(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(OQ UTATAY
`
`(43) International Publication Date
`14 November 2013 (14.11.2013)
`
`WIPO!IPCT
`
`\=
`
`(10) International Publication Number
`WO 2013/167865 Al
`
`Agents: KING, Lawrence et al; A A THORNTON &
`Co., 235 High Holbom, London WC1V 7LE (GB).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU,
`RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ,
`T™, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM,ZW.
`
`GD)
`
`International Patent Classification:
`A61LK 9/00 (2006.01)
`A61K 47/44 (2006.01)
`A61K 47/16 (2006.01)
`A61LK 31/506 (2006.01)
`AGIK 47/14 (2006.01)
`
`(74)
`
`(81)
`
`(21)
`
`International Application Number:
`
`PCT/GB2013/00021 1
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(7)
`
`(71)
`
`(72)
`
`Filing Language:
`
`Publication Language:
`
`10 May 2013 (10.05.2013)
`
`English
`
`English
`
`Priority Data:
`1444/MUM/2012_
`
`11 May 2012 (11.05.2012)
`
`IN
`
`Applicant: CIPLA LIMITED [IN/IN]; Mumbai Central,
`Mumbai - 400 008 (IN).
`
`Applicant (for MW only): KING, Lawrence [GB/GB];
`A.A. Thornton & Co., 235 High Holborn, London
`WC1V7LE (GB).
`
`Inventors: PURANDARE, Shrinivas; B/25, Naperol
`Tower Condominium, 2nd Floor, Rafi Ahemad Kidwai
`Marg, Wadala (w), Mumbai
`- 400 031 (IN). MALHO-
`‘TRA, Geena; 4 Anderson House, Opposite Mazgaon Post
`Office, Mazgaon, Mumbai-400 010, Maharashtra (IN).
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU,IE, IS, IT, LT, LU, LV,
`MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SIL SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`ML, MR, NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`(54) Title: PHARMACEUTICAL COMPOSITION
`
`(57) Abstract: The present invention relates to a pharmaceutical composition comprising voriconazole and an aqueous, non-
`aqueous, or oily vehicle, or a mixture thereof, and optionally one or more pharmaceutically acceptable excipients; to a process for
`preparing such a composition, and to the use of such a composition for the prevention or treatment of fungal infections.
`
`
`
`wo2013/167865A1IIITNMIIMTANNUITYAGITAAA
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`

`

`WO 2013/167865
`
`PCT/GB2013/000211
`
`Pharmaceutical Composition
`
`Field of the Invention
`
`The present invention relates to a pharmaceutical composition of voriconazole, to'a process for
`preparing such a composition, and to therapeutic uses and a method of treatment employing the
`same.
`
`Backgroundand Prior art
`
`(2R,3S)-2-(2,4-Difluoropheny!)-3-(5-fluoro-4-
`as
`designated
`chemically
`Voriconazole,
`pyrimidinyl)-1-(1 H-1,2,4-triazol-1-yl)-butan-2-ol, is indicated for the treatment of various fungal
`infections caused by Aspergillusfumigatus and Aspergillusother than A.fumigatus, Candidemia,
`Esophageal candidiasis and serious fungal infections caused by Scedosporium apiospermum. It
`has the following chemical structure:
`
`
`
`Voriconazole is disclosed in European patent EP0440372. U.S. Patent Nos. 5,116,844;
`_ 5,364,938; 5,567,817; 5,773,443 and 6,632,803 describe voriconazole and its formulations.
`
`Voriconazole has a low aqueoussolubility (0.61 mg/m! at a pH 7; 0.2 mg/ml at a pH 3), and is
`not stable in water (an inactive enantiomer is formed from combination of the retro-aldol
`- products of hydrolysis). Degradation of voriconazole occurs in aqueous solution, particularly
`under basic conditions. Thus, development of an aqueous formulation with a sufficient shelf life.
`is difficult. These problems are further magnified by the semipolar nature of the compound (log
`D=1.8) which meansthat it
`is not generally solubilized by conventional means such asoils,
`surfactants or water miscible co-solvents. Additionally, voriconazole is not stable in water
`leading to increase in impurity. Therefore, development of voriconazole compositions generally
`with a controlled impurity profile poses a considerable developmental challenge.
