water,

one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug and

optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,

by including an effective amount of at least one preservative and at least one co-solvent in the composition.

In a preferred embodiment, the method of preserving an injectable pharmaceutical composition provides an injectable pharmaceutical composition having a minimum broached vial antimicrobial effectiveness of 7 days, preferably 28 days or more.

The effective amount of at least one preservative and at least one co-solvent in the injectable pharmaceutical composition means the concentration of the at least one preservative and the concentration of the at least one co-solvent is sufficient for the injectable pharmaceutical composition to have a minimum broached vial antimicrobial effectiveness of 7 days, preferably 28 days or more.

In another embodiment, the method of preserving an injectable pharmaceutical composition provides an injectable pharmaceutical composition that complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

In another embodiment for the method of preserving a pharmaceutical composition, the injectable pharmaceutical composition comprises one hydrophobic drug.

In another embodiment for the method of preserving a pharmaceutical composition, the injectable pharmaceutical composition comprises more than one hydrophobic drug.

In yet another embodiment for the method of preserving a pharmaceutical composition, the injectable pharmaceutical composition comprises at least one hydrophobic drug and further comprises at least one hydrophilic drug.

In another aspect, the invention provides a use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition comprising:

- water,
- one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug and
- optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- by introducing at least one co-solvent and at least one preservative into the composition.

In a preferred embodiment, the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition provides an injectable pharmaceutical composition having a minimum broached vial antimicrobial effectiveness of 7 days, preferably a broached vial antimicrobial effectiveness of 28 days or more.

In another embodiment, the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition provides an injectable pharmaceutical composition that complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

In another embodiment, the invention provides a use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition as herein described wherein the injectable pharmaceutical composition comprises one hydrophobic drug.

In another aspect, the invention provides an injectable pharmaceutical composition of the invention for treating an animal. In one embodiment the treatment is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.

Herein the term “animal” comprises: warm blooded animals, including mammals (comprising but not limited to dogs, cats, cattle, pigs sheep and horses), reptiles, fish and amphibians.

In another aspect, the invention provides an injectable pharmaceutical composition of the invention for treating a human being. In one embodiment the treatment is for the purpose of anaesthetising the human being.

In another aspect, the invention provides a method of treating an animal, comprising administering to an animal an injectable pharmaceutical composition of the invention. In one embodiment the treatment is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.

In another aspect, the invention provides a method of treating a human being, comprising administering to a human being an injectable pharmaceutical composition of the invention. In one embodiment the treatment is for the purpose of anaesthetising the human being.

In another aspect, the invention provides a use of an injectable pharmaceutical composition of the invention, in the preparation of a medicament for treating an animal. In one embodiment the treatment is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.

The invention also provides a use of an injectable pharmaceutical composition of the invention, in the preparation of a medicament for treating a human being. In one embodiment the treatment is for the purpose of anaesthetising the human being.

DESCRIPTION OF DRAWINGS

FIG. 1—Discloses the concentration of alfaxalone in plasma (mg/L) versus time after IV administration of Alfaxan® or Formulation W (Table 1) to dogs (n=12 per time point).

FIG. 2—Discloses the concentration of alfaxalone in plasma (mg/L) versus time after IV administration of Alfaxan® or Formulation W (Table 1) to cats (n=12 per time point).

DETAILED DESCRIPTION OF THE INVENTION
Buffer

In a preferred embodiment the invention optionally comprises a buffer effective to stabilise the hydrophobic drug or drugs in the injectable pharmaceutical composition, and provides a pH in a range of from about 4.0 to about 9.0.

In another embodiment, the buffer, if present, can be chosen from the group comprising: phosphate based, acid-phosphate based and citrate based buffers.

In another embodiment the buffer, if present, is phosphate based.

In another embodiment the buffer, if present, is acid-phosphate based.

In yet another embodiment the buffer, if present, is citrate based.

In yet another embodiment the buffer, if present, is a combination of phosphate and citrate based buffers.

Preservatives

In the current invention at least one preservative is present in the injectable pharmaceutical composition.

A number of preservatives are available which can kill or prevent the growth of commonly encountered contaminants; these contaminants include, but are not limited to: the bacteria P. aeruginosa, E. coli and S. aureus; the yeast C. albicans; and the mould A. brasiliensis.

The presence of at least one preservative allows for the injectable pharmaceutical composition to be used over a period of at least 7 days, preferably 28 days or more once the container holding the composition is broached. The injectable pharmaceutical composition has a minimum broached vial antimicrobial effectiveness of 7 days and preferably a broached vial antimicrobial effectiveness of 28 days or more. 7 days is the minimum duration, after broaching, for the preservative/preservatives present to be effective and may allow for the pharmaceutical composition to be viable for use and/or treatment beyond this period. Preferably this time period is 28 days or more.

The incorporation of a preservative or preservatives within the pharmaceutical composition does not hinder the solubility of the hydrophobic drug or drugs and the final compositions are still able to pass a test method complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products when the compositions are comprised of at least one co-solvent and one or more water soluble complexes, each complex comprised of a cyclodextrin, or a cyclodextrin derivative, and a hydrophobic drug. Nor does the presence of an optional buffer, effective to stabilise the hydrophobic drug or drugs and provide a pH in the composition in a range of from about 4.0 to about 9.0, hinder the preservative from passing the necessary preservative tests applied to the composition.

In a preferred embodiment at least one preservative is present in the pharmaceutical composition and can be selected from a group comprising but not limited to: m-cresol, chlorocresol, parabens including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben, their derivatives and salts, chlorobutanol, quaternary ammonium compounds, their derivatives and salts including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof.

The preservative or preservatives are present in an amount which is effective to impart the desired preservative characteristics and allows the final composition to comply with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

In one embodiment the injectable pharmaceutical composition comprises m-cresol, wherein the m-cresol is present in an amount in a range of about 0.1 to about 1% w/v, preferably in a range of about 0.1 to about 0.5% w/v, most preferably in a range of about 0.1 to about 0.2% w/v.

