DE2736777A1 - SPRAYABLE Germicidal Foam Compositions - Google Patents

Description

EISEN FÜHR & SPEISER patent attorneys

Om. INO GÜNTHER EISENFUHR

CHPL Inü DIETER K. SPEISER

BREMEN DB PtHNATHORST ZINNGRj

US. CHARACTER: M 445

ANMELOEH / ₍ NH: MüNDIPHARMA AG reference number: New registration

: August 11, 1977

MÜNDIPHARMA AG, Alban-Vorstadt 94, 4006 Basel , Switzerland

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Sprayable germicidal foam compositions

The invention relates to new sprayable germicidal compositions, which can be applied as foam directly to an injured commercial surface and there in a permanent, semi-permeable germicidal protective layer for the skin and mucous membranes, which is essentially painless form. A particular benefit of the new composition is that it is easy to distribute from pressurized containers so that the germicidal foam formed directly on a wound Abraded, burned or injured tissue surfaces with minimal impact on the craft or injury the fabric can be applied.

More particularly, the invention relates to sprayable compositions comprising an active germicidal agent which is selected from the group consisting of the following compounds: silver sulfadiazine, silver sulfaphenol, antibiotic compounds of their salts, iodophor, including povidone-iodine and complexes of elemental - iodine with detergents; a silicon compound such as dimethylpolysiloxane; a non-ionic surfactant Smock; a fatty alcohol and a fatty acid and an aqueous one

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Glycol solvent for the production of a stable base, the whole packaged in one under pressure standing vessel with a gas aerosol propellant.

In particular, when the germicidal composition is applied to injured tissue, the developed foam possesses a desirably long life and durability to an extent not previously achieved compared to other foams from pressure vessels. The permanent, durable properties along with the uniformly microporous Build up a cheap semi-permeable germicidal protective layer for injured tissue surfaces in order to To prevent infections and at the same time avoid tissue maceration due to the vapor permeability. Furthermore, the use of the new sprayable germicidal compositions adds considerable pain eliminated, which is usually to be expected when the germicidal preparations currently in use on the Applied to the patient's skin for the treatment and prevention of infections on burned or injured skin will. Layers of skin that have been burned, abraded, and / or otherwise damaged are extraordinary susceptible to infection, so it is necessary to build up a protective germicidal layer to prevent infection Avoid causing death in extensive tissue injury. Infection is one of the main factors for the complication of treating patients with severe burns, and for recovery one exists therapeutic compulsion to sterilize burnt, sore or abraded skin.

The entire range of agents that kill microorganisms, in particular antibacterial agents, is used to disinfect injured persons Skin and mucous membrane have been used. It is well known that iodine is perhaps the best germicidal agent.

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in view of its broad antibacterial spectrum, and the newer organic iodine derivatives known as iodophores as a major benefit, reduce the harmful, toxic properties of iodine; however, it is still the Use of elemental iodine is generally restricted in the treatment of patients with severe burns and with heavily abraded sore skin and mucous membranes.

Trying to use the metal salts of sulfa drugs too also failed because of the inherent allergic reactions to this class of antiseptic drugs when applied topically, and also because of the additional toxic effect of the silver ion when using the silver salts of the sulfa compounds, e.g. Silver sulfadiazine. These agents not only do not improve the patient's morbidity, but they increase it Number of toxic reactions and serious side effects known for these agents. The silver salts of the sulfa compounds such as silver sulfadiazine and silver sulfaphenazole bring as a further limitation on their Application of the well-known reactions between silver ions and halide ions that occur in all physiological exudates occurrence. This chemical reaction not only destroys the ionic balance of the injured tissue area, it also destroys it also poisons the tissue cell by combining the cellular protein with the silver ion. They also call Salts of the antibiotics either have an acidic pH or an alkaline pH, resulting in pain and Tissue irritation brings problems and leads to different activity of the drug as the physiological fluids have neutralizing properties.

Another problem that limits the sterilization of injured skin arises from the nature of pharmaceuticals Compositions bearing the germicidal ingredient

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as well as from their application. A common method to obtain a local antiseptic effect, the application of antiseptic ointments, solutions or _# is on the injured surface, in such a strength that a germicidal protective layer over the entire wounded area is laid. However, this mechanical spread of such germicidal ointments and / or solutions causes pain so severe that anesthetics and narcotics are sometimes required. Since the application of the known germicides must often be repeated daily and since these compositions have no adhesion and are washed out of the physiological exudates, the harmful effects of pain and the consequent administration of analgesic, anesthetic and narcotic drugs form a serious threat for the life of the patient and greatly increase morbidity.

Another inherent limitation on the known compositions for sanitizing severely injured, burned ones or abraded skin is the lack of vapor permeability to maceration of the wounded Avoid skin surface. Hence a »; thick layer of ointment Effectively exclude airborne contamination over the injured area, but it also prevents the essential Gas and water vapor exchange, which is necessary for the healing process. In addition, the exclusion of air creates anaerobic Bags that serve as incubators for foci of infection. When solutions are applied to the skin, they will through the tissue exudates and transudates were rapidly washed away.

Given the inherent limitations of the well-known antibacterial compositions for disinfecting burned, miraculous or broken skin, the ideal antibacterial composition for these uses should have the following properties own:

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a) Essentially painless application to injured < Tissue even with a variety of therapeutic measures repeated several times a day.

b) Creation of effective germicidal protection that allows moisture and gas exchange and thus which avoids tissue maceration.

c) Lasting and long-term effect of the composition when used on abraded and / or burned skin without being washed out by tissue exudates.

d) Convenient and easy application of the germicidal compositions on the injured skin area.

e) Pharmaceutical stability, reproducible and homogeneous properties of the germicidal compositions as well antibacterial effectiveness.

f) Safe use, especially free of side effects of germicidal compositions for humans and animals.

