FORM 2 i
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention:
"ISAVUCONAZOLE ORAL COMPOSITIONS"
Applicant:
Macleods Pharmaceuticals Ltd., an Indian Company, having its
Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol
Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
Preamble
The following specification particularly describes the invention and the
manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition for oral administration comprising Isavuconazole with combination of surfactants and co-surfactants and other pharmaceutically acceptable excipients that provides rapid dissolution and enhanced absorption of the Isavuconazole.
BACKGROUND OF THE INVENTION
Fungi are ubiquitous in nature and are usually considered to cause opportunistic infections. Hence fungal infections are quite common in humans. While most fungal infections affect areas such as the skin and nails, few others can lead to more serious and potentially life-threatening conditions. Since the COVID-19 pandemic, fungal infections are on the rise in patients with severe COVID-19 infection as they have a compromised immune system and are prescribed high-dose corticosteroids and immunomodulatory drugs which make them particularly vulnerable to bacterial and fungal infections. The most common fungal infections in patients with COVID-19 include aspergillosis, mucormycosis or invasive candidiasis. These infections may lead to severe illness and death. The treatment for these sorts of fungal infections frequently involves use of antifungals, including amphotericin B, posaconazole, voriconazole or isavuconazole. Isavuconazole, as disclosed in U.S. Patent No. 6,300,353, is chemically 4-[2-[(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-4-(l,2,4-triazol-l-yl)butan-2-yl]-l,3-thiazol-4-yl]benzonitrile. It is a broad-spectrum antifungal drug from the class of triazole antifungal agents with activity against yeasts, moulds, and dimorphic fungi. It acts by inhibiting the synthesis of ergosterol, a key component of the fungal cell membrane thereby weakening the membrane structure and altering its function which leads to fungal cell death. Isavuconazole is a BCS class II drug having a poor aqueous solubility. Owing to limited solubility in aqueous media, its oral bioavailability is rather low after oral administration, and it is difficult to retain a therapeutically effective concentration of the drug in plasma. Hence, most

antifungal formulations use a water-soluble azaheterocycle sulfate salt prodrug of isavuconazole viz. isavuconazonium sulfate. Upon administration, isavuconazonium sulfate is hydrolyzed by plasma esterases to yield the active moiety isavuconazole. Advantages of using this prodrug include excellent bioavailability of the oral formulation, and predictable pharmacokinetics. Oral and injectable formulations of isavuconazonium sulfate are approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of invasive aspergillosis and mucormycosis and are sold under the brand name Cresemba by Pfizer.
U.S. Patent No. 6,812,238; 7,189,858; 7,459,561 discloses azolium derivatives which have antifungal activity and are useful for the treatment of fungal diseases.
Besides prodrug synthesis, means for improving the bioavailability of poorly water soluble compounds that are well known in the art are: drug particle size reduction technologies, formation of inclusion complexes with cyclodextrins, using Lipid-based delivery systems viz. liposomes and solid lipid nanoparticles, porous microparticle technology, use of hydrates or solvates, selective adsorption on insoluble carriers, formation of solid solutions or solid dispersions and the like, each appropriately incorporated into orally deliverable formulations (like solutions, suspensions, tablets or capsules). These technologies improve the intrinsic dissolution of such compounds, leading to an increase in the concentration gradient at the epithelial cell barrier in the gastro-intestinal (GI) tract, enhancing the oral bioavailability.
One such approach for improving the bioavailability of poorly soluble drugs after oral administration is the formulation of said drugs in Self-Emulsifying Drug Delivery Systems (SEDDS) or Self-Microemulsifying Drug Delivery Systems (SMEDDS). SEDDS/SMEDDS are isotropic mixtures of oils, surfactants, solvents and co-solvents used for improving the oral absorption of lipophilic drugs. SEDDS typically produce emulsions when they - come in contact with gastrointestinal fluids with a droplet size between 100 and 300 nm while

