HK1184056B - Injectable flowable composition comprising buprenorphine - Google Patents

Description

Injectable flowable compositions comprising buprenorphine

Technical Field

The present disclosure relates to a buprenorphine sustained release delivery system for treating a condition ameliorated by a buprenorphine compound. The sustained release delivery system comprises: a flowable composition containing buprenorphine, a metabolite thereof, or a prodrug thereof, and an implant containing buprenorphine, a metabolite thereof, or a prodrug thereof.

Background

Buprenorphine (also known as (2S) -2- [ (-) - (5R,6R,7R,14S) -9 α -cyclopropylmethyl-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl ] -3, 3-dimethylbut-2-ol, sold under the tradenames SUBUTEX (TM) and SUBOXONE (TM)) is useful for the relief of opioid addiction.

Formula (1) shows the chemical structure of buprenorphine.

Formula (1)

The most common use of buprenorphine is in the treatment of symptoms resulting from opioid addiction and for long-term pain relief. The current commercial products are SUBUTEX (TM) and SUBOXONE (TM) sold by RB Pharma Inc. These products are tablet formulations, the purpose of which is to deliver therapeutic levels of buprenorphine over a short period of time, up to several hours, and are typically buccal or sublingual. However, patients need to replenish the dose regularly and often have problems with diversion in patients with opioid dependence problems. There is therefore a need for a long-term, non-reversible method of administering buprenorphine which is capable of delivering a constant and effective dose of active to a patient over a period of up to 30 days, and which does not result in the unwanted accumulation of residual active in the metabolism of the patient.

In the pharmaceutical industry, various sustained release methods are used, for example, systems such as biodegradable solid rods or non-degradable storage bags. However, these systems typically require surgical implantation and, for non-degradable delivery systems, a second surgical procedure is required to remove the empty reservoir.

There is a continuing need to develop products that increase the bioavailability of buprenorphine. In particular, there is a need to develop sustained release formulations of buprenorphine that: the preparation has no problems of low bioavailability, poor release kinetics, toxicity at injection site, large injection volume, and inconvenient short release time.

Disclosure of Invention

The present invention relates to a buprenorphine sustained release delivery system capable of delivering buprenorphine, a metabolite thereof, or a prodrug thereof for a period of about 14 days to about 3 months. The buprenorphine sustained release delivery system comprises: flowable compositions and solid implants for the sustained release of buprenorphine, a metabolite or prodrug thereof. The implant is made from the flowable composition. The buprenorphine sustained release delivery system provides a1 month and 3 month release profile in situ, characterized by extremely high bioavailability and minimal risk of permanent tissue damage, and generally no risk of muscle necrosis.

In one embodiment, a buprenorphine sustained release delivery system is provided. The delivery system comprises a flowable composition and a controlled release sustained release implant. The flowable composition of this embodiment comprises: a biodegradable thermoplastic polymer; a biocompatible polar organic liquid; and buprenorphine, a metabolite thereof, or a prodrug thereof. The flowable composition may be converted into the implant by contact with water, body fluids, or other aqueous media. In one embodiment, the flowable composition is injected into the body, whereby it is converted in situ to a solid implant.

Thus, according to a first embodiment of the invention, there is provided an injectable flowable composition comprising:

(a) at least one biodegradable thermoplastic polymer, said thermoplastic polymer being at least substantially insoluble in body fluids;

(b) a biocompatible polar aprotic (aprotic) organic liquid comprising an amide, an ester, a carbonate, a lactam, an ether, a sulfonyl, or any combination thereof; the solubility of the organic liquid in aqueous media or body fluids ranges from insoluble to completely soluble in all proportions; and

(c)1 to 10% by weight of buprenorphine, a metabolite or prodrug thereof;

wherein the composition is converted to a solid implant in situ by contact with water, body fluids or other aqueous media.

The thermoplastic polymers of the flowable compositions and implants are at least substantially insoluble in aqueous or body fluids, or generally completely insoluble in such media. The thermoplastic polymer may be a homopolymer, copolymer or terpolymer of repeating monomer units linked by, for example: an ester group, an anhydride group, a carbonate group, an amide group, a carbamate group, an urea group, an ether group, an ester amide group, an acetal group, a ketal group, an orthocarbonate group, and any other organic functional group that can be hydrolyzed by an enzymatic reaction or a hydrolysis reaction (i.e., has biodegradability by the hydrolysis). The thermoplastic polymer may be a polyester composed of units of about one or more hydroxycarboxylic acid residues or diol and dicarboxylic acid residues, wherein the distribution of the different residues may be random, block, paired, or sequential. The polyester may be a combination of about one or more diols and about one or more dicarboxylic acids. The one or more hydroxycarboxylic acids may also be in the form of a dimer.

When the biodegradable thermoplastic polymer is a polyester, the polyester comprises: for example, polylactide, polyglycolide, polycaprolactone, copolymers, terpolymers, or any combination thereof, and optionally incorporating a third mono-or polyol component. More preferably, the biodegradable thermoplastic polyester is polylactide, polyglycolide, copolymers thereof, terpolymers thereof, or combinations thereof, and optionally incorporates a third mono-or polyol component. Preferably, the polyester is 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10 or 95/5 poly (DL-lactide-co-glycolide) with carboxyl end groups, or 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, 80/20, 85/15, 90/10 or 95/5 poly (DL-lactide-co-glycolide) without carboxyl end groups. More preferably, a suitable biodegradable thermoplastic polyester is about 50/50 poly (DL-lactide-co-glycolide) (hereinafter PLG) having carboxyl end groups, or 75/25 or 85/15PLG having carboxyl end groups or PLG having about one or more mono-or polyol units in its composition. When a mono-or polyol is incorporated into the polyester, the mono-or polyol constitutes the third covalent component of the polymer chain. When a monohydric alcohol is incorporated, the carboxyl end groups of the polyester are esterified with the monohydric alcohol. When incorporated into the polyol, it extends the chain of the polyester and optionally branches it. The polyol serves as the polymerization point of the polyester, wherein the polyester chain extends from a plurality of hydroxyl moieties of the polyol, and these hydroxyl moieties are esterified with the carboxyl groups of the polyester chain. In embodiments where a diol is used, the polyester is linear, wherein the polyester chain extends from two esterified hydroxyl groups. In embodiments where a triol or higher polyol is used, the polyester may be linear or branched, with the polyester chain extending from the esterified hydroxyl group. Suitable polyols include, for example: aliphatic and aromatic diols; sugars such as glucose, lactose, maltose, sorbitol; trihydric alcohols such as glycerol and fatty alcohols, etc.; a tetrahydric alcohol; a pentahydric alcohol; a hexahydric alcohol; and so on.

The biodegradable thermoplastic polymer can be present in any suitable amount, so long as the biodegradable thermoplastic polymer is at least substantially insoluble in an aqueous medium or body fluid. Preferably, the biodegradable thermoplastic polyester is present in an amount of about 5% to about 95% by weight of the flowable composition, or in an amount of about 15% to about 70% by weight of the flowable composition, or in an amount of about 25% to about 50% by weight of the flowable composition.

Preferably, the biodegradable thermoplastic polyester has a weight average molecular weight of from about 5,000 daltons (Da) to about 40,000 daltons, more preferably from about 10,000 daltons to about 20,000 daltons.

The flowable composition further comprises a biocompatible polar organic liquid. The biocompatible polar liquid may be an amide, an ester, a carbonate, an ether, a sulfonyl or any other organic compound that is liquid at room temperature and has polarity. The organic liquid may be of very low solubility in the body fluid or may be completely soluble in the body fluid up to all ratios. Although the organic liquid should generally have a similar solubility profile in aqueous media and body fluids, body fluids are generally more lipophilic than aqueous media. Thus, some organic liquids that are insoluble in aqueous media should be at least slightly soluble in body fluids. These examples of organic liquids are included in the definition of organic liquid.

Preferably, the organic liquid comprises N-methyl-2-pyrrolidone, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin or any combination thereof. More preferably, the organic liquid is N-methyl-2-pyrrolidone. Preferably, the polar organic liquid is present in an amount of about 10% to 90% by weight of the composition, or in an amount of about 30% to 70% by weight of the composition.

The buprenorphine, metabolite or prodrug thereof comprises from about 1% to about 30%, preferably from 5% to 25%, more preferably from 8% to 22% by weight of the flowable composition.

In one embodiment, the buprenorphine, a metabolite thereof, or a prodrug thereof in the flowable composition may be neutral or in the free base form. In another embodiment, the buprenorphine, a metabolite, or prodrug thereof in the flowable composition may be in the form of a salt, and the counterion to the salt may be from a pharmaceutically acceptable organic or inorganic acid, or the counterion may be a polycarboxylic acid.

In a further preferred aspect, the weight ratio of buprenorphine, a metabolite or prodrug thereof to the biodegradable thermoplastic polymer is from 0.001:1 to 1.5: 1.

The flowable composition is formulated into an injectable delivery system. The flowable composition preferably has a volume of about 0.10ml to about 2.0ml, or preferably about 0.20ml to about 1.0 ml. The injectable compositions are preferably formulated for administration about once a month, about once every three months, or about once every four months, to about once every six months. Preferably, the flowable composition is a liquid or gel composition suitable for injection into a patient. The flowable composition may have the property of producing minimal tissue necrosis upon subcutaneous injection.

The buprenorphine sustained release delivery system may further comprise excipients, release modifiers, plasticizers, pore formers, gelling liquids, inactive bulking agents, and other components. Some of these additional components (e.g., gelling liquid and release modifier) should remain with the implant after the flowable composition is applied, while other additional components (e.g., pore former) should be dispersed separately and/or dispersed with the organic liquid.

In one embodiment, there is provided a method of forming a flowable composition for use as a controlled release implant, the method comprising mixing, in any order: a biodegradable thermoplastic polymer, a biocompatible polar aprotic liquid, and buprenorphine, a metabolite thereof, or a prodrug thereof. The biodegradable thermoplastic polymer is at least substantially insoluble in aqueous media or body fluids. The ingredients, their properties and preferred amounts are as disclosed above. Allowing the mixing to proceed for a time sufficient to effectively form the flowable composition for use as a controlled release implant. Preferably, the biodegradable thermoplastic polymer and the biocompatible polar aprotic organic liquid are mixed together to form a mixture, which is then combined with buprenorphine, a metabolite thereof, or a prodrug thereof to form the flowable composition. Preferably, the flowable composition is a solution or dispersion of buprenorphine, a metabolite or prodrug thereof and a biodegradable thermoplastic polymer in an organic liquid, with solutions being particularly preferred. The flowable composition preferably comprises: an effective amount of a biodegradable thermoplastic polymer; an effective amount of a biocompatible polar aprotic organic liquid; and an effective amount of buprenorphine, a metabolite thereof, or a prodrug thereof. The ingredients, preferred ingredients, their properties and preferred amounts are as disclosed above.

In one embodiment, the biodegradable implant formed in situ in a patient is provided by the steps of: injecting a flowable composition comprising a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluids, a biocompatible polar aprotic organic liquid, and buprenorphine, a metabolite or prodrug thereof, into the body of a patient and allowing the biocompatible polar aprotic liquid to escape to produce a biodegradable solid or gel implant. The flowable composition comprises: an effective amount of a biodegradable thermoplastic polymer, an effective amount of a biocompatible polar aprotic liquid, and an effective amount of buprenorphine, a metabolite, or prodrug thereof; the solid implant releases an effective amount of buprenorphine, a metabolite, or prodrug thereof over time as the solid implant biodegrades in a patient, and optionally the patient is a human.

