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US 20120129819A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0129819 A1 Vancaillie et al. (43) Pub. Date: May 24, 2012

(54) GEL COMPOSITIONS FOR Publication Classi?cation ADMINISTRATION OF (51) Int Cl PHARMACEUTICALLY ACTIVE A 61K 31/565 (200601) COMPOUNDS A61P 31/00 (2006.01) A61P 29/00 2006.01 (75) Inventors: Thierry Vancaillie, Castlecrag A 611, 5/24 g2oo6~olg (AU), Alan Hewitt, Wrexham (GB) A611) 13/00 (200601) A61P 23/00 2006.01 (73) Assignee: Medortus (UK) Ltd, Wrexham A611; 25/04 E200601; (GB) A61P 1 7/00 (2006.01) A61P 15/00 (2006.01) (21) Appl' No" 13/264311 (52) us. Cl...... 514/170; 514/182; 514/171 (22) PCT Filed: Apr. 14, 2010 (57) ABSTRACT

(86) PCT No... PCT/AU10/00408 The P resent invention P rovides a P harmaceutical com P osition in the form of a Water-based gel comprising: at least one § 371 (6X1), pharmaceutically active compound; at least one gelling agent; (2)’ (4) Date; Feb 9, 2012 a solubilising agent; and Water, Wherein said composition is free or substantially free of unsubstituted monohydric alco (30) Foreign Application Priority Data hols having between 1 and 6 carbon atoms. The invention also relates to methods for preparing the compositions and uses Apr. 14, 2009 (AU) ...... 2009901585 thereof. US 2012/0129819 A1 May 24, 2012

GEL COMPOSITIONS FOR ders (such as skin disorders), a compound useful in the con ADMINISTRATION OF trol of infection, a compound useful in the treatment of PHARMACEUTICALLY ACTIVE in?ammatory conditions, a compound useful in the treatment COMPOUNDS of sexual dysfunction, a compound useful in the treatment of urological disorders, a compound useful in anaesthesia, an TECHNICAL FIELD analgesic compound, a compound Which is an ot-adrenergic [0001] The present invention relates to Water-based gel receptor agonist, a hormone or a prohormone. compositions comprising at least one pharmaceutically active [0015] The hormone may be a , a thyroid hor compound, and also to methods of administering the compo mone or a groWth hormone. sitions. [0016] The sex hormone may be an estrogen (for example estriol), an (for example ) or a proge BACKGROUND OF THE INVENTION stagen. [0017] The hormone may be a hormone used in hormone [0002] A major dif?culty encountered With pharmaceutical replacement therapy. compounds, particularly those of higher molecular Weight, is [0018] In one embodiment, the hormone is a natural or that they are insoluble in aqueous solution. Because the bio synthetic estrogen, for example estriol, estrone or . availability and hence e?icacy of many pharmaceutical com [0019] The composition may comprise at least tWo phar pounds is largely dependent on their presence in a soluble maceutically active compounds selected from the group con form, the formulation of Water-insoluble compounds in aque sisting of: a natural or synthetic estrogen, an analgesic com ous delivery vehicles is problematic. pound, a compound useful in anaesthesia and an ot-adrenergic [0003] In the context of topical delivery vehicles this prob receptor agonist. lem has been addressed by the incorporation of an organic [0020] The composition may comprise at least tWo phar solvent into the vehicle Which improves the solubility of the maceutically active compounds, Wherein one of the pharma Water-insoluble compound(s), and hence increases bioavail ceutically active compounds is a natural or synthetic estro ability. Where the Water-insoluble compounds are gen, and the other pharmaceutically active compound(s) hormones loWer alcohols (i.e. alcohols having betWeen 1 and is/are selected from the group consisting of: an analgesic 6 carbon atoms) are typically used to enhance solubility. compound, a compound useful in anaesthesia and an ot-adr HoWever, loWer alcohols such as ethanol have the undesired energic receptor agonist. effect of drying skin as a result of solubilisation of the hydro [0021] The analgesic compound may be tramadol, the com phobic components thereof. In addition, stinging also occurs pound useful in anaesthesia may be aicaine anaesthetic and When loWer alcohols come into contact With sensitive mem the ot-adrenergic receptor agonist may be clonidine. branes such as the vagina. A further problem associated With [0022] The hormone or prohor'mone may be selected from the use of ethanol is that it cannot be included in halal medi the group consisting of: thyroxine, diiodothyrosine, melato cations. nin, epinephrine, natural and synthetic estrogens, dehydroe [0004] There is therefore a need for compositions Wherein piandrosterone, ketodehydroepiandrosterone, testosterone, Water-insoluble compounds can be effectively solubilised in and human groWth hormone. the absence of loWer alcohols. [0023] The at least one pharmaceutically active compound may be a steroidal compound. SUMMARY OF THE INVENTION [0024] The at least one gelling agent may be selected from [0005] In a ?rst aspect, the present invention provides a the group consisting of: algae extracts, gums, polysaccha pharmaceutical composition in the form of a Water-based gel rides, starches, pectins, hydrolysed proteins, cellulose deriva comprising: tives and polymers comprising pendant carboxylic acid [0006] (i) at least one pharmaceutically active compound; groups, or esters thereof, or comprising pendant anhydrides [0007] (ii) at least one gelling agent; of dicarboxylic acid groups and block co-polymers based on [0008] (iii) a solubilising agent; and ethylene oxide and/or propylene oxide. The gelling agent [0009] (iv) Water, may be natural, synthetic or semi-synthetic. Wherein said composition is free or substantially free of [0025] In one embodiment, the gelling agent may be unsubstituted monohydric alcohols having betWeen 1 and 6 selected from the group consisting of: polymers comprising carbon atoms. pendant carboxylic acid groups, or esters thereof, or compris [0010] The at least one pharmaceutically active compound ing pendant anhydrides of dicarboxylic acid groups and block may be present in the composition in an amount betWeen co-polymers based on ethylene oxide and/or propylene oxide. about 0.0005% (W/W) and about 