SMEDDS form transparent microemulsions with a droplet size of less than 50 nm. SEDDS/ SMEDDS can be administered into oral dosage forms Many formulation related factors are attributed to the enhancement of oral absorption of the lipophilic drug through such systems viz. selection of a specific surfactant and co-surfactant combination, surfactant concentration, drug:surfactant ratio, droplet size and charge. Only very specific combinations of excipients, especially the surfactants and co-surfactants will cause self emulsification or microemulsification of the formulation. These surfactant and co-surfactant combinations are very peculiar and work optimally only for a particular drug-composition. Because of a thoroughly selected combination of incorporated surfactant(s) and co-surfactant(s), these systems tend to instantly form micelles when they come in contact with an aqueous media, thus leading to rapid solubilization and enhanced absorption of the drug from the gastrointestinal (GI) ' tract.
US 8,536,208 (hereinafter referred to as '208 patent) discloses a composition of Isavuconazole that essentially contains a solubilizer component for the antifungally effective component having an HLB value of less than 20, said solubilizer component comprising: (a) a mixture of glycerol mono-, di- and/or triesters and of polyethylene glycol mono- and/or diesters, said esters being formed with at least one fatty acid selected from the group consisting of lauric acid and oleic acid; and/or (b) a mixture of glycerol mono-, di- and/or triesters and of polyethylene glycol mono- and/or diesters, said esters being formed with caprylic acid and capric acid. Specific examples of solubilizer components disclosed in the '208 patent are GELUCIRE® 44/14, LABRAFIL® M1944CS, LABRASOL®, CAPRYLOL® 90, LAUROGLYCOL® 90 as the surfactant system. Lipid digestion of SEDDS/ SMEDDS after coming in contact with gastrointestinal fluids, will induce supersaturation of the drug due to decreased solubilizing power of the SEDDS. This supersaturation acts as a driving force for increase in the flux across membranes, thereby increasing the absorption of drug. However, it is important that this super saturated state of the drug is maintained

till it gets absorbed. A major disadvantage of the SEDDS compositions with the surfactants essentially chosen in the '208 patent having HLB value less than 20 is that, they may not be able to maintain the supersaturated state of the drug which leads to the precipitation of the drug into their favourable crystalline form when it comes in contact with aqueous gastrointestinal fluids, especially the intestinal fluids having higher pH, prior to absorption. This may cause a decrease in bioavailability of the drug. Thus, it is essential that surfactant systems are chosen considering their ability to inhibit drug precipitation. Ideally, SEDDS/ SMEDDS should be formulated in a manner such that the supersaturated state of the drug is maintained for a time till it is completely absorbed.
US 6,054,136 (hereinafter referred to as '136 patent) discloses "a composition which can be administered, in particular, orally, for pharmaceutical or cosmetic use, capable of forming a microemulsion in situ with the biological fluid of the body; the invention relates more especially to a composition composed of a self-microemulsifying carrier system for active agents, designated in the art by the English term "SMEDDS" (self-microemulsifying drug delivery system); these systems have the property of emulsifying in water at the temperature of the human body". US '136 patent further discloses that "if the HLB value is greater than 16, the mixture becomes too hydrophilic, and this does not promote the microemulsion. It has been observed that best results are obtained when the HLB value is in the neighbourhood of 14, since microemulsions can be formed over a widest range".
However inventors of present invention have found and developed a stable pharmaceutical composition using suitable surfactants having HLB value more than 20 which is self-emulsifying on contact with aqueous gastrointestinal fluids and forms oil in water emulsion or micro-emulsion.
It is thus an objective of the present invention to employ suitable surfactants and co-surfactants so as to prevent isavueonazole precipitation from the

SEDDS/SMEDDS after contacting the gastroinstestinal fluids and thereby maintaining the supersaturated form of the drug for its complete absorption.
The inventors of the invention have surprisingly found that by using suitable surfactants and co-surfactants in the formulation; along with pharmaceutically acceptable excipients, the composition shown not only good characteristics of self-emulsifying on contact with aqueous gastrointestinal fluids and forming oil in water emulsion or micro-emulsion and but also excellent storage stability.
SUMMARY OF THE INVENTION
In one general aspect, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) a mixture of at least two co-surfactants; d) other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5% for at least 12 months.
In another aspect, the composition is self-emulsifying on contact with aqueous gastrointestinal fluids and forms oil-in-water emulsion or micro-emulsion.
In another aspect the one or more surfactants have HLB value more than 20 and the mixture of at least two co-surfactants is present in a weight ratio of 1:1 to 1:10.
In another aspect the one or more surfactants having HLB value more than 20 and the mixture of at least two co-surfactants is present in a weight ratio of 1:3.
In another aspect, the mixture of at least two co-surfactants is selected from one or more hydrophilic co-surfactant which is free from fatty acids; one or more hydrophilic co-surfactants which is higher fatty acid ester of polyethylene glycol and or a combination thereof.
In another aspect, the one or more surfactants having HLB value more than 20, the one or more hydrophilic co-surfactants which are free from fatty acids and the one or more hydrophilic co-surfactants which are higher fatty acid esters of polyethylene glycol are present in a weight ratio of 1:1:1 to 1:10:10.

