WO1998007412A1

WO1998007412A1 - Controlled release microparticles with a hydrophobic material

Info

Publication number: WO1998007412A1
Application number: PCT/US1997/014320
Authority: WO
Inventors: Yan Zhang; R. Craig Urian
Original assignee: Alkermes Controlled Therapeutics, Inc.
Priority date: 1996-08-21
Filing date: 1997-08-14
Publication date: 1998-02-26
Also published as: AU3981097A

Abstract

A pharmaceutical composition and a method of forming said composition for the sustained release of biologically active agent. The pharmaceutical composition of the invention comprises (a) a sustained release delivery device consisting essentially of (i) a drug delivery device having a biologically active agent disposed within said device and characterized by a plurality of interior spaces, and (ii) a hydrophobic material wherein said material is contained within a substantial number of interior spaces of the drug delivery device as to have a beneficial effect and (b) a pharmaceutical carrier. Alternatively, the pharmaceutical composition of the invention is in the substantial absence of a pharmaceutical carrier. The method of the invention includes imbibing the interior spaces of the drug delivery device with a hydrophobic material and removing the hydrophobic material from the exterior surface, thereby obtaining a pharmaceutical composition with a significantly reduced initial burst.

Description

CONTROLLED RELEASE MICROPARTICLES WITH A HYDROPHOBIC MATERIAL

Background of the Invention

Many illnesses or conditions require administration of a constant or sustained level of a medicament or biologically active agent to provide the most effective prophylactic or therapeutic. This may be accomplished through a multiple dosing regimen or by employing a system that releases the medicament in a sustained fashion. Attempts to sustain medication levels include the use of biodegradable materials, such as polymeric matrices, containing the medicament. The use of these matrices, for example, in the form of microparticles or microcarriers, provides an improvement in the sustained release of medicaments by utilizing the inherent biodegradability of the polymer to control the release of the medicament and provide a more consistent, sustained level of medication and improved patient compliance.

However, these controlled release devices typically exhibit high release of biologically active agent over the first 24 hours, commonly referred to as an initial burst. In some instances this burst can result in unacceptably high levels of biologically active agent and minimal release of agent thereafter. Therefore, a need exists to exert additional control over release kinetics by reducing the initial burst of medicament or biologically active agen . Summary of the Invention

This invention is based upon the discovery that initial burst can be controlled by imbibing a sufficient number of interior spaces of a sustained release delivery device with a hydrophobic material and removing the excess hydrophobic material .

This invention relates to a pharmaceutical composition, and methods of forming and using said composition, for the sustained release of a biologically active agent. The pharmaceutical composition of this invention comprises (a) a sustained release delivery device consisting essentially of (i) a drug delivery device having a biologically active agent disposed within said device and characterized by a plurality of interior spaces, and (ii) a hydrophobic material wherein said material is contained within a substantial number of interior spaces of the drug delivery device as to have a beneficial effect and (b) a pharmaceutical carrier, with the proviso that the pharmaceutical carrier is not the same as the hydrophobic material contained within the interior spaces of the drug delivery device. Alternatively, the pharmaceutical composition can be in the substantial absence of a pharmaceutical carrier.

The method of the invention, for forming a pharmaceutical composition for the sustained release of a biologically active agent includes, imbibing a substantial number of interior spaces of the drug delivery device with a hydrophobic material. Preferably, the device is a polymeric matrix. The formation of the drug delivery device includes dissolving a biocompatible polymer in a polymer solvent to form a polymer solution, dispersing or dissolving the biologically active agent in the polymer solution, and then solidifying the polymer to form a polymeric matrix having said biologically active agent disposed within. The imbibition of the interior spaces of the drug delivery device includes suspending the drug delivery device in a hydrophobic material for a period of time or under conditions sufficient to allow the hydrophobic material to occupy a substantial number of interior spaces of the drug delivery device without physically or chemically altering the device. Excess hydrophobic material, being that material which is not contained in the interior spaces of the drug delivery device, can be removed by methods known to those of skill in the art. Suitable methods include for example, vacuum filtration or filtration using a centrifugal filter unit. Conditions are selected in order to retain the desired quantity of hydrophobic material in the interior spaces of the drug delivery device. The method of using the pharmaceutical composition of the present invention comprises providing a continuous and controlled rate of biologically active agent delivery, in a subject, over a therapeutically useful period of time, wherein the typical burst of material seen over the first 24 hours is reduced, by administering to the subject a dose of said pharmaceutical composition.

The advantages of this sustained release formulation include lower initial burst of biologically active agent, increased therapeutic benefits by providing a more consistent level of biologically active agent, increased patient compliance and acceptance by reducing the required number of doses of biologically active agent necessary to achieve effective therapy.

Brief Description of the Drawings Figure 1 is a plot of the % oil composition versus centrifugation time for the three hGH-containing microsphere formulations in the Table.

Figure 2A is a plot of the % cumulative release of hGH in vi tro in HEPES buffer, from hGH-containing microspheres having either a 22% or a 48% minimum oil content and their respective controls, versus time over a 28 day interval.

Figure 2B is a plot of the % cumulative release of hGH in vi tro in HEPES buffer, from hGH-containing microspheres having in excess of the minimum oil content and their respective controls, versus time over a 28 day interval.

Figure 3 is a plot of the % cumulative release of RNase from samples of RNase-containing microspheres employing the "5K polymer" (as described herein) having a sesame oil content of 41%, an olive oil content of 50% and the appropriate control (no oil) in vi tro in HEPES buffer, versus time over a 24 day interval.

Figure 4 is a plot of the % cumulative release of RNase from RNase-containing microspheres employing the "RG 502H polymer" (as described herein) having an olive oil content of 43%, a sesame oil content of 41% and a soybean oil content of 44% in vi tro in HEPES buffer, versus time over a 28 day interval.

Figure 5 is a plot of the IFN concentration (IU/ml) found in the serum of rats, which were injected subcutaneously with Zn⁺²- IFN-containing microspheres having a 16% or 0% oil content, versus time over a 168 hour interval (7 days) .