In one embodiment the injectable pharmaceutical composition comprises chlorocresol, wherein the chlorocresol is present in an amount in a range of about 0.1 to about 1% w/v, preferably in a range of about 0.1 to about 0.5% w/v, most preferably in a range of about 0.1 to about 0.2% w/v.

In one embodiment the injectable pharmaceutical composition comprises methyl-, ethyl-, propyl- or butyl-paraben, wherein the methyl-, ethyl-, propyl- or butyl-paraben is present in an amount in a range of about 0.005 to about 1% w/v, preferably in a range of about 0.01 to about 0.5% w/v, most preferably in a range of about 0.01 to about 0.2% w/v.

In another embodiment the injectable pharmaceutical composition comprises chlorobutanol, wherein the chlorobutanol is present in an amount in a range of about 0.05 to about 1% w/v, preferably in a range of about 0.05 to about 0.5% w/v, most preferably in a range of about 0.1 to about 0.5% w/v.

In another embodiment the injectable pharmaceutical composition comprises benzethonium chloride, wherein the benzethonium chloride is present in an amount in a range of about 0.005 to about 1% w/v, preferably in a range of about 0.005 to about 0.1% w/v, most preferably in a range of about 0.005 to about 0.05% w/v.

In another embodiment the injectable pharmaceutical composition comprises benzalkonium chloride, wherein the benzalkonium chloride is present in an amount in a range of about 0.001 to about 1% w/v, preferably in a range of about 0.001 to about 0.5% w/v, most preferably in a range of about 0.001 to about 0.05% w/v.

In another embodiment the injectable pharmaceutical composition comprises boric acid, wherein the boric acid is present in an amount in a range of about 0.25 to about 5% w/v, preferably in a range of about 0.25 to about 2% w/v, most preferably in a range of about 0.25 to about 1% w/v.

In another embodiment the injectable pharmaceutical composition comprises benzyl alcohol, wherein the benzyl alcohol is present in an amount in a range of about 0.1 to about 5% w/v, preferably in a range of about 0.1 to about 2% w/v, most preferably in a range of about 0.1 to about 1% w/v.

In another embodiment the injectable pharmaceutical composition comprises cetylpyridinium chloride, wherein the cetylpyridinium chloride is present in an amount in a range of about 0.0001 to about 0.5% w/v, preferably in a range of about 0.0001 to about 0.01% w/v, most preferably in a range of about 0.0001 to about 0.001% w/v.

In another embodiment the injectable pharmaceutical composition comprises cetrimide, wherein the cetrimide is present in an amount in a range of about 0.001 to about 1.0% w/v, preferably in a range of about 0.001 to about 0.5% w/v, most preferably in a range of about 0.001 to about 0.01% w/v. In another embodiment the injectable pharmaceutical composition comprises phenol, wherein the phenol is present in an amount in a range of about 0.05 to about 1% w/v, preferably in a range of about 0.05 to about 0.5% w/v, most preferably in a range of about 0.05 to about 0.1% w/v.

In another embodiment the injectable pharmaceutical composition comprises phenylethanol, wherein the phenylethanol is present in an amount in a range of about 0.1 to about 2% w/v, preferably in a range of about 0.1 to about 1.5% w/v, most preferably in a range of about 0.1 to about 1.0% w/v.

In another embodiment the injectable pharmaceutical composition comprises phenoxyethanol, wherein the phenoxyethanol is present in an amount in a range of about 0.1 to about 2% w/v, preferably in a range of about 0.1 to about 1.5% w/v, most preferably in a range of about 0.1 to about 1.0% w/v.

In yet another embodiment injectable pharmaceutical composition is comprised of a mixture of any of the recited preservatives disclosed herein, wherein each preservative is present in an amount stated in the ranges as disclosed herein.

Solvent

In the present invention the solvent is water. In a preferred embodiment the water is pharmaceutically quality purified water. In another preferred embodiment the pharmaceutical composition contains sufficient water to produce a composition of the invention in the desired dosage.

Co-Solvents

The current invention incorporates at least one co-solvent into the injectable pharmaceutical composition.

In a preferred embodiment the co-solvent or co-solvents are miscible with water.

The invention provides at least one co-solvent to be present in the injectable pharmaceutical composition, which allows a hydrophobic drug to remain in the hydrophobic cavity of a cyclodextrin or cyclodextrin derivative in the presence of at least one preservative.

When more than one hydrophobic drug is present in the injectable pharmaceutical composition, the presence of at least one co-solvent means that each hydrophobic drug is able to remain in the hydrophobic cavity of a cyclodextrin or cyclodextrin derivative in the presence of at least one preservative.

In a preferred embodiment the co-solvent or co-solvents can be selected from the group comprising, but not limited to: ethanol, glycerin, propylene glycol, isopropyl alcohol, glycerol formal, tetraglycol, polyethylene glycol and mixtures thereof.

The co-solvent or co-solvents are present in the composition in a pharmaceutically acceptable amount that does not stop the preservative or preservatives which are also present from complying with a test method complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

In one embodiment the injectable pharmaceutical composition comprises ethanol, wherein the ethanol is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises glycerin, wherein the glycerin is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises propylene glycol, wherein the propylene glycol is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises isopropyl alcohol, wherein the isopropyl alcohol is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises glycerol formal, wherein the glycerol formal is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises tetraglycol, wherein the tetraglycol is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v.

In another embodiment the injectable pharmaceutical composition comprises polyethylene glycol, wherein the polyethylene glycol is present in an amount in a range of about 1 to about 30% w/v, preferably in a range of about 1 to about 25% w/v, most preferably in a range of about 1 to about 20% w/v In yet another embodiment injectable pharmaceutical composition is comprised of a mixture of any of the recited co-solvents disclosed herein, wherein each co-solvent is present in an amount stated in the ranges above.

Cyclodextrin and Cyclodextrin Derivatives

The present invention provides an injectable pharmaceutical composition comprising one or more water soluble complexes, each complex comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug.

