WO2015048930A1 - 一种含氯诺昔康和聚维酮碘的药物组合物 - Google Patents

一种含氯诺昔康和聚维酮碘的药物组合物 Download PDF

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WO2015048930A1
WO2015048930A1 PCT/CN2014/087953 CN2014087953W WO2015048930A1 WO 2015048930 A1 WO2015048930 A1 WO 2015048930A1 CN 2014087953 W CN2014087953 W CN 2014087953W WO 2015048930 A1 WO2015048930 A1 WO 2015048930A1
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group
pharmaceutical composition
lornoxicam
transdermal patch
wound
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PCT/CN2014/087953
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English (en)
French (fr)
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徐静
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徐静
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone

Definitions

  • the present invention relates to a pharmaceutical composition containing lornoxicam and povidone iodine as an active ingredient, and a use thereof, which is useful for preparing a preparation for external use, for various body pain sites, surgery Analgesic and anti-inflammatory for wounds or various skin wounds (including burns, burns).
  • Lornoxicam is a non-steroidal anti-inflammatory analgesic, a thiazide derivative with strong analgesic and anti-inflammatory effects. Its chemical name is 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thiophene-[2,3-e]-1,2-thiazin-3-carboyl 2 Diamine-1,1-dioxide, the structural formula is as follows:
  • Lornoxicam is a known drug with a wide range of effects. Its mechanism of action includes: 1. Inhibition of prostaglandin synthesis by inhibiting cyclooxygenase (COX) activity; however, lornoxicam does not inhibit 5-- The activity of lipid oxidase does not inhibit the synthesis of leukotrienes, nor does it divert arachidonic acid to the 5-lipoxy oxidase pathway. 2. Activate the opioid neuropeptide system to exert a central analgesic effect.
  • COX cyclooxygenase
  • the concentration in the synovial fluid of the joint is higher than the plasma concentration, which is more suitable for the treatment of joint pain.
  • Lonoxicam has dual pharmacological effects of pain relief and anti-inflammatory, and both pharmacological effects are required for wounds; lornoxicam is also a small molecule (molecular weight 371.82), small size (4-8mg per day orally)
  • the drug, the small molecular weight makes it easy to penetrate the skin to reach the site of action, and the small size means that it is easy to reach the drug loading required for the preparation process and to reach the clinically required therapeutic dose easily through the skin.
  • the lornoxicam patch we produced was proved by transdermal test in vitro in rats. It reached 6.4 mg/day ⁇ 10 cm 2 .
  • measured transdermal volume measured sample content in the receiving liquid / test sample area
  • Transdermal per hour measured transdermal volume / sample test time
  • Daily transdermal volume measured transdermal volume / sample test time ⁇ 24h]
  • oxime drugs with the same pharmacological effects include piroxicam and meloxicam, but the clinical daily dose of these two drugs is large (piroxicam 20 mg/day, meloxicam 15 mg/day), and the unit of the external preparation. It is difficult to achieve an ideal pharmacodynamic effect in an area transdermal dose, and thus lornoxicam is preferred.
  • Povidone Iodine is a complex of polyvinylpyrrolidone and iodine, also known as iodophor, containing 9-12% of effective iodine. It is a broad-spectrum strong disinfectant for viruses, bacteria, Both fungi and mold spores have a strong killing effect. This product is less irritating to the skin, low in toxicity, long lasting, safe and simple to use. It is basically non-irritating to tissues and is used for skin and mucous membrane disinfection, such as pre-operative cleaning, surgical site and wound disinfection.
  • Povidone iodine can release free iodine in water to maintain the bactericidal power for a long time, and at the same time solve the problem of iodine volatilization. It kills microorganisms through the oxidation of the latter, kills bacteria better than ⁇ , and has certain lethality to bacterial spores.
  • This product has significant killing effect on Candida albicans, Staphylococcus aureus, Escherichia coli and Bacillus subtilis; the sterilization time of Pseudomonas aeruginosa and Candida albicans is similar to that of compound iodine solution and iodine in the same concentration, but the toxicity is only It is 1/4 to 1/9.
  • Povidone iodine gradually releases iodine in a solvent to provide a sustained release effect.
  • the powerful bactericidal mechanism is to oxidize the active group of the pathogen protein of the pathogen and bind it to the amino group of the protein to denature it, thus effectively Kill pathogens such as bacteria, spores, fungi, viruses and protozoa. It has strong bactericidal power and wide range of sterilization. It can directly kill bacteria, fungi, viruses, spores and protozoa. The sterilization speed is fast, most bacteria can kill within 30 seconds, and it is enough to kill for 5 minutes for individual bacteria.
  • bactericidal and bacteriostatic drugs for external use have the problems of large side effects and easy drug resistance.
  • nano-silver has been proved to have strong external bactericidal and bacteriostatic effects, but it has been found to have great side effects such as skin discoloration and visceral accumulation after systemic absorption.
  • Other topical antibiotics produce microbial resistance to varying degrees, so that the efficacy is gradually decreased, so povidone iodine is preferred.
  • the invention creatively combines lornoxicam and povidone iodine, selects the best ratio combination of the two, prepares various external preparations, and locally applies to various pain parts of the human body, and exerts the anti-inflammatory effect of lornoxicam.
  • the efficacy of analgesia also exerts the antibacterial, anti-inflammatory and antiseptic effects of povidone iodine.
  • the anti-inflammatory and analgesic effects of burns and burns are more obvious.
  • the product of the invention has good effect on skin wound treatment and has obvious synergistic effect. It is reflected in: after application, it has significant analgesic, anti-inflammatory and significant relief or elimination of scarring effect, which is better than single application, and is easy to use, quick to heal and can be applied for several days.
  • the pharmaceutical composition of the present invention itself has significant creativity in the treatment of skin wounds and in the treatment of skin wounds.
  • the pharmaceutical composition of lornoxicam and povidone iodine of the present invention is not simply superimposed, but needs to be researched and explored after a relatively complicated and innovative pharmaceutical manufacturing process, in order to find advanced, Applicable processes to produce qualified process products.
  • the invention is not limited to any particular form of lornoxicam, and the drug may be lornoxicam or a pharmaceutically acceptable analogous derivative.
  • the invention is not limited to the specific form of povidone iodine, and the drug may be povidone iodine or any pharmaceutically acceptable iodine disinfectant preservative.
  • composition comprising lornoxicam and povidone iodine.
  • the composition can be used for various painful parts of the human body, including post-operative wounds or various skin wounds (including burns, burns) for pain relief and anti-inflammatory, and has a significant synergistic effect.
  • compositions of lornoxicam and povidone iodine of the present invention are inventive in therapeutic effects.
  • the specific creativity is reflected in:
  • compositions of lornoxicam and povidone iodine of the present invention are inventive in the manner of treatment of skin wounds.
  • the specific creativity is reflected in:
  • a method for simultaneously achieving anti-inflammatory and analgesic effects on a product After using the product of the present invention, we have surprisingly found that the anti-inflammatory and analgesic effects are simultaneously achieved, and the anti-inflammatory effect is superior to the use of one of the drugs alone and not Additional painkillers need to be used. In the traditional treatment of skin wounds, it is usually wrapped in anti-inflammatory drugs on the wound surface, and then Or inject painkillers for pain relief.
  • composition of the present invention can be used for preparing a preparation for external use, acting on a body pain site, and for treating various causes, including pain caused by surgical wounds or various skin traumas, and symptoms of inflammation.
  • the pharmaceutical composition of the present invention is characterized in that the weight ratio of lornoxicam to povidone iodine is from 1:0.4 to 25, more preferably from 1:1.0 to 5.0, still more preferably 1:2.
  • compositions formed by lornoxicam and povidone iodine both can enter the soft tissue fluid of the wound surface of the skin at a high skin penetration rate, rapidly reaching a stable therapeutic concentration, Anti-inflammatory and analgesic effects; we also found that the composition is very versatile and can be made into a variety of clinically needed external dosage forms to meet various clinical needs (including surgical wounds and various skin injuries), such as: A transdermal patch for controlling the release of a drug by controlled release membrane, a skeletal transdermal patch with a skeleton-type pressure-sensitive adhesive as a controlled release medium, and a gel-type transdermal with a hydrogel as a controlled release medium External dosage forms such as patches, ointments, sprays, suppositories, and the like.
  • a molding material or a substrate required for various preparations such as carbomer, polyisobutylene pressure sensitive adhesive or the like may be added.
