EP0983085A2 - Compositions and means for the treatment of burns and other cutaneous traumas - Google Patents

Compositions and means for the treatment of burns and other cutaneous traumas

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Publication number
EP0983085A2
EP0983085A2 EP19980921713 EP98921713A EP0983085A2 EP 0983085 A2 EP0983085 A2 EP 0983085A2 EP 19980921713 EP19980921713 EP 19980921713 EP 98921713 A EP98921713 A EP 98921713A EP 0983085 A2 EP0983085 A2 EP 0983085A2
Authority
EP
Grant status
Application
Patent type
Prior art keywords
debriding
wound
skin
agent
debrided
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP19980921713
Other languages
German (de)
French (fr)
Inventor
Lior Rosenberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LRR & D Ltd
L R R and D Ltd
Original Assignee
LRR & D LTD
L R R and D Ltd
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

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L15/00Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/38Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F15/00Auxiliary appliances for wound dressings; Dispensing containers for dressings or bandages
    • A61F15/001Packages or dispensers for bandages, cotton balls, drapes, dressings, gauze, gowns, sheets, sponges, swabsticks or towels
    • 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
    • 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)
    • A61K38/4873Cysteine endopeptidases (3.4.22), e.g. stem bromelain, papain, ficin, cathepsin H
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00Bandages or dressings; Absorbent pads
    • A61F2013/00089Wound bandages
    • A61F2013/00157Wound bandages for burns or skin transplants

Abstract

A skin pre-healing composition, for the pre-treatment of traumatized skin, comprising an interface layer-forming effective amount of a debriding agent.

Description

COMPOSITIONSAND MEANS FOR THE TREATMENT OFBURNS AND OTHER CUTANEOUS TRAUMAS

Field of the Invention

The present invention relates to the treatment of traumatized skin. More

particularly, the invention relates to compositions and means for promoting

the heahng of skin by a suitable selective eschar removal and wound

heahng promotion.

Background of the Invention

Trauma to the skin is the commonest trauma in humans. The trauma may

be acute or chronic due to any kind of offensive physical agent (such as

thermal, chemical, pressure, shearing, degloving etc.). Due to its sudden

onset, severity, complexity, short and long term implications the cutaneous burn trauma will be used here as an example to other cutaneous traumas.

The burn is one of the most severe and dreaded traumas in the modern,

developed parts of the world, and even more so in its less developed areas.

Up to 100,000 American are severely burned each year and need

specialized, intensive burn unit facilities for their treatment. More than a

million Americans each year are treated in general surgery or other non-speciahzed medical units. The numbers of small burns are practically

unfathomed and may be estimated to be far beyond 10,000,000 each year.

The traumatized skin (burned tissue) the eschar, may be of different depths,

including parts or the entire thickness of the skin and even other, deeper

tissues. The eschar characteristics may depend on the traumatizing agent

(thermal, chemical and electrical), the eschar's age and the conditions that

influenced the eschar since the onset of the trauma. Leaving the dead

eschar in place will extend and deepen the damage into the neighboring, originally undamaged tissues. This dead eschar will serve as a medium for bacteria growth, and a source of infection, contamination and sepsis that

may lead even to the patient's death. Some modern studies highlight the

relation between the presence of the eschar and deterioration of the general

immune and resistance systems, a phenomenon that promotes the oncoming

sepsis.

The assessment of the primary tissue damage in burns is difficult. The

burn's depth is changing from point to point and the eschar' color and

texture may be misleading even to the expert's eye. Very often the burn

depth may be determined only after few days, when the secondary damage

already extends beyond the original burn eschar. In order to prevent the

above mentioned complications, it is imperative to remove at the earliest

stage, as much as possible of the offending eschar. This removing of the dead tissue is termed "debridement". The concept of debridement is as old as

medicine itself but its execution is extremely difficult and not free of risks.

The most obvious and direct debridement method is surgery. In small,

limited necrotic areas excision of the entire dead tissue up to healthy,

bleeding tissues is the procedure of choice. In the case of burns, because of

the large surfaces of dead eschar, a tangential excision (with the help of

special knives called dermatomes) of the dead eschar, layer after layer is

done. The excision should be carried down into the healthy intact tissue to

make sure that no trace of the dreaded eschar remains. It is estimated that up to 30% -50% of healthy tissue may be sacrificed in this procedure. This

healthy tissue, if preserved, could serve as a source for the natural heahng

processes. These surgical procedures are long, difficult, demanding of

patient's and medical resources with profuse bleeding. Surgery was and still

is the most common debridement technique but because of its cost and

implications should not be chosen lightly without a critical assessment of

each patient and each burn site.

The raw surface that is left after the thorough debridement should be

protected and covered immediately to prevent desiccation and further tissue

death. Due to the depth of the surgical debridement, grafting with

autogenous or non-autogenous grafts is practically the only answer. The harvesting of the skin graft demands extending surgery into other healthy

skin areas intact until now. In large burns, only few and precious potential

donor sites exist. Thus, hard to find omografts or expensive (and not too

effective) synthetic skin substitutes or biological dressings are used.