The cyclodextrin or cyclodextrin derivative is chosen in order to enhance the solubility of a hydrophobic drug in water by the formation of a water soluble complex.

The hydrophobic drug and cyclodextrin or cyclodextrin derivative form a host guest complex wherein the hydrophobic drug is the guest and the cyclodextrin or cyclodextrin derivative is the host.

The invention allows for one, or more than one, hydrophobic drug to be present in the pharmaceutical composition. Each hydrophobic drug is able to form a water soluble complex with a cyclodextrin or cyclodextrin derivative present in the pharmaceutical composition.

In a preferred embodiment the cyclodextrin or cyclodextrin derivative can be chosen from a group that is comprised of, but is not limited to: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl substituted cyclodextrins, ethyl substituted cyclodextrins, hydroxyalkyl substituted cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrins, or a modified form thereof, and mixtures thereof.

The specific cyclodextrin or cyclodextrin derivative is chosen so as to form a water soluble complex with a hydrophobic drug that can be utilised in an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products. The composition further comprises water, at least one co-solvent, at least one preservative and optionally a buffer effective to stabilise the hydrophobic drug, or drugs, and provide a pH in the composition in a range of from about 4.0 to about 9.0.

The cyclodextrin or cyclodextrin derivative is chosen so as to form water soluble complexes with a hydrophobic drug, or drugs when more than one hydrophobic drug is present, wherein the complexes are stable in water and wherein, once the pharmaceutical composition is delivered via injection, the hydrophobic drug is displaced from the cyclodextrin or cyclodextrin derivative molecule to deliver the desired pharmacological and physiological response.

In a preferred embodiment the binding of a hydrophobic drug to the cavity of a cyclodextrin or cyclodextrin derivative in a water soluble complex is reversible allowing the hydrophobic drug to be displaced from the cyclodextrin or cyclodextrin derivative upon the injection of the composition which incorporates the water soluble complexes.

The amount of cyclodextrin or cyclodextrin derivative present in the invention is sufficient to solubilise the hydrophobic drug, or drugs if more than one hydrophobic drug is present, selected so as to form stable water soluble complexes.

In one embodiment the cyclodextrin derivative is preferably 2-hydroxypropyl-β-cyclodextrin.

In one embodiment the injectable pharmaceutical composition comprises a cyclodextrin or cyclodextrin derivative, wherein the cyclodextrin or cyclodextrin derivative is present in an amount in a range of about 1 to about 50% w/v, preferably in a range of about 1 to about 40% w/v, most preferably in a range of about 5 to about 25% w/v.

In yet another preferred embodiment the injectable pharmaceutical composition comprises 2-hydroxypropyl-β-cyclodextrin, wherein the 2-hydroxypropyl-β-cyclodextrin derivative is present in an amount in a range of about 1 to about 50% w/v, preferably in a range of about 1 to about 40% w/v, most preferably in a range of about 5 to about 25% w/v.

Hydrophobic Drugs

The invention provides for the solubilisation and preservation of a hydrophobic drug, or drugs, each contained within complexes, each complex comprising a cyclodextrin or a cyclodextrin derivative, for a period of at least 7 days, preferably 28 days or more, whereby the drug(s) remain(s) active and viable for the intended treatment in a patient for at least 7 days, preferably 28 days or more in the presence of at least one preservative and at least one co-solvent, once a vial has been broached.

The invention allows for one or more than one hydrophobic drug to be present in the pharmaceutical composition. Each hydrophobic drug is able to form a water soluble complex with a cyclodextrin or cyclodextrin derivative present in the pharmaceutical composition.

The invention may further comprise at least one hydrophilic drug. In a preferred embodiment, the hydrophobic drug, or drugs, is/are selected in that it/they can be delivered via injection.

The hydrophobic drug, or drugs, is/are combined with an appropriately selected cyclodextrin or cyclodextrin derivative to form a water soluble complex which is included in a pharmaceutical composition which further comprises: water, at least one preservative, at least one co-solvent and optionally a buffer effective to stabilise the hydrophobic drug and provide a pH in the composition in a range of from about 4.0 to about 9.0, wherein the composition can be delivered via injection and wherein the pharmaceutical composition complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.

The hydrophobic drug, or drugs, is/are preserved after broaching for at least 7 days, preferably 28 days or more in an injectable pharmaceutical composition and stored as a medicament in volumes appropriate for single or multiple doses.

The hydrophobic drug, or drugs, is/are combined with an appropriately selected cyclodextrin or cyclodextrin derivative to form a water soluble complex that once delivered via injection, the hydrophobic drug, or drugs is/are displaced from the central cavity of the cyclodextrin or cyclodextrin derivative and induce the required physiological and pharmacological response.

The hydrophobic drug, or drugs, is/are stable once it/they has/have been complexed with the appropriate cyclodextrin or cyclodextrin derivative to form water soluble complexes, in the presence of at least one co-solvent and at least one preservative wherein the co-solvent or co-solvents and preservative or preservatives are appropriately chosen, prior to being delivered by injection.