  • an auxiliary solubilizing substance may be added to increase the solubility of lornoxicam and povidone iodine, such as Tween-80, arginine, ethanol, glycerin and the like.
  • a transdermal absorption enhancer may be added during the preparation of the external preparation, preferably azone, oleic acid or a mixture thereof. It may also be added with isopropyl myristate, triethyl citrate, ethyl laurate, Tween-80, borneol or a mixture thereof.
  • composition of the present invention is applied to the preparation of a topical preparation, and the specific preparation method is as follows:
  • the gel-type transdermal patch is prepared by uniformly mixing the composition with a suitable gel matrix and curing to form a semi-solid or thick liquid having gel properties. Apply to the backing material and cover the protective layer. The gel-type transdermal patch containing the composition is cut and packaged as needed.
  • the storage type transdermal patch preparation method comprises the steps of: mixing the composition with a suitable polymer material or polymer to form a drug storage; and coating the adhesive on the protective layer, heating and drying, and coating the controlled release.
  • the membrane is made into a composite membrane; the controlled release membrane of the composite membrane is oriented upward, and the drug reservoir is placed on the controlled release membrane, covered with a backing layer, and the drug reservoir is sealed in the controlled release membrane layer and the protective layer. Between, the desired size is cut and packaged to form a reservoir-type transdermal patch containing the composition.
  • the skeletal type transdermal patch preparation method comprises the steps of: mixing the composition with a suitable polymer viscous material or pressure sensitive adhesive, coating the backing material, heating and drying, covering the protective layer, and cutting according to the required size.
  • Packaging that is, made with the combination Rack type transdermal patch.
  • the preparation method of the preparation is as follows: mixing the composition with a suitable ointment and/or cream base to form a
  • the paste is encapsulated in an appropriate packaging container such as an ointment tube (tin tube, aluminum tube or plastic tube) or a metal box. Ointment.
  • the spray is prepared by mixing the composition with a suitable propellant and filling it into a particular container to produce a spray containing the composition.
  • the suppository is prepared by uniformly mixing the composition with a suitable suppository base, injection molding, cooling at room temperature, demolding, and packaging to prepare a suppository containing the composition.
  • the external preparation of the present invention can be used to output a drug in contact with the wound and the surface of the skin, and the action is rapid.
  • the drug is evenly distributed in the external preparation, and the release rate is uniform and stable; for each administration, the therapeutic effect can last for 1-7 days.
  • the prescription ratio of the pharmaceutical composition of Example 1 was:
  • the prescription ratio of the pharmaceutical composition of Example 2 was:
  • the prescription ratio of the pharmaceutical composition of Example 3 was:
  • the preparation method of the pharmaceutical composition of the present invention for preparing a gel-type transdermal patch is as follows:
  • the preparation method of the lornoxicam composition of the present invention for preparing a paste is as follows:
  • the preparation method of the pharmaceutical composition of the present invention for preparing a skeleton type transdermal patch is as follows:
  • Example 7 The lornoxicam and povidone-iodine compositions of the present invention are modeled as a full-thickness skin wound wound in rats, with a blank group, a lornoxicam single component group, and a povidone iodine single component. Experimental study on the synergistic effect of the group on pain relief, anti-inflammatory, anti-infection, wound healing process and prognosis of scar status
  • mice were randomly divided into group A (blank control group), group B (positive control: 10% povidone iodine cream), group C (positive control: lornoxicam powder for injection), group D (experimental group) , 10 animals per group. 2 wounds per animal, a total of 80 wounds. The wound was treated after 2 hours.
  • the blank control group (group A) was treated with conventional disinfection: deionization with hydrogen peroxide, washing with sterile saline, and then covering with sterile dressing, once a day, and observing the healing of the wound (the “conventional disinfection method” described below) Refers to this method and does not repeat the description).
  • the positive control group (group B) was treated with conventional disinfection method, and the wound was dried with a sterile dressing. Appropriate amount of 10% povidone iodine cream was applied to the surface of the wound. It was required to cover all wounds, and the thickness was not suitable for seeing the wound. Then, cover the sterile dressing once a day and observe the healing of the wound.
  • the positive control group (group C) was treated with conventional disinfection method, and lornoxicam (1 mg/kg) was given once a day, and the wound healing was observed.
  • the experimental group (Group D) was treated with a conventional disinfection method, and then the lornoxicam and povidone-iodine compositions of the present invention were applied and patched, and the dressing was changed once every 5 days, and the wound healing was observed daily.
  • the wounds of group B were clean, the granulation tissue was red and tender, and it showed uniform and fine granular shape. There were scars and grade 2 scars.
  • the wounds of group D were clean and the granulation tissue was red and tender. It showed uniform and fine granular shape, no scar and no grade 1 scar. See Table 2 for details.
  • Grade 3 moderate, the scar is significantly higher than the surrounding normal skin, local thickening and hardening.
  • the surface is red, flushed or purple;
  • the povidone iodine in the patch can effectively inhibit the growth and reproduction of the bacteria and maintain the clean environment of the wound; the patch can be formed as a whole.
  • a layer of wound protection layer to maintain the wet environment of the wound.
  • lornoxicam can also promote the phagocytic bacteria and necrotic tissue of inflammatory cells, thereby accelerating wound debridement, shortening the inflammatory phase of wound healing, and promoting the release of various growth factors by inflammatory cells. Accelerate granulation tissue growth, epithelial tissue regeneration, and accelerate wound healing.
  • Example 8 The large, medium and small doses of the lornoxicam and povidone iodine compositions of the present invention were modeled as a full-thickness skin wound wound in rats, and the analgesic, anti-inflammatory and anti-infective groups were controlled by a blank group. Screening experimental study on the optimal component ratio of wound healing process and prognosis scar state
  • mice were randomly divided into blank control (Group A), Lornoxicam and Povidone iodine compositions of the present invention in large, medium and small dose groups (Groups B, C, and D), with 10 animals in each group. 2 wounds per animal, a total of 80 wounds. The wound was treated after 2 hours.
  • the blank control group (group A) was treated with conventional disinfection method once a day, and the wound healing was observed.
  • the experimental group (groups B, C, and D) was treated with conventional disinfection method, and then the lornoxicam and povidone-iodine compositions of the present invention were applied to the large, medium and small doses (2.0 mg: 2.5 mg, 1.25).
  • Mg 2.5 mg, 0.75 mg: 2.5 mg
  • W lornoxicam W povidone iodine
  • the dressing was changed once every 5 days, and the wound healing was observed daily.
  • lornoxicam and povidone-iodine compositions of the present invention have large, medium and small doses (large dose: 2.0 mg: 2.5 mg, medium dose: 1.25 mg: 2.5 mg, small dose 0.75 mg). :2.5mg, W lornoxicam : W povidone iodine ) can significantly shorten the wound healing time after covering the wound, no scarring, no scar, no pain, no frequent dressing change, the effect is better than the conventional dressing group Compared with the three doses of large, medium and small doses, the analgesic effect of the large and medium dose groups is quite better than that of the low dose group, so the prescription of the medium dose should be the best proportion prescription of the invention.
  • Example 9 The lornoxicam and povidone-iodine compositions of the present invention are modeled as post-operative pain in rats, with a blank Experimental study on synergistic effects of pain relief, anti-inflammatory, anti-infection, wound healing process and prognosis of scar status
  • Model 10% chloral hydrate 0.1ml/100g rat intraperitoneal injection anesthesia group A, B with 75% medical alcohol disinfection cloth towel, 2cm skin incision along the midline of the middle and lower abdomen, cut the superficial fascia, align the skin The incision cuts the abdominal muscle layer and the peritoneal layer, exposes the abdominal cavity, and then sutures the abdominal cavity with a layer of suture, suturing the superficial fascia and the skin.
  • the blank control group A was treated with conventional disinfection method, once a day, and the wound healing was observed.
  • the experimental group (group B) was treated with a conventional disinfection method, and then the lornoxicam and povidone-iodine compositions of the present invention were applied and patched, and the dressing was changed once every 5 days, and the wound healing was observed daily.
  • Observation index 1 The mechanical mechanical threshold (MWT) of the skin around the abdominal incision of the rat was measured by an electromechanical pain field tester (Model 2390, IITC Life Science, Italy), and the midline of the lower abdomen was observed in each rat. The skin was taken at 3 different sites for a total of 3 measurements, each interval of 5 min. The mean value of each measurement represents MWT. Rat baseline values (T0), postoperative 6h (T1), 24h (T2), 48h (T3), and 72h (T4) MWT scores were determined and recorded.
