INJECTABLE COMPOSITION FOR CONTROLLED-RELEASE OF ACTIVE INGREDIENT TO MANAGE POSTOPERATIVE PAIN OR NEUROPATHIC BACK PAIN

FIELD OF THE INVENTION

The present invention relates to an injectable pharmaceutical composition for controlled-release of an active ingredient and a method for managing pain using the same. Particularly, the present invention relates to an in situ forming implant

composition or formulation for controlled-release of an active ingredient to treat postoperative pain or neuropathic back pain comprising a biodegradable/biocompatible polymer and an active ingredient, and a method of treating the pain by administering the formulation.

BACKGROUND OF THE INVENTION

Pain is a ubiquitous problem and there are enormous costs, efforts, and risks associated with pain management in today’s health care system. The total incremental cost of health care due to pain approaches $300 billion. Twenty percent of non-cancer pain or pain-related diagnoses are prescribed opioids, and opioid use and deaths from overdose quadrupled from 1999 to 2014. In addition, there is not enough evidence that opioids improve chronic pain, function, and quality of life.

In addition to the vast costs associated with pain management there is a growing epidemic of opioid abuse and dependence. This public health crisis reveals an unmet medical need for non-opioid pain management.

Postoperative pain may be a result of surgery or other treatments such as management of acute pain following burns or non-surgical trauma. The goal for postoperative pain management is to reduce or eliminate pain and discomfort with medication that causes minimum or no side effects.

Neuropathic back pain is a chronic syndrome arising from injury, disease, or physical damage to the nerve roots of the spine innervating the limbs. Neuropathic back pain is thought to be a component in 55-90% of adult cases of chronic lower back pain in the U.S. and Europe and is associated with reduced quality of life, increased medical co-morbidity, and high health care costs. Neuropathic back pain is difficult to manage and remains under-treated due to inadequate and sometimes ineffective response to standard analgesic therapy, and the risks associated with over-prescription of opioids. Less than half of patients with neuropathic back pain derive pain relief from currently used oral pharmaceutical formulations.

Ketorolac is a non-steroidal anti-inflammatory drug that is often prescribed for the treatment of pain including postoperative pain and inflammation. However, effective management of pain and inflammation can require frequent administration of ketorolac.

Also, multimodal oral treatment approaches are considered more effective than monotherapy for many types of neuropathic pain, but problems with this approach persist due to the risk of adverse effects with high-dose formulations and potential drug- drug interactions.

Some patents describe extended release formulations of ketorolac, several being related to the eye. One uses complexing agents that create a mass of increased viscosity after intravitreal injection to generate the desired active ingredients release profile (US Patent No. 9,446,093,“Injectable aqueous ophthalmic composition and method of use thereof”). Another claims an intravitreal injection containing polymer precursors that cross-link when exposed to bodily fluids to trap the drug and produce a controlled-release of the drug (US Patent No. 9,125,807,“Adhesive hydrogels for ophthalmic drug delivery”). However, neither of these uses a biocompatible, water insoluble polymer in a biocompatible solvent.

The controlled release of NSAIDs from polymeric formulations is described in some patents. One is an implantable medical device that includes a component containing the drug embedded in a biodegradable polymer and another includes a biocompatible, non-biodegradable polymer (US. Patent No. 8,691 ,264). However, implants of this type are designed to serve a purpose inside of the body (e.g. a urethral stent). The drug simply eases the pain associated with the implantation.

There are other inventions that consist of a polymer matrix and an active ingredient to be released over an extended period (US Patent No. 8,871 ,241“Injectable sustained release delivery devices”, US Patent No. 8,652,525“NSAID delivery from polyarylates”, US Patent No. 8,623,396“Compositions and methods for delivering clonidine and bupivacaine to a target tissue site”, US Patent No. 8,956,636“Methods and compositions for treating postoperative pain comprising ketorolac”). However, these are all pre-fabricated solid implants that are inserted or injected into the patient, some using specific active ingredients or polymers.

Several pharmaceutical formulations have been developed for the delivery of a pain-relieving agent to the site that requires it, one being to deliver the agent within a polymeric matrix that is associated with an injectable or insertable formulation. Once the injectable formulation is placed at the desired location within a patient, the therapeutic agent is released from the polymeric matrix.

