HK1188408B - A sustained release formulation of a non-steroidal anti-inflammatory drug - Google Patents

Abstract

Disclosed are formulations comprising multivesicular liposomes and one or more non-steroidal anti-inflammatory drugs which minimize the side effects of unencapsulated non-steroidal anti-inflammatory drugs while maintaining or improving efficacy. Methods of making and administering the formulations comprising multivesicular liposomes and one or more non-steroidal anti-inflammatory drugs and their use as medicaments are also provided.

Description

Sustained release formulations of non-steroidal anti-inflammatory drugs

Cross Reference to Related Applications

This application claims priority from U.S. application No. 61/407,872 filed on 28/10/2010, which is hereby incorporated by reference in its entirety.

Background

Technical Field

The present application relates to multivesicular liposome (MVL) formulations of non-steroidal anti-inflammatory drugs (NSAIDs) that minimize the side effects of NSAIDs while maintaining or improving their effectiveness. In particular, embodiments of the invention relate to compositions comprising NSAIDs and multivesicular liposomes and methods of administering the compositions. Also provided are methods of making multivesicular liposomes comprising NSAIDs and their use as medicaments.

Background information

Orally administered NSAID compounds are effective pain and inflammation relievers in a variety of treatment regimens. Because of their effectiveness, the use of oral NSAIDs for the treatment of acute and chronic Joint pain and inflammation is rapidly increasing (BJORkman, am.J.Med.,107(6A):3S-10S (1999); Barnard et al, Drug Safety,29(7):613-20(2007); Bardou et al, Joint Bone Spine,77(1):6-12 (2010)). NSAIDs are also widely used to treat post-operative pain, usually by intravenous or oral administration. However, oral NSAID treatment has been associated with a variety of serious gastrointestinal complications, including gastric ulceration, peptic perforation, bleeding, colonic ulceration, and colitis (Hollenz et al, Dig dis.,24(1-2):189-94(2006); Yamagata et al, Nippon Rinsho,65(10):1749-53(2007); Shibuya et al, ColorectalDis. (2009)). Gastrointestinal (GI) symptoms may occur within the first two weeks of treatment. Thus, patients with acute and chronic disease states are affected (Peris et al, Pharmacoeeconomics, 19(7):779-90 (2001)). GI toxicity and the increased morbidity that results therefrom account for a large portion of the costs associated with NSAID therapy. It threatens the utility and economic viability of NSAID therapy for the treatment of pain and inflammation (Bjorkman, am. j. med.,107(6A):3S-10S (1999)). Gastroprotective combination therapy has been developed as a solution to the problem of GI toxicity; however, this method is currently considered cost prohibitive (Id.).

Generally, GI toxicity may be attributed to the amount and duration of drug exposure in the GI tract after oral administration and to the amount and duration of drug exposure at high systemic levels of drug required to achieve effective drug levels at the site of synovial fluid action. A key to improving the effectiveness of NSAID therapy and reducing GI or opioid-related side effects is the development of treatments that provide effective and prolonged drug levels directly to the joint synovial cavity or surgical wound without GI or high systemic exposure. Effective NSAIDs such as Diclofenac (DCF), Meloxicam (MLX) and Piroxicam (PRX) are typically administered systemically at doses of 100-150 mg/day, 7.5-15 mg/day and 20 mg/day, respectively. These relatively high side-effect inducing doses are necessary to achieve effective drug levels within the synovial cavity or wound site. Drug levels achieved in the synovial cavity following systemic NSAID administration have been shown to be significantly lower than those achieved in plasma (Bannwart et al, int.J.Clin.Pharmacol.therapy,39(1):33-36(2001); Hundal et al, Scand.J.Rheumatol, 22(4):183-187 (1993)). For example, chronic systemic administration of diclofenac at 100 mg/day produces effective synovial fluid levels of 200ng/mL or less. In 25mL synovial space (this volume represents the diseased knee; the normal volume is 2mL), this corresponds to an intra-articular dose of about 5 μ g, which is a dose readily achievable with the formulations described herein (Fowler, Eur. J. Clin. Pharmacol.,31(4):469-472 (1986)). For more potent NSAIDs such as MLX and PRX, lower synovial drug concentrations are required for efficacy.

The local residence time of the drug in the synovial cavity is closely related to the potency of the drug (Foong et al, J.Pharm. Pharmacol.,40(7): 464-Pharmacol 468(1988); Foong et al, J.Pharm. Pharmacol.,45(3): 204-Pharmacol., 209,15 (1993)). However, drugs are usually cleared from the synovial fluid within a matter of hours (Neander et al, Eur. J. Clin. Pharmacol.,42(3): 301-Sci 305(1992); Larsen et al, J. pharm. Sci.,97(11):4622-4654 (2008)). Thus, a single dose of unencapsulated NSAID drug, whether they be administered intra-articularly or orally, has limited opportunity to achieve its therapeutic effect.

Methods for preparing Liposomes encapsulating therapeutic agents are not described in Hwang et al, int.J.pharm.179(1):85-95(1999); (Cullis et al, 1987, in Liposomes from Biophysics to Therapeutics (in Biophysics to Therapeutics) (Ostro, Ed.), Marcel Deker Inc., pp.60-65); and (Zhang, Trends in Bio/pharm. ind.,4:19-24 (2008)). .

The formulations and methods of the present application address the shortcomings of current NSAID therapies and formulations and also provide other advantages.

Summary of The Invention

The present embodiments provide a formulation of one or more non-steroidal anti-inflammatory drugs, comprising one or more non-steroidal anti-inflammatory drugs; and multivesicular liposomes, wherein said one or more non-steroidal anti-inflammatory drugs are encapsulated in said multivesicular liposomes. In certain embodiments, the one or more non-steroidal anti-inflammatory drugs are selected from the group consisting of indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, lornoxicam, cinoxicam, sudoxicam, and tenoxicam.

In other embodiments, the multivesicular liposomes further comprise cholesterol, one or more phospholipids, including salts of phospholipids, and one or more triglycerides. In certain embodiments, the phospholipid is phosphatidylcholine, phosphatidylglycerol and salts thereof, or a combination of these. In other embodiments, the phosphatidylglycerol is DPPG. In another embodiment, the phosphatidylcholine is DEPC. In another embodiment, the phosphatidylcholine is DOPC. In certain embodiments, the triglyceride is triolein, tricaprylin, or a combination of the two.

In another embodiment, the multivesicular liposomes further comprise a pH adjusting agent. In another embodiment, the pH adjusting agent is lysine or glutamic acid or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, or an inorganic base.