  • n 12, compared with T0, *P ⁇ 0.05; compared with group A, ⁇ P ⁇ 0.01.
  • n 12, compared with T0, *P ⁇ 0.01; compared with group A, ⁇ P ⁇ 0.01.
  • the epithelial and granulation tissue of the wound surface of group A showed rapid growth, uneven surface, uneven granulation and swelling of individual parts, 4 ⁇ 0.8 days of scarring time and 8 ⁇ 0.6 days of dislocation time. Level 3 scars.
  • group B the wounds were clean and the granulation tissue was red and tender, showing uniform and fine granular shape.
  • the wound healing time was 4.12 ⁇ 0.6 days, no infection, no scarring, and grade 1 scar.
  • Example 10 The lornoxicam and povidone-iodine compositions of the present invention are modeled as a rat scalded wound, and the synergistic effect of analgesia, anti-inflammatory, anti-infection, wound healing process and prognosis of scar state by blank group control.
  • group A a blank control group
  • Lornoxicam of the present invention a blank control group
  • Group B Experimental group of povidone iodine composition patch
  • the blank control group (group A) was treated with conventional disinfection method once a day, and the wound healing was observed.
  • the experimental group (group B) was treated with a conventional disinfection method, and then the lornoxicam and povidone-iodine compositions of the present invention were applied and patched, and the dressing was changed once every 5 days, and the wound healing was observed daily.
  • the mechanical stimulation pain threshold of the skin around the burn wound of the rat hip was measured by an electromechanical pain field tester (Model 2390, IITC Life Science, Italy). Mechanical Threshold, MWT), three different sites were taken from the skin around each wound of the rats, and the total measurement was performed three times. The mean value of each measurement was 5 times at each interval, and the degree of pain in the wounds of each group of experimental animals was calculated.
  • Example 11 The lornoxicam and povidone-iodine compositions of the present invention are based on a mouse burn wound model, and the synergistic effect of the analgesic, anti-inflammatory, anti-infective, wound healing process and prognosis of the scar state by the blank group as a control.
  • Group A (blank control group) was treated with conventional disinfection method, once a day, and the wound healing was observed.
  • Group B (experimental group) was treated with conventional disinfection method, and then the lornoxicam and povidone iodine compositions of the present invention were applied and patched, and the dressing was changed once every 5 days, and the wound healing was observed daily.
  • mice After 3 days and 2 groups of burned mice were modeled and treated accordingly, all the mice were subjected to eyeball extraction for 15 days, and the mice were sacrificed by dislocation. The blood of the mice was centrifuged for 10 minutes in a low speed centrifuge (3000 rpm). Serum was taken to detect the content of interleukin-1 (IL-1).
  • IL-1 interleukin-1
  • the mechanical stimulation pain threshold of the skin around the back incision of the rat was determined by an electromechanical pain field tester (Model 2390, IITC Life Science, Italy). Mechanical withdrawal threshold (MWT), three different sites were taken from the skin around each wound of the rats. The total measurement was performed 3 times, with an interval of 5 minutes. The mean values of each measurement represented MWT, and the pain level of the wounds of each group of experimental animals was calculated.
  • Capillary capillary permeability and serum interleukin-1 (IL-1) content in mice wounds in burned mice treated with the lornoxicam and povidone iodine compositions of the present invention The area was significantly lower than that of the blank control group, and there was a significant difference P ⁇ 0.01. After 15 days, the serum interleukin-1 (IL-1) level was also significantly decreased (P ⁇ 0.05). It is indicated that the lornoxicam and povidone-iodine composition patches of the present invention can significantly reduce the capillary permeability of burned mice, reduce the release of inflammatory mediators, and accelerate their healing.
  • the lornoxicam and povidone-iodine composition patches of the present invention can reduce the capillary permeability of burned mice, thereby reducing the release of inflammatory mediators such as IL-1, IL in the underarm edema fluid.
  • the accumulation of -1 was reduced, and the inflammatory mediators entering the blood circulation were also reduced.
  • the serum levels of interleukins in burned mice were significantly lower than those in the blank control group, and there was a significant difference in IL-1 content. Then the repair of the tissue is more advantageous, which can reduce the leakage of body fluids and inhibit the occurrence of inflammation.
  • Burn wounds are basically flat after healing, no scarring, no scars! Is worth promoting the burning, burn wounds external application!
  • Example 12 The lornoxicam and povidone-iodine compositions of the present invention were modeled as a full-thickness skin wound wound in rats, and the continuous analgesic, anti-inflammatory, anti-infective, wound healing process and prognosis were performed with a blank group as a control.
  • the blank control group (group A) was treated with conventional disinfection.
  • the dressing was changed once every 5 days, and the wound healing was observed daily.
  • the experimental group (group B) was treated with conventional disinfection method, and the lornoxicam and povidone-iodine composition patches of the present invention were applied, and the patch was applied. After 40 hours, the patch was removed, and the conventional sterilization method was used for dressing, and the MWT was measured for 48 hours. value.
  • the patch of lornoxicam and povidone-iodine composition of the present invention was reapplied for 70 hours, and the MWT value was measured at 72 hours, and then the dressing was changed once every 5 days, and the wound healing was observed daily.
  • the experimental group (group C) was treated with a conventional disinfection method, and then the lornoxicam and povidone-iodine compositions of the present invention were applied and patched, and the dressing was changed once every 5 days, and the wound healing was observed daily.
  • the mechanical mechanical stimulation pain threshold (mechanical withdraw) around the back incision of the rat was determined by an electromechanical pain field tester (Model 2390, IITC Life Science, Italy). Threshold, MWT), three different sites were taken from the skin around each wound of the rats. The total measurement was performed 3 times, with an interval of 5 minutes. The mean values of each measurement represent MWT, and the pain level of the wounds of each group of experimental animals was calculated.
  • the patch of lornoxicam and povidone-iodine composition of the present invention was changed once every 5 days, and 80% of the wounds were conventionally treated with infection.
  • the wound using the patch of the present invention has no infection. It is further proved that the combination of lornoxicam and povidone iodine can effectively inhibit the growth and reproduction of bacteria, maintain the clean environment of the wound, reduce the release of inflammatory mediators, and play an anti-inflammatory and analgesic effect.
  • the present study shows that the patch of lornoxicam and povidone-iodine composition of the present invention is used for treating skin-infected wounds, and has obvious curative effects on antibacterial, anti-inflammatory and analgesic effects, and is worthy of further clinical application.

