WO2011071986A1 - Enzymatic wound debriding compositions with enhanced enzymatic activity - Google Patents
Enzymatic wound debriding compositions with enhanced enzymatic activity Download PDFInfo
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- WO2011071986A1 WO2011071986A1 PCT/US2010/059409 US2010059409W WO2011071986A1 WO 2011071986 A1 WO2011071986 A1 WO 2011071986A1 US 2010059409 W US2010059409 W US 2010059409W WO 2011071986 A1 WO2011071986 A1 WO 2011071986A1
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Definitions
- the present invention relates generally to topical enzymatic wound debriding compositions and methods of treating wounds in need of debridement.
- many wound debriding compositions are made with anhydrous, hydrophobic bases such as petrolatum, mineral oil and/or vegetable oil as disclosed in US 3,821 ,364 and US 6,479,060, both of which are herein incorporated by reference.
- hydrophobic bases such as petrolatum, mineral oil and/or vegetable oil as disclosed in US 3,821 ,364 and US 6,479,060, both of which are herein incorporated by reference.
- enzymatic wound debriding compositions based on hydrophobic bases are generally not miscible in the aqueous environment of a wound bed, and thus contact of the proteolytic enzyme with the wound bed is generally hindered.
- compositions are made with anhydrous, hydrophilic bases such as propylene glycol or poloxamers as disclosed in US 6,548,556, US 2003/0198631 and US 2003/0198632, all of which are herein incorporated by reference.
- the present invention is directed to topical enzymatic wound debriding compositions with enhanced enzymatic activity. These compositions comprise a dispersed phase comprising at least one proteolytic enzyme and at least one hydrophilic polyol; and a continuous phase comprising a hydrophobic base.
- the wound debriding compositions of the present invention possess enhanced enzymatic activity over wound debriding compositions of the prior art.
- a wound debriding composition comprising a dispersed phase comprising a liquid hydrophilic polyol and at least one proteolytic enzyme; and a continuous phase comprising a hydrophobic base; wherein the amount of liquid hydrophilic polyol is within ⁇ 10% w/w of the optimum amount of the liquid hydrophilic polyol. For example, if the optimum amount was about 30% w/w, the amount of liquid hydrophilic polyol that could be used would be between about 20% w/w and about 40% w/w of the total formulation to achieve enhanced enzymatic activity of the formulation.
- the amount of liquid hydrophilic polyol is within ⁇ 9%, 8%, 7%, or 6% w/w of the optimum amount of the liquid hydrophilic polyol. In still another aspect, the amount of liquid hydrophilic polyol is within ⁇ 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% w/w of the optimum amount of the liquid hydrophilic polyol.
- liquid hydrophilic polyol in a composition comprising (a) a dispersed phase including a liquid hydrophilic polyol and at least one proteolytic enzyme; and (b) a continuous phase comprising a hydrophobic base can be determined by the method described in Section A of the Detailed Description section of this specification, which is incorporated into this section by reference.
- the optimum amount of liquid hydrophilic polyol for compositions with different proteolytic enzymes can differ. Additionally, the optimum amount of liquid hydrophilic polyol for compositions with a specific proteolytic enzyme can differ depending on the ingredients of the composition. For example, the optimum amount of liquid hydrophilic polyol in a collagenase composition containing PEG-400 and petrolatum can be different from the optimum amount of liquid hydrophilic polyol in a collagenase composition containing PEG-600 and petrolatum, or different from a collagenase composition containing poloxamer-124 and petrolatum.
- hydrophilic polyol means water-soluble, polar aliphatic alcohols with at least two hydroxyl groups and includes, but is not limited to, polymeric polyols (e.g., polyethylene glycols and poloxamers).
- polyethylene glycol or “poloxamer” means that the material is in the liquid state at 25 °C.
- polyethylene glycol or “poloxamer” means that the material is in the solid state at 25 °C.
- a method of treating a wound in need of debridement comprising: applying to the wound a composition comprising a dispersed phase comprising a liquid hydrophilic polyol, and an effective debriding concentration of at least one proteolytic enzyme; and a continuous phase comprising a hydrophobic base; wherein the amount of liquid hydrophilic polyol is within ⁇ 10% w/w of the optimum amount. In another aspect, the amount of liquid hydrophilic polyol is within ⁇ 9%, 8%, 7%, or 6% w/w of the optimum amount. In still another aspect, the amount of liquid hydrophilic polyol is within ⁇ 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% w/w of the optimum amount.
- the proteolytic enzyme is a metalloprotease, a cysteine protease, a serine protease, or an aspartic peptidase.
- the optimum amount of hydrophilic polyol for compositions comprising a metalloprotease, a cysteine protease or a serine protease is from about 10%, 1 1 %, 12%, 13%, 14%, 15%, 16% 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% w/w to about 40% w/w, or any range or numerical amount derivable therein.
- hydrophilic polyol for compositions comprising an aspartic peptidase is from about 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61 %, 62%, 63%, 64%, 65%, 66%, 67% w/w to about 68% w/w or any range or numerical amount derivable therein.
- the metalloprotease is collagenase.
