PT100964B - PHARMACEUTICAL COMPOSITIONS FOR TOPIC APPLICATION OF HIGH PENETRATION THROUGH THE SKIN COMPARING CERTAIN SPECIFIC CATIONIC POLYMER - Google Patents

Abstract

A new topical pharmaceutical compsn. having enhanced penetration through the skin comprises (a) a safe and effective amt. of a pharmaceutical active; and (b) from 0.1-10.0% of a high molecular wt. crosslinked cationic polymer of the formula (A)l(B)m(C)n where the polymer contains a crosslinking agent, where (A) is dialkylaminoalkyl acrylate monomer or its quat. ammonium or acid addn. salt; (B) is a dialkylaminoalkyl methacrylate monomer or its quat. ammonium or acid addn. salt; (C) is acrylamide; l is an integer of 0 or greater; m is an integer of 1 or greater; n is an integer of 0 or greater.

Description

TECHNICAL FIELD

The present invention relates to compositions for the topical administration of drugs, and especially compositions of this type that allow high penetration of the drug through the skin.

Mod.? L · 20,000 ex. - 5M | 0d

BACKGROUND OF THE INVENTION

Given the accessibility and the large area of the skin, this has long been considered a promising route for drug administration, whether skin, local or synthetic effects are desired.

Advantages of topically administering a drug include: preventing risks and inconveniences of parenteral treatment; impediment of variable absorption and metabolism associated with oral treatment; continuity of drug administration, allowing the use of pharmacologically active agents with reduced biological half-lives; potential reduction of gastro-intestinal irritation by systemic administration; and treatment of cutaneous manifestations of diseases usually treated systemically.

However, skin impermeability is well known, serving as a barrier to the penetration of pathogens and toxic chemicals and as an outlet for physiological fluids. This impermeability is the result of normal physiological changes in skin development. A typical epidermis cell is formed in the basal layer. It typically takes about thirty days for a cell to migrate from the basal layer of the epidermis, (until it separates and appears) in the outer layers of the stratum corneum. As the cell migrates out of the basal layer, it keratinizes progressively until it is relatively imper = 2

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Mod. 21 · 20,000 ex. W / 08 movable. The result is stratum corneum, an extremely thin surface layer (10 microns) with important barrier properties. The cell shells of stratum corneum cells tend to be mainly polar lipids, such as ceramides, sterols, and fatty acids while the cytoplasm of stratum corneum cells remains polar and aqueous. Despite the close proximity of the cells, about 15% of the stratum corneum is intercellular and, generally, based on lipids. Generally, it is recognized that during the very short period, penetration occurs through the hair follicles and the sebá ceo apparatus; penetration over long periods occurs through cells (non-polar pathway). The poor penetration of many drugs through the epidermal lipid barrier has, until now, frustrated attempts to deliver clinically significant doses of many drugs topically.

One route of internal drug distribution is through transcutaneous administration. Transcutaneous drug administration can be used in many cases to achieve therapeutic levels of drugs in the systemic circulatory system, as well as for more localized drug dosing. Where such therapeutic levels of drugs can be achieved by transcutaneous administration, there are several potential advantages over other routes of administration. An advantage of transcutaneous administration of the drug is often the (continuity) of its systemic distribution (controlled at) therapeutic levels but lower than the toxic ones, for long periods of time with a single continuous application. The potential contamination of internal tissues by unwanted foreign substances by microbes, often associated with parenteral drug administration is avoided with transcutaneous administration of the drug. Oral administration of many drugs is undesirable or impractical • 65,390

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Mod. 71 20,000 ex. · 90/00 because the drug breaks down in the harsh environment of the gastro-intestinal tract, needs sufficient absorption of the gastro-intestinal tract, or causes gastric-intestinal disturbances or tissue damage in the gastro-intestinal tract. The first step in the metabolism of orally administered drugs and thereby increase the undesirable side effects of the parent drug or metabolites. Maintaining uniform, systemically optimal drug levels over long periods of time is often difficult through oral administration. Such problems can often be reduced or avoided by transcutaneous administration of the drug.

Despite the important potential benefits of transcutaneous drug administration, there are relatively few drugs administered in this way. The skin is a formidable barrier to the passage of most drugs. Often, it is necessary to provide a composition that contains a vehicle for intensifying penetration into the skin, in order to provide a transcutaneous penetration of the drug sufficient to achieve therapeutic levels of the same in the internal tissue to which it is intended. penetration of drugs into the skin, including those present in the following references: US Patent No. 3,536,816, issued to Kellner on October 27, 1970; US Patent No. 4,00,218, issued to Sipos on February 1, 1977; US Patent No. 4,124,720, issued to Wenmaekers on November 7 ^: 1978; US Patent No. 4,126,681, issued to Reller on November 21, 1978; US Patent No. 4,299,826, issued to Luedders on November 10, 1981; US Patent No. 4,305,936, issued to Klein on December 15, 1981; US Patent No. 4,309,414, issued to Inagi, Muramatsu '& Nagai on January 5, 1982; US Patent No. 4,338,306, issued to Kitao & Nishimura on July 6, 1982; Pa4 • 65.3-90

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Mod. 71 20.000 and «. - M / Ofl

US Patent No. 4,442.OÇO, issued to Kakeya, Kitao & Nishimura on April 10, 1984; US Patent No. 4,485,033, issued to Kitao & Nishimura in 2? November 1984; US Patent No. 4,537,776 issued to Cooper on August 27, 1985; US Patent No. 4,552,872, issued to Cooper, on December 10, 1985; US Patent No. 4,573,995, issued to Chen, Chun & Enscore on March 4, 1986; US Patent No. 4,626,539, issued to Aungst & DiLuocio on December 2, 1986; US Patent No. 4,637,930, issued to Konno, Kawata, Aruga, Sonobe & Mitomi on January 20, 1987; US Patent No. 4,695,465, issued to Kigasawa, Ohtani, Tanaka and Hayashida on September 22, 1987; European Patent Application No. 0,043,738 to The Procter & Gamble Con pany in the name of Wickett, Cooper & Loomans, published on June 13, 1982; European Patent Application No. 0,095,813 to The Procter & Gamble Company in the name of Cooper, published December 7, 1983; PCT International Patent Application No. W0 87/03490 to Key Pharmaceuticals, Inc., in the name of Bodor & Loftson, published June 18, 1987; M. Washitake, T. Anmo, I. Tanaka, T. Arita and M. Nakano, Percutaneous Absorption of Drugs from Oily Vehicles, Journal of Pharmaceutical Sciences, Vol. 64, No. 3 (March 1975), pp. 397-401; V. Shahi & J. L.

