U.S. patent application number 15/949956 was filed with the patent office on 2018-08-16 for formulation for topical wound treatment.
The applicant listed for this patent is HASAN CICEK, AHMET KILIC. Invention is credited to HASAN CICEK, AHMET KILIC.
Application Number | 20180228904 15/949956 |
Document ID | / |
Family ID | 50735897 |
Filed Date | 2018-08-16 |
United States Patent
Application |
20180228904 |
Kind Code |
A1 |
KILIC; AHMET ; et
al. |
August 16, 2018 |
FORMULATION FOR TOPICAL WOUND TREATMENT
Abstract
The present invention relates to new formulations, particularly
useful in the topical treatment of skin and orormucosal wounds.
Formulations can be either a solution or a gel form consisting of a
Polyhexamethylene biguanide as an antimicrobial agent, purified
water and a tri-blockcopolymer, particularly a triblockcopolymer of
polyethylene oxide and polypropylene oxide, and more particularly a
poloxamer.
Inventors: |
KILIC; AHMET; (BRAUNSCHWEIG,
DE) ; CICEK; HASAN; (GOETTINGERN, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KILIC; AHMET
CICEK; HASAN |
BRAUNSCHWEIG
GOETTINGERN |
|
DE
DE |
|
|
Family ID: |
50735897 |
Appl. No.: |
15/949956 |
Filed: |
April 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15111916 |
Jul 15, 2016 |
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PCT/EP2015/050857 |
Jan 19, 2015 |
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15949956 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 17/02 20180101;
A61K 47/18 20130101; A61K 47/34 20130101; A61K 31/155 20130101;
A61L 26/0052 20130101; A61L 26/0019 20130101; A61K 47/26 20130101;
A61K 36/328 20130101; A61K 47/10 20130101; A61L 26/0066 20130101;
A61L 26/0023 20130101; A61K 9/006 20130101; A61K 9/06 20130101;
A61L 2300/30 20130101; A61L 2430/34 20130101; A61L 2300/404
20130101; A61L 2300/206 20130101; A61L 26/0057 20130101; A61L
26/008 20130101; A61K 47/38 20130101; A61K 9/0014 20130101; A61K
36/30 20130101; A61K 36/30 20130101; A61K 2300/00 20130101; A61K
36/328 20130101; A61K 2300/00 20130101; A61K 31/155 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 47/34 20060101
A61K047/34; A61K 9/00 20060101 A61K009/00; A61K 47/18 20060101
A61K047/18; A61K 47/10 20060101 A61K047/10; A61K 36/30 20060101
A61K036/30; A61K 31/155 20060101 A61K031/155; A61K 36/328 20060101
A61K036/328; A61L 26/00 20060101 A61L026/00; A61K 9/06 20060101
A61K009/06; A61K 47/38 20060101 A61K047/38; A61K 47/26 20060101
A61K047/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 20, 2014 |
TR |
201400655 |
May 14, 2014 |
EP |
14168228.6 |
Nov 24, 2014 |
EP |
14003947.0 |
Claims
1-15. (canceled)
16. A formulation consisting of polyhexamethylene biguanide,
purified water and at least one poloxamer for use in the topical
and/or oromucosal treatment of wounds.
17. The formulation according to claim 16, consisting of 0.1%
polyhexamethylene biguanide by weight, 1.0% poloxamer by weight and
98.9% purified water by weight.
18. A formulation consisting of polyhexamethylene biguanide,
purified water, humectant, gelling agent and at least one poloxamer
for use in the topical and/or oromucosal treatment of wounds.
19. The formulation according to claim 18, consisting of 0.1%
polyhexamethylenbiguanid (PHMB) by weight, 1.0% poloxamer by
weight, 8.6% humectant, 1.8% by weight hydroxyethyl cellulose and
88.5% purified water by weight.
20. The formulation according to claim 19, wherein the poloxamer is
selected from poloxamer 124, poloxamer 188, poloxamer 237,
poloxamer 338 and poloxamer 407.
21. The formulation according to claim 20, wherein the poloxamer is
poloxamer 188.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention particularly relates to gel and
solution formulations containing polyhexamethylene biguanide
(PHMB), purified water and tri-blockcopolymers of polyethylenoxide
and polypropylenoxide, which are used for wound treatment.
PRIOR ART
Wound Treatment
[0002] The integrity of the structures forming the skin and mucosa
deteriorates due to various reasons. A wound is a lesion that
occurs as a result of a disruption of the damaging of tissue
integrity of the body due to an external trauma. Soft tissue
defects or open wounds may result from a variety of events
including, but not limited to trauma, burns, diabetic ulcers,
severe infections, such as necrotizing fasciitis, venous stasis
disease, and pressure ulcerations. Microorganisms are present in
all type of wounds, although number, virulence, species and mixture
can vary.
[0003] Today, various topically applied solutions and gels are used
for disinfection through cleaning of wounds and body surfaces. The
formulations used in the prior art contain Polyhexamethylene
biguanide (PHMB) and excipients such as surface active agents
and/or gelling agents. However, such antiseptic components
contribute to wound healing only by cleansing and protecting the
wound from pathogenic microorganisms.
[0004] Hereinafter Polyhexamethylene biguanide is referred to as
PHMB.
[0005] The effectiveness of the existing products is cleaning the
layers on the wound surface particularly at the chronic wounds and
ensuring wound antisepsis. The wound surface contains layers such
as wound exudate, excised and thickened fibrin layers, necrotic
tissue and cell debris, etc. Such layers provide a suitable medium
for the pathogenic microorganisms to infect the wound. Even in the
absence of infectious microorganisms, removal of the layers on the
wound surface and cleaning and disinfection of the wound is an
extremely important factor for accelerating recovery process.
[0006] In the mixtures used for the treatment of the wound in the
prior art, PHMB is a suitable compound as a microbicide substance
with good tissue tolerance. Wound treatment products containing
PHMB and a surface active agent in liquid or gel formulations are
present [1, 2]. However, those products might produce cases such as
failure to ensure satisfactory protection, to cleanse the wounds
from harmful substances, to ease the pain, to accelerate cell
reproduction and cell regeneration, incompatibility with supporting
treatments, and inability to provide enough moisture [3].
[0007] It is observed that the active ingredients or excipients
from fully synthetic origins are used in wound treatment. Taking
into consideration the fact that the acute or chronic wounds might
be a systemic disease, hence, intake of another synthetic substance
might pose an extra risk for the patient. Povidone-iodine might be
a good example for such subject matter. Povidone-iodine is used as
a pharmaceutical antimicrobial and antiviral agent against
microorganisms affected by iodine. It is readily absorbed by the
tissue and contains iodine at a rate that might disturb the thyroid
function tests. Another example to this subject matter is
chlorhexidine gluconate. Chlorhexidine gluconate is also readily
absorbed by tissues and affects all cells without any
discrimination. Moreover, it accumulates in the livers and might
affect the liver functions. Such formulations with synthetic
content affect the body functions and might lead to problems that
have a negative impact on human health.
Formulations with PHMB
[0008] One of the patents in the literature concerning this subject
matter is the patent EP1404311 B1 [1]. The application entitled
"Wound treatment agent" is formulated for use as a washing or
shower gel, as a moisturizing gel or as a moist wound covering, as
a dissolving gel for dissolving incrustations or scabs from body
surfaces or wounds or for removing dressings and for changing moist
dressings. Said formulation contains PHMB, minimum one unbranched
fatty acid derivative surfactant and hydroxyethyl cellulose.
However, the application does not contain any compound that
accelerates cell reproduction, cell regeneration; provides
anti-inflammatory effects, or enhances collagen formation at the
wound. Such an ingredient does not have any direct contribution to
the healing process of the wound but may have indirect contribution
by protecting and cleaning the wound. Besides, EP1404311 B1 teaches
the synergistic effects of Polyhexanid and betaine type amphoteric
surfactants in wound treatment [1]. However, a recent publication
showed that use of said formulation may have negative effect on the
further treatment of wounds [3].
[0009] DE 100 12 026 B4 discloses a gel containing PHMB, glycerin
and hydroxyethyl cellulose. It has been recognized that PHMB has
microbicidal activity as well as distinctive conserving activity. A
cytotoxic activity, as e.g. known for chlorhexidine was not
observed. However this formulation does not include a surface
active agent, which is important for a formulation that is claimed
to be used as a washing or shower gel, as a moisturizing gel or as
a moist wound covering, as a dissolving gel for dissolving
incrustations or scabs from body surfaces or wounds or for removing
dressings and for changing moist dressings.
Formulations with Surfactants
[0010] As mentioned above, EP1404311 B1 [1] discloses a formulation
containing PHMB, and minimum one surfactant, which is stated to be
a derivative of an unbranched fatty acid, and overcomes the problem
of DE 100 12 026 B4.
[0011] Surfactants are commonly added to cleaning and healing
formulations in view of their surface activity. Surfactants are
compounds that lower the surface tension (or interfacial tension)
between two liquids or between a liquid and a solid. Surfactants
may act as detergents, wetting agents, emulsifiers, foaming agents,
and dispersants.
[0012] It is emphasized that the surfactants preferred in
combination with PHMB are amphoteric or non-ionic surfactants,
because of the structural property of PHMB, which is neutralized by
anionic surfactants. Thus, when anionic surfactants are used, the
microbicidal activity of PHMB is affected, which is
undesirable.
[0013] The surfactant in the EP1404311 B1 is preferably selected
from a glycine derivative and/or a sulfosuccinate and/or an amide
based on an unbranched fatty acid. Furthermore, it is stated that
the preferred surfactant for this formulation is a betaine and, in
particular, an amidoalkyl betaine of a fatty acid.
[0014] Sulfosuccinate derivatives of fatty acids are present at a
specific pH (isoelectric point) in a nonionic form and in this way
they are used in the patent EP1404311 B1, although they are
structurally anionic molecules. The nonionic structure, however, is
not a structural form but a physical state that changes according
to the environmental conditions and can be described as a
pseudo-nonionic state. Therefore it is not comparable to real
non-ionic surfactants, which do not carry any negative (-) or
positive (+) charge in any case.
