DE2114169A1 - Gelled solutions for the treatment of burns - Google Patents

Description

Dr. Ing.VV & iisr AbU- 24 m &. _z 1971

_ .... , "R- r. η.,., r «-co Ö915

Dr. Dieter r. iviui \

ITEK CORPORATION lexington, Massachusetts, V. St. A.

Gelled solutions for the treatment of burns

The invention relates to media for treating burns and especially gelled media for the treatment of burns,

A variety of pharmaceutical and therapeutic agents have been made in gelled or gel-like form. Some examples of these include: alcohol / water carriers for cosmetics that are gelled with sodium acyl lactylate (see U.S. Patent 3,472,940); cosmetic gel-like products containing quaternary ammonium salt derivatives (see US Pat. No. 3,427,251); clear pharmaceutical flavorful gels for topical rubs (see US Pat. No. 3,444,091); Glycerol fatty acid partial ester gels which serve as carriers for drugs (see US Pat. No. 2,976,251)> solid pharmaceutical gel carriers for oral administration which contain medicaments of a therapeutic nature (see US Pat. No. 3,028,308); gelled systems which serve as carriers for therapeutic agents useful in combating acne (see US Pat. No. 3,137,622); Gels of the clear mineral oil / water type for removing dandruff and for general hair care (see US Pat. No. 3,110,301); Cosmetic oil-in-water gels, which adjuvants may be eye sets (see. U.S. Patent No. 3,341,465) and drugs gelled bit offset preparations which contain antihistamines and the like. "The stationary orally or under pressure

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Doses can be administered (see US Pat. No. 3,134,720).

New compositions for treating burn wounds were constantly being developed. One of the most recent developments is a "ringing gel" formed from an aqueous solution of a silver salt and containing 18-50 # of a polyoxyethylene-polyoxypropylene block copolymer (see Dutch Patent 69 09333). These gels have the disadvantage that they harden when cooled to low \ temperatures, which implies that they are applied in a patient at low temperatures and washed off.

Although various pastes, ointments and vegetable-like materials For the treatment of burns heretofore proposed and used, true gelled media have been those described here Kind not used. It is important to note that the gelled media described herein differ from the preparations for the treatment of burns according to the prior art, which as creams, viscous jelly-like, rubber-like pastes or even classified as gel-like preparations differ in characteristic ways. The new media are . real gels that have a strength or rigidity and shape accordingly Have solids. Viscosity is a meaningless term in terms of describing these gelled ones Media, because the three-dimensional network structure of the gelling agent is destroyed in an attempt to measure the viscosity * These new gels are best known for their breaking strength and elasticities.

To be effective, burn treatment must perform many tasks. A good discussion of these tasks is given by Milton A. Lesser in "Modern Burn Therapy" ¹ Drug and Cosmetic Industry, June 1951 "68.6, pp. 732 ff. To agree

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The requirements mentioned by Lesser include: (1) releasing current pain, avoiding further pain; (2) preventing and fighting infections; (3) rasehest possible guarantee of regeneration or replacement of skin and (4) revitalization of the normal function of the injured Share and also maintain the patient's frame of mind. Besides these tasks, Lesser does it It is clear that burn treatment should be as simple as is consistent with achieving the desired goals.

Although many complex burn treatments have been attempted, there has been a recent trend towards minimal drug use. Sterile gauze dressings were used, and efforts were made to clean the wound as far as health tolerated is to disturb as little as possible. These .sterile dressings contain a layer of the treatment cream and the like. or, if a solution of the combustion treatment agent is used, they are kept saturated.

One of the most common treatments has been the use of finer meshes Gauze bandages that have been kept saturated with an aqueous solution of silver nitrate used as an anti-infectious agent served. While this treatment has been shown to be successful, it is not without its problems. The sterile bandages must be changed frequently, and the patient experienced great physical and emotional pain during this dressing change Depression as the gauze tends to stick to the burned areas. Because of the associated pain, the patient defends himself against dressing changes, which means that large amounts of silver nitrate solution are sprayed over the area. This leads to wasted Silver nitrate solution and far worse to stain bed sheets, pillowcases and the like. These stains cannot be washed out by conventional methods, and consequently has

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the bedding often looks ugly although fresh has been washed. So severe was this pollution problem that some major burn treatment centers refused to use silver nitrate solutions despite their effectiveness as anti-infectious agents.

Except for the problems associated with changing dressings it is also difficult to handle liquid silver nitrate at other times during treatment.

It is also very troublesome to hold the gauze so that it always stays is saturated with solution.