In one embodiment, a method of forming a biodegradable implant in situ in a living patient is provided. The method comprises the following steps: injecting a flowable composition comprising a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluids, a biocompatible polar aprotic organic liquid, and buprenorphine, a metabolite or prodrug thereof, into the body of a patient and allowing the biocompatible polar aprotic organic liquid to escape to produce a biodegradable solid implant. Preferably, the biodegradable solid implant releases an effective amount of buprenorphine, a metabolite thereof, or a prodrug thereof by diffusion, erosion, or a combination of diffusion and erosion, when the solid implant biodegrades in the patient.

In one embodiment, a method of treating or preventing a disease in a mammal ameliorated, cured or prevented by buprenorphine, a metabolite thereof or a prodrug thereof is provided. The method comprises the following steps: administering to a patient in need of such treatment or prevention (preferably a human patient) an effective amount of a flowable composition comprising: a biodegradable thermoplastic polymer, a biocompatible polar aprotic organic liquid, and buprenorphine, a metabolite thereof, or a prodrug thereof.

In another embodiment, a kit is provided. In a preferred form of this embodiment, the kit comprises a first container and a second container. The first container comprises a composition comprising a biodegradable thermoplastic polymer and a biocompatible polar aprotic organic liquid. The biodegradable thermoplastic polymer may be at least substantially insoluble in aqueous media or body fluids. The second container comprises buprenorphine, a metabolite thereof, or a prodrug thereof. The ingredients, their properties and preferred amounts are as disclosed above. Preferably, the first container is a syringe and the second container is a syringe. The kit may preferably include, for example, instructions. Preferably, the first container may be in communication with the second container. More preferably, the first container and the second container are each configured to be in direct communication with each other. In another form of this embodiment, the kit comprises a single syringe comprising a composition comprising a biodegradable thermoplastic polymer that is at least substantially insoluble in body fluids, a biocompatible polar aprotic liquid, and buprenorphine, a metabolite or prodrug thereof.

In another embodiment, a solid implant is provided. The solid implant consists of at least a biodegradable thermoplastic polymer and buprenorphine, a metabolite thereof or a prodrug thereof, and is substantially insoluble in body fluids. The biodegradable thermoplastic polymer may be at least substantially insoluble in aqueous media or body fluids, although the buprenorphine, metabolite or prodrug thereof itself has at least some solubility in body fluids, its sequestration in the substantially insoluble implant allows for its slow, sustained release into the body.

The solid implant has a solid matrix or a solid microporous matrix. The substrate may be a core surrounded by a skin. The implant may be solid and microporous. If microporous, the core preferably contains pores having a diameter of about 1 micron to about 1000 microns. If microporous, the skin preferably contains pores of smaller diameter than the pores of the core. In addition, the pores of the sheath are preferably sized such that the sheath is functionally non-porous as compared to the core. The solid implant may optionally comprise, for example, one or more biocompatible organic substances which may act as excipients as described above, or may act as plasticizers, release profile modifiers, emulsifiers and/or sequestering carriers for buprenorphine, its metabolites or prodrugs thereof. The biocompatible organic liquid may also serve as an organic substance of the implant and/or may provide additional functions (e.g., a plasticizer, a regulator, an emulsifier, or a release carrier). Two or more organic liquids may be present in the flowable composition such that the primary organic liquid acts as a blending, solubilizing or dispersing agent, while one or more supplemental organic liquids provide additional functionality within the flowable composition and the implant. Alternatively, there may be an organic liquid which may serve at least as a blending agent, solubilizer or dispersant for the other ingredients, and may also provide additional functionality. As a second or additional component, other kinds of biodegradable organic liquids are typically combined with the flowable composition and remain with the implant as the applied flowable composition sets.

When used as a plasticizer, the biocompatible organic material provides properties to the implant such as elasticity, flexibility, moldability, and drug release profile. When used as a modulator, the biocompatible organic material also provides the implant with buprenorphine release modifying properties. Typically, the plasticizer increases the release rate of buprenorphine, a metabolite, or a prodrug thereof, while the modulator slows the release rate of buprenorphine, a metabolite, or a prodrug thereof. Furthermore, there may also be structural overlap between the two organic species acting as plasticizer and rate modifier.

When used as an emulsifier, the biocompatible organic material enables, at least in part, the formation of a homogeneous mixture of buprenorphine, a metabolite thereof, or a prodrug thereof in flowable compositions and implants. When used as a barrier vehicle, the biocompatible organic substance should act to encapsulate, barrier or otherwise enclose molecules or nanoparticles of buprenorphine, its metabolites or prodrugs thereof, to at least partially prevent its burst release, and to protect the buprenorphine, its metabolites or prodrugs thereof from degradation by other ingredients in the flowable composition and implant.

The amount of biocompatible organic material optionally remaining in the solid or gel implant is preferably small, for example, from about 0% to about 20% by weight (or a nearly negligible amount) of the composition. In addition, the amount of biocompatible organic material optionally present in the solid or gel implant preferably decreases over time.

The solid implant may also comprise, for example, a biocompatible organic liquid which may be extremely soluble in bodily fluids to the extent of being completely soluble in all proportions and which at least partially dissolves at least part of the thermoplastic polymer; optionally, the amount of the biocompatible organic liquid is less than about 5% by weight of the total weight of the implant, and optionally, the amount of the biocompatible organic liquid decreases over time.

The solid implant may also comprise, for example, a core comprising pores having a diameter of about 1 micron to about 1000 microns, and optionally, the skin comprises pores having a diameter smaller than the diameter of the pores of the core, and optionally, the pores of the skin are sized such that the skin is functionally non-porous compared to the core.

In one embodiment, the flowable composition has an initial limited burst followed by a substantially linear release profile followed by a gradual slow release period. Preferably, the linear release profile lasts 28 days.

In one embodiment, there is provided a method of treating a patient suffering from a medical condition comprising administering to the patient an effective amount of buprenorphine, a metabolite or prodrug thereof, in combination with an at least substantially water-insoluble biodegradable thermoplastic polymer and a biocompatible polar aprotic organic liquid, wherein the medical condition comprises opioid addiction and chronic pain. The method of treatment may include, for example, therapy in combination with another known pharmaceutical compound designated for the treatment of the adverse condition.

Preferably, the flowable composition is formulated for administration about once every month, or about once every three months, or about once every four months, or about once every six months.

In one embodiment, there is provided a method of treating a patient having a medical condition, the method comprising administering a flowable composition to the patient, thereby providing a biodegradable implant comprising buprenorphine, a metabolite, or prodrug thereof, and a biodegradable polymer, wherein the implant releases a therapeutically effective dose of buprenorphine, a metabolite, or prodrug thereof in a dose of about 0.1 to about 10 milligrams (mg) per day, or preferably about 1 to about 5 milligrams (mg) per day of buprenorphine, a metabolite, or prodrug thereof. The therapeutically effective dose of buprenorphine, a metabolite or prodrug thereof may be achieved within about five days after administration of the implant or, preferably, within about one day after administration of the implant. A therapeutically effective dose of buprenorphine, a metabolite, or a prodrug thereof may be delivered for at least about 15 days after administration of the implant, or preferably for about 28 days after administration of the implant, or preferably for about 45 days after administration of the implant, or preferably for about 60 days after administration of the implant.

Drawings

Figure 1 is a graphical representation of the 49-day release of buprenorphine from a selected AtriGEL (TM) formulation of buprenorphine hydrochloride following subcutaneous injection into rats.

Figure 2 is a graphical representation of the release of buprenorphine over 35 days following injection into rats of a selected Atrigel (TM) formulation of the buprenorphine free base.

Figure 3 is a graphical representation of the 35 day release of buprenorphine from other selected AtriGEL (TM) formulations of buprenorphine free base following injection into rats.

Figure 4 is a graph showing the 180 day plasma concentration of active buprenorphine in dogs injected with the Atrigel/(buprenorphine hydrochloride) formulation.

Figure 5 is a graphical representation of 195-day release of buprenorphine from a selected Atrigel (tm) formulation in dogs injected with an Atrigel/(buprenorphine free base) formulation.

Definition of

As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a formulation" includes a plurality of such formulations, and thus a formulation of compound X includes a plurality of formulations of compound X.

The term "acceptable salt" as used herein refers to derivatives wherein the parent compound is modified by formation of its acid or base salt. Suitable acceptable salts include, but are not limited to: mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and so on. Acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, the conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid; and salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methane-sulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid. In particular, the acceptable salts may include, for example, those salts that occur naturally in the body of a mammal.

The term "biocompatible" as used herein means that the material, substance, compound, molecule, polymer or system in which the term is employed should not cause serious toxicity, serious adverse biological reactions or mortality to the animal to which it is administered at reasonable doses and rates.

The term "biodegradable" as used herein refers to materials, substances, compounds, molecules, polymers or systems that are broken down, oxidized, hydrolyzed, or otherwise broken down by hydrolysis, enzymatic, or other mammalian biological processes for metabolism into chemical units that are assimilated or excreted by the body of the mammal.

The term "bioerodible" as used herein refers to a material, substance, compound, molecule, polymer, or system that biodegrades or is mechanically removed by biological processes in mammals, thereby revealing a new surface.

The average molecular weight as used herein is the weight average molecular weight of the polymer as determined by gel permeation chromatography (also known as GPC or Size Exclusion Chromatography (SEC)) using Tetrahydrofuran (THF) as a solvent and using a molecular weight calibration curve with polystyrene as a standard.

The term "therapeutically effective amount" as used herein is intended to include an amount of buprenorphine, a metabolite or prodrug thereof, a pharmaceutically acceptable salt thereof, a derivative thereof, or any combination of the foregoing, that is useful in treating or preventing an underlying disorder or disease, or treating a symptom of the host associated with the underlying disorder or disease. Synergy occurs as described, for example, by Chou and Talalay, adv.enzyme Regul.22,27-55(1984) when the effect of buprenorphine, a metabolite or prodrug thereof, a pharmaceutically acceptable salt thereof or a derivative thereof in combination is greater than the additive effect of buprenorphine, a metabolite or prodrug thereof, a pharmaceutically acceptable salt thereof or a derivative thereof when administered alone as a single agent. In general, the synergistic effect is most clearly shown at sub-optimal concentrations of buprenorphine, a metabolite or prodrug thereof, a pharmaceutically acceptable salt thereof or a derivative thereof. The synergy may be lower cytotoxicity, higher activity or some other beneficial effect exhibited by the combination when compared to the individual ingredients.

The term "flowable" as used herein refers to the ability of a "flowable" composition to be delivered under pressure to a patient. For example, the flowable composition may have a low viscosity like water and may be injected under the skin of a patient by using a syringe. Alternatively, the flowable composition may have a high viscosity such as a gel and can be delivered to a patient by high pressure delivery devices such as high pressure syringes, cannulas, and needles. The ability of a composition to be injected into a patient will generally depend on the viscosity of the composition. Thus, the composition should have a suitable viscosity range from a low viscosity like water to a high viscosity like a gel to enable the composition to be forced through a delivery device (e.g., a syringe) into a patient.

The term "gel" as used herein refers to a substance having gel-like, jelly-like or colloidal properties. See, for example, CONCISE CHEMICAL AND TECHNICAL DICTIONARY, 4 th edition, Chemical publishing Co., Inc., p.567, New York, NY (1986).

The term "liquid" as used herein refers to a substance that deforms continuously under shear stress. See, e.g., CONCISE CHEMICAL AND TECHNICAL DICTIONARY, 4 th edition, Chemical Publishing Co., Inc., p.707, New York, NY (1986).

