WO1995023614A1 - Enzymatic debridement compositions and methods - Google Patents

Enzymatic debridement compositions and methods

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Publication number
WO1995023614A1
WO1995023614A1 PCT/US1995/002798 US9502798W WO1995023614A1 WO 1995023614 A1 WO1995023614 A1 WO 1995023614A1 US 9502798 W US9502798 W US 9502798W WO 1995023614 A1 WO1995023614 A1 WO 1995023614A1
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WO
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Patent type
Prior art keywords
subtilisin
composition
method
carrier
antibiotics
Prior art date
Application number
PCT/US1995/002798
Other languages
French (fr)
Inventor
Barry Constantine
Karen Monte
Original Assignee
E.R. Squibb & Sons, Inc.
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
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46Hydrolases (3)
    • A61K38/48Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482Serine endopeptidases (3.4.21)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/52Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
    • C12N9/54Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea bacteria being Bacillus
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/96Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12YENZYMES
    • C12Y304/00Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21Serine endopeptidases (3.4.21)
    • C12Y304/21062Subtilisin (3.4.21.62)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions

Abstract

In accordance with the present invention, novel methods and compositions including the enzyme subtilisin A or including the combination of an enzyme such as subtilisin A and one or more pharmaceutical agents, e.g. antibiotics, are disclosed. Topical formulations of subtilisin A have been found to have enhanced stability over prior art subtilisin formulations. Debridement activity of enzymes such as subtilisin A, subtilisin, bromelain and the like is enhanced when combined with one or more antibiotics. The enzymatic formulations according to this invention are preferably non-aqueous, and the debridement provided by these and other enzyme formulations is enhanced when used under an occlusive hydrocolloid-containing dressing.

Description

ENZYMATIC DEBRIDEMENT COMPOSITIONS AND METHODS

This invention relates to a novel therapeutic composition and process for debriding eschar tissue and is principally concerned with the timely removal of non-viable burn tissue to promote wound healing and reduce the risk of infection to the patient.

There are many instances in patient treatment that necrotic or devitalized tissue must be removed from the patient. These instances include, but are not limited to, decubitus ulcers, pressure sores, incisional, traumatic and peripheral wounds and ulcers secondary to peripheral vascular disease. As a result, a great deal of research has been performed to uncover materials which promote the removal of such tissue and, preferably, materials which are capable of distinguishing between viable and non-viable tissue. Preferably, these materials digest devitalized tissue while not attacking viable tissue. Such agents would make it possible to remove the devitalized tissue without the pain and risk of surgery. The removal of devitalized or contaminated tissue is generally defined as debridement.

One area where there is a considerable need for debridement in patient care is in the treatment of burn patients. Removal of non-viable tissues in burn patients in a timely fashion is important because the risk of infection is a major problem in the treatment of patients who suffer from serious burn injuries. The burn frequently destroys the skin's normal barrier to bacterial invasion and a large necrotic tissue mass formed by the body from the burn can act as a bacterial substrate thereby providing an environment where bacteria can multiply rapidly. The presence of a bacterial infection in burn tissue can transform a partial thickness burn into a full thickness wound requiring considerably more treatment and care. In addition, the patient's condition can be seriously affected by infection during treatment.

Debridement has become a standard step in the treatment of burn patients. Thus, after

resuscitation of the burn victim occurs, the burned area is thoroughly cleaned and generally debrided of non-viable tissue. Generally, debridement can be accomplished in a variety of ways. These methods include surgical, natural enzymatic, commercially prepared enzymatic and mechanical. Surgical

debridement while the most common form of debridement has attendant problems not the least of which is further pain to the burn patient and frequently heavy bleeding. This can create serious problems in recovery as the patient is already in a weakened condition due to the burn. Natural enzymatic

cleavage of collagen to separate dead tissue while considerably less painful to the patient is an extremely slow process and can be dangerous in large burns where an infection arising before debridement is complete may jeopardize the patients life. The slow debridement of natural enzymes can create treatment problems since the tissues typically debrided in burn treatment are most often the ones which serve as an ideal culture medium for the growth of infectious micro-organisms. Commercially prepared enzymes work more quickly than natural enzymes but these commercially prepared enzymes have met with only limited success. See Journal of the Maine Medical Association September 1964, and Research in Burns, Han Huber, Publishers Bern Stuttgart Vienna 1971. it has been recognized that the materials disclosed in these publications have not been

considered satisfactory since there has been

difficulty in reproducing the results.