Historically, the burn area was defined appropriately debrided only if it

could host a Irving skin graft. This is achieved by removal of tissue deeper

than the eschar, which results in heavy bleeding of the wounded healthy

tissue. The bleeding itself serves as the sign of appropriately debrided

wound, assuming that tissue that does not bleed heavily will not be able to support a skin graft. The severed blood vessels are the ones that will grow

into the graft and provide the necessary blood supply necessary for its

survival. The appearance of the bleeding bed and its "graftability" is crucial

in defining the debridement efficacy according to the known art. In fact, one

of the problems encountered with the chemical debridement of wounds is that some debriding agents have been known to be unsuitable for therapy,

because they did not leave a heavily bleeding tissue bed, and therefore

caused the failure of skin grafting. The appearance of the surgically

debrided tissue is typical and made of healthy dermal collagen, subdermal

tissue and vessels all transected by the tangential excision Due to the abovementioned difficulties (of treating large traumatized body

areas of a very unstable patient, difficult diagnosis of the damage's extent,

extensive and risky surgery with immense blood loss, need for huge

quantities of grafts (that is only rarely available) there have been always a

tendency to continue a "conservative" treatment of the burned areas leaving

the burn eschar in place. If the eschar is left untreated, autolisis and

decomposition due mainly to the activities of the growing germs within the

dead eschar will lead to what was coined as "spontaneous sloughing" (not

unlike the "laudable pus" of old). Obviously this phenomenon is nothing more than an immense purulent, inflammatory reaction on large areas of

the immune compromised patient's body. The violent sepsis and inflammation process leads to propagation of tissue damage inward:

transforming second degree and partial thickness damage into a full

thickness third degree one. The sloughing phenomenon takes 2-4 weeks

while the patient is severely, and some times terminally, septic. If the

patient survives the ordeal he is left with most of the originally burned

areas completely exposed and raw or covered with granulation tissue that

eventually will evolve (even if grafted at this stage) into deforming and contracted scar tissue. In order to treat the dangerous inflammatory stage

several topical treatment modalities, using topical antiseptic or antibiotic

preparations were developed (some with rather severe side effects). Some of

these treatments do partially prevent some of the inflammatory and sepsis

problem but with a price: A severe delay of the eschar sloughing with increase granulation/scar tissue formation and late scarring sequels and

increase in heahng time.

The idea of using a debriding enzymes or chemical agents to "dissolve" the

burn eschar and to prevent at least the severely traumatic surgical

debridement is not new. Ideally, it has been postulated that one would wish

for an ointment or other local preparation that could be easily applied, as

soon as possible on the fresh burn without extending the original trauma

and harming undamaged tissues. This ideal debriding agent should separate quickly and selectively only the damaged tissues leaving an intact

raw surface that could support a skin graft.

Many chemicals with proteolitic activity such as Salicilic acid, Benzoic acid,

Malic acid (Aserbin), Collagenase (Naridase, Santyl) , Trypsin (Trypur) and

Fibrinolysin-desoxyribonuclease (Elase) compounds were or still are in

current clinical use since the second world war. Several enzymes, of

microbacterial, vegetable or even animal origin were tested and some even

reached the market. These enzymes derives from microorganisms such as

Bacillus subtilis: Sutilains (Travase), Streptococci:

Streptokinase-streptodornase, plants such as the Papaya (Papain) or

Bromelain from the Pineapple (Debridase, Escharase, Ananain). Even

enzymes made of krill or pancreatic powder were tried. Most of these compounds demand one or two daily dressing changes for five to ten days.

By the time the entire eschar is removed a rich granulation tissue has been

developed in many areas with a future scar and contracture formation.

Unfortunately all of them, including the newly developed ones such as

Travase and Genzyme Ananain require several daily dressing changes for

no less than five and sometimes more than twelve days. The use of these

enzymes was followed in several cases by a violent sepsis and even septic

shock probably due to bacteremia from exposure of the raw tissues to

several days old, contaminated and partially dissolved eschar. The debrided

tissue could not support an autogenous or non autogenous living graft

without an additional surgical debridement, thus, the debrided tissue

underwent a secondary damage through desiccation and exposure with a

secondary increase of the tissue necrosis.

Based on the above-mentioned data that represent the "state of the art" of

burn treatment the following choices of burn treatment protocols may be

considered to date:

1. The ages-old "conservative" supportive treatment of the eschar using

locally applied antiseptic and antibacterial preparations that results in a

late spontaneous eschar sloughing (two-four weeks), accompanied often by

sepsis and resulting in granulation tissues, the originator of heavy and

deforming scars. Once the burn is clean of the eschar and a healthy granulation tissue has been developed, an autogenous skin should be

grafted to prevent the late sequel. The area that needs to be grafted is

usually most of the entire second and third degree burn (the second and

mixed depth burns has been transformed into deep burns through the

secondary burn propagation and infection/inflammation process).

2. The "surgical" approach that consists of a tangential excision of the

eschar that sacrifices healthy tissues and needs immediate biological

coverage and grafting to prevent transformation of the new clean raw debrided tissue into a new necrotic one. This protocol shortens hospitalization/healing time and when performed early enough may prevent

sepsis and scar contraction. The drawbacks are that the surgery is

extensive, risky, with a very heavy load on the hospital resources, faculties

and highly trained manpower. The need of an immediate grafting of the

raw debrided tissue dictates usually an autograft with an additional

increase of at least 10-15% of the exposed, denuded TBSA (Total Body

Surface Area) or a scarce and costly omograft or substitutes. Due to the

present surgical techniques the debrided area that need grafting is usually

most of the second and all the third degree burns.

Thus, in both treatment modalities the final tissues death and necrosis and

skin defect that follows is more extensive than the original traumatized

tissue. Summarv of the Invention

It has now been found, And this is an object of the present invention, that it

is possible to provide means for treating wounds of the type described above,

without suffering from the disadvantages of the state of the art treatments.

The new treatment means are based on the discovery that both the above

mentioned traditional treatment modalities are based on two opposing

misconceptions. The first is an undertreatment, leaving the dead eschar

on the patient with all the severe, often lethal, drawbacks, complications

and sequels. The second is an overtreatment, debriding aggressively the

dead eschar but paying dearly with blood, precious healthy tissues,

dangerous procedures and the necessity of grafting immediately the

exposed, raw, debrided areas.