Zatz, Effect of Formulation Factors on Penetration of Hydrocortisone Through Mouse Skin, Journal of Pharmaceutical Sciences, Vol. 67. N2 6 (June 1978), pp. 789-792; E.R. Cooper, 'Increased Skin Permeability for Lipophilic Mocecules, Journal of Pharmaceutical Sciences, Vol. 73, No. 8 (August 1984), pp. 1153-1156;

B. J. Aungst, N.J. Rogers & E. Shefter, Enhancement of Naloxone Penetration through Human Skin In Viro Using Fatty Acids, Fatty Alcohols, Surfactants, Sulfoxides and Amides, International Journal of Pharmaceutics, Vol.

(1986), pp. 225-234; P.G. Green & J. Hadgraft, Fa5

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BolM · · «ooo re · iz en> w cilitated Transfer of Cationic Drugs Across a Lipoidal Membrane by Oleie Acid and Lauric Acid, International Journal of Pharmaceutics, Vol 37, (July 1987), pp. 251-255.

It is an object of the present invention to provide new compositions to increase the penetration of drugs into the skin.

It is still an object of the present invention to provide such compositions providing an intensification of penetration into the skin sufficient to obtain therapeutic levels of the drugs in the internal tissues to which they are intended. clink.

It is still an object of the present invention to provide such compositions with reduced skin irritation, especially in compositions that require a low pH.

It is yet another object of the present invention to provide such compositions having good stability and cosmetic properties.

SUMMARY OF THE INVENTION

The present invention relates to pharmaceutical compositions for topical application with high penetration through the skin comprising:

(a) a safe and effective amount of a pharmaceutical active ingredient; and (b) between about 0.1% and about 10.0% of a high molecular weight cross-linked cationic polymer of the formula:

(A) _d (B) (C) in which (A) is a monomer

N m n = 6 =

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BOlM · · '000'08 · 17 dialkylaminoalkyl acrylate or its quaternary acid or ammonium addition salt (B) is a diakylaminoalkyl methacrylate monomer or its quaternary acid or ammonium addition salt, (C) is a monomer having a carbon-carbon double bond, 1 is an integer of 0 or greater, m is an integer of 1 or greater, and n is an integer of 0 or greater, wherein said polymer contains a crosslinking agent.

In additional embodiments the cross-linked cationic polymer is of the formula where (C) is acrylamide.

In further embodiments the cross-linked cationic polymer is of the formula where (C) is acrylamide and 1 is zero.

In further embodiments, the cross-linked cationic polymer is a homopolymer in which both 1 and n are zero.

All concentrations and ratios here are by weight of the composition and all measurements are at 25 ° C, unless otherwise specified.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves compositions comprising certain specific cationic polymers that can be applied topically to the skin and which result in an improvement in the transcutaneous penetration of drugs through the skin. These compositions also have a high tolerance to solvents; that is, they can be in7

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Mod. 71 - 20,000 and «. - »0/0« included in these compositions high levels of solvents such as alcohol and other water-soluble components that may be necessary to solubilize the active ingredient

Active Drug

The compositions of the present invention comprise a safe and effective amount of an active drug. The phrase safe and effective amount, as used herein, means an amount of a drug sufficiently high to positively and significantly modify the condition being treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio) ), in the spirit of sound medical judgment. A safe and effective amount of the drug will vary with the specific drug, the ability of the composition to penetrate the drug through the skin, the amount of the composition to be applied, the particular condition to be treated, the age and physical condition of the patient to be treated. being treated, the severity of the condition, the duration of treatment, the nature of concomitant therapy and similar factors.

The drug compounds present in the compositions of the present invention preferably comprise from about 0.1% to about 20% by weight of the compositions, more preferably from about 0.1% to about 10% and most preferably from about 0.1% to about 5%. Mixtures of active drugs can also be used.

Active drugs useful in the compositions of the present invention include anti-acne drugs. Preferred anti-acne drugs for use in the present invention include keratolytics, such as salicylic acid, sulfur, lactic acid, glycolic acid, pyruvic acid, urea, resorcinol and N-acetylcysteine;

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Case 4504 · retinoids, (eg tromycin, azelaic acid such as retinoic acid and its cis and trans derivatives) antibiotics and antimicrobials, peroxide and benzoyl, octopirox, zinc, tetracycline, triclosan and their derivatives , phenoxy-ethanol, ethylacetate, sebostats such as erphen aphenoxy-proponol clocycline;

alpha and beta hydroxyls; and Esquimnol and its salicylic acid is preferred in prices such as.

cholate and cholate.

feels invention.

Qes of this non-steroid clindamycin and flavinoids; bile salts such as derivatives, deoxyActive drugs useful in compositions include anti-inflammatory drugs (A.I.N.E.s). NSAIDs can be selected from the following categories:

Mod. 71 · 20,000 and «. · 9U / 0B derived from propionic acid; acetic acid derivatives; derivatives of phenamic acid; biphenylearboxylic acid derivatives; and oxicams. All of these are described in detail in U.S. Patent 4,985,459 issued to Sunshine et al. On January 15, 1991, incorporated herein by reference. The most preferred are the Α.Ι.Ν, Ε. 'S mind, benoxaprofen aspirin, hay, zine, prophenic hay and thi-inflammatory including, but not ibuprofen, fenoprofen, carprofen, acetaminophen, flurbiprofen, indoprofen, pyrprofen, pranoprofen,, alminoprofen, buccoxic acid.

exclusive steroids inproxen, ketoprooxapro9, miroprofen, thioxaprofen, su thiaprofenic acid, fluopro Drugs including hydrocortisone and the like are also useful.