Furthermore, various polymers have been used for the manufacture of pharmaceutical formulations to control the release of an active ingredient. Selecting a suitable polymer for the maintenance of the active ingredient in the formulation and the release of the active ingredient in a controlled-release fashion to show pain relief for a long time is required, as well as making the formulation biocompatible/biodegradable upon injection at or near the site of pain. This is called injectable implant or in-situ implant.

In situ implants, implants that form upon injection into the body, are also described in some patents. These include in situ gel delivery systems, which use polyether solvents with other biodegradable polymers and an active ingredient (US Patent No. 6,303,137“Injectable implant”, US Patent No. 9,566,336“In situ gelling drug delivery system”). These inventions however use different formulations forming a gel rather than a solid implant.

Some literatures disclose ketorolac microspheres for controlled-release. For example, Sinha VR, Trehan A ( Drug Deliv. 2005 May-June 12(3): 133-9) discloses ketorolac tromethamine-loaded biodegradable microspheres prepared with PLGA (poly lactic-co-glycolic acid) or its blend with PCL (polycaprolactone). However,

microspheres or microcapsules are sometimes difficult to produce on a large scale, and their storage and injection characteristics present problems. Also, another limitation of the microcapsule or small-particle system is their lack of reversibility without extensive surgical intervention. If there are complications after they have been injected, it is considerably more difficult to remove them from the body than with solid implants.

As such, there have been limited options for relief of pain, particularly

postoperative pain or neuropathic back pain using ketorolac, alone or in combination with other effective FDA-approved drugs. There has been a growing need for new formulations to effectively manage postoperative or neuropathic pain that act for a long time to facilitate patient compliance without the adverse effects from systemic administration.

SUMMARY OF INVENTION

The present invention relates to a locally-injectable biodegradable polymer formulation containing one or more active ingredients providing long-lasting pain relief for postoperative or neuropathic back pain for about 7 to 9 days or longer without the adverse effects from systemic administration.

One aspect of the present invention therefore provides an in situ forming implant formulation for the controlled-release of an active ingredient to better manage pain, particularly postoperative or neuropathic back pain. The formulation comprises a biodegradable polymer and one or more active ingredients of analgesic agents, providing long-lasting pain relief for about 7 to 9 days without the adverse effects from systemic administration.

In one embodiment, the formulation comprises a biodegradable polymer, and a therapeutically effective amount of one or more active ingredients selected from ketorolac or a pharmaceutically acceptable salt thereof, dexamethasone or a

pharmaceutically acceptable salt thereof, ketamine or a pharmaceutically acceptable salt thereof.

In another embodiment, the formulation comprises a biodegradable polymer and a therapeutically effective amount of ketorolac, particularly ketorolac tromethamine.

In another embodiment, the formulation comprises a biodegradable polymer and a therapeutically effective amount of dexamethasone or a pharmaceutically acceptable salt thereof.

In another embodiment, the formulation comprises a biodegradable polymer and a therapeutically effective amount of ketamine or a pharmaceutically acceptable salt thereof.

In another embodiment, the formulation comprises a biodegradable polymer and a therapeutically effective amount of ketorolac in combination with dexamethasone, or a pharmaceutically acceptable salt thereof. The amount of ketorolac and dexamethasone may be in a ratio of 1 : 1 to 1 :2.

In another embodiment, the formulation comprises a biodegradable polymer, and a therapeutically effective amount of ketorolac, dexamethasone and ketamine, or a pharmaceutically acceptable salt thereof. The amount of ketorolac, dexamethasone and ketamine may be in a ratio of 1 :1 :1 to 1 :2:1.

In another embodiment, the formulation forms a solid implant upon injection to the body.

In another embodiment, the formulation comprises a biodegradable polymer selected from the group consisting of polylactide, polyglycolide, polycaprolactone, polyhydroxyalkanoates, polypropylene fumarate), polyanhydrides, glycosaminoglycans, poly(lactide-co-glycolide)(PLGA) and a combination thereof, PLGA being preferred.

In another embodiment, the biodegradable polymer is acid-terminated PLGA or ester-terminated PLGA.

In another embodiment, the formulation provides a sustained release of ketorolac over a period of about 3 weeks after being injected in vivo to the site of action.