It is an object of the invention to provide biologically active compositions for

the debridement of dead eschar, which leave what will be termed

hereinafter an "interface layer" (LL.) between the dead, necrotic eschar and

the entirely normal unharmed (graftable) tissues. This interface layer,

achieved by a suitable enzymatic/chemical debridement, is characterized by

a rather normal looking collagen fibers and anatomical microstructure but

with very few open blood vessels (such as encountered in a surgically

debrided wound where the level of incision is entirely within the normal tissue). The behavior of this interface layer is different compared to the

dead eschar or to the surgically debrided wound. The absence of dead,

necrotic tissue prevents secondary germ's contamination and sepsis. Its

structure does not tend to readily receive a skin graft and when applied, it

may survive only for very few days due to the first stage of "graft tack" that

is a passive serum imbibition. The second and definite stage of

neo-vascularization does not proceed as readily in the interface layer as in

the surgically debrided wounds because of the relative poverty of open blood

vessels. In surgically debrided wounds the open vessels eventually support

the graft with their host/graft direct anasthomosis or budding potential.

Otherwise, this interface layer, if protected from desiccation or heavy

contamination and treated in the correct way, exhibits a remarkable potential for a spontaneous reepithelialization and healing. Once the

epithelial remnants in the skin adnexae are given the right conditions for

proliferation and propagation, the newly debrided collagen bed provides

adequate conditions for a fast reepithelialization. Fast (less than three

weeks) epithelialization prevents the formation of the granulation tissue

that eventually develops into heavy and contracted scar tissue.

Once all the dermal remnants are epithelializated (in the cases of second or

mixed depth burns) only a small percent of the originally damaged skin (usually part of the full thickness, deep-or third degree burns) remains to

treat. Correctly treated, by the end of second to fourth week post-burn,

most of the burn is healed by epithelialization and the few, relatively small

areas that are not epithelializated are clean, free of necrotic tissue and have

an adequate capillary bed to support and host a graft. At this stage, with

the patient's general condition improved, these areas may be grafted by

autogenous graft. Obviously, as the grafted area is rather small, the donor

site areas and the extent of the graft harvesting and grafting procedure is

very limited.

The conditions for the preservation of the newly debrided skin and provision

of the condition of fast, spontaneous epithelialization depends on the right

cover (such as the natural split thickness graft) of the row, debrided areas.

The required features of this cover are as follows:

- Readily available after debridement

- Adheres to the exposed, debrided areas

- Allows epithelial propagation along and under its structure

- Provides the right physical conditions (temperature, humidity, etc.)

for the wound heahng process

- Optionally provides also the important growth factors for wound

healing and epithelialization process. Thus, the main advantages of the treatment made possible by the invention

are as follows:

1. Early, complete debridement of all necrotic tissues.

2. Non-traumatic, bloodless and low-risk non-surgical debridement.

3. Accurate early assessment of damage extent (depth and surface).

4. Natural fast epithelialization of most of the burn surface with

little or no scarring.

5. Grafting of only small part of the original burned area.

6. Fast epithelialization and grafting of the debrided areas prevents

scar formation.

7. Very cost effective compared to the state of the art treatment

modahties.

The clinical implications of these advantages are:

1. prevention of tissue secondary damage propagation.

2. preservation of all viable tissue components.

3. prevention of sepsis due to tissue necrosis.

4. early diagnosis of the extent of tissue damage.

5. early enhancement of "spontaneous" skin heahng wherever it is possible

by a maximum exploitation of the tissue's entire regenerative potential . 6. autogenous grafting exclusively of the remaining full thickness defects.

Thus, the present invention provides, inter alia, a skin pre-heahng

composition, for the pre-treatment of traumatized skin, comprising an

interface layer-forming effective amount and application means of a

debriding agent. The debriding agent is present in an amount and nature

that does not interfere with unharmed tissue under or around the eschar, or

induce substantial bleeding after debridement is completed. The

debridement does not harm or dissect the normal dermis or its

collagen/elastin fibers.

According to one preferred embodiment of the invention, the debriding agent

comprises one or more enzymes. In another preferred embodiment of the

invention the debriding agent is derived from pineapple. Typical debriding

agents of this kind include, e.g., Bromelain or a derivative or fraction

thereof, such as Debridase, Escharase or Ananain.

In another aspect, the invention is directed to an early coverage set for the

protection of an interface layer of a wound debrided by a composition as

described above and promotion of its heahng, comprising a protective dressing that may be provided with Keratocyte growth promoting agent(s). According to a preferred embodiment of the invention, the Keratocyte

growth promoting agent comprises an artificial dermis. According to another

preferred embodiment of the invention, the Keratocyte growth promoting

agent comprises one or more growth hormones.

The invention further provides a method for treating a patient suffering from trauma of the skin, said method comprising the steps of:

(a) pre-treating the wound by humidification;

(b) treating the wound with a debriding agent in an amount and

for a period of time that leave the untraumatized tissues unharmed, do not promote substantial bleeding and/or contamination, and which generate an

interface layer, as defined herein;

(c) covering the debrided wound with a matrix and layer which

promotes keratocytes propagation, for a period of time sufficient to permit

spontaneous heahng of the interface layer; and

(d) grafting areas of deeper wound which were not healed through

keratocytes propagation as described in (c) above.

Preferably, but non-hmitatively, the debridement procedure is carried out

for a period of time that does not exceed 4 hours. Keratocyte propagation , in

turn, is allowed to proceed for about 2 to 4 weeks. Other objects and advantages of the invention will become apparent as the

description proceeds.

Brief Description of the Drawings

The above and other characteristics and advantages of the invention will be

more readily apparent through the following detailed description of

preferred embodiments thereof, with reference to the appended drawings,

wherein:

Figure 1 is a photography of a fresh, mixed depth, scaled burn of the

right thigh, 2% circa TBSA. Most of the keratin bhster has been

removed, the pink-reddish periphery numbered 1 (seen in greyscale in

the figure) seems to be of a second-superficial depth. The center,

white-gray area 2 is deeper and is of a second-deep (deep-dermal)

depth.

