US20140275261A1

US20140275261A1 - Diclofenac parenteral compositions

Info

Publication number: US20140275261A1
Application number: US14/212,838
Authority: US
Inventors: Franklin Okumu; Andrew Xian Chen; Hailiang Chen
Original assignee: Dr Reddys Laboratories Inc
Current assignee: Dr Reddys Laboratories Ltd; Dr Reddys Laboratories Inc
Priority date: 2013-03-15
Filing date: 2014-03-14
Publication date: 2014-09-18
Also published as: US20160038414A1; WO2014145710A1; US10369101B2; EP2968575A1; EP2968575B1

Abstract

The present application provides parenteral compositions of diclofenac or its pharmaceutically acceptable salt and methods for making and using such compositions.

Some of the compositions of the present application has one or more following properties: (1) ready to be injectable, (2) in the form of an oil-water emulsion, (3) stable under appropriate storage conditions, (4) containing therapeutically effective amount of diclofenac or its pharmaceutically acceptable salt, (5) sterilizable by filtration (6) containing components acceptable by regulatory agencies (e.g. the FDA), (7) containing low oil content and thus not exacerbating hyperlipidemia, and (8) is neither hypoallergenic nor vein irritating.

Description

FIELD OF THE INVENTION

The present invention relates to parenteral composition comprising diclofenac or its pharmaceutically acceptable salt. The present invention also provides methods for preparing and using such parenteral composition.

BACKGROUND

In postoperative pain management, health care professionals generally are required to administer opioids, which is a potent analgesic. Although opioids have proven pain management properties, they also have a significant number of potential side effects, including nausea, vomiting, constipation, pruritus, urinary retention, respiratory depression, and sedation. On the other hand nonsteroidal, anti-inflammatory drugs (NSAIDs) provide anti-inflammatory and analgesic effects, but they are limited to oral or rectal administrations greatly limiting the use of NSAIDs under postoperative conditions. Currently, ketorolac tromethamine is only NSAID that can be administered intravenously or intramuscularly, but its chronic use is limited due to GI toxicity.
Diclofenac, chemical name o-(2,6-dichloroanilino)phenylacetic acid, is known as a potent analgesic and antirheumatic and is described, in U.S. Pat. No. 3,558,690. Diclofenac is sold commercially as immediate release, delayed release (enteric coated) and extended-release (sustained-release) dosage forms. Due to the relatively large “first-pass-effect” of the substance and for faster flooding it is desirable to use injection solutions, in which an amount of 75 mg should be used per injection. For intramuscular/intravenous injections, the volume is to be kept as low as possible.
Due to the relatively poor solubility of diclofenac in water an aqueous injection solution with a reasonable volume cannot be obtained. Further, diclofenac is relatively instable in solution.
Examples of Diclofenac injectable compositions known in the art are:
U.S. Pat. No. 4,593,044 to Merckle GmbH describes a ready-to-use injection solution with as high an active compound content as possible in a small volume. The solubilization of diclofenac is achieved by using lysinate salt form of diclofenac and solubilizers such as propylene glycol, glycerol or polyoxyalkylenes.
U.S. Pat. No. 5,283,067 to Ciba-Geigy Corporation describes a lyophilized formulation comprising micronized diclofenac sodium, which is meant for intramuscular injection. This lyophilized formulation, after being suspended in an aqueous liquid vehicle, is converted into a dosage form for parenteral administration.
U.S. Pat. No. 5,389,681 to Ciba-Geigy Corporation describes a sterilizable parenteral solution comprising a diclofenac salt and stabilizers, such as ethyl lactate combined with glutathione or N-acetylcysteine.
U.S. Pat. No. 7,423,028 to IbsalnstitutBiochemique S.A. discloses aqueous solution comprising a complex of diclofenac and hydroxypropyl-β-cyclodextrin in the molar ratio of 1:1 and 1:1.3. The composition further comprises polysorbate in lower concentration.
Although several of above references disclose various diclofenac injectable compositions, there exists a long felt need to develop a stable composition that is ready-to-inject intramuscularly or intravenously and does not cause any irritation to the tissues at the site of the injection.
It has been challenging to design a stable diclofenac parenteral composition that can be readily administered (without dilution or forming suspension) to alleviate pain or inflammation, especially in unconscious/unresponsive patients. Further the composition should not be inducing GI ulceration or bleeding after surgery, and other concurrent damage to the GI membranes or layers.
The present inventors provided a composition meant for parenteral administration comprising diclofenac or its pharmaceutically acceptable salt to a subject that can be used in postoperative pain management, with minimal or no side-effects.