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Abstract

一种药物组合物，由氯诺昔康和聚维酮碘组成，其重量比优选为1：2。该组合物可用于制备外用给药制剂，用于人的各种身体疼痛部位、手术创口或各种皮肤外伤创面（包括烧伤、烫伤）的止痛和消炎。

Description

一种含氯诺昔康和聚维酮碘的药物组合物
技术领域：本发明涉及含氯诺昔康和聚维酮碘作为有效成分的药物组合物及其用途，即该组合物可用于制备外用给药制剂，用于人的各种身体疼痛部位、手术创口或各种皮肤外伤创面(包括烧伤、烫伤)的止痛和消炎。
背景技术：氯诺昔康属于非甾体类抗炎镇痛药，系噻嗪类衍生物，具有较强的镇痛和抗炎作用。其化学名为6－氯－4－羟基－2－甲基－N－2－吡啶基－2H－噻吩－〔2，3－e〕－1，2－噻嗪－3－碳乙二酰乙二胺－1，1－二氧化物，结构式如下：
Figure PCTCN2014087953-appb-000001
氯诺昔康是一种已知的药物，有效范围广，它的作用机制包括：1、通过抑制环氧化酶(COX)活性进而抑制前列腺素合成；但是氯诺昔康并不抑制5－脂质氧化酶的活性，因此不抑制白三烯的合成，也不将花生四烯酸向5－脂质氧化酶途径分流。2、激活阿片神经肽系统，发挥中枢型镇痛作用。
研究人员已针对各种疼痛和炎症性疾病，就氯诺昔康各种治疗剂量及其临床疗效进行了研究。此外，也有研究对氯诺昔康的临床有效剂量和已经确立疗效的非甾体抗炎药进行了对比性试验。得出结论如下：
——药效学作用是NSAID类药品中最强的。
——临床镇痛效果明显优于其它NSAID类药品，和吗啡相当。
——适用于多种原因引起的多种疼痛(骨科疼痛、手术疼痛、肿瘤疼痛)。
——关节滑液中的浓度高于血浆浓度，更适于关节疼痛治疗。
——安全性良好，和传统NSAID类药品比较无特异性不良反用，不良反应发生概率低。且适于长期治疗使用，无成瘾性。
——老年、肝肾损伤患者药物动力学参数和年轻健康者无差异，适用人群广。
经研究，氯诺昔康具备止痛和消炎的双重药理作用，且这两种药理作用都是创口所需要的；氯诺昔康还是小分子(分子量371.82)、小规格(口服每天4-8mg)药物，小分子量使其易于透过皮肤达到作用部位，小规格意味着易于达到制剂工艺需要的载药量、易于透过皮肤达到临床需要的治疗剂量。我们制成的氯诺昔康贴片经大鼠体外透皮实验证明，透
Figure PCTCN2014087953-appb-000002
达到6.4mg/天·10cm2。
表1氯诺昔康贴片在豚鼠皮肤上的透皮试验结果(n＝6)
Figure PCTCN2014087953-appb-000003
【说明：测得透皮量＝实测接收液中样品含量/试验样品面积
每小时透皮量＝测得透皮量/样品试验时间 每日透皮量＝测得透皮量/样品试验时间×24h】
而具有同样药理作用的其它昔康类药物有吡罗昔康、美洛昔康，但这两种药物临床日用量大(吡罗昔康20mg/天，美洛昔康15mg/天)，其外用制剂的单位面积透皮剂量难以达到理想的药效学作用，因此优选氯诺昔康。
聚维酮碘(Povidone Iodine,PVP Iodine)是聚乙烯吡咯烷酮与碘的复合物，又称碘伏，含有效碘9-12％，是一种广谱的强力杀菌消毒剂，对病毒、细菌、真菌及霉菌孢子都有较强的杀灭作用。本品对皮肤刺激性小，毒性低，作用持久，使用安全、简便。对组织基本无刺激性，用于皮肤及粘膜消毒，如手术前清洗、手术部位及伤口消毒。
聚维酮碘在水中能释放出游离碘，以保持较长时间的杀菌力，同时很好地解决了碘的挥发问题。其通过后者的氧化作用对微生物起杀灭作用，对细菌的杀灭效果优于冼必泰，并对细菌孢子有一定的杀伤力。本品对白色念珠菌、金萄菌、大肠杆菌、枯草杆菌等均有显著的杀灭作用；对绿脓杆菌、白色念珠菌的杀菌时间与同浓度的复方碘溶液、碘酊相仿，但毒性仅为其1/4～1/9。聚维酮碘在溶剂中逐渐释放出碘，起到一种缓释作用，强大的杀菌机制是氧化病原体原浆蛋白的活性基团，并能与蛋白质的氨基结合而使其变性，因而有效地杀死细菌、芽孢、真菌、病毒及原虫等病原体。具有杀菌力强，杀菌范围广，能直接杀灭细菌、真菌、病毒、芽孢与原虫。杀菌速度快，大多数细菌30秒内可杀灭，对个别细菌5分钟足以杀灭。对皮肤粘膜无刺激，可用于体腔、粘膜及溃疡面的消毒与治疗。无毒性。不易使微生物产生耐药性，不易发生过敏反应。使用持久，稳定性好，贮存有效期长。易溶于水，易清洗，不污染或损坏织物及其它物品。
而其它外用的杀菌、抑菌药物均存在副作用大、易产生抗药性的问题。如：纳米银经试验证明外用杀菌、抑菌作用很强，但发现其全身吸收后能够产生皮肤变色、内脏蓄积等方面很大的副作用。其它外用的抗菌素均不同程度地产生微生物耐药性，从而使药效逐渐下降，因此优选聚维酮碘。
本发明创造性地将氯诺昔康和聚维酮碘进行组合研究，筛选出两者最佳比例组合，制备成各种外用制剂，局部应用在人体的各种疼痛部位，在发挥氯诺昔康抗炎镇痛的药效也发挥了聚维酮碘的抗菌、消炎、防腐的功效。尤其是对手术后创口或各种皮肤外
Figure PCTCN2014087953-appb-000004
烧伤、烫伤)创面的消炎和止痛作用更为明显。当前临床上没有此种组合物产品，
Figure PCTCN2014087953-appb-000005
开报道。且经过初步动物和人体试验显示，本发明产品对于皮肤创伤治疗的效果好，且具有明显的协同作用。体现在：贴敷后，同时具有显著的止痛、消炎和显著的减轻或消除愈后瘢痕效果，优于单独应用其中任一一种，且使用方便、愈合快、并可持续贴敷数日。
本发明的药用组合物本身、在皮肤创伤治疗效果上、在皮肤创伤治疗方式上均具有显著的创造性。本发明的氯诺昔康和聚维酮碘的药用组合物，不是简单地叠加，而是需要经过比较复杂的、创新性的药物制造工艺的研究、探索后，才能摸索出具有先进性、适用性的工艺，从而制造出合格的工艺产品。
发明内容：
本发明不限于任何氯诺昔康的具体形式，并且药物即可为氯诺昔康也可为药学上可接受的类似衍生物。
本发明不限于聚维酮碘的具体形式，并且药物即可为聚维酮碘，也可为药学上任何可接受的碘类消毒防腐药。
本发明的目的是制备了一种药物组合物，包括氯诺昔康与聚维酮碘。我们发现，该组合物可以用于人体的各种疼痛部位，包括手术后创口或各种皮肤外伤创面(包括烧伤、烫伤)的止痛和消炎，并具有明显的协同作用。
我们惊奇地发现，本发明的氯诺昔康和聚维酮碘的药用组合物，在治疗效果上产生了创造性。具体的创造性体现在：
(1)不结痂、愈合后无瘢痕或瘢痕轻微：用本发明产品后，我们惊奇地发现，创面愈合过程中不结痂、愈合后无瘢痕或瘢痕轻微，具备显著的创造性。而在传统的皮肤创伤治疗中，均经过结痂过程，结痂脱落后会留下明显的疤痕。
(2)在一种产品上同时实现消炎和止痛的治疗效果：用本发明产品后，对于皮肤创面既有消炎效果同时又具有止痛效果，具备显著的创造性。而在传统的皮肤创伤治疗中，没有同时具有消炎和止痛效果的产品。
(3)实现了两种药物同时给药在同一创伤部位：由于治疗目的是皮肤局部创伤，两种药物需要同时给药在该创伤部位，所以，只有将两种产品组合成一个产品才可以实现同时给药在该创伤部位的目的，从而达到消炎和止痛的两种效果，两种独立的药物剂型(如：贴片)无法同时给药在同一创伤部位。
我们还惊奇地发现，本发明的氯诺昔康和聚维酮碘的药用组合物，在皮肤创伤治疗方式上具有创造性。具体的创造性体现在：
(1)在一种产品上同时实现消炎和止痛的治疗方式：用本发明产品后，我们惊奇地发现，同时达到了消炎和止痛的效果，并且消炎效果优于单独使用其中一种药物并且不需要另外使用其它止痛药物。而在传统的皮肤创伤治疗中，一般在创面使用消炎药后包扎，再
Figure PCTCN2014087953-appb-000006
或注射止痛药进行止痛。
(2)不需要每天换药包扎：用本发明产品后，我们惊奇地发现，连续贴敷5天，直止住了疼痛并没有感染，一般可持续贴敷3—5日(有时刮、碰导致贴片提前脱落 要每天换药包扎。而在传统的皮肤创伤治疗中，一般需要每天换药、包扎一次。