- the metalloprotease is collagenase and the optimum amount of the hydrophilic polyol is from about 10%, 1 1%, 12%, 13%, 14%, 15%, 16% 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% w/w to about 40% w/w or any range or numerical amount derivable therein.
- the metalloprotease is thermolysin.
- the metalloprotease is thermolysin and the optimum amount hydrophilic polyol is from about 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38% w/w to about 39% w/w or any range or numerical amount derivable therein.
- the cysteine protease is papain.
- cysteine protease is papain and the optimum amount of the hydrophilic polyol is from about 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38% w/w to about 39% w/w or any range or numerical amount derivable therein.
- the serine protease is trypsin.
- the serine protease is trypsin and the optimum amount of hydrophilic polyol is from about 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%, 12%, 13%, 14%, 15%, 16% 17%, 18%, 19%, 20%, 21%, 22%, 23% w/w to about 24% w/w or any range or numerical derivable therein.
- the aspartic peptidase is pepsin.
- the aspartic peptidase is pepsin and the optimum amount of hydrophilic polyol is from about 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67% w/w to about 68% w/w or any range or numerical amount derivable therein.
- the proteolytic enzyme is suspended in the dispersed phase. In other embodiments the proteolytic enzyme is dissolved in the dispersed phase.
- the liquid hydrophilic polyol is a liquid polyethylene glycol or a liquid poloxamer, or mixtures thereof.
- the dispersed phase may further comprise a solid hydrophilic polyol in order to help physically stabilize the composition or reduce or prevent phase separation.
- the solid hydrophilic polyol is a solid poloxamer, or a solid polyethylene glycol, or mixtures thereof.
- the hydrophobic base comprises petrolatum, mineral oil, or vegetable oil, or mixtures thereof.
- the base comprises petrolatum.
- the hydrophobic base comprises a vegetable oil.
- the hydrophobic base comprises mineral oil.
- the hydrophobic base comprises petrolatum and mineral oil, petrolatum and vegetable oil, mineral oil and vegetable oil, or petrolatum, mineral oil, and vegetable oil.
- the hydrophobic base comprises a vegetable oil, wherein the vegetable oil is castor oil.
- the composition is a semisolid. In another embodiment, the composition is a liquid. In other embodiments, the composition is impregnated on a pad, gauze, or sponge. In one embodiment, the composition is sterile or anhydrous or both.
- the composition can be packaged in any package appropriate for dispensing a wound debrider.
- the compositions can be packaged in multi-use, single-dose, or metered dose packages.
- Non-limiting examples include a tube, bottle, jar, pump container, pressurized container, bladder container, aerosol container, aerosol spray container, non-aerosol spray container, syringe, pouch, or sachet.
- a method of determining the optimum amount of liquid hydrophilic polyol to add to a target composition comprising a dispersed phase including a proteolytic enzyme and a continuous phase including a hydrophobic base, the method comprising: (1) obtaining a series of compositions comprising the dispersed phase and the continuous phase, wherein the dispersed phase further includes a liquid hydrophilic polyol, and wherein each composition in the series of compositions include an identical amount of proteolytic enzyme and a different amount of the liquid hydrophilic polyol; (2) determining the enzymatic activity of each composition in the series of compositions; (3) determining the highest point on a graph that plots the enzymatic activity versus the amount of liquid hydrophilic polyol(s) included in each composition of the series of compositions, wherein the highest point on the graph correlates to the optimum amount of liquid hydrophilic polyol to add to the target composition.
- a method of increasing enzymatic activity in a target composition comprising a dispersed phase including a proteolytic enzyme and a continuous phase including a hydrophobic base, the method comprising: (1) obtaining a series of compositions comprising the dispersed phase and the continuous phase, wherein the dispersed phase further includes a liquid hydrophilic polyol, and wherein each composition in the series of compositions includes an identical amount of proteolytic enzyme and a different amount of the liquid hydrophilic polyol; (2) determining the enzymatic activity of each composition in the series of compositions; (3) determining the highest point on a graph that plots the enzymatic activity versus the amount of liquid hydrophilic polyol(s) included in each composition of the series of compositions, wherein the highest point on the graph correlates to an optimum amount of liquid hydrophilic polyol to add to the target composition, and (4) adding + 10% w/w of the optimum amount of liquid hydrophilic polyo
- the amount of polyol in the series of compositions can vary from each composition randomly or by a selected amount.
- the amount of polyol in each composition of the series of compositions can be 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%
- anhydrous means that the compositions contain less than about 5% w/w, or less than about 3% w/w, or less than about 1% w/w, or less than about 0.5% w/w, or less than about 0.1% w/w in relation to the total composition, or 0%, of free or added water, not counting the water of hydration, bound water, or typical moisture levels present in any of the raw ingredients of the compositions.
- compositions and methods for their use can "comprise,” “consist essentially of,” or “consist of any of the ingredients or steps disclosed throughout the specification. With respect to the transitional phase “consisting essentially of,” and in one non-limiting aspect, a basic and novel characteristic of the compositions and methods disclosed in this specification includes the composition's enhanced enzymatic activity.
- FIG. 1 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising collagenase and PEG-400, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG-400 comprised in the series of compositions (x-axis).
- FIG. 2 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising collagenase and PEG-600, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG-600 comprised in the series of compositions (x-axis).
