate of octreotide release from the implant. Under these conditions, as the molecular weight of the polymer increases, the rate of octreotide release from the system decreases. This phenomenon can be advantageously used in the formulation of systems for the controlled release of octreotide. For relatively quick release of octreotide, low molecular weight polymers can be chosen to provide the desired release rate. For release of a octreotide over a relatively long period of time, a higher polymer molecular weight can be chosen. Accordingly, an octreotide sustained release delivery system can be produced with an optimum polymer molecular weight range for the release of octreotide over a selected length of time. The molecular weight of a polymer can be varied by any of a variety of methods. The choice of method is typically determined by the type of polymer composition. For example, if a thermoplastic polyester is used that is biodegradable by hydrolysis, the molecular weight can be varied by controlled hydrolysis, such as in a steam autoclave. Typically, the degree of polymerization can be controlled, for example, by varying the number and type of reactive groups and the reaction times.

The control of molecular weight and/or inherent viscosity of the thermoplastic polymer is a factor involved in the formation and performance of the implant. In general, thermoplastic polymers with higher molecular weight and higher inherent viscosity will provide an implant with a slower degradation rate and therefore a longer duration. Changes and fluctuations of the molecular weight of the thermoplastic polymer following the compounding of the delivery system will result in the formation of an implant that shows a degradation rate and duration substantially different from the degradation rate and duration desired or predicted.

The thermoplastic polymers useful according to the invention may have average molecular weights ranging from about 1 kiloDalton (kD) to about 1,000 kD, preferably from about 2 kD to about 500 kD, more preferably from abut 5 kD to about 200 kD, and most preferably from about 5 kD to about 100 kD. The thermoplastic polymers may also have average molecular weights as described for any of the polymers of the invention, for example, the polymers described in the Examples section. The molecular weight may also be indicated by the inherent viscosity (abbreviated as "I.V.", units are in deciliters/gram). Generally, the inherent viscosity of the thermoplastic polymer is a measure of its molecular weight and degradation time (e.g., a thermoplastic polymer with a high inherent viscosity has a higher molecular weight and longer degradation time). Preferably, the thermoplastic polymer has a molecular weight, as shown by the inherent viscosity, from about 0.05 dL/g to about 2.0 dL/g (as measured in chloroform), more preferably from about 0.10 dL/g to about 1.5 dL/g. Characteristics of Preferred Polyesters

The preferred thermoplastic biodegradable polymer of the flowable composition of the invention is a polyester. Generally, the polyester may be composed of units of one or more hydroxycarboxylic acid residues wherein the distribution of differing units may be random, block, paired or sequential. Alternatively, the polyester may be composed of units of one or more diols and one or more dicarboxylic acids. The distribution will depend upon the starting materials used to synthesize the polyester and upon the process for synthesis. An example of a polyester composed of differing paired units distributed in block or sequential fashion is a poly(lactide-co-glycolide). An example of a polyester composed of differing unpaired units distributed in random fashion is poly (lactic acid-co-glycolic acid). Other examples of suitable biodegradable thermoplastic polyesters include polylactides, polyglycolides, polycaprolactones, copolymers thereof, terpolymers thereof, and any combinations thereof.

Preferably, the suitable biodegradable thermoplastic polyester is a polylactide, a polyglycolide, a copolymer thereof, a terpolymer thereof, or a combination thereof.

The terminal groups of the poly(DL-lactide-co-glycolide) can either be hydroxyl, carboxyl, or ester depending upon the method of polymerization.

Polycondensation of lactic or glycolic acid will provide a polymer with terminal hydroxyl and carboxyl groups. Ring-opening polymerization of the cyclic lactide or glycolide monomers with water, lactic acid, or glycolic acid will provide polymers with these same terminal groups. However, ring-opening of the cyclic monomers with a monofunctional alcohol such as methanol, ethanol, or 1-dodecanol will provide a polymer with one hydroxyl group and one ester terminal group. Ring-opening polymerization of the cyclic monomers with a polyol such as glucose, 1 ,6-hexanediol or polyethylene glycol will provide a polymer with only hydroxyl terminal groups. Such a polymerization of dimers of hydroxylcarboxylic acids and a polyol is a chain extension of the polymer. The polyol acts as a central condensation point with the polymer chain growing from the hydroxyl groups incorporated as ester moieties of the polymer. The polyol may be a diol, triol, tetraol, pentaol or hexaol of 2 to 30 carbons in length. Examples include saccharides, reduced saccharides such as sorbitol, diols such as hexane-l ,6-diol, triols such as glycerol or reduced fatty acids, and similar polyols. Generally, the polyesters copolymerized with alcohols or polyols will provide longer duration implants.

The type, molecular weight, and amount of the preferred biodegradable thermoplastic polyester present in the flowable composition will typically depend upon the desired properties of the controlled sustained release implant. For example, the type, molecular weight, and amount of biodegradable thermoplastic polyester can influence the length of time in which the octreotide is released from the controlled sustained release implant. Specifically, in one embodiment of the present invention, the composition can be used to formulate a one month sustained release delivery system of octreotide. In such an embodiment, the biodegradable thermoplastic polyester can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) having a carboxy terminal group, preferably a 50/50 poly (DL-lactide-co-glycolide) having a carboxy terminal group; can be present in about 20 wt.% to about 70 wt.% of the composition; and can have an average molecular weight of about 15,000 to about 45,000, about 23,000 to about 45,000, or about 20,000 to about 40,000.

In another embodiment of the present invention, the flowable composition can be formulated to provide a three month sustained release delivery system of octreotide. In such an embodiment, the biodegradable thermoplastic polyester can be a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) without a carboxy terminal group; preferably be a 75/25 poly (DL-lactide-co-glycolide) without a carboxy terminal group; can be present in about 20 wt.% to about 70 wt.% of the composition; and can have an average molecular weight of about 20,000 to about 40,000, or about 15,000 to about 25,000; or can be an 85/15 poly (DL-lactide-co-glycolide) containing a 1 ,6-hexane diol chain extender, at a weight percentage of about 20 wt.% to about 70 wt.% of the flowable composition and at an average molecular weight of about 15,000 to about 30,000. Any polyester that has a terminal carboxyl group can optionally be extended with a diol moiety. For example, a polyester that was not prepared using a diol initiator can be 'chain extended' by adding a diol to link terminal carboxyl groups of the polyesters to provide polyesters linked together by the diol moiety. Polar Aprotic Organic Solvent

Organic liquids suitable for use in the flowable composition of the invention are biocompatible and display a range of solubilities in aqueous medium, body fluid, or water. That range includes complete insolubility at all concentrations upon initial contact, to complete solubility at all concentrations upon initial contact between the organic liquid and the aqueous medium, body fluid or water.

While the solubility or insolubility of the organic liquid in water can be used as a solubility guide according to the invention, its water solubility or insolubility in body fluid typically will vary from its solubility or insolubility in water. Relative to water, body fluid contains physiologic salts, lipids, proteins and the like, and will have a differing solvating ability for organic liquids. This phenomenon is similar to the classic "salting out" characteristic displayed by saline relative to water. Body fluid displays similar variability relative to water but in contrast to a "salting out" factor, body fluid typically has a higher solvating ability for most organic liquids than does water. This higher ability is due in part to the greater lipophilic character of body fluid relative to water, and also in part to the dynamic character of body fluid. In a living organism, body fluid is not static but rather moves throughout the organism. In addition, body fluid is purged or cleansed by tissues of the organism so that body fluid contents are removed. As a result, body fluid in living tissue will remove, solvate or dissipate organic liquids that are utterly insoluble in water.

Pursuant to the foregoing understanding of the solubility differences among water, aqueous media and body fluid, the organic liquid used in the present invention may be completely insoluble to completely soluble in water when the two are initially combined. Preferably the organic liquid is at least slightly soluble, more preferably moderately soluble, especially more preferably highly soluble, and most preferably soluble at all concentrations in water. The corresponding solubilities of the organic liquids in aqueous media and body fluid will tend to track the trends indicated by the water solubilities. In body fluid, the solubilities of the organic liquids will tend to be higher than those in water.

When an organic liquid that is insoluble to only slightly soluble in body fluid is used in any of the embodiments of the sustained release delivery system, it will allow water to permeate into the implanted delivery system over a period of time ranging from seconds to weeks or months. This process may decrease or increase the delivery rate of the octreotide and in the case of the flowable composition, it will affect the rate of coagulation or solidification. When an organic liquid that is moderately soluble to very soluble in body fluid is used in any of the embodiments of the delivery system, it will diffuse into body fluid over a period of minutes to days. The diffusion rate may decrease or increase the delivery rate of the octreotide. When highly soluble organic liquids are used, they will diffuse from the delivery system over a period of seconds to hours. Under some circumstances, this rapid diffusion is responsible at least in part for the so-called burst effect. The burst effect is a short-lived but rapid release of octreotide upon implantation of the delivery system followed by a long-lived, slow release of octreotide.

Organic liquids used in the delivery system of the present invention include aliphatic, aryl, and arylalkyl; linear, cyclic and branched organic compounds that are liquid or at least flowable at ambient and physiological temperature and contain such functional groups as alcohols, alkoxylated alcohols, ketones, ethers, polymeric ethers, amides, esters, carbonates, sulfoxides, sulfones, any other functional group that is compatible with living tissue, and any combination thereof. The organic liquid preferably is a polar aprotic or polar protic organic solvent. Preferably, the organic liquid has a molecular weight in the range of about 30 to about 1000.

Preferred biocompatible organic liquids that are at least slightly soluble in aqueous or body fluid include N-methyl-2-pyrrolidone, 2-pyrrolidone; C| to Ci₅ alcohols, diols, triols and tetraols such as ethanol, glycerine, propylene glycol, butanol; C₃ to Ci₅ alkyl ketones such as acetone, diethyl ketone and methyl ethyl ketone; C₃ to Ci₅ esters and alkyl esters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, and glyceryl triacetate; Ci to Ci₅ amides such as dimethylformamide, dimethylacetamide and caprolactam; C₃ to C₂₀ ethers such as tetrahydrofuran, or solketal; tweens, triacetin, decylmethylsulfoxide, dimethyl sulfoxide, oleic acid, 1 -dodecylazacycloheptan-2-one, N-methyl-2-pyrrolidone, esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate, and dimethyl carbonate; alkyl ketones such as acetone and methyl ethyl ketone; alcohols such as solketal, glycerol formal, and glycofurol; dialkylamides such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and dimethylsulfone; lactones such as epsilon-caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; triacetin and diacetin; aromatic amides such as N,N-dimethyl-m-toluamide, and mixtures and combinations thereof. Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate, solketal, triacetin, glycerol formal, isopropylidene glycol, and glycofurol.

Other preferred organic liquids are benzyl alcohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate, glycerin, glycofural, isopropyl myristate, isopropyl palmitate, oleic acid, polyethylene glycol, propylene carbonate, and triethyl citrate. The most preferred solvents are N-methyl-2- pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, triacetin, and propylene carbonate because of their solvating ability and their compatibility.

The type and amount of biocompatible organic liquid present in the flowable composition will typically depend on the desired properties of the controlled release implant as described in detail below. Preferably, the flowable composition includes about 0.001 wt % to about 90 wt %, more preferably about 5 wt % to about 70 wt %, most preferably 5 to 60 wt % of an organic liquid.

The solubility of the biodegradable thermoplastic polymers in the various organic liquids will differ depending upon their crystallinity, their hydrophilicity, hydrogen-bonding, and molecular weight. Lower molecular- weight polymers will normally dissolve more readily in the organic liquids than high-molecular-weight polymers. As a result, the concentration of a thermoplastic polymer dissolved in the various organic liquids will differ depending upon type of polymer and its molecular weight. Moreover, the higher molecular-weight thermoplastic polymers will tend to give higher solution viscosities than the low-molecular-weight materials.

When the organic liquid forms part of the flowable composition of the invention, it functions not only to enable easy, non-surgical placement of the sustained release delivery system into living tissue. It also facilitates transformation of the flowable composition to an in situ formed implant. Although it is not meant as a limitation of the invention, it is believed that the transformation of the flowable composition is the result of the dissipation of the organic liquid from the flowable composition into the surrounding body fluid and tissue and the infusion of body fluid from the surrounding tissue into the flowable composition. It is believed that during this transformation, the thermoplastic polymer and organic liquid within the flowable composition partition into regions rich and poor in polymer.

For the flowable composition of the invention, the concentration of the thermoplastic polymer in the organic liquid according to the invention will range from about 0.01 g per mL of organic liquid to a saturated concentration.

Typically, the saturated concentration will be in the range of 80 to 95 wt % solids or 4 to almost 5 gm per mL of organic liquid, assuming that the organic liquid weighs approximately 1 gm per mL.

For polymers that tend to coagulate slowly, a solvent mixture can be used to increase the coagulation rate. In essence, one liquid component of the solvent mixture is a good solvent for the polymer, and the other liquid component of the solvent mixture is a poorer solvent or a non-solvent. The two liquids are mixed at a ratio such that the polymer is still soluble but precipitates with the slightest increase in the amount of non-solvent, such as water in a physiological environment. By necessity, the solvent system must be miscible with both the polymer and water. An example of such a binary solvent system is the use of N- methyl pyrrolidone and ethanol. The addition of ethanol to the NMP/polymer solution increases its coagulation rate.

For the formed implant of the invention, the presence of the organic liquid can serve to provide the following properties: plasticization, moldability, flexibility, increased or decreased homogeneity, increased or decreased release rate for the bioactive agent, leaching, promotion or retardation of body fluid influx into the implant, patient comfort, compatibility of thermoplastic polymer and bioactive agent and the like. Generally the concentration of organic liquid in the formed implant may range from about 0.001 wt. % to as much as about 30 wt. %. Generally, the concentration will be less than an amount that would cause reversion of the formed implant into a flowable composition. Also, the organic liquid may preferentially be chosen so as to display less than substantial ability to dissolve the thermoplastic polymer. The pliability of the implant can be substantially maintained throughout its life if additives such as the organic liquid are maintained in the implant. Such additives also can act as a plasticizer for the thermoplastic polymer and at least in part may remain in the implant. One such additive having these properties is an organic liquid of low water solubility to water insolubility. Such an organic liquid providing these pliability and plasticizing properties may be included in the delivery system as the sole organic liquid or may be included in addition to an organic liquid that is moderately to highly water soluble.