25% (W/W), or betWeen [0026] The gelling agent may be a carbomer. about 0.001% (W/W) and about 5% (W/W). [0027] The carbomer may be a polymer of acrylic acid [0011] The at least one pharmaceutically active compound cross-linked With polyalkenyl ethers or divinyl glycol. may be a compound Which is insoluble in Water or sparingly [0028] The carbomer may be a copolymer of acrylic acid soluble in Water. and long chain alkyl acrylates crosslinked With polyalkenyl [0012] The composition may further comprise at least one ethers. pharmaceutically active compound Which is soluble in Water. [0029] The gelling agent may be present in the composition [0013] The at least one pharmaceutically active compound in an amount betWeen about 0.01% (W/W) and about 50% may be any compound Which provides a therapeutic bene?t or (W/W), or betWeen about 0.05% (W/W) and about 10% (W/W). a cosmetic bene?t to a subject. [0030] The solubilising agent may be selected from the [0014] The at least one pharmaceutically active compound group consisting of pyrrolidone or a derivative thereof, castor may be a compound active in the gynaecological ?eld, a oil, polyethoxylated castor oil, diethylene glycol monoethyl compound useful in the treatment of epithelial tissue disor ether, propylene glycol caprylate, propylene glycol mono US 2012/0129819 A1 May 24, 2012

caprylate, medium chain glycerides, 2-methacryloxyeth ily solely”. Furthermore, variations of the Word “compris ylphosphonylcholine, cyclodextrins and derivatives thereof, ing”, such as “comprise” and “comprises”, have correspond lecithin, polysorbates, PEG-phospholipids, phospholipids, ingly varied meanings. cholesterol-PEG and saturated polyglycolised CS-Cl0 glyc [0053] In the context of the present speci?cation, the term erides. “unsubstituted monohydric alcohols having between 1 and 6 [0031] The solubilising agent may be a non-alcoholic solu bilising agent. carbon atoms” is understood to mean compounds having a single hydroxy group and a total of between 1 and 6 carbon [0032] The solubilising agent may be an N-alkyl-pyrroli done such as N-methylpyrrolidone. atoms, Wherein the carbon atoms are not substituted With any [0033] The composition may comprise betWeen about 30% other functional groups. The term excludes monohydric alco (W/W) and about 90% (W/W) of Water. hol compounds having carbon chains interrupted by heteroa [0034] The composition may comprise betWeen about 50% toms, for example oxygen and nitrogen. In one embodiment (W/W) and about 90% (W/W) of Water. of the invention the unsubstituted monohydric alcohol having [0035] The composition may be adapted for topical or between 1 and 6 carbon atoms is ethanol. parenteral administration. In one embodiment, the composi [0054] In the context of the present speci?cation, the term “ tion is a topical composition. . . . or a derivative thereof ’ in relation to pyrrolidone includes [0036] The composition may further comprise one or more pyrrolidone compounds having a Cl-Cl0 alkyl or a Cl-C6 emollients, moisturisers or humectants. alkyl group attached to the nitrogen and/or one or more [0037] The composition may be adapted for gynaecologi Cl-Cl0 alkyl groups or one or more Cl-C6 alkyl groups cal application, for example for application to the vaginal attached to one or more of the carbon atoms of the pyrrolidone epithelial tissue. nucleus. Examples of pyrrolidone derivatives include, but are [0038] The composition may be free or substantially free of not limited to: N-methyl pyrrolidone, N-vinyl pyrrolidone, monohydric alcohols having between 1 and 6 carbon atoms. l,4-dimethyl-2-pyrrolidone and l-ethyl-5-propyl-2-pyrroli [0039] The composition may have a viscosity betWeen done. about 40,000 and 70,000 mPa~s at 25° C. [0055] In the context of the present speci?cation, the term [0040] In a second aspect, the present invention provides a “about” is understood to refer to a range of values that a method for preparing a pharmaceutical composition in the person of skill in the art Would consider equivalent to the form of a Water-based gel, the method comprising: recited value in the context of achieving the same function or [0041] (i) admixing a pharmaceutically active compound result. and a solubilising agent; [0042] (ii) adding Water; and [0056] In the context of the present speci?cation, the term [0043] (iii) adding a gelling agent and agitating the result “Water-based” means that Water is a, or the, major component ing mixture for a period of time su?icient to form a gel. of the composition. [0044] Step (i) may further comprise agitating the resulting [0057] In the context of the present speci?cation, the terms mixture for a period of time su?icient to at least partially “substantially soluble” and “substantially solubilise” mean solubilise the pharmaceutically active compound. that the majority of the pharmaceutically active compound is [0045] Each of the components recited in the second aspect dissolved in the composition. For example, at least 60%, or at may be as de?ned in the ?rst aspect. least 70%, or at least 80%, or at least 90%, or at least 95%, or [0046] In a third aspect, the present invention provides a at least 98%, or at least 99% of the pharmaceutically active method for topically administering at least one pharmaceuti compound may be dissolved in the composition. cally active compound to a subject, the method comprising [0058] In the context of the present speci?cation, the term administering to an epithelial layer of a tissue or organ of the “gel” means a material comprising a continuous solid net subject a composition of the ?rst aspect. Work that is assembled from particles or polymers embedded [0047] The at least one pharmaceutically active compound in an aqueous phase. The term “gel” also includes a compo may be a compound active in the gynecological ?eld, for sition that comprises at least one gelling agent described example an estrogen. herein. [0048] The subject may be a female. [0059] In the context of the present speci?cation, the term [0049] The epithelial tissue may be vaginal epithelial tis “dissolved” means that all of the pharmaceutically active sue compound