Sprayable compositions have been suggested as one possibility (US Pat. No. 2,782,975 and 2,801,201) to explain the disadvantages of the compositions and methods of disinfecting burned, injured, and abraded tissues but overcome those proposed Compositions for such sprays have not achieved their stated aim and in fact have raised new problems. For example, the pain when using the spray compositions became not eliminated and the spray compositions for disinfecting injured skin contain local anesthetics.

Both solutions and ointments have been used as the sprayable composition but have solved the problem

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the porosity for the gas exchange and also caused the formation of pockets, which as Microorganism incubators were used. If continue to use hydrophilic compositions as ointments or solutions were used, they were quickly washed out and did not adhere permanently to the injured skin area. Hydrophobic compositions such as mineral oil preparations coated the wet, abraded skin unevenly and again formed pockets that formed an incubator for microorganisms and thus a source of infection. The known sprayable compositions do not yet reach the goal, essentially painlessly To create a germicidal protective layer that has permanent adhesive properties.

The unexpected result was that the application of a new sprayable composition to burned, abraded or wounded skin and mucous membranes with the following content a permanent foam with all the properties of the ideal remedy described above and a safe, i.e. in particular free of side effects, and effective, painless, germicidal protection for burned, abraded or wounded skin and mucous membranes formed. This new sprayable composition contains:

a) A therapeutically sufficient amount of an antibacterial active substance, or a substance that has an active microbicidal effect.

b) An aliphatic fatty alcohol and an aliphatic fatty acid in a critical weight ratio to one another, and although with an acceptable range of this critical ratio of 0.5 parts by weight to 2.0 parts by weight Fatty alcohol to 1 to 3 parts by weight of fatty acid, but the ratio of 1: 2 is particularly preferred.

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c) A non-ionic surface tension reducing agent Agents with a concentration of at least half the total weight of the fatty alcohol and fatty acid substances, but not greater than three times the weight of the fatty alcohol present.

d) An aqueous aliphatic glycol mixture in a critical ratio of preferably 1 part aliphatic glycol with a preferred range of the critical ratio of 0.5 to 1.5 parts by weight of the glycol 7.5 to 30 parts by weight of water.

e) A suitable aerosol propellant in sufficient amount so that a ratio of 0.5 to 3 parts by weight of the Propellant gives 7 to 9.5 parts by weight of the sprayable composition.

The composition is placed in a vessel under pressure. When the pressure is relieved, the composition from the vessel onto the burned, grazed or injured skin or mucous membrane in the form of a foam applied, which has the desired long-term properties, and forms a uniform and reproducible microporous Matrix or framework that allows gas exchange while it is an effective germicidal agent Forms protection for the tissue surface. The active germicidal argens are full from the local foam for the injured Tissue available and the rate of active ingredient release avoids rapid flooding of the area. The foam retains its structure on the exposed tissue surface for up to 9 hours after application.

It was also unexpectedly found that the inclusion of from 0.1 parts by weight up to 5 parts by weight of one pharmaceutically acceptable silicon compound, e.g., dimethylpolysiloxane. Dimethylsiloxane or methylsiloxane, the amalgamation of the

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Microporous scaffolding prevented active germicides with the corresponding change in foam properties when pH were used. Therefore, agents with the ability to shift the hydrogen ion potential require ials the composition, which increases the foam properties are influenced, the silicone stabilization, the foam coalescence and thus the reduction of the To prevent steam exchange on damp skin.

The ease of use of the foam avoids tissue irritation and pain. However, it is important that the The painless properties of the sprayable composition described here are not based on it is a foam, or on the easy application, since comparative tests of the foam according to the invention with known foam preparations reveal that other foam compositions containing the same ingredients cause pain on injured skin when used, in contrast to the spray compositions according to the invention. The preparations described here are stable and homogeneous with reproducible physical and pharmaceutical Properties as well as being safe and effective for use in sterilizing human and animal species Tissues.

In order to achieve effective sterilization, it is preferable to use an agent with a broad antibacterial effect Spectrum. Elemental iodine is known to be perhaps the most effective germicidal agent; its corrosive to the fabric irritant properties, however, have its use for disinfection confined by wounded tissue. The newer iodine derivatives, such as compounds from the class of iodophor compounds, while being reversed, have reversed some of the harmful effects of elemental iodine desired broad antibacterial spectrum is retained.

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The preferred iodophor compound is the first discovered member of the class of iodophor compounds, namely the povidone iodine, which is available under the trade name BETADIN and has been since its description has been extensively studied scientifically in U.S. Patent 2,739,922. It is important, that the class of organic iodophor compounds consisting of essentially two different types of iodine derivatives consists. Those that act as a loose mixed complex of elemental iodine with a surface-active detergent are formed and the organic iodine compounds not formed with a detergent. Povidone iodine is the only one well-known detergent-free iodine compound, which has proven to be suitable and sufficiently safe for use at Humans and animals has proven and consists of the complex compound of elemental iodine and povidone. the other organic compounds from the class of iodophor compounds consist of a loosely bound Complex of iodine with a surfactant detergent, e.g. such surfactant detergents such as nonylphenoxypoly (ethylene oxy) ethanol, polyoxypropylenepolyoxyethanol, Sodium-N-coco-N-methylaurate, amides of coconut oil fats and undecoyliuro chloride, and thus form the corresponding iodine-iodophores complexes. If a compound from the class of those described above pdophoric, germicidal agent than the active disinfectant Agent is used, the concentration of the special iodophor compound of your choice is between 1 to 15 percent by weight the composition.