Organic liquids of low water solubility or water insolubility, such as those forming aqueous solutions of no more than 5% by weight in water, can function as a pliability, plasticizing component and in addition can act as the solvating component for the flowable composition embodiment of the invention. Such organic liquids can act as plasticizers for the thermoplastic polymer. When the organic liquid has these properties, it is a member of a subgroup of organic liquids termed "plasticizer". The plasticizer influences the pliablity and moldability of the implant composition such that it is rendered more comfortable to the patient when implanted. Moreover, the plasticizer has an effect upon the rate of sustained release of octreotide such that the rate can be increased or decreased according to the character of the plasticizer incorporated into the implant composition. In general, the organic liquid acting as a plasticizer is believed to facilitate molecular movement within the solid or gel thermoplastic matrix. The plasticizing capability enables polymer molecules of the matrix to move relative to each other so that pliability and easy moldability are provided. The plasticizing capability also enables easy movement of octreotide so that in some situations, the rate of sustained release is either positively or negatively affected.

High Water Solubility Organic Liquids

A moderate to highly water soluble organic liquid can be generally used in the flowable composition of the invention, especially when pliability will not be an issue after formation of the implant. Use of the highly water soluble organic liquid will provide an implant having the physical characteristics of an implant made through direct insertion of the flowable composition. Use of a moderate to highly water soluble organic liquid in flowable composition of the invention will facilitate intimate combination and mixture of the other components therein. It will promote solid or gel homogeneity and pliability of an ex vivo formed implant so that such an implant can be readily inserted into appropriate incisions or trocar placements in tissue.

Useful, highly water soluble organic liquids include, for example, substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone; C₂ to Cio alkanoic acids such as acetic acid and lactic acid, esters of hydroxy acids such as methyl lactate, ethyl lactate, alkyl citrates and the like; monoesters of polycarboxylic acids such as monomethyl succinate acid, monomethyl citric acid and the like; ether alcohols such as glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-l,3-dioxolone-4-methanol; Solketal; dialkylamides such as dimethylformamide and dimethylacetamide; dimethylsulfoxide (DMSO) and dimethylsulfone; lactones such as epsilon, caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; and mixtures and combinations thereof. Preferred organic liquids include N-methyl- 2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, glycofurol, glycerol formal, and isopropylidene glycol.

Low Water Solubility Orfianic Liquids/Solvents

As described above, an organic liquid of low or no water solubility (hereinafter low/no liquid) may also be used in the sustained release delivery system. Preferably, a low/no liquid is used when it is desirable to have an implant that remains pliable, is to be extrudable is to have an extended release and the like. For example, the release rate of the biologically active agent can be affected under some circumstances through the use of a low/no liquid. Typically such circumstances involve retention of the organic liquid within the implant product and its function as a plasticizer or rate modifier.

Examples of low or nonsoluble organic liquids include esters of carbonic acid and aryl alcohols such as benzyl benzoate; C₄ to Ci₀ alkyl alcohols; Ci to C₆ alkyl C₂ to C₆ alkanoates; esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate and dimethyl carbonate, alkyl esters of mono-, di-, and tricarboxylic acids, such as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate and glyceryl triacetate; alkyl ketones such as methyl ethyl ketone; as well as other carbonyl, ether, carboxylic ester, amide and hydroxy containing liquid organic compounds having some solubility in water. Propylene carbonate, ethyl acetate, triethyl citrate, isopropyl myristate, and glyceryl triacetate are preferred because of biocompatitibility and pharmaceutical acceptance.

Additionally, mixtures of the foregoing high and low or no solubility organic liquids providing varying degrees of solubility for the matrix forming material can be used to alter the life time, rate of bioactive agent release and other characteristics of the implant. Examples include a combination of N- methyl pyrrolidone and propylene carbonate, which provides a more hydrophobic solvent than N-methyl pyrrolidone alone, and a combination of N- methyl pyrrolidone and polyethylene glycol, which provides a more hydrophilic solvent than N-methyl pyrrolidone alone.

The organic liquid for inclusion in the composition should be biocompatible. Biocompatible means that as the organic liquid disperses or diffuses from the composition, it does not result in substantial tissue irritation or necrosis surrounding the implant site.

Organic Liquid for the Preferred Flowable Composition

For the preferred flowable composition incorporating a thermoplastic polyester, any suitable polar aprotic organic liquid can be employed, provided that the suitable polar aprotic solvent displays a body fluid solubility within a range of completely soluble in all proportions to only very slightly soluble.

Suitable polar aprotic organic liquids are disclosed, e.g., in Aldrich Handbook of Fine Chemicals and Laboratory Equipment, Milwaukee, WI (2000); U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194. A suitable polar aprotic liquid should be able to diffuse over time into body fluid so that the flowable composition coagulates or solidifies. The diffusion may be rapid or slow. It is also preferred that the polar aprotic liquid for the biodegradable polymer be non-toxic and otherwise biocompatible.

The polar aprotic organic liquid is preferably biocompatible. Examples of suitable polar aprotic organic liquid include those having an amide group, an ester group, a carbonate group, a ketone, an ether, a sulfonyl group, or a combination thereof. Examples are mentioned above.

Preferably, the polar aprotic organic liquid can be N-methyl-2- pyrrolidone, 2-pyrrolidone, N, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin, or any combination thereof. More preferably, the polar aprotic organic solvent can be N-methyl-2-pyrrolidone.

The solubility of the biodegradable thermoplastic polyesters in the various polar aprotic liquids will differ depending upon their crystal Unity, their hydrophilicity, hydrogen-bonding, and molecular weight. Thus, not all of the biodegradable thermoplastic polyesters will be soluble to the same extent in the same polar aprotic organic liquid, but each biodegradable thermoplastic polymer or copolymer should be soluble in its appropriate polar aprotic solvent. Lower molecular-weight polymers will normally dissolve more readily in the liquids than high-molecular- weight polymers. As a result, the concentration of a polymer dissolved in the various liquids will differ depending upon type of polymer and its molecular weight. Conversely, the higher molecular-weight polymers will normally tend to coagulate or solidify faster than the very low- molecular-weight polymers. Moreover the higher molecular-weight polymers will tend to give higher solution viscosities than the low-molecular-weight materials.

For example, low-molecular-weight polylactic acid formed by the condensation of lactic acid will dissolve in N-methyl-2-pyrrolidone(NMP) to give a 73% by weight solution which still flows easily through a 23-gauge syringe needle, whereas a higher molecular-weight poly(DL-lactide) (DL-PLA) formed by the additional polymerization of DL-lactide gives the same solution viscosity when dissolved in NMP at only 50% by weight. The higher molecular- weight polymer solution coagulates immediately when placed into water. The low-molecular-weight polymer solution, although more concentrated, tends to coagulate very slowly when placed into water. It has also been found that solutions containing very high concentrations of high molecular weight polymers sometimes coagulate or solidify slower than more dilute solutions. It is believed that the high concentration of polymer impedes the diffusion of solvent from within the polymer matrix and consequently prevents the permeation of water into the matrix where it can precipitate the polymer chains. Thus, there is an optimum concentration at which the solvent can diffuse out of the polymer solution and water penetrates within to coagulate the polymer.

The concentration and species of the polar aprotic organic liquid for the preferred flowable composition of the invention incorporating a thermoplastic polyester will typically depend upon the desired properties of the controlled release implant. For example, the species and amount of biocompatible polar aprotic solvent can influence the length of time in which the octreotide is released from the controlled release implant. Specifically, in one embodiment of the present invention, the flowable composition can be used to formulate a one month delivery system of octreotide. In such an embodiment, the biocompatible polar aprotic solvent can preferably be N-methyl-2-pyrrolidone and can preferably present in about 30 wt.% to about 60 wt.% of the composition. Alternatively, in another embodiment of the present invention, the composition can be used to formulate a three month delivery system of octreotide. In such an embodiment, the biocompatible polar aprotic solvent can preferably be N- methyl-2-pyrrolidone and can preferably present in about 20 wt.% to about 60 wt.% of the composition.

Octreotide

Octreotide is a known oligopeptide of the peptide sequence Phe-Cys-Phe- Trp-Lys-Thr-Cys (SEQ ID NO. l). Octreotide typically includes a disulfide link between the cysteines, and the phenylalanine (Phe) and the tryptophan (Trp) are in the D configuration although their L configurations may also be included. The C-terminus cysteine may be terminated as a carboxyl or may be amidated with an organic amine such as an alkyl amine, a dialkyl amine, or a hydroxylalkyl amine. Preferably, the amidating group is 2-hydroxy-l - hydroxymethyl propyl amine. The C-terminus cysteine may also be amidated with an additional amino acid unit such as threonine (Thr), serine (Ser) or tyrosine (Thy) and the resulting C-terminus of the amidating amino acid may be carboxyl or amidated as described for the C-terminus cysteine. The preferred amidating amino acid group is threonine. The peptide sequence may also be glycosylated at the N-terminus. The glycosylation groups may be galactosyl, glucosyl, glucosyl-fructosyl as well as other disaccharidysyl glycosylation groups.

Octreotide may be administered in its unneutralized basic form owing to the basic side chains of the tryptophan and lysine units, or as a salt of an organic or inorganic acid. Examples include the octreotide salts wherein the gegenion (counter-ion) is acetate, propionate, tartrate, malonate, chloride, sulfate, bromide, and other pharmaceutically acceptable organic and inorganic acid gegenions. Preferred are organic acids with multiple carboxylic acid groups such as malonic acid, citric acid, itaconic acid, adipic acid and di-, tri- and tetra-carboxylic acids of four to 40 carbon atoms.

Octreotide is preferably lyophilized prior to use. Typically, the octreotide can be dissolved in an aqueous solution, sterile filtered and lyophilized in a syringe. In a separate process, the thermoplastic polymer/organic liquid solution can be filled into a second syringe. The two syringes can then be coupled together and the contents can be drawn back and forth between the two syringes until the thermoplastic polymer, organic liquid and the octreotide are effectively mixed together, forming a flowable composition. The flowable composition can be drawn into one syringe. The two syringes can then be disconnected and a needle attached to the syringe containing the flowable composition. The flowable composition can then be injected through the needle into the body. The flowable composition can be formulated and administered to a patient as described in, e.g., U.S. Patent Nos. 5,324,519; 4,938,763; 5,702,716; 5,744,153; and 5,990,194; or as described herein. Once administered, the organic liquid dissipates, the remaining polymer gels or solidifies, and a matrix structure is formed. The organic liquid will dissipate and the polymer will solidify or gel so as to entrap or encase the octreotide within the matrix.

The release of octreotide from the implant of the invention will follow the same general rules for release of a drug from a monolithic polymeric device. The release of octreotide can be affected by the size and shape of the implant, the loading of octreotide within the implant, the permeability factors involving the octreotide and the particular polymer, and the degradation of the polymer. Depending upon the amount of octreotide selected for delivery, the above parameters can be adjusted by one skilled in the art of drug delivery to give the desired rate and duration of release.

The amount of octreotide incorporated into the sustained release delivery system of the invention depends upon the desired release profile, the concentration of octreotide required for a biological effect, and the length of time that the octreotide has to be released for treatment. There is no upper limit on the amount of octreotide incorporated into the sustained release delivery system except for that of an acceptable solution or dispersion viscosity for injection through a syringe needle. The lower limit of octreotide incorporated into the sustained release delivery system is dependent upon the activity of the octreotide and the length of time needed for treatment. Specifically, in one embodiment of the present invention, the sustained release delivery system can be formulated to provide a one month release of octreotide. In such an embodiment, the octreotide can preferably be present in about 1 wt.% to about 20 wt.%, preferably about 8wt.% to about 15 wt.% of the composition. Alternatively, in another embodiment of the present invention, the sustained release delivery system can be formulated to provide a three month delivery of octreotide. In such an embodiment, the octreotide can preferably be present in about 1 wt.% to about 20 wt.%, preferably about 8 wt.% to about 15 wt.% of the composition. The gel or solid implant formed from the flowable composition will release the octreotide contained within its matrix at a controlled rate until the implant is effectively depleted of octreotide.

Adjuvants and Carriers The sustained release delivery system may include a release rate modifier to alter the sustained release rate of octreotide from the implant matrix. The use of a release rate modifier may either decrease or increase the release of octreotide in the range of multiple orders of magnitude (e.g., 1 to 10 to 100), preferably up to a ten-fold change, as compared to the release of octreotide from an implant matrix without the release rate modifier.

With the addition of a hydrophobic release rate modifier such as hydrophobic ethyl heptanoate, to the sustained release delivery system, and formation of the implant matrix through interaction of the flowable composition and body fluid, the release rate of octreotide can be slowed. Hydrophilic release rate modifiers such as polyethylene glycol may increase the release of the octreotide. By an appropriate choice of the polymer molecular weight in combination with an effective amount of the release rate modifier, the release rate and extent of release of a octreotide from the implant matrix may be varied, for example, from relatively fast to relatively slow.

Useful release rate modifiers include, for example, organic substances which are water-soluble, water-miscible, or water insoluble (i.e., hydrophilic to hydrophobic).

The release rate modifier is preferably an organic compound which is thought to increase the flexibility and ability of the polymer molecules and other molecules to slide past each other even though the molecules are in the solid or highly viscous state. Such an organic compound preferably includes a hydrophobic and a hydrophilic region. It is preferred that a release rate modifier is compatible with the combination of polymer and organic liquid used to formulate the sustained release delivery system. It is further preferred that the release rate modifier is a pharmaceutically-acceptable substance.

Useful release rate modifiers include, for example, fatty acids, triglycerides, other like hydrophobic compounds, organic liquids, plasticizing compounds and hydrophilic compounds. Suitable release rate modifiers include, for example, esters of mono-, di-, and tricarboxylic acids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, glycerol triacetate, di(n-butyl) sebecate, and the like; polyhydroxy alcohols, such as propylene glycol, polyethylene glycol, glycerin, sorbitol, and the like; fatty acids; triesters of glycerol, such as triglycerides, epoxidized soybean oil, and other epoxidized vegetable oils; sterols, such as cholesterol; alcohols, such as C₆ -C|₂ alkanols, 2-ethoxyethanol, and the like. The release rate modifier may be used singly or in combination with other such agents. Suitable combinations of release rate modifiers include, for example, glycerin/propylene glycol, sorbitol/glycerine, ethylene oxide/propylene oxide, butylene glycol/adipic acid, and the like. Preferred release rate modifiers include dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerin, and hexanediol. The amount of the release rate modifier included in the flowable composition will vary according to the desired rate of release of the octreotide from the implant matrix. Preferably, the sustained release delivery system contains about 0.5-30%, preferably about 5-10%, of a release rate modifier. Other solid adjuvants may also be optionally combined with the sustained release delivery system to act as carriers, especially isolation carriers. These include additives or excipients such as a starch, sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, and/or polyvinylpyrrolidone.

Additional adjuvants may include oils such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil as well as esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Also included are alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum may also be used in the formulations. Pectins, carbomers, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or carboxymethyl cellulose may also be included. These compounds can serve as isolation carriers by coating the octreotide thereby preventing its contact with the organic solvent and other ingredients of the flowable composition. As isolation carriers, these compounds also help lower the burst effect associated with the coagulation of the flowable composition in situ. Optionally, other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, bioavailability modifiers and combinations of these are included. Emulsifiers and surfactants such as fatty acids, or a non-ionic surfactants including natural or synthetic polar oil, fatty acid esters, polyol ethers and mono-, di- or tri-glycerides may also be included.

