HK1086190A

HK1086190A - Injectable depot compositions and uses thereof

Info

Publication number: HK1086190A
Application number: HK06106303.3A
Authority: HK
Inventors: G.陈; P．R．休斯敦; L．W．克莱纳; J．C．莱特
Original assignee: 阿尔扎有限公司
Priority date: 2001-11-14
Filing date: 2002-11-14
Publication date: 2006-09-15

Description

Injectable depot compositions and uses thereof

Cross reference to related patent applications

This patent application claims the benefit of U.S. provisional patent application No. 60/336,307 filed on 11, 14/2001.

Background

Technical Field

The long acting compositions of the present invention may be injected into a desired location in a patient to form an implant that provides sustained release of a beneficial agent. The invention also relates to methods of administering a benefit agent to a patient with a long acting composition.

Description of the related Art

Biodegradable polymers have been used in medical applications for many years. Illustrative devices composed of biodegradable polymers include sutures, surgical clips, staples, implants, and drug delivery systems. Most of these biodegradable polymers are based on glycolide, lactide, caprolactone and copolymers thereof.

Biodegradable polymers may be thermoplastic, meaning that they can be heated and formed into a variety of shapes such as fibers, clips, pins, films, and the like. In addition, they can form thermoset materials through a crosslinking reaction, resulting in high molecular weight materials that do not melt or form flowable liquids at high temperatures.

Although thermoplastic and thermoset biodegradable polymers have many useful biomedical applications, their use in various animals, including humans, animals, birds, fish and reptiles, has some important limitations. Since these polymers are solids, all cases, including their use, require the initial formation of polymeric structures in vitro, followed by insertion of the solid structures into the body. For example, sutures, clips, and staples are formed from thermoplastic biodegradable polymers prior to use. They retain their original shape when inserted into the body. While this characteristic is necessary for many applications, it is a disadvantage when trying to flow the material into a filled void or cavity, which is most desirable.

Drug delivery systems employing thermoplastic or thermoset biodegradable polymers must also be formed in vitro. At this time, the drug is incorporated into the polymer while the mixture is formed into a shape such as a column, a disk or a fiber for implantation. The drug delivery system is inserted into the body through the incision with such a solid implant. These incisions are sometimes larger than desired by the physician and occasionally result in patients who are reluctant to accept such implants or drug delivery systems. Nonetheless, biodegradable and non-biodegradable implantable drug delivery systems have been widely used successfully.

Us patent 5,085,866 describes a reservoir device with a rate-controlling membrane and zero-order (zero-order) release of the agent specifically designed for intraoral implantation. The device is made of a core sprayed with a solution containing a polymer and a solvent, the solvent consisting of a fast-evaporating, low-boiling first solvent and a slow-evaporating, high-boiling second solvent.

Examples of other osmotic delivery systems are described in U.S. patents: 3,797,492, respectively; 3,987,790; 4,008,719, respectively; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,151,093, respectively; 5,234,692; 5,234,693; 5,279,608 and 5,336,057. Pulsatile delivery systems are also known which can deliver beneficial agents in a pulsatile manner, as described in U.S. Pat. nos. 5,209,746; 5,308,348 and 5,456,679.

One way to implant drug delivery systems that avoids incisions is to inject them as small particles, microspheres, or microcapsules. For example, U.S. Pat. No. 5,019,400 describes the preparation of controlled release microspheres by a very low temperature casting process. These materials may or may not contain drugs that can be released into the body. Although these substances can be injected into the body with a syringe, they do not necessarily satisfy the requirements for biodegradable implants. By being substantially granular, they do not form a continuous film or solid implant with the structural integrity required for some prostheses. These small particles, microspheres or microcapsules are difficult to retain due to their small size and discrete nature when inserted into body cavities where much fluid flows, such as the mouth, periodontal pocket, eye or vagina. Furthermore, these particles have a tendency to aggregate and therefore their behaviour is difficult to predict. In addition, microspheres or microcapsules prepared from these polymers and containing a drug to be released into the body are sometimes difficult to mass-produce, and their storage and injection properties are problematic. Furthermore, one of the major limitations of the microcapsule or small particle system is its lack of reversibility without surgical intervention. That is, if there are complications after injection, they are much more difficult to remove from the body than solid implants. A further limitation to micro-particles or microencapsulation is the difficulty in encapsulating protein or DNA based drugs without degradation due to solvents and extreme temperatures.

Various drug delivery systems have been developed in the art to address the above challenges. For example, U.S. patent 4,938,762 and its divisional application U.S. patent 5,278,201 relate to a biodegradable polymer for providing an injectable, in situ formed, solid biodegradable implant for an animal. In one embodiment, a thermoplastic system is used in which a non-reactive polymer is dissolved in a biocompatible solvent to form a liquid for placement in an animal, and the solvent is dispersed in the animal to produce a solid implant. Alternatively, a thermoset system is used wherein an effective amount of a liquid acrylate-terminated, biodegradable prepolymer and a hardening agent are formed, the liquid mixture is placed in an animal, and the prepolymer is hardened to form a solid implant. Such a system is said to provide an injectable, solid biodegradable delivery system by adding an effective level of a biologically active agent to the liquid prior to injection into an animal.

U.S. Pat. No. 5,599,552 describes thermoplastic and thermoset polymeric compositions that employ a solvent, such as N-methyl-2-pyrrolidone, which is miscible in water, which allows the polymer solution to rapidly absorb water from the surrounding tissue. The polarity of the solvent should be effective to provide at least about 10% solubility in water. This polymer matrix system is described as forming a porous core around porous skin.

U.S. Pat. No. 5,242,910 describes a sustained release composition for the treatment of periodontal disease. The composition comprises a copolymer of lactide and glycolide, triacetin (as a solvent/plasticizer), and an agent for alleviating oral disease. The composition may be in the form of a gel and may be inserted into the periodontal cavity by syringe using a needle or catheter. As further optional ingredients, the composition may contain surfactants, flavouring agents, viscosity control agents, complexing agents, antioxidants, other polymers, gums, waxes/oils and colouring agents. One illustrative viscosity control agent listed in one example is polyethylene glycol 400. U.S. Pat. nos. 5,620,700 and 5,556,905 relate to polymeric compositions for injectable implants using solvents and/or plasticizers.

The polymeric compositions for injectable implants of the prior art use solvents and/or plasticizers that are very or relatively soluble in aqueous body fluids to promote rapid solidification of the graft site polymer and to promote diffusion of the drug from the implant. However, it has now been observed that a serious problem associated with prior art polymeric implants utilizing water-soluble polymer solvents is the rapid migration of water into the polymeric composition when the implant is placed in the body and exposed to aqueous body fluids. This characteristic often results in uncontrolled release of the beneficial agent, as evidenced by the initial, rapid release of the beneficial agent from the polymeric composition, corresponding to a "burst" of beneficial agent released from the implant. The burst typically results in the release of most, if not all, of the benefit agent over a short period of time, such as hours or 1-2 days. Such an effect may be unacceptable, particularly in some cases where sustained delivery is desired, i.e., the beneficial agent is delivered in a controlled manner over a period of 1 week or 1 month or more, or where the therapeutic window is narrow and excessive release of the beneficial agent may result in adverse consequences to the subject being treated, or where it is desired to mimic the naturally occurring daily profile of the beneficial agent, e.g., hormones and the like, in the subject being treated.

In an attempt to control burst and regulate and stabilize the delivery of benefit agents, the prior art has coated particles of an effective agent to delay its release into an aqueous environment and extend the release of the benefit agent for a period of time. Alternatively, various stability or release modifiers are used, such as metal salts as described in U.S. Pat. Nos. 5,656,297, 5,654,010, 4,985,404 and 4,853,218. U.S. patent 3,923,939 describes a method of reducing the initial burst of active agent from a delivery device by removing the outer surface of the delivery device prior to implantation and by extending the active agent from the outer surface of the device by at least one layer 5% of the total thickness of the body.

Despite some success, those methods that effectively deliver large amounts of beneficial agents through implants are not entirely satisfactory because in most cases the conditioning and stabilizing effect is the result of the complex formation of the metal ion and the beneficial agent. When such complexes are not formed, the stabilizing/modulating effect is insufficient to prevent an undesirable "burst" of beneficial agent at the site of implantation.

The phenomena exhibited by prior art devices of rapid water uptake into the polymeric implant and dispersion of solvent into the body fluids often result in implants having pore structures that are not uniform in size and shape. Typically, the surface employs a finger-like pore structure extending up to 1/3 cm or more into the implant from the implant surface, such finger-like pores being open to the environment of use at the implant surface. The internal pores tend to be smaller and not accessible to the liquids present in the environment of use. Thus, when the device is implanted, the finger-like pores can very quickly take aqueous body fluids into the implant, followed immediately and quickly by dissolution of large amounts of the beneficial agent without preventing the beneficial agent from diffusing into the environment of use, which produces the above-mentioned explosive effect.

Furthermore, rapid absorption of water may result in premature precipitation of the polymer, resulting in a hardened implant or skin stiffening. The internal pores and the interior of many benefit agent-containing polymers are closed from contact with body fluids and the significant reduction in benefit agent release may result in a period of time that is not useless ("lag time"). This delay time is not required from the standpoint of controlled, sustained release of the beneficial agent to the subject being treated. A burst of beneficial agent released is then observed for a short period of time after implantation, with no or little beneficial agent released for a delay period, followed by continued delivery of beneficial agent (assuming beneficial agent remains after burst) until the supply of beneficial agent is exhausted.

Solvent-based depot compositions are composed of a polymer dissolved in a solvent, which solidifies upon injection as the solvent diffuses from the depot. Since these compositions need to be non-viscous for injection, large amounts of drug are released when a solvent diffusion system is formed. This effect is known as a "burst" effect. In this regard, solvent-based compositions typically release 30-75% of the contained drug within 1 day of initial injection at the time of a drug burst.

An additional problem encountered with previous solvent-based depot compositions is the relatively high viscosity of the injectable composition, particularly when higher molecular weight polymers are used, and thus the injection force required to introduce the composition into a patient (see, e.g., U.S. patent 6,130,200). To address this problem, workers in the art use lower molecular weight polymers and relatively volatile water-soluble solvents such as ethanol. See, e.g., Dunn et al, U.S. patent 5,733,950; 5,780,044 and 5,990,194 and international patent application WO 98/27962. However, these methods can result in precipitation of drug particles and/or a higher initial release burst and/or a relatively large amount of emulsifier, such as about one-third of the total weight of the composition. Moreover, solvent volatility is problematic from a manufacturing standpoint, and monohydric lower alkanols (e.g., ethanol) can be used to modify protein and peptide drugs. Furthermore, bioerodible polymers having low molecular weights need to be completely limited from a production standpoint.

Summary of The Invention

The present invention addresses the above-mentioned need in the art by providing injectable depot compositions that exhibit improved shear thinning properties and thus enable reduced injection forces and the use of small diameter (e.g., 16 gauge and higher) needles (and/or catheters). The compositions provide sustained release of the benefit agent while limiting any initial burst effect, increasing formulation flexibility with respect to polymer/solvent ratio and bioerodible polymer molecular weight. Furthermore, the compositions of the present invention are free of volatile solvents and/or solvents that may denature, such as ethanol.

Then, in one aspect, the invention relates to an injectable depot composition comprising:

a bioerodible, biocompatible polymer;

an aromatic alcohol having miscibility in water of less than or equal to 7% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith; and

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

In another aspect, the invention relates to an injectable depot composition comprising:

about 5% to about 90% by weight of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight ranging from about 1,000 to about 120,000, preferably about 5,000 to about 50,000, more preferably about 8,000 to about 30,000;

an aromatic alcohol having miscibility in water of less than or equal to 7% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the formula (I)

Ar-(L)_n-OH (I)

Wherein Ar is a substituted or unsubstituted aryl or heteroaryl group, n is 0 or 1, and L is a linking moiety; and

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

a bioerodible, biocompatible polymer;

a solvent selected from the group consisting of esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25 ℃ and present in an amount effective to plasticize the polymer and form a gel therewith;

an effective contact amount of an aromatic alcohol having a miscibility in water of less than or equal to 7%; and

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

an ester of an aromatic acid having miscibility in water of less than or equal to 7% at 25 ℃ and present in an amount effective to plasticize the polymer and form a gel therewith;

an effective contact amount of an aromatic alcohol having a miscibility in water of less than or equal to 7%, wherein the aromatic alcohol has formula (I), wherein Ar, n, and L are as defined above; and

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

Preferred compositions are free of not only monohydric lower alkanols, but also solvents having a miscibility in water of less than or equal to 7 wt.% at 25 ℃.

In another aspect, the invention includes a method of administering a beneficial agent to a subject, either topically or systemically, comprising implanting the injectable composition as described above beneath the surface of the subject. The composition comprises a benefit agent, a bioerodible, biocompatible polymer, and a fragrant alcohol having miscibility in water of less than or equal to 7% at 25 ℃, wherein the fragrant alcohol is present in the composition in an amount effective to plasticize the polymer and form a gel therewith. Preferably, the system releases 40% or less by weight of the beneficial agent present in the viscous gel within the first 24 hours after implantation by the subject. More preferably, 30% or less by weight of the beneficial agent is released within the first 24 hours after implantation and the burst index of the implant composition is 12 or less, preferably 8 or less.

In another aspect, the invention includes a method for topically or systemically administering a beneficial agent to a subject, the method comprising implanting below the surface of the subject a composition comprising a bioerodible, biocompatible polymer, a solvent, an effective amount of a contact variable of an aromatic alcohol, the miscibility in water of which is less than or equal to 7% at 25 ℃. The solvent is selected from the group consisting of aromatic acid esters, aromatic ketones, and mixtures thereof, and has a miscibility in water of less than or equal to 7% at 25 ℃, and is present in an amount effective to plasticize the polymer and form a gel therewith.

In yet another aspect, the invention relates to injectable depot compositions and methods of administering the above compositions in which the viscous gel further comprises a polymer selected from the group consisting of polylactides, polyglycolides, poly (caprolactones), polyanhydrides, polyamines, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, polyphosphoesters, polysaccharides, chitin, chitosan, hyaluronic acid and copolymers, terpolymers and mixtures thereof. In a preferred embodiment, the polymer is a lactic acid-based polymer. Preferably, the polylactic acid polymer may have a weight average molecular weight ranging from about 1,000 to about 120,000, preferably from about 5,000 to about 50,000, more preferably from about 8,000 to about 30,000.

In a preferred embodiment, the solvent is selected from the group consisting of aromatic alcohols, lower alkyl and aralkyl esters of aryl acids; aryl, aralkyl and lower alkyl ketones; lower alkyl esters of citric acid. Preferably, the solvent is selected from benzyl alcohol, benzyl benzoate and ethyl benzoate. In a preferred embodiment, the composition is free of solvents having a miscibility in water of greater than 7 wt.% at 25 ℃. Preferably less than 7% by weight of solvent, more preferably less than 5% by weight, even more preferably less than 3% by weight, miscible in water.

