LV13654B - Antiseptic material for dressings - Google Patents

Abstract

Invention relates to wound dressings having anti-septic properties. The dressing is made as two-layer article consisting of bandage gauze soaked with medicines and coated with plastified biopolimer. The wound dressing provides for prolonged effect of medicines.

Description

ANTISEPTIC TRANSMISSION MATERIAL

The present invention relates to medical consumables, in particular, materials which can be used to make specific antiseptic dressings (hereinafter ASP) and which are useful in the protection and healing (wounds, burns, frostbite, donor sites) of medical institutions or in the field of significant skin loss. in first aid.

The primary purpose of dressings is to provide the optimum wound healing environment by alleviating the patient's pain and protecting against injury and potential infection, so it is considered [1] that optimal dressing should:

1) maintain a moist environment on the wound surface, preventing premature hardening of the superficial layer, and promote skin cell regeneration;

2) below the bandage should provide a temperature as close as possible to the human body temperature, creating favorable conditions for the functioning of the enzymes;

3) the bandage must be "breathable" - water vapor and air permeable.

The best-known tissue protection materials are traditionally classified into several categories [2] - absorbent or integrated dressings, synthetic dressings, such as - semi-permeable films, foam dressings, hydrogels, hydrocolloids, and so-called "biological dressings" for skin cell regeneration, made up of human or animal tissues.

The patent (prototype) [3] offers a solution for the use of polyhydroxybutyrate (PHB) in the protection of skin wounds by forming a polymer protective coating by spraying 5-12% PHB in chloroform directly on the patient's wounded skin with subsequent solvent evaporation and antibiotics in the polymer solution.

The main disadvantage of the prototype is the way the coating is applied, since chloroform can irritate the skin, causing allergic reactions (especially burns), its vapor is harmful to the respiratory tract, and currently medical use of chloroform is restricted for these reasons, emphasizing its carcinogenic effect.

Also, the sterility of the coating by sterilizing the PHB powder prior to the preparation of the solution as well as the use of higher alcohols (propanol) to dissolve the PHB are also negatively evaluated. As a positive moment, the authors mention the close application of the created coating to the patient's skin, which is absolutely unacceptable, eg for the protection and treatment of burns, as it can damage the epithelization of the wound and injure newly formed skin cells by removing the polymer barrier.

The RU patent [4], in turn, offers colorless polyvinyl alcohol (PVA) dressing,

-2 in the form of a transparent film containing certain concentrations of antibacterial substances (chlorhexidine bigluconate and lysocin) and sodium tetraborate, which have the function of regulating the adsorption and cross-linking the PVA to ensure the stability of the dressing.

As the wound is applied to the wound, it swells strongly, plasticizes and congruently adheres to the surface of the skin, absorbing the wound, completely in contact with it. Drawbacks of the dressing material offered: only one combination of antimicrobial agents and relatively high concentrations of substances, which limits its use; the need to introduce special additives for film stability; a negative application for burn wounds, where one of the main prerequisites for the benefit is the use of a non-stick dressing.

An anti-adhesive dressing [5] using a polyethylene or polyvinyl chloride film for coating wounds sprayed with antibiotic powder (6-8% talc-based antibiotics) is also known. The disadvantages of this dressing include the uncontrolled, high levels of antibiotics in the wound and the adverse effects of certain polyvinyl chloride plasticizers on the human body.

The object of the present invention is to provide a specific and effective dressing material using biocompatible matrices of biocompatible antiseptic, antimicrobial and local anesthetic agents, and to provide a gradual and controlled diffusion of the administered AC.

The proposed product is considered to be a specific dressing made in accordance with the basic principles of the development of monolithic macromolecular therapeutic systems by administering to the polymer matrix therapeutic agents (AC) followed by sustained release into the body following a specified program. For the preparation of the ASP of the invention, biopolymers - microbiologically synthesized polyester - polyhydroxybutyrate (PHB) and synthetic biopolymer - polyvinyl alcohol (PVA) - are used as polymer matrices.

Unlike the prototype, the developed ASPs are two-layer materials made of, for example, medical gauze with an AAV-containing plasticized biopolymer coating. The polymer coating (polymer matrix) used microbially synthesized thermoplastic, biodegradable and biocompatible polyester PHB, its copolymers with hydroxy valerate (PHB / HV) and synthetic biopolymer PVA. PHB Synthetic Culture Azotobacter chroococcum 23 is capable of accumulating up to 90% of cellular dry matter under local culture conditions, using local raw materials glucose, sucrose, molasses, potato starch hydrolyzate under specific culture conditions. High yields of PHB up to 82% PHB have been achieved in the batch fermentation process with feeding [6l. PVS

LV 1365 ^z

The use of -3 facilitates the introduction of AC into the polymer matrix solutions since the AC is mainly soluble in water or alcohol. The use of a gauze pad ensures durability, dimensional stability and mechanical strength of the finished ASP mold.

