Composition and method for forming biodegradable implants in situ and uses of these implants

The invention discloses a composition having a mixture of a pharmaceutically, medically or veterinarily acceptable polymer, preferable a poly (lactic-co-glycolic acid) copolymer (PLGA) containing between about 10 and 100 wt. % lactic acid (LA) units, preferably between about 50 and 90 wt. % LA units, and .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl) (glycofurol). Methods of forming solid implants in situ in an animal body, said implants optionally comprising a drug or other biologically active agent, as well as the use of the compositions of the invention in the treatment of animal bodies, are also disclosed.

FIELD OF THE INVENTION
 This invention relates to a composition useful in the in situ formation of
 biodegradable polymeric implants of polymers and copolymers of lactic and
 glycolic acid, to a method of forming such implants in situ using the
 composition of the invention, to implants formed thereby, and to uses of
 such composition, method or implants as a space-filler, for soft or hard
 tissue regeneration, and for the controlled release of drugs.
 BACKGROUND OF THE INVENTION
 The use of biodegradable polymers in medical applications, such as sutures,
 staples, surgical clips, implant and drug delivery systems, is well known.
 A particular use is the in situ formation of biodegradable implants or
 inserts; in this application, the term "biodegradable implant" and
 "biodegradable insert" will be used interchangeably. The in situ formation
 of biodegradable implants is described, for example, in U.S. Pat. No.
 4,938,763; Duysen et al., Pharmaceutical Research, 1994, Amer. Assoc. of
 Pharm. Scientists, Presentation #7575; Frank et al., Pharmaceutical
 Research, 1994, Amer. Assoc. of Pharm. Scientists, Presentation #2070;
 Dunn et al., Proc. Int. Symp. Control. Rel. Bioact. Mater., 22 (1995);
 Dunn et al., Portland Bone Symposium, Aug. 2-5, 1995, Portland, Oreg.;
 Andreopoulos, Clinical Materials 15 (1994) 89-92; Lambert & Peck, J.
 Controlled Release 33 (1995) 189-195; Shah et al., J. Controlled Release
 27 (1993) 139-147; Shively et al., J. Controlled Release 33 (1995)
 237-243; Lowe et al., 19th Ann. Mtg. Soc. Biomaterials.
 Such implants serve two main purposes: as space-filling material, e.g.
 where tissue has been removed or where bone regeneration is required; and
 as a mechanism for controlled release of drugs. The advantages of forming
 such inserts in situ as opposed to outside the body are described in the
 foregoing references, and include the ability to insert the implant
 without resorting to surgery, as well as the capability of the implant to
 be formed exactly to the dimensions of the cavity being filled when
 space-filling is the goal of the implant.
 As described in U.S. Pat. No. 4,938,763, one of the methods (the
 "thermoplastic system") which may be employed for the in situ formation of
 implants is the injection of a solution containing a water-immiscible
 biodegradable polymer and a water-miscible biologically compatible
 (non-toxic) solvent into an animal. The solvent is quickly carried away
 from the injection site, and the polymer left behind in the aqueous
 environment of the body quickly coagulates or solidifies into a solid
 matrix structure. If the implant is meant to serve as a drug-delivery
 system, then the drug is incorporated into the solution prior to
 injection, and is trapped in the solid matrix formed upon coagulation of
 the polymer. As will be appreciated by persons skilled in the art,
 different degrees of coagulation, and thus different rates of
 biodegradation and/or, if applicable, drug release, may be achieved, by
 varying the characteristics of the polymer or copolymer (e.g., degree of
 hydrophobicity or average molecular weight), the solvent, and the relative
 amount of each component prior to injection. The relative amount of the
 drug and the identity of the drug are also important factors when the
 implant serves as a controlled-release device.
 The polymers and copolymers known in the art to be suitable for use in the
 "thermoplastic method" of in situ implant formation disclosed in U.S. Pat.