Figure 2 is a photography of the same burn of Fig. 1 after an enzymatic

debridement (Debridase for 4 hours). The periphery of the more

superficial mid depth burn shows some small capillaries punctuate

bleeding, area 3. The central deeper area 4 shows the typical aspect of

the LL. of a second-superficial (mid depth) burn with an abundant

dermis preserved. Few punctuate bleeding vessels with no active,

intense bleeding can be seen. One may note the typical granular aspect of the LL. due to the irregularity of the original damage: the

tissue around the skin adnexae is better preserved and the epidermal

remnants there presented are the source for the future heahng and

epithelialization process.

Figure 3 is a photography of a deep (nominal third degree) burn of the

arm and forearm. The burn was enzymatically debrided (Debridase for

4 hours). At the lateral and posterior aspect there are two islands of

non debrided tissue that shows clearly the eschar thickness and its

typical yellow-gray color where the original keratin exists (numbered

5) and white area 6 where the keratin was peeled off and only the full

thickness dermal eschar is present. The whitish areas marked 7 shows clearly a very thin LL. with its typical granular pinkish aspect and

shghtly bleeding capillaries. At the center, area marked 8 is a full

thickness burn with the viable fat and thrombosed vein that shows

under the LL. 7. At the right hand side, the elbow area numbered 9 is

of a somewhat thicker LL. and a less damaged dermis.

Figure 4 is a photography of a wider field and general appearance of

the figure 3 burn. One may see areas 5 and 6 of the non debrided

eschar, areas 7 of a deeper burn and thin preserved I.L., area 9 of a

thicker LL. (second deep or deep dermal burns) and areas 10 of a more

superficial burns, a thicker LL. with the typical punctuate capillary bleeding similar to area 3 in Figure 2 due to the preserved dermal

papillary layer.

Figure 5 is a photography of a deep mixed flame burn (similar in

nature to the burns in Figures 3 & 4) after a formal tangential

excision. It is evident that the nature of the debrided dermis (area 11

where the blood was wiped dry) is different from the LL. It is smooth

and shiny in comparison to the rather opaque and granular nature of

the LL. The profuse bleeding of the surgically excised skin is apparent

in comparison to the sluggish, punctuate, capillary bleeding that stops

spontaneously after a few seconds.

Figure 6 is a drawing of a soaking dressing whereas 12 represents the

dressing that is of an occlusive type (such as the M.D.O.D.)or an open,

absorbent material that moisturizes the wound's surface by capillary

transfer. Container 13 represents the germ-free soaking liquids that

may be within infusion bag or other form of container connected to the

dressing by tube 14. If a vigorous soaking is required, a draining tube 15 drains the access fluids from the wounds site into a collecting

container 16.

Figure 7 is a schematic drawing representing the piglet bioassay site

(see below) whereas 17 represents the healthy, nontraumatized skin,

18 is the area of a mixed depth burn where it is more superficial at the periphery and deeper as it approaches the center. The central area

numbered 19 is the deep, full thickness burn. The lenticular biopsy

excision 20 represents all the different areas (17, 18 and 19) of the

assay.

Figure 8 is a drawing representing the biopsy (Fig 7 no. 20) where the

different zones are represented in their cross section. Zone 21 is the

healthy skin, 22 is the rather superficial mixed (second degree) depth

burn, 23 is the deeper second degree (deep dermal) burn and 24 is the

full thickness, third degree burn.

Fig. 9 is a drawing of a unit dose debriding matrix carrier saturated with lyophihzed enzyme, with an optional rigid frame 125 made of

inert matrrials such as plastic as in figs. 10 and 11.

Fig. 10 iUustrates a placing device for the matrix carrier, with or

without the frame 225, in cross section. When pressure is applied to

the handles 41, one towards the other, possibly with one hand, the

catches 42, are moved apart from each other and the unit dose

debriding matrix carrier, 40, is released.

Fig. 11 is a drawing of a placing device for the matrix carrier in cross

section. Said device comprises a cartridge, 43, which contains one or more unit dose debriding matrix carriers, 44, may be separated one

from the other by optional protecting disks, 25. These disks may be in

the form of a rigid frame with large openings for the passage of the

debriding agent's solvent or may be a part of the matrix carrier itself

designed to contain the debriding agent and provide rigidity when

needed. Pressure is apphed on the matrix carriers and protecting disks

towards the opening of the cartridge, by a spring, 26. A spring, 29,

applies pressure on a catch, 28, and thus said catch is held in place to

prevent the release of the disks and matrix carriers. The spring loaded

trigger, 27, is pulled and the catch is moved in such a way that either

one disk or one matrix carrier is released. Thus, a matrix carrier can be

released from a protected, sterile container and placed into an accurate

position using one hand.

Fig. 12 is a drawing of a unit dose, uniform, dispersal device in cross section. Said device comprises a cartridge, 30, which contains

Debridase or other debriding powder, 31, and a spring, 32, which

apphes pressure on a disk, 33, which transfers pressure to the

debriding powder towards the opening of the cartridge. The bottom

side of the cartridge is a flat plate, 34, movable in hnear reciprocal

motion, in the directions of arrow 35. By pulhng the spring loaded

trigger, 27, said side is moved in a full cycle, i.e. in such a way that the

"peeling blade", 36, is moved from close to side 37 to close to side 38, and back to close to side 37. At the first half of each cycle, i.e. when

said "peeling blade" is moved from close to side 37 to close to side 38, a

uniform layer of powder, consisting a constant quantity of powder, is

"peeled" and released to the outside of the cartridge, and covers a

rectangular area beneath said cartridge with a homogeneous layer of

powder. The "peehng blade" 36 may be in the form of a "peeling

cylinder" that by turning releases a predetermined quantity of powder.

Figs. 13a and 13b are drawings of an example of a disposable, unit

dose, mixing device-system. Fig. 13c is a schematic partial cross-section of the round inlet 50 as herinafter described. Said system

comprises a tubular container 39 containing dry debriding powder.

