Title:  Topical application of cetirizine and loratadine

United States Patent:  6,790,847

Issued:  September 14, 2004

Inventors:  Walch; Hatto (Baden, DE)

Assignee:  Oramon Arzneimittel GmbH (Laupheim, DE)

Appl. No.:  334331

Filed:  December 30, 2002

Abstract

The present invention relates to a drug composition containing the non-sedating H₁ antihistamines cetirizine, loratadine, mixtures or pharmaceutically acceptable salts thereof for topical application in the form of a gel.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical composition for topical application in the form of a gel, comprising 0.05 to 5 wt. %, preferably 0.5 to 5.0 wt. % of a non-sedating H₁ antihistamine selected from the group consisting of cetirizine, loratadine and mixtures and pharmaceutically acceptable salts thereof as well as at least one pharmaceutical carrier or excipient which is a solvent for the antihistamine.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has now been found that the above objects may be achieved and the disadvantages of the prior art overcome by a pharmaceutical composition for topical application in the form of a gel, comprising 0.05 to 5.0 wt.-% of a non-sedating H₁ antihistamine selected from the group consisting of cetirizine, loratadine and mixtures and pharmaceutically acceptable salts thereof as well as at least one pharmaceutical carrier or excipient which is a solvent for the antihistamine.

It is one advantage of the topical application of the non-sedating H₁ antihistamine cetirizine and/or loratadine in the form of a gel of the invention that the active ingredient counteracts the locally released histamine by binding competitively to the relevant receptor so that symptoms may largely be avoided or reduced. In addition, the formulation of the invention surprisingly produced a faster onset of the effect in comparison with known topical formulations.

Without wishing to be bound by theory, the inventors believe that this may be due to the fact that the active ingredient is not merely suspended in the formulations of the invention, but is present in the form of a genuine solution. In turn, the resulting molecular distribution could increase the speed of resorption.

The gels of the invention are preferably intended for the therapy of a disease or disorder selected from the group consisting of urticaria, allergy-based dermatoses (allergic skin reactions), atopical eczema, itching, redness, sunburn and insect bites.

The gels of the invention permit easy spreading on the skin, especially since these disorders tend to affect large areas, and may have a cooling effect perceived as pleasant by the patient. According to the invention, resorption may be accelerated by formulating the active ingredient in a gel which is easily broken down and therefore releases said active ingredient on the skin more rapidly.

As described above, the pharmaceutical compositions of the invention contain a non-sedating H₁ antihistamine selected from the group consisting of cetirizine, loratadine as well as mixtures and pharmaceutically acceptable salts thereof. Such pharmaceutically acceptable salts may be the hydrochloride, hydrobromide, hydroiodide, citrate, carbonate, malate, tartrate etc. Mixtures of cetirizine and loratadine and/or salts thereof may also be used according to the invention.

The gels contain the non-sedating H₁ antihistamine and/or a pharmaceutically acceptable salt thereof in an amount of 0.05 to 5.0 wt. %, preferably 0.5 to 5.0 wt. %. More preferably, the formulation contains 0.8 to 1.5 wt.-% of the active ingredient.

In addition, the gels of the invention contain one or more pharmaceutical excipients or carriers. Such pharmaceutical excipients or carriers are preferably selected from pharmaceutical excipients and carriers which are known and suitable for the formulation of the above mentioned composition form. At least one of the excipients and carriers is a solvent for the active ingredient used. As possible pharmaceutical excipients and carriers, mention may be made of solvents such as water, alcohols, especially C₁ -C₅ alcohols such as ethanol, n-propanol, 2-propanol, isopropanol, t-butyl alcohol; ethers such as MTBE; ketones such as acetone, methyl ethyl ketone; humectants such as glycerol; glycols such as ethylene glycol, propylene glycol; emulsifiers such as lower, optionally polyhydric C_1-5 alcohols partially esterified with long-chain (C₁₂ -C₂₄) fatty acids such as glycerol monostearate, isopropyl myristate, fatty acid ester of sugar alcohols such as sorbitan mono-fatty acid ester, polyethoxylated derivatives of such compounds, polyethoxyethylene fatty acid ester and fatty alcohol ether, cholesterol, cetyl stearyl alcohol, wool wax alcohols and synthetic surfactants with a low HLB value; solubilisers such as carbopol; low-viscosity paraffins, triglycerides; lipophilic substances such as isopropyl myristate; pH regulators such as TEA, carbonates and phosphates; chelating agents such as EDTA and salts thereof; as well as preservatives.

In addition to these pharmaceutical excipients and carriers, the pharmaceutical compositions of the invention may contain one or more cosmetic excipients. Such cosmetic excipients are well known to pharmaceutical formulators. In particular, they may be selected from the group consisting of humectants, smoothing agents, UV filters, pigments, dyes, perfumes, vitamins and bleaching agents. Humectants, smoothing agents and perfumes are especially preferred.

As far as the gels to be used according to the invention are concerned, we must distinguish between hydrophilic gels and hydrophobic gels. In the invention, both may be used, optionally depending on the indication to be treated. As is well known, hydrophilic gels are gels having a high water content (80 to 90%).

