RU2093146C1 - Liquid self-foaming pharmaceutical composition - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: composition has an active component 0.05-20 wt.-%, surface-active agent 0.01-20 wt.-% and solvent - the rest up to 100 ml. Composition can be placed in the dosing capacity fitted with a valve for foam feeding. An active components: antifungal, antiinflammatory, immunomodulating, wound-healing, antihyperemic, amino acids, vitamins, steroids and other drugs. Surface-active agents: alkylaminobetaines, ammonium quaternary salts, phospholipids and others. Composition is used for oral, skin and intravaginal using. EFFECT: improved quality of composition. 6 cl, 4 tbl

Description

 The present invention relates to pharmaceutical compositions in the form of a foam.

 Topical application of active ingredients allows for maximum concentration of the drug directly near the biophase and timely avoid dispersion of the drug into tissues that are not associated with the presence of special receptors or “target” organs for the drug, where it can cause an unjustified risk of toxicity or intolerance.

 Recently, special attention has been focused on the development of high consistency compositions such as gel, ointments and liquid compositions, which are used with special adapters such as nasal inhalers or nebulizers, vaginal showers or creams, etc. on the skin or on the mucous membrane of certain cavities of the body.

 The residence time of the composition at the place of use critically depends on the consistency of the pharmaceutical composition, therefore, a non-optimal carrier may adversely affect the therapeutic effect.

 This problem is especially significant in the case of intravaginal administration, since a slightly viscous consistency is immediately diluted and removed; on the contrary, a composition with a high consistency such as a cream prevents the diffusion of the active ingredients, which limits their activity only to the place of its application. Antibacterial and antifungal drugs are generally poorly absorbed, and the blocked diffusion of the active ingredient leads only to a partial therapeutic effect. In addition, reduced diffusion of the drug can cause irritation and an increase in local side effects.

 In the case of skin application, the high viscosity of the composition requires a more intensive smearing, which causes burns or pain if the tissue becomes inflamed or damaged.

 On the contrary, the inviscid composition can be quickly removed from the place of application.

 A foaming composition for topical contraceptive use is known containing an active ingredient, a surfactant, or a mixture thereof, a solvent, or a mixture thereof. The composition may contain fillers and other target additions. (US Pat. US N 4252787, CL A 61 K 9/12, 1981).

 The choice of the foaming agent of the composition depends on many factors, such as compatibility with gestogenic agents and other ingredients, such as solvents, thickeners, foam stabilizers, etc.

 The present invention was the creation of a composition that allows to obtain stable foams in the presence of drugs with a wide spectrum of action.

 This problem is solved by creating a liquid self-foaming composition comprising an active principle, one or more surface-active agents and at least one solvent, while the composition contains surface-active agents as substances from the group consisting of alkyl amidobetaine, quaternary ammonium salts, poloxamers and phospholipids . The composition: active principle 0.05-20% wt./about. surface active agents 0.01-20 wt. /% solvent, rest up to 100 ml.

 Known devices can be used to shape the compositions of the present invention as a foam. Particularly preferred devices are those described in EP-A-336188, which consist of a mixer into which the flow of liquid or air, appropriately controlled by the size of the openings, is guided through the aforementioned openings, which are free or provided with exhaust pipes, or similar means.

 For the purpose of skin and intravaginal use, cannulas of an appropriate shape can be inserted into the delivery channels in a known manner in order to facilitate the distribution and localization of the foam.

Surfactants in accordance with the present invention should be placed on the gas-liquid interface, facilitating the inclusion in the liquid mass of air or gas, which is enough to form the necessary consistency of the foam. Among the synthetic surface-active agents, alkyl amidobetaine, quaternary ammonium salts, poloxamers and the like are preferred, whereas among natural surface-active agents, phospholipids and the like. are preferred. In any case, the percentage varies from 0.01 to 20%
The compositions of the present invention can be used not only for application to the skin and intravaginally, but also orally.

 In general, the solvent of the composition is water or a water-ethanol mixture. In addition, other pharmaceutically acceptable solvents may be used.

 Examples of active ingredients that can be effectively included in the compositions of the present invention, not necessarily in combination with each other, include antifungal (cyclopiroxolamine), anti-inflammatory (diclofenac, benzidamine, piroxicam, tiaprofen, ketoprofen, tetridamine), corticosteroids (hydrocortisone and others ), immunomodulatory (Pidotimod and others), mucosecretolytic (sobrerol, carboxymethylcysteine), wound healing agents, plant extracts (Triticumvulgaris), amino acids, vitamins, XA ntines (cyclopropylmethylxanthine).

 The active ingredients are contained in the compositions of the invention in percentages that depend on the nature of the active ingredient, but generally range from 0.01 to 20% w / v.

 These compositions also contain fillers such as preservatives, stabilizers, thickening agents, gelling agents, colorants, co-solvents, structuring agents, etc. which are selected depending on the method of application and the type of active ingredient.

