CZ283238B6 - Liquid pharmaceutical preparation - Google Patents

Abstract

The present invention relates to a pharmaceutical composition which can be administered using a suitable foam-free device without the use of a propellant, the composition comprising: a) at least one natural or synthetic, ionic or non-ionic, acidic, basic or neutral wetting agent; c) an active ingredient or mixture of active ingredients and d) optionally an excipient or carrier. The composition is for topical or oral administration

Description

The invention relates to a liquid pharmaceutical composition for administration in the form of a foam orally, on the skin or intravaginally, the composition does not require the use of a propellant.

BACKGROUND OF THE INVENTION

Topical administration of the active ingredients is very advantageous because the maximum concentration is reached directly at the point where the use of the active ingredient is desired and at the same time there is no easy spread of the active ingredient into non-target tissues. Indeed, an excessive spread of the active substances may lead to an undesirable risk, in particular as regards the toxicity or poor tolerability of the active substance.

Recently, great attention has been paid to devices that are very cohesive, such as gels, ointments or liquid formulations, administered by special types of different devices, such as inhalation devices, sprays, rinses or creams for vaginal, skin or mucosal administration some body cavities.

The duration of action of the composition at the site of administration is highly dependent on the consistency of the pharmaceutical composition, i.e., an inappropriate vehicle environment may adversely affect the therapeutic effect.

This problem is particularly critical in the case of vaginal administration, since the composition with too low a viscosity is immediately diluted and flows out, and the composition with too high a consistency, for example a cream, prevents diffusion of the active ingredient and reduces the effect only on the application site. Antibacterial and antifungal agents are usually poorly absorbed, and limited diffusion of the active ingredient may cause only partial therapeutic effect. In addition, reduced diffusion of the active ingredient may cause irritation and excessive local effect.

When administered to the skin, high viscosity of the composition may require stronger spreading, which may cause burning sensation or pain if the tissues are irritated or damaged.

On the other hand, too low a viscosity of the composition may cause it to be quickly removed from the site of administration.

SUMMARY OF THE INVENTION

The present invention provides a liquid pharmaceutical composition for oral or topical administration of antimycotics, anti-inflammatory agents, healing agents, amino acids or immune system modulators together with adjuvants or carriers in solution in a physiologically acceptable solvent in the form of a foam without propellant. The foamable surfactant composition comprises trimethylacetylammonium p-toluenesulfonate, aliphatic acid diethanolamide, alkylamidobetaine, a betaine-type quaternary surfactant, polyoxyethylene-polyoxypropylene copolymers, lecithin or cholesterol.

Conventional devices may be used to apply the pharmaceutical composition of the present invention in the form of a foam. Particularly suitable is the apparatus described in European Patent Specification No. 336,188, which comprises a mixing means from which the liquid and air flow is pushed through openings of suitable size, the openings being free or provided with tubes. Similar devices may also be used.

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For application to the skin or vagina, a cannula of suitable shape can be attached to the outlet opening for easier placement or placement of the formed foam.

The wetting agents in the composition of the invention are deposited at the gas-liquid interface and thus assist in the mixing of the liquid with air or gas to produce sufficient intense foam. The surfactant content is from 0.01 to 20% by weight.

The compositions of the invention may be administered not only to the skin and vagina, but also orally.

Generally, the solvent for the pharmaceutical composition is water or a mixture of water and ethanol, but other pharmaceutically acceptable solvents may also be used.

Examples of active ingredients of the composition of the invention are antifungal agents, for example ciclopirox olamine, anti-inflammatory agents such as diclofenac, benzidamine, piroxicam, tiaprofen, ketoprofen, tetridamine, corticosteroids such as hydrocortisone and other hormones, immune system modulators and others mucosecretolytic agents such as sobrerol or carboxymethylcysteine, wound healing accelerators, plant extracts such as Triticum vulgaris, amino acids, vitamins and xanthines such as cyclopropylmethylxanthine, mixtures of the above compounds may also be used.

The compositions according to the invention contain the active ingredient in an amount which depends largely on the nature of the active ingredient, usually in the range of 0.01 to 20 g / 100 ml.

The pharmaceutical compositions may contain excipients such as preservatives, stabilizers, thickeners, gel formers, flavoring agents, coloring agents, co-solvents, agents providing the desired structure of the composition, and the like, depending on the intended route of administration and the nature of the active ingredient. folders.

The advantages of the composition of the invention have been demonstrated in the following pharmacological and clinical tests.

The foam containing 2% ciclopirox olamine of Example 1 for vaginal administration was tested using an aqueous formulation containing the same active ingredient at the same concentration as a comparator in the treatment of vaginal Candida albicans infection in rats.

Female rats of Sorague Dawley strain (C. River) weighing 100 g were anesthetized with nembutal 40 mg / kg i.p. and the uterus and ovaries were removed.

Three weeks after surgery, rats were injected subcutaneously with 100 µg of estradiol daily in sesame oil to induce pseudoestres, which was monitored by vaginal smear inspection by microscope.

Pseudoestrus-infected rats were infected with 10 ⁶ Candida albicans cells in 0.2 ml saline.