SUMMARY

The present application provides parenteral compositions of diclofenac or its pharmaceutically acceptable salt and methods for making and using such compositions.
The compositions of the present application has one or more following properties: (1) ready to be injectable, (2) in the form of an oil-water emulsion, (3) stable under appropriate storage conditions, (4) containing therapeutically effective amount of diclofenac or its pharmaceutically acceptable salt, (5) sterilizable by filtration (6) containing components acceptable by regulatory agencies (e.g. the FDA), (7) containing low oil content and thus not causing hyperlipidemia, and (8) not hypoallergenic or vein irritating.
In one aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) an oil component,
(c) a phospholipid component, and
(d) water.
In another aspect, the present application provides a method of treating inflammation, pain and/or fever in a mammal, which comprises parenterally administering the aforesaid parenteral composition to the mammal

DETAILED DESCRIPTION

The present application will be described in more detail below.
While the specification concludes with the claims particularly pointing and distinctly claiming the invention, it is believed that the present invention will be better understood from the following description. The present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein. As used herein, “comprising” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range “between” two values.

DEFINITIONS

The terms as used herein have the following meanings:
Diclofenac as used herein also encompasses pharmaceutically acceptable salts. The solid state form of diclofenac used in the composition of the present invention is not critical. For example, diclofenac can be amorphous or crystalline.
The term “pharmaceutically acceptable salts” as used herein includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the pharmaceutically active substance having a free base function with a suitable organic acid or inorganic acid.
Examples of pharmaceutically acceptable nontoxic acid addition salts include, but not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other methods used in the art such as ion exchange techniques. Other pharmaceutically acceptable salts include, but not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, diethylamine, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartarate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
The phrase ‘therapeutically effective amount’ as used herein, means an amount of diclofenac, sufficient to reduce the pain, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The effective amount of the diclofenac will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, and like factors within the knowledge and expertise of the attending physician.
The terms such as ‘about’, ‘up to’, ‘generally’, ‘substantially’ and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technical error and instrumental error for a given experiment, technique or an instrument used to measure a value.
The term “oil-in-water emulsion” as used herein, refers to a colloidal dispersion system in which liquid oil is dispersed in small droplets (the discrete phase, also referred to as “the oil phase”) in an aqueous medium (the continuous phase, also referred to as “the aqueous phase”), wherein in excess of 80% of the drug is dissolved and remains in the oil droplets. In certain embodiments, greater than 85%, 90%, 95% or 99% of the drug is present in the oil phase.
The term “oil” as used herein, means a general sense to identify hydrocarbon derivatives, carbohydrate derivatives, or similar organic compounds that are liquid at body temperatures, e.g., about 37 C., and are pharmacologically acceptable in injectable compositions. It includes glycerides or non-glycerides.
The term “oil component” refers to an oil, or a combination of multiple oils.
In certain embodiments, the oil component of the present application comprises a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof. In certain embodiments, the oil component comprises an ester formed between one or more fatty acids and an alcohol other than glycerol.
In certain embodiments, the oil refers to a “vegetable oil”. Vegetable oil refers to oil derived from plant seeds or nuts. Exemplary vegetable oils include, but are not limited to, almond oil, borage oil, black currant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, castor oil, etc. Vegetable oils are typically “long-chain triglycerides,” formed when three fatty acids (usually about 14 to about 22 carbons in length, with unsaturated bonds in varying numbers and locations, depending on the source of the oil) form ester bonds with the three hydroxyl groups on glycerol. In certain embodiments, vegetable oils of highly purified grade (also called “super refined”) are generally used to ensure safety and stability of oil-in-water emulsions. In certain embodiments, hydrogenated vegetable oils, which are produced by controlled hydrogenation of the vegetable oil.
In certain embodiments, the oil refers to “medium chain triglycerides”. Medium chain triglycerides (MCT's) are another class of triglyceride oil that can be either naturally derived or synthetic. MCT's are made from fatty acids that are usually about 8 to about 12 carbons in length. Like vegetable oils, MCT's have been used extensively in emulsions designed for injection. Such oil is commercially available as Miglyol 812 from SASOL GmbH, Germany, CRODAMOL GTCC-PN from Croda Inc. of Parsippany, N.J., or Neobees M-5 oil from PVO International, Inc., of Boonton, N.J. Other low-melting medium chain oils may also be used in the present invention.
In one aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) an oil component,
(c) a phospholipid component, and
(d) water.
In one embodiment of the above aspect, the present application relates to a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) a medium chain triglyceride,
(c) one or more phospholipids, and
(d) water.
In another aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) an oil component,
(c) a phospholipid component,
(d) at least one tonicity modifying agent, and
(e) water.
In another aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) an oil component,
(c) a phospholipid component,
(d) at least one antioxidant, and
(e) water.
In another aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac or its pharmaceutically acceptable salt,
(b) medium chain triglycerides
(c) a phospholipid component,
(d) acryoprotectant,
(d) at least one tonicity modifying agent, and
(e) water.
In one embodiment of the present application, medium chain triglyceride is selected from Miglyol 812.
In another embodiment of the present application, a phospholipid is selected from egg lecithin (such as LIPOID E-80) or soy lecithin (such as LIPOID S-100).
In another embodiment the composition comprises an oil component and is vegetable oil.
In another embodiment the composition is selected from almond oil, borage oil, black currant seed oil, corn oil, safflower oil, soybean oil, sesame oil, cotton seed oil, peanut oil, olive oil, rapeseed oil, coconut oil, palm oil, canola oil, and castor oil.
In another embodiment, vegetable oil is soybean oil.
In another aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac sodium,
(b) MIGLYOL 812,
(c) Egg lecithin,
(d) EDTA disodium dehydrate USP, and
(e) water.
In one embodiment, the above composition comprises cryoprotectant.
In another embodiment, the cryoprotectant is sucrose.
In one embodiment, the above composition comprises antioxidant.
In another embodiment, the antioxidant is sodium sulfite, sodium bisulfate, sodium metabisulfite, butylatedhydroxytoluene, butylatedhydroxyanisole or a mixture thereof.
In another aspect, the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
(a) diclofenac sodium,
(b) MIGLYOL 812,
(c) Soy lecithin,
(d) EDTA disodium dehydrate USP, and
(e) water.
In one embodiment, the above composition comprises cryoprotectant.
In another embodiment, the cryoprotectant is Sucrose.
In another embodiment, the present application relates to a parenteral composition in the form of oil-in-water emulsion that comprises:

- (a) diclofenac or its pharmaceutically acceptable salt,
- (b) an oil component comprising combination of vegetable oil and a medium chain triglyceride,
- (c) one or more phospholipids, and
- (d) water.

In certain embodiments, the combinations of vegetable oil and MCT oil are used in the present application. Such combinations generally have long record of safe use in combination in injectable emulsions and provide the superior stability for the emulsion. The specific type of vegetable oil used (i.e., soy bean oil, corn oil, or safflower oil, etc.) is not critical, so long as it is safe, well tolerated, pharmaceutically acceptable, chemically stable and provides emulsion droplets having a desired size range.
In certain embodiments, the vegetable oil to medium chain triglyceride ratio in an oil-in-water emulsion is within a range of about 9:1 to about 1:1, by weight. In certain embodiments, the ratio of the vegetable oil to MCT oil is about 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1 or 1:1.
The content of the total oil component may be within a range of 1% to 50%, by weight. In certain embodiments, the total concentration of the oil component is about at most about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. In certain embodiments, the oil-in-water emulsions comprise oil in an amount that does not result in hyperlipidemia when administered to a subject.
In certain embodiments, the average diameter of the droplets in the emulsions of the composition is from about 50 to about 250 nm. In certain embodiments, the average diameter of the oil droplets may be within a range of about 50 to about 200 nm, or about 50 nm to about 150 nm. In certain embodiments, the average droplet diameter is about 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 nm.
In certain embodiments, the composition of the present application may be filter sterilized using via 0.2 μm filters.
The term “filter sterilized” means a composition that has passed through a filter having a pore size sufficiently small to result the composition free or substantially free of bacterial contaminants. Bacteria generally range in size from about 0.2 μm to about 600 μm, with most bacteria having a size in the range of about 1 μm to about 10 μm. Filters having pore size of about 0.22 μm or less are considered to produce sterile filtrates and are sufficiently small to result in a filter sterilized composition. Such filters and filter kits are available from Millipore Corporate, as well as other manufacturers.
An “emulsifier” refers to a compound that prevents the separation of the injectable emulsion into individual oil and aqueous phases. Emulsifiers useful in the present invention generally are (1) compatible with the other ingredients of the oil-in-water emulsions of the present invention, (2) do not interfere with the stability or efficacy of the diclofenac in the emulsions, (3) are stable and does not deteriorate in the preparation, and (4) are non-toxic.
Suitable emulsifiers include, but are not limited to, propylene glycol mono- and di-fatty acid esters, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypr-opylene co-polymers and block co-polymers, salts of fatty alcohol sulphates, sorbitan fatty acid esters, esters of polyethylene-glycol glycerol ethers, oil and wax based emulsifiers, glycerol monostearate, glycerinesorbitan fatty acid esters and phospholipids.
A “phospholipid” refers to a triester of glycerol with two fatty acids and one phosphate ion. Exemplary phospholipids useful in the present invention include, but are not limited to, phosphatidyl choline, lecithin (a mixture of choline ester of phosphorylated diacylglyceride), phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid with about 4 to about 22 carbon atoms, and more generally from about 10 to about 18 carbon atoms and varying degrees of saturation. The “phospholipid component” can be either a single phospholipid or a mixture of several phospholipids. The phospholipids should be acceptable for the chosen route of administration.
The ‘phospholipids’ can be of natural origin or synthesized.
Naturally occurring lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid, commonly called phosphatidylcholine, and can be obtained from a variety of sources such as eggs and soya beans. Soy lecithin and egg lecithin (including hydrogenated versions of these compounds) have a long history of safety, possess combined emulsification and solubilization properties, and tend to be broken down into innocuous substances more rapidly than most synthetic surfactants. Commercially available soya phospholipids are the CENTROPHASE and CENTROLEX products marketed and sold by Central Soya, PHOSPHOLIPON from Phospholipid GmbH, Germany, LIPOID by Lipoid GmbH, Germany, and EPIKURON by Degussa.
Phospholipids can also be synthesized. Exemplary common synthetic phospholipids include, but not limited to Diacylglycerols such as 1,2-Dilauroyl-sn-glycerol (DLG), 1,2-Dimyristoyl-sn-glycerol (DMG), 1,2-Dipalmitoyl-sn-glycerol (DPG), 1,2-Distearoyl-sn-glycerol (DSG); Phosphatidic Acids such as 1,2-Dimyristoyl-sn-glycero-3-phosphatidic acid, sodium salt (DMPA,Na), 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid, sodium salt (DPPA,Na), 1,2-Distearoyl-sn-glycero-3-phosphatidic acid, sodium salt-(DSPA,Na); Phosphocholines such as 1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC); Phosphoethanolamines such as 1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE), 1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE), 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE); Phosphoglycerols such as 1,2-Dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt (DLPG), 1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG), 1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonium salt (DMP-sn-1-G,NH₄), 1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt (DPPG,Na), 1,2-Distearoyl-sn-glycero-3-phosphoglycerol, sodium salt (DSPG,Na), 1,2-Distearoyl-sn-glycero-3-phospho-sn-1-glycerol, sodium salt (DSP-sn-1G,Na); Phosphoserines such as 1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt (DPPS,Na); Mixed Chain Phospholipids such as 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt (POPG,Na), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, ammonium salt
