This invention is directed to the field of medical implants, and more specifically to biodegradable injectable implants and their methods of manufacture and use. The injectable implants disclosed herein comprise glycolic acid and bio-compatible/bio-absorbable polymeric particles containing a polymer of lactic acid. The particles are small enough to be injected through a needle but large enough to avoid engulfment by macrophages. The injectables of this invention may be in a pre-activated solid form or an activated form (e.g., injectable suspension or emulsion).

Description of the Invention

SUMMARY OF THE INVENTION

The present invention solves many of the problems inherent in the art by providing a biocompatible, biodegradable, injectable bulking agent or implant that degrades slowly under biological conditions, is hypoallergenic, non-migratory, relatively inexpensive and simple to apply.

Aspects of the present invention encompass a biodegradable, injectable bulking agent or implant (also referred to herein as an "injectable") intended for use in reconstructive surgery to restore form and/or function to soft tissues altered by age, trauma, disease, or other defect comprising a solution containing glycolic acid monomer (referred to herein as "GA") and a particle suspension or emulsion of particles of a polymer containing or comprising lactic acid repeat units (also referred to herein as "PLA") as well as injectables in pre-activated solid form and related methods of production and use.

The injectables disclosed herein solve many problems inherent in the art. For example, the injectables of the present invention have flow properties superior to those available in the art. It is believed that the low molecular weight and hydrophilicity of GA (GA is highly soluble in water) inhibits aggregation and facilitates the flow of the denser PLA (higher molecular weight and having a hydrophobic surface), thereby avoiding clogging of the needle and the formation of nodules in the body. Thus, when added to a suspension of hydrophobic microparticles, the hydrophilic properties of GA in solution apparently overcomes the tendency for the hydrophobic particles to aggregate.

In addition, upon injection, the GA flows to and hydrates the upper layers of the dermis, renewing its elasticity and promoting a healthier skin, thereby enhancing physical appearance and improving the effect of the PLA microparticles. More specifically, as the PLA degrades, the body initiates a fibrosis response, resulting in increased deposition of collagen in the treated area. The filled area also reacts with the improved elasticity promoted by the action of GA. This characteristic allows PLA to work independently but complementarily with the GA.

The injectable implants disclosed herein are preferably biodegradable and biocompatible. The PLA and GA components are substantially, if not completely, degraded by the body. Polymers of lactic acid may be non-enzymatically hydrolized in vivo. The hydrolysis products may then be metabolized (for example, the lactic acid or other repeat units are typically metabolized) and excreted or excreted fully or partially intact. Although not wishing to be bound by any theory, it is believed that the PLA degrades via water diffusion followed by hydrolysis, fragmentation and further extension hydrolysis accompanied with phagocytosis, diffusion, and metabolization. This degradation process may typically take up to 12 months and is regulated by variables in the formulation and manufacturing of the injectables disclosed herein, including the features of polymers, excipients, and production method. The degradation by-products may be mainly expelled via normal respiration and excretion.

Thus, one aspect of the present invention relates to a biodegradable injectable bulking agent or implant comprising glycolic acid and a bio-compatible/bio-absorbable polymeric particle having a size that is small enough to be injected through a needle but large enough to avoid engulfment by macrophages.

The injectable implants disclosed herein are typically administered as a suspension of the polymeric particles in a pharmaceutically acceptable carrier with glycolic acid being present in the solution phase. However, it is envisioned that it may be desirable to store the injectables disclosed herein in a variety of physical forms to increase their shelf-life (for example, the freeze-dried form which has a shelf life of greater than 12 months), aid in shipment of product to customers, etc. Thus, aspects of the present invention include injectables which are in their activated form (i.e. ready for administration) as well as in pre-activated form (i.e. requiring additional manipulation or processing prior to administration). Thus, embodiments of the present invention encompass, but are not limited to, dehydrated, sterilized, typically freeze-dried powders, emulsions, suspensions, aqueous emulsions, and the like.

The bulking agents/injectables of the present invention include glycolic acid (GA). The concentration of GA will vary depending upon the particular application and the form of the implant. Typically, one of skill in the art is concerned with the concentration of the GA that will be administered to the patient. For example, when the injectable implant is in the form of a suspension of particles in a pharmaceutically acceptable carrier (e.g., an activated form), the GA may typically be present in a concentration of from about 1.8 mcg to about 18.2 mcg GA per 100 ml of the pharmaceutically acceptable carrier (or from about 0.0018% to about 0.0002% by weight), from about 11 mcg to 14 mcg per 100 ml of the pharmaceutically accentable carrier, and preferably from about 12 mcg to 13 mcg per 100 ml of the pharmaceutically acceptable carrier, or about 12.7 mcg per 100 ml of the pharmaceutically acceptable carrier. However, when the implant is in a pre-activated solid form, the GA may typically comprise from about 0.002% to about 0.02% by weight, prefereably about 0.014% by weight.

The size and shape of the polymeric particles may vary depending on the intended application. However, the polymeric particles included in the injectables typically have a diameter of from 20.mu. to about 120.mu., preferably from about 40.mu. to about 80.mu., and more preferably have a mean diameter of from about 50.mu. to about 70.mu., or from about 55 to about 65.mu., or about 60.mu.. Although the shape of the particles may vary widely depending upon the intended application and various production parameters, a preferred shape is substantially spherical (often referred to in the injectable art as a microsphere). The polymeric particles having the desired shape and size are preferably made by pulverizing the polymer to a powder; and cold micronizing the powder to the desired shape and size.

The polymeric particles comprise a polymer which contains a substantial amount of lactic acid repeats units (typically from 10 to 100% lactic acid repeat units by weight, preferably from 50%, 60%, 70%, 80% or 90% up to about 100%. Thus, embodiments of the present invention encompass implants wherein the polymer comprises homopolymers of lactic acid, such as poly-l-lactic acid or poly-d,l-lactic acid, and co-polymers of lactic acid.

