USOO585833OA United States Patent (19) 11 Patent Number: 5,858,330 Boltri et al. (45) Date of Patent: *Jan. 12, 1999

54). PHARMACEUTICAL FORMULATIONS IN 52 U.S. Cl...... 424/45; 424/450; 424/484; FORM OF THIXOTROPIC GEL 424/401; 514/772 58 Field of Search ...... 424/45, 450, 484; 75 Inventors: Luigi Boltri, Antonietta Coppola; 514/772 Marco Gentile; Gaetano Clavenna, all of Milan, Italy 56) References Cited 73) ASSignee: Dompe' S.p.A., L'Aquila, Italy U.S. PATENT DOCUMENTS * Notice: This patent issued on a continued pros- 4,992.256 2/1991 Skaggs ...... 424/45 ecution application filed under 37 CFR 4,996,240 2/1991 Osipow et al.. 1.53(d), and is subject to the twenty year patent term provisions of 35 U.S.C. Primary Examiner Rebecca Cook 154(a)(2). Attorney, Agent, or Firm-Griffin, Butler, Whisenhunt & Szipl, LLP

22 Filed: Mar 18, 1996 The present invention relates to a topical formulation of 30 Foreign Application Priority Data gel-like consistency, but nebulizable by a mechanical pump, containing colloidal Silices as gelifying agent. Mar. 22, 1995 IT Italy ...... MI95AO568 (51) Int. Cl...... A61L 9/04 9 Claims, No Drawings 5,858,330 1 2 PHARMACEUTICAL FORMULATIONS IN Surface area from 50 to 400 m/g FORM OF THXOTROPIC GEL Average diameter from 7 to 40 nm. All of these materials give Similar gelification phenomena The present invention relates to a topical formulation of but, Since gelification occurs through adsorption, the Surface gel-like consistency, but nebulizable by mechanical pump, area characteristics become paramount for the choice of the containing colloidal Silices as gelifying agent. type and amount of colloidal Silica to use. Suitable Silices according to the invention have a Surface PRIOR ART area ranging from 130 to 300 m/g and an average diameter The preparation of a Semi-Solid System nebulizable by of 12 nm. means of a Spray mechanical System seemed up to now to be The present invention uses Specifically as colloidal Silices an unsurmountable problem. In fact, efforts to prepare 1O Aerosils, preferably colloidal Silices with characteristics formulations making use of the conventional, most used similar to Aerosil 200. gelifying agents lead to the production of gels which, Aerosil characteristics of pseudoplasticity and thixotropy although being highly valid, are absolutely not sprayable. are well known, however up to now Said characteristics have Even making a compromise, namely decreasing the System not been made use of in order to Spray/nebulize a product in Viscosity, at the most the emission of the product from the 15 the form of gel by the Simple preSSure of a finger. mechanical pump is obtained, but not the nebulization. In essentially aqueous Systems, aerosils (only) at high Moreover, decreasing Viscosity, the product tends to leak concentrations (5-15%) cause the structuration of water once Sprayed on the concerned part. through adsorption phenomena, until a consistence of gel In the cosmetic field, the So-called gel-Sprays exist, which (or, more correctly, magma). The Aerosil-Water bond is very however have an exceedingly low Viscosity, thereby tending mild and it can be cleaved by even slight Stresses, Such as to leak after the emission, therefore they cannot be even those caused by a mechanical pump. During the StreSS, and defined gels. Moreover they are usually prepared using therefore during the Spray, the Viscosity of the System acrylates Such as Carbopols. remarkably decreases, thereby