(3)很便捷地实现了持续5天止痛：用本发明产品后，贴敷给药一次，药物可以持续释放在创伤部位，在持续贴敷的3—5日内可以达到持续止痛效果；而在传统的皮肤创伤治疗中，要想达到持续止痛目的，需要每隔4—8小时口服或注射给药一次，这种复杂和繁琐的给药方式很难实现，并给患者带来很大痛苦，尤其夜间更难实现按时给药，因此难以实现持续止痛目的。
本发明的该组合物的用途为：可用于制备外用给药制剂，作用于身体疼痛部位，用于治疗各种原因，包括手术创口或各种皮肤外伤引发的疼痛、发炎的症状。
本发明的药物组合物，其特征在于，所述的氯诺昔康与聚维酮碘的重量比为1：0.4～25，更优选为1：1.0～5.0，进一步优选为1：2。
我们惊奇地发现：氯诺昔康与聚维酮碘形成的药物组合物中，两者均可以以很高的皮肤渗透速率进入皮肤创伤面的软组织体液中，快速达到稳定的治疗浓度，起到消炎和止痛的作用；我们还发现，该组合物适用性非常广泛，可以制成各种临床上需要的外用剂型，以满足各种临床需要(包括手术创口和各种皮肤外伤)，如：制成以控释膜控制药物稳定释放的储库型透皮贴剂、以骨架型压敏胶为控释介质的骨架型透皮贴剂、以水凝胶为控释介质的凝胶型透皮贴剂、膏剂、喷雾剂、栓剂等外用剂型。
本发明的药物组合物，在制备外用制剂过程中，可以加入成型材料或各种制剂所需基质，如卡波姆、聚异丁烯压敏胶等等。
本发明的药物组合物，在制备外用制剂过程中，可以加入增加助溶物质以增加氯诺昔康、聚维酮碘溶解度，比如吐温-80、精氨酸、乙醇、甘油等。
本发明的药物组合物，在制备外用制剂过程中，可以加入透皮吸收促透剂，首选为氮酮、油酸或它们的混合物。还可以加入肉豆蔻异丙酯、柠檬酸三乙酯、月桂酸乙酯、吐温-80、冰片或它们的混合物。
将本发明的药物组合物应用于外用制剂的制备，具体制备方法如下：
凝胶型透皮贴剂制备方法为：将该组合物与适宜的凝胶基质混合均匀，经固化制成具凝胶特性的半固体或稠厚液体。涂于背衬材料上，再覆盖上保护层。按需要尺寸切割，包装，即制成含该组合物的凝胶型透皮贴剂。
储库型透皮贴剂制备方法为：将该组合物与适宜的高分子材料或聚合物混合，形成药物贮厍；另将胶黏剂涂布于保护层上，加热干燥，覆以控释膜，制成复合膜材；调整复合膜材的控释膜面向上，将上述药物贮库置于控释膜上，覆以背衬层，将药物贮库封闭于控释膜层与保护层之间，按需要尺寸切割，包装，即制成含该组合物的储库型透皮贴剂。
骨架型透皮贴剂制备方法为：将该组合物与适宜的高分子黏性材料或压敏胶混合，涂于背衬材料上，加热烘干，再覆盖上保护层，按需要尺寸切割，包装，即制成含该组合
Figure PCTCN2014087953-appb-000007
架型透皮贴剂。
膏剂制备方法为：将该组合物与适宜的软膏和/或乳膏剂基质混合均匀，制成含
Figure PCTCN2014087953-appb-000008
膏料，封装于软膏管(锡管、铝管或塑料管)、金属盒等适宜包装容器中，即制成含
Figure PCTCN2014087953-appb-000009
的膏剂。
喷雾剂的制备方法为：将该组合物与适宜的抛射剂混合均匀，装入特定容器中，即制成含该组合物的喷雾剂。
栓剂的制备方法为：将该组合物与适宜的栓剂基质混合均匀，注模成型，室温下冷却，脱模，包装，即制成含该组合物的栓剂。
本发明所述的外用制剂与创口及皮肤表面接触的部分都可以输出药物，起效迅速。外用制剂中药物分布均匀，释药速率均一、稳定；每给药1次，疗效持续可长达1-7天。
具体实施方式：下面用实施例进一步说明本发明，应该理解的是，这些实施例仅仅是用于说明本发明，而不是用于限制本发明。
实施例1药物组合物的处方比例为：
氯诺昔康：2.5g
聚维酮碘：5.0g
实施例2药物组合物的处方比例为：
氯诺昔康：4.0g
聚维酮碘：18.0g
实施例3药物组合物的处方比例为：
氯诺昔康：8.0g
聚维酮碘：6.0g
实施例4制备凝胶型透皮贴剂：
将本发明的药物组合物，用于制备凝胶型透皮贴剂的制备方法为：
Figure PCTCN2014087953-appb-000010
Figure PCTCN2014087953-appb-000011
按下述制备工艺进行制备：
①将氯诺昔康、聚维酮碘分别于预先准备好的精氨酸水溶液中，加入油酸，混合均匀；②PVPK30、NP700、氢氧化铝与处方量甘油充分混匀，加入上述溶液，使其溶涨，混合均匀；③涂布于背衬材料上，50℃干燥4小时，再覆盖上保护层。④按需要尺寸切割，包装，即制成含药物组合物的凝胶型透皮贴剂。
②
实施例5制备膏剂：
将本发明的氯诺昔康组合物，用于制备膏剂的制备方法为：
Figure PCTCN2014087953-appb-000012
按下述制备工艺进行制备：
①将氯诺昔康、聚维酮碘、月桂醇硫酸钠、丙二醇、尼泊金甲酯预先准备好的吐温-80乙醇水溶液中，并加热至75℃，保温，备用；②取硬酯醇与白凡士林在水浴上熔化，加热至75℃，加入至①所述混合溶液中，搅拌至冷凝。③通过胶林磨或匀化器以增进产品的均匀性。④包装，即制成含药物组合物的膏剂。
实施例6制备骨架型透皮贴剂：
将本发明的药物组合物，用于制备骨架型透皮贴剂的制备方法为：
Figure PCTCN2014087953-appb-000013
按下述制备工艺进行制备：
①将氯诺昔康、聚维酮碘溶解于乙醇、丙酮混合液中，加入丙烯酸酯压敏胶压敏胶混合均匀。②将混匀的胶浆涂于背衬材料上，加热烘干，再覆盖上保护层。③按需要尺寸切割，包装，即制成含药物组合物的骨架型透皮贴剂。
实施例7：本发明的氯诺昔康与聚维酮碘组合物以大鼠全层皮肤切除伤创面为模型，以空白组、氯诺昔康单组份组、聚维酮碘单组份组为对照进行的止痛、消炎、抗感染、创面愈合过程和预后瘢痕状态的协同作用实验研究
健康SD大鼠40只，体重200～250g，雌雄各半。动物分笼饲养，统一饲料，自由饮食。动物背部剪毛后，涂硫化钠脱毛，温水清洗后拭干。次日用2％的戊巴比妥钠(4～5mg/100g体重)腹腔注射麻醉后，常规消毒铺巾，用利刃在脊柱两侧旁1cm处，切取直径1.8cm的圆形创面，深及深筋膜及部分肌层，止血后备用。测定面积，经计算平均面积2.5cm2。随机将动物分成A组(空白对照组)、B组(阳性对照：10％聚维酮碘乳膏)、C组(阳性对照：注射用氯诺昔康粉针)、D组(实验组)，每组10只动物。每只动物2个创面，共80个创面。2h后处理创面。
空白对照组(A组)采用常规消毒治疗：双氧水清创，无菌生理盐水清洗，后覆盖无菌敷料后包扎，每日1次，并观察创面愈合情况(以下所述“常规消毒法”即指此方法，不再重复描述)。
阳性对照组(B组)采用常规消毒法处理创面，用灭菌敷料将创面擦干，取适量10％聚维酮碘乳膏涂于创面表面，要求覆盖所有创面，厚度以看不见创面为宜，然后给予无菌敷料覆盖，每天1次，并观察创面愈合情况。
阳性对照组(C组)采用常规消毒法处理创面，注射给予氯诺昔康(1mg/kg)每天1次，并观察创面愈合情况。
实验组(D组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，每5日换药1次，每日观察创面愈合情况。
检测指标：
1)每日换药时，分别记录残余创面面积大小及各组实验动物创面的愈合时间,
Figure PCTCN2014087953-appb-000014
均愈合时间。同时观察各组实验动物创面愈合过程及创面愈合情况。
2)在未创伤前、创伤后2h及1、2、3、5天，采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠背部切口周围皮肤机械刺激痛阈(mechanical withdraw threshold，MWT)，每只大鼠创面周围皮肤取3个不同位点，共测量3次，每次间隔5min，取各次测量均值代表MWT，计算各组实验动物创面的疼痛程度。
结果：1、平均愈合时间与愈合情况比较：A组、C组创面较为清洁，肉芽组织生长较快,表面凸凹不平。个别部位肉芽水肿明显，4～5天结痂，8～12天脱痂，脱痂后有瘢痕。B组创面清洁，肉芽组织红嫩，呈现均匀微细的颗粒状，有结痂、2级瘢痕，D组创面清洁，肉芽组织红嫩，呈现均匀微细的颗粒状，无结痂、1级瘢痕。详细情况见表2。