- FIG. 3 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising collagenase and poloxamer-124, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the poloxamer-124 comprised in the series of compositions (x-axis).
- FIG. 4 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising trypsin and PEG-400, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG- 400 comprised in the series of compositions (x-axis).
- FIG. 5 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising papain and PEG-400, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG- 400 comprised in the series of compositions (x-axis).
- FIG. 6 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising thermolysin and PEG-400, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG-400 comprised in the series of compositions (x-axis).
- FIG. 7 Plot of the in-vitro collagenolysis activity (mg/ml) of a series of compositions comprising a dispersed phase comprising pepsin and PEG-400, dispersed in a hydrophobic phase comprising white petrolatum (y-axis) versus the percentage of the PEG- 400 comprised in the series of compositions (x-axis).
- FIG. 9 Enzyme stability in PEG-in- white petrolatum dispersion compared with oil-in-water emulsion cream.
- FIG. 10 Debridement efficacy in Eschar removal in pig burn wound.
- compositions with enhanced enzymatic activity. These compositions comprise a dispersed phase comprising at least one proteolytic enzyme and a hydrophilic polyol; and a continuous phase comprising a hydrophobic base.
- the hydrophilic polyol is a liquid hydrophilic polyol.
- compositions of the present invention which are dispersions of a hydrophilic polyol and a proteolytic enzyme in a hydrophobic base
- enzymatic activity e.g., in vitro collagenolysis
- the enzymatic activity of enzyme compositions based solely on a proteolytic enzyme and hydrophobic base combination i.e., no hydrophilic phase such as a hydrophilic polyol
- those enzyme compositions based solely on a proteolytic enzyme and hydrophilic base combination i.e., no hydrophobic phase such as petrolatum.
- the dispersion composition of hydrophilic and hydrophobic phases of the present invention had the highest enzymatic activity correlating to an optimum amount of the hydrophilic polyol which was more than 0% and less than 100% of the hydrophilic polyol in the composition.
- compositions of the present invention are suitable for treatment of a wound in need of debridement by applying to the wound a composition comprising a dispersed phase comprising a hydrophilic polyol, and an effective debriding concentration of at least one proteolytic enzyme; and a continuous phase comprising a hydrophobic base; wherein the amount of hydrophilic polyol is within ⁇ 10% w/w of the optimum amount, or ⁇ 9%, 8%, 7%, or 6% w/w of the optimum amount, or ⁇ 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% w/w of the optimum amount of hydrophilic polyol.
- compositions can be used to create the Series of Compositions.
- liquid hydrophilic polyol e.g., PEG 400
- proteolytic enzyme e.g., collagenase at 1% w/w
- hydrophobic base e.g., white petrolatum
- composition one in the Series of Compositions use 0% of the liquid hydrophilic polyol, use the selected amount of proteolytic enzyme, and q.s the batch with the hydrophobic base to 100%.
- composition one of the Series of Compositions would have: 0 % w/w PEG 400, 99% w/w of white petrolatum, and 1 % w/w of collagenase.
- composition two in the Series of Compositions use 10% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%. (Note that it is permissible to use some solid hydrophilic polyol in the makeup of the liquid hydrophilic polyol as necessary to produce a physically stable dispersion for compositions in the Series of Compositions).
- composition three in the Series of Compositions use 20% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition four in the Series of Compositions use 30% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition five in the Series of Compositions use 40% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition six in the Series of Compositions use 50% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition seven in the Series of Compositions use 60% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition eight in the Series of Compositions use 70% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition nine in the Series of Compositions use 80% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- (xi) For composition ten in the Series of Compositions, use 90% w/w of the liquid hydrophilic polyol, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophobic base to 100%.
- composition eleven in the Series of Compositions use 0% of the hydrophobic base, the same amount of the proteolytic enzyme, and q.s. the batch with the hydrophilic polyol.
- (xiii) determine the enzymatic activity of each of the eleven compositions in the Series of Compositions by using the in vitro artificial eschar testing model for the following sample collection times: 6, 12, 18 and 24 hours, as described in Section H of the Detailed Description section of this specification.
- (ivx) plot a curve of the enzymatic activity of each composition versus the correlating amount of liquid hydrophilic polyol(s) present in each composition of the Series of Compositions cumulatively for each data collection time. The highest point on the curve for the cumulative 24-hour data collection time correlates to the optimum amount of liquid hydrophilic polyol that can be used in a dispersion.
- compositions e.g. , polyol(s) proteolytic enzyme(s), hydrophobic base, and additional ingredients within the dispersed phase, and/or additional ingredients within the continuous hydrophobic phase
- the Series of Compositions can be created by (1) varying the amount of hydrophilic polyol as discussed above for each composition in the series, (2) using the determined amount of proteolytic enzyme, and (3) q.s.-ing the batch to 100% with the amount of the additional ingredients including the hydrophobic base; except for composition eleven, where the batch would be q.s.-ed to 100% with the amount of the additional ingredients including the hydrophilic polyol.