`
`_
`
`In the lyophilized formulation of voriconazole for injection which is marketed by Pfizer Co.
`-under the trade name Vfend®, the solubility of voriconazole is increased by using a solubilizer,
`_: sulfobutyl ether. B-cyclodextrin sodium (SBECD). The amount of SBECDin1 milligram. of |
`“lyophilized formulation of approved voriconazole (labeled amount) is about 15 mg to 18 mg
`. (1:15). To increasethe solubility of the drug, a large amount of SBECD has to be used in the
`lyophilized formulation.
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`PCT/GB2013/000211
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`- Accordingly, various attempts have been made in the prior art to improve the stability of
`voriconazole in formulations.
`
`European Patent EP0440372 discloses co-formulation with cyclodextrin derivatives to improve
`solubility; however, it is always desirable to keep the numberof ingredients. in a formulation to a
`minimum so as to minimize possible adverse reactions in patients. Further, underivatised or
`-unmetabolised cyclodextrin may havetoxic effects on the body and so may be unsuitable as a
`pharmaceutical excipient.
`
`the solubility of voriconazole in water can be increased by
`WO 98/58677 discloses that
`molecular encapsulation with sulphoalkylether cyclodextrin derivatives of the type disclosed in
`WO 91/11172, particularly beta-cyclodextrin derivatives wherein the cyclodextrin ring is
`substituted by sulphobutyl ‘groups. However, the said cyclodextrin encapsulated voriconazole
`may not remain stable when developed into aqueous ready-to-use compositions. Moreover, there
`are complex manufacturing issues associated with cyclodextrin formulations which also increase
`manufacturing cost significantly.
`
`W097/28169 discloses a phosphate pro-drug of voriconazole, which exhibits increasedsolubility
`and aqueous stability. However,
`the pro-drug may not exhibit 100% bioequivalence to
`voriconazole.
`
`US2005 112204 discloses a pharmaceutical formulation of voriconazole, in particular an aqueous
`micellar poloxamer preparation comprising voriconazole, and one or more poloxamer. The
`pharmaceutical acceptability of various poloxamers is well established, with certain species
`approved for parenteral administration. However, there have been problems with targeting and -
`dispensing drugs using poloxamers. Munish et al., [cancer letters, 118(1997), 13-19] found that
`in some cases it was not possible for the drug to release, unless ultrasound was used to disrupt
`the micelles. The requirement of the use of ultrasound is expensive and. undesirable.
`
`Thus, as can.be noted herein above there is insufficient disclosure about how to formulate a
`stable ready-to-use voriconazole composition. Hence there still exists a need to develop
`pharmaceutical compositions of voriconazole havingimproved stability over the storage period
`when formulated in the form of ready-to-use composition. There is also a need for suitable/stable
`voriconazole compositions that exhibit a controlled impurity profile.
`
`Despite the above-noted inherent difficulties associated with formulating voriconazole, we have.
`surprisingly found that stable compositions of the drug may be prepared with a variety of
`aqueous, non-aqueous, or oily vehicle, or mixtures thereof.
`
`

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`WO 2013/167865
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`PCT/GB2013/000211
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`Object of the Invention
`
`An object of the present invention is to provide a ready-to-use pharmaceutical composition of
`voriconazole having improved stability.
`Another object of the present invention is to provide a ready to use ready-to-use pharmaceutical
`composition of voriconazole having improved stability and exhibiting controlled impurity
`profile.
`
`Yet another object of the present invention is to provide a process for preparing a ready-to-use
`pharmaceutical composition comprising voriconazole having improved stability with the ease of
`manufacturing.
`
`A further object of the present invention is to provide a method for prophylaxis or treatment of
`patients
`in need thereof which comprises administering a ready-to-use pharmaceutical
`composition comprising voriconazole having improved stability.
`Still another object of the present
`invention is
`to provide the use of a ready-to-use
`pharmaceutical composition comprising voriconazole having improved stability for preventing
`or treating a topical or systemic fungal infection.