As a result of polymer matrix modification, non-toxic, mainly low molecular weight plasticizers (polyethylene glycols, glycerol, etc.), plant-based fillers (solid), as well as γ-radiation sterilization, balance and control the deformation properties (strength and elasticity) of polymer coatings. AC excretion rate.

The selected ACs are antiseptics - methyl violet, chlorhexidine, brilliant green (Viride nitens), iodine; antibacterial agents - furacillin, dioxidine, administered alone or in combination with local anesthetics (novocaine, lidocaine).

The initial AC content in the polymer matrices was selected based on information on acceptable single or daily doses and route of administration to patients [7]. UV PVA in polymeric matrix solutions is injected using its original aqueous or alcoholic solutions as specially formulated (brilliant green, quinifuryl and iodine solutions in chloroform or methylene chloride in PHB and PHB / HV polymer matrices).

The production of ASP materials involves the following steps:

1. Preparation of PHB and PVA Matrix Solutions for Coatings:

(a) Dissolve PHB or PHB / HV in chloroform or methylene chloride at 40 ... 50 ° C in a reflux condenser or in a pilot reactor heated stirrer. To the 3% to 5% solution, add the OA and the plasticizer of choice;

b) 5 to 10% aqueous solution of PVA is prepared at 70 ° C in a similar manner as in (a); after the homogeneous solution is obtained, add a plasticizer and AC according to the formulation;

c) starch can be added to both PHB and PVA solutions by changing the functionality of ASP. In the PHB solution, the starch is administered in the form of fine dispersion filler with the addition of surfactants. In the case of PVA, pre-prepared aqueous solutions of starch and PVA are mixed.

2. Attach a medical gauze to a smooth, solid substrate (glass, metal) and apply a polymer matrix solution with a special device - the applicator. The applicator is equipped with a micrometric adjustable slit height, which allows to obtain ASP with different thickness of coating.

Coatings can also be obtained using solution spray technology.

Table -41

Composition of polymer coatings

Components Content, mass. % Polymer - PHB 74.1 - - PVS - 75.5 ... 76.5 Plasticizer - Polyethylene glycol PEG 300 22.2 - - Glycerol - 22.7 ... 23.0 Antiseptics or antibacterials 3.7 * 0.2 ... 0.8 Local anesthetics - 0.4 to 0.8 * The content of AC in the PHB coatings is higher ak because their retention time does not occur

swelling of the polymer matrix.

3. Dry the substrate with the applied polymer matrix solution at ~ 60 ° C and then under vacuum until complete removal of the solvent. The thickness of the manufactured ASP ranges from 0.25 to 0.35 mm.

4. The ASP is sterilized by γ-radiation (25 kGy) or hot steam at 121 ° C. Hygienic testing of polymer matrix films by determining the total amount of microorganisms in the washings indicates an appropriate ASP sterility. It should be noted that even non-sterilized AC-containing samples contain small amounts of microorganisms.

Ultraviolet (UV) spectroscopy has been used to evaluate the effect of OA concentration, other administered additives (plasticizers, fillers), as well as γ-radiation on the release rate of ΔV due to γ-radiation induced destruction processes in the release of ΔB from PHB and PHB / HV matrices. In contrast, γ-radiation in PVA polymer matrices causes cross-linking, resulting in a slower release of AC. The introduction of plasticizers and starch, as well as the higher concentration of AC in ASP systems, make it possible to regulate the release of AC and one of the most important characteristics of dressings, barrier properties, i.e. water vapor and air permeability. ASPs are primarily for the protection and treatment of burns, frostbite, donor sites, or other long-healing wounds. The ASP is fixed to the patient's healthy skin along the outer contour of the wound with a fixative patch (such as MEFIX) or gauze bandage.

The dressing is used until the wound spontaneously epithelizes or is prepared for surgery - a graft.

At the donor site (the site where the skin is removed for transplantation), the ASP is left forever until the wound epithelizes.

LV 1365Χ

-5According to the opinion of the Central Medical Ethics Committee (decision No. 34 of 07.10.2004) that the developed ASP comply with bioethical norms, the permission of the "National Agency for Health Statistics and Medical Technologies" to start clinical research in the National Burn Center was obtained.