In certain embodiments, the cyclodextrin is selected from the group consisting of (2, 6-di-O-) ethyl- β -cyclodextrin, (2-carboxyethyl) - β -cyclodextrin sodium salt, (2-hydroxyethyl) - β 0-cyclodextrin, (2-hydroxypropyl) - β 2-cyclodextrin, sulfobutyl ether- β -cyclodextrin, (2-hydroxypropyl) - β -cyclodextrin, 6-monodeoxy-6-monoamino- β -cyclodextrin, 6-O- β 5-maltosyl- β -cyclodextrin, butyl- β -cyclodextrin, butyl- γ -cyclodextrin, carboxymethyl- β -cyclodextrin, methyl- β -cyclodextrin, succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, triacetyl-9634-cyclodextrin, and α.

Another embodiment provides a method of treating pain and inflammation comprising injecting an NSAID-MVL formulation described herein into an individual in need thereof. In certain embodiments, the one or more non-steroidal anti-inflammatory drugs are selected from the group consisting of indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, lornoxicam, cinnoxicam, sudoxicam, and tenoxicam. In other embodiments, the formulation in the method comprises a pharmaceutically acceptable carrier for injection.

In other embodiments, the multivesicular liposomes further comprise cholesterol, one or more phospholipids, including salts of phospholipids, and one or more triglycerides. In other embodiments, the multivesicular liposomes further comprise DPPG, DEPC, DOPC, tricaprylin, lysine, glutamic acid, and combinations thereof.

In certain embodiments, administration may be subcutaneous injection. In certain embodiments, administration may be intramuscular injection. In other embodiments, the administration may be intra-articular injection. In certain embodiments, direct osmotic administration is by local injection into the wound margin or instillation into the incision post-operatively, or a combination thereof. In certain embodiments, the administration is topical. In certain embodiments, topical administration may be ocular, nasal, or otic. In other embodiments, the administration is intraocular. In other embodiments, administration is every 1 to 7 days.

Another embodiment provides a method of making a multivesicular liposomal formulation, the method comprising providing a first emulsion by mixing a first aqueous phase and a volatile water-immiscible solvent phase, the solvent phase comprising at least one amphipathic lipid and at least one neutral lipid, mixing and emulsifying the first and second aqueous phases to provide a second emulsion, the second emulsion comprising a continuous aqueous phase, removing the volatile water-immiscible solvent from the second emulsion to form a blank multivesicular liposomal particle composition; loading a non-steroidal anti-inflammatory drug into the multivesicular liposomes by remote encapsulation, wherein there is a gradient of low pH outside the MVL to high pH inside the MVL to push the NSAID into the MVL.

In certain embodiments, the multivesicular liposomes further comprise a pH adjusting agent. In other embodiments, the pH adjusting agent is lysine or glutamic acid, or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof. In other embodiments, the glutamic acid is adjusted to a pH of about 4.7 to about 9.2. In certain embodiments, the pH gradient is from about 1 to about 2 pH units.

In one embodiment, the non-steroidal anti-inflammatory drug may be diclofenac. In another embodiment, the nsaid may be piroxicam. In another embodiment, the non-steroidal anti-inflammatory drug may be meloxicam. In another embodiment, the non-steroidal anti-inflammatory drug may be ketorolac.

Another embodiment provides a method of making a multivesicular liposomal formulation, the method comprising providing a first emulsion by mixing at least one NSAID, a first aqueous phase and a volatile water-immiscible solvent phase comprising at least one amphipathic lipid and at least one neutral lipid, mixing and emulsifying the first and second aqueous phases to provide a second emulsion comprising a continuous aqueous phase, removing the volatile water-immiscible solvent from the second emulsion to form a blank multivesicular liposomal particle composition. In certain embodiments, the NSAID is added to the first aqueous solution prior to mixing. In certain embodiments, the NSAID is added to the volatile, water-immiscible solvent phase prior to mixing. In certain embodiments, the NSAID is added to the first aqueous solution and the volatile water-immiscible solvent phase prior to mixing.

In certain embodiments, the multivesicular liposomes further comprise a pH adjusting agent. In other embodiments, the pH adjusting agent is lysine or glutamic acid, or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof.

In certain embodiments, the non-steroidal anti-inflammatory drug is diclofenac. In certain embodiments, the non-steroidal anti-inflammatory drug is piroxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is meloxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is ketorolac.

Another embodiment provides a multivesicular liposome formulation of the present application prepared by a process of providing a volume of a first emulsion by mixing a first aqueous phase and a volatile, water-immiscible solvent phase comprising at least one amphipathic lipid and at least one neutral lipid, providing a volume of a second emulsion by mixing and emulsifying the first and second aqueous phases, the second emulsion comprising a continuous aqueous phase, removing volatile, water-immiscible solvent from the second emulsion to form a multivesicular liposome particle composition; and loading the non-steroidal anti-inflammatory drug into the multivesicular liposomes with a gradient of low pH outside the MVL to high pH inside the MVL to push the NSAID into the MVL. In certain embodiments, the multivesicular liposomes further comprise a pH adjusting agent. In other embodiments, the pH adjusting agent is lysine or glutamic acid, or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof. In other embodiments, the glutamic acid is adjusted to a pH of about 4.7 to about 9.2. In certain embodiments, the pH gradient is from about 1 to about 2 pH. In certain embodiments, the non-steroidal anti-inflammatory drug may be diclofenac. In certain embodiments, the non-steroidal anti-inflammatory drug may be piroxicam. In certain embodiments, the non-steroidal anti-inflammatory drug may be meloxicam. In certain embodiments, the non-steroidal anti-inflammatory drug may be ketorolac.

Another embodiment provides a multivesicular liposome formulation of the present application prepared by mixing at least one NSAID, a first aqueous phase and a volatile water-immiscible solvent phase comprising at least one amphipathic lipid and at least one neutral lipid to provide a volume of a first emulsion, mixing and emulsifying the first and second aqueous phases to provide a volume of a second emulsion comprising a continuous aqueous phase, removing the volatile water-immiscible solvent from the second emulsion to form the multivesicular liposome particle composition. In certain embodiments, the NSAID is added to the first aqueous solution prior to mixing. In certain embodiments, the NSAID is added to the volatile, water-immiscible solvent phase prior to mixing. In certain embodiments, the NSAID is added to the first aqueous solution and the volatile water-immiscible solvent phase prior to mixing. In certain embodiments, the multivesicular liposomes further comprise a pH adjusting agent. In other embodiments, the pH adjusting agent is lysine or glutamic acid, or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof. In certain embodiments, the non-steroidal anti-inflammatory drug is diclofenac. In certain embodiments, the non-steroidal anti-inflammatory drug is piroxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is meloxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is ketorolac.