In one preferred embodiment the hydrophobic drug, or drugs, can be chosen from a group that is comprised of, but is not limited to:

- Steroids, their derivatives and salts including alfaxalone (alphaxalone), prednisolone, hydrocortisone, alphadolone (alfadolone), allopregnanolone, alphadolone (alfadolone) acetate, and pro-drugs thereof.
- Oxicam NSAIDs, their derivatives and salts including meloxicam, piroxicam, and pro-drugs thereof.
- Propionic acids, their derivatives and salts including carprofen, ibuprofen, naproxen, and pro-drugs thereof.
- Phenols, their derivatives and salts including propofol, and pro-drugs thereof.
- Benzimidazoles, their derivatives and salts including albendazole, triclabendazole, and pro-drugs thereof.
- Hexahydropyrazines, their derivatives and salts including praziquantel, and pro-drugs thereof.
- Beta-lactams, their derivatives and salts including ampicillin, penicillin, cefixime, and pro-drugs thereof.
- Sulfonamides, their derivatives and salts, and pro-drugs thereof.
- Pyridines and pyrimidines, their derivatives and salts, and pro-drugs thereof.
- Oxazolidones, their derivatives and salts, and pro-drugs thereof.
- Ansamycins, their derivatives and salts, and pro-drugs thereof.
- Glycopeptides, their derivatives and salts, and pro-drugs thereof.
- Benzodiazepines, their derivatives and salts including diazepam, and pro-drugs thereof.
- Hormones, their derivatives and salts including estradiol, and pro-drugs thereof.
- Amino-amides, their derivatives and salts including lidocaine, and pro-drugs thereof.
- Barbiturates, their derivatives and salts including thiopental, and pro-drugs thereof.
- Salicylates, their derivatives and salts including aspirin, and pro-drugs thereof.
- Salicylanilides, their derivatives and salts including closantel, and pro-drugs thereof.

The hydrophobic drug, or drugs, is/are present in an amount sufficient to induce the required therapeutic effect(s) in a patient when delivered via injection.

In one embodiment, the hydrophobic drug, or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating an animal from the group comprising: warm blooded animals, including birds and mammals, reptiles, fish and amphibians.

In another embodiment, the hydrophobic drug, or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating an animal from the group comprising: dogs, cats, cattle, pigs, sheep and horses.

In one embodiment, the hydrophobic drug, or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating a human being.

In one embodiment, the hydrophobic drug is an anaesthetic.

In another embodiment, the hydrophobic drug is an anaesthetic for animals including: warm blooded animals, including birds and mammals, reptiles, fish and amphibians.

In another embodiment, the hydrophobic drug is an anaesthetic for a human being.

In another embodiment, one hydrophobic drug is present in the injectable pharmaceutical composition, wherein the one hydrophobic drug is selected from alfaxalone, meloxicam, propofol, or carprofen.

In another embodiment, more than one hydrophobic drug is present in the injectable pharmaceutical composition, wherein at least one hydrophobic drug is selected from alfaxalone, meloxicam, propofol, or carprofen.

In yet another embodiment, the hydrophobic drug is alfaxalone, wherein the alfaxalone is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.

In a further embodiment, the hydrophobic drug is propofol, wherein the propofol is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.

In another embodiment, the hydrophobic drug is meloxicam, wherein the meloxicam is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.

In yet another embodiment, the hydrophobic drug is carprofen, wherein the carprofen is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.

In yet another embodiment, a composition of the invention can further comprise a compound which enhances the solubility of a hydrophobic drug or drugs as herein described. Examples of compounds which enhance the solubility of meloxicam in a composition of the invention can be selected from the group comprising, but not limited to N-vinylpyrrolidone polymers.

In another embodiment the N-vinylpyrrolidone polymers have a molecular formula of (C₆H₉NO)_n, where n is in a range from about 20 to about 27000 providing polymers with molecular weights from about 2220 g mol⁻¹to about 3108000 g mol⁻¹.

In a further embodiment, the N-vinylpyrrolidone polymers, if present in a composition of the invention, are included in a concentration from about 1% w/v to about 20% w/v, preferably from about 1% w/v to about 10% w/v, most preferably from about 1% w/v to about 5% w/v.

In yet another embodiment a compound which enhances the solubility of a hydrophobic drug or drugs as herein described in a composition of the invention can also modify the viscosity of said composition.

Hydrophilic Drugs

The invention provides for the injectable pharmaceutical composition to optionally further comprise at least one hydrophilic drug. In one embodiment the hydrophilic drug can be chosen from the group comprised of but not limited to: opioids, including but not limited to tramadol and its M1 metabolite, buprenorphine, opioid like substances and α₂-adrenergic agonists including, but not limited to, medetomidine.

In one embodiment the injectable pharmaceutical composition comprises tramadol and its M1 metabolite, wherein the tramadol and its M1 metabolite is present in an amount in a range of about 1 to about 200 mg/mL, preferably in a range of about 10 to about 100 mg/mL, most preferably in a range of about 25 to about 75 mg/mL.

In one embodiment the injectable pharmaceutical composition comprises buprenorphine, wherein the buprenorphine is present in an amount in a range of about 0.01 to about 5 mg/mL, preferably in a range of about 0.1 to about 1 mg/mL, most preferably in a range of about 0.1 to about 0.5 mg/mL.

In one embodiment the injectable pharmaceutical composition comprises medetomidine, wherein the medetomidine is present in an amount in a range of about 0.01 to about 10 mg/mL, preferably in a range of about 0.05 to about 5 mg/mL, most preferably in a range of about 0.1 to about 2 mg/mL.

In one embodiment, the injectable pharmaceutical composition comprises one or more hydrophobic drug(s), as described herein, and further comprises at least one hydrophilic drug, wherein each of the one or more hydrophobic drug(s) forms a water soluble complex with an appropriately chosen cyclodextrin or cyclodextrin derivative. The at least one hydrophilic drug, as described herein, is present in an amount sufficient to induce the required pharmacological and physiological response.

In another embodiment, the injectable pharmaceutical composition comprises one or more hydrophobic drug(s), wherein at least one hydrophobic drug is selected from alfaxalone, meloxicam, propofol, or carprofen, and further comprises at least one hydrophilic drug, as described herein, wherein each of the one or more hydrophobic drug(s) forms a water soluble complex with an appropriately chosen cyclodextrin or cyclodextrin derivative. The at least one hydrophilic drug is present in an amount sufficient to induce the required pharmacological and physiological response.

In yet another embodiment, the injectable pharmaceutical composition allows for combination analgesic injections comprising oxicam NSAIDs and opioids and/or opioid like substances as described herein. In one embodiment, the hydrophilic drug or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating an animal from the group comprising: warm blooded animals, including birds and mammals, reptiles, fish and amphibians

In another embodiment, the hydrophilic drug, or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating an animal from the group comprising: dogs, cats, cattle, pigs, sheep and horses.