U.S. Patent No. 4,329,430 to Klein discloses hydrolytic enzyme materials that may be useful for dissection of devitalized tissues. The enzyme

material disclosed in Klein is bromelin which may be obtained from the stem of the pineapple plant. U.S. Patent No. 3,409,719 relates to the use of the enzyme bacillus subtilis in a hydrophobic ointment for the debridement of tissue.

Another enzymatic material used for the debridement of tissue is a mixture of exo- and endopeptidase which have been isolated from krill. See U.S. Patents No. 4,946,792. Similarly, U.S.

Patent No. 5,120,656 to O'Leary relates to a process for debriding bone using proteolytic or collagen digesting enzymes. The proteolytic enzymes include ficin, pepsin, trypsin, chymotrypsin, papain and elastase. The collagen digesting enzymes include collagenase and stromelysin. However, these

materials have not received widespread application because of the time necessary to debride the tissue and because these enzymes do not appear to have the same efficacy in non-bone debriding applications.

One reason for this is that the tissue debrided in burn treatments does not have the same

characteristics as the bone tissue being debrided.

As a result, there is a need for improved compositions for enzymatic debridement of non-viable tissue, particularly burn tissue.

Summary of the Invention

In accordance with the present invention, novel methods and compositions including the enzyme subtilisin A or including the combination of an enzyme such as subtilisin A and one or more

pharmaceutical agents, e.g., antibiotics, are disclosed. Debridement activity of enzymes such as subtilisin A, subtilisin, bromelain and the like is enhanced when combined with one or more antibiotics. The enzymatic formulations according to this

invention are preferably non-aqueous and the

debridement provided by these and other enzyme formulations is enhanced when used under an occlusive dressing.

Brief Description of the Drawings

FIGURE 1 is a bar graph demonstrating the results of tests comparing full thickness burn debridement using the composition of the present invention to a control where there was no treatment.

Detailed Description of the Invention

The present invention provides novel and improved enzymatic debridement formulations which exhibit advantages over the prior art. Although subtilisin formulations based on enzyme obtained from B . subtilis are known for use in the debridement of necrotic tissue (e.g., Travase® from Baxter Travenol as disclosed in U. S. 3,409,719), the use of the enzyme subtilisin A for debridement has not been heretofore disclosed or suggested. Contrary to previous belief that antibiotics adversely affect enzyme debridement activity, it has also now been found that antibiotics can be combined with debridement enzymes with advantageous results, and in some cases enhanced activity. Finally, enzymatic debridement ointments in general have been found to work much more effectively when covered by an occlusive, preferably hydrocolloid-containing, adhesive-type dressing. In this way enzymatic debridement has now been achieved within 24 to 48 hours as opposed to seven days in the prior art.

For the formulations of this invention which contain subtilisin A, that term as used herein refers to an endoprotease of the serine variety having a molecular weight of about 27,500 Daltons consisting of a single polypeptide chain of approximately 274 amino acid residues as follows:

Subtilisin A is also known as subtilisin Carlsberg and/or subtilopeptidase A and/or bacillus

licheniformis derived subtilisin and is typically derived by fermentation from Bacillus licheniformis, although any other chemical, recombinant or synthetic routes for its preparation could be used. Subtilisin A is commercially available as Enzeco® Licheniformis Protease Concentrate from Enzyme Development

Corporation.

For the formulations of this invention containing a debriding enzyme in combination with one or more antibiotics or for the methods involving a debriding enzyme under an occlusive hydrocolloid dressing, any suitable debriding enzyme can be employed. Suitable debridement enzymes include subtilisin A (under any of the various names

discussed above), subtilisin (from Bacillus

Subtilis), bromelain, including crude bromelain, collagenase, chymotrypsin, ficin, pepsin, elastase, trypsin, papain and stromelysin.

Antibiotics for use in the present invention can be any of those known in the pharmaceutical art. One or more antibiotics can be incorporated into the present formulations either singly or premixed, i.e., as double or triple antibiotics known in the art.