Active drugs useful in compositions include antihistamine drugs. The preferred antihistamine drugs for inclusion in the present

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in compositions of the present invention include pharmaceutically acceptable salts of chlorpheniramine, triprolidine, diphenhydramine, · promethazine, carbinoxamine, pheniramine, doxylamine, cyproheptadine, tripelinenamine bromopheniramine, pyrilamine, phenindamine, azatadine, clemastine, phenylamine, termine, phenylamine, termine and mixtures thereof.

Mod. 71 20,000 «. νύ / Οϋ

Active drugs useful in the compositions of the present invention include antitussive drugs. Preferred antitussive drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of dextromethorphan, codeine, caramifene and carbetapentane.

Active drugs useful in the compositions of the present invention include antipruritic drugs. Preferred antipruritic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of methyldizine and trimeprazine.

Active drugs useful in the compositions of the present invention include anticholinergic drugs. Preferred anticholinergic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of scopolamine, atropine, homatropine, levodopa, dicyclomine, hyoscyamine, procyclidine, trihexylphenidyl and ethopropazine.

Active drugs useful in the compositions of the present invention include anti-emetic and anti-nausea drugs. The preferred anti-emetic and anti-nausea drugs for inclusion in compositions of the present invention do not include pharmaceutically acceptable salts of cyclizine, meclizine, chloropromazine, biclizine, metoclopramide,

I / 7 7, O

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Mad. 71 - 20,000 ex. 9O | O8 prochloroperazine and trimethobenzamide.

Active drugs useful in the compositions of the present invention include anorexic drugs. Preferred anoretic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of benzaetamine, phentermine, chlorofentermine, fenfluramine, diethylpropion and phendimetrazine.

Active drugs useful in the compositions of the present invention include centrally stimulating drugs Preferred centrally stimulating drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of amphetamine, methamphetamine, dextroamphetamine and methylphenidate ·

Active drugs useful in the compositions of the present invention include anti-arrhythmic drugs. Preferred anti-arrhythmic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of propanolol, procainamide, disopyramide, quinidine, encainidine, flecainide, mexiletine and tocainide. Other antiarrhythmic drugs preferred for inclusion in compositions of the present invention include pharmaceutically acceptable salts of the quinidine derivatives disclosed in US Patent No. 4,716,171 issued to Jarreau and Koening on December 29, 1987, which is incorporated herein in full by reference . The highly preferred compounds included in this class comprise pharmaceutically acceptable salts of 3S-hydroxy-10,11-dihydroquinidine, 3R-hydroxy-10,11-dihydroquinidine, 3R-hydroxy-O-acetyl-10,11-dihydroquinidine and 3S-hydroxy- 0-acetyl-10,11-dihydroquinidine, especially 3S-hydroxy-10,11-dihydroquinidine.

Active drugs useful in compositions

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ΡΟ / Μ · ”ΟΟΟΊΚ · ΙΖ of the present invention include / β-adrenergic blocking drugs. Preferred β-adrenergic blocking drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of metoprolol, ace butolol, betaxolol, labetalol and timolol. The most preferred β-adrenergic blocking drugs for inclusion in compositions of the present invention include metoprolol tartrate, acebutolol hydrochloride, betaxolol hydrochloride, labetalol hydrochloride and timolol maleate.

Active drugs useful in the compositions of the present invention include cardiotonic drugs. Preferred cardiotonic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of milrinone, amrinone and dobutamine. Other preferred cardiotonic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of 14-amino-steroid derivatives, some of which are disclosed in US Patent Nos. 4,325,879, 4,552,868 and 4,584,289, granted to Jarreau and Koening, respectively, on 20 April 1982, 12 November

1985 and April 22, 1986, each of which is incorporated herein in its entirety by reference.

Active drugs useful in the compositions of the present invention include antihypertensive drugs. Preferred antihypertensive drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of enalapril, clonidine, hydralazine minoxidil which is also a drug (which stimulates) hair growth, guanadrel, guanetidine, guanfacine, mecamylamine, methyldopate, pargyline , phenoxybenzamine and prazosin.

Active drugs useful in compositions

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Mod. 71 20.000 and «. 3/20 of the present invention include diuretic drugs. Preferred diuretic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of amiloride and hydrochlorothiazide. The most preferred diuretic drugs for inclusion in compositions of the present invention include amiloride hydrochloride.

Active drugs useful in the compositions of the present invention include vasodilator drugs. Vasodilator drugs preferred for inclusion in compositions of the present invention include pharmaceutically acceptable salts of diltazem, amiodarone, isoxsuprine, nilhydrin, tolazoline and verapamil.

Active drugs useful in the compositions of the present invention include vasoconstrictor drugs. Preferred vasoconstrictor drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of dihydroergotamine, ergotamine and methysergide.

Active drugs useful in the compositions of the present invention include anti-ulcer drugs. Preferred anti-ulcer drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of ranitidine and cimetidine.

Active drugs useful in the compositions of the present invention include anesthetic drugs. Preferred anesthetic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of lidocaine, bupivacaine, chloroprocaine, dibucaí.

na, etidocaine, mevicacaine, tetracaine, diclonin, hexylcaine, procaine, cocaine, ketamine, pramoxin, dichlonine, hexylcaine, procaine cocaine ketamine, pramoxin and phenol.

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Active drugs useful in the compositions of the present invention include antidepressant drugs. Preferred antidepressant drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of imipramine, desipramine, amitriptyline, nortriptyline, protriptyline, dosepine, maprotiline, phenenzyl, tranylcypromine, ..... tradozone and trimipramine.

Active drugs useful in the compositions of the present invention include tranquilizers and sedatives. Preferred tranquilizer and sedative drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of chlordiazepoxide, benactizine, benzquinamide, flurazepam, hydroxyzine, loxapine and promazine.