is solubilised in the composition. [0050] In a fourth aspect, the present invention provides a [0060] In the context of the present speci?cation, the term method for parenterally administering at least one pharma “therapeutic bene?t” means that the compound or com ceutically active compound to a subject, the method compris pounds to Which it refers provide a bene?cial effect in the ing injecting Within tissue planes of a subject a composition of treatment of a disease or condition, or any symptoms thereof, the ?rst aspect. or in the prevention of a disease or condition in a subject, for example a human. DEFINITIONS [0061] In the context of the present speci?cation, the term [0051] In the context of the present speci?cation, the terms “cosmetic bene?t” means that the compound or compounds “a” and “an” are used herein to refer to one or to more than one to Which it refers provide a bene?cial effect in relation to (i.e. to at least one) of the grammatical object of the article. By cleansing, beautifying, promoting attractiveness or altering Way of example, “an element” means one element or more the appearance of a subject, for example a human. than one element. [0062] In the context of the present speci?cation, the term [0052] In the context of the present speci?cation, the term “epithelial layer” means external and internal epithelial sur “comprising” means “including principally but not necessar faces of the body. US 2012/0129819 A1 May 24, 2012

[0063] In the context of the present speci?cation, the term , gestonorone, , , medrox “non-alcoholic solubilising agent” means an agent Which is yprogesterone, and , selective estro free or substantially free of alcohols, including polyhydric gen receptor modulators such as tamoxifen, raloxifene, alcohols. toremifene and clomiphene, compounds useful in the treat [0064] In the context of the present speci?cation, the term ment of endometriosis such as and triptorelin, com “substantially free” is understood to mean less than about pounds useful for inducing labour and/or cervical ripening 0.01%, or less than about 0.005%, or less than about 0.001% such as oxytocin and misoprostol, spermicidal compounds of the recited component. and such as testosterone. In one embodiment, the [0065] In the context of the present speci?cation, the term compounds active in the gynaecological ?eld may be natural “carbomer” means homopolymers, copolymers and inter or synthetic estrogens. In another embodiment, the com polymers based on an acrylic acid backbone Which may or pounds useful in the gynaecological ?eld may be selected may not be cross-linked. from the group consisting of: estrone, estradiol, estriol, test [0066] In the context of the present speci?cation, the term osterone and progesterone. “prohormone” is understood to mean a compound that can be [0073] Examples of compounds active in the treatment of converted into a hormone. For example, a compound that can sexual dysfunction or urological disorders include, but are not be converted into a hormone Within the body (i.e. in vivo). limited to clomipramine, phentolamine, apomorphine, pape varine and pro staglandin. DETAILED DESCRIPTION OF THE INVENTION [0074] Examples of compounds useful in anaesthesia [0067] The present invention is directed to a pharmaceuti include local anaesthetics such as ester and amide anaesthet cal composition in the form of a Water-based gel comprising ics, for example procaine, amethocaine (tetracaine), cocaine, at least one pharmaceutically active compound, at least one lidocaine, prilocaine, bupivicaine, levobupivacaine, ropiv gelling agent, a solubilising agent and Water, Wherein said acaine, mepivacaine, dibucaine and other4caine anaesthet composition is free or substantially free of unsubstituted ics. monohydric alcohols having betWeen 1 and 6 carbon atoms. [0075] Examples of hormones include sex hormones, thy [0068] The present invention is based on the discovery by roid hormones and groWth hormone, such as for example, the inventors that pharmaceutically active compounds Which thyroxine, diiodothyrosine, melatonin, epinephrine, natural are insoluble or sparingly soluble in Water are able to be and synthetic estrogens, , ketodehy solubilised in a Water-based gel composition in the presence droepiandrosterone, testosterone, progesterone and human of a gelling agent and a solubilising agent. Because the gel groWth hormone. compositions of the present invention are free or substantially [0076] Examples of analgesic compounds include narcotic free of unsubstituted monohydric alcohols having betWeen 1 and non-narcotic analgesics such as tramadol, acetomi and 6 carbon atoms, application to epithelial tissue does not nophen, ibuprofen, naproxen, buprenorphine, morphine; result in a drying effect nor a stinging sensation When applied codeine, propoxyphene, fentanyl and amitriptyline. to sensitive membranes such as the vagina. Typically, the gel [0077] Examples of ot-adrenergic receptor agonists compositions of the invention are clear or transparent gels. include: clonidine, guanfacine, methoxamine, oxymetaZoline [0069] In one embodiment of the invention, the at least one and guanabenZ. pharmaceutically active compound may be substantially [0078] In one embodiment, the ot-adrenergic receptor ago soluble or dissolved in the composition. The inclusion of the nist is an otZ-adrenergic receptor agonist. pharmaceutically active compound in a soluble or substan [0079] Examples of anti-bacterial compounds include, but tially soluble form in the composition may increase its bio are not limited to antibiotics such as erythromycin, spiramy availability as compared to When the compound is present in cin, clarithromycin, clindamycin and tretinoin. Examples of a suspended form. anti-viral compounds include, but are not limited to acyclovir, [0070] The at least one pharmaceutically active compound amantadine, valacyclovir and rimantadine. Examples of anti may be any compound Which provides a therapeutic bene?t or fungal compounds include, but are not limited to chlorphen a cosmetic bene?t to a subject, for example an animal such as esin, clioquinol, haloprogin, undecylenic