It can be concluded that ASP is flexible and patient-friendly as it fulfills the basic conditions for burn wound healing - preserving intact epithelial cells, combating infection and reducing pain (combined with antibacterial and anesthetic AC), providing a microclimate and facilitating rapid cleansing and epithelialization.

Clinical tests at the burn center prove the effectiveness of the developed ASP in covering donor sites.

The material and articles provided in the invention are illustrated by the following examples:

Example 1:

Prepare a 3% solution of PHB in chloroform with stirring at 40 ° C. After dissolving the polymer, add the plasticizer - polyethylene glycol PEG 300 and the antibacterial UV - brilliant green in the form of a preformed chloroform solution. Composition of the obtained polymer matrix (% w / w): PHB - 74.1; PEG 22.2; brilliant green - 3.7. The film is removed from the solution and used for testing after evaporation of the solvent in a vacuum and drying. The resulting ASP thickness is 0.25 mm. Films and ASP are sterilized by γ-radiation (25 kGy) and steam at 121 ° C. The deformation properties of the films are determined: o _st = 18.2 MPa; ε = 119%; water vapor permeability - WVTR = 24.04 g / 24 h .m ² ; kinetics of crystalline green release by UV spectroscopy after a change in absorbance (optical density) A of the substance. Comparison of A values of irradiated and non-irradiated films after 46 hours in saline: A = 0.159 for unirradiated specimen; starotam - A = 0.178. The differences are due to γ-radiation-induced partial destruction of the PHB matrix. The effect of different sterilization techniques on the sterility of the test specimens was tested: for non-sterilized specimens; steam sterilized (autoclaved in a special "Biobag - 30" package for 15 minutes at 121 ° C); sterilized with a 25 kGy dose of γ-radiation. Surface scrubbing assay methodology was used to determine the total amount of microorganisms after washings on selective organized media: a) R 2A - Dextrose Tryptone Agar medium (Code CM 75, "OXOID")

-6Recommended for determination of total number of tennophilic and mesophilic bacteria in sterility test; (b) NB Organized Medium (Code CM 3, OXOID) for the detection of a broad range of micro-organisms; (c) 'Feed medium A', similar in composition to MaIt Extract Agar medium (Code CM 59, 'OXOID') for the detection of yeast and mold.

Table 2

Sterility of PHP coated ASP

No. w / w Examples Colony forming units, cfu / cm R2A NB Malt A 1. Not sterile 1 E + 02 1 E + 01 0 2. Steam sterilized 0 1 E + 01 0 J. Sterilized with γ-radiation 1 E + 01 0 0

Example 2:

A 3% solution of PHB is prepared by the addition of a plasticizer, PEG 300 and AAV quinifuryl, similar to Example 1. Addition of dried potato starch (Aloja Starkelsen). To ensure a homogeneous dispersion of the starch in the polymeric matrix solution, it is pre-treated with a solution of the surfactant stearic acid chloroform. Polymer Matrix Composition (w / w): PHB 69.5; PEG 20.6; starch - 8.5; quinifuril - 2.1; stearic acid - 0.9. Films and ASP are made as in Example 1. WVTR Polymer Matrix = 70.3 g / 24 h. M ² ; for a non-irradiated sample (after 46 h) A = 3.09; irradiated (after 46 h) A = 3.48. Even the presence of a small amount of starch intensifies the absorption of water vapor and the release rate of the injected AC. The optimum starch content in the polymer matrix is up to 40% by weight.

Example 3:

Prepare a 10% aqueous solution of PVA at 70 ° C in a reflux condenser or in a heated pilot reactor. Add the glycerol plasticizer to the solution and continue stirring until a homogeneous solution is obtained. Then add the required amount of OA solution: pre-prepared 0.14% furacillin alcohol solution and 2% original dioxidine aqueous solution. Peel off the polymer matrix film and prepare a 0.35 mm thick ASP as in Example 1 by applying a layer of the prepared solution with the applicator on a pre-moistened gauze pad. Dry at 40 ° C then vacuum. Composition of the obtained polymer matrix (% by weight): PVA - 76.5; glycerol - 23; dioxidine -0.26; furacillin 0.08. Characteristics of polymer matrix films: a _st = 38.7

-7MPa; ε = 590%; WVTR => 100 g / 24 h .m ² . The optical density values after 46 h in saline are: A = 2.4 for non-irradiated specimen; for star A-1.8.

The effect of γ-radiation on the release kinetics of OVs introduced into PVA polymer matrices is different from that of PHB polymer matrices. PVAs are characterized by cross-linking reactions that partially inhibit the release of AC from the spatial structure.