In another aspect, the invention relates to injectable depot compositions and methods of administering the above compositions, wherein the beneficial agent is selected from the group consisting of drugs, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs and metabolites, analogs, derivatives, fragments, and purified, isolated, recombinant, and chemically synthesized species. In a preferred embodiment, the beneficial agent is human growth hormone, methionine-human growth hormone; des-phenylalanine human growth hormone, alpha-, beta-or gamma-interferon, erythropoietin, glugacon, calcitonin, heparin, interleukin-1, interleukin-2, factor VIII, factor IX, luteinizing hormone, relaxin, follicle stimulating hormone, atrial natriuretic factor, filgrastim Epidermal Growth Factor (EGFs), Platelet Derived Growth Factor (PDGFs), insulin like growth factor (IGFs), Fibroblast Growth Factor (FGFs), Transforming Growth Factor (TGFs), Interleukins (ILs), colony stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EPOs), Erythropoietin (EGFs), Angiopoietins (ANGs), placenta derived growth factor (PIGFs), and hypoxia-induced transcriptional regulators (HIFs). The benefit agent is preferably present in a combined amount of polymer from 0.1 to 50% by weight. In a preferred embodiment, the benefit agent is in the form of particles dispersed or dissolved in a viscous gel, wherein the particle form of the benefit agent has an average particle size of from 0.1 to 250 microns. In some preferred embodiments, the benefit agent is in the form of a particle, wherein the particle further comprises an ingredient selected from the group consisting of stabilizers, fillers, chelating agents, and buffers.

Brief description of the drawings

The foregoing and other objects, features and advantages of the invention will be more readily understood from the following detailed description taken in conjunction with the accompanying drawings, in which:

figure 1 illustrates the rheological properties of long acting carriers made with different solvents, i.e. formulations 5,6 and 7.

Figure 2 illustrates the injection force required to disperse formulations 5,6 and 7 from a 24 gauge needle at 1 ml/min at room temperature.

Figure 3 illustrates the injection force required to disperse an injectable depot composition from a 24 gauge needle at 1 ml/min at room temperature, the composition being made with different poly (lactide-co-glycolide) weight average molecular weights in combination with benzyl benzoate or benzyl alcohol.

Figure 4 illustrates the injection force required to disperse an injectable depot composition from a 24 gauge needle at 1 ml/min at room temperature, the composition being made with different poly (lactide-co-glycolide) weight average molecular weights in combination with benzyl benzoate or benzyl alcohol.

Fig. 5 illustrates the in vivo release profiles of human growth hormone obtained from different depot formulations, including the formulations of the invention (formulations 8-10).

Figure 6 illustrates the in vivo release profiles of human growth hormone obtained from different depot formulations (formulations 10 and 11).

Figure 7 illustrates the in vivo release profiles of bupivacaine obtained from different depot formulations, including the formulations of the invention (formulations 12 and 13).

Figure 8 illustrates the in vivo release profiles of bupivacaine obtained from different depot formulations, including the formulations of the invention (formulations 13 and 14).

Figure 9 illustrates the in vivo release profile of bupivacaine obtained from a depot formulation, including the formulations of the present invention (formulations 15 and 16).

Figure 10 illustrates the stability of hGH in different long acting formulations, including the formulations of the present invention, as a function of time at 5 ℃.

Figure 11 illustrates the injection force of different depot formulations, including the formulations of the invention (formulations 8-10 and 17).

Figure 12 illustrates the stability of PDGF in different long acting formulations, including the formulations of the present invention (formulations 36-39), as a function of time at 5 ℃.

Figure 13 illustrates the stability of PDGF in different long acting formulations, including the formulations of the present invention (formulations 36-39), as a function of time at 25 ℃.

Figure 14 illustrates the stability of PDGF in different long acting formulations, including the formulations of the present invention (formulations 36-39), as a function of time at 40 ℃.

Figure 15 illustrates the in vivo release profiles of PDGF obtained from different long acting compositions, including the compositions of the present invention (formulations 36-39).

Detailed Description

Summary and definition:

the present invention relates to injectable depot compositions that are useful as implant sustained release beneficial agent delivery systems after injection into a patient. The composition is a gel formed from a bioerodible, biocompatible polymer and an aromatic alcohol having miscibility in water of less than or equal to 7% at 25 ℃, preferably less than or equal to 5% at 25 ℃. The aromatic alcohol may be present in combination with an aromatic acid ester, an aromatic ketone, or both.

The composition provides sustained release of the beneficial agent by limiting water migration from the aqueous environment surrounding the implanted system, thereby delivering the beneficial agent over an extended period of time. The uptake of water is controlled by means of water-immiscible aromatic alcohols. Because the polymer of the composition is bioerodible, the implant system cannot be surgically removed after the implant is depleted of beneficial agent.

In general, the inventive composition is gel-like, and even when it hardens, forms a substantially uniform non-porous structure throughout the implant upon implantation and drug delivery. In addition, the polymer gel graft hardens slowly when placed in an aqueous environment, and the hardened implant can maintain the glass transition temperature T_gA rubber-like (non-rigid) composition below 37 ℃.

Because the aromatic alcohol in these compositions acts as a thixotropic agent itself, thereby significantly increasing shear thinning and composition uniformity, it is generally not necessary to introduce an additional thixotropic agent. However, in some embodiments, shear thinning and/or homogeneity (and thus release properties) may be further improved by incorporating additional thixotropic agents. While pore formers and solubility modifiers for the beneficial agent may be added to the implant system to provide the desired release profile from the implant system, typical pharmaceutical excipients and other additives do not alter the beneficial aspects of the present invention.

Preferred compositions herein enable the incorporation of benefit agents into the polymer at levels above that required to saturate the benefit agent in water, thereby promoting zero order release of the benefit agent. In addition, preferred compositions provide a viscous gel having a glass transition temperature of less than 37 ℃ so that the gel remains non-rigid for a period of time after 24 hours or more of implantation.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, "solvent" includes a single solvent as well as mixtures of two or more different solvents, "benefit agent" includes a single benefit agent as well as mixtures of two or more different benefit agents, "aromatic alcohol" includes a single aromatic alcohol as well as mixtures of two or more different aromatic alcohols, and the like.

The term "beneficial agent" refers to an agent that affects a desired beneficial effect when administered to a human or animal, usually a pharmacological effect, whether alone or in combination with other pharmaceutical excipients or inert ingredients.

As used herein, the term "polynucleotide" refers to a polymeric form of nucleotides of any length, either ribonucleotides or deoxyribonucleotides, including double-and single-stranded DNA and RNA. It also includes known types of modifications, substitutions, and internucleotide modifications known in the art.

As used herein, the term "recombinant polynucleotide" refers to a polynucleotide of genomic, cDNA, semisynthetic, or synthetic origin, which, depending on its origin or manipulation: not linked to all or part of the polynucleotide to which it is naturally associated; ligating polynucleotides other than those to which they are naturally associated; or not naturally occurring.

As used herein, the term "polypeptide" refers to a polymer of amino acids, including, for example, peptides, oligopeptides, proteins and derivatives, analogs and fragments thereof, as well as other naturally occurring and non-naturally occurring modifications known in the art.

As used herein, the terms "purify" and "isolate" when referring to a polypeptide or nucleotide sequence indicate that the referenced molecule is present in the substantial absence of other biological macromolecules of the same type. As used herein, the term "purified" preferably means that at least 75% by weight, more preferably at least 85% by weight, even more preferably at least 95% by weight, and most preferably at least 98% by weight of the same type of biological macromolecule is present.

The term "AUC" refers to the area under the curve obtained in vivo in a subject as measured from the time of transplantation of the composition to the time "t" post-transplantation by plotting the plasma concentration of the beneficial agent in the subject versus time. The time t corresponds to the stage of delivery of the benefit agent to the subject.

The term "burst index" refers to the coefficient formed for a composition particularly useful for systemic delivery of a beneficial agent by dividing the AUC calculated at the 1 st time period following (i) implantation of the composition into a subject by the number of hours (t) of the 1 st time period₁) (ii) AUC calculated over the benefit agent delivery period divided by the number of hours (t) of the total duration of the delivery period₂). For example, the burst index of 24 hours is determined by(i) The AUC calculated for the first 24 hours after implantation of the composition into a subject divided by the number 24, (ii) the coefficient formed by the AUC calculated for the period of beneficial agent delivery divided by the number of hours for the total duration of the delivery period.

The phrase "dissolve or disperse" is meant to include all methods of establishing the presence of a benefit agent in a gel composition, including dissolving, dispersing, suspending, and the like.

The term "systemic" refers to the delivery or administration of a beneficial agent to a subject, which beneficial agent is detectable at bio-significant levels in the plasma of the subject.

The term "topical" refers to reference to delivery or administration of a beneficial agent to a subject, the beneficial agent being delivered to a localized site in the subject but not being detectable at bio-significant levels in the plasma of the subject.

The term "gel carrier" refers to a composition formed by mixing a polymer and a solvent in the absence of a benefit agent.

The term "duration" refers to the period of time, generally about 1 week or more, preferably about 30 days or more, during which the beneficial agent is released from the implant of the present invention.

The term "initial burst" refers to a particular composition of the invention, the coefficient being obtained by dividing by (i) the weight of benefit agent released from the composition in a predetermined initial period of time after implantation, (ii) the total amount of benefit agent to be delivered from the implanted composition. It is understood that the initial burst may vary depending on the implant shape and surface area. Thus, the percentages and burst indices described herein relating to the initial burst apply to the composition, which is tested in the form of a composition dispensed from a standard syringe.

The term "solubility modulator" refers to an agent that, with respect to a benefit agent, alters the solubility of the benefit agent, with respect to a polymer solvent or water, from the solubility of the benefit agent in the absence of the modulator. The modifier may increase or retard the solubility of the benefit agent in the solvent or water. However, in the case of highly water-soluble benefit agents, the solubility modifier is generally an agent that hinders the solubility of the benefit agent in water. The effect of the solubility modifier of the benefit agent may result from the interaction of the solubility modifier with the solvent, or with the benefit agent itself, such as forming a complex, or both. For purposes herein, when a solubility modulator is "associated with" a benefit agent, it is meant that all such interactions or formations may occur. The solubility modifier may suitably be mixed with the benefit agent prior to incorporation of the viscous gel, or may be added to the viscous gel prior to the addition of the benefit agent.

The terms "subject" and "patient" refer to an animal or human to which the compositions of the invention are administered.

Since all solvents are soluble in water (i.e., miscible with water) to some very limited extent, at least at the molecular level, the term "immiscible" as used herein means that 7% or less by weight of the solvent is soluble in or miscible with water, preferably 5% or less. For the purposes of this disclosure, it is believed that the solubility value of the solvent in water is determined at 25 ℃. Since it is generally believed that the reported solubility values are not always miscible with or soluble in water as part of a range or upper limit under the same conditions, solubility limits recited herein may not be absolute. For example, if the upper limit of solvent solubility in water as referenced herein is "7% by weight" and no further solvent limitation is provided, the aqueous solubility of the solvent "triacetin" is reported as 7.17 grams in 100ml of water, considered to be included within the 7% limitation. As used herein, a solubility limit in water of less than 7% by weight does not include the solvent triacetin or solvents having a solubility in water equal to or greater than triacetin.

The term "bioerodible" refers to a material that gradually decomposes, dissolves, hydrolyzes, and/or erodes in situ. Generally, a "bioerodible" polymer herein is a hydrolyzable polymer that bioerodes in situ, primarily by hydrolysis.

The term "thixotropic" is used in a conventional sense to refer to a gel composition that liquefies or at least exhibits a reduction in apparent viscosity upon application of mechanical force, such as shear force. The degree of reduction when the gel is subjected to shear is in part a function of the shear rate of the gel. When the shear force is removed, the viscosity of the thixotropic gel returns to at or near the viscosity it exhibited prior to being subjected to the shear force. Thus, thixotropic gels can be subjected to shear forces when injected from a syringe, temporarily reducing their viscosity during the injection process. When the injection process is complete, the shear force is removed and the gel returns to a state very close to its front.

As used herein, the term "thixotropic agent" refers to an agent that increases the thixotropy of a composition that includes a thixotropic agent that promotes shear thinning and enables the use of reduced injection forces.

The polymers, solvents and other agents of the present invention must be "biocompatible"; i.e. they do not cause irritation, inflammation or necrosis in the environment of use. The environment of use is a fluid environment and may include subcutaneous, intramuscular, intravascular (high/low flow), intramyocardial, adventitial, intratumoral or intracerebral portions, wound sites, tight junction spaces or body cavities of a human or animal.

The following definitions apply to the molecular structures described herein:

as used herein, the phrase "having a formula" or "having a structure" is not intended to be limiting and is used in the same manner as the term "comprising" is commonly used.

As used herein, the term "alkyl" refers to the typical saturated hydrocarbon family, although not necessarily containing 1 to about 30 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like. Generally, although alkyl groups herein need not necessarily contain 1 to about 12 carbon atoms. The term "lower alkyl" is used for alkyl of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. "substituted alkyl" refers to alkyl substituted with 1 or more substituent groups, and the terms "heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in which at least 1 carbon atom is replaced with a heteroatom. The terms "alkyl" and "lower alkyl" include linear, branched, cyclic, unsubstituted, substituted and/or heteroatom-containing alkyl or lower alkyl, if not otherwise specified.

Unless otherwise specified, the term "aryl" as used herein refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings fused together, covalently linked, or attached to a common group such as a methylene or ethylene moiety. Preferably, the aryl group contains 1 aromatic ring or 2 fused or linked aromatic rings, such as phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like, with the most preferred aryl group being a monocyclic ring. "substituted aryl" refers to an aryl moiety substituted with one or more substituent groups, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to an aryl group in which at least 1 carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term "aryl" includes heteroaryl, substituted aryl, and substituted heteroaryl.

The term "aralkyl" refers to an alkyl group substituted with an aryl group, wherein alkyl and aryl are as defined above. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group. Unless otherwise indicated, the term "aralkyl" includes heteroaralkyl and substituted aralkyl as well as unsubstituted aralkyl. In general, the term "aralkyl" herein refers to aryl-substituted lower alkyl groups, preferably phenyl-substituted lower alkyl groups such as benzyl, phenethyl, 1-phenylpropyl, 2-phenylpropyl, and the like.

The term "heteroatom-containing" in "heteroatom-containing hydrocarbyl" refers to a molecule or fragment of a molecule in which one or more carbon atoms are replaced with an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon. Similarly, the term "heterocycle" refers to a cyclic substituent that is heteroatom-containing, the term "heteroaryl" refers to an aryl substituent that is heteroatom-containing, and the like.

