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United States Patent (19) 11 Patent Number: 5,858,330 Boltri Et Al

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United States Patent (19) 11 Patent Number: 5,858,330 Boltri Et Al 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.
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