The Implant

When the implant of the invention is formed, the implant has the physical state of a solid or a gel. The solid embodiments may be rigid so that they cannot be flexed or bent by squeezing them between the fingers or they may be flexible or bendable so that they can be compressed or flexed out of original shape by squeezing between the fingers (i.e., a low amount of force). The gel embodiments may be jelly-like in consistency and will flow under pressure. The thermoplastic polymer functions as a matrix in these embodiments to provide integrity to the single body solid or gel and to enable controlled release of the bioactive agent upon implantation.

The thermoplastic polymer matrix is preferably a solid matrix and especially preferably is microporous. In an embodiment of the microporous solid matrix, there is a core surrounded by a skin. The core preferably contains pores of diameters from about 1 to about 1000 microns. The skin preferably contains pores of smaller diameters than those of the core pores. In addition, the skin pores are preferably of a size such that the skin is functionally non-porous in comparison with the core.

Because all of the components of the implant are biodegradable or can be swept away from the implant site by body fluid and eliminated from the body, the implant eventually disappears. Typically the implant components complete their biodegradation or disappearance after the octreotide has been essentially completely released. The structure of the thermoplastic polymer, its molecular weight, the density and porosity of the implant and the body location of the implant all affect the biodegradation and disappearance rates.

The implant is typically formed subcutaneously in a patient. It can be molded in place upon injection to provide comfort to the patient. The implant volume typically may be between 0.25 mL to 2 or 3 mL in size.

Therapeutic Use

Surprisingly, it has been discovered that the sustained release delivery system according to the present invention is more effective in delivering octreotide than the Sandostatin LAR^® product. Specifically, as shown in the Examples below, the blood levels of octreotide obtained with the sustained release delivery system of the present invention are higher at extended times in humans compared with those produced by the Sandostatin LAR" product, and also at the three month point in humans, compared to the value reported in the literature for the Sandostatin LAR^® product. Many of the advantages of this invention (e.g. superior release kinetics with minimal burst, increased duration of drug release with less frequent injections; markedly improved bioavailability; improved local tissue tolerance due to a small injection volume and the ability to use of a subcutaneous injection rather than intramuscular injection) are useful for the treatment of eye diseases. This includes eye diseases that involve excessive cellular proliferations, including but not limited to neovascular diseases of the eye, such as choroidal neovascularization, as occurs in age related macular degeneration, and retinal neovascularization, as occurs in diabetic retinopathy. In general, any disease which may be ameloriated, treated, cured or prevented by administration of somatostatin or a somatostatin analog may be treated by administration of the flowable composition of the invention. These diseases relate to those having at least a partial basis in hypersecretion of growth hormone or somatotropin, imbalance in pathways involving insulin, glucagon and/or somatotropin, imbalance or malconditions involving somatostatin and/or somatotropin receptors, and malconditions associated with gastrointestinal ailments. The following specific malconditions are exemplary of such diseases. These may all be treated by appropriate, effective administration of a flowable composition of the invention formulated to deliver an effective amount of octreotide. These malconditions include: a. Diarrhea associated with carcinoid syndrome and vasoactive intestinal peptide (VIP) tumors; b. Neuroendocrine tumors; c. Acromegaly; d. Chemotherapy-induced diarrhea; e. Pancreatitis; f. Bleeding esophageal varices; g. Fluid accumulation associate with portacaval shunting; h. Irritable bowel syndrome; i. Seizures; j. Formation of advanced glycation end (AGE) products (e.g. Hemoglobin

AlC) in diabetic patients, and additional diabetic complications; k. Neovascular proliferative eye diseases (specific examples given in separate list below); 1. Other types of proliferative eye diseases (specific examples given in separate list below);

Examples of neovascular proliferative eye diseases that may be treated by a flowable composition of the invention include: a. Retinal neovascularization in patients with diabetic retinopathy (with or without associated macular edema; with or without pre-retinal hemorrhage; with or without retinal detachment); b. Retinal neovascularization as in patients with retinopathy of prematurity; c. Choroidal neovascularization in patients with the wet form of age- related macular degeneration (with or without macular edema; with or without hemorrhage; with or without retinal detachment); d. Choroidal neovascularization in patients with ocular and systemic diseases other than age-related macular degeneration; e. Corneal neovascularization;

Examples of other types of proliferative eye diseases that may be treated by a flowable composition of the invention include: a. Fibroblastic proliferations: Proliferative vitreoretinopathy or pterygium; b. Autoimmune and inflammatory conditions: Graves' ophthalmopathy with periocular and/or intraocular lymphocytic proliferation; c. optic neuritis; any type of uveitis, iridocyclitis or scleritis caused by lymphocytic or monocytic cell proliferation; d. Hematolymphoid neoplasms: intraocular lymphoma or leukemia; e. Solid tumors: retinoblastoma, melanoma, rhabdomyosarcoma, embryonal sarcoma, metastatic malignant solid tumors or any other malignant or benign intraocular tumor; any oncogenic neovascularization of the eye.

Diabetic eye diseases that may be treated by a flowable composition of the invention include: a. Non-proliferative retinopathy; b. Early proliferative, non-high risk, retinopathy; c. Proliferative retinopathy; d. Severe retinopathy in patients who have failed photocoagulation ; e. Diabetic macular edema, including custoid macular edema; The use of the flowable composition to treat diabetic eye conditions includes stand alone therapy, and combinations with other treatments. Examples include: a. Laser photocoagulation therapy; b. Locally injected steroids including intravitreal, retro-bulbar, subconjunctival and sub-Tenon injections of any steroidal compound. The flowable composition of the invention may also be used as a stand alone therapy to treat CNV associated with many eye diseases and syndromes such as AMD. Such malconditions include for example: a. Wet age-related macular degeneration "AMD" (including predominantly classic AMD, minimally classic AMD and occult AMD subtypes). AMD is the major disease associated with CNV lesions; b. CNV lesions also develop in other conditions of the eye: pathologic myopia, angioid streaks, presumed ocular histoplasmosis syndrome (POHS), serous choroiditis, optic head drusen, idiopathic central serous chorioretinopathy, retinal coloboma, Best's disease, retinitis pigmentosa with exudates, serpiginous choroiditis, Behcet's syndrome, chronic uveitis, acute multifocal posterior placoid pigment epitheliopathy, birdshot chorioretinopathy, choroidal rupture, ischemic optic neuropathy, chronic retinal detachment, other conditions of the posterior segment of the eye.

The flowable composition of the invention may also be used as a treatment for CNV lesions in combination with other treatments, such as by combination with: a. Photodynamic therapy (e.g. verteporfin (Visudyne, QLT, Inc.), SnET2

(etiopurpurin, Miravant, Inc.); b. Locally injected anti-angiogenic agents. For example, intravitreal or subconjunctival anti-VEGF agents: Macugen/Eyetech, Pharmaceuticals, Inc; Lucentis/Genentech, Inc.; and VEGF Trap/Regeneron Pharmaceuticals, Inc.; c. Locally injected angiostatic steroids (e.g. anecortave, Retanne/Alcon) which is administered as a sub-Tenon injection; or any corticosteroid that is administered locally to the ocular tissues (e.g. triamcinolone); d. Systemic therapies for CNV, such as squalamine [Genaera, Inc] and other systemically administered anti-angiogenic agents (e.g. Avastin). Additional malconditions susceptible to ameloriation, prevention or cure by treatment with octreotide include ocular manifestations of thyroid disease (i.e. Graves disease, Hashimoto's thyroiditis or other causes of hyperthyroidism) (See the references Krassas, G. E. et al, 1998; Pasquali, D. et al, 2002). The use of the flowable composition in the treatment of thyroid related ocular disease include its use as a stand alone therapy, and its use in combination with other treatments, such as steroids and other systemic immunosuppressive agents. Further malconditions treatable with the flowable composition of the present invention include cystoid macular edema (Kuijpers, R. et al, 1998; Rothnova, A. et al, 2002), and visual field defects associated with pituitary adenomas that compress the optic nerve (e.g. in patients with acromegaly) (McKreage, K. et al, 2003).

Dosages

The amount of flowable composition administered will typically depend upon the desired properties of the controlled release implant. For example, the amount of flowable composition can influence the length of time in which the octreotide is released from the controlled release implant. Specifically, in one embodiment of the present invention, the composition can be used to formulate a one month delivery system of octreotide. In such an embodiment, about 0.20 mL to about 0.40 mL of the flowable composition can be administered. Alternatively, in another embodiment of the present invention, the composition can be used to formulate a three month delivery system of octreotide. In such an embodiment, about 0.75 mL to about 1.0 mL of the flowable composition can be administered.

The amount of octreotide within the flowable composition and the resulting implant will depend upon the disease to be treated, the length of duration desired and the bioavailability profile of the implant. Generally, the effective amount will be within the discretion and wisdom of the patient's attending physician. Guidelines for administration include dose ranges of from about 100 to 5000 micrograms of octreotide per day as applied for proliferative and non-proliferative eye diseases. The typical flowable composition effective for such sustained delivery over a 1 month period will contain from about 5 to about 100 mg of octreotide per ml of total volume of flowable composition. The injection volume will range from 0.2 to 1.5 mL per implant. The typical flowable composition effective for such sustained delivery of a 3 month period will contain from about 12 to about 30 mg of octreotide per ml of total volume of flowable composition. The injection volume will range from 0.75to 1.0 mL per implant. The polymer formulation will be the primary factor for obtaining the longer sustained release, as discussed above.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention will now be illustrated with the following non-limiting examples.

The following Examples employ the ATRIGEL^® formulation of poly(lactide-coglycolide) and N-methyl pyrrolidone in combination with octreotide as the flowable composition.

Controlled Release Systems

Copolymer compositions adapted for use in controlled release delivery systems such as biodegradable and bioerodible implants are known. See, for example, U.S. Patent Nos. 7,019,106; 6,565,874; 6,528,080; RE37,950; 6,461,631 ; 6,395,293; 6,355,657; 6,261,583; 6,143,314; 5,990,194; 5,945,1 15; 5,792,469; 5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950; 5,702,716; 5,681 ,873; 5,599,552; 5,487,897; 5,340,849; 5,324,519; 5,278,202; and 5,278,201. Such controlled release systems are in general advantageous because they provide for the controlled and sustained release of medications, often directly at or near the desired site of action, over the period of days, weeks or even months.

Controlled release systems can include polymer matrices that are known to be broken down in the body by various endogenous substances such as enzymes and body fluids, such as polyesters including poly-lactide, poly- glycolide, and copolymers thereof ("PLG copolymers") prepared from glycolide (l ,4-dioxan-2,5-dione, glycolic acid cyclic dimer lactone) and lactide (3,6- dimethyl-l ,4-dioxan-2,5-dione, lactic acid cyclic dimer lactone), or from glycolate (2-hydroxyacetate) and lactate (2-hydroxypropionate). These copolymer materials are particularly favored for this application due to their facile breakdown in vivo by body fluids or enzymes in the body to non-toxic materials, and their favorable properties in temporally controlling the release of medicaments and biologically active agents ("bioactive agents") that may be contained within a mass of the controlled release formulation incorporating the polymer that has been implanted within a patient's body tissues. Typically, controlled release systems are adapted to provide for as constant a rate of release as possible of the bioactive agent over the time period that the implant persists within the body.

Flowable delivery systems, such as the Atrigel^® systems, are disclosed in U.S. Patent Numbers 6,565,874, 6,528,080, 6,461 ,631, 6,395,293, and references found therein. Flowable delivery systems like the Atrigel^® system include a polymer, a bioactive agent, and an organic solvent that has at least a very slight solubility in body fluids. When the substantially liquid ("flowable") solution of the delivery system is injected into a patient's tissues, typically as a single bolus, the organic solvent diffuses into surrounding body fluids, causing precipitation or gelation of the water-insoluble polymer containing the bioactive agent. It is believed that initially a skin or membrane-like barrier forms on the outer portion of the deposited liquid mass, bringing about formation of the semi-solid deposit known as a "depot" that contains the remaining solution of the polymer and the bioactive agent in the solvent.

As the depot resides in tissue for a period of time, the solvent continues to diffuse out and body fluids to diffuse in, bringing about ongoing precipitation of the polymer with the bioactive agent, until a gelled or solid mass remains. Channels or pores may form in the depot as part of this process. Due to the biodegradable nature of the polymer in the presence of body fluids and enzymes within the body, the polymer slowly degrades into soluble non-toxic hydrolysis products, releasing the contained bioactive agent over a period of time. This process continues until the depot is substantially completely dissolved and all the bioactive agent is released. It is understood that such depots can be adapted to persist for various lengths of time within the body, such as about 30 days, about 60 days, or about 3 months, 4 months, or 6 months.

In this manner, a relatively constant level of a bioactive agent, such as octreotide, can be maintained within the patient's body for the period of time over which the formulation is adapted to release the agent. It is generally undesirable to have fluctuations in the rate of release of the bioactive agent, which results in fluctuations of serum levels of the agent within the patient's body. The most desirable rate of release is typically a constant, or zero-order, rate of release, wherein the amount of the bioactive agent released per time interval is substantially constant, up until the point of complete, or near complete, dissolution of the controlled release implant in the patient's body.

At least two problems involving a less than optimal rate of release have been found using known PLG copolymers in controlled release systems. First, there is often an initial burst effect, and there is often a degree of variability in the subsequent rate of release over the lifetime of the depot in the body. It has been found that the release of many bioactive agents such as peptides, proteins, and small molecule drugs from controlled release systems can occur at a higher than optimal rate during the first 24 hours after implantation under certain conditions. This is known in the art as the "burst effect" or the "initial burst effect," and is generally undesirable, as overdosing of the patient can result. The second effect involves a variable, non-linear rate of release of the bioactive agent as the implanted formulation undergoes its period of degradation in the body that deviates from linearity or zero-order kinetics. This effect can occur when using purified copolymer formulations adapted to reduce or minimize the initial burst effect as well as when using unpurified copolymers.

After a depot has been formed within a patient's body by introduction of a flowable delivery system, it has been observed on occasion that the rate of release of the bioactive agent tends to vary as the depot undergoes biodegradation in the body through the effects of body fluids and enzymes. Thus, the later stages of the period that the depot persists within the body can be marked by an increased or a decreased rate of delivery of the bioactive agent, which is generally undesirable.

Constant Release Copolymer System The constant release copolymer system described herein can be used in, for example, a flowable delivery system like an Atrigel " system, to provide for a substantially constant rate release of octreotide over the period of time that the depot persists after its emplacement within the tissues of a patient, resulting in an improved release profile. Atrigel^® delivery systems are described in U.S. Patent Nos. 6,565,874, 6,528,080, 6,461 ,631 , 6,395,293, and references found therein. For example, controlled release compositions involving the constant release copolymer systems described herein have been surprisingly found to reduce variations in the rate of release of the bioactive agent, especially later in the process of dissolution of the implanted depot.