Three days after infection, treatment with 2% vaginal foam or an aqueous solution with the same ciclopirox olamine content was initiated and continued for 10 days. From day four, a vaginal swab was collected every morning with a sterile cotton swab. This swab was deposited in Sabouraud agar containing 20 units / ml penicillin G and 40 micrograms / ml streptomycin for microbiological examination for infection status.

The results, which are summarized in Table 1 below, show that both formulations containing said active ingredient suppress the experimental infection, but the effect of vaginal foam is far from

-238 283238 B6 faster than the effect of the aqueous composition due to the above properties of the individual compositions.

Table 1

Comparison of the effect of vaginal foam and aqueous solution of ciclopirox olamine against vaginal infection

10 Candida albicans in rat means number of female rats 4 number of animals with negative microbiological test- 5 6 in the day 7 8 9 10 15 Dec sodium chloride solution 20 May 0/20 0/20 0/20 0/20 0/20 0/20 0/20 2% vaginal foam of ciclopirox olamine 20 May 10/20 14/20 18/20 20/20 20/20 20/20 20/20 20 May 2% solution of ciclopirox olamine in water 20 May 5/20 7/20 10/20 13/20 17/20 20/20 20/20

In addition, it was shown that vaginal foam containing the active ingredient was well tolerated by both rat and rabbit females when administered for one month in toxicity tests.

In the case of topical application to the skin, a high surfactant concentration and lightness of the foam allows easy spreading of the pharmaceutical composition over the entire skin, while breaking the foam, which can be controlled by the composition of the pharmaceutical composition, results in a homogeneous and continuous film in the application area. mechanical pressure to spread the composition, which is usually used for high viscosity compositions.

A 2% tetridamine foam for topical administration of Example 2 was tested in the rat for carrageenin-induced inflammation, and an aqueous solution containing the same amount of drug was used for comparison.

The anti-inflammatory effect was tested using the carrageenin edema suppression test of Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962, the analgesic effect was tested in the same rats using the Randall and Selitt test of Arch. Int. Pharmacodyn. 111, 409, 1957. 200 g of Sprague Dawley (C. River) male rats were injected with a 2% solution of carrageenin in physiological saline 45 in an amount of 0.1 ml / rat into the front right paw and treated three times. either by administering a tetridamine-containing foam or by administering a solution containing it, three times at 20 minute intervals. The volume of inflamed paw was measured before and 1, 2, 3, 4 or 5 hours after carrageenin injection by plethysmograph (Basile, Italy).

Table 2

Local anti-inflammatory effect of tetridamine foam compared to the effect of aqueous solution in carrageenin edema treatment number of differences in inflamed paw volume versus rats original volume in ml after hours

1 2 3 4 5 NaCl saline 10 0.48+ 0,62 ± 0.60 ± 0.60 ± 0.3 8 ± 0.02 0.03 0.04 0.05 0.02 2% tetridamine foam 10 0,36 ± 0.22+ 0.23+ 0,24 ± 0.18 ± 0,02 ^x 0,02 ^x 0,03 ^x 0,03 ^x 0.02 2% aqueous tetridamine solution 10 0,39 ± 0,30+ 0.40+ 0.40 ± 0,30+ 0,03 ^x 0,03 ^x 0,04 ^x 0,04 ^x 0.02

^x P less than 0.01 Dunnett's t control

P less than 0.01, Student's t versus aqueous solution.

Table 3

Topical analgesic effect of tetridamine foam for topical administration compared to the effect of an aqueous solution, Randall and Selitta test treating the number of differences in susceptibility to pain versus rats of initial susceptibility in grams (h)

1 2 3 4 5 NaCl saline 10 85.6+ 96,7+ 75.8 ± 70.3 ± 55.4 ± 8.1 10.1 8.3 9.5 8.7 2% tetridamine foam 10 27.8 ± 25.6 ± 26.7 ± 28.3 ± 20.6 ± 4,5 ^X 3,2 ^X 4,5 ^X 4,5 ^X 4,6 ^X 2% aqueous tetridamine solution 10 36,7+ 39.7 ± 40.6 ± 50.6 ± 43.2 ± 6, 1 ^x 4,3 ^X 5,2 ^X 6.2 ^X 6,7 ^X

^x P less than 0.01 Dunnett's t control

P less than 0.01, Student's t versus aqueous solution.

Sensitivity to pain in inflamed paw was measured in grams of weight before and 1, 2, 3, 4 and 5 hours after carrageenin injection using a conventional pain sensing device (Basile, Italy).

It is apparent from Table 2 that the anti-inflammatory effect of tetridamine foam is higher and longer than that of an aqueous solution of the tetridamine foam.

CZ 283238 B6

Similarly, Table 3 demonstrates that topical foam containing the same substance can provide a stronger and longer analgesic effect in the rat. The cause of this phenomenon is the composition of the foam, which allows better and longer absorption of tetridamine as the active ingredient of the composition.

When administered tetridamine foam for a month, the foam was very well tolerated.

The pharmaceutical composition in the form of a foam may also be administered orally after appropriate flavoring, which may be particularly suitable for patients with difficulty swallowing, for example in the elderly or children.