Detailed Description of the Invention A pharmaceutical composition, as defined herein, comprises a sustained release delivery device which can be either in the presence or substantial absence of a pharmaceutical carrier. The sustained release delivery device, as defined herein, consists essentially of a drug delivery device and a hydrophobic material. The drug delivery device, as defined herein, is characterized by a biologically active agent disposed within said device and a plurality of interior spaces. Preferably the device comprises a matrix which is polymeric. Interior spaces, as defined herein, are any areas of the matrix which are recessed below the outer surface of the device and are accessible from the outside. Interior spaces include for example, pores, channels, surface craters, indentations, recesses, crevices, grooves, hollows, depressions or the like, preferably having a configuration sufficient to retain, contain or entrap the hydrophobic material upon removal of the hydrophobic material from the greater exterior surface of the device. As such, the claimed invention does not "coat" the microsphere, inasmuch as the hydrophobic material is not retained upon the greater exterior or outer surface of the device, but selectively on or in the interior surfaces or spaces . The hydrophobic material, as defined herein, is any substance which has limited miscibility with water. Suitable hydrophobic materials are for example, oils and waxes. The hydrophobic material is further described as being contained within a substantial number of interior spaces of the drug delivery device. The pharmaceutical carrier, as defined herein, is any carrier known in the art with the proviso that it is not the same as the hydrophobic material contained within the interior spaces of the drug delivery device.

A biologically active agent, as defined herein, is an agent, or its pharmaceutically acceptable salt, which is in its molecular, biologically active form when released in vivo, thereby possessing the desired therapeutic and/or prophylactic properties in vivo . Examples of suitable biologically active agents include proteins such as immunoglobulin-like proteins, antibodies, cytokines (e.g., lymphokines, monokines, chemokines) , interleukins, interferons, erythropoietin, nucleases, tumor necrosis factor, colony stimulating factors, insulin, enzymes (e.g. superoxide dismutase, a plasminogen activator), tumor suppressors, blood proteins, hormones (e.g., growth hormone, luteinizing hormone releasing hormone (LHRH) and adrenocorticotropic hormone), vaccines (e.g., bacterial and viral antigens) , antigens, blood coagulation factors; growth factors; peptides such as protein inhibitors; nucleic acids, such as antisense molecules ,- oligonucleotides; and ribozymes . Other small molecular weight agents suitable for incorporation include, antitumor agents such as bleomycin hydrochloride, methotrexate and adriamycin; antibiotics such as gentamicin, tetracycline hydrochloride and ampicillin; antipyretic, analgesic and anti -inflammatory agents; antitussives and expectorants such as ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride and codeine phosphate; sedatives such as chlorpromazine hydrochloride, prochlorperazine hydrochloride and atropine sulfate; muscle relaxants such as tubocurarine chloride; antiepileptics such as sodium phenytoin and ethosuximide ; antiulcer agents such as metoclopramide ; antidepressants such as clomipra ine ; antiallergic agents such as diphenhydramine ; cardiotonics such as theophillol; antiarrhythmic agents such as propranolol hydrochloride; vasodilators such as diltiazem hydrochloride and bamethan sulfate; hypotensive diuretics such as pentolinium and ecarazine hydrochloride; antidiuretic agents such as metformin; anticoagulants such as sodium citrate and sodium heparin; hemostatic agents such as thrombin, menadione sodium bisulfite and aceto enaphthone ; an ituberculous agents such as isoniazide and etha butol; hormones such as prednisolone sodium phosphate and methimazole; and narcotic antagonists such as nalorphine hydrochloride . A sustained release of biologically active agent which includes a reduction in the initial release of biologically active agent, is a release which occurs over a period of time longer than that which would be obtained following direct administration and which has the added advantage of reducing the initial release or burst of biologically active agent, typically seen with sustained release compositions. The release profile and amount of biologically active agent released can be affected by the loading of biologically active agent, selection of excipients to produce the desired effect and/or by other conditions such as the type of polymer used, the fabrication process employed and the ultimate geometry of the device. Reduction of the initial release or burst of biologically active agent in the pharmaceutical composition of the present invention, is achieved by imbibing the interior spaces of the polymeric matrix of the sustained release device with a hydrophobic material. "Imbibing", in this invention, is intended to include and be essentially synonymous with impregnating, permeating, imbuing, saturating, filling, infiltrating and the like.

A sustained release delivery device, as defined herein, consists of a drug delivery device characterized by a plurality of interior spaces, comprising a matrix and a biologically active agent disposed within the matrix; and a hydrophobic material contained within a substantial number of interior spaces of the drug delivery device.

A preferred matrix of the drug delivery device of the present invention is a biocompatible polymeric matrix. Polymers suitable to form a polymeric matrix of the drug delivery device of this invention are biocompatible polymers which can be either biodegradable or non- biodegradable polymers, or blends or copolymers thereof. A polymer, or polymeric matrix, is biocompatible if the polymer, and any degradation products of the polymer, are substantially non-toxic to the recipient and also present no unacceptable, deleterious or untoward effects on the recipient's body, such as a significant immunological reaction at the site of administration.

Biodegradable, as defined herein, means the composition will degrade or erode in vi vo to form smaller chemical species which are biometabolizable and excretable . Degradation can result, for example, by enzymatic, chemical and/or physical processes. Suitable biocompatible, biodegradable polymers include, for example, poly (lactides) , poly (glycolides) , poly ( lactide-co- glycolides) , polydactic acid)s, poly (glycolic acid)s, poly (lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids) , polyorthoesters, polyacetals, polycyanoacrylates, polyetheresters, poly (dioxanone) s, poly (alkylene alkylates)s, copolymers of polyethylene glycol and polyorthoester, biodegradable polyurethanes , blends and copolymers thereof .

Biocompatible, non-biodegradable polymers suitable for a sustained release device include non-biodegradable polymers selected from the group consisting of polyacrylates, polymers of ethylene-vmyl acetates and acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinyl imidazole) , chlorosulphonate polyolefins, polyethylene oxide, blends and copolymers thereof .

Further, the terminal functionalities or pendant groups of the polymers can be modified, for example, to modify the rate of degradation or other physical properties of the polymer, for example the glass transition temperature (T ) .

Acceptable molecular weights for polymers used in this invention can be determined by a person of ordinary skill in the art taking into consideration factors such as the desired polymer degradation rate, physical properties such as mechanical strength, and rate of dissolution of polymer in solvent. Typically, an acceptable range of molecular weights is of about 2,000 Daltons to about 2,000,000 Daltons. In a preferred embodiment, the polymer is a biodegradable polymer or copolymer. In a more preferred embodiment, the polymer is a poly (lactide-co-glycolide) (hereinafter "PLGA").

The amount of biologically active agent which is contained in the sustained release delivery device is a therapeutically or prophylactically effective amount which can be determined by a person of ordinary skill in the art taking into consideration factors such as body weight, condition to be treated, type of device used, and release rate from the device.