Perhaps the hardest part with using with! Liquid The problem with impregnated gauze dressings is their tendency to affect the skin cells that have grown during treatment are to destroy. These new ones. Cells are essential to the healing process. Because the impregnated gauze on the wound sticks, and also because gauze has loose fibers around which the new cells grow, gauze removal often leads to destroy the new cells, which significantly delays healing.

The invention relates to the treatment of burns with gelled liquid media. These gelled media contain a burn treatment agent in a suitable Liquid is included.

The treatment can be done by applying the gelled medium directly to the burned area, using the burn treatment agent diffused from the gel structure to the burn wound. The application of the gelled medium is made easier, when it is shaped in the form of a pad of a suitable size to cover the burned area. The upholstery

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can by making some suitable backing materials, such as or gauze flexible plastic that can be directly connected to the patient to be held in place.

When a gelled medium containing a fire treatment agent is brought into contact with the patient's skin, a boundary layer is immediately formed between the gelled Medium and the patient's skin. This boundary layer is active in the sense that the combustion treatment agent migrates through it, once contact is made between the gelled medium and the skin. Thus is the mechanism for transportation of the burn treatment agent to the burn wound has a two-step process: (1) Diffusion from within the gelled Medium to the surface; (2) Diffusion from the surface of the gelled medium through the healing skin tissue interface. Certain liquid exudates from the burn wound will pass through precisely from the wound to the interior of the gelled medium transported the same two-step process in reverse.

Gelled liquid media, which have a high degree of elasticity and plasticity combined with good strength, form excellent boundary layers. A small amount of syneresis in the gelled medium is useful in wetting the surface with the fire treatment substance, so that the transition to the Burned tissue begins immediately after application of the medium, and is also useful for removing the medium from it a shape.

The gelled liquid media of the invention possess these properties and provide many advantages for the treatment of Burns as opposed to using simple liquids.

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A cushion of gelled medium does not tend to stick or Adhesive to the wound like the gauze bandages saturated with silver nitrate solution, and trotedem the pad provides the same extent physical protection for incineration. Gauze bandages may stick, in part because the gauze is loose Fibers at the edges in contact with the burn wound containing new skin cells and other substances on the burn surface become entangled, while the gelled medium is plastic in nature and a clean, practically dry one has continuous non-stick surface that comes into contact with the burn wound. So if the gelled When the medium is removed, it will not tear the new layers of skin that have grown on, which will help promote healing. This is a "particularly significant benefit when making skin transfers." have been made on burned areas.

Another advantage is that gelled pads do not need to be changed as frequently as ungelled liquid impregnated dressings. The pads provide a continuous supply of agent to the burn surface in a constant concentration for longer periods of time than gauze bandages. This may be due to the two-way diffusion inherent in the medium. That is, the burn treatment agent diffuses toward the burned skin _; and at the same time certain fluids, such as pus excreted from the burn wound, diffuse away from the burned area, towards the outer surface of the gelled medium. The ability to maintain good healing for extended periods of time between dressing changes provides secondary benefits such as reducing the risk of secondary infection, preventing circulatory stagnation, and eliminating much of the pain and associated shock _and repetitive pain Dressing changes occur.

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The gelled media also provide other handling advantages over the ungelled solutions. It is easier to apply gelled pads to the patient because there is no problem with the liquid "which, ; every time ^ when the patient moves, over the surroundings and the nursing staff is splashed. The ease of use is a main advantage in emergency situations and can for example the treatment of combustion in large fire places in a core attack and djjl. make it much easier.

These gelled burn treatment media are more plastic Nature, which results in even more advantages. For example, pads made of gelled material adapt well to cracks in the skin or cracks, crevices and the like, whereby a good contact between all areas of a burn wound and the upholstery surface is guaranteed. Also, the gelled medium easily forms around any solid material on the burned surface, like burnt meat, hair, sand and the like.

It is also possible to bring about a continuous cooling effect for the burned area by using limited areas a gelled solution, especially if it is an aqueous solution, are exposed to air. After this Suspension vaporizes water or other liquid, creating cooling that helps reduce pain of the patient contributes.

As mentioned ^ it is possible to form gelled liquid media in cushion form, often prepackaged. In this form, the gelled media meet burn dressing requirements, including: the avoidance of contamination; the application of firm but elastic pressure; the absence of damage to the skin tissue; the ability _{> to be} easily removed. As indicated above, the gelled media are general

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the currently available gauze dressings for compliance superior to these requirements.