- composition of Interest a composition comprising (a) a dispersed phase including a liquid hydrophilic polyol and at least one proteolytic enzyme; and (b) a continuous phase comprising a hydrophobic base (referred to as "Composition of Interest") is within ⁇ 10% of the Optimum Amount of liquid hydrophilic polyol by using the following protocol:
- Step One Obtain a Composition of Interest that includes: (i) a dispersed phase including a liquid hydrophilic polyol(s) and a proteolytic enzyme and (ii) a continuous phase including a hydrophobic base.
- Step Two Prepare a series of compositions (referred to as "Series of
- compositions based on the Composition of Interest. Note that the amount (% w/w) of proteolytic enzyme in the Series of Compositions is held constant and is the same as the amount (% w/w) present in the Composition of Interest. The following steps can be used to prepare the Series of Compositions:
- (ii) Determine the total amount of the continuous phase in the Composition of Interest (% w/w).
- the Composition of Interest includes 15% w/w liquid hydrophilic polyol (e.g., PEG 400), 1% w/w proteolytic enzyme (e.g., collagenase), and 84% w/w hydrophobic base (e.g., white petrolatum), then the Composition of Interest would be 84% w/w continuous phase and 16 %w/w dispersed phase.
- liquid hydrophilic polyol e.g., PEG 400
- proteolytic enzyme e.g., collagenase
- 84% w/w hydrophobic base e.g., white petrolatum
- Step Three Prepare the Series of Compositions in a manner described above in Section A of this specification (e.g., this would include preparing 11 compositions in a manner described in Section A of this specification).
- Step Four Determine the enzymatic activity of each of the eleven compositions in the Series of Compositions by using the in vitro artificial eschar testing model for each of the following sample collection times: 6, 12, 18 and 24 hours as described in Section H of the Detailed Description section of this specification.
- Step Five Plot a curve of the enzymatic activity of each composition versus the correlating amount of liquid hydrophilic polyol(s) present in each composition of the Series of Compositions cumulatively for each data collection time. The highest point on the curve for the cumulative 24-hour data collection time correlates to the optimum amount of liquid hydrophilic polyol for the Composition of Interest.
- Step Six Compare the amount of liquid hydrophilic polyol present within the Composition of Interest to determine whether it is within ⁇ 10% w/w of the optimum amount of liquid hydrophilic polyol for the Composition of Interest.
- proteolytic enzymes break down protein by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain of a protein. They are divided into four major groups on the basis of catalytic mechanism: serine proteases, cysteine proteases, metalloproteases, and aspartic proteases. Some proteases have been identified with other catalytic amino acids in the active site, such as threonine and glutamic acid; however, they do not form major groups.
- Serine proteases depend upon the hydroxyl group of a serine residue acting as the nucleophile that attacks the peptide bond.
- the major clans found in humans include the chymotrypsin-like, the subtilisin-like, the alpha/beta hydrolase, and signal peptidase clans.
- serine proteases were originally digestive enzymes. In mammals, they evolved by gene duplication to serve functions in blood clotting, the immune system, and inflammation. These proteases have a broad substrate specificity and work in a wide pH range.
- Non-limiting examples of serine proteases include trypsin, chymotrypsin, subtilisin, sutilains, plasmin, and elastases.
- cysteine proteases in which the nucleophile that attach the scissile peptide bond in the sulfhydryl group of a cysteine residue are known as cysteine proteases.
- Cysteine proteases are commonly encountered in fruits including papaya, pineapple, and kiwifruit. Cysteine proteases have a broad specificity and are widely used under physiological conditions. In this family, papain has been used extensively for wound debridement for a long time. Other cysteine proteases, such as bromelain and analain, have also been investigated for the applications in wound debridement.
- cysteine proteases include calpain, caspases, chymopapain, and clostripain.
- Metalloproteases are among the proteases in which the nucleophilic attach on a peptide bond is mediated by a water molecule, while a divalent metal cation, usually zinc but sometimes cobalt, manganese, nickel or copper, activates the water molecule.
- the metal ions are extremely important for the activity. Any compounds that have potential to interact with the metal ion, chelating or oxidation, will affect the enzymatic activity.
- Non-limiting examples of metalloproteases in this family include thermolysin, collagenases, matrix metallo proteinases (MMPs), bacillolysin, dispase, vibriolysin, pseudolysin, stromelysin, and various bacterial derived neutral metalloproteases.
- MMPs matrix metallo proteinases
- bacillolysin bacillolysin
- dispase bacillolysin
- vibriolysin pseudolysin
- pseudolysin pseudolysin
- stromelysin stromelysin
- various bacterial derived neutral metalloproteases include thermolysin, collagenases, matrix metallo proteinases (MMPs), bacillolysin, dispase, vibriolysin, pseudolysin, stromelysin, and various bacterial derived neutral metalloproteases.
- Aspartic peptidases are so named because aspartic acid residues are the ligands of the activated water molecule. In most enzymes in this family, a pair of aspartic residues act together to bind and activate the catalytic water molecule. All or most aspartic peptidases are endopeptidases. Most aspartic peptidases have a broad specificity. However, the optimum pH of most aspartic peptidases is in the acidic range.
- Non-limiting examples of aspartic peptidases are pepsin, chymosin, beta-secretase, plasmepsin, plant acid proteases and retroviral proteases.