The biologically active agent in a drug delivery device of the present invention can also contain other excipients, such as stabilizers, bulking agents or aggregation-stabilizing agents. Stabilizers are added to maintain the potency of the biologically active agent during device fabrication, storage and over the duration of the agent's release. Suitable stabilizers include, for example, carbohydrates, amino acids, fatty acids and surfactants which are known to those skilled in the art. For amino acids, fatty acids and carbohydrates, such as sucrose, lactose, mannitol, inulin, maltose, dextran and heparin, the mass ratio of carbohydrate to biologically active agent is typically between about 1:10 and about 20:1. For surfactants, such as polysorbates (e.g., Tween™) and polyoxamers and polyoxamines (e.g.,

Pluronic™) , the mass ratio of surfactant to agent is typically between about 1:1000 and about 1:2.

Aggregation-stabilizing agents are agents which stabilize the biologically active agent against significant aggregation in vivo over the sustained release period.

Typically an aggregation-stabilizer reduces the solubility of the biologically active agent, precipitates out a salt of the agent or forms a complex of the agent . The aggregation-stabilizer and the biologically active agent can be separately contained within the drug delivery device, such as a device containing particles of aggregation-stabilizer and separate particles of biologically active agent, and/or can be combined together in complexes or particles which contain both the aggregation-stabilizer and the biologically active agent. The use of aggregation-stabilizing agents to form stabilized particles of erythropoietin (EPO) is further described in Example 5.

Metal cations can be suitable as aggregation- stabilizing agents. These metal cations include cations of transition metals, such as Zn⁺², Cu⁺², Co⁺², Fe⁺³ and Ni⁺². The use of metal cations to form aggregation-stabilized particles of the biologically active agents, human growth hormone (hGH) and interferon (IFN) are further described in Examples 1 and 3 respectively.

The use of aggregation-stabilizing agents, is also described in co-pending U.S. Patent Application 08/279,784, filed July 25, 1994, co-pending U.S. Patent Application 08/521,744, filed August 31, 1995, PCT Patent Application PCT/US95/07348, filed June 7, 1995, and U.S. Patent Applications 08/473,544, 08/477,725, 08/478,502 and 08/483,318 each filed on June 7, 1995 the teachings of which are incorporated herein by reference in their entirety. In another embodiment, a sustained release delivery device also contains a metal cation component which is dispersed within the polymer. This metal cation component acts to modulate the release of biologically active agent from the polymeric matrix. A metal cation component used in modulating release typically contains at least one type of multivalent metal cation. Examples of metal cation components suitable to modulate release of biologically active agent, include, or contain, for instance, Mg(0H)₂, MgC0₃ (such as 4MgC0₃.Mg(OH) ₂"5H₂0) , ZnC0₃ (such as 3Zn (OH) ₂ ^• 2ZnC0₃ ) , CaC0₃, Zn₃ (C₆H₅0₇)₂, Mg(OAc)₂, MgS0₄ , Zn(OAc)₂, ZnS0₄ , ZnCl₂, MgCl₂ and Mg₃ (C₆H₅0₇) ₂. A suitable ratio of metal cation component-to-device is between about 1:99 to about 1 : 1 by weight. The optimum ratio depends upon the polymer and the metal cation utilized.

A polymeric matrix containing a dispersed metal cation component to modulate the release of a biologically active agent from the polymeric matrix is further described in co- pending U.S. Patent Application No. 08/237,057, filed May 3, 1994, and co-pending PCT Patent Application

PCT/US95/05511, the teachings of which are incorporated herein by reference in their entirety.

Bulking agents typically comprise inert materials. Suitable bulking agents are known to those skilled in the art.

Typically, a polymeric drug delivery device of the invention will contain from about 0.01% (w/w) to approximately 50% (w/w) of biologically active agent (dry weight of the composition) . The amount of agent used will vary depending upon the desired effect of the agent, the planned release levels, and the time span over which the agent will be released. A preferred range of agent loading is between about 0.1% (w/w) to about 30% (w/w) agent. A more preferred range of agent loading is between about 0.5% (w/w) to about 20% (w/w) agent.

A wide variety of hydrophobic materials are suitable for use in this invention. Such materials are preferably substantially biocompatible and non-reactive with the biologically active agent and the polymeric matrix. Normally, the hydrophobic material will function by imbibing, impregnating, permeating, imbuing or saturating a substantial number of interior spaces, for example any pores, channels, surface craters, indentations, recesses, crevices, grooves, hollows, depressions or the like, of the drug delivery device. Preferably, the interior spaces have a configuration (e.g. depth, size and curvature) sufficient to retain, contain or entrap the hydrophobic material upon removal of the hydrophobic material from the greater exterior surface of the device. Hydrophobic materials suitable for use in the present invention include biocompatible oils and waxes. The oils and waxes are preferably chosen from those oils which are physiologically acceptable. The oil or wax may be natural or synthetic. A combination of oils and/or waxes may be used. Oils may be selected for example from vegetable oils, mineral oils, fish oils, silicone oils and any combination thereof. Preferred oils are vegetable oils such as soybean oil, safflower oil, peanut oil, sesame oil, cottonseed oil, corn oil, olive oil, castor oil, palm oil, coconut oil, almond oil and any combination thereof. The most preferred oils are acceptable for use in parenteral products and include sesame oil, soybean oil, cottonseed oil, peanut oil and any combination thereof. Waxes which are suitable for use in this invention are for example isopropyl esters of fatty acids such as isopropyl myristate, diisopropyl adipate, isopropyl laurate, isopropyl linoleate, isopropyl pal itate and cetyl esters of fatty acids such as cetyl palmitate and any combination thereof . The sustained release delivery device of this invention can be formed into many shapes such as a film, a pellet, a cylinder, a wafer, a disc or a microparticle . A microparticle, as defined herein, comprises a polymeric component having a diameter of less than about one millimeter and having biologically active agent dispersed therein. A microparticle can have a generally spherical, non-spherical or irregular shape. Typically, the microparticle will be of a size suitable for injection. A preferred size range for microparticles is from about 1 to about 250 microns in diameter. The sustained release device in the form of a wafer or disc, for example, will typically be of a size suitable for implantation and can be manufactured by various methods including, for example, compressing microparticles as described in U.S. Patent Application No. 08/649,128.

The present invention can be used to incorporate and deliver a wide variety of active substances. Most often, the composition of the present invention will be used to deliver an active substance to a human or other animal for purposes of therapy, hygiene, analgesics, cosmetics or the like. Such uses where the compositions are delivered to a human or other animal will generally be referred to as in vivo uses. The composition of the present invention will also have in vi tro uses where an active substance is being delivered to an environment or system other than a human or animal such as in the sustained release of agrochemicals or in diagnostics. One of the major in vivo uses for the composition of the present invention will be for the delivery of drugs and other pharmaceutical agents in human and veterinary applications. For both in vi vo and in vi tro uses, the compositions will deliver the active substance to a surrounding environment where the release rate to the environment is controlled or modulated at least in part by the presence of a hydrophobic material contained within a substantial number of interior spaces of the delivery device .