 No. 4,938,763 include poly(L-lactic acid), poly(D-lactic acid),
 poly(DL-lactic acid), poly(L-lactide), poly(D-lactide), poly(DL-lactide),
 poly(DL-lactide-co-glycolide), poly(lactic-co-glycolic) acid,
 polyglycolide, and polyglycolic acid. Solvents known in the art include
 N-methyl pyrrolidone, propylene glycol, triacetin, triethyl citrate, and
 dimethyl sulfoxide. As stated, it will be appreciated that the degree of
 coagulation of the polymer, and thus the rate of biodegradation and/or
 drug release, is dependent in part on the choice of solvent used. On the
 other hand, the ability of a given biocompatible solvent to dissolve a
 given biodegradable polymer, and to provide a solution that can be used in
 a method for the in situ formation of a biodegradable polymeric implant
 is, at best, unpredictable. Not every biocompatible solvent can be used
 with any given biodegradable polymer, and not every biodegradable polymer
 can be used with any given solvent to provide the desired solution for use
 in in situ formation of a biodegradable polymeric implant. Furthermore, in
 view of the fact that, ultimately, the above biocompatible
 solvent-biodegradable polymer containing solutions are intended for
 administration in humans, it is essential that such solutions be
 acceptable pharmacologically, i.e., that their administration will be
 essentially harmless to the patient. Likewise, in veterinary medicine,
 when such implants are to be formed in, for example, domestic animals, it
 is essential that the solutions administered to the animals are
 essentially harmless.
 Accordingly, in view of the above-mentioned medical and veterinary
 considerations, the number of potential biocompatible
 solvent-biodegradable polymer combinations useful for administration to
 humans and/or animals for in situ biodegradable implant formation is
 considerably restricted. One of the drawbacks of the prior art noted above
 is the general failure to provide specific, harmless solutions that can be
 used for the in situ formation of biodegradable polymers; often, at least
 some of the polymers to be dissolved therewith are not suitable for human
 or animal administration.
 Another drawback of the above prior art is that often, when a desirable
 solvent-polymer combination is obtained that is fit for medical and/or
 veterinary use, the process by which such a combination, i.e., solution,
 is produced is often tedious, requiring special conditions for production.
 For example, in the above-noted U.S. Pat. No. 4,938,763, there are
 described various methods for preparing some solvent-polymer combinations
 for use as in situ forming biodegradable implants, many of which methods
 require the use of catalysts, more than one solvent, high temperatures and
 other special conditions to provide the solvent-polymer solution to be
 administered.
 Poly(lactic-co-glycolic acid) copolymer (PLGA) is used for injection in man
 and used for parenteral applications. Glycofurol
 (.alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)) is
 used as a solvent in parenteral products for intravenous or intramuscular
 injection of concentrations of up to 50% v/v; when administered
 parenterally to humans, quantities of glycofurol should not exceed 0.07 ml
 per kg of body weight per day (Handbook of Pharmaceutical Excipients, Am.
 Pharmac. Assoc. and Pharm. Soc. of Gr. Br., 1994). However, heretofore,
 there has not been described a solution useful for the in situ formation
 of a biodegradable implant that is comprised of a biocompatible solvent
 being glycofurol and a biodegradable polymer being composed of lactic acid
 (LA) and/or glycolic acid (LG) units, e.g. PLGA, of which both polymer and
 solvent have been approved for human administration, and which are
 compatible with each other, such that the polymer may be readily dissolved
 in the solvent at room temperature, without the need for other additives
 such as catalysts, additional solvents or the like; and which solution is
 useful for the in situ formation of a biodegradable implant for tissue or
 bone replacement, and for the controlled release of drugs.
 It is therefore an object of the invention to provide a composition
 comprising a polymer which is PLGA containing from 10-100 wt. % lactic
 acid (LA) units, preferably from 50-90 wt. % LA units, and a solvent which
 is glycofurol for use in the formation of a biodegradable implant.
 It is another object of the invention to provide a method which employs the
 composition of the invention in the in situ formation of a biodegradable
 implant.