A variety of burn treatment agents can be incorporated into gelled liquid media using the techniques of the invention. One such class of agents are the anti-infectants, which are used to prevent infection of the burned areas. A common anti-infectious agent is silver. Silver salts that are soluble in water, such as silver nitrate, silver sulfate, silver acetate and silver lactate, are particularly advantageous for this application. These solutions are usually very dilute with respect to the silver salt. For example, aqueous solutions of silver nitrate are used, from about 0.1 $> io to about 1 silver nitrate, by weight, contain, and particularly preferred silver nitrate solutions contain from about 0.5 9δ silver nitrate. .

Two agents that have recently been shown to be effective for treating Proven burns are silver sulfadiazine and mafenide acetate (sold under the trade name "Sulfamylon" by Winthrop Laboratories). These agents are also suitable for use in the context of the invention.

Antibiotics, topical anesthetics, enzymes, and the like are examples of other substances that are used to treat burns which can be incorporated into the gelled liquid media for application to combustion areas. Many other such agents are known to those skilled in the art.

A solvent or a liquid carrier phase that gels is required for the burn treatment agent. Water is a preferred liquid, however you can also other liquids, for example inert organic

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Solvent alone or in combination with water under BiI- ' It is possible to use solutions or dispersions that can be gelled and applied to burned surfaces can be. Mineral oil is such an inert organic Liquid. There are many others too.

Although many burn treatment agents are solids, it should be noted that liquid burn treatment agents are gelled for use on burns can. Such liquids can be gelled by themselves or can be mixed with other liquids with which they are miscible or are emulsifiable, are combined prior to gelation.

Any gelling agent that forms a gelled medium that is plastic, flexible, and clean practical dry continuous non-stick surface can be used. Of course, the remedy should be physiological be inert. Another property of certain desirable gelling agents is that they are temperature dependent in that sense are that the liquid medium and the gelling agent are heated above a certain critical gel temperature have to be and then have to be cooled below a certain solidification temperature before gelatinization occurs - and in some cases these gels are heat reversible.

Although certain natural as well as certain synthetic Remedies proved to be useful, it was found that natural remedies are generally synthetic Means are superior. This is due to the fact that d ^ e natural means gelled med ^ n, with the necessary ^? 4g§n, -echaften to produce combustion abehan ^ lWg, whereby little ifen means exist and they tend to be.

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Examples of natural gelling agents include red seaweed derivatives such as agar, agarose, carrageenan and furcellaran; Fiber gums such as locust bean gum, xanthan gum, guar gum, gum arabic and the like; Algin compounds such as sodium alginate and alginic acid or combinations of any of these substances. A preferred gelling agent is a combination of xanthan gum and locust bean gum because this leads to a highly plastic but strongly gelled solution which is particularly advantageous for use on burns. One such material, which is commercially available, comprises a 5Q / 50 mixture of xanthan gum and locust bean gum and is sold under the designation "Kelgum" by KeIco Company, Clark, Few Jersey. Most preferred combinations include about A $> to $ 90> xanthan gum and about $ 10 to about 60 % locust bean gourami based on total gelling agent present.

To Beispfelen of suitable synthetic gel-forming agent include copolymers Hethylvinylather ¹ and maleic anhydride, polyvinyl pyrrolidones, polyacrylic acids, ammonium polyacrylates, copolymers of ethylene and maleic anhydride, copolymers of acrylamide and ifjN'-methylene-bisacrylamide and polyacrylamide.

The amount of gelling agent required is only that Amount sufficient to produce a gel with satisfactory plasticity? - and surface properties. In general, synthetic agents require more than natural agents Means. Usually μηΐβΓηβ ^ is a set of about 10 $ by weight and often an amount below about 2 #, based on the total solution, sufficient for natural means.

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There are many suitable methods of applying the gelled medium to the burn wounds. There is a suitable method in forming the gelled medium in the form of a cushion as shown in the figure. As shown, this is gelled Medium 1 integrally connected to a layer of open-cell foamed material 2, which in turn is integral with a flexible plastic base 3, e.g. made of polyethylene. The flexible plastic base 3 is used to prevent the gelled To give medium strength and rigidity while maintaining its flexibility and also to prevent evaporation from the back of the gelled medium. The pad also ensures a comfortable surface when bandaging the Patient. The open-pored foamed material 2 becomes the connection of the gelled medium 1 with the pad 3 is used. A very suitable open-cell foamed material is Polyurethane foam with a density of 0.9 kg (two pounds) and 20-60 open pores per 2.5 cm from Scott Paper. The strenght each layer, the length and width and the specific used Materials are parameters that can be routinely adjusted to the specific burn to be treated. In some cases it may also be desirable to use a pad of the gelled medium alone with no backing materials or to use the gelled medium only with the open-pored foamed material as the back, in order to enable that some amount of evaporation takes place through the back of the pad, or just the flexible one To use underlay.