Another embodiment provides a method of treating pain and inflammation over an extended period of time by wound penetration, the method comprising administering a multivesicular liposome (MVL) formulation by local injection into the wound margin or instillation into an incision, or a combination thereof, wherein the formulation comprises one or more non-steroidal anti-inflammatory drugs and multivesicular liposomes, wherein the one or more non-steroidal anti-inflammatory drugs are encapsulated in the multivesicular liposomes. In certain embodiments, the non-steroidal anti-inflammatory drug is selected from the group consisting of indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam, lornoxicam, cinnoxicam, sudoxicam, and tenoxicam.

In certain embodiments, the non-steroidal anti-inflammatory drug is diclofenac. In certain embodiments, the non-steroidal anti-inflammatory drug is piroxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is meloxicam. In certain embodiments, the non-steroidal anti-inflammatory drug is ketorolac.

In other embodiments, the multivesicular liposomes further comprise cholesterol, one or more phospholipids, including salts of phospholipids, and one or more triglycerides. In certain embodiments, the phospholipid is phosphatidylcholine, phosphatidylglycerol and salts thereof, or a combination thereof. In one embodiment, the phosphatidylglycerol is DPPG. In another embodiment, the phosphatidylcholine is DEPC. In another embodiment, the triglyceride is triolein, tricaprylin, or a combination of the two.

In certain embodiments, the multivesicular liposomes further comprise a pH adjusting agent. In other embodiments, the pH adjusting agent is lysine or glutamic acid, or a combination thereof. In other embodiments, the pH adjusting agent may be an organic acid, an inorganic acid, an organic base, an inorganic base, or a combination thereof.

In certain embodiments, the cyclodextrin is selected from the group consisting of (2, 6-di-O-) ethyl- β -cyclodextrin, (2-carboxyethyl) - β -cyclodextrin sodium salt, (2-hydroxyethyl) - β 0-cyclodextrin, (2-hydroxypropyl) - β -cyclodextrin, sulfobutyl ether- β 1-cyclodextrin, (2-hydroxypropyl) - β -cyclodextrin, 6-monodeoxy-6-monoamino- β -cyclodextrin, 6-O- β 5-maltosyl- β -cyclodextrin, butyl- β -cyclodextrin, butyl- γ -cyclodextrin, carboxymethyl- β -cyclodextrin, methyl- β -cyclodextrin, succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, triacetyl- β -cyclodextrin, and α.

Detailed Description

The present embodiments provide formulations comprising multivesicular liposomes (MVLs) containing an amount of one or more NSAIDs that minimizes the side effects of the NSAIDs while maintaining or improving potency (NSAID-MVL formulations below). The use of the NSAID-MVL formulation in this embodiment results in the release of the NSAID for the treatment of pain and inflammation over an extended period of time.

Intra-articular administration of the NSAID-MVL formulations of the present application addresses all of the above-mentioned shortcomings of current NSAID treatments to achieve increased therapeutic advantages by delivering the drug directly to the site of action, reducing plasma drug concentrations and concentration-dependent side effects, and extending drug exposure of the affected joint from hours to days or weeks. This embodiment is useful for acute treatment due to injury, seizure or surgery, as well as for chronic disease states such as Rheumatoid Arthritis (RA) or Osteoarthritis (OA), where inflammation is localized to a limited number of joints. The sustained release NSAID-MVL formulations of the present application provide pain relief and reduce inflammation while avoiding the side effects associated with current oral treatments. Using multivesicular liposome slow release technology, NSAID-MVL formulations can be administered directly to the affected joint or permeated by local injection into the wound margin or instillation into the incision following surgery. The NSAID-MVL formulations of the present application may also be administered by other routes of administration to treat local inflammation or pain. Topical administration may include topical, ocular, intraocular, nasal, and otic delivery. Topical administration significantly reduces dosage requirements, thereby reducing the potential for gastric and systemic toxicity associated with oral NSAID administration. The NSAID-MVL formulations of the present application release the drug for up to two weeks, so the patient requires low frequency administration.

The post-operative wound penetration of the NSAID-MVL formulations of the present application also allows for a reduction in the use of opioids and thus the side effects associated with opioids. Direct injection or instillation of the NSAID-MVL into the surgical site may enhance the local effect of the NSAID by increasing the local tissue concentration while reducing the total NSAID dosage normally used after surgery.

Subcutaneous or intramuscular administration of the NSAID-MVL formulations of the present application also allows for systemic treatment of pain as an alternative to oral treatment. The advantage of this approach is that MVL formulations can provide a flatter pharmacokinetic profile than oral immediate release dosage forms. Thus, subcutaneous or intramuscular administration provides longer duration and reduced plasma concentration related side effects.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although methods and materials similar to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

Non-steroidal anti-inflammatory drugs

In embodiments of the present application, the non-steroidal anti-inflammatory drugs are encapsulated in the MVLs. NSAIDs of the present application are acidic NSAIDs. NSAIDs include, but are not limited to, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, propionic acid derivatives, such as ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, and oxaprozin, and enolic acids, such as piroxicam, meloxicam, and other oxicams, such as ampiroxicam, droxicam, pivoxicam, lornoxicam, cinnoxicam, sudoxicam, and tenoxicam. In particular, the NSAIDs in the formulations of the present application may comprise Piroxicam (PRX). The NSAIDs in the formulations of the present application may also include Meloxicam (MLX). The NSAIDs in the formulations of the present application may also include Diclofenac (DCF). NSAIDs in the formulations of the present application may also include ketorolac.

Multivesicular liposomes

Embodiments of the present application relate to MVLs comprising one or more NSAIDs. MVLs reported by Kim et al (Biochim, Biophys. acta,728:339-348,1983) are one of a large diameter class of synthetic membrane vesicles that include other lipid-based delivery systems, such as unilamellar liposomes (Huang, Biochemistry,8:334-352, 1969; Kim, et al, Biochim. Biophys. acta,646:1-10,1981) and multilamellar liposomes (Bangham, et al, J mol. Bio.,13:238-252, 1965). The main structural difference between multivesicular liposomes and unilamellar liposomes (also known as unilamellar vesicles) is that multivesicular liposomes comprise multiple aqueous chambers per particle. The main structural difference between multivesicular liposomes and multilamellar liposomes (also known as multilamellar vesicles) is that the multiple aqueous compartments in multivesicular liposomes are non-concentric. Structural differences between unilamellar, multilamellar, and multivesicular liposomes are exemplified in U.S. Pat. No.5,766,627 issued on 6.16.1998 and U.S. Pat. No.6,132,766 issued on 10.17.2000 by Sankaram et al.