The term "patient" as used herein refers to a warm-blooded animal, preferably a mammal, such as a cat, dog, horse, cow, pig, mouse, rat or primate (including humans). The term "polymer" as used herein refers to a molecule comprised of one or more repeating monomer residue units covalently bonded together by means of one or more repeating chemical functional groups. The term includes all polymeric forms, for example, linear, branched, star-shaped, random, block, and graft, and the like. Including homopolymers formed from a single monomer, copolymers formed from two or more monomers, terpolymers formed from three or more polymers, and polymers formed from more than three monomers. Different forms of polymers may also have more than one repeating, covalently bonded functional group. The term may also refer to substantially linear polyesters, also referred to herein as "PLG copolymers", which is formed mainly from lactic acid esters and glycolic acid esters of hydroxy acid monomers or from lactide and glycolide of hydroxy acid dimers, and include, for example, compositions known in the art as poly (lactate-glycolate), poly (lactate (co) glycolate), poly (lactide-glycolide), poly (lactide (co) glycolide), PLG, PLGH, and the like, it being understood that additional moieties may also be included, such as core groups/initiator groups (e.g., diols and hydroxy acids, etc.), end capping groups (e.g., esters of terminal carboxyl groups, etc.), and other pendant or chain extending groups (including groups that crosslink with a substantially linear polyester molecular chain) covalently attached to or within the polyester backbone, without departing from the meaning specified herein. The term PLG copolymer as used herein includes molecular chains having terminal hydroxyl groups, terminal carboxyl groups (i.e., acid-terminated, sometimes referred to as PLGH), and terminal ester groups (i.e., blocked).

The term "polyester" as used herein refers to a polymer containing repeating monomers that are at least partially-OC (= O) -or-C (= O) O-linking groups.

The terms "skin" and "core" in the context of a skin and core matrix as used herein mean that the cross-section of the matrix should exhibit a discernible contour between the exterior and interior of the matrix. The outer surface is the crust, and the inside is the core. The term "thermoplastic" as used herein to modify a polymer means that the polymer should melt upon repeated heating and solidify upon cooling. This means that there is no or only a slight degree of crosslinking between the polymer molecules. The term should be distinguished from the term "thermoset," which indicates that the polymer should cure or substantially crosslink upon heating or upon application of a similar reaction process, and should no longer undergo a melt-cure cycle upon heating and cooling.

The term "treating" as used herein includes (i) preventing the occurrence (e.g., prevention) of a pathological condition (e.g., schizophrenia); (ii) inhibiting or arresting the development of a pathological condition (e.g., schizophrenia); and (iii) relief of the pathological condition (e.g., relief of symptoms associated with schizophrenia).

Detailed Description

The present invention relates to a buprenorphine sustained release delivery system. The sustained release delivery system comprises a flowable composition and a solid implant. The delivery system provides for in situ sustained release of buprenorphine, a metabolite or prodrug thereof. The flowable composition achieves sustained release through its use to create an implant. The implants have a lower implant capacity and provide long term delivery of buprenorphine, a metabolite thereof, or a prodrug thereof. The flowable composition enables the implant to be formed in situ subcutaneously with little or no tissue necrosis. The in situ implant provides therapeutic plasma levels of buprenorphine, a metabolite thereof, or a prodrug thereof immediately after injection and maintains steady state plasma levels for four to six weeks.

Another advantage of one embodiment includes a simple manufacturing process and delivery system. For example, buprenorphine, a metabolite or prodrug thereof is loaded into a syringe, the syringe is sealed, and the entire drug syringe is terminally sterilized by gamma irradiation. The biodegradable polymer used was dissolved in N-methyl-2-pyrrolidone and then loaded into the second syringe. The syringe is sealed and the delivery system is terminally sterilized by gamma irradiation. During injection, the two syringes are interconnected through Luer lock connectors to circulate the ingredients between the two syringes, thereby forming the product. In this way the drug is mixed into the delivery system with minimal loss in the device.

The flowable composition is a combination of: a biodegradable at least substantially water-insoluble thermoplastic polymer, a biocompatible polar aprotic organic liquid, and buprenorphine, a metabolite thereof, or a prodrug thereof. The solubility of the polar aprotic organic liquid in body fluids ranges from almost insoluble to completely soluble in all proportions. Preferably, the thermoplastic polymer is a polyester of about one or more hydroxycarboxylic acids or about one or more diols and dicarboxylic acids. It is particularly preferred that the thermoplastic polymer is a polyester of about one or more hydroxy carboxyl dimers (e.g., lactide, glycolide, and dihexanolide, and the like).

Specific and preferred biodegradable thermoplastic polymers and polar aprotic solvents described herein; the concentration of the thermoplastic polymer, the polar aprotic organic liquid, and buprenorphine, a metabolite thereof, or a prodrug thereof; the molecular weight of the thermoplastic polymer; as well as the weight or molar range of the components in the solid implant, are exemplary. They do not exclude other biodegradable thermoplastic polymers and polar aprotic organic liquids; other concentrations of thermoplastic polymer, polar aprotic liquid, and buprenorphine, a metabolite thereof, or a prodrug thereof; other molecular weights of the thermoplastic polymer; and other components in solid implants.

In one embodiment, a flowable composition suitable for providing controlled release sustained release implants, methods of forming the flowable composition, methods of using the flowable composition, biodegradable sustained release solid or gel implants formed from the flowable composition, methods of forming biodegradable implants in situ, methods of treating diseases by using biodegradable implants, and kits comprising the flowable composition are provided. The flowable composition may preferably be used to provide an in situ formed biodegradable or bioerodable microporous implant in an animal. The flowable composition is comprised of a biodegradable thermoplastic polymer in combination with a biocompatible polar aprotic organic liquid and buprenorphine, a metabolite thereof, or a prodrug thereof. The biodegradable thermoplastic polymer is substantially insoluble in aqueous media and/or body fluids, is biocompatible, and is biodegradable and/or bioerodable in the patient's body. The flowable composition can be applied to tissue as a liquid or gel and formed into an implant in situ. Alternatively, the implant may be formed in vitro by combining a flowable composition with an aqueous medium. In this embodiment, the preformed implant may be surgically administered to the patient. In any of the above embodiments, when the flowable composition is contacted with a body fluid, aqueous medium, or water, the organic liquid escapes, disperses, or leaches from the flowable composition as the thermoplastic polymer solidifies or solidifies to form a solid or gel implant. The coagulation or solidification causes other ingredients of the flowable composition (e.g., buprenorphine, metabolites or prodrugs thereof, excipients, organic substances, etc.) to be entangled or trapped, thereby causing the ingredients to be dispersed in the gelled or solidified implant matrix. The flowable composition is biocompatible and the polymer matrix of the implant does not cause significant tissue irritation or necrosis at the implant site. The implants deliver sustained levels of buprenorphine, a metabolite, or prodrug thereof to a patient. Preferably, the flowable composition can be a liquid or gel suitable for injection into a patient (e.g., a human).

One embodiment surprisingly improves the bioavailability of a sustained release formulation of buprenorphine, a metabolite, or prodrug thereof. Additionally, one embodiment provides: (a) relatively low volume injections; (b) improved tolerance of local tissues at the injection site; (c) there is an opportunity to use subcutaneous injection rather than intramuscular injection; and (d) a reduced frequency of injection compared to other products.

The buprenorphine sustained release delivery system will provide, in contrast to formulations derived from other sustained release drug delivery technologies: (a) excellent release kinetics with minimal burst release; (b) the duration of drug release is improved, and the injection frequency is reduced; (c) the bioavailability is obviously improved; (d) improved local tissue tolerance due to smaller injection volumes; and (e) subcutaneous injection can be used rather than intramuscular injection. This feature, taken together, results in a highly beneficial buprenorphine sustained release delivery system.

Biodegradable thermoplastic polymers

The flowable composition is made by combining: a solid biodegradable thermoplastic polymer, buprenorphine, a metabolite or prodrug thereof, and a biocompatible polar aprotic organic liquid. The flowable composition may be administered to a patient in need of treatment by means of a syringe and needle. Any suitable biodegradable thermoplastic polymer may be used as long as the biodegradable thermoplastic polymer is at least substantially insoluble in body fluids.

Biocompatible, biodegradable thermoplastic polymers can be composed of a plurality of monomers forming a polymer chain, or of a plurality of monomeric units joined together by linking groups. The thermoplastic polymer is comprised of a polymer chain or backbone comprising monomer units, wherein the monomer units are joined by, for example, the following linking groups: an ester group, an amide group, a urethane group, an anhydride group, a carbonate group, a urea group, an ester amide group, an acetal group, a ketal group, or an orthocarbonate group, and any other organic functional group that can be hydrolyzed by an enzymatic reaction or a hydrolysis reaction (i.e., is biodegradable by the hydrolysis). The thermoplastic polymer is typically formed by reacting starting monomers containing reactant groups that should form backbone linking groups. For example, the alcohol and carboxylic acid should form an ester linkage. The isocyanate and amide or alcohol should form a urea or urethane linking group, respectively.

Any aliphatic, aromatic or arylalkyl starting monomer having a specific functional group can be used to form the thermoplastic polymer, as long as the polymer and its degradation products are biocompatible. The one or more monomers used to form the thermoplastic polymer may have a single identity or multiple identities. The resulting thermoplastic polymer should be a homopolymer formed from one monomer or group of monomers (e.g., when using diols and diacids), or a copolymer, terpolymer, or multipolymer formed from two/two or more groups or three/three or more groups of monomers. Details of the biocompatibility of such starting monomers are known in the art. The thermoplastic polymer is substantially insoluble in aqueous media and body fluids, preferably completely insoluble in such media and fluids. The polymers are also capable of being dissolved or dispersed in selected organic liquids having a water solubility ranging from completely soluble to insoluble in water in all proportions. The thermoplastic polymer is also biocompatible.

When used in a flowable composition, the combination of the thermoplastic polymer and organic liquid provides the flowable composition with a viscosity that ranges from a 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. Typically, the polymeric component comprises about 5% to about 95% by weight of the flowable composition, preferably in an amount of about 15% to about 70% by weight of the flowable composition, or more preferably in an amount of about 25% to about 50% by weight of the flowable composition.

In one embodiment, the biodegradable, biocompatible thermoplastic polymer may be a linear polymer, it may also be a branched polymer, or it may be a combination of both. According to one embodiment, any selection may be used. In order to provide branched thermoplastic polymers, a portion of one of the starting monomers may be at least trifunctional, and preferably multifunctional. This multifunctionality characterises the branching of the resulting polymer chains at least in part. For example, when the selected polymer contains ester linkages along its polymer backbone, the starting monomer should generally be a hydroxycarboxylic acid, a cyclic dimer of a hydroxycarboxylic acid, a cyclic trimer of a hydroxycarboxylic acid, a diol, or a dicarboxylic acid. Thus, in order to provide a branched thermoplastic polymer, at least a portion of the starting monomers that are polyfunctional (e.g., triols or tricarboxylic acids) are included in the combination of monomers to be polymerized to form the thermoplastic polymer. In addition, depending on the stoichiometry of the polymerization reaction, the polymer may incorporate more than one, and typically many, polyfunctional units per polymer molecule. The polymer may also optionally incorporate at least about one multifunctional unit per polymer molecule. When about one multifunctional unit is incorporated into one polymer molecule, so-called star-shaped or branched polymers are formed. Preferred thermoplastic polymers may be formed from monomers such as hydroxycarboxylic acids or dimers thereof. Alternatively, the thermoplastic polyester may be formed from a dicarboxylic acid and a diol. If a branched polyester is desired, a branching monomer (e.g., a dihydroxy carboxylic acid) should be included with the first type of starting monomer, or a triol and/or tricarboxylic acid should be included with the second type of starting monomer. Similarly, if a branched or star-shaped polyester is desired, a triol, tetraol, pentaol, or hexaol (e.g., sorbitol or glucose) should be included with the first type of starting monomer. The same applies to polyamides. Triamine and/or triacid acids should be included with the diamine and dicarboxylic acid starting monomers. The aminodicarboxylic acid, diaminocarboxylic acid or triamine should be included with the starting monomeric amino acids of the second class. Any aliphatic, aromatic or arylalkyl starting monomer having a particular functional group can be used to form the branched thermoplastic polymer, so long as the polymer and its degradation products are biocompatible. Details of the biocompatibility of such starting monomers are known in the art.

