Note: Descriptions are shown in the official language in which they were submitted.
53
ENZYME OINTMENT
BACKGROUND OF THE INVENTION
In~ury to body tissues is immediately followed by
acute local reaction characterized largely by a variety of
vascular changes at the site of the inJury. These changes
include the outpouring of plasma fluids, proteins, and white
6 blood cells, known collectively as exudate. This inflammatory
response to inJury is virtually identical regar~less of the
site of trauma in the body. See, Robbins & Angell, Basic
B
g Pathology 32 (2nd ed. 1976)
1 Certain prostaglandins, i.e. P5E, and thromboxanes
11 are thought to be synthesized at the trauma site and are
12 believed to be important mediators of the vascular adjustments
13 to be made in the inflammatory response of the body. See,
14 Rob~ins ~ An~,ell, Basic Pathology 38 (2nd ed. 1976). As the
prostaglandin level increases, a series of changes occur at
16 the trauma site. Platelet aggregation occurs, which is
17 followed by the release Or clotting factors such as fibrin and
18 thrombin. There is a release of en~yme blocking factors which
19 prevent fibrin dissolution and further strengthen the
response. Smooth muscle contraction then leads to decreased
21 vascular permeability, trapping excess fluid and necrotic
22 debri~ within this fortified network. The body eventually
23 completely lsolates the damaged area and the physical symptoms
2~ of edema, heat, erythema and pain become prevalent.
Thus, once sub~ected to trauma the body tends to
26 isolate and "wall-in" at the trauma site exudate 7 necrotic
27 debris, which is primarily protein in nature, and any
28 entrapped bacteria ard viruses, ~hich are primarily composed
29 Of protein and lipids. Particularly in She case of acute
trauma, which i prevalent with respect to ~kin-~urface
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in~uries, the accumulation of these substances may be
substantial if there is a significant loss of tissue. When
3 this situation occurs, the system is overwhelmed thereby
retarding tissue repair.
Plasma proteins such as plasminogen and fibrinolysin
6 and the hepatic anticoagulent heparin are usually able to
7 control inflammation during normal homeostasis. When the
8 ~ystem is overwhelmed, however, as in the case of acute
g trauma, additional aid is needed by the body to control and
alleviate the symptoms of inflamm~tion, since restoration of
11 the damaged tissue cannot be initiated until inflammation is
12 reduce~.
13 The accumulation of white blood cells as part of the
14 exudate, principally neutrophils and macrophaees, is part of
the body' 9 response to alleviate the symptoms of inflammation.
16 For instance, both neutrophils and macrophaees contain an
17 abundance of lysosomes containing proteolytic enzymes which
18 are capable of digesting protein matter and bacteria.
19 Moreover, the lysosomes of macrophages are known to contain
large qu~ntities of lipases, which are capable of digeqtine
21 the thick lipid membranes of certain bacteria. See Guyton,
22 Textbook Or Medical Physiology 70 (5th ed. 1976).
23 These defenses, however, are often inadequate to
24 effectuate rapid healing, particularly in acute skin-surface
25 ~ wounds, when there are exce~slve quantities of protein~ and
26 liquids "walled off" from the rest of the body. Thus, while
27 the human body does in fact utilize proteolytic and other
28 enzymes to effectuate an anti-inflammatory respon~e, the full
29 potential o~ these and other enæymes in con~unction wlth other
3~ sub~tances ~or the alleviation o~ skin-surface wound
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1 inflammation in a topical application has not heretofore been
2 realized.
3 It is therefore an ob~ect of the present invention
4 to provide co~positions whereby effective wound-healin~
amounts of proteolytic and other enzymes, in conjunction with
6 other wound-healing ~ubstances, may be topically applied to a
7 skin-surface wound.
8 It is another object of the present invention to
9 enhance the normal anti-inflammatory activity of proteoly~ic
enzymes.
11 It is yet another object of the present invention to
12 provide substances in a composition which act synergistically
13 to reduce swelling and pain at the site of skin-surface trauma
14 and degeneration.
Other ob~ects and advantages of the invention will
16 become apparent upon consideration of the accompanying
17 disclosure.
18 BRIEF DESCRIPTION OF TH~ INVENTION
19 The compositions of the present invention are
ointments comprising a carrier mixture of penetrating and
21 non-penetrating emollient oils and a polyhydric alcohol
22 emollient; the proteolytic and other enzymes papain,
23 bromelain, trypsin, chymotrypsin, pancreatin, lipase and
24 a~ylase; aloe extract; and an organic astringent agent. The
carrier mixture, enzymes, aloe extract and the organic
26 astringent agent function synergistically so as to provide an
27 effective wound-healing topical ointment.