- a suitable proteolytic enzyme for wound debridement is the metalloprotease collagenase.
- the collagenase can be substantially pure or it may contain detectable levels of other proteases.
- the potency assay of collagenase is based on the digestion of undenatured collagen from (bovine Achilles tendon) at pH 7.2 and 37°C for 24 hours. The number of peptide bonds cleaved is measured by reaction with ninhydrin. Amino groups released by a trypsin digestion control are subtracted. One net collagenase unit will solubilize ninhydrin reactive material equivalent to 1 nanomole of leucine equivalents per minute.
- the amount (potency or concentration) of collagenase in the compositions of the present invention is at an effective level to debride the wound.
- the potency of collagenase in the compositions can vary from about 1 to about 10,000 collagenase units per gram of product, based on the activity of the collagenase used in the product.
- the potency expressed as collagenase units per gram of product, is from about 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500 to about 10000, or any range or numerical amount derivable therein.
- the concentration of collagenase in the compositions generally can vary from about 0.001% w/w to about 8% w/w.
- the concentration, expressed as percentage weight by weight is from about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.010 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, 0.100, 0.125, 0.150, 0.175, 0.20, 0.25, 0.30 ,0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1, 2, 3, 4, 5, 6, 7 to about 8 or any range or numerical amount derivable therein.
- the collagenase is derived from Clostridium histolyticum; however, in other embodiments the collagenase can be derived from other sources.
- Methods for producing a suitable collagenase are disclosed in US patents 3,705,083; 3,821,364; 5,422,261 ; 5,332,503; 5,422,103; 5,514,370; 5,851,522; 5,718,897; and 6,146,626 all of which are herein incorporated by reference.
- Another suitable proteolytic enzyme for wound debridement is the serine protease trypsin.
- trypsin is derived from the pancreas of healthy bovine or porcine animals, or both. Trypsin can also be derived from recombinant sources.
- the pharmaceutical grade (USP/NF) of trypsin is known as Crystallized Trypsin. It contains not less than 2500 USP Trypsin Units per mg, calculated on the dried basis, and not less than 90.0% and not more than 1 10.0%) of the labeled potency.
- the potency assay of trypsin as well as the definition of a USP Trypsin Unit are found in the Crystallized Trypsin monograph of the USP 31 (Official August 1 , 2008) herein incorporated by reference.
- the amount (potency or concentration) of trypsin in the compositions of the present invention is at an effective level to debride the wound.
- the potency of trypsin in the compositions can vary from about 90 to about 60,000 USP Trypsin Units per gram of product.
- the potency of trypsin, expressed as USP Trypsin Units per gram of product is from about 90, 100, 150, 200, 250, 300, 320, 350, 375, 400, 500, 600, 675, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 10000, 20000, 30000, 40000, 50000 to about 60000, or any range or numerical amount derivable therein.
- the concentration of trypsin in the compositions generally can vary from about
- the concentration of trypsin is from about 0.0025, 0.0050, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035, 0.040, 0.045, 0.050, 0.055, 0.060, 0.065, 0.070, 0.075, 0.080, 0.085, 0.090, 0.095, 0.10, 0.15, 0.20 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95 to about 1, or any range or numerical amount derivable therein.
- Hydrophilic polyols of the present invention are water-soluble, polar aliphatic alcohols with at least two hydroxyl groups, and include polymeric polyols, e.g., polyethylene glycols and poloxamers.
- the hydrophilic polyol in the dispersed phase is a liquid hydrophilic polyol.
- the liquid hydrophilic polyol is a liquid polyethylene glycol or a liquid poloxamer, or mixtures thereof.
- Solid hydrophilic polyols such as solid polyethylene glycols or solid poloxamers can also be added to the dispersed phase of the invention to help physically stabilize the dispersion.
- liquid hydrophilic polyols include but are not limited to propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, glycerin, hexylene glycol, methoxy polyethylene glycol, propylene carbonate, and ethoxydiglycol, and these may also be added to the dispersed phase. 1.
- Polyethylene Glycols include but are not limited to propylene glycol, butylene glycol, pentylene glycol, hexylene glycol, glycerin, hexylene glycol, methoxy polyethylene glycol, propylene carbonate, and ethoxydiglycol, and these may also be added to the dispersed phase. 1.
- Polyethylene Glycols polyethylene glycol, butylene glycol, pentylene glycol, hexylene glycol, glycerin, hexylene glycol, methoxy polyethylene glycol, propylene carbonate, and ethoxydiglycol
- Polyethylene glycols are homo-polymers of ethylene glycol and water represented by the formula:
- H(OCH 2 CH 2 ) (OCH 2 CH 2 )
- n represents the average number of oxyethylene groups.
- Polyethylene glycols can be either liquid or solid at 25 °C depending on their molecular weights.
- liquid polyethylene glycols are described using USP nomenclature: polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, and polyethylene glycol 600.
- liquid and solid polyethylene glycols are available commercially from the
- Poloxamers are synthetic block copolymers of ethylene oxide and propylene oxide represented by the formula:
- a is from 2 to 150 and b is from 15 to 70 depending on the particular poloxamer.
- Poloxamers can be either liquid or solid at 25 °C depending on their molecular weights.