ΡΟ / ΟΛ - ’« 000'W ΙΖ ροίΝ

Active drugs useful in the compositions of the present invention include antipsychotic drugs. Preferred antipsychotic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of chlorprothixene, fluphenazine, haloperidol, melindone, thioridazine and trifluoperazine ·

Active drugs useful in the compositions of the present invention include antimicrobial drugs (antibacterial, antifungal, antiparasitic and antiviral drugs). Preferred antimicrobials for inclusion in compositions of the invention include pharmaceutically acceptable salts of β -lactamicas drug, quinolones, ciprofloxacin, norfloxacin, tetracycline, erythromycin, preomicina, tetracycline, amikacin, clindamycin chlorhexidine, triclosan, doxycycline, caclorotetraciclina, oxiteetambutol, metroriidazol, pentamidine, metacycline, tilmycin, gentamicin, methenamine, paromomycin, kanamycin, lineomycin, minocycline, neomycin, neestreptomycin, tobramycin,

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Mod. 71 - 20,000 «. - 8/8 miconazole and amantadine. Preferred antimicrobial drugs for inclusion in compositions of the present invention include tetracycline hydrochloride, erythromycin stolate; erythromycin stearate (salt), amikacin sulfate, doxycycline hydrochloride, capreomycin sulfate, chlorhexidine hydrochloride, chlorhexidine hydrochloride, chlorethetracycline hydrochloride, oxytetracycline hydrochloride, clindamycin hydrochloride, etamol hydrochloride, ethamol hydrochloride pentamidine hydrochloride, gentamicin sulfate, kanamycin sulfate, lineomycin hydrochloride, metacycline hydrochloride, methenamine hypurate, methenamine mandelate, minocycline hydrochloride, neomycin sulfate, netylmycin sulfate, paromomycin sulfate, streptomycin sulfate Tobramycin, mi-conazole hydrochloride, amantadine hydrochloride, amantadine sulfate, triclosan, octopirox, parachloromethaxylenol, nystatin, tolnaftate and clotrimazole.

Active drugs useful in the compositions of the present invention include antineoplastic drugs. Preferred antineoplastic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of bleomycin, daunorubicin, doxorubicin, meclorethamine, procarbazine, quinacrine, tamoxifen, vinblastine and vincristine.

The active drugs useful in the compositions of. The present invention includes preferred antimalarial drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of chloroquine, hydroxychloroquine, primaquine and quinine.

Active drugs useful in the compositions of the present invention include muscle (relaxant) drugs. The preferred muscle (relaxant) drugs for | c | C

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Mod. 71 · 2Q.U0Q ex. TO | 08 (

Inclusion in compositions of the present invention include pharmaceutically acceptable salts of cinamedrine, cyclobenzaprine, flavoxate, orphenadrine, papaverine, mebeverine, idaverine, ritodrine, defenoxylate, dantrolene and azumolene.

Active drugs useful in the compositions of the present invention include antispasmodic drugs. Preferred antispasmodic drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of the compounds disclosed in US Patent No. 3,856,825 issued to Wright, Burch and Goldenburg on December 24, 1974, which is incorporated herein in full as a reference.

Active drugs useful in the compositions of the present invention include antidiarrheal drugs. Preferred antidiarrheal drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of loperamide.

Active drugs useful in the compositions of the present invention include drugs with bone activity. Preferred bone-active drugs for inclusion in compositions of the present invention include pharmaceutically acceptable salts of diphosphonate drug compounds and phosphonoalkylphosphinate drug compounds, including the prodrug esters thereof. Such compounds are disclosed, for example, in U.S. Patent Nos. 3,683,080 issued to Francis on August 8, 1972; 4,304,734 granted to

Jary, Rihakova and Zobakova on December 8, 1981; 4,687,768 granted to Benedict & Johnson on August 18, 1987; 4,711,880 granted to Stahl & Schmitz on 8

December 1987; and 4,719,203 granted to Bosies & Gall on January 12, 1988; Co-pending U.S. Patent Applications No. 808,584 Series, by Benedict & Parkins deposit16

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Mod. 71 · 20,000 ex. - 90/08 adopted on 13 December 1985; 945,069 to Ebetino, Buckingham & McOsker filed December 19, 1986; 945,068 to Ebetino & Benedict filed on December 19, 1986; and 0.69,666 Ebetino deposited on July 6, 1987; and European Patent Application No. 0,001,584 to Blum, Hempel & Worms., published on May 2, 1979; 0.039,033 published April 11, 1981;

0.186.405 by Benedict & Perkins, published on July 2, 1986; and 0.243.173 by Oku, Todo, Kasahara, Nakamura, kayakiri and Hashimoto, published on October 28, 1987; which are hereby incorporated in their entirety as a reference.

Also useful in the present invention are sunless tanning agents that include dihydroxyacetone, glyceraldehyde, indois and their derivatives, and the like. These sunless tanning agents can also be used in combination with conventional sun protection agents such as those disclosed by Segarin and others, in Cosmetics Science and Technology, Chapter VIII, pages 189 et seq., Incorporated herein by reference, signed as with healing agents such as peptide derivatives, yeast, panthenol, laminin and kinetin.

Other active ingredients useful in the skin include skin whitening (or brightening) agents containing, but not limited to, hydroquinone, ascorbic acid, cyclic acid and sodium metabisulfite.

Water Soluble Polymer

The polymers useful in the present invention are certain cationic polymers. These polymers are generally described in U.S. Patent 5,100,660 issued March 31, 1992 and Hawe et al; U.S. Patent

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Mod. 71 · 20,000 and «. 90/00

4,849,484, granted to Heard, on July 18, 1989; U.S. Patent 4,835,206 issued to Farrar et al., On May 30, 1989; U.S. Patent 4,628,078 issued to Glover et al., December 9, 1986; U.S. Patent 4,599-379, issued to Flesher et al. On July 8, 1986; and European Patent 228,868 to Farrar et al., published on July 15, 1987, all patents being incorporated herein by reference.

The compositions of the present invention with: comprise from about 0.1% to about 10%, preferably from about 0.1% to about 7.5%, and still preferably from about 0.1% to about 5% of the polymer.

In general these polymers are high molecular weight materials that contain cationic nitrogen portions, commonly quaternized. These polymers can be characterized by the general formula: (A) ^ B) (C) in which (A) is a dialkylaminoalkyl acrylate monomer or its quaternary acid or ammonium addition salt, (B) is a dialkylaminoalkyl methacrylate monomer or its quaternary acid or ammonium addition salt, (C) is a monomer with a carbon-carbon double bond, 1 is an integer of 0 or greater, m is an integer of'1 or greater, and n is an integer 0 or greater. The monomer (C) can be chosen from any monomers commonly used. Non-limiting examples of these monomers include ethylene, propylene, butylene, isobutylene, eicosene, maleic anhydride, acrylamide, methacrylamide, maleic acid, acrolein, cyclohexene, ethyl vinyl ether and methyl vinyl ether. In the cationic polymers of the present invention, (C) is preferably acrylamide.