Said container has an enlarged lower end 140 closed by a peel off film

141. A special plunger 142 is placed within the tubular container and

has an inferior extension rod 143 with two pairs of flexible,

hydrodynamic propelling stirring arms 144 (the superior) and 45 (the

inferior one). On the superior part of the plunger a handle 46 join the

plunger by a bi-directional joint 47 and to the other end of the handle

a "T" like jointed pressing cross bar 48. Another component of the system is a round container 49 for the debriding powder, aqueous or

liquid vehicle, solvent or activating medium gel. On its top there is a

round inlet port 50 that fits inside the lower extended end 140 of the

tubular container 39 and covered with a peel off film 51, and an inner ledge or a groove 52 in the inner surface of said port that engages the

plunger 142. A second outlet port in the center of the inferior container

surface is closed with flap or cover 54. Two elastic or other kind of

chps 55 & 56 on the container's 49 external wall hold the tubular

container of the debriding powder in place.

The quantity of the debriding agent and the solvent vehicle may be

precisely predetermine. After unchpping the tubular container 39 from

the holding chps, the peel off films 141 and 51 are removed and the

extended end 140 engages the superior, inlet port 50. After

extending-straightening the handle 46 it is pressed downward by

pressing the pressing surface 48 of the cross bar and the plunger being

pressed down pushes-extracts the debriding powder from its container

into the solvent gel. The plunger reaches and locks into the groove 52

and the two pairs of the stirring arms 144 & 45 straighten up into a

straight angle (relative to the center rod 143). The tubular container is

removed over the plunger handle that is bent parallel to the gel

container top. The pressing surface is releasing into a cross bar

position thus forming with the handle a rotating stirring crank,

rotating the stirring arms with the handle thus, mixing the powder

and gel unit doses thoroughly. When the flap cover 54 is opened the

rotation of the arms propels the mixed and activates gel-powder

mixture out of the outlet port. In other configurations the powder

container may be an integral part of the vehicle container (inside or outside) with the plunger system designed to open the communication

between the two containers, mix the components and expels the

mixture.

Detailed Description of Preferred Embodiments

The invention can be carried out using a variety of systems and means,

one of which is described hereinafter in detail for the purpose of

illustration. The different components of a system according to one

embodiment of the invention, which is useful for the new

comprehensive treatment made possible by the invention are:

1. Pre- and post- debridement sets.

2. Debridement sets.

3. Early coverage sets.

4. Late grafting sets.

5. General dressing sets.

These elements will be described in greater detail hereinafter.

1. Pre- and post-debridement preparation sets

This preparatory set is designed to provide specific means for the treatment

of the traumatized skin before and after debridement. The goal of this

treatment is to preserve as much as possible of the living tissues in the harsh conditions of a traumatized skin with impaired local circulation at the

periphery of the dead eschar and the denuded wound's bed after the

debridement of the dead eschar.

The set that provides the protective micro-environment may be composed of

an occlusive or open, non-occlusive dressing. An occlusive dressing such as

the Multipurpose Dynamic Occlusive Dressing (M.D.O.D.), (which is the

subject of a copending patent application filed by the same apphcant herein,

on the same day as this apphcation and identified as Attorney Docket no.

4132/96) may provide all the changing, dynamic needs of the wound but a combination of different occlusive and non occlusive dressings may also

fulfill the physical and chemical needs. In principle, the first needs are to

humidify the dry, traumatized tissues (dry eschar) and to provide the

necessary moisture to the surrounding tissues. A water containing

hydrating dressings, gel, soaking dressing, ointments or creams may be

used. The use of these dressings inside the M.D.O.D. or a traditional

occlusive chamber increases the efficacy and the bioactivity of the various

components and a special attention should be paid not to surpass the

therapeutic phase and in some cases, even harming the sensitive tissues. In

the case of non-occlusive dressings the danger is usually the desiccation of

the dressing and the adjacent tissues with sometimes an adverse effect of

the increased concentration of the solutes on the wound. In such cases a

change or correction of the dressing is mandatory. The M.D.O.D allows a minute control of the occlusive chamber ambient and its continuing changes

and electrical and ionophoretic enhancement of the process according to

need. The following alternative dressings may be used as pre and post

debridement environmental dressings.

1. An occlusive dressing as previously described.

2. A continuous irrigation/soaking dressing. A thick gauze or fibrous

knotted (Kerlix type) dressing with an irrigation tube that is imbedded in

the dressing and allows a continuos irrigation with the desired hquid (Fig

6).

3. A traditional heavy gauze or knotted dressing that is soaked with desired liquids at the desired intervals.

2. The debridement set.

The debridement process is designed to produce within few hours a wound

bed, clean of dead eschar and covered with the above mentioned interface

layer (LL.).

The debridement timing is important. The older the eschar is, more

susceptible it is to contain contaminating germs. The debridement process

(whether surgical or chemical) introduces these germs with their toxic

products into the blood stream causing bacteremia and toxemia. The longer the debridement process, the more germs and toxic materials are inoculated. In order to prevent this bacteremia and toxemia the debridement should be

performed on the freshest possible eschar and the process should be as short

and as fast as possible.