The hydrophobic or so-called "oleogels" are greasing gels which are formed with liquid paraffins, polyethylene glycols, triglycerides etc. as the base together with gelatinising agents such as highly dispersed silica or aluminum or zinc soaps. In the invention, hydrophilic gels are particularly well suited for the indications insect bites and sunburn, whereas oleogels are specifically used for atopical eczema.

According to a first embodiment, a gel composition containing

0.05 to 5 wt. %, preferably 0.5 to 5 wt.-%, more preferably 0.8 to 1.5 wt.-% of antihistamine (preferably cetirizine, hydrochloride cetirizine, loratadine hydrochloride, loratadine);

1 to 2 wt.-% of solubiliser, especially carbopol;

0 to 1 wt.-%, especially 0 to 0.4 wt.-% of a chelating agent, especially EDTA;

20 to 40 wt.-%, especially 30 to 40 wt.-%, of alkylene glycol, especially propylene glycol;

5 to 20 wt.-%, preferably 10 to 20 wt.-%, of alcohol, especially n-propanol, isopropanol, 0 to 4 wt.-%, preferably 1 to 4 wt.-%, of pH regulator, especially triethanol amine, and

a residual amount of purified water ad 100%, i.e. 20 to 70 wt.-%, preferably 30 to 60 wt.-%, most preferably 35 to 50 wt.-%, the weight ratios of the components adding up to 100% and being based on the overall weight of the composition,

is especially preferred.

According to a second preferred embodiment of the invention, a gel is provided containing

0.05 to 5 wt.-%, preferably 0.5 to 5 wt.-%, more preferably 0.8 to 1.5 wt.-% of the active ingredient (preferably cetirizine hydrochloride, cetirizine, loratadine hydrochloride, loratadine);

5 to 20 wt.-%, preferably 10 to 15 wt.-%, of alkylene glycol, especially propylene glycol;

2 to 10 wt.-%, preferably 5 to 10 wt.-%, of ethoxylated partial glycerides of fatty acids, especially medium-chain fatty acids such as the product sold under the trademark Softigen.RTM. 767;

3 to 10 wt.-%, preferably 3 to 5 wt.-% of cellulose derivatives, especially cellulose ether such as metholose; and

a residual amount of purified water ad 100%, i.e. 50 to 90 wt.-%, preferably 55 to 90 wt.-%, and most preferably 80 to 90 wt.-%, the weight ratios of the above-mentioned substances adding up to 100% and being based on the overall weight of the composition.

According to a third preferred embodiment of the invention, a gel is provided containing

0.05 to 5 wt.-%, preferably 0.5 to 5 wt.-%, more preferably 0.8 to 1.5 wt.-% of the active ingredient (preferably cetirizine hydrochloride, cetirizine, loratadine hydrochloride, loratadine);

1 to 2 wt.-%, preferably 0.6 to 1.0 wt.-% of solubiliser, especially carbopol;

0.2625 to 0.4375 wt.-%, preferably 0.3 to 0.4 wt.-% of an at least 25% aqueous solution of ammonia;

1.5 to 2.5 wt.-%, preferably 1.8 to 2.2 wt.-% of an ester of a C_10-20 fatty acid with a lower C_2-5 alcohol, especially isopropyl myristate;

4.5 to 7.5 wt.-%, preferably 5.5 to 6.5 wt.-% of CETIOL V, the generic designation being oleyl oleate;

0.0375 to 0.0625 wt.-%, preferably 0.045 to 0.055 wt.-% of a chelating agent, especially Na-EDTA;

2.25 to 3.75 wt.-%, preferably 2.75 to 3.25 wt.-% of MACROGOL 400 the generic designation being polyethylene glycol;

15.0 to 25.0 wt.-%, preferably 17.0 to 22.0% of a lower secondary C_2-5 alcohol, especially 2-propanol; and

a residual amount of purified water ad 100%, i.e. 47.1625 to 83.9375 wt.-%, preferably 55 to 65 wt.-%, the weight ratios of the above-mentioned substances adding up to 100% and being based on the overall weight of the composition.

The latter gel is a formulation which breaks down especially rapidly on the skin and therefore permits excellent penetration.

The administration form of a gel according to the invention helps avoid the systemic detour and also permits administration of much lower amounts of the active ingredient than required in the past and described as necessary for oral therapy. For example, when 200 mg (approx. 200 .mu.l) of gel with a weight concentration of 0.05 to 5 wt. % of active ingredient are applied, 1 mg of active ingredient is administered.

Claim 1 of 9 Claims

What is claimed:

1. A drug composition for topical application in the form of a gel, comprising

0.05 to 5.0 wt.-% of a non-sedating H₁ antihistamine selected from the group consisting of cetirizine, loratadine and mixtures thereof;

1.0 to 2.0 wt.-% of carbopol;

0 to 0.4 wt.-% of EDTA;

20 to 40 wt.-% of n-propanol;

10 to 20 wt.-% of triethanol amino; and

water ad 100%.

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