28 DETAILED DESCRIPTION OF THE INVENTION
The general pathology o~ wound~processes involved in
overt skin-~urface degeneration (ulcer~) and traumatic wounds
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l (cuts, bruises, etc.) has been discussed herein~bove, alon~
~ with the action of certain enzymes in the healing process.
3 The natural limitations of the human body in the
4 healing process, however, creates a need to expedite healing
thereby decreasing the discomfort experienced by the afflicted
6 1ndividual.
7 In this regard, the compositions Or the present
8 invention are formulated so as to deliver w3und-healing
g amounts of proteolytic enzymes to the scarred or otherwise
traumatized site, in conjunction with reparative qua~tities of
ll an aloe extract, an organic astringent agent, lipase, amylase,
12 and carrier emollient oils. The phrase "wound-healing" as
13 used herein is intended to refer to the process of tissue
14 repair and to the reAuction of symptoms of inflam~ation
present due to the body' 9 response to the cellular disruption
16 of skin-surface mammalian tissue which is either traumatic, as
17 in the case of a burn or cut, or on the other hand,
18 representative of a degenerative proce~s, such as an ulcer.
19 As an essential ingredient, the compositions of the
present invention include a plurality of proteolytic enzymes,
21 which generally function to hydrolize or to lyse proteins into
22 their component amino acids, thereby providing these essential
23 amino acid3 in nutritionally adequate amounts. Fibrolytic,
24 proteolytic enzymes po3sess the added capacity to lyse or
digest fibrin clot~ at wound sites. This action tends to
26 reAtore the free ~low of blood through the circulatory system
27 thereby accelerating the healing process at wound ~ites and
28 minimizing the development of scar ti~sue.
29 Moreover, proteolytic enzymes are believed to aid in
the prevention of blood platelet aggregation, to increa~e
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~2~2~3
l tissue permeabllity and to enhance the natural proteolytic and
2 fibrlnolytic activity of the blood. Proteolytic enzymes ha~e
3 also been implicated as inhibitors of the en2yme~blocking
4 factors previously discussed. In effect, these anti-
inflammatory agenSs are prostaglandin inhibitors. Thus 7 the
6 compositions of the invention will comprise one or more of the
7 proteolytic enzymes streptokinase, urokinase, trypsin,
8 chymotryp~in, papain, bromelain and pancreatin. In a
g preferred embodiment, all Or these enzymes except
streptokinase and urokinase are contained in the composition.
ll Trypsin and chymotrypsin have been demonstrated to
12 be successful in the dissolution of the clotting factor
13 fibrin, necrotic tis~ue and proteinaceous exudates. When
14 applied topically to post-thrombotic leg ulcers, they have
shown remarkable success in acceleratine the healing process.
16 See, C.ordon, The Use of Topical Proteolytic Enzy~es in the
17 Treatment of Post-thrombotic Leg Ulcers, Brit. J. Clin. Prac.,
18 29, 143 (1975). Moreover, trypsin and chymotrypsin are
l9 thought to have a favurable influence on the inflammatory
process in thromophlebitis. It is expected that streptokinase
21 and urokinase would exhibit similar actions when applied
22 topically in an active form, and may be used in addition to,
23 or as replacements for, the trypsins.
24 While trypsin and chymotrypsin are often used in
25 1! combination for the prevention and treatment of inflammati~n
26 from in~ury, each may be used in the formulation of the
27 pre~ent invention withouS the other. Preferably, trypsin will
28 make up about .025-2.5~ by weight and chymotrypsin about
29 .001-1~ by ~eight of the compositions of the pre~ent invention
and most preferablyi about .05-1% and .002~ , respectively.
--5--
53
l Papain has been reported to achieve excellent
2 results in promoting the healine of wounds. See, Hwang & Ivy,
3 A Review of the Literature on the Potential Therapeutic
4 Significance of Papain, Annals N.Y. Acad. Science, 54, 151
(1951-52). Indeed, papain has demonstrated clinical efficacy
6 as a local agent to debride or solubilize collections of
7 proteinaceous materials in an anti-inrlammatory role. See,
8 Emele et al., The Analgesic-Anti-Inflammatory activity of
9 Papain, Arch. int. Phar~acodyn., 159, 126 (1966). Moreover,
papain acts not only upon ~ibrinogen, the precursor of fibrin,
ll and other proteins, but alqo to destroy certain bacteria and
12 viruses which may be contained in the wound. See, Hwang &
13 Ivy, A Review of the Literature on the Potential Therapeutic
14 Significance of Papain, Annals N.Y. Acad. ~Scl_nce, 54, 161
(1951-52).