Suitable antibiotics include but are not limited to neomycin, polymixin B sulfate, bacitracin (each singly or as the triple antibiotic neosporin), bacitracin with zinc, silver sulfadiazine,

gramicidin, fucidic acid, povidone iodine and

pseudomonic acid, including mixtures thereof.

A preferred range of subtilisin A or other enzyme is about 20,000 to 120,000. proteolytic casein units (PCU) per gram of ointment. A more preferred range is 61,500 to 102,500. Alternatively, when viewed as a function of PCU's /cm2 of wound area, the enzyme, e.g., subtilisin A, should be delivered to the wound in an amount above about 150-200 PCU/cm2, preferably above about 350-400 PCU/cm2 and more preferably above about 750 PCU/cm2. Most preferred are formulations which provide between about 3000-6000 PCU/cm2 of wound area, but of course, the strength can be varied as known in the enzymatic debridement art according to the particular

wound/burn needs.

The preferred range of antibiotic, e.g., Neomycin, is about 0 to 10 mg. A more preferred range is 0 to 5 mg. A preferred range of Polymyxin B Sulfate is about 0 to 20,000 units/g. A more

preferred range is 0 to 10,000 units/g. A preferred range of Bacitracin is about 0 to 1,000 units/g. A more preferred range is about 0 to 550 units/g.

Similarly, other antibiotics can be employed at their known therapeutic or subtherapeutic doses as

required.

A preferred combination product in accordance with this invention includes subtilisin or subtilisin A at concentrations comparable to the subtilisin concentration in the commercially available Travase® ointment (i.e., about 8,200 PCU/100 mg of ointment) and also a single, double or triple (e.g., Neosporin) antibiotic at commercially available strengths within a carrier.

The pharmaceutically acceptable carrier must be non-aqueous so as to avoid premature activation of the enzyme which would adversely result in depletion of enzyme activity. Hydrophobic powder formulations and cream or ointment formulations are well known in the art. For example, lactose powder formulations may be employed wherein powder forms of the enzyme are incorporated into lactose powder. A preferred vehicle is Plastibase® (mineral oil with 5%

polyethylene, E. R. Squibb & Sons) although any known hydrophobic ointment, cream or gel can be employed, such as Aquaphor, Petrolatum or mineral oil.

The enzyme can also be used in formulations such as those commercially available for the cleaning of contact lenses. For example, subtilisin A is commercially available in formulations, e.g., tablets, under the names Ultrazyme® (Allergen) and Re-Nu® (Bausch & Lomb). These enzyme-containing tablets have been found to provide significant debridement of necrotic tissue on animal burns, especially when used under an occlusive dressing.

When enzyme preparations, e.g., Subtilisin A and others, are used in the present method with occlusive dressings, any convenient occlusive

dressings can be employed. Suitable commercially available dressings include but are not limited to Bioclusive (Johnson & Johnson), Opsite (Smith &

Nephew) and DuoDerm® CGF (Convatec). Preferred are hydrocolloid-containing dressings, e.g., the DuoDerm® line products from ConvaTec.

As stated above, a preferred embodiment of this invention comprises an enzyme with one or more antibiotics. Not only is there no adverse affect on the enzyme activity but enzyme activity is actually enhanced in some instances. Further, the presence of antibiotics can preclude the need for irradiative sterilization of the debridement product. This is advantageous since irradiation is believed to

adversely affect enzymatic activity. The present invention will be further

described by the following examples.

Animal Protocol

For the examples below, the animals were housed communally for at least seven days prior to initiating the experiment. They were fed a basal diet of Purina feed, and water ad-libitum. The animals were kept in a controlled environment

(temperature 19-21°C, 12 hr light/dark cycle, 50% relative humidity).

Guinea pigs were zip wax® depilated four days prior to receiving bilateral scald wounds. When a surgical plane of anesthesia was reached, each animal was immersed in 90°C for 20 seconds. The normal skin surrounding the burn site was protected from scald with a fiberglass embedded latex rubber sheet that also has an 8 × 8" piece of DuoDerm® dressing adhered to one side. A one inch circular hole was cut through the sheeting so that only 10% of the animal's TBSA was exposed to the 90°C water.

A 20 second application produced a 5 cm2 circular, full-thickness thermal scald wound. A total of two, randomized burn sites were produced. Burns were divided into treatment groups according to a randomized schedule.