One suitable method for forming a sustained release composition from a polymer solution is the solvent evaporation method described in U.S. Patent No. 3,737,337, issued to Schnoring e t al . , U.S. Patent No. 3,523,906, issued to Vranchen et al . , U.S. Patent No. 3,691,090, issued to Kitajima et al . , or U.S. Patent No. 4,389,330, issued to Tice et al . . Solvent evaporation can be used as a method to form microcarriers and other shaped sustained release devices. In the solvent evaporation method, a polymer solution containing a dispersion of particles of a biologically active agent, containing oil droplets of an active agent dissolved in an immiscible phase, or containing the active agent co-dissolved with the polymer solution, is mixed in or agitated with a continuous phase, in which the polymer solvent is partially miscible, to form an emulsion. The continuous phase is usually an aqueous solvent. Emulsifiers are often included in the continuous phase to stabilize the emulsion. The polymer solvent is then evaporated over a period of several hours or more, thereby solidifying the polymer to form a polymeric matrix having the biologically active agent contained therein.

In this method, care must be taken not to heat the polymer solution to a temperature at which degradation of the biologically active agent in the particles could occur.

.Another suitable method for solidifying a polymer solution to form a polymeric matrix, containing particles of biologically active agent, is the phase separation method described in U.S. Patent No. 4,675,800, which is incorporated herein in its entirety by reference. In this method, polymer within a polymer solution containing particles of biologically active agent is precipitated around the particles by the addition of a polymer non- solvent to the polymer solution to form an emulsion, wherein the polymer non-solvent is immiscible with the polymer solvent .

Preferred methods for forming the drug delivery device using rapid freezing and solvent extraction are described in U.S. Patent No. 5,019,400, issued to Gombotz e t al . , co- pending U.S. Patent Application No. 08/443,726, filed May 18, 1995, and co-pending U.S. Patent Application No. 08/649,128, filed May 14, 1996 (hereinafter "Method One", "Method Two" and "Method Three" respectively) , the teachings of which are incorporated herein by reference in their entirety. These methods of formation, as compared to other methods, such as phase separation, additionally reduce the amount of biologically active agent required to produce a sustained release composition with a specific content and also minimize the loss of biological activity during microparticle formation.

In Methods One and Two referenced above, the polymer solution, containing the biologically active agent, is processed to create droplets, wherein at least a significant portion of the droplets contain polymer solution and the biologically active agent. These droplets are then frozen by means suitable to form microparticles . Examples of means for processing the polymer solution dispersion to form droplets include directing the dispersion through an ultrasonic nozzle, pressure nozzle,

Rayleigh jet, or by other known means for creating droplets from a solution.

Means suitable for freezing droplets to form microparticles include directing the droplets into or near a liquified gas, such as liquid argon and liquid nitrogen to form frozen microdroplets which are then separated from the liquid gas. The frozen microdroplets are then exposed to a liquid extraction solvent, which is miscible with the polymer solvent but is a poor solvent for the polymer, such as ethanol, or ethanol mixed with hexane or pentane . In

Method One the liquified gas overlays the frozen extraction solvent. In Method Two the liquified gas and the cold extraction solvent are maintained in a distinct "freezing zone" and an "extraction zone". The purpose of the extraction solvent is to extract, as a solid and/or a liquid, the solvent in the frozen microdroplets, to form biologically active agent containing microparticles. Mixing ethanol with other suitable extraction solvents, such as hexane or pentane, can increase the rate of solvent extraction, above that achieved by ethanol alone, from certain polymers, such as poly (lactide-co-glycolide) polymers .

A wide range of sizes of biologically active agent sustained release microparticles can be made by varying the droplet size, for example, by changing the ultrasonic nozzle frequency or diameter. If larger microparticles are desired, the polymer solution containing the biologically active agent can be processed by passage through a syringe or pipet, for example, directly into the cold liquid. Increasing the viscosity of the polymer solution can also increase microparticle size. The size of the microparticles which can be produced by this process, are for example microparticles ranging from greater than about 1000 to about 1 micrometers in diameter. In Method Three above (co-pending U.S. Patent

Application No. 08/649,128), the method comprises forming a polymer solution/biologically active agent mixture comprising a polymer dissolved in an organic solvent and a co-dissolved or suspended biologically active agent. Solvent is then removed from the polymer solution/ biologically active agent mixture, thereby forming a solid polymer/biologically active agent matrix. The polymer/ biologically active agent matrix is then fragmented at a temperature below the glass transition temperature of the polymer/biologically active agent matrix, thereby forming polymer/biologically active agent microparticles.

Yet another method of forming a sustained release composition, from a polymer solution, includes film casting, such as in a mold, to form a film or a shape. For instance, after putting the polymer solution containing the biologically active agent into a mold, the polymer solvent is then removed by means known in the art, or the temperature of the polymer solution is reduced, until a film or shape, with a consistent dry weight, is obtained. Film casting of a polymer solution, containing a biologically active agent, is further described in co- pending U.S. Patent Application No. 08/237,057.

It is believed that the release of the biologically active agent can occur by at least two different mechanisms. First, release can occur due to degradation of the polymer. The rate of degradation can be controlled by changing polymer properties that influence the rate of hydration of the polymer. These properties include, for instance, the ratio of different monomers, such as lactide and glycolide, comprising a polymer; the use of the L- or D- iso er or racemic mixture of a chiral monomer; a polymer, such as a poly (lactide-co-glycolide) polymer that has, for instance, a hydrophobic or a hydrophilic end group; the morphology of the particle as impacted for example, by choice of solvent for polymer during preparation; and the molecular weight of the polymer. These properties can affect hydrophilicity and crystallinity, which control the rate of hydration of the polymer. Hydrophilic excipients such as salts, carbohydrates and surfactants can also be incorporated to increase hydration and which can alter the rate of erosion of the polymer.

Second, biologically active agent can be released by diffusion through the channels generated in the polymeric matrix, such as by the dissolution of the biologically active agent or by voids or pores created by the removal of the polymer's solvent during the synthesis of the drug delivery device. The present invention exploits the discovery that the imbibition of a substantial number of interior spaces of the drug delivery device with a hydrophobic material slows the release of the biologically active agent by diffusion and/or degradation.