It is seen in photo no. 2 that the LL. (numeral 4) is the first tissue layer

immediately adjacent to the traumatized tissue and is characterized by a

normal microscopic appearance of the various structures, especially the collagen fibers but most of the patent, functioning blood vessels are not

transacted by the selective debridement process. At the level that most

traumatized vessels are debrided they are still occluded by thrombi or vasoconstriction at their end. This differs from a surgically debrided tissue

where the level of transaction is within a healthy tissue and the vessels are

transacted and bleed freely (Fig. 5) until the natural or artificially assisted

hemostasis phenomenon take place. The macroscopic representation is of a

whitish layer with few (compared to a surgically debrided tissue) bleeding points (Photo nos. 2,3,4, numeral 3,4,7,8,9,10). This layer is able to support

the first imbibition phase of skin graft "take" where the exudate serum from

the raw surface nourishes the graft. In this phase the raw dermal side of

the graft adheres to the debrided surface, protects it and serves as a matrix

for the propagation of the remaining epithelial (epidermal keratocytes) cells

that survived in the skin adnexa and at the wounds perimeters. In spite of

what was said before, in many cases (especially with thin, partial thickness

skin grafts) the LL. may also support the second stage of skin graft take: The neo-vascularization phase that is the anastomosis of some of the opened

blood vessels with some of the grafts vessels and the ingrown of capillary

endothehal buds into the graft. Meshing the graft (inserting it in a mesh

form) for expansion and drainage may also enhance the healing process.

Nevertheless, the main objective of the treatment modality is to promote

first the spontaneous healing of the wound by epithelialization and not to

graft it permanently. The autogeneous grafting procedure is reserved only

to full thickness wounds without any dermal remains that could not be

epithelialized within 2-4 weeks.

General Procedures

The specific method of producing the LL. by a chemical or enzymatic

debridement will now be fully explained through a standard in vivo,

bioassay test, comprising the following steps:

1. An anesthetized 10 kg. piglet is used for the bioassay. Its back hair

is clipped, the hair should not be shaved or dissolved with epilating

products, in order not to change the skin integrity and fine structure.

Radiant, contact and scald burns are inflicted in order to produce 5x5

centimeters mixed depth burns where the center of at least 2x2

centimeters are of a full thickness burn and the rest gradually bevels

to a superficial burn. Such burn imitates most of the clinical conditions. Ten burns for each etiologic agent, symmetrically placed

five on each side are inflicted.

2. According to the specific debriding agent the debridement procedure

may change. The debriding agent should have the following

characteristics:

- Does not harm the healthy or untraumatized tissues.

- Does not have toxic side effects in the prescribed uses.

- Fast action (very few hours; less than 12, preferably less than 4

hours).

Throughout this specification Debridase (Bromalein) (described, e.g., in

US 4226854) is used as an example for the debriding agent, it being

understood that the invention is in no way limited to any specific

debriding agent. However, as will be appreciated by the skilled person

the amount and the concentration of the debriding agent in the

debriding composition may change from one debriding agent to

another. For this reason, the appropriate interface layer-forming

effective amount of debriding agent should be determined in each case,

using the standard test described herein, or a comparable test.

After removing epithehal blisters a saline soaking dressing (such as

previously described) is applied on the burns for two hours. After the soaking the remaining epithehal bhsters and burned epidermis are removed

by rubbing it with a sahne wet gauze. An adherent barrier is applied

around the burns including 1 centimeter of healthy, undamaged skin as

first step for the MDOD occlusive dressing. The burn is sprinkled with

warm sahne at 37 centigrade or covered with thin layer of hydrating gel and

the dry Debridase is apphed in unit dose of descending values.

The unit doses may be achieved by using a unit dose debriding matrix or by

using unit dose powder sprinklers such as described later. It is possible to

mix a predetermine amount of dry Debridase in its hydrating gel using a

device as previously described but in this case the amount of enzyme that is

in actual contact with the eschar is hard to determine. It is important to be

able to determine the exact quantity of the debriding agent in order to find

its efficacy. When using the Debridase of US 4,226,854, an amount of 2

grams for 100 cm2 burn was used.

The dry enzyme is sprinkled with 37 centigrade warm sahne (5 cc. for each

100 cm2) covered with 25 cc. of hydrating gel. (according to U.S. 4,226,854)

and the occluding film is apphed over the adherent barrier in tight contact

with the debriding agent in order to exclude air. When using the M.D.O.D.,

the air may be sucked out after closure of the film. Special care is taken to

keep the piglet back temperature at 37 centigrade. After 4 hours the dressings are removed, the gel and the enzyme with or

without the carrier matrix are wiped away and the treated areas are

vigorously scraped using dry gauze, 20 times for each burn. The burns are

assessed and photographed. At this stage the overdebrided areas will show

a profuse bleeding from many vessels. A bleeding from very few bleeding

vessels does not mean overdebridement. The LL. will show as whitish

layer with an pink color showing from underneath and several punctuate,

very slowly bleeding points. This will happen wherever dermis exist. At the

center, where the burn is full thickness, the exposed fat with or without bleeding vessels shows. The underdebrided burns will appear as areas with

white or gray, partially digested eschar. Between such island of undebrided

eschar several areas of LL. may exist, as represented and described in

photographs 2, 3 and 4.

The debrided areas are soaked as previously described for 2-4 hours. After

this post-treatment soaking the wound is reassessed for the presence of I.L., eschar, bleeding vessels, exposed fat or deeper tissues.

The reassessment is confirmed by a radial inscisional biopsy containing at

one end the healthy intact skin and at the other end the deepest wound at

the center of the test area as represented and described in Figs. 7 and 8. The clinical application of the debriding set is essentially the same, using

predetermined quantities of debriding agent in occlusive dressing after

removal of the burned epithehum and blisters and soaking.

3. Early coverage set

The goal of the early cover is to promote a fast, spontaneous

epithelialization of the debrided wound by providing the optimal physical,

chemical and hormone factors needed for the remaining dermal and

epidermal components that were preserved in the debridement process.

The early cover for the debrided wound should provide the following

features:

1. Adherence: The dressing should adhere intimately to the wounds

bed in order to provide the right survival conditions for the exposed

raw tissues. The adherence preserves adequate humidity and protects

against desiccation, contamination and propagation of infection. The

adherent surfaces provide some of the necessary condition for the

Keratocytes propagation.