acid, tolnaftate, ?u a human. conaZole, butoconaZole, clotrimaZole, econaZole, [0071] The at least one pharmaceutically active compound miconaZole, terconaZole and tioconaZole. Examples of anti may be a compound active in the gynaecological ?eld, a protoZoal compounds include, but are not limited to anti compound useful in the treatment of epithelial tissue disor malarial drugs, spiramycin and clioquinol. ders (such as skin disorders), a compound useful in the con [0080] Examples of compounds useful in the treatment of trol of infection, for example an anti-bacterial, anti-viral, epithelial disorders include, but are not limited to steroidal anti-fungal or anti-protoZoal compound, a compound useful compounds such as . in the treatment of in?ammatory conditions, a compound [0081] Examples of compound useful in the treatment of useful in the treatment of sexual dysfunction, a compound in?ammatory conditions include, but are not limited to useful in the treatment of urological disorders, a compound NSADDS. useful in anaesthesia, an analgesic compound, a compound [0082] In another embodiment the at least one pharmaceu Which is an ot-adrenergic receptor agonist, a hormone or a tically active compound is a steroidal compound. Examples prohormone. of steroidal compounds include, but are not limited to estra [0072] Examples of compounds active in the gynaecologi diol and esters thereof, ethinyl estradiol, conjugated estro cal ?eld include, but are not limited to natural and synthetic gens, testosterone and esters thereof, , dro estrogens such as estriol, estradiol, estrone, ethinyl estradiol, spirenone, etonogestrel, , , mestranol, dienestrol, quinestrol and diethylstilbestrol, , norethisterones, , norethindrone, progestagens such, as , gestodene, levonorgestrel, norethindrone acetate, norethynodrel, norgestimate, norg , norgestimate, desogestrel, , estrel, , acetate, proges US 2012/0129819 A1 May 24, 2012

terone, spironolactones, , canrenoate, , betWeen about 0.05% (W/W) and about 30% (W/W), or , mexrenoate, prorenoate, epostane, , betWeen about 0.05% (W/W) and about 20% (W/W), or oxprenoate, , , prorenone, , betWeen about 0.05% (W/W) and about 10% (W/W), or beclomethasone dipropionate, betamethasone, betametha betWeen about 0.05% (W/W) and about 5% (W/W), or betWeen sone valerate, budesonide, clobetasol propionate, clobeta about 0.05% (W/W) and about 3% (W/W), or betWeen about sone butyrate, acetate, , dexamethasone, 0.1% (W/W) and about 2% (W/W). Where a gelling agent sold ?udrocortisone acetate, , , alfacalci under the trade name Carbopol® is employed, the amount dol, calcifediol, calciferol and calcitriol. used may be in the range of betWeen about 0.05% (W/W) and [0083] In an embodiment of the invention, the composi about 5% (W/W). Where a gelling agent sold under the trade tions comprise at least one pharmaceutically active com name Pluronic® is employed, the amount used may be in the pound that is insoluble in Water or sparingly soluble in Water, range of betWeen about 1% (W/W) and about 40% (W/W). and at least one pharmaceutically active compound Which is soluble in Water. [0091] The solubilising agent may be selected from the group consisting of: pyrrolidone or a derivative thereof, cas [0084] The at least one pharmaceutically active compound tor oil, polyethoxylated castor oil, diethylene glycol monoet may be present in the composition in an amount betWeen hyl ether, propylene glycol caprylate, propylene glycol mono about 0.0005% (W/W) and about 20% (W/W), or betWeen caprylate, medium chain glycerides, 2-methacryloxyeth about 0.0005% (W/W) and about 10% (W/W), or betWeen ylphosphonylcholine, cyclodextrins and derivatives thereof, about 0.005% (W/W) and about 5% (W/W), or betWeen about lecithin, polysorbates, PEG-phospholipids, phospholipids, 0.005% (W/W) and about 3% (W/W), orbetWeen about 0.005% (W/W) and about 1% (W/W), or betWeen about 0.005% (W/W) cholesterol-PEG, saturated polyglycolised CS-Cl0 glycer ides. In one embodiment, the solubilising agent is a non and about 0.5% (W/W). alcoholic solubilising agent, for example pyrrolidone or a [0085] Gelling agents that may be used in the compositions derivative thereof. of the invention include, but are not limited to: algae extracts, gums, polysaccharides, starches, pectins, hydrolysed pro [0092] The solubilising agent may be present in an amount teins, cellulose derivatives, polymers comprising pendant suf?cient to ensure that the pharmaceutically active com carboxylic acid groups, or esters thereof, polymers compris pound is substantially soluble or dissolved in the composi ing pendant anhydrides of dicarboxylic acid groups and block tion. The amount of solubilising agent present in the compo co-polymers based on ethylene oxide and/ or propylene oxide. sition Will be dependent on the degree of insolubility of the [0086] Algae extracts that may be used include, but are not pharmaceutically active compound(s). Those skilled in the art limited to alginates and carrageenans. Cellulose derivatives Will, by routine trial and experimentation, be able to deter that may be used include, but are not limited to methylcellu mine the amount of solubilising agent required to either dis loses, ethylcelluloses hydroxypropylmethylcelluloses, solve or substantially solubilise the pharmaceutically active hydroxyethylcelluloses and carboxymethylcelluloses, Which compound. The solubilising agent may be present in an may or may not be cross-linked. Hydrolysed proteins include amount betWeen about 1% (W/W) and about 40% (W/W), or but are not limited to gelatin. betWeen about 1% (W/W) and about 30% (W/W), or betWeen [0087] Polymers comprising pendant carboxylic acid about 1% (W/W) and about 20% (W/W), or betWeen about 1% groups may be homopolymers, copolymers or interpolymers (W/W) and about 15% (W/W), or betWeen about 1% (W/W) and comprising an acrylic acid backbone, for example carbomers. about 10% (W/W). In one embodiment, the gelling agent is a polymer of acrylic [0093] The compositions may comprise Water in an amount acid cross-linked With polyalkenyl ethers or divinyl glycol. In betWeen about 50% (W/W) and about 90% (W/W), or