WO2006014518A2 - Activation de la cicatrisation - Google Patents

Activation de la cicatrisation Download PDF

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Publication number
WO2006014518A2
WO2006014518A2 PCT/US2005/024045 US2005024045W WO2006014518A2 WO 2006014518 A2 WO2006014518 A2 WO 2006014518A2 US 2005024045 W US2005024045 W US 2005024045W WO 2006014518 A2 WO2006014518 A2 WO 2006014518A2
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WO
WIPO (PCT)
Prior art keywords
growth factors
elastase inhibitors
wound
pharmaceutical product
wound healing
Prior art date
Application number
PCT/US2005/024045
Other languages
English (en)
Other versions
WO2006014518A3 (fr
Inventor
Alicia Essler
Lorraine Nisbet
Original Assignee
University Of Massachusetts
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0418664A external-priority patent/GB2415903A/en
Application filed by University Of Massachusetts filed Critical University Of Massachusetts
Publication of WO2006014518A2 publication Critical patent/WO2006014518A2/fr
Publication of WO2006014518A3 publication Critical patent/WO2006014518A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/32—Proteins, polypeptides; Degradation products or derivatives thereof, e.g. albumin, collagen, fibrin, gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A61L2300/414—Growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures

Definitions

  • the invention relates to the combination of one or more elastase inhibitors (e.g. alpha- 1 -antitrypsin) and one or more growth factors for simultaneous, sequential or separate administration to promote wound healing.
  • one or more elastase inhibitors e.g. alpha- 1 -antitrypsin
  • growth factors for simultaneous, sequential or separate administration to promote wound healing.
  • Wound healing is a complex dynamic process that results in the restoration of anatomic continuity and function; an ideally healed wound is one that has returned to normal anatomic structure, function and appearance.
  • the purpose of this invention is to facilitate the wound healing process, as delayed or compromised wound healing remains a significant unmet need.
  • the present invention relates to the use of elastase inhibitors (e.g. alpha-1- antitrypsin (AAT)) and growth factors for the treatment of wounds.
  • elastase inhibitors e.g. alpha-1- antitrypsin (AAT)
  • AAT alpha-1- antitrypsin
  • Alpha- 1 -antitrypsin also known as alpha- 1 -proteinase inhibitor or serpin
  • AAT is a mammalian polypeptide having a molecular weight of approximately 54 kDa. It is a potent fluid phase inhibitor of serine proteases, and forms a tightly bound, stoichiometric complex with elastase. It can be inactivated by cleavage within its reactive centre. For example, neutrophil collagenase (MMP8) is know to degrade and inactivate AAT.
  • MMP8 neutrophil collagenase
  • AAT deficiency is a congenital disorder that is principally associated with liver disease in children and emphysema in young adulthood. It is thought that AAT deficiency results in loss of protection in the lung against neutrophil elastase, resulting in breakdown of the architecture of the lung. AAT has been administered in intravenous and aerosol formats for the treatment of pulmonary emphysema.
  • EGF epidermal growth factor
  • PDGF platelet derived growth factor
  • FGF fibroblast growth factor
  • the present invention provides for an increase in the rate of wound healing or the extent of wound healing through the use of one or more elastase inhibitors and one or more growth factors.
  • the said one or more elastase inhibitors and said one or more growth factors exhibit a synergistic effect in the promotion of wound healing.
  • a first aspect of the invention provides a pharmaceutical product comprising: (a) one or more elastase inhibitors (e.g. AAT); and (b) one or more growth factors.
  • the pharmaceutical product is for simultaneous, separate or sequential administration.
  • the pharmaceutical product further comprises a pharmaceutically acceptable carrier, diluent or excipient.
  • the pharmaceutical product may be provided in the form of a combined preparation or a pharmaceutical composition (i.e. as an admixture of one or more elastase inhibitors and one or more growth factors).
  • a combined preparation includes a "kit of parts" in the sense that the combination partners (a) and (b) as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i. e. simultaneously, separately or sequentially.
  • the parts of the kit of parts can then, for example, be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • a second aspect of the invention provides the pharmaceutical product of the first aspect of the invention for use in medicine (e.g. therapy).