表2两组大鼠创面的平均愈合时间与愈合情况对比表
Figure PCTCN2014087953-appb-000015
*与空白对照组对比，P<0.05。
瘢痕分级：(以下各实施例所述*级瘢痕即指此分级方法，不再重复描述)。
1级---极轻微，与周围正常皮肤平整连接，只有颜色稍有差别；
2级---轻微，表面粗糙，局部平坦、柔软，有时与周边正常皮肤界限不清，有时有色素改变；
3级---中度，瘢痕明显高于周围正常皮肤，局部增厚变硬。表面呈红色、潮红或紫色；
4级---重度，瘢痕坚硬、平坦或略高于皮肤表面，扪之较硬，弹性差，与周围正常皮肤有较明显的界限，局部氧或痛。
2、四组大鼠不同时间点创面疼痛程度比较：大鼠经皮肤切除后，与T0比较，2小时点，A、B、C、四组MWT变化显著下降(P<0.01)，表明创伤后疼痛明显；与2小时点比，C组、D组24h、48h、72h、120h点MWT显著增加(P<0.05)，表明达到了完全的止痛效果；与A组比，C组、D组24h、48h、72h点显著增加(P<0.01)，表明达到了完全的止痛效果。
表3四组大鼠不同时间点创面疼痛程度对比表
Figure PCTCN2014087953-appb-000016
Figure PCTCN2014087953-appb-000017
*与空白对照组对比，P<0.01。△与2h点对比，P<0.05。
结论：本发明的氯诺昔康与聚维酮碘组合物的贴片覆盖创面后，贴片中聚维酮碘既可以有效抑制细菌生长繁殖，保持创面的清洁环境；贴片整体又可以形成一层创面保护层，保持创面的湿性环境。而氯诺昔康除可起到抗炎止痛的作用外，亦可促进炎症细胞吞噬细菌及坏死组织，从而使创面清创加速，缩短创面愈合的炎症期，促进炎症细胞释放各类生长因子，加速肉芽组织生长、上皮组织再生，而加速创面愈合。本研究表明，使用本发明的氯诺昔康与聚维酮碘组合物的贴片治疗皮肤感染性创面，可明显缩短创面愈合时间，无结痂，无瘢痕(极轻微)、不疼痛，不用频繁换药，效果优于常规换药组及两个阳性对照组(10％聚维酮碘乳膏、注射用氯诺昔康粉针)，充分显示出了本复方的协同作用。
实施例8：本发明的氯诺昔康与聚维酮碘组合物大、中、小剂量组以大鼠全层皮肤切除伤创面为模型，以空白组为对照进行的止痛、消炎、抗感染、创面愈合过程和预后瘢痕状态的最佳组分比例筛选实验研究
健康SD大鼠40只，体重200～250g，雌雄各半。动物分笼饲养，统一饲料，自由饮食。动物背部剪毛后，涂硫化钠脱毛，温水清洗后拭干。次日用2％的戊巴比妥钠(4～5mg/100g体重)腹腔注射麻醉后，常规消毒铺巾，用利刃在脊柱两侧旁1cm处，切取直径1.8cm的圆形创面，深及深筋膜及部分肌层，止血后备用。测定面积，经计算平均面积2.5cm2。随机将动物分成空白对照(A组)、本发明的氯诺昔康和聚维酮碘组合物贴片大、中、小剂量组(B、C、D组)，每组10只动物。每只动物2个创面，共80个创面。2h后处理创面。
空白对照组(A组)采用常规消毒法处理创面，每日1次，并观察创面愈合情况。
实验组(B、C、D组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片大、中、小剂量(2.0mg:2.5mg、1.25mg:2.5mg、0.75mg:2.5mg，W氯诺昔康：W聚维酮 碘)，包扎。每5日换药1次，每日观察创面愈合情况。
检测指标：
1)每日换药时，分别记录残余创面面积大小及各组实验动物创面的愈合时间,计算出平均愈合时间。同时观察各组实验动物创面愈合过程及创面愈合情况。
2)在未创伤前、创伤后2h及1、2、3、5天，采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠背部切口周围皮肤机械刺激痛阈(mechanical withdraw threshold，MWT)，每只大鼠创面周围皮肤取3个不同位点，共测量3次，每次间隔5min，取各次测量均值代表MWT，计算各组实验动物创面的疼痛程度。
结果：1、平均愈合时间与愈合情况比较：A组创面较为清洁，肉芽组织生长较快,表面凸凹不平。个别部位肉芽水肿明显，4～5g天结痂，8～12天脱痂，脱痂后有瘢痕。B、创面清洁，肉芽组织红嫩，呈现均匀微细的颗粒状，无结痂、无瘢痕。愈合情况详见
表4两组大鼠创面的平均愈合时间与愈合情况对比表
Figure PCTCN2014087953-appb-000018
*与空白对照组对比，P<0.05。
2、四组大鼠不同时间点创面疼痛程度比较：大鼠经皮肤切除后，与T0比较，2小时点，A、B、C、D四组MWT显著下降(P<0.01)，表明疼痛明显；与2小时点比，B、C、D组24h、48h、72h、120h点MWT显著增加(P<0.01)，表明达到了明显/显著的止痛效果；与A组比，B、C、D组24h、48h点显著增加(P<0.01)，表明达到了明显的止痛效果。
表5四组大鼠不同时间点创面疼痛程度对比
Figure PCTCN2014087953-appb-000019
*与空白对照组对比，P<0.01。△与2h点对比，P<0.01。
结论：研究表明，本发明的氯诺昔康和聚维酮碘组合物贴片大、中、小剂量(大剂量：2.0mg:2.5mg、中剂量:1.25mg:2.5mg、小剂量0.75mg:2.5mg，W氯诺昔康：W聚维酮碘)覆盖创面后，均可明显缩短创面愈合时间，无结痂，无瘢痕、不疼痛，不用频繁换药，效果优于常规换药组，大、中、小三个剂量相比，大、中两个剂量组止痛效果相当并优于小剂量组，因此中剂量的处方应为本发明的最佳比例处方。
实施例9：本发明的氯诺昔康与聚维酮碘组合物以大鼠术后疼痛为模型，以空白
Figure PCTCN2014087953-appb-000020
进行的止痛、消炎、抗感染、创面愈合过程和预后瘢痕状态的协同作用实验研究
清洁级雄性SD大鼠24只，体重(215±10)g，随机分为2组(n＝12)，空白对照组(A组)、本发明的氯诺昔康与聚维酮碘的贴片实验组(B组)。大鼠饲养于20～24℃的专用饲养房，避免外界刺激，保持昼夜节律，自由摄食摄水。
模型制作10％水合氯醛0.3ml/100g大鼠腹腔注射麻醉，A、B组用75％医用酒精消毒铺巾后沿中下腹部正中线行2cm的皮肤切口，剪开浅筋膜，对齐皮肤切口切开腹肌层和腹膜层，暴露腹腔，随后用丝线逐层缝合关闭腹腔，缝合浅筋膜和皮肤。空白对照组A组采用常规消毒法处理创面，每日1次，并观察创面愈合情况。实验组(B组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，每5日换药1次，每日观察创面愈合情况。
观察指标1、采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠腹部切口周围皮肤机械刺激痛阈(mechanical withdraw threshold，MWT)，每只大鼠中下腹部正中线周围皮肤取3个不同位点，共测量3次，每次间隔5min，取各次测量均值代表MWT。测定并记录大鼠基础值(T0)、手术后6h(T1)、24h(T2)、48h(T3)及72h(T4)MWT计分。
2、记录大鼠相关行为的数目，评价疼痛反应，每观察点计30min：舔或轻咬腹部或外阴区域(A)，腹部收缩(B)，伸展躯体(C)和全身收缩(D)；疼痛计分S＝1A+2B+3C+4D。测定并记录大鼠基础值(T0)、手术后6h(T1)、24h(T2)、48h(T3)及72h(T4)疼痛反应计分。
3、观察创面愈合情况、愈合时间及是否有感染情况发生。
结果
1、腹部切口周围皮肤MWT变化大鼠行腹部切口后，与T0比较，T1及T2、T3、T4时点B组大鼠腹部切口周围皮肤MWT显著下降(P＜0.05)，表明疼痛明显；与A组比较，T1、T2、T3及T4时点B组腹部切口周围皮肤MWT显著增加(P＜0.01)，达到了显著的止痛效果，见表1。
表6大鼠腹部机械痛阈变化(单位：g)
Figure PCTCN2014087953-appb-000021