[0015] Betaines are zwitterion chemical compounds with a positively
charged cationic functional group such as a quaternary ammonium or
phosphonium cation (generally: onium ions) which bears no hydrogen
atom and with a negatively charged functional group such as a
carboxylate group which may not be adjacent to the cationic
site.
[0016] It is disclosed that fatty acid sulfosuccinate and fatty
acid amides can also be used in the formulation either together
with glycine derivatives of fatty acids or as an alternative to
them. Fatty acid amides are nonionic molecules. They are
synthesized through an amidization reaction of a fatty acid and an
amine.
[0017] Thus, none of the above surfactants commonly used in
combination with PHMB is non-ionic independent of the surrounding
pH. The surfactants thus may interact with PHMB and alter its
efficacy. Further formulations with PHMB and betaine type
amphoteric surfactants may have negative effect on the further
treatment of wounds [3].
Formulations with Polymers
[0018] The patent application DE 10 2010 013 075 A1 discloses
antimicrobial wound dressings comprising a polymeric substrate and
a composition with an antimicrobial active agent (in particular
PHMB) and a cytotoxicity reducing agent selected amongst others
from betaine-derivatives. The preferred polymeric substrates are
polyurethanes due to their high liquid-absorbing abilities. The
application thus uses the well-known formulations containing PHMB
and betaine-derivatives for producing wound dressings. The polymers
disclosed in the application are used in order to produce the
polymeric substrate into which the active ingredient and surfactant
are incorporated and hence the formulation comprises wound
dressings but no wound treatment agents. Additionally, the
application areas, i.e. as a washing or shower gel, as a
moisturizing gel or as a moist wound covering, as a dissolving gel
for dissolving incrustations or scabs from body surfaces or wounds
or for removing dressings and for changing moist dressings, which
are claimed in the patent EP 1404311 B1, are not mentioned or
claimed in the patent application with the number DE 10 2010 013
075 A1. Therefore, said patent deals only with a wound dressing
formulation but not a wound treatment agent formulation.
Herbal Ingredients
[0019] The medicinal properties of many plants have been identified
with specific chemical compounds which have been isolated, purified
and, in many cases, synthetically reproduced. Many well-known drugs
were originally derived from plants. Salicylic acid the precursor
for aspirin, was originally isolated from White Willow bark and the
Meadowsweet plant. Quinine, which is used to treat malaria, was
derived from Cinchona bark. Vincristine, which is used in cancer
treatment, comes from Periwinkle. Perhaps most famous are morphine
and codeine, which are derived from the Opium Poppy.
[0020] Modern physicians, particularly in the United States, tend
to rely on treatments using synthetic or chemically manufactured
drugs. Rather than using whole plants or plant extracts for
treatment, pharmacologists tend to identify, isolate, extract and
synthesize the active compounds from plants for use in treatment.
This approach, however, has drawbacks. In addition to individual
physiologically active compounds present in a plant, there are also
minerals, vitamins, glycosides, oils, alkaloids, bioflavonoids, and
other substances which can be important in supporting the medicinal
properties of a particular plant. These additional substances can
provide a synergistic effect which is absent when purified or
synthetic physiologically active compounds are used alone.
Additionally, the toxicity of purified physiologically active
compounds is generally higher than when the physiologically active
compounds are present with the other plant substances. The efficacy
of various herbal remedies, extracts, potions and treatments is
well known, and therapeutic herb products are increasingly
recognized as desirable alternatives. U.S. Pat. No. 4,886,665
teaches the use of a pharmaceutical preparation of oats and nettle
extracts. U.S. Pat. No. 4,671,959 discloses the use of mixtures of
natural oils for stress reduction. U.S. Pat. No. 5,064,675 relates
an herbal extract composition, which provides a calming effect.
U.S. Pat. No. 5,407,675 discloses an herbal extract used for scalp
treatment. U.S. Pat. No. 5,178,865 discloses an herbal extract mix,
which inhibits infection of human immunodeficiency virus or HIV in
vitro.
[0021] U.S. Pat. No. 5,500,340 and U.S. Pat. No. 5,294,443 disclose
the use of herbal extracts for immunosuppression and treatment of
autoimmune disorders.
[0022] One patent in the literature concerning this subject matter
is the patent application No. WO 2009106963 A2 entitled Dental
composition for preventing and treating stomatitis and mouth
ulcers. Said composition comprises Myrrh resin as fluid extract and
chloride or other soluble zinc salt; wherein a glycyrrhetic acid is
added to the Myrrh resin, to the disinfecting substance and to the
soluble zinc salt. However, said formulation includes Myrrh fluid
extract, which was not prepared as tincture by apple cider
vinegar.
[0023] The present invention deals with the drawbacks of the prior
art, i.e., amongst others, i) the relatively high toxicity of
commonly employed surfactants, in particular betaine-derivatives;
ii) the regularly observed inactivation of microbicidal agents such
as PHMB by commonly employed surfactants, iii) the pH-dependent
surface activity of commonly employed surfactants, iv) negative
effects of amphoteric surfactants on further treatments.
[0024] In conclusion, the technique of the prior art mentioned
above fails to provide solutions to the existing problems, and thus
an improvement in the concerned technical field is required.
OBJECTIVE OF THE INVENTION
[0025] The present invention relates to a formulation used for
wound treatment which meets the aforementioned requirements,
eliminates all disadvantages and introduces some additional
advantages.
[0026] The preferred objective of the invention is to develop a
formulation used topically for treatment of wounds, thus preventing
any negative outcomes that might affect human health when compared
to formulations of the prior art by virtue of the fact that the
formulation contains the tri-blockcopolymers of the present which
are amphiphilic, non-toxic and have non-ionic properties and thus
have beneficial effects on the treatment of wounds, as will be
described below. Such tri-blockcopolymers are preferably
tri-blockcopolymers from polyethylene oxide and polypropylene oxide
and more particularly poloxamers.
[0027] Another objective of the present invention is to support the
healing process under an acidic pH medium or basic pH medium by
using said tri-blockcopolymers. Chronic wounds have alkali
environment and wound healing starts in acidic environment [4].
Therefore said compounds facilitate the healing process by
providing surfactants that work independent of the surrounding
environmental pH.
[0028] Another objective of the present invention is to use the
formulation for treatment of acute or chronic oromucosal wounds
through topical applications as being produced in liquid and gel
form.
[0029] Another objective of the present invention is to treat
patients suffering another systemic disease by virtue of the
tri-blockcopolymers without any toxic effect on the body. In this
manner, any risks on health are prevented.
[0030] A similar objective of the present invention is its use for
the treatment of the wounds through topical applications as the
formulation is produced in solution and gel form.
[0031] Another objective of the present invention is its use as a
bath or shower gel for cleaning body surfaces from harmful
materials by virtue of microbicide effect. Besides, its use in
wound dressing as a gel and solution form which facilitates
removing and changing the bandage is also present.
[0032] In order to fulfill the aforementioned objectives; the
present invention comprises a solution formulation containing PHMB,
purified water (e.g. distilled water or deionized water), and
tri-blockcopolymers used for topical treatment of skin and
oromucosal wounds.
[0033] In order to fulfill the aforementioned objectives, the
present invention provides a production method of the liquid
formulation for topical treatment of skin and oromucosal wounds
comprising the process steps of adding and mixing polyhexamethylene
biguanide (PHMB) and purified water (Solution A), and adding and
mixing solution A to tri-blockcopolymers to get the end
product.
[0034] In order to fulfill the aforementioned objectives, the
present invention provides a gel formulation containing PHMB,
purified water, tri-blockcopolymers, and a gelling agent used for
topical treatment of skin and oromucosal wounds.
[0035] In order to fulfill the aforementioned objectives, the
present invention provides a production method of the gel
formulation for topical treatment of skin and orornucosal wounds
comprising the process steps of adding gelling agent to purified
water and mixing thereof by heating, followed by adding PHMB,
cooling the mixture obtained to room temperature (Solution B), and
finally adding and mixing solution B to tri-blockcopolymers to get
the end product.
[0036] The structural and characteristic properties of the
invention and all advantages introduced shall be understood more
clearly by virtue of the detailed description given below and
therefore evaluation should be performed taking this detailed
description into consideration.
DETAILED DESCRIPTION OF THE INVENTION
[0037] In this detailed description, the preferred embodiments of
the formulation used for wound treatment of the invention are
described for a better understanding of the invention without any
limitations.
[0038] The present invention relates to a wound healing formula
comprising at least one antimicrobial active substance and at least
one triblockcopolymer, which is amphiphilic, non-toxic and has
non-ionic properties.
[0039] The present invention pertains to the use of
tri-blockcopolymers that have amphiphilic properties and are
non-ionic, in particular amphiphilic tri-blockcopolymers from
polyethylene oxide and polypropylene oxide, more particularly to
poloxamers and even more particularly to poloxamer 188 in
combination with PHMB for the treatment of persons and animals
suffering from acute or chronic wounds, for example, in wound
antiseptics, wound irrigation solutions, ointments, creams, gels,
solutions and wound dressings.
[0040] Products containing such active substances do not have a
harmful effect on human tissue. This is of even greater importance
if such products come into contact, not only with healthy skin, but
especially for products used in wound treatment.
[0041] The invention has two different fields of application as gel
and liquid formulations. The main ingredients commonly used in said
gel and liquid forms are as follows:
MAIN INGREDIENTS
Polyhexamethylene Biguanide (PHMB) (Cas No: 32289-58-0)
[0042] Polyhexamethylene biguanide is a powerful cationic
antiseptic derived from biguanide with wide spectrum polymeric
structure showing high tissue compatibility. It has strong
antimicrobial effect due to its selective binding property to
acidic lipids on bacterial cell membranes. PHMB has a broad
spectrum of activity against Gram-positive and Gram-negative
bacteria, fungi, yeasts, viruses and biofilms. It is widely used
for the treatment of local infections. The tissue compatibility of
PHMB based on its activity against the acid lipids contained within
the bacterial cell membranes and minor effect on the neutral lipids
of human cell membranes. This helps to prevent damage to the
surrounding healthy tissue. Therefore it can be applied over a long
period of time due to its low toxicity. In addition, PHMB is less
likely to cause allergic reactions, sensitization or
resistance.