The co-polymers encompassed in the present invention may have varying compositions depending upon the intended application and production parameters. For example, co-polymers of lactic acid and glycolic acid may be employed. Further, homo-and co-polymers of lactic acid may be employed which incorporate different repeat units (such as lactones) having a desired functionality. Thus, polymers containing repeat units which allow for crosslinking or which increase or decrease the rate of degradation of the polymer or affect the metabolism of the hydrolysis products produced by degradation or which bind preferentially to drugs or other bioactive compounds that may be administered at the site of the injection of the implant may be employed. In addition, homo- and co-polymers of lactic acid may be functionalized or modified after their synthesis and/or before, during or after their processing to discrete particles to incorporate additional chemical groups, moieties or functionalities or to modify the surface or other properties of the polymer or particles thereof.

The polymer is preferably substantially free of impurities, and preferably employed in a highly-purified form.

The properties of the polymer employed with injectables disclosed herein vary widely depending upon the intended application and composition and are typically not critical as long as one of skill in the art can form biodegradable, biocompatible hydrophobic particles therewith. Thus, for injectable applications, the polymeric particles should be suitable for injection through a suitably-sized syringe. Typically, the polymers employed herein exhibit an intrinsic viscosity of from about 3.0 to about 4.5 dl/g, more typically of from about 3.5 to about 3.8 dl/g or from about 3.60 to about 3.75 dl/g. The polymers employed herein may also have a density of from about 1.0 to about 1.5 kg/l, preferably about 1.24 kg/l, and a melting point ranging from about 170.degree. to about 200.degree. C.

The molecular weight as determined by viscosity of the polymer will typically be in the range of from about 100,000 to about 250,000 Daltons, preferably from about 150,00 to about 200,000 or 220,000 Daltons, and more preferably from about 165,00 to about 180,000 Daltons or about 172,000 Daltons.

The implants disclosed herein may include varying amounts of polymeric particles and may typically include in the activated form from about 30 mg to about 40 mg of polymer per 100 ml of the pharmaceutically acceptable carrier, preferably from about 36 mg to about 37 mg of polymer per 100 ml of the pharmaceutically acceptable carrier. However, when the implant is in a pre-activated solid form, the polymeric particles may typically comprise from about 36% to about 45% by weight of the solid, preferably from about 40 to about 41% by weight.

An embodiment of the present invention also encompasses an implant which further comprises a gelling agent. The gelling agent may typically comprise a cellulose derivative, such as hydroxypropylmethylcellulose or carboxymethylcellulose, or a pharmaceutically acceptable acid or ester. Exemplary pharmaceutically acceptable acid or ester gelling agents include synthetic hyaluronic acids, lactic acid esters, sodium carmellose, and caproic acid esters. The gelling agent, if present, is typically present in the activated implant in a concentration of from about 0-10% by weight, more typically from about 1% to about 5% by weight, with from about 2% to about 3% by weight being preferred. The pre-activated lyophilized powder form for the injectable may comprise from about 0-40%, preferably from about 20 to about 30%, or from about 22 to about 26%, by weight gelling agent, if any.

Injectables disclosed herein may also contain a surfactant, such as polyoxyethylene sorbitan, a polysorbate or pluronic acid, with polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monopalmitate, and polyoxyethylene sorbitan monolaurate being preferred.

Other embodiments encompass injectables which further comprise a cryoprotecting agent. Suitable cryoprotecting agents include sugars and carbohydrates, for example, d-mannitol, lactose, sucrose, fructose, and dextran.

In other embodiments, the inclusion of stabilizers into the injectables disclosed herein (such as buffering agents--e.g. dibasic and monobasic phosphates and citrates) permit the safe preservation for 30 to 45 days once the injectable product is reconstituted, or activated, with water or other pharmaceutically acceptable carrier. (A similar product, once activated, has a life of no more than 72 hours.)

Thus, the injectable implants of this invention may also include a buffering agent or system. The buffering agent(s) may be any pharmaceutically acceptable buffer, including but not limited to phosphate and citrate buffers. The buffering agent, if present, may typically be present in the activated form in a concentration of from about 0-0.1 mg per 100 ml of the pharmaceutically acceptable carrier, or from about 0.08 mg to about 0.1 mg per 100 ml of the pharmaceutically acceptable carrier, with about 0.09 mg per 100 ml of suspension being preferred. The lyophilized powder form for the injectable may typically comprise from 0-0.2% by weight, or from about 0.09% to about 0.11% by weight buffering agent, if any.

An aspect of the present invention also encompasses injectable implants that comprise a medicament. This medicament may be any bioactive composition, pharmaceutical, drug or compound which one desires to administer to the site of the injection of the implant. For example, the medicament may comprise an anesthetic to decrease the pain or discomfort associated with injecting the implant or a composition that facilitates the integration of the polymer or decreases the trauma to the injection site. Exemplary anesthetics include but are not limited to lidocaine, xylocaine, novocaine, benzocaine, prilocaine, ripivacaine, and propofol. Typically the anesthetic will be used with an aqueous base and thus will be mixed with the pharmaceutically acceptable carrier and added to the inactive form of the injectable prior to administration.

Other medicaments that can be employed in the injectables disclosed herein include peptides, a tissue regeneration agent, an antibiotic, a steroid, fibronectin, a cytokine, a growth factor, an analgesic, an antiseptic, alpha-, beta, or gamma-interferon, erythropoietin, glucagons, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, cDNA, DNA, proteins, peptides, HGH, luteinizing hormone, atrial natriuretic factor, Factor VIII, Factor IX, and follicle-stimulating hormone.

An embodiment also encompasses the implant in the form of a suspension of the polymeric particles in a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers include but are not limited to water, saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, and plasma, with water being preferred.

