WO2006069540A1 - Burn-treating drug delivery system containing trehalose and hyaluronic acid and its producing method - Google Patents

Abstract

A burn-treating drug delivery system and its producing method are disclosed. The system of the invention is containing trehalose and hyaluronic acid as the main ingredients. The system can optionally contain active ingredients for burn-treating and pharmaceutically acceptable adjuvants. The system has significant characteristics and advantage, and retrieves the shortage of the burn-treating drug delivery system in the art.

Description

 Burns containing trehalose and hyaluronic acid

 Drug delivery system and preparation method thereof

 The present invention relates to a burn drug delivery system and a preparation method thereof, and more particularly, the burn drug delivery system of the present invention contains a hyaluronic acid and/or a hyaluronic acid pharmaceutically acceptable salt and a conventional pharmaceutical auxiliary acceptable for burns. . Background technique

 Burn refers to tissue damage caused by heat, chemicals, electrical energy, radiation, etc., mainly refers to skin, mucous membranes, soft tissues, and deep bones, internal organs and the like. Among them, thermal energy, including hydrothermal (water, soup, oil, etc.), steam, high temperature gas, flame, hot metal, etc., is called thermal injury; thermal damage caused by hydrothermal fluid and steam , called scald, so burns include thermal injuries (including burns), chemical burns, electr ic burns, and rat iat ion burns. Burns are extremely common in people's lives. It is estimated that the annual incidence of burns in China is about 2%, that is, more than 20 million people suffer from different degrees of burns every year. Burns are a serious threat to human health. They can destroy the skin barrier function, in addition to causing local tissue damage, but also lead to a series of changes in local metabolism and function, such as local degeneration, necrotic tissue, a variety of proteases and inflammatory mediators. Such substances can cause wound infection, body fluid extravasation, lead to sepsis, shock, etc., and even life-threatening. Not only that, the scar after healing of the wound also brings psychological and spiritual pain to the patient.

Therefore, people have great hopes for products that prevent burns. At present, there are various local topical drugs for treating burns in the clinic, mainly antibacterial external drugs, such as metal salts. Classes, antibiotics and sulfonamides. However, the presence of these drugs is insufficient. For example, drugs can not quickly relieve pain, the drug is irritating, the adverse reactions are large, and the scar on the prognosis is ineffective. In addition, the dryness of the wound often leads to the formation of scars, which seriously affects the absorption of drugs. Even worsened the condition. For example: 0. 5% of silver nitrate in the wound wet, can relieve pain, but can not penetrate the scar; 1% silver pyrimidine bone can penetrate into the scar, but it is easy to cause adverse reactions such as leukopenia. The most feasible solution to avoid the above-mentioned deficiencies while making the drug effective is to innovate the delivery system of the burn drug (del ivery sys tem ), so that the delivery system has the following characteristics: On the one hand, it can fundamentally improve the wound cells. The anti-drying ability makes the wound always fresh and physiologically moist, which is beneficial to the absorption of medicine and the effect of medicine; on the other hand, it can relieve pain, reduce infection, accelerate wound healing and reduce scar formation. The current drug delivery system for burns is mostly limited to how to improve the absorption of drugs. There is still no good way to solve the above problems at the same time. Summary of the invention

 SUMMARY OF THE INVENTION An object of the present invention is to provide a novel burn drug delivery system comprising trehalose and hyaluronic acid and/or a hyaluronic acid pharmaceutically acceptable salt and a conventional pharmaceutical auxiliary acceptable for burns.

 The present invention provides a novel drug delivery system for burns, the main components of which are trehalose and hyaluronic acid and/or pharmaceutically acceptable salts of transparent shield acid. The delivery system not only has the characteristics of trehalose anti-drying, biological preservation, etc., but also has the characteristics of hyaluronic acid intelligent moisturizing, anti-inflammatory, pain relief, acceleration and scar-free healing, and the combination of the two, complementary and synergistic, make up for At present, the shortage of burn drug delivery system has obvious advantages, and it is an ideal new drug delivery system for burns.

The burn drug delivery system of the invention can also be used for transferring active ingredients and enhancing the same The active ingredient is delivered, absorbed and stabilized. Therefore, the burn delivery system can also contain one or more active ingredients for burns, which are used to treat burns and reduce the formation of healing scars. The active ingredient for burns is preferably selected from the group consisting of an antimicrobial agent, a non-steroidal anti-inflammatory drug, an adrenocortical hormone drug, an antiallergic drug, a vasoconstrictor, a local anesthetic, a disinfectant preservative, a softening scar, a healing agent, Genetic engineering drugs and other active ingredients. Preferably, the antimicrobial drug is an antibiotic drug such as mupirocin, amphotericin 8, bacitracin, neomycin sulfate, etc.; or the antimicrobial drug is a quinolones such as enoxacin or norfloxacin. Sand star, levofloxacin, ofloxacin, ciprofloxacin, lomefloxacin, pefloxacin, etc.; or the antimicrobial agent is a sulfonamide such as silver sulfadiazine, zinc sulfadiazine, or the like; or the antimicrobial The drug is a nitroimidazole drug such as metronidazole, tinidazole or the like; or the antimicrobial drug is an antiviral drug such as acyclovir, ribavirin, etc.; or the antimicrobial drug is an antifungal agent Drugs such as butenafine, terbinafine, fluconazole and the like. Preferably, the non-anti-inflammatory drug is, for example, diclofenac sodium, piroxicam or the like; the adrenocortical hormone drug is, for example, dexamethasone, hydrocortisone, triamcinolone acetonide or the like; the antiallergic drug is, for example, a color Sodium citrate or the like; the vasoconstrictor is, for example, norepinephrine, seroxazoline hydrochloride, guanidazoline hydrochloride, ephedrine hydrochloride, etc.; the local anesthetic is, for example, procaine hydrochloride, lidocaine hydrochloride, and the like; The disinfectant antiseptic is, for example, zinc sulfate, povidone iodine, puro violet, chlorhexidine, benzalkonium bromide, borax, etc.; the softening scar is, for example, heparin, low molecular weight heparin, etc.; For example, urinary steroid, chitosan and its derivatives, chondroitin sulfate, etc.; the genetic engineering drugs are, for example, basic fibroblast growth factor, epidermal growth factor, etc.; other active ingredients are, for example, amino acids, peptides, phospholipids , vitamins and a variety of Chinese medicine.