betWeen an alternative embodiment, the gelling agent is a copolymer about 60% (W/W) and about 80% (W/W). of acrylic acid and long-chain alkyl acrylates crosslinked With [0094] The compositions may further comprise additional polyalkenyl ethers, for example allyl pentaerythritol. pharmaceutically acceptable excipients knoWn in the art, for [0088] Carbomers suitable for use in the present invention example diluents, adjuvants, humectants, emollients (mois include, but are not limited to, those commercially available turisers) and preservatives. The inclusion of humectants and under the trade names Carbopol® (LubriZol Advanced Mate emollients provide a moisturising effect to the topical com rials, Inc.), Pemulen® (LubriZol Advanced Materials, Inc.), positions When applied repeatedly to the skin thereby further Noveon® (LubriZol Advanced Materials, Inc.), Synthalen® minimising any drying effect that the composition may (3V Sigma) and Hivis Wako® (Wako Pure Chemicals Co.). impart When applied to sensitive membranes such as the Carbomers used in the present invention may be carbomers vagina. having Brook?eld viscosities in the range of about 40,000 to [0095] A Wide variety of suitable emollients are knoWn to 70,000 mPa-s at 250 C. In one embodiment, the carbomer is those skilled in the art. See for example the International Carbopol®980. Cosmetic Ingredient Dictionary and Handbook, Eds. Wen [0089] Block co-polymers based on ethylene oxide and/or ninger and McEWen, The Cosmetic, Toiletry, and Fragrance propylene oxide that are suitable for use in the present inven Assoc., Washington, DC, 7”’ Edition, 1997. Emollients use tion include those commercially available under the trade ful in the present invention include, but are not limited to: name Pluronic®. In one embodiment, the block co-polymer glycerin, propylene glycol (for example PEG300), sorbitol, based on ethylene oxide and/or propylene oxide is lanolin, lanolin derivatives, polyethylene glycol, aloe vera, Pluronic®F127 NP. glucamate DOE 120, allantoin, alginates, monoester salts of [0090] The amount of gelling agent present in the compo sulfosuccinates, ceramides, and mixtures thereof. sition Will depend on the particular gelling agent being used. [0096] Examples of humectants include, but are not limited Typically the amount of gelling agent present in the compo to glycerol, sorbitol, polyethylene glycol, mono- and oligo sition is betWeen about 0.01% (W/W) and about 50% (W/W), or meric sugars, natural extracts such as quillaia, lactic acid and betWeen about 0.05% (W/W) and about 40% (W/W), or urea. US 2012/0129819 A1 May 24, 2012

[0097] Examples of preservatives include but are not lim sition may further comprise an emollient, for example aloe ited to benZyl alcohol and parabens. vera. The composition is free, or substantially free of unsub [0098] In an embodiment of the ?rst aspect, the composi stituted monohydric alcohols having betWeen 1 and 6 carbon tion comprises: atoms. [0099] (i) a pharmaceutically active compound Which is an [0116] The present invention also relates, in a second estrogen; aspect, to a method for preparing a pharmaceutical composi [0100] (ii) a gelling agent Which is a carbomer; tion in the form of a Water-based gel, the method comprising: [0101] (iii) a solubilising agent Which is pyrrolidone or a (i) admixing a pharmaceutically active compound and a solu derivative thereof; and bilising agent; (ii) adding Water, and (iii) adding a gelling [0102] (iv) Water. agent and agitating the resulting mixture for a period of time [0103] The estrogen may be a natural or synthetic estrogen, suf?cient to form a gel. The method does not include addition and may be present in an amount betWeen about 0.01% (W/W) of an unsubstituted monohydric alcohol having betWeen 1 and about 3% (W/W). The carbomer may be a polymer sold and 6 carbon atoms. under the trade name Carbopol® and may be present in an [0117] Step (i) may further comprise agitating the resulting amount betWeen about 0.05% (W/W) and about 2% (W/W). mixture for a period of time su?icient to at least partially The pyrrolidone or a derivative thereof may be N-methyl-2 solubilise the pharmaceutically active compound. The agitat pyrrolidone (for example the product sold under the trade ing may be performed by standard methods knoWn to those name Pharmasolve® by International Specialty Products) skilled in the art such as stirring, sWirling and/or heating as and may be present in an amount betWeen about 1% (W/W) required. In one embodiment agitation is performed until the and 20% (W/W). The composition may further comprise an pharmaceutically active compound is dissolved in the solu emollient, for example aloe vera. The composition is free, or bilising agent. substantially free of unsubstituted monohydric alcohols hav [0118] The method may further comprise admixing the ing betWeen 1 and 6 carbon atoms. solution obtained folloWing step (i) or step (ii) With a mixture [0104] In an alternative embodiment of the ?rst aspect, the comprising at least one further pharmaceutically active com composition comprises: pound Which is soluble in Water. [0105] (i) an estrogen, clonidine and tramadol; [0119] In an embodiment of the second aspect, the method [0106] (ii) a gelling agent Which is a block co-polymer comprises: based on ethylene oxide and/or propylene oxide; [0120] (i) admixing at least one pharmaceutically active [0107] (iii) a solubilising agent Which is pyrrolidone or a compound Which is insoluble in Water or sparingly soluble in derivative thereof; and Water and a solubilising agent; [0108] (iv) Water [0121] (ii) admixing the mixture obtained in step (i) With a [0109] The estrogen may be a natural or synthetic estrogen. mixture comprising at least one further pharmaceutically The estrogen, clonidine and tramadol may be present in active compound Which is soluble in Water; amounts betWeen about 0.005% (W/W) and about 10% (W/W). [0122] (iii) admixing the mixture obtained in step (ii) With The block co-polymer based on ethylene oxide and/ or propy a gelling agent, and agitating the resulting mixture for a lene oxide may be a polymer sold under the