In another embodiment, the formulation provides a sustained release of ketorolac and dexamethasone alone or in combination over a period of about 7 to 9 days or longer after being injected in vivo near the site of action.

In another embodiment, the formulation provides a sustained release of dexamethasone and ketamine alone or in combination over a period of about 7 days or 9 days or longer after being injected in vivo near the site of action.

In another embodiment, the formulation provides a sustained release of ketorolac, dexamethasone and ketamine in combination over a period of at least 7 days after injection in vivo near the site of action.

Another aspect of the present invention relates to a method for treating pain in patients suffering from postoperative or neuropathic back pain, comprising

administering to the patients an in situ forming implant formulation comprising a biodegradable polymer and one or more active ingredients of analgesic agents selected from ketorolac or a pharmaceutically acceptable salt thereof, dexamethasone or a pharmaceutically acceptable salt thereof, ketamine or a pharmaceutically acceptable salt thereof.

In one embodiment of the method, the formulation is intramuscularly injected.

In another embodiment of the method, the formulation forms a solid implant at the site of action.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates release of ketorolac into aqueous media from PLGA implants.

FIG. 2A and FIG. 2B illustrate release profile of ketorolac and dexamethasone alone in acid or ester terminated PLGA polymers.

FIG. 3A and FIG. 3B illustrate release profile of ketorolac and dexamethasone together in the same acid or ester terminated PLGA polymers.

DETAILED DESCRIPTION

Definition

"Combined (or combining) with a biodegradable polymer matrix" as used herein refers to mixed with, dissolved and/or dispersed within, encapsulated by, or coupled to a biodegradable polymer matrix.

"Biodegradable polymer" as used herein refers to a polymer or polymers which degrade in vivo, and wherein degradation of the polymer or polymers over time occurs concurrent with or subsequent to release of the pharmaceutically active ingredient. A biodegradable polymer may be a homopolymer or a copolymer comprising two or more different structural repeating units. "Suitable or configured for insertion (or implantation) at or near the site of pain/action" as used herein with regard to an implant, an injectable formulation, or an in situ forming implant includes an implant which has a dimension such that it can be inserted or implanted without causing excessive tissue damage of the site into which the implant is implanted or inserted.

"Treating" or“treatment" as used herein includes any beneficial effect at or near the site of pain of patients or to the patients with such pain produced by the present method and/or formulation, which effect can be a reduction in, retardation of, or relief from one or more signs and/or symptoms of the pain. A reduction of one or more signs and/or symptoms may include, but is not necessarily limited to, a reduction in pain itself or related discomfort. Treatment may alleviate, relieve, mitigate, remove, or improve pain and therefore the wellbeing and health of the patients with pain.

“Therapeutically effective amount" or "effective amount" as used herein refers to the level or amount of an active ingredient needed to treat pain or related symptoms without causing significant negative or adverse side effects to the site which the active is administered.

"Cumulative percent release" refers to the cumulative total percent of an active ingredient (e.g., ketorolac) released from a formulation (e.g., an implant) into the site in vivo over time or into a specific release medium (e.g., aqueous medium) in vitro over time.

“In situ forming implant formulation” or“-situ forming implant composition” as used herein refers to a pharmaceutical composition capable of forming in situ implant.

“In situ implant” or“in situ forming implant” as used herein refers to a gel or semisolid or solid implant structure formed when a pharmaceutical composition is injected into a subject (e.g., mammalian body) and is intended to remain at the site of injection and releases the drug for a period of at least 24 hours, in the body of the subject, preferably for a period of 24 hours to one month.

“Solid implant” as used herein refers to a solid composition, injected into a subject (e.g., mammalian body) and is intended to remain at the site of injection and release the drug for a period of at least 24 hours, preferably for a period over 24 hours to one month.

“Controlled release” or“sustained release” as used herein refers to release of an active ingredient for at least 24 hours, preferably from 24 hours to one week, two weeks, three weeks, or one month, more preferably from 24 hours to 15 days, most preferably from 24 hours to 5 days, 7 days, or 9 days.