Antibiotic substances can also be used as disinfectants Use constituent in the composition of the invention, and the entire range of antibiotic compounds, that in local anti-infectious therapy

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can be included in the new compositions. Examples of the different classes of antibiotics useful as germicidal ingredients in the present compositions, include:

a) Aminoglycosides, which are characterized in that

they contain one or more amino sugars, e.g. glucosamine or neosamine, and via glucose bridges with 6-membered Base carbon ring are connected, e.g. streptidine or Strephin. Examples of such antibiotics are gentamycin, kanamycin sulfate, streptomycin sulfate and other salts, Neomycin sulfate and neomycin undecylenate.

b) The cephalosporins, which are characterized by the fact that the cephalosporan acid component contains substances such as cephalexin, Cephaloglycine, Cephaloridin, Cephalothin Sodium, Cefazolin Sodium and contains cephapirin sodium.

c) The macrolides are a special group of antibiotic compounds that contain a macrocyclic lactone content Contain 12 or more carbon atoms in the main ring. Macrolides as active antibacterial agents in the .invention Compositions contain substances such as Erthoromycin, Nystatin, Rifampin, Amphotericin-B, Mitasamycin, Oleandomycin, spromycin, proleandomycin and their salts and mixtures of the substances mentioned.

d) Penicillin antibiotics as natural products obtained from cultivated Pencillium species, now also contain synthetic ones Antibiotics that are 6 -oC- carboxy-amino derivatives and substances such as ampicillin, penicillin G and its salts Cabenicillin Disodium, Dicloxacillin Sodium, Methicillin Sodium, Nafcillin Sodium, Oxacillin Sodium, and Phenethicillin Potassium contain.

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e) The tetracycline antibiotics contain tetracyclines and their salts, chlorotetracycline hydrochloride. Demeclycline and its acid, salts, doxycycyl and its salts, methacycline hydrochloride, minacycline hydrochloride, Oxytetracycline and its salts.

f) Antibiotic mixtures contain bacitracin and its metal salts, colistin, capre omycin sulfate, gramicidin as well as polymyxin B sulfate.

The concentration range for the antibiotic substances in the compositions will vary with the individual compound and ranges from 0.1 to 15 percent by weight of the composition. The exact concentration of the selected antibiotic Contribution to membership of the composition will vary with the needs of the patient as well as with the germicidal defenses and the sensitivity of the treated organism.

The members of the class of p-aminobenzene-sufonamide derivatives known as sulfa drugs, which are used in dermatological therapy are particularly useful for the disinfection of burnt skin. In particular, such sulfa drugs as silver sulfacetamide, silver sulfadiazine, Silver sulfaphenazole and sulfamylon are preferred compounds of this class for addition to the present Compositions. When the sulfa drugs are used to sterilize the skin, the usual concentration is that Composition between 0.5 and 5% by weight of the composition.

Other antibacterial agents for disinfection in the present compositions include silver nitrate, Silver proteinate, nitrofuran compounds, hexachlorophene, Ghent Violet and the quaternary ammonium sanitizers, including the alkylbenzyldimethyl amino salts.

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physico-chemical limits for use in foam compositions. It therefore turns out to be necessary to formulate the aqueous solvent in order to overcome the physical limits of water, while at the same time the dielectric constant is retained to such an extent that it causes the formation of a hydrogen-bonded one Complex carries through a solution reaction. The surface tension limit of less than 2 dynes / cm between the immiscible liquid aerosol propellant and the germicidal composition is essential to a uniformly microporous character of the Achieve foam so that the micelle porosity is less than 40 microns in diameter, creating an optimal Release of the active ingredient on the skin surface as well as gas exchange to prevent tissue maceration is guaranteed.

Unexpectedly, it was found that when the amounts of the ingredients for the various phases were changed, so that these Amounts exceed the quantities given above, in the foam then formed the desired properties of the new foam compositions. If, moreover, the relationship of the various phases to each other was changed from the stated value, the foam formed did not have the desired physical properties of the new foams and also did not release the active ingredient to the desired extent. It's the special properties of the new three-phase composition which distinguishes the foams of the invention from the known ones.

It is known that polar solvents consist of strongly dipolar molecules and have pronounced hydrogen-binding properties and react with dissociated chemical compounds. The interaction between a solvent

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When the germicidal compositions are used to disinfect, treat or disinfect sores, scraped off or When used on burned skin, they are applied topically as a finished foam of a three-phase system:

a) The foam matrix or the foam structure, which is a hydrogen-bonded complex of an aliphatic fatty alcohol of the formula ROH, where R is an unsaturated and / or saturated hydrocarbon chain and is composed of a chain of 10 to 18 carbon atoms, hydrogen-bonded with a saturated and / or unsaturated aliphatic fatty acid of the formula RCOOH, where R consists of a chain of 14 to 18 carbon atoms consists.

b) A solution and / or suspension of a therapeutically active ingredient in a specially formulated aqueous solution with a sufficient dielectric constant to support the hydrogen bond between the fatty alcohol in the fatty acid and

c) an immiscible liquid aerosol propellant with an interfacial tension of less than 2 dynes / cm at the interface of the liquid aqueous solvent.

Consider the relationship of the various phases to the unexpected new and novel properties of the new hydrogen-bonded foams, which distinguish this composition from the known foam compositions. The hydrogen-bonded foam matrix creates a micellular foam structure that absorbs the liquid germicidal composition and at the same time gives it foam strength. Water, a strongly polar solvent, has the necessary dielectric properties Constant to form a hydrogen-bonded complex through a solution reaction, but it also has inherent

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and a dissociable chemical compound is called dissolution (solvation) and leads to the orientation of the Molecules of the solvent around the formed ions and / or charged particles of the solute come here. However, such an orientation only takes place when the dipoles of the solvent have hydrogen bonds directed at or complexed with the charged particles or ions of the solute are. A polar solvent that enters a solvated hydrogen bonded complex and him must have the ability to keep the solvate-charged particles separated with a minimum of energy and these properties are expressed in the dielectric constant of the solvent.

Chemical substances with a strong tendency to dissociate and form hydrogen-bonded complexes are not attacked or dissociated as easily by strongly polar solvents as compounds with a less tendency to form hydrogen bonds. As is well known, water is a very strongly polar solvent with a dielectric constant of 78.5, one molar Depolarization of 17.4 and a dipole moment of 1.85, and therefore occurs in solution reactions with formation strongly hydrogen-bonded complexes. While water in general has highly desirable electrical properties as a polar solvent for foams, offers its Applying certain problems as a solvent in which a hydrogen-bonded matrix is between two hydrophobic ones Fractions is formed, e.g. a fatty alcohol and a fatty acid, since the complex formation would counteract the strong dissolving properties of the water. Further there are various other limits to the use of water in medicinal foam compositions, so that the properties of water as a solvent in

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such a foam composition must be modified.