The structural and functional characteristics of multivesicular liposomes cannot be directly predicted from the current knowledge of unilamellar vesicles and multilamellar vesicles. Multivesicular liposomes have very different internal morphologies which can be produced by specific methods used in the pharmaceutical industry. Topologically, a multivesicular liposome is defined as having multiple non-concentric chambers within each particle, similar to a "foam-like" matrix; while multilamellar vesicles contain multiple concentric chambers within each liposome particle, similar to "layers of onions".

The presence of an inner membrane distributed in the form of a network throughout the multivesicular liposomes may help impart increased mechanical strength to the vesicles. The particles themselves may occupy a significant proportion of the total formulation volume. The Packed Particle Volume (PPV) of MVLs, measured in a manner similar to a hematocrit, represents the volume of the formulation occupied by the particles and can approach as high as 80%. Typically, the PPV is about 50%. At 50% PPV, multivesicular liposome formulations typically consist of less than 5% w/w lipid. Thus, the volume of encapsulation is about 50% with a relatively low lipid concentration. The multivesicular nature of multivesicular liposomes also suggests that, unlike unilamellar vesicles, a single breach in the outer membrane of the synthetic membrane vesicle will not result in total release of the internal aqueous contents.

Thus, the multivesicular liposomal formulation consists of microscopic spherical particles comprising a plurality of non-concentric aqueous chambers for encapsulating the NSAID drug to be delivered. The individual compartments are separated by a lipid bilayer membrane, which includes synthetic copies of naturally occurring lipids, forming a biocompatible and biodegradable delivery vehicle. The NSAID-MVL formulations of the present application provide sustained delivery at a local site or systemically, and can be administered into muscle tissue and joints by a number of routes including subcutaneous administration. Preparation of multivesicular liposomes is exemplified by Sankaram et al (U.S. Pat. No.5,766,627), issued on day 16, 1998, and by Sankaram et al (U.S. Pat. No.6,132,766), issued on day 17, 10, 2000.

Cyclodextrin

Cyclodextrins are chiral, cyclic molecules formed by the action of the enzyme cyclodextrin transglycosylase on starch these cyclic oligomers contain 6-12 glucose units bonded by α - (1,4) -linkages three of the smallest homologs, α -cyclodextrin, β -cyclodextrin and gamma-cyclodextrin are commercially available, the larger homolog must be prepared and isolated separately secondary 2-and 3-hydroxyl groups are aligned along the cyclodextrin cavity mouth and have staggered orientation.the primary 6-hydroxyl group is located on the opposite side of the molecule.the interior of the cyclodextrin cavity is relatively hydrophobic because all hydroxyl groups are directed to the outside of the molecule.

Such cyclodextrins include, but are not limited to, (2, 6-di-O-) ethyl- β -cyclodextrin, (2-carboxyethyl) - β -cyclodextrin sodium salt, (2-hydroxyethyl) - β 0-cyclodextrin, (2-hydroxypropyl) - β 2-cyclodextrin, sulfobutyl ether- β 1-cyclodextrin, (2-hydroxypropyl) - β 3-cyclodextrin, 6-monodeoxy-6-monoamino- β 4-cyclodextrin, 6-O- β 5-maltyl- β 6-cyclodextrin, butyl- β -cyclodextrin, butyl- γ -cyclodextrin, carboxymethyl- β -cyclodextrin, methyl- β -cyclodextrin, succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, triacetyl- β -cyclodextrin, α -cyclodextrin, β -cyclodextrin, and γ -cyclodextrin.

Generally, the concentration of cyclodextrin used to prepare MVLs of the embodiments of the present application is that which provides the appropriate solubility or slows the release of the pharmacological compound from the MVL upon administration to a subject. Preferably, the cyclodextrin is present in the liposome composition in an amount of about 10 milligrams per milliliter to about 400 milligrams per milliliter. More preferably, the amount of cyclodextrin in the liposome is about 100 mg/ml. The use of cyclodextrins in the preparation of MVLs is described in Kim's U.S. Pat. No.5,759,573 issued on 6.2.1998.

Preparation method

The formulations of the embodiments of the present application use NSAID-encapsulated multivesicular liposomes (hereinafter NSAID-MVL formulations) that encapsulate and provide the modulated and sustained release of NSAIDs described above. The present NSAID-MVL formulations are prepared by the following method.

A "water-in-oil" type emulsion is formed from two immiscible phases, a lipid phase and a first aqueous phase. The lipid phase consists of at least one amphiphilic lipid and at least one neutral lipid in a volatile organic solvent, and optionally cholesterol and/or cholesterol derivatives. The term "amphipathic lipid" refers to a molecule having a hydrophilic "head" group and a hydrophobic "tail" group and may have membrane-forming ability. Amphiphilic lipids as used herein include those having a net negative charge, a net positive charge, and zwitterionic lipids (which do not have a net charge at their isoelectric point). The term "neutral lipid" refers to an oil or fat that does not have vesiculation capability by itself and lacks a charged or hydrophilic "head" group. Examples of neutral lipids include, but are not limited to, glycerol esters, ethylene glycol esters, tocopherol esters, sterol esters lacking a charged or hydrophilic "head" group, and alkanes and squalene.

Amphiphilic lipids are selected from a wide range of lipids having hydrophobic and hydrophilic regions within the same molecule. Suitable amphiphilic lipids are zwitterionic phospholipids, including phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, lysophosphatidylcholine and lysophosphatidylethanolamine. Anionic amphiphilic phospholipids are also suitable, such as phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, phosphatidic acid and cardiolipin. Cationic amphiphilic lipids are also suitable, such as acyltrimethylammonium propane, diacyldimethylammonium propane, stearamide, and the like. Preferred amphiphilic lipids include Dioleoylphosphatidylcholine (DOPC), dicapryl-phosphatidylcholine or 1, 2-dicapryl-sn-glycero-3-phosphocholine (DEPC) and dipalmitoyl-phosphatidylglycerol or 1, 2-dipalmitoyl-sn-glycero-3-phospho-rac- (1-glycerol) (DPPG). In certain embodiments, amphiphilic lipids for NSAID-MVL formulations of the present application include DOPC and DEPC and DPPG.

Suitable neutral lipids are triglycerides, propylene glycol esters, ethylene glycol esters and squalene. Examples of triglycerides that can be used in the formulations and methods of the present application are Triolein (TO), tripalmitin, trimyristin, trilinolein, tributyrin, trihexanoic acid, tricaprylin, and tricaprin. The fatty chains in the triglycerides useful herein may all be the same or not (mixed chain triglycerides), including all different. The two propylene glycol esters may be mixed diesters of caprylic acid and capric acid.

