Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

• 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.
• opioids which is a potent analgesic.
• 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.
• nonsteroidal, anti-inflammatory drugs NSAIDs
• 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.
• diclofenac 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.
• Diclofenac injectable compositions are:
• 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.
• 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- ⁇ -cyclodextrin in the molar ratio of 1:1 and 1:1.3.
• the composition further comprises polysorbate in lower concentration.
• 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.
• the present application provides parenteral compositions of diclofenac or its pharmaceutically acceptable salt and methods for making and using such compositions.
• 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.
• regulatory agencies e.g. the FDA
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• 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
• 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.
• “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.
• 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.
• diclofenac can be amorphous or crystalline.
• 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.
• 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.
• inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
• 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.
• 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
• 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.
• terapéuticaally effective amount 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.
• oil-in-water emulsion 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.
• 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.
• oil component refers to an oil, or a combination of multiple oils.
• 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.
• 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.
• vegetable oils of highly purified grade also called “super refined” are generally used to ensure safety and stability of oil-in-water emulsions.
• hydrogenated vegetable oils which are produced by controlled hydrogenation of the vegetable oil.
• the oil refers to “medium chain triglycerides”.
• Medium chain triglycerides 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.
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• the present application relates to a parenteral composition in the form of oil-in-water emulsion that comprises:
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• medium chain triglyceride is selected from Miglyol 812.
• a phospholipid is selected from egg lecithin (such as LIPOID E-80) or soy lecithin (such as LIPOID S-100).
• composition comprises an oil component and is vegetable oil.
• 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.
• vegetable oil is soybean oil.
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• the above composition comprises cryoprotectant.
• cryoprotectant is sucrose.
• the above composition comprises antioxidant.
• the antioxidant is sodium sulfite, sodium bisulfate, sodium metabisulfite, butylatedhydroxytoluene, butylatedhydroxyanisole or a mixture thereof.
• the present application provides a parenteral composition in the form of oil-in-water emulsion that comprises:
• the above composition comprises cryoprotectant.
• cryoprotectant is Sucrose.
• the present application relates to a parenteral composition in the form of oil-in-water emulsion that comprises:
• 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.
• 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.
• 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.
• 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.
• 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 ⁇ m to about 600 ⁇ m, with most bacteria having a size in the range of about 1 ⁇ m to about 10 ⁇ m.
• Filters having pore size of about 0.22 ⁇ m 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.
• 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.
• 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 (
• 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
• the amount of phospholipids, by weight may be within a range of about 0.5% to about 6%.
• 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.
• the ratio of the oil component to phospholipid in the emulsions may range from about 1:20 to about 20:1 (w/w).
• 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.
• 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.
• 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.
• such additives assist in stabilizing the emulsion or the drug in
• 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.
• 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.”
• 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.
• 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.
• 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.
• the concentration of EDTA in the emulsion can be from about 0.0001% to about 0.01% w/v.
• the sulfite, bisulfite, or metabisulfite is a sodium or potassium salt.
• the concentration of sulfite, bisulfite, or metabisulfite is from about 0.001% to about 0.2% w/v, or from about 0.01% to about 0.1% w/v.
• the concentration of butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHT) is from about 0.0001% to about 0.002% w/v.
• 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.
• EDTA sodium metabisulfite
• sodium benzoate benzyl alcohol, bronopol, parabens, cresol, phenol, phenoxyethanol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, sorbate, benzoate, sorbic acid thimerosal,
• 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.
• the components of the oil-in-water emulsion e.g., the drug, an oil component, a phospholipid component, a stabilizer, and a tonicity modifier
• the components of the oil-in-water emulsion 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.
• 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.
• 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.
• 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.
• 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.
• composition of the present application relates to emulsions that are ready-to-use for intravenous injection/infusion/intramuscular injection.
• 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.
• the present emulsions may be parenterally administered to a subject.
• Parenterally includes any mode of administration that does not go through the digestive tract, but excludes trans-membrane delivery such as skin patches.
• the mode of administration of the present emulsions is by intravenous, intra-arterial, intrathecal, intraperitoneal, intraocular, intra-articular, intramuscular or subcutaneous injection.
• 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.
• 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.
• 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).
• 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.
• cryoprotectants include, but not limited to, polyols, monosaccharides, disaccharides, polysaccharides, amino acids, peptides, proteins, and hydrophilic polymers, or mixtures thereof.
• 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.
• the concentration of a cryoprotectant sufficient for stabilizing the oil droplets of an emulsion 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.
• 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:
• 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 ⁇ m filter.
• composition of present application may be sterilized by autoclave methods.
• 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.
• 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.
• mamal is defined as any class of warm-blooded higher vertebrates that includes humans.
• 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.
• 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.
• Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Composition (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
• Example Example Example Example 7 8 9 10 Composition (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
• compositions are prepared as per the procedure mentioned earlier.
• compositions are prepared as per the procedure mentioned earlier.
• compositions are prepared as per the procedure mentioned earlier.
• compositions are prepared as per the procedure mentioned earlier.
• 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 USP Sucrose, USP/NF 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 Purified water q.s. q.s.
• compositions are prepared as per the procedure mentioned earlier.
• Example Example Example Example Example 30 31 32 33 34 Composition (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
• compositions are prepared as per the procedure mentioned earlier.
• Example Example Example Example 35 36 37 38 Composition (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)

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• 2014
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