The delivery system of the present invention does not add other active ingredients, and its basic constitution (trehalose and hyaluronic acid and/or hyaluronic acid pharmaceutically acceptable salt) can also be directly used for the treatment of burns and to reduce the formation of scars after healing. In the burn drug delivery system of the present invention, preferably, the composition is trehalose 0.11 - 80 g, (preferably 1 - 50 g, more preferably 3 -), based on ^ 100 liters or 100 g of the burn drug delivery system. 30克), hyaluronic acid and / or hyaluronic acid pharmaceutically acceptable salt 0. 01-80 grams (preferably 0. 05- 50 grams, more preferably 0. 1 - 30 grams), other active ingredients for burns 0 an appropriate amount, the amount of conventional pharmaceutical preparations. The invention also provides a method of the burn medication delivery system, the method comprising:

 If all the ingredients in the formula are soluble in water, according to the formula and dosage of the burn drug delivery system of the present invention, the medicinal salt of trehalose and hyaluronic acid and/or glass acid is placed in an appropriate amount of water to be dissolved and used; The appropriate amount of auxiliary materials is dissolved. If necessary, add other pharmacologically active ingredients to dissolve. After the solution is cooled, add trehalose and glass acid solution, and then add purified water to the volume to obtain trehalose and hyaluronic acid and/or glass acid. a solution preparation or a gelling agent for medicinal salt, after sterilization, and dispensing and sealing, thereby obtaining the burn drug delivery system of the present invention;

 If all the ingredients in the formulation are soluble in water or have water-insoluble ingredients, according to the formulation and dosage of the burn delivery system of the present invention, trehalose and hyaluronic acid and/or pharmaceutically acceptable salt of glass acid and other ingredients are conventional. Preparing a dispersion preparation or a paste or an ointment, etc., to obtain a dispersion preparation or a green preparation or a chondral preparation, and sterilizing, and then dispensing and sealing, thereby obtaining the burn medicine delivery system of the present invention;

 If it is necessary to prepare a solid preparation such as a powder, according to the formulation and dosage of the present invention, trehalose and hyaluronic acid and other ingredients (including active ingredients of burns) can be pulverized by conventional sieving or emulsified and dried to obtain a solid such as a powder. Formulation, sterilization, and dispensing and sealing, that is, the burn drug delivery system of the present invention.

The present invention also provides a combination of trehalose and hyaluronic acid and/or a hyaluronic acid pharmaceutically acceptable salt for preparing a burn for treating burns, accelerating wound healing or reducing scar formation. The use of a drug delivery system.

 The present invention also provides the use of trehalose in combination with hyaluronic acid and/or a hyaluronic acid pharmaceutically acceptable salt for the preparation of a burn drug delivery system for promoting the delivery and stability of active ingredients of other burn medications, said burn drug activity Ingredients may be selected from the group consisting of antimicrobials, non-steroidal anti-inflammatory drugs, adrenocortical drugs, antiallergic drugs, vasoconstrictors, local anesthetics, disinfectant preservatives, softening scars, healing agents, genetic engineering drugs, and others. The pharmacologically active ingredient, the active ingredient of the burn medication may be one or more of a plurality or different categories of the same category.

 The present invention also provides a method of treating burns, accelerating wound healing, or reducing scar formation, including administering to a patient in need thereof a burn medication delivery system according to the present invention.

 The present invention also provides a method for promoting the delivery and stability of an active ingredient of a burn medication in a burn medication delivery system, the method comprising adding trehalose and hyaluronic acid and/or hyaluronic acid to the burn medication delivery system. Salt, the active ingredient of the burn medication may be selected from the group consisting of an antimicrobial drug, a non-anti-inflammatory drug, an adrenocortical hormone drug, an antiallergic drug, a vasoconstrictor drug, a local anesthetic drug, a disinfectant preservative, a softening scar drug, and a healing agent. , genetically engineered drugs and other pharmacologically active ingredients, the active ingredients of the burned drug may be one or a plurality of different types or different categories.