The results of the sterility tests according to the procedure of Example 1 are summarized in Table 3.

Table 3

Sterility of PVA-coated ASP

No. w / w Examples Colony forming units, cfu / cm R2A NB Malt A 1. Steam sterilized 1 E + 01 0 0 2. Sterilized with γ-radiation 1 E + 03 0 1 E + 01

It is also possible to introduce starch into PVA polymer matrices. In this case, prepare the starch water solution separately by pre-swelling the starch in cold water with subsequent heating at ~ 90 ° C. The PVA solution is then mixed with the starch solution and heated under stirring for ~ 2 hours with the addition of glycerol and the necessary AU. The warm solution is filtered and applied with a applicator on a moistened gauze pad. The starch content in PVA polymer matrices is ~ 20% by weight of the total weight.

Experimental and clinical testing of AAV-containing biopolymer matrices and ASPs indicate that ASPs are considered as new types of dressings with the following advantages:

• easy to apply, non-sticking to the injury, obstructing movement and providing the wound needed to heal the wound;

• is breathable and vapor permeable;

• protects the wound from infection and relieves pain due to the simultaneous administration of antibacterial and local anesthetics;

• Compared to [4], the range of ACs offered and their combinations are expanded;

• As a result of polymer matrix modification (introduction of plasticizers and fillers), the functionality, deformation and barrier properties of ASP are ensured and adjusted according to the application specifics;

• antimicrobial protection is provided at a lower AC concentration,

-8 • Bandages can be done less frequently, no ointments, creams and colloidal bandages are needed - thus saving funds;

• Gauze base provides ASP shape stability and dimensional stability;

• Can be sterilized.

• Clinical trials show the effectiveness of ASP in covering donor sites.

Literature used

1. Kane J., Tompkins R., Yarmush M., Burke J. Burn Dressings. In: Biomaterials Science. An Introduction to Materials in Medicine. l ^st ed. Ratner, B., et al., New York: Academic Press, 1996, pp. 360-370.

2. Gatti Α. M., Pinchiorri P. Physical characterization of nevv biomaterial for vvound management // Journal of Material Science: Materials in Medicine.1994, -N5.-P. 190-193.

3. Webb, J. R. Adsetts. Wound dressings. GB pat. 2,166,354 A (prototype).

4. V. I. Chissov, I. V. Reshetov et al. Bandage for treating wounds. RU Pat. 2,174,847 (in Russian).

5. R. Breitman. Analgetic dressings for the treatment of booms. In: IV European Bums Congress. Barcelona, September 23-26, 1991.

6. Savenkova L., Zagreba J., Gercberga Z. Production of Azotobacter chroococcum strain 23 by poly-P-hydroxybutyric acid. Patent of the Republic of Latvia LV 5297, - 1993: P-93-635 (in Latvian).

Medicines Register of the Republic of Latvia: official publication / Riga: non-profit organization State A / S State Medicines Agency, 2004.

Claims (7)

Formula of the Invention 1. An antiseptic dressing (ASP) contains a protective coating formed by a biopolymer solution containing a therapeutic agent (OA), characterized in that the protective coating material is made, for example, of a medical gauze impregnated with an AO-containing plasticized biopolymer. 2. ASP according to claim 1, characterized in that the protective coating is made from microbially synthesized, biodegradable and biocompatible polyhydroxybutyrate (PHB), copolymers or a synthetic (PVA) -based poly (polyvinyl alcohol) as the polymer matrix material. injectable plasticizers, fillers, surfactants, OA. The ASP according to claim 2, wherein said plasticizers are polyethylene glycol and glycerol, the filler is potato starch, the surfactant is stearic acid, the AAV is an antiseptic, an antibacterial agent, a local anesthetic, and combinations thereof. The ASP of claim 3, wherein said antiseptics are methyl violet, brilliant green, iodine, chlorhexidine, the antibacterial agents are furacillin, dioxidine, quinifuril, and the local anesthetic agents are novocaine and lidocaine. 5. ASP according to claim 2, the plasticizers are ~ 30% by weight of the polymer, the fillers are up to 40% by weight of the composition, the surfactant is 0.5 to 1.0% by weight of the PHB. 6. The ASP according to claim 4, the antiseptic and antibacterial agents being in the range of 0.2-0.8 wt.% In polyvinyl alcohol coatings and up to 3.7 wt.% In polyhydroxybutyrate coatings and local anesthetics, as well as said substance. combinations range from 0.4 to 0.8 7.% w / w. The ASP according to claim 1 is sterilized in γ-rays.