  • a third aspect of the invention provides for the use of one or more elastase inhibitors (e.g. AAT) and one or more growth factors in the manufacture of a pharmaceutical product for the promotion of wound healing in a patient in need thereof.
  • elastase inhibitors e.g. AAT
  • growth factors e.g. growth factor
  • a pharmaceutical product according to the present invention may be a pharmaceutical composition or a combined preparation.
  • a fourth aspect of the invention provides for the use of one or more elastase inhibitors in the manufacture of a medicament for the treatment of a wound wherein the treatment comprises the simultaneous, separate or sequential administration of one or more growth factors to the patient.
  • a fifth aspect of the invention provides for the use of one or more growth factors in the manufacture of a medicament for the treatment of a wound wherein the treatment comprises the simultaneous, separate or sequential administration of one or more elastase inhibitors to the patient.
  • the pharmaceutical product of the first aspect of the invention is provided in the form of a wound dressing and the medicament of the third, fourth and fifth aspects of the invention is a wound dressing.
  • manufacture of a medicament includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.
  • a sixth aspect of the invention provides a method of promoting wound healing, said method comprising administering one or more elastase inhibitors and one or more growth factors to a patient in need thereof.
  • the one or more elastase inhibitors and the one or more growth factors may be administered in the same composition or by separate compositions.
  • the one or more elastase inhibitors and the one or more growth factors may be administered to the patient simultaneously, sequentially or separately.
  • a seventh aspect of the invention provides: (i) a package comprising one or more elastase inhibitors together with instructions for use in combination with one or more growth factors for the promotion of wound healing,
  • a package comprising one or more elastase inhibitors and one or more growth factors together with instructions for use in the promotion of wound healing.
  • An eighth aspect of the invention provides a wound dressing comprising one or more elastase inhibitors and one or more of growth factors.
  • the wound dressing is provided in the form of a solid substrate with one or more elastase inhibitors and the one or more growth factors dispersed on or in the solid substrate.
  • elastase inhibitors and one or more growth factors are administered concurrently
  • in combination is used to mean they are administered, if not simultaneously, then “sequentially” within a timeframe that they both are available to act therapeutically within the same time-frame.
  • administration “sequentially” may permit one agent to be administered within 5 minutes, 10 minutes or a matter of hours after the other provided that both the one or more elastase inhibitors and one or more growth factors are concurrently present in therapeutically effective amounts.
  • the time delay between administration of the components will vary depending on the exact nature of the components, the interaction there between, and their respective half-lives.
  • FIG. 1 PDGF retrieval after exposure to CWF in presence of protease inhibitors.
  • the figure shows a synergistic effect on activity when PDGF is combined with alpha 1 antitrypsin.
  • elastase inhibitors examples include: elastinil, elafm, secretory leukocyte proteinase inhibitor alpha- 1-macroglobulin, and alpha-1- antitrypsin (AAT).
  • a particularly preferred elastase inhibitor is AAT.
  • the "one or more elastase inhibitors" is AAT only or AAT in combination with one or more other elastase inhibitors.
  • alpha-1-antitrypsin encompasses all naturally occurring polymorphs of AAT. It also encompasses functional fragments of AAT, chimeric proteins comprising AAT or functional fragments thereof, homologs obtained by analogous substitution of one or more amino acids of AAT, and species homologs.
  • the AAT is a product of recombinant DNA technology, and more preferably the AAT is a product of transgenic technology.
  • the gene coding for AAT can be inserted into a mammalian gene encoding a milk whey protein in such a way that the DNA sequence is expressed in the mammary gland (e.g. as described in WO88/00239).
  • elastase inhibitors i.e. elastinil, elafm, secretory leukocyte proteinase inhibitor and alpha- 1-macroglobulin
  • elastinil elastinil, elafm, secretory leukocyte proteinase inhibitor and alpha- 1-macroglobulin
  • alpha- 1-macroglobulin elastinil, elafm, secretory leukocyte proteinase inhibitor and alpha- 1-macroglobulin
  • growth factors examples include: epidermal growth factor (EGF), platelet derived growth factor (PDGF; one or more of the three subtypes may be used: AA, AB, and B), Vascular Endothelial Growth Factor (VEGF), blood-derived growth factor, fibroblast growth factor (FGF) (including basic FGF), keratinocyte growth factor transforming growth factor, tissue growth factor, TGF-alpha, TGF-beta and insulin-like growth factor (e.g. IGF-I).