In highly preferred embodiments, these polymers also contain a crosslinking agent, which is very typically a material containing a

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Mod. 71 · 20,000 «. - 90 / Οΰ or more unsaturated functional groups. Non-limiting examples of suitable crosslinking agents include those chosen from methylene bisacrylamides, diallylalkyl ammonium halides, polyalkenyl polyethers of polyhydric alcohols, allyl acrylates, vinyloxyalkylacrylates, and polyfunctional vinylidenes. Specific examples of crosslinking agents useful here include those chosen from the group consisting of methylenebisacrylamide, ethylene glycol di- (meth) acrylate, di- (meth) acrylamide, cyanomethylacrylate, vinyloxyethylacrylate, vinyloxyethylmethacrylate, allyl pentaerythritol, trimethylpropylene, trimethylpropyl , divinyl benzene, divinyl naphthalene, ethyl vinyl ether, methyl vinyl ether, and allyl acrylate. Other cross-linking agents include formaldehyde and glyoxal. Methylenebisacrylamide is preferred for use in the present invention as a crosslinking agent.

When the crosslinking agent is present, amounts (very varied) can be employed depending on the desired properties in the final polymer, e.g. (viscosification) effect. Without being limited by theory, it is believed that the incorporation of a crosslinking agent in these cationic polymers provides a material that is a more effective (viscosification) agent without negative effects such as decreased viscosity and fibrous qualities in the presence of electrolytes. The crosslinking agent, when present, can comprise from about 1 ppm to about 1000 ppm, preferably from about 5 ppm to about 750 ppm, more preferably from about 25 ppm to about 500 ppm, even more preferably from about 100 ppm to about 500 ppm, and more preferably from about 250 ppm to about 500 ppm of the total weight of the polymer on a weight / weight basis.

In a group of embodiments, es = 19 =

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Mod. 71 M.OOO and «. . 90/08 th eionic polymers are made from processes that generally require polymerization of a solution containing about 20? at about 60%, generally from about 25% to about 40%, by weight of monomer, in the presence of an initiator (commonly redox or thermal) until polymerization is complete. The initial temperature is generally low, e.g., 0 ° to 95 ° C. The polymerization can be conducted by forming an inverted phase dispersion of an aqueous phase of the monomers in a non-aqueous liquid, e.g., mineral oil and the like.

When the polymer contains acrylamide, the molar ratio of acrylamide, based on the total molar amount of acrylamide, dialkylaminoalkyl acrylate and dialkylaminoalkyl methacrylate is generally about 20% to about 99% · The amount of acrylamide is preferably at least minus 50%, often at least $ 60 to below about $ 95. All percentages describing the polymer in the present invention are in moles unless otherwise specified.

Where monomer A is present, the ratio of monomer A: monomer B used in this process, and thus the proportion of groups A and B in the final polymer, on a molar basis is preferably about 80:20 to about 20:80. In a class of processes, the ratio is about 5:95 to 50:50, i.e., the cationic monomer is mainly methacrylate. In these processes, the ratio is generally achieved within the range of about 25:75 to about 5: '95.

In another class of processes, the A: B portion is from about 50:50 to about 85:15, with the monomeres being mainly acrylate. The A: B ratio is preferably about 60:40 to 85:15, more preferably about 75:25 and 85:15.

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It is preferred where monomer A is not present and the ratio of monomer B: monomer C is from about 30:70 to about 70:30, preferably from about 40:60 to about 60:40 and still preferably about 45:55 to about 55:45.

The polymerization is preferably carried out under known conditions so that the polymers are soluble in water and have a high molecular weight, generally about 1 million, for example up to 30 million. The intrinsic viscosity, measured in a molar sodium chloride solution at 25 ° C, is generally above 6, for example 8 to 14.

Mod. 71 20,000 ex. 08/50

A cationic polymer useful here is one that conforms to the general structure (A). (B) (C) where 1 is zero, B is methyl quaternized dimethylaminoethyl methacrylate, the ratio of B: C is about 45:55 about 55:45, and the optional crosslinking agent is methylenebisacrylamide. This polymer with the designation CTFA ^{: proposed} , Polyquaternium 32 and Mineral oil, is available in the trade as Salcare SC92 from Allied Colloids Ltd. (Nor folk, VA).

Alternatively in another group of preferred embodiments, these cationic polymers do not contain the acrylamide monomer, i.e., n is zero. In these polymers the monomer components (A) and (B) are as described above. An especially preferred group of non-acrylamide containing polymers is one where 1 is also Zero. In this example the polymer is essentially a homopolymer of a dialkylaminoalkyl methacrylate monomer or a quaternary ammonium or acid addition salt. These dialkylaminoalkyl methacrylate copolymers and homopolymers preferably contain a crosslinking agent as described above.

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Mod. 71 20.000 and «. 08/20 ___.— y.

f / /

A cationic homopolymer useful here is one according to the general structure (A). (B) (C) where 1 is zero, B is methyl quaternized dimethylaminoethylmethacrylate, n is zero, and the crosslinking agent is methylenebisacrylamide. This polymer, which does not yet have a CTFA designation, will be referred to here as crosslinked methyl quaternized dimethylaminoethyl methacrylate and mineral oil. This polymer is commercially available as SalCare SC95 from Allied Colloids Ltd. (Norfolk, VA).

Vehicle

The compositions of the present invention are used in conjunction with pharmaceutically acceptable carrier components (or vehicles). The term pharmaceutically acceptable carrier components as used herein, means compatible solid or liquid filler diluents that are suitable for administration to a lower human or animal. The term compatible, as used herein, means that the components are likely to be mixed with the drug compounds, and other components of the compositions of the present invention in such a way that there is no interaction that substantially reduces the pharmaceutical efficacy of the compositions of the present invention. under normal conditions of use. The pharmaceutically acceptable carrier components must, of course, be of sufficiently high purity and of sufficiently low toxicity to be suitable for administration to humans, or animals below, which are to be treated.