It has unexpectedly been discovered that a mixture of a PLG copolymer and a relatively hydrophobic PLG oligomer ("PLG oligomer") yields a copolymer (referred to hereinafter as a "constant release copolymer") that, when incorporated into a controlled release formulation for octreotide, provides for a substantially constant rate of release of the octreotide from a depot over the entire period of time that the depot persists in the patient's body tissues. The PLG copolymer can be a PLG copolymer of the type that when incorporated into a controlled release formulation of the Atrigel^® type provides a reduced initial burst effect (referred to hereinafter as a "low burst copolymer"). When a constant release copolymer includes a low burst PLG copolymer and the PLG oligomer, a low burst, constant release copolymer is obtained. The PLG oligomer can be an oligomer comprising lactide and glycolide units wherein the lactide units are present at a level of about 50-99% on a molar basis, and wherein the average molecular weight of the oligomer is less than about 10 kDa, preferably about 7-8 kDa.

One significant advantage of a constant release copolymer as described herein is that when incorporated into a flowable delivery system, it reduces or minimizes alterations in the rate of release of octreotide over the period of time that the depot persists within the patient's body tissue, compared to known copolymer systems. The period of time that the depot persists within the patient's body tissue can be defined as the point in time when the depot finally completely dissolves due to biodegradation, or the point in time when the depot no longer retains octreotide within its matrix. In particular, a decrease or an increase in the rate of release of the agent as the depot nears the end of its time of residence in the body (immediately prior to final dissolution of the depot) is avoided through use of the constant release copolymer. The constant release copolymer can include as a PLG copolymer a low burst PLG copolymer such as is described in U.S. Ser. No. 60/901 ,435. In such embodiments, the initial burst effect is minimized and the rate of release of the bioactive agent over the lifetime of the depot within the patient's body is kept at a more constant level than is observed with known delivery systems.

The present invention provides a constant release copolymer that includes a mixture of a PLG copolymer and a relatively hydrophobic PLG oligomer substantially lacking carboxylic end groups. The constant release copolymer can be adapted for use in a controlled release formulation for release of octreotide from a depot within a patient's body tissues. The formulation can provide a substantially constant rate of release of the agent over a period of time that the depot persists within the body tissues. The constant rate of release is particularly significant during a period of time immediately prior to the complete dissolution of the depot, i.e., at the end of the time period for which the depot is adapted to release the agent.

A controlled release formulation prepared from the constant release copolymer, octreotide, and an organic solvent having at least a very slight solubility in body fluids when emplaced as a depot in body tissues, delivers the octreotide at a substantially constant rate over the period of time that depot persists. The PLG copolymer of the constant release copolymer system can be a low burst PLG copolymer, which, when incorporated into the controlled release formulation together with the hydrophobic PLG oligomer, avoids the undesired initial burst effect as well as providing the substantially constant rate of release.

The present invention further provides a method of preparing a controlled release formulation adapted for providing a substantially constant rate of release of octreotide in a patient, involving combining a hydrophobic PLG oligomer to a PLG copolymer to provide a constant release copolymer, then forming the controlled release formulation incorporating the constant release copolymer, the octreotide, and an organic solvent having at least a very slight solubility in body fluids.

The present invention further provides a method of administering octreotide to a patient over a prolonged period of time, wherein a substantially constant rate of release of the bioactive agent is achieved, comprising administering to the patient a controlled release formulation comprising a copolymer as described herein, octreotide, and an organic solvent having at least a very slight solubility in body fluids. For example, Figure 12 shows a cumulative release profile for octreotide from a depot of a controlled release formulation emplaced in rats, the formulations including a control containing as a copolymer only a purified PLGH(p), and four test systems each containing a copolymer system including the purified PLGH(p) and a PLG oligomer such as a PLA or 65/35 PLG oligomer. The four test systems clearly show significant zero order release of octreotide through a 90-day study.

Sustained Release Embodiments with Added Oligomers in the Polymer Formulation

The present invention provides a constant release copolymer including a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups. The inventive constant release copolymer is adapted for use in a controlled release formulation for release of octreotide from a depot within a patient's body tissues, the formulation providing a substantially constant rate of release of the agent over a period of time that the depot persists within the body tissues, for example, about 90 days.

As discussed above, controlled release formulation such as the Atrigel^® type, incorporating PLG copolymers, including purified PLG copolymers such as PLG(p) copolymers, can exhibit less than optimal non-linear kinetics of release of the bioactive agent, especially late in the depot's lifetime. It has surprisingly been found that addition of a defined amount of a hydrophobic PLG oligomer that lacks free carboxylic acid groups to the PLG copolymer and incorporation into a flowable delivery system that is emplaced within body tissues to form a depot can result in improved linearity of release of the octreotide (See Fig. 12). As a result, the release profile of the octreotide over time more closely approximates a zero-order kinetics model than known sustained release products.

The PLG copolymer used in the inventive copolymer system can be of the PLGH type, i.e., having acidic carboxylic acid end groups on the molecular chains. The PLGH copolymer can be either purified or unpurified. When a purified PLGH of the PLGH(p) type is used, addition of about 5 wt% of PLG oligomers having an average molecular weight of about 5-10 kDa, and lacking free carboxylic acid groups, results in an increased linearity of the cumulative release profile of a contained bioactive agent, particularly in the later stages of the depot's lifetime in the body. The PLG oligomer can be, for example, polylactide or of 65/35 poly(lactide-glycolide), either material having an average molecular weight of about 5-10 kDa, for example about 7 or 8 kDa, lacking free carboxylic acid groups.

Figure 12 shows data for the release of octreotide, a peptide analog of molecular weight slightly greater than 1000, from a controlled release formulation adapted to release the drug over a period of 90 days. The control (circles) shows the cumulative percent release of the octreotide over the 90 day period from a controlled release formulation using a purified PLGH without any PLG oligomer. The cumulative release curve deviates significantly from the ideal, which is a straight line between 0% at 0 days and about 90% at 90 days. After some initial burst between 0 and about 2 days, the control release profile reaches a maximum variance above the ideal release line at about 40 days, then tapers off to lower release levels late in the period, particularly at about 70-90 days.

The other four lines in Figure 12 represent various combinations of PLG copolymer and oligomer. The black squares and triangles represent the release profiles of the octreotide from 85/15 PLGH(p) formulations including 4.5% PLA of about 7 kDa average molecular weight and lacking carboxylic acid end groups, when PLGH(p) concentrations are respectively 50% and 45%. The open squares and triangles represent the release profiles of octreotide from PLGH(p) copolymer formulations comprising 4.5% 65/35 PLG oligomers of less than 10 kDa molecular weight and lacking carboxylic end groups, when PLGH(p) concentrations are respectively 50% and 45%.

As can be observed in Figure 12, the curves depicting the copolymer systems that include the PLG oligomers more closely approximate a linear representation of zero order kinetics. This is particularly true after day 14. In this system, the PLA oligomer is even more effective at the later period, especially from about 60 to 90 days after emplacement of the depot in the test animal, than the 65/35 PLG oligomer, with respect to the cumulative release profile. This is even more apparent when taking the initial burst into account and defining the linear ideality as starting at about 10% total release at 2 days, instead of at 0% total release at 0 days. The inventive copolymer system is thus adapted to control non-linearity of release and, especially when used with a low burst PLG copolymer such as a PLGH(p), provides for substantially more linearity of release, e.g., a closer approach to zero-order release kinetics, than currently known copolymer systems. Incorporation of an oligomer of a relatively lipophilic and non-ionic (neutral) character, i.e., substantially lacking carboxylic acid end groups, can have an effect both on the partition of the octreotide between the depot and the body fluids, affecting the release from the depot mass, and on the biodegradation of the depot mass by body fluids and enzymes in the body tissues of the patient, affecting the kinetics of depot dissolution.

The depot, which can be emplaced within a patient's body tissues as a single liquid bolus with an Atrigel^® system, initially begins solidification from the liquid, flowable composition as the solvent, such as NMP, diffuses out of the bolus into surrounding body fluids. The body fluids also then diffuse into the depot, bringing about precipitation of the copolymer. As the solvent diffuses out of the depot, it can carry octreotide with it, in solution or a suspension form. As the solvent within the depot begins to be diluted with body fluids, the octreotide, which has limited water solubility, is in equilibrium between absorption on the precipitating polymer and dissolution in the body fluid/NMP mixture. Addition of a relatively hydrophobic oligomer may serve to better hold the octreotide during a period when the solvent content is relatively high and octreotide release typically is enhanced, such as after the initial burst up to about halfway through the depot dissolution process, thus reducing early release and leveling the release rate throughout the dissolution of the depot. It is understood that many parameters of this copolymer system can be varied by the skilled artisan to adjust the properties of the copolymer system and of a controlled release formulation incorporating the system. For example, the relative proportion of the PLG oligomer in the constant release copolymer and the molecular properties of the oligomer as well as of the PLG copolymer can be varied to achieve a particular desired result in terms of the release profile for octreotide to provide the desired release profile. For example, the hydrophobicity of the oligomer and of the PLG copolymer can be adjusted by altering the relative proportions of lactide and glycolide units. The molecular weights of the PLG copolymer and, to a lesser extent, of the oligomer, can be varied. Typical molecular weights of the PLG copolymer can be between about 10 kDa and 50 kDa. For a low burst PLG copolymer, for example a PLG(p) copolymer, the weight average molecular weight can be about 10-50 kDa with a PDI of about 1.4-2.0, having separated therefrom a copolymer fraction characterized by a weight average molecular weight of about 4-10 kDa and a polydispersity index of about 1.4 to 2.5.

The solvent used in the controlled release formulation can be varied, as can be carried out by a person of ordinary skill in the art without undue experimentation, to adjust the controlled release properties of the formulation. The solvent has at least a small degree of solubility in body fluids. The solvent can be soluble in the body fluids. The organic solvent can be N- methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, polyethylene glycol 200, polyethylene glycol 300, or methoxypolyethylene glycol 350, or any mixture thereof. To further adjust the system properties, the concentrations of the octreotide and of the PLG copolymer/oligomer system in the solvent can be varied, and the amount of the formulation emplaced within the patient can also be adjusted. Furthermore, it is understood that biodegradable polyesters other than poly(lactide-glycolide), such as, for example, poly(caprolactone), can be components of the inventive copolymer.

The controlled release formulation can be prepared by combining the PLG copolymer, the PLG oligomer, octreotide, and the organic solvent. For example, the PLG copolymer and the oligomer can be premixed as solids, then dissolved in the solvent, followed by addition of octreotide immediately prior to emplacement of the formulation in the patient. The formulation can be sterilized by means known in the art, for example, gamma irradiation.

The invention further provides a method of administering octreotide to a patient over a prolonged period of time, wherein a substantially constant rate of release of the octreotide is achieved, the method involving administering to the patient the inventive controlled release formulation of the octreotide. A controlled release formulation can be made up by dissolving the copolymer system in a water-soluble organic solvent at a suitable concentration and adding octreotide. The depot can be emplaced at any suitable position within the patient's body tissues, for example, subcutaneously adjacent to the abdominal wall, or within the abdominal cavity, within a muscle, within an eyeball, within a cerebral ventricle, or the like. Typically a depot of the Atrigel " type is emplaced with a hypodermic syringe, but other devices or methods as are known in the art can be employed. Octreotide contained within the controlled release formulation including an inventive copolymer system can be adapted to treat, for example, acromegaly. Formulations adapted to release octreotide over various periods of time can be used as medically indicated, for example, a period of 3 months, 6 months, or more. This serves to reduce the pain and inconvenience of multiple depot emplacements, which is highly desirable in light of currently used octreotide formulations.

Sustained Release Embodiments with Alkanediol Core Polymers

The present invention provides a biodegradable polymer for use in a controlled release formulation with a relatively long-lived duration of effectiveness, that is, with a relatively long time period over which a medicament is released from the polymer in therapeutically effective quantities. A flowable composition comprising the novel polymer for use as a controlled release formulation further includes a solvent and a medicament, as is described in U.S. Patent No. 6,773,714 and documents cited therein, which are incorporated herein by reference. The flowable composition may be used to provide a biodegradable or bioerodible microporous implant formed in situ in animals.

A polymer of the present invention comprises two poly(lactide-glycolide) copolymer segments, or two poly(lactate-glycolate) copolymer segments, or two polylactide polymer segments, or two polylactate polymer segments, respectively covalently bonded to the two hydroxyl groups of an alkanediol core unit. In contrast to many polymers known in the art, the polymers of the invention do not comprise titratable carboxylic acid groups, being hydroxyl- terminated at the distal ends of both PLG or PLGA copolymer segments or PL or PLA polymer segments. This is due to the fact that the carboxyl ends of the copolymer segments are bonded in ester linkages with the hydroxyl groups of the alkanediol core. The absence of titratable carboxylic acid groups in the polymer of the invention means that the chemical functionality present on the terminal ends of the polymer, that is, on the groups at the distal ends of the copolymer segments linked to the alkanediol, are chemically neutral. By chemically neutral it is meant that the groups are not acidic or alkaline, and are not ionizable in aqueous solution at around neutral pH. The chemical neutrality of the polymer is an outstanding advantage of the invention in that no acidic groups are present in the polymer to bring about auto-catalytic degradation through hydrolysis of the ester bonds of the polymer, or to catalyze degradation of a contained medicament, such as octreotide, or to react with the contained medicament, such as with the amine groups on octreotide.

A polymer of the present invention can be represented structurally as a compound of Formula (I):

(I) wherein "L/G" signifies a PLG copolymer segment, the H atoms at both distal ends signify the hydrogen atoms borne by the terminal hydroxyl groups, and R^a is an alkylene diradical. The R^b and R^c groups shown on either side of the R^a core moiety may be either hydrogen or methyl, with the proviso that both R^b groups are either hydrogen or methyl concurrently, and both R^c groups are either hydrogen or methyl concurrently, but R^b and R^c need not be the same.

The groups indicated as "L/G" in Formula (I) thus signify lactide/glycolide copolymer segments of the structure:

wherein the R groups are independently hydrogen or methyl, again with the proviso that as described above, hydrogen substituents or methyl substituents are found in pairs due to their incorporation in pairs as repeating units from the dimeric lactide or glycolide reagents. Other than this requirement of R^d groups being in pairs, methyl groups and hydrogen groups are arranged randomly throughout the copolymer segments L/G, with the understanding that due to the higher rate of reaction of G-G groups, these will tend to be more frequently found adjacent to R^a. The wavy lines signify points of attachment to other radicals, for example hydrogen atoms at the distal ends and the core alkanediol hydroxyl groups at the proximal ends. The number of repeating units n range from about 20 up to about 750 for each copolymer segment, providing a polymer of a molecular weight of about 6 kD ranging up to about 200 kD in weight. It is understood that the two L/G copolymer segments need not be identical, and likely are not identical, either in sequence or in the molecular weight of each copolymer segment in a given polymer molecule. Further, the specific composition of each molecule within a sample of the polymer varies in the same manner.