 It is yet another object of the invention to provide biodegradable
 polymeric implants which can be as controlled-delivery devices for drugs
 or other biologically active agents.
 It is another object the invention to provide implants the properties of
 which may be manipulated so as to enable the use of said implants with
 both hard and soft tissues.
 It is still another object of the invention to provide biodegradable
 polymeric implants comprising as polymer PLGA containing from 10-100 wt. %
 LA units, preferably 50-90 wt. % LA units, whenever prepared from the
 composition of the invention or by the method of the invention.
 Other objects of the invention will become apparent as the description
 proceeds.
 SUMMARY OF THE INVENTION
 The present invention is based on the surprising finding that solutions of
 the polymer PLGA (poly(lactic-co-glycolic acid) containing from 10-100 wt.
 % LA units, preferably 50-90 wt. % LA units, in glycofurol
 (.alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)),
 optionally comprising a drug or other biological agent, may be used to
 form biodegradable implants in situ.
 The composition of the invention comprises a mixture of a polymer which is
 poly(lactic-co-glycolic acid) (PLGA) containing from 10-100 wt. % LA
 units, preferably 50-90 wt. % LA units, and a solvent which is
 .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)
 (glycofurol), optionally comprising a drug or other biologically active
 agent dissolved, dispersed or suspended in the mixture.
 The method for in situ formation of a biodegradable implant, according to
 the invention, comprises the steps of:
 a--dissolving a polymer which is poly(lactic-co-glycolic acid) (PLGA)
 containing from 10-100 wt. % LA units, preferably 50-90 wt. % LA units, in
 a solvent which is
 .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)
 (glycofurol) to form a liquid;
 b--administering a suitable amount of said liquid to an animal body; and
 c--allowing said glycofurol to dissipate in said animal body, whereby to
 produce a solid implant composed of a PLGA polymeric matrix.
 Optionally, a drug or other biologically active molecule may be dissolved,
 dispersed or suspended in the liquid prior to, concurrent with or
 subsequent to said dissolution of said polymer.
 The term "animal body" as used herein includes the human body.
 The invention also comprises compositions comprising a mixture of
 .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)
 (glycofurol) and a pharmaceutically acceptable, medically acceptable, or
 veterinarily acceptable polymer which is soluble in glycofurol.
 Other aspects and embodiments of the invention are set forth hereinbelow,
 or will readily arise from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION
 Preferably, the average molecular weight of the glycofurol is between about
 146.24 and 190.24. The density may be between about 1.07 and 1.09
 g/cm.sup.3 at 20.degree. C.
 The polymer used in the invention may range in average molecular weight
 from about 2000 to about 100,000. The inherent viscosity may be between
 about 0.2 dl/g and 7.2 dl/g.
 In the compositions of the invention, the weight ratio of glycofurol to
 polymer may be from about 99:1 to about 1:1. Preferably, the weight ratio
 of glycofurol to polymer is in the range of from about 9:1 to about 7:3.
 For use in the method of the invention, PLGA may be present in the liquid
 composition prior to administration to the animal body in a weight ratio
 of about 1:99 to about 1:1 relative to glycofurol. Often, good results may
 be obtained with PLGA in weight ratio of between about 1:9 and 3:7
 relative to glycofurol.
 As used herein, the term "drug" "biologically active molecule" includes any
 substance which is physiologically or pharmacologically active which acts
 locally or systemically in a body. Thus these molecules may be selected
 from among organic molecules, such as steroids; peptides or polypeptides;
 proteins, such as insulin, cytokines, their respective receptors and other
 therapeutic hormones and their receptors; oligo- or polynucleotides; or
 other biologically active molecules. The amount of biologically active
 molecule present in the solution prior to placement in the animal may be
 up to an amount equal to the weight of the polymer present prior to
 placement in the animal. Preferably, when a drug or biologically active
 molecule is incorporated into the solution, the weight ratio of the
 polymer to the biologically active molecule is between about 10000:1 and
 about 1:1.