The oral foam containing Pidotimod of Example 4 was tested in two groups of patients, the comparative substance being an aqueous solution with the same concentration of active substance. The first group contained 40 children, girls and boys aged 6 to 10 years. The second group comprised 40 elderly patients, both men and women, aged 65 to 80 years.

Patients were able to choose between both means at will, the drug was administered twice a day at 8 am and 8 pm. After a week, patients were asked to indicate which form they prefer.

The result is shown in Table 4

Table 4

Preference data when two Pimotimod-containing agents were administered to two groups of patients

means children elderly people (number of persons favoring the device) Pidotimod oral foam 35/40 28/40 Pidotimod aqueous solution 5/40 12/40

It is clear from Table 4 that most patients in both groups preferred a pharmaceutical composition in the form of a foam.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

200 g of ciclopirox olamine were dissolved in a small amount of propylene glycol, then 3.5 liters of an aqueous solution containing 0.2% trimethylacetylammonium p-toluenesulfonate and 3.5% aliphatic diethanolamide were added.

-5GB 283238 B6

The solution was made up to 10 liters with fragrances, natural plant extracts and propylene glycol, and the pH was adjusted to physiological value by the addition of lactic acid.

The above solution provided a soft and stable foam when mixed in an appropriate device, which could be easily rubbed onto the skin for the treatment of fungal infections or injected into the vaginal cavity by cannula.

The same effect could be achieved when the mixture was placed in a pressure vessel and a conventional propellant gas under pressure or in a gaseous state without pressure was used, such as isobutane using a conventional pressure vessel.

Example 2

10 g tetridamine maleate, 30 g alkylamidobetaine, 1 g sodium methyl p-hydroxybenzoate were dissolved in 500 ml deionized water. The clear solution was adjusted to pH 4.5 by the addition of lactic acid buffer and the volume was adjusted to 1 liter. The solution was transferred to vials with an appropriate aperture through which a vaginal cannula could be fitted to deliver anti-inflammatory foam.

Example 3

A salt of 100 g of thiaprofenic acid was formed with a stoichiometric amount of tromethamine 25 in 500 g of an aqueous solution containing an appropriate amount of antimicrobials.

100 g of alcohol and 100 g of quaternary betaine surfactant were then added.

The solution was adjusted to a pH of about 7, filtered, and placed in suitable containers with a foam applicator. The attachment has been provided with an appropriate valve so that the foam can be easily spread over the skin near the joints to improve the penetration of the active ingredient and to have an anti-inflammatory effect.

Example 4 g of Pidotimod was dissolved, 40 g of tromethamine in 500 g of a solution containing conventional sweeteners, antimicrobials, 150 g of sorbitol, 50 g of a polyoxyethylene-polyoxypropylene copolymer and an appropriate amount of flavorants were used to form the salt. Then the pH was adjusted to a slightly acidic value and the formulation was made up to a volume of 1 liter. The resulting solution was dispensed into containers fitted with a foam valve. Foam, obtained by pushing the valve by hand, was used for administration in children. The taste of the foam was pleasant and the composition was very suitable for administration to children with swallowing difficulties. The same composition could be stored in anodized propellant gas pressure aluminum cans and used to form a consistency foam.

Example 5

An ethanol solution containing 50 g of lecithin, 10 g of cholesterol and 20 g of ciclopirox olamine was mixed with 800 g of an aqueous solution of alkylamidobetaine, sodium methyl p-hydroxybenzoate was added as a preservative, and the composition was acidified with lactic acid.

The liposome suspension was then transferred to a vial equipped with a foam valve and optionally a vaginal cannula. A similar result was achieved with the migration

The aqueous and alcoholic solution is added to the vial and isobutane is used as a propellant. At the pressure on a conventional aerosol valve, the propellant vaporized, so that the more volatile alcohol immediately caused the formation of liposome foam.

Example 6

The procedure of Example 2 was followed, but tetridamine was replaced by 60 g of Triticum vulgare extract, the dry matter being equivalent to 200 mg / 100 ml, providing a composition which, even when placed in a vial with an appropriate valve, provided skin healing foam.

Example 7

The procedure of Example 4 was followed, but instead of Pidotimod a mixture of amino acids, 6 g of L-phosphoserine, 15 g of L-arginine hydrochloride, 2 g of L-phosphothreonine, 7.5 g of L-glutamine and 50 mg of vitamin B was used as active ingredient. ₂ .

The resulting edible foam had a characteristic odor and was pleasant to swallow.

Claims (1)

A liquid pharmaceutical composition for oral or topical administration of active substances from the group of antimycotics, anti-inflammatory agents, healing agents, amino acids or immune system modulators, together with adjuvants or solution carriers in a physiologically acceptable propellant-free foam solvent, characterized in that The composition according to claim 1, wherein the foaming surfactant is trimethylacetylammonium p-toluenesulfonate, aliphatic acid diethanolamide, alkylamidobetaine, a betaine-type quaternary surfactant, polyoxyethylene-polyoxypropylene copolymers, lecithin or cholesterol.