Title:  Controlled release liquid delivery compositions with low initial drug burst

United States Patent:  6,630,155

Issued:  October 7, 2003

Inventors:  Chandrashekar; Bhagya L. (Fort Collins, CO); Zhou; Mingxing (Fort Collins, CO); Jarr; Eileen M. (Fort Collins, CO); Dunn; Richard L. (Fort Collins, CO)

Assignee:  Atrix Laboratories, Inc. (Fort Collins, CO)

Appl. No.:  643289

Filed:  August 22, 2000

Abstract

The invention provides a controlled release polymeric composition which includes a base polymer or copolymer, an organic solvent, a polymeric controlled release additive, and a biologically active agent. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it is solidifying to form the solid implant. The controlled release additive is preferably a poly(lactide-co-glycolide)/polyethylene glycol block copolymer.

SUMMARY OF THE INVENTION

The invention is directed to a polymer composition which includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a biologically active agent; and a polymeric controlled release additive. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer. When brought in contact with an aqueous enviroment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a solid matrix or implant. The biologically active agent is trapped or encapsulated within the polymeric matrix as the implant solidifies. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it is solidifying to form the solid implant. Once the solid implant is formed, the biologically active agent is released from the solid matrix by diffusion or dissolution from within the polymeric matrix and/or by the degradation of the polymeric matrix.

The invention is also directed towards methods of using the controlled release composition.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an in situ forming biodegradable implant useful as a delivery system for a biologically active agent to adjacent or distant tissues and organs in an animal. The polymer composition of the invention includes a base polymer that is a pharmaceutically acceptable, biocompatible, biodegradable and/or bioerodible, thermoplastic polymer or copolymer which is substantially insoluble in an aqueous medium; a pharmaceutically-acceptable, organic solvent that is miscible to dispersible in an aqueous medium; a polymeric controlled release additive; and a biologically active agent. Preferably, the controlled release additive is a poly(lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer.

When brought in contact with an aqueous environment, such as body or tissue fluids which typically surround tissues or organs in an organism, the organic solvent dissipates or disperses into the aqueous or body fluid. Concurrently, the substantially insoluble thermoplastic base polymer precipitates or coagulates to form a flexible matrix or film which traps or encapsulates the biologically active agent. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it coagulates to form a solid implant. Because the polymeric controlled release additive is also a thermoplastic polymer, it too, coagulates to form a part of the matrix. Once the solid implant is formed, the biologically active agent is released from the implant by diffusion or dissolution from within the polymeric matrix and/or the biologically active agent is released as the matrix is biodegraded, bioeroded or bioabsorbed.

Thermoplastic Polymers.

Thermoplastic polymers useful as base polymers in the polymeric composition include pharmaceutically acceptable polymers that are biodegradable, bioabsorbable, and/or bioerodible. The thermoplastic polymers are capable of substantially dissolving in a water-soluble carrier, or solvent, to form a solution. Examples of suitable biodegradable polymers include, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(amino acids) and copolymers, terpolymers and combinations thereof. Preferred thermoplastic polymers are polylactides, polyglycolides, polycaprolactones, polyanhydrides, and polyorthoesters.

The inherent viscosity (abbreviated as "I.V."; units are in deciliters/gram) of the thermoplastic polymer is a measure of its molecular weight and degradation time (e.g., a thermoplastic polymer with a high inherent viscosity has a higher molecular weight and longer degradation time). Typically, a thermoplastic polymer with a high molecular weight provides a stronger matrix and the matrix takes more time to degrade. In contrast, a thermoplastic polymer with a low molecular weight degrades more quickly and provides a softer matrix. Preferably, the thermoplastic polymer has a molecular weight, as shown by the inherent viscosity, from about 0.10 dL/g to about 1.2 dL/g (as measured in chloroform), more preferably from about 0.10 dL/g to about 0.40 dL/g.

The molecular weight of the thermoplastic polymer can be varied by many methods known in the art. The choice of method is typically determined by the type of polymer. For example, the degree of polymerization can be controlled by varying the amount of initiator and/or reaction time.

Suitable thermoplastic polymers are soluble in an organic solvent. The solubility of a thermoplastic polymer in a solvent varies depending on the crystallinity, hydrophobicity, hydrogen-bonding and molecular weight of the polymer. Lower molecular weight polymers will normally dissolve more readily in an organic solvent than high-molecular weight polymers. A polymeric composition which includes a high molecular weight polymer tends to coagulate or solidify more quickly than a polymeric composition which includes a low-molecular weight polymer. Polymeric formulations which include high molecular weight polymers also tend to have a higher solution viscosity than a polymeric composition which includes a low-molecular weight polymer.