`
`Summary of the Invention
`
`‘According to one aspect of the invention, there is provided a stable composition comprising
`voriconazoleorits salt, solvate, ester, derivatives, hydrate, enantiomer, polymorph, prodrugs,
`complex or mixtures thereof wherein the said drug is dispersed in an aqueous, non-aqueous, or
`oily vehicle, or mixtures thereof.
`
`According to a second aspectof the present invention, there is provided a process for preparing a
`ready-to-use pharmaceutical
`composition “comprising voriconazole
`or pharmaceutically
`acceptablesalt, solvate, ester, derivatives, hydrate, enantiomer, polymorph, prodrugs, complexor.
`mixtures thereof wherein the said drug is dispersed in an aqueous, non-aqueous, or oily vehicle,
`
`or mixturesthereof.
`
`‘According to third aspect of the present invention, there is provided a method of improving the
`stability of the pharmaceutical composition comprising voriconazole by dispersing the said drug
`or pharmaceutically acceptable salt, solvate, ester, derivatives, hydrate, enantiomer, polymorph,
`prodrugs, complex or mixtures thereof in an aqueous, non-aqueous, or oily vehicle, or mixtures
`thereof.
`
`According to fourth: aspect of the present invention, there is provided use of a pharmaceutical -
`composition comprising voriconazole or pharmaceutically acceptable salt; solvate, ester,
`derivatives, hydrate, enantiomer, polymorph, prodrugs, complex or mixtures thereof dispersedin
`
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`WO 2013/167865
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`PCT/GB2013/000211
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`in the manufacture of a
`/ an aqueous, non-aqueous, or oily vehicle, or mixtures thereof,
`. medicamentfor treating topical or systemic fungal infection in patients in need thereof.
`
`According to fifth aspect of the present invention, there is provided a method of preventing or
`treating patients in need thereof comprising administering a ready-to-use pharmaceutical
`composition comprising voriconazole or pharmaceutically acceptable salt,
`solvate, ester,
`‘derivatives, hydrate, enantiomer, polymorph, prodrugs , complex or mixtures thereof dispersed in
`an aqueous, non-aqueous,or Oily vehicle, or mixtures thereof.
`
`Detailed Description
`
`Various studies have been reported for preparing topical voriconazole formulation from the
`commercialized lyophilized product which is available for parenteral administration (Vfend® 200
`mg IV, Pfizer) wherein lyophilized powder, is diluted with sodium chloride 0.9% understerile
`conditions. (Preparation and Stability of Voriconazole Eye Drop Solution. Antimicrob, Agents
`Chemother. February 2009 vol. 53 no. 2 798-799),
`
`The potential of Voriconazole for the treatment of ophthalmic diseases like keratomycosis have
`been reported by several authors. Nevertheless several studies have been reported wherein
`patients having ophthalmic diseases are being treated with lyophilized powder for injection
`formulation diluted with sodium chloride. 0.9% under sterile conditions. However from the
`practicability aspect, such dilutions are not feasible at the consumer/patient level.
`
`Further, due to poor stability of the molecule in aqueous vehicle and the various concerns as
`discussed above,
`there is an unmet need to develop a stable, ready-to-use composition of
`- voriconazole.
`
`The inventors of the present invention have surprisingly found that ready-to-use voriconazole
`compositions may be prepared by dispersing the drug in an aqueous, non-aqueous, or oily
`medium, or mixture thereof, without compromising the stability of the drug. Such compositions
`may also advantageously exhibit controlled impurity profiles.
`
`The present invention thus provides a pharmaceutical composition comprising voriconazole and
`an aqueous, non-aqueous, or oily medium, or mixture thereof, and optionally one or more
`pharmaceutically acceptable excipients.
`
`composition comprising
`a pharmaceutical
`the invention ‘provides
`‘In one embodiment,
`voriconazole, an oily medium or mixture thereof, and optionally one or more pharmaceutically
`acceptable excipients.
`
`

`

`WO 2013/167865
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`PCT/GB2013/000211
`
`invention provides. a pharmaceutical composition comprising
`the
`‘In .one embodiment,
`voriconazole, .an oily medium or mixture thereof, a surfactant, and optionally one or more
`pharmaceutically acceptable excipients.