 Trehalose (English: trehalose) is widely distributed throughout the biological world, including bacteria, fungi, insects, other plants and animals, which have special protective effects on biomolecules:

Anti-drying properties ("water substitution" effect): Trehalose is a disaccharide that plays a key role in the dehydration. It can keep many organisms under abnormal conditions such as high temperature, dehydration, freezing and drying. The original activity enhances the cell's ability to resist drying. None of the hyaluronic acid and cellulose ether compounds in the experiment exhibited anti-drying properties.

 Stabilizing the role of biofilms: Human skin, cell membranes, etc. are biofilms. Trehalose can protect the biofilm by lowering the phase transition temperature and keeping the membrane lipid under dehydration conditions in a liquid crystal state.

 Protection against biomolecules such as proteins: Trehalose has a significant protective effect on dehydrated and dried living substances. Even in extremely harsh environments such as extreme dryness, it can stabilize biomolecules such as proteins and protect them from damage.

 The role of preparation stabilizers and preservatives: Trehalose has been widely used as a formulation stabilizer and preservative, which is unmatched by other carbohydrates.

 It can be seen from the above that trehalose can enter the cell and directly act on the cell, exert its unique water substitution stress factor, and improve the ability of the cell to resist the harsh environment such as drying and freezing, thereby improving the ability of the cell to adapt to the environment. To maintain the freshness and vitality of cells; to maintain the stability of biofilms and proteins such as biofilms and proteins, to reduce the toxicity and systemic toxicity of drugs to wound tissues; as a preservative for preparations and as a preservative for products, to extend Shelf life; good biocompatibility, etc.

 Hyaluronic acid (English: hyaluronic acid, also known as hyaluronic acid) is naturally present in humans. Hyaluronic acid is present and applied in the form of its sodium salt, sodium hyaluronate. The hyaluronic acid according to the present invention includes a salt of hyaluronic acid, that is, a salt of sodium hyaluronate or other hyaluronic acid. Hyaluronic acid is a chemically inert substance with unique viscoelastic and non-Newtonian properties and important pharmacological and physiological functions:

Intelligent moisturizing effect: Hyaluronic acid is called the ideal natural moisturizing factor. Its carboxyl group and other polar groups in the molecule can form hydrogen bonds with water to bind a large amount of water. Moreover, hyaluronic acid can automatically adjust the amount of water absorption according to the humidity of the environment. This kind of smart protection Wet action keeps the wound at a suitable humidity.

 Lubrication: Hyaluronic acid solution has good viscoelasticity. At low impact frequency, ie low shear rate, the solution is viscous, which can reduce the friction between tissues. At high impact frequency, ie high shear rate, the solution is elastic. , to avoid tissue damage.

 Repair and promote healing: Hyaluronic acid is an indispensable substance in wound-free scar repair, which inhibits inflammation, accelerates healing, and repairs damage.

 Viscosity enhancement: The bioavailability of the drug is positively correlated with the viscosity of the drug solution within a certain range. Maintaining proper viscosity is an important prerequisite for the drug to play an effective role. Hyaluronic acid As a natural biomacromolecular polysaccharide, it can increase the viscosity of the preparation, thus prolonging the residence time of the drug in the wound.

 Bioadhesiveness: Compared with other high molecular polymers, hyaluronic acid has the same solution viscosity and even lower viscosity, which enables the drug to obtain higher bioavailability due to the interaction of hyaluronic acid with mucin, organism. Adhesion, thus delaying the elimination of drugs.

 Spreading Wetting Ability: As a mucopolysaccharide, hyaluronic acid can increase the viscosity of the drug, and even spread the drug evenly on the wound surface to enhance the effect of the drug.

 Slow-drying effect: Hyaluronic acid has the effect of slowing down the drug and is determined by its molecular specificity. The drug can be embedded in the macromolecular network of hyaluronic acid by non-covalent bonding. The hyaluronic acid molecule acts like a dynamic molecular sieve, and the drug adheres to the wound surface for a longer period of time.

 Pain relief: Hyaluronic acid masks pain receptors and relieves pain in the wound area.

It can be seen from the above: Hyaluronic acid is an intrinsic component of the human body. It can act on the intercellular space and connective tissue, improve the functions of hydration, moisturizing and lubrication, improve the living environment of cells, and keep the wound tissue always physiological. Sexually moist; has anti-inflammatory and pain-relieving effects; can be thickened by it, bioadhesive, spreading, moisturizing, slowing, and good The biocompatibility, prolonging the residence time of the 3⁄4 substance in the wound, improving the bioavailability of the drug, reducing the toxic side effects of the drug, and reducing the irritation of the drug.

 The delivery system of the present invention does not add other active ingredients, and its basic constitution can also be directly used for the treatment of burns and to reduce the formation of scars after healing.

 The trehalose of the present invention refers to trehalose of any origin, which is obtained by extracting and separating from plants, animal tissues, microbial fermentation, and genetic engineering preparation, and the like. The trehalose of the present invention means trehalose in any form, including trehalose containing no crystal water and trehalose containing crystal water, and the like.

 The hyaluronic acid of the present invention refers to a transparent and wide acid of any source, which is obtained by extracting and separating from animal tissues, microbial fermentation, and genetic engineering preparation, and the like. The hyaluronic acid of the present invention includes hyaluronic acid and salts thereof such as sodium hyaluronate (also known as sodium hyaluronate) and zinc hyaluronate (also known as hyaluronic acid). The hyaluronic acid of the present invention refers to any hyaluronic acid of a relative molecular mass. Unless otherwise specified, hyaluronic acid as referred to herein includes hyaluronic acid and/or a pharmaceutically acceptable salt thereof.