allowing the nebulization. DISCLOSURE OF THE INVENTION Once applied to the skin, the Sprayed product, no longer The present invention overcomes the problems of the 25 Stressed, quickly returns to its original State, acquiring back prior art, by the use of a high Viscosity System, which is a gel-like consistence. nearly Semisolid, characterized in that it is destructurated by It is particularly Surprising that, when in the formulation a mechanical StreSS of the invention besides Aerosil and water, a leSS polar The pharmaceutical formulations in form of thixotropic Solvent is also present, Such as glycerol, polyoxyethylene gel of the present invention will contain, besides an active glycol, diethylene glycol monoalkyl ether (TranscutolTM), ingredient, a colloidal Silica in an amount from 2 to 15% by N-methylpyrrollidone, glycofurol, isopropanol, ethylene weight, propylene glycol in an amount from 1 to 10% by glycol, propylene glycol, Viscosity falls upon the Slightest weight. Water and any excipients conventionally used in the mechanical StreSS, in the absence of Said Solvent, Such a pharmaceutical technique S, Such as Surfactants, phenomenon appears leSS markedly, but anyhow So as not to preservatives, flavouring agents, co-Solvents and lipophilic 35 affect adversely the thixotropic characteristics according to phases can also be present. Particularly preferred Surfactants the invention. The use of the propylene glycol is particularly are those belonging to the following classes: preferred. Sorbitan esters (for example Span 20, Span 40, Span 60, The topical gel formulation of the present invention can Span 65, Span 80, Span 85); be administered with a Suitable dosage, through doser 40 mechanical pumps which dispense prefixed volumes. Polyoxyethylene Sorbitan esters (for example Tween 80, The topical formulations of the present invention can be Tween 60, Tween 40, Tween 20); used, besides for the topical administration on the skin, also Polyoxyethylalkyl ethers (for example Cremophor A, for the vaginal, nasal, otological administration, wherein the Bryj, Texofor A); absence of leakage and the in loco persistence are particu Polyoxyethylene stearates (for example Myri 52, Myri 45 larly important. 53). The gels of the present invention will preferably be The pharmaceutical formulations of the invention will dispensed by means of mechanical pump dispensers. preferably contain a colloidal Silica having a Surface area of The formulations of the invention can also contain all of 175–225 m/g and an average diameter of 12 nm, in amounts the active ingredients whose topical administration is thera ranging from 2 to 8%, more preferably from 2.5 to 7% by 50 peutically effective. Examples of active ingredients which weight. can be used in the formulations of the invention comprise: In the pharmaceutical formulations of the invention, water non-Steroidal antiinflammatory agents, Such as ketoprofen, may be present in an amount ranging from 60 to 97% by ibuprofen (including optical isomers and Salts thereof), weight. naproxen, diclofenac, diflunisal, nimeSulide, ketorolac, The present invention provides a System characterized by: 55 flurbiprofen, indomethacin, acetylsalicylic acid and the like; Pseudoplasticity: the Viscosity decreases with the increase antifungal drugs. Such as miconazole, econazole, in the intensity of the applied StreSS, fluconazole, tyrothricin, antibacterials/antibiotics Such as Thixotropy: the Viscosity