Another polymer of the present invention can be represented structurally as a compound of Formula (II):

(H) wherein "Lt/Gt" signifies a PLGA copolymer segment, the H atoms at both distal ends signify the hydrogen atoms borne by the terminal hydroxyl groups, and R^a is an alkylene diradical. The R^b and R^c groups shown on either side of the R^a core moiety may be either hydrogen or methyl. There is no restriction that the methyl groups or the hydrogen atoms occur in pairs.

The groups indicated as "Lt/Gt" in Formula (II) thus signify lactate/glycolate copolymer segments of the structure:

wherein the R^d groups are independently hydrogen or methyl. Methyl groups and hydrogen groups are arranged randomly throughout the copolymer segments L/G, with the understanding that due to the possibly higher rate of reaction of G groups, these may tend to be more frequently found adjacent to R^a. The wavy lines signify points of attachment to other radicals, for example hydrogen atoms at the distal ends and the core alkanediol hydroxyl groups at the proximal ends. The number of repeating units n may range from about 20 up to about 185 for each copolymer segment, providing a polymer of a molecular weight of about 6 kD ranging up to about 50 kD in weight. It is understood that the two PLGA copolymer segments need not be identical, and likely are not identical, either in sequence or in the molecular weight of each copolymer segment in a given polymer molecule. Further, the specific composition of each molecule within a sample of the polymer varies in the same manner.

Yet another polymer of the present invention can be represented structurally as a compound of Formula (III):

(III) wherein L signifies a polylactide or polylactate polymer segment, the H atoms at both distal ends signify the hydrogen atoms borne by the hydroxyl groups, and R^a is an alkylene diradical. The R^b groups on either side of the R^a core moiety are all methyl.

As is described above, in the polymers of formulas (I), (II), and (III), the distal ends of the copolymer segments comprise hydroxyl groups. The proximal ends of the copolymer segments therefore comprise the carboxyl moieties at the opposite end of the lactide or the glycolide repeating unit, which are linked in ester bonds with hydroxyl groups of the core alkanediols. This structural element is an outstanding feature of the present invention, as it results in the lack of titratable carboxylic acid groups in a polymer of the invention, the product being a neutral polymer. The core alkanediol can be an α,ω-diol to which the copolymer segments are bonded via the two primary hydroxyl groups. Specific examples of α,ω-diols include 1,4-butanediol, 1 ,5-pentanediol, 1 ,6-hexanediol, 1,7-heptanediol and 1 ,8- octanediol. A particularly preferred alkanediol is 1 ,6-hexanediol.

The polymer of Formula (I) may be formed by a polymerization reaction wherein the core alkanediol comprising R^a serves as a site for initiation of ring- opening polymerization of the lactide and glycolide reagents. The molar percent, and thus the weight percentage, of the alkanediol that is present in the polymerization reaction has an influence on the molecular weight of the biodegradable polymer that is formed. Use of a higher percentage of the alkanediol in the polymerization reaction provides, on the average, a polymer of lower molecular weight that has relatively shorter PL or PLG copolymer segments linked to the alkanediol core.

A preferred embodiment according to the present invention is a method of preparation of a polymer of Formula (I), comprising contacting an alkanediol, glycolide, lactide, and a catalyst, the catalyst being adapted to catalyze the ring- opening polymerization of the lactide and the glycolide initiated on the alkanediol.

A polymer of the present invention comprising PLG copolymer segments is preferably prepared using a catalyst suitable for ring-opening polymerization of lactide and glycolide. The catalyzed ring opening reaction initially takes place between the lactide or glycolide reagent and a hydroxyl group of the alkanediol core unit such that the lactide or a glycolide unit forms an ester bond. Thus, after the first step of polymerization, only hydroxyl groups on the growing polymer chain continue to be available for further lactide or glycolide addition. As polymerization continues, each step continues to result in formation only of hydroxyl-terminated copolymer segments attached to the alkanediol. In this manner, polymerization takes place until the supply of lactide and glycolide reagents is exhausted, producing the hydroxyl group terminated polymer. It is understood that a polymer of the present invention comprising PL copolymer segments can be made in the same manner, only omitting the glycolide reagent. The alkanediol can be an α,ω-diol such as 1,6-hexanediol. The alkanediol may be present in the polymerization reaction mixture in amounts ranging from about 0.05% to about 5.0%, preferably from about 0.5% to about 2.0%. The catalyst may be any catalyst suitable for ring-opening polymerization, but a preferred catalyst is a tin salt of an organic acid. The tin salt may be either in the stannous (divalent) or stannic (tetravalent) form. A particularly preferred catalyst is stannous octanoate. The catalyst may be present in the polymerization reaction mixture in any suitable amount, typically ranging from about 0.01 to 1.0 percent.

The polymerization reaction may be carried out under a variety of conditions of temperature, time and solvent. Alternatively, solvent may be absent and the polymerization be carried out in a neat melt. The polymerization reaction wherein the reactants comprise an alkanediol (such as hexane-l ,6-diol), lactide, and glycolide in defined proportions by weight, and a catalyst such as stannous octanoate, is preferably carried out as a neat melt in the absence of oxygen at elevated temperature for a period of at least several hours. Preferably the reaction is carried out at about 140 ⁰C, either under vacuum or under an atmosphere of an inert gas such as nitrogen.

The weight percent, and thus mole percent, of lactide or glycolide repeating units in the polymer can be varied by altering the weight percentages of the two reactants present in the polymerization reaction mixture. The properties of the polymer can be changed by variations in the ratio of the lactide to the glycolide monomer components, and by the percent of the alkanediol initiator that is present.

Specifically, the molecular weight range of the polymer can be controlled by the amount of core alkanediol present in the polymerization reaction. The greater the weight percentage, and thus the greater the mole fraction of the alkanediol in the polymerization reaction mixture, the shorter are the chain lengths of the polymers attached to the alkanediol core due to the decreased availability of lactide or glycolide reagent molecules per initiating hydroxyl group.

The ratio of lactide to glycolide in the PLG copolymer segment is within a range of about 45/55 to about 99/1. Preferably, the ratio is within a range of about 70/30 to about 90/10. In a specific example, the ratio is about 75/25. In another specific example the ratio is 85/15.

The weight average molecular weight of the polymer can be about 19 to about 30 kD and the polydispersity index about 1.4 to about 1.8. In a specific example, the weight average molecular weight is about 21 kD and the polydispersity index is about 1.5. The inherent viscosity of the polymer determined in chloroform can be about 0.23 to 0.31 dL/gm. In a specific example the inherent viscosity is 0.25 dL/gm. In another specific example the inherent viscosity is 0.27 dL/gm. In a method of manufacture according to the present invention, these variables may be controlled by a person of skill in the art through controlling the relative starting weights of the lactide and the glycolide in the polymerization reactor, the relative amount of the alkanediol initiator, and the identify and relative quantity of the catalyst used, among other factors. Another method for preparing a polymer of the invention comprising

PLGA copolymer segments comprises contacting an alkanediol, glycolic acid, lactic acid, and a catalyst, the catalyst being adapted to catalyze condensation of the lactate and the glycolate with the alkanediol. Again, the alkanediol can be a linear α,ω-diol. A specific example is hexane-l,6-diol. A typical catalyst for the condensation of lactate and glycolate units is an ion exchange resin, a metal oxide such as zinc oxide or antimony oxide, or the reaction is self-catalyzed by lactic acid and/or glycolic acid.

Yet another method for preparing a polymer of the invention comprising PLA copolymer segments comprises contacting an alkanediol, lactic acid, and a catalyst, the catalyst being adapted to catalyze condensation of the lactic acid with the alkanediol. Again, the alkanediol can be a linear α,ω-diol. A specific example is hexane-l,6-diol. A typical catalyst for the polymerization of lactic acid is an ion exchange resin, a metal oxide such as zinc oxide or antimony oxide, or the reaction is self-catalyzed by lactic acid. A polymer of the present invention is substantially insoluble in water and body fluid, biocompatible, and biodegradable and/or bioerodible within the body of an animal. A flowable composition comprising a polymer of the invention, a medicament, and an organic solvent, is administered as a liquid or flowable gel to tissue wherein the controlled release implant is formed in situ. The composition is biocompatible and the polymer matrix does not cause substantial tissue irritation or necrosis at the implant site. The implanted composition can be used to deliver octreotide over a period of time, as is useful for treatment of macular degeneration, among other malconditions.

A flowable composition is provided in which a polymer of the invention and a medicament, preferably octreotide, are dissolved in a biocompatible polar aprotic solvent to form the composition, which can then be administered via a syringe and needle. After administration, the flowable composition coagulates in contact with body fluid to produce a controlled release formulation of the medicament. The properties of the controlled release formulation will typically depend upon the molecular weight and amount of biodegradable thermoplastic polyester present. For example, the molecular weight of the polymer and the amount present in the composition can influence the length of time over which the octreotide is released into the surrounding tissue. The polymer can be present in about 40 wt. % to about 50 wt. % of the composition; and can have an average molecular weight of about 15,000 to about 30,000, as is disclosed in U.S. Pat. No. 6,773,714. The octreotide can be present in various quantities, but preferably is present in the range of about 3% to about 15% by weight. Use of a polymer of the present invention in a controlled release formulation has surprisingly been found to provide for a relatively long duration of release of the medicament from the formulation. Specifically, in preferred embodiments of the present invention, the composition can be used to formulate a three month, a four month, or a six month controlled release delivery system for octreotide for use in a human patient. A general method for the preparation of polymers with an alkanediol core is as follows. In a jacketed stainless steel polymerization vessel, appropriate amounts of lactide and glycolide are added and the vessel contents are placed under a nitrogen atmosphere. The temperature of the vessel is increased until the reagents melt. An appropriate amount of an alkanediol is then added, followed by addition of stannous octanoate catalyst. The vessel is then heated at about

135-145 ⁰C under nitrogen atmosphere for about 3-4 hours with constant stirring. Then, to remove unreacted lactide and glycolide monomers, the vessel is evacuated and the monomers are vacuum distilled out of the polymerization mixture. The hot melt is then extruded into cooling pans. After cooling, the solid mass is cryo-ground to a fine powder and dried. Polymer compositions and methods of using this type of polymer are described in U.S. Serial No. 1 1/469,392, which is incorporated herein by reference in its entirety.

Sustained Release Embodiments with Purified Polymer Formulations The copolymers of the present invention when used in, for example, the controlled delivery systems known as liquid delivery systems, otherwise known as flowable delivery systems, like the Atrigel^® systems that are disclosed in U.S. Patent Numbers 6,565,874, 6,528,080, 6,461,631 , 6,395,293, and references found therein, provide for substantially improved release rates for a bioactive agent, both a reduced initial burst and a desirable long-term sustained rate of release.

Unexpectedly, it has been discovered that use of these copolymer materials in the flowable delivery system effectively reduces the initial burst effect in the release of bioactive agents from the controlled release formulation after its implantation within living tissue, without loss of desirable long-term sustained rates of release of bioactive agents, particularly for those systems adapted to release a bioactive agent over a relatively prolonged period, such as 30 days to 6 months. The present invention provides a biocompatible, biodegradable PLG low- burst copolymer material adapted for use in a controlled release formulation, the low-burst copolymer material being characterized by a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4-2.0, and being further characterized by having separated therefrom a copolymer fraction characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5 (hereinafter the "removed copolymer fraction"). The inventive PLG low-burst copolymer material is prepared from a starting PLG copolymer material without a step of hydrolysis of a higher molecular weight PLG copolymer material, by dissolving the starting copolymer material, which is not a product of hydrolysis of a higher molecular weight PLG copolymer material, in a solvent, then precipitating the inventive low-burst copolymer material with a non-solvent. This process, as applied to a starting material that has never been subjected to hydrolysis, separates out an amount of the removed copolymer fraction effective to confer desirable controlled release properties including low initial burst upon the copolymer of the invention.

The starting PLG copolymer material can be prepared by any suitable means, including ring-opening polymerization of cyclic dimeric esters lactide and glycolide and condensation of lactic and glycolic acids. Preferably, the ring- opening polymerization of lactide and glycolide is used to prepare the starting copolymer from which the low-burst PLG copolymer of the invention is prepared. The ring-opening polymerization reaction, which can be a catalyzed reaction, for example using a tin salt such as stannous octanoate as a catalyst, incorporates two lactate or two glycolate units at a time as the polymerization progresses.

It is well known that a weight average molecular weight of a polymer material or fraction of a polymer material describes an average property derived from the individual molecular weights of all the individual polymer molecules making up the material or fraction. For any given weight average molecular weight that a polymer material or fraction may have there are many possible distributions of individual molecular weights of the molecules making up the material or fraction. Thus, in the present invention, the removed copolymer fraction having a weight average molecular weight of about 4 kDa to 10 kDa can include copolymer molecules with individual molecular weights ranging from a few hundred (oligomers) up to well in excess of 10 kDa. There are many different combinations of individual molecular weights that can yield any given value of the weight average molecular weight of a polymer sample. The breadth of the distribution of the individual molecular weights of the copolymer molecules making up the removed copolymer fraction of the invention is at least partially expressed by the polydispersity index, which can range from about 1.4 to about 2.5. Whatever the distribution of individual molecular weights may be in the removed copolymer fraction, the mass of the removed copolymer fraction amounts to about 2-20% of the sum of the masses of the removed copolymer fraction and the PLG low-burst copolymer material obtained thereby, more preferably about 3-15% of the sum of the masses, and yet more preferably about 5-10% of the sum of the masses. Typically, the greater the weight average molecular weight of the removed copolymer fraction within the defined range of about 4 kDa to 10 kDa, the greater is the weight average molecular weight of the inventive PLG low-burst copolymer material within the range of about 10 kDa to about 50 kDa.

The present invention provides a PLG low-burst copolymer material composed of a set of individual PLG copolymer molecular chains. A predominant proportion of these molecular chains predominantly include lactide/lactate residues adjacent to at least one end of each copolymer molecular chain and predominantly include glycolide/glycolate resides in internal domains of each copolymer molecular chain. It is believed that this distribution of lactide/lactate versus glycolide/glycolate units in the inventive copolymers may be responsible for their unexpected low burst and desirable sustained release properties.