trade name period of time su?icient to form a gel, Wherein Water is added Pluronic® and may be present in an amount betWeen about as part of, or betWeen, steps (i), and/or (ii), and/or (iii). The 1% (W/W) and about 30% (W/W). The pyrrolidone or a deriva method does not include addition of an unsubstituted mono tive thereof may be N-methyl-2 -pyrrolidone (for example the hydric alcohol having betWeen 1 and 6 carbon atoms. product sold under the trade name Pharmasolve® by Interna [0123] The Water may be added as part of, orbetWeen, steps tional Specialty Products) and may be present in an amount (ii) and/or (iii). betWeen about 1% (W/W) and 20% (W/W). The composition [0124] The Water may be added as part of step (ii) and/or may further comprise an emollient, for example aloe vera. (iii). The composition is free, or substantially free of unsubstituted [0125] Each of the components recited above in connection monohydric alcohols having betWeen 1 and 6 carbon atoms. With the second aspect may be as de?ned in the ?rst aspect. [0110] In another embodiment of the ?rst aspect, the com [0126] Where the composition is adapted for topical position comprises: administration, the method may further comprise the addition [0111] (i) an estrogen, tetracaine and clonidine; of one or more emollients, moisturisers or humectants. The [0112] (ii) a gelling agent Which is a block co-polymer one or more emollients, moisturisers or humectants may be based on ethylene oxide and/or propylene oxide; added during or after admixture of the pharmaceutically [0113] (iii) a solubilising agent Which is pyrrolidone or a active compound and the solubilising agent, simultaneously derivative thereof; and When, before or after adding the Water, and/ or simultaneously [0114] (iv) Water When, before or after adding the gelling agent. In one embodi [0115] The estrogen may be a natural or synthetic estrogen. ment, the one or more emollients, moisturisers or humectants The estrogen, tetracaine and clonidine may be present in are added before and after the gelling agent. The method may amounts betWeen about 0.005% (W/W) and about 10% (W/W). further comprise adding additional Water after addition of the The block co-polymer based on ethylene oxide and/ or propy gelling agent. In one embodiment, multiple emollients, mois lene oxide may be a polymer sold under the trade name turisers or humectants are prepared separately and added Pluronic® and may be present in an amount betWeen about prior to or after the addition of the gelling agent. 1% (W/W) and about 30% (W/W). The pyrrolidone or a deriva [0127] Where the compositions are adapted for parenteral tive thereof may be N-methyl-2 -pyrrolidone (for example the administration, one or more non-toxic parenterally accept product sold under the trade name Pharmasolve® by Interna able diluents or carriers may be added to the compositions, for tional Specialty Products) and may be present in an amount example Ringer’s solution, isotonic saline, glucose solution, betWeen about 1% (W/W) and about 20% (W/W). The compo distilled Water or phosphate buffered saline. US 2012/0129819 A1 May 24, 2012

[0128] The present invention is also directed to a method for topically administering at least one pharmaceutically -continued active compound to a subject, the method comprising admin istering to an epithelial layer of a tissue or organ of the subject Component Amount the composition of the ?rst aspect. In one embodiment, the Carbopol ® 980 0.6 g pharmaceutically active compound is a compound active in Aloe Vera Powder (freeze dried) 0.2 g the gynaecological ?eld, for example an estrogen, androgen PEG 300 7.5 ml Glycerol 7.5 ml or progestagen. The subject may be a human, and in one Benzoyl alcohol 100 pl embodiment is a female. The epithelial tissue may be any Trolamine 1 drop epithelial tissue Which is accessible on the body of the sub Distilled Water q.s to 100 ml ject. In one embodiment, the epithelial tissue is the vaginal epithelial tissue. The gel compositions of the present inven tion are mucoadhesive and hence are effectively retained on Example 1.2 mucosal surfaces for extended periods of time. Accordingly the gel compositions are effective at delivering pharmaceuti [0134] cally active compounds to mucosal epithelia. [0129] The present invention is further directed to a method for parenterally administering a pharmaceutically active compound to a subject, the method comprising injecting Component Amount Within tissue planes of a subject a composition of the ?rst Estriol (E3) 15 mg aspect. The tissue planes may de?ne a body cavity such as, but Pharmasolve ® 4 ml Propylene Glycol 3.5 ml not limited to: joint cavities, synovial cavities, bursa, muscle Tetracaine USP 1.12 g compartments, the carpel tunnel or Alcock canal. The com Aloe Vera PoWder (freeze dried) 0.2 g position may be injected Within a tissue plane so as to alloW PEG 300 4.5 ml the pharmaceutically active compound to come into contact Glycerol 4.0 ml Clonidine 3.8 mg With synovia, tendon sheaths, fascia or neurovascular Benzoyl alcohol 100 pl bundles. Pluronic ® (F127 NF) 30% solution 80 ml [0130] In one embodiment, the method may involve inj ec 36% hydrochloric acid 0.3 ml tion of a local anaesthetic Within the Alcock canal for block Distilled Water q.s to 100 ml ing pudendal nerve pain. Injection of the gel compositions of the present invention Will also result in a reduction in the stinging sensation associated With the injection because the Example 1.3 compositions are free or substantially free of unsubstituted monohydric alcohols having betWeen 1 and 6 carbon atoms. [0135] In addition, injection of a gel composition Within tissue planes may, in addition to providing increased solubility and hence bio-availability, result in a longer retention time of the Component Amount pharmaceutically active compound(s) at the desired site. [0131] The invention Will noW be described in more detail, Estriol (E3) 15 mg by Way of illustration only, With respect to the folloWing Pharmasolve ® 4 ml Propylene Glycol 3.5 ml examples. The examples are intended to serve to illustrate this Tramadol HCl 3.4 g invention and