The use of the terms“a”,“an”,“the” and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Throughout this specification and the appended claims it is to be understood that the words“comprise” and“include” and variations such as“comprises”,“comprising”, “includes”,“including” are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

Injectable composition for in situ forming implant

One aspect of the present invention is to provide an in situ forming implant formulation for controlled-release of an active ingredient for pain management, comprising: a biodegradable polymer, and a therapeutically effective amount of one or more active ingredient selected from the group consisting of ketorolac or a

pharmaceutically acceptable salt thereof, dexamethasone or a pharmaceutically acceptable salt thereof, ketamine or a pharmaceutically acceptable salt thereof.

By the definition, the in situ forming implant formulation refers to an injectable pharmaceutical composition for forming in situ implant upon injection to the body (at or near the site of pain). The in situ implant is formed as solid when the polymer-active- solvent is injected and contacts an aqueous environment. Upon injection, the solvent (e.g., N-methyl pyrolidone) partitions from the injection mass and results in the water insoluble polymer (e.g., PLGA) precipitating and trapping the active ingredients in a matrix.

The injectable composition may be formulated to a liquid solution, which may be lyophilized and then reconstituted upon use. It may be formulated to a homogenous solution, a suspension, or a dispersion. Where the active ingredients are soluble in the solvent, a homogeneous solution of the polymer and active ingredients is available for injection. Where the active ingredients are insoluble in the solvent, a suspension or dispersion of the ingredients in the polymer solution results. This suspension or dispersion may also be injected into the body. When injected, the solvent dissipates and the polymer solidifies and entraps or encases the active within the solid matrix.

The release of active ingredients from the solid implant follow the same general rules for release of active ingredients from a monolithic polymeric device. The release of active ingredients may be affected by several factors, such as the size and shape of the implant, the loading of active ingredients within the implant, the permeability involving the active ingredients and particular polymers, and the degradation of the polymers.

Non-limiting examples of the active ingredients that may be added to the present formulation include non-narcotic analgesics, such as, ketorolac or a pharmaceutically acceptable salt thereof (e.g., ketorolac tromethamine), other analgesics, anti- inflammatories, steroids, local anesthetic agents, antispasmodic agents, and other pain relieving agents, with ketorolac tromethamine being preferably used, alone or in combination with other active ingredients such as dexamethasone and ketamine.

In a preferred embodiment, the formulation comprises ketorolac tromethamine alone or in combination with dexamethasone and/or ketamine in a biodegradable and biocompatible polymer construct to effectively manage postoperative or neuropathic back pain. In another embodiment, the formulation comprises dexamethasone and ketamine each alone or in combination. The use of ketorolac, dexamethasone and ketamine, or a pharmaceutically acceptable salt thereof as the active ingredients, each alone or in any combination, is based on the fact that parenteral administration of these active ingredients is well-understood and has been approved for decades. These active ingredients can be administered locally, are stable in polymer constructs, and are effective at reducing, managing and treating pain.

Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) having anti- inflammatory effects similar to opioids although it is not an opioid. Ketorolac as an NSAID also has antipyretic activities to reduce elevated body temperature. It has the chemical name of (+/-)-5-benzoyl-2,3-dihydro-1 H-pyrrolizine-1 -carboxylic acid or 5- benzoyl-1 ,2-dihydro-3H-pyrrolo[1 ,2-a]pyrrole-1 -carboxylic acid, and a molecular weight of 255.27g/mol.

Ketorolac is comprised in the present formulation as ketorolac tromethamine but is not limited to this salt. Any pharmaceutically acceptable salt of ketorolac may be used. The effective amount of Ketorolac or ketorolac tromethamine used in the present formulation is about 20 mg to 75 mg. In one embodiment, ketorolac is used in the amount of about 68 mg.

Dexamethasone is a corticosteroid, known as

(8S,9R, 10S, 11 S, 13S, 14S, 16R, 17R)-9-Fluoro-11 , 17-dihydroxy-17-(2-hydroxyacetyl)- 10,13,16-trimethyl-6,7,8, 11 ,12,14,15,16-octahydro-cyclopenta[a]phenanthren-3-one. It is commercially available in the form of dexamethasone acetate and dexamethasone sodium phosphate. The effective amount of dexamethasone or a pharmaceutically acceptable salt thereof used in the present formulation is about 50 mg to 100mg. In one embodiment, dexamethasone is used in the amount of about 82 mg.