  • EGF epidermal growth factor
  • PDGF platelet derived growth factor
  • FGF fibroblast growth factor
  • IGF-I insulin-like growth factor
  • At least PDGF and/or EGF is used.
  • PDGF vascular endothelial growth factor
  • EGF EGF
  • basic FGF IGF
  • TGF-beta VEGF
  • the growth factors above encompass all naturally occurring polymorphs of the growth factors.
  • functional fragments, chimeric proteins comprising one of said growth factors or a functional fragment thereof, homologs obtained by analogous substitution of one or more amino acids of the growth factor, and species homologs are encompassed.
  • the one or more growth factors is a product of recombinant DNA technology, and more preferably the one or more growth factors is a product of transgenic technology.
  • platelet derived growth factor may be provided in the form of a recombinant PDGF.
  • the combination of elastase inhibitor and one or more growth factors have an additive effect.
  • the combination can have greater-than-additive effect.
  • Such an effect is referred to herein as a "supra-additive" effect, and may be due to synergistic or potentiated interaction.
  • P-value refers to the p-value of the Two-Tailed One-Sample T-Test or other suitable statistical basis.
  • the /?-value indicates how likely it is that the result obtained by the experiment is due to chance alone.
  • a />-value of less than .05 is considered statistically significant, that is, not likely to be due to chance alone.
  • the p- value is used to measure whether there is any statistically significant supra-additive promotion of wound healing (or other indicator of effect) when an elastase inhibitor and one or more growth factors are administered.
  • the term "supra-additive promotion of wound healing” refers to a mean wound healing produced by administration of a combination of an elastase inhibitor and one or more growth factors, that is statistically significantly higher than the sum of the wound healing produced by the individual administration of either an elastase inhibitor or one or more growth factors alone. Whether produced by combination administration of an elastase inhibitor and one or more growth factors is "statistically significantly higher" than the expected additive value of the individual compounds may be determined by a variety of statistical methods as described herein and/or known by one of ordinary skill in the art.
  • the te ⁇ n “synergistic” refers to a type of supra-additive inhibition in which both the elastase inhibitor and one or more growth factors individually have the ability to promote wound healing.
  • the term “potentiated” refers to type of supra-additive inhibition in which only one of the elastase inhibitor or one or more growth factors individually have the ability to promote wound healing.
  • potentiation may be assessed by determining whether the combination treatment produces a mean wound healing increase in a treatment group that is statistically significantly supra-additive when compared to the sum of the mean wound healing increases produced by the individual treatments in their treatment groups respectively.
  • the mean wound healing increase may be calculated as the difference between control group and treatment group mean wound healing.
  • the fractional increase in wound healing, "fraction affected" (F a ) may be calculated by dividing the treatment group mean wound healing increase by control group mean wound healing. Testing for statistically significant potentiation requires the calculation of F a for each treatment group.
  • the expected additive F 3 for a combination treatment may be taken to be the sum of mean F a s from groups receiving either element of the combination.
  • the Two-Tailed One-Sample T-Test may be used to evaluate how likely it is that the result obtained by the experiment is due to chance alone, as measured by the /"-value.
  • a /rvalue of less than .05 is considered statistically significant, that is, not likely to be due to chance alone.
  • F a for the combination treatment group must be statistically significantly higher than the expected additive F a for the single element treatment groups to deem the combination as resulting in a potentiated supra-additive effect.
  • CI values are calculated for different dose-effect levels based on parameters derived from median-effect plots of the elastase inhibitor alone, the one or more growth factors alone, and the combination of the two at fixed molar ratios.
  • This analysis may be performed using computer software tools, such as CalcuSyn, Windows® Software for Dose Effect Analysis (Biosoft®, Cambridge UK). Any method known or later developed in the art for analyzing whether a supra- additive effect exists for a combination therapy is contemplated for use in screening for suitable elastase inhibitors and/or growth factors.
  • one or more other, conventional wound healing agents may also be used in the manufacture of the medicament, pharmaceutical compositions and combined preparations according to the invention.
  • Such conventional wound healing agents may also be used in the method of the present invention. The inclusion of these agents may allow a synergistic effect on wound healing.