Some examples of substances that can serve as pharmaceutically acceptable carrier components are glycerol; ethanol; Water; antioxidants; surfactants; chelating agents; preservatives; thickeners; anti-bacterial agents; as well as other compatible non-toxic substances used in formulations. 65,390

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pharmaceutical companies.

Mod. 71 · 20,000 cx. 6/90

These compositions may also contain one or more additional humectants / humidifiers, many of which may also be useful as active ingredients. Various humectants / humidifiers can be employed and can be present at a level of about 0.5% to about 30%, more preferably from about 2% to about 8%, and still preferably from about 3% to about 5%. These materials include polyhydroxy alcohols such as sorbitol, glycerin, hexanotriol, hexylene glycol and the like; sugars and starches; starch and sugar derivatives (e.g., alkoxylated glucose); D-panthenol and its derivatives; hyaluronic acid; lactamide monoethanolamine; acetamide monoethanolamine; and mixtures thereof.

Humectants / humidifiers are preferred for use with glycerin diols and triols.

in the compositions of the present invention are the

C3- Cg. Triol is especially preferred

The compositions of the present invention ροζ 'may also optionally comprise at least one emollient. Examples of suitable emollients include, but are not ²⁵ limited to them, volatile silicone oils and non - volatile, highly branched hydrocarbons, and mixtures thereof. Emollients useful in the present invention are described in more detail in US 4,919,934 Patentee to Deckner et al, issued on 24 April ³⁰ 1990, which is incorporated herein in its entirety by reference.

Emollients can typically comprise a total of about 1% to about 50%, preferably from about 1% to about 25%, and I still prefer = 23

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Mod. 71 20,000 c <- 20/08 from about 1% to about 10% by weight of the compositions of the present invention.

The compositions of this invention may also contain optional pharmaceutically acceptable components that modify the therapeutic and / or physical effects of the compositions. Such optional components can include, for example, additional solvents, gelling agents, fragments, preservatives, anti-bacterial agents, and stabilizers. However, such optional materials must not unduly interfere with the transcutaneous release of the active ingredient of the drug. Optional components useful in the compositions of this invention are described in the following patent documents, incorporated herein by reference: European Patent Publication 43,738 of

Wickett et al., Published January 13, 1982; U.S. Patent 4,552,872 to Cooper et al., Issued November 12, 1985.

The most preferred compositions here are those of the gel type.

Another optional material is a solvent or co-solvent material. Such solvent materials include, for example, alcohols and short-chain ethers. Preferred optional solvent materials include polyethylene glycols, dipropylene glycol, ethylene glycol, monoethyl ether, ethanol, isopropanol, and (dimethylisoorbide). Water with a solvent or co-solvent can be used in the compositions of this invention. If water is used in a saturated system, a gel or emulsion is preferably formed.

The most preferred compositions here have a low pH of about 5, preferably below about 4, and still preferably below about 3 · Without being limited by theory, the pH of a formulation can

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Mod. 71 20,000 ex. - 90/08 is an important factor in the release and availability of an active ingredient. For example, for the active ingredient salicylic acid, at pH values above its pK4 in a particular matrix, salicylic acid (exists) mainly in its ionized form and does not (penetrate) so quickly into the skin. Thus, a range of acid formulation is preferred for salicylic acid compositions in order to eliminate ionization and increase its penetration into the stratum corneum.

A wide variety of acids, bases and buffers can be used to adjust and / or maintain the pH of the useful compositions of the present invention. Useful materials for adjusting and / or maintaining the pH include sodium carbonate, sodium hydroxide, hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, sodium acetate, sodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, citrate sodium, sodium bicarbonate, triethanolamine and the like.

Although particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications can be made to the compositions disclosed herein without departing from the spirit and scope of the invention. It is intended to cover in the appended claims, all those modifications that are within the scope of the present invention.

Test Method

Transcutaneous drug penetration is conveniently determined and compared from various vehicles using the apparatus and procedure described below.

Human thigh skin is obtained with the

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Mod. 71 20,000 and *. · 90/08 total thickness, excising it from corpses, whose hair has been shaved and the skin washed. The skin samples are then bathed in 10% glycerin and kept frozen. Glycerin prevents the formation of ice crystals that could possibly damage keratinized cells and / or the intercellular lipid matrix. After rapid defrosting, the skin is conditioned for 24 hours in Hank's Balanced Saline Solution with 15? Antibacterial-antimycotton solution. The skin is then washed with distilled water. A single skin donor is used for each experiment, with the individual sections used selected based on the integrity of the stratum corneum (visual determination). The 2 selected areas are cut to 1 cm using a scalpel.

The tests are conducted using glass diffusion cells placed in agitation modules with temperature regulation. The skin sections are mounted on the cells, adding the receptor phase. The receiving phase is 50% Hank's Balance Saline Solution with 1% antibiotic-antimycotic solution. Each diffusion cell has an exposed area of 0.69 cm and a reception capacity of 5 ml. Sufficient formulation (750 jul) is applied to the surface of the skin to ensure infinite dose conditions and the diffusion cell is covered with plastic or film to prevent product evaporation. At each sampling time, the receptor phase is removed for analysis of the drug content. The receiving phase is replenished at each sampling moment in order to maintain the conditions of submersion. Preferably, 3 to 6 repetitions are performed with sampling intervals occurring at 1, 2, 4 and 6 hours.

The penetration speed (Flow) corresponds to the amount of drug that penetrates a measured area of skin per hour, during the 5 hour interval between 1 hour and 6 hours. Generally, a state is reached = 26

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constant before 1 hour. The rate of penetration is usually expressed in µg of drug per cm of skin per hour.

The following examples further describe and demonstrate embodiments within the spirit of the present invention. The examples are given for illustrative purposes only and should not be interpreted as limitations of the present invention, since many variations are possible without departing from the spirit and scope of the invention.

The ingredients are identified by the chemical name or CTFA.

Mod. 71-20.000 and «. · »08/08

EXAMPLES

Example I An anti-acne composition is prepared by combining the following components and using conventional mixing technology.