16 Papain is considered to be clinically efficacious in
a topical application in removing clotted blood, purulent
18 exudate and necrotic ti3sue from skin-surface wounds and
l9 ulcers. Preferably, papain will make up about .05-5% by
weight of the compositions according to the invention and most
21 preferably, about .1-2%.
It has been proposed that the proteolytic thiol-
enzyme ("SH-enzyme") bromelain acts to selectively inhibit the
biosynthesi~ of proinflammatory prostaglandins, Quch as the
platelet-aggregating thromboxane~. The use of bromelain is
26 indicated since the endogenous proteases such as circulatin~
27 plasmin, trypsin, chymotrypsin, and lipa~es are inhibited by
28 trauma or exposure to excessive str0s~. Bromelain also acts
on fibrinogen and fibrin to yield products ~imilar to those
formed by plasmin and which stimulate the biosynthesis of
--6--
l anti-inflamatory prostaglandins such as PGI2. Indeed, it has
2 been reported that the efficacious results achieved in
3 revers~ng the inflammatory state may be a direct action of
4 bromelain on the proteins, including fibrin, deposited at the
trauma site. See, S.J. Taussig, ~ed. Hypth., 6, 99 (1930), and
6 J.M. Miller et al. Exptl Med. Surg., 22, 277 (1964).
7 Preferably, bromelain will make up about .05-5~ by
8 weight o~ the total enzyme component of the composition
9 according to the invention and most preferably, abo~lt .1~2~.
The compositions of the invention will also
ll preferably incorporate an amount of pancreatin, or of the
12 individual primary enzymes incorporated therein, or of
13 mixtures of the individual enzymes with pancreatin.
14 Pancreatin primarily contains amylase, protease and lipase;
digestive enzymes which act to break down dietary starch,
16 protein and fat, respectively. Since pancreatic deficiency or
17 overload is implicated in many situations involving wounds, it
18 is believed that a supplemental amount o~ pancreatin is a
l9 beneficial adjunct to the administration of the fibrinolytic
and anti-inflammatory enzymes. Pancreatin aids in the
21 restoration of normal digestive processes, including the
22 proper metabolism of fats, which is necessary for the
achievement of e~fective plasma levels of anticlotting and
antiinflammatory prostaglandins. Pancreatin and/or its
component enzymes preferably compri e up to about .1-10% by
26 weight o~ the compositions of the present invention, most
27
preferably about .2-2%.
28 The compositions of the present invention will also
29
preferably include topically wound-clean~ing amounts of
pancreatic digestive enzymes such aq lipa es and~or amylases,
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1 which are thought to effect the fats and carbohydrates
2 contained in the structure of bacteria and viruses. For
3 instance, many types of viruses possess an outer cell envelope
4 composed of protein, lipid and carbohydrate constituents.
Amylase and/or lipase, in conjunction with the proteolytic
6 enzymes of the present invention, are thought to act
7 synergistically to degrade the cell envelope and protein an~
8 lipid components of the virus particle so as to inactivate the
9 pathenogicity of viruses contained in or entering the wound.
Similarly, the cell wall and me.~brane of many
11 strains of bacteria are rich in proteins, carbohydrates and
12 fat~. Consequently, a topical application of the compositions
13 of the invention are thought to act on the cell wall and
14 membrane of the bacterial cell leadin~ to the lysing of the
microorganism with a consequent loss of virulence. In this
16 manner, wound-healing is aided by the control of infectious
17 microorganisms.
18 Preferably, the pancreatic digestive en~yme~ such as
19 lipase and amylase will each make up about .01-5% of the
compositionC of the present invention and most preferably,
21 about .05~
22 In order to enhance the reparative qualities of the
~ hereinbefore discussed enzymes, the compositions according to
24 the invention may also include an aloe extract and an organic
astringent agent.