The concentrations of amphiphilic lipids, neutral lipids and cholesterol present in the water-immiscible solvent used to prepare MVLs are typically 1-40mM, 2-40mM and 0-60mM, respectively. In certain embodiments, the concentrations of amphipathic lipids, neutral lipids, and cholesterol may be about 30mM, 25mM, and 25mM, respectively. If a charged amphiphilic lipid is included, it is typically present at a lower concentration than the zwitterionic lipid.

Many types of volatile organic solvents can be used in this application, including ethers, esters, halogenated ethers, hydrocarbons, halogenated hydrocarbons, or freons. For example, diethyl ether, chloroform, dichloromethane, tetrahydrofuran, ethyl acetate, and any combination thereof are suitable for use in preparing the formulation.

Optionally, but very desirably, other components are also included in the lipid phase. Wherein the component is antioxidant, antibacterial agent, antiseptic, cholesterol or phytosterol.

In certain embodiments, the first aqueous phase may include one or more NSAIDs, pH adjusting agents including organic or inorganic acids and bases (e.g., lysine and glutamic acid), optionally cyclodextrin, and osmotic agents (e.g., sodium chloride, sucrose, glucose, fructose, or mixtures thereof). The lipid phase and the first aqueous phase are mixed by mechanical turbulence, for example by using rotating or vibrating blades, shaking, extrusion through a baffle structure or perforated tube, or by ultrasound to produce a water-in-oil emulsion. If NSAIDs are included, the NSAIDs of the present application are directly encapsulated (directly loaded) in the first step of MVL preparation.

The water-in-oil emulsion can then be dispersed into the second aqueous phase by the method described above to form solvent globules suspended in the second aqueous phase to form a water-in-oil-in-water multiple emulsion. The term "solvent globule" refers to a microscopic spherical droplet of organic solvent in which a plurality of smaller droplets of aqueous solution are suspended. The second aqueous phase may comprise additional components such as pH adjusting agents, osmotic agents, and combinations thereof. Non-limiting examples of pH adjusting agents include lysine, arginine, and the like. Non-limiting examples of osmotic agents include monosaccharides (e.g., glucose, etc.), disaccharides (e.g., sucrose, etc.), and polyols (e.g., sorbitol, mannitol, etc.).

The volatile organic solvent is then removed from the pellet, for example by surface evaporation from the suspension. When the solvent is substantially or completely evaporated, MVLs are formed. Gases that may be used for evaporation include nitrogen, argon, helium, oxygen, hydrogen and carbon dioxide and mixtures thereof, or clean compressed air. Alternatively, the volatile solvent may be removed by bubbling, rotary evaporation, diafiltration, or using a solvent selective membrane.

Methods of preparing MVL formulations of the present application can also be found in the following patent documents: hartouian et al (WO99/25319(PCT/US98/2426), published on 27.5.1999; US 2002-.

As described above, NSAIDS can be incorporated into MVLs by including them in the first aqueous phase. NSAIDS may also be incorporated into the MVL by including it in the lipid phase or in both the lipid phase and the first aqueous phase.

Surprisingly, the present NSAIDs can be remotely packaged into MVLs to give NSAID-MVL formulations of the present application. Due to the structural complexity of MVLs, it has surprisingly been found that NSAIDs can drive through multilayer films (e.g., up to one hundred layers) of MVLs. The method of the present application is distinguished from the aforementioned Hwang et al. For example, in the present embodiment, MVLs serve as receptors for NSAIDs and only pH gradients are used. Further, there is a gradient of low pH outside the MVLs to high pH inside the MVLs to drive NSAIDs into the MVLs. Furthermore, embodiments of the present application do not rely on the use of calcium acetate or sodium acetate or a precipitation mechanism. Once blank MVLs (containing no active compound) are formed by the above method, NSAID-MVL formulations can be prepared by adding drug-containing solutions to the suspension of MVLs. In this case, there is a gradient of low pH outside the MVLs to high pH inside the MVLs to drive NSAIDs into the MVLs.

Furthermore, remote envelope loading may be driven by precipitating NSAIDs once within MVLs. In this case, cations will be included in the blank MVLs, which will form low solubility salts with NSAIDs. Cations may include, but are not limited to, sodium, calcium, magnesium, aluminum, and the like.

Method of administration

Current features of post-operative analgesia include wound infiltration with local anesthetics in combination with systemic administration of NSAIDs and opioids. Opioids have considerable drawbacks, including the time and resources required to monitor and treat the side effects associated with opioids. It is desirable to reduce the use of postoperative opioids to reduce the incidence and severity of opioid-induced side effects, such as respiratory depression, nausea, vomiting, constipation, lethargy, pruritis, and urinary retention. Embodiments of the present application provide extended release formulations of NSAIDs to a wound site, thereby avoiding the use of systemic opioids.

In any embodiment, the NSAID-MVL formulations of the present application may be administered by bolus injection, such as subcutaneous bolus injection, intra-articular bolus injection, intramuscular bolus injection, intradermal bolus injection, and the like. In any embodiment, administration can be by infusion, such as subcutaneous infusion, intra-articular infusion, intramuscular infusion, intradermal infusion, and the like. In any embodiment, administration may be direct wound penetration by local injection into the wound margin or instillation into the incision, or a combination thereof. The NSAID-MVL formulations may also be administered by other routes of administration to treat local inflammation or pain, including but not limited to topical, ocular, intraocular, nasal, and otic delivery.

Administration of the NSAID-MVL formulations of the present application is accomplished using standard methods and devices, e.g., pens, syringe systems, needles and syringes, hypodermic port delivery systems, and the like. See, for example, Hall et al, U.S. patent No. 3,547,119 issued on 12/15/1970, Konopka et al, U.S. patent No. 4,755,173 issued on 7/5/1988, Yates issued on 7/30/1985, U.S. patent No. 4,531,937, Gerard issued on 1/19/1982, U.S. patent No. 4,311,137, and Fischell et al, U.S. patent No.6,017,328 issued on 1/25/2000, each of which is incorporated herein by reference in its entirety.

In preferred embodiments, the NSAID-MVL formulation is administered subcutaneously, intramuscularly or intraarticularly. Such administration may occur at a dose of about 7.5mg to about 200mg at intervals of about 1 day to about 7 days for systemic application, and about 0.1mg to about 10mg for intra-articular application. The exact dosage will vary depending on patient factors such as age, sex, general condition, etc. One skilled in the art can readily take these factors into account and use them to establish effective therapeutic concentrations without undue experimentation.