 The burn delivery delivery system of the present invention can be prepared as any suitable dosage form for burn treatment, including liquid preparations, such as: solution, suspension, emulsion; solid preparation ( Solid preparation), for example: powder (owder), pillicle; gel; chont (ointment); hardener (plaster); cream (cream, commonly known as cream), paste (paste ), liposome, and the like.

When the burn drug delivery system of the present invention is formulated into a solution, the commonly used solvents are: water, glycerin, liquid paraffin, vegetable oil and the like. When the burn delivery system of the present invention is formulated as a suspension, the usual suspensions are Tween, Span, Triethanolamine and the like. When the burn delivery system of the present invention is formulated into an emulsion, the commonly used substrates are: lanolin, fatty alcohol, polysorbate, sodium soap, triethanolamine, soap, and the like. When the burn drug delivery system of the present invention is formulated into a powder, the commonly used substrates are: chitosan (deacetylated chitin), dextran Wait. When the burn delivery system of the present invention is formulated into a gelling agent, commonly used gel aqueous substrates are: glycerin, propylene glycol, cellulose ether compounds, carbomer, gelatin, chitosan, etc.; commonly used gel oily matrix There are: liquid paraffin, fatty oil, aluminum soap and so on. When the burn drug delivery system of the present invention is formulated into a paste, the commonly used substrates are: vegetable oil, red dan, official powder and the like. When the burn delivery system of the present invention is formulated into an ointment, the commonly used substrates are: polyethylene glycol, petrolatum, paraffin, liquid paraffin, silicone oil, beeswax, stearyl alcohol, stearic acid, white petrolatum, monostearyl Appropriate amount of acid glyceride, polysorbate, etc. When the burn drug delivery system of the present invention is made into a hard bone agent, the commonly used substrates are: fatty acid salts, resins, rubbers and the like. When the burn delivery system of the present invention is formulated into a milk bone, the commonly used base shields are: petrolatum, white petrolatum, cetyl alcohol, lanolin, stearic acid, sodium lauryl sulfate, and the like. When the present burn delivery system is used as a paste, the commonly used substrates are: glycerin, lanolin, starch, petrolatum and the like. When the burn drug delivery system of the present invention is prepared into a liposome preparation, commonly used substrates are: phospholipids, cholesterol, and the like.

 The pH of the burn medication delivery system can also be adjusted to a pH range acceptable for conventional burn medications, preferably pH 4-9, more preferably pH 5-8, by adding a conventional pH adjuster to the burn medication delivery system of the present invention. 5至五。 5. The most preferred pH is 6. 5-7. 5. The conventional pH adjusting agent may be a pharmaceutically acceptable organic or inorganic acid or base, preferably sodium hydroxide, hydrochloric acid, boric acid, borax, phosphoric acid-phosphate buffer system, boric acid-borax buffer system, acetic acid-acetate Buffer system and so on.

 The osmotic pressure adjusting agent may also be added to the burn drug delivery system of the present invention, for example, preferably any combination of one or more of the following: sodium chloride, low molecular weight dextran, glycerin, boric acid, borax, phosphoric acid - Phosphate buffer system, boric acid-borax buffer system and acetic acid-acetate buffer system can be used as pH adjusters or as osmotic pressure regulators.

Conventional preservatives such as hydroxyethyl ester, thimerosal, EDTA, phenylacetic acid, ethanol, sorbic acid, chlorhexidine, and chlorhexidine acetate may also be added to the burn delivery system of the present invention. And so on.

 Conventional antioxidants such as vitamin 8, vitamin C and the like may also be added to the burn delivery system of the present invention.

 More specifically, the method for preparing the burn drug delivery system of the present invention is: if all the components in the formulation are soluble in water, preferably, the formulation and amount of the burn drug delivery system according to the present invention, trehalose and hyaluronic acid and/or Or hyaluronic acid pharmaceutically acceptable salt into a suitable amount of water, so that it is dissolved and ready for use; take appropriate amount of the auxiliary agent, if necessary, add other pharmacologically active ingredients to dissolve, dissolve the solution, add trehalose and hyaluronic acid solution, then Adding purified water to the volume to obtain a solution or gel containing trehalose and hyaluronic acid, and filtering or sterilizing or dry heat sterilization or moist heat sterilization or chemical sterilization, and then sealing and sealing, thereby obtaining the burn of the present invention Drug delivery system.

 The preparation method of the burn drug delivery system of the present invention may further be: if the formulation has water-insoluble components, or all components are soluble in water, according to the formula and dosage of the burn drug delivery system of the present invention, trehalose and hyaluronic acid and/or Or a pharmaceutically acceptable salt of hyaluronic acid and other ingredients, which are prepared according to a conventional method for preparing a dispersion preparation or a bone or a chont preparation, etc., to obtain a dispersion preparation (including liposome solution, micelle solution, microemulsion, etc.) or A dosage form such as a bone agent or an ointment, which is sterilized by filtration or dry heat sterilization or moist heat sterilization or chemical sterilization, and sealed after being dispensed, obtains the burn drug delivery system of the present invention.