`-
`In one embodiment,
`the invention provides a pharmaceutical composition comprising
`voriconazole, an oily medium or mixture thereof, a surfactant, a pH. adjusting agent, and
`optionally one or morepharmaceutically acceptable excipients.
`
`the invention provides a pharmaceutical composition comprising
`In one embodiment,
`voriconazole, an aqueous medium, a surfactant, and optionally one or more pharmaceutically
`acceptable excipients.
`composition comprising
`the invention provides a pharmaceutical
`In one embodiment,
`_Voriconazole, an aqueous medium,a surfactant, a pH adjusting agent, and optionally one or more
`pharmaceutically acceptable excipients.
`
`invention provides a pharmaceutical composition comprising
`the
`In one embodiment,
`voriconazole, a non-aqueous medium, and optionally one or more pharmaceutically acceptable
`excipients.
`
`the invention provides a pharmaceutical composition comprising
`In one embodiment,
`voriconazole, a non-aqueous medium, a surfactant and optionally one or more pharmaceutically .
`acceptable excipients.
`
`the invention provides a pharmaceutical composition comprising
`In one embodiment,
`voriconazole, a non-aqueous medium, a surfactant, a pH adjusting agent and optionally one or
`more pharmaceutically acceptable excipients.
`:
`
`Preferably, the pharmaceutical composition ofthe present invention is in ready-to-use form.
`
`reference to the term “voriconazole” is used
`invention,
`Within the scope of the present
`_throughout the description in broad sense to include not only the voriconazole per se but also
`pharmaceutically acceptable
`salts,
`solvates,
`esters, hydrates,
`enantiomers,
`derivatives,
`polymorphsand prodrugsthereof.
`include pharmaceutical compositions in which
`As used herein,
`the term “dispersed” shall
`voriconazoleis dispersed, suspended or dissolved in an aqueous, non-aqueous, or oily medium,
`or mixture thereof. The term “dispersing” shall be interpreted accordingly.
`AS used herein the term “vehicle”, “media”or “medium” are used interchangeably throughout
`the specification.
`In one embodiment, the pharmaceutical composition of the present invention comprises an-oily
`vehicle or. mixture thereof. The oil or mixture of oils may comprise any pharmaceutically
`acceptable oi] which is systemically or topically well tolerated.
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`

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`WO 2013/167865
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`PCT/GB2013/000211
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`Examples ofoils suitable for use in a composition according to the present invention: include, but
`are not limited to, castor oil, medium chain triglycerides (MCTs), mineral oils, vegetable oils,
`oily fatty acids, oily fatty alcohols, esters of sorbitol, fatty acids, oily |sucrose esters, and any
`combination thereof. Examples of suitable vegetable oils include cotton seed oil, ground nutoil,
`corm oil, germ oil, olive oil, palm oil, soybean oil, sweet almond oil, sesame oil, and any
`combination thereof. Examples suitable of mineraloils include silicone oil, petrolatum oil,
`liquid paraffin and any combination thereof. Examples of suitable medium chain triglycerides
`include coconut oil; hydrogenated oils comprising. hydrogenated cottonseed oil, hydrogenated
`palm oil, hydrogenated castor oil, hydrogenated soybean oil and any combination thereof.
`Preferably, the oily medium is liquid paraffin, castor oil, a medium chain triglyceride, or any
`combination thereof.
`
`|
`
`In another embodiment, the. pharmaceutical composition of the present invention comprises a
`non-aqueous medium or mixture thereof. The non-aqueous medium, or mixture thereof, may
`comprise any pharmaceutically acceptable non-aqueous medium. Examples of non-aqueous
`vehicle suitable for use in a composition according to the present invention include, but are not
`limited to, glycerin, polyethylene glycol, propylene glycol, or any combination thereof.
`
`invention
`the pharmaceutical composition of the present
`In an alternative embodiment,
`In one embodiment,- the pharmaceutical composition of the
`comprises an aqueous vehicle.