 The advantages of the present invention are illustrated by the following pharmacological and clinical trials.

 A foam containing 2% cyclopiroxolamine (Example No. 1) for intravaginal administration was tested for comparison with an aqueous composition containing the same active ingredient at the same concentration in the treatment of vaginal infection in rats (infection from Candida albicans).

 Female Sprague Dawley rats (C. River) weighing 100 g were subjected to ovariectomy and hysterectomy with Nembutal anesthesia (40 mg / kg intraperitoneally).

 About three weeks after the operation, rats were injected subcutaneously with 100 μg / day of estradiol in sesame oil in order to induce pseudo-erosion, which was analyzed using a vaginal smear placed under a microscope.

Rats that developed pseudo-eustration were infected with 10 ⁶ Candida albicans cells diluted in 0.2 ml of saline.

 Treatment with 2% vaginal foam cyclopirox olamine or with an aqueous solution began three days after infection and lasted 10 days. Starting on the fourth day, samples were taken from the vagina every morning using a sterile cotton swab on the shaft. The swab was placed on Saburo agar containing 20 IU / ml penicillin G and 40 m / ml streptomycin for microbiological analysis of the infection.

 The results shown in table 1 show that both cyclopiroxolamine preparations were active relative to experimental infections, but the vaginal foam was much more operational compared to the aqueous composition, due to the above characteristics.

 In addition, the form of the cyclopiroxolamine vaginal foam was actively tolerated during the one-month toxicity test carried out on female rats and rabbits.

 In the case of topical skin application, a high concentration of the surface-active agent and the “fragility” of the foam allow it to easily spread throughout the tissue and skin endings: a foam rupture, which can be modulated by the selection of preparation parameters, allows a uniform and continuous film of the solution to form on the application area without the need to use mechanical the effort to spread the drug, unlike what happens with highly structured carriers.

 A 2% topical tetridamine foam (Example 2) was tested in comparison with an aqueous solution containing the same amount in accordance with the test for inflammation caused by carrageenin and the test for analgesic activity in rats.

 Anti-inflammatory activity was determined on edema caused by carrageenin (Winter et al. Proc. Soe. Exp. Biol. Med. T. III, p. 544, 1962); analgesic activity was determined on the same rats in accordance with the test described by Pandall and Sellitto (Arch. Int. Pharmacodyn vol. III, p. 409, 1957). Female rats Spread Dowley (C. River) weighing 200 g were injected with a 2% saline solution of carrageenin (0.1 ml / rat) in the upper right paw and treated three times with tetridamine foam for topical application or solution for topical application (3 times at 20 minute intervals). The volume of the inflamed paw was measured before and after 1, 2, 3, 4, or 5 hours after injection of carrageenin using a plethysmograph (Basill Italy).

 Pain sensitivity of an inflamed paw was measured in grams of mass before and after 1, 2, 3, 4, and 5 hours after infection with carrageenin using a tester (Basill, Italy).

 Table 2 shows that the topical tetridamine foam had a higher and longer lasting local anti-inflammatory activity compared to the aqueous form of the drug.

 Similarly, table 3 shows that the topical foam makes it possible to obtain stronger and longer lasting analgesic activity in rats. These results are related to the composition of the foam, which allows for a higher and longer absorption of the active ingredient tetridamine.

 Tetridamine foam for topical application was actively tolerated in toxicity tests for one month.

 In the case of oral administration, the appearance of the dose to be applied, if appropriately aromatized, can be made more acceptable for patients who have difficulty swallowing, such as elderly patients or children, in accordance with the prescribed dosage.

 Pidotimod oral foam (Example 4) was tested in two groups of patients in comparison with an aqueous solution having the same concentration. The first group included 40 children, boys and girls, aged 6 to 10 years; the second group included 40 elderly people, men and women, aged 65 to 80 years.

 The patient could take one of two compositions of his choice, twice a day (8.00 a.m. and 8.00 a.m.). A week later, each patient had to choose a preferred composition.

 Table 4 clearly shows that both groups of patients most preferred an oral foam composition.

 The following examples further illustrate the present invention.

Example 1
200 g of cyclopiroxolamine was dissolved in a minimum amount of propylene glycol, then 3.5 L of an aqueous solution containing 0.2% trimethylacetyl ammonium p-toluenesulfonate and 3.5% fatty acid diethylate was added.

 A flavoring agent, natural plant extract and propylene glycol were added to this solution to a volume of 10 liters, adjusting the pH to physiological values with lactic acid.

 The solution described above, after being placed in a vessel equipped with an appropriate agent, gives a light and stable foam that can be applied to the skin to treat skin mucus or directly to the vaginal cavity using a cannula.

 A similar result was achieved using the aforementioned composition using a gas atomizer at normal pressure such as isobutane in a standard pressure vessel.