Ingredient% P / P

Purified Water54.0

SD 4040.0 Alcohol

Poliquaternium-32 and Mineral Oil ^ 4.0

Salicylic acid2.0

Salt Care SC92 available from Allied Colloids, Suffolk, VA

Water is added to a suitably sized container. While mixing at a moderate speed (300 rpm), poliquaternium-32 and mineral oil are

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added to the water. Separately, the alcohol is separated into a container and capped. Using a Lightnin mixer with a three-blade paddle propellant, salicylic acid is added to the alcohol and mixed at low speed (100 rpm) until all the salicylic acid has dissolved. The alcohol is added slowly to the aqueous phase to form a gel. The resulting gel is mixed at moderate speed until uniform.

Mod. 71 · 20,000 eu. 90 / Od

The compositions (present cutaneous penetration) of the active ingredient of salicylic acid as well as improvement of the sensation in the skin and of the residue characteristics together with excellent characteristics of humidification, emollience, penetration through rubbing and absorption.

Alternatively, the above composition is prepared (replacing) polyquaternium-32 and mineral oil with cross-linked methyl quaternized dimethylaminoethyl methacrylate and mineral oil, available as SalCare SC95 from Allied Colloids (Suffolk, VA).

EXAMPLE II

An anti-acne and / or analgesic composition is prepared by combining the following ingredients and using conventional mixing techniques as described above in Example I.

Ingredient % P/ Purified water 55.0 Isoprof en 2.0 Alcohol SDA 40 40.0 Poliquaternium-32 e mineral oil 4.0

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The compositions present penetration (cutaneous) of the active ingredient Iburophen as well as improvement in skin teaching and residue characteristics, together with excellent characteristics of humidification, emollience, penetration through rubbing and absorption.

Alternatively, the above composition is prepared by replacing polyquaternium-32 and mineral oil with cross-linked methyl quaternized dimethylaminoethyl methacrylate and mineral oil, available as SalCare SC95 from Allied Colloids (Suffolk, VA).

nolM »’ ΟΟΟ'Οί 17 P ° W example III

A keratolytic composition for dermatological disorders is prepared by combining the following ingredients and using conventional mixing techniques as described above in Example I.

Ingredient % P / P Water 56.5 Urea 10.0 Benzilic alcohol 0.5 Poliquaternium-32 e mineral oil 4.0

The compositions (present cutaneous penetration) active ingredient of Urea as well as improvement of the sensation in the skin and the characteristics of residue, together with excellent characteristics of humidification, emollience, penetration through rubbing and absorption

Alternatively, the above composition is prepared by replacing poliquaternium-32 and mineral oil = 29

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/ per dimethylamino ethyl methacrylate quaternized from recycled methyl and mineral oil, available with SalCare SC95 from Allied Colloids (Suffolk, VA).

EXAMPLE IV

A composition for sunless tanning is prepared by combining the following ingredients and using conventional mixing techniques as described above in Example I.

ηο / οό · ”ooo oí ιζ pow

Water

Benzilic alcohol

Poliquaternium-32 and Mineral Oil

Dihydroxyacetiona

Glycerin% P / P

91.5

0.5

3.0

3.0

2.0

The compositions present better cutaneous penetration of dihydroxyacetone, as well as improved skin sensation and residue characteristics, together with excellent characteristics of humidification, emollience, penetration through rubbing and absorption

Alternatively, the above composition is prepared by replacing polyquaternium-32 and mineral oil with cross-linked methyl quaternized dimethylaminoethyl methacrylate and mineral oil, available as SalCare SC95 from Allied Colloids (Suffolk, VA).

= 30 =

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Lisbon, -ί. ^! ·; Ίΐ.ιά3

By RICHARDSON-VICKS INC.

'4SCO Máf / Q _U f _S ' 7 - Cfclíl ^Λί >'·· ώ <! « _{Índ usi} , _irti

Oro - «rco rf. „—3 L-. _{Í) 0eiettoA}

Mod.? L · 20,000 ex. 8/90

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Claims (7)