`present invention comprises an aqueous vehicle and is substantially free from cyclodextrin or a
`
`derivative thereof.
`
`invention is in semi-solid or liquid form.
`The pharmaceutical composition of the present
`Examples of suitable semi-solid forms include creams, ointments, lotions and the like. Examples-
`of suitable liquid forms include dispersions, suspensionsand solutions and thelike.
`
`In one embodiment, the pharmaceutical composition of the present invention is in a form thatis
`suitable for topical or systemic administration.
`
`The pharmaceutical composition of the inventionfor topical use may be formulated to administer
`directly to the eye or ear. The pharmaceutical composition may take the form of drops, a
`suspension, a nanosuspension, an ointment, a cream, a biodegradable dosage form such as an
`absorbable gel, a sponge, or collagen, a non-biodegradable dosage form such as (e.g. silicone)
`implants, wafers, lenses and particulate or vesicular systems, such as niosomes, emulsion, or a
`microemulsion andthe like.
`
`The pharmaceutical composition of the invention for systemic use may be formulated and
`administered. parenterally via intravenous,
`intramuscular,
`subcutaneous,
`intraperitoneal,
`intrathecal routes of administration. The pharmaceutical composition may take the form of a
`suspension, a nanosuspension,or a particulate or vesicularsystem, such. as niosomes, emulsion,
`liposomes, or a microemulsion andthelike. .
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`WO 2013/167865
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`According to another embodiment, the pharmaceutical compositions of the invention may also
`be developed into dosage forms suitable to administer topically to the skin or mucosa, that.is,
`‘dermallyor transdermally. Typical formulations for this purpose may comprise gels, hydrogels,
`lotions, solutions, creams, ointments, dressings, foams, films, skin patches, wafers,
`implants,
`sponges, fibres, bandages and microemulsions.
`iontophoresis,
`Other means of topical administration include delivery by electroporation,
`phonophoresis, sonophoresis and microneedle or needle-free (e.g. Powderject'1™ Bioject™™,
`etc.) injection.
`
`The pharmaceutical composition of the invention may also be administered intranasally or by
`inhalation, typically as an aerosol spray from a pressurized container or nebulizer, with or
`without
`the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-
`heptafluoropropane or mixtures thereof.
`
`Compositions for inhaled/intranasal administration may be formulated to be immediate and/or
`modified release. Modified release formulations include delayed, sustained, pulsed, controlled,
`targeted and programmedrelease.
`
`In addition to the aqueous, non-aqueous, or oily medium, or mixture thereof, the pharmaceutical
`composition of the present invention may comprise one or more additional pharmaceutically
`acceptable excipients. Examples of suitable pharmaceutically acceptable excipients include one -
`Or more polymers, wetting agents or surfactants, pH adjusting agents,
`isotonicity adjusting
`agents, preservatives, buffers, and chelating agents, or any combination thereof.
`limited. to,
`Examples of suitable pharmaceutically acceptable polymers inchide, but. are not
`_ cellulose
`derivates
`(such
`as
`hydroxypropylcellulose,
`hydroxymethylcellulose,
`hydroxypropylmethylcellulose, methylcellulose
`polymers,
`hydroxyethylcellulose,
`sodium
`carboxymethyicellulose, carboxymethylene and carboxymethyl hydroxyethylcellulose or any
`combination thereof); and acrylics (such as acrylic acid, acrylamide, and maleic anhydride
`polymers, copolymers or their mixtures thereof) and mixtures thereof. Polymer biends may also
`be employed. A preferred pharmaceutically acceptable polymeris hydroxyethy! cellulose.
`In
`an embodiment, the pharmaceutically acceptable polymer is present in an amount from about
`0.01% to about 5.0% (w/v), preferably from about 0.05% to about 2% (w/v), and more
`preferably from about 0.1% to about 1.0% (w/v), such as about 0.1, 0.2, 0.5, 1.0% (w/v).
`Examples of suitable pharmaceutically acceptable wetting agents or surfactants include, but are
`. not
`limited to, amphoteric, non-ionic, cationic or anionic molecules.