A preferred method for reducing the initial release of biologically active agent from the polymeric drug delivery device includes suspending the drug delivery device containing a biologically active agent, in a hydrophobic material at a suitable temperature and for a period of time sufficient to allow the hydrophobic material to occupy a substantial number of interior spaces of the drug delivery device. Excess hydrophobic material, being that material which is not contained in the interior spaces of the drug delivery device, can be removed by methods known to those of skill in the art. Suitable methods include for example, centrifugation including centrifugal filtration for a period of time and at a speed and temperature suitable to retain the desired percentage of hydrophobic material in the interior spaces of the drug delivery device or any filtration means also at a suitable temperature and with sufficient force to remove excess hydrophobic material while retaining the hydrophobic material in the interior spaces of the drug delivery device. A suitable temperature for use during centrifugation is one which is below the glass transition temperature, or Tg, of the polymer of the polymeric matrix and which is low enough to preserve the biological activity of the biologically active agent, but is sufficiently high to maintain the fluidity of the hydrophobic material .

In a highly preferred embodiment, the microspheres containing biologically active agent are suspended in Super Refined^® sesame, soybean or olive oil (Croda, Inc., Edison, NJ) for a period of about 12 to 24 hours at a temperature of about 4°C. Following incubation the suspension is centrifuged in a centrifugal filter device (microfilterfuge tube) at about 9000 rev/min, at a temperature of about 4°C to remove the excess oil. The duration of centrifugation will vary depending on the amount of oil one desires to remain in the microspheres.

Eventually the amount of oil retained in the microspheres can be reduced essentially no further by centrifugal filtration. That is, the amount of oil retained by the microspheres becomes essentially fixed. This fixed amount of oil is referred to as the minimum oil content and indicates the oil accessible interior spaces of that given preparation. In general, the minimum oil content relates to the volume of the oil accessible interior spaces of the microspheres.

This relationship between minimum oil content and volume of interior spaces is demonstrated by imbibing the interior spaces of porous glass beads of known porosity. Porous glass beads with a known volume of accessible pores were obtained from Control Pore Glass, Inc., Lincoln Park, NJ (Catalog Numbers: CPG00120A, CPG00120C, CPG00350A and CPG00350C) . The beads were added to the inside chamber of a microfilterfuge tube as described above. An excess of oil was added and the samples were incubated at 4°C for 12 hours. The samples were spun for 1 minute, excess oil was removed, and the samples were respun for increasing time periods to verify the porosity of the beads. The results demonstrated that, after prolonged centrifugation, the glass beads retained a fixed amount of oil which correlated with the known porosity of the beads.

Typically, the amount of oil retained by the microparticles of the sustained release device of this invention will be the minimum oil content. The advantage of using the minimum oil content is that a formulation with a determinable and controllable % oil composition will be obtained.

The sustained release device of this invention can be administered to a human, or other animal, by injection or implantation (e.g, subcutaneously , intramuscularly, intraperitoneally, intracranially, intraocularly , intravaginally and intradermally) , administration to mucosal membranes (e.g., intranasally or by means of a suppository), or in si tu delivery (e.g. by enema or aerosol spray) to provide the desired dosage of an agent based on the known parameters for treatment with that agent of the various medical conditions.

Even though the invention has been described with a certain degree of particularity, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art m light of the foregoing disclosure. Accordingly, it is intended that all such alternatives, modifications, and variations which fall within the spirit and scope of the invention be embraced by the defined claims.

Example 1 Preparation of Particles of hGH Purified recombinant human growth hormone (hGH) , whose DNA sequence is as described in U.S. Patent 4,898,830, issued to Goeddel et al . , was used in this Example. The hGH was dissolved in samples of a 4 mM sodium bicarbonate buffer (pH 7.2) to form hGH solutions with concentrations between 0.1 and 0.5 mM hGH. The human growth hormone was stabilized by forming a complex with Zn⁺² ions, wherein the complex has a lower solubility in aqueous solutions than does non-complexed hGH. That is, a 0.9 mM Zn⁺² solution was prepared from deionized water and zinc acetate dihydrate and then was added to the hGH solutions to form a Zn⁺²-hGH solution with a molar ratio of 6:1. The pH of the Zn⁺²-hGH solution was then adjusted to between 7.0 and 7.4 by adding 1% acetic acid. A cloudy suspended precipitate, comprising Zn⁺²-stabilιzed hGH formed.

The suspension of Zn⁺²-stabιlιzed hGH was then icronized using an ultrasonic nozzle (Type VIA; Somes and Materials, Danbury, CT) and sprayed into a polypropylene tub (17 cm diameter and 8 cm deep) containing liquid nitrogen to form frozen particles. The polypropylene tub was then placed into a -80 °C freezer until the liquid nitrogen evaporated. The frozen particles, which contained Zn⁺²-stabilized hGH, were then lyophilized to form aggregation-stabilized hGH particles.

Alternatively, the hGH was not Zn⁺²-stabilized. In this case the hGH/4mM sodium bicarbonate solution was micronized under cryogenic conditions as described above and then lyophilized to form hGH particles.

Example 2 Preparation of PLGA Microparticles Containing hGH and Aggregation-Stabilized hGH Microparticles containing aggregation-stabilized hGH (as prepared in Example 1) were prepared from either poly ( lactide-co-glycolide) (PLGA) polymer with hydrophilic end groups, RG502H, (50:50 PLGA, 9,300 Daltons; Boehringer Ingelheim Chemicals, Inc.) (hereinafter "RG502H") or a PLGA polymer with hydrophobic end groups, (50:50 PLGA, 5,000 Daltons; Birmingham Polymers, Inc., Birmingham, AL) (hereinafter "5K PLGA"). The microparticles formed contained 15% w/w hGH (6:1 Zn:hGH protein complex) and 1% w/w zinc carbonate. The polymer was dissolved in methylene chloride at room temperature. Either the lyophilized hGH or aggregation-stabilized hGH particles were added to the polymer solution and zinc carbonate, which was sieved through a 38 micrometer (#400) sieve, was also added. The mixture was then sonicated to give a homogenous suspension. As described in the method of U.S. Patent No. 5,019,400, "Method One", the suspension was atomized through a sonicating nozzle onto a bed of frozen ethanol, overlaid with liquid nitrogen. The vessel containing the microparticles was stored at -80°C to extract the methylene chloride and the resulting microparticles were either cold filtered or filtered at room temperature and then freeze- dried to give a free- flowing powder. Alternatively, the suspension was atomized through a sonicating nozzle into a chamber of liquified nitrogen gas as described in U.S. Serial No. 08/443,726, "Method Two". The microdroplets froze upon contact with the liquified gas, then were separated from the liquified gas and contacted with cold liquid extraction solvent (ethanol) at a temperature below the melting point of the frozen microdroplets. The ethanol was warmed in order to extract the methylene chloride into the ethanol, thereby creating porous microparticles. The resulting microparticles were separated from the ethanol either by filtering at room temperature with room temperature ethanol or cold filtering and dried under vacuum for 24 hours to give a free- flowing powder