Following scalding, all wounds were hydrated with 0.1cc of saline before application of the enzymes and the control dressings described more specifically in the examples below. All drrssings were secured with elastic tape and debridement activity assessed at 24 hours. Dressings were removed, and the digested tissue was wiped away using a gauze sponge. A subjective assessment of tissue digested by the enzymes activity in percent of wound area was reported. The wounds were then

photographed.

At post-op day one, the guinea pigs were reanesthetized in order to perform the first evaluation of the treatments.

Example 1

Subtilisin A Powder Dose Response Study in the Guinea

Pig Scald Model

The objective of the study was to determine the minimum amount of the enzyme, in a powder

formulation, needed to degrade necrotic tissue from a fairly uniform 5 square cm, full-thickness dermal scald wound in a guinea pig model.

Subtilisin A (Novo) was combined with 100 mg USP Lactose at different concentrations expressed as Proteolytic Casein Units (PCU's) ranging from 30,000 PCU's to 900 PCU's per 100 mg powder. 0.2 cc (16,400 PCU's) of Travase Ointment (subtilisin from Bacillus Subtilis) was used as a control. All wounds were dressed with the respective enzyme product (within 1/2 hour of wounding) and low MVTR (Moisture Vapor Transmission Rate) polyurethane film, occlusive dressings to prevent leakage of the exudate/enzyme mix. The wounds were evaluated 24 hours after treatment at which time a visual estimation of percent debridement is made.

Results

PCU ' s/ 100mg %Debridement mg Subt i l is in A powder PCU ' s /sq . cm n w/ in 24 hr

20 29,872.6 6000 6 100

10 14,936.3 3000 6 73

5 7,468.2 1500 11 76

2.5 3,734.1 750 11 79

1.25 1,867.0 375 5 51

0.625 933.5 187 5 10

Travase Control

0.2 grams 16,400.0 3280 9 55

No adverse ef fects were noted to vital tissue . Example 2

Subtilisin A Ointment (with and without an antibacterial component) vs Travase Ointment

This example compares the efficacy of Travase® Ointment with an experimental preparations of

Subtilisin A Ointment, one of which contained a

Triple antibiotic component.

82,000 PCU's of Subtilisin A per gram of

Plastibase® 50W (mineral oil/5.0% polyethylene, E. R. Squibb) Ointment were combined to prepare a master batch which served as a control. A volume of this preparation was taken and further combined with the following ingredients:

4.2 mg Neomycin/gram ointment

5,500 units Polymixin B Sulfate/gram ointment 500 units Bacitracin/gram ointment

The resultant formulation essentially

contained the Travase equivalent of subtilisin activity combined with the antibacterial compliment of Neosporin Ointment®.

Comparison was made with Travase Ointment® (Boots Pharm.). Travase Ointment contains 82,000 PCU's Subtilisin per gram of Plastibase® 50W (mineral oil/5.0% polyethylene) ointment. Samples were stored at room temperature for approximately 13 weeks prior to testing.

As described previously, scald wounds were treated with the respective enzymatic ointments, dressed with occlusive dressings and evaluated at 24 hours. A non-treated, occluded group served as control. Hydrocolloid, occlusive dressings (DuoDerm Extra Thin® - ConvaTec) were used in this study. Results

Treatment n %Debridement after 24 hours

Subtilisin A Ointment 7 95

Travase Ointment 7 95

Subtilisin A/Antiobiotic

Ointment 6 99.1

Non-treated, Occluded

Controls 6 0

No damage to vital tissue was noted.

Example 3

Subtilisin A in OTC contact lens cleaning tablets

This example evaluates the efficacy of commercial OTC contact lens cleaning tablets which contain Subtilisin A to degrade wound necrotic tissue.