^ CLAIMS ^ 15 - Pharmaceutical composition for topical application with improved penetration through the skin characterized by comprising: (a) a safe and effective amount of a pharmaceutical active ingredient; and (b) from 0.1% to 10.0% of a high molecular weight cross-linked cationic polymer of the formula: Mod. 71 · 20,000 t «. · 90 / M (A) -i (B) (C) in which (A) is a dialkylaminoalkyl acrylate monomer or its quaternary acid or ammonium addition salt (B) is a dialkylaminoalkyl methacrylate monomer or its addition salt of quaternary acid or ammonium, (C) is mida, 1 and an integer of 0 or bigger , m is one whole number of 1 or bigger , and n is one whole number of 0 or bigger , on what O said polymer contains a cross-linking agent. Composition according to Claim 1, characterized in that the crosslinking agent is chosen from the group consisting of methylene-bisacrylamide, ethylene glycol di (meth) acrylate, di- (meth) acrylamide, cyanomethylacrylate, vinyloxyethylacrylate, vinyloxyethylmethacrylate , allyl pentaerythritol, trimethylolpropane diallyl ether, allyl sucrose, butadiene, isoprene, divinyl-benzene, divinyl-naphthalene, 65,390 Case 4504R Mod. 71 · 20,000 ex. 8/20 allyl acrylate, and mixtures thereof, wherein the crosslinking agent is preferably methylenebisacrylamide. 3§ - Composition according to claim 2, characterized in that said active pharmaceutical ingredient is chosen from the group consisting of anti-acne drugs, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, sunless tanning agents , sun protection agents, healing agents, agents for whitening or lightening the skin, antihistamine drugs, anti-tussive drugs, anti-pruritic drugs, anti-cholinergic drugs, anti-emetic drugs and anti-nausea drugs, anorexic drugs , centrally stimulating drugs, anti-arrhythmia drugs, β-adrenergic blocking drugs, cardiotonic drugs, antihypertensive drugs, diuretic drugs, vasodilator drugs, vasoconstrictor drugs, anti-ulcer drugs, anesthetic drugs, anti-depressant drugs, trans-user drugs and sedatives, antipsychotic drugs, antimicrobial drugs, antineoplastic drugs, antimalarial drugs, relaxation drugs muscle, anti-spasmodic drugs, anti-diarrhea drugs and drugs with bone activity and mixtures thereof. Composition according to claim 3, characterized in that said pharmaceutical active ingredient is an anti-acne drug chosen from the group consisting of salicylic acid, sulfur, resorcinol, N-acetylcysteine, octopirox, retinoic acid and its derivatives, benzoyl peroxide , erythromycin, zinc, tetracycline, azelaic acid and its derivatives, phenoxy-ethanol and phenoxy-propanol, ethyl acetate, clindamycin and meclocycline, flavinoids, lactic acid, glycolic acid, pyruvic acid, urea, = '2 = 65,390 Case 4504R Esquimnol sulfate and its derivatives, deoxycholate and cholate and mixtures thereof, wherein said anti-acne drug is preferably salicylic acid. 5- Composition according to vindication 4, characterized in that the amount of (C) in the cationic polymer is from 50 to 90? molar. Composition according to Claim 4, characterized in that 1 in the cationic polymer is 0 and the ratio of (B) :( C) is 45:55 to 55:45. Mod. 71 20,000 ex. 8/90 7 ^ã - Composition according to vindication 4, characterized in that both 1 and n are zero in the cationic polymer. Composition according to claim 7, characterized in that it also comprises from 3% to 5% glycerin. 9. Composition according to claim 3, characterized in that said antihistamine drug is chosen from the group consisting of chlorpheniramine maleate, chlorpheniramine tannate, triprolidine hydrochloride, diphenhydramine, triprolidine, diphenhydramine ascorbate, doxylamine succinate oxalate, diphenhydramine maleate, pyrilamine, pyrilamine hydrochloride, pyrilamine tannate, phenindamine tartrate, promethazine hydrochloride, cyproheptadine hydrochloride, azatadine maleate, klemastine chlorate, carbamate hydrochloride, carbamate hydrochloride, carbamide trypananamine, trypanenamine citrate, dexchlorpheniramine maleate, brompheniramine maleate and chlorcyclizine hydrochloride and mixtures thereof; per 65,390 Case 4504R the said antitussive drug is chosen from the group consisting of dextromethorphan hydrobromide, carbetapentane citrate, codeine phosphate and hydrochloride Codeine N-oxide and mixtures thereof; for said Mod. 71 - 20,000 ex. 90/08 anti-cholinergic drug be chosen from the group consisting of scopolamine hydrobromide, scopolamine hydrochloride, atropine sulfate, atropine mucate, homatropin hydrobromide and homatropin hydrochloride and mixtures thereof; in that said anti-nausea or anti-emetic drug is chosen from the group consisting of cyclizine hydrochloride, meclizine hydrochloride, chlorpropazine hydrochloride and chlorpromazine maleate and mixtures thereof; in that said anoretic drug is chosen from the group consisting of benzophetamine hydrochloride, phentermine hydrochloride, chlorfenternine hydrochloride and fenfluramine hydrochloride and mixtures thereof; because the said antimicrobial drug was chosen from the group consisting of drugs / ^ - lactam drugs quinolone, ciprofloxacin, norfloxacin, tetracycline, erythromycin, amikacin, triclosan, doxycycline, capreomycin, chlorhexidine, chlortetracycline, oxymethridine, pentaminicine, clindamycin, clindamycin, clindamycin, clindamycin, clindamycin, methacrylamine, clindamycin. , metacycline, netylmycin, gentamicin, kanamycin, lineomycin, methenamine, minocycline, neomycin, paromomycin, streptomycin, tobramycin, miconazole and amanfadine, their pharmaceutically acceptable salts and mixtures thereof; in that said anti-arrhythmic drug is chosen from the group consisting of propanolol hydrochloride, procainamide hydrochloride, quinidine sulfate and quinidine gluconate and mixtures thereof; the said antihypertensive drug is chosen from the group consisting of analapril maleate, clonidine hydrochloride, hydralazine hydrochloride and hydralazine sulfate and mixtures of the same 30 65,390 4504R Wool; in that said anesthetic or anti-pruritic drug is chosen from the group consisting of lidocaine hydrochloride, bupivacaine hydrochloride, chlorprocaine hydrochloride, dibucaine hydrochloride, ethidocaine, mepivacaine hydrochloride, tetracaine, hydrochloride hydrochloride hydrochloride and hydrochloride hydrochloride hexylcaine and mixtures thereof; for said Mod. 71 · 20,000 and ». - 90/08 drug with bone activity to be chosen from the group consisting of 6-amino-1-hydroxy-hexane-1,1-diphosphonic acid, 3-amino-1-hydroxy-propane-1,1-diphosphonic acid, octahydro-1-pyridine-6,6-diphosphonic acid, 2- (2'-piperidinyl) -ethane-1,1-diphosphonic acid, 2- (3'-piperidinyl) -ethane-1,1-diphosphonic acid 2- (2'-piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, 2- (3 '-piperidinyl) -1-hydroxy-ethane-1,1-diphosphonic acid, N- [2' - (3'20 methyl) -piperidimylidene ] -amino-methane-diphosphonic acid N- [2 '- (1', 3'-diazinylidene)] - aminomethane-diphosphonic acid and N- [2- (3-methylpiperidinylidene) Jaminomethanophosphono-methylphosphine, or their esters and mixtures thereof; since said non-steroidal anti-inflammatory drug is chosen from the group consisting of propionic acid derivatives, acetic acid derivatives, phenamic acid derivatives, biphenylcarboxylic acid derivatives and oxycames and mixtures thereof, preferably with said anti-inflammatory drug -inflammatory non-steroid is a derivative of propionic acid chosen from the group consisting of aspirin, acetaminophen, ibuprofen, naproxen, benoxaprofen, flurbiprofen, fenoprofen, mdoprofen, pyrprofen, pranoprofen, miroprofen, alminoprofen, buccal acid thiaproo and mixtures of the phenolic acids , ketoprofen, carprofen, oxaprozine, thioxaprofen, suprofen, phenolic, fluprofen and acids; and in that said sunless agent is chosen from the group consisting of dihydroxyacetone, indole derivatives and mixtures thereof. 65,390 Case 4504R 10. The composition of claim 9, further comprising a sun protection agent.