- liquid poloxamers are described using CTFA/INCI nomenclature: poloxamer 101 , poloxamer 105, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, poloxamer 182, poloxamer 183, poloxamer
- poloxamer 212 poloxamer 231, poloxamer 282, poloxamer 331, poloxamer 401, and poloxamer 402.
- liquid and solid poloxamers are available commercially from the BASF
- the hydrophobic bases of the present invention can comprise, but are not limited to, plant, animal, paraffinic, and synthetic derived fats, butters, greases, waxes, solvents, and oils; mineral oils, vegetable oils, petrolatum, water insoluble organic esters and triglycerides, silicones, or fluorinated compounds; or mixtures thereof.
- the hydrophobic phase comprises petrolatum.
- Plant derived materials include, but are not limited to, arachis (peanut) oil, balsam Peru oil, carnauba wax, candellila wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cotton seed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orange wax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, shea butter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil, and hydrogenated vegetable oil.
- arachis (peanut) oil balsam Peru oil, carnauba wax, candellila wax, castor oil, hydrogenated castor oil, cocoa butter, coconut oil, corn oil, cotton seed oil, jojoba oil, macadamia seed oil, olive oil, orange oil, orange wax, palm kernel oil, rapeseed oil, safflower oil, sesame seed oil, shea butter, soybean oil, sunflower seed oil, tea tree oil, vegetable oil, and hydrogenated
- Non-limiting examples of animal derived materials include beeswax, cod liver oil, emu oil, lard, mink oil, shark liver oil, squalane, squalene, and tallow.
- paraffmic materials include isoparaffm, microcrystalline wax, heavy mineral oil, light mineral oil, ozokerite, petrolatum, and paraffin.
- Suitable non-limiting examples of organic esters and triglycerides include CI 2-
- alkyl benzoate isopropyl myristate, isopropyl palmitate, medium chain triglycerides, trilaurin, and trihydroxy stearin.
- Non-limiting examples of silicones are dimethicone and cyclomethicone.
- a non-limiting example of a fluorinated compound is polytetrafluoroethylene (PTFE).
- Petrolatum is a purified mixture of semisolid hydrocarbons obtained from petroleum and varies from dark amber to light yellow in color.
- White petrolatum is wholly or nearly decolorized petrolatum and varies from cream to snow white in color.
- Petrolatum and White Petrolatum can also vary in melting point, viscosity, and consistency.
- PENRECO ® ULTIMA PENRECO ® SUPER
- PENRECO ® SNOW PENRECO ® REGENT
- PENRECO ® LILY PENRECO ® CREAM
- PENRECO ® ROYAL PENRECO ® BLOND
- PENRECO ® AMBER PENRECO ® ULTIMA
- PENRECO ® SUPER PENRECO ® SUPER
- PENRECO ® SNOW PENRECO ® REGENT
- PENRECO ® LILY PENRECO ® CREAM
- PENRECO ® ROYAL PENRECO ® BLOND
- PENRECO ® AMBER PENRECO ® AMBER
- Petrolatum and White Petrolatum are available in cosmetic grade and pharmaceutical (USP/NF) grade and both are suitable for the present invention.
- the topical compositions of the present invention are dispersions comprising a hydrophilic dispersed phase in a hydrophobic continuous phase.
- the dispersed phase comprises a proteolytic enzyme and a hydrophilic polyol.
- the hydrophilic polyol is a liquid hydrophilic polyol.
- the liquid hydrophilic polyol is a liquid polyethylene glycol or a liquid poloxamer, or mixtures thereof.
- the continuous phase comprises a hydrophobic base.
- the hydrophobic base can be petrolatum.
- compositions can be anhydrous as defined herein.
- the compositions can be semisolid or liquid.
- the composition can be impregnated on a pad, gauze, or sponge.
- the compositions can also be sterile.
- compositions can include additional materials known in the art that are suitable for topical compositions of this nature, e.g., absorbents, deodorizers, surfactants, solvents, rheology modifiers, film formers, stabilizers, emollients, moisturizers, preservatives, antimicrobials, antioxidants, chelating agents, fragrances, and colorants.
- additional materials known in the art e.g., absorbents, deodorizers, surfactants, solvents, rheology modifiers, film formers, stabilizers, emollients, moisturizers, preservatives, antimicrobials, antioxidants, chelating agents, fragrances, and colorants.
- compositions can also include additional pharmaceutical active ingredients known in the art that are suitable for topical compositions of this nature, e.g., antimicrobial agents, wound healing agents, anesthetic agents, vulnerary agents, and haemostatic agents.
- additional pharmaceutical active ingredients known in the art that are suitable for topical compositions of this nature, e.g., antimicrobial agents, wound healing agents, anesthetic agents, vulnerary agents, and haemostatic agents.
- a vulnerary agent is balsam Peru.
- compositions can be packaged in any package suitable for dispensing a wound debrider.
- the compositions can be packaged in multi-use, single-dose, or metered dose packages.
- Non-limiting examples include a tube, bottle, jar, pump container, pressurized container, bladder container, aerosol container, aerosol spray container, non-aerosol spray container, syringe, pouch, or sachet.