`Suitable surfactants
`include, but are not limited to, polysorbates, sodium dodecyl! sulfate (sodium fauryl sulfate),
`lauryl. dimethyl, amine oxide, docusate sodium, cetyl trimethyl ammonium bromide (CTAB),
`polyethoxylated alcohols, polyoxyethylene.sorbitan, octoxynol, N, N—dimethyldodecylamine-N—
`oxide, _hexadecyltrimethylammonium ‘bromide, polyoxy! -10 lauryl: ether,brij® surfactants
`(polyoxyethylene-vegetable-based fatty. ethers derived from lauryl, cetyl, stearyl. and oleyl.
`
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`WO 2013/167865
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`PCT/GB2013/000211
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`alcohols), bile ‘salts {such as sodium deoxycholate and sodium cholate), polyoxyl castor oil;.
` nonylpheno} .ethoxylate, cyclodextrins,
`lecithin, methylbenzethonium chloride, carboxylates,
`sulphonates, petroleum sulphonates, alkylbenzenesulphonates, naphthalenesulphonates, olefin
`sulphonates, alkyl sulphates, sulphates, sulphated natural oils and. fats, sulphated esters,-
`sulphated alkanolamides, alkylphenols
`(ethoxylated and sulphated), ethoxylated aliphatic
`alcohol,
`polyoxyethylene
`surfactants,
`carboxylic
`esters, polyethylene
`glycol
`esters,
`-anhydrosorbitol ester and ethoxylated derivatives thereof,
`glycol esters of fatty acids,
`carboxylic amides, monoalkanolamine condensates,
`polyoxyethylene fatty acid amides,
`"quaternary ammonium salts, amines with amide linkages, polyoxyethylene alkyl] and alicyclic
`amines, N,N,N,N tetrakis substituted ethylenediamines, 2- alkyl 1- hydroxyethyl 2-imidazolines,
`N
`-COCco |
`3-aminopropionic
`acid/ —
`sodium
`salt
`N-tallow 3 -iminodipropionate disodium. salt, N--carboxymethyl n dimethy] n-9 octadeceny!
`ammonium hydroxide, n-cocoamidethy! n-hydroxyethylglycine sodium salt and the hike,
`polyoxyethylene, sorbitan monolaurate and stearate, cremophor® (polyethoxylated castor oil),
`solutol® (ethylene oxide/12-hydroxy stearic acid), polysorbate, tyloxapol and any combination
`thereof. Preferred pharmaceutically- acceptable surfactants include tyloxapol and Span® 80
`(sorbitane monooleate) or a mixture thereof.
`In an embodiment, the pharmaceutically acceptable
`wetting agent or surfactant is present in an amount from about 0.01% to about 5.0% (w/v),
`preferably from about 0.05% to about 2% (w/v), and more preferably from about 0.1% to about
`1.0% (w/v), such as about 0.1, 0.2, 0.5, 1.0% (w/v).
`
`Examples of suitable pharmaceutically acceptable isotonicity adjusting agents include, but are
`not
`limited to, D-mannitoi, glucose, glycerol, sodium chloride, potassium chloride, calcium
`chloride and magnesium chloride, or any combination thereof. Variousnitrates, citrates, acetates
`or mixtures thereof may also be employed.
`In an embodiment, the pharmaceutically acceptable
`isotonicity adjusting agents is present in an amount from about 0.1%. to about 5.0% (w/v),
`preferably from about 1% to about 3% (w/v).
`
`invention may
`The pharmaceutical composition of: voriconazole according to the present
`comprise. a suitable pharmaceutically acceptable pH adjusting agent, for example to adjust the
`PH of the composition suitable for
`topical or systemic adiministration.
`It ‘would also be
`appreciated that pH of the pharmaceutical composition of the present invention can be modified
`based on the route of administration, dosage delivery form and particular patient need. For
`example,
`in the case of an ophthalmic composition, the pH of the composition is suitably
`adjusted between about pH 4 to 7.