POPG,NH₄); Lysophospholipids such as 1-Palmitoyl-2-lyso-sn-glycero-3-phosphocholine (P-lyso-PC), 1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine (S-lyso-PC); Pegylated Phospholipids such as N-(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DPPE, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt, N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt, N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DPPE, 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt, N—(Carbonyl-methoxypolyethyleneglycol 750)-MPEG-750-DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt, N—(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt.
The amount of phospholipids, by weight may be within a range of about 0.5% to about 6%. In certain embodiments, the phospholipids in the emulsions are at a concentration, by weight, about 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or 6% by weight.
In certain embodiments, the ratio of the oil component to phospholipid in the emulsions may range from about 1:20 to about 20:1 (w/w).
The compositions of the present invention may optionally contain additives such as acidifying, alkalizing, buffering, chelating, complexing and solubilizing agents, antioxidants and antimicrobial preservatives, suspending and/or viscosity modifying agents, tonicity modifying agents, and other biocompatible materials or therapeutic agents. Such agents generally are present in the aqueous phase of the emulsion. In certain embodiments, such additives assist in stabilizing the emulsion or the drug in the emulsion and in rendering the composition biocompatible.
The aqueous phase generally has an osmolality of approximately 300 mOsm and may include potassium or sodium chloride, trehalose, sucrose, sorbitol, glycerol, mannitol, polyethylene glycol, propylene glycol, albumin, amino acid and mixtures thereof. In certain embodiments, a tonicity of at least 250 mOsm is achieved with an agent that also increases viscosity, such as sorbitol or sucrose. The compounds useful for modifying osmolality of the emulsions of the present invention are referred to “tonicity modifiers” or “osmolality modifiers.”
In certain embodiments, the concentration of the tonicity modifying agent is sufficient for providing tonicity of at least 250 mOsm and may be present in the range of about 1% to about 40% w/w, about 2% to about 30% w/w and about 5% to about 20% w/w.
“Antioxidants” used in this invention refers primarily to metal ion chelators and/or reducing agents that are safe to use in an injectable product. A metal ion chelator functions as an antioxidant by binding to metal ions and thereby reduces the catalytic effect of metal ion on the oxidation reaction of the drug, oil or phospholipid components. Metal chelators useful in this invention include, but are not limited to, EDTA, glycine and citric acid or salts thereof.
In another embodiment, the reducing agent useful in this invention include, but are not limited tosulfite, bisulfite, metabisulfite, butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHT) or a mixture thereof. A reducing agent inhibits oxidation reaction of the drug, oil or phospholipid components and prevents discoloration of the emulsions.
In certain embodiments, the concentration of antioxidant in the emulsion can be from about 0.0001% to about 1% w/v. In certain embodiments, the concentration is from about 0.001% to about 0.1% w/v, or from about 0.001% to about 0.005% w/v.
In certain embodiments, the concentration of EDTA in the emulsion can be from about 0.0001% to about 0.01% w/v.
In certain embodiments, the sulfite, bisulfite, or metabisulfiteis a sodium or potassium salt.
In certain embodiments, the concentration of sulfite, bisulfite, or metabisulfiteis from about 0.001% to about 0.2% w/v, or from about 0.01% to about 0.1% w/v.
In certain embodiments, the concentration of butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHT) is from about 0.0001% to about 0.002% w/v.
As used herein, the term “preservatives” refers to agents that can prevent microbial growth in the emulsion formulation of this invention. The oil-in-water emulsions of the present application may be conducive for microbial growth or contamination. Therefore, a preservative may be desirable in the composition, especially for a vialed product that is intended to provide multiple doses where multiple punctures of the vial stopper by syringe needles are needed. The preservatives useful for this invention include, but are not limited to, sodium edetate (EDTA), sodium metabisulfite, sodium benzoate, benzyl alcohol, bronopol, parabens, cresol, phenol, phenoxyethanol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, sorbate, benzoate, sorbic acid thimerosal, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, benzalkonium chloride and benzethonium chloride or a mixture thereof.
The aqueous phase of an oil-in-water emulsion of the present composition is usually at a concentration of at least about 70% by weight of the emulsion composition. In certain embodiments, the aqueous phase is at a concentration of at least about 75%, 80%, 85%, 90% or 95%, by weight of the emulsion composition.