The high vapor pressure, volatility and high evaporation rate of the water require a foam with a limited lifespan. If. Such watery foams exposed to the atmosphere, all hydrogen-bonded ones formed by a solution reaction Complexes are destroyed and the foam quickly collapses. This collapse of the foam structure would lead to the formation result in a water- and vapor-resistant barrier over the bare skin, so that gas and vapor exchange do not occur would be possible.

Since the cohesive outer phase of the foam matrix is hydrophobic, the release of the enclosed in the active ingredients contained in the aqueous liquid and the therapeutic effect inhibited. The total volatility and high vapor pressure of the aqueous solvent along with the solvated breakdown the foam matrix causes rapid drying out after the local application of the foam, combined with not satisfactory release of the active ingredient.

Unexpectedly, it was found that when a critical amount of a semi-polar, non-volatile, humidifying solvent was added to the strongly polar solvent water a modification in the overall dielectric properties of the Solvent mixture entered, which resulted in a reduced dielectric constant of the solvent mixture, which does not destroy the foam matrix formed by hydrogen bonding through solution. This reduced dielectric Constant for the solvent mixture now carries the hydrogen bond of the foam matrix formed, so that the formed complex of fatty alcohol-fatty acid is stabilized, which new and unexpected long-term properties of the

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Foam results. An increase in gas and steam exchange the foam as well as the desired delivery of the active ingredient from the foam onto the surface of the skin and mucous membranes arises. Da 'the process of dissociation is a basic step for the process of hydrogen bonding, and a separation of cations and anions followed of an orientation of the molecules of the solvent around which includes the charged ions, becomes the dielectric Strength and the nature of the polarity of the solvent are the important determinants of its ability to form an educated to support covalent hydrogen bonding. The more the electric The dissolving power of the solvent decreases, the more permanent the complex formed between one hydrophobic fatty alcohol and a hydrophobic fatty acid, which form the foam matrix.

Propylene glycol, glycerine and a polyoxyethylene glycol compound with a molecular weight of 200 to 800 are used as semi-polar solvents to reduce the electrical properties of the polar solvent Modify water. These semi-polar solvents include propylene glycol, glycerine and polyoxyethylene glycol are strongly dipolar molecules, but they do not enter into these solvation reactions by forming solvated hydrogen bonds and thereby reduce the solvation capacity of a solvent mixture. The change the strongly polar dielectric properties of water due to propylene glycol, glycerine and polyoxyethylene glycol not only contributes materially to the strengthening of the fatty alcohol-fatty acid matrix, but also transfers moisturizing, non-volatile properties to maintain a polar-semi-polar fluid balance, which controls the overall stability of the foam, both for gas and vapor exchange and for the release of the active one Ingredients which translate into the overall desired improved therapeutic activity of these foam compositions precipitates.

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It also turned out to be surprising that the ratio of fatty alcohol and fatty acid for the formation of hydrogen Bound complex of the foam matrix is a critical variable, and that the ratio of this complex to the volume of the polar solvent is also critical, as is the ratio of the semi-polar solvent to the polar solvent for the establishment of a desired electrical equilibrium for the Solvent. A particularly favorable value of the critical ratio is 1 part by weight of fatty alcohol to 2 parts by weight Fatty acid; an acceptable good range is from 0.5 to 1.5 parts by weight fatty alcohol to 1.0 to 3.0 Parts by weight of fatty acid. The critical relationship of the semi-polar solvent to the polar solvent was preferably 1:15 with a good range from 0.5 to 1.5 parts by volume of the semi-polar solvent to 7.5 parts to 30 parts by volume wetter than strongly polar solvent Solvent. The critical ratio of the combined fatty alcohol-fatty acid component to the semi-polar solvent is 1:27 with a range of 1.5 to 4.5 parts by weight combined fatty alcohol-fatty acid ingredient too 45.0 points by weight of solvent.

When the compositions described above are added with a portion of a suitable aerosol gas propellant each nine parts of the composition are mixed and the mixture is transferred to a pressurized container with a When the dispensing valve is packaged, a germicidal foam with the desired properties is formed when the pressure is relieved. This foam has superior properties as well as durability and can be a desirable one create germicidal topical coating of the skin and mucous membrane. It is necessary to have a uniform dispersion or To achieve solution of the aerosol gas propellant in the liquid composition, so that in the foam formed

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St.

uniform porosity is created, which at the same time a satisfactory "gas exchange and a germicidal Barrier guaranteed. It resulted from the addition of a non-ionic surface tension reducing agent Means with a critical concentration of 1 to 3 parts by weight and at least half the total weight the fatty alcohol-fatty acid matrix that the interfacial tension between the liquid germicidal

centrate and the propellant reduced to less than 2 dynes / cm so that the foam formed was uniformly microporous.

A non-ionic one that reduces surface tension Agents from the known groups of non-ionic surface tension reducing agents and / or mixtures thereof can reduce the interfacial tension can be used between the liquefied propellant phase and the liquid phase to ensure a uniform phase distribution to create a fine, microporous foam transforms. The following non-ionic surface tension Reducing agents can be used advantageously:

a) The poly (oxyethylene) -poly (oxypropylene) -polyethylene Polyol compounds known commercially as Pluronic Polyols and sold by BASF Wjandotte Corporation and described in U.S. Patent 2,674,619;

b) Octylphenoxy poly (ethyleneoxy) ethanol compounds, commercially known as Igepal CA Compounds and sold by GAF Corporation, New York City;

c) fatty acid polyoxyalkyl esters of hexahydro alcohols, known commercially as Spans and Tweens and published in the Carolina Journal of Pharmacy, Volume 33, page 465 (1952) as well as in the Merck Index, 8th edition, page 973 are described.