  • Such additional wound healing agent(s) may be administered separately, simultaneously or sequentially with the one or more elastase inhibitors and/or the one or more growth factors.
  • a therapeutically effective amount of each of the combination partners i.e. the one or more elastase inhibitors and said one or more growth factors
  • the components may be administered separately or as a fixed combination.
  • the pharmaceutical products, pharmaceutical compositions, combined preparations and medicaments of the invention may, for example, take the form of solutions, suspensions, tablets, pills, capsules, salves, creams, wound dressings, sustained release formulations, or powders, and typically contain l%-95% of active ingredient(s), preferably
  • the said one or more elastase inhibitors and/or said one or more growth factors may be mixed with physiological tolerable and compatible diluents, excipients and pharmaceutically acceptable carriers.
  • physiological tolerable and compatible diluents, excipients and pharmaceutically acceptable carriers are, for example, water, saline, dextrose, glycerol, or the like, and combinations thereof.
  • auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents may also be present.
  • pharmaceutically acceptable carrier refers to any pharmaceutical carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which can be administered without undue toxicity.
  • Suitable carriers can be large, slowly metabolized macromolecules such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids and amino acid copolymers. Such carriers are well known to those of ordinary skill in the art.
  • Pharmaceutically acceptable carriers in therapeutic compositions can include liquids such as water, saline, glycerol and ethanol.
  • salts can also be present e.g. mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • the one or more elastase inhibitors and the one or more growth factors are provided in the form of a wound dressing. That to say, the one or more elastase inhibitors and the one or more growth factors are provided in the form of a liquid, semi- solid or solid composition for application directly to the surface of a wound, or the composition is applied to the surface of, or incorporated into, a solid wound contacting layer such as a wound dressing gauze or film.
  • the wound dressing composition may be provided in the form of a fluid or a gel.
  • the one or more elastase inhibitors and the one or more growth factors may be provided in combination with conventional pharmaceutical excipients for topical application to a wound.
  • Suitable carriers include: Hydrogels containing cellulose derivatives, including hydroxyethyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose and mixtures thereof; and hydrogels containing polyacrylic acid (Carbopols). Suitable carriers also include creams/ointments used for topical pharmaceutical preparations, e.g. creams based on cetomacrogol emulsifying ointment.
  • the above carriers may include alginate (as a thickener or stimulant), preservatives such as benzyl alcohol, buffers to control pH such as disodium hydrogen phosphate/sodium dihydrogen phosphate, agents to adjust osmolality such as sodium chloride, and stabilisers such as EDTA.
  • alginate as a thickener or stimulant
  • preservatives such as benzyl alcohol
  • buffers to control pH such as disodium hydrogen phosphate/sodium dihydrogen phosphate
  • agents to adjust osmolality such as sodium chloride
  • stabilisers such as EDTA.
  • the wound dressing composition may be a slow release solid composition, in which the one or more elastase inhibitors and/or one or more growth factors is dispersed in a slow release solid matrix such as a matrix of alginate, collagen, or a synthetic bioabsorbable polymer.
  • a slow release solid matrix such as a matrix of alginate, collagen, or a synthetic bioabsorbable polymer.
  • the wound dressing composition is sterile.
  • wound dressing in this specification refers to a dressing for topical application to a wound and excludes compositions suitable for systemic administration.
  • the one or more elastase inhibitors and/or the one or more growth factors may be dispersed in or on a solid sheet of wound contacting material such as a woven or nonwoven textile material, or may be dispersed in a layer of foam such as polyurethane foam, or in a hydrogel such as a polyurethane hydrogel, a polyacrylate hydrogel, gelatin, carboxymethyl cellulose, pectin, alginate, and/or hyaluronic acid hydrogel, for example in a gel or ointment.
  • the AAT and/or said one or more growth factors are dispersed in or on a biodegradable sheet material that provides sustained release of the active ingredients into the wound, for example a sheet of freeze-dried collagen, freeze-dried collagen/algmate mixtures (available under the Registered Trade Mark FIBRACOL from Johnson & Johnson Medical Limited) or freeze-dried collagen/oxidized regenerated cellulose (available under the Registered Trade Mark PROMOGRAN from Johnson & Johnson Medical Limited).