"substituted" in some of the above definitions referring to "substituted alkyl", "substituted aryl", and the like, means that at least one carbon atom-bound hydrogen atom in the alkyl or aryl moiety, respectively, is replaced with one or more non-interfering substituents, such as hydroxy, alkoxy, thio, amino, halo, and the like.

Bioerodible, biocompatible polymers:

the polymers used in conjunction with the methods and compositions of the present invention are bioerodible, i.e., they gradually hydrolyze, dissolve, physically erode, or otherwise disintegrate in the aqueous fluid of the patient's body. Generally, polymer bioerosion is the result of hydrolysis or physical erosion, although the primary bioerosion process is usually hydrolysis.

Such polymers include, but are not limited to, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid and copolymers, terpolymers and mixtures thereof.

The presently preferred polymers are polylactides, i.e. polymers based on lactic acid, copolymers which may be based on lactic acid alone or may be based on lactic acid, glycolic acid and/or caprolactone, and may comprise small amounts of other comonomers which do not significantly affect the advantageous results which can be obtained according to the present invention. As used herein, the term "lactic acid" includes the isomers L-lactic acid, D-lactic acid, DL-lactic acid and lactide, and the term "glycolic acid" includes glycolide. Most preferred are poly (lactide-co-glycolide) copolymers, commonly referred to as "PLGA". The polymer may have a lactic acid/glycolide monomer ratio of from about 100: 0 to about 15: 85, preferably from about 75: 25 to about 30: 70, more preferably from about 60: 40 to about 40: 60, with particularly useful copolymers having a lactic acid/glycolide monomer ratio of about 50: 50.

The poly (caprolactone-co-lactic acid) (PCL-co-LA) polymer has a caprolactone/lactic acid comonomer ratio of from about 10: 90 to about 90: 10; preferably from about 35: 65 to about 65: 35, more preferably from about 25: 75 to about 75: 25. In some embodiments, the lactic acid-based polymer comprises a mixture of about 0-90% caprolactone, about 0-100% lactic acid, and about 0-60% glycolic acid.

The weight average molecular weight of the lactic acid based polymer is from about 1,000 to about 120,000, preferably from about 5,000 to about 50,000, more preferably from about 8,000 to about 30,000, as determined by Gel Permeation Chromatography (GPC). In contrast to the previous polymer-based injectable depot formulations, the present invention may use higher molecular weight polymers, so long as the aromatic alcohol of the composition provides excellent shear thinning even with high molecular weight polymers. As shown in the above-mentioned U.S. patent No. 5,242,910, the polymer may be prepared according to the techniques of U.S. patent No. 4,443,340. Alternatively, the lactic acid based polymer may be prepared directly from lactic acid or a mixture of lactic acid and glycolic acid (with or without further comonomers) according to U.S. Pat. No. 5,310,865. All of these patents are incorporated by reference. Suitable lactic acid based polymers are commercially available. For example, 50: 50 lactic acid-glycolic acid copolymers having molecular weights of 8,000, 10,000, 30,000, and 100,000 are available from Boehringer Ingelheim (Petersburg, Va.), Medisorb Technologies International L.P. (Cincinatti, OH), and Birmingham Polymers, Inc. (Birmingham, AL), described below.

Examples of polymers include, but are not limited to, poly (D, L-lactide) monomers^*L104, PLA-L104, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG502, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG502H, PLGA-502H, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG503, PLGA-503, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG506, PLGA-506, Poly-L-lactide MW 2,000 (Resomer)^*L206、Resomer^*L207、Resomer^*L209、Resomer^*L214); poly D, L lactide (Resomer)^*R104、Resomer^*R202、Resomer^*R203、Resomer^*R206、Resomer^*R207、Resomer^*R208); poly L-lactide-co-D, L-lactide 90: 10 (Resomer)^*LR 209); polyglycolide (monomer)^*G205) (ii) a Poly D, L-lactide-co-7-lactide 50: 50 (Resomer)^*RG504H、Resomer^*RG504、Resomer^*RG 505); poly D-L-lactide-co-glycolide 75: 25 (Resomer)^*RG752、Resomer^*RG755、Resomer^*RG 756); poly D-L-lactide-co-glycolide 85: 15 (monomer)^*RG 858); poly L-lactide-co-trimethylene ester 70: 30 (Resomer)^*LT 706); polydioxanKetones (monomer)^*X210)(Boehringer Ingelheim Chemicals，Inc.，Petersburg，VA)。

Additional examples include, but are not limited to, DL-lactide/glycolide 100: 0 (MEDISORB)^*Polymer 100 DLhigh, MEDISORB^*Polymer 100DL Low); DL-lactide/glycolide 85/15 (MEDISORB)^*Polymer 8515 DL High, MEDISORB^*Polymer 8515 DL Low); DL-lactide/glycolide 75/25 (MEDISORB)^*Polymer 7525 DL High, MEDISORB^*Polymer 7525 DL Low); DL-lactide/glycolide 65/35 (MEDISORB)^*Polymer 6535 DL High, MEDISORB^*Polymer 6535 DL Low); DL-lactide/glycolide 54/46 (MEDISORB)^*Polymer 5050DL High, MEDISORB^*Polymer 5050DL Low); DL-lactide/glycolide 54/46 (MEDISORB)^*Polymer 5050DL 2A (3), MEDISORB^*Polymer 5050DL 3A (3), MEDISORB^*Polymer 5050DL 4A (3)) (Medisorb Technologies Ihter-national l.p.cincinnatti, OH); and poly D, L-lactide-co-glycolide 50: 50; poly D, L-lactide-co-glycolide 65: 35; poly D, L-lactide-co-glycolide 75: 25; poly D, L-lactide-co-glycolide 85: 15; poly DL-lactide; poly-L-lactide; polyglycolide; poly-epsilon-caprolactone; poly DL-lactide-co-caprolactone 25: 75; and poly DL-lactide-co-caprolactone 75: 25(Birmingham Polymers, Inc., Birmingham, AL).

The biocompatible polymer is present in the gel composition in an amount ranging from about 5 to about 90% by weight, preferably from about 10 to about 85% by weight, preferably from about 15 to about 80% by weight, preferably from about 20 to about 75% by weight, preferably from about 30 to about 70% by weight, and usually from about 35 to about 65% by weight of a viscous gel comprising a combined amount of the biocompatible polymer and the aromatic alcohol. Solvents were added to the polymer in the amounts described below to provide an implantable gel or a viscous gel. Again, the aromatic alcohol can have a much wider polymer/solvent ratio than previously obtained.

Solvents and thixotropic agents:

in a first embodiment, the injectable depot composition of the invention comprises a water-immiscible aromatic alcohol in addition to the bioerodible polymer and the beneficial agent. In this embodiment, the aromatic alcohol acts as a solvent and thixotropic agent to facilitate dissolution of the bioerodible polymer and to promote shear thinning behavior upon injection. The compositions do not contain monohydric lower alkanols because such solvents are volatile, which can cause problems in manufacture and may denature or react with the benefit agent. The compositions described herein also preferably do not contain solvents having a miscibility in water of greater than 7 wt.% at 25 ℃.

The aromatic alcohol must be biocompatible and should form a viscous gel with the polymer, limiting water absorption into the implant. Suitable aromatic alcohols significantly limit the water uptake of the implant, as indicated above, and may be characterized as immiscible with water, i.e. a solubility or miscibility in water of at most 7% by weight. The water solubility of the aromatic alcohol is preferably 5% by weight or less, more preferably 3% by weight or less, and even more preferably 1% by weight or less. Most preferably, the aromatic alcohol has a solubility in water of 0.5 weight percent or less.

Water miscibility can be determined experimentally as follows: water (1-5g) was placed in a tared clear container at a controlled temperature of about 25 deg.C and weighed, and the candidate solvent was added dropwise. The solution was swirled to observe phase separation. When the saturation point determined by phase separation observation was reached, the solution could be kept overnight and reviewed on day 2. If the solution is still saturated, as determined by phase separation observation, the percentage of solvent added (w/w) is then determined. Otherwise more solvent is added and the process is repeated. Solubility or miscibility is determined by dividing the total weight of added solvent by the final weight of the solvent/water mixture. When solvent mixtures are used, they are premixed before the addition of water.

The aromatic alcohol has the structural formula (I)

Ar-(L)_n-OH (I)

Wherein Ar is a substituted or unsubstituted aryl or heteroaryl group, n is 0 or 1, and L is a linking moiety. Ar is preferably monocyclic aryl or heteroaryl, optionally substituted with one or more non-interfering substituents, such as hydroxy, alkoxy, thio, amino, halo, and the like. Ar is more preferably an unsubstituted 5-or 6-membered aryl or heteroaryl group such as phenyl, cyclopentadienyl, pyridyl, pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thiophenyl, thiazolyl, isothiazolyl and the like. The subscript "n" is 0 or 1, meaning that the linking moiety L may or may not be present. Preferably, n is 1 and L is typically a lower alkylene linkage such as methylene or ethylene, wherein the linkage may include a heteroatom such as O, N or S. Most preferably, Ar is phenyl, n is 1 and L is methylene, such that the aromatic alcohol is benzyl alcohol.

In another embodiment, in addition to the biocompatible, bioerodible polymer and the beneficial agent, the injectable depot composition of the invention comprises: (1) a solvent selected from the group consisting of esters of aromatic acids, aromatic ketones, and mixtures thereof, having a miscibility in water of less than or equal to 7% at 25 ℃, and present in an amount effective to plasticize the polymer and form a gel therewith; and (2) an effective contact amount of the above aromatic alcohol. Generally, the weight ratio of aromatic alcohol to ester or ketone is in the range of about 1% to about 99%, preferably in the range of about 10% to about 90%, more preferably in the range of about 20% to about 80%, even more preferably in the range of about 25% to about 75%, and most typically in the range of about 25% to about 50%. In this case, the aromatic alcohol acts primarily as a thixotropic agent, but also as a cosolvent for the bioerodible polymer. Like the injectable composition of the first embodiment, the composition is also free of monohydric lower alkanol.

The aromatic acid ester or ketone must be biocompatible and should form a viscous gel with the polymer to limit water absorption into the implant. Like aromatic alcohols, suitable aromatic acid esters and ketones significantly limit the absorption of water by the implant, and as indicated above, can be characterized as immiscible with water, i.e., having a solubility or miscibility in water of up to 7% by weight. The water solubility of the solvent alcohol is preferably 5% by weight or less, more preferably 3% by weight or less, and even more preferably 1% by weight or less. Most preferably, the solvent has a solubility in water equal to or less than 0.5 weight percent.

The aromatic acid ester or ketone may be selected from the group consisting of alkyl esters of lower alkyl and aromatic acids, aryl and aralkyl ketones. Typically, although not necessarily, the aromatic acid esters and ketones have the formula (II) or (III), respectively

In the ester of formula (II), R¹Is a substituted or unsubstituted aryl, aralkyl, heteroaryl or heteroaralkyl group, preferably a substituted or unsubstituted aryl or heteroaryl group, more preferably a monocyclic or bicyclic aryl or heteroaryl group, optionally substituted with one or more non-interfering substituents, such as hydroxy, carboxy, alkoxy, thio, amino, halo and the like, more preferably a 5-or 6-membered aryl or heteroaryl group such as phenyl, cyclopentadienyl, pyrimidinyl, pyridinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thiophenyl, thiazolyl or isothiazolyl, most preferably a 5-or 6-membered aryl group. R²Is a hydrocarbyl or heteroatom-substituted hydrocarbyl group, typically lower alkyl or substituted or unsubstituted aryl, aralkyl, heteroaryl or heteroaralkyl, preferably lower alkyl or substituted or unsubstituted aralkyl or heteroaralkyl, more preferably lower alkyl or mono-or bicyclic aralkyl or heteroaralkyl, optionally substituted with one or more non-interfering substituents, such as hydroxy, carboxy, alkoxy, thio, amino, halo and the like, more preferably lower alkyl or 5-or 6-membered aralkyl or heteroaralkyl, most preferably lower alkyl or 5-or 6-membered aryl, optionally substituted with one or more further substituents having the structure-O- (CO) -R¹By ester group of (a). The most preferred esters are benzoic acid and phthalic acid derivatives.

In the ketone of formula (III), R³And R⁴May be selected from any of the above-identified R¹And R²A group.

The solvent having the desired solubility can be selected from benzoic acid derivatives, and the benzoic acid derivatives identified in the art include without limitation: 1, 4-cyclohexylenedimethanol dibenzoate, diethylene glycol dibenzoate, dipropylene glycol dibenzoate, polypropylene glycol dibenzoate, propylene glycol dibenzoate, diethylene glycol benzoate and dipropylene glycol benzoate mixtures, polyethylene glycol (200) dibenzoate, isodecyl benzoate, neopentyl glycol dibenzoate, glyceryl tribenzoate, pentaerythritol tetrabenzoate, cumylphenyl benzoate, trimethylpentanediol dibenzoate.

The solvent having the desired solubility may be selected from phthalic acid derivatives, which are identified in the art to include: alkyl benzyl phthalate, di-cumyl-phenylisophthalate, dibutoxyethylphthalate, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, diisobutyl phthalate, butyl octyl phthalate, diisoheptyl phthalate, diisononyl phthalate, nonylundecylphthalate, dioctyl phthalate, diisooctyl phthalate, didecyl phthalate, mixed alcohols phthalates, di- (2-ethylhexyl) phthalate, linear heptyl, nonylphthalate, linear heptyl, nonyl, undecyl phthalate, linear nonyl-undecylphthalate, linear dinonyl-dinonyl, didecyl phthalate (diisodecyl phthalate), Diundecyl phthalate, ditridecyl phthalate, undecyldodecyl phthalate, decyltridecyl phthalate, a mixture of dioctyl phthalate and didecyl phthalate (50/50), butyl benzyl phthalate and dicyclohexyl phthalate.

Most preferably, the solvent is a derivative of benzoic acid, including but not limited to methyl benzoate, ethyl benzoate, n-propyl benzoate, isopropyl benzoate, butyl benzoate, isobutyl benzoate, sec-butyl benzoate, tert-butyl benzoate, isoamyl benzoate, benzyl benzoate most preferably.

In addition to the water-immiscible solvent, the composition may also include one or more additional miscible solvents ("component solvents") provided that any such additional solvent is other than the lower alkanol. The constituent solvents that are compatible and miscible with the primary solvent may have a high water miscibility and the resulting mixture still significantly limits water absorption into the implant. Such a mixture is referred to as a "compositional solvent mixture". Useful compositional solvent mixtures may exhibit a solubility in water greater than the primary solvent itself, typically from 0.1 weight percent up to and including 50 weight percent, preferably up to and including 30 weight percent, and most preferably up to and including 10 weight percent, without adversely affecting the water uptake limitations of the inventive implants.