- compositions of the present invention can be prepared by techniques and methods known by one of ordinary skill in the art by dissolving or suspending the proteolytic enzyme in part or all of the available hydrophilic polyol.
- the resulting solution or suspension can be mixed with a hydrophobic base to form a dispersion, wherein the hydrophobic base becomes the continuous phase and the hydrophilic polyol/enzyme phase becomes the dispersed phase.
- These compositions can be prepared using processing equipment known by one of ordinary skill in the art, e.g., blenders, mixers, mills, homogenizers, dispersers, dissolvers, etc.
- Enhancement of the enzymatic activity of the compositions was established by testing the compositions using an in vitro artificial eschar model as described below and in the publication "Study on the debridement efficacy of formulated enzymatic wound debriding agents by in vitro assessment using artificial wound eschar and by an in vivo pig modeV Shi et. ah, Wound Repair Regen, 2009, 17(6):853, herein incorporated by reference.
- Bovine collagen (Type I), bovine fibrinogen, and elastin were used to make an Artificial Wound Eschar (AWE) substrate.
- Collagen-FITC labeled, elastin-rhodamine, and fibrin-coumarin were the raw materials used for producing the AWE substrate.
- AWE substrate 650 mg Collagen-FITC and 100 mg each of elastin-rhodamine and fibrin-coumarin were weighed into a 50 mL tube and homogenized in 10 mL of Tris buffer saline. In a separate tube, 10 mL of fibrinogen solution was prepared at 15 mg/mL with Tris buffer saline. The two solutions were combined and thoroughly mixed. A thrombin solution (0.25 mL at 50 U/mL) was added, quickly mixed, and the solution was poured into a Petri dish containing a 90 mm nonreactive membrane filter.
- the material began to form a soft sheet on top of the membrane filter by clotting the dyed proteins into a solid matrix.
- the clotted AWE substrate was allowed to solidify for 30 minutes and then rinsed with water for 15 minutes to remove the thrombin.
- the AWE substrate was further dehydrated to 75% moisture content in preparation for use. [0109] With the AWE substrate still attached to the membrane, a 35 mm diameter piece was punched out using a hole punch.
- the AWE substrate punch was placed on the top flat face of a Franz Diffusion Cell System (Hanson Research, Chatsworth, CA), and a TEFLON® sample holder placed on top.
- the debriding ointment samples were loaded in the center of the sample holder, and any excess sample was removed by scraping.
- the solution in the receptor cells was Tris buffer at a pH of 7.4 for samples containing collagenase, papain, thermolysin, or trypsin; and was sodium acetate buffer at a pH of 2 for samples containing pepsin.
- the solution in receptor cells was sampled in 1 mL increments at the following sample collection times: 0, 1, 2, 3, 6, 12, 18 and 24 hours. Once finished, the samples were analyzed by fluorescence measurement of FITC dye at 485nm (excitation wavelength) and 520nm (emission wavelength) to determine the digestion of collagen (collagenolysis) reported in mg/ml.
- the BCA Protein Assay combines the well-known reduction of Cu 2+ to Cu 1+ by protein in an alkaline medium with the highly sensitive and selective colorimetric detection of the cuprous cation (Cu 1+ ) by bicinchoninic acid.
- the first step is the chelation of copper with protein in an alkaline environment to form a blue-colored complex.
- the biuret reaction peptides containing three or more amino acid residues form a colored chelate complex with cupric ions in an alkaline environment containing sodium potassium tartrate. This became known as the biuret reaction because a similar complex forms with the organic compound biuret (NH 2 -CO-NH-CO-NH 2 ) and the cupric ion.
- Biuret a product of excess urea and heat, reacts with copper to form a light blue tetradentate complex.
- BCA a highly sensitive and selective colorimetric detection reagent reacts with the cuprous cation (Cu 1+ ) that was formed in step 1.
- the purple-colored reaction product is formed by the chelation of two molecules of BCA with one cuprous ion.
- the BCA/copper complex is water-soluble and exhibits a strong linear absorbance at 562 nm with increasing protein concentrations. The purple color may be measured at any wavelength between 550 nm and 570 nm with minimal (less than 10%) loss of signal.
- Example 1 Dispersions of Collagenase/PEG 400 in Petrolatum
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- Example 2 Dispersions of Collagenase/PEG 600 in Petrolatum
- Polyethylene Glycol 600 (PEG-600) dispersed in Petrolatum.
- Poloxamer 124 dispersed in Petrolatum.
- Example 4 Dispersions of Trypsin/PEG 400 in Petrolatum
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- Example 5 Dispersions of Papain/PEG 400 in Petrolatum
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- Example 6 Dispersions of Thermolysin/PEG 400 in Petrolatum
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- PEG-1450 was added to PEG-400 to form a semi-solid resulting in approximate total PEG of 97%
- Example 7 Dispersions of Pepsin/PEG 400 in Petrolatum
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- Example 8 Dispersions of Collagenase/PEG 400 in Petrolatum for Physical Release of Enzyme
- Polyethylene Glycol 400 (PEG-400) dispersed in Petrolatum.