The monomers used to form the biocompatible thermoplastic polymer should produce a polymer or copolymer having thermoplastic, biocompatible, and biodegradable properties. Suitable thermoplastic, biocompatible, biodegradable polymers suitable for use as biocompatible thermoplastic branched polymers include, for example: polyesters, polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamides, polyurethanes, polyesteramides, polydioxanones, polyacetals, polyketals, polycarbonates, polyorthocarbonates, polyorthoesters, polyphosphoesters, polyphosphazenes, polyhydroxybutyrates, polyhydroxyvalerates, polyalkylene oxalates, polyalkylene succinates, poly (malic acid), poly (amino acids), and copolymers, terpolymers, compositions, or mixtures of the above materials. Examples of such biocompatible, biodegradable thermoplastic polymers are disclosed in, for example, U.S. Pat. nos. 4,938,763, 5,278,201, 5,324,519, 5,702,716, 5,744,153, 5,990,194, 6,461,631, and 6,565,874.

The polymer component may also comprise, for example, polymer mixtures of the polymer with other biocompatible polymers, as long as they do not adversely interfere with the biodegradable properties of the component. Mixtures of the polymer with the other polymers may provide further greater flexibility in designing the precise release profile required for targeted drug delivery or the precise biodegradation rate required for an implant.

Preferred biocompatible thermoplastic polymers or copolymers are those that have lower crystallinity and are more hydrophobic. These polymers and copolymers are more readily soluble in biocompatible organic liquids than highly crystalline polymers having a higher degree of hydrogen bonding (e.g., polyglycolide). Preferred materials having the desired solubility parameters are polylactide, polycaprolactone, and copolymers of these materials with glycolide to provide more amorphous regions to increase solubility. Generally, biocompatible, biodegradable thermoplastic polymers are substantially soluble in organic liquids, such that solutions, dispersions, or mixtures containing up to about 50-60% by weight solids can be prepared. Preferably, the polymer is generally completely soluble in the organic liquid, so that a solution, dispersion or mixture containing up to about 85% to 98% by weight solids can be prepared. In addition, the polymer is at least substantially insoluble in water, such that the polymer dissolved or dispersed in water should be less than about 0.1g/ml water. Preferably, the polymer is generally completely insoluble in water, such that the polymer dissolved or dispersed in water should be less than about 0.001g/ml water. At this preferred level, a flowable composition with a fully water-miscible organic liquid should convert almost immediately to a solid implant.

Optionally, the delivery system may also comprise a non-polymeric material in combination with an amount of a thermoplastic polymer. The combination of non-polymeric materials and thermoplastic polymers can be tailored and designed to provide a more consistent buprenorphine sustained release delivery system. Useful non-polymeric materials are materials that are biocompatible, substantially insoluble in water and body fluids, biodegradable and/or bioerodable within the body of an animal. The non-polymeric material is capable of being at least partially dissolved in an organic liquid. In flowable compositions containing certain organic liquids or other additives, when the flowable composition comes into contact with bodily fluids, the organic liquid components escape, disperse, or leach from the flowable composition, at which time the non-polymeric material is also able to set or cure, thereby forming a solid or gel implant. The matrix of all embodiments of the implant comprising the non-polymeric material should have a consistency ranging from gelatinous to plastic and formable to hard, dense solids.

Non-polymeric materials that can be used in the delivery system generally include, for example, any material having the aforementioned characteristics. Suitable useful non-polymeric materials include, for example: sterols, such as cholesterol, stigmasterol, beta-sitosterol, and estradiol; cholesterol esters, such as cholesterol stearate; ci8-C36 monoglycerides, diglycerides and triglycerides, such as glycerol monooleate, glycerol monolinoleate, glycerol monolaurate, glycerol monobehenate, glycerol monomyristate, glycerol monodecanoate, glycerol dipalmitate, glycerol dibehenate, glycerol dimyristate, glycerol tribehenate, glycerol trimyristate, glycerol tridecenate, glycerol tristearate and mixtures thereof; sucrose fatty acid esters such as sucrose distearate and sucrose palmitate; sorbitan fatty acid esters such as sorbitan monostearate, sorbitan monopalmitate and sorbitan tristearate; ci6-Ci8 fatty alcohols, such as cetyl alcohol, myristyl alcohol, stearyl alcohol and cetearyl mixed alcohol; esters of fatty alcohols with fatty acids, such as cetyl palmitate and cetostearyl palmitate; anhydrides of fatty acids, such as stearic anhydride; phospholipids including phosphatidylcholine (lecithin), phosphatidylserine, phosphatidylethanolamine, phosphatidylinositol and their dissolved derivatives; sphingosine and derivatives thereof; sphingomyelins, such as stearoyl sphingomyelin, palmitoyl sphingomyelin, and eicosatriyl sphingomyelin; ceramides, such as stearoyl ceramide and palmitoyl ceramide; glycosphingolipids; lanolin and lanolin alcohols; and combinations and mixtures of the foregoing. Preferred non-polymeric materials include, for example, cholesterol, glycerol monostearate, glycerol tristearate, stearic acid, stearic anhydride, glycerol monooleate, glycerol monolinoleate and acetylated monoglycerides. The polymeric and non-polymeric materials may be selected and/or combined to control the rate of biodegradation, bioerosion, and/or bioabsorption within the implant site. Generally, the disintegration of the implant matrix should be for a period of about 1 week to about 12 months, preferably for a period of about 1 week to about 4 months.

Molecular weight of thermoplastic polymers

The molecular weight of the polymer can affect the rate of release of buprenorphine, a metabolite thereof, or a prodrug thereof from the implant. Under these conditions, the rate of release of buprenorphine, a metabolite or prodrug thereof from the system decreases as the molecular weight of the polymer increases. This phenomenon can be advantageously used to formulate controlled release systems for buprenorphine, its metabolites or its prodrugs. For faster release of buprenorphine, its metabolites or its prodrugs, low molecular weight polymers may be selected to provide the desired release rate. To release buprenorphine, a metabolite thereof or a prodrug thereof over a relatively long period of time, a higher molecular weight polymer may be selected. Thus, the buprenorphine sustained release delivery system can be manufactured with an optimum range of polymer molecular weights to release buprenorphine, a metabolite or prodrug thereof for a selected length of time. The molecular weight of the polymer can be varied in any of a variety of ways. The choice of method is generally dependent on the type of polymer component. For example, if a thermoplastic polyester is used that is biodegradable by hydrolysis, the molecular weight can be varied by controlled hydrolysis (e.g., in a steam autoclave). In general, the degree of polymerization can be controlled by, for example, varying the number and type of reactive groups and the reaction time.

Control of the molecular weight and/or intrinsic viscosity of the thermoplastic polymer is a factor related to the formation and performance of the implant. Generally. Thermoplastic polymers with higher molecular weight and higher intrinsic viscosity will provide implants with slower degradation rates and therefore longer durations. The changes and fluctuations in the molecular weight of the thermoplastic polymer that occur after the combination of the delivery system will result in the formation of such implants: the implant exhibits a degradation rate and duration that is quite different from the desired or expected degradation rate and duration.

An effective thermoplastic polymer may have an average molecular weight of about 1 kilodaltons (kDa) to about 100 kDa. Preferably, the biodegradable thermoplastic polymer has an average molecular weight of from about 5,000 daltons (Da) to about 40,000 daltons, or more preferably from about 10,000 daltons to about 20,000 daltons.

Molecular weight may also be expressed in terms of intrinsic viscosity (abbreviated as "IV" in deciliters per gram). Generally, the intrinsic viscosity of a thermoplastic polymer is a measure of its molecular weight and degradation time (e.g., a thermoplastic polymer with a high intrinsic viscosity has a higher molecular weight and a longer degradation time). Preferably, the molecular weight of the thermoplastic polymer, expressed as intrinsic viscosity, is from about 0.05dL/g to about 0.5dL/g (as measured in chloroform), more preferably from about 0.10dL/g to about 0.30 dL/g.

Characteristics of the preferred polyesters

The preferred thermoplastic biodegradable polymer of the flowable composition is a polyester. Typically, the polyester is comprised of units of about one or more hydroxycarboxylic acid residues, wherein the distribution of the different units can be random, block, paired, or sequential. Alternatively, the polyester may be comprised of units of about one or more diols and about one or more dicarboxylic acids. The distribution should depend on the starting materials and synthesis processes used to synthesize the polyester. An example of a polyester composed of different pairs of monomers distributed in a block or sequential manner is poly (lactide-co-glycolide). An example of a polyester composed of different unpaired units distributed in a random fashion is poly (lactic-co-glycolic acid). Suitable biodegradable thermoplastic polyesters include, for example, polylactide, polyglycolide, polycaprolactone, copolymers thereof, terpolymers thereof, and any combination thereof. Preferably, suitable biodegradable thermoplastic polyesters are polylactide, polyglycolide, copolymers thereof, terpolymers thereof, or combinations thereof.

The terminal groups of the poly (DL-lactide-co-glycolide) can be hydroxyl, carboxyl or ester, depending on the polymerization method. The polycondensation of lactic acid or glycolic acid will provide a polymer with hydroxyl end groups and carboxyl end groups. The ring-opening polymerization of cyclic lactide or glycolide monomers with water, lactic acid or glycolic acid will provide polymers having the same end groups as described above. However, ring-opening polymerization of cyclic monomers with monofunctional alcohols (e.g., methanol, ethanol, or 1-dodecanol) provides a polymer having about one hydroxyl group and about one ester end group. Ring-opening polymerization of cyclic monomers with polyols (e.g., glucose, 1, 6-hexanediol, or polyethylene glycol) provides polymers with multiple hydroxyl end groups. Such dimer polymerization of hydroxycarboxylic acids and polyols is a chain extension of the polymer. The polyol serves as a central condensation point, and the polymer chain grows from the hydroxyl groups, allowing the hydroxyl groups to be incorporated as ester moieties of the polymer. The polyol can be a diol, triol, tetraol, pentaol, or hexaol, from about 2 to about 30 carbon atoms in length. Examples include: sugars, reducing sugars, such as sorbitol; diols, such as 1, 6-hexanediol; triols, such as glycerol; or a reduced fatty acid; and similar polyols.

Generally, polyesters copolymerized with alcohols or polyols will provide implants of longer duration.

The type, molecular weight and amount of the preferred biodegradable thermoplastic polyesters present in the flowable composition will generally depend on the desired properties of the controlled release sustained release implant. For example, the type, molecular weight and amount of biodegradable thermoplastic polyesters can affect the length of time that buprenorphine, a metabolite or prodrug thereof is released from a controlled release sustained release implant. In particular, in one embodiment, the compositions are useful for formulating a one month sustained release delivery system for buprenorphine, a metabolite, or prodrug thereof. In this embodiment, the biodegradable thermoplastic polyester may be 50/50, 55/45, 75/25, 85/15, 90/10, or 95/5 poly (DL-lactide-co-glycolide) having carboxyl end groups, preferably 50/50 poly (DL-lactide-co-glycolide) having carboxyl end groups; it may be present in an amount of about 20% to about 70% by weight of the composition; the average molecular weight may be from about 5,000 daltons to about 40,000 daltons, or preferably from about 10,000 daltons to about 20,000 daltons.