Ketamine is recognized as an anesthesia used to reduce pain. It has the chemical name of (R,S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. The effective amount of ketamine or a pharmaceutically acceptable salt thereof used in the present formulation is about 25 mg to 70 mg. In one embodiment, ketamine is used in the amount of about 50 mg.

These non-opioid active ingredients, ketorolac (an anti-inflammatory),

dexamethasone (a steroid), and ketamine (an anesthetic) inhibit or suppress pain- mediating mechanisms in neuropathic and nociceptive pain compared to opioid drugs which act mainly on opioid receptors in the CNS. Pain-mediating mechanisms include non-opioid active ingredient combinations of COX 1 and 2 prostaglandin synthesis inhibitors (via ketorolac action), NMDA receptor antagonism (via ketamine action), and anti-inflammatory effects (via dexamethasone action). In addition, ketorolac and dexamethasone help treat the neuropathic component of pain, while ketamine helps alleviate the nociceptive or perceptive component of pain. With these active ingredients, particularly in combination, multiple pain-mediating mechanisms are inhibited at the same time with much smaller doses of the active ingredients (and locally released in a controlled fashion), compared to currently used amounts for opioids (Schneider et al. Clin. Med. Res. 2003; Morasco et al. Pain. 2010.) and single monotherapy non-opioids (Raffa et al. J. Pain. 2010)

Non-limiting examples of the biodegradable polymer that may be used in the present invention may include, but not limited to, polylactide, polyglycolide,

polycaprolactone, (and other polyesters), polyhydroxyalkanoates, poly (propylene fumarate), polyanhydrides, glycosaminoglycans (e.g. hyaluronic acid), poly(lactide-co- glycolide)(PLGA), and other copolymers), and a combination thereof. These polymers and copolymers are soluble in the biocompatible solvents used in the present invention.

In one embodiment, PLGA polymer is preferable as the biodegradable polymer. The terminal groups of PLGA can either be hydroxyl, carboxyl, or ester depending upon the method of polymerization. Either the acid-terminated or the ester-terminated PLGA may be used in the present invention. The acid terminated PLGA polymers were found in the present invention degraded faster than the ester terminated PLGA polymers.

The injectable composition for an in situ forming implant according to the present invention may have a total weight of about 400 mg to about 4,000 mg including the active ingredients and the polymer. It may be in the range of about 400 mg to about 3,500 mg, about 500 mg to about 3,000 mg, about 1000 mg to about 2500 mg, about 1500 mg to about 2500 mg, or about 2,000. The active ingredients may be in an amount of 1 to 50% by weight, and the polymer is in an amount of 10 to 95% by weight of the total mass of the implant. Preferably, the active ingredient(s) may be in the amount of about 1 to 30%, about 1 to 25%, about 2 to 20%, about 5 to 15%, or about 3 to 15% and the polymer may be in the amount of about 15 to 75%, 20 to 60%, 30 to 50%, 35 to 45 based on the total weight of the implant.

The formulation in one embodiment of the present invention is in the form of polymer matrix-active ingredient where the active ingredient is distributed throughout the polymer.

The biocompatible solvents used in the present are generally organic solvents that do not react or cause any interaction with biological tissues. The biocompatible solvents may include but are not limited to triacetin, ethanol, benzyl alcohol, 1 -butanol, 2-butanol, chloroform, acetic acid, isopropyl alcohol, acetonitrile, N-methyl-2- pyrrolidone, 2-pyrrolidone, glycerol, methyl acetate, methyl isobutyl ketone, benzyl benzoate, propylene glycol, dimethyl isosorbide, propylene carbonate, ethyl acetate, ethyl lactate, dimethyl sulfone, N,N-diethyl-m-toluamide, methyl ethyl ketone, dimethylformamide, dichloromethane, benzonitrile, dimethyl isosorbide, dimethyl sulfoxide, dimethyl acetamide, tetrahydrofuran, caprolactam, decymethylsulfoxide, oleic acid, and l-dodecylazacyclo-heptan-2-one or mixtures thereof. In one embodiment, N- methyl-2-pyrrolidone is preferably used.