2. Matrix for Keratocytes (epithelial cells) propagation: The dressing

should enhance or be the matrix for the multiphcation and propagation

of the epithelial cells. These cells will originate within the skin remnants and/or may be imported to the wound's site from other areas

of the patient (autogeneous graft) or other patients (omograft). The

natural Keratocyte's matrix is the dermis thus, any graft containing

dermis that will not provoke an immune response from the host may be

appropriate. An artificial "dermis" made of various collagen fibers may

under certain circumstances serve as such a matrix (e.g. Ortec's

Composite Cultured Skin - Ortec CCS, Integra artificial dermis etc.).

3. Wound healing and epithelialization enhancement: The right

hormone growth factors apphed in the right amount and sequence is essential for an optimal epithehahzation process. Though, many of the

factors are known and some of them even synthesized, the exact combination and sequence of the entire hormone system is still

unknown. One way to overcome this problem is to graft onto the

heahng wound an exogenous source that will produce the entire

hormone system. This "hormone factory" is the epithehal cell

(Keratocyte) itself and grafting these cells either as omograft,

Keratocyte culture, cell suspension or combined biological dressing

that contain Keratocytes and a collagen matrix may serve this purpose.

The coverage set includes a biological cover with the above mentioned

features and any necessary devices, instruments or dressings (some of these may be part of the late grafting set). An example for such a coverage is the

omograft (a partial thickness skin graft of human donor) in the form of

plain sheathes or meshed. The Ortec CCS is a semi synthetic "omograft"

made of an artificial collagen layer (serving as a dermis) and live, donor's

Keratocytes suspension. In both cases the dressing's collagen layer provides

the physical condition for protection and heahng of the debrided wound and

the living cells the hormones and growing factors for the Keratocytes

multiphcation and propagation.

Other biological covers may include the Integra artificial dermis, Seprafilm

(Genzyme), and preparations combined with hving cells such as Dermagraft-TC, (Advanced Tissue Science -ATS; La JoUa, Ca), Cariel

(Medical Sciences Inc. Princeton, NJ), Aphgraft (Organogenesis, Canton,

MA ), Adcon-T.N. and Adcon-L (Ghatech inc. Cleveland).

The combination of the LL. and the coverage is the key for the optimal

healing process, where by the end of 2-4 weeks large parts or even most of the burn are covered by newly formed epithelium on a collagen (dermal)

foundation and the coverage remains sloughed off.

The process of Keratocytes propagation and wound healing enhancement may demand a dressing that will provide the adequate cover, support and

protection to the heahng wound but will not interfere with its dynamic

behavior. The traditional cottonwool derivatives such as the gauze provide

good cover and propagation environment but the Keratocytes and the

granulation tissue tend to grow into the fibers and fibers become imbedded in to the heahng and growing tissues. Dressing changes besides being a

traumatic experience to patients and personnel, disrupts the heahng

process. It has been found, and this is a furthere aspect of the invention

that a silicon impregnated dressing provides all the benefits of the gauze,

without its drawbacks by not allowing the heahng tissues ingrowth.

In several cases of extensive, deep burns some areas may still show raw bed

or with the beginning of development of granulation tissue. These areas

may need an autogeneous skin grafting (autograft) for complete closure or

be left for spontaneous heahng (by secondary intention) and scarring.

4. Late grafting set.

The late grafting set is designed to provide the means for grafting the areas that were not healed by the early debridement and enhanced heahng

procedure previously described. The grafting technique and the use of devices such as prep razor/disposable dermatomes, manual or powered

dermatomes (for skin graft harvesting), manual or powered meshers is well

rooted in the daily practice of wound treatment (US 4,690,139 and patent

application PCT/IL96/00174).

As the heahng of the grafted wound depends very much on the same factors

as the enhanced heahng of the covered I.L., a similar approach may be used

here as well. Basically the wound bed is clean without dermal or epidermal remnants that could be used as healing foci. An autograft containing

autogeneous dermis and Keratocytes is imported and spread over the

recipient bed. In cases where a large area should be covered, in order to

save healthy donor skin the small skin grafts may be meshed and thus

expanded (Patent Application PCT/IL96/00174). The heahng process and

the final results of meshed grafts are not as good as with plain sheet grafts.

The use of a heahng enhancing coverage as previously described over a

meshed autograft speeds the heahng time and the end results are much

better than without it. The use of early covers as previously described

allows the use of a very widely meshed autografts with a farther save of

donor skin. Such a cover can be used as a carrier for the meshed autograft

for an easier handhng and apphcation on the recipient site. A wound

enhancing coverage of the omograft or Ortec CCS type will serve not only as

a physical carrier and stabilizer for the meshed autograft but by performing all the roles of an early cover for a debrided wound previously mentioned,

will speed the epithehahzation of the mesh defects. A fast epithehalization

will reduce scarring and will lead to a better function and aesthetic results.

5. General dressing set.

A component of the late heahng process is the epithehahzation and the scar

modulation phenomenon. The heahng enhancing covers (such as the

omograft and the Ortec CCS) may serve as epithehahzation dressings but

they are expensive and in many cases a less costly general dressing set may be used as dressing for the epithehalizing wound. This dressing should be

able to serve as a matrix for the epithelialization process without being

incorporated and/or interfering with it. Such a dressing may be of the film

type (such as the Omiderm or Opsite type), medicated gauze ( such as the

Sofratule or Rafuracin gauze) or the specially prepared silicon-impregnated

dressing that is part of this invention and previously described.

All the above description of preferred embodiments has been provided for

the purpose of illustration, and is not intended to limit the invention. Many

modifications can be made in the various materials and methods employed.

For instance, different debriding agents can be used, or different dressings and Keratocyte growth promoting agents can be employed, all without

exceeding the scope of the invention.