Other embodiments encompass the injectables disclosed herein in a ready for use prefilled sterile syringe; in a vial in the form of a sterile suspension; in the form of a lyophilized powder; and in a two-compartment prefilled syringe, wherein one compartment contains a powder, preferably freeze-dried, and the other compartment contains a pharmaceutically acceptable carrier.

The implants disclosed herein may optionally be sterilized by gamma or E-beam irradiation or exposure to ethylene oxide gas.

Another embodiment encompasses a biodegradable, injectable implant comprising glycolic acid and particles comprised of polylactic acid (including but not limited to poly-1-lactic acid or poly-d,1-lactic acid, and co-polylactide-polyglycolide), wherein the particles have a mean diameter of from about 40.mu. to about 80 .mu..

A further embodiment encompasses a biodegradable, injectable implant comprising: a) glycolic acid; b) particles of polylactic acid, wherein the particles have a mean diameter of from about 40.mu. to about 80.mu.; c) a gelling agent; d) a surfactant; e) a cryoprotecting agent; and f) a buffering agent.

The processes for producing the injectable implants disclosed herein also represents a significant advance over the art. More specifically, the disclosed separation, washing and drying techniques disclosed herein avoid several transfer and contaminating steps employed in the art, thereby facilitating an aseptic process--a problem that has plagued the manufacture and supply of analogous products. The processes of the present invention also save time, which considerably lowers production cost.

Thus, an aspect of the present invention encompasses a method of making a biodegradable, injectable implant comprising: a) pulverizing a polymer comprising lactic acid repeat units to a first powder; b) cold micronizing the first powder to form particles having a mean diameter of from about 20.mu. to about 120.mu., preferably from about 40.mu. to about 80.mu.; c) forming an emulsion or suspension comprising the particles; d) obtaining a solution which comprises glycolic acid; e) mixing the emulsion and solution during heating to obtain an aqueous slurry; f) drying the aqueous slurry, typically under vacuum and a stream of dry air, to obtain a second powder; and g) lyophilizing the second powder.

The injectables so prepared may also optionally include gelling agents, surfactants, cryoprotecting agents, and buffering agents.

An aspect of the invention also encompasses the further step of comprising forming a suspension of the second powder in a pharmaceutically acceptable carrier, such as water, saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, or plasma.

A further aspect of the present invention encompasses a method of using the injectable bulking agents and implants disclosed herein to replace facial fat loss (lipoatrophy), for example, to provide volume in areas of the patient's soft tissues which suffer from fat, collagen or muscle loss for reasons of old age or disease.

Another aspect of the present invention encompasses a method of using the injectable bulking agents and implants disclosed herein for the treatment of a sphincter deficiency, such as a deficiency of the urinary or pyloric or lower esophageal sphincter, or for treatment of erectile dysfunction. For example, in cases of incontinence the bulking agent may be injected endoscopically at the sphincter controlling the bladder, whereas to treat acid reflux, the bulking agent may be endoscopically injected at the duodenal sphincter.

The injectable implants disclosed herein may also be used to treat wrinkles and scars by injection at the site of the wrinkle or scar or to treat certain conditions of the vocal cords or to support tendons by injection at those sites.

Thus, an aspect of the invention encompasses a method for soft tissue augmentation comprising injecting a mammal, such as a human at an injection site in need of such soft tissue augmentation a bulking agent comprising glycolic acid and polymeric particles comprising lactic acid repeat units, wherein the particles have a mean diameter of from about 20.mu. to about 120.mu., preferably from 40.mu. to about 80.mu..

The injection site may be a congenital anomaly, a scar, such as a chicken pox or acne scar, or a wrinkle. Further, the bulking agent may be used to augment facial fat loss in the human or to treat a sphincter deficiency. When used to treat a sphincter deficiency, the injection site may be urethral or periurethral tissue or tissue at or proximal to the pyloric or lower esophageal sphincter. The injection site may also be tissue defining a vocal cord.

If the injectables used include a medicament or other component in sufficient volume and/or that is readily absorbed by the body, it may be desirable to overfill the injection site with the bulking agent/implant, thus providing sufficient filler at this site after the medicament or other component is absorbed or otherwise integrated into or dispersed to the site and surrounding tissue.

It has also been surprisingly found that injection of GA alone has a remarkable re-hydrating effect of the skin. Therefore, an aspect of the present invention encompasses a method for improving the appearance of a wrinkle on a human comprising injecting glycolic acid into the human at the wrinkle.

DETAILED DESCRIPTION

1 Biodegradable, Injectable Bulking Agents and Implants

The biodegradable, injectable implants and bulking agents disclosed herein comprise bioactive molecules of glycolic acid (GA) and polymers containing lactic acid repeat units (also referred to herein as PLA). The PLA preferably forms a hydrophilic matrix in a microsphere-based delivery system, designed to assure the stability of GA and PLA molecules and the desired profile of a safe implant. Both GA and the preferred PLA compositions have been scientifically proven to be innocuous, biodegradable, biocompatible and bioabsorbable medical components, devoid of side effects or allergic reactions.

It is believed that interaction from the microspheres is governed by diffusion of the bioactive molecule through the microsphere and by biodegradation of the polymer. The process is modulated through a number of formulation and manufacture variables, including glycolic acid, the addition of gelling, cryoprotecting and tenso-active agents, and a pH stabilizer.

The injectables are typically packaged in vials as a freeze-dried, free-flowing powder. Once activated with distilled injectable water or other pharmaceutically acceptable carrier, the gelatinous (suspension) fluid may be implanted by subcutaneous injection.

Therefore, an aspect of the present invention encompasses biodegradable, injectable bulking agents and implants (herein referred to as "injectables") comprising glycolic acid ("GA") monomer and biocompatible, biodegradable particles of polymers comprising lactic acid ("PLA"). The injectables typically comprise PLA particles, preferably microspheres, having a diameter ranging primarily from about 20.mu. to about 120.mu., typically from about 40.mu. to about 80.mu., preferably with a mean diameter of approximately 60.mu.. It is preferred to employ microspheres having diameters larger than about 40.mu. to minimize immediate phagocytosis by macrophages and intra-capillary diffusion. Diameters smaller than 80.mu. are preferred to minimize the granular texture of the injectable and facilitate the free flow of the injectable through intradermal needles (typically 26-28 gauge).