n＝12，与T0比较，*P<0.05；与A组比较，△P<0.01。
2、痛反应及疼痛积分变化各组大鼠在手术前表现出较少舔咬下腹部、外阴区域或臀部外侧区的行为。腹部切口后的痛反应行为增加，B组与A组比较，B组疼痛积分在T1、T2和T3时显著降低(P＜0.01)，说明止痛效果明显。见表7。
表7大鼠疼痛积分变化
Figure PCTCN2014087953-appb-000022
n＝12，与T0比较，*P<0.01；与A组比较，△P<0.01。
3、愈合过程中，A组可见创面边缘上皮及肉芽组织生长较快,表面凸凹不平,个别部位肉芽红肿发炎明显，结痂时间4±0.8天，脱痂时间8±0.6天，脱痂后有3级瘢痕。而B组创面清洁,肉芽组织红嫩,呈现均匀微细的颗粒状，创面愈合时间为4.12±0.6天，无感染情况，未结痂、1级瘢痕。
结论：本实验研究表明，在大鼠术后疼痛模型中，给予本发明的氯诺昔康与聚维酮碘组合物的贴片后，与空白对照组相比，大鼠的机械刺激痛域阈值明显提高，痛反应及疼痛积分显著降低，表明本发明的氯诺昔康与聚维酮碘组合物的贴片对术后疼痛有很好的镇痛作用，作用时间持久、有效。此外，贴片中聚维酮碘可以有效抑制细菌生长繁殖，保持术后创面的清洁环境，避免术后炎症反应的出现，使得愈合的伤口未结痂、瘢痕轻微。其效果明显优于常规处理组。
实施例10：本发明的氯诺昔康与聚维酮碘组合物以大鼠烫伤创面为模型，以空白组为对照进行的止痛、消炎、抗感染、创面愈合过程和预后瘢痕状态的协同作用实验研究
取Wistar大鼠20只，雌雄各半，体重220－270g，按体重将大鼠随机分为2组，每组10只，分别为空白对照组(A组)，本发明的氯诺昔康与聚维酮碘组合物贴片的实验组(B组)。先在臀部剪毛，然后用8％硫化钠脱毛。次日，用水合氯醛将大鼠麻醉，75％乙醇消毒脱毛皮肤。在直径2.5cm的玻璃瓶内加入80℃的热水10ml，将瓶口固定在皮肤上，停留15s。烫伤后第二天，开始给药。空白对照组(A组)采用常规消毒法处理创面，每日1次，并观察创面愈合情况。实验组(B组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，每5日换药1次，每日观察创面愈合情况。
观察指标：1、从烫伤之日起，每5天用透明硫酸纸描绘烫伤面积大小，在电子天平上称重。用t检验比较组间显著性。涂药第20天，分别记录每组痊愈的大鼠数量，做X2检验，比较组间显著性。
2、在烫伤前、给药后2h及1、2、3、5天，采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠臀部烫伤创面周围皮肤机械刺激痛阈(mechanical
Figure PCTCN2014087953-appb-000023
threshold，MWT)，每只大鼠创面周围皮肤取3个不同位点，共测量3次，每次间隔5各次测量均值代表MWT，计算各组实验动物创面的疼痛程度。
结果：从表8中可见，与用药前比较，实验组的烫伤面积的图纸重量与空白对
Figure PCTCN2014087953-appb-000024
有明显差异，其中实验组给药后10天、15天的图纸重量与空白对照组相比差异显著(P<0.01)，说明实验组比空白对照组愈合的快；从表9中可见，连续给药20天时，本发明的实验组有9只大鼠痊愈，空白对照组只有2只痊愈，差异显著(P<0.05)，说明实验组比空白对照组愈合的更快；从表10中可见，与T0比较，2小时点A、B二组MWT变化显著下降(P<0.01)，说明烫伤后疼痛剧烈；与2小时点比，B组24h、48h、72h、120h点MWT显著增加(P<0.01)，说明达到了完全的止痛效果；与A组比，B组24h、48h、72h点显著增加(P<0.01)，表明本发明的氯诺昔康与聚维酮碘组合物可明显降低大鼠烫伤皮肤的疼痛程度。
表8本发明的氯诺昔康与聚维酮碘组合物对烫伤的治疗作用
Figure PCTCN2014087953-appb-000025
Figure PCTCN2014087953-appb-000026
与空白对照组比较*P<0.05，**P<0.01。
表9本发明的氯诺昔康与聚维酮碘组合物贴片对烫伤的治疗作用
Figure PCTCN2014087953-appb-000027
注：与空白对照组相比，*P<0.05
表10两组大鼠不同时间点创面疼痛程度对比表
Figure PCTCN2014087953-appb-000028
与空白对照组对比，*P<0.01，与2h对比△P<0.01。
结论：在本次研究的大鼠烫伤模型中，与空白对照组相比，给予本发明的氯诺昔维酮碘组合物的贴片后的大鼠，创面愈合率更高，愈合速度快，愈合过程中大鼠的机 痛域阈值明显提高，愈合后创伤面未结痂、瘢痕轻微。实验表明，使用本发明的氯诺昔康与聚维酮碘组合物的贴片治疗烫伤创面，可明显促进创面修复愈合，效果明显优于常规处理组。
实施例11：本发明的氯诺昔康与聚维酮碘组合物以小鼠烧伤创面为模型，以空白组为对照进行的止痛、消炎、抗感染、创面愈合过程和预后瘢痕状态的协同作用实验研究
取清洁级昆明小鼠40只，雌雄各半，随机分为2组:空白对照组(A组)、治疗组(B组)造模前以10％硫化钠溶液脱去小鼠背部毛，称重，并按公式S＝K*0.5W计算出小鼠体表面积(T:体表面积；K值9；W:小鼠体重)，于背部画出15％体表面积的圆，将小鼠乙醚麻醉固定，背部均匀涂以无水酒精0.5ml，立即点燃15s扑灭，即制成15％深Ⅱ度烧伤小鼠模型。
2h后处理创面：A组(空白对照组)采用常规消毒法处理创面，每日1次，并观察创面愈合情况。B组(实验组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，每5日换药1次，每日观察创面愈合情况。
实验观察及检测指标
1、烧伤小鼠创面毛细血管通透性的测定2组烧伤小鼠在造模且进行相应处理后7d，进行创面毛细血管通透性的测定，采用伊文斯兰尾静脉注射法。
2、烧伤小鼠创面愈合时间的测定2组烧伤小鼠在造模且进行相应处理后，每日观察创面愈合情况，进行愈合时间的测定；
3、2组烧伤小鼠在造模且进行相应处理后，15d所有小鼠均进行摘眼球取血，并脱臼处死小鼠,小鼠血液用低速离心机(3000转/分)离心10分钟，取血清以检测其白介素-1(IL-1)的含量。
4、分别在未烧伤前、烧伤后2h及1、2、3、5天，采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠背部切口周围皮肤机械刺激痛阈(mechanical withdraw threshold，MWT)，每只大鼠创面周围皮肤取3个不同位点，共测量3次，每次间隔5min，取各次测量均值代表MWT，计算各组实验动物创面的疼痛程度。
结果：
1、小鼠创面毛细血管通透性与血清中白介素-1(IL-1)含量测定：采用本发明的氯诺昔康和聚维酮碘组合物贴片治疗后的烧伤小鼠创面蓝染面积明显低于空白对照组，并有显著差异P<0.01，15d后小鼠血清中白介素-1(IL-1)含量亦显著降低(P<0.05)。说明本发明的氯诺昔康和聚维酮碘组合物贴片能显著降低烧伤小鼠毛细血管通透性，减少其炎症介质的释放，从而加速其愈合。
表112组小鼠创面毛细血管通透性与血清中IL-1含量测定结果表
Figure PCTCN2014087953-appb-000029
与空白对照组对比，*P<0.05，**P<0.01。
2、烧伤小鼠创面愈合情况：本发明的氯诺昔康和聚维酮碘组合物贴片治疗的烧伤小鼠无论是创面基本愈合时间还是创面愈合时间均显著低于空白对照组，P<0.01。而空白对照组小鼠痂周出现明显红肿，痂下有脓液或溃疡。结果见表12
表12烧伤小鼠创面愈合情况对比
Figure PCTCN2014087953-appb-000030
注：与空白对照组对比，*P<0.05。
愈合:烧伤处结痂完整脱落，修复后组织表面新鲜且较平坦；
基本愈合:烧伤处间断脱痂，新生组织表面不够平坦且有小范围的少许渗出物，但无明显感染灶；
感染:痂周出现明显红肿，痂下有脓液或溃疡。