Claims

Claims
1. A skin pre-heahng composition, for the pre-treatment of traumatized
skin, comprising an interface layer-forming effective amount of a debriding
agent.
2. A composition according to claim 1, wherein the debriding agent is
present in an amount that does not substantially harm untraumatized
tissue, does not induce substantial bleeding after debridement is completed,
and does not substantially remove healthy collagen or other healthy tissues.
3. A composition according to claim 1, wherein the debriding agent
comprises one or more enzymes.
4. A composition according to claim 3, wherein the enzyme is a proteolitic enzyme.
5. A composition according to claim 3, wherein the debriding agent
comprises a material selected from among maleic acid, collagenase, Trypsin,
Fibrinolisin-desoxyribonuclease, Sutilain, Streptokinase-streptodornase,
Papain, Bromelain, Debridase, Escharase and Ananain, or a mixture of two
or more of said materials.
6. A composition according to claim 3, wherein the debriding agent is
derived from pineapple.
7. A composition according to claim 6, wherein the debriding agent is
Bromelain or a derivative or fraction thereof.
8. A composition according to claim 7, wherein the debriding agent is
Debridase or Escharase.
9. An early coverage set for promoting the heahng of an interface layer of a wound debrided by a composition of any one of claims 1 to 8, comprising a
protective dermis-like dressing made of collagen or collagen derivatives or of
human or animal dermis or dermis derivatives.
10. An early coverage set for promoting the heahng of an interface layer of a
wound debrided by a composition of any one of claims 1 to 8, comprising a
protective dressing provided with Keratocyte growth promoting agent(s).
11. A set according to claim 10, wherein the Keratocyte growth promoting
agent comprises an artificial dermis.
12. A set according to claim 10, wherein the dressing is made of a
non-autogeneous graft (omo- or zynograft).
13. A set according to claim 10, wherein the Keratocyte growth promoting
agent comprises one or more growth hormones.
14. A method for treating a patient suffering from trauma of the skin,
comprising the steps of:
(a) pre-treating the wound by humidification;
(b) treating the wound with a debriding agent in an amount and
for a period of time that do not promote substantial bleeding, and which
generate an interface layer, as defined herein;
(c) covering the debrided wound with a matrix which protects the
interface layer and promotes keratocytes propagation for a period of time
sufficient to permit spontaneous heahng of the interface layer; and
(d) grafting areas of deeper wound which were not healed through
keratocytes propagation as described in (c) above.
15. A method according to claim 14, wherein Keratocyte propagation is
allowed to proceed for about 2 to 4 weeks.
16. A method according to claim 14, wherein the debridement procedure is
carried out for a period of time that does not exceed 12 hours
17. A method according to claim 14, wherein Keratocyte propagation is
allowed to proceed for about 2 to 4 weeks.
18. An impregnated, unite, silicon gauze whereby the gauze does not
adhere to the wound and promotes Keratocyte propagation along its fibers
on the debrided wound or interface layer.
19. A unit dose debriding matrix carrier, comprising a housing containing
lyophihzed or otherwise dried debriding agent, said housing being made of
porous material so as to allow passage of the debriding agent therethrough
when a liquid is apphed thereto, said carrier further having a polygonal shape such that a plurality of identical carriers can be placed around it, to
fill a wound area.
20. A placing device for a unit dose debriding matrix carrier, comprising
elastic holding means to hold the matrix in place within the device and to
release the carrier when a light pressure is apphed on the device.
21. A device according to claim 21, which comprises a container for a
plurahty of debriding matrix carriers, and means for releasing only one
carrier each time a pressure is applied on the device.
22. A placing device for a powder debriding material comprising an
ergonomic holding handle, a powder debriding agent container and means
for activating a unit dose separation and deposition mechanism such as
peeling off an accurate quantity of the powder and releasing it on a given
surface area asepticly.
23. A unit dose powder/vehicle-carrier-gel mixing and placing device
comprising unit dose powder and vehicle containers and means for joining
said containers and mixing the countenance asepticly and extracting the
mixture onto the wound.
24. a method for treating trauma of the skin, essentially as described and
illustrated.
EP19980921713 1997-05-26 1998-05-25 Compositions and means for the treatment of burns and other cutaneous traumas Withdrawn EP0983085A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
IL12090997 1997-05-26
IL12090997 1997-05-26
PCT/IL1998/000237 WO1998053850A3 (en) 1997-05-26 1998-05-25 Compositions and means for the treatment of burns and other cutaneous traumas

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Publication number Priority date Publication date Assignee Title
US7128719B2 (en) 2000-08-03 2006-10-31 Mediwound Ltd. System for enhanced chemical debridement
WO2004069147A3 (en) * 2003-02-03 2004-12-02 Mediwound Ltd System for enhanced chemical debridement
US20020106353A1 (en) 2001-02-07 2002-08-08 Wood Fiona M. Cell suspension preparation technique and device
WO2003090598A3 (en) * 2002-04-23 2005-04-21 Mediwound Ltd Apparatus and methods for enzymatic escharotomy in burn induced compartment syndrome
WO2004089406A1 (en) * 2003-04-09 2004-10-21 Torres Harold Armando Gomez Topical composition in the form of a gel for treating skin burns
CA2572895A1 (en) * 2004-07-13 2006-01-19 Mediwound, Ltd. Compositions and methods for dermatological wound healing
US8624077B2 (en) 2008-10-02 2014-01-07 L.R.R.&D. Ltd. Interface layer wound dressing

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EP0040862A1 (en) * 1979-01-11 1981-12-02 Key Pharmaceuticals, Inc. Burn matrix, method of its preparation and delivery device comprising said matrix
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
US5296222A (en) * 1989-02-23 1994-03-22 University Of Utah Percutaneous drug delivery system
EP0498532A1 (en) * 1991-01-10 1992-08-12 E.R. SQUIBB & SONS, INC. Necrotic tissue debridement powder composition containing a proteolytic enzyme
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JP2002501525A (en) 2002-01-15 application
WO1998053850A2 (en) 1998-12-03 application
WO1998053850A3 (en) 1999-08-12 application
KR20010012952A (en) 2001-02-26 application

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