 The preparation method of the injectable drug delivery system may further be: if a solid preparation such as a powder is prepared, the trehalose and hyaluronic acid and other ingredients (including active ingredients of burns) are pulverized according to the formula and dosage of the present invention. A method such as sieving or emulsification drying obtains a solid preparation such as a powder, and is subjected to dry heat sterilization or chemical sterilization to dispense and seal, thereby obtaining the burn drug delivery system of the present invention.

The burn drug delivery system containing trehalose and hyaluronic acid has the following significant advantages: 1 Trehalose acts as a biological preservative, can enter the cell, directly acts on the cell, exerts its unique water substitution stress factor, and enhances cell resistance. Dry, anti-freezing ability, Thereby improving the ability of cells to adapt to the environment, keeping the cells fresh and fresh; maintaining the stability of biofilms and proteins such as biofilms and proteins, reducing the toxicity and systemic toxicity of the drugs on wound tissues; and acting as stabilizers and products for preparations. Preservative, used to extend shelf life; it has good biocompatibility. 2 hyaluronic acid as a smart moisturizer, can act on the intercellular space and connective tissue, improve the role of hydration, moisturizing, lubrication, etc., improve the living environment of cells; as an important component of scar-free wound healing, hyaluronic acid can promote wounds No scar healing; Hyaluronic acid has anti-inflammatory effects and can mask pain receptors and relieve wound pain; it can also prolong drug by its adhesion, bioadhesion, spreading wetting and sustained release and good biocompatibility The survival time of the wound surface improves the bioavailability of the drug, reduces the toxic side effects of the drug, and reduces the irritation of the drug. 3 combination of trehalose and hyaluronic acid, biological preservation, intelligent moisturizing, phlegm and stasis muscle, thus complementing each other and enhancing mutual effects; used in burn drug delivery system, can significantly improve wound tissue against external drying, freezing, etc. The ability to provide harsh environment; provide a physiological moist environment for wounds; form a protective film on the wound surface, effectively seal, cover, protect the wound, prevent body fluid extravasation, inhibit bacterial invasion, promote granulation tissue growth and wound healing, The skin does not leave or leave scars; it is beneficial to the healing of the wound; it is beneficial to the absorption of the drug; prolongs the shelf life of the drug; prolongs the residence time of the drug in the wound, improves the bioavailability of the drug, and plays a long-term and slow-acting effect; The toxic side effects of the drug; reduce the irritation of the drug. 4 Trehalose is a chemically inert substance. Hyaluronic acid is basically a chemically inert substance. It can be used for the treatment of various active ingredients for burns, for preventing burns and reducing the formation of scars.

The molecular structure of trehalose is as follows:

 The molecule of trehalose is formed by the condensation of two glucose molecules through a hemiacetal hydroxyl group. Trehalose is present in a variety of forms, the most common being dihydrate crystals, which lose crystal water and become anhydrous crystals. Regardless of the form of trehalose, its physicochemical properties are stable and chemically inert.

 The molecular structure of hyaluronic acid is as follows.

 Transparent Shield Acid is a linear mucopolysaccharide composed of glucuronic acid and acetyl glucosamine as disaccharide units. detailed description

 Formulation example

 Example 1 (a cream that can be used for burns)

5克的透明。 Transparent burns drug delivery system, in 100 grams, trehalose 6. 5 grams, transparent Sodium sulphate 1. 5 g, sulfadiazine silver 2. 0 g, cetyl alcohol 9 g, liquid paraffin 6 g, white petrolatum 14 g, sodium lauryl sulfate, glycerol amount, sodium chloride amount, hydroxybenzene The amount of ethyl ester is appropriate, and the rest is purified water. The milk is prepared in a conventional manner.

 Example 2 (a solution that can be used for burns)

 The burn drug delivery system of the present invention is 100 liters, trehalose 1. 5 g, sodium hyaluronate 0.31 g, sodium chloride 0. 70 g, hydroxyphenyl ethyl ester, and the rest is purified water. The solution is prepared in a conventional manner.

 Example 3 (a solution that can be used for burns)

 The burn drug delivery system of the present invention is 100 liters, trehalose 1. 5 g, sodium hyaluronate 0.1 g, bisexin B 3 g, sodium chloride in an appropriate amount, and the rest is purified water. The solution is prepared in a conventional manner.

 Example 4 (a solution that can be used for burns)

 The burn drug delivery system of the present invention comprises 100 liters of citrate, 1.5 g of trehalose, 0.1 g of sodium hyaluronate, 5 g of povidone iodine, and an appropriate amount of sodium chloride, and the rest is purified water. The solution is prepared in a conventional manner.

 Example 5 (a liposome suspension that can be used for burns)

 The gram of the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose, the sucrose The amount of ester is the same, and the rest is purified water. Liposomal suspensions were prepared in a conventional manner.

 Example 6 (a kind of powder that can be used for burns)

 The burn drug delivery system of the present invention comprises, in 100 g, trehalose 20. 0 g, sodium hyaluronate 20. 0 g, chlorhexidine acetate 0. 05 g, and the rest is deacetylated chitin. The powder is prepared in a conventional manner.

 Example 7 (a gelling agent that can be used for burns)

5克的透明, transparent, sulphate, 5. 5g, transparent 2的酸盐缓冲溶液。 The sodium phosphate 1. 2 grams, the amount of hydroxyethyl phenoxylate, the rest of the pH of 7.0 phosphate buffer. The gel was prepared in accordance with a conventional method.