In yet another embodiment, the hydrophilic drug or drugs, is/are appropriately chosen by a person skilled in the art, to be effective when treating a human being.

Isotonic Agent

The injectable pharmaceutical compositions of the invention as disclosed herein can further comprise an isotonic agent. Examples of isotonic agents include, but are not limited to sodium chloride and dextrose.

In one embodiment the isotonic agent is sodium chloride or dextrose wherein the sodium chloride or dextrose is present in a composition of the invention in an amount which renders the composition isotonic with the blood of a subject being treated.

In another embodiment the isotonic agent is sodium chloride, wherein the sodium chloride is present in an amount of about 0.9% w/v.

In another embodiment the isotonic agent is dextrose, wherein the dextrose is present in an amount of about 5% w/v.

Stability

The stability of the injectable compositions is very important. In general terms the compositions described herein will be physically and chemically stable for at least 3 months when stored below 30° C., preferably at least 6 months when stored below 30° C., more preferably at least 1 year when stored below 30° C., most preferably at least 3 years when stored below 30° C.

Examples Embodiments

- A. An injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0.
- B. The injectable pharmaceutical composition according to example embodiment A, wherein at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen.
- C. The injectable pharmaceutical composition according to example embodiment B, wherein:
  - alfaxalone is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - propofol is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - meloxicam is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - carprofen is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.
- D. The injectable pharmaceutical composition according to any one of example embodiments A to C, wherein the cyclodextrin or cyclodextrin derivative is selected from a group comprising: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl substituted cyclodextrins, ethyl substituted cyclodextrins, hydroxyalkyl substituted cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrins or a modified form thereof, and mixtures thereof.
- E. The injectable pharmaceutical composition according to any one of example embodiments A to D, wherein the cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl-β-cyclodextrin.
- F. The injectable pharmaceutical composition according to any one of example embodiments A to E, wherein at least one preservative is selected from a group comprising: m-cresol, chlorocresol, parabens (including, but not limited to: methylparaben, ethylparaben, propylparaben or butylparaben), their derivatives and salts, chlorobutanol, benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof.
- G. The injectable pharmaceutical composition according to any one of example embodiments A to F, wherein at least one co-solvent is selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, glycerol formal, tetraglycol and mixtures thereof.
- H. The injectable pharmaceutical composition according to any one of example embodiments A to G, wherein the buffer effective to stabilise the hydrophobic drug and provide a pH in the composition in a range of from about 4.0 to about 9.0 is selected from a group of buffers comprising: phosphate based, acid-phosphate based and citrate based buffers.
- I. The injectable pharmaceutical composition according to any one of example embodiments A to H, wherein the composition further comprises at least one hydrophilic drug.
- J. A method to produce an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products, wherein the method comprises:
  - preparing a first composition by:
    - a) dissolving a cyclodextrin or cyclodextrin derivative or a mixture thereof in water;
    - b) adding one or more hydrophobic drugs to the solution;
    - c) optionally introducing additional water to fully dissolve the cyclodextrin or cyclodextrin derivative and the one or more hydrophobic drugs;
    - d) optionally adding buffer salts;
    - e) optionally adjusting the pH;
  - preparing a second composition by: dissolving at least one preservative in one or more co-solvent(s);
  - and forming the injectable pharmaceutical composition by:
    - a) combining the first and second compositions;
    - b) optionally adding additional water to raise the combined composition to a required volume; and
    - c) sterilizing the combined composition.
- K. The method according to example embodiment J, wherein the cyclodextrin or cyclodextrin derivative is selected from a group comprising: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl substituted cyclodextrins, ethyl substituted cyclodextrins, hydroxyalkyl substituted cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrins or a modified form thereof, and mixtures thereof.
- L. The method according to example embodiment J or K, wherein at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen.
- M. The method according to any one of example embodiments J to L, wherein:
  - alfaxalone is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - propofol is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - meloxicam is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - carprofen is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.
- N. The method according to any one of example embodiments J to M, wherein at least one preservative is selected from a group comprising: m-cresol, chlorocresol, parabens including but not limited to methylparaben, ethylparaben, propylparaben, butylparaben, their derivatives and salts, chlorobutanol, quaternary ammonium compounds, their derivatives and salts including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and mixtures thereof.
- O. The method according to any one of example embodiments J to N, wherein the one or more co-solvent(s) are selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, glycerol formal, tetraglycol and mixtures thereof.
- P. The method according to any one of example embodiments J to O, wherein the buffer is effective to stabilise the hydrophobic drug and provide a pH in the first composition in a range of from about 4.0 to about 9.0 and is selected from a group of buffers comprising: phosphate based, acid-phosphate based and citrate based buffers.
- Q. The method according to any one of example embodiments J to P, wherein the injectable pharmaceutical composition is sterilised by autoclaving.
- R. The method according to any one of example embodiments J to Q, wherein the pharmaceutical composition further comprises at least one hydrophilic drug, wherein the at least one hydrophilic drug is added in the making of the first, second or the forming of the injectable pharmaceutical composition.
- S. A method of preserving an injectable pharmaceutical composition comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0
    