The present formulation may include additional active ingredients that help managing postoperative or neuropathic back pain, including but not limited to other analgesics, steroids and anesthetics.

The present formulation may include a pharmaceutically acceptable excipient selected from but not limited to a thickening agent, antioxidant, buffering agent, wetting agent, viscosity modifying agent, release rate retarding agent, isotonicity agent, preservative, stabilizer, pH adjusting agent, plasticizers and the like or mixtures thereof. Examples for each of the excipients are known in the art and may be selected depending on the type of formulations, polymers and active ingredients.

The present formulation releases the active ingredients in a sustained release fashion. In one embodiment, the formulation releases ketorolac for about 3 weeks. In another embodiment, the formulation releases ketorolac, dexamethasone and/or ketamine for about or at least 7 days or 9 days in a sustained fashion. In the

formulations containing ketorolac in combination with dexamethasone and/or ketamine, ketorolac releases higher at 1 and 3 days compared to dexamethasone or ketamine, and ketorolac in this respect may provide advantageous release profile in providing immediate pain relief, by acting as a loading dose. See FIGs. 2A, 2B, 3A, and 3B.

To prepare the in situ forming implant of the present invention, the active ingredient(s) is mixed with a biodegradable polymer (e.g., PLGA) in a biocompatible solvent (e.g. N-methyl-pyrollidone). For example, ketorolac, dexamethasone and ketamine each alone or in any combination is added to 75% N-methyl pyrolidone/25% PLGA solution. The mixture is vortexed to dissolution and injected into an aqueous environment, such as in water or phosphate buffered saline (PBS). The solvent partitions from the active ingredient-polymer combination and a solid drug containing implant is expected to form by precipitation in an aqueous environment.

The present composition may be formulated to a solid implant. To prepare a solid implant, the active ingredient(s) is added to the biodegradable polymer (e.g., PLGA) solution, mixed by vortexing to dissolve or suspend the active ingredient(s), and added to ethanol (or other anti-solvent) to precipitate the polymer (e.g., PLGA) which traps the active ingredient(s) in the solid implant. The implant is vacuum dried to remove residual solvent.

Method for treating pain

In another aspect, the present invention is directed to a method for treating pain in a subject in need thereof, comprising administering to the patients an in situ forming implant formulation comprising a biodegradable polymer and one or more active ingredients of analgesic agents selected from ketorolac or a pharmaceutically

acceptable salt thereof, dexamethasone or a pharmaceutically acceptable salt thereof, ketamine or a pharmaceutically acceptable salt thereof, at or near the site of pain in the subject. In an embodiment, the composition is injected with a syringe at or near the site of pain. In another embodiment, it may be inserted to the site of pain in a different route.

The composition delivers ketorolac preferably for about 3 weeks after being injected at or near the site of pain in a sustained release fashion.

The delivered amount of the active ingredient may be about 5 mg to about 500 mg per milliliter of formulation administered.

Advantages

The present formulation and/or method for pain management have the following advantageous characteristics: 1 ) it is a single-injection at or near the site of pain by a health care provider, 2) it provides days to weeks of pain management, 3) it contains non-narcotic, active pharmaceutical ingredients that are approved in other dosage forms and routes of administration, and A) it utilizes biomaterials with known safety profile, are widely available, and are FDA approved products.

The following examples are set forth as representative of the present invention. These examples are not to be construed as limiting the scope of the invention as these and other equivalent embodiments will be apparent in view of the present disclosure, figures, and accompanying claims.

EXAMPLES

Example 1 : Preparation of Aqueous solution of Ketorolac (Control)

Ketorolac tromethamine (21.08 mg) was dissolved in 2 mL of water to prepare a 10.54 mg/mL solution.

Example 2: Preparation of PLGA Implant of Ketorolac

179.3 mg of ketorolac tromethamine was added to 807.7 mg of a 75% N-methyl pyrolidone/25% PLGA solution. The mixture was vortexed to dissolution and added to 5.0 g of ethanol. The polymer precipitates to trap the ketorolac in the implant. The supernatant was decanted and analyzed for ketorolac content.