In another aspect, the one or more surfactants having HLB value more than 20 is selected from sodium stearoyl-2-lactylate, potassium oleate, Poloxamer 407, Poloxamer 188, sodium octanoate, sodium dodecanoate, and or sodium octyl sulfate.
In another aspect, the one or more hydrophilic co-surfactants which is free from fatty acids is alpha-D-tocopherol poly(ethylene glycol) succinate.
In another aspect, the one or more hydrophilic co-surfactants which is higher fatty acid ester of polyethylene glycol is selected from polyoxyl 15 hydroxystearate (Kolliphor HS15), polyoxyl 8 stearate, polyoxyl 40 stearate.
In another aspect, the other pharmaceutically acceptable excipients are selected from sweetener, stabilizer, solubilizer, co- solubilizer, flavoring agent, vehicle or solvent, surfactant, pH modifying agent and or combination thereof.
In another general aspect9 there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) mixture of alpha-D-tocopherol poly(ethylene glycol) succinate and polyoxyl 15 hydroxystearate; d) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In another general aspect, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) a mixture of at least two co-surfactants having HLB value less than 20; d) other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5% for at least 12 months.
In one general aspect there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactants which is free

from fatty acids; d) one or more hydrophilic co-surfactants which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer; and f) other pharmaceutically acceptable excipients.
In another general aspect, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer ; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of the surfactant having HLB value more than 20 : one or more hydrophilic co-surfactant which is free from fatty acids ; or or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is 1:1:1 to 1:10:10; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In another general aspect, the optionally water miscible co-solubilizer is selected from povidone.
In another general aspect, the composition is in the form of solution, suspension, emulsion, syrup, elixir and liquid-filled capsules.
In yet another aspect, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) alpha-D-tocopherol poly(ethylene glycol) succinate; d) polyoxyl 15 hydroxystearate; e) povidone; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
The pharmaceutical composition of the present invention exhibits excellent storage stability over the storage period of at least 6 months at 40 ±2°C and 75 ± 5 % relative humidity, at least 12 months at 30 ±2°C and 75 ± 5 % relative humidity and at 25 ±2°C and 60 ± 5 % relative humidity.

DETAILED DESCRIPTION OF THE INVENTION
The term "Isavuconazole" used throughout the specification refers to only Isavuconazole per se, and not to their other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.
"Pharmaceutical composition" or "pharmaceutical formulation" or "pharmaceutical dosage form" can be used interchangeably and refers to the combination of one or more active ingredients and one or more excipients.
"Pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions well known in the art and includes any pharmaceutically acceptable salt soluble in water to form an aqueous solution.
"Pharmaceutically acceptable excipients" refers to non-active pharmaceutical ingredient substances which are within the scope of sound medical judgment suitable for use in formulating pharmaceutical products.
Pharmaceutical excipients that can be used in the pharmaceutical composition of the present invention can be selected from a group comprising one or more surfactants, co-surfactants, emulsifiers, stabilizers, solubilizers, dispersing agents, suspending agents, thickening agents, preservatives, co-solvents, vehicles, pH-adjusting agents, flavorants and sweeteners or the combinations thereof
The term "surfactant" as used herein, relates to a chemical compound possessing two groups, the first polar or ionic, which has a great affinity for water, the second which contains a longer or shorter aliphatic chain and is hydrophobic, these chemical compounds having marked hydrophilic character are intended to cause the formation of micelles in aqueous or oily solution.

The term "co-surfactants", as used herein is also a chemical compound but having hydrophobic character intended to cause the mutual solubilisation of the aqueous or oily phases in a micro emulsion.
The term "HLB", as used herein relates to hydrophilic-lipophilic balance (HLB) is the balance of the size and strength of the hydrophilic and lipophilic moieties of a surfactant molecule. The hydrophilic-lipophilic balance value (HLB value) of a surfactant or co-surfactant is a measure of the degree to which it is hydrophilic or lipophilic, determined by calculating values for the different regions of the molecule.
The term "stable" as used herein relates to the ability of a pharmaceutical product to retain its chemical, physical, and microbiological and biopharmaceutical properties within specified limits throughout its shelf-life.
In one general embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) a mixture of at least two co-surfactants; d) other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5% for at least 12 months.
In another embodiment, the composition is self-emulsifying on contact with aqueous gastrointestinal fluids and forms oil in water emulsion or micro-emulsion.
In another embodiment, the one or more surfactants having HLB value more than 20 and the mixture of at least two co-surfactants is present in a weight ratio of 1:1 to 1:10.
In another embodiment the one or more surfactants having HLB value more than 20 and the mixture of at least two co-surfactants is present in a weight ratio of 1:1 to 1:10 or 1:1 to 1:7 or 1:1 to 1:5 or any possible combination thereof or preferably in the range of 1:1.5 to 1:4.5, more preferably in the range of 1:2.5 to 1:3.5.