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Furthermore, the reduced surface tension served the aqueous phase and the reduced interfacial tension (to less than 2 dynes / cm) between the liquid propellant and the liquid phase to provide an even distribution of the liquefied gas propellant in the liquid lipophilic and hydrophilic phases, resulting in a uniformly microporous structure of the foam precipitates. This microporous foam is used for the release of the germicidal agent and the gas exchange to improve so that the foam formed locks a substantially improved germicidal activity and effectiveness unfolds.

Any pharmaceutically acceptable liquefiable gas aerosol can be used as a propellant for the present compositions Propellants are used. Preferred propellants are liquefied aerosol propellants, e.g. the fluorinated hydrocarbons, the fluorochlorinated Hydrocarbons, hydrocarbons and inert gases. The halogenated hydrocarbons are mainly derived from methane, ethane and cyclobutane and replaced by them one or more hydrogen atoms of these compounds produced by one or more chlorine and / or fluorine atoms. The fluorinated and / or chlorinated hydrocarbons are non-polar compounds, those with non-polar Solvents and are for the most part immiscible with water.

Among the preferred halogenated hydrocarbon blowing agents include trichlorofluoromethane, having a boiling point of about 24 ⁰ C; Dichlorodifluoromethane having a boiling point of about -30 ⁰ C; Dichlorofluoromethane with a boiling point of about 9 ° C; Chlordi fluorine than with a boiling point of about 48 ⁰ C; and dichlorotetrafluoroethane with a boiling point of about 4 ⁰ C. Mixtures of the halogenated

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Sated hydrocarbon propellants can be used, in particular a mixture of trichlorofluoromethane and dichlorodifluoromethane is recommended.

The hydrocarbon blowing agents are also useful for the formation of germicidal foams, but their flammability limits their general use. However, it is possible to mix it with a fluorinated and / or chlorinated hydrocarbon and / or inert gas such as carbon dioxide and nitrogen, the risk of ignition to lower. The hydrocarbon propellants have several specific benefits for the present Three-phase aerosol foam systems are desirable, because they are particularly chemically stable and do not react Halogens and have better solubility properties than the other liquefied gas propellants.

When using the selected aerosol propellant, there is a preferred proportion of propellant gas of the composition from one part of gas propellant to nine parts of the composition packaged in an appropriate one pressurized container with a suitable dispensing valve. When the dispensing valve of the container is activated, the foam formed extrudes as the most beneficial composition for creating a germicidal topcoat to protect and disinfect burned, injured and / or abraded skin and mucous membranes. The educated Foam has an average pore size less than 20 microns in diameter ranging from 5 to 40 microns in pore diameter. After an hour of open exposure, the foam height is 100% of the original value with an estimated Half-life of about 5 to 7 hours. There is no phase separation after four hours of completion Exposed at room temperature.

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A preferred composition for making an effective germicidal foam layer over sore, burned, and / or abraded skin is obtained by pouring 75 parts by weight of purified water into a suitable one Container with stirrer and heating device, addition of 5 parts by weight of propyl glycol, 0.3 parts by weight of nonylphenoxypolyäthylenoxyäthanol and 1.7 parts by weight of poly (oxyethylene) -PoIy (oxypropylene) -Polyäthylenpolyol, known under the trade name Pluronic F-68. The whole thing is stirring constantly heated until a clear solution is obtained.

In a separate vessel, one part by weight of cetyl alcohol is mixed with two parts by weight of stearic acid and melted. The melt of the cetyl-alcohol-stearic acid mixture is added with vigorous stirring to the heated aqueous propylene glycol solution, which was previously prepared and kept at the same temperature. The pH of the composition is adjusted so that it is not greater than pH = 6 and expediently does not fall below pH = 4. The heating device is then removed. When the composition cools, 10 parts by weight of povidone iodine are added and the composition is stirred until completely dissolved. The pH of the solution is adjusted to not less than pH 4.8 and not more than pH 6. The finished composition is a thick, amber colored liquid with a surface tension of less than 30 dynes / cm ² .

The composition is placed in suitable pressurized containers and a suitable liquid aerosol propellant added so that the ratio of the liquid propellant to the composition is in the range of 1 part by weight of propellant to 9 parts by weight of the composition is preferably in the range of 1 part by weight of propellant and 4 parts by weight of composition up to 1 part by weight Propellant and 14 parts by weight of the composition. A

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The preferred propellant for the above composition contains 1 part by weight of a mixture of 1.5 parts by weight of dichlorodifluoromethane and 1.0 part by weight of dichlorotetrafluoromethane, but a mixture of 9.1 parts of isobutane and one part of propane can also be used. The container is filled so that a vapor pressure of not less and not achieved more than 55 psig 35 psig at 70 ⁰ F (etv / a 21 ⁰ C).

When the dispensing valve is opened, the foam formed extrudes uniform and has the following properties:

a) Pore size and its distribution :

The preferred pore size for the foam formed is no smaller than 1 micron in diameter and no larger than 40 microns in diameter with an area of microporous distribution of

Pore size% area measured

(Microns) distribution% rate of distribution

1-5 0-10% 8% 5-10 10-20% 14%

10-20 45-60% 53% 20-30 20-30% 22% 30-40 0-10% 3%

b) foam stability

After an hour of exposure to air, the 2-inch height of the foam column was unchanged but decreased 9 hours together. The estimated range for the half-life of the extruded foam is 5 to 7 hours.

c) phase reversal

The phase inversion index for a sample of 1 g of the foam formed is after 4 hours with the cover covered No more than 1% exposure at room temperature as demonstrated by separation, seepage and drainage.

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Suitable pharmaceutical aids can be added to the formulation given above, e.g. buffers, Silicon compounds such as dimethylpolysiloxane, methylpolysiloxane and phenyldimethylpolysiloxane.

If the foam is burned, scraped and / or injured Skin brought from humans or animals, no pain is apparently felt, in contrast to that severe pain and trauma caused by the use of conventional sanitizers. The repeated Daily use up to 4 times a day for long periods does not reveal any tendency towards tissue sensitization and / or local irritation. An effective disinfection of the skin and mucous membrane is quickly achieved and effected smooth healing with minimal need for skin transfer.