[0043] EP 1404311 B1 teaches the synergistic effects of
Polyhexanide and betaine type amphoteric surfactants in wound
treatment [1]. However, a recent publication showed that use of
said formulation may have negative effect on the further treatment
of wounds [3].
[0044] In another formulation a mixture of polyhexanid, various
surfactants and some excipients such as allantoin that may present
in the comfrey extract used as wound dressing formulation. In fact
said study deals with a wound dressing formulation and does not
take the synergistic effect of other biomolecules that present in
the extract of comfrey such as rosmarinic acid, mucilage, tannins
and inulin with allantoin in to consideration [5].
Emulsifying Agent (Surfactant)
[0045] As surfactant, tri-blockcopolymers are used in the
formulation as emulsifying/wetting/surface active agent. Said
tri-blockcopolymers are preferably amphiphilic and have non-ionic
properties.
[0046] In a preferred embodiment, the tri-blockcopolymers are
tri-blockcopolymers of polyethylene oxide and polypropylene oxide.
Tri-blockcopolymer of polyethylene oxide and polypropylene oxide
are amphiphilic, non-ionic and relatively non-toxic surfactants.
Due to these properties, they are particularly preferred in the
present invention. Due to the amphiphilic property, they have
superior cleaning efficiency on the wound to be treated. Because of
their surface active nature they reduce the surface tension on
skin, hence they minimize the adhesion of microorganisms on wounds
thus prevent development of infection. Due to the non-ionic
property, they do not interact with PHMB and after its efficacy,
compared to other surfactants that are anionic or change their
charge depending on the surrounding pH. Due to the non-toxicity,
they are beneficially used in formulations for wound treatment in
combination with PHMB.
[0047] A particularly preferred kind of tri-blockcopolymer of
polyethylene oxide and polypropylene oxide are poloxamers described
below.
[0048] Poloxamers are amphiphilic, non-ionic and relatively
non-toxic surfactants. Poloxamers are synthetic tri-blockcopolymers
of polyethylene oxide and polypropylene oxide, and have the
following chemical structure (I) and general formula (II) (FIG.
1).
##STR00001##
FIG. 1: Molecular structure and general formula of poloxamer
[0049] Various grades of poloxamer are included in the PhEur 6.0
and USP32-NF27. The PhEur 6.0 states that a suitable antioxidant
may be added. Poloxamer types differ in the number of ethylene
oxide (a) and propylene oxide units (b). Generally, `a` is in
between 2 to 130 and `b` is in between 15 to 67, although it will
be appreciated that: other values for `a` and `b` are also
possible. (a) and (b) values in several poloxamer types are listed
in table 1.
TABLE-US-00001 TABLE 1 (a) and (b) values in various poloxamer
types: Poloxamer a b 124 12 20 188 80 27 237 64 37 338 141 44 407
101 56
[0050] Poloxamers generally occur as white, waxy, free-flowing
prilled granules, or as cast solids. They are practically odorless
and tasteless. Poloxamers are stable materials. Aqueous solutions
are stable in the presence of acids, alkalis, and metal ions. They
are nonionic polyoxyethylene-polyoxypropylene copolymers used
primarily in pharmaceutical formulations as a dispersing agent,
emulsifying agent, solubilizing agent, tablet lubricant, wetting
agent, gelling agent and thickener. The polyoxyethylene segment is
hydrophilic while the polyoxypropylene segment is hydrophobic.
[0051] The chemical name of poloxamer is
.alpha.-Hydro-.omega.-hydroxypoly(oxyethylene)poly(oxypropylene)
poly-(oxyethylene) block copolymer.
[0052] All of the poloxamers are chemically similar in composition,
differing only in the relative amounts of propylene and ethylene
oxides added during manufacture. Their physical and surface-active
properties vary over a wide range and a number of different types
are commercially available. Poloxamers are used as emulsifying
agents in intravenous fat emulsions, and as solubilizing and
stabilizing agents to maintain the clarity of elixirs and syrups.
Poloxamers (Cas No: 9003-11-6) may also be used as wetting agents;
in ointments, suppository bases, and gels; and as tablet binders
and coatings.
[0053] Chemical properties of poloxamer types included in the PhEur
6.0 and USP32-NF27 are shown in Table 2.
TABLE-US-00002 TABLE 2 Chemical properties of most known Poloxamers
are as follows: pH, 2.5% Cloud Cloud Molecular Pour/Melting aqueous
point, 1% point, 1% Poloxamer Physical Form Weight Point solution
Solution Solution 124 Liqiud 2390-2363 16.degree. C. 5.0-7.5
65.degree. C. 71-75.degree. C. 188 Solid 7680-9510 52.degree. C.
5.0-7.5 >100.degree. C. >100.degree. C. 237 Solid 6840-8830
49.degree. C. 5.0-7.5 >100.degree. C. >100.degree. C. 338
Solid 12700-17400 57.degree. C. 5.0-7.5 >100.degree. C.
>100.degree. C. 407 Sol d 9840-14600 56.degree. C. 5.0-7.5
>100.degree. C. >100.degree. C.
[0054] Poloxamers are amphiphilic molecules. The Polypropylene
oxide center consists of the hydrophobic core, whereas polyethylene
oxide chains consist of the hydrophilic part of the molecule.
Because of their surface active nature they reduce the surface
tension on skin, hence they minimize the adhesion of microorganisms
on wounds thus prevent development of infection.
[0055] Poloxamers may also be used therapeutically as wetting
agents in eye-drop formulations, in the treatment of kidney stones,
and as skin-wound cleansers.
[0056] Particularly preferred poloxamers used in the present
invention can be selected from poloxamer 124, poloxamer 188,
poloxamer 237, poloxamer 338 and poloxamer 407, whose properties
are summarized in Table 2 above. Among these poloxamers, poloxamer
188 is particularly preferred.
[0057] Poloxamer 188 has been used as an emulsifying agent for
fluorocarbons used as artificial blood substitutes, and in the
preparation of solid-dispersion systems. More recently, poloxamers
have found use in drug-delivery systems.
[0058] Therapeutically, poloxamer 188 is administered orally as a
wetting agent and stool lubricant in the treatment of constipation;
it is generally used in combination with a laxative.
[0059] The addition of the non-toxic surfactant poloxamer 188 to a
fine-pore-size sponge minimizes the tissue damage, while
maintaining the bacterial removal efficiency of mechanical
cleansing. Its innocuous property prevents irritation of patient's
conjunctiva. This wound cleanser does not alter the wound's
resistance to infection and healing, nor the cellular components of
blood. Although, it exhibits no antibacterial activity, it
minimizes the adhesion of microorganisms on wounds thus prevents
the development of infection.
[0060] Other poloxamers that may be used in the present invention
are Poloxamer 338 and 407. Poloxamer 338 and 407 are used in
solutions for contact lens care. Studies on poloxamer 407, which
shows thermoreversibie properties, for optimizing drug formulation
temperature have demonstrated immunomodulation and cytotoxicity
promoting properties.
[0061] Poloxamers are branded under two categories by BASF Corp.,
namely Pluronic and Kolliphor. Pluronic brand is for use in the
cosmetic industry as oil-in-water emulsifiers, cleanser for mild
facial products, and dispersing agent, whereas Kolliphor brand is
for use as medical instrument or drug excipient.
[0062] Poloxamers are used in a variety of oral, parenteral, and
topical pharmaceutical formulations, and are generally regarded
nontoxic and non-irritant materials. Poloxamers are not metabolized
in the body. Animal toxicity studies, with dogs and rabbits, have
shown poloxamers to be non-irritating and non sensitizing when
applied 5% w/v and 10% w/v concentration to the eyes, gums, and
skin. In a 14-day study of intravenous administration at
concentrations up to 0.5 g/kg/day to rabbits, no overt adverse
effects were noted. A similar study with dogs also showed no
adverse effects dosage levels up to 0.5 g/kg/day. In a longer-term
study, rats fed 3% w/w or 5% w/w of poloxamer in food for up to 2
years did not exhibit any significant symptoms of toxicity.
However, rats receiving 7.5% w/w of poloxamer in their diet showed
some decrease in growth rate. No hemolysis of human blood cells was
observed over 18 hours at 258 QC, with 0.001-10% w/v poloxamer
solutions.
[0063] Included in the FDA Inactive ingredients Database (IV
injections; inhalations, ophthalmic preparations; oral powders,
solutions, suspensions, and syrups; topical preparations).
[0064] Included in non-parenteral medicines licensed in the UK.
Included in the Canadian List of Acceptable Non-medicinal
Ingredients.
FURTHER EXCIPIENTS
Purified Water
[0065] In the present invention, purified water is preferably used
in the formulations. Purified water can in particular be obtained
by distilling water or deionizing water. Thus purified water in the
present application relates to water that is mechanically filtered
or processed to be cleaned. Distilled water and deionized (DI)
water are the most common forms of purified water, but water can
also be purified by other processes including reverse osmosis,
carbon filtration, microfiltration, ultrafiltration, ultraviolet
oxidation, or electrodialysis.
[0066] In the present invention, distilled water is preferably
used.
Co-Surfactants
[0067] The formulation may additionally contain further
co-surfactants to improve the solubility of any herbal ingredients
that may be added (cf. description below) or to further reduce the
cytotoxicity of the formulation.
[0068] The patent EP1404311 B1 teaches synergistic effect of PHMB
and some amphoteric surfactants, which are to be glycine,
sulfosuccinate and Amide derivatives of an unbranched fatty acid.
Said patent claims a formulation including PHMB and an unbranched
fatty acid derivative surfactant. Additionally, the patent claims
that unbranched fatty acid derivative has to be glycine,
sulfosuccinate or amide derivative. The surfactants described in EP
1404311 B1 can also be used in the present invention as
co-surfactants in combination with the tri-blockcopolymers.
However, the surfactants described in EP 1404311 B1 may not always
be preferably for wound treatment formulations.
[0069] It has presently been found that amphoteric surfactants
other than the unbranched fatty acid derivatives described in EP
1404311 B1, present at least the same synergistic effect.
[0070] Such surfactants are described in the following and are
particularly used in the present formulations.