should not be construed as limiting the gener Aloe Vera PoWder (freeze dried) 0.2 g ality of the disclosure of the description throughout this speci PEG 300 4.5 ml ?cation. Glycerol 4.0 ml Clonidine 3.8 mg Benzoyl alcohol 100 pl EXAMPLES Pluronic ® (F127 NF) 30% solution 80 ml Example 1 Distilled Water q.s to 100 ml Water-Based Gel Compositions Comprising an Estrogen Example 2 [0132] Water-based gel compositions in accordance With Preparation of the Water-Based Gel Composition of the invention comprise the folloWing components in the Example 1.1 amounts speci?ed: [0136] The Water-based gel composition of Example 1.1 Example 1.1 may be prepared by the folloWing method: [0133] [0137] 1.1 Disperse 0.2 g Aloe Vera PoWder in 20 ml of Warm (50° C.) puri?ed Water. Continue stirring over heat until the poWder has completely gelled. [0138] 1.2 Whilst mixing, add 7.5 ml of PEG 300 and 7.5 Component Amount ml glycerol. [0139] 1.3 Weigh 30 mg estriol directly into a separate Estriol (E3) 30 mg Pharmasolve ® 8 ml beaker. Propylene Glycol 5 ml [0140] 1.4 Add 8 ml of Pharmasolve® and sWirl until the estriol has completely dissolved. US 2012/0129819 A1 May 24, 2012

[0141] 1.5 Add 40 ml of puri?ed Water and agitate by mix [0162] 4.4 Add 1 drop of trolamine to the mix. NOTE: a gel ing. Will rapidly form so the beaker should be secured to prevent [0142] 1.6 Whilst mixing add 5 ml of propylene glycol. it rotating With the stirrer. [0143] 1.7 Continue mixing and sift the Carbopol® 980 [0163] 4.5 Transfer the prepared gel to an appropriate siZe powder into Water making sure that no lumps are formed. dispensing jar. The shelf life of the gel is estimated to be 6 [0144] 1.8 Stir until the Carbopol® 980 is completely dis months. persed in the Water phase. Example 4 [0145] 1.9 Add mixture prepared in step 1.2 and continue Preparation of the Water-Based Gel Composition of stirring until completely mixed. Example 1.2 [0146] 1.10 Continue mixing and take volume to 100 ml [0164] The Water-based gel composition of Example 1.2 With puri?ed Water. may be prepared by the folloWing method: [0147] 1 .1 1 Add one drop of Trolamine and continue to mix until Trolamine is evenly distributed in the gel. Increase 1. Preparation of Clonidine Stock Solution mixing speed as gel increases in viscosity but avoid intro [0165] 1.1 Accurately Weigh 1 10 mg Clonidene HCl into a ducing too many air bubbles. 100 ml volumetric ?ask. Dilute to 100 ml With puri?ed [0148] 1.12 Pack into 100 ml opaque dispensing jar. Expiry Water. The solution contains 1.1 mg Clonidine HCl per ml, date is estimated to be 6 months. or 0.95 mg/ml Clonidine. 2. Preparation of Solution A Example 3 [0166] 2.1 Accurately Weigh 1.12 g of Tetracaine into a clean glass beaker. Alternative Preparation of the Water-Based Gel [0167] 2.2 Add 0.3 ml of 36% HCl folloWed by 4 ml of Composition of Example 1.1 clonidiene stock solution prepared in 1 above. [0149] The Water-based gel composition of Example 1.1 [0168] 2.3 Mix the solution. The tetracaine Will begin to may also be prepared by the folloWing method: dissolve. [0169] 2.4 Add the propylene glycol, glycerol and PEG 300 and continue to mix until a clear solution is formed. 1. Preparation of Solution 1 [0170] 2.5 Add 4 ml of solution 2 (see Example 3 above) [0150] 1.1 Warm 100 ml ofpuri?ed Water to 50° C. Whilst and 100 [1.1 of benZoyl alcohol and mix Well. stirring, disperse 1.0 g Aloe Vera PoWder into the Water. [0171] 2.6 Weigh out 0.2 g ofAloe Vera poWder, add to the Continue stirring over heat until the poWder has completely solution prepared in 2.3 above and mix until the Aloe Vera gelled. poWder is dissolved. [0151] 1.2 AlloW to cool then add 37.5 ml of PEG 300 and [0172] 2.7 Place the solution in the refrigerator and alloW to 37.5 ml glycerol. When completely dissolved add 250 [1.1 of cool for 30 minutes. benZoyl alcohol. 3. Preparation of the Gel Composition [0173] 3.1 Remove the base from a 100 ml Topitec Jar and 2. Preparation of Solution 2 place both jar and base in refrigerator. [0174] 3.2 Measure 80 ml of cold 30% Pluronic® solution [0152] 2.1 Accurately Weigh 300 mg of pure estriol into a in a pre-cooled cylinder. 250 ml beaker. [0175] 3 .3 Add the Pluronic® solution to solutionA (Which [0153] 2.2 Add 80 ml of Pharmasolve® and stir until dis has been cooled) prepared above stirring With a pre-cooled solved. glass rod. [0154] 2.3 Transfer to a 100 ml amber bottle. [0176] 3 .4 When Well mixed, transfer the gel solution to the cold Topitec jar. 3. Preparation of Solution 3 [0177] 3.5 Place the jar and liquid mix on the bench and [0155] 3.1 Place 250 ml of puri?ed Water into a beaker. alloW to Warm to room temperature. [0156] 3.2 Heat the Water to 70° C. With continual stirring. [0178] 3 .6 Once the solution has gelled (When the tempera ture exceeds about 15° C.), ?t the base to the jar. [0157] 3.3 Gradually add 3 g of Carbopol® (via a sieve), and continue mixing until the Carbopol® is Well dispersed [0179] 3.7 Expiry date is estimated to be 6 months. The gel in the Water. AlloW the solution to cool Whilst continuing to should NOT be stored refrigerated. mix. Example 5 [0158] 3.4 Once cool, add 25 ml propylene glycol and 250 Preparation of the Water-Based Gel Composition of [1.1 benZoyl alcohol to the mixture. Continue to mix until Example 1.3 dispersed. [0180] The Water-based gel composition of Example 1.3 may be prepared by the folloWing method: 4. Preparation of the Gel Composition 1. Preparation of Clonidine Stock Solution [0159] 4.1 Accurately transfer 35 ml of Solution 1 to a 200 [0181] 1.1 Accurately Weigh 110 mg of Clonidene HCl into ml glass beaker. Place the beaker under the Eka mixer and a 100 ml volumetric ?ask. Dilute to 100 ml With puri?ed begin to mix. Water. The solution contains 1.1 mg Clonidine HCl per ml [0160] 4.2 Accurately transfer exactly 8.0 ml of Solution 2 or 0.95 mg/ml Clonidine. to the beaker. Continue mixing to achieve a homogeneous mix. 2. Preparation of Solution A [0161] 4.3 Accurately transfer 55 ml of Solution 3 to the [0182] 2.1 Transfer 4 ml of Clonidiene stock solution pre mix and continue stirring. pared in 1 above into a small clean glass beaker. US 2012/0129819 A1 May 24, 2012