In one embodiment, the flowable composition may be formulated to provide a sustained release delivery system for buprenorphine, a metabolite thereof, or a prodrug thereof. In this embodiment, the biodegradable thermoplastic polyester may be 50/50, 55/45, 75/25 poly (DL-lactide-co-glycolide) with carboxyl end groups, preferably 50/50 poly (DL-lactide-co-glycolide) with carboxyl end groups; it may be present in an amount of about 20% to about 50% by weight of the composition; the average molecular weight may be from about 5,000 daltons to about 40,000 daltons, or preferably from about 10,000 daltons to about 20,000 daltons.

Polar aprotic organic liquids

Organic liquids suitable for use in the flowable composition are biocompatible and exhibit a range of solubility in aqueous media, body fluids, or water. The range includes: the organic liquid is completely insoluble at all concentrations to completely soluble at all concentrations when initially contacted with an aqueous medium, body fluid or water.

Although the solubility or insolubility of an organic liquid in water may be used as an indicator of solubility, its solubility or insolubility in body fluids will generally be different from its solubility or insolubility in water. Body fluids contain physiological salts, lipids, proteins, etc. as opposed to water, and have different solvating powers for organic liquids. This phenomenon is similar to the classic "salting out" properties exhibited by saline water relative to water. Body fluids exhibit similar variability as water, but unlike "salting out" factors, body fluids generally have a higher solvating power than water for most organic liquids. This higher capacity is partly due to the higher lipophilicity of body fluids than water and partly also due to the dynamic nature of body fluids. In living organisms, the body fluid is not static, but moves throughout the organism. In addition, the body fluid is decontaminated or cleansed from the tissues of the organism, thereby removing the contents of the body fluid. Thus, bodily fluids within living tissue will remove, solvate or dissipate organic liquids that are completely insoluble in water.

Based on the above knowledge of the solubility differences between water, aqueous medium and body fluids, the organic liquid may be completely insoluble in water, up to completely soluble in water, when the organic liquid is initially combined with water. Preferably, the organic liquid is at least slightly soluble in water, more preferably moderately soluble in water, even more preferably highly soluble in water, most preferably soluble in water at all concentrations. The corresponding solubility of organic liquids in aqueous media and body fluids will tend to follow the trend exhibited by water solubility. In body fluids, the solubility of organic liquids should tend to be higher than the solubility in water. When an organic liquid ranging from insoluble to slightly soluble in bodily fluids is used in any of the embodiments of the sustained release delivery system, the organic liquid will allow water to penetrate into the implanted delivery system within a period of seconds to weeks or months. This process can reduce or increase the rate of delivery of buprenorphine, a metabolite or prodrug thereof, and in the case of a flowable composition, will affect the rate of coagulation or solidification. When a moderately to highly soluble organic liquid is used in any embodiment of the delivery system, the organic liquid will diffuse into the body fluid over a period of minutes to days. The rate of diffusion may reduce or increase the rate of delivery of buprenorphine, a metabolite or prodrug thereof. When highly soluble organic liquids are used, these organic liquids will diffuse out of the delivery system over a period of seconds to hours. In some cases, this rapid diffusion is at least partly responsible for the so-called burst effect. The burst effect is a short-term but rapid release of buprenorphine, a metabolite thereof, or a prodrug thereof upon implantation of the delivery system, followed by a long-term slow release of buprenorphine, a metabolite thereof, or a prodrug thereof.

Organic liquids for use in the delivery system include, for example, aliphatic, aryl and arylalkyl, linear, cyclic and branched organic compounds that are liquid or at least flowable at room and physiological temperatures and contain the following functional groups: for example, alcohols, alkoxylated alcohols, ketones, ethers, polyethers, amides, esters, carbonates, sulfoxides, sulfones, any other functional group compatible with living tissue, and any combination thereof. The organic liquid is preferably a polar aprotic organic solvent or a polar protic organic solvent. Preferably, the organic liquid has a molecular weight of about 30 to about 1000.

Preferred biocompatible organic liquids that are at least slightly soluble in aqueous or body fluids include, for example: n-methyl-2-pyrrolidone, 2-pyrrolidone; (C1-C15) alcohols, diols, triols and tetrols, such as ethanol, glycerol, propylene glycol and butanol; (C3-C15) esters and alkyl esters of monocarboxylic, dicarboxylic and tricarboxylic acids, such as 2-ethoxyethyl acetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate, diethyl malonate, diethyl glutamate, tributyl citrate, diethyl succinate, glyceryl tributyrate, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, and glyceryl triacetate; (C1-C15) amides such as dimethylformamide, dimethylacetamide and caprolactam; (C3-C20) ethers, such as tetrahydrofuran or acetonide; tween, triacetin, decyl dimethyl sulfoxide, oleic acid, l-dodecyl-azacycloheptane-2-one, N-methyl-2-pyrrolidone; esters of carbonic acid with alkyl alcohols, such as propylene carbonate, ethylene carbonate and dimethyl carbonate; alcohols such as glycerol acetonide, glycerol formal and tetraethylene glycol terepthalate; dialkylamides such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, and dimethylsulfone; lactones, such as caprolactone and butyrolactone; cyclic alkyl amides such as caprolactam; triacetin and diacetin; aromatic amides such as N, N-dimethyl-m-toluamide; and mixtures and combinations of the foregoing. Preferred solvents include, for example, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, propylene carbonate, glycerol acetonide, triacetin, glycerol formal, isopropylidene glycol and tetraethylene glycol.

Other preferred organic liquids are benzyl alcohol, benzyl benzoate, dipropylene glycol, tributyrin, ethyl oleate, glycerol, tetraethylene glycol, isopropyl myristate, isopropyl palmitate, oleic acid, polyethylene glycol, propylene carbonate and triethyl citrate. The most preferred solvents are N-methyl-2-pyrrolidone, dimethyl sulfoxide, triacetin and propylene carbonate due to their solvating power and compatibility.

The type and amount of biocompatible organic liquid present in the flowable composition will generally depend on the desired properties of the controlled release implant described in detail below. Preferably, the flowable composition comprises from about 10 wt% to about 90 wt% or more preferably from about 30 wt% to about 70 wt% of the organic liquid.

The solubility of biodegradable thermoplastic polymers in various organic liquids will vary depending on their crystallinity, hydrophilicity, hydrogen bonding, and molecular weight. Lower molecular weight polymers will generally be more soluble in organic liquids than higher molecular weight polymers. Thus, the concentration of thermoplastic polymer dissolved in various organic liquids will vary depending on the type of polymer and its molecular weight. In addition, higher molecular weight thermoplastic polymers may tend to produce higher solution viscosities than lower molecular weight materials.

When the organic liquid forms part of a flowable composition, it functions to enable easy, non-surgical placement of the sustained release delivery system within living tissue. It also facilitates the conversion of the flowable composition into an in situ formed implant. Although it is not meant to limit the invention, it is believed that the conversion of the flowable composition is a result of the escape of organic liquid from the flowable composition into the surrounding bodily fluids and the infusion of bodily fluids from the surrounding tissues into the flowable composition. It is believed that during this transition, the thermoplastic polymer and organic liquid in the flowable composition are divided into a polymer-rich zone and a polymer-lean zone.

If additives such as organic liquids remain in the implant, the implant is able to substantially retain its flexibility throughout its lifetime. Such additives may also act as plasticizers for the thermoplastic polymer and may be at least partially retained in the implant. One such additive having these properties is an organic liquid having low water solubility to water insolubility. The organic liquid that provides these flexibilities and plasticizations may be included in the delivery system as the only organic liquid or may be included with organic liquids having moderate to high water solubilities. In embodiments of the flowable composition, organic liquids having low water solubility or water insolubility (e.g., those that form aqueous solutions of no more than about 5% by weight in water) are capable of acting as the flexible plasticizing component and may additionally act as the solvating component. Such organic liquids can act as plasticizers for thermoplastic polymers. When an organic liquid has these properties, it is a member of a subgroup of organic liquids known as "plasticizers". Plasticizers affect the flexibility and moldability of the implant composition, making it more comfortable for the patient when implanted. In addition, the plasticizer has an effect on the rate of sustained release of buprenorphine, a metabolite or prodrug thereof, such that the rate can be increased or decreased depending on the nature of the plasticizer incorporated into the implant composition. It is generally believed that the organic liquid acting as a plasticizer may facilitate molecular movement in the solid or gel thermoplastic matrix. The plasticizing ability enables the polymer molecules in the matrix to move relative to each other, thereby providing flexibility and formability. The plasticizing ability also allows buprenorphine, its metabolites, or its prodrugs to move easily, thereby having a positive or negative impact on the sustained release rate in some cases.

Highly water-soluble organic liquids

Moderately to highly water soluble organic liquids are often used in flowable compositions, especially where flexibility is not an issue after formation of the implant. The use of a highly water soluble organic liquid will provide an implant with the physical properties of an implant formed by direct insertion of the flowable composition.

The use of moderately to highly water soluble organic liquids in flowable compositions will facilitate the intimate combination and mixing of the other ingredients in the composition. It will improve the solid or gel homogeneity and flexibility of the implant formed in vitro, thereby allowing the implant to be easily inserted into a suitable incision in tissue or into a site where a trocar is placed.

Useful highly water-soluble organic liquids include, for example: heterocyclic compounds having a substituent such as N-methyl-2-pyrrolidone (NMP) and 2-pyrrolidone; (C2-C10) alkanoic acids such as acetic acid and lactic acid; esters of hydroxy acids such as methyl lactate, ethyl lactate, and alkyl citrates, and the like; monoesters of polycarboxylic acids such as monomethyl succinate and monomethyl citrate, and the like; ether alcohols such as tetraethylene glycol, glycerol formal, isopropylidene glycol and 2, 2-dimethyl-l, 3-dioxolenone-4-methanol; condensing acetone into glycerol; dialkylamides such as dimethylformamide and dimethylacetamide; dimethyl sulfoxide (DMSO) and dimethyl sulfone; lactones, such as caprolactone and butyrolactone; cycloalkylamides, such as caprolactam; and combinations and mixtures of the foregoing. Preferred organic liquids include, for example, N-methyl-2-pyrrolidone, dimethyl sulfoxide, ethyl lactate, tetraethylene glycol, glycerol formal and isopropylidene glycol.

Organic liquids/solvents of low water solubility

As mentioned above, organic liquids with low or no water solubility (hereinafter referred to as low/no liquid) can also be used in sustained release delivery systems. Preferably, low/no liquid is used when it is desired to obtain an implant that remains flexible, extrudable, and has extended release, etc. For example, the release rate of a bioactive agent can be affected in some cases by using low/no liquids. Typically, such conditions involve retention of the organic liquid within the implant product, as well as its function as a plasticizer or rate modifier. Suitable low-solubility or insoluble organic liquids include, for example: esters of carbonic acid with aryl alcohols, such as benzyl benzoate; (C4-C10) an alkyl alcohol; (C1-C6) alkyl (C2-C6) alkanoate; esters of carbonic acid with alkyl alcohols, such as propylene carbonate, ethylene carbonate and dimethyl carbonate; alkyl esters of monocarboxylic, dicarboxylic and tricarboxylic acids, such as 2-ethoxyethyl acetate, ethyl acetate, methyl acetate, ethyl butyrate, diethyl malonate, diethyl glutamate, tributyl citrate, diethyl succinate, glyceryl tributyrate, isopropyl myristate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate and glyceryl triacetate; alkyl ketones such as methyl ethyl ketone; and other liquid organic compounds containing carbonyl, ether, carboxylate, amide and hydroxyl groups that have some solubility in water. Propylene carbonate, ethyl acetate, triethyl citrate, isopropyl myristate and triacetin are preferred because of their biocompatibility and pharmaceutical acceptability. In addition, mixtures of high-solubility, low-solubility or non-solubility organic liquids that provide various degrees of solubility to the materials used to form the matrix can be used to alter the useful life of the implant, the release rate of the bioactive agent, and other characteristics. Examples include a combination of N-methyl-2-pyrrolidone and propylene carbonate, which provides a more hydrophobic solvent than N-methyl-2-pyrrolidone alone, and a combination of N-methyl-2-pyrrolidone and polyethylene glycol, which provides a more hydrophilic solvent than N-methyl-2-pyrrolidone alone.