In some embodiments, the injectables may also comprise gelling agents, such as cellulose derivatives, hydroxypropylmethylcellulose ("HPMC"), or carboxymethylcellulose ("CMC"); surfactants or tensoactive agents, such as polyoxyethylene sorbitan monooleate (Tween 80.TM.) or pluronic acid; cryoprotecting agents, such as apirogen mannitol (d-mannitol), dextran, and others known to those of ordinary skill in the art, and buffering agents to stabilize pH, such as basic sodium phosphate and citrate buffers. The injectables may also include a medicament, such as a local anesthetic to minimize stinging and burning during the injection procedure.

Interaction among particles is affected by precise manufacturing/formulation variables--including characteristics of polymers and excipients (inert substances).

The injectable implants disclosed herein are typically administered as a suspension of the polymeric particles with the GA being present in the solution phase. However, it may be desirable to store the injectables disclosed herein in a variety of physical forms, including both activated form (i.e. ready for administration) and pre-activated form (i.e. requiring additional manipulation or processing prior to administration).

The activated form is typically a suspension of the polymeric particles in a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers include but are not limited to water, saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, or plasma, with water being preferred. The pre-activated form is typically a dried powder lacking the pharmaceutically acceptable carrier and/or one or more other ingredients that are soluble in the pharmaceutically acceptable carrier (such as the glycolic acid, buffering agent(s), cryoprotecting agent, gelling agent, surfactant, medicament, anesthetic, etc.)

The injectable of the present invention may be typically provided in a ready for use prefilled sterile syringe, or in a vial in the form of a sterile suspension. In preferred embodiments, the injectable may be in the form of a lyophilized powder to facilitate sterilization and storage. In these embodiments, the end user adds water or other pharmaceutically acceptable carrier and/or additional components prior to injection. The injectable may also be provided in a two-compartment prefilled syringe, one containing the freeze-dried powder and the other containing water or other pharmaceutically acceptable carrier. If reconstituted extemporaneously, e.g., by double distilled water, for injectable preparations, the gel-like fluid (suspension) may then be applied by intradermal or subcutaneous injection. The viscosity of the suspension is inversely proportional to temperature.

The biodegradable polymers used must have proper mechanical properties to comply with the medical object of the particular application. They should not cause significant swelling or have toxic effects and are preferably substantially metabolized upon degradation.

The relationship between the polymer composition and the mechanical and degradation properties of the materials may be important for device or drug release activity. Generally, the mechanical properties and the time of degradation should match the needs of the application. The preferred polymer for a particular application should be configured so that it: Has mechanical properties that match the application, remaining sufficiently strong until the surrounding tissue has healed; Does not invoke an inflammatory or toxic response; Is metabolized in the body after fulfilling its purpose, leaving no trace; Is easily processable into the final product form; Demonstrates acceptable shelf life; and Is easily sterilized.

The factors affecting the mechanical performance of biodegradable polymers include monomer selection, initiator selection, process conditions, and the presence of additives. These factors in turn influence the polymer's hydrophobicity, crystallinity, melt and glass-transition temperatures, molecular weight, molecular-weight distribution, end groups, sequence distribution (random versus blocky), and presence of residual monomer or additives.

Once implanted, a biodegradable bulking agent or implant should maintain its mechanical properties until it is no longer needed and then be absorbed and excreted by the body, leaving little or no trace. Simple chemical hydrolysis of the hydrolytically unstable backbone is the prevailing mechanism for the degradation of the polymers employed herein. This occurs in two phases. In the first phase, water penetrates the bulk of the PLA particle, preferentially attacking the chemical bonds in the amorphous phase and converting long polymer chains into shorter water-soluble fragments. Because this occurs in the amorphous phase initially, there is a reduction in molecular weight without a loss in physical properties, since the polymer matrix is still held together by the crystalline regions. The reduction in molecular weight is soon followed by a reduction in physical properties, as water begins to fragment the particle. In the second phase, enzymatic attack and metabolization of the fragments occurs, resulting in a rapid loss of polymer mass. This type of degradation--when the rate at which water penetrates the particle exceeds that at which the polymer is converted into water-soluble materials (resulting in erosion throughout the device)--is called bulk erosion. Commercially available synthetic devices and sutures degrade by bulk erosion.

A second type of biodegradation, known as surface erosion, occurs when the rate at which the water penetrates the particles is slower than the rate of conversion of the polymer into water-soluble materials. Surface erosion results in the device thinning over time while maintaining its bulk integrity. Polyanhydrides and polyorthoesters are examples of materials that undergo this type of erosion--which typically occurs when the polymer is hydrophobic, but the chemical bonds are highly susceptible to hydrolysis. In general, this process is referred to in the literature as bioerosion. The degradation-absorption mechanism is the result of many interrelated factors, including: The chemical stability of the polymer backbone; The presence of catalysts, additives, impurities, or plasticizers; and The geometry of the device.

Factors that accelerate polymer degradation include: More hydrophilic backbone; More hydrophilic endgroups; More reactive hydrolytic groups in the backbone; Less crystallinity; More porosity; and Smaller device size.

Particles incorporating biodegradable polymeric lactic acid are preferably not subjected to autoclaving, and are optionally sterilized by gamma or E-beam irradiation or by exposure to ethylene oxide (EtO) gas. There are certain disadvantages, however, to both irradiation and EtO sterilization. Irradiation, particularly at doses above 2 Mrd, can induce significant degradation of the polymer chain, resulting in reduced molecular weight as well as influencing final mechanical properties and degradation times. Because the highly toxic EtO can present a safety hazard, great care must be taken to ensure that all the gas is removed from the device before final packaging. The temperature and humidity conditions should also be considered when submitting devices for sterilization. Temperatures must be kept below the glass-transition temperature of the polymer to prevent the part geometry from changing during sterilization. If necessary, parts can be kept at 0.degree. C. or lower during the irradiation process.