`
`suitable pharmaceutically acceptable pH adjusting agents include, -but are not
`Examples of
`limited to, sodium +hydroxide,. citric acid, hydrochloric acid, boric acid, acetic acid, phosphoric
`‘acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium
`: oxide; calciumcarbonate, magnesium carbonate,’ magnesium aluminum silicates, malic acid,
`“potassium citrate, sodium citrate, sodium: phosphate,lactic. acid,. giuconié -acid, tartaric’ acid,
`_.1,2,3,4-butane tetracarboxylic acid, fumaric -acid, diethanolamine, monoethanolamine, sodium -
`
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`WO2013/167865
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`.
`
`In an embodiment,
`carbonate, sodium bicarbonate, tnethanolamine, or.any combination thereof.
`the pharmaceutically acceptable pH adjusting agent is present in an amountfrom about 0.01% to
`about 2.0% (w/v), preferably from about 0:05% to about 1% (w/v).
`Examples of suitable pharmaceutically acceptable preservatives include, but are not limited to,
`benzalkonium chloride, benzethonium chloride and cetyl pyridinium chloride, benzy)] bromide,
`‘benzyl alcohol, disodium EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal,
`- merthiolate, acetate and phenylmercury borate, polymyxin B sulphate, chlorhexidine, methyl and
`propyl parabens, phenylethy! alcohol, quaternary ammonium chloride, sodium benzoate, sodium —
`propionate, stabilized oxychloro complex, and sorbic acid or their mixtures thereof. Preferred
`pharmaceutically acceptable preservatives include disodium EDTA (edetate disodium) and
`benzalkonium chloride or a mixture thereof.
`In an embodiment,
`the pharmaceutically
`acceptable preservative is present in an amount
`from about 0.01% to about 2.0% (w/v),
`preferably from about 0.05% to about 1%(w/v).
`
`.
`
`-
`
`Examples of suitable pharmaceutically acceptable buffers include, but are not limited to, sodium
`chloride, dextrose, lactose and phosphate buffered saline (PBS) or any combination thereof.
`Other suitable pharmaceutically acceptable buffers include, but are not limited to, disodium
`succinate hexahydrate, borate, citrate, phosphate, acetate, physiological saline, tris-HC1(tris-
`(hydroxymethyl)-aminomethane hydrochloride), HEPES (N-2-hydroxyethyl piperazine-NI-2-
`ethane sulfonic acid), sodium phosphate , sodium borate, physiological saline, citrate, carbonate,
`phosphate and/or mixtures thereof to achieve the desired osmolarity.
`In an embodiment, the
`pharmaceutically acceptable buffer is present in an amount from about 0.01% to about 2.0%
`(w/v), preferably from about 0.05% to about 1% (w/v).
`.
`
`‘Examples of suitable pharmaceutically acceptable chelating agents include, but are not limited
`to; ethylenediaminetetraacetic acid (EDTA), disodium EDTA andderivatives thereof, citric acid
`_and derivatives ‘thereof, niacinamide and derivatives thereof, and sodium deoxycholate and
`derivatives
`thereof or mixtures of chelating agents
`thereof.
`In an embodiment,
`the
`pharmaceutically acceptable chelating agent is present in an amount from about 0.01% to about
`2,0% (w/v), preferably from about 0.05% to about 1% (w/v).
`
`there is provided a pharmaceutical composition comprising’
`In a preferred embodiment,
`voriconazole, an aqueous medium and one or more wetting agents, preferably tyloxapo). The
`composition may further comprise one or more polymers, pH adjusting agents,
`isotonicity -
`adjusting agents, preservatives, buffers, and chelating agents, or any combination thereof, of the
`types described herein.
`
`In a further preferred embodiment, thereis provided a pharmaceutical composition comprising
`-voriconazole, an oily médium, preferably liquid’ paraffin, a medium chain triglyceride and/or ”
`castor oil; and one Gr more wetting agents, preferably tyloxapol. The composition may further’
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`compriseone or more ‘polymers, pH adjusting agents, isotonicity adjusting agents, preservatives,
`buffers, and chelating agents, or any combination thereof, as. described herein.
`oS
`
`‘In a further preférred embodiment, there is provideda pharmaceutical composition comprising
`voriconazole, an oily vehicle,
`‘preferably liquid paraffin, and a pteservative, preferably
`benzalkonium chloride.