  • a biodegradable sheet material that provides sustained release of the active ingredients into the wound, for example a sheet of freeze-dried collagen, freeze-dried collagen/algmate mixtures (available under the Registered Trade Mark FIBRACOL from Johnson & Johnson Medical Limited) or freeze-dried collagen/oxidized regenerated cellulose (available under the Registered Trade Mark PROMOGRAN from Johnson & Johnson Medical Limited).
  • a therapeutically effective amount of each of the combination partners of the combination of the invention may be administered simultaneously or sequentially and in any order, and the components may be administered separately or as a fixed combination.
  • the individual combination partners of the combination of the invention can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the one or more elastase inhibitors and said one or more growth factors may be administered by the same or different routes.
  • one or both of said one or more elastase inhibitors and said one or more growth factors are delivered by topical administration (peripherally or directly to a wound), including but not limited to topical administration using solid supports (such as dressings and other matrices) and medicinal formulations (such as mixtures, suspensions and ointments).
  • the solid support comprises a biocompatible membrane.
  • the solid support comprises a wound dressing.
  • a wash solution comprising the one or more elastase inhibitors and/or one or more growth factors can be used locally to promote healing of the wound.
  • Alternative routes of administration include: intravenously, intradermal and subcutaneous administration.
  • each of the combination partners employed in the combination of the invention may vary depending on a number of factors including the particular compound or pharmaceutical composition employed, the mode of administration, the frequency of administration, the condition being treated, the severity of the condition being treated, the route of administration, the needs of a patient sub-population to be treated or the needs of the individual patient which different needs can be due to age, sex, body weight, etc. of the patients.
  • the effective dose for a given situation can be determined by routine experimentation and is within the judgement of the skilled person. For example, in order to formulate a range of dosage values, cell culture assays and animal studies can be used.
  • the dosage of such compounds preferably lies within the dose that is therapeutically effective for at least 50% of the population, and that exhibits little or no toxicity at this level.
  • Dosage of each elastase inhibitor and growth factor in the combinations may be based on the amount of elastase inhibitor and growth factor per kg body weight of the patient. For example, dosage levels between about 1 nanogram (ng)/kg and about 100 mg/kg body weight per day of each of the agents described herein are useful for promoting wound healing.
  • the dosage of each of the subject compounds will generally be in the range of about 1 ng to about 1 microgram per kg body weight, about 1 ng to about 0.1 microgram per kg body weight, about 1 ng to about 10 ng per kg body weight, about 10 ng to about 0.1 microgram per kg body weight, about 0.1 microgram to about 1 microgram per kg body weight, about 20 ng to about 100 ng per kg body weight, about 0.001 mg to about 100 mg per kg body weight, about 0.01 mg to about 10 mg per kg body weight, or about 0.1 mg to about 1 mg per kg body weight.
  • the dosage of each of the subject compounds will generally be in the range of about 0.001 mg to about 0.01 mg per kg body weight, about 0.01 mg to about 0.1 mg per kg body weight, about 0.1 mg to about 1 mg per kg body weight, about 1 mg to about 10 mg per kg body weight or about 10 mg to about 100 mg per kg body weight.
  • the dosage of each elastase inhibitor and growth factor need not be in the same range as the other.
  • the dosage of one agent may be between about 0.01 mg to about 10 mg per kg body weight, and the dosage of another agent may be between about 0.1 mg to about 1 mg per kg body weight.
  • Other amounts will be known to those of skill in the art and readily determined.
  • the dosage of each of the agents in the combinations of the subject invention may be determined by reference to the composition's concentration in plasma or other bodily fluid.
  • the maximum plasma (or other bodily fluid) concentration (C m a x ) and the area under the plasma (or other bodily fluid) concentration-time curve from time 0 to infinity (AUC (0-4)) may be used.
  • Plasma (or other fluid) concentrations in the range of about 1 picogram (pg) to about 1 g per milliliter (ml) of each of the agents described herein are useful for promoting wound healing.