The component solvent used to make up the solvent mixture is miscible with the primary solvent or solvent mixture, including, but not limited to, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethylglycerol, triethyl phosphate, diethyl phthalate, diethyl tartrate, mineral oil, polybutene, silicone fluids, glycerol, ethylene glycol, polyethylene glycol, octanol, ethyl lactate, propylene glycol, propylene carbonate, ethylene carbonate, butyrolactone, ethylene oxide, propylene oxide, N-methyl-2-pyrrolidone, glycerol formal, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, glycofurol (glycofurol), dimethyl sulfoxide, tetrahydrofuran, caprolactam, decyl methyl sulfoxide, and mixtures thereof, Oleic acid, 1-dodecyl aza-cyclo-hept-2-one and mixtures thereof.

In a particularly preferred embodiment, the solvent is selected from the group consisting of lower alkyl and aralkyl esters of benzoic acid, an aromatic alcohol is present as the thixotropic agent, and the polymer is a lactic acid-based polymer, most preferably having a number average molecular weight between about 1,000-120,000, preferably about 5,000-50,000, more preferably about 8,000-30,000. Currently, the most effective solvents are benzyl benzoate and the lower alkyl esters of benzoic acid, and the most preferred thixotropic agent is benzyl alcohol as described above.

The solvent or solvent mixture is capable of dissolving the polymer to form a viscous gel, and can maintain particles of the benefit agent dissolved or dispersed and isolated from the environment of use prior to release. The compositions of the present invention provide implants having a low burst index. Water absorption is controlled by using a solvent or mixture of component solvents that solubilize or plasticize the polymer, but significantly limit water absorption into the implant.

The solvent or component solvent mixture is generally present in an amount of from about 95 to about 5 weight percent of the viscous gel, preferably from about 75 to about 15 weight percent, and most preferably from about 65 to about 20 weight percent. Viscous gels formed by mixing the polymer and solvent generally exhibit a viscosity of from about 100 to about 200,000 poise, preferably from about 500 to about 50,000 poise, usually from about 1,000 to about 50,000 poise, with a Haake rheometer for 1 second about 1 to 2 days after mixing is complete^-1Shear rate and 25 ℃. Mixing of the polymer and solvent may be accomplished using conventional low shear equipment such as a Ross double planetary mixer for about 10 minutes to about 1 hour, although shorter and longer periods of time may be selected by one skilled in the art depending on the particular physical characteristics of the composition being prepared. Since it is often desirable to administer implants as injectable compositions via an injection catheter, a compensatory consideration when forming a viscous gel implant is that the polymer/solvent/thixotropic agent/beneficial agent composition has a viscosity low enough that it is forced through a small diameter needle, such as 16 gauge and higher, preferably 20 gauge and higher, more preferably 22 gauge and higher, even more preferably 24 gauge and higher. If necessary, the viscosity of the gel can be adjusted with the above-mentioned emulsifier for injection. Thus, such compositions should have suitable dimensional stability to remain in place and be removable if necessary. The particular gel or gel-like composition of the present invention meets this need.

The beneficial agent is as follows:

the beneficial agent may be a physiologically or pharmacologically active substance or a substance optionally in combination with a pharmaceutically acceptable carrier and additional ingredients such as antioxidants, stabilizers, penetration enhancers, and the like, without significantly adversely affecting the beneficial results achievable with the invention. The benefit agent may be any agent known to be delivered to the human or animal body, preferably dissolved in water rather than a polymer-dissolving solvent. These agents include pharmaceuticals, drugs, vitamins, nutrients, and the like. The types of agents that meet this description include lower molecular weight compounds, proteins, peptides, genetic material, nutrients, vitamins, food supplements, sex sterilants, fertility inhibitors, and fertility promoters.

Agents that may be delivered by the present invention include drugs that act on the peripheral nerve, adrenergic receptors, cholinergic receptors, the skeletal muscle, the cardiovascular system, smooth muscle, the blood circulatory system, synaptic sites, sites of neuroeffector connections, the endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system, the auto-hormonal system, the digestive and excretory systems, the histamine system and the central nervous system. Suitable agents may be selected from, for example, drugs, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents including corticosteroids, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs and metabolites, analogs (including synthetic and substituted analogs), derivatives (including aggregated conjugates/fused by methods known in the art to other macromolecules and covalent conjugates with unrelated chemical moieties) fragments, and these species purified, isolated, recombinant, and chemically synthesized.

Examples of drugs that may be delivered by the compositions of the present invention include, but are not limited to, procaine hydrochloride, tetracaine hydrochloride, cocaine hydrochloride, chloroprocaine hydrochloride, proparacaine hydrochloride, perocaine, peroxocaine hydrochloride, cocaine hydrochloride, nanoecaine hydrochloride, benzocaine, benzoxinate hydrochloride, cyclomecaine sulfate, lidocaine hydrochloride, bupivacaine hydrochloride, mepivacaine hydrochloride, prilocaine hydrochloride, dibucaine and dibucaine hydrochloride, etidocaine, benzocaine, propoxycaine, dyclonine, pramoxine, oxybuprocaine, mepivacaine mesylate, ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride, procainamide hydrochloride, Amphetamine sulfate, methamphetamine hydrochloride, amphetamine hydrochloride, isoproterenol sulfate, phenmetrazine hydrochloride, clobecholine, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, iodosopromide, triethyleneaniline chloride (tridihexenyl chloride), phenformin hydrochloride, methylphenidate hydrochloride, choline theophyllinate, cefradine hydrochloride, diphenidol, chlorpheniramine hydrochloride, chlorpromazine maleate, phenoxybenzamine, thiethylperazine maleate, anisindione, tolfendione, benzidine, erythritol tetranitrate, digoxin, isopropafluorophos, acetazolamide, mechlorethamine, bendroflumethiazide, chlorpromazine, tolazamide acetate, chlormadinone, allopurinol, aspirin, methotrexate, acesulfame, erythromycin, hydrocortisone acetate, dexamethasone acetate, and derivatives thereof such as beclomethasone acetate, dexamethasone acetate, and derivatives thereof, Triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol-3-methyl ether, prednisolone, 17 alpha-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethiederone, progesterone, norgestrel, norethindrone, aspirin, indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, tetrametidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, alidomide, erythromycin, haloperidol, zomepirac, ferrous lactate, vincamine, diazepam, phenoxybenzamine, diltiazem *, metyrazone, metrazone, prednisolone, 17 alpha-hydroxyprogesterone acetate, 19-norgestrel, norethinone, norethindrone, nore, Cefamandole, quinbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenufen, flurprofen, tolmetin, alclofenac, mefenamic acid, flufenamic acid, difuininal, nimodipine, nitrendipine, nitidipine, nicardipine, felodipine, ridofloxacin, tiapamil, golopamid, amlodipine, mifeprine, lisinopril, enalapril, enalaprilat, captopril, ramipril, famotidine, nizatidine, sucralfate, ethidine, tetrolol, minoxidil, chlorodiazepam, diazepam, amitriptyline and imipramine. Further examples are proteins and peptides including, but not limited to, bone morphogenic protein, insulin, colchicine, glucagon, thyroid stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotropin, thyroid stimulating hormone, follicle stimulating hormone, chorionic gonadotropin, gonadotropin releasing hormone, bovine somatotropin, porcine somatotropin, oxytocin, vasopressin, GRF, somatostatin, lysinestrenol, pancreatin, luteinizing hormone, LHRH agonists and antagonists, leuprolide, interferons such as interferon alpha-2 a, interferon alpha-2 b and consensus interferon, interleukins, growth factors such as Epidermal Growth Factor (EGF), platelet-derived growth factor (PDGF), Fibroblast Growth Factor (FGF), transforming growth factor-alpha (FGF-alpha), Transforming growth factor-beta (TGF-beta), Erythropoietin (EPO), insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), interleukin-1, interleukin-2, interleukin-6, interleukin-8, tumor necrosis factor-alpha (TNF-alpha), tumor necrosis factor-beta (TNF-beta), interferon-alpha (INF-alpha), interferon-beta (INF-beta), interferon-gamma (INF-gamma), interferon-omega (INF-omega), Colony Stimulating Factor (CSF), vascular cell growth factor (VEGF), Thrombopoietin (TPO), stromal cell derived factor (SDF), placental growth factor (PIGF), Hepatocyte Growth Factor (HGF), Granulocyte macrophage colony stimulating factor (G-CSF), glial cell derived neurotrophic factor (GDNF), granulocyte colony stimulating factor (G-CSF), ciliary neurotrophic factor (CNTF), Bone Morphogenetic Protein (BMP), blood coagulation factors, human pancreatic hormone releasing factor, analogs and derivatives of these compounds, pharmaceutically acceptable salts of these compounds, or analogs or derivatives thereof.

Additional examples of drugs that may be delivered by the compositions of the present invention include, but are not limited to, antiproliferative/antimitotic agents containing natural products such as vinca alkaloids (i.e., vinblastine, vincristine, and vinorelbine), paclitaxel, epidopodophyllotoxins (i.e., etoposide, teniposide), antibiotics (IDactinomycin, actinomycin D, daunorubicin, doxorubicin and daunorubicin), anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase, which systemically metabolizes L-asparagine and removes cells that cannot synthesize self-asparagine); antiplatelet agents such as G (GP) II_bII_aInhibitors and vitronectin receptor antagonists; antiproliferative/antimitotic alkylating agents such as nitrogen mustards (dichloroethylmethylamine, cyclophosphamide and the like, melphalan, chlorambucil), ethylenimine and methyl melamines (hexamethylmelamine and thiotepa), alkylsulfonic acid-busulfan, nitrosoureas (carmustine (BCNU) and the like, streptozocin), trazene-Dacarbazine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs, and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine (clenband)); platinum coordination complexes (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e., estrogens); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (e.g., histiocytotropin proactivator, streptokinase, and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, elbimab; an anti-migratory agent; anti-secretory drugs (breveldin); anti-inflammatory drugs: such as adrenocorticosteroids (cortisol, cortisone, fludrocortisone, prednisone, prednisolone, 6 alpha-methylprednisolone, triamcinolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, i.e., aspirin; p-aminophenol derivatives, i.e., acetominophen); indole and indene acetic acids (indomethacin, sulindac and ethindoacetic acid), heteroaryl acetic acids (tolmetin, diclofenac and ketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid and meclofenamic acid), enolic acids (piroxicam, dinoxicam, phenylbutazone and oxyphenthatrazone), nabumetone, gold compounds (auranofin, gold thioglucoside, gold sodium thiomalate); immunosuppressant: (Cyclosporine, tacrolimus (FK-506), sirolimus (rapamycin), azathioprine, mycophenolic acid, mycophenolate mofetilFlyover); an angiogenic agent: vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF); angiotensin receptor blockers; a nitric oxide donor; antisense oligonucleotides and combinations thereof; cell cycle inhibitors, mTOR inhibitors and growth factor signal transduction kinase inhibitors, analogs and derivatives of these compounds, pharmaceutically acceptable salts of these compounds, or analogs or derivatives thereof.

In some preferred embodiments, beneficial agents include chemotactic growth factors, proliferative growth factors, stimulatory growth factors, and transforming peptide growth factors, including genes, precursors, post-translational variants, metabolites, binding proteins, receptors of the following growth factor families, receptor agonists and antagonists: epidermal Growth Factors (EGFs), platelet-derived growth factors (PDGFs), insulin-like growth factors (IGFs), Fibroblast Growth Factors (FGFs), Transforming Growth Factors (TGFs), Interleukins (ILs), colony stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs), Erythropoietin (EPOs), Angiopoietins (ANGs), placenta-derived growth factors (PIGFs), and hypoxia-inducible transcriptional regulators (HIFs).

The present invention also uses chemotherapeutic agents for topical application of these agents to avoid or minimize systemic side effects. The gel of the present invention containing the chemotherapeutic agent can be injected directly into the tumor tissue to deliver the chemotherapeutic agent continuously over time. In some cases, particularly after resection of the tumor, the gel may be directly transplanted into the resulting cavity or may be applied to the remaining tissue as a coating. In the case of post-operative implantation of gels, gels with higher viscosity can be used because they do not pass through small diameter needles. Representative chemotherapeutic agents which may be delivered in accordance with the practice of the present invention include, for example, carboplatin, cisplatin, paclitaxel, BCNU, vincristine, camptothecin, etoposide, cytokines, ribozymes, interferons, oligonucleotides and oligonucleotide sequences which inhibit translation or transcription of tumor genes, functional derivatives of the foregoing, and generally known chemotherapeutic agents as described in U.S. Pat. No. 5,651,986. The present application is particularly useful for the sustained delivery of water-soluble chemotherapeutic agents, such as cisplatin and carboplatin, and water-soluble derivatives of paclitaxel. The inventive feature of minimizing the burst effect is particularly advantageous for administration of all kinds of water-soluble benefit agents, but particular compounds that are clinically useful and effective may have adverse side effects.

For aspects not mentioned above, the benefit agents described in the above-mentioned U.S. Pat. No. 5,242,910 may also be used. A particular advantage of the present invention is that materials such as proteins, cDNA and DNA exemplified by lysozyme are incorporated into viral and non-viral vectors which are difficult to microencapsulate or process into microspheres which can be incorporated into the compositions of the present invention without degradation levels caused by exposure to denaturing solvents commonly found in high temperature and other processing techniques.

The benefit agent is preferably incorporated into a viscous gel formed from the polymer and solvent in particulate form, the particles typically having an average particle size of from about 0.1 to about 250 microns, preferably from about 1 to about 200 microns, and typically from 30 to 125 microns. For example, particles having an average particle size of about 5 microns are produced by spray drying or freeze drying an aqueous mixture containing 5% sucrose and 50% chicken lysozyme (on a dry weight basis) and a mixture of 10-20% hGH with 15-30mM zinc acetate. Such particles are used in some of the examples shown in the figures. Conventional lyophilization processes can also be used to form different sized particles of benefit agent, using appropriate freezing and drying cycles.

To form a suspension or dispersion of particles of benefit agent in a viscous gel formed from polymer and solvent, any conventional low shear device such as a Ross double planetary mixer at ambient conditions may be used. In this way, an efficient distribution of the benefit agent can be achieved in large quantities without degrading the benefit agent.