In certain embodiments, the components of the oil-in-water emulsion (e.g., the drug, an oil component, a phospholipid component, a stabilizer, and a tonicity modifier) are safe, well tolerated, and acceptable by the FDA for intravenous/intramuscular injection.
A component of oil-in-water emulsions is regarded as “safe” if it does not cause undesired systemic or local reactions (e.g., anaphylactic shock) in patients. A component of oil-in-water emulsions is regarded as “well tolerated” if it does not result in substantially adverse effects at the injection site, such as phlebitis, vein inflammation or vein irritation.
In certain embodiments, the oil-in-water emulsions of the present composition are vein non-irritable. “Vein non-irritable” refers to the property of a compound or composition, when administered intravenously, does not cause substantial irritation at the injection site, as evident by, for example, thickened skin, necrotic skin, local redness, local swelling, venous dilation with blood clog formation, or venous embolism with subcutaneous inflammation.
In certain embodiments, the present compositions are both chemically and physically stable. A composition is “chemically stable” if thediclofenac or its pharmaceutically acceptable salt in the composition is not substantially chemically degraded after storage under appropriate conditions for at least 1 month. In certain embodiments, the concentration of the intact diclofenac or its pharmaceutically acceptable salt in the composition is reduced by less than about 1%, 3%, 5%, 8%, or 10% under appropriate storage conditions (e.g., at 2-8° C. or room temperature) for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.
An emulsion composition is “physically stable” if it may be stored under appropriate conditions for at least 1 month without increase in its average droplet size by more than 100%, or evidence of phase separation, creaming, or particle aggregation. In certain embodiments, the average size of particles of a composition of the present invention does not increase by more than about 10%, 20%, 25%, 30%, 40%, 50%, 75%, or 100% under appropriate storage conditions (e.g., 2-8° C. or room temperature) for at least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.
In still another aspect, the composition of the present application relates to emulsions that are ready-to-use for intravenous injection/infusion/intramuscular injection. The term “ready to use” means that the pharmaceutical compositions can be used as is or without a need for further dilution, mixing, or other alteration of its composition prior to use.
In certain embodiments, the present emulsions may be parenterally administered to a subject. “Parenteral” includes any mode of administration that does not go through the digestive tract, but excludes trans-membrane delivery such as skin patches.
In certain embodiments, the mode of administration of the present emulsions is by intravenous, intra-arterial, intrathecal, intraperitoneal, intraocular, intra-articular, intramuscular or subcutaneous injection.
Besides being ready-to-use oil-in-water emulsions, the compositions of the present application can also be prepared with a cryoprotectant(s) as-a lyophilized solid, i.e., “an oil-in-solid dispersion system” that can be reconstituted at a later date and diluted with water to reform the oil-in-water emulsion before injection.
As used herein, the term “an oil-in-solid dispersion system” refers to a solid matrix prepared by freeze-drying (lyophilizing) an oil-in-water emulsion, which can reform an oil-in-water emulsion of similar droplet size upon mixing with water (reconstitution). In certain embodiments, the average droplet size of the reformed emulsion is no more than about 500%, 400%, 300%, 200%, or 150% of the average droplet size of the emulsion before the freeze-drying. An oil-in-solid dispersion system of this invention may be optionally prepared by spray drying.
“Cryoprotectants” refers to those ingredients which are added to maintain the discrete and submicron droplets of the emulsion during the freeze-drying process and, upon the removal of water of the emulsion, to provide a solid matrix for the droplets to form the oil-in-solid dispersion system. Exemplary cryoprotectants include, but not limited to, polyols, monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, or mixtures thereof. Examples of polyols include glycerin, mannitol, erythritol, maltitol, xylitol, sorbitol, polyglycitol or mixtures thereof. Examples of monosaccharides include glucose, mannose, fructose, lactulose, allose, altrose, gulose, idose, galactose, talose, ribose, arabinose, xylose, lyxose or mixtures thereof. Examples of disaccharides include sucrose, lactose, maltose, isomaltose, trehalose, cellubiose or mixtures thereof. Examples of polysaccharides include cellulose, amylose, inulin, chitin, chitosan, amylopectin, glycogen, pectin, hyaruronic acid or mixtures thereof. Examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine or mixtures thereof. Examples of peptides include diglycine and triglycine. Examples of proteins include albumin, collagen, casein, and gelatin Examples of hydrophilic polymers include, but are not limited to, polyethylene glycols, povidones, poloxamers, polyvinyl alcohols or mixtures thereof.
In certain embodiments, the concentration of a cryoprotectant sufficient for stabilizing the oil droplets of an emulsion and may be present in the range of about 2% to about 40% w/w, about 5% to about 25% w/w and about 10% to about 20% w/w.
In one aspect the present application also provides methods for preparing parenteral composition in the form of oil-in-water emulsions for delivering diclofenac or its pharmaceutically acceptable salt as described herein.
Such emulsion may be prepared by the process comprising the steps of:

- (a) forming a mixture that comprises appropriate amounts of
  - (i) diclofenac or its pharmaceutically acceptable salt, (ii) an oil component (e.g., a vegetable oil, or a combination of a vegetable oil and a medium chain triglyceride), and
  - (iii) a phospholipid component, and
- (b) forming an oil-in-water emulsion with the mixture of step (a) and an aqueous solution.

In certain embodiments, step (b) may be performed by adding the aqueous solution to the mixture of step (a) to form a primary emulsion. The aqueous solution may be water or a buffer solution, and may contain antioxidant(s), preservative(s), cryoprotectant(s), additive(s) and/or tonicity modifier(s). The formation of the primary emulsion may be performed or facilitated by the use of mechanical homogenization (e.g., high shear mixing, high pressure extrusion, and microfluidization) or other suitable techniques.
The methods may further comprise one or more of the following steps: (A) adjusting the pH of the emulsion to a desirable range, (B) homogenizing with high shear the emulsion to provide an emulsion with an average droplet diameter less than about 200 nm, and (C) sterilizing the emulsion by filtration using a 0.2 μm filter.
In certain embodiments, the composition of present application may be sterilized by autoclave methods.
The composition of present application provides methods of treating spinal cord injuries, traumatic brain injuries, strokes, injuries to the peripheral nerves system, injuries to the central nerves systems or injuries to other systems having nerve tissue, preferably the injury has associated with it inflammation, where the methods include the step of administering a composition of this invention to an mammal including a human or directly to the site of injury or into the blood or other bodily fluid of the mammal including a human.
The composition of present application provides methods of treating field injuries such as combat injuries or accident injuries, where the methods include the steps of administering an amount of a composition of this invention directly to the injury or to the surrounding tissue to reduce inflammation while preventing ulceration of the injury or while maintaining the integrity of hydrophobic membranes and/or layers that may be associated with the injured site, where the amount of the composition administered is sufficient to cause a desired pharmacological effect.
The term “mammal” is defined as any class of warm-blooded higher vertebrates that includes humans.
In certain embodiments, the compositions of present application are used in pain management. The composition can be used in postoperative pain management, battle field pain management, accident pain management, or other pain management under emergency conditions without the significant side effects of alternative pain management medications such as opiates.
In another embodiment, the present application also provides an injection apparatus including a reservoir including a volume of a composition of this invention sufficient to cause a desired pharmacological effect, a plunger operably connected to the reservoir and a needle operably connected to an other end of the reservoir, where the volume is injected through the needle when the plunger is depressed.
The present application also provides a kit for emergency administration of a sterile injectable pain relieving diclofenac compositions, where the kit includes an injector apparatus including a manual or electrically powered syringe, a needleless injection system or other apparatus that can inject the composition into a body of a mammal including a human. The kit also includes containers including doses of at least one diclofenac composition sufficient to cause desired pharmacologic effects.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.