One tablet of each of the commercially available contact lens cleaning products:

Ultrazyme (Allergan)

or

Re-Nu (Bausch and Lomb) was applied to the standard full-thickness scald wound model in the guinea pig. Each wound and tablet preparation was dressed using a film occlusive dressing. Twenty-four hours after wounding/treatment the wounds were evaluated for debridement activity. Results

Treatment n %Debridement after 24 hours

Ultrazyme 5 62

Re-Nu 7 35

Claims

What is claimed is:
1. A method for the debridement of necrotic tissue in a wound or burn in a mammalian species comprising administering to said wound or burn of a mammalian specie in need thereof an effective amount of the enzyme subtilisin A.
2. The method according to claim 1 wherein said subtilisin A is contained within an acceptable pharmaceutical carrier in an amount of from about 20,000 to about 120,000 proteolytic casein units per gram of carrier.
3. The method according to claim 2 wherein said subtilisin A is present in an amount of from about 61,500 to about 102,500 proteolytic casein units per gram of carrier.
4. The method of claim 1 wherein said subtilisin A is delivered in an amount of at least about 750 proteolytic casein units per square
centimeter of wound area.
5. The method of claim 2 wherein said pharmaceutical carrier is a nonaqueous cream or ointment.
6. The method of claim 5 wherein said ointment comprises mineral oil and polyethylene.
7. The method according to claim 1 wherein said subtilisin A is administered concommitantly or in combination with one or more pharmaceutically active agents.
8. The method of claim 7 wherein said subtilisin A is administered with one or more
antibiotics.
9. The method of claim 8 wherein said antibiotic is selected from neomycin, polymixin B sulfate, bacitracin, bacitracin with zinc, silver sulfadiazine, gramacidin, fucidic acid, povidone iodine and pseudomonic acid or mixtures thereof.
10. The method of claim 9 wherein up to 10 mg of neomycin per gram of carrier is administered in combination with said subtilisin A.
11. The method of claim 9 wherein up to 20,000 units of polymixin B sulfate per gram of carrier is administered in combination with said subtilisin A.
12. The method of claim 9 wherein up to 1000 units of bacitracin or bacitracin zinc per gram of carrier is administered in combination with said subtilisin A.
13. A composition comprising subtilisin A in a pharmaceutically acceptable carrier .
14 . The composition of claim 13 wherein said subtilisin A is present in an amount of from about
20,000 to about 120,000 proteolytic casein units per gram of carrier.
15. The composition of claim 14 wherein said subtilisin A is present in an amount of from about 61,500 to about 102,500 proteolytic casein units per gram of carrier.
16. The composition of claim 13 wherein said pharmaceutical carrier is an ointment or cream.
17. The composition of claim 16 wherein said ointment comprises mineral oil and polyethylene.
18. The composition of claim 13 further comprising one or more pharmaceutical agents.
19. The composition of claim 18 wherein said pharmaceutical agents are antibiotics.
20. The composition of claim 19 wherein said one or more antibiotics are selected from the group consisting of neomycin, polymixin B sulfate,
bacitracin, bacitracin with zinc, silver
sulfadiazine, gramacidin, fucidic acid, povidone iodine and pseudomonic acid or mixtures thereof.
21. A composition comprising an enzyme in combination with one or more antibiotics which combination is contained within a pharmaceutically acceptable carrier, wherein said enzyme is selected from a form of subtilisin, bromelain, collagenase, and chymotrypsin.
22. The composition of claim 21 wherein said enzyme subtilisin is selected from subtilisin derived from bacillus subtilis, subtilisin A derived from bacillus licheniformis, subtilisin derived from amyloliquefacieus.
23. The composition of claim 21 wherein said one or more antibiotics are selected from neomycin, polymixin B sulfate, bacitracin, bacitracin with zinc, silver sulfadiazine, gramacidin, fucidic acid, povidone iodine and pseudomonic acid.
24. The composition of claim 21 being a topical formulation.
25. A method for the debridement of necrotic tissue in the burn or wound of a mammalian species comprising administering to said burn or wound of a mammalian species in need thereof an effective amount of the composition of claim 21.
26. A method for enhancing the enzymatic debridement activity of an enzymatic debridement composition comprising the incorporation of one or more antibiotics into said composition.
27. A method for enhancing the sterility of an enzymatic debridement composition without need for a sterilization process comprising the incorporation of one or more antibiotics into said composition.
28. The method of claim 25 wherein said wound or burn is covered with an occlusive dressing during treatment.
29. The method of claim 28 wherein said dressing contains one or more hydrocolloids.
PCT/US1995/002798 1994-03-01 1995-02-28 Enzymatic debridement compositions and methods WO1995023614A1 (en)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998053850A2 (en) * 1997-05-26 1998-12-03 L.R.R & D Ltd. Compositions and means for the treatment of burns and other cutaneous traumas
WO2002051436A2 (en) * 2000-12-27 2002-07-04 Healthpoint, Ltd. Stable enzymatic wound debrider
WO2003066088A2 (en) * 2002-02-06 2003-08-14 Trommsdorff Gmbh & Co. Kg Arzneimittel Protease screening and novel use of proteases
EP1539225A2 (en) * 2002-04-23 2005-06-15 Mediwound, Ltd. Apparatus and methods for enzymatic escharotomy in burn induced compartment syndrome
WO2006006167A3 (en) * 2004-07-13 2006-03-16 Marian Gorecki Compositions and methods for dermatological wound healing
WO2006135506A2 (en) * 2005-06-08 2006-12-21 Collegium Pharmaceutical, Inc. Compositions for topical enzymatic debridement
US7785584B2 (en) 2003-08-13 2010-08-31 Healthpoint, Ltd. Ointment wound spray
WO2016063265A3 (en) * 2014-10-24 2016-06-16 Palmeira De Oliveira Rita Manuela Topical formulation for treating skin or mucosal infections, preparation method and uses thereof
WO2016046234A3 (en) * 2014-09-22 2016-08-11 Nexttobe Ab Recombinant phe-free proteins for use in the treatment of phenylketonuria