Other application methods are possible. For example, if the gelation temperature is low enough, a burned Limb, e.g. an arm, can simply be immersed in the treatment solution, which gels when cooled slightly, or the gellable solution can be poured onto the burn. In the case of minor burns, such as sunburn,

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it is possible to take a liquid from an aerosol can spray a burn and gel the liquid directly on top of the burn. In some of these applications it is preferred to use a gelling agent which forms a thermally reversibly gelled medium.

Other embodiments that are within the scope of the invention, will be apparent to those skilled in the art.

The following examples illustrate the invention further on the basis of specific embodiments.

example 1

This example illustrates the manufacture of a sterile gelled silver nitrate burn antiseptic treatment pad. Five grams of Kelgum 2997 gelling agent ($ 50 locust bean gum / 50 % xanthan gum), manufactured and sold by Kelco Company, Clark, New Jersey, is added to 175 ml of room temperature distilled water and dispersed evenly with gentle stirring. 300 ml of distilled boiling water are added to the dispersion and stirring is continued until the entire dispersion ^{is heated to a temperature of 71 °} C (160 ^° F). The dispersion is held at this temperature for about 5 minutes, after which it is transferred to a 1,000 ml Ehrlenmeyer flask and placed in an autoclave. The dispersion is autoclaved for 10 minutes and then allowed to cool for 20 minutes so that it can be handled.

A silver nitrate solution is made by dissolving 2.6 g of silver nitrate powder in 25 ml of distilled water. These . Solution is added to the autoclaved dispersion immediately after it has been removed from the autoclave. The dispersion is stirred and then put into appropriate shapes

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poured. After cooling, the dispersion forms a highly elastic one however, strongly gelled solution. This yellowish solution will be stored in the mold under sterile conditions.

For use, the gelled solutions are removed from the mold and cut into appropriately sized pads. The upholstery are applied directly to the combustion. Gauze is placed over the gelled pad and the whole thing can be connected will.

A gel pad with a flexible plastic backing can according to the procedure of this example with additional lining of the mold with the backing or backing material getting produced.

Example 2

This example illustrates how to make a gelled antiseptic Silver nitrate burn treatment pad using an alternative gelling agent, agarose. A Agarose pads can be made using one of the following methods:

a) a 2 #iger dehydrated Agarosefilm as teLspielsweise those available from the Marine Colloids, Inc. Springfield, New Jersey are prepared, is rehydrated by the film 2 hours at 24 ⁰ C (75 ⁰ F) in a 0.5 # aqueous silver nitrate solution is brought. During rehydration, the film swells into a cushion as the silver nitrate solution is soaked into the gel structure.

b) 20 g of agarose are dispersed in 925 ml of distilled water at room temperature (24 ^° C., 75 ^° F.). The mixture is ^{heated to 99 °} C. (210 ^° F.) with constant mixing and held at this temperature for 5 minutes. It is then set to 60 ⁰ C (140 ⁰ F)

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chilled.

5 g of silver nitrate are dissolved in 50 ml of distilled water at 24 ^° C. (75 ^° F.). This solution is added to the above gel mixture after the gel mixture to 60 ⁰ C (140 ⁰ P) was cooled. The two are mixed for 2 minutes.

"The combined solution is poured into suitable molds, and allowed to cool for 15 minutes, after which the gelled silver nitrate pads have formed.

Example 3

Equal quantities (5 »5 g) xanthan gum and locust bean gum are dispersed in 950 ml of distilled water at room temperature (24 ⁰ C). The solution is mixed constantly and heated to 75 ⁰ C (165 ⁰ P) and held there for 5 minutes.

A second solution of 5 »0 g of silver nitrate, dissolved in 50 ml of water., Is produced at 24 ^° C. The second solution is added to the first gel mixture after the 5 minutes period at 75 ⁰ C (165 ⁰ F). The two solutions are mixed for 2 minutes.

After mixing, the combined solution is poured into suitable molds and allowed to cool in ambient air for 15 minutes, after which the gelatinized silver nitrate pads have formed.

A test pad prepared as described above was used to determine the effectiveness of the antibacteriological properties of the gelled silver nitrate pad checked. The test was negative, so no sterilization of the pad was necessary prior to application to the burns.