The viscosity of the flowable polymeric composition can vary from low viscosity, similar to that of water, to a high viscosity, similar to that of a paste, depending on the molecular weight and concentration of the thermoplastic polymer used in the composition. The viscosity can be varied such that the polymeric composition can be applied to a patient s tissues by any convenient technique, for example, by brushing, spraying, extruding. dripping, injecting, or painting. Different viscosities of the polymeric composition are preferable depending on the technique used to apply the composition. For example, spraying, via aerosolization, requires a polymeric composition having a low viscosity. In contrast, a polymeric composition with a higher viscosity may be desirable for other application techniques, for example, a polymeric composition having a putty-like consistency may be more preferable for bone regeneration applications. Typically, the polymeric composition includes about 10 wt % to about 80 wt %, more preferably about 30 wt % to about 60 wt % of a thermoplastic polymer.

Organic Solvents

Suitable organic solvents are those that are biocompatible, pharmaceutically acceptable, and miscible to dispersible in aqueous or body fluids. The organic solvent is capable of diffusing, dispersing, or leaching from the composition in situ into aqueous tissue or body fluid of the implant site, such as blood, serum, lymph, cerebral spinal fluid (CSF), or saliva.

Examples of suitable solvents include substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP), 2 pyrrolidone; esters of carbonic acid and alkyl alcohols such as propylene carbonate, ethylene carbonate and dimethyl carbonate; alkyl esters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutonate, tributyl citrate, diethyl succinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, glyceryl triacetate; alkyl ketones such as acetone and methyl ethyl ketone; alcohols such as solketal, glycerol formal, and glycofurol; dialkylamides such as dimethylformamide, dimethylacetamide; dimethylsulfoxide (DMSO) and dimethylsulfone; tetrahydrofuran; lactones such as .epsilon.-caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; aromatic amides such as N,N-dimethyl-m-toluamide, and 1-dodecylazacycloheptan-2-one; and mixtures and combinations thereof. Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethylsulfoxide, ethyl lactate, and propylene carbonate, solketal, glycerol formal, and glycofurol.

Typically, the polymeric composition includes about 20 wt % to about 90 wt %, more preferably about 40 wt % to about 70 wt % of an organic solvent.

Polymeric Controlled Release Additive

The polymeric composition of the invention also includes a polymeric controlled release additive. The presence of a polymeric controlled release additive in the polymeric composition substantially reduces the "intitial burst" of biologically active agent released from the polymeric composition during the initial 24 hours after implantation. As used herein, the term "substantially reduces" means a decrease of at least 15% of biologically active agent released from the polymeric composition compared to a composition without the additive. Preferably, the polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition by about 15% to about 70%, more preferably about 30% to about 60%, compared to a polymeric composition which does not include a controlled release additive.

According to the invention, the controlled release additive is a thermoplastic polymer having poly(lactide-co-glycolide) (PLG) moieties and polyethylene glycol (PEG) moieties. Preferably the controlled release additive is a PLG/PEG block copolymer which includes from about 50 mole % to about 90 mole % lactide monomers and about 50 mole % to about 10 mole % glycolide monomers. More preferably, the PLG/PEG block copolymer includes from about 50 mole % to about 75 mole % lactide monomers and about 50 mole % to about 25 mole % glycolide monomers. Preferably the PEG moiety has a molecular weight of about 1,000 Daltons to about 10,000 Daltons, more preferably about 5000 Daltons. The PEG portion of the block copolymer ranges from about 1 wt % to about 20 wt % of the total weight of the block copolymer. The percentage is dependent on the molecular weight of the block copolymer that is prepared and the molecular weight of the polyethylene glycol that is used. Thus, a block copolymer with a weight average molecular weight of 100,000 Daltons (I.V. approx. 0.8 dL/g) prepared with PEG having a molecular weight of 5,000 Daltons will contain about 5 wt % PEG. If PEG with a molecular weight of 1,000 Daltons is used, the block copolymer will include about 1 wt % of PEG.