The benefit agent is typically dissolved or dispersed in the composition in an amount of from about 0.1% to about 50% by weight, with the combined amount of polymer, solvent and benefit agent preferably being in an amount of from about 1% to about 4%, more preferably in an amount of from about 2% to about 30%, and typically 2 to 20% by weight. Depending on the amount of benefit agent present in the composition, different release profiles and burst indices may be obtained. More particularly, for particular polymers and solvents, a release profile can be obtained by adjusting the amount of these ingredients and the amount of benefit agent, the release profile depending on whether the polymer degrades more than the benefit agent diffuses from the composition or vice versa. In this regard, a release profile that reflects polymer degradation is generally obtained at a lower beneficial agent loading rate, where the release rate increases over time. A diffusion-induced release profile of the benefit agent is generally obtained at higher loading rates, where the release rate decreases over time. A combined release profile is obtained at intermediate loading rates, so that a significantly constant release rate can be obtained if desired. To minimize burst, the benefit agent is preferably loaded in the order of 30% or less by weight of the total gel composition, i.e., polymer, solvent, and benefit agent, more preferably 20% or less.

The release rate and loading of the beneficial agent is adjusted to provide therapeutically effective delivery of the beneficial agent over a sustained delivery period. The benefit agent is preferably present in the polymer gel at a concentration above the saturation concentration of the benefit agent in water to provide drug storage of the dispersed benefit agent. The release rate of the benefit agent depends on the particular circumstances, such as the benefit agent to be administered, and the release rates obtainable are in the order of about 0.1 microgram/day to about 30 mg/day, preferably about 1 microgram/day to about 20 mg/day, more preferably about 10 microgram/day to about 10 mg/day, for a period of time from about 24 hours to about 180 days, preferably 24 hours to about 120 days, more preferably 24 hours to about 90 days, typically 3 days to about 90 days. In addition, the beneficial agent dosage can be adjusted by adjusting the amount of the injectable depot gel. A greater amount may be delivered if the delivery occurs in a shorter period of time. In general, greater release rates are possible if a larger burst can be tolerated. Where the gel composition is surgically implanted or used as a "leave-on" depot, higher doses of the normal administration can be provided if the implant is injected when surgery is performed simultaneously to treat a disease state or another condition. In addition, the beneficial agent dosage can be controlled by adjusting the volume of the implant gel or injectable gel. Preferably, 40% or less by weight of the beneficial agent present in the viscous gel is systemically released within the first 24 hours after transplantation in the subject. More preferably, 30% or less by weight of the beneficial agent is released within the first 24 hours after implantation and the burst index of the implant composition is 12 or less, preferably 8 or less.

Optional additional ingredients:

other ingredients may be present in the gel composition to the extent that they require or provide useful properties to the composition, such as polyethylene glycol, humectants, stabilizers (e.g., surfactants like tween 20, tween 80, and the like, sugars like sucrose, trehalose, and the like, salts, antioxidants), pore formers, bulking agents (e.g., sorbitol, mannitol, glycine, and the like), chelating agents (e.g., divalent metal ions including zinc, magnesium, calcium, copper, and the like), buffering agents (e.g., phosphates, acetane, succinate, histidine, TRIS, and the like), and others. When the composition comprises peptides or proteins that are soluble or labile in an aqueous environment, it is highly desirable to include solubility modifiers, such as stabilizers, in the composition. Various modulators are described in U.S. Pat. Nos. 5,654,010 and 5,656,297, the disclosures of which are incorporated herein by reference. For example in the case of hGH, it is preferred to include an amount of a divalent metal salt, preferably zinc. Such modifiers and stabilizers may be complexed or otherwise associated with the benefit agent to provide a stabilized or modified release effect, examples include metal cations, preferably divalent, present in the composition as magnesium carbonate, zinc carbonate, calcium carbonate, magnesium acetate, magnesium sulfate, zinc acetate, zinc sulfate, zinc chloride, magnesium oxide, magnesium hydroxide, other antacids, and the like. The amount of these agents used depends on the nature of the complex formed or the nature of the association between the benefit agent and the agent. The molar ratio of solubility modifier or stabilizer to benefit agent which may be used is generally from about 100: 1 to 1: 1, preferably from 10: 1 to 1: 1.

Porogens include biocompatible materials that dissolve, disperse, or degrade when contacted with body fluids to create pores or channels in the polymer matrix. In general, water-soluble organic or non-organic substances such as sugars (e.g., sucrose, dextrose), water-soluble salts (e.g., sodium chloride, sodium phosphate, potassium chloride, and sodium carbonate), water-soluble solvents such as N-methyl-2-pyrrolidone and polyethylene glycol, and water-soluble polymers (e.g., carboxymethylcellulose, hydroxypropylcellulose, etc.) can be conveniently used as the pore-forming agent. Such materials may be present in varying amounts, from about 0.1% to about 100% by weight of the polymer, but typically less than 50% and more typically less than 10-20% by weight of the polymer.

Utility and application:

the method of administering the implant is not limited to injection, although a mode of delivery is generally preferred. When the implant is applied as a leave-on product, it may be formed after the procedure is completed to fit the existing body cavity or applied as a flowable gel, by brushing or clipping the gel onto the remaining tissue or bone. Such use allows the beneficial agent to be loaded into the gel at the concentrations typically found in the above injectable compositions.

The compositions of the present invention without beneficial agents are useful for wound healing, bone repair and other structural support purposes.

To further understand various aspects of the present invention, the results shown in the above figures are obtained according to the following examples.

Example 1

Gel carriers for injectable depot compositions are prepared as follows. The glass containers were weighed net on a Mettler PJ3000 top loader balance. Poly (D, L-lactide-co-7-lactide) (PLGA) as a 50: 50Resomer^*RG502(PLGA RG502) was weighed in a glass container. The glass container containing PLGA was weighed dry and the corresponding solvent was added. The amounts expressed as percentages of different polymer/solvent combinations are listed in table 1 below. The polymer/solvent mixture was stirred manually with a stainless steel square-top spatula to give a viscous amber paste-like mass containing white polymer particles. The vessel containing the polymer/solvent mixture was sealed and placed in a temperature controlled incubator equilibrated to 39 ℃. When a clear amber homogeneous gel appeared, the polymer/solvent mixture was removed from the incubator. The incubation time interval ranges from 1 to 4 days, depending on the solvent and polymer type and solvent and polymer ratio. Thereafter, the mixture was placed in an oven (65 ℃ C.) for 30 minutes. It was noted that PLGA-504 dissolved in the mixture upon removal from the oven.

Additional depot gel carriers were prepared with the following solvents or mixtures: benzyl benzoate, benzyl alcohol, propylene glycol, ethanol, and the following polymers: poly (D, L-lactide) Resomer^*L104, PLA-L104, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG502, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG502H, PLGA-502H, poly (D, L-lactide-co-glycolide) 50: 50Resomer^*RG503, Poly L-lactide MW 2,000 (Resomer)^*L206、Resomer^*L207、Resomer^*L209、Resomer^*L214); poly D, L lactide (Resomer)^*R104、Resomer^*R202、Resomer^*R203、Resomer^*R206、Resomer^*R207、Resomer^*R208); poly L-lactide-co-D, L-lactide 90: 10 (Resomer)^*LR 209); poly D-L-lactide-co-glycolide 75: 25 (Resomer)^*RG752、Resomer^*RG755、Resomer^*RG 756); poly D-L-lactide-co-glycolide 85: 15 (monomer)^*RG 858); poly L-lactide-co-trimethylene carbonate 70: 30 (Resomer)^*LT 706); polydioxanone (monomer)^*X210) (Boehringer ingelheim chemicals, inc., Petersburg, VA); DL-lactide/glycolide 100: 0 (MEDISORB)^*Polymer 100DL High, MEDISORB^*Polymer 100DL Low); DL-lactide/glycolide 85/15 (MEDISORB)^*Polymer 8515 DL High, MEDISORB^*Polymer 8515 DL Low); DL-lactide/glycolide 75/25 (MEDISORB)^*Polymer 7525 DL High, MEDISORB^*Polymer 7525 DL Low); DL-lactide/glycolide 65/35 (MEDISORB)^*Polymer 6535 DL High, MEDISORB^*Polymer 6535 DL Low); DL-lactide/glycolide 54/46 (MEDISORB)^*Polymer 5050DL High, MEDISORB^*Polymer 5050 DLLow); DL-lactide/glycolide 54/46 (MEDISORB)^*Polymer 5050DL 2A (3), MEDISORB^*Polymer 5050DL 3A (3), MEDISORB^*Polymer 5050DL 4A (3)) (Medisorb technologies international l.p., cincincinnati, OH); to be provided withAnd poly D, L-lactide-co-glycolide 50: 50; poly D, L-lactide-co-glycolide 65: 35; poly D, L-lactide-co-glycolide 75: 25; poly D, L-lactide-co-glycolide 85: 15; poly DL-lactide; poly-L-lactide; polyglycolide; poly-epsilon-caprolactone; poly DL-lactide-co-caprolactone 25: 75; poly DL-lactide-co-caprolactone 75: 25(Birmingham Polymers, Inc., Birmingham, AL). Representative gel carriers are described in table 1 below.

TABLE 1

Preparation	Polymer gm (%)	Benzyl benzoate gm (%)	Benzyl alcohol gm (%)	Propylene glycol gm (%)
Preparation	Polymer gm (%)	Benzyl benzoate gm (%)	Benzyl alcohol gm (%)	Propylene glycol gm (%)	1	5.0365	4.5093	0.5178	-
2	5.0139	3.7553	1.2560	-	1	5.0365	4.5093	0.5178	-
2	5.0139	3.7553	1.2560	-	3	5.0350	4.5193	-	0.5206
4	5.0024	3.7547	-	1.2508	3	5.0350	4.5193	-	0.5206
4	5.0024	3.7547	-	1.2508	5	5.0068	5.0044	-	-

Example 2

The rheological properties of long-acting vehicles made with different solvents were tested. The vehicle, comprising 50% by weight of polymer (PLGARG502) and 50% by weight of solvent (benzyl alcohol), was prepared according to the procedure outlined in example 1. For comparison purposes, solvents comprising benzyl benzoate (e.g., formulation 5) or benzyl benzoate in combination with ethanol (e.g., formulation 7) were also prepared. Table 2 lists the formulations used for the tests.

TABLE 2

Preparation	Polymer (%)	Benzyl benzoate (%)	Benzyl alcohol (%)	Ethanol (%)
Preparation	Polymer (%)	Benzyl benzoate (%)	Benzyl alcohol (%)	Ethanol (%)	5	50.0	50.0	0.0	0.0
6	50.0	0.0	50.0	0.0	5	50.0	50.0	0.0	0.0
6	50.0	0.0	50.0	0.0	7	45.0	52.8	0.0	2.2

Formulations 5,6, 7 were tested for viscosity at different shear rates. As shown in fig. 1, significant shear thinning properties were observed when benzyl alcohol was used as the solvent (e.g., formulation 6), as opposed to formulations using benzyl benzoate (e.g., formulation 5) and benzyl benzoate in combination with ethanol, respectively, as the thixotropic agent (e.g., formulation 7).

Example 3

The 3 formulations identified in example 2 were evaluated for the injection force required to disperse the depot vehicle. The formulation was injected through a 24 gauge needle at 1 ml/min room temperature. As shown in fig. 2, a significant reduction in injection force was observed when benzyl alcohol was used as the solvent (e.g., formulation 6), as opposed to formulations using benzyl benzoate (e.g., formulation 5) and benzyl benzoate in combination with ethanol, respectively, as the thixotropic agent (e.g., formulation 7). It was noted that at lower shear rates, formulations using benzyl alcohol as the solvent (e.g., formulation 6) and benzyl benzoate in combination with ethanol as the thixotropic agent (e.g., formulation 7) exhibited significantly reduced injection force while maintaining a viscosity equal to or greater than the formulation using benzyl benzoate (e.g., formulation 5) due to the shear thinning properties; thus maintaining the integrity of the depot after injection into an animal.

Example 4

A series of vehicles were evaluated for the injection force required to disperse the depot vehicle. Formulations containing different weight percentages of PLGA RG502 were each combined with the following solvents: 100% benzyl benzoate; 75% by weight of benzyl benzoate, 25% by weight of benzyl alcohol; 100% benzyl alcohol. The amount of solvent added is such that the total formulation is 100%, for example if 45% by weight PLGA-502 is used, 55% by weight solvent is used. The formulation was then tested for injection force, which was required to pass the formulation through a 24 gauge needle at room temperature of 1 ml/min. As shown in fig. 3, benzyl alcohol provides flexibility in formulation of long acting carriers, enabling the formulation of long acting carriers with much higher PLGA molecular weights while maintaining a relatively low injection force compared to similar benzyl benzoate-containing formulations. Furthermore, for any particular PLGA-502 percentage in the formulation, the injection force decreased as the percent benzyl alcohol increased, as shown in fig. 4.

Example 5

Preparation of hGH pellets

Human growth hormone (hGH) particles (optionally containing zinc acetate) were prepared as follows:

the hGH solution (5mg/mL) was concentrated to 10mg/mL in water using a concentration/dialysis selector diafiltration unit (BresaGen Corporation, Adelaide, Australia). The diafiltered hGH solution was washed with 5 volumes of tris or phosphate buffered solution (pH 7.6). The hGH particles are then prepared by spray drying or freeze drying using conventional techniques. Phosphate buffered solutions (5 or 50mM) containing hGH (5mg/mL) (optionally different levels of zinc acetate (0 to 30mM) when preparing Zn composite particles) were spray dried using a Yamato mini spray dryer with the following parameters:

spray dryer parameters	Is provided with
spray dryer parameters	Is provided with	Atomizing air	2psi
Inlet temperature	120℃	Atomizing air	2psi
Inlet temperature	120℃	Aspirator dial	7.5
Solution pump	2-4	Aspirator dial	7.5
Solution pump	2-4	Main air valve	40-45psi

Lyophilized particles prepared from hGH (5mg/mL) in tris buffer: (5 or 50 mM: ph7.6), prepared with a Durastop μ P freeze-dryer according to the following freeze and drying cycles:

refrigeration cycle	Slowly dropping to-30 deg.C at 2.5 deg.C/min and holding for 30 min
		Slowly dropping to-30 deg.C at 2.5 deg.C/min and holding for 30 min
	Drying cycle		Slowly raised to 10 ℃ at 0.5C/min and held for 960 minutes
Slowly increasing to 20 ℃ at 0.5C/min and keeping for 480 min			Slowly raised to 10 ℃ at 0.5C/min and held for 960 minutes
		Slowly increasing to 25 ℃ at 0.5C/min and keeping for 300 min
Slowly increasing to 30 ℃ at 0.5C/min and keeping for 300 min
		Slowly increasing to 5 deg.C at 0.5C/min and maintaining for 5000 min

Example 6

Preparation of hGH-stearic acid particles

Human growth hormone (hGH) granules were prepared as follows: lyophilized hGH (3.22 g, Pharmacia-Upjohn, Stockholm, Sweden) and stearic acid (3.22 g, 95% purity, Sigma-Aldrich Corporation, St. Louis, Mo.) were mixed and milled. The milled material was compressed in a 13mm round die using 10,000 pounds of pressure for 5 minutes. The compressed tablets were milled and passed through a 70 mesh screen followed by a 400 mesh screen to obtain granules in the size range of 38-212 microns.