    by including an effective amount of at least one preservative and at least one co-solvent in the composition.
- T. The method according to example embodiment S, wherein the cyclodextrin or cyclodextrin derivative is selected from a group comprising: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl substituted cyclodextrins, ethyl substituted cyclodextrins, hydroxyalkyl substituted cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrin or a modified form thereof, and mixtures thereof.
- U. The method according to example embodiment S or T, wherein at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen.
- V. The method according to any one of example embodiments S to U, wherein:
  - alfaxalone is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - propofol is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - meloxicam is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - carprofen is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.
- W. The method according to any one of example embodiments S to V, wherein at least one preservative is selected from a group comprising: m-cresol, chlorocresol, parabens (including but not limited to methylparaben, ethylparaben, propylparaben or butylparaben), their derivatives and salts, chlorobutanol, quaternary ammonium compounds, their derivatives and salts including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and mixtures thereof.
- X. The method according to any one of example embodiments S to W, wherein at least one co-solvent is selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, glycerol formal, tetraglycol and mixtures thereof.
- Y. The method according to any one of example embodiments S to X, wherein the buffer is effective to stabilise the hydrophobic drug and provide a pH in the first composition in a range of from about 4.0 to about 9.0 and is selected from a group of buffers comprising: phosphate based, acid-phosphate based and citrate based buffers.
- Z. The method according to any one of example embodiments S to Y, wherein the injectable pharmaceutical composition complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.
- AA. The method according to any one of example embodiments S to Z, wherein the pharmaceutical composition further comprises at least one hydrophilic drug.
- AB. Use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- by introducing at least one co-solvent and at least one preservative into the composition.
- AC. The use according to example embodiment AB, wherein the cyclodextrin or cyclodextrin derivative is selected from a group comprising: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl substituted cyclodextrins, ethyl substituted cyclodextrins, hydroxyalkyl substituted cyclodextrins, including 2-hydroxypropyl-β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrins or a modified form thereof, and mixtures thereof.
- AD. The use according to example embodiment AB or AC, wherein at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen.
- AE. The use according to any one of example embodiments AB to AD, wherein:
  - alfaxalone is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - propofol is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - meloxicam is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL; and/or
  - carprofen is present in an amount in a range of from about 1 to about 100 mg/mL, more preferably about 1 to about 75 mg/mL, most preferably about 1 to about 50 mg/mL.
- AF. The use according to any one of example embodiments AB to AE, wherein at least one preservative is selected from a group comprising: m-cresol, chlorocresol, parabens (including but not limited to methylparaben, ethylparaben, propylparaben or butylparaben), their derivatives and salts, chlorobutanol, quaternary ammonium compounds, their derivatives and salts including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and mixtures thereof.
- AG. The use according to any one of example embodiments AB to AF, wherein at least one co-solvent is selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, glycerol formal, tetraglycol and mixtures thereof.
- AH. The use according to any one of example embodiments AB to AG, wherein the buffer is effective to stabilise the hydrophobic drug and provide a pH in the first composition in a range of from about 4.0 to about 9.0 and is selected from a group of buffers comprising: phosphate based, acid-phosphate based and citrate based buffers.
- AI. The use according to any one of example embodiments AB to AH, wherein the injectable pharmaceutical composition complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products.
- AJ. The use according to any one of example embodiments AB to AI, wherein the pharmaceutical composition further comprises at least one hydrophilic drug.
- AK. An injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- for treating an animal.
- AL. The composition according to example embodiment AK, wherein the treating an animal is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.
- AM. An injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- for treating a human being.
- AN. The composition according to example embodiment AM, wherein the treating a human being is for the purpose of anaesthetising the human being.
- AO. A method of treating an animal, comprising administering to an animal an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products, the composition comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0.
- AP. The method according to example embodiment AO, wherein the method of treating an animal is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.
- AQ. A method of treating a human being, comprising the administering to a human being an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products, the composition comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0.
- AR. The method according to example embodiment AQ, wherein the method of treating a human being is for the purpose of anaesthetising the human being.
- AS. Use of an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products comprising:
  - water,
  - one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
  - at least one preservative,
  - at least one co-solvent and
  - optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- in the preparation of a medicament for treating an animal.
- AT. The use according to example embodiment AS, wherein the treating an animal is for at least one of the purposes of: anaesthetising the animal, alleviating pain, or alleviating inflammation.
- AU. Use of an injectable pharmaceutical composition complying with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least the B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing for Category 1 (injectable) products comprising:
- water,
- one or more water soluble complexes, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug,
- at least one preservative,
- at least one co-solvent and
- optionally a buffer effective to provide a pH in the composition in a range of from about 4.0 to about 9.0,
- in the preparation of a medicament for treating a human being.
- AV. The use according to example embodiment AU, wherein the treating a human being is for the purpose of anaesthetising the human being.

EXAMPLES

In order to better understand the nature of this invention, a number of illustrative examples will now be described.

The scope of the invention is not limited to the examples provided below. The examples merely demonstrate the effectiveness of the invention.

Example 1: Compositions of the Invention Comprising Alfaxalone
Synthesis of Pharmaceutical Compositions Comprising Alfaxalone

Six different formulations: S, V, W, X, Y and Z, are shown in Table 1. All six formulations comprise alfaxalone but are composed of various solvents and preservatives in different amounts.

TABLE 1

Six examples of formulations, exemplifying the invention,

which comprise alfaxalone as the hydrophobic drug.

Formulation

Component
S
V
W
X
Y
Z

Alfaxalone
10
g
10
g
10
g
10
g
10
g
10
g

2-
80
g
80
g
80
g
80
g
80
g
80
g

Hydroxypropyl-

β-cyclodextrin

Sodium
8
g
8
g
8
g
8
g
8
g
8
g

chloride (NaCl)

Disodium
940
mg
940
mg
940
mg
940
mg
940
mg
940
mg

phosphate,

anhydrous

(Na₂HPO₄)

Potassium
450
mg
450
mg
450
mg
450
mg
450
mg
450
mg

dihydrogen

phosphate

(KH₂PO₄)

Glycerin
—
—
—
—
—
100
g

Ethanol
150
g
150
g
150
g
100
g
100
g
100
g

(undenatured)

Chlorocresol
1.2
g
1
g
1.5
g
1
g
1
g
1
g

Benzethonium
—
200
mg
200
mg
—
200
mg
200
mg

chloride

Water for
q.s. 1 L
q.s. 1 L
q.s. 1 L
q.s. 1 L
q.s. 1 L
q.s. 1 L

injection (WFI)

The formulations of Table 1 were prepared according to the following standard procedure which is based on Formulation X:

- 1. 200 mL of WFI to was heated to 45° C.-50° C. Whilst mixing, 2-hydroxypropyl-β-cyclodextrin was slowly added. The solution was mixed until all the solid had completely dissolved.
- 2. Alfaxalone was added to the solution from Step 1. The solution was mixed until it turned clear.
- 3. The solution was made up to 400 mL using WFI.
- 4. Whilst stirring, NaCl, Na₂HPO₄and KH₂PO₄were added. The solution was mixed until all the salts had completely dissolved.
- 5. The pH of the solution was checked and adjusted to specification (6.0-7.5) using 10% HCl and 10% NaOH as required.
- 6. The ethanol was transferred to a separate container. Whilst stirring, chlorocresol was slowly added. It was mixed until all the solid had completely dissolved.
- 7. The solution from Step 6 was transferred to the bulk solution.
- 8. The solution was made up to volume (1 L) using WFI and mixed well.