In another embodiment the one or more surfactants having HLB value more than 20 and the mixture of at least two co-surfactants is present in a weight ratio of 1:3.
In another embodiment, the mixture of at least two co-surfactants is selected from one or more hydrophilic co-surfactant which is free from fatty acids; one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol and or combination thereof.
In another embodiment, the one or more surfactants having HLB value more than 20, the one or more hydrophilic co-surfactant which is free from fatty acids and the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol are present in a weight ratio of 1:1:1 to 1:10:10.
In another embodiment, the one or more surfactants having HLB value more than 20, the one or more hydrophilic co-surfactant which is free from fatty acids and the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol are present in a weight ratio of 1:1:1 to 1:10:10 or 1:1:1 to 1:1:5 or 1:1:1.5 to 1:1:3 or 1:1:1 to 1:5:1 or 1:1:1 to 1:3:1 or any possible combination thereof or preferably 1:1:1 to 1:1:2 or 1:1:2 to 1:1:3, more preferably 1:1:2.
In another embodiment, the one or more surfactants having HLB value more than 20, the one or more hydrophilic co-surfactant which is free from fatty acids and the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol are present in a weight ratio of 1:1:2.
In another embodiment, the one or more surfactants having HLB value more than 20 is selected from sodium stearoyl-2-lactylate, potassium oleate, Poloxamer 407, Poloxamer 188, sodium octanoate, sodium dodecanoate, and or sodium octyl sulfate.
In another embodiment, the one or more hydrophilic co-surfactant which is free from fatty acids is alpha-D-tocopherol poly(ethylene glycol) succinate.

In another embodiment, the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is selected from polyoxyl 15 hydroxystearate (Kolliphor HS15), polyoxyl 8 stearate, polyoxyl 40 stearate.
In another embodiment, the other pharmaceutically acceptable excipients are selected from sweetener, stabilizer, solubilizer, co-solubilizer, flavoring agent, vehicle or solvent, surfactant, pH modifying agent and or combination thereof.
In one embodiment, the pH-modifying agents include inorganic acids such hydrochloric acid or sulphuric acid or organic edible acids such as citric acid, fumaric acid, succinic acid, lactic acid, acetic acid and base includes sodium hydroxide and or the combinations thereof.
In one embodiment, the sweetener is selected from natural sweeteners like sucrose, glucose, fructose, maltose, sorbitol, glycerol, honey, liquorice and the like or artificial sweeteners like saccharin, aspartame, sucralose, acesulfame K, xylitol, neotame and or the combinations thereof.
In one embodiment, the flavourants are selected from peppermint, raspberry, cherry, citrus, vanilla, butterscotch, banana, pineapple and or the combinations thereof.
In one embodiment, the vehicle of the said composition can be aqueous or non-aqueous.
In another embodiment, the composition is in the form of solutions, suspensions, emulsions, syrups, elixirs and liquid-filled capsules.
In another general embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) mixture of alpha-D-tocopherol poly(ethylene glycol) succinate and polyoxyl 15 hydroxystearate; d) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.

In another general embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) a mixture of at least two co-surfactants having HLB value less than 20; d) other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5% for at least 12 months.
In one general embodiment there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer; and f) other pharmaceutically acceptable excipients.
In another general embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer ; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of the surfactant having HLB value more than 20 : one or more hydrophilic co-surfactant which is free from fatty acids : one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is 1:1:1 to 1:10:10; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In another general embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer ; and f). other pharmaceutically acceptable excipients; wherein the weight ratio of the surfactant

having HLB value more than 20 : one or more hydrophilic co-surfactant which is free from fatty acids : one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is 1:1:2 ; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In yet another embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) alpha-D-tocopherol poly(ethylene glycol) succinate; d) polyoxyl 15 hydroxystearate; e) povidone; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In one embodiment there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer; and f) other pharmaceutically acceptable excipients.
In another embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) one or more hydrophilic co-surfactant which is free from fatty acids; d) one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol; e) optionally co-solubilizer ; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of the surfactant having HLB value more than 20 : one or more hydrophilic co-surfactant which is free from fatty acids : one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is 1:1:1 to 1:10:10; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.