For systemic administration, the amount of DCF administered daily is preferably from about 150mg to about 200 mg. The amount of PRX administered daily is preferably about 20 mg. The amount of MLX administered daily is preferably from about 7.5mg to about 15 mg.

For intra-articular administration, the amount of DCF, PRX and MLX given per dose will be significantly lower than that given subcutaneously. For example, the amount of DCF administered daily can be from about 0.5mg to about 2.0 mg. The amount of PRX administered daily may preferably be about 0.2 mg. The amount of MLX administered daily is preferably from about 0.075mg to about 0.15 mg.

In certain embodiments, the NSAID-MVL formulation optionally includes a pharmaceutically acceptable carrier. Effective injectable compositions containing these compounds may be in the form of suspensions or solutions. In the preparation of suitable formulations, it will be appreciated that in general the water solubility of the acid addition salts is greater than that of the free bases. Similarly, bases are more soluble in dilute acids or acidic solutions than neutral or basic solutions.

In solution form, the compound is dissolved in a physiologically acceptable medium. Such media include suitable solvents, isotonic agents, for example, sucrose or saline, preservatives, for example benzyl alcohol, and buffers, as desired. For example, useful solvents include water and aqueous alcohols, glycols, and carbonates, such as diethyl carbonate.

Injectable suspension compositions require a liquid suspending vehicle with or without adjuvant as the medium. The suspending vehicle may be, for example, an aqueous solution of sodium chloride, sucrose, polyvinylpyrrolidone, polyethylene glycol or a combination of the foregoing.

Suitable physiologically acceptable adjuvants are required to keep the compound suspended in the suspension composition. Adjuvants may be selected from thickening agents such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates. Many surfactants can also be used as suspending agents. Lecithin, alkylphenol polyethylene oxide adducts, naphthalene sulfonates, alkylbenzene sulfonates, and polyoxyethylene sorbitan esters are useful suspending agents.

Many substances which influence the hydrophilicity, density and surface tension of the liquid suspending vehicle may help in the preparation of injectable suspensions in each case. For example, silicone antifoam, sorbitol and sugar may be useful suspending agents.

The term "individual" as used herein includes animals and humans. In a preferred embodiment, the individual is a human.

Non-limiting disclosure and incorporation by reference

While certain therapeutic agents, compositions and methods of the present invention have been specifically described in accordance with certain embodiments, the following examples are intended to be illustrative of the compositions and methods of the present invention only and are not intended to be limiting.

Examples

Example 1-Remote control packing loading

The remote control encapsulated loaded NSAID-MVL formulation was prepared as follows: a blank MVL formulation was prepared in a manner similar to that reported by Kim et al (Biochim. Biophys. acta,728:339-348, 1983). MVLs were prepared in which aqueous solutions adjusted to a specific pH and in some cases containing cyclodextrins (Kim, U.S. patent No.5,759,573 issued at 6/2 of 1998) were emulsified with lipid-containing chloroform solutions to form water-in-oil (W/O) emulsions. Then, the W/O emulsion is emulsified in the second aqueous solution to prepare a W/O/W emulsion. Then, the W/O/W emulsion was stirred under a nitrogen stream at 37 ℃ to remove chloroform by evaporation. The resulting blank MVLs were centrifuged and the supernatant was replaced with physiological saline. After washing, the blank MVLs were diluted into physiological saline to produce a product having about 50% filled particle volume (PPV). PPV is the fraction of the total formulation volume occupied by MVL particles.

NSAID compounds were then loaded into blank MVLs by remote encapsulation by incubating pH-adjusted NSAID solutions described in tables 1,2 and 3 below with blank MVL particle suspensions under mild agitation. Tables 1,2 and 3 are a summary of the components and results for NSAID-MVL formulations, where NSAIDs are PRX, DCF and MLX, respectively. After dispensing NSAIDs into blank MVLs, the suspension is washed in physiological saline to remove unencapsulated or free NSAIDs.

Further, an inner part having an amplitude of about 1.5 is used: external pH gradient MVL formulations of table 2 above were prepared. The inner and outer solutions are adjusted to a higher pH, which provides improved DCF solubility. The loading solution contained 4.2mg/mL of NaHPO₄DCF of (1), pH7.5, and the internal solution comprises lysine-glutamic acid, pH 9-9.2. Using these reduced gradients-higher pH conditions, significantly higher DCF recoveries were obtained, i.e., 17-61%, than those described by Hwang et al, supra (see table 2).

NSAID recovery in MVLs of the present application was analyzed by the following steps: the NSAID-containing MVL was first lysed by mixing one part of the suspension with three parts of isopropanol, vortexing to dissolve, and then further diluted with six parts of RP-HPLC (reverse phase high pressure liquid chromatography) running buffer described in the usp method for each NSAID.

TABLE 1 solution composition and Final product characteristics of PRX-MVL formulations

TABLE 2 solution composition and Final product characteristics of DCF-MVL formulations

TABLE 3 solution composition and Final product characteristics of MLX-MVL formulations

^*SBE is sulfobutyl ether-cyclodextrin

As shown in Table 4 below, the amino acid was purified in the presence of 182mM lysine/glutamic acid (+5mM calcium acetate (Ca (OAc))₂) In the formulation) the DCF loading was higher in the formulation containing longer chain phosphatidylcholine (83% vs.0% recovery in DEPC versus Dioleoylphosphatidylcholine (DOPC). The lysine/glutamic acid containing formulation at higher concentration (182vs.93mM) and increased pH gradient (9.0vs.7.5) had improved DCF loading (78% v43% recovery). In the 300mM lysine/glutamic acid formulation, increasing the DCF loading concentration to 4.6mg/ml resulted in batch failures. In the 100mM lysine/glutamic acid formulation, encapsulation and recovery decreased with increasing DCF concentration in the loading solution. Encapsulation and recovery were significantly improved by the addition of about 2 to about 10% HPB-CD. In certain embodiments, 2% HPB-CD may be added. In a further embodiment, 3% HPB-CD may be added. Similarly, 4% HPB-CD may be added. In further embodiments, about 5 to about 9% HPB-CD may be added. In further embodiments, about 6 to about 15% HPB-CD may be added. In further embodiments, about 2 to about 15% HPB-CD may be added.

In the lysine/glutamate only formulation, osmolarity adjustment with 15% HPB-CD added increased the DCF encapsulation of the particles to 4.6mg/mL (67% recovery). With other NSAIDS (i.e., PRX), HPB-CD is not necessary to achieve high encapsulation (7.2 mg/mL). Higher concentration buffer conditions still provide improved encapsulation and recovery in HPB-CD containing lysine/glutamic acid formulations.