The germicidal foam described above was used to disinfect a patient's skin with 35% partial or used full of burns on the face, forearms, hands and both legs. The application of the germicidal Foam did not cause any pain, the patient became after 10 days of treatment with no signs of local Infection and discharge without skin transfer.

Another study on burn patients showed that multiple applications of the present foam effected rapid disinfection of the skin so that no local infection occurred during treatment as well as smooth Healing was noticeable. If the foam was used to cover abraded skin, as it was after occupational Accidents can cease, rapid painless sterilization occurred without any evidence of local infection during treatment. When the foam was used under a bandage, there was no maceration of the skin

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recognize, as is sometimes noticeable with conventional local preparations when they close the skin.

The following examples explain the invention without being restricted by the details given will.

example 1

If a germicidal foam is to be made, the following method of making it can be used will:

First step :

In a suitable container equipped with a stirrer and heater, add 15 pounds of propylene glycol, 4.5 pounds of Poloxamer-188, commercially available as Pluronic F-68 Wyandotte Chemicals Corporation of Michigan, 3 pounds of disodium phosphate, 2.2 pounds of citric anhydride, and 220 pounds pounds of purified water. The mixture is stirred until completely dissolved and then 1 pound of Igepal-CO-630 is added to the solution, commercially available from General Aniline and Film Corporation, New York. The solution is ^{heated to about 70 °} C. and then filtered.

Second step:

In a further container, 3 pounds of cetyl alcohol are melted and 6 pounds of stearic acid are dissolved in this melt with gentle heating. The temperature is maintained at about 65 ° to 70 ⁰ C and 0.3 pounds of dimethyl polysiloxane of the melt from cetyl alcohol and stearic acid is added. The mixture is stirred and the temperature is maintained at 65 ° to 70 ° C.

Third step :

The molten cetyl alcohol, stearic acid, silicon mixture obtained from the second step becomes the one obtained in the first

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Step solution obtained and stirred until homogeneous distribution.

Fourth step ;

When uniform dispersion is cooled to 30 ⁰ C, then 30 pound povidone-iodine powder are added and stirred until it is completely dissolved. The pH is constantly monitored so that it never falls below pH 4.0 or rises above pH 6.

Fifth step :

Sufficiently purified water is added so that the weight of the mass is brought to 300 pounds. It will continued stirring until the temperature equals room temperature. Then the composition becomes over power left to stand in a tightly sealed container. This product is now available as a concentrate dispersion and has a surface tension between 25 and 28 dynes / cm at 25 ° C and a pH value of 5.5.

Sixth step :

After standing for a sufficiently long time, the concentrate dispersion is packaged in a pressurized container with a liquid aerosol propellant such as isobutane and / or propane or halogenated hydrocarbons. The ratio of concentrate dispersion to propellant is 9 parts by weight of the concentrate dispersion to one part by weight of the liquid propellant. The interfacial tension between the concentrate and the liquid propellant is between 0.5 and 1.5 dynes / cm at 4 ° C. When the liquid propellant / concentrate dispersion is filled into a pressurized container, the container and pressure should not be not less than 35 psig higher than 55 psig at 70 ⁰ F.

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The pore size distribution in the foam formed is as follows:

Pore size Percentage (Micron) distribution 0-5 7% 5-10 13% 10-20 51% 20-30 24% 30-40 5%

The height of a 2 inch column of foam remains unchanged after an hour of exposure to air and drops nine hours standing together. After four hours of standing under the cover it remains at room temperature return a 1g foam fracture sample without phase reversal.

Example 2

10 g of polyethylene glycol-400, 15 g of Igepal CO-630 and 150 g of purified water are placed in a suitable container equipped with a stirrer and heating device. The mixture is stirred until solution is complete and then heated to about 70 ⁰ C; a melt of 10 g of lauryl alcohol and 20 g of linoleic acid is added with vigorous stirring so that a uniform distribution is obtained. The pH of the dispersion is adjusted to pH 5.5. It is then cooled to room temperature and 5% by weight of silver sulfadiazine are added. The mixture is then stirred until the silver sulfadiazine is uniformly distributed and the whole is left at room temperature overnight. The upper

2 The surface tension of the concentrate is 24 dynes / cm at 25 ° C. The concentrate dispersion is packaged in a pressurized container with a dispensing valve using a mixture of 40% dichlorodifluoromethane and 60% dichlorotetrafluoromethane. The interfacial tension between the blowing agent and the concentrate is 0.7 dynes. The region of the container internal pressure is not below 35 psig or above 55 psig at 70 F. ⁰ The micropore distribution of the produced

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Foam is the following:

Pore size percentages

(Micron) distribution

0-5 5%

5-10 12%

10-20 54%

20-30 24% 30-40 4%

The pH of the foam produced is 5.5. Example 3

o, 5 g of stearyl alcohol and 1.5 g lauric acid are mixed with 3 g of glycerol, and the whole was heated to 70 ⁰ C. When full solution is reached, a solution of 1g Pluronic F-68 dissolved in 45g water is added and the mixture is stirred vigorously while the temperature is kept at 70 ^° C. The temperature is then lowered to room temperature and 3% by weight of erythromycin are added. The surface

2 tension of the concentrate is 27 dynes / cm at 25 ° C. The concentrate dispersion is then packaged in a suitable pressurized container using a liquefied, fluorinated hydrocarbon is used, such as the commercially known freon, which serves as a propellant. The interfacial tension between the propellant and the concentrate is 0.8 dyn. The resulting sprayable composition creates the desired foam that is used to treat burned, sore and chafed skin can and has the following micropore distribution:

Pore size Percentage (Micron) distribution 0-5 7% 5-10 25% 10-20 49% 20-30 18% 30-40 1%

The pH of the foam formed is 3.2.