Example 2
10 g of tetridamine maleate, 30 g of alkylamidobetaine, 1 g of sodium methyl para-hydroxybenzoate were dissolved in approximately 500 ml of deionized water. The clear solution was buffered to pH 4.5 with lactic acid and the volume was adjusted to 1 L. This solution was transferred into vessels equipped with a delivery system and a vaginal cannula, which would allow the delivery of foam with anti-inflammatory and analgesic properties.

Example 3
100 g of thiaprofenic acid was used to form a salt stoichiometrically with tromethamine in 500 g of an aqueous solution containing the corresponding amounts of antimicrobial agents.

 Then, 100 g of alcohol and 100 g of the quaternary surface-active agent of the betaine type were added.

 This solution was buffered to a pH of about 7, filtered, and placed in appropriate containers equipped with a foam dispensing valve. The foam thus obtained can be easily applied to the skin near the joints in order to accelerate the penetration of the active ingredient and initiate a known anti-inflammatory activity.

Example 4
80 g of Pidotimod was dissolved by salt formation with 40 g of tromethamine in 500 g of a solution containing known flavoring agents, antimicrobial agents, 150 g of sorbitol, 50 g of a polyoxyethylene-polyoxypropylene copolymer and an appropriate amount of flavoring agents. The pH was adjusted to slightly acidic values, and the final volume was adjusted to 1 L. The resulting solution was dispensed into appropriate dispensing flasks equipped with a valve for foam formation. The foam that was obtained using simple "manual" pressure was collected and used as a carrier for pediatric use. In fact, the foam showed specific palatability and perfect edible qualities for that type of application when it comes to problems with swallowing and chewing. The same composition, placed in an anodized aluminum gas bottle in the presence of an appropriate amount of a spraying agent, was supplied through a generally used foam dispensing valve, and a stable foam of the same consistency was obtained.

Example 5
An ethanol solution containing 50 g of lecithin, 10 g of cholesterol and 20 g of cyclopiroxolamine was mixed with 800 g of an aqueous solution of alkylamidobetaine, protected against bacterial infection with an appropriate amount of sodium methyl para-hydroxybenzoate and acidified with lactic acid.

 The liposome suspension was then transferred to a vessel equipped with a foam-forming valve and optionally equipped with a cannula for intravaginal administration. A similar result was obtained if the aforementioned aqueous solution and an alcohol solution were transferred to a gas vessel in which increased pressure was generated with a sufficient amount of isobutane: by pressing the button of the standard aerosol valve, the atomizing agent begins to evaporate, while the alcohol, which is a more volatile component, causes the immediate formation of liposomal foam.

Example 6
Using a procedure similar to that described in Example 2, tetridamine was replaced with 60 g of Triticum vulgare extract (dried residue equivalent to 200 mg / ml), a composition was obtained which, after being placed in a flask equipped with a supply valve, could produce a foam that helps treat skin tissue that needs repair.

Example 7
Using a procedure similar to that described in Example 4, instead of Pidotimod, a mixture of amino acids consisting of 6 g of L-phosphoserine, 15 g of L-arginine hydrochloride, 2 g of L-phosphotreonin, 7.5 g of L-glutamine and 50 g was used Vitamin B-12 as an active ingredient.

 An edible foam was obtained which has a characteristic odor and very good swallowing properties.

Claims (6)

1. A liquid self-foaming pharmaceutical composition comprising an active principle, one or more surface active agents and at least one solvent, characterized in that it contains substances from the group consisting of alkyl amidobetaine, quaternary ammonium salts, poloxamers and phospholipids in the following components:
The active principle of 0.05 to 20 wt./about.  Surfactant agent 0.01 to 20 wt.  Solvent Remaining up to 100 ml.  2. The composition according to claim 1, characterized in that it is enclosed in a dosing container equipped with a foam supply valve having a micro-hole, to which the composition and part of the air or gas contained in the container are sent separately when manually acting on the container.  3. The composition according to claim 1 or 2, characterized in that the active principle is one or more agents selected from the group consisting of antifungal, anti-inflammatory, immunomodulatory, mucosecretolytic, wound healing, restorative, antihyperemic agents, amino acids, vitamins and corticosteroids.  4. The composition according to any one of claims 1 to 3, characterized in that the active principle is cyclopiroxolamine.  5. The composition according to any one of claims 1 to 3, characterized in that the active principle is a substance selected from the group consisting of tetrylamine base or its salt, benzidamine base or its salt, Pidotimoda base, its salt or derivative, Triticum Vulgare extract, soluble vitamins or amino acids in water or oil, a mixture of these amino acids with their mineral salts, mineral salts of amino acids, carboxymethylcysteine and / or its salt, or its derivative, sobrerol, 3-cyclopropylmethylxanthine, hydrocortisone, its salt, piroxicam, its complex with cyclodextrin, ketoprofen, a salt thereof, and a salt thereof ditsiklofenak.  6. The composition according to PP.4 and 5, characterized in that it contains an active principle in an amount of 1 to 3 wt./about.

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