The organic liquid contained in the composition should be biocompatible. By biocompatible is meant that the organic liquid does not cause significant tissue irritation or necrosis around the implantation site when it is dispersed or diffused out of the composition.

Organic liquids for preferred flowable compositions

To obtain a preferred flowable composition comprising a thermoplastic polyester, any suitable polar aprotic organic liquid may be used as long as the suitable polar aprotic solvent exhibits a body fluid solubility in the range from completely soluble to very low solubility in all proportions. Suitable polar aprotic organic liquids are disclosed in, for example, ALDRICH hardbokof FINE CHEMICALS AND laborary EQUIPMENT, Milwaukee, WI (2000) and U.S. patent nos. 5,324,519, 4,938,763, 5,702,716, 5,744,153 and 5,990,194. Suitable polar aprotic liquids should be capable of diffusing into the body fluid over time to set or cure the flowable composition. Diffusion can occur rapidly or slowly. It is also preferred that the polar aprotic liquid used for the biodegradable polymer is non-toxic and otherwise biocompatible.

The polar aprotic organic liquid is preferably biocompatible. Suitable polar aprotic organic liquids include, for example, organic liquids having amide groups, ester groups, carbonate groups, ketones, ethers, sulfonyl groups, or combinations thereof. Preferably, the polar aprotic organic liquid comprises N-methyl-2-pyrrolidone, N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, triacetin or any combination thereof. More preferably, the polar aprotic organic solvent is N-methyl-2-pyrrolidone.

The solubility of biodegradable thermoplastic polyesters in various polar aprotic liquids will vary depending on their crystallinity, hydrophilicity, hydrogen bonding and molecular weight. Thus, not all biodegradable thermoplastic polyesters will have the same degree of solubility in the same polar aprotic organic liquid, but each biodegradable thermoplastic polymer or copolymer will be soluble in its suitable polar aprotic solvent. Low molecular weight polymers should generally be more soluble in liquids than high molecular weight polymers. Thus, the concentration of polymer dissolved in the various liquids will vary depending on the type of polymer and its molecular weight. Conversely, higher molecular weight polymers will generally tend to set or cure more quickly than very low molecular weight polymers. In addition, higher molecular weight polymers may tend to produce higher solution viscosities than lower molecular weight materials.

For example, low molecular weight polylactic acid formed by the condensation of lactic acid will dissolve in N-methyl-2-pyrrolidone (NMP) to give an approximately 73 weight percent solution that will still flow easily through a 23 gauge syringe needle; while higher molecular weight poly (DL-lactide) (DL-PLA), formed by the polyaddition of DL-lactide, gave the same solution viscosity when dissolved in N-methyl-2-pyrrolidone at about 50% by weight. The higher molecular weight polymer solution solidifies immediately upon being placed in water. Lower molecular weight polymer solutions, although more concentrated, tend to set very slowly after being placed in water.

It has also been found that solutions containing very high concentrations of high molecular weight polymers sometimes set or solidify slower than more dilute solutions. It is believed that the high concentration of polymer prevents solvent from diffusing out of the interior of the polymer matrix and thus prevents water from penetrating into the matrix where it can precipitate the polymer chains. Thus, there is an optimum concentration at which the solvent can diffuse out of the polymer solution while water penetrates therein to coagulate the polymer.

The concentration and type of polar aprotic organic liquid of the preferred flowable composition containing the thermoplastic polyester will generally depend on the desired properties of the controlled release implant. For example, the type and amount of the biocompatible polar aprotic solvent can affect the length of time that the buprenorphine, a metabolite thereof, or prodrug thereof is released from the controlled release implant.

In particular, in one embodiment, the flowable composition can be used to formulate a one month delivery system for buprenorphine, a metabolite thereof, or a prodrug thereof. In this embodiment, the biocompatible polar aprotic solvent may preferably be N-methyl-2-pyrrolidone, and is preferably present in an amount of from about 30% to about 70% by weight of the composition.

Alternatively, in another embodiment, the composition can be used to formulate a three month delivery system for buprenorphine, a metabolite thereof, or a prodrug thereof. In this embodiment, the biocompatible polar aprotic solvent may preferably be N-methyl-2-pyrrolidone, and is preferably present in an amount of from about 30% to about 70% by weight of the composition.

Buprenorphine

Buprenorphine (also known as (2S) -2- [ (-) - (5R,6R,7R,14S) -9 α -cyclopropylmethyl-4, 5-epoxy-6, 14-ethano-3-hydroxy-6-methoxymorphinan-7-yl ] -3, 3-dimethylbut-2-ol, sold under the tradenames subutex (tm) and suBOXONE (tm)) is an opioid agonist belonging to the thebaine derivative chemical class. Buprenorphine, a metabolite thereof, or a prodrug thereof may be administered in an unneutralized basic form, or as a salt of an organic or inorganic acid. Examples include salts of buprenorphine, its metabolites or its prodrugs, wherein the counterion (counter ion) is acetate, propionate, tartrate, malonate, chloride, sulfate, bromide, and other organic and inorganic acid counterions that are pharmaceutically acceptable.

Buprenorphine, a metabolite thereof, or a prodrug thereof may be lyophilized prior to use. Typically, buprenorphine, a metabolite thereof, or a prodrug thereof, may be dissolved in an aqueous solution, sterile filtered, and lyophilized in a syringe. In a separate step, the thermoplastic polymer/organic liquid solution may be loaded into a second syringe. The two syringes may be connected together and the contents may be pumped back and forth between the two syringes until the thermoplastic polymer, the organic liquid, and the buprenorphine, a metabolite thereof, or a prodrug thereof are effectively mixed together to form a flowable composition. The flowable composition can be drawn into a syringe. The two syringes may be disconnected and the needle connected to the syringe containing the flowable composition. The flowable composition may be injected into the body through a needle. The flowable composition can be formulated and administered to a patient as described, for example, in U.S. patent nos. 5,324,519, 4,938,763, 5,702,716, 5,744,153, and 5,990,194 or as described herein. Once applied, the organic liquid will escape, the remaining polymer will gel or solidify, and a matrix structure will be formed. The organic liquid should escape and the polymer should cure or gel, thereby entrapping or encapsulating the buprenorphine, its metabolites, or its prodrugs in the matrix.

The release of buprenorphine, a metabolite thereof or a prodrug thereof from the implant will follow the same general rules as the release of the drug from the monolithic polymeric device. The following parameters can influence the release of buprenorphine, a metabolite thereof, or a prodrug thereof: the size and shape of the implant, the loading of buprenorphine, its metabolites or its prodrugs within the implant, permeability factors relating to buprenorphine, its metabolites or its prodrugs and specific polymers, and degradation of the polymers. Depending on the amount of buprenorphine, its metabolites, or its prodrugs selected for delivery, one skilled in the art of drug delivery can adjust the above parameters to provide the desired rate and duration of release.

The amount of buprenorphine, a metabolite, or prodrug thereof incorporated into the sustained release delivery system depends on: a desired release profile, the concentration of buprenorphine, a metabolite thereof, or a prodrug thereof to achieve a biological effect, and the length of release of buprenorphine, a metabolite thereof, or a prodrug thereof necessary for treatment. There is no upper limit on the amount of buprenorphine, a metabolite, or prodrug thereof incorporated into the sustained release delivery system other than the upper limit required for acceptable solution or dispersion viscosity for injection through a syringe needle. The lower limit of the amount of buprenorphine, a metabolite or prodrug thereof incorporated into the sustained release delivery system depends on the activity of the buprenorphine, a metabolite or prodrug thereof, and the length of time required for treatment. In particular, in one embodiment, the sustained release delivery system may be formulated to provide a one month release of buprenorphine, a metabolite thereof, or a prodrug thereof. In this embodiment, buprenorphine, a metabolite thereof or a prodrug thereof may preferably be present in an amount of from about 0.5% to about 50% by weight of the composition, preferably from about 1% to about 30% by weight. Alternatively, in another embodiment, the sustained release delivery system may be formulated to provide three months of release of buprenorphine, a metabolite, or prodrug thereof. In this embodiment, buprenorphine, a metabolite thereof or a prodrug thereof may preferably be present in an amount of from about 0.5% to about 50% by weight of the composition, preferably from about 1% to about 30% by weight. A gel or solid implant formed from a flowable composition will release buprenorphine, a metabolite thereof, or a prodrug thereof contained within its matrix at a controlled rate until the implant is effectively depleted of buprenorphine, a metabolite thereof, or a prodrug thereof.

Adjuvants and carriers

The sustained release delivery system may include, for example, a release rate modifier to alter the rate of sustained release of buprenorphine, a metabolite or prodrug thereof from the implant matrix. The use of a release rate modifier may reduce the release of buprenorphine, a metabolite thereof or a prodrug thereof by a factor or increase by a factor compared to the release of buprenorphine, a metabolite thereof or a prodrug thereof from the implant matrix without the use of a release rate modifier.

The release rate of buprenorphine, a metabolite or prodrug thereof may be slowed by the addition of a hydrophobic release rate modifier (e.g., hydrophobic ethyl heptanoate) to the sustained release delivery system and formation of an implant matrix by interaction of the flowable composition with body fluids. Hydrophilic release rate modifiers (e.g., polyethylene glycol) can increase the release rate of buprenorphine, its metabolites, or its prodrugs. The rate and extent of release of buprenorphine, a metabolite or prodrug thereof from the implant matrix can be varied, for example from relatively fast to relatively slow, by appropriate selection of the molecular weight of the polymer in combination with an effective amount of a release rate modifier.

Useful release rate modifiers include, for example, water-soluble, water-miscible or water-insoluble (i.e., hydrophilic to hydrophobic) organic materials.

The release rate modifier is preferably the following organic compound: the organic compounds are believed to increase the flexibility and ability of the polymer molecules to slide over each other even when the molecules are in a solid or highly viscous state. Preferably, the release rate modifier is biocompatible in combination with the polymer and organic liquid used to formulate the sustained release delivery system. It is also preferred that the release rate modifier is a pharmaceutically acceptable substance.

Useful release rate modifiers include, for example, fatty acids, triglycerides, other similar hydrophobic compounds, organic liquids, plasticizing compounds, and hydrophilic compounds. Suitable release rate modifiers include, for example: esters of monocarboxylic, dicarboxylic and tricarboxylic acids, such as 2-ethoxyethyl acetate, methyl acetate, ethyl acetate, diethyl phthalate, dimethyl phthalate, dibutyl phthalate, dimethyl adipate, dimethyl succinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, triacetin, di (n-butyl) sebacate, and the like; polyhydric alcohols such as propylene glycol, polyethylene glycol, glycerin, sorbitol, and the like; a fatty acid; triglycerides of glycerol, such as triglycerides, epoxidized soybean oil and other epoxidized vegetable oils; sterols, such as cholesterol; alcohols such as (C6-C12) alkanols and 2-ethoxyethanol and the like. These release rate modifying agents may be used alone or in combination with other such agents. Suitable combinations of release rate modifying agents include, for example: glycerol/propylene glycol, sorbitol/glycerol, ethylene oxide/propylene oxide, butylene glycol/adipic acid, and the like. Preferred release rate modifiers include, for example, dimethyl citrate, triethyl citrate, ethyl heptanoate, glycerol, and hexylene glycol.