`
`{t will be appreciated that the precise therapeutic dose of voriconazole will depend on the age
`and condition of the patient and the nature of the condition to be treated and will be at the.
`ultimate discretion of the physician.
`In an embodiment, the pharmaceutical composition of the
`invention comprises between about 50 mg to about 200 mg of voriconazole, such as 50, 100, 150
`or 200 mg.
`
`The present invention also provides processes for preparing stable pharmaceutical compositions
`comprising voriconazole.
`
`‘In one embodiment, there is provided a process for preparing a pharmaceutical composition
`comprising voriconazole, which process comprises dispersing,
`suspending or dissolving
`voriconazole in an aqueous, non-aqueous, or oily medium, or a mixture thereof. Preferably, the -
`pharmaceutical composition is a ready-to-use composition. Preferably, the medium is an oil, or
`mixture thereof.
`
`invention provides a process of preparing a
`According to one embodiment, the present
`pharmaceutical composition comprising voriconazole, which process comprises the steps of: (a)
`dissolving one or more of a chelating agent, buffering agent,
`isotonicity agent and/or
`preservative in a suitable aqueous medium, such as water for injection; (b) milling voriconazole
`in the presence of one or more surfactants; (c) adding the milled drug to the product of step (a);
`(d). preparing a separate mixture of a suitable polymer such as hydroxyethyl! cellulose and an
`aqueous medium, and autoclaving the mixture; (e) adding the drug mixture obtainedin step (c)
`to polymer mixture obtained in step (a); and optionally (f} making the volume with water for
`injection and adjusting the pH.
`ae
`the present
`According to another embodiment,
`invention provides.a process of preparing a
`pharmaceutical composition comprising voriconazole, which process comprises the steps of: (a)
`dispersing; suspending or dissolving voriconazole in a mixture of one or more oils and one or
`more surfactants; (o) adding a suitable preservative such as benzalkonium chloride to the drug-
`containing mixture; and optionally (c) adding additional oi] to make up the final volume.
`According to yet another embodiment, the present invention provides a process of preparing a
`-pharmaceutical composition comprising’ voriconazole, which process comprises thesteps of: (a)
`dispersing, suspending or dissolving voriconazole: and a_
`suitable preservative ‘such as
`benzalkonium ‘chlorideiin one or more oils; and optionally(b) adding additional oi! to make up
`the.final. volume. The present invention also.provides a method of preventing or treating, a.
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`‘topical or systemicfungal infection comprising’ administering a ready-to-use pharmaceutical
`composition comprising voriconazole to a patient in need thereof.
`
`. Further, the present invention also provides use of a ready-to-use pharmaceutical composition
`comprising voriconazole in the manufacture of a medicament for treating topical or systemic |
`funga! infection.
`,
`
`_
`
`The following examples are for the purpose of illustration of the invention only and are not
`
`intended in any way to limit the scope of the present invention.
`
`Example 1: Suspension formulation
`
` Water for injection
`
`q.s.to 100 mi
`
`\. Tyloxapo! was solubilized in water with the aid of heat. | Drug was added to this solution .
`followed by autoclave at 121°C for 30 min. Mixture was cooled and then ball milled.
`
`2. Hydroxyethylcellulose was added to water and heated.
`3. Edetate disodium, Boric acid, Sodium Chloride, and Benzalkonium chloride were added to
`water.andfiltered, followed by addition of the.drug part (1).
`
`4. Step 3 mixture was added to step 2, final volume was made up with water and pH was
`adjusted.
`
`Example 2: Oily formulation
`
`Ingredients
`
`Quantity
`(*wiv)
`ee =
`Voriconazole ee O03. |
`
`Benzalkonium chloride . -
`
`
`
`
`oo
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` Liquid Paraffin ar Tqs.to 100 mir
`
`Process: |
`1. Voriconazole was dispersed in span 80 and part of the liquid paraffin added under
`stirring, followed by addition of Benzalkonium chloride.
`—
`:
`
`2. Final volume was madeup with liquid paraffin.
`
`_ Example 3: Oily formulat