Example 3

Preparation of Particles of Interferon IFN-α.,2b, which was used in the present examples, is identical to IFN-α.,2 as described in Rubenstem et al . , Bioche . Biophys . Acta , 695: 705-716 (1982), with the exception that the lysme at position 23 of IFN-α.,2 is an argimne in IFN-α,2b. The IFN was stabilized by forming a complex with Zn⁺² ions, wherein the complex has a lower solubility m aqueous solutions than does non-complexed IFN. The IFN was complexed as follows. The IFN-α,2b was dissolved in different volumes of 10 mM sodium bicarbonate buffer (pH 7.2) to form IFN solutions with concentrations between 0.1 and 0.5 mM IFN. A 10 mM Zn⁺² solution was prepared from deionized water and zinc acetate dihydrate and then was added to the IFN solutions to form Zn⁺²-IFN solutions with a final IFN concentration of about 1.3 mg/ml and a Zn"² : IFN molar ratio of either 2:1, 4.1 or 10:1 The pH of the Zn⁺²-IFN solution was then ad usted to 7.1 by adding 1% acetic acid. A cloudy suspended precipitate, comprising aggregation-stabilized IFN wherein the IFN is stabilized as a complex with Zn⁺², formed in each solution. The suspension of aggregation-stabilized IFN was then micronized under cryogenic conditions as described in Example 1 for Zn⁺²-stabilized hGH. The frozen particles, which contained Zn⁺²-stabilized IFN, were then lyophilized to form aggregation-stabilized IFN particles.

Example 4 Preparation of PLGA Microparticles Containing Aggregation- Stabilized IFN

Microparticles containing 6% w/w of the Zn⁺²- stabilized IFN having a 2:1 Zn:IFN molar ratio as described in Example 3, were prepared from the 5K PLGA polymer. Both of the methods described in Example 2, were utilized. The microparticles formed also contained 10% w/w zinc carbonate, which was sieved through a 38 micrometer (#400) sieve, prior to addition.

Example 5 Preparation of Particles of EPO Erythropoietin was derived as described in U.S. Patent No. 4,703,008. The EPO was dissolved in deionized water to form an aqueous solution having a concentration of approximately 1 mg/ml. The EPO solution was then dialyzed against three changes of formulation buffer (5 mM Citrate/5mM Phosphate buffer) . Following dialysis, the concentration of EPO in the dialyzed solution was verified to be approximately 1 mg/ml as determined by measuring absorbance at 280 nm ( e = 1.345 L gm^"1 cm^"1) .

The dialyzed EPO solution was then mixed with a concentrated solution of ammonium sulfate (prepared in the same buffer used to dialyze the EPO solution to which they were subsequently added) . The EPO formulation prepared consisted of 10 wt % EPO, 66.8 wt % ammonium sulfate, 22.1 wt % 5mM Citrate/5mM Phosphate Buffer and 1.1 wt % inulin which were mixed by gentle inversion.

Lyophilized, aggregation-stabilized EPO particles were then formed from the EPO solution as described in Example 1 for hGH. The EPO particles were removed from the lyophilizer under an atmosphere of dry nitrogen, handled in a low humidity environment, and stored desiccated at -80°C.

Example 6 Preparation of PLGA Microparticle Containing Aggregation- Stabilized EPO Microparticle containing the aggregation-stabilized EPO formulation of Example 5 were prepared from the RG502H polymer or the 5K PLGA polymer. The methods for formation of microparticles, as described in Example 2, were utilized. The microparticles formed contained 0.5% w/w EPO and 10% w/w magnesium carbonate.

Example 7

Preparation of Particles of RNAse RNAse was obtained from Sigma Chemical Corp. (St. Louis, MO) . Particles of RNAse protein were prepared as follows. RNAse was dissolved in deionized water to form a 1% RNAse solution. The solution of RNAse was then micronized under cryogenic conditions as describe in Example 1, for Zn⁺²-stabilized hGH. The frozen particles of RNAse were then lyophilized to form solid RNAse particles .

Example 8

Preparation of PLGA Microparticles Containing Particles of

RNAse Micrparticles containing RNAse particles (as prepared in Example 7) were prepared from the RG502H polymer and the 5K PLGA polymer. The final formulation contained 10% w/w RNase and 10% w/w zinc carbonate, which was sieved as described in Example 2 through a 38 micrometer (#400) sieve prior to addition.

Example 9 Imbibition of Microparticles with a Hydrophobic Material Approximately 10 to 60 mg of preweighed microparticles were added to the inside chamber of a Microfilterfuge Tube™, having a Nylon- 66 filter membrane with a 0.45 urn pore size (Catalog #7016-022; Rainin Instrument Co., Inc., Woburn, MA) . An excess amount (approximately 0.6 ml) of oil either sesame, soybean or olive oil was added to the tube containing the microparticles. The resulting microparticle suspension was then incubated at 4°C for 12 to 14 hours . Following incubation, the tubes were spun in a microcentrifuge for 1 minute at 4°C, to bring the microparticles to the filter, while keeping the temperature constant and the polymer well below its Tg . Visible excess liquid oil was removed from the filtrate compartment of the tube by pipet, and the sample of microparticles was respun at 9000 rev/min at 4°C for increasing time periods (up to approximately 60 minutes) to remove remaining excess oil from the samples. The oil content of the microparticles was controlled by the duration of centrifugation and filtration. After prolonged centrifugation, the amount of oil retained in a sample could not be reduced further. This amount was referred to as the minimum oil content. If microparticles having more than the minimum amount of oil are desired, shorter centrifugation times are used to achieve the desired result.

The minimum amount of oil retained by a sample of microparticles was demonstrated by plotting the percent (by weight) of oil remaining in a sample as a function of centrifugation. This minimum amount of oil retained relates to the porosity of the microparticles which can be calculated using the Formula above .

Example 10 Imbibition of hGH Containing Microparticles with a Hydrophobic Material

Three separately prepared batches of hGH containing microparticles prepared as described in Example 2, were employed. The % oil composition of these samples was determined according to the method described in Example 9. Croda Super Refined^® sesame oil (Croda Inc., Edison, NJ) was employed. Details of the microparticle formulations used, % oil composition determined and reduction of initial burst can be found in the following Table. Figure 1 graphically depicts the % oil composition for these same microparticle formulations. Figure 1 shows that the minimum oil content for the three hGH-containing microparticle formulations of the following Table are 22%, 48% and 52% respectively. In addition, the Table reports a significant reduction in the initial burst of hGH for the microparticle formulations employed.

The initial in vi tro burst of hGH was quantified by BCA, BioRad Protein Assay (BioRad, Inc., Richmond, CA) , and/or High Performance Liquid Chromatography (HPLC) (Size Exclusion Chromatography (SEC)) analysis.