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Example 4

Instead of the fatty alcohol mentioned in Examples 1-3, equal parts by weight of a saturated or unsaturated one can be used Fatty alcohol selected from the following group: decyl alcohol, dodecyl alcohol, lauryl alcohol, Myristyl alcohol, cetyl alcohol, stearyl alcohol, Oleyl alcohol, linoleyl alcohol and mixtures thereof. The ratio of the fatty alcohol to the fatty acids according to Examples 1 to 3 and Example 5 is 1: 2, with one good range also ranges from 0.5 to 1.5 parts by weight of fatty alcohol to 1 to 3 parts by weight of fatty acid. the the other process steps are the same and the foam formed can be used to disinfect burnt, Abraded or injured skin and mucous membranes can be used.

Example 5

Instead of the fatty acids mentioned in Examples 1 to 3 above, equal parts by weight of other fatty acids can be used which are taken from the following group:

Lauric acid, myristic acid, stearic acid, linolenic acid, linoleic acid, oleic acid and mixtures of these substances. the other process steps are the same and the resulting foam can be used to disinfect burned, scraped off or broken skin or mucous membranes.

Example 6

Instead of the non-ionic surface tension reducing Agents described in Examples 1-5 can

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equal parts by weight of non-ionic surface tension reducing agents can be used, which can be taken from the following group: poly (oxyethylene) - poly (oxypropylene) -polyethylene Polyol compounds known commercially as Pluronic Polyol e; Octylphenoxypoly (Etiienoxy) Xthanone Compounds, known commercially as Igepal CA compounds; the fatty acid polyoxyalkyl esters of hexahydro alcohols, known commercially as spans and tweens, and mixtures of these fabrics. The preferred concentration of non-ionic surface tension reducing substances is at least half that

Total weight of fatty alcohol and fatty acid fractions, however no greater than three times the weight of the fatty alcohol present. The rest of the process is the same and the resulting foam can be used to sanitize burned, abraded, or injured skin or mucous membrane.

Example 7

Instead of the aliphatic glycols used in Examples 1-3 above, equal parts by weight can be more liquid Glycol compounds are used, which can be taken from the following group: Polyoxyethylene glycols with a molecular weight of 200 to 800, propylene glycol, glycerine and mixtures of these substances. The ratio of selected glycol compounds for the amount of water contained in the end product is 1 part by weight of glycol 15 parts by weight of water, with a preferred range of 0.5 to 1.5 parts by weight of the selected glycol compound from 7.5 to 30 parts by weight of water, with the remainder of the process steps being the same as they are resulting foam can be used to disinfect burned, injured or abraded skin and connective tissues.

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Example 8

Instead of the dimethylpolysiloxane used in Example 1 above, equal parts by weight of others can be used pharmaceutically acceptable silicone compounds can be used, for example methylpolysiloxane and phenyldimethylpolysiloxane. The preferred concentration range of the silicone compound used is from 0.05 percent by weight to 1.0 percent by weight .

The above-mentioned silicone compound can also be used in the foam of Examples 2 to 7 in a preferred concentration range of 0.05 percent by weight to 1.0 percent by weight be used.

Example 9

If demonstration of active germicidal agent delivery from the foam formed is desired, then tryptic Soya-agar-agar plates inoculated with a test microorganism, for example Staphylococcus aureus, ATC6538; Escherichia Coli, ATCC 11229; Proteus Vulgaris, ATCC 13315; Streptococcus fecailis, ATCC804-3; Pseudomonas seruginosa ATCC 104145; Aerobacter Aerogenes ATCC 13048; Streptococcus Pyogenes. Approximately 0.5 g of the foam formed roughly according to Examples 1 to 7 is applied to the surface in each The inoculated plate is applied and the plates are then incubated at 37 ° C. for 7 days and the zone of inhibition is measured. Representative results of this test on the foam formed from Examples 1, 2 and 3 are as follows:

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TEST ORGANISM

Staphylococcus aurcus,

ATCC 6538 Escherichia coli,

ATCC 11229 Proteus vulgaris,

ATCC 13315 Streptococcus fecal is,

ATCC 8043 Pseudomonas seruyinosa,

ATCC 104145 Aerobacter aeroQenes,

ATCC 13048

StroptDcoccuo pyo'jenes

Zone of inhibition of bacterial growth with a foam from the

Example 1 Example 2 Example 3

27 mm. 19 mm. 18 mm. 26th mm. 21 min. 16 Htm. 25th mm. 20 mm. 12 mm. 27 well. 21 miii. 19 nan. 24 only.. 22 mm. 17 mm. 2ß ilKTl. 19 mm. 14 min. 22nd 19 mm. 17 mm.

Example 10

If burned skin of a person or an animal is to be sterilized, then the foam formed according to Examples 1 to 8 is applied to the injured tissue and / or the mucous membrane. Applied 1 to 6 times a day. A layer of foam at least 1/2 nominal height is applied to the injured area, which can be covered or left uncovered, depending on the patient's specific needs. The film surface formed by the foam over the injured skin creates an antibacterial barrier and at the same time enables gas exchange that avoids maceration. The burned areas treated heal quickly so that minimal skin transfer is required. A notable effect is the lack of pain during and after the germicidal foam is applied to the injured area. In a similar way , abraded and sore skin and mucous membranes can be sterilized by using the germicidal foam 1 to 6 times a day. _809810/0667

Overall, a sprayable, germicidal foam composition has been described which is therapeutically sufficient Amount of an antibacterial agent, an aliphatic fatty alcohol and an aliphatic Contains fatty acids which are in a critical ratio to one another, namely advantageously 1: 2 parts by weight, a good range for this critical ratio of 0.5 parts by weight to 2.0 parts by weight of fatty alcohol to 1 to 3 parts by weight of fatty acid is enough, a non-ionic surface tension reducing agent Agents in a concentration of at least equal to half the total weight of the fatty alcohol and fatty acid portions, however no greater than three times the existing fatty alcohol weight, an aqueous aliphatic glycol mixture in a critical ratio of suitably 1 part aliphatic »glycol to 15 parts water, with a good range the critical ratio of 0.5 to 1.5 parts by weight of glycol to 7.5 to 30 parts by weight of water, and a suitable one Aerosol propellant in sufficient quantity at a ratio of 0.5 parts by weight to 3 parts by weight of propellant contains from 7 to 9.5 parts by weight of the sprayable composition, all in one under pressure standing container is packed with a dispensing valve. When the dispensing valve is actuated, it becomes a permanent one Foam extruded, which provides a safe, in particular free of side effects, effective painless, germicidal protection for burned, scraped or sore skin and forms the mucous membrane of humans and animals when applied 1 to 6 times a day.