The amount of release rate modifier contained in the flowable composition should vary depending on the desired release rate of buprenorphine, its metabolites or prodrugs thereof from the implant matrix. Preferably, the sustained release delivery system comprises from about 0.5% to about 30%, preferably from about 5% to about 10%, of the release rate modifier.

Other solid adjuvants may also optionally be combined with the sustained release delivery system to act as carriers, especially sequestering carriers. These include, for example, additives and excipients, such as starch, sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, sorbitol, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides, and/or polyvinylpyrrolidone.

Other adjuvants may include, for example: oils such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil; and esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. Also included are alcohols such as, but not limited to, ethanol, isopropanol, cetyl alcohol, glycerol, and propylene glycol. Also used in this formulation are: ethers such as, but not limited to, polyethylene glycol; petroleum hydrocarbons such as mineral oil and petrolatum. Pectin, carbomer, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose may also be included. These compounds act as sequestering carriers by coating the buprenorphine, its metabolites, or its prodrugs to prevent contact with organic liquids and other ingredients in the flowable composition. As a separate carrier, these compounds also help to reduce the burst effect associated with in situ solidification of the flowable composition.

Optionally, other compounds, such as, but not limited to, stabilizers, antimicrobials, antioxidants, pH modifiers, bioavailability modifiers, and combinations thereof, are also included. Emulsifiers and surfactants may also be included, such as fatty acids or nonionic surfactants, including natural or synthetic polar oils, fatty acid esters, polyol ethers, and mono-, di-, or triglycerides.

Implant and method of manufacturing the same

When the implant is formed, the physical state of the implant is solid. These solid bodies may be rigid so that they cannot be bent or flexed by squeezing between fingers, or they may be flexible or bendable so that they can be compressed or flexed from their original shape by squeezing between fingers (i.e., a small amount of force). The thermoplastic polymer acts as a matrix in these entities, providing integrity to the single solid and enabling controlled release of the bioactive agent after implantation.

The thermoplastic polymer matrix is preferably a solid matrix, particularly preferably microporous. In an embodiment of the microporous solid matrix, there is a core surrounded by a sheath. The core preferably contains pores having a diameter of about 1 micron to about 1000 microns. The sheath preferably contains pores having a diameter smaller than the diameter of the pores of the core. In addition, the pores of the sheath are preferably sized such that the sheath is functionally non-porous compared to the core.

The implant eventually disappears because all components of the implant are biodegradable or they can be cleared from the implantation site by body fluids and expelled from the body. The components of the implant may complete their biodegradation or disappearance before, after or simultaneously with the complete release of buprenorphine, its metabolites or its prodrugs as is common. The structure of the thermoplastic polymer, its molecular weight, the density and porosity of the implant, and the in vivo location in which the implant is located all affect the rate of biodegradation and the rate of disappearance. The implant is typically formed subcutaneously in the patient. It can be suitably molded after injection to provide comfort to the patient. The volume size of the implant may typically be from about 0.25mL to about 3 mL.

Therapeutic applications

Surprisingly, it has been found that the sustained release delivery system is extremely effective in delivering buprenorphine. In particular, as shown in the examples below, blood levels of buprenorphine obtained with the sustained release delivery system in dogs after injection of a 60mg dose of buprenorphine to beagle dogs are in the range of from about 0.5 nanograms per milliliter (ng/mL) to about 20 ng/mL.

In general, any disease that can be ameliorated, treated, cured or prevented by the administration of buprenorphine, a metabolite or prodrug thereof or a buprenorphine analogue can be treated by the administration of the flowable composition. These diseases involve mental impairment. The following specific adverse conditions are examples of such diseases. These can all be treated by suitably and effectively administering a flowable composition formulated to deliver an effective amount of buprenorphine, a metabolite or prodrug thereof. These adverse conditions include: addiction to opioids, chronic pain, and the like.

Dosage form

The amount of flowable composition administered will generally depend on the desired properties of the controlled release implant. For example, the amount of flowable composition can affect the length of time that buprenorphine, a metabolite, or prodrug thereof is released from the controlled release implant. In particular, in one embodiment, the composition may be used to formulate a one month delivery system for buprenorphine, a metabolite thereof, or a prodrug thereof, in which embodiment about 0.20mL to about 2.0mL of the flowable composition may be administered. Alternatively, in another embodiment, the composition may be used to formulate a three month delivery system for buprenorphine, a metabolite thereof, or a prodrug thereof, in which embodiment about 0.5mL to about 2.0mL of the flowable composition may be administered. The amount of buprenorphine, a metabolite or prodrug thereof in the flowable composition and resulting implant will depend on the disease to be treated, the desired duration and the bioavailability profile of the implant. Generally, an effective amount will be within the judgment and ability of the attending physician of the patient. The administration guidance includes, for example, the following applied dosage ranges: about 1 to about 16 milligrams (mg) of buprenorphine, a metabolite thereof or a prodrug thereof per day, preferably about 1 to about 5 milligrams (mg) of buprenorphine, a metabolite thereof or a prodrug thereof per day. A common flowable composition effective for sustained delivery for one month should contain about 3 to about 300mg of buprenorphine, a metabolite, or prodrug thereof per ml of the total volume of the flowable composition. The injection volume should be about 0.2 to about 2.0mL per implant. A common flowable composition effective for sustained delivery for three months should contain about 9 to about 900mg of buprenorphine, a metabolite, or prodrug thereof per ml of the total volume of the flowable composition. The injection volume should be about 0.5 to about 2.0mL per implant. As mentioned above, the polymer formulation should be the first factor to obtain a long-term sustained release.

All publications, patents, and patent documents are incorporated by reference herein, as if individually incorporated by reference. The invention will now be described with reference to the following non-limiting examples. The following examples use ATRIGEL (TM) formulations of poly (lactide-co-glycolide) and N-methyl-2-pyrrolidone in combination with buprenorphine as flowable compositions.

Examples

In the following examples, ATRIGEL (TM)/buprenorphine refers to the ATRIGEL (TM)/buprenorphine formulation; ATRIGEL (TM) is a registered trademark of QLT-USA, Fort Collins, CO. The specific form of ATRIGEL (TM) product used in these embodiments will be provided with these embodiments. Unless otherwise specified, the ATRIGEL (TM) product is a thermoplastic polymer poly (lactide-co-glycolide) (PLG), a thermoplastic polymer poly (lactide-co-glycolide, extended with 1, 6-hexanediol) (PLG), or PLGH in an organic solvent, N-methyl-2-pyrrolidone. SUBUTEX (TM) and SUBUTEX (TM) are registered trademarks of Janssen, L.P., Titusville, New Jersey.

The ATRIGEL (TM) drug delivery system is a biodegradable polymeric delivery system that can be injected as a liquid. Upon injection of the formulation, the polymer solidifies, encapsulating the drug. When the biodegradation process begins, the drug is slowly released. The type and molecular weight of the polymer and the drug loading of the constructed product enable control of the rate of drug release from this type of delivery system. Thus, the system can be tailored to meet the needs of the patient.

The ATRIGEL (TM) delivery system is currently used in the American food and drug administration approved products ELIGARD (TM) (one, three and four month subcutaneous storage formulation of leuprolide acetate) and ATRIDOX (TM) (doxycycline hydrochloride administered to periodontal pockets). Clinical studies and post-market experience with these products demonstrate that the atrigel (tm) delivery system itself is well tolerated and provides constant, sustained release of the drug it contains over the specified administration period.

These characteristics represent various improvements independent of the specific application (i.e. any buprenorphine-responsive disease).

Unless otherwise indicated, all numbers expressing quantities of ingredients, properties (e.g., molecular weights), reaction conditions, and so forth, used in the specification and claims are to be understood as being modified in all instances by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Test program

Preparation of Polymer solutions

A stock polymer solution was prepared by weighing a known amount of each polymer solid in a separate 20mL scintillation vial. To each polymer was added a known amount of N-methyl-2-pyrrolidone and the vials were then placed on a horizontal jar mill. The vial was rotated overnight (possibly for several days) to produce a visually clear polymer solution indicating that the polymer had dissolved. Sterilization of the polymer solution may be accomplished by gamma irradiation or electron beam irradiation.

Preparation of Test Article (TA) syringes

The "B" syringe (male syringe) contained buprenorphine powder and was prepared by weighing the drug powder in a 3.00mL Becton Dickinson (BD) male syringe. "A" syringes (female syringes) were prepared by weighing ATRIGEL (TM) polymer stock in 1.0mL female syringes.

Preparation of test substance for injection (reconstituted formulation)

At the time of injection, the "a" syringe and the "B" syringe were put in communication with each other, and mixing was performed by circulating the contents from one syringe to the other syringe for 60 cycles. The mixed formulation is finally transferred to a male administration syringe for injection. Formulations may also be prepared by dissolving buprenorphine in an ATRIGEL (TM) polymer stock solution. In this case, buprenorphine and the selected AtriGEL (TM) are weighed in scintillation vials, and the vials are briefly shaken and/or heated to completely dissolve the buprenorphine. The resulting drug, ATRIGEL (TM), solution is then loaded into an administration syringe for injection.

Reversed phase high performance liquid chromatography for quantification of buprenorphine

The conditions of the high performance liquid chromatography were as follows: mobile phase A: water containing 0.065% sodium octane sulfonate and 0.1% trifluoroacetic acid; mobile phase B: 90/10 acetonitrile/water containing 0.065% sodium octane sulfonate and 0.1% trifluoroacetic acid; flow rate: 1.0 ml/min; temperature of the auto sampler: room temperature; column temperature: 30 ℃; and (3) detection: 285 run (UV); total run time: 21 minutes; sample introduction volume: 20 mu L of the solution; column: phenomenex Luna C18250 × 4.6mm,5 μm; column storage: 70/30 acetonitrile/water; each sample was run according to the following gradient program:

approximate residence time of buprenorphine: 15.4 minutes.

The standard solution was prepared as follows: approximately 10mg of buprenorphine was dissolved in 10mL of a 1:1 formulation solution [90/5/5 acetonitrile/glacial acetic acid/water]/H₂O to prepare a standard stock. Diluting the standard stock solution with water to obtain a series of standard solutions of 40 ppm-500 ppm.

Implant extraction procedure for implant retrieval studies

The tissue surrounding the freshly retrieved implant is carefully removed using a surgical knife or scissors. The implant can be analyzed immediately after the procedure, or it can be stored in a freezer at-20 ℃ until later use. For analysis, exactly 10mL of the formulation dissolution [90/5/5 acetonitrile/glacial acetic acid/water ] was added to the implant vial. The vial was then shaken on a rotary shaker at room temperature at about 200rpm for at least 2 hours. The vial was then centrifuged at 2500rpm for 10 minutes. After centrifugation, the vials were carefully removed from the centrifuge. A portion of the supernatant in the vial was transferred to an HPLC vial and the transferred solution in the vial was further diluted with formulation dissolvent as necessary to achieve a concentration suitable for HPLC analysis. The vials were then analyzed for buprenorphine content by high performance liquid chromatography as described above.

Buprenorphine analysis in rat plasma samples

This program was adopted from Li-Heng Pao et al, Journal of Chromatography B,746(2000), 241-. To 1.0mL or an appropriate amount of rat plasma samples were added 20 μ l of internal standard [ acid rearrangement product of buprenorphine, RX2001M, supplied by RBP ], 1mL of 0.5m sodium bicarbonate solution and 3mL of a mixture of n-hexane-isoamyl alcohol (9:1 volume/volume). The solution was then agitated at 200rpm in a shaker at room temperature for at least 30 minutes. After centrifugation at 3000rpm for 10 minutes, the solution was placed in a freezer at-86 ℃ for 30 minutes. The top organic layer was then transferred to a clean test tube and evaporated to dryness at 65 ℃ under a stream of nitrogen. Samples were reconstituted in 200. mu.L of mobile phase and 50. mu.L aliquots were then injected onto the column.