EXAMPLES

Examples 1-6


	Example 1	Example 2	Example 3	Example 4	Example 5	Example 6
Composition	(%)	(%)	(%)	(%)	(%)	(%)

Diclofenac sodium	3.75	3.75	3.75	3.75	3.75	3.75
Medium chain	0	2.5	5	0	0	0
triglycerides
(MIGLYOL 812)
Soybean oil, super	5	2.5	0	5	5	5
refined
Egg lecithin (LIPOID	10	10	10	15	0	0
E-80)
Soy lecithin (LIPOID	0	0	0	0	10	15
S-100)
EDTA disodium	0.0055	0.0055	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Purified water	q.s.	q.s.	q.s.	q.s.	q.s.	q.s.
pH	7.4	7.65	7.52	7.47	7.83	7.82

Procedure:

- i. All the components are weighed in a clean container and mixed well with a high shear mixer.
- ii. The mixture of step i. is subjected to microfluidzation homogenization.
- iii. The pH of the mixture step ii. is adjusted to the required pH.
- iv. The mixture of step iii. is passed through a 0.22μ filter.

Examples 7-10


	Example	Example	Example	Example
	7	8	9	10
Composition	(%)	(%)	(%)	(%)

Diclofenac sodium	3.75	3.75	3.75	3.75
Medium chain tri-	5	5	5	5
glycerides
(MIGLYOL 812)
Egg lecithin	10	10	10	10
(LIPOID E-80)
EDTA disodium	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Sucrose, USP/NF	15	15	15	15
Purified water	q.s.	q.s.	q.s.	q.s.
pH	7.5	8.5	8.0	7.0

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 11-15


	Example	Example	Example	Example	Example
	11	12	13	14	15
Composition	(%)	(%)	(%)	(%)	(%)

Diclofenac	3.75	3.75	3.75	3.75	3.75
sodium
Medium chain	5	5	5	5	5
triglycerides
(MIGLYOL
812)
Egg lecithin	10	10	10	10	10
(LIPOID E-80)
EDTA disodium	0.0055	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Sucrose,	10	5	10	5	6
USP/NF
Purified water	q.s.	q.s.	q.s.	q.s.	q.s.
pH	7.5	7.5	8.1	7.9	7.9

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 16-20


	Example	Example	Example	Example	Example
	16	17	18	19	20
Composition	(%)	(%)	(%)	(%)	(%)

Diclofenac	3.75	3.75	3.75	3.75	3.75
sodium
Medium chain	5	5	5	5	5
triglycerides
(MIGLYOL
812)
Egg lecithin	10	10	10	10	10
(LIPOID E-80)
EDTA disodium	0.0055	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Sucrose,	7	8	8	10	8
USP/NF
Purified water	q.s.	q.s.	q.s.	q.s.	q.s.
pH	7.9	7.9	7.9	7.9	8.0

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 21-25


	Example	Example	Example	Example	Example
	21	22	23	24	25
Composition	(%)	(%)	(%)	(%)	(%)