 Example 8 (a gelling agent that can be used for burns)

 The gram of the medicinal delivery system of the present invention, the gram of ketose, 1.0 g, the transparent sulphate 1.0 g, piroxicam 0. 5 g, carbomer 0.5 g, triethanolamine amount, hydroxybenzene The amount of ester is the same, and the rest is purified water. The gel was prepared in a conventional manner.

 Example 9 (a gel that can be used for burns)

 The medicinal delivery system of the present invention, 100 g, trehalose 5.0 g, transparent sodium citrate 0.3 g, low molecular weight heparin 30000 IU, carbomer 0.8 g, triethanolamine amount, hydroxyphenyl ethyl ester amount The rest is purified water. The gel was prepared in a conventional manner.

 Example 10 (a gelling agent that can be used for burns)

 00克, glycerin 5. 00g, 00g, glycerin 2. 00g, glycerin 2. 00g, glycerin 2. 00g, glycerin 2. 00g , the amount of triethanolamine, the amount of hydroxyethyl ester, the rest is purified water. The gel was prepared in the usual manner.

 Example 11 (an ointment that can be used for burns)

 The medicinal delivery system of the present invention, in 100 g, trehalose 5.0 g, sodium hyaluronate 1.0 g, mupirocin 2 g, polyethylene glycol amount, stearyl alcohol amount, white petrolatum amount , the appropriate amount of chlorhexidine acetate, the rest is purified water. Cartilage is made in a conventional manner.

 Example 12 (a cartilage agent that can be used for burns)

 The medicinal delivery system of the present invention, in 100 g, trehalose 5.0 g, sodium hyaluronate 1.0 g, neomycin 200 OOOu, bacitracin 25 000 u, propylene glycol amount, stearyl alcohol, white petrolatum Appropriate amount, clopidogrel acetate, the rest is purified water. Make an ointment according to the usual method.

Example 13 (a cartilage agent that can be used for burns) The gram of sucrose, 1.0 g, sodium hyaluronate, 1.0 g, lomefloxacin hydrochloride, 0.3 g, glyceryl monostearate, paraffin amount, liquid paraffin Appropriate amount, polysorbate 80, amount of chlorhexidine acetate, the rest is purified water. An ointment is prepared in a conventional manner. Test Example 1

 Thirty rats were randomly divided into 3 groups, 10 in each group, namely the experimental group (Inventive Example 7) and the positive control group (sodium hyaluronate gel, homemade, the active ingredient was sodium hyaluronate, The bacterial agent was hydroxyethyl ester) and the negative control group (blank control group), and the therapeutic effect of Example 7 of the present invention on burns was examined by making a shallow second scald model of rats.

Rat model of second degree scald: Apply sodium sulfide depilatory on the back of the rat. After a few minutes, gently scrape off and wash with water to make the back hair removal area 8 cm X 6 cm. 24 hours after depilation, the rats were anesthetized with 1.8% pentobarbital sodium 36 mg.kg- ¹ , and the rats were fixed on the modeling board in the supine position, and the back skin of the rats was exposed to the template holes. The template was placed in an electric constant temperature water bath at 70 ° C, and the burn time was 15 s, causing a shallow second degree burn.

 5°/。 After the scalding, the water stain was lightly wiped with a gauze, first with 0. 1% benzalkonium bromide solution, and then 0. 05 ° /. Disinfect the wound with chlorhexidine acetate. For the experimental group rats, the present invention was applied to the scalded portion to make a uniform layer; in the positive control group, the sodium hyaluronate gel was applied to the burned site to make a uniform layer; The control group did not give any medicine. Single cage feeding. Observation indicators: (1) wound area of wounds 7 days and 15 days after burns; (2) healing time of dislocation.

Results: As shown in Table 1, Example 7 of the present invention made the rats 2 days after the second degree of burns. The wound area of the wound was reduced and the healing time of the dislocation was shortened in 15 days. Compared with the negative control group, the difference was significant. Compared with the wound area of the wound in the positive control group 15 days after the burn, the healing time was significantly reduced. Significantly shortened. Table 1 Effect of Example 7 of the present invention on shallow second degree scald in rats (±s,

 2=10)

Group wound surface area / cm ² dislocation healing time / day 7 days after burns 15 days after burn

Negative control group 16.6 ± 2.9 8.4 ± 1.2 23.6 ± 2.5 Positive control group 15.0 ± 1.9 6.8 ± 1.8 · 20.1 ± 1.7 ' Inventive Example 7 14.6 ± 2.5 · 5.3 ± 2.2 ' ^Δ 18.3 ± 1.2 * ^Δ

* 0.05, compared with the negative control group, there was a significant difference; m.05, compared with the positive control group, there was a significant difference.

 Test Example 2

 Thirty rats were randomly divided into 4 groups, 10 in each group, namely the experimental group (Example 6) and the positive control group 1 (humid burn ointment, Shandong Changqing Pharmaceutical Factory, the active ingredients were: Astragalus, Cork, Huang Lian, etc., for routine treatment of burn preparations), positive control group 2 (sodium hyaluronate powder, homemade, active ingredient sodium hyaluronate, excipient is chitosan, bacteriostatic agent is chlorhexidine acetate) and The negative control group (blank control group) was examined for the therapeutic effect of the preparation of Example 6 on burns by preparing a deep second degree burn model of rats.