When benzethonium chloride was incorporated into a formulation, it is added at Step 4 along with the buffering salts.

When glycerin was included in a formulation, it is added after the pH adjustment (Step 5) and prior to the addition of the chlorocresol in ethanol.

Stability Tests for Formulations X, Y and Z

Autoclaving the formulations for 20 minutes at 121° C. showed no significant decrease in alfaxalone concentration and the increase in degradation products was comparable to that in WO 01/70234 without preservative after autoclaving.

Storage of the formations at −20° C. and 0° C. for 3 months showed no detrimental effect on the active or preservative content. There was no apparent precipitation in the formulations.

Storage of the formulations for 12 months at 25° C./60% relative humidity (RH), 30° C./65% RH and 40° C./75% RH had no detrimental effect on the active or preservative content.

The inventors found that the addition of chlorocresol in the absence of a co-solvent caused the precipitation of the alfaxalone from a solution of water soluble complexes of alfaxalone and 2-hydroxypropyl-β-cyclodextrin. Similar effects were seen with benzyl alcohol, parabens, phenol and phenylethanol. Titrations performed with benzyl alcohol showed significant precipitation occurring with a benzyl alcohol content of 0.2% w/v upwards to 1% w/v (typical content).

Preservation Studies for Formulations X, Y, Z, V and S

The formulations X, Y and Z were examined against three microbes: Pseudomonas aeruginosa (P. aeruginosa) (bacteria, gram negative), Escherichia coli (E. coli) (bacteria, gram negative) and Candida albicans (C. albicans) (yeast). Formulations S and V were examined against five microbes: Pseudomonas aeruginosa (P. aeruginosa) (bacteria, Gram negative), Escherichia coli (E. coli) (bacteria, Gram negative) Staphylococcus aureus (S. aureus) (bacteria, Gram positive), Candida albicans (C. albicans) (yeast) and Aspergillus brasiliensis (A. brasiliensis) (mould). The European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, A and B criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing criteria for Category 1 (injectable) products are shown in Table 2. The antimicrobial tests for formulations X, Y and Z in light of these criteria are shown in Table 3. The antimicrobial tests for formulations S and V in light of these criteria are shown in Table 4.

TABLE 2

The standards required for the injectable compositions in order to

comply with the European Pharmacopoeia 2011 Test for Efficacy of

Antimicrobial Preservation, A and B criteria for parenterals, and

the United States Pharmacopeia 2011 Guidelines for Antimicrobial

Effectiveness Testing criteria for Category 1 (injectable) products.

Log Reduction^a)

Guidelines
6 hours
24 hours
7 days
14 days
28 days

Bacteria

A Criteria
2
3

NR^b)

B Criteria

1
3

NI^c)

USP^d)

1
3
NI^c)

Fungi^f)/Yeast

& Mold^f)

A Criteria

2

NI^c)

B Criteria

1
NI^c)

USP^e)

NI^d)
NI^d)
NI^d)

in the number of viable micro-organisms compared to the initial reading;

^a)Numerical values relate to the minimum log reduction required in relation to the initial readings/count;

^b)NR = no recovery;

^c)NI = no increase in number of viable micro-organisms compared to the previous reading;

^d)NI = no increase

^e)category 1 criteria, applicable for injections;

^f)the term “Fungi” is used in the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation; the phrase “Yeast & Mold” is applied to the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing.

TABLE 3

Assessing the antimicrobial effects for Formulations X, Y and

Z on P. aeruginosa, E. coli and C. albicans. Where

the test complies with the A criteria for parenterals according

to the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial

Preservation and the Category 1 (injectable) criteria according

to the United States Pharmacopeia 2011 Guidelines for Antimicrobial

Effectiveness Testing, “(Pass)” is shown.

Acceptance Criteria

Results

[Log] Reduction

From Inoculation

Formu-

Co-
Challenge
24
7

lation
Preservative(s)
solvent(s)
Microbe
hours
days

X
0.1%
10%
P.
6.0
N/A

Chlorocresol
Ethanol
aeruginosa
(Pass)

E. coli
6.1
N/A

(Pass)

C. albicans
N/A
4.2

(Pass)

Y
0.1%
10%
P.
6.0
N/A

Chlorocresol +
Ethanol
aeruginosa
(Pass)

0.02%

E. coli
6.1
N/A

Benzethonium

(Pass)

chloride

C. albicans
N/A
5.2

(Pass)

Z
0.1%
10%
P.
6.0
N/A

Chlorocresol +
Glycerin +
aeruginosa
(Pass)

0.02%
10%

Benzethonium
Ethanol

chloride

The results from Table 3 show that the formulations X, Y and Z comply with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, A criteria for parenterals, and the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing criteria for Category 1 (injectable) products and incidentally, the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation B criteria for parenteral products. Compliance for Formulations X, Y and Z was only assessed for 3 of 5 microbes at 24 hour (P. aeruginosa and E.coli) and 7 days (C. albicans) unlike Formulation S and V which were assessed using all the necessary microbes from 6 hour post inoculation to 28 days for a 28 day shelf-life after initial broaching of the product.