2 Chemical Components of the Injectables

2.1 Glycolic Acid ("GA")

The injectables of the present invention comprise glycolic acid (HOCH.sub.2COOH). Glycolic acid is a moderately strong organic acid and is the first member of the alphahydroxy acid series. GA is very soluble in water, methanol, ethanol, acetone, acetic acid, and ethyl acetate, but poorly soluble in diethyl ether, and very poorly soluble in hydrocarbon solvents. At high concentrations, free glycolic acid exists in equilibrium with low molecular weight, polyester oligomers. Upon dilution, neutralization, etc., these components revert to free glycolic acid.

GA for use in the present invention may be obtained commercially or produced by methods well known by those of skill in the art. Preferably, purified GA suitable for use in biomedical applications is employed.

While not wishing to be bound by any theories, it is believed that the glycolic acid serves many purposes in the injectables of the present invention. First, it is believed to promote the ease of flow of the hydrophobic PLA microparticles through the fine intradermal needles employed, thereby avoiding clogging--a significant problem with known polylactic acid injectable implants. Presumably, the GA which is highly hydrophilic, is dissolved in the fluid phase (which is typically aqueous). Second, the glycolic acid may facilitate rapid diffusion of the implant microparticles into the injection site, preventing the formation of nodules--another complication with known polylactic acid injectables.

The glycolic acid may also facilitate infiltration of the implant and hydration of the injected area thereby also reducing inflammation (as a result of tissue trauma caused by the necessary injection procedure). In this regard, the hydrophilic glycolic acid easily diffuses throughout the intracellular aqueous phase without the need for plasmatic retinoid proteins. GA may also serve as a keratin regulator, inhibiting cohesion of corneocytes growing on the cornea layer mantles. Thus, the GA also promotes increased flexibility, hydration, and turgidity of the outer layers of the skin. GA degradation at the injection presumably occurs in a few weeks.

All of these factors facilitate the microparticle implant's infiltration, assimilation and ultimate degradation and promote a healthier epidermis in support of the tissue filling/contouring purpose of the injectable.

For embodiments of the present invention wherein the injectables are in the form of a suspension of PLA particles, the GA may typically be dissolved in a pharmaceutically acceptable carrier, preferably water.

The concentration of the GA in the injectable will vary depending upon the intended application, particulars related to the PLA composition and particles, and the identity of the other components of the injectable, if any. Typically, one of skill in the art is concerned with the concentration of the GA that will be administered to the patient, that is, the concentration of GA in the injectable implant in its activated form. Thus, when the injectable implant is in the form of a suspension of particles in a pharmaceutically acceptable carrier (e.g., an activated form), the GA may typically be present in a concentration of from about 1.8 mcg to about 18.2 mcg GA per 100 ml of the pharmaceutically acceptable carrier (or from about 0.0018% to about 0.0002% by weight), and preferably from about 12 mcg to 13 mcg per 100 ml of the pharmaceutically acceptable carrier, or about 12.7 mcg per 100 ml of the pharmaceutically acceptable carrier.

However, it is contemplated one may desire to make, store, and transport the injectable implants disclosed herein in a pre-activated solid form. When the implant is in a pre-activated solid form, the GA may typically comprise from about 0.002% to about 0.02% by weight, preferably about 0.014% by weight.

2.2 Polylactic Acid ("PLA")

The injectables of the present invention comprise a polymer containing lactic acid repeat units, PLA. While not wishing to be bound by any theories, it is believed that the PLA serves many purposes in the injectables of the present invention. First, the PLA serves as the bulking or tissue contouring agent. The PLA also facilitates an enzymatic process while the PLA is being degraded or assimilated in the patient's body. During the polymer's assimilation, a limited tissue response occurs which is the body's reaction to the presence of a foreign body. This triggers fibrosis (a neocollagenesis process) to replace the lost tissue mass and/or bulk the areas where the product is so infiltrated. The biocompatibility of the PLA makes it a superior support for cellular growth and tissue regeneration.

2.2.1 PLA Composition and Properties

The PLA may comprise any polymer of lactic acid, that is, a polymer which contains more than a nominal number of lactic acid repeat units. Thus, the PLA employed in the disclosed injectables may typically contain a substantial amount of lactic acid repeats units (typically from 10 to 100% lactic acid repeat units by weight, and preferably from 50%, 60%, 70%, 80% or 90% up to about 100%).

Polymers are high molecular weight molecules made up of low molecular weight repeating units called monomers. The process of joining monomers to produce polymers is called polymerization.

Polylactic acid is a poly-.alpha.-hydroxyacid containing repeat units derived from lactic acid (HOCH(CH.sub.3)COOH). Polylactic acid may be present as one of several different optical isomers or mixtures thereof, such as L, D, meso, and racemic (50% L and 50% D) isomers. A typical range of properties for L-PLA and L,D-PLA are as follows -- see Original Patent.

Various forms of polylactic acid are commercially available or may be prepared by methods well known to those of skill in the art, such as polymerization of lactide dimers (Kronenthal, 1975). Thus, in some preferred embodiments, L-lactide may be polymerized at elevated temperatures using stannous octoate as a catalyst/initiator and lauryl alcohol (dodecanol) as a co-initiator. After polymerization and purification (to remove residual monomer), the polymer may be ground to small granules.

Poly(l-lactide) is a biodegradable, immunologically inactive, biocompatible, and bioabsorbable synthetic polymer that belongs to the family of aliphatic polyesters. Degradation occurs naturally when in contact with live tissue or an aqueous environment by hydrolysis to lactic acid which may be further biodegraded.