Rat model of deep second degree scald: Apply sodium sulfide depilatory on the back of the rat. After a few minutes, gently scrape off and wash with water to make the back hair removal area 8 cm X 6 cm. 24 hours after depilation, rats were anesthetized with 1.8% sodium pentobarbital 36 mg · kg- ¹ , supine position The rat was fixed on a mold-making board, and the back skin of the rat was exposed to the template hole. The template was placed in an electric thermostatic water bath at 80 ° C for 12 seconds, and the total burned area was about 10%, causing secondary burns.

 Dosing: After ironing, gently wipe the water stain with gauze, first scrub with 0.1% benzalkonium bromide solution, then disinfect the wound with 0.05% chlorhexidine acetate solution. For the experimental group rats, the preparation of Example 6 of the present invention was sprinkled on the scalded portion to make a uniform layer, and the dose per dose was (140 soil 0.7) gram; the positive control group 1 rat was transparent. Sodium sulphate powder is scattered on the burned area to make a uniform layer. The amount of each dose is (140 soil 0.7) gram; the positive control group 2 applies the moist burn cream with cotton swabs to the burned parts, each giving The dose was (300 ± 50) gram; the negative control group did not give any medicine. Single cage feeding. Observation indicators: (1) wound area of wounds 7 days and 15 days after burns; (2) time of dislocation healing.

 Results: As shown in Table 2, the preparation of the present invention reduced the scar area of the wound and shortened the healing time of the wound at 7 days and 15 days after the deep second degree burn in the rat, and the difference was significant compared with the negative control group. Compared with the positive control group 1 and group 2, the wound area of the wound was significantly reduced 15 days after the burn, and the healing time was significantly shortened. Table 2 Effect of the preparation of Example 6 of the present invention on deep second degree scald in rats (土 s,

Group wound surface area / cm ² dislocation healing time / day 7 days after burns 15 days after burn

 Negative control group 26.3 ±2.8 14.6 ±4.1 28.0±2.3 Positive control Group 1 26.0±3.3 10.7 ±2.7' 23.1 ± 3. 阳性 Positive control Group 2 25.6 ±2.7 8.2 ±4.3· 23.8 ±2.7*

Example 6 24.7 ±3.2* 6.1 ±2.2* ^Δ 20.2 ±2.6* ^Δ

05, compared with the negative control group, there is a significant difference; ^Δ 0.05, and positive Significant difference compared with the control group

 Test Example 3:

 120 patients with second degree burns were randomized to clinical trials. Patients in the treatment group (60 patients) were given the formulation of Example 1 and wrapped or exposed with sterile gauze twice a day. 60 cases in the control group were treated with sulfadiazine silver paste wet compress, 2 times / day. Before treatment, the treatment group and the control group were cleaned and disinfected with benzalkonium bromide solution. The efficacy evaluation was performed by the self-control method, and the evaluation criteria were evaluated according to the criteria of cure, improvement, and ineffectiveness. Cure: The wound heals more than 90%; no skin grafting is required. Improved: wound healing 70% "90%; no systemic symptoms; no abnormalities in the test results. Invalid: wound healing 50 ° /. The following or not cured; complications (such as sepsis), etc. did not improve; multiple wound scar formation, The affected function also needs skin grafting. The experimental results are shown in Table 3.

 Efficacy evaluation of the preparation of the first embodiment of the present invention for second degree burns cure rate improvement rate inefficiency total effective rate group patient age

 /n (%) /n (3⁄4) /n ( ) /n (%) Formulation of Example 1 38 ± 18 57 (95) 3 (5) 0 60 (100) Common sulfadiazine silver milk side 43 ± 22 26 (43) 18 (30) 16 (27) 44 (73) Thus, the preparation of Example 1 of the present invention can significantly improve the therapeutic effect compared with the conventional preparation, mainly due to the delivery of trehalose and hyaluronic acid. The system increases the transmission, absorption and stability of silver sulfadiazine and increases bioavailability.