The present invention further provides a method of preparation of a PLG low-burst copolymer material, wherein a removed copolymer material is separated from a starting PLG copolymer material by a step of dissolving the starting copolymer material in a solvent and precipitating the low-burst copolymer material by admixture of a non-solvent, without any step of hydrolysis of a higher molecular weight PLG copolymer being used in the process. The method of the present invention requires avoidance of a step of hydrolysis of a higher molecular weight copolymer material in order to provide a low-burst copolymer material of the invention. The inventive low-burst copolymer material exhibits surprisingly low initial burst properties as well as a surprisingly high sustained release effect. It is believed that this unexpectedly favorable low-burst property arises from the differing distributions of the more lipophilic lactate/lactide units adjacent to at least one end of the polymer chains in the present inventive polymer versus a polymer prepared with a step of hydrolysis. Copolymers prepared by a method including a step of hydrolysis can have a greater predominance of polymer chains that have the less lipophilic glycolate or glycolide units adjacent to both the molecular chain ends due to the hydrolysis of ester bonds in glycolate/glycolide rich internal domains. In a low-burst PLG copolymer material prepared from a starting PLG copolymer that was made without using a core initiator, i.e., a PLG copolymer having a carboxyl group at one end of each chain and a hydroxyl group at the other end, the acid content per gram is lower in an inventive polymer than in a PLG copolymer prepared by a method including a step of hydrolysis of a higher molecular weight polymer, but the low-burst property of the inventive polymer is surprisingly at least as good as or better than that of the polymer prepared with a step of hydrolysis.

The relatively low acid content of the low-burst copolymers of the invention can be advantageous because the inventive copolymer material suffers from less acid-catalyzed auto-hydrolysis over time. If the starting PLG copolymer material comprises a PLGH, or acid terminated copolymer, the inventive process decreases the acid content per unit mass by removal of oligomers. The implication of a lower auto-hydrolysis rate of the polymer is that, for example, when implanted in the tissue of a patient, this lessening of auto-hydrolysis of the inventive copolymer enables a smooth monotonic, long lasting release profile of the bioactive agent contained in a controlled release formulation, the copolymer also possessing a low initial burst.

The preparation of an inventive low-burst copolymer material can be carried out "without a step of hydrolysis of a higher molecular weight PLG copolymer material." By this is meant that, following the initial copolymerization of the monomers lactate and glycolate, or lactide and glycolide, to prepare a starting material for preparation of the inventive low- burst copolymer material, no conditions are applied, such as treatment with acid or alkali, that would hydrolyze ester bonds between adjacent monomeric units in the polymer. Therefore, a "higher molecular weight PLG copolymer material" as the term is used herein refers to a PLG copolymer material of a weight- average molecular weight that is greater than the weight average molecular weight possessed by a combination of the PLG low-burst copolymer material of the invention plus the removed copolymer fraction, such as exists in the starting PLG copolymer material prior to the step of separation of the removed copolymer fraction from the PLG low-burst copolymer material. This kind of hydrolysis does not refer to complete hydrolysis of a PLG copolymer back to its constituent monomers (lactate and glycolate), but rather to a step of partial hydrolysis whereby longer molecular chains are cleaved to yield shorter molecular chains, as is the case with certain art polymers adapted for use in controlled release formulations. Therefore, following the polymerization reaction, of whatever type it may be, that provides the starting PLG copolymer material, no step of hydrolysis is interposed prior to the separation of the removed copolymer fraction from the PLG low-burst copolymer material in the method of the invention, and the product of the invention has therefore not been subjected to a hydrolysis step. As discussed below, this absence of hydrolysis has implications for the distributions of lactide/lactate versus glycolide/glycolate units at the end domains of and in the internal domains of the molecular chains making up the inventive PLG low-burst copolymer material. As discussed above, PLG copolymer chains are enriched in G residues near the site of initiation of the polymerization reaction, and enriched in L residues in the regions incorporated late in the polymerization reaction. This implies that in PLG copolymer materials synthesized using, for example, a diol core from which polymerization proceeds in both directions, the internal domains of the polymer molecule near the core will be G-rich and both ends will be L-rich. In contrast, a PLG copolymer material of the PLGH type, which is polymerized from a lactic acid initiator, wherein polymerization takes place only at the hydroxyl end of the lactic acid, will be G-rich at the end of the molecular chain adjacent to the initiating lactic acid and L-rich at the distal end of the chain that is formed late in the polymerization reaction.

The term "acid content per unit mass" when used herein refers to the content of carboxylic acids, which are titratable using standard procedures well known in the art, divided by a unit mass such as 1 gram. PLG copolymers, being chains of hydroxyacids joined by ester bonds, typically have a single titratable carboxylic acid group at one end of the molecular chain. Thus, a sample of a copolymer made up of short molecular chains has a higher acid content per unit mass relative to a sample of a copolymer made up, on average, of longer (higher molecular weight) molecular chains. The sample made up of shorter, lower molecular weight chains has relatively more individual polymer chains and thus relatively more carboxylic acid groups per gram.

The low-burst copolymer materials of the present invention are particularly useful in reducing the initial burst effect in controlled release formulations such as those of the Atrigel type. The inventive copolymer material ("low-burst copolymer material") is characterized as being a derived from a sample of a PLG starting copolymer ("starting copolymer material"). The low-burst copolymer material is prepared without the use of a step of hydrolysis of a high molecular weight PLG copolymer. The inventive low-burst copolymer material is characterized by a weight average molecular weight of about 10 kilodaltons (kDa) to about 50 kDa and a polydispersity index of about 1.4-2.0. The low-burst copolymer material is obtained from a starting PLG copolymer material that is prepared by any suitable polymerization method but not including a step of hydrolysis in its preparation, from which a copolymer fraction ("removed copolymer fraction") that is characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5, has been removed.

The inventive copolymer material from which the removed copolymer fraction has been separated is prepared by purification from a PLG starting copolymer material. The PLG starting copolymer material is not a reaction product resulting from hydrolysis of a high molecular weight polymer, but otherwise can be made according to any of the standard methods well-known in the art, such as condensation polymerization of a mixture of lactate and glycolate, or ring-opening polymerization of a mixture of lactide and glycolide. Preferably, the ring-opening polymerization of lactide and glycolide is used to prepare the starting copolymer from which the low-burst PLG copolymer of the invention is prepared. The ring-opening polymerization reaction, which can be a catalyzed reaction, for example using a tin salt such as stannous octanoate as a catalyst, incorporates two lactate or two glycolate units at a time as the polymerization progresses

In the inventive process, the removed copolymer fraction is separated from the starting copolymer material by dissolving the starting copolymer material in a solvent, then by adding a non-solvent to precipitate the low-burst polymer, and then collecting the inventive low-burst copolymer material, leaving the removed copolymer fraction in the supernatant.

The separation of the removed copolymer fraction that is characterized by a weight average molecular weight of about 4 kD to about 10 kD and a polydispersity index of about 1.4 to 2.5, to yield the low-burst copolymer material may be accomplished by methods according to the present invention. The separation is carried out by dissolution of the starting copolymer material in a solvent and precipitation of the low-burst copolymer material by mixture of this solution with a non-solvent. The solvent and non-solvent can be miscible. Specifically, the polymer can be dissolved in dichloromethane and precipitated with methanol. In one embodiment according to the present invention, the low-burst copolymer material can have a weight average molecular weight of about 15 kDa to about 50 kDa, and a polydispersity index of about 1.4-1.8. Compared to the starting copolymer material from which the removed copolymer material has been separated, not only are the weight-average and the number-average molecular weights of the low-burst copolymer material somewhat greater, but even more significantly, the width of the spread of the individual molecular weights of the copolymer molecules is less, i.e., the molecular weight distribution is narrower. This narrowness is reflected in the relatively low polydispersity index of the low-burst copolymer according to the present invention.

When an inventive low-burst copolymer material was formulated as part of a controlled release system, such as the Atrigel " system, it was surprisingly found that a reduction of the initial burst effect in the release of a variety of peptide or protein bioactive agents was observed. This reduction was demonstrated by measurement of the amount of bioactive agent released from the controlled release system as a function of time.

The low-burst copolymer material of the present invention, which is adapted to be used in the Atrigel^® system, inter alia, was compared to the same formulation containing a polymer that was not purified by the inventive method. The formulation containing the low-burst copolymer material of the invention displayed a lower drug release in the first 24 hours and later time points. Thus, use of the low-burst copolymer in the Atrigel^® system demonstrates a simple, effective process to improve in vivo drug release kinetics, especially with respect to drug release during the first 24 hours after administration.

The starting copolymer material can be prepared by any means known in the art, such as: polymerization of a mixture of the cyclic dimer esters, lactide and glycolide, for example with a catalyst such as stannous octanoate, with or without a core/initiator such as lactic acid or a diol; polymerization of a mixture of lactic acid and glycolic acid, for example with an acid catalyst, under dehydrating conditions; or any other suitable method. The starting copolymer material is not subjected to a step of hydrolysis prior to the steps of separation. This non-hydrolysis factor is believed to be significant in providing the unexpected low-burst properties of the inventive copolymer materials. It is well known in the art that in the polymerization of lactide and glycolide in the presence of a catalyst, a suitable means for preparing the starting copolymer material of the invention, the glycolide molecules react in the ring- opening polymerization reaction at a higher rate than do the lactide molecules, due to the lesser steric hindrance of glycolide relative to lactide (lactic acid bearing a methyl group in place of a hydrogen atom of glycolic acid). This results in the early-polymerizing regions of the growing copolymer chain predominantly deriving from glycolide incorporation. As the glycolide concentration in the reaction mixture drops during the course of the polymerization process due to this selective depletion of monomer, the late- polymerizing regions of the copolymer chain predominantly are derived from lactide incorporation. Thus, as polymerization occurs in both directions, the internal regions or internal domains of the molecular chains are composed predominantly of glycolide residues, and the ends of the chains are composed predominantly of lactide residues.

By "predominantly" is meant herein that the one component, lactide or glycolide, is found more frequently than the other component; i.e., a predominantly glycolide-incorporating or glycolide-containing domain or region of a copolymer chain has more glycolide residues than lactide residues in the domain on a molar basis as defined relative to the molar concentrations of the monomers in the starting reaction mixture; or, in other words, glycolide is over- represented in that region or domain of the polymer relative to its initial proportion in the polymerization reaction mixture. In a predominantly glycolide- or glycolate-containing domain, glycolide/glycolate residues are found at a higher molar percentage in that domain than they represent in the starting reaction mixture, and lactide/lactate residues are found at a lower molar percentage in the domain than they represent in the starting reaction mixture. The difference in distribution of lactide/lactate vs. glycolide/glycolate moieties along the polymer chain will vary from slight to significant depending upon the reaction time allowed for post polymerization rearrangement. This post-polymerization period is balanced against increasing weight average molecular weight of the copolymer material. Accordingly, within the weight average molecular weight parameters of this invention, the difference in distribution will be moderate to significant, preferably in the range of 5 to 35%, more preferably 10-25%, on a molar basis.

Thus, the molecular chains making up a low-burst copolymer material of the invention, as a result of the method of preparation either from lactate/glycolate or from lactide/glycolide without a step of hydrolysis following polymerization, are believed to have predominantly lactide/lactate residues in the end domains of the molecular chains and glycolide/glycolate residues in the internal domains of the molecular chains. It is well-known in the art that lactide/lactate residues have a higher degree of hydrophobicity than do glycolide/glycolate residues, as a result of the presence in lactide/lactate residues of a hydrophobic methyl group. Based on this fact, it is believed that a low-burst copolymer material of the invention can present a more hydrophobic domain to its surroundings, as the ends of the chains are likely more accessible to other molecules in the surrounding environment. This enhanced hydrophobicity of the chain end domains may be a cause of the unexpected low-burst properties of the inventive copolymers. While not wishing to be bound by theory, it is believed that this degree of hydrophobicity may cause, at least in part, the unexpected but desirable low-burst properties of an inventive polymer relative to art polymers due to its hydrophobic interactions with the contained bioactive agent and resulting changes in the partition coefficients of the bioactive agent between the copolymer matrix and the surrounding solutions of body fluids when implanted in a patient.

An art copolymer, such as can be prepared by hydrolysis of a high molecular weight precursor copolymer, is believed to differ from an inventive polymer in that the molecular chains making up the art copolymer material do not have predominantly lactide/lactate containing domains at both ends of the molecular chains. This difference is the result of hydrolysis of a high molecular weight precursor. Upon hydrolysis of a high molecular weight precursor polymer, the resulting cleavage causes one end (the newly formed end) to contain predominantly glycolide/glycolate residues rather than lactide/lactate residues. This effect occurs to a great extent within the interior domain on a purely statistical basis, and is further enhanced by the well-known fact of the reduction of the rate of ester hydrolysis reactions due to steric hinderance. Thus, less hindered ester bonds (such as glycolate bonds as opposed to lactate bonds) are expected to hydrolyze at a higher rate under given conditions than are more hindered ester bonds.

As a result, hydrolysis of the ester bond between adjacent glycolate residues (G-G) is believed to take place more readily, at a higher rate, than hydrolysis of the ester bond between a lactate and a glycolate residue (L-G or G- L) which is likewise believed to take place more readily, at a higher rate, than hydrolysis of the ester bond between to lactate residues (L-L). As a consequence, in a copolymer chain that consists of all three types (G-G, G-L/L- G, and L-L) of ester bonds, an ester bond would be more frequently cleaved at the G-G ester linkages than at any of the other types of ester linkages, with L-L ester linkages occurring least often at the lowest relative rate. Thus, a G-G rich domain such as the internal domain of the copolymer will more frequently be the site of hydrolysis than any other domain. Therefore, a copolymer molecular chain that has undergone hydrolysis will yield, as a reaction product copolymer, molecular chains that will tend to have at least one end of the product chain or possibly both ends of a product chain formed predominantly of glycolide/glycolate residues, rather than being formed predominantly of lactide/lactate residues as in the inventive copolymers.

As a result, copolymer materials that have been prepared by a method including a step of hydrolysis of a high molecular weight copolymer chain will be made up of copolymer molecular chains that have more ends formed predominantly of glycolide/glycolate residues than of lactide/lactate residues. This would be expected to result in a less hydrophobic environment that the end regions of these copolymer molecular chains present to the surrounding environment, and may account for the less desirable high initial burst properties of art copolymers prepared by the hydrolysis method compared to the more desirable low initial burst properties of inventive copolymers as disclosed and claimed herein.