In another embodiment, the composition is self-emulsifying on contact with aqueous gastrointestinal fluids and forms oil in water emulsion or micro-emulsion upon oral administration.
In another embodiment, the composition provides rapid dissolution and enhanced absorption of the Isavuconazole.
In another embodiment of the present invention employs suitable surfactants and co-surfactants in the self-emulsifying composition of Isavuconazole wherein at least one surfactant has HLB value more than 20.
In another embodiment, the one or more surfactant having HLB value more than 20 is selected from sodium stearoyl-2-lactylate, potassium oleate, Poloxamer 407, Poloxamer 188, sodium octanoate, sodium dodecanoate, and or sodium octyl sulfate.
A further embodiment employs one or more adjuvant co-surfactants which may be free from fatty acids or are PEG esters of higher fatty acids.
In another embodiment, the one or more hydrophilic co-surfactant which is free from fatty acids is alpha-D-tocopherol poly(ethylene glycol) succinate.
In another embodiment, the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is selected from polyoxyl 15 hydroxystearate (Kolliphor HS15), polyoxyl 8 stearate, polyoxyl 40 stearate.
In another embodiment the optionally water miscible co-solubilizer is selected from povidone.
In another embodiment, the other pharmaceutically acceptable excipients are selected from surfactants, co-surfactants, emulsifiers, stabilizers, solubilizers, dispersing agents, suspending agents, thickening agents, preservatives, co-solvents, vehicles, pH-adjusting agents, flavourants and sweeteners.
In one of the embodiment, the surfactant of HLB value more than 20 is typically Poloxamer 188 (copolymer of polyethylene and polypropylene ether glycol),

surfactant that is essentially free from fatty acid is tocophersolan (alpha-D-tocopherol poly(ethylene glycol) 2000 succinate), surfactant containing higher fatty acids is Kolliphor HS15 (polyoxyl 15 hydroxystearate). Cosolvents that are used are selected from propylene glycol, liquid grades of polyethylene glycols, glycerine, etc. The vehicle used is water
In another embodiment, the composition is in the form of solutions, suspensions, emulsions, syrups, elixirs and liquid-filled capsules.
In yet another embodiment, there is provided a pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) alpha-D-tocopherol poly(ethylene glycol) succinate; d) polyoxyl 15 hydroxystearate; e) povidone; and f) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.
In another embodiment, the pharmaceutical composition of the present invention retains more than 95% w/w of total potency of Isavuconazole after storage at 40 ± 2°C and 75 ± 5 % relative humidity for at least 6 months.
In another embodiment, the pharmaceutical composition of the present invention retains more than 95% w/w of total potency of Isavuconazole after storage at 30 ± 2°C and 75 ± 5 % relative humidity for at least 12 months.
In another embodiment, the pharmaceutical composition of the present invention retains more than 95% w/w of total potency of Isavuconazole after storage at 25 ± 2°C and 60 ± 5 % relative humidity for at least 12 months.
The pharmaceutical composition of the present invention exhibits excellent storage stability over the storage period of at least 6 months at 40 ±2°C and 75 ± 5 % relative humidity, at least 12 months at 30 ±2°C and 75 ± 5 % relative humidity and at 25 ±2°C and 60 ± 5 % relative humidity.

The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1: Isavuconazole Oral Solution 10 mg/mL

S.No. Ingredients A

(Qty in mg/mL)
1. Isavuconazole 10
2. Propylene glycol 800
3. Fumaric acid 21
4. Povidone 2
5. Neotame 4
6. Polyoxyl 15 hydroxysteate 29
7. D- a -tocopherol polyethylene glycol 15
8. Poloxamer 188 15
9. Purified water q.s.
10. Banana N flavour 10
11. Honey mint flavour 10
12. Hydrochloric acid q.s.
13. Sodium hydroxide q.s.
14. Propylene glycol q.s. to lmL
Manufacturing Process:
1. Propylene glycol was transferred in manufacturing tank and heated to 55°C-65°C, fumaric acid was added in to it and temperature was maintained
2. Povidone and neotame was added to step 1 under stirring to get clear solution