Table: % Oil Composition and % Initial Release of Various hGH-containing Microparticles

Lyophilized Drug Polymer; Initial Initial % Zinc % Oil Burst % Burst % Substance Carbonate Method Composition (No Oil) (Oil)

15% w/w hGH (6:1 ZnrhGH protein RG502H;l%w/w Method One 22 18 9 complex) (Cold

Filtered)

15% w/w hGH (6:1 Zn:hGH protein RG502H;l%w/w Method One 48 46 11 I complex) (Filtered I at room temperature with room temperature ethanol)

15% w/w hGH (6:1 RG502H;l%w/w Method Two Zn:hGH protein (Cold 52 64 26 complex) Filtered)

Example 11 Comparison of In Vi tro Release Rates for Oil Imbibed and Non-Oil Imbibed hGH-Containing Microparticles The hGH-containing microparticles of Example 10 having a 22% and 48% minimum oil content were evaluated for their initial in vi tro burst of drug, as well as for sustained release kinetics of the agent. hGH- containing microparticles were hydrated in buffer (50 mM HEPES, lOmJM KCL, 0.1% NaN₃) at 37°C. Samples of buffer were removed at varying timepoints over a 28 day time period. After each sampling, fresh buffer was added to replace the volume removed. Released protein, at each timepoint, was quantified by BCA Biorad Protein Assay (BioRad, Inc., Richmond, CA) , and/or HPLC (SEC) analysis.

The release kinetics for the hGH-containing microparticles with both 22% and 48% oil content and their respective controls (no oil treatment) are shown in Figure 2A. The initial burst of hGH from the microparticles containing 22% oil was 9% with the control exhibiting an initial burst of 18%. Similarly, the initial burst of hGH from the microparticles containing 48% oil was approximately 11%, with the control exhibiting an initial burst of 46%. These results are presented in both Figure 2A and the preceding Table. The results demonstrate that imbibing the hGH-containing microparticles with oil reduces the initial burst of protein and alters the release kinetics . A sample of the hGH-containing microparticles of Example 10 shown to have a 22% minimum oil content was treated with Croda Super Refined^® sesame oil and filter centrifuged for a period of time to retain in excess of the minimum oil content, that is a 58% oil content. Similarly, a sample of the hGH-containing microparticles of Example 10 shown to have a 48% minimum oil content was treated with Croda Super Refined^® sesame oil and filter centrifuged for a period of time to retain in excess of the minimum oil content, that is a 69% oil content.

The hGH-containing microparticles having the 58% and 69% oil composition were then evaluated for their initial in vi tro burst of drug, as well as for sustained release kinetics of the agent as described above.

The release kinetics for the hGH-containing microparticles with both 58% and 69% oil content and their respective controls (no oil treatment) are shown in Figure 2B . The initial burst of hGH from the microparticles containing 58% oil was approximately

4.5%, with the control exhibiting an initial burst of approximately 18%. Similarly, the initial burst of hGH from the microparticles containing 69% oil was approximately 4.5%, with the control exhibiting an initial burst of approximately 45%. These results demonstrate that imbibing the hGH-containing microparticles with oil reduces the initial burst of protein and alters the release kinetics.

Example 12 Oil Containing RNase Microparticles

Experiments comparing the release kinetics of RNase for RNase microparticles, prepared as described in Example 8, and further treated with two different oils, sesame and olive, were performed. RNase containing microparticles prepared as described in Example 8, using the "5K PLGA" were treated with Spectrum® sesame oil or olive oil (Spectrum Chemical Manufacturing Corp., New Brunswick, NJ) following the procedure described in Example 9. A sa ple of RNase containing microparticles was left untreated to be used as a control . The sesame oil treated microparticles retained approximately 41% oil and the olive oil treated microparticles retained approximately 50% oil.

The samples were then evaluated for their initial in vi tro burst of drug, as well as for sustained release kinetics of agent, using the Pierce BCA assay (Pierce Chemical Co., Rockford, IL) . The release kinetics for these samples of RNase containing microparticles are shown in Figure 3.

Figure 3 shows that the initial burst of drug from the control (non-oil treated) microparticles was greater than 50%. In contrast, the initial burst of drug from the sesame oil treated and olive oil treated RNase containing microparticles was less than 10%. Hence, a significant reduction in initial burst of agent from the microparticle was achieved.

In addition, comparison of the release kinetics for the microparticles treated with either olive oil or sesame oil (Figure 3) shows that the RNase release achieves the same maximum level within the twenty- four day period.

In a second experiment, RNase containing microparticles were prepared using the RG502H polymer. Samples of the microparticles were treated with Croda Super Refined^® sesame, olive oil or soybean oil and evaluated for initial burst, as well as for sustained release kinetics, as described above. Figure 4 shows that, for all three oil treated samples the initial burst is reduced from approximately 27% to less than 10%. The observed sustained release kinetics were similar for all three oils in microparticles prepared from the RG502H. Example 13 In Vivo Release of IFN from Oil Containing Microparticles Studies were conducted in immune suppressed rats to evaluate various oil-filled microparticle formulations for the initial in vivo release rate of Zn⁺²-stabilized IFN. Sprague-Dawley rats weighing 400+50 g (S.D.) were administered daily intraperitoneal injections of 10 mg cyclosporin A (Sandimmune^® Injection, Sandoz, East Hanover, NJ) and 5 mg hydrocortisone (Spectrum Co., Gardena, CA) in 0.5 ml sterilized saline for injection (USP) per kilogram of body weight for days 0 to 7. These injections were to suppress the response of the rats' immune systems to the release of IFN in vivo .

Zn⁺²-IFN containing microparticles, were prepared as in Example 4, and treated with Croda Super Refined^® soybean oil according to the procedure of Example 9, to retain a minimum oil content of 16%. The second sample of Zn⁺²-IFN containing microparticles was untreated.

These samples were injected into the immune suppressed rats described above, to test for the in vivo release of IFN. Rats were injected subcutaneously in the intrascapular region with a dose of approximately 0.9 mg/kg of IFN on day 0 in a vehicle containing 0.5% gelatin, 1% glycerol , 0.9% w/w NaCl and 2% carboxymethyl cellulose (CMC) (low viscosity) . Blood samples were taken from the tail vein of each rat at 1, 2, 4, 9, 24, 30, 48, 72, 120, 144 and 168 hours after injection. The IFN concentration in the rat serum samples was determined using an IFN-α. immunoradiometric assay (Celltech, Slough U.K.), hereinafter "IRMA".

Figure 5 shows that the Cmax as well as the Area Under the Curve (AUC) between 0 and 24 hours, is much greater for the untreated IFN microparticles than for the IFN microparticles containing the minimum oil content of 16%.