As a consequence of the above-discussed rate of incorporation and rate of hydrolysis factors, the removed copolymer material of the present invention is also different than copolymer fractions that may be removed in art processes using solvent/non-solvent precipitation techniques. The art copolymer for use in controlled-release formulations that has been prepared by a method including hydrolysis of a high molecular weight copolymer, following by dissolution in a solvent and precipitation of a fraction of the hydrolyzed copolymer with a non- solvent, will not only have different distributions of lactide/lactate (L) and glycolide/glycolate (G) in the precipitated fraction, but the art non-precipitated material will also have different distributions of L and G along the molecular chains compared to the non-precipitated fraction of the present invention. The non-precipitated, typically lower molecular weight, copolymers resulting from a process involving hydrolysis would likewise be expected to have a higher proportion of G residues at or near the chain termini than copolymers that had not undergone a hydrolysis step. Furthermore, due to the unexpectedly good low-burst properties of the inventive polymers, the acid content of a copolymer used in a controlled release formulation such as an Atrigel^® system can be reduced yet still achieving a comparable decrease in the undesired burst effect. It is well known in the art that a higher acid content per unit mass can diminish the undesired burst effect, and art copolymers used in this application have been tailored to achieve this result. However, from another perspective a relatively higher acid content per unit mass is undesirable, in that the rate of auto-catalyzed hydrolysis of the PLG copolymer ester bonds would be greater due to the higher acid catalyst concentration in situ. Auto-hydrolysis of copolymer ester bonds is known to result in more rapid decomposition of the polymer, which would tend to interfere with achieving a desirable smooth, monotonic release of the bioactive ingredient formulated with the copolymer in a controlled release preparation such as Atrigel^®.

Therefore, the inventive products by process can be clearly distinguished structurally over the products produced by a step of hydrolysis of high molecular weight copolymers.

The starting copolymer of the present invention can be prepared by any available method, not including a step of hydrolysis of a high molecular weight copolymer, but including ring-opening polymerization of mixtures of lactide and glycolide precursors, dehydrative polymerization of lactic acid and glycolic acid, and the like. Purification of the starting copolymer by a method of the invention is carried out by dissolving the starting copolymer material in a solvent, for example, dichloromethane or any other suitable organic liquid. Precipitation is carried out by contacting that solution with a non-solvent, for example either by adding the copolymer solution to a volume of a non-solvent, or by adding a volume of a non-solvent to the copolymer solution. An example of a typical non-solvent is methanol. Preferably, the solvent and the non-solvent liquids are miscible, or at least substantially soluble, in each other. The mixing of the copolymer solution and the non-solvent can take place under a wide variety of temperatures, concentrations, and modes of mixing.

A copolymer of the invention can be used to advantage in a number of differing types of controlled release formulations, each of which can embody a variety of different bioactive agents and used for the treatment of different malconditions. The low-burst property of the inventive polymers are particularly well-suited to use with bioactive agents wherein overdose and potential toxicity of the agent are of medical concern, as well as with bioactive agents with which it is medically indicated to maintain a relatively constant dosage over a prolonged period of time. Examples of bioactive agents that can advantageously be used with controlled release formulations incorporating a copolymer of the invention include octreotide, its isomers, and its derivatives. The inventive copolymers can be used in differing types of controlled release formulations. A flowable delivery system such as in an Atrigel^® system, comprising an inventive copolymer, a water-soluble organic solvent such as N-methylpyrrolidone, N₅N- dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, polyethylene glycol 200, polyethylene glycol 300, or methoxypolyethylene glycol 350, and a bioactive agent such as octreotide, can be advantageously used in a patient to avoid or minimize the initial burst effect while providing for a prolonged period of sustained release of the bioactive agent. Likewise, both monolithic and microparticulate solid implants incorporating a bioactive agent that are preformed from an inventive copolymer offer similar benefits of low initial burst and prolonged sustained release of the bioactive agent. Other embodiments of sustained release systems and compositions will be apparent to those of skill in the art.

A flowable delivery system such as an Atrigel^® system comprising an inventive PLG low-burst copolymer material can be used in the treatment of a variety of malconditions. The invention provides a method for the treatment of a malcondition using such a flowable delivery system. Implantation of a flowable composition subcutaneously results in the formation of a semi-solid depot as the organic solvent diffused into surrounding tissues and body fluid, as body fluid diffuses into the bolus. This semi-solid or solid depot then serves to release the octreotide in a controlled or sustained manner over a prolonged period of time, which can be in the order of months. Use of the inventive copolymer materials is effective in reducing the undesirable initial burst effect that can result from the use of art copolymers in a similar system.

Bioactive agents can be used in the treatment of various types of malconditions when it is medically indicated to provide the bioactive agent to the patient over the course of weeks or months. For example, a flowable delivery system incorporating octreotide can be used to form a depot for the treatment of acromegaly, the treatment of diarrhea and flushing episodes associated with carcinoid syndrome, and treatment of diarrhea in patients with vasoactive intestinal peptide-secreting tumors. In the treatment of the malcondition of glaucoma, a flowable delivery system of the Atrigel" type incorporating an inventive PLG copolymer and comprising a bioactive agent suitable for the treatment of glaucoma, for - example, octreotide, can be advantageously used to deliver the bioactive agent over a prolonged period while avoiding the initial burst effect. The flowable delivery system to be used to form a depot either intraocularly, through direct injection into the eyeball, or in proximity to the eye through implantation in a nearby tissue. Other conditions and appropriate medicaments for treatment will be apparent to those of skill in the art.

Polymer compositions and methods of using polymer compositions that can be used with the compositions and methods described herein are also described in U.S. Application Serial Nos. 1 1/667,433 and 1 1/793,296, and PCT Application Serial No. PCT/US2008/001887, which are incorporated herein by reference in their entireties.

The following Examples are intended to illustrate the above invention and should not be construed as to narrow its scope. One skilled in the art will readily recognize that the Examples suggest many other ways in which the present invention could be practiced. It should be understood that many variations and modifications may be made while remaining within the scope of the invention.

EXAMPLES Example 1. Octreotide 3-month Depots (90 mg, 60 mg, and 45 mg)

Formulation Development for these examples of drug product formulations began with implant retrieval studies in rats to determine the effect of various formulation variables on the release of octreotide from the implants.

Pharmacokinetic studies were then done in rats and then rabbits with certain specific formulations. The final rabbit studies also included determination of pharmacodynamics, specifically suppression of insulin-like growth factor- 1

(IGF-I) levels.

. Once the formulation components and the quantitative composition had been identified, experiments were then done using the syringes and needles selected for clinical use to determine the proper fill weights in the two syringes and the proper number of syringe-to-syringe mixing cycles to consistently deliver the desired dosage of octreotide.

Throughout the formulation development process, a two syringe product configuration was used. This was done to avoid any potential problems that could be associated with lack of long term stability of octreotide and polymer when stored in a single syringe with NMP. This is the same type of two syringe system as used in the commercial ELIGARD^® products (ELIGARD^® 7.5 mg;

ELIGARD^® 22.5 mg; ELIGARD^®30 mg; and ELIGARD^®45 mg products) as well as others, such as the one month ATRIGEL^® /Octreotide formulation.

Part I:

ATRIGEL^®/Octreotide 90 mg 3-month Depot (Formulation AL3937.01) Studies

Several nonclinical studies were performed in rats and rabbits to develop a formulation with the desired 90 day release profile. Important formulation attributes that were found to affect release rate were polymer molecular weight, polymer lactide to glycolide ratio, and polymer concentration in the delivery system. These were tightly controlled through the polymer specifications and the delivery system preparation process. Early investigations conducted in rats focused on release rates of octreotide from ATRIGEL^®/Octreotide formulations. These investigations were performed using what was termed octreotide drug powder (ODP). ODP is the product of the lyophilization of an aqueous octreotide acetate and citric acid solution. In the development of an ATRIGEL^®/Octreotide 20 mg 1 -month Depot formulation, it was found that the addition of citric acid to the formulation was helpful to limiting the initial release of octreotide. ODP was made by combining octreotide acetate and citric acid in a 1 : 1 molar ratio in water and lyophilizing this mixture. This powder was then hand filled in syringes for combination with various ATRIGEL^® Delivery Systems that had been irradiated in the 18-28 kiloGray range, which is typical for terminal sterilization of ATRIGEL^® delivery systems.

Implant retrieval methodology was used to generate release profiles by determining the octreotide remaining in the solidified depot at selected time points. From the results of these studies, formulations containing 12% and 15% octreotide drug powder (ODP) loading and 85/15 PLGH polymers were moved forward into 3 -month release and pharmacokinetic (PK) studies in rats.

In one of these implant retrieval studies in rats, ATRS-897, the Group II formulation consisting of 12% ODP in a delivery system with a 50% w/w 85/15 polymer PLGH and 50% w/w NMP showed a desirable release profile (Figure 1). Note that the error bars are equal to one standard deviation in all graphs in this example.

Another study, ATRS-932, was conducted in rats to identify the optimal drug loading for the 50% 85/15 PLGH, 50% NMP delivery system. Formulations were prepared with ODP loading in the range of 12-15%. Rats in this study were injected with approximately 100 mg of formulation, and PK data from this study, shown in Figure 2, indicated that the 12% ODP formulation had a comparable plasma level of octreotide to the groups with a higher dose. This formulation had the highest weight percent of delivery system, which was likely the source of the comparable PK profile, despite having the lowest octreotide amount.

The ATRIGEL^®/Octreotide 90 mg 3 -month Depot formulation candidate was also assessed in a rabbit model. In ATRS-981, rabbits received a 90 mg dose of octreotide from a 12% ODP in 50% w/w 85/15 PLGH, 50% NMP delivery system. Proof of concept was achieved by analyzing octreotide plasma levels and insulin-like growth factor 1 (IGF-I) levels in a 100 day study. As shown in Figure 3, pharmacokinetic analysis demonstrated detectable levels of octreotide in the plasma for 90 days, complemented by suppressed IGF-I levels over the same timeframe. This formulation was chosen as the

ATRIGEL^®/Octreotide 90 mg (Formulation AL3937.01) product to be tested in the clinic.

Formulation Delivery Techniques Syringe A contained the delivery system consisting of the solution 50%

(w/w) 85/15 PLGH and 50% (w/w) NMP. Throughout formulation development the delivery system was gamma irradiated at dosages in the 18-28 kGy range, which is typical for terminal sterilization of ATRI GEL^® Delivery System syringes. This ensures that any polymer molecular weight degradation due to the irradiation process is comparable to what will be seen when the clinical product is sterilized by gamma irradiation in this range.

Syringe B contained the solid cake that results from lyophilization of an aqueous solution of octreotide acetate and citric acid. This syringe was filled with the solution, lyophilized and stoppered under aseptic conditions for clinical lots.

Part II:

ATRIGEL^®/Octreotide 60 mg 3-month Depot (Formulation AL3937.02) Studies The investigation of various ATRIGEL^®/Octreotide 60 mg 3-month

Depots included ATRS- 1041 , a pharmacokinetic study in rabbits. Two variations of the 90 mg formulation (Formulation AL3937.01) were tested over 96 days. Three monthly injections of Sandostatin LAR were given to one group to act as a comparator. One group of rabbits received Formulation AL3937.01 , but with a lower injection volume (60 mg octreotide administered). A second group received the same composition and amount of delivery system as in the previous group, but a lower drug loading (8% ODP) in Syringe B was used. The pharmacokinetic results are shown in Figure 4. Implant retrieval studies were then done in rats to assess the effect of increasing the lactide to glycolide ratio in the polymer and increasing the polymer molecular weight while maintaining the drug loading at the level used for ATRIGEL^®/Octreotide 90 mg 3-month Depot (AL3937.01). Both of these changes were expected to slow polymer degradation, and presumably drug release rate, particularly at later time points as polymer degradation becomes a more important factor in drug release.

This expected effect is shown by the results illustrated in Figure 5. At the final time points, Days 84 and 91, the cumulative release is significantly different for the four groups despite the very comparable cumulative release at day 42 for the same groups. At Day 91, the test articles in Group 1 (Formulation AL3937.01, 85/15 PLGH polymer with a post irradiation molecular weight of 22 kDa) had a considerably higher percent release than Group 2, which contained a higher molecular weight polymer of the same composition. Even lower release is seen with the Group 3 formulation (90/10 PLGH with a post irradiation molecular weight of 22 kDa). Still lower release through Day 91 is seen with the 95/05 PLGH, accordingly the 90/10 PLGH formulation provides an advantageous release rate for octreotide delivery.

QRS-L093-05 was a pharmacokinetics and pharmacodynamics study in rabbits that evaluated three potential ATRIGEL^®/Octreotide 60 mg formulations (60 mg octreotide dose) with ATRIGEL^®/Octreotide 90 mg 3 -month Depot (AL3937.01, 90 mg octreotide dose) and an ATRIGEL^® Delivery System only injection as controls. Pharmacokinetic and pharmacodynamic (serum IGF-I) analyses were done. Figure 6 shows the plasma octreotide graph for this study. Figure 7 shows the serum IGF-I levels of QRS-L093-05 rabbits from 7 days prior to injection through 90 days post dosing. This shows that the 60 mg formulation with the 90/10 PLGH (Group IV) was effective in suppressing IGF- 1 through day 90. This formulation was chosen for ATRIGEL^®/Octreotide 60 mg 3-month Depot and was designated Formulation AL3937.02.

Part III:

ATRIGEL^®/Octreotide 45 mg 3-month Depot (Formulation AL3937.02) Studies One study was performed to select a 45 mg formulation: a rabbit pharmacokinetic and pharmacodynamic study, QRS Ll 73-06.

Figures 8, 9 and 10 give the mean octreotide plasma levels for three 45 mg formulations tested over the first 24 hours, the first 21 days and the entire study respectively. All the formulations have the same Syringe B composition as in the 60 mg and 90 mg drug product but a lower fill weight. The first formulation is AL3937.01 (using a 50% 85/15 PLGH and 50% NMP delivery system). The second formulation is AL3937.02 (using a 50% 90/10 PLGH and 50% NMP delivery system). The third formulation has a delivery system of 50% 95/5 PLGH and 50% NMP.

All three formulations tested at a 45 mg dose gave significant levels of octreotide in the plasma past 90 days. The AL3937.02 formulation with the 90/10 PLGH has the lowest octreotide level at one hour and the most consistent levels at later time points. Figure 1 1 shows the IGF-I data for the three 45 mg test articles. This shows that all three are comparably effective at lowering serum IGF-I levels. The AL3937.02 formulation appears to give somewhat lower and more consistent IGF-I levels.

Based on the lower 1 hour octreotide level and the consistent performance of the AL3937.02 formulation at the 45 mg octreotide dose, plus a desire for consistency with the 60 mg dose (which is also AL3937.02 ), the AL3937.032 formulation was chosen for the 45 mg octreotide drug product.

Example 2. Rate of Release of Octreotide in Rats from Atrigel depots containing PLG Oligomers

Two samples of PLG oligomers were prepared: 100 mole % lactide, and 65 mole % lactide / 35 mole % glycolide, both using a hexane-l ,6-diol core such that the product oligomers possessed terminal hydroxyl groups with substantially no free carboxylic acid groups. The 100 mole% polylactide had an average molecular weight of 7 kDa, and the 65/35 lactide-glycolide oligomer had an average molecular weight of 8 kDa. These oligomers were mixed in defined weight proportion (4.5 wt%) with PLGH copolymers, both unpurified and purified, with an added 15 wt% octreotide. Control formulations omitted the oligomers but added an addition 4.5 wt% of the copolymer to correct for solids content. Flowable compositions were made using 50 and 55 wt% N- methylpyrrolidone (NMP) solvent. Depots were then formed in the body tissues of the rats, and the cumulative quantities of risperidone released was determined at time points of 1, 7, 14, 28, 42, 60, 76 and 90 days. Results are shown in Figure 12.