TABLE 4 Effect of Phosphatidylcholine (PC) chain length, buffer concentration and HPB-CD on NSAID encapsulation

a drug loading solutions were prepared in 150mM sodium phosphate unless otherwise stated.

In addition to the formulations prepared using the lysine-glutamic acid solution, blank MVLs (as summarized in table 5 below) were prepared using the lysine-acetic acid solution. Table 5 is a summary of the components and results of the DCF-MVL formulation loaded using lysine and acetic acid remote encapsulation. Blank MVLs at low internal pH were also studied. The pH of the blank MVL was as low as 2.1 units below the pH of the loading solution. Significantly lower concentrations of lysine-acetic acid solution (10-25mM versus 120-150 mM calcium or sodium acetate as reported by Hwang) were used. This method using a lower concentration lysine-acetic acid solution results in NSAID loading by using a membrane permeable acid such as acetic acid. As illustrated in table 5 below, the recovery of NSAID-MVL formulations was higher in solutions with higher pH.

TABLE 5 remote encapsulation of loaded DCF-MVL particles with lysine and acetic acid

Example 2 direct Loading

The direct-loaded NSAID-MVL formulation was prepared as follows: NSAID-containing MVLs are prepared by a conventional direct loading process in which the active (NSAID) drug is dissolved in a first aqueous solution and then encapsulated as described in Hartouian et al (WO99/25319(PCT/US98/2426), published on month 5, 1999, 27, and US2002-0039596, published on month 4, 2002). As shown in table 6, this process produced MVL particles with NSAIDs that were inefficiently encapsulated or not encapsulated at all.

TABLE 6 direct Loading of NSAIDs into MVLs

Failure a indicates that the MVL particles are not formed or very aggregated.

MVLs containing DCF were also prepared by placing the NSAID only in the lipid solution (at a concentration up to solubility in the solvent), or by placing a portion of the NSAID in the first aqueous solution and the lipid solution (see table 7 below). This process can be used to prepare MVLs, typically yielding final NSAID concentrations of 0.1 to 1 mg/mL.

TABLE 7 partitioning of DCF from lipid solution (or lipid and aqueous phases) into MVLs

Example 3 stability

The stability of the NSAID-MVL formulations of the present application (stored in type I borosilicate glass vials, sealed with ETFE-faced butyl stoppers) is acceptable to industry standards. Stability data for the formulations in tables 1 and 2 above are shown in tables 8 and 9 below. The properties evaluated include drug content ("total") and percent unencapsulated drug (% free) as determined by RP-HPLC methods, packed particle volume ("PPV") as evaluated in a manner similar to hematocrit, and particle size as evaluated by laser light scattering. No significant change was observed within 3 months at refrigeration temperature (5 ℃).

TABLE 8 storage stability of DCF-MVL at 5 deg.C

TABLE 9 storage stability of PRX-MVL at 5 ℃

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be included within the scope of the appended claims.

Claims (52)

1. A multivesicular liposome formulation, comprising:

one or more active pharmaceutical ingredients;

a multivesicular liposome;

one or more pH adjusting agents; and

one or more penetrants;

wherein the one or more active pharmaceutical ingredients are selected from one or more non-steroidal anti-inflammatory drugs selected from meloxicam, piroxicam, diclofenac, and ketorolac,

wherein the one or more active pharmaceutical ingredients, the one or more pH adjusting agents, and the one or more osmotic agents are encapsulated in the multivesicular liposomes; and

wherein the multivesicular liposome formulation is prepared by a process comprising:

providing a first emulsion by mixing a first aqueous phase and a volatile, water-immiscible solvent phase comprising at least one amphipathic lipid and at least one neutral lipid; wherein the first aqueous phase has a pH of 9.0, 9.1, or 9.2;

dispersing the first emulsion in a second aqueous phase to form solvent globules suspended in the second aqueous phase to provide a second emulsion;

removing the volatile water-immiscible solvent from the solvent pellet to form a multivesicular liposome particle composition; and

remotely loading the one or more non-steroidal anti-inflammatory drugs into the multivesicular liposomes, wherein the presence of only a gradient of low pH outside the multivesicular liposomes to high pH within the multivesicular liposomes drives the one or more non-steroidal anti-inflammatory drugs into the multivesicular liposomes, and wherein the gradient is from 1 to 2 pH units.

2. The formulation of claim 1, wherein the non-steroidal anti-inflammatory drug is meloxicam.

3. The formulation of claim 1, wherein the multivesicular liposomes comprise one or more phospholipids, one or more triglycerides and optionally cholesterol, wherein the phospholipids optionally comprise a salt of the phospholipids.

4. The formulation of claim 3, wherein the phospholipid is phosphatidylcholine or a salt thereof, phosphatidylglycerol or a salt thereof, or a combination thereof.

5. The formulation of claim 4, wherein the phosphatidylglycerol is 1, 2-dipalmitoyl-sn-glycerol-3-phospho-rac- (1-glycerol).

6. The formulation of claim 4, wherein the phosphatidylcholine is 1, 2-dicaprylyl-sn-glycero-3-phosphocholine.

7. The formulation of claim 3, wherein the triglyceride is triolein, tricaprylin, or a combination of both.

8. The formulation of claim 1, wherein the pH adjusting agent is lysine or glutamic acid, or a combination thereof.

9. The formulation of claim 1, wherein the pH adjusting agent is an inorganic acid.

10. The formulation of claim 1, wherein the pH adjusting agent is an organic acid or an organic base.

11. The formulation of claim 1, wherein the pH adjusting agent is an inorganic base.

12. The formulation of claim 1, wherein the multivesicular liposome further comprises a cyclodextrin.

13. The formulation of claim 12, wherein the cyclodextrin is complexed with the non-steroidal anti-inflammatory drug within the multivesicular liposomes at a concentration of 10mg/ml to 400 mg/ml.

14. The formulation of claim 13, wherein the cyclodextrin is selected from the group consisting of (2, 6-di-O-) ethyl- β -cyclodextrin, (2-carboxyethyl) - β -cyclodextrin sodium salt, (2-hydroxyethyl) - β 0-cyclodextrin, (2-hydroxypropyl) - β 2-cyclodextrin, sulfobutyl ether- β 1-cyclodextrin, (2-hydroxypropyl) - β 3-cyclodextrin, 6-monodeoxy-6-monoamino- β 4-cyclodextrin, 6-O- β 5-maltosyl- β 6-cyclodextrin, butyl- β -cyclodextrin, butyl- γ -cyclodextrin, carboxymethyl- β -cyclodextrin, methyl- β -cyclodextrin, succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, triacetyl- β -cyclodextrin, α -cyclodextrin, β -cyclodextrin, and γ -cyclodextrin.