Degradation starts by water diffusion (initially at the more amorphous zones) followed by hydrolysis, material fragmentation and, finally, a more extensive hydrolysis along with phagocitosis, diffusion, and metabolization. The degradation by-products are eliminated, essentially, via the respiratory tract.

The PLA is degraded by nonspecific hydrolysis. Degradation may be slower as crystallinity, L-PLA content or the molecular weight is increased or as repeat units that are less susceptible to hydrolysis or allow for the formation of crosslinks are incorporated. Thus, the resorbability time may be adjusted by changing these properties.

The mechanical and pharmaceutical properties of assimilation also depend on the chemical make-up of the polymer and its molecular weight. For example, a crystalline formation (mostly made up of L-lactide) and a high molecular weight (>100,000 Dalton) may allow for extended assimilation (slightly over a year). Different formulas allow regulation of the assimilation speed (radical add-ons to chains).

Thus, embodiments of the present invention encompass implants wherein the polymer comprises homopolymers of lactic acid, such as poly-l-lactic acid or poly-d,l-lactic acid, and co-polymers of lactic acid.

The co-polymers encompassed in the present invention may have varying compositions depending upon the intended application and production parameters. For example, co-polymers of lactic acid and glycolic acid may be employed. Further, homo-and co-polymers of lactic acid may be employed which have incorporated different repeat units (e.g., lactones) having a desired functionality. Thus, for example, repeat units which allow for crosslinking or which are more or less susceptible to hydrophilic attack or which bind preferentially to drugs or other compounds that may be administered at the site of the injection of the implant may be employed.

The polymer is preferably substantially free of impurities, and preferably employed in a highly-purified form.

The properties of the polymer employed in the injectables disclosed herein vary widely depending upon the intended application and are typically not critical as long as one of skill in the art can form hydrophobic particles therewith. Thus, for injectable applications, the polymeric particles should be suitable for injection through a suitably-sized syringe. The intrinsic viscosity for the PLA which may be important to certain aspects of the present invention is typically from about 3.0-4.5 dl/g (measured in chloroform at 25.degree. C.), preferably from about 3.2-4.2 dl/g, more preferably from about 3.5 or 3.6 to about 3.8 dl/g, and even more preferably from about 3.62-3.75 dl/g or around 3.7 dl/g. The PLA employed may typically have a density of from about 1.0 to about 1.5 kg/l, and preferably has a density of about 1.24 kg/l.

The molecular weight as determined by viscosity of the polymer will typically be in the range of from about 100,000 to about 250,000 Daltons, preferably from about 150,000 to about 200,000 or 220,000 Daltons, or from about 160,000 or 165,000 to 180,000 Daltons. The melting point range is usually from about 170.degree.-200.degree. C. (as determined by differential scanning calorimetry ("DSC"), 10.degree. C./min), and preferably from 175.degree.-195.degree. C.

The implants disclosed herein may include varying amounts of polymeric particles and may typically include in the activated suspension from about 30 mg to about 40 mg of polymer per 100 ml of the pharmaceutically acceptable carrier, preferably from about 36 mg to about 37 mg of polymer per 100 ml of the pharmaceutically acceptable carrier. When the implant is in a pre-activated solid form, the polymeric particles may typically comprise from about 36% to about 45% by weight, preferably from about 40 to about 41% by weight.

In preferred embodiments, poly-L-lactide is employed, preferably PURASORB.RTM. PL from PURAC and polymer poly (L-lactide), manufactured by Birmingham Polymers, Inc., Birmingham, Ala., U.S.A. For biomedical applications, purified and/or highly purified polylactic acid is preferred such that residual solvent is <0.01% and residual monomers <0.1%.

2.2.2 Preparation of PLA Particles

The PLA particles that may be employed in the injectables of the present invention typically are prepared by processing the PLA particles to an appropriate size and/or shape. Thus, in some embodiments, the PLA may be subjected to a two-stage grinding process. In the first step, the PLA is pulverized and in the second step the solid is cold micronized (e.g., at -80.degree. C.) to obtain particles having a diameter of the appropriate size, typically from about 20.mu. to about 120.mu. or from about 40.mu. to about 80.mu., and preferably having a mean diameter of from about 40.mu., 50.mu., or 55.mu. to about 65.mu., 70.mu. or 80.mu. and/or having a mean diameter of about 60.mu.. This process is particularly preferred for embodiments employing crystalline PLA.

Although the shape of the particles may vary widely depending upon the intended application and various production parameters, a preferred shape is substantially spherical (often referred to in the injectable art as a microsphere).

2.3 Gelling Agents

For some embodiments, the injectables may be administered as a gel or relatively homogenous suspension of PLA particles. The injectables may also comprise a gelling agent and water or other pharmaceutically acceptable carrier for ease of injection. Gelling agents are well known in the art and are ingredients that aid gel formation. Suitable gelling agents include, but are not limited to, cellulose derivatives, such as hydroxypropylmethylcellulose ("HPMC") and carboxymethylcellulose ("CMC"), synthetic hyaluronic acids, lactic acid esters, sodium carmellose, caproic acid esters, and the like, with HPMC being preferred.

The concentration of the gelling agent in the activated form will vary depending upon the intended application, and particulars related to the PLA composition and particles, identity of the gelling agent, etc., but, may typically vary from about 0-10% by weight, more typically from about 1% to about 5% by weight, with from about 2% to about 3% by weight being preferred. The pre-activated powder form for the injectable may typically comprise from about 0-40%, preferably from about 20% to about 30%, or from about 22% to about 26%, by weight gelling agent, if any. The amount of gelling agent is typically chosen to obtain a suspension having the desired flow properties, i.e., not too thick or gelatinous or too liquid.