Diclofenac	3.75	3.75	3.75	3.75	3.75
sodium
Medium chain	5	5	4	3	2
triglycerides
(MIGLYOL
812)
Egg lecithin	10	10	10	10	10
(LIPOID E-80)
Sodium oleate	0	0.03	0	0	0
EDTA disodium	0.0055	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Sucrose,	5	8	8	8	8
USP/NF
Purified water	q.s.	q.s.	q.s.	q.s.	q.s.
pH	8.0	8.0	8.0	8.0	8.0

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 26-29


	Example	Example	Example	Example
	26	27	28	29
Composition	(%)	(%)	(%)	(%)

Diclofenac sodium	3.75	3.75	3.75	3.75
Medium chain triglycerides	1	7.5	2.5	1
(MIGLYOL 812)
Egg lecithin (LIPOID E-80)	10	7.5	12.5	14
Sodium oleate	0	0.03	0	0
EDTA disodium dehydrate	0.0055	0.0055	0.0055	0.0055
USP
Sucrose, USP/NF	8	8	8	8
Purified water	q.s.	q.s.	q.s.	q.s.
pH	8.0	8.0	8.0	8.0

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 30 to 35


	Example	Example	Example	Example	Example
	30	31	32	33	34
Composition	(%)	(%)	(%)	(%)	(%)

Diclofenac	3.61	3.75	3.75	3.61	3.61
sodium
Medium chain	5	5	5	5	5
triglycerides
(MIGLYOL
812)
Egg lecithin	10	10	10	10	10
(LIPOID E-80)
EDTA disodium	0.0055	0.0055	0.0055	0.0055	0.0055
dehydrate USP
Sodium	0	0.2	0	0	0
bisulfate
Ascorbic acid	0	0	0.2	0	0
L-cysteine	0	0	0	0.1	0
L-Methionine	0	0	0	0	0.3
Sucrose,	5	5	5	5	5
USP/NF
Purified water	q.s.	q.s.	q.s.	q.s.	q.s.
pH	8.0	8.0	8.0	8.0	8.0

Procedure:

The compositions are prepared as per the procedure mentioned earlier.

Examples 35-38


	Example	Example	Example	Example
	35	36	37	38
Composition	(%)	(%)	(%)	(%)

Diclofenac sodium	3.61	3.75	3.75	3.61
Medium chain	5	5	5	5
triglycerides
(MIGLYOL 812)
Egg lecithin	10	10	10	10
(LIPOID E-80)
EDTA disodium	0.0055	0.0055	0.0055	0.0055
dehydrate USP
DL, α-tocopherol	0.075	0	0	0
Butylatedhydroxy-	0	0.0003	0	0.0003
anisol (BHA)
Butylatedhydroxy-	0	0	0.002	0.002
toluene (BHT)
Sucrose, USP/NF	5	5	5	5
Purified water	q.s.	q.s.	q.s.	q.s.
pH	8.0	8.0	8.0	8.0

Although the invention has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Claims

What is claimed is:

1. A parenteral composition in the form of oil-in-water emulsion that comprises:

(a) diclofenac or its pharmaceutically acceptable salt,

(b) an oil component,

(c) a phospholipid component, and

(d) water.

2. The composition of claim 1, wherein the oil component comprises a monoglyceride, a diglyceride, a triglyceride, or a mixture thereof.

3. The composition of claim 2, wherein the triglyceride is medium chain triglycerides.

4. The composition of claim 1, wherein the oil component comprises combination of vegetable oil and a medium chain triglyceride.

5. The composition of claim 1, further comprises a cryoprotectant.

6. The composition of claim 1, wherein the phospholipid component comprises a phosphatidyl choline, lecithin, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, or a mixture thereof.

7. The composition of claim 6, wherein the lecithin comprises soy lecithin and egg lecithin.

8. The composition of claim 1, wherein the composition optionally comprise additives such as acidifying, alkalizing, antioxidant, buffering, chelating, complexing and solubilizing agents, antioxidants and antimicrobial preservatives, suspending and/or viscosity modifying agents, tonicity modifying agents, and other biocompatible materials or therapeutic agents.

9. The composition of any of the claims 1-8, wherein the composition has an osmolality of at least 250 mOsm.

10. The composition of any of the claims 1-9, comprises at least one tonicity modifying agent.

11. The composition of any of the claims 1-10, is vein non-irritable.

12. The composition of any of the claims 1-11, is filter sterilizable.

13. The composition of claim 5, wherein the cryoprotectant is sucrose.