decreases with time, as the poly my Xin, neomycin, kanamycin, gentamycin, applied StreSS goes on. tetracycline, meclocycline, clindamycin; antiviral drugs The System of the present invention uses as gelifying 60 Such as acyclovir, cytarabine, corticosteroids, antihista agent colloidal Silices, which are excipients widely used in mines; Sympathomimetic drugs, antiallergic drugs. Such as the topical field as thickening and Suspending agents, and in disodium cromoglycate; local anesthetics, cicatrizants, the oral Solid as lubricants. capillary-protective Substances, bioflavonoids, retinoids, It should be noted that within the definition “colloidal Vitamins, enzymes, growth factors. Silica’ lie Several commercial products used as pharmaceu 65 Some examples of pharmaceutical and parapharmaceuti tical excipients, whose characteristics can be Summarized as cal formulations containing active ingredients at therapeu follows: tical concentrations are reported hereinbelow. 5,858,330 4 a.i.-active ingredient -continued polysorbate 80 0.5 PHARMACEUTICAL FORMULATIONS sodium methyl-p-hydroxybenzoate O.15 OSC CSSCCC O.2 EXAMPLE 1. demin. water q.S. to 1OO EXAMPLE 8 a.i. Ketoprofen Lys 15 colloidal silica a.i. fluocinolone acetonide propylene glycol propylene glycol Tween 8O 0.5 colloidal silica Na nipagin O1 gliceryl monostearate self-emulsifier Nerolene lavender O1 Span 60 0.5 demin. water q.S. to 1OO sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 2 avender essence O.2 demin. water q.S. to 1OO a.i. miconazole nitrate EXAMPLE 9 propylene glycol 1O 15 colloidal silica a.i. betametasone valerate esterified polyoxyethylene glycols propylene glycol polysorbate 80 0.5 colloidal silica sodium methyl-p-hydroxybenzoate O.15 isopropyl alcohol malva perfume 0.5 polysorbate 80 0.5 demin. water q.S. to 1OO sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 3 avender essence O1 demin. water q.S. to 1OO a.i. disodium cromoglycate EXAMPLE 10 propylene glycol colloidal silica a.i. meclocycline anhydrous sulfosalicylate 2.914 sodium edetate S. propylene glycol polysorbate 80 25 glycerin U.P. benzalkonium chloride S. colloidal silica 3.5 menthol esterified polyoxyethylene glycols eucalyptol polysorbate 80 0.5 demin. water q.S. to sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 4 OSC CSSCCC O.2 demin. water q.S. to 1OO a.i. Oxymetazoline hydrochloride O.OSO EXAMPLE 11 monobasic sodium phosphate 1.O2O dibasic sodium phosphate 1110 a.i. naproxene 1O EDTA O.OO colloidal silica propylene glycol 5.0 ethyl alcohol 1O colloidal silica 5.0 35 polysorbate 80 0.75 Tween 20 0.5 sodium methyl-p-hydroxybenzoate O.15 sodium methyl-p-hydroxybenzoate O.15 camphor menthol 0.4 demin. water q.S. to eucalyptol O1 EXAMPLE 12 demin. water q.S. to 1OO EXAMPLES a.i. escin 40 Sodium heparin U. a.i. menthol 0.4 diethylamine salicylate camphor 0.4 transcutol eucalyptol O.2 colloidal silica sodium phosphate monobasic 1.02 ethyl alcohol sodium phosphate dibasic 1.11 polysorbate 80 EDTA O.O1 45 sodium methyl-p-hydroxybenzoate propylene glycol 8.0 camphor colloidal silica 4.0 lavender essence polysorbate 80 1.O demin. water q.S. to sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 13 demin. water q.S. to 1OO EXAMPLE 6 50 a.i. capsaicin OleOresin 1 g S. (= 0.01 g capsaicin) a.i. tyrothricin propylene glycol cethyltrimethylammonium bromide colloidal silica benzocaine ethyl alcohol PEG 200 polyoxyethylen glycol 300 colloidal silica polysorbate 80 55 sodium