2.4 Cryoprotecting Agent

For some embodiments, the injectables may also contain a cryoprotecting agent. A cryoprotecting agent is a chemical which inhibits or reduces the formation of damaging ice crystals in biological tissues during cooling. Suitable cryoprotecting agents include, but are not limited to sugars and carbohydrates, such as d-mannitol, lactose, sucrose, fructose, and dextran, with d-mannitol being preferred. The concentration of the cryoprotecting agent in the activated suspension to be injected will vary depending upon the intended application, and particulars related to the PLA composition and particles, identity of the cryoprotecting agent, but will vary from about 0-50 mg per 100 ml of suspension, typically from about 27 to about 35 mg per 100 ml of the pharmaceutically acceptable carrier, with concentrations in the range of from about 29 to about 32 mg per 100 ml of the pharmaceutically acceptable carrier being preferred. The lyophilized powder form for the injectable may typically comprise 0-45% by weight, or from about 30% to about 40% or from about 33% to about 38% or about 35% by weight, cryoprotecting agent, if any.

2.5 Surfactants or Tensoactive Agents

For some embodiments, the injectables may also contain a surfactant or tensoactive agent. A surfactant is a chemical that reduces the surface tension in a solution, allowing small, stable bubbles to form. Suitable surfactants include, but are not limited to, polysorbates, such as polyoxyethylene sorbitans, or pluronic acid, preferably polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan trioleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate, polyoxyethylene sorbitan monopalmitate, or polyoxyethylene sorbitan monolaurate, with polyoxyethylene sorbitan monooleate (Tween 80.TM.), polyoxyethylene sorbitan monostearate (Tween 60.TM.), and polyoxyethylene sorbitan monolaurate (Tween 20.TM.) being preferred, and polyoxyethylene sorbitan monooleate(Tween 80.TM.), being even more preferred.

In these embodiments, the surfactant is typically present in the activated form of the implant in a concentration of from 0-0.03% by weight, more typically from about 0.019% to about 0.024%, preferably about 0.021%. The lyophilized powder form for the injectable may comprise from 0-0.3%, preferably from about 0.22% to about 0.27% or about 0.24% by weight surfactant, if any.

2.6 Buffering Agents

For some embodiments, the injectables may also contain a buffering agent. A buffering agent is a chemical compound or compounds that is added to the solution to allow that solution to resist changes in pH as a result of either dilution or small additions of acids or bases. Effective buffer systems employ solutions which contain large and approximately equal concentrations of a conjugate acid-base pair (or buffering agents). The buffering agents employed herein may be any such chemical compound(s) which is pharmaceutically acceptable, including but not limited to salts (conjugates acids and/or bases) of phosphates and citrates. The concentration of the buffering agent(s) will depend upon its strength, the composition of the implant and its intended purpose, but may typically range in the activated form from about 0-0.1 mg per 100 ml of the pharmaceutically acceptable carrier, or from about 0.08 mg to about 0.1 mg per 100 ml of the pharmaceutically acceptable carrier, with about 0.09 mg per 100 ml of suspension being preferred. The lyophilized powder form for the injectable may typically comprise from 0-0.2% by weight, or from about 0.09% to about 0.11% by weight buffering agent, if any.

2.7 Medicaments

The injectable implants may also contain a medicament. As used herein, a "medicament" may be any bioactive composition, pharmaceutical, drug or compound which one desires to administer to the site of the injection of the implant. For example, the medicament may comprise an anesthetic to decrease the pain or discomfort associated with injecting the implant or a composition that facilitates the integration of the polymer or decreases the trauma to the injection site. Exemplary anesthetics include but are not limited to lidocaine, xylocaine, novocaine, benzocaine, prilocaine, ripivacaine, and propofol.

Other medicaments that can be employed in the injectables disclosed herein include medicament comprises a peptide, a tissue regeneration agent, an antibiotic, a steroid, fibronectin, a cytokine, a growth factor, an analgesic, an antiseptic, alpha-, beta, or gamma-interferon, erythroietin, glucagons, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, cDNA, DNA, proteins, peptides, HGH, luteinizing hormone, atrial natriuretic factor, Factor VIII, Factor IX, and follicle-stimulating hormone. The medicament is often added to the injectable just prior to the injection during activation mixing with a pharmaceutically acceptable carrier.

3 Methods of Preparation of the Injectables

The injectables disclosed herein are typically made by combining particles containing a polymer containing lactic acid repeat units having the desired size and shape with glycolic acid and any other components, such as any cryoprotecting, buffering, gelling or tensoactive agents. The polymer may be obtained commercially or synthesized and/or modified by techniques and reactions that are well known by those of skill in the art. Polymeric particles having the desired shape and size are then preferably made by pulverizing the polymer to a powder; and cold micronizing the powder to the desired shape and size.

In preferred embodiments solutions containing the other components are obtained and then mixed with a slurry of the polymeric particles to form an emulsion, which is washed, filtered and ultimately dried to obtain a powder. This powder is then further processed (typically lyophilized) to form the pre-activated injectable implants. These pre-activated injectables are ultimately reconstituted, or activated, to form an activated suspension of polymeric particles.

An important step in preparing products based on microparticles or microspheres is the recovery of the solid from slurry and drying the final product. This becomes increasingly difficult as the size of the particles decreases. The standard methods such as centrifugation and filtration, followed by vacuum drying and lyophylization involve several transfer steps resulting in loss of product and risk of contamination, the latter being quite serious when an aseptic process is required, not withstanding 3 to 4 days required by the known standard methods.

The present method represents an advance over known methods as it is capable of separating microspheres from slurry media, washing them on the screen and drying the recovered microspheres. The original characteristics of the microspheres are maintained and the process time is no more than 7/8 hours.

4 Methods of Use of the Injectables

The injectables disclosed herein may be used as bulking agents to augment soft tissue in mammals in a variety of treatments, such as the cosmetic treatment of scars, wrinkles and facial fat loss, the treatment urinary or pyloric sphincter deficiency, such as deficiencies contributing to incontinence or acid reflux, the treatment of vocal cord paralysis, and the correction of congenital anomalies. The present injectables may also be used as drug delivery vehicles to administer a medicament to a mammal in need thereof. Preferred mammals for treatment are humans.