Example 7

Preparation of bupivacaine-stearic acid granules

Bupivacaine particles were prepared as follows: bupivacaine hydrochloride (100 g, Sigma-Aldrich Corporation, St. Louis, Mo.) was screened through a 63-125 micron screen. Bupivacaine particles and stearic acid (100 g, 95% purity, Sigma-Aldrich Corporation, st. louis, MO) were mixed and milled. The milled material was compressed in a 13mm round die using 5,000 pounds of pressure for 5 minutes. The compressed tablets were milled and passed through a 120 mesh screen followed by a 230 mesh screen to obtain granules ranging in size from 63 to 125 microns.

Example 8

Drug loading

The compressed particles contain the benefit agent/stearic acid prepared above, the particles are added to the gel carrier in an amount of 10-20% by weight and mixed by hand until the dry powder is completely wet. The milky white yellowish particle/gel mixture was then thoroughly mixed by conventional mixing using a Caframo mechanical stirrer with a square-topped metal spatula attached. The resulting formulation is shown in table 5 below. The final homogeneous gel formulation was transferred to a 3, 10 or 30cc disposable syringe for storage or dispersion.

TABLE 2

Preparation	Polymer (%)	Benzyl benzoate (%)	Benzyl alcohol (%)	Ethanol (%)
Preparation	Polymer (%)	Benzyl benzoate (%)	Benzyl alcohol (%)	Ethanol (%)	8^a	45.0¹	45.0	0.0	0.0
9^a	39.6¹	49.5	0.0	0.9	8^a	45.0¹	45.0	0.0	0.0
9^a	39.6¹	49.5	0.0	0.9	10^a	45.0¹	33.8	11.3	0.0
11^a	45.0²	33.8	11.3	0.0	10^a	45.0¹	33.8	11.3	0.0
11^a	45.0²	33.8	11.3	0.0	12^b	58.5³	31.5	0.0	0.0
13^b	58.5³	0.0	31.5	0.0	12^b	58.5³	31.5	0.0	0.0
13^b	58.5³	0.0	31.5	0.0	14^b	67.5³	0.0	22.5	0.0
15^b	67.5⁴	0.0	22.5	0.0	14^b	67.5³	0.0	22.5	0.0
15^b	67.5⁴	0.0	22.5	0.0	16^c	60.0⁴	0.0	20.0	0.0

PLGA RG502 polymer (MW 16,000);

2-PLGA-L/G50/50 polymer (MW 22,600);

3＝PLGA L/G 50/50(MW 8,000)；

4＝PLGA L/G 50/50(MW 10,000)；

a＝5％hGH，5％SA；

b-10% bupivacaine;

c-10% bupivacaine, 10% SA.

A representative number of implantable gels were prepared according to the procedure described above and tested for release of beneficial agent as a function of time in vitro and rats were studied in vivo to determine beneficial agent release as a function of time, release being determined by serum or plasma concentration of the beneficial agent.

Example 9

hGH in vivo Studies

In vivo studies in rats were performed following published protocols to determine serum levels of hGH upon systemic administration of hGH via the inventive transplantation system. The long acting gel hGH formulation was filled into a 0.5cc disposable syringe. A disposable 16 gauge needle was attached to the syringe and heated to 37 ℃ with a circulating bath. Long acting gel hGH formulations were injected into immunosuppressed rats and blood was collected at specific time intervals. All serum samples were stored at 4 ℃ prior to analysis. Samples were analyzed for intact hGH content using Radioimmunoassay (RIA). At the end of the study, rats were euthanized for gross clinical observation and the depot was withdrawn for complete observation.

Figures 5 and 6 illustrate representative in vivo release profiles of human growth hormone ("hGH") obtained in rats from a variety of long acting formulations, including formulations of the present invention. The in vivo release profile of long acting formulations with benzyl alcohol (e.g., formulations 10 and 11) was comparable to control formulations (without benzyl alcohol, e.g., formulations 8 and 9). Thus, the long acting formulations of the present invention significantly reduce the injection force without including the in vivo release profile of the beneficial agent.

At the end of the study (i.e., day 28), the depot was withdrawn from the rats. Typically, recovery of 1 intact round depot corresponds to each injected depot in the animal.

Example 10

Bupivacaine in vivo study

In vivo studies in rats (4 per group) were performed following published protocols to determine the plasma levels of bupivacaine when systemically administered via the transplantation system of the present invention. The long acting gel bupivacaine formulation was filled into a 0.5cc disposable syringe. A disposable 18 gauge needle was attached to the syringe and heated to 37 ℃ with a circulating bath. Depot gel bupivacaine formulations were injected into rats and bled at specific time intervals (1 hour, 4 hours, days 1, 2, 5,7, 9 and 14) and analyzed for bupivacaine by LC/MS. At the end of the study (i.e., day 14), rats were euthanized for gross clinical observation and the depot was withdrawn for complete observation.

Figures 7, 8 and 9 illustrate representative in vivo release profiles of bupivacaine obtained in rats from a variety of long acting formulations, including the formulations of the present invention. The in vivo release profile of long acting formulations with benzyl alcohol (e.g., formulations 13-16) was comparable to the control formulation (without benzyl alcohol, e.g., formulation 12). Thus, the long acting formulations of the present invention significantly reduce the injection force without including the in vivo release profile of the beneficial agent.

At the end of the study (i.e., day 14), the depot was withdrawn from the rats. Typically, 1 intact round depot is recovered corresponding to each injected depot in the animal.

Example 11

Stability of hGH in Long acting formulations

Long-acting gel hGH formulations were stored at 5 ℃. At a predetermined time point, long acting gel hGH formulation (0.3ml) was treated with a cooled organic solvent (50/50 mixture of dichloromethane/acetone, 5 ℃, 3X 3ml) to extract the polymer and solvent from the long acting gel formulation. The remaining hGH thus obtained was dissolved in PBS buffer (2ml, pH7.4) and the purity of hGH was analyzed by Size Exclusion Chromatography (SEC). Fig. 16 illustrates hGH stability as a function of time at 5 ℃ in various long acting gel hGH formulations, including formulations of the present invention. hGH stability in benzyl alcohol containing depot formulations was comparable to control formulations without benzyl alcohol. Thus, the long acting formulation of the present invention significantly reduces the injection force without compromising the stability of the beneficial agent, such as hGH.

Example 12

Parameters influencing the injection force

The following parameters affect the injection force of a particular formulation at a preset temperature: syringe radius (r); the inner radius (R) of the needle; needle length (L); injection speed (Q). The effect of these 4 parameters on injection force was determined using a partial factorial design method (8 trials), with 1 near-center point for confirmation. The design details are summarized in Table 3 (runs 1-9). The injection force was tested with the following formulation (n ═ 3): the vehicle contained PLGA RG502/BB/BA (40/45/15% by weight) and lysozyme particles (10% by weight 30 μm). The correlation between injection force and test parameters was established with JMP software (much like Power law prediction) as follows:

TABLE 3

Test of	Needle ID^a(mm)	Needle length^b(mm)	Syringe ID^c(mm)	Speed of injection (mL/min)	Injection force (N)
					Injection force (N)		Mean value of	Standard deviation of
					1	0.191	Mean value of	Standard deviation of	12.7	2.3	0.05	14.6	0.8
2	0.292	50.8	3.25	0.5	1	0.191	172.2	5.3	12.7	2.3	0.05	14.6	0.8
2	0.292	50.8	3.25	0.5	3	0.292	172.2	5.3	12.7	3.25	0.05	8.6	0.2
4	0.191	12.7	3.25	0.5	3	0.292	176.0	2.6	12.7	3.25	0.05	8.6	0.2
4	0.191	12.7	3.25	0.5	5	0.292	176.0	2.6	50.8	2.3	0.05	13.4	0.3
6	0.292	12.7	2.3	0.5	5	0.292	30.0	2.5	50.8	2.3	0.05	13.4	0.3
6	0.292	12.7	2.3	0.5	7	0.191	30.0	2.5	50.8	3.25	0.05	127.0	2.3
8	0.191	50.8	2.3	0.5	7	0.191	161.4	4.5	50.8	3.25	0.05	127.0	2.3
8	0.191	50.8	2.3	0.5	9	0.241	161.4	4.5	25.4	2.3	0.25	48.8	0.5

^aThe needles used had the following gauge: 24G (ID 0.292mm), 25G (ID 0.241mm) and 27G (ID 0.191 mm);

^bthe needles used had the following lengths: 0.5 inch (12.7mm), 1 inch (25.4mm), 2 inch (50.8 mm); (ii) a

^cTwo different syringes (Hamilton): 250 μ L (ID ═ 2.30 mm); 500 μ L (ID 3.25 mm).

Example 13

Effect of drug particle size and Loading on injectability of Long-acting formulations

The particle size and loading of the beneficial agent, i.e., drug, is an additional factor that potentially affects the injectability of the depot. The long acting gel lysozyme formulation was used to determine the effect of drug particle size and loading on the injection force of the long acting formulation. The long-acting gel lysozyme preparation contains lysozyme with different amounts (5-30% loading) and particle sizes (5-50 μm), and the preparation uses a No. 27 2 needle to test the injection force. The injection rate was set at 50. mu.l/min. The test formulations are summarized in table 4. As shown in fig. 11, the injection force of the depot increased with increasing drug particle loading. At 10% weight loading of the particles, the injection force increased by about 50% compared to the corresponding gel formulation, regardless of the composition of the gel formulation. The injection force appears to be proportional to the amount of benzyl alcohol in the gel formulation, further indicating that benzyl alcohol significantly reduces the injection force of the long acting gel formulation of the present invention.

TABLE 4

Preparation	PLGA RG502 (wt%)	Benzyl benzoate (BB, wt%)	Benzyl alcohol (BA,% by weight)	Particle loading (% by weight)	Particle size (. mu.m)
Preparation	PLGA RG502 (wt%)	Benzyl benzoate (BB, wt%)	Benzyl alcohol (BA,% by weight)	Particle loading (% by weight)	Particle size (. mu.m)	18	38.0	42.8	14.2	5	5
19	34.0	38.3	12.8	15	5	18	38.0	42.8	14.2	5	5
19	34.0	38.3	12.8	15	5	20	38.0	42.8	14.2	5	50
21	34.0	38.3	12.8	15	50	20	38.0	42.8	14.2	5	50
21	34.0	38.3	12.8	15	50	22	36.0	40.5	13.5	10	20
23	38.0	-	57.0	5	5	22	36.0	40.5	13.5	10	20
23	38.0	-	57.0	5	5	24	34.0	-	51.0	15	5
25	38.0	-	57.0	5	50	24	34.0	-	51.0	15	5
25	38.0	-	57.0	5	50	26	34.0	-	51.0	15	50
27	36.0	-	54.0	10	20	26	34.0	-	51.0	15	50
27	36.0	-	54.0	10	20	28	30.8	34.7	11.6	23	50
29	28.0	31.5	10.5	30	50	28	30.8	34.7	11.6	23	50
29	28.0	31.5	10.5	30	50	30	30.8	-	46.2	23	50
31	28.0	-	42.0	30	50	30	30.8	-	46.2	23	50
31	28.0	-	42.0	30	50	32	40.0	45.0	15.0	0	-
33	40.0	-	60.0	0	-	32	40.0	45.0	15.0	0	-

Example 14

Preparation of PDGF Pre-formulations

Various platelet-derived growth factor (PDGF) pre-formulations were prepared as follows:

dialysis

The following buffers were prepared for dialysis:

(A) histidine buffer (10mM, pH6, 2L) was prepared as follows. L-histidine (3.10g) was weighed in a volumetric flask (2L). Milli-Q water (1800ml) was added to the flask and the mixture was stirred until the solids dissolved. HCl (0.1N, 8ml) was added, the pH checked and adjusted to 6. The solution was diluted to 2L volume with milli-Q water.

(B) Succinate buffer (10mM, pH6, 2L) was prepared as follows. Succinic acid (5.91g) was weighed in a volumetric flask (250ml) and milli-Q water was added to obtain a succinic acid solution (0.2M). The NaOH solution (4g, 50% w/w) was measured in a volumetric flask (250ml) and diluted with milli-Q water to obtain a NaOH solution (0.2M). The succinic acid solution (0.2M, 100ml) was mixed in a volumetric flask (2L) with NaOH solution (0.2M, 165ml) and milli-Q water (1600ml), checked for pH and adjusted to 6. The solution was diluted to 2L volume with milli-Q water.

The PDGF-BB bulk solution, i.e., the aqueous PDGF solution in acetate buffer, was thawed to room temperature. Aliquots of various PDGF-BB solutions were diluted appropriately for UV absorbance measurements using a 1cm pathlength cell from 400 to 250 nm. The absorbance was recorded at 280nm and the light scattering in the range of 400 to 330nm was corrected by extrapolation of the log (absorbance) versus the log (wavelength). PDGF-BB concentration was determined using an extinction coefficient of 0.574ml/mg × cm. The PDGF-BB solution was concentrated using a Milliporl tangential flow filtration system (with storage (100ml) and Pellicon XLPLCC 5000 MWCO regenerated cellulose membrane) and the protein was split into two fractions. Half of the protein was diafiltered against histidine buffer (10mM, pH6) according to the manufacturer's instructions; the other half of the protein was diafiltered against succinate buffer (10mM, pH 6). After diafiltration, aliquots of each fraction were diluted appropriately as described above for UV absorbance measurements and analyzed by reverse phase and size exclusion High Pressure Liquid Chromatography (HPLC). Protein solutions were removed from the TFF system according to millipore TFF instructions.

PDGF-BB pre-formulations

Various PDGF-BB preformulations are prepared by adding different excipients to the above diafiltered PDGF-BB solution, such as sucrose, Tween 20, zinc acetate or a combination thereof; the solution was buffered with histidine or succinate to obtain a final PDGF-BB concentration of about 5mg/ml in the solution (as listed in tables 5 and 6). These solutions were lyophilized at conditions lower than those used to obtain the dry PDGF-BB formulation.

Freeze-drying

The freeze-dry freezing cycle was initiated with shelf temperature equilibration at 4 ℃ at 2.5 ℃/min and held at this temperature for 30 minutes. The temperature was then lowered to-50 ℃ at 2.5 ℃/min and held for 3 hours. For the primary drying cycle, the applied vacuum and shelf temperature are increased as follows: (i) -20 ℃ at 0.14 ℃/min for 24 hours; (ii) -15 ℃ at 0.14 ℃/min for 24 hours; (iii)0 ℃ at 0.14 ℃ per minute for 12 hours. For the secondary drying cycle, the shelf temperature is increased as follows: (i) at 20 ℃ for 12 hours at 0.14 ℃/min; (ii)30 ℃ at 0.14 ℃ per minute for 4 hours. After drying, the shelf temperature was lowered to 0 ℃ or 4 ℃ and maintained until removed from the instrument. The vial was capped with a rack stopper, the run terminated and the vial removed.