Claims

A burn drug delivery system characterized by comprising trehalose and a pharmaceutically acceptable salt of hyaluronic acid and/or hyaluronic acid, and a conventional pharmaceutical excipient.  2. The burn medication delivery system according to claim 1, further comprising one or more active ingredients for burns, wherein the burn active active ingredient may be selected from the group consisting of an antimicrobial agent, a non-steroidal anti-inflammatory drug, and a gonadotropin drug, an antiallergic drug, a vasoconstrictor, a local anesthetic, a disinfectant preservative, a softening scar, a healing agent, a genetic engineering drug, and other pharmacologically active ingredients, and the active ingredient of the burn drug may be a kind Or multiple or multiple categories of the same category. 3. The burn medication delivery system according to claim 2, wherein the antimicrobial drug is an antibiotic drug, preferably selected from the group consisting of mupirocin, amphotericin B, bacitracin and neomycin sulfate; Or a quinolone, preferably selected from the group consisting of enrofloxacin, norfloxacin, levofloxacin, ofloxacin, ciprofloxacin, lomefloxacin and pefloxacin; or a sulfonamide, preferably selected from the group consisting of sulfonamides Silver pyrimidine and zinc sulfadiazine; or nitroimidazole, preferably selected from metronidazole and tinidazole; or antiviral, preferably selected from acyclovir and ribavirin; or antifungal a drug, preferably selected from the group consisting of butenafine, terbinafine and fluconazole; wherein the non-anti-inflammatory drug is preferably selected from the group consisting of diclofenac sodium and piroxicam; wherein the adrenocortical hormone drug is preferably selected from the group consisting of dexamethasone And hydrocortisone and triamcinolone acetonide; wherein the antiallergic agent is preferably sodium cromoglycate; wherein the vasoconstrictor is preferably selected from the group consisting of norepinephrine, seroxazoline hydrochloride, imidazoline and ephedrine hydrochloride ; among them The local anesthetic is preferably selected from the group consisting of procaine hydrochloride and lidocaine hydrochloride; wherein the disinfectant antiseptic is preferably selected from the group consisting of zinc sulfate, povidone iodine, methyl violet, chlorhexidine, benzalkonium bromide and borax; The softening scar drug is preferably selected from the group consisting of heparin and low molecular weight heparin; wherein the promoting healing agent is preferably selected from the group consisting of allantoin, chitosan and derivatives thereof, and chondroitin sulfate; The engineering drug is preferably selected from the group consisting of basic fibroblast growth factor and epidermal growth factor; wherein the other active ingredient is preferably selected from the group consisting of amino acids, peptides, phospholipids, vitamins, and various traditional Chinese medicines.  The medicinal delivery system of the present invention is characterized in that the component is trehalose 0. 01-80 g (preferably 1). 0-1 克克优选优选优选为0. 1 - 3 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克 克0 g), other pharmacological active ingredients 0 ~ appropriate amount, appropriate amount of pharmaceutical excipients.  The burn drug delivery system according to any one of claims 1 to 4, which is a liquid preparation such as a solution, a suspension, an emulsion; a solid preparation such as a powder, a film; a gel; Cartilage; osteoclast; breast, cream, paste, liposome, etc.  A method of preparing a burn medication delivery system according to any one of claims 1 to 5, the method comprising:  If all the ingredients in the formulation are soluble in water, according to the formula and dosage of the burn drug delivery system of the present invention, the trehalose and the hyaluronic acid and/or the hyaluronic acid pharmaceutically acceptable salt are placed in an appropriate amount of water to be dissolved and used; Take appropriate amount of pharmaceutical auxiliary materials. If necessary, add other pharmacologically active ingredients to dissolve. After cooling the solution, add trehalose and hyaluronic acid solution, then add purified water to volume to obtain trehalose and hyaluronic acid and / Or a solution preparation or a gelling agent of a hyaluronic acid pharmaceutically acceptable salt, after sterilization, and dispensing and sealing, thereby obtaining the burn drug delivery system of the present invention; If all the ingredients in the formula are soluble in water or have water-insoluble ingredients, according to the formulation and dosage of the burn delivery system of the present invention, trehalose and hyaluronic acid and/or hyaluronic acid pharmaceutically acceptable salt and other ingredients are Formulation is carried out by a conventional method for preparing a dispersion preparation or a bone or a chont preparation, etc., to obtain a dispersion preparation or a paste or cartilage. After sterilization, the package is sealed, that is, the burn drug delivery system of the present invention; or, if a solid preparation such as a powder is prepared, the trehalose and hyaluronic acid and/or hyaluronic acid are prepared according to the formulation and dosage of the present invention. The pharmaceutically acceptable salt and other ingredients are pulverized by a conventional sieving or emulsification drying method to obtain a solid preparation of a powder, which is sealed after drying or sterilizing by chemical sterilization, thereby obtaining the burn drug delivery system of the present invention.  7. The use of trehalose in combination with hyaluronic acid and/or hyaluronic acid pharmaceutically acceptable salts for the preparation of a burn delivery system for treating burns, accelerating wound healing or reducing scar formation. 8. Use of trehalose in combination with a pharmaceutically acceptable salt of hyaluronic acid and/or hyaluronic acid for the preparation of a burn delivery delivery system for promoting the delivery and stability of active ingredients of other burn medications, which may be selected from active ingredients of the burn medication Self-antimicrobial, non-steroidal anti-inflammatory drugs, adrenocortical drugs, antiallergic drugs, vasoconstrictors, local anesthetics, disinfectant preservatives, softening scars, healing agents, genetic engineering drugs, and other pharmacologically active ingredients The active ingredient of the burn medication may be one or more of a plurality or different categories of the same category. A method of treating burns, accelerating wound healing, or reducing scar formation, comprising administering a burn medication delivery system according to any one of claims 1 to 5 to a patient in need thereof. 10. A method for promoting the delivery, absorption and stability of an active ingredient of a burn medication in a burn medication delivery system, the method comprising adding trehalose and a transparent shield acid and/or a hyaluronic acid pharmaceutically acceptable salt to the burn medication delivery system The active ingredient of the burn medication may be selected from the group consisting of an antimicrobial drug, a non-steroidal anti-inflammatory drug, an adrenocortical hormone drug, an antiallergic drug, a vasoconstrictor drug, a local anesthetic drug, a disinfectant antiseptic, a softening scar drug, and a healing agent. , genetically engineered drugs and other pharmacologically active ingredients, the active ingredients of the burned drug may be one or a plurality of different types or different categories.