methyl-p-hydroxybenzoate ethyl alcohol camphor Cremophor A11 menthol sodium saccharine sodium methyl-p-hydroxybenzoate demin. water q.S. to peppermint Oil EXAMPLE 1.4 demin. water q.S. to 60 a.i. sodium heparin E. B. EXAMPLE 7 ethyl alcohol propylene glycol a.i. polymixin B sulfate 1.OOOOOO colloidal silica neomycin sulfate 0.5 polysorbate 80 O.SO lidocaine chloride 4 sodium methyl-p-hydroxybenzoate O.15 propylene glycol 65 camphor colloidal silica 3 demin. water q.S. to 5,858,330 S 6 -continued -continued EXAMPLE 1.5 peppermint oil demin. water q.S. to a.i. sodium heparin U. EXAMPLE 22 escin phosphatidylcholine O.8 a.i. escin isopropyl alcohol 15 levothyroxine propylene glycol ethyl alcohol colloidal silica propylene glycol polysorbate 80 colloidal silica 3.5 sodium methyl-p-hydroxybenzoate esterified polyeoxyethylene glycols lavender essence polysorbate 80 demin. water q.S. to sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 16 lily of the valley essence O.3 demin. water q.S. to 1OO a.i. sodium heparin S.OOO B EXAMPLE 23 jalurononidase S.OOO I 15 desametasone O.OS a.i. vitamin E 550 U. tetracaine hydrochloride O1 propylene glycol retinol palmitate 25.OOO U. Jojoba oil ethyl alcohol colloidal silica colloidal silica anhydrous lanolin propylene glycol Labrafil M1944 CS Myri 52 polyoxyethylene glycol palmitostearate sodium methyl-p-hydroxybenzoate O.15 Tween 20 menthol sodium methyl-p-hydroxybenzoate O.15 EXAMPLE 17 rose perfume 0.5 demin. water q.S. to 1OO a.i. hydrocortisone acetate EXAMPLE 24 benzocaine 25 sodium heparin a.i. beclometasone dipropionate 1O S. colloidal silica propylene glycol 1O propylene glycol colloidal silica 3.5 isopropyl myristate polysorbate 80 O.7 polysorbate 80 sodium methyl-p-hydroxybenzoate O.15 sodium methyl-p-hydroxybenzoate menthol O.3 menthol camphor O.2 demin. water q.S. to demin. water q.S. to 1OO EXAMPLE 1.8 EXAMPLE 25 a.i. Hamamelis hydroalcoholic extract a.i. 2,4-dichlorobenzyl alcohol tannic acid 35 propylene glycol benzalkonium chloride colloidal silica ethyl alcohol ethyl alcohol propylene glycol polysorbate 80 colloidal silica sodium saccharine Cetomacrogol 1000 sodium methyl-p-hydroxybenzoate sodium methyl-p-hydroxybenzoate mint essence bergamot oil 40 menthol demin. water q.S. to balsamic flavor EXAMPLE 19 S.S. demin. water q.S. to EXAMPLE 26 a.i. chlorhexidine ethyl alcohol a.i. hiocolchicoside 0.25 isopropyl myristate 45 propylene glycol propylene glycol colloidal silica 3.5 colloidal silica 70% sorbitol 5.0 polysorbate 80 polysorbate 80 0.5 sodium methyl-p-hydroxybenzoate sodium methyl-p-hydroxybenzoate O.15 bergamot oil avender essence 0.5 demin. water q.S. to 50 demin water q.s. to 1OO EXAMPLE 20 EXAMPLE 27 a.i. benzyl alcohol a.i. Ketoprofene lysine salts 15 benzocaine propylene glycol 5.5 chloroxylenol O. colloidal silica 2.5 ethyl alcohol 55 polysorbate 80 0.5 propylene glycol methyl-p-hydroxybenzoate O.15 colloidal silica camphor O1 Bryi 35 avender essence O1 sodium methyl-p-hydroxybenzoate demin. water q.S. to 1OO bergamot oil EXAMPLE 28 demin. water q.S. to EXAMPLE 21 60 a.i. sodium heparin 1OOOO propylene glycol a.i. acyclovir colloidal silica 3.5 ethyl alcohol 70% sorbitol propylene glycol polysorbate 80 0.5 colloidal silica methyl-p-hydroxybenzoate O.15 polysorbate 80 0.5 65 nerolene lavender sodium methyl-p-hydroxybenzoate O.15 demin. water q.S. to 5,858,330 7 8 -continued -continued EXAMPLE 29 demin. water q.S. to 100 g EXAMPLE 35 a.i. benzalkonium chloride 