3、2组大鼠不同时间点创面疼痛程度比较：大鼠皮肤烧伤后，与T0比较，2小时点，A、B两组MWT变化显著下降(P<0.01)；与2小时点比，B组24h、48h、72h、120h点MWT显著增加(P<0.01)；与A组比，B组24h、48h、72h点显著增加(P<0.05)。
表13四组大鼠不同时间点创面疼痛程度对比表
Figure PCTCN2014087953-appb-000031
*与空白对照组对比，P<0.05。△与2h点对比，P<0.01。
经过本实验证实，本发明的氯诺昔康和聚维酮碘组合物贴片可降低烧伤小鼠的毛细血管通透性，从而减少炎症介质如IL-1的释放，痂下水肿液中IL-1的堆积则减少，进入血循环的炎症介质也减少，则在实验干预后的15d确实发现烧伤小鼠血清中白介素的含量明显低于空白对照组，有显著性差异，IL-1含量降低，那么对组织的修复是比较有利的，可减少体液渗出和抑制炎症的发生。故实验组烧伤小鼠的创面愈合率和创面愈合时间显著低于空白对照组本发明的氯诺昔康和聚维酮碘组合物贴片治疗烧伤的疗效是肯定的。烧伤创面愈合后基本平整，不结痂，无瘢痕疙瘩！是值得推广的烧、烫伤创面外敷药！
实施例12：本发明的氯诺昔康与聚维酮碘组合物以大鼠全层皮肤切除伤创面为模型，以空白组为对照进行的持续止痛、消炎、抗感染、创面愈合过程和预后瘢痕的实验研究
健康SD大鼠30只，体重200～250g，雌雄各半。动物分笼饲养，统一饲料，自由饮食。动物背部剪毛后，涂硫化钠脱毛，温水清洗后拭干。次日用2％的戊巴比妥钠(4～5mg/100g体重)腹腔注射麻醉后，常规消毒铺巾，用利刃在脊柱两侧旁1cm处，切取直径1.8cm的圆形创面，深及深筋膜及部分肌层，止血后备用。2h后测定面积，经计算平均面积2.5cm2。随机将动物分成空白对照组(A组)、实验组(B组、C组)，每组10只动物。每只动物2个创面，共60个创面。
空白对照组(A组)采用常规消毒法治疗。每5日换药1次，每日观察创面愈合情况。
实验组(B组)采用常规消毒法处理创面，贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，40h后揭去贴片，采用常规消毒法包扎，48h测定MWT值。70h重新贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，72h测定MWT值，然后每5日换药1次，每日观察创面愈合情况。
实验组(C组)采用常规消毒法处理创面，然后贴敷本发明的氯诺昔康和聚维酮碘组合物贴片，包扎，每5日换药1次，每日观察创面愈合情况。
检测指标：
3)每日换药时，分别记录残余创面面积大小及各组实验动物创面的愈合时间,计算出平均愈合时间。同时观察各组实验动物创面愈合过程及创面愈合情况。
4)在未创伤前、创伤后2h及24h、50h、74h、120h，采用电子机械痛域测定仪(2390型，意大利IITC Life Science公司)测定大鼠背部切口周围皮肤机械刺激痛阈(mechanical withdraw threshold，MWT)，每只大鼠创面周围皮肤取3个不同位点，共测量3次，每次间隔5min，取各次测量均值代表MWT，计算各组实验动物创面的疼痛程度。
结果：1、平均愈合时间与愈合情况比较：A组有16个创面发生感染，肉芽水肿明显，肉芽组织生长较快,表面凸凹不平。7～8天结痂，15～17天脱痂，脱痂后有瘢痕。B组和C组创面清洁，肉芽组织红嫩，呈现均匀微细的颗粒状，无结痂、无瘢痕。详细情况见表14。
表14两组大鼠创面的平均愈合时间与愈合情况对比表
Figure PCTCN2014087953-appb-000032
与空白对照组对比，*P<0.05，**P<0.01
2、四组大鼠不同时间点创面疼痛程度比较：大鼠经皮肤切除后，与T0比较，2小 B、C组MWT变化显著下降(P<0.01)；与2小时点比，B组的24h、74h、120h点显著增加(P<0.01)，C组24h、50h、74h、120h点显著增加(P<0.01)；与A组比，B组24h、74h点MWT显著增加(P<0.01)，C组24h、50h、74h点MWT显著增加(P<0.01)。
表15四组大鼠不同时间点创面疼痛程度对比表
Figure PCTCN2014087953-appb-000033
*与空白对照组对比，P<0.01。△与2h点对比，P<0.01。
结论：在B组试验中，本发明的氯诺昔康与聚维酮碘组合物的贴片覆盖创面后，中途第40h揭下贴片8小时后，触碰伤口又再次疼痛，70h重新贴敷贴片2小时后，疼痛明显减轻，贴片持续贴敷可实现持续止痛，证明创面应用本发明的贴片后持续不再疼痛是药物的作用，而不是自身的痊愈。
而在A组与C组的对比试验中，本发明的氯诺昔康与聚维酮碘组合物的贴片与常规治疗对比，都5天换一次药，常规治疗80％的创面发生了感染，而使用本发明贴片的创面无感染例。进一步证明氯诺昔康与聚维酮碘组合物，既可以有效抑制细菌生长繁殖，保持创面的清洁环境；又可以减少炎症介质的释放，起到抗炎止痛的作用。本研究表明，使用本发明的氯诺昔康与聚维酮碘组合物的贴片治疗皮肤感染性创面，抗菌、消炎、止痛疗效明显，值得临床进一步推广应用。

Claims (10)

  1. 一种药物组合物，其特征在于所述的组合物包括氯诺昔康和聚维酮碘。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述的氯诺昔康与聚维酮碘的重量比为1：0.4～25，更优选为1：1.0～5.0，进一步优选为1：2。
  3. 根据权利要求1所述的药物组合物，其特征在于：该组合物用于人的各种身体疼痛部位、手术创口或各种皮肤外伤创面(包括烧伤、烫伤)的止痛和消炎。
  4. 根据权利要求1所述的药物组合物，其特征在于：可以用于制备外用药物制剂，作用于身体疼痛部位用于止痛和消炎。外用药物制剂包括凝胶型透皮贴剂、储库型透皮贴剂、骨架型透皮贴剂、膏剂、喷雾剂、栓剂。
  5. 根据权利要求1至4之一的药物组合物，其特征在于，在制备外用制剂过程中，加入吐温-80、精氨酸、乙醇或甘油以增加氯诺昔康、聚维酮碘溶解度。
  6. 根据权利要求1至4之一的药物组合物，其特征在于，在制备外用制剂过程中，加入透皮吸收促透剂，优选氮酮、油酸或它们的混合物，或者加入肉豆蔻异丙酯、柠檬酸三乙酯、月桂酸乙酯、吐温-80、冰片或它们的混合物。
  7. 根据权利要求1至4之一的药物组合物，其特征在于：该药物组合物用于制备凝胶型透皮贴剂，优选所述凝胶型透皮贴剂的制备方法为：将该组合物与适宜的凝胶基质混合均匀，经固化制成具凝胶特性的半固体或稠厚液体；涂于背衬材料上，再覆盖上保护层；按需要尺寸切割，包装，即制成含该组合物的凝胶型透皮贴剂。
  8. 根据权利要求1至4之一的药物组合物，其特征在于：该药物组合物用于制备储库型透皮贴剂，优选所述储库型透皮贴剂制备方法为：将该组合物与适宜的高分子材料或聚合物混合，形成药物贮厍；另将胶黏剂涂布于保护层上，加热干燥，覆以控释膜，制成复合膜材；调整复合膜材的控释膜面向上，将上述药物贮库置于控释膜上，覆以背衬层，将药物贮库封闭于控释膜层与保护层之间，按需要尺寸切割，包装，即制成含该组合物的储库型透皮贴剂。
  9. 根据权利要求1至4之一的药物组合物，其特征在于：该药物组合物用于制备骨架型透皮贴剂，优选所述骨架型透皮贴剂制备方法为：将该组合物与适宜的高分子黏性材料或压敏胶混合，涂于背衬材料上，加热烘干，再覆盖上保护层，按需要尺寸切割，包装，即制成含该组合物的骨架型透皮贴剂。
  10. 根据权利要求1至9之一所述的药物组合物用于制备对人的各种身体疼痛部位、手术创口或各种皮肤外伤创面(包括烧伤、烫伤)进行止痛和消炎的药物的用途。
PCT/CN2014/087953 2013-10-06 2014-09-30 一种含氯诺昔康和聚维酮碘的药物组合物 WO2015048930A1 (zh)

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