TABLE 4

Assessing the antimicrobial effects for Formulations S and V on P. aeruginosa,

E. coli S. aureus, C. albicans and A. brasiliensis. Where the test

complies with the A criteria for parenterals according to the European Pharmacopoeia

2011 Test for Efficacy of Antimicrobial Preservation and the Category 1 (injectable)

criteria according to the United States Pharmacopeia 2011 Guidelines for Antimicrobial

Effectiveness Testing, “(Pass (P))” is shown.

Acceptance Criteria Results

Co-
Challenge
[Log] Reduction From Inoculation

Form.
Preserv
solvent
Microbe
6 hr
24 hr
7 d
14 d
28 d

S
0.12%
15%
P. aeruginosa
5.3
5.3
N/A
N/A
5.3

Chlorocresol
Ethanol

(P)
(P)

(*P)

E. coli
5.2
5.2
N/A
N/A
5.2

(P)
(P)

(*P)

S. aureus
3.2
5.8
5.8
N/A
5.8

(P)
(P)
(P)

(*P)

C. albicans
N/A
N/A
5.8
5.8
5.8

(P)
(P)
(^†P)

A. brasiliensis
N/A
N/A
3.4
5.1
5.1

(P)
(P)
(^†P)

V
0.1%
15%
P. aeruginosa
5.9
5.9
N/A
N/A
5.9

Chlorocresol +
Ethanol

(P)
(P)

(*P)

0.02%

E. coli
5.8
5.8
N/A
N/A
5.8

Benzethonium

(P)
(P)

(*P)

chloride

S. aureus
3.0
6.0
6.0
N/A
6.0

(P)
(P)
(P)

(*P)

C. albicans
N/A
N/A
5.8
5.8
5.8

(P)
(P)
(^†P)

A. brasiliensis
N/A
N/A
3.9
4.7
4.7

(P)
(P)
(^†P)

*No recovery (NR) of microorganisms at 28 days post-inoculation (EP-A).

^†No increase (NI) in microbial concentration from 7 to 28 days post-inoculation (EP-A).

The results from Table 4 Preservative efficacy testing of Formulations S and V show that both formulations meet the requirements of the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation A criteria for a parenteral or ophthalmic product against the microorganisms: Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis at 6 and 24 hours, and 7, 14 and 28 days post-inoculation. Hence, Formulations S and V also satisfy the United States Pharmacopeia 2011 Guidelines for Antimicrobial Effectiveness Testing criteria for Category 1 (injectable) products and the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation B criteria for parenterals.

Example 2: Compositions of the Invention Comprising Meloxicam
Synthesis of Pharmaceutical Compositions Comprising Meloxicam

TABLE 5

An exemplified composition of the invention

comprising meloxicam, Formulation U.

Component
Amount (g/L)

Meloxicam
5.0

2-Hydroxypropyl-β-cyclodextrin
21.0

Plasdone ® K25
5.0

Ethanol
150.0

Chlorocresol
1.0

Sodium Chloride
9.0

Water For Injection (WFI)
q.s. 1 L

Formulation U was prepared according to the following procedure:

- 1. 600 mL of WFI to was transferred to a beaker. Whilst stirring, sodium chloride was added and the solution mixed until all solid was completely dissolved.
- 2. Whilst mixing, 2-hydroxypropyl-β-cyclodextrin and Plasdone® K25 (obtainable from International Specialty Products Inc. (ISP)) was slowly added. The solution was mixed until all the solid had completely dissolved.
- 3. Meloxicam was added to the solution from Step 1. The solution was mixed until all solid was completely suspended.
- 4. The pH of the solution was adjusted to 12.0-12.5 using sodium hydroxide solutions as required. The solution was stirred until clear.
- 5. The pH of the clear solution was adjusted to 8-9 using hydrochloric acid solution.
- 6. The ethanol was transferred to a separate container. Whilst stirring, chlorocresol was slowly added. It was mixed until all the solid had completely dissolved.
- 7. The solution from Step 6 was transferred to the bulk solution.
- 8. The solution was made up to volume (1 L) using WFI and mixed well.

Stability Tests

Formulation U shows no significant change to active or preservative content when stored for 6 months at 30° C./65% RH.

Preservation Studies

Preservative efficacy testing of Formulation U showed it to meet the requirements for USP 2011 for efficacy of Anti-Microbial Preservation for a parenteral or ophthalmic product against the microorganisms Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis 7, 14 and 28 days post-inoculation

TABLE 6

Preservative Efficacy Test - United State Pharmacopeia

2011 Parenteral & Ophthalmic - Formulation U.^a)

P.

C.

aeruginosa
E. coli
albicans
A. niger

S. aureus
AMS
AMS
AMS
AMS

AMS
095
006
003
032

Time
027
(ATCC
(ATCC
(ATCC
(ATCC

point
(ATCC6538)
9027)
8739)
0231)
16404)

Inoculum
9.1 ×
4.0 ×
7.4 ×
8.9 ×
1.6 ×

cfu/ml
10⁵
10⁵
10⁵
10⁵
10⁵

0 days
8.5 ×
2.8 ×
6.4 ×
6.7 ×
1.7 ×

10⁵
10⁵
10⁵
10⁵
10⁵

7 days
<10
<10
<10
<10
<10

14 days
<10
<10
<10
<10
<10

28 days
<10
<10
<10
<10
<10

^a)All results are expressed as cfu (colony forming unit) per ml.

Example 3: Compositions of the Invention Comprising Carprofen
Synthesis of Pharmaceutical Compositions Comprising Carprofen

Table 7 lists the components required to make 1 L of Formulation T.

TABLE 7

An exemplified composition of the invention

comprising carprofen, Formulation T.

Component
Formulation T

Carprofen
50
g

2-Hydroxypropyl-β-cyclodextrin
200
g

Sodium hydroxide (NaOH)
12
g

Hydrochloric acid (10M)
11
g

Ethanol (undenatured)
100
g

Chlorocresol
1
g

Water for injection (WFI)
q.s. 1 L