1 g Astringent facial masque propylene glycol 5 g 5 colloidal silica 3.5 g. a.i. Burdock hydroalcoholic extract 1 g polysorbate 80 0.5 g. Cornflower hydroalcoholic extract 1 g methyl-p-hydroxybenzoate 0.15 g propylene glycol S. lavender essence 0.2 g colloidal silica 3.5 g. lemon essence 0.4 g polysorbate 80 0.5 g. demin. water q.S. to 100 g 1O methyl-p-hydroxybenzoate 0.15 g EXAMPLE 30 apricot flavour 0.2 g demin. water q.S. to 100 g a.i. deschlorpheniramine maleate 1 g EXAMPLE 36 ethyl alcohol 3 g Face detergent propylene glycol 5 g gliceryl monostearate self-emulsifier 5 g 15 a.i. Ruscus hydroalcoholic extract 1 g 70% sorbitol 5 g Asparagus hydroalcoholic extract 1 g colloidal silica 3.5 g. propylene glycol 5 g polysorbate 80 0.7 g colloidal silica 3 g methyl-p-hydroxybenzoate 0.15 g polysorbate 80 0.5 g. OSC CSSCCC 0.1 g methyl-p-hydroxybenzoate 0.15 g demin. water q.S. to 100 g OSC CSSCCC 0.3 g EXAMPLE 31 2O demin. water q.S. to 100 g a.i. metronidazole 1 g ethyl alcohol 5 g We claim: propylene glycol 10 g colloidal silica 3.0 g 1. A pharmaceutical thixotropic gel composition compris polysorbate 80 1 g 25 ing an active ingredient, from 2 to 15% of a colloidal Silica methyl-p-hydroxybenzoate 0.15 g having a Surface area ranging from 130 to 300 m/g, water lily of the valley essence 0.5 g. in an amount of from 60 to 97% by weight and, optionally, demin. water. q.S. to 100 g one or more excipients. PARA-PHARMACEUTICAL FORMULATIONS 2. The pharmaceutical composition according to claim 1 3O EXAMPLE 32 further comprising a Solvent Selected from glycerol, poly Facial astringent masque oxyethylene glycol, diethylene glycol monoalkyl ether, N-methylpyrrollidone, glycofurol, isopropanol, ethylene a.i. Hamamelis hydroalcoholic extract 5 g nettle oily extract 2 g glycol, propylene glycol in an amount from 1 to 10% by propylene glycol 5 g 35 weight. colloidal silica 5 g 3. The pharmaceutical composition according to claim 2, polysorbate 60 1 g sodium methyl-p-hydroxybenzoate 0.15 g wherein the Solvent is propylene glycol. lemon essence 0.07 g 4. The pharmaceutical composition according to claim 1, demin. water q.S. to 100 g wherein the colloidal Silica has an average diameter of 12 EXAMPLE 33 . Sun shield gel 40 5. The pharmaceutical composition according to claim 1, a.i. B carotene solution in vegetable oil 3 g wherein the colloidal Silica has a Surface area ranging from Hypericum oily extract 2 g propylene glycol 2 g 200–250 m/g and an average diameter of 12 nm. colloidal silica 5 g 6. The pharmaceutical composition according to claim 1 polysorbate 80 1 g 45 wherein the one or more excipients is Selected from a sodium methyl-p-hydroxybenzoate 0.15 g Surfactant, a preservative, a flavouring agent, a co-Solvent sandalwood essence 0.1 g demin. water q.S. to 100 g and a lipophilic phase. EXAMPLE 34 7. The pharmaceutical composition according to claim 1, Face spray gel detergent further comprising a Surfactant Selected from the group 50 a.i. Sulfur glycolic solution 1 g consisting of a Sorbitan ester, a polyoxyethylene Sorbitan benzoyl peroxide 4 g ester, a polyoxyalkyl ether, and a polyoxyethylene Stearate. isopropyl alcohol 4 g 8. A composition according to claim 1, containing from 2 propylene glycol 10 g to 7% by weight of colloidal silica. colloidal silica 5 g 9. A container having a mechanical Spray pump and polysorbate 80 0.7 g 55 sodium methyl-p-hydroxybenzoate 0.15 g comprising the composition of claim 1. OSC CSSCCC 0.3 g