  • the plasma or fluid concentration of each of the subject compounds will generally be in the range of about 1 pg to about 1 ng/ml, about 1 pg to about 0.1 ng/ml, about 1 pg to about 10 pg/ml, about 10 pg to about 100 pg/ml, about 10 pg to about 1 ng/ml, about 100 pg to about lng/ml, about 1 pg to about 1 lnicrogram/ml, about 10 pg to about 1 microgram/ml, about 100 pg to about 1 microgram/ml, about 1 ng to about 1 microgram/ml, about 1 ng to about 100 ng/ml, about 1 ng to about 10 ng/ml, about 10 ng/ml to about 100 ng/ml, about 10 ng/ml to about 1 microgram/ml, about 100 ng to about 1 microgram/ml, about 1 microgram to about 1 milligram/ml, about 1
  • each elastase inhibitor and growth factor need not be in the same range as the other. Other amounts will be known to those of skill in the art and readily determined.
  • the combined use of several compounds may reduce the required dosage for any individual component because the onset and duration of effect of the different components may be complementary.
  • the different active agents may be delivered together or separately, and simultaneously or at different times within the day.
  • wound refers broadly to injuries to the skin and subcutaneous tissue initiated in different ways (e.g., pressure sores from extended bed rest and wounds induced by trauma) and with varying characteristics. Wounds may be classified into one of four grades depending on the depth of the wound: i) Grade I: wounds limited to the epithelium; ii) Grade II: wounds extending into the dermis; iii) Grade III: wounds extending into the subcutaneous tissue; and iv) Grade IV (or full-thickness wounds): wounds wherein bones are exposed (e.g., a bony pressure point such as the greater trochanter or the sacrum).
  • Grade I wounds limited to the epithelium
  • Grade II wounds extending into the dermis
  • Grade III wounds extending into the subcutaneous tissue
  • Grade IV or full-thickness wounds
  • partial thickness wound refers to wounds that encompass Grades I-III; examples of partial thickness wounds include burn wounds, pressure sores, venous stasis ulcers, and diabetic ulcers.
  • deep wound is meant to include both Grade III and Grade IV wounds.
  • the present invention contemplates treating all wound types, including deep wounds and chronic wounds.
  • chronic wound refers to a wound that has not healed within 30 days. The delay in healing may, for example, be caused by elevated levels of matrix metalloproteinases (MMP's).
  • MMP's matrix metalloproteinases
  • the wound is a chronic wound. Preferably, it is selected from the group consisting of venous ulcers, pressure sores, diabetic ulcers and decubitus ulcers.
  • the patient will usually be a mammal, such as a horse ⁇ e.g. a racehorse), a dog ⁇ e.g. greyhound), a cow, etc.
  • a mammal such as a horse ⁇ e.g. a racehorse), a dog ⁇ e.g. greyhound), a cow, etc.
  • Preferred patients are humans, including children, adults and the elderly.
  • Chronic wound fluid was spiked with PDGF-AA (to a final concentration of 500pg/ml) and was then incubated with AAT (1.25mg/ml) for 24 hours. This was also repeated replacing the CWF with PBS. After incubation the solutions were assayed for final PDGF-AA concentration using ELISA.

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  • Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Materials Engineering (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne des combinaisons formées d'un inhibiteur de l'élastase, tel qu'une alpha-1-antitrypsine, et d'un ou plusieurs facteurs de croissance, destinées à être administrées de façon simultanée, séquentielle ou séparée, pour activer la cicatrisation.
PCT/US2005/024045 2004-07-07 2005-07-07 Activation de la cicatrisation WO2006014518A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US58605304P 2004-07-07 2004-07-07
US60/586,053 2004-07-07
GB0418664A GB2415903A (en) 2004-07-07 2004-08-20 Pharmaceutical preparation which promotes wound healing
GB0418664.9 2004-08-20

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CN108524543A (zh) * 2018-07-12 2018-09-14 济南磐升生物技术有限公司 人弹性蛋白酶抑制剂在皮肤创伤愈合中的应用

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US6638909B1 (en) * 1996-11-01 2003-10-28 Ethicon, Inc. Wound healing compositions containing alpha-1-antitrypsin

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US6638909B1 (en) * 1996-11-01 2003-10-28 Ethicon, Inc. Wound healing compositions containing alpha-1-antitrypsin
US20020012693A1 (en) * 2000-02-29 2002-01-31 Cohen Kelman I. Wound dressings with protease-lowering activity

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108524543A (zh) * 2018-07-12 2018-09-14 济南磐升生物技术有限公司 人弹性蛋白酶抑制剂在皮肤创伤愈合中的应用

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