The inherent viscosity (abbreviated as "I.V."; units are in deciliters/gram) of the polymeric controlled release additive is a measure of its molecular weight. Preferably, the inherent viscosity of the controlled release additive is from about 0.50 dL/g to about 1.0 dL/g (as measured in chloroform), more preferably from about 0.70 dL/g to about 0.90 dL/g.

Suitable polymeric controlled release additives include any PLG/PEG block copolymer with the previously mentioned attributes. Examples of suitable polymeric controlled release additives include 50/50 PLG/PEG-5000 (0.81); 70/30 PLG/PEG-5000 (0.73); and 70/30 PLG/PEG-5000 (0.79).

The polymeric controlled release additive is present in the polymeric composition in an amount effective to reduce the initial burst of biologically active agent released from the polymeric composition during the first 24 hours after implantation. Preferably, the polymeric composition includes about 1 wt % to about 50 wt %, more preferably about 2 wt % to about 20 wt % of the polymeric controlled release additive.

Biologically-Active Agent.

The polymeric composition also includes a biologically-active agent. Biologically-active agents which may be used alone or in combination in the polymer system include medicaments, drugs, or other suitable biologically-, physiologically-, or pharmaceutically-active substances capable of providing a local or systemic biological, physiological or therapeutic effect and of being released from the resulting matrix into adjacent or surrounding tissue fluids. Upon implantation, the biologically active agent becomes incorporated into the implant matrix. The biologically active agent is capable of being released from the matrix into the adjacent tissue fluid and to the pertinent body tissue or organ, either adjacent to or distant from the implant site, preferably at a controlled rate. The release of the biologically active agent from the matrix may be varied, for example, by the solubility of the biologically active agent in an aqueous medium, the distribution of the agent within the matrix, the size, shape, porosity and solubility and biodegradability of the solid matrix.

The biologically-active agent may be soluble in the polymeric composition, to form a homogeneous mixture, or insoluble in the polymer formulation to form a suspension or dispersion. Preferably, the polymer formulation includes the biologically-active agent in an amount effective to provide the desired level of biological, physiological, pharmacological and/or therapeutic effect in the animal. The amount of biologically active agent incorporated into the polymeric formulation depends upon the desired release profile, the concentration of biologically active agent required for a biological effect, and the length of time that the drug should be released for treatment. There is generally no critical upper limit on the amount of the biologically active agent that can be included in the polymeric composition. However, the biologically active agent should not be present in such a high concentration that the biologically active agent significantly alters the viscosity of the polymeric composition and interferes with its application to a patient's tissues. The lower limit of the amount of biologically active agent incorporated into the polymer formulation depends on the activity of the biologically active material and the period of time desired for treatment. Typically, the polymeric composition includes about 2 wt % to about 40 wt %, more preferably about 5 wt % to about 10 at % of a biologically active agent.

Examples of biologically active agents that are useful include substances capable of preventing an infection systemically in an animal or locally at the defect site, for example, anti-inflammatory agents such as hydrocortisone or prednisone; antibacterial agents such as penicillin, cephalosporins, bacitracin, tetracycline, doxycycline, gentamycin, quinolines, neomycin, clindamycin, kanamycin, or metronidazole; antiparasitic agents such as quinacrine, chloroquine, or vidarabine; antifungal agents such as nystatin; antiviral agents such as acyclovir, ribarivin, or interferons; analgesic agents such as salicylic acid, acetaminophen, ibuprofen, naproxen, piroxicam, flurbiprofen, or morphine; local anaesthetics such-as cocaine, lidocaine, bupivacaine, and benzocaine; immunogens (vaccines) for stimulating antibodies against hepititis, influenza, measles, rubella, tetanus, polio, and rabies; peptides such as leuprolide acetate (an LH-RH agonist), nafarelin, or ganirelix.

Substances which are capable of promoting growth and survival of cells and tissues or augmenting the functioning of cells, or metabolic precursors thereof are also useful biologically active agents, for example, a nerve growth promoting substance such as a ganglioside or a nerve growth factor; a hard or soft tissue growth promoting agent such as fibronectin (FN), human growth hormone (HGH), a colony stimulating factor, bone morphogenic protein, platelet-derived growth factor (PDGP), insulin-derived growth factor (IGF-I, IGF-II), transforming growth factor alpha (TGF-.alpha.), transforming growth factor beta (TGF-.beta.), epidermal growth factor (EGF), fibroblast growth factor (FGF), or interleukin-1 (IL-1); an osteoinductive agent or bone growth promoting substance such as bone chips, or demineralized freeze-dried bone material; antineoplastic agents such as methotrexate, 5-fluorouracil, floxuridine, adriamycin, vinblastine, cisplatin, tumor-specific antibodies conjugated to toxins or tumor necrosis factor (TNF).