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AS

Some gelatinized silver nitrate pads made as above were with the 0.5 ^ igen standard silver nitrate solution with regard to the treatment of burn wounds in rats and excisions with grafts of split thickness in an attempt to stimulate the re-epithelializing margins in human burn wounds. When not infected The rate of healing was comparable to wounds and possibly a little faster with the gelled pad. For wounds infected with a known amount of staph, the toilet toilet properties of the dressings used in the case of the solutions supplied by the wound toilet itself, however, it was possible to achieve this with the use of the gelled pad a more powerful mechanical wound toilet is required for the same healing rate. All laboratory observations were done macroscopically. Wound healing took place both by re-epithelialization and by contracture, the latter being the case is not common in human wounds. The Wunaen were none Approximately 5 x 0.5 cm and quantitative cultures were used to monitor infected wounds.

It has thus been used in preclinical experiments with rats This new method of delivering silver nitrate to a burn wound demonstrated that: 1) A gelled silver nitrate pad is sterile; 2) Silver nitrate of a combustion surface in constant concentration in the tested fire cushions is made available; 3) the rate of wound healing with silver nitrate solution in non-infected Wounds is comparable and possibly a little faster; 4) in the wound toilet, wound healing in an infected rat about just as quickly with the gelled cushions, however, more manual wound toilet is required; 5) the gelled pad opposite Re-epithelialization effects during dressing changes is less damaging than the counterpart solution and 6) the gelled Cushions are both technically easier to handle and

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JPS 8918 Dressings and laundry soiling less than the solution.

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Claims (23)

21U16S JFS 8918 1? Claims 1. Gelled medium for the treatment of burns, labeled by a) a liquid phase, b) a combustion treatment agent in the liquid phase and c) an amount of gelling agent sufficient to maintain the liquid phase when the medium is above the critical gel temperature has been heated and then cooled below the gel setting temperature to gel. 2. Medium according to claim 1, characterized in that the liquid phase comprises water. 3. Medium according to claim 2, characterized in that the gelling agent in an amount of less than about 10 wt .- ^ is present. 4. Medium according to claim 1 to 3, characterized in that the combustion treatment agent comprises an anti-infectious agent. 5. Medium according to claim 4, characterized in that the anti-infectious agent has a silver compound. 6. Medium according to claim 5 »characterized in that the silver compound comprises silver nitrate. 7. Medium according to claim 6, characterized in that the silver nitrate is present in an amount of about 0.1 to about 1 % . ' - 17 - . . 1Q9842 / 1836 21U169 JPS 8918 8. Medium according to claim 1 to 7 »characterized in that the gelling agent consists of natural gums, derivatives of red seaweed and / or alginates. 9. Medium according to claim 8, characterized in that the gel ■ education agent has a derivative of red seaweed. 10. Medium according to claim 9, characterized in that the gelling agent Having agarose. 11. Medium according to claim 8, characterized in that the gelling agent has at least one natural rubber. 12. Medium according to claim 11, characterized in that the gelling agent a mixture of xanthan gum and locust bean gum. That the Gelbildungsgemisch 13 having medium according to claim 12, characterized in that about 40 $ to about 9.0 $ xanthan gum and about 10 io to about 60% locust bean gum. 14 ·. Medium according to claim 13 »characterized in that the gel-formation mixture about $ 50 xanthan gum and about # 50 Locust bean gum has " 15. Medium according to claim 11 to 14 *, characterized in that the gelling agent is present in an amount below 2% by weight. 16. Medium according to claim 15 * characterized in that the Silver nitrate is present in an amount of about 0.5% by weight. 17. Medium according to claim 1 to 16, characterized in that it is in the form of a cushion. - 18 109842/1836 2114189 JPS 8918 18. Medium according to claim 1 to 17, characterized in that the medium is plastic and flexible and a clean, practically dry, continuous and non-stick surface having. 19. Product for the treatment of burns ,, labeled by a flexible backing material with a layer of gelled combustion treatment medium integral therewith connected is. 20. Product according to claim 19, characterized in that the plastic substrate is wholly or partially made of polyethylene consists. 21. Product according to claim 20, characterized in that an open-cell foamed material is the base with the gelled medium connects. 22. A method for the treatment of burns, characterized in that that a) a combustion treatment medium according to claim 1 to 21 is produced and b) the gelled medium is brought into contact with the burn wound to be treated. 23. Gellable mass, characterized by a) a liquid phase, b) a combustion treatment agent dispersed in the liquid phase and c) an amount of a gelling agent sufficient to gel the liquid phase when the medium has been heated above the critical gel temperature and then cooled below the gel hardening temperature. - 19- 109842/1036 Blank page