In these methods, the injectables are typically introduced into the tissue site to be treated or medicated typically by intradermal or subcutaneous syringe injection. Although any syringe may be employed, a carpules syringe is preferred.

4.1 Cosmetic Treatment of Scars, Wrinkles and Facial Fat Loss

The injectable implants of the present invention may be used to fill and smooth out soft tissue defects such as pock marks or scars (such as chicken pox or acne scars, congenital anomalies (such as cleft lips) and wrinkles. The implants may also be used as bulking agents to augment facial fat loss in the human.

The anatomical area for the efficient use of the injectable implant or injection site may be the skin typically of the facial region. Structurally, the skin consists of two principal parts: the epidermis 1, which is the outer, thinner portion, which is composed of epithelium and attached to the inner, thicker, connective tissue and a subcutaneous, adipose tissue (fat) 2. Typical injection sites for various cosmetic and lipodystrophy treatments are shown in FIG. 1 (see Original Patent) and include sites for treating acne scars and fine facial lines 3, deeper sites for treating wrinkles, creases and modeling of facial profile 4 and deeper sites 5 for treating lipodystrophy.

4.2 Treatment of Sphincter Deficiency (Urinary and Pyloric)

The injectables disclosed herein may be used to treat various sphincter deficiencies In instances of urinary incontinence, or after a prostatectomy in men, it is necessary to compress the urethra to assist the sphincter muscle to avoid leakage of urine from the bladder.

Urinary incontinence (loss of bladder control), has various classifications:

Stress due to physical movement (coughing, sneezing, exercising);

Urge or leakage of large amounts at unexpected times, including sleep; and

A mixture of these, that is, an occurrence of stress and urge together.

All types of incontinence can be treated regardless of the patient's age. Continence is dependent upon a compliant reservoir and sphincter efficiency that has 2 components: (1) the involuntary smooth muscle on the bladder neck 6; and (2) the voluntary skeletal muscle 7 of the external sphincter.

Thus, an aspect of the present invention encompasses using the disclosed bulking agents/injectables to add bulk and localize compression to the sphincter muscle or urethra 8, thereby reducing the lumen size through one or more injections of the bulking agent and thus substantially reduce or eliminate urinary stress incontinence, see FIGS. 2A and 2B (see Original Patent). In these instances the implant may be inserted by injection into urethral or periurethral tissue. Thus, a typical procedure involves injecting the bulking agent with the aid of a cystoscope into the tissues around the neck of the bladder 6 creating increased tissue bulk, as shown in the photographic inserts 9-11 in FIG. 2B, and subsequent coaptation of the urethral lumen. The implant adds bulk and helps to close the urethra to reduce stress incontinence. The injection may typically be repeated yearly for optimal results. The product can be injected in about half an hour using local anesthesia.

In cases of acid reflux, the bulking agents may be used to treat a deficiency of the pyloric sphincter. Gastroesophageal reflux disease (GERD) involves the regurgitation of stomach 12 gastric acid and other contents into the esophagus 13 or diaphragm 14. 70% of reflux episodes occur during spontaneous relaxations of the lower esophageal sphincter, or due to a prolonged relaxation after swallowing. 30% occur during periods of low sphincter pressure. The primary symptom is heart bum (30 to 60 minutes after meals). Atypical manifestations of GERD include: asthma; chronic cough; laryngitis; sore throat; and non-cardiac related chest pain. GERD is a lifelong disease that requires lifestyle modifications as well as medical intervention.

Thus, an aspect of the present invention encompasses using the disclosed bulking agents/injectables to add bulk and localize compression to the lower esophageal sphincter 15. Thus, a typical procedure involves injecting the bulking agent with the aid of a endoscope into the tissues around the lower esophageal sphincter 15 creating increased tissue bulk, see FIG. 3 (see Original Patent), and subsequent coaptation, normalizing sphincter pressure. The implant adds bulk and helps to close the sphincter to reduce reflux. The injection may be repeated yearly for optimal results. The product can be injected in about 45 minutes to one hour using local anesthesia.

4.3 Treatment of Erectile Dysfunction

Erectile dysfunction (ED), or the consistent inability to maintain an erection, is generally categorized as: organic, psychogenic, or both (organic and psychogenic). Most cases of male erectile disorders have an organic rather than a psychogenic cause. Organic ED is the result of an acute or chronic physiological condition, including endochrinologic, neurologic or vascular etiologies. Approximately 80% of cases are secondary to organic disease, 70% of those to arterial or venous abnormalities. Further, transient lost or inadequate erection affects men of all ages.

Thus, an aspect of the present invention encompasses using the disclosed bulking agents/injectables to treat ED. A typical procedure involves injecting the bulking agent directly at the deep fascia 16 throughout the length of the corpus cavernosum 17 as shown in FIG. 4 (see Original Patent) which also shows the urethra 18, the superficial dorsal vein 19, the deep dorsal vein 20, and the deep artery 21.

4.4 Treatment of Vocal Cords

An aspect of the present invention encompasses the use of the injectable implants disclosed herein as a bulking agent for intracordal injections of the laryngeal voice generator by changing the shape of this soft tissue mass.

4.5 Drug Delivery Vehicles

The present invention also relates to compositions and methods for providing controlled release of beneficial pharmaceutically active agents or medicaments.
 

Claim 1 of 69 Claims

1. A biodegradable, injectable implant comprising glycolic acid monomer and particles comprised of a polymer comprising lactic acid repeats units, wherein the particles have a diameter of from about 20 .mu. to about 120 .mu. and are suspended in a pharmaceutically accentable carrier, and the glycolic acid monomer is present in a concentration of from about 1.8 mcg to about 18.2 mcg glycolic acid monomer per 100 ml of the pharmaceutically acceptable carrier.
 

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