The conditions of the high performance liquid chromatography were as follows: mobile phase: 80/20 acetonitrile/5 mM sodium acetate buffer (pH 3.75); flow rate: 1.2 mL/min; temperature of the automatic sampler: room temperature; column temperature: 25 ℃; and (3) detection: fluorescence (excitation at 215nm, emission at 355 nm); total run time: 14 minutes; sample introduction volume: 50 mu L of the solution; column: phenomenex Luna Silica (2) 250X 4.6mm,5 μm; column storage: 100% acetonitrile; approximate residence time of buprenorphine and internal standard: 7.9 minutes and 8.7 minutes.

Analysis of buprenorphine and norberaprorphine (norberprenorphine) in canine plasma samples

Plasma samples from the canine study were analyzed for buprenorphine and norbuprenorphine levels using the LC-MS method by a laboratory signed for analytical services. The method was developed and validated by a contracting laboratory. This is a proprietary method of LC-MS analysis after the use of a liquid-liquid extraction step.

In vivo study in animals

The experimental process comprises the following steps: all preclinical studies in rats were performed with male Sprague-Dawley rats. Five rats corresponding to each test article at each time point were injected with about 100mg of the test article in the area of the dorsal surface (DT) under general anesthesia by intramuscular injection or subcutaneous injection.

During the course of the study, the animals were observed for overt toxicity, and any existing abnormalities at the test site were observed and recorded, including redness, bleeding, swelling, pus discharge, bruising, and test squeeze-out at the injection site. In addition, the weight of the injection was recorded at the time of administration, and body weights were taken and recorded at the time and end of administration. If blood samples for the study were collected, five rats corresponding to each test article were anesthetized at selected time points and exsanguinated via cardiac puncture (approximately 5 mL). Blood was collected in labeled potassium ethylenediaminetetraacetate tubes. The blood was centrifuged at 3000rpm for 10 minutes. The plasma fractions were transferred to labeled 5mL plastic culture tubes and stored at-86 ℃. Plasma was analyzed using the liquid-liquid extraction method described above.

After blood collection, or when no blood sample is needed for the study, the rats are sacrificed with carbon dioxide and the implant is retrieved. The implant was cleaned of excess tissue and stored at-20 ℃ prior to analysis. The buprenorphine content of the retrieved implants was analyzed using the implant analysis method described above.

Male beagle dogs were used for pharmacokinetic studies in larger animals. In these studies, male beagle dogs weighing 8 to 12kg were selected. The 6 dogs in each group were given a dorsal thoracic subcutaneous injection at a buprenorphine equivalent dose of 60 mg/dog. By weighing the syringe before and after each injection, an accurate injection dose is obtained. After injection, beagle dogs were periodically bled to collect their plasma samples. All plasma samples were stored in a freezer at-80 ℃ prior to analysis. These animals were also observed periodically for any signs of toxicity and reaction at the injection site.

The levels of buprenorphine and norbuprenorphine were measured in canine plasma samples using a validated LC/MS method by the qualified, contracted analytical laboratory described above.

Example 1: buprenorphine Atrigel in rats^TM24 hours burst

8 buprenorphine ATRIGEL were prepared according to the above method^TMAnd (4) preparing the preparation. The buprenorphine hydrochloride formulation has a double syringe configuration with the buprenorphine free base formulation being a solution. The eight preparations have the following compositions.

Test article for example 1:

1.10% buprenorphine hydrochloride in 45%50/50PLGH (26kD) and 55% NMP

2.10% buprenorphine hydrochloride in 55%65/35PLGH (17kD) and 45% NMP

3.10% buprenorphine hydrochloride in 48%55/45PLG (22kD), 2% PEG5000-70/30PLG (59kD) and 50% NMP

4.10% buprenorphine free base in 45%50/50PLGH (26kD) and 55% NMP

5.10% buprenorphine free base in 50%65/35PLGH (17kD) and 50% NMP

6.10% buprenorphine free base in 55%65/35PLGH (17kD) and 45% NMP

7.10% buprenorphine free base in 50%55/45PLG (22kD) and 50% NMP

8.10% buprenorphine free base in 48%55/45PLG (22kD), 2% PEG5000-70/30PLG (59kD) and 50% NMP

The initial release (initial burst) of these formulations over 24 hours is shown in table 1. All formulations had a lower initial burst of less than 10%.

TABLE 1 subcutaneous injection of ATRIGEL in rats^TMBuprenorphine 24 hour release after formulation (initial burst)

Example 2: buprenorphine hydrochloride-derived ATRIGEL in rats^TM49 days of buprenorphine release

Three buprenorphine hydrochloride atrogel formulations were prepared using an a/B dual syringe configuration^TMAnd (4) preparing the preparation. A total of 135 male SD rats were injected subcutaneously with these formulations. At each time point, five rats per group were euthanized and the implants were retrieved. The time points were 2 hours, 1 day, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, and 49 days. The formulations and buprenorphine release profiles are shown in table 2 and figure 2.

Test article for example 2

1.20% buprenorphine hydrochloride in 50%50/50PLGH (15kD) and 50% NMP

2.20% buprenorphine hydrochloride in 50%65/35PLGH (10kD) and 50% NMP

3.20% buprenorphine hydrochloride in 50%65/35PLGH (17kD) and 50% NMP

TABLE 2 subcutaneous injection of buprenorphine hydrochloride Atrigel in rats^TMBuprenorphine release following formulation

Example 3: ATRIGEL FROM BURPENINE FREE-BASE IN MORTAR^TM35 days release and pharmacokinetic profile of buprenorphine

Mixing four buprenorphine free base ATRIGEL^TMThe formulations were prepared as solutions in syringes ready for injection. These formulations were injected subcutaneously into a total of 160 male SD rats. At each time point, five rats per group were anesthetized and blood samples were obtained by cardiac puncture. Rats were then euthanized and the implants were retrieved. The retrieved implants and plasma samples were analyzed for buprenorphine as described above. The results are shown in fig. 3 and 4.

Test article for example 3

1.15% buprenorphine free base in 45%50/50PLGH (26kD) and 55% NMP

2.20% buprenorphine free base in 40%50/50PLGH (17kD) and 50% NMP

3.20% buprenorphine free base in 20%50/50PLGH (26kD), 20%50/50PLGH (12kD) and 60% NMP

4.20% buprenorphine free base in 45%50/50PLGH (12kD) and 55% NMP

TABLE 3 subcutaneous injection of buprenorphine free base ATRIGEL in rats^TMBuprenorphine release following formulation

TABLE 4 subcutaneous injection of buprenorphine free base ATRIGEL in rats^TMPlasma buprenorphine levels following formulation

Example 4: buprenorphine hydrochloride Atrigel for two dogs^TMPharmacokinetic study of

Adopt A/B double-injector structure to prepareTwo buprenorphine hydrochloride atrogel^TMAnd (4) preparing the preparation. A total of 12 male beagle dogs were injected subcutaneously with these formulations. The dogs were then bled periodically at each time point to collect their plasma samples. These plasma samples were analyzed by a signed analytical services company using a validated LC/MS method.

Test article for example 4

TA 1: 20% buprenorphine hydrochloride in 50%50/50PLGH (12kD) and 50% NMP

TA 2: 20% buprenorphine hydrochloride in 50%50/50PLGH (21kD) and 50% NMP

TABLE 5 beagle dogs were injected subcutaneously with two buprenorphine hydrochloride ATRIGEL' s^TMMean plasma levels of buprenorphine after formulation

Example 5: for four buprenorphine free base, Atrigel in dogs^TMPharmacokinetic study of

Mixing four buprenorphine free base ATRIGEL^TMThe formulations were prepared as solutions in syringes ready for injection. These formulations are sterilized by irradiation or sterile filtration. A total of 24 male beagle dogs were injected subcutaneously with these formulations. The dogs were then bled periodically at each time point to collect their plasma samples. These plasma samples were analyzed by a signed analytical services company using a validated LC/MS method.

Test article for example 5

TA 1: 20% buprenorphine free base, in 40%50/50PLGH (26kD) and 60% NMP, irradiated

TA 2: 20% buprenorphine free base in 40%50/50PLGH (12kD) and 60% NMP irradiated

TA 3: 20% buprenorphine free base, in 40%50/50PLGH (21kD) and 60% NMP, irradiated

TA 4: 20% buprenorphine free base, in 40%50/50PLGH (21kD) and 60% NMP, filtered

TABLE 6 beagle dogs were injected subcutaneously with the four buprenorphine free base, ATRIGEL^TMMean plasma levels of buprenorphine after formulation

Claims (16)

1. An injectable flowable pharmaceutical composition comprising:

(a)25 to 50 weight percent 50/50, 55/45, 60/40, 65/35, 70/30, 75/25, or 80/20 poly (DL-lactide-co-glycolide) with or without carboxyl end groups;

(b)30 to 70 weight percent of N-methyl-2-pyrrolidone; and

(c) from 8% to 22% by weight buprenorphine in free base form or in pharmaceutically acceptable salt form.

2. The flowable pharmaceutical composition of claim 1, wherein the buprenorphine is in free base form.

3. The flowable pharmaceutical composition of claim 1, wherein said biodegradable thermoplastic poly (DL-lactide-co-glycolide) copolymer is 50/50 poly (DL-lactide-co-glycolide) having carboxyl end groups.

4. The flowable pharmaceutical composition of claim 1, wherein the biodegradable thermoplastic poly (DL-lactide-co-glycolide) copolymer of the flowable pharmaceutical composition has an average molecular weight of 5,000 to 40,000 daltons.

5. The flowable pharmaceutical composition of claim 1, wherein the biodegradable thermoplastic poly (DL-lactide-co-glycolide) copolymer of the flowable pharmaceutical composition has an average molecular weight of 10,000 to 20,000 daltons.

6. The flowable pharmaceutical composition of claim 1, having a volume of 0.10ml to 2.0 ml.

7. The flowable pharmaceutical composition of claim 1, wherein said flowable pharmaceutical composition forms a solid implant when contacted with bodily fluid or water.

8. The flowable pharmaceutical composition of claim 1, wherein said flowable pharmaceutical composition forms a solid implant when contacted with an aqueous medium.

9. The flowable pharmaceutical composition of claim 1, formulated for administration once monthly or once every three months.

10. Use of the flowable pharmaceutical composition of any one of claims 1-9 in the manufacture of a medicament for treating a patient suffering from pain or opioid dependence by subcutaneously injecting the medicament into the patient once a month or once every three months.

11. The use as claimed in claim 10, wherein the medicament delivers a therapeutically effective dose of buprenorphine in the range of 0.1 to 10mg per day.

12. The use of claim 10, wherein the medicament achieves a therapeutically effective level of buprenorphine within one day after administration.

13. Use of a flowable pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a medicament for forming a biodegradable implant in situ in a patient by injecting the medicament into the patient's body to allow N-methyl-2-pyrrolidone to escape to produce a biodegradable solid implant.

14. A solid microporous matrix formed in situ in a patient from the flowable pharmaceutical composition of any one of claims 1-9.

15. The solid microporous matrix of claim 14, which is a core surrounded by a skin; wherein the core contains pores having a diameter of 1 to 1000 microns; and wherein the skin contains pores having a diameter smaller than the diameter of the pores of the core.

16. A solid implant formed in situ in a patient from the flowable pharmaceutical composition of any one of claims 1-9.