Other useful substances include hormones such as progesterone, testosterone, and follicle stimulating hormone (FSH) (birth control, fertility enhancement), insulin, or somatotrophins; antihistamines such as diphenhydramine, or chlorphencramine; cardiovascular agents such as digitalis, nitroglycerine, papaverine, or streptokinase; anti-ulcer agents such as cimetidine hydrochloride, or isopropamide iodide; bronchodilators such as metaprotenal sulfate, or aminophylline; vasodilators such as theophylline, niacin or minoxidil; central nervous system agents such as a tranquilizer, .beta.-adrenergic blocking agents, or dopamine; antipsychotic agents such as risperidone, olanzapine; narcotic antagonists such as naltrexone, naloxone or buprenorphine.

Polymeric Composition

The polymeric composition of the invention includes a base polymer, an organic solvent, a controlled release additive and a biologically active agent. According to the invention, the base polymer is a thermoplastic polymer that is soluble in the organic solvent and the organic solvent is miscible to dispersible in an aqueous medium, such as body or tissue fluids. Upon contact with an aqueous medium, the organic solvent diffuses or dissipates from the polymeric composition into the aqueous medium and the base polymer slowly precipitates or coagulates to form a solid matrix. The controlled release additive reduces the burst of biologically active agent released from the polymeric composition as it is coagulating to form the solid matrix or implant. The controlled release additive is preferably a PLG/PEG block copolymer.

The concentration of polymer (both the base polymer and the controlled release additive) in the polymeric composition may affect the rate at which the composition coagulates to form a matrix (e.g., a polymeric composition with a higher concentration of polymer may coagulate more quickly).

The percentage of polymer present in the composition may also affect the viscosity of the polymeric composition. For example, a composition having a higher percentage by weight of polymer is typically thicker and more viscous than a composition having a lower percentage by weight of polymer. A more viscous composition tends to flow more slowly. Therefore, a composition having a lower viscosity may be preferred in some instances, for example. when applying the formulation via an aerosol spray.

Formation of a Polymer Matrix

In general, a solid implant or matrix is formed by dispensing the flowable polymeric composition either into a tissue or onto the surface of a tissue which is surrounded by an aqueous medium. The composition can be applied to a patient's tissues by any convenient technique, for example, by brushing, spraying, extruding, dripping, injecting, or painting.

Optionally, after the polymeric composition is applied to a tissue defect, an aqueous solution, such as a saline solution, can be applied over the polymeric composition to enhance coagulation of the thermoplastic polymer to form the matrix.

The Polymer Matrix

When the polymeric composition is applied to a tissue, the organic solvent slowly dissipates into the surrounding aqueous or body fluids and the substantially insoluble thermoplastic polymer precipitates or coagulates to form a polymer matrix. The polymeric controlled release additive reduces the initial burst of biologically active agent released from the polymeric composition as it coagulates to form a solid implant. Once the solid implant is formed, the biologically active agent is released from the implant by diffusion or dissolution from within the polymeric matrix and/or the biologically active agent is released as the matrix is biodegraded, bioeroded or bioabsorbed.

According to the invention, the resulting matrix is solid but is also able to conform with the irregular surface of the tissue.

The solid implant will slowly biodegrade within the body and will release the biologically active agent contained within its matrix at a controlled rate until depleted. With certain drugs, the polymer will degrade after the biologically active agent has been completely released. With other biologically active agents, such as peptides or proteins, the biologically active agent will be completely released only after the polymer has degraded to a point where the non-diffusing biologically active agent has been exposed to body or tissue fluids.

Claim 1 of 13 Claims

What is claimed is:

1. A polymeric composition for forming a controlled release implant within a body, comprising:

a biocompatible, biodegradable, thermoplastic base polymer that is insoluble in aqueous or body fluids;

a biocompatible, organic solvent that is soluble in aqueous or body fluid;

a poly(lactide-co-glycolide)/polyethylene glycol block copolymer; and

a biologically active agent

wherein the polymeric composition is capable of forming the controlled release implant by dissipation or dispersement of the organic solvent within the body.

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