26 The aloe extract, which iQ preferably incorporated
27 as an aloe concentrate, e.g. aloe vera or aloe perryi
concentrate, is thought to promote healing and has been
applled aY a soothing cream to skin-surface wound~, burns and
~car ti~sue. In addition to being a rapid penetrator o~ the
~2~5~3
1 ~ariou~ ~kin layer~, the aloe extract contains enzymes which
~ promote the removal of dead skin ~hile ~timulating the normal
3 ~rowth of livin~ ti~ue. As defined herein, the term "aloe
4 extract" refers to the inspissated Juice of the aloe plant as
well as to its dried concentrates which contain aloe-emodin,
aloin or other active anthraquinone principles.
7 The preferable organic astringent agent is witch
~ hazel, a herb ~ubstance which ha~ demonstrated effectiveness
9 as an astringent for the treatment Or itchin~, skin
irritations and burns., This compound acts to inhibit the
11 pathological transcapillary movement of plasma protein thereby
12 reducins inflammation, edema and exudation. Witch hazel has
13 been u~ed in an anti~eptic capacity for the healing of wounds
14 and for cleansing the skin surface.
The composition~ of the pre~ent invention may also
16 include one or more of a mixture of carrier emollients of a
17 penetrating emollient oil, a non-penetrating emollient oil and
18 a polyhydric alcohol emollient.
Preferably, the penetrating emollient oil will be
ethoxylated lanolin. In addition to its skin softening
21 propert~es, lanolin is known to be er~ect~ve as a mois~urizer
22 and lubricant. The ~ubstance penetrates into the skin sur~ace
quickly and is quite beneficial when applied to skin-surface
wound~ ~ince lt acts to prevent a dre~sing ~rom sticking to
the wound~ Thi~ ef~ecti~e penetra~or al~o acts to repleni~h
26 Yaluable lipids in the wound area. Other characteristics of
27 lanolin are ~i~clo~ed in U.S. Patent No. 2,47~,820
28
29
U~eful compound~ of thls type are formed by the conden~aticn
o~ about 10-80 moles of ethylene oxlde per ~ole o~ lanolin or
~.~zz~53
l ~ by the llnking of ~orbltol and lanolin w~th a polyoxyethylene
2 1l chain containing 10-80 mole~ Or ethylene oxlde.
3 Particularly useful compounds o~ this type are
4 commercially available from ICI Americas, Wilmington, Del. as
Atla~ G-1790 (20 mole~ of ethylene oxide~mole of lanolin),
¦1 AtlaY~ G-14~1 (40 mole~ of ethylene oxide linking ~orbitol and
7 l~ lanolin) and Atlas~ C 1471 ~75 moles of ethylene oxide llnking
8 l ~orbitol and lanolin).
9 1I The preferred non-penetrating emollient oil is
lO 1l petrolatum, which is known to aid in restoring the natural
texture Or the ~kin ~urrace. Unlike ethoxylated lanolin,
12 I petrolatum i~ a non-penetrating moisturizer and lubricant for
13 ii the ~kin surface and a~ such, act~ to aid in the topical
14 ll act~on Or the compo~ition of the present invention.
15 I The preferred polyhydric alcohol emollient is
6 ll glycerin. Its main utility is in moi~turizing the ~kin and
!I providing a medium solvent. It is also reported to pos~e~
¦I therapeutic uses ~uch a~ itq application to reduce corneal
l9 ll sdema. See, Remington's Pharmaceutical Sciences, A. O~ol ed,
2 1i Mack Pub., Boston, Ma~s. (16th ed. 1980) at page 1255.
21 ll The weight percent of the carrier emollient~ i
1 sub~tantially greater than that o~ any Or the other components
23 of the invention. Preferably, the carrier emollient~ compri3e
about 85-99~ o~ the total weight Or the compo~1tion~ of the
presen~ invention and mo~t preferably, about 93-97~.
26 1
~7 ¦ The compo~itions Or the present in~ention may alYo
I include one or more antibaeterial pre~ervatiYes, pre~erably
2~ 1 from the C1-C4 lower alkyl benzoates such as ~ethyl and propyl
paraben, each with a total weight percent in the compo~ition~
Or about .025-1.5~; preferably.
... , . _ .. .. . __ _. ,. _ . . _ . _ ... _ . _ . . _ . . . . . . . .. . . .. . .
~L222~;3
l I The total weight percent Or the components of the
2 ,I compo~itions Or the pre~ent invention may be varied over a
3 1! wide range. For example, the weight percent of all of the
4 enzymes in the compositionq is preferably ~bout .2-20% and of
S ~ust the proteolytic enzymes, about .2-15~. The weight
6 Ij percent of aloe extract preferably ranges rrom about .05_3
7 and the weight percent of the organic astringent agent
8 preferably rangeq from about .o6-3~.