 As compositions according to the invention, the liquid compositions used in
 carrying out the method of the invention are part of the invention.
 The invention also comprises a method of treatment of an animal in need of
 a prosthetic implant, comprising the steps of:
 a--dissolving poly(lactic-co-glycolic acid) copolymer (PLGA), containing
 from 10-100 wt. % lactic acid (LA) units, preferably from 50-90 wt. % LA
 units, in
 .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)
 (glycofurol) to form a liquid;
 b--administering said liquid to an animal body; and
 c--allowing said glycofurol to dissipate to leave a solid implant in said
 animal body.
 The invention also comprises a method of treating an animal, including man,
 in need of controlled or sustained release of a drug or other biologically
 active agent, comprising the steps of:
 a--dissolving poly(lactic-co-glycolic acid) copolymer (PLGA) containing
 from 10-100 wt. % lactic acid (LA) units, preferably from 50-90 wt. % LA
 units, in
 .alpha.-(tetrahydrofuranyl)-.omega.-hydroxypoly(oxy-1,2-ethandiyl)
 (glycofurol) to form a liquid;
 b--administering a suitable amount of said liquid to an animal in need of
 such administration; and
 c--allowing said glycofurol to dissipate in said animal to leave a solid
 implant composed of a PLGA polymeric matrix;
 wherein said liquid further comprises said drug or other biologically
 active agent, which has been dissolved, dispered or suspended in said
 glycofurol prior to, concurrently with, or subesquent to said dissolution
 of PLGA.
 The invention also comprises biodegradable implants, whenever prepared by
 the method of the invention or from a solution of the invention.
 As stated, biodegradable implants can serve several functions, including
 use as a prosthetic or orthodontic implant. The present invention may thus
 be used where tissue regeneration is desired, e.g. where a growth has been
 removed from a body and the resulting space requires filling as the tissue
 grows back, or where ingrowth of bone tissue into a space is necessary.
 The present invention may also be used for the sustained release of a drug
 or other biologically active agent. In the context of the invention, a
 wide variety of drugs and other biological agents, such as peptides (e.g.
 peptide hormones), proteins (e.g. growth factors, interferons, cytokines
 and cytokine-binding proteins), oligo- or polynucleotides, and organic
 compounds (e.g captopril, steroids, prostaglandins and the like), and
 other molecules with biological function (e.g narcotic antagonists,
 anti-arrhythmics, anticancer agents, hormone antagonists, contraceptive
 agents, and anti-inflammatory agents) may be incorporated into the
 composition; and thus the invention may be employed in the treatment of a
 variety of diseases or conditions. For example, a controlled-release
 device containing insulin, prepared from the composition of the invention,
 can be used in the treatment of diabetes. Other drugs which at present may
 be delivered by controlled-release systems--such as those systems using
 microspheres--e.g. leutinizing hormone releasing hormone (LHRH),
 bromocriptine, or contraceptives, may also be used in context of the
 present invention.
 According to the invention, in those aspects of the invention which require
 administration to an animal body, the mode of administration of the
 composition of the invention may be any suitable mode of administration.
 It will be understood that since one of the advantages of the present
 invention is the ability to place an implant in an animal body without
 resorting to surgery, a preferred mode of administration is injection,
 e.g. through a syringe and needle. It will also therefore be understood
 that preferred compositions of the invention are those which are
 injectable, and that preferred methods of the invention are those which
 employ injection as the means of administration of the compounds of the
 invention.
 EXAMPLES
 The foregoing characteristics and advantages of the invention, such as the
 use of components which have independently been approved for use by the
 U.S. Food and Drug Administration (FDA) and other national health
 authorities, will be better understood through the following illustrative
 and non-limitative examples.
 Example 1
 Formation and Degradation of Polymeric Composition
 Five samples of implants (listed in Table 1) were prepared as follows:
 Poly(lactic-co-glycolic acid) coplymer (PLGA) (0.6 or 0.8 g) was dissolved
 in glycofurol (3.4 g or 3.2 g, respectively) at room temperature. A sample
 of each liquid (4 g) in drops of 250 .mu.l was then poured into water (10
 ml phosphate buffered saline solution, PBS, pH 7.4 at 37.degree. C. on
 shaker bath), and immediately the polymer solidified to form a polymeric
 composition. The PBS medium was changed daily and the composition surface
 photographed under a scanning electron microscope at intervals of 4-7
 days. As can be seen from FIGS. 1A-1E, which shows the surface of each
 sample composition from Table 1 at the times after formation indicated,
 the compositions slowly decay in the aqueous solvent.
 TABLE 1
 Weight inherent
 Sample ratio LA/GA viscosity, wt. % PLGA relative Appears
 # units in PLGA dl/g to total wt. of sol'n as Fig. no.
 1 50/50 0.38 15 1A
 2 50/50 0.38 20 1B
 3 50/50 0.47 15 1C
 4 75/25 0.59 20 1D
 5 75/25 0.59 15 1E
 Example 2
 Polymeric Composition Containing Protein (BSA) and Effects of Composition
 on Release Characteristics
 This example shows that the invention may be used to prepare a
 controlled-release device, e.g. for medical use, as well as the effects of
 polymer concentration on the characteristics of release. Three samples as
 shown in Table 2 were prepared by dissolving PLGA (50/50 LA/GA weight
 ratio) in glycofurol as in Example 1, but powdered bovine serum albumin
 (BSA) was dispersed into the PLGA solution using vortex and probe
 sonication at 50 W for 30 s, while the solution was kept on ice. In vitro
 release profiles were obtained by injecting 0.25 ml of the solution
 containing BSA into 10 ml of PBS to obtain solid matrices containing BSA.
 Samples were continuously shaken at 37.degree. C. Release of BSA was
 quantitated by measuring the absorbence of the PBS at 280 nm. FIG. 2 shows
 the release profile of BSA as a function of the PLGA concentration in
 glycofurol.
 TABLE 2
 Sample PLGA, Glycofurol, BSA,
 no. g g g shorthand
 6 0.4 3.6 0.012 10% PLGA 50/50, 3% BSA
 loading
 7 0.6 3.4 0.018 15% PLGA 50/50, 3% BSA
 loading
 8 0.8 3.2 0.024 20% PLGA 50/50, 3% BSA
 loading
 Example 3
 Effects of Inherent Viscosity on Release Kinetics of BSA
 Two samples analogous to sample 7 were prepared, but using PLGA with
 inherent viscosity of 0.38 dl/g or 0.47 dl/g. FIG. 3 shows the release
 kinetics for the matrices so obtained.
 Example 4
 Effects of BSA Loading on Release Kinetics
 Samples analogous to sample 7 were prepared using PLGA of inherent
 viscosity 0.38 dl/g, but the amount of BSA incorporated was varied to be
 2, 3, 10, 20 or 30 wt. % relative to the PLGA (2, 3, 10, 20 and 30%
 loading, respectively) prior to injection. The release profiles of the
 matrices so obtained can be seen in FIG. 4.
 Example 5
 Effects of Ratio of LA/GA Unit Ratio on Release Kinetics
 Samples analogous to sample 6 were prepared using PLGA containing an LA/GA
 weight ratio of 3:1 (inherent viscosity 0.59 dl/g), with BSA loading
 varied to be 1.5, 3, 10, 20 or 30%. The release profiles of the matrices
 so obtained can be seen in FIG. 5.
 Example 6
 Effects of Inherent Viscosity on Release Kinetics of sp55-R
 Four samples analogous to sample 6 were prepared, using PLGA (1:1 LA/GA
 weight ratio) with inherent viscosity of 0.24 dl/g, 0.38 dl/g, 0.47 dl/g
 and 0.55 dl/g, and using a powder mixture of sp55-R and BSA (3 wt. % total
 protein relative to polymer) in a 1:20 weight ratio. FIG. 6 shows the
 release kinetics for the matrices so obtained.
 Example 7
 Effects of Inherent Viscosity and Ratio of LA/GA Unit Ratio on Release
 Kinetics of sp55-R
 Four samples analogous to sample 6 were prepared, using PLGA (1:1 or 3:1
 LA/GA weight ratio) with inherent viscosity of 0.24 dl/g or 0.55 dl/g, and
 using a powder mixture of sp55-R and BSA (3 wt. % total protein relative
 to polymer) in a 1:20 weight ratio. FIG. 7 shows the release kinetics for
 the matrices so obtained.
 Example 8
 Release Kinetics of Mixtures of BSA and sp55-R
 Samples analogous to sample 6, containing either BSA alone, sp55-R alone,
 or a combination of BSA and sp55-R in a weight ratio of 20:1 or 3600:1,
 and loaded with 3 wt. % or 10 wt. % total protein relative to the weight
 of the polymer (PLGA with a 1:1 weight ratio of LA/GA), were prepared.
 FIG. 8 shows the release kinetics of protein from these matrices.
 Example 9
 Release Kinetics of Mixtures of BSA and sp55-R
 Samples analogous to sample 6, containing either BSA alone, sp55-R alone,
 or a combination of BSA and sp55-R in a weight ratio of 20:1, and loaded
 with 3 wt. % or 10 wt. % total protein relative to the weight of the
 polymer (PLGA with a 3:1 weight ratio of LA/GA), were prepared. FIG. 9
 shows the release kinetics of protein from these matrices.
 Example 10
 Release of sp55-R From Compositions in Mice and Protection of Mice From
 Chronic Exposure to Tumor Necrosis Factor (TNF)
 Balb/c and Balb/c nude female mice, aged 8-9 weeks and weighing 20-21 g
 each, were injected with formulations of the invention containing sp55-R
 alone or in combination with BSA (or with formulations devoid of protein),
 and the release kinetics of sp55-R (and BSA) from the implant which
 resulted were measured; when the formulations contained sp55-R, the
 receptor was present in an amount of about 7-20 .mu.g per mouse. As shown
 in the FIGS. 10-14, the formulations used contained 10 wt. % (and in FIGS.
 11 and 13, 20 wt. % as well) PLGA (with a 1:1 weight ratio LA/GA units in
 FIGS. 10 and 11, and a 3:1 LA/GA weight ratio in FIGS. 12 and 13) in
 glycofurol, 3 wt. % to 10 wt. % total protein loading vs. polymer when
 containing protein, and BSA and sp55-R in a weight ratio of 20:1 when a
 mixture of BSA and sp55-R was used.
 Serum samples were collected periodically after injections by tail bleeding
 and via the eye artery, and allowed to clot. The sp55-R level in these
 serum samples was determined by a 2-site capture enzyme-linked
 immunosorbent assay (ELISA). FIGS. 10A and 12A show that after about 36
 hours, the rate of release of protein remained stable for the next several
 days, and FIGS. 10B, 11, 12B and 13 show that this rate of release
 remained stable over a period of several weeks. FIGS. 11 and 13 show that
 the concentration of polymer used (10 wt. % vs. 20 wt. %) had negligible
 effect on the release profile.
 Some of the mice used to determine the protein release profiles were also
 used to determine the effectiveness of the formulation of the invention as
 a means for mitigating the effects of chronic exposure to TNF. Balb/c nude
 female mice, aged 8-9 weeks and weighing 20-21 grams, were inoculated
 subcutaneously in the flank area with Chinese hamster ovary (CHO) cells
 transfected with the TNF gene and expressing TNF. Injection of the PLGA
 formulation into these mice was performed 5 days after tumor cell
 inoculation.
 It is known that nude mice bearing TNF-producing tumors exhibit severe
 cachexia, leading to death (Oliff et al., Cell 50:555-563 (1987)).
 Injection of TNF-binding proteins, such as TNF-binding antibodies or TNF
 receptors, can temporarily mitigate these effects, but the injected
 proteins are rapidly cleared from the body, making direct injection of
 TNF-binding compounds a less-than-ideal means for mitigating the effects
 of chronic TNF exposure.
 In accordance with the invention, however, injection of PLGA formulations
 containing sp55-R into such tumor-bearing mice (about 7 to 20 .mu.g
 receptor/mouse) prevented body weight loss (body weight increased
 naturally). This is illustrated in FIG. 14, which shows that over a period
 of 50 days, the weight of tumor-bearing mice treated with a formulation of
 the invention (10 wt. % PLGA (3:1 LA:GA ratio), 0.59 dl/g in glycofurol, 3
 wt. % loading of sp55-R with BSA (7.1 .mu.g sp55-R)) (.DELTA.) increased
 at a similiar rate to that of healthy Balb/c nude mice (.circle-solid.);
 whereas untreated tumor-bearing mice (.largecircle.) and tumor-bearing
 mice injected with a formulation of the invention containing only polymer
 (.box-solid.) lost about 25% body weight over the course of the
 experiment. In FIG. 16, it can be seen that tumor-bearing mice mice
 injected with TNF-loaded implants containing 20 wt. % polymer relative to
 glycofurol (.tangle-solidup.) gained weight at a rate comparable to the
 rate of weight gain of tumor-bearing mice injected with TNF-loaded
 formulation containing 10 wt. % polymer relative to glycofurol (.DELTA.).
 Similarly, FIG. 15 shows the survival rate for various groups of
 tumor-bearing mice. Only those tumor-bearing mice which were untreated
 (.largecircle.) or treated with empty PLGA formulation (.box-solid.) died
 over the course of the experiment; tumor-bearing mice injected with
 formulations containing sp55-R(.DELTA.and .tangle-solidup., 10% wt. %
 polymer and 20 wt. % polymer, respectively, relative to glycofurol),
 healthy mice injected with empty formulation (.quadrature.), and healthy
 mice which did not receive injections (.circle-solid.), all survived the
 test period.
 Example 11
 Degradation of Implants in PBS
 Implants were prepared in vitro by direct injection into PBS (pH 7.4) of
 200 mg of formulations containing 10 or 20 wt. % polymer (inherent
 viscosity 0.38, 0.24, or 0.55 dl/g) relative to glycofurol, with a 1:1
 ratio of LA to GA units. The implants thus formed were maintained at
 37.degree. C. on a shaker bath, and then dried under vacuum at various
 intervals for use in gel permeation chromatography (GPC). The average
 molecular weight of the implants was determined using a Waters 510 pump
 with a Waters RI-410 refractive index detector. Tetrahydrofuran (THF) was
 use for the mobile phase, at a flow rate of 1 ml/min and temperature of
 30.degree. C. Implants were dissolved in THF (0.25 wt. % polymer sample in
 THF), filtered and then injected as a 20 .mu.l same into a set of four
 .mu.-Styragel columns (Waters) with nominal pore sizes of 10.sup.-5,
 10.sup.-6, 10.sup.-7, and 10.sup.-8 m. Average molecular weights were
 calculated using a series of polystyrene standards which ranged from 162
 to 194000 molecular weight (Mw). The results are shown in FIG. 17.
 Example 12
 Degradation of Implants in PBS
 The procedure of Example 11 was followed, but the implants were prepared
 from formulations containing PLGA (inherent viscosities of 0.24 and 0.59
 dl/g) containing a 3:1 ratio of LA to GA units. The results are shown in
 FIG. 18.
 The foregoing examples are given for illustrative purposes only. Within the
 scope of the invention, many modifications on the foregoing can be made.
 For example, small organic molecules, peptides, polypeptides, oligo- or
 polynucleotides, in various concentrations, can be incorporated into the
 solution; the average molecular weight of the polymer can be varied; the
 relative amounts of lactic acid and glycolic acid units can be varied; and
 the relative amounts of polymer and solvent can be varied, all without
 exceeding the scope of the invention.