[0183] 2.2 Add the propylene glycol, glycerol and PEG 300 8. The composition of claim 6, Wherein the analgesic com and mix until a clear solution is formed. pound is amitriptyline. [0184] 2.3 Add 4 ml of solution 2 (see Example 3 above) 9. The composition of claim 1, further comprising corti and 100 pl of benZoyl alcohol, mix Well. sone. [0185] 2.4 Weight out 0.2 g ofAloe Vera powder, add to the 10. The composition of claim 6, Wherein the analgesic solution prepared in 2.3 above and mix until the Aloe Vera compound is tramadol, the compound useful in anaesthesia is poWder is dissolved. a4caine anaesthetic and the ot-adrenergic receptor agonist is [0186] 2.5 Weigh out 3.4 g Tramadol HCl (equivalent to clonidine. 2.98 g of Tramadol free base) poWder and add to the solu 11. The composition of claim 1, Wherein the gelling agent is selected from the group consisting of: algae extracts, gums, tion prepared in 2.4 above. Mix until all poWder has dis polysaccharides, starches, pectins, hydrolysed proteins, cel solved and a clear solution is obtained. lulose derivatives and polymers comprising pendant carboxy [0187] 2.6 Place the solution in the refrigerator and alloW to lic acid groups, or esters thereof, polymers comprising pen cool for 30 minutes. dant anhydrides of dicarboxylic acid groups and block co-polymers based on ethylene oxide and/or propylene oxide. 3. Preparation of the Gel Composition 12. The composition of claim 11, Wherein the gelling agent [0188] 3.1 Remove the base from a 100 ml Topitec Jar and is selected from the group consisting of: polymers comprising place both jar and base in refrigerator. pendant carboxylic acid groups, or esters thereof, or compris [0189] 3.2 Measure 80 ml of cold 30% Pluronic solution in ing pendant anhydrides of dicarboxylic acid groups and block a pre-cooled cylinder. co-polymers based on ethylene oxide and/or propylene oxide. [0190] 3.3 Add the Pluronic® solution to solutionA (Which 13. The composition of claim 12, Wherein the polymer has been cooled) prepared above stirring With a pre-cooled comprising pendant carboxylic acid groups is a carbomer. glass rod. 14. The composition of claim 13, Wherein the carbomer is a polymer of acrylic acid cross-linked With polyalkenyl ethers [0191] 3.4 When Well mixed, transfer the gel solution to the or divinyl glycol. cold Topitec jar. 15. The composition of claim 13, Wherein the carbomer is [0192] 3.5 Place the jar and liquid mix on the bench and a copolymer of acrylic acid and long-chain alkyl acrylates alloW to Warm to room temperature. crosslinked With polyalkenyl ethers. [0193] 3 .6 Once the solution has gelled (When the tempera 16. The composition of claim 1, Wherein the gelling agent ture exceeds about 15° C.), ?t the is base to the jar. is present in the composition in an amount betWeen about [0194] 3.7 Expiry date is estimated to be 6 months. The gel 0.01% (W/W) and about 50% (W/W). should NOT be stored refrigerated. 17. The composition of claim 1, Wherein the composition 1. A pharmaceutical composition in the form of a clear has a viscosity betWeen about 40,000 and 70,000 mPa~s at 250 Water-based gel comprising: C. (i) at least one pharmaceutically active compound_Which 18. The composition of claim 1, Which is a topical compo is an estrogen, androgen or progestagen; sition. (ii) at least one gelling agent; 19. The composition of claim 18, Wherein the composition (iii) a solubilising agent Which is N-methylpyrrolidone; comprises one or more emollients, moisturisers or humec and tants. (iv) Water, 20. The composition of claim 1, Wherein the composition is Wherein said composition is free or substantially free of adapted for gynaecological application. unsubstituted monohydric alcohols having betWeen 1 and 6 21. A method for preparing a pharmaceutical composition carbon atoms. 2. The composition of claim 1, Wherein the at least one in the form of a clear,Water-based gel, the method comprising: pharmaceutically active compound is present in the compo (i) admixing an estrogen, androgen or progestagen and sition in an amount betWeen about 0.0005% (W/W) and about N-methylpyrrolidone; 25% (W/W). (ii) adding Water; and 3. The composition of claim 2, Wherein the at least one (iii) adding a gelling agent and agitating the resulting mix pharmaceutically active compound is present in the compo ture for a period of time su?icient to form a gel, Wherein sition in an amount betWeen about 0.001% (W/W) and about the method does not include addition of an unsubstituted 5% (W/W). monohydric alcohol having betWeen 1 and 6 carbon 4. The composition of claim 1, further comprising at least atoms. one pharmaceutically active compound Which is soluble in 22. The method of claim 21, Wherein step (i) further com Water. prises agitating the mixture for a period of time su?icient to at 5. The composition of claim 1, Wherein the at least one least partially solubilise the estrogen, androgen or proge pharmaceutically active compound is an estrogen. stagen. 6. The composition of claim 1, comprising at least tWo 23. A method for topically administering at least one phar pharmaceutically active compounds selected from the group maceutically active compound to a subject, the method com consisting of: a natural or synthetic estrogen, an analgesic prising administering to an epithelial layer of a tissue or organ compound, a compound useful in anaesthesia and an ot-adr of the subject a composition of claim 1. energic receptor agonist. 24. The method of claim 23, Wherein the epithelial tissue is 7. The composition of claim 6, comprising at least tWo vaginal epithelial tissue. pharmaceutically active compounds, Wherein one of the phar 25. A method for parenterally administering at least one maceutically active compounds is a natural or synthetic estro pharmaceutically active compound to a subject, the method gen, and the other pharmaceutically active compound(s) comprising injecting Within tissue planes of a subject a com is/are selected from the group consisting of: an analgesic position of claim 1. compound, a compound useful in anaesthesia and an ot-adr energic receptor agonist.