- FIG. 9 provides data comparing the stability of collagenase in a dispersion of the present invention ("30% PEG in WP dispersion") and an oil-in-water emulsion ("Aqueous cream”). These data suggest that collagenase was more stable in the 30% PEG in WP dispersion when compared to the Aqueous cream. Tables 9-10 provide descriptions of the 30%) PEG in WP dispersion and Aqueous cream formulations.
- Aqueous cream was prepared as follows: (A) Active Phase: (1 ) 0.2 grams of collag mixed with 20 grams of deionized water. (B) Main Phase: ( 1) 20.36 grams of white petrolatum was mixed with 4.5 grams of emulsifying wax, 4.5 grams of Incroquate TMS, and 19.83 grams of glycerin (96%) at 70°C until uniform; (2) the mixture was cooled to 35-40°C. Added Active Phase to Main Phase followed by stirring for 30 minutes or until homogenous mixture obtained. [0132] FIG.
- Aqueous cream was prepared as follows: (1 ) parabens were melted in buffer at high temperature (>70°C) along with glycerin; (2) emulsifying wax and isopropyl palmitate were added; (3) the mixture was mixed at high temperature for 45 min and then cooled to about 35°C; (4) thermolysin was added as a slurry in the buffer; (5) the mixture was cooled to room temperature (20-25°C). TABLE 13 (Hydrogel)*
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ES10793386.3T ES2613495T3 (es) | 2009-12-08 | 2010-12-08 | Composiciones de desbridamiento enzimático de heridas con actividad enzimática mejorada |
NZ600403A NZ600403A (en) | 2009-12-08 | 2010-12-08 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
CA2782622A CA2782622C (en) | 2009-12-08 | 2010-12-08 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
US13/514,945 US9694100B2 (en) | 2009-12-08 | 2010-12-08 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
BR112012013812A BR112012013812A2 (pt) | 2009-12-08 | 2010-12-08 | "composições para desbridamento enzimático de feridas com atividade enzimática melhorada" |
CN201080055918.6A CN102711808B (zh) | 2009-12-08 | 2010-12-08 | 具有增强的酶活性的酶学伤口清创组合物 |
MX2012006661A MX2012006661A (es) | 2009-12-08 | 2010-12-08 | Composiciones enzimaticas de desbridamiento de heridas con actividad enzimatica mejorada. |
RU2012126852/15A RU2585373C2 (ru) | 2009-12-08 | 2010-12-08 | Ферментная композиция и способ обработки ран |
EP10793386.3A EP2509624B1 (en) | 2009-12-08 | 2010-12-08 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
JP2012543231A JP5997612B2 (ja) | 2009-12-08 | 2010-12-08 | 増幅された酵素活性の酵素創傷壊死組織除去組成物 |
AU2010328269A AU2010328269B2 (en) | 2009-12-08 | 2010-12-08 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
IL220121A IL220121A0 (en) | 2009-12-08 | 2012-06-03 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
ZA2012/04148A ZA201204148B (en) | 2009-12-08 | 2012-06-06 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
US15/358,937 US10155061B2 (en) | 2009-12-08 | 2016-11-22 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
US16/171,070 US10556037B2 (en) | 2009-12-08 | 2018-10-25 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
US16/717,185 US20200129656A1 (en) | 2009-12-08 | 2019-12-17 | Enzymatic wound debriding compositions with enhanced enzymatic activity |
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EP (1) | EP2509624B1 (zh) |
JP (3) | JP5997612B2 (zh) |
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CN (1) | CN102711808B (zh) |
AU (1) | AU2010328269B2 (zh) |
BR (1) | BR112012013812A2 (zh) |
CA (1) | CA2782622C (zh) |
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JP5997612B2 (ja) | 2016-09-28 |
EP2509624A1 (en) | 2012-10-17 |
CN102711808B (zh) | 2015-08-19 |
US20200129656A1 (en) | 2020-04-30 |
JP2013512965A (ja) | 2013-04-18 |
US20130045196A1 (en) | 2013-02-21 |
US9694100B2 (en) | 2017-07-04 |
US10556037B2 (en) | 2020-02-11 |
AU2010328269A1 (en) | 2012-06-21 |
CN102711808A (zh) | 2012-10-03 |
IL220121A0 (en) | 2012-07-31 |
BR112012013812A2 (pt) | 2018-05-29 |
ES2613495T3 (es) | 2017-05-24 |
US20190060509A1 (en) | 2019-02-28 |
ZA201204148B (en) | 2013-02-27 |
KR20120117995A (ko) | 2012-10-25 |
RU2585373C2 (ru) | 2016-05-27 |
RU2012126852A (ru) | 2014-01-20 |
CA2782622A1 (en) | 2011-06-16 |
JP2015057420A (ja) | 2015-03-26 |
RU2619351C1 (ru) | 2017-05-15 |
CA2782622C (en) | 2018-05-22 |
EP2509624B1 (en) | 2016-11-23 |
JP2016185994A (ja) | 2016-10-27 |
US20170072029A1 (en) | 2017-03-16 |
AU2010328269B2 (en) | 2014-07-10 |
JP6030621B2 (ja) | 2016-11-24 |
MX2012006661A (es) | 2012-11-12 |
US10155061B2 (en) | 2018-12-18 |
NZ600403A (en) | 2014-01-31 |
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