3. Polyoxyl 15 hydroxysteate, D- a -tocopherol polyethylene glycol and
Poloxamer 188 were added in step 2 under stirring and temperature was maintained to 50°C-60°C.
4. Isavuconazole was added in step 3 under stirring and temperature was maintained to 50°C-60°G
5. The solution of step 2 was added to step 4 under continuous stirring for 15-20 minutes, the solution was allowed to cool to room temperature.
6. Purified water and flavours were added with stirring to get light yellow solution
7. pH was adjusted with hydrochloric acid and sodium hydroxide to 2.5-4.0
8. Finally volume was made up to 1 mL with propylene glycol and mixed for 20-30 minutes and filtered the solution through nylon cloth to get oral solution of Isavuconazole.
Example 2: Stability study of Oral solution of Isavuconazole of Example 1
Composition of Example 1 was studied for the stability study for the parameters of weight per mL; pH; assay and related substances. The result of the stability study is shown as below:

Storage Condition: 30±2°C and RH 75±5%.
Sr. No. Parameter Initial 3 Months 6 Months 12 Months
1 Weight per mL 1.036 1.047 1.046 1.046
2 . pH 2.93 3.79 4.01 3.28
3 Assay mg/mL 10.13 10.23 10.36 9.81

% label claim 101.3 102.3 103.6 98.1
Related Substances Impurity
Triazole Impurity ND 0.04 0.09 0.03

Any unknown impurity 0.45 0.45 0.48 0.54
Total impurity 0.70 0.74 0.88 1.06

Storage Condition: 25±2°C and RH 60±5%.
Sr. No. Parameter Initial 3 Months 6 Months 12 Months
1 Weight per mL 1.036 1.046 1.045 1.046
2 pH 2.93 3.68 4.01 3.28
3 Assay mg/mL 10.13 10.24 10.20 9.86

% label claim 101.3 102.4 102 98.6
Related Substance
Triazole Impurity ND 0.03 0.06 0.04
Any unknown impurity 0.45 0.44 0.45 0.50
Total impurity 0.70 0.69 0.73 0.81

Claims We Claim:
1. A pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) one or more surfactants having HLB value more than 20; c) a mixture of at least two co-surfactants; d) other pharmaceutically acceptable excipients; wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5% for at least 12 months.
2. The pharmaceutical composition of claim 1, wherein the composition is self-emulsifying on contact with aqueous gastrointestinal fluids and forms oil in water emulsion or micro-emulsion.
3. The pharmaceutical composition of claim 1, wherein the one or more surfactants having HLB value more than 20 and the mixture of at least two co-surfactants are present in a weight ratio of 1:1 to 1:10.
4. The pharmaceutical composition of claim 1, wherein the mixture of at least two co-surfactants is selected from one or more hydrophilic co-surfactant which is free from fatty acids; one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol and or combination thereof.
5. The pharmaceutical composition of claim 3 and 4, wherein the one or more surfactants having HLB value more than 20, the one or more hydrophilic co-surfactant which is free from fatty acids and the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol are present in a weight ratio of 1:1:1 to 1:10:10.
6. The pharmaceutical composition of claim 1, wherein the one or more surfactants having HLB value more than 20 is selected from sodium stearoyl-2-lactylate, potassium oleate, Poloxamer 407, Poloxamer 188, sodium octanoate, sodium dodecanoate, and or sodium octyl sulfate.

7. The pharmaceutical composition of claim 4, wherein the one or more hydrophilic co-surfactant which is free from fatty acids is alpha-D-tocopherol poly(ethylene glycol) succinate.
8. The pharmaceutical composition of claim 4, wherein the one or more hydrophilic co-surfactant which is higher fatty acid ester of polyethylene glycol is selected from polyoxyl 15 hydroxystearate (Kolliphor HS15), polyoxyl 8 stearate, polyoxyl 40 stearate.
9. The pharmaceutical composition of claim 1, wherein the other pharmaceutically acceptable excipients are selected from sweetener, stabilizer, solubilizer, co-solubilizer, flavoring agent, vehicle or solvent, surfactant, pH modifying agent and or combination thereof.
10. A pharmaceutical composition for oral administration comprising: a) Isavuconazole; b) Poloxamer 188; c) mixture of alpha-D-tocopherol poly(ethylene glycol) succinate and polyoxyl 15 hydroxystearate; d) other pharmaceutically acceptable excipients; wherein the weight ratio of Poloxamer 188: alpha-D-tocopherol poly(ethylene glycol) succinate : polyoxyl 15 hydroxystearate is 1:1:2; and wherein the pharmaceutical composition is stable when stored at 30±2°C and RH 75±5%.