Example 15

Preliminary stability of PDGF preformulation in gel Carrier

All lyophilized protein formulations listed in tables 5 and 6 were mixed into a gel vehicle having a PLGARG 502/Benzyl Benzoate (BB)/Benzyl Alcohol (BA) composition of 40/50/15, loaded with about 10% by weight of the protein formulation. After storage at 5 ℃ for 1 day, the mixture was extracted with an organic solvent mixture of dichloromethane and acetone (50/50 ratio) as described in example 15 above. The purity of PDGF-BB was analyzed by reverse phase HPLC (rpHPLC) and Size Exclusion Chromatography (SEC). Stability data for the PDGF-BB formulation after mixing with the gel carrier are summarized in tables 5 and 6. Generally, no distinguishable PDGF-BB degradation was found in PDGF-BB formulations incorporating the excipients described in example 14 and incorporating the gel carrier of the present invention.

TABLE 5

Preparation	SA-1	SA-2	SA-3	SA-4	SA-5	Autologous PDGF
Preparation	SA-1	SA-2	SA-3	SA-4	SA-5	Autologous PDGF	PDGF(mg)	1	1	1	1	1
Sucrose (mg)	1	1	0	0	0		PDGF(mg)	1	1	1	1	1
Sucrose (mg)	1	1	0	0	0		Tween 20(mg)	0	0.2	0.2	0	0
Succinate (mg)	0.24	0.24	0.24	0.24	0.24		Tween 20(mg)	0	0.2	0.2	0	0
Succinate (mg)	0.24	0.24	0.24	0.24	0.24		Zinc acetate (mg)	0	0	0	0	0.02
Gel carrier (mg)^a	20.16	21.96	12.96	11.16	11.34		Zinc acetate (mg)	0	0	0	0	0.02
Gel carrier (mg)^a	20.16	21.96	12.96	11.16	11.34		PDGF monomer by SEC%	98.90	98.82	98.02	98.51	98.59	99.27
PDGF doublet by SEC%	1.10	1.18	1.98	1.49	1.41	0.73	PDGF monomer by SEC%	98.90	98.82	98.02	98.51	98.59	99.27
PDGF doublet by SEC%	1.10	1.18	1.98	1.49	1.41	0.73	RRT by rp-HPLC 0.93 time Peak%	11.5	11.1	10.7	12.7	11.0	11.1
RRT by rp-HPLC ═ 1.00 time peak%	87.3	87.6	87.6	86.2	87.8	87.7	RRT by rp-HPLC 0.93 time Peak%	11.5	11.1	10.7	12.7	11.0	11.1
RRT by rp-HPLC ═ 1.00 time peak%	87.3	87.6	87.6	86.2	87.8	87.7	RRT by rp-HPLC ═ 1.10 time peak%	1.1	1.2	1.1	1.1	1.1	1.2
Other Peak% by rp-HPLC	0.0	0.1	0.6	0.0	0.0	0.0	RRT by rp-HPLC ═ 1.10 time peak%	1.1	1.2	1.1	1.1	1.1	1.2

a＝PLGA RG502/BB/BA-40/45/15

TABLE 6

Preparation	HA-1	HA-2	HA-3	HA-4	HA-5	Autologous PDGF
Preparation	HA-1	HA-2	HA-3	HA-4	HA-5	Autologous PDGF	PDGF(mg)	1	1	1	1	1
Sucrose (mg)	1	1	0	0	0		PDGF(mg)	1	1	1	1	1
Sucrose (mg)	1	1	0	0	0		Tween 20(mg)	0	0.2	0.2	0	0
Histidine (mg)	0.31	0.31	0.31	0.31	0.31		Tween 20(mg)	0	0.2	0.2	0	0
Histidine (mg)	0.31	0.31	0.31	0.31	0.31		Zinc acetate (mg)	0	0	0	0	0.02
Gel carrier (mg)^a	20.79	22.59	13.59	11.79	11.97		Zinc acetate (mg)	0	0	0	0	0.02
Gel carrier (mg)^a	20.79	22.59	13.59	11.79	11.97		PDGF monomer by SEC%	99.15	99.15	99.07	99.01	99.04	99.27
PDGF doublet by SEC%	0.85	0.85	0.93	0.99	0.96	0.73	PDGF monomer by SEC%	99.15	99.15	99.07	99.01	99.04	99.27
PDGF doublet by SEC%	0.85	0.85	0.93	0.99	0.96	0.73	RRT by rp-HPLC 0.93 time Peak%	11.3	11.0	10.9	10.8	10.9	11.1
RRT by rp-HPLC ═ 1.00 time peak%	87.6	87.8	87.7	88.0	88.0	87.7	RRT by rp-HPLC 0.93 time Peak%	11.3	11.0	10.9	10.8	10.9	11.1
RRT by rp-HPLC ═ 1.00 time peak%	87.6	87.8	87.7	88.0	88.0	87.7	RRT by rp-HPLC ═ 1.10 time peak%	1.1	1.1	1.2	1.2	1.1	1.2
Other Peak% by rp-HPLC	0.0	0.0	0.2	0.0	0.0	0.0	RRT by rp-HPLC ═ 1.10 time peak%	1.1	1.1	1.2	1.2	1.1	1.2

a＝PLGA RG502/BB/BA-40/45/15

Example 16

Preparation of PDGF particles

PDGF-BB formulations with sucrose in histidine buffer and without sucrose in succinate buffer were prepared in analogy to example 14 above (Table 7): thawing PDGF-BB bulk solution. The solution was combined in a graduated cylinder and the volume measured. Aliquots were taken and diluted appropriately for UV absorbance measurements. The absorbance from 400 to 250nm in a 1cm pathlength cell was recorded. The absorbance was recorded at 280nm and the light scattering in the range of 400 to 330nm was corrected by extrapolation of the log (absorbance) versus the log (wavelength). PDGF-BB concentration was determined using an extinction coefficient of 0.574ml/mg × cm. The Millipore tangential flow filtration system (with 100ml of storage and Pellicon XL plcc 5000 MWCO regenerated cellulose membrane) was used, and half of the protein was diafiltered against 10mM histidine pH6 and concentrated, and the other half was diafiltered against 10mM succinate pH6, as indicated by TFF, if concentration was required. After diafiltration, aliquots were removed from each fraction and diluted appropriately for UV absorbance measurement and analyzed by reverse phase and size exclusion HPLC. Protein solutions were removed from the TFF system according to millipore TFF instructions. For PDGF-BB in 10mM histidine, sucrose was added to produce a final ratio of 1: 1 to protein (PDGF-BB final concentration of 5 mg/ml). For PDGF-BB in 10mM succinate pH6, it was diluted with 10mM succinate to give a final protein concentration of about 5 mg/ml. Aliquots of the formulation were placed in glass lyophilization vials and lyophilized under the conditions described in example 18 to obtain lyophilized dry PDGF-BB formulation. The lyophilized PDGF-BB formulation was milled in an agate mortar and pestle. The milled granules were sieved through a US #230 mesh (63 μm) sieve and collected on a US #500 mesh (25 μm).

TABLE 7

Preparation	PDGF-BB (% by weight)	Succinate salt (% by weight)	Histidine (% by weight)	Sucrose (wt%)
Preparation	PDGF-BB (% by weight)	Succinate salt (% by weight)	Histidine (% by weight)	Sucrose (wt%)	34	81	19	-
35	43	-	14	43	34	81	19	-

Example 17

Preparation of PDGF long-acting formulations

PDGF long-acting formulations were prepared in two steps. The first step is to prepare a gel formulation by the following procedure. Appropriate amounts of pre-irradiated PLGA RG502 and solvent were dispersed in a Keyence hybridization mixing bowl (produced from High Density Polyethylene (HDPE)). The mixing bowl was tightly sealed, placed in a hybridization mixer (model HM-501, Keyence Corp., Japan) and mixed (5-10 minutes) at mixing speed (2000 rpm rotation, 800rpm rotation).

Mixing of the particles in the gel was performed at room temperature in a glass syringe (10ml or 25 ml). The PDGF particles and gel were first weighed and transferred to a syringe. The PDGF particles and gel mixture were then thoroughly mixed by conventional mixing using a Caframo mechanical stirrer with a square-top metal spatula attached. The resulting formulations are listed in table 8 below.

TABLE 8

Preparation	Polymer (%) (PLGA RG-502, MW 16,000)	Benzyl benzoate (%)	Benzyl alcohol (%)
Preparation	Polymer (%) (PLGA RG-502, MW 16,000)	Benzyl benzoate (%)	Benzyl alcohol (%)	36^a	31.5	43.9	14.6
37^b	31.5	43.9	14.6	36^a	31.5	43.9	14.6
37^b	31.5	43.9	14.6	38^a	31.5	29.3	29.2
39^b	31.5	29.3	29.2	38^a	31.5	29.3	29.2

^a10% formulation 34;

^b10% formulation 35.

Example 18

Stability of PDGF in Long-acting formulations

Long acting gel PDGF formulations were stored at 5, 25 and 40 ℃ for different periods of time, respectively. At predetermined time points, long acting gel PDGF-BB formulations were treated with cooled organic solvent (50/50 mixture of dichloromethane/acetone, 5 ℃, 3X 3.0 ml). The resulting remaining PDGF-BB was dissolved in PBS buffer (2ml, pH7.4) and PDGF purity was analyzed by reverse phase HPLC (rpHPLC) and Size Exclusion Chromatography (SEC) HPLC. Figures 12-14 illustrate PDGF stability in various long acting formulations, including the formulations of the present invention, as a function of time at 5 ℃ (figure 12), 25 ℃ (figure 13) and 40 ℃ (figure 14), respectively. Table 9 summarizes the chemical stability of PDGF in various long acting formulations tested by rpHPLC, including the formulations of the present invention, as a function of time at 5 ℃, 25 ℃ and 40 ℃, respectively. As shown in fig. 12-14, the sucrose-containing long acting gel PDGF formulations demonstrated surprising stability with minimal loss of monomer content compared to the long acting gel PDGF formulations without sucrose at all measured temperatures.

TABLE 9

Preparation	Temperature of	Time (sky)	RP-HPLC (% Peak region)
			RP-HPLC (% Peak region)				(RRT 0.93) peak value	Peak value of (RRT 1.00)	Peak value of (RRT 1.09)	Other peak values
			Autologous PDGF		0	11.1	(RRT 0.93) peak value	Peak value of (RRT 1.00)	Peak value of (RRT 1.09)	Other peak values	87.7	1.2	0
36		0	Autologous PDGF		0	11.1	13.03±0.12	85.04±0.43	1.2±0.35	0.72±0.09	87.7	1.2	0
		0	5℃	14	12.77±0.28	85.94±0.17	13.03±0.12	85.04±0.43	1.2±0.35	0.72±0.09	1.06±0.03	0.23±0.19
	5℃	28	5℃	14	12.77±0.28	85.94±0.17	12.17±0.32	86.03±0.77	1.11±0.34	0.69±0.08	1.06±0.03	0.23±0.19
	5℃	28	5℃	90	12.14±0.35	86.14±0.42	12.17±0.32	86.03±0.77	1.11±0.34	0.69±0.08	0.78±0.01	0.94±0.08
	25℃	14	5℃	90	12.14±0.35	86.14±0.42	9.57±0.14	89.52±0.18	(shoulder shape)	0.91±0.03	0.78±0.01	0.94±0.08
	25℃	14	25℃	28	8.24±0.12	90.98±0.09	9.57±0.14	89.52±0.18	(shoulder shape)	0.91±0.03	(shoulder shape)	0.78±0.04
	25℃	90	25℃	28	8.24±0.12	90.98±0.09	8.96±0.21	90.16±0.23	(ineffective)	0.88±0.01	(shoulder shape)	0.78±0.04
	25℃	90	40℃	14	7.22±0.06	91.96±0.09	8.96±0.21	90.16±0.23	(ineffective)	0.88±0.01	(shoulder shape)	0.83±0.02
	40℃	28	40℃	14	7.22±0.06	91.96±0.09	5.54±0.13	93.80±0.09	(shoulder shape)	0.66±0.09	(shoulder shape)	0.83±0.02
	40℃	28							(shoulder shape)	0.66±0.09
	37								0	13.25±0.16	84.97±0.34	1.5±0.36	0.28±0.86
5℃			14	13.07±0.04	85.32±0.34	1.43±0.36	0.18±0.03		0	13.25±0.16	84.97±0.34	1.5±0.36	0.28±0.86
5℃		5℃	14	13.07±0.04	85.32±0.34	1.43±0.36	0.18±0.03	28	12.93±0.08	85.62±0.43	1.27±0.37	0.18±0.06
5℃		5℃	90	14.07±0.25	83.87±0.41	1.39±0.44	0.67±0.28	28	12.93±0.08	85.62±0.43	1.27±0.37	0.18±0.06
5℃		25℃	90	14.07±0.25	83.87±0.41	1.39±0.44	0.67±0.28	14	12.19±0.10	86.28±0.52	1.25±0.33	0.28±0.13
25℃		25℃	28	11.79±0.27	86.82±0.09	1.30±0.35	0.10±0.02	14	12.19±0.10	86.28±0.52	1.25±0.33	0.28±0.13
25℃		25℃	28	11.79±0.27	86.82±0.09	1.30±0.35	0.10±0.02	90	14.57±0.11	83.84±0.57	1.43±0.46	0.17±0.00
40℃		25℃	14	12.93±0.08	85.65±0.26	1.26±0.39	0.16±0.07	90	14.57±0.11	83.84±0.57	1.43±0.46	0.17±0.00
40℃		40℃	14	12.93±0.08	85.65±0.26	1.26±0.39	0.16±0.07	28	13.09±0.24	85.18±0.17	1.59±0.43	0.15±0.04
								28	13.09±0.24	85.18±0.17	1.59±0.43	0.15±0.04
						38		0	12.39±0.28	85.91±0.26	0.96±0.02	0.73±0.04
5℃	14	12.21±0.29	86.05±0.34	1.10±0.32	0.64±0.38			0	12.39±0.28	85.91±0.26	0.96±0.02	0.73±0.04
5℃	14	12.21±0.29	86.05±0.34	1.10±0.32	0.64±0.38		5℃	28	11.38±0.18	87.11±0.70	0.81±0.04	0.97±0.08
25℃	14	8.50±0.19	90.40±0.27	(shoulder shape)	1.10±0.08		5℃	28	11.38±0.18	87.11±0.70	0.81±0.04	0.97±0.08
25℃	14	8.50±0.19	90.40±0.27	(shoulder shape)	1.10±0.08		25℃	28	7.73±0.19	91.25±0.18	(shoulder shape)	1.02±0.04
25℃	90	7.48±0.64	91.67±0.66	Ineffective)	0.86±0.01		25℃	28	7.73±0.19	91.25±0.18	(shoulder shape)	1.02±0.04
25℃	90	7.48±0.64	91.67±0.66	Ineffective)	0.86±0.01		40℃	14	(shoulder shape)	99.17±0.00	(shoulder shape)	0.83±0.04
40℃	28	(shoulder shape)	99.56±0.00	(shoulder shape)	0.44±0.03		40℃	14	(shoulder shape)	99.17±0.00	(shoulder shape)	0.83±0.04
40℃	28	(shoulder shape)	99.56±0.00	(shoulder shape)	0.44±0.03
39		0	12.71±0.14	85.90±0.26	1.1±0.01								0.3±0.03
		0	12.71±0.14	85.90±0.26	1.1±0.01	5℃	14	13.04±0.25	85.10±0.60	1.45±0.37	0.41±0.13		0.3±0.03
	5℃	28	12.67±0.20	86.05±0.17	1.04±0.02	5℃	14	13.04±0.25	85.10±0.60	1.45±0.37	0.41±0.13	0.24±0.05
	5℃	28	12.67±0.20	86.05±0.17	1.04±0.02	5℃	90	14.65±0.08	83.65±0.07	1.04±0.01	0.66±0.13	0.24±0.05
	25℃	14	12.94±0.06	85.27±0.43	1.50±0.33	5℃	90	14.65±0.08	83.65±0.07	1.04±0.01	0.66±0.13	0.29±0.10
	25℃	14	12.94±0.06	85.27±0.43	1.50±0.33	25℃	28	12.64±0.19	85.55±0.34	1.51±0.41	0.30±0.09	0.29±0.10
	25℃	90	14.11±0.15	84.68±0.10	1.01±0.01	25℃	28	12.64±0.19	85.55±0.34	1.51±0.41	0.30±0.09	0.21±0.04
	25℃	90	14.11±0.15	84.68±0.10	1.01±0.01	40℃	14	12.10±0.18	85.76±0.34	1.26±0.39	0.87±0.46	0.21±0.04
	40℃	28	11.12±0.22	88.05±0.88	(shoulder shape)	40℃	14	12.10±0.18	85.76±0.34	1.26±0.39	0.87±0.46	0.19±0.03