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Claims (16)

-ar- claims 1. Sprayable pharmaceutical composition for topical use Application to injured human or animal skin containing a) an aliphatic fatty alcohol of the formula ROH, where R is a saturated or unsaturated alkyl group of 10 up to 18 carbon chain atoms and mixtures of these substances; b) aliphatic fatty acid of the formula RCOOH, where R is a saturated or unsaturated alkyl group of 14 to 18 carbon is chain atoms and mixtures of these substances, and the concentration of the fatty acid from 1 to 3 parts by weight Fatty acid for each part by weight of fatty alcohol; c) a non-ionic surface tension reducing agent Agents selected from the group of the following substances: poly (oxyethylene) -poly (oxypropylene) -polyethylene-polyol compounds; Octylphenoxypoly (ethyleneoxy) ethanol compounds; fatty acid Polyoxyalkyl esters of hexahydro alcohols and mixtures of these substances, the concentration of the non-ionic surface tension reducing agent being at least equal half of the combined weight of the fatty alcohol and fatty acid components, but not greater than three times is the weight of fatty alcohol present; d) a mixture of water and aliphatic »Glykpl, where the Glycol is selected from the following group: polyoxyethylene glycol having a molecular weight of 200 to 800; Propylene glycol, glycerine and mixtures of these substances in critical proportions from 0.5 to 2.0 parts by weight of glycol to 7.5 to 30 parts by weight of water; e) a therapeutically sufficient amount of a microbicidal, in particular antibacterial, agent; 809810/0667 -7ΠΓ- f) a suitable liquid aerosol propellant selected from the group containing the following substances: propane, Isobutane, dichlorodifluoromethane, dichlorofluoromethane, Chlorodifluoromethane, 1,1,2 trichloro-1,2,2 trifluoroethane, Dichlorotetrafluoroethane, carbon dioxide, nitrogen and mixtures of these substances, wherein the liquid propellant is used in 9 parts by weight for each dispersion part obtained as a result of e), wherein all can be filled into a suitable pressurized container containing a dispensing valve with which the foam formed can be released for application to the injured skin. 2. Composition according to claim 1, characterized in that the fatty alcohol is cetyl alcohol. 3. Composition according to any one of the preceding claims, characterized in that the fatty alcohol is stearyl alcohol is. 4. Composition according to any one of the preceding claims, characterized in that the aliphatic acid is stearic acid is. 5. Composition according to any one of the preceding claims, characterized in that the aliphatic acid is palmitic acid is. 6. Composition according to any one of the preceding claims, characterized in that the aliphatic alcohol is cetyl alcohol and the fatty acid is stearic acid. 7. Composition according to any one of the preceding claims, characterized in that the non-ionic surface tension reducing agent is Igepal CO-630. 8U9810 / 0667 8. Composition according to any one of the preceding claims, characterized in that the non-ionic surface tension Pluronic F-68 reducing agent is. 9. Composition according to any one of the preceding claims, characterized in that the aliphatic glycol Is propylene glycol. 10. Composition according to one of the preceding claims, characterized in that the antibacterially active agent is povidone iodine. 11. Composition according to any one of the preceding claims, characterized in that the antibacterially active The agent is nonylphenoxyethyleneoxyethanol-iodine. 12. Composition according to one of the preceding claims, characterized in that the antibacterially active agent is silver sulfadiazine. 13. Composition according to any one of the preceding claims, characterized in that the antibacterially active Medium.Silver sulfazetamide or silver sulfaphenazole is. 14. Composition according to any one of the preceding claims, characterized in that the antibacterially active Means sulfamylon is. 15. Process for the preparation of the composition according to one of the preceding claims, consisting of the following steps: a) Mixing 0.5 to 1.5 parts by weight of an aliphatic glycol selected from the polyoxyethylene glycol group with a molecular weight of 200 to 800, propylene glycol and glycerin, with water from 7.5 to 30 parts by weight; b) Adding a non-ionic surface tension reducing 809810/0667 decorative agent selected from the group of substances poly (oxyethylene) -poly (oxypropylene) -polyethylene Polyol compounds; Octylphenoxypoly (ethyleneoxy) ethanol compounds; Fatty acid polyoxyalkyl esters of hexahydro alcohols and Mixtures of these substances, in a concentration of at least half the combined weight of the Fatty alcohol and fatty acid fractions from step c); c) melting one part by weight of a fatty alcohol the group of substances containing fatty alcohol with the formula ROH, where R is a saturated or unsaturated alcyl group has from 10 to 18 carbon atoms in chain length with 2 to 3 parts by weight of a fatty acid of the formula RCOOH, where R is a saturated or unsaturated alkyl group is from 14 to 18 chain carbon atoms; d) Mixing the melted fat-alcohol / fatty acid mixture from step c) with the water / glycol solution from step b) and mixing into a homogeneous dispersion; e) Adding a therapeutically sufficient amount of a germicidal agent and stirring until homogeneous Dispersion gives; f) adding part of a pharmaceutically acceptable Liquid aerosol propellant selected from the group of substances containing propane, isobutane, dichlorodifluoromethane, dichlorofluoromethane, Chlorodifluoromethane, 1,1,2 trichloro-1,2,2 trifluoroethane, dichlorotetrafluoroethane, carbon dioxide, Nitrogen and mixtures of these substances to 9 parts each of the dispersion obtained from step e), and packaging in a suitable pressurized container with a dispensing valve. 16. The method according to claim 15, characterized in that that a suitable pharmaceutically acceptable buffer to maintain the pH of the concentrate between pH 4 and pH 6 is added. 809810/0667