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US4668228A (en) * 1985-03-12 1987-05-26 Johnson & Johnson Products, Inc. Debriding tape
US4784653A (en) * 1987-06-22 1988-11-15 Johnson & Johnson Patient Care, Inc. Absorbent adhesive dressing
US5206026A (en) * 1988-05-24 1993-04-27 Sharik Clyde L Instantaneous delivery film

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US3983209A (en) * 1975-01-28 1976-09-28 Alza Corporation Method for treating burns
US4122158A (en) * 1976-09-23 1978-10-24 Alza Corporation Topical therapeutic preparations
US4668228A (en) * 1985-03-12 1987-05-26 Johnson & Johnson Products, Inc. Debriding tape
US4784653A (en) * 1987-06-22 1988-11-15 Johnson & Johnson Patient Care, Inc. Absorbent adhesive dressing
US5206026A (en) * 1988-05-24 1993-04-27 Sharik Clyde L Instantaneous delivery film

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998053850A3 (en) * 1997-05-26 1999-08-12 Lrr & D Ltd Compositions and means for the treatment of burns and other cutaneous traumas
WO1998053850A2 (en) * 1997-05-26 1998-12-03 L.R.R & D Ltd. Compositions and means for the treatment of burns and other cutaneous traumas
WO2002051436A2 (en) * 2000-12-27 2002-07-04 Healthpoint, Ltd. Stable enzymatic wound debrider
WO2002051436A3 (en) * 2000-12-27 2002-10-03 Healthpoint Ltd Stable enzymatic wound debrider
US6548556B2 (en) 2000-12-27 2003-04-15 Healthpoint, Ltd. Stable enzymatic wound debrider
WO2003066088A3 (en) * 2002-02-06 2004-04-01 Trommsdorff Arzneimittel Protease screening and novel use of proteases
WO2003066088A2 (en) * 2002-02-06 2003-08-14 Trommsdorff Gmbh & Co. Kg Arzneimittel Protease screening and novel use of proteases
EP1539225A4 (en) * 2002-04-23 2010-12-08 Mediwound Ltd Apparatus and methods for enzymatic escharotomy in burn induced compartment syndrome
EP1539225A2 (en) * 2002-04-23 2005-06-15 Mediwound, Ltd. Apparatus and methods for enzymatic escharotomy in burn induced compartment syndrome
US7785584B2 (en) 2003-08-13 2010-08-31 Healthpoint, Ltd. Ointment wound spray
WO2006006167A3 (en) * 2004-07-13 2006-03-16 Marian Gorecki Compositions and methods for dermatological wound healing
WO2006135506A2 (en) * 2005-06-08 2006-12-21 Collegium Pharmaceutical, Inc. Compositions for topical enzymatic debridement
WO2006135506A3 (en) * 2005-06-08 2007-05-24 Collegium Pharmaceutical Inc Compositions for topical enzymatic debridement
WO2016046234A3 (en) * 2014-09-22 2016-08-11 Nexttobe Ab Recombinant phe-free proteins for use in the treatment of phenylketonuria
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