Example 19

In vitro release of PDGF from depot formulations

In vitro release of PDGF from long acting gel PDGF formulations of the present invention is performed as follows. Long-acting gel PDGF formulation (80-120mg) was packed in tea bags and placed in 20mL scintillation vials, and release medium (5mL, Phosphate Buffered Saline (PBS) + 0.1% Tween 20, pH7.4) was added to the vials. The tubes were incubated in a 37C water bath with gentle agitation. The medium was changed every day for the first 5 days, 2 times in the following 1 week until the end of the release duration. The amount of PDGF released from the depot was measured by Size Exclusion Chromatography (SEC) HPLC. As shown in fig. 15, sustained release of PDGF from the long acting formulation of the present invention was achieved for more than 1 month.

The above-described exemplary embodiments are intended to be illustrative in all respects, rather than restrictive, of the present invention. Thus, the present invention is capable of many variations in detailed implementation that can be derived from the description contained herein by a person skilled in the art. All such variations and modifications are considered to be within the scope and spirit of the present invention.

Claims

1. An injectable depot composition, comprising:

a bioerodible, biocompatible polymer;

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

2. The composition of claim 1 wherein said aromatic alcohol is of formula (I)

Ar-(L)_n-OH (I)

Wherein Ar is aryl or heteroaryl, n is 0 or 1, and L is a linking moiety

3. The composition of claim 2, wherein Ar is a monocyclic aryl or heteroaryl group, n is 1, and L is a lower alkylene group optionally containing at least one heteroatom.

4. The composition of claim 3, wherein Ar is a monocyclic aryl group and L is a lower alkylene group.

5. The composition of claim 4, wherein Ar is phenyl and L is methylene.

6. The composition of claim 1, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid and copolymers, terpolymers, and mixtures thereof.

7. The composition of claim 1, wherein the polymer is a lactic acid-based polymer.

8. The composition of claim 7, wherein the polymer is a copolymer of lactic acid and glycolic acid.

9. An injectable depot composition, comprising:

about 5% to about 90% by weight of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight ranging from about 5,000 to about 50,000;

an aromatic alcohol having miscibility in water of less than or equal to 5% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the formula (I)

Ar-(L)_n-OH (I)

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

10. The composition of claim 9, wherein the polymer represents from about 25% to about 85% by weight of the composition.

11. The composition of claim 10, wherein the polymer represents from about 35% by weight to about 75% by weight of the composition.

12. The composition of claim 9, wherein the polymer is a copolymer of lactic acid and glycolic acid.

13. The composition of claim 12, wherein the aromatic alcohol is benzyl alcohol.

14. An injectable depot composition, comprising:

a bioerodible, biocompatible polymer;

a solvent selected from the group consisting of esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith;

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

15. The composition of claim 14, wherein the solvent is an ester of an aromatic acid.

16. The composition of claim 15, wherein the solvent is a lower alkyl or aralkyl ester of benzoic acid.

17. The composition of claim 14, wherein Ar is a monocyclic aryl or heteroaryl group, n is 1, and L is a lower alkylene group optionally containing at least one heteroatom.

18. The composition of claim 17, wherein Ar is monocyclic aryl and L is lower alkylene.

19. The composition of claim 18, wherein Ar is phenyl and L is methylene.

20. The composition of claim 14, wherein the ratio of aromatic alcohol to solvent ranges from 10% to about 99% (by weight).

21. The composition of claim 20, wherein the ratio of aromatic alcohol to solvent ranges from about 20% to about 99% (by weight).

22. The composition of claim 14, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid and copolymers, terpolymers, and mixtures thereof.

23. The composition of claim 14, wherein the polymer is a lactic acid-based polymer.

24. The composition of claim 23, wherein the polymer is a copolymer of lactic acid and glycolic acid.

25. An injectable depot composition, comprising:

esters of aromatic acids said esters having a miscibility in water of less than or equal to 7% at 25 ℃, in an amount effective to plasticize the polymer and form a gel therewith;

an effective contact amount of an aromatic alcohol having a miscibility in water of less than or equal to 7%, wherein the aromatic alcohol has the formula (I),

Ar-(L)_n-OH (I)

the beneficial agent(s) is (are),

wherein the composition is free of monohydric lower alkanol.

26. The composition of claim 25, wherein the polymer represents from about 25% to about 80% by weight of the composition.

27. The composition of claim 26, wherein the polymer represents from about 35% by weight to about 75% by weight of the composition.

28. The composition of claim 25, wherein the polymer is a copolymer of lactic acid and glycolic acid.

29. The composition of claim 25, wherein the aromatic alcohol is benzyl alcohol

30. The composition of claim 25, wherein the solvent is a lower alkyl or aralkyl ester of benzoic acid.

31. The composition of claim 30, wherein the solvent is benzyl benzoate.

32. The composition of claim 29, wherein the solvent is benzyl benzoate.

33. The composition of claim 25, wherein the ratio of aromatic alcohol to solvent ranges from about 10% to about 99% (by weight).

34. The composition of claim 33, wherein the ratio of benzyl alcohol to benzyl benzoate ranges from about 20% to about 80% by weight.

35. A composition according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 5% (by weight) at 25 ℃.

36. A composition according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 3 wt% at 25 ℃.

37. A composition according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 1 wt% at 25 ℃.

38. A composition according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 0.5 wt% at 25 ℃.

39. The composition of any of the preceding claims, wherein the composition further comprises at least one of: a pore-forming agent; a solubility modifier for the benefit agent; and a penetrant.

40. A composition according to any preceding claim, wherein the composition is free of solvents having a miscibility in water of greater than 7 wt% at 25 ℃.

41. The method of any of the preceding claims, wherein the beneficial agent is selected from the group consisting of drugs, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs and metabolites, and analogs, derivatives and fragments thereof.

42. The composition of claim 41, wherein the benefit agent is present in an amount of from 0.1% to 50% (by weight) of the combined amount of polymer, solvent and benefit agent.

43. The composition of claim 41, wherein the benefit agent is in the form of particles dispersed or dissolved in a viscous gel.

44. The composition of claim 43, wherein the benefit agent is in the form of particles, wherein the particles further comprise an ingredient selected from the group consisting of stabilizers, fillers, chelating agents, and buffers.

45. A method of administering a beneficial agent to a subject, the method comprising the steps of:

(1) administering to a subject an injectable depot composition at a site within the subject, the composition comprising

(a) A bioerodible, biocompatible polymer;

(b) an aromatic alcohol having miscibility in water of less than or equal to 7% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith; and

(c) a benefit agent, wherein the composition is free of monohydric lower alkanol; and

(2) forming an implant at the site, wherein the implant provides for sustained release of the beneficial agent at the site.

46. The method of claim 45, wherein the aromatic alcohol is of formula (I)

Ar-(L)_n-OH (I)

Wherein Ar is aryl or heteroaryl, n is 0 or 1, and L is a linking moiety.

47. The method of claim 46, wherein Ar is a monocyclic aryl or heteroaryl group, n is 1, and L is a lower alkylene group optionally containing at least one heteroatom.

48. The composition of claim 46, wherein Ar is a monocyclic aryl group and L is a lower alkylene group.

49. The method of claim 48, wherein Ar is phenyl and L is methylene.

50. The method of claim 45, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid and copolymers, terpolymers, and mixtures thereof.

51. The method of claim 45, wherein the polymer is a lactic acid-based polymer.

52. A method of administering a beneficial agent to a subject, the method comprising the steps of:

(a) A bioerodible, biocompatible polymer;

(b) a solvent selected from the group consisting of ester aromatic ketones of aromatic acids and mixtures thereof, said solvent having a miscibility in water of less than or equal to 7% at 25 ℃ and being present in an amount effective to plasticize the polymer and form a gel therewith;

(c) an effective contact amount of an aromatic alcohol having a miscibility in water of less than or equal to 7%; and

(d) a benefit agent, wherein the composition is free of monohydric lower alkanol; and

53. The method of claim 52, wherein the polymer represents from about 25% to about 80% by weight of the composition.

54. The method of claim 53, wherein the polymer represents from about 35% to about 75% by weight of the composition.

55. The method of claim 52, wherein the polymer is a copolymer of lactic acid and glycolic acid.

56. The method of claim 55, wherein the aromatic alcohol is benzyl alcohol.

57. A method of administering a beneficial agent to a subject, the method comprising the steps of:

(a) About 5% to about 90% by weight of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight ranging from about 1,000 to about 120,000;

(b) an aromatic alcohol having miscibility in water of less than or equal to 5% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith; wherein the aromatic alcohol has a structural formula (I),

Ar-(L)_n-OH (I)

(c) a benefit agent; wherein the composition is free of monohydric lower alkyl alcohols; and

58. The method of claim 57, wherein the solvent is an ester of an aromatic acid.

59. The method of claim 58, wherein the solvent is a lower alkyl or aralkyl ester of benzoic acid.

60. The method of claim 57, wherein Ar is a monocyclic aryl or heteroaryl group, n is 1, and L is a lower alkylene group optionally containing at least one heteroatom.

61. The method of claim 60, wherein Ar is monocyclic aryl and L is lower alkylene.

62. The method of claim 61, wherein Ar is phenyl and L is methylene.

63. The method of claim 57, wherein the ratio of aromatic alcohol to solvent ranges from about 10% by weight to about 99% by weight.

64. The method of claim 63, wherein the ratio of aromatic alcohol to solvent ranges from about 20% by weight to about 80% (by weight).

65. The method of claim 57, wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly (malic acid), poly (amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid and copolymers, terpolymers, and mixtures thereof.

66. The method of claim 57, wherein the polymer is a lactic acid-based polymer.

67. The method of claim 66, wherein the polymer is a copolymer of lactic acid and glycolic acid.

68. A method of administering a beneficial agent to a subject, the method comprising the steps of:

(1) administering to a subject an injectable depot composition at a site within the subject, the composition comprising:

(a) about 5% to about 90% by weight of a poly (lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of from about 1,000 to about 120,000;

(b) about 5 wt% to about 90 wt% of an aromatic alcohol solvent having a miscibility in water of less than or equal to 7% at 25 ℃, present in an amount effective to plasticize the polymer and form a gel therewith; and

69. The method of claim 68, wherein the polymer represents from about 25% to about 80% by weight of the composition.

70. The method of claim 69, wherein the polymer represents from about 35% to about 75% by weight of the composition.

71. The method of claim 68, wherein the polymer is a copolymer of lactic acid and glycolic acid.

72. The method of claim 68, wherein the aromatic alcohol is benzyl alcohol.

73. The method of claim 68, wherein the solvent is a lower alkyl or aralkyl ester of benzoic acid.

74. The method of claim 73, wherein the solvent is benzyl benzoate.

75. The method of claim 72, wherein the solvent is benzyl benzoate.

76. The method of claim 68, wherein the ratio of aromatic alcohol to solvent ranges from about 10% to about 99% (by weight).

77. The method of claim 76, wherein the ratio of benzyl alcohol to benzyl benzoate ranges from about 20% to about 80% (by weight).

78. A process according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 5 wt% at 25 ℃.

79. A process according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 3 wt% at 25 ℃.

80. A process according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 1 wt% at 25 ℃.

81. A process according to any preceding claim, wherein the aromatic alcohol has a miscibility in water of less than or equal to 0.5 wt% at 25 ℃.

82. The method of any of the preceding claims, wherein the composition further comprises at least one of: a pore-forming agent; a solubility modifier for the benefit agent; and a penetrant.

83. A method according to any preceding claim, wherein the composition is free of solvents having a miscibility in water of greater than 7 wt% at 25 ℃.

84. The method of any of the preceding claims, wherein the beneficial agent is selected from the group consisting of drugs, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs and metabolites, and analogs, derivatives and fragments thereof.

85. The method of claim 84, wherein the benefit agent is present in an amount from 0.1% to 50% by weight of the combined amount of polymer, solvent and benefit agent.

86. The method of claim 84, wherein the benefit agent is in the form of particles dispersed or dissolved in a viscous gel.

87. The method of claim 68, wherein the benefit agent is in the form of particles, wherein the particles further comprise an ingredient selected from the group consisting of stabilizers, fillers, chelating agents, and buffers.