Example 3: Preparation of PLGA in situ forming implant of Ketorolac and dexamethasone

68 mg of ketorolac tromethamine and/or 82mg of dexamethasone was added to 1 -2 mL of 75% N-methyl pyrolidone/25% PLGA solution. The mixture was vortexed to dissolution and administered through a small gauge needle. The polymer precipitates upon contact with an aqueous solution.

Example 4: In vitro release test for Ketorolac and dexamethasone

A USP dissolution apparatus was utilized to measure the in vitro release of ketorolac and dexamethasone from the polymer formulations. Paddle speed was set to 30 rpm in 500 mL of release media (de-ionized water at 37 °C). Solutions or implants were added to a cellulose, semi-permeable dialysis tubing (6.4 mm x 10 mm). Formulations in the dialysis tubing were weighted down with metal clips and added to the USP test apparatus at time zero. At each time point (15 minutes, 1 hour, 2 hours, 1 day, etc.), a 5-mL sample was removed from each vessel and replaced with 5 ml_ of de- ionized water. Ketorolac concentration was determined by measuring the UV

absorbance at 323 nm and calculating the amount release by comparing to a known standard (FIG. 1 ). The concentration of ketorolac and dexamethasone released over time was also measured by high performance liquid chromatography (Waters, Acquity UPLC FI Class System, Massachusetts, USA) (FIGs. 2A and 2B; FIGs. 3A and 3B). Percentages of ketorolac and dexamethasone released per time were analyzed from the peak areas.

The results are shown by the graphs in FIG. 1 representing the cumulative amount of ketorolac released as a function of time. Nearly all of the ketorolac was released in the first day from an aqueous injection, but ketorolac was released from the polymer formulations over weeks 1 through 3 (FIG. 1 ). The high initial burst of the drug in the first 24 hours may be advantageous as it can provide immediate relief from pain and the slow release from the polymer for at least 3 weeks provides a maintenance dose.

As previously described, PLGA in situ forming implant formulations were prepared with ketorolac and dexamethasone alone and in combination in the amount as listed in Table 1 below. The formulations were then pipetted into dialysis tubing and placed in a USP dissolution apparatus to assess for controlled release.

Table 1

FIGs. 2A and 2B and FIGs. 3A and 3B show ketorolac and dexamethasone released from in situ PLGA polymers in a controlled-fashion for 9 days. FIGs. 2A and 2B show release profile of ketorolac and dexamethasone alone in acid or ester terminated PLGA polymers. As shown in FIG. 2A, higher percentage of ketorolac in acid and ester terminated PLGA is released over time compared to dexamethasone. Ketorolac has a higher rate of release at 1 and 3 days compared to dexamethasone as shown in FIG. 2B. The large initial amount of ketorolac released after 1 day may be advantageous in providing immediate pain relief (i.e. acting as a loading dose), while the later amounts released from the polymer may help maintain pain relief over a period of weeks (i.e. acting as a maintenance dose).

FIGs. 3A and 3B show release profile of ketorolac and dexamethasone together in the same acid or ester terminated PLGA polymers. As shown in FIG. 3A, higher percentage of ketorolac in acid and ester terminated PLGA is released over time compared to dexamethasone. As shown in FIG. 3B, Ketorolac has a higher rate of release at 1 and 3 days compared to dexamethasone.

Release profile in FIGs. 2A and 2B is similar to that of FIGs. 3A and 3B, demonstrating that the release profiles of the two active ingredients (ketorolac and dexamethasone) together are independent of the PLGA polymer construct. The acid terminated PLGA polymers degraded faster than the ester terminated PLGA polymers (data not shown).

Example 5: Preparation of PLGA in situ forming implant of Ketorolac,

Dexamethasone and Ketamine

PLGA in situ forming implant formulations are prepared with ketorolac, dexamethasone and ketamine alone or in combination in the amount as listed in Table 2 below and with the two types of PLGA as listed in Table 2. Ketorolac, dexamethasone and ketamine alone and all 3 in combination are mixed with their respective acid- terminated or ester-terminated PLGA polymers, and vortexed to dissolution. The formulations are then pipetted into dialysis tubing and placed in a USP dissolution apparatus to assess for controlled release.

Table 2

Using the same USP apparatus 2 - Paddle method as described in Example 4, percentages of ketorolac, dexamethasone and ketamine released per time are analyzed from the peak areas.