Example 14 Comparison of In Vi tro Release Rates for Oil Imbibed and Non-Oil Imbibed EPO

Containing Microparticles A 120 mg sample of EPO containing microparticles prepared as described in Example 6 using RG502H was divided into two portions. The first portion was treated with Croda Super Refined^® sesame oil and filter centrifuged as described in Example 9, to retain the minimum oil content of 36%. A second portion was untreated.

The two portions of EPO containing microparticles described above were then evaluated for their initial in vi tro burst of drug. Released protein was quantified by HPLC (SEC) . The initial burst of EPO from the microparticles containing 36% oil was 20.3% +_ 2.6. The initial burst from the untreated EPO containing microparticles was 52.7% +. 1.5. These results show a significant reduction in the initial burst of EPO from the oil imbibed microparticles.

Equivalents

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to specific embodiments of the invention described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS We claim:

1. A pharmaceutical composition comprising:

(a) a sustained release delivery device for the sustained release of a drug, consisting essentially of :

(i) a drug delivery device characterized by a biologically active agent disposed within the device, and a plurality of interior spaces; and

(ii) a hydrophobic material, wherein said material is contained within a substantial number of interior spaces of the drug delivery device; and

(b) optionally, a pharmaceutical carrier, wherein the pharmaceutical carrier is not the same as the hydrophobic material of (ii) .

2. The pharmaceutical composition of Claim 1, wherein the hydrophobic material is a biocompatible oil or wax or a combination thereof.

3. The pharmaceutical composition of Claim 2, wherein the hydrophobic material is a biocompatible oil selected from the group consisting of: vegetable oils, mineral oils, fish oils, silicone oils and any combination thereof.

4. The pharmaceutical composition of Claim 3, wherein the biocompatible oil is vegetable oil selected from the group consisting of: sesame oil, soybean oil, olive oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil and any combination thereof.

5. The pharmaceutical composition of Claim 2, wherein the hydrophobic material is a biocompatible wax selected from the group consisting of isopropyl myristate, diisopropyl adipate, isopropyl laurate, isopropyl linoleate, isopropyl palmitate and cetyl palmitate and any combination thereof .

6. The pharmaceutical composition of Claim 1, wherein drug delivery device comprises a matrix wherein the matrix is a biocompatible polymer.

7. The pharmaceutical composition of Claim 6, wherein the biocompatible polymer is selected from the group consisting of: poly (lactides) , poly (glycolides) , poly (lactide-co-glycolides) , poly (lactic acid)s, poly (glycolic acid)s, poly (lactic acid-co-glycolic acid)s, polycaprolactone , polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p- dioxanone) , poly (alkylene oxalate)s, biodegradable polyurethanes, blends and copolymers thereof.

8. A pharmaceutical composition of Claim 7, wherein the biocompatible polymer is polydactide co- glycolide) .

9. The pharmaceutical composition of Claim 6, wherein the drug delivery device is in the form of microparticles .

10. The pharmaceutical composition of Claim 1, wherein the biologically active agent is an immunoglobulin protein, an antibody, a cytokine, an interleukin, an interferon, erythropoietin, a nuclease, tumor necrosis factor, a colony stimulating factor, insulin, an enzyme, a tumor suppressor, a hormone, an antigen, a vaccine, a growth factor, a peptide, a protein, a polypeptide or a polynucleotide .

11. A sustained release delivery device for the sustained release of a drug, consisting essentially of : (i) a drug delivery device characterized by a biologically active agent disposed within the device, and a plurality of interior spaces; and

(ii) a hydrophobic material, wherein said material is contained within a substantial number of interior spaces of the drug delivery device .

12. The device of Claim 11, wherein the hydrophobic material is a biocompatible oil, or wax or a combination thereof .

13. The device of Claim 12, wherein the hydrophobic material is biocompatible oil selected from the group consisting of: vegetable oils, mineral oils, fish oils, silicone oils and any combination thereof.

14. The device of Claim 13, wherein the biocompatible oil is vegetable oil selected from the group consisting of: sesame oil, soybean oil, olive oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil and any combination thereof .

15. The device of Claim 12, wherein the hydrophobic material is a biocompatible wax selected from the group consisting of: isopropyl myristate, diisopropyl adipate, isopropyl laurate, isopropyl linoleate, isopropyl palmitate, cetyl palmitate and any combination thereof.

16. The device of Claim 11, wherein the device comprises a matrix wherein the matrix is a biocompatible polymer.

17. The device of Claim 16, wherein the biocompatible polymer is selected from the group consisting of : poly (lactides) , poly (glycolides) , poly ( lactide-co- glycolides) , poly (lactic acid)ε, poly (glycolic acid)s, poly (lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters , polycyanoacrylates , poly(p- dioxanone) , poly (alkylene oxalate)s, biodegradable polyurethanes, blends and copolymers thereof.

18. A device of Claim 17, wherein the biocompatible polymer is polydactide co-glycolide) .

19. The device of Claim 16, wherein the drug delivery device is in the form of microparticles.

20. A method for making the sustained release delivery device of Claim 11 comprising imbibing a substantial number of said interior spaces of said drug delivery device with a hydrophobic material, and removing substantially all hydrophobic material from the exterior surface of the device.

21. The method of Claim 20, wherein the hydrophobic material is a biocompatible oil or wax or a combination thereof.

22. The method of Claim 21, wherein the hydrophobic material is a biocompatible oil selected from the group consisting of: vegetable oils, mineral oils, fish oils, silicone oils and any combination thereof .

23. The method of Claim 22, wherein the biocompatible oil is vegetable oil selected from the group consisting of: sesame oil, soybean oil, olive oil, safflower oil, peanut oil, cottonseed oil, coconut oil, linseed oil, corn oil and any combination thereof.

24. The method of Claim 21 wherein the hydrophobic material is a biocompatible wax selected from the group consisting of: isopropyl myristate, diisopropyl adipate, isopropyl laurate, isopropyl linoleate, isopropyl palmitate, cetyl palmitate and any combination thereof.

25. A method for providing a therapeutically effective level of a biologically active agent in a subject for a sustained period, with a reduction in the initial burst of biologically active agent, comprising administering to the subject a dose of the pharmaceutical composition of Claim 1.

26. The method of Claim 25, wherein the pharmaceutical composition is administered by injection.

27. A method for providing a therapeutically effective level of a biologically active agent in a subject for a sustained period, with a reduction in the initial burst of biologically active agent, comprising administering to the subject a dose of the sustained release delivery device of Claim 11.

28. The method of Claim 27, wherein the pharmaceutical composition is administered by injection.

29. The method of Claim 27, wherein the pharmaceutical composition is administered by implantation.