9 Thus, ln a preferred embodiment of the composition
according to the invention, the respecSive weight percents
11 I would be as follows: enzymes, .2-20%; aloe extract, 0.02-10%,
12 or preferably .05-3~; organic aqtringent agent, .025-ô~, or
13 . pre~erably .06-3~; petrolatum, 40-80%; ethoxylated lanolin,
14 , 5_30~; glycerine 5-30~, and preservative~ .05-3%.
lS ,I Preferably, the compo~itions of the pre~ent
16 . invention will be formulated ~uch that the total enzyme
17 ll component will comprise, by weight, papain, about 15-40%;
l 1, trypsin, about 5-15S; chymotrypsin, about .2-.6%; bromel~in,
about 10-30~; pancreatin, about 30~50%; lipase, about 2-8~;
l and amylase, about 2-8~.
¦l The wound-healing, reparative quality of the
ointment may be erfectuated by means of the method according
~j to the pre~ent invention. The method compr-i~es the topical
¦ adminiqtration of an effective amount of the hereinabove
!l di~cussed composition~ to traumatic or degenerative skin-
26 il
I' surface wounds.
27 ',
ij The ointmeDts are typ~cally prepared by ~irst mixing
2~ ll
Il the carrier emollients. A 3econd homogeneou~ mixture of
29
en~ymes and aloe extract i~ then slowly incorporated into a
¦ 3mall a~ount vf the carrier emollient mixture. The re~ultant
~2~2~53
!l
paste i~ then added to the remainder o~ the carrier emollient
Il mixture while mixing in a mixer. A second homogeneous paste,
3 ll composed of the organic astringent agent and a ~mall quantity
4 o~ the carrier emollient mixture ls then added to the mixer
5 and mixing o~ all the component~ is continued until the
6 I compo3it~0n begins to solidify. At this time~ the compo~ition
7 ll ls poured into a tube filling apparatus, pre~sure is applied
8 ll and the ointment ls tubed.
9 !I The invention will be ~urther described by reference
lO I to the following detailed example.
1 I! EXAMPLE - ENZYME OINTMENT
12 ~1 A melt o~ 15,162 g of petrolatum, 4,364 g of
13 1 ethoxylated lanolin and 3,50g g of glycerin was prepared in a
14 I stainless steel container. Small amounts of a ~econd
l5 i homogeneous mixture of 252 g o~ pancreatin, 153 g papain, 113
16 ll g of bro~elain, 25 g of lipase, 25 g of amylase, 60 g of
1 j tryp~in, 2.~ ~ of chymotrypsin and 42 g of aloe vera powder
8 ll extract ~ere added to small quantities of the melt in a 2
Il gallon ~tainless steel container. The resultant paste was
2 1l added to a larger quantity of the melt while mixing untll
l 1I homogeneous in a "J.H. Day~ mixer.
Il A second paste wa~ made of 84 g of witch hazel
23 1 extract and a small amount of melt. ~hen the paste ~a~
I homogeneous, lt was added to the fir3t paste with mixing.
25 ~ When the homogeneous mixture began to 901idify, it wa~ poured
i, ~nto a "Colton~ tube ~iiling machine and one ounce tubes were
illed under 30 lbs. pres~ure.
The o~ntment of this inv~ntion has been u~ed in the
29 treatment of ~uperflcial wounds and bru~es and haR been
¦ reported as e~fectlve ~or such applications in providing
I
122Z~ 3
1 Isymptomatic relie~. The recommended mode of application ~ to
2 ' apply a thin layer of the oint~ent to the afflicted area and
3 optionally cover ~ith a sterlle gauze dres~ing.
Q ~q a re~ult of the present invention, a novel
ointment for skin-3urf`ace wound-heallng has been provided.
6 ¦ Although a preferred embodiment of the prlnciple~ of this
7 ¦, invention ha~ been deqcribed in detail herein, it should be
8 ll realized that the 3ame are not limited to the particular
g l' embodiments described and that modification~ thereof` are
10 I contemplated and can be made without departing from the broad
plrit and 3cope of thiq invention a~ defined in the appended
12 Ij claims.
13
14
1 5 1 '
6 I
7 !
18 1!
19
21
2-
27
29
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