15. The formulation of claim 8, wherein the glutamic acid is adjusted to a pH of 4.7 to 9.2.

16. Use of the formulation of claim 1 in the manufacture of a medicament for the treatment of pain and inflammation.

17. The use of claim 16, further comprising a pharmaceutically acceptable carrier for injection.

18. The use of claim 16, wherein the multivesicular liposomes comprise one or more phospholipids, one or more triglycerides and optionally cholesterol, wherein the phospholipids optionally comprise a salt of the phospholipids.

19. The use of claim 16, wherein said multivesicular liposome comprises 1, 2-dipalmitoyl-sn-glycero-3-phospho-rac- (1-glycerol), 1, 2-dicaprylyl-sn-glycero-3-phosphocholine, and tricaprylin.

20. The use of claim 16, wherein the multivesicular liposome comprises lysine.

21. The use of claim 16, wherein the multivesicular liposome comprises glutamic acid.

22. The use of claim 16, wherein the formulation is for subcutaneous injection.

23. The use of claim 16, wherein the formulation is for intramuscular injection.

24. The use of claim 16, wherein the formulation is for intra-articular injection.

25. The use of claim 16, wherein the formulation is for wound penetration by local injection into the wound margin, or instillation into the incision, or a combination thereof.

26. The use of claim 16, wherein the formulation is for topical administration.

27. The use of claim 26, wherein the topical administration is ocular.

28. The use of claim 26, wherein the topical administration is nasal.

29. The use of claim 26, wherein the topical administration is otic.

30. The use of claim 16, wherein the formulation is for intraocular administration.

31. The use of claim 16, wherein the formulation is for administration every 1 to 7 days.

32. Use of a multivesicular liposome (MVL) formulation in the manufacture of a medicament for the treatment of pain and inflammation by wound infiltration over an extended period of time, the use comprising administering the formulation by local injection into the wound margin or instillation into the incision, or a combination thereof, wherein the formulation comprises:

one or more active pharmaceutical ingredients;

a multivesicular liposome;

one or more pH adjusting agents; and

one or more penetrants;

wherein said one active pharmaceutical ingredient is selected from one or more non-steroidal anti-inflammatory drugs selected from meloxicam, piroxicam, diclofenac and ketorolac,

wherein the one or more active pharmaceutical ingredients, the one or more pH adjusting agents, and the one or more osmotic agents are encapsulated in the multivesicular liposomes, and wherein the multivesicular liposomes are characterized by an internal pH of 8.08, 8.09, 8.10, 8.14, 8.15, 8.18, 8.20, 8.21, 8.23, 8.24, 8.27, 8.28, 8.30, 8.31, 8.32, 8.34, 8.38, or 8.69.

33. The use according to claim 32, wherein the non-steroidal anti-inflammatory drug is meloxicam.

34. The use of claim 32, wherein the multivesicular liposomes comprise one or more phospholipids, one or more triglycerides and optionally cholesterol, wherein the phospholipids optionally comprise a salt of said phospholipids.

35. The use of claim 34, wherein the phospholipid is phosphatidylcholine or a salt thereof, phosphatidylglycerol or a salt thereof, or a combination thereof.

36. The use of claim 35, wherein the phosphatidylglycerol is 1, 2-dipalmitoyl-sn-glycerol-3-phospho-rac- (1-glycerol).

37. The use of claim 35, wherein the phosphatidylcholine is 1, 2-dicaprylyl-sn-glycero-3-phosphocholine.

38. The use of claim 34, wherein the triglyceride is triolein, tricaprylin, or a combination of both.

39. The use of claim 32, wherein the pH adjusting agent is lysine or glutamic acid, or a combination thereof.

40. The use of claim 32, wherein the pH adjusting agent is an inorganic acid.

41. The use of claim 32, wherein the pH adjusting agent is an organic acid or an organic base.

42. The use of claim 32, wherein the pH adjusting agent is an inorganic base.

43. The use of claim 32, wherein the multivesicular liposome further comprises a cyclodextrin.

44. The use of claim 43, wherein the cyclodextrin is complexed with the NSAID within the multivesicular liposomes at a concentration of 10mg/ml to 400 mg/ml.

45. The use of claim 43, wherein the cyclodextrin is selected from the group consisting of (2, 6-di-O-) ethyl- β -cyclodextrin, (2-carboxyethyl) - β -cyclodextrin sodium salt, (2-hydroxyethyl) - β 0-cyclodextrin, (2-hydroxypropyl) - β 2-cyclodextrin, sulfobutyl ether- β 1-cyclodextrin, (2-hydroxypropyl) - β 3-cyclodextrin, 6-monodeoxy-6-monoamino- β 4-cyclodextrin, 6-O- β 5-maltosyl- β 6-cyclodextrin, butyl- β -cyclodextrin, butyl- γ -cyclodextrin, carboxymethyl- β -cyclodextrin, methyl- β -cyclodextrin, succinyl- α -cyclodextrin, succinyl- β -cyclodextrin, triacetyl- β -cyclodextrin, α -cyclodextrin β -cyclodextrin, and γ -cyclodextrin.

46. A multivesicular liposome formulation, comprising:

an acidic non-steroidal anti-inflammatory drug selected from meloxicam, piroxicam, diclofenac, and ketorolac;

a multivesicular liposome;

one or more pH adjusting agents; and

one or more penetrants;

wherein said acidic non-steroidal anti-inflammatory drug, said one or more pH adjusting agents and said one or more osmotic agents are encapsulated in said multivesicular liposomes; and

wherein the multivesicular liposome is characterized by an internal pH of 8.08, 8.09, 8.10, 8.14, 8.15, 8.18, 8.20, 8.21, 8.23, 8.24, 8.27, 8.28, 8.30, 8.31, 8.32, 8.34, 8.38, or 8.69.

47. The formulation of claim 46, wherein the multivesicular liposome further comprises a pH adjusting agent.

48. The formulation of claim 47, wherein the pH adjusting agent is lysine or glutamic acid or a combination thereof.

49. The formulation of claim 47, wherein the pH adjusting agent is an inorganic acid.

50. The formulation of claim 47, wherein the pH adjusting agent is an organic acid or an organic base.

51. The formulation of claim 47, wherein the pH adjusting agent is an inorganic base.

52. The formulation according to claim 46, wherein the acidic NSAID is meloxicam.