Polymer Synthesis

All polymers used in the examples were prepared by bulk copolymerization of DL lactide and glycolide using tin(Il) 2-ethylhexanoate (stannous octoate) as the catalyst. PLG polymers were prepared using 1 ,6- hexanediol as the initiator and a reaction temperature of approximately 145 °C. The PLGH polymers were prepared using glycolic acid as the initiator and a reaction temperature of approximately 165 °C. The ratio of initiator to comonomers was varied to change the molecular weight of the polymer. The higher this ratio, the lower the molecular weight of the polymer. The reactions were run for approximately 2.5 hours. This was followed by an approximately 2 hour period at the same temperature of pulling a vacuum on the reaction mixture to remove unreacted monomer. The molten polymer was then removed from the reactor and allowed to cool in dry conditions.

Polymer Molecular Weight Analysis

The molecular weights described in this document are all weight average molecular weights obtained by gel permeation chromatography (GPC) using a Polymer Laboratories, PLgel MIXED-D, 5μm, 30cm x 7.5mm GPC column at 40 °C with tetrahydrofuran as the solvent. A volume of 50 μL of an approximately 0.5% (w/v) polymer in tetrahydrofuran was injected. The flow rate was 1 ml/min. Narrow molecular weight distribution polystyrene molecular weight standards were used to create a calibration curve.

The PLGH can be purified, and then the purified polymer and the oligomer can be dissolved in a solvent such as NMP to provide a delivery system.

Animal Study Procedure All rat preclinical studies were conducted in Sprague-Dawley rats. Five rats per Test Article per time point were injected subcutaneously under full anesthesia in the dorsal thoracic (DT) region with approximately 100 mg of the Test Article. Each injection weight was recorded. During the course of the study, the animals were observed for overt toxicity and any existing test site abnormalities, including redness, bleeding, swelling, discharge, bruising and Test Article extrusion at the injection site. In addition, injection weights were recorded at administration and body weights were taken and recorded at administration and at termination. At selected time points, five rats per Test Article were terminated with carbon dioxide and the implants were retrieved.

The present invention provides a copolymer adapted for use in a controlled release formulation for octreotide, such as a formulation adapted for implantation within a patient's body tissues as a depot to release the octreotide over a period of time, wherein the copolymer provides a substantially constant rate of release of the octreotide over the time period for which the depot persists in the body tissues. The copolymer can include a PLG copolymer and a relatively hydrophobic PLG oligomer of about 5-10 kDa average molecular weight and lacking free carboxylic acid groups.

Concentrations, amounts, percentages, time periods, etc., of various components or use or effects of various components of this invention, including but not limited to the flowable composition, implants, indications of reduction in malcondition symptoms, and treatment time periods, are often presented in a range or baseline threshold format throughout this patent document. The description in range or baseline threshold format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range or baseline threshold should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range or above that baseline threshold. For example, description of octreotide administration from about 80 to about 100 days should be considered to have specifically disclosed subranges, such as 82 to 95 days, 84 to 91 days, 85 to 90 days, etc., as well as individual numbers within that range, such as 81 days, 82 days, 83 days, 94 days, 98 days, etc. This construction applies regardless of the breadth of the range or baseline threshold and in all contexts throughout this disclosure.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

What is claimed is:

1. A controlled release formulation comprising:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, and wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups;

(c) octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the composition; wherein the composition is formulated to persist in a mammal for about 80 to about 100 days.

2. The formulation of claim 1 having a substantially linear cumulative release profile.

3. The formulation of claim 1 or 2 wherein the composition does not release degraded octreotide components.

4. The formulation of any one of claims 1 -3 wherein the PLG copolymer is a low burst PLG copolymer.

5. The formulation of any one of claims 1 -4 wherein the PLG copolymer is a PLG(p) copolymer.

6. The formulation of any one of claims 1 -3 wherein the PLG copolymer is a PLGH copolymer.

7. The formulation of claim 6 wherein the PLGH copolymer is a low burst PLGH.

8. The formulation of claim 6 wherein the PLGH copolymer is a PLGH(p) copolymer.

9. The formulation of any one of claims 1-8 wherein the formulation is a low burst formulation.

10. The formulation of any one of claims 1 -9 wherein the PLG oligomer comprises at least about 50 mole% lactide residues and has a weight average molecular weight of about 5-10 kDa.

1 1. The formulation of any one of claims 1-10 wherein the PLG oligomer has at least about a 65 mole% of lactide residues.

12. The formulation of any one of claims 1-1 1 wherein the oligomer comprises 100 mole% of lactide residues.

13. The formulation of any one of claims 1-12 wherein the PLG oligomer has a weight average molecular weight of about 7 to about 8 kDa.

14. The formulation of any one of claims 1-13 wherein the hydroxy carboxylic acid or acids are in the form of dimers, and wherein wherein the polyester is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, or any combination thereof.

15. The formulation of any one of claims 1-13 wherein the biodegradable thermoplastic polyester is a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL- lactide-co-glycolide) having a carboxy terminal group, or is a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) without a carboxy terminal group, and the polyester without a terminal carboxyl group is extended with a diol.

16. The formulation of any one of claims 1 -13 wherein the biodegradable thermoplastic polyester is present in about 30 wt.% to about 70 wt.% of the composition, and the biodegradable thermoplastic polyester has an average molecular weight of from about 15,000 to about 45,000 Daltons.

17. The formulation of any one of claims 1-13 wherein the biocompatible polar aprotic liquid is 7V-methyl-2-pyrrolidone.

18. The formulation of any one of claims 1-13 wherein the biocompatible polar aprotic liquid is present from about 30 wt.% to about 70 wt.% of the formulation.

19. The formulation of any one of claims 1-13 wherein the octreotide is present in about 5 wt.% to about 12 wt.% of the formulation.

20. The formulation of any one of claims 1-13 that is an injectable subcutaneous formulation and has a volume of about 0.20 mL to about 2 rnL.

21. The formulation of any one of claims 1-13 wherein the octreotide is in the form of a salt and the salt gegenion is derived from a pharmaceutically acceptable organic or inorganic acid.

22. The formulation of any one of claims 1-13 having the property of production of minimal tissue necrosis when injected subcutaneously.

23. A biodegradable implant formed in situ, in a patient, by the steps comprising:

(a) injecting a formulation of claim 1 into the body of the patient; and

(b) allowing the biocompatible polar aprotic liquid to dissipate to produce a solid or gel biodegradable implant; wherein the formulation comprises an effective amount of the biodegradable thermoplastic polymer; an effective amount of the biocompatible polar aprotic liquid; and an effective amount of octreotide, and wherein the solid implant releases an effective amount of octreotide over time as the solid implant biodegrades in the patient.

24. A method of forming a biodegradable implant in situ, in a living patient, comprising the steps of:

(a) injecting the formulation of claim 1 into the body of a patient; and

(b) allowing the biocompatible polar aprotic liquid to dissipate to produce the solid or gel biodegradable implant; wherein the solid biodegradable implant releases an effective amount of octreotide by diffusion, erosion, or a combination of diffusion and erosion as the implant biodegrades in the patient.

25. An implant comprising:

(a) a biocompatible thermoplastic polymer that is at least substantially insoluble in aqueous medium or body fluid, wherein the biodegradable thermoplastic polymer is a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein the polymer is a constant release copolymer comprising a mixture of a PLG copolymer and a hydrophobic PLG oligomer substantially lacking free carboxylic acid groups;

(b) a biocompatible organic liquid that is very slightly soluble to completely soluble in all proportions in body fluid and at least partially dissolves at least a portion of the thermoplastic polyester, and the amount of biocompatible organic liquid is less than about 5 wt.% of the total weight of the implant; and

(c) octreotide, or a salt thereof; wherein the implant has a solid or gel monolithic structure, and a microporous solid matrix or gelatinous matrix, the matrix being a core surrounded by a skin; and wherein the core contains pores of diameters from about 1 to about 1000 microns, and the skin contains pores of smaller diameters than those of the core pores.

26. A method for treatment of a patient having a malcondition associated with somatotropin hypersecretion, gastrointestinal syndrome, with an imbalance, hyper or hypo activity of an insulin, glucagon or somatotropin pathway, or with a somatotropin or somatostatin receptor function, comprising administering to the patient an effective amount of the formulation of claim 1.

27. A controlled release formulation comprising:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer comprises a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein at least one of the polymers is a polymer of formula I:

(I) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms;

R^b is hydrogen or methyl with the proviso that both R^b groups are identical;

R^c is hydrogen or methyl with the proviso that both R^c groups are identical; each L/G independently comprises a lactide/glycolide copolymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 200 kD;

(c) octreotide, wherein the octreotide is present in about 0.01 wt.% to about 15 wt.% of the formulation; wherein the formulation is formulated to persist in a mammal for about 80 to about 100 days.

28. A controlled release formulation comprising:

(H) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms;

R^b is hydrogen or methyl;

R^c is hydrogen or methyl; each Lt/Gt independently comprises a lactate/glycolate copolymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 50 kD;

29. A controlled release formulation comprising:

(a) a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluid, wherein the biodegradable thermoplastic polymer comprises a polyester of one or more hydroxy carboxylic acids, or is a polyester of a combination of one or more diols and one or more dicarboxylic acids, wherein at least one of the polymers is a polymer of formula III:

(III) wherein:

R^a is an alkane diradical comprising about 4 to about 8 carbon atoms;

R^b is methyl; each L comprises a polylactide or poly-lactate polymer segment; the polymer has substantially no titratable carboxylic acid groups, and the polymer has a weight average molecular weight of from about 6 kD to about 200 kD;

(b) a biocompatible polar aprotic organic liquid, wherein the biocompatible polar aprotic liquid comprises 2-pyrrolidone, 7V-methyl-2- pyrrolidone, ethyl acetate, dimethylacetamide, dimethylformamide, dimethylsulfoxide, propylene carbonate, caprolactam, triacetirr, a polyethyleneglycol or a combination thereof; and

30. The formulation of claim 27 wherein L/G comprises a lactide/glycolide copolymer segment with a lactide/glycolide ratio of about 45/55 to about 99/1.

31. The formulation of any of claims 27, 28, or 29 wherein the polymer has a weight average molecular weight of about 8 kD to about 100 kD.

32. The formulation of claim 31 wherein R^a is a linear unsubstituted carbon chain.

33. The formulation of claim 32 wherein R^a is a linear unsubstituted carbon chain of about 4 to about 8 carbon atoms.

34. The formulation of claim 33 wherein a polydispersity of the polymer is about 1.2 to about 2.0.

35. The formulation of claim 31 wherein an inherent viscosity of the polymer is about 0.20 dL/gm to about 0.60 dL/gm.

36. The formulation of any one of claims 27-35 wherein the biodegradable thermoplastic polyester is a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL- lactide-co-glycolide) having a carboxy terminal group, or is a 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) without a carboxy terminal group.

37. The formulation of any one of claims 27-35 wherein the biodegradable thermoplastic polyester is present in about 30 wt.% to about 70 wt.% of the composition, and the biodegradable thermoplastic polyester has an average molecular weight of from about 15,000 to about 45,000 Daltons.

38. The formulation of any one of claims 27-35 wherein the biocompatible polar aprotic liquid is N-methyl-2-pyrrolidone.

39. The formulation of any one of claims 27-35 wherein the biocompatible polar aprotic liquid is present about 30 wt.% to about 70 wt.% of the formulation.

40. The formulation of any one of claims 27-35 wherein the octreotide is present in about 5 wt.% to about 12 wt.% of the formulation.

41. The formulation of any one of claims 27-35 that is an injectable subcutaneous formulation, and has a volume of about 0.20 mL to about 2 mL.

42. The formulation of any one of claims 27-35 wherein the octreotide is in the form of a salt and the salt gegenion is derived from a pharmaceutically acceptable organic or inorganic acid, or the gegenion is a polycarboxylic acid.

43. The formulation of any one of claims 27-35 having the property of production of minimal tissue necrosis when injected subcutaneously.

44. The formulation of any one of claims 1 -22 or 27-43 wherein the biodegradable thermoplastic polymer is a biocompatible, non-hydrolyzed PLG low-burst copolymer material for a controlled release formulation having a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4-2.0, and from which a copolymer fraction characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5 has been removed; and the low-burst copolymer material comprises copolymer molecular chains wherein a predominant proportion of the molecular chains comprise predominantly lactate or lactide residues in at least one end domain of each molecular chain and predominantly glycolate or glycolide resides in an internal domain of each molecular chain.

45. The low-burst copolymer material of claim 44 prepared, without a step of hydrolysis of a higher molecular weight PLG copolymer material, from a starting PLG copolymer material by dissolving the starting PLG copolymer in a solvent, precipitating the low-burst copolymer material with a non-solvent, and collecting the PLG low-burst copolymer material; wherein the removed copolymer fraction is about 2% to about 20% by weight of the sum of the weights of the removed copolymer fraction and the PLG low-burst copolymer material; and wherein the solvent and the non-solvent are miscible.

46. The formulation of claim 44 or 45 wherein the PLG low-burst copolymer material has a weight average molecular weight of about 15 kDa to about 50 kDa, and a polydispersity index of about 1.4-1.8; and wherein the content of unreacted lactide and glycolide is less than about 1.0 weight % and 0.1 weight % respectively.

47. The formulation of claim 44 wherein the removed copolymer fraction is about 3% to about 15% by weight, or about 5% to about 10% by weight, of the sum of the weights of the removed copolymer fraction and the PLG low-burst copolymer material.

48. The formulation of claim 44 wherein the starting PLG copolymer material is prepared by a ring-opening polymerization reaction of lactide and glycolide, and wherein the ring-opening polymerization reaction of lactide and glycolide is catalyzed by a tin salt.

49. The formulation of claim 45 wherein the solvent is dichloromethane or chloroform and the non-solvent is methanol or ethanol.

50. Use of the formulation of claim 1 in the manufacture of a medicament for treatment of a patient having a malcondition associated with somatotropin hypersecretion, gastrointestinal syndrome, with an imbalance, hyper or hypo activity of an insulin, glucagon or somatotropin pathway, or with a somatotropin or somatostatin receptor function.

51. Use of the formulation of claim 1 in the manufacture of a medicament for treatment of a patient having a malcondition associated with a somatostatin- responsive disease selected from the group consisting of retinal neovascularization, choroidal neovascularizaton, diabetes, cardiovascular failure, abnormal cardiovascular performance, angiopathy, carcinoid syndrome, somatotropin receptor associated cancer and somatostatin receptor associated cancer.