[0071] When a surfactant exhibits both anionic and cationic groups,
it is called amphoteric or zwitterionic. Although they carry
positive and negative charges on different atoms in an aqueous
solution at their isoelectronic point, they are electrically
neutral. Depending on the composition and conditions of pH value,
the surfactants can have anionic or cationic properties. However,
some amphoteric surfactants are resistant to pH and their net
charge is not affected by pH change. Amphoteric surfactants can be
classified mainly in 3 groups, betaine, amine oxide and imidazolium
derivatives. Betaines on the other hand can be divided in three
subgroups, namely glycine betaine, sultaine and phostaine. Glycine
betaine is the natural form of betaine and bears a carboxylic group
(FIG. 2a), whereas sultaine bears a sulfopropyl group (FIG.
2b).
##STR00002##
FIG. 2: General structure of alkyl betaines (a) and alkyl sultaines
(b). R: long chain branches of an unbranched alkyl (saturated) or
alkenyl (unsaturated) group.
[0072] The co-surfactants according to the present invention are
preferably selected from glycine, sulfosuccinate and amide
derivatives of an unbranched fatty acid, alkyl betaines, alkyl
sultaines, alkyl amine oxides, alkyl imidazolium derivatives and
panthenol derivatives. Among these, the co-surfactants according to
the present invention are more preferably selected from alkyl
betaines, alkyl sultaines, alkyl amine oxides, alkyl imidazolium
derivatives and panthenol derivatives. Amine oxide and imidazolium
surfactants can also be an unbranched fatty acid derivative. On the
other hand, betaines type surfactants can be selected from fatty
alcohol or amine derivatives. The antimicrobial activity of said
surfactants is well known [6-8].
[0073] Of said co-surfactants, alkyl betaines, alkyl sultaines,
alkyl amine oxides, alkyl imidazolium derivatives and panthenol
derivatives are preferred as the co-surfactants for the present
formulations. The alkyl group in either case can be branched or
unbranched having 8-18 carbon atoms, preferably 10-16 carbon atoms
and most preferably 10-14 carbon atoms. Moreover the alkyl group
can be either saturated or unsaturated carbon chain. Preferred
alkyl betaines include Lauryldimethylbetaine (Cas No: 683-10-3),
Cocobetaine (Cas No: 68424-94-2), Myristyl betaine (Cas No:
2601-33-4), Decyl betaine (Cas No: 2644-45-3), Lauryl sultaine (Cas
No: 14933-08-5), Oleyldimethylbetaine (Cas No: 871-37-4),
Dodecylbetaine (Cas No: 55142-08-0), Caprylyl betaine (Cas No:
27593-14-2), and Behenyl betaine (Cas No: 26920-62-7). Preferred
amine oxides include Lauramine oxide (Cas No: 1643-20-5),
Lauramidopropylamine oxide (Cas No: 61792-31-2), Cocamine oxide
(Cas No: 61788-90-7), Cocamidopropylamine Oxide (Cas No:
68155-09-9), Myristamine oxide (Cas No: 3332-27-2),
Soyamidopropylamine Oxide (Cas No: 223707-70-8). Preferred
imidazoline surfactants include Disodium cocoamphodiacetate (Cas
No: 68650-39-5), Disodium lauroamphodiacetate (Cas No: 14350-97-1),
Sodium lauroamphoacetate (Cas No: 26837-33-2), Disodium
cocoamphodipropionate (Cas No: 68604-71-7), Sodium cocoamphoacetate
(Cas No: 68334-21-4).
[0074] Furthermore, panthenol derivative cationic surfactants can
also be used in the formulation. An example of this type of
cationic surfactants is panthenyl hydroxypropyl steardimonium
chloride (Cas No: 132467-76-6) and depicted in FIG. 3.
##STR00003##
FIG. 3: Structure of Panthenyl hydroxypropyl steardimonium
chloride. R is CH.sub.3(CH.sub.2).sub.17--
[0075] Panthenol (Cas No: 81-13-0) is the alcohol derivative of
pantothenic acid (vitamin B5), and is thus a provitamin of B5.
Panthenol improves hydration, reduces itching and inflammation of
the skin, and accelerates the recovery of epidermal wounds. Besides
being a derivative of Panthenol, panthenyl hydroxypropyl
steardimonium chloride carries a quaternary ammonium group, which
may present additional antimicrobial activity to the
formulation.
[0076] It is noted that panthenol derivative surfactants are
particularly preferred as the co-surfactants for the present
formulations.
[0077] However, the selection of the co-surfactant is not limited
as long as it is suitable for contact with the skin and wounds and,
exclusively, does not cause any increase in cytotoxicity and induce
any damage to the wound.
Gelling Agents
[0078] Gelling agents, usually polymers are used in the gel
formulations to decrease the mobility and increase the viscosity of
a product. They build a three-dimensional network in a formulation
so that intermolecular forces bind the solvent molecules to the
polymeric network, and thus the reduced mobility of these molecules
results in a structured system with increased viscosity [9].
[0079] Gelling agent used in the gel form of said formulation can
be either a cellulose derivative or another commercially available
gelling agent. Preferred gelling agents are cellulose derivatives
(e.g. methyl cellulose, hydroxypropyl methyl cellulose,
carboxymethylcellulose, hydroxyethyl cellulose) and/or modified
acrylic acid polymers (e.g. carbopol), either alone or in
combination.
[0080] Cellulose, a .beta.-glucose polymer is a major constituent
of the plant cell wall. It is a linear condensation homopolymer
consisting of .beta.-1,4 linked D-anhydroglucopyranose units (AGU).
Cellulose derivatives are obtained by adding functional groups to
cellulose polymer through a chemical or enzymatic process. There
are many cellulose derivatives commercially available and used in
formulations for several purposes (i.e. gelling agent, thickener,
binder, film former). The preferred cellulose derivatives and CAS
numbers are listed in table 3. However any other cellulose
derivative may also be used in order to get gel form of the present
invention either alone or in combination with other gelling
agents.
TABLE-US-00003 TABLE 3 Examples to commercially available cellulose
derivatives Cellulose Derivative CAS NO Methylcellulose 9004-67-5
Hydroxypropyl Methylcellulose 9004-65-3 Hydroxyethyl
Methylcellulose 9032-42-2 Hydroxyethyl cellulose 9004-62-0
Carboxymethylcellulose 9000-11-7 Sodium Carboxymethylcellulose
9004-32-4
[0081] Other preferred gelling agents are known under the trade
name POLYOX.TM., which are non-ionic poly (ethylene oxide) polymers
that form hydrogels that initiate and regulate release of active
ingredients. Because of their non-ionic structure no interaction
between the active ingredients of the formulations and the POLYOX
is to be expected.
[0082] Another preferred gelling agent is carhoxypolymethylene (CAS
No: 9007-20-9), also known as Carbopol, which is a modified acrylic
acid polymer. In the molecular structure of carbomer, there are
many carboxyl groups, a property that allows increasing the volume
in the presence of water. When dissolved in water, carbopol
molecules change their configuration and increase the viscosity of
the liquid, resulting in the formation of a gel. Although there are
several subtypes of the said carbomer, they are available under the
trade name Carbopol.RTM.. Some carbopol types that can be used in
the formulation of the present invention and their CAS numbers are
given in table 4.
TABLE-US-00004 TABLE 4 Some Carbopol types and their CAS numbers
Carbopol Type CAS No Carbopol 940 9003-01-4 Carbopol 934 [USAN:NF]
9007-16-3 Carbopol 907 82642-95-3 Carbopol 941 9062-04-8 Carbopol
Ultrez 10 195739-91-4 Carbopol 5984 139637-85-7
[0083] Although preferred gelling agents are to be in non-ionic
form, anionic molecules (i.e. carboxymethylcellulose and carbopol)
can also be used in the formulation in the presence of a cationic
excipient, which may be a co-surfactant (e.g. Panthenyl
hydroxypropyl steardimonium chloride, Cas No: 132467-76-6). In fact
a study showed that negatively charged polysaccharides as
carboxymethylcellulose, bind growth factors, which are important in
wound recovery [10, 11].
Humectants
[0084] Skin dryness is an additional limiting factor in wound
healing. Humectants (also named Humidifiers or Moisturizing agents)
are molecules used in formulations to increase the moisture content
of the skin. Hereinafter such components will be referred to as
humectant. Humectants prevent skin from drying by binding moisture.
Humectants can be chosen form commercially available humectants.
Preferable humectants are beta-sitosterol, inositol, glycerin,
urea, glyceryl stearate, panthenol, propylene glycol, polyethylene
glycol and its derivatives (i.e. methyl gluceth 10 and methyl
gluceth 20), and Xylitol.
[0085] Another preferred humectant is hydroxyethyl urea (Urea,
NN-(hydroxyethyl)-; Cas No: 1320-51-0), which is for example
available under the trade name Hydrovance.RTM..
Herbal Excipients
[0086] The World Health Organization has estimated that about 80%
of the world population relies on herbal medicines for their
primary health care needs. Since botanical medicine is the most
frequently encountered of these therapeutic agents, it is safe to
say that the majority of the people in the world rely on plants as
medicine. During the past 25 years, about 25% of all prescription
drugs in the U.S. contain active constituents obtained from
plants.
[0087] Extract and tincture obtained from following plants are used
in the formulation as herbal content:
Comfrey (Symphytum officinale L.) Herb Extract (Cas No:
84696-05-9)
[0088] Comfrey herbs are perennial herbaceous plants that can grow
30-120 cm, that has a body structure covered with hard hair and
that blooms white, purple and rarely pink flowers from mid of June
to end of September. The roots of said plant contain pyrrolizidine
alkaloids. Pyrrolizidine alkaloids (PAs) are capable of generating
some side effects on the human health [12]. Therefore, said
formulation is produced with the extract obtained from the aerial
part of the plant.
[0089] Comfrey has a centuries-old tradition as a medicinal plant.
Today, multiple randomized controlled trials have demonstrated the
efficacy and safety of comfrey preparations for the topical
treatment of pain, inflammation and swelling of muscles and joints
in degenerative arthritis, acute myalgia in the back, sprains,
contusions and strains after sports injuries and accidents, in
adults as well as in children aged 3 or 4 and over [13].
[0090] The extract is used in the formula as an agent that reduces
the cytotoxic effects of antimicrobial active ingredients.
Moreover, therapeutic properties of the Comfrey plant based on
anti-inflammatory and analgesic effects, it induces granulation and
is used for wound treatment as it supports tissue regeneration
[14]. The German Commission E positively assessed compounds
containing Comfrey (Symphytum officinale L.) herb in treatment of
wounds. European Medicines Agency approved the use of this plant on
skin. European Scientific Establishment issued an availability
report for Comfrey herb in Phytotherapy Monographs [15]. In
addition, Comfrey is also described in Hager Monographs [16].
[0091] The therapeutic properties of comfrey are based on its
anti-inflammatory and analgesic effects [17]. Comfrey also
stimulates granulation and tissue regeneration, and supports callus
formation. However, the key activity-determining constituents of
comfrey extracts and its molecular mechanisms of action have not
been completely elucidated. Allantoin and Rosmarinic acid are
probably of central importance to its pharmacodynamic effects
[18].
[0092] Hereinafter Comfrey (Symphytum officinale L.) herb extract
referred to as herbal extract or herbal substance or herbal
excipient.
Myrrh (Commiphora Molmol) Tincture (Cas No: 84929-26-0)
[0093] Myrrh (Commiphora molmol) is the aromatic resin of a number
of small, thorny tree species of the genus Commiphora, which is an
essential oil, termed as an oleoresin. The tincture is used in the
formulation as a natural anti-bactericide and anti-fungicide with
limited bioavailability [19].
[0094] In pharmacy, myrrh is used as an antiseptic in mouthwashes,
gargles, and toothpastes for prevention and treatment of gum
disease. Myrrh usage in oromucosal wound treatment as tincture is
demonstrated in the clinical studies. Myrrh is currently used in
some liniments and healing salves that may be applied to abrasions
and other minor skin ailments. Myrrh has also been recommended as
an analgesic for toothaches, and can be used in liniment for
bruises, aches, and sprains. The oleo gum resins of a number of
other Commiphora species are also used as perfumes, medicines (such
as wound dressings), and incense ingredients. Other fields of use
include wound, abscess and dermal inflammation treatment.
[0095] Gum resin of Commiphora molmol Engler and/or other species
of Commiphora, complying with the monograph of the European
Pharmacopoeia (01/2008:1349) is used for tincture production.
Sesquiterpenes that present in myrrh are furanodesma-1.3-diene,
curzarene, furanodiene, furanodiene-6-one and
metyhoxyfuranoguaia-9-ene-8-one. It is reported that they have
antibacterial, antifungal, analgesic and local anesthetic
effects.
[0096] The current use of myrrh in the form of tincture for
oromucosal treatment of minor ulcers and inflammation in the mouth
(stomatitis and gingivitis) is well documented in recent handbooks
[20].
[0097] Another current use of myrrh tincture is the topical
application to minor wounds, abrasions, furuncles and skin
inflammations [20]. Despite the extraction solvent of myrrh
tincture according to Ph. Eur. Monograph (01/2008:1877) is 90%
(v/v) ethanol, in this formulation the solvent is preferably apple
cider vinegar.
[0098] Ethanol has a tendency to denature some organic compounds,
rendering them ineffective. This is one reason why ethanol is an
antimicrobial agent. This tendency can also have undesirable
effects when extracting botanical constituents, for instance,
polysaccharides. Certain other constituents, common among them
proteins, can become irreversibly denatured, extracted for highly
complex aromatic components that are denatured by alcohol's
intrinsic cleaving action upon an aromatic's complex structure into
simpler inert-rendered compounds. A basic tenet of organic
chemistry teaches that denaturation of biologically viable
component will reduce or negates its prior biological viability.
This fact must be considered by the clinician and/or consumer from
both the standpoint of efficacy and dosage when choosing
ethanol-based botanical tinctures.
[0099] Ether and propylene glycol based tinctures are not suitable
for internal consumption, although they are used in preparations
for external use, such as personal care creams and ointments
[21].
[0100] During the past 50 years there have been tremendous advances
in cultivation and extraction techniques that have resulted in
improvements in the quality of botanical substances that are
available. Research is demonstrating that crude extracts often have
greater therapeutic benefit than the isolated `active` constituent.
An extract is a concentrated form of the herb obtained by mixing
the crude herb with an appropriate solvent and then removing the
solvent.
[0101] The strengths of herbal preparations are expressed in two
ways. In terms of concentration, a 4:1 concentration means that one
part of the herbal extract is equivalent to or derived from four
parts of the crude herb.
[0102] A tincture usually has a concentration of 1:10 v/v
(herb/solvent) or 1:5 v/v (herb/solvent); while a fluid extract is
usually 1:1 v/v (herb/solvent). In this formulation, however, the
tincture concentration is 1:3 v/v (herb/solvent).
[0103] For the competence concentration of an extract, there may be
great variation in the quality of an herb from batch to batch and
in extraction techniques that may cause further variation from the
standard. If the most important plant constituent is known, an
extract can be assayed for standard amounts of that constituent.
This method is generally accepted in Europe, where crude botanical
extracts have been used and standardized in this way for many
years. With this method dosages are based on active
constituents.
[0104] Hereinafter Myrrh (Commiphora molmol) tincture referred to
as herbal extract or herbal substance or herbal excipient.
FORMULATIONS ACCORDING TO THE PRESENT INVENTION
Formulations According to the Present Invention Comprising PHMB and
Tri-Blockcopolymers
[0105] The formulation is preferably provided in two forms, which
are gel and solution:
[0106] The formulation used for topical and oromucosal treatment of
wounds according to the present invention comprise
polyhexamethylene biguanide (PHMB) as active agent, purified water
as solvent and at least one tri-blockcopolymer according to the
present invention.
[0107] The tri-blockcopolymers according to the present invention
are amphiphilic. They further are non-toxic and thus can be added
to formulations for wound treatment. The tri-blockcopolymers
further are non-ionic, such that they do not interfere with the
active agent PHMB, as compared to anionic surfactants that reduce
the bactericidal activity of PHMB due to reacting with it.
Furthermore the tri-blockcopolymers are non-ionic, independent from
the surrounding pH. Thus the tri-blockcopolymers can be used for
the treatment of open wounds that often have a basic environment or
in combination with acid components that are used to generate an
acidic environment on the wound, such that wound healing can
start.
[0108] Particularly preferred tri-blockcopolymers are
tri-blockcopolymers of polyethylene oxide and polypropylene oxide.
Said tri-blockcopolymers of polyethylene oxide and polypropylene
oxide are amphiphilic, non-toxic and non-ionic.
[0109] One kind of tri-blockcopolymers of polyethylene oxide and
polypropylene oxide are poloxamers, which are particularly
preferred in the present invention. Particularly preferred
poloxamers used in the present invention can be selected from
poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338 and
poloxamer 407, whose properties are summarized in Table 2 above.
Among these poloxamers, poloxamer 188 is particularly preferred.
However, several different tri-blockcopolymers of polyethylene
oxide and polypropylene oxide or some other co-surfactants (i.e.
Panthenyl hydroxypropyl steardimonium chloride, Cas No:
132467-76-6) described above may be used in combination.
[0110] In a preferred aspect, the formulation is a solution
comprising 0.05-10.0% Polyhexamethylene biguanide (PHMB) by weight,
0.1-40% tri-blockcopolymer by weight and completed to 100% by
adding purified water in order to act the final wound treatment
solution.
[0111] In yet another preferred aspect, the formulation is a gel
comprising 0.05-2.0% Polyhexamethylene biguanide (PHMB) by weight,
0.1-40% tri-blockcopolymer by weight, 1.0-10.0% Humectant by
weight, 0.5-5.0% gelling agent by weight and completed to 100% by
adding purified water in order to get the final wound treatment
solution.
[0112] In another preferred aspect, the humectant is selected from
glycerine and hydroxyethyl urea.
[0113] In another preferred aspect, the formulation comprises at
least one co-surfactant. Such co-surfactants may improve the
solubility of any herbal ingredients that may be added or to
further reduce the cytotoxicity of the formulation.
[0114] The preferred concentration of co-surfactants in any
formulation is 0-2% by weight, more preferably 0.01-2% by weight,
even more preferably 0.05-1% by weight and most preferably 0.1% by
weight.
[0115] The co-surfactants according to the present invention can be
chosen freely, as long as they are suitable for contact with the
skin and wounds and, do not cause any increase in cytotoxicity or
induce any damage to the wound.
[0116] The co-surfactants according to the present invention are
preferably selected from glycine, sulfosuccinate and amide
derivatives of an unbranched fatty acid, alkyl betaines, alkyl
sultaines, alkyl amine oxides, alkyl imidazolium derivatives,
unbranched fatty acid derivatives of amine oxide and unbranched
fatty acid derivatives of imidazolium. Among these, the
co-surfactants according to the present invention are more
preferably selected from alkyl betaines, alkyl sultaines, alkyl
amine oxides and alkyl imidazolium derivatives. On the other hand,
betaines type surfactants can be selected from fatty alcohol or
fatty amine derivatives. The alkyl group in said compounds can be
branched or unbranched having 8-18 carbon atoms, preferably 10-16
carbon atoms and most preferably 10-14 carbon atoms. Moreover the
alkyl group can be either saturated or unsaturated carbon
chain.
[0117] Of said co-surfactants, alkyl betaines, alkyl sultaines,
alkyl amine oxides, alkyl imidazolium derivatives and panthenol
derivatives are preferred as the co-surfactants for the present
formulations. The panthenol derivative surfactants are particularly
preferred as the co-surfactants for the present formulations.
[0118] The alkyl betaines are preferably selected from
Lauryldimethylbetaine, Cocobetaine, Myristyl betaine, Decyl
betaine, Lauryl sultaine, Oleyldimethylbetaine, Dodecylbetaine,
Caprylyl betaine, and Behenyl betaine. The alkyl amine oxides are
preferably selected from Lauramine oxide, Lauramidopropylamine
oxide, Cocamine oxide, Cocamidopropylamine Oxide, Myristamine
oxide, and Soyamidopropylamine Oxide. The imidazoline derivatives
are preferably selected from Disodium cocoamphodiacetate, Disodium
lauroamphodiacetate, Sodium lauroamphoacetate, Disodium
cocoamphodipropionate and Sodium cocoamphoacetate. The panthenol
derivative is preferably selected from Panthenyl hydroxypropyl
steardimonium chloride.
[0119] In a preferred aspect, the formulation may further comprise
a substance substances obtained from herbs, as described above.
Such substances obtained from herbs may have the beneficial
properties described above in the according section.
[0120] Thus, in a preferred aspect, the formulation in form of a
solution or a gel further comprises a substance/substances obtained
from herbs. The substance/substances obtained from said herbs
is/are preferably Comfrey (Symphytum officinale L) herb extract
and/or Myrrh (Commiphora molmol) tincture. It is noted that the
formulations according to the present invention also has beneficial
effects compared to those commonly used when no such
substance/substances obtained from said herbs is/are used. However,
the addition of substance/substances obtained from said herbs may
further improve the effect of the formulations according to the
present invention.
[0121] The substance/substances obtained from herbs is/are
preferably Comfrey herb extract and/or Myrrh tincture. The Comfrey
herb extract is preferably obtained from the leaves of comfrey
herb.
[0122] However, the formulations according to the present invention
do not require the presence of substances obtained from herbs. Also
a formulation in form of a solution or gel as described above, not
containing any substances obtained from herbs can have the desired
effect for the treatment of wounds. In this respect it is noted
again that the tri-blockcopolymers, in particular poloxamers
according to the present invention, are amphiphilic, non-toxic and
non-ionic surfactants and thus can be used in combination with PHMB
for the treatment of wounds with the desired beneficial
effects.
[0123] The use of additional substances obtained from herbs may
thus simply further increase the beneficial effect already obtained
by using PHMB with tri-blockcopolyrners according to the present
invention.
[0124] Accordingly, in one aspect, the formulation in form of a
solution or a gel thus does not contain any substance/substances
obtained from herbs. As described above, substance/substances
obtained from herbs may have beneficial effects for the treatment
of wounds. However it has been recognized that also PHMB with
poloxamer alone (i.e. without any substance/substances obtained
from herbs) can have the desired effect on wounds. Thus, a
formulation comprising PHMB and poloxamer in addition with other
excipients such as purified water, co-surfactants, humectants and
gelling agents may be used, without adding any substance/substances
obtained from herbs.
[0125] Thus, in a preferred aspect, the formulation in form of a
solution only consists of polyhexamethylene biguanide (PHMB) as
active agent, purified water as solvent, at least one
tri-blockcopolymer and at least one co-surfactant chosen among
those described above.
[0126] In yet another preferred aspect, the formulation in form of
a solution only consists of polyhexamethylene biguanide (PHMB) as
active agent, purified water as solvent and at least one
tri-blockcopolymer.
[0127] The formulation may thus consist of 0.05-10.0% PHMB by
weight, 0.1-40% tri-blockcopolymer by weight and completed to 100%
by adding purified water in order to get the final wound treatment
solution. The formulation in form of a solution may thus consist of
0.1% PHMB by weight, 1.0% tri-blockcopolymer (such as poloxamer
188) by weight and 98.9% purified water by weight.
[0128] Thus, in a preferred aspect, the formulation in form of a
gel only consists of polyhexamethylene biguanide (PHMB) as active
agent, purified water as solvent, humectant, gelling agent, at
least one tri-blockcopolymer and at least one co-surfactant chosen
among those described above.
[0129] The formulation may thus consist of 0.05-10.0% PHMB by
weight, 0.1-40% tri-blockcopolymer by weight, 0.01-2% co-surfactant
by weight and completed to 100% by adding purified water in order
to get the final wound treatment solution. The formulation in form
of a solution may thus consist of 0.1% PHMB by weight, 1.0%
tri-blockcopolymer by weight, 0.1% co-surfactant by weight and
98.8% purified water by weight.
[0130] In yet another preferred aspect, the formulation in form of
a gel only consists of polyhexamethylene biguanide (PHMB) as active
agent, purified water as solvent, humectant, gelling agent and at
least one tri-blockcopolymer.
[0131] The gelling agents are preferably selected from polymers
usually used in gel formulations to decrease the mobility and
increase the viscosity of a product. Gelling agent are preferably a
cellulose derivative or another commercially available gelling
agent. Preferred gelling agents are cellulose derivatives (e.g.
methyl cellulose, hydroxypropyl methyl cellulose,
carboxymethylcellulose, hydroxyethyl cellulose) and/or modified
acrylic acid polymers (e.g. carbopol), either alone or in
combination. Particularly preferred gelling agents are
Methylcellulose, Hydroxypropyl Methylcellulose, Hydroxyethyl
Methylcellulose, Hydroxyethyl cellulose, Carboxymethylcellulose and
Sodium Carboxymethylcellulose. Other preferred gelling agents are
non-ionic poly (ethylene oxide) polymers. Another preferred gelling
agent is carboxypolymethylene, also known as Carbopol, which is a
modified acrylic acid polymer, preferably selected from Carbopol
940, Carbopol 934 [USAN:NF], Carbopol 907, Carbopol 941, Carbopol
Ultrez 10 and Carbopol 5984.
[0132] Although preferred gelling agents are to be in non-ionic
form, anionic molecules (i.e. carboxymethylcellulose and carbopol)
can also be used in the formulation in the presence of a cationic
excipient, which may be a co-surfactant (e.g. Panthenyl
hydroxypropyl steardimonium chloride.
[0133] The Humectants are preferably chosen from beta-sitosterol,
inositol, glycerin, urea, hydroxyethyl urea, glyceryl stearate,
panthenol, propylene glycol, polyethylene glycol and its
derivatives (i.e. methyl gluceth 10 and methyl gluceth 20), and
Xylitol. The humectants are even more preferably selected from
glycerin and hydroxyethyl urea.
[0134] The formulation consists in a preferred aspect of 0.05-2.0%
PHMB by weight, 0.1-40% tri-blockcopolymer by weight, 1.0-10.0%
Humectant by weight, 0.5-5.0% gelling agent by weight and completed
to 100% by adding purified water in order to get the final wound
treatment solution. The formulation in form of a gel may thus
consist of 0.1% PHMB by weight, 1.0% tri-blockcopolymer (such as
poloxamer 188) by weight, 8.6% glycerin by weight, 1.8% by weight
hydroxyethyl cellulose by weight and 88.5% purified water by
weight.
[0135] The formulation consists in another preferred aspect of
0.05-2.0% PHMB by weight, 0.1-40% tri-blockcopolymer by weight,
0.01-2% co-surfactant by weight, 1.0-10.0% Humectant by weight,
0.5-5.0% gelling agent by weight and completed to 100% by adding
purified water in order to get the final wound treatment solution.
The formulation in form of a gel may thus consist of 0.1% PHMB by
weight, 1.0% tri-blockcopolymer (such as poloxamer 188) by weight,
0.1% co-surfactant by weight, 8.6% glycerin by weight, 1.8% by
weight hydroxyethyl cellulose by weight and 88.4% purified water by
weight.
[0136] Another aspect of the present invention is a method for
producing a topical and oromucosal treatment formulation for the
treatment of wounds, the method comprising the process steps of
adding water to the mixer, adding and mixing polyhexamethylene
higuanide (PHMB) and purified water (solution A) and adding and
mixing said solution A to tri-blockcopolymer to get the end
product.
[0137] Another aspect of the present invention is a method for
producing a topical and oromucosal treatment formulation for the
treatment of wounds, the method comprising the process steps of
adding gelling agent to distilled water and mixing thereof by
heating followed by adding PHMB (solution B), cooling said solution
B and adding and mixing said cooled solution B to triblockcopolymer
to get the end product.
[0138] The formulation according to the present invention may only
contain the above-described PHMB and tri-blockcopolymers, purified
water, humectants (e.g. glycerin, inositol, panthenol, xylitol . .
. etc.), gelling agents (e.g. carbopol, carboxymethylcellulose,
hydroxyethyl cellulose, methyl cellulose . . . etc.), i.e. without
any additional compounds such as substance/substances obtained from
herbs.
EXEMPLARY FORMULATIONS
Formulations A, B and C Containing PHMB and Tri-Blockcopolymers
[0139] In the following, two exemplary formulations according to
the present invention, one in the form of a solution and one in the
form of a gel are described. These formulations are also compared
later to commonly known formulations in the experimental
section.
Exemplary Formulation A of a solution according to the present
invention:
TABLE-US-00005 Component Content (g) Function PHMB* 0.1 g (=0.1
w.-%) Active substance Poloxamer 188 1.0 g (=1.0 w.-%) Auxiliary
substance Distilled water Ad 100 Solvent *20% PHMB (0.5 g) are
used; 0.5 .times. 20/100 = 0.1 g
Exemplary Formulation B of a gel according to the present
invention:
TABLE-US-00006 Component Content (g) Function PHMB* 0.1 g (=0.1
w.-%) Active substance Poloxamer 188 1.0 g (=1.0 w.-%) Auxiliary
substance Glycerin 8.6 g (=8.6 w.-%) Auxiliary substance
Hydroxyethyl cellulose 1.8 g (=1.8 w.-%) Auxiliary substance
Distilled water Ad 100 Solvent *20% PHMB (0.5 g) are used; 0.5
.times. 20/100 = 0.1 g
Exemplary Formulation C of a gel according to the present
invention:
TABLE-US-00007 Component Content (g) Function PHMB* 0.1 g (=0.1
w.-%) Active substance Poloxamer 188 1.0 g (=1.0 w.-%) Auxiliary
substance Hydroxyethyl Urea 8.6 g (=8.6 w.-%) Auxiliary substance
Hydroxyethyl cellulose 1.8 g (=1.8 w-%) Auxiliary substance
Distilled water Ad 100 Solvent *20% PHMB (0.5 g) are used; 0.5
.times. 20/100 = 0.1 g
Formulations Comprising PHMB, Tri-Blockcopolymers and
Co-Surfactants
[0140] Formulations according to the present invention may also
include co-surfactants as an additional excipient either to improve
the solubility of any added herbal contents or to incorporate
additional synergistic effects to the formulation. Following
examples, one in the form of a solution and one in the form of a
gel, are describing the basic formulation with co-surfactants.
Example 1
[0141] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning and/or treating wounds.
TABLE-US-00008 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 Purified Water 98.8
Example 2
[0142] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning and/or treating wounds.
TABLE-US-00009 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Lauramine oxide 0.1 Purified Water 98.8
Example 3
[0143] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning and/or treating wounds.
TABLE-US-00010 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Sodium cocoamphoacetate 0.1 Purified Water 98.8
Example 4
[0144] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning and/or treating wounds.
TABLE-US-00011 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 PHSC* 0.1 Purified Water 98.7 *Panthenyl
hydroxypropyl steardimonium chloride
Example 5a
[0145] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00012 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 Glycerin 8.6 Hydroxyethyl cellulose 1.8 Purified
Water 88.4
to Example 5b
[0146] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00013 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 Hydroxyethyl Urea 8.6 Hydroxyethyl cellulose 1.8
Purified Water 88.4
Example 6a
[0147] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00014 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Lauramine oxide 0.1 Glycerin 8.6 Hydroxyethyl cellulose 1.8
Purified Water 88.4
Example 6b
[0148] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00015 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Lauramine oxide 0.1 Hydroxyethyl Urea 8.6 Hydroxyethyl cellulose
1.8 Purified Water 88.4
Example 7a
[0149] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00016 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Sodium cocoamphoacetate 0.1 Glycerin 8.6 Hydroxyethyl cellulose 1.8
Purified Water 88.4
Example 7b
[0150] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00017 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Sodium cocoamphoacetate 0.1 Hydroxyethyl Urea 8.6 Hydroxyethyl
cellulose 1.8 Purified Water 88.4
Example 8a
[0151] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00018 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 PHSC* 0.1 Glycerin 8.6 Hydroxyethyl cellulose 1.8
Purified Water 88.3 *Panthenyl hydroxypropyl steardimonium
chloride
Example 8b
[0152] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00019 Component Amount (wt. %) PHMB 0.1 Poloxamer 1.0
Cocobetaine 0.1 PHSC* 0.1 Hydroxyethyl Urea 8.6 Hydroxyethyl
cellulose 1.8 Purified Water 88.3 *Panthenyl hydroxypropyl
steardimonium chloride
Formulations Comprising PHMB, Tri-Blockcopolymers and Further
Substances Obtained from Herbs
[0153] Further to the above-described compounds, the formulations
may contain substance/substances obtained from herbs, as described
above. Such substances obtained from herbs may have the beneficial
properties described above in the according section.
[0154] However, the formulations according to the present invention
do not require the presence of substances obtained from herbs. Also
a formulation in form of a solution of gel as described above, not
containing any substances obtained from herbs can have the desired
effect for the treatment of wounds. In this respect it is noted
again that the tri-blockcopolyrners, in particular poloxamers
according to the present invention, are amphiphilic, non-toxic and
non-ionic surfactants and thus can be used in combination with PHMB
for the treatment of wounds with the desired beneficial
effects.
[0155] The use of additional substances obtained from herbs may
thus simply further increase the beneficial effect already obtained
by using PHMB with tri-blockcopolymers according to the present
invention.
Formulations in Form of a Solution Comprising PHMB,
Tri-Blockcopolymers and Further Substances Obtained from Herbs
[0156] The present invention thus further comprises a solution
formulation containing one or more herbal substance, PHMB, an
emulsifying agent (a tri-blockcopolymer), and purified water to use
for the topical treatment of skin and oromucosal wounds.
[0157] The solution formulation is intended to be used for a
mixture preparation composed of PHMB, purified water, an
emulsifying agent and/or Comfrey (Symphytum officinale L.) extract
and/or Myrrh (Commiphora molmol) tincture, and optionally a
co-surfactant or a mixture of co-surfactants.
[0158] The preferred concentration of Comfrey (Symphytum officinale
L.) extract in any solution formulation is 1.0-15.0% (w/w), more
preferably 3.0-12.0% (w/w), and most preferably 10.0% (w/w).
[0159] The preferred concentration of Myrrh (Commiphora molmol)
tincture in any solution formulation is 1.0-20.0% (w/w), more
preferably 3.0-12.0% (w/w), and most preferably 5.0% (w/w).
[0160] The preferred concentration of Polyhexamethylene biguanide
(PHMB) in any solution formulation is 0.05-2.0% (w/w), more
preferably 0.08-0.3% (w/w), and most preferably 0.1% (w/w).
[0161] The preferred concentration of emulsifying agent in any
solution formulation is 0.1-40.0% (w/w), more preferably 0.5-20%
(w/w), and most preferably 1.0% (w/w). The preferred concentration
of co-surfactants in any solution formulation is 0-2% (w/w), more
preferably 0.01-2% (w/w), even more preferably 0.05-1% (w/w), and
most preferably 0.1% (w/w). The mixture prepared by mixing the
ingredients above listed is completed to 100% by adding distilled
water in order to get final wound treatment solution.
TABLE-US-00020 TABLE 3 Usable and preferred quantities of
ingredients in a solution formulation. Usable Preferred quantity by
quantity by Substance Function weight (%) weight (%) Herbal content
1 Anti-inflammatory and analgesic 1.0-15.0 10.0 Comfrey (Symphytum
effects, it induces granulation and officinale L) Extract is used
for wound treatment as it supports tissue regeneration Herbal
content 2 Antibacterial, antifungal and local 1.0-20.0 5.0 Myrrh
(Commiphora anaesthetic effects molmol) tincture Poloxamer
Emulsifying agent; dispersing 0.1-40.0 1.0 agent; wetting agent;
solubilizing agent; lubricant, detergents Polyhexamethylene
Protective agent; algaecides, 0.05-2.0 0.1 biguanide (PHMB)
bactericides/bacteriostatics, fungicides/fungistatics,
microbicides/microbiostatics, disinfectants, regulators, and
sanitizers. Purified Water Diluting agent/supplementary 23.0-98.0
73.5 agent Co-surfactant improve solubility of herbal 0.01-2.0 0.1
ingredients, reduce the cytotoxicity of the formulation
[0162] In order to fulfill the aforementioned objectives the
production steps of the solution formulation is as follows: adding
and mixing herbal substance/substances, Poloxamer and optionally a
co-surfactant: or a mixture of co-surfactants for providing
Solution X, separately adding and mixing polyhexamethylene
higuanide (PHMB) and distilled water for providing Solution Y and
finally; adding and mixing Solution X to Solution Y to get the end
product. After that the final solution obtained after the process,
is objected to filtration.
Production of various solutions formulations according to invention
further including substances obtained from herbs is described in
detail as examples below:
Example 1
[0163] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning and/or treating wounds.
TABLE-US-00021 Comfrey (Symphytum officinale L) Extract 10.0 Myrrh
(Commiphora molmol) Tincture 5.0 Poloxamer 1.0 Polyhexamethylene
biguanide (PHMB) 0.1 Purified Water 83.9
Example 2
[0164] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning/treating wounds.
TABLE-US-00022 Comfrey (Symphytum officinale L) Extract 10.0
Poloxamer 1.0 Polyhexamethylene biguanide (PHMB) 0.1 Purified Water
88.9
Example 3
[0165] By mixing the following ingredients listed in the usual way
a wound solution is made for cleaning/treating wounds.
TABLE-US-00023 Myrrh (Commiphora molmol) Tincture 5.0 Poloxamer 1.0
Polyhexamethylene biguanide (PHMB) 0.1 Purified Water 93.9
Formulations in Form of a Gel Comprising PHMB, Tri-Blockcopolymers
and Further Substances Obtained From Herbs
[0166] The present invention further comprises a gel formulation
containing one or more herbal substance, PHMB, an emulsifying agent
(a tri-block copolymer), a gelling agent, a humectant and purified
water to use for the topical treatment of skin and oromucosal
wounds.
[0167] The gel formulation is intended to be used for a mixture
preparation composed of PHMB, purified water, an emulsifying agent,
a gelling agent, a humectant and/or Comfrey (Symphytum officinale
L) extract and/or Myrrh (Commiphora molmol) tincture, and
optionally a co-surfactant or a mixture of co-surfactants.
[0168] The preferred concentration of Comfrey (Symphytum officinale
L.) extract in any gel formulation is 1.0-15.0% (w/w), more
preferably 3.0-12.0% (w/w), and most preferably 10% (w/w).
[0169] The preferred concentration of Myrrh (Commiphora molmol)
tincture in any gel formulation is 1.0-20.0% (w/w), more preferably
3.0-12.0% (w/w), and most preferably 5.0% (w/w).
[0170] The preferred concentration of Polyhexamethylene biguanide
(PHMB) in any gel formulation is 0.05-2.0% (w/w), more preferably
0.08-0.3% (w/w), and most preferably 0.1% (w/w).
[0171] The preferred concentration of emulsifying agent in any gel
formulation is 0.1-40.0% (w/w), more preferably 0.5-20% (w/w), and
most preferably 1.0% (w/w).
[0172] The preferred concentration of gelling agent in any gel
formulation is 0.5-5.0% (w/w), more preferably 1.0-3.0% (w/w), and
most preferably 1.8% (w/w).
[0173] The preferred concentration of a humectant in any gel
formulation is 1.0-10.0% (w/w), more preferably 5.0-9.0% (w/w), and
most preferably 8.6% (w/w). The preferred concentration of
co-surfactants in any gel formulation is 0-2% (w/w), more
preferably 0.01-2% (w/w), even more preferably 0.05-1% (w/w), and
most preferably 0.1% (w/w). The mixture prepared by mixing the
ingredients above listed completed to 100% by adding distilled
water in order to get final wound treatment gel.
TABLE-US-00024 TABLE 4 Gel content and preferred/usable quantities
by weight Usable Preferred quantity by quantity by Substance
Function weight (%) weight (%) Herbal content 1 Anti-inflammatory
and analgesic 1.0-15.0 10.0 Comfrey (Symphytum effects, it induces
granulation and officinale L) Extract is used for wound treatment
as it supports tissue regeneration Herbal content 2 antibacterial,
antifungal and local 1.0-20.0 5.0 Myrrh (Commiphora anaesthetic
effects molmol) tincture Poloxamer Emulsifying agent; dispersing
0.1-40.0 1.0 agent; wetting agent; solubilizing agent; lubricant,
detergents Polyhexamethylene Protective agent; algaecides, 0.05-2.0
0.1 biguanide (PHMB) bactericides/bacteriostatics,
fungicides/fungistatics, microbicides/microbiostatics,
disinfectants, regulators, and sanitizers. Glycerin or Humectant
1.0-10.0 8.6 Hydroxyethyl urea Hydroxyethylcellulose Gelling agent
0.5-5.0 1.8 Purified Water Diluting agent/supplementary 8.0-96.3
73.5 agent Co-surfactant improve solubility of herbal 0.01-2.0 0.1
ingredients, reduce the cytotoxicity of the formulation
[0174] In order to fulfill the aforementioned objectives the
production steps of the gel formulation is as follows: adding and
mixing herbal substance/substances, poloxamer and optionally a
co-surfactant or a mixture of co-surfactants for providing Solution
X, separately adding gelling agent to purified water and mixing
thereof by heating and followed by adding PHMB for providing
Solution Z, cooling the Solution Z and finally; adding and mixing
Solution X to Solution Z to get the end product. After that the
final solution, obtained after the process, is objected to
filtration.
[0175] Production of various gel formulations according to
invention further including substances obtained from herbs is
described in detail as examples below:
Example 4a
[0176] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00025 Comfrey (Symphytum officinale L) Extract 10.0 Myrrh
(Commiphora molmol) Tincture 5.0 Poloxamer 1.0 Polyhexamethylene
biguanide (PHMB) 0.1 Glycerin 8.6 Hydroxyethyl cellulose 1.8
Purified Water 73.5
Example 4b
[0177] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00026 Comfrey (Symphytum officinale L) Extract 10.0 Myrrh
(Commiphora molmol) Tincture 5.0 Poloxamer 1.0 Polyhexamethylene
biguanide (PHMB) 0.1 Hydroxyethyl urea 8.6 Hydroxyethyl cellulose
1.8 Purified Water 73.5
Example 5a
[0178] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00027 Comfrey (Symphytum officinale L) Extract 10.0
Poloxamer 1.0 Polyhexamethylene biguanide (PHMB) 0.1 Glycerin 8.6
Hydroxyethylcellulose 1.8 Purified Water 78.5
Example 5b
[0179] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00028 Comfrey (Symphytum officinale L) Extract 10.0
Poloxamer 1.0 Polyhexamethylene biguanide (PHMB) 0.1 Hydroxyethyl
urea 8.6 Hydroxyethylcellulose 1.8 Purified Water 78.5
Example 6a
[0180] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00029 Myrrh (Commiphora molmol) Tincture 5.0 Poloxamer 1.0
Polyhexamethylene biguanide (PHMB) 0.1 Glycerin 8.6
Hydroxyethylcellulose 1.8 Purified Water 83.5
Example 6b
[0181] By mixing the following ingredients listed in the usual way
a wound gel is made for cleaning/treating wounds.
TABLE-US-00030 Myrrh (Commiphora molmol) Tincture 5.0 Poloxamer 1.0
Polyhexamethylene biguanide (PHMB) 0.1 Hydroxyethyl urea 8.6
Hydroxyethylcellulose 1.8 Purified Water 83.5
APPLICATION AREAS
[0182] The present formulations can be used for cleaning,
decontamination, irrigation and moistening of infected, dried and
disintegrated (chronic and acute) skin and mucosa; it is also used
before application of bandages, gauzes, compresses, wound Fillers
and other absorbent materials.
EXPERIMENTAL RESULTS
General Results with Formulations Containing PHMB and Poloxamer 188
According to Formulations A and B
[0183] It has been shown that the solution (Exemplary Formulation
A) according to the present invention has good decolonization
properties for Methicillin-resistant S. aureus (MRSA).
Methicillin-resistant S. aureus is a gram positive bacterial
strain, which causes pneumonia, wound and hospital infections. They
are resistant to several antibiotics. The solution according to the
present invention has a strong bactericidal effect on MRSA and can
easily be applied onto the infected area.
[0184] The same results were achieved for Vancomycin-resistant
Enterococci (VRE), another strain of gram positive bacteria, which
cause severe hospitals infections mainly in chronic hemodialysis
patients. Also here the according to the present invention has a
strong bactericidal effect on VRE and can easily be applied onto
the infected area.
[0185] Also for Acinetobacter baumannii, gram negative pleomorphic
bacteria, which can remain alive for a long time in extreme
environmental conditions and as an opportunistic pathogen in
humans, easily colonize and affecting people with compromised
immune systems in hospital, good effects were achieved. It has been
demonstrated that PHMB is effectively used on animate and inanimate
surfaces that is colonized with multi drug-resistant Acinetobacter
for antisepsis and disinfection.
Bactericidal and Yeasticidal Efficacy of the Formulations A and
B
General Description of the Test Method for Bactericidal
Efficacy:
[0186] The bactericidal activity of a solution containing PHMB and
poloxamer 188 according to the present invention was evaluated in
accordance with the European Standard EN 13727
(2012/FprA1:2013).
[0187] A suspension of test organisms in a solution of the
interfering substance is added to a sample of the solution
according to the present invention (diluted with hard water). The
mixture is maintained at 20.+-.1.degree. C. for the required
contact times. At the end of the contact time, an aliquot of 1 ml
is taken; the microbicidal activity in this portion is immediately
neutralized. Two 1 ml samples (per dilution step, diluent
containing neutralizer) of this suspension are spread on at least 2
plates each. The number of surviving test organisms in the test
mixture is calculated for each sample and the reduction is
determined with respect to the corresponding test suspension No.
The experimental conditions (control A), the non-toxicity of the
neutralizer (control B) and the dilution-neutralization method
(control C) are validated.
[0188] The formulation in form of a solution used contains 0.1 g
PHMB, 1.0 g Poloxamer 188 and 98.9 g distilled water per 100 g.
[0189] The formulation in form of a gel used contains 0.1 g PHMB,
1.0 g poloxamer 188, 8.6 g glycerin, 1.8 g hydroxyethyl cellulose
and 88.5 g distilled water per 100 g.
[0190] The test with the solution according to the present
invention was performed under dirty conditions (0.3% albumin+0.3%
sheep erythrocytes) using Psuedomonas aeruginosa (ATCC 15442),
Escherichia coil (NCTC 10538), Enterococcus hirae (ATCC 10541) and
Staphylococcus aureus (ATCC 6538), as test-organisms. 80%, 50% and
25% test solutions of the formulation containing 0.1% PHMB (CAS
Nr.: 32289-58-0) and 1% Poloxamer (CAS Nr.: 9003-11-6) were used.
The pH-values were 6.21 (100%), 7.36 (80%), 7.35 (50%) and 6.88
(WSH). As neutralizer, 4% Tween80+3% Saponin+0.4% Lecithin+0.5% SDS
(Neutralizer XXIII) were used. Results are presented below.
[0191] Furthermore the solution is tested against MRSA (ATCC
33592), VRE (DSM 17050) and Acinetobacter baumannii (ATCC 19606).
The test performed under dirty (MRSA and VRE) as described above
and clean conditions (0.3 g/l bovine albumin). Results are
presented below.
[0192] The test with the gel according to the present invention was
performed under dirty conditions (0.3% albumin+0.3% sheep
erythrocytes) using Psuedomonas aeruginosa (ATCC 15442),
Escherichia coli (NCTC 10538), Enterococcus hirae (ATCC 10541) and
Staphylococcus aureus (ATCC 6538) as test-organisms. 80%, 50%, 25%
and 5% test solutions of the formulation containing 0.1% PHMB (CAS
Nr.: 32289-58-0) and 1% Poloxamer (CAS Nr.: 9003-11-6) were used.
The pH-values were 6.20 (80%), 7.19 (50%), 7.22 (25%), 7.68 (5%)
and 7.05 (WSH). As neutralizer, 4% Tween80+3% Saponin+0.4%
Lecithin+0.5% SDS (Neutralizer XXIII) were used. Results are
presented below.
Results for Bactericidal Activity:
[0193] The solution according to the present invention possesses
bactericidal activity (log.sub.10 RF.gtoreq.5) at 20.degree. C.
under dirty conditions for reference strains P. aeruginosa, E.
coil, S. aureus and E. hirae within a contact time of 1 min at a
product concentration of 80%, and within a contact time of 5 min,
at a product concentration of 25%. Furthermore, the said solution
possesses a bactericidal activity (log.sub.10 RF.gtoreq.5) at
20.degree. C. under dirty conditions in 5 and 10 minutes when
diluted at 80% and 50% (v/v) in distilled water for the reference
strain Staphylococcus aureus (MRSA) and in 1, 5 and 10 minutes when
diluted at 80% and 50% (v/v) in distilled water for the reference
strain Enterococcus faecium (VRE). The test result at 20.degree. C.
under clean conditions for the reference strain Acinetobacter
baumannii showed that the solution possesses a bactericidal
activity (log.sub.10 RF.gtoreq.5) in 5 and 10 minutes when diluted
at 80% and 50% (v/v) in distilled water.
[0194] The gel according to the present invention possesses
bactericidal activity (log.sub.10 RF.gtoreq.5) at 20.degree. C.
under dirty conditions for reference strains P. aeruginosa, E.
coli, S. aureus and E. hirae within a contact time of 1 min at a
product concentration of 50%.
General Description of the Test Method for Yeasticidal
Efficacy:
[0195] Die yeasticidal activity of a solution containing PHMB and
poloxamer 188 according to the present invention was evaluated in
accordance with the European Standard EN 13624 (2013).
[0196] A suspension of test organisms in a solution of the
interfering substance is added to a sample of the solution
according to the present invention (diluted with hard water). The
mixture is maintained at 20.+-.1.degree. C. for the required
contact times. At the end of the contact time, an aliquot of 1 ml
is taken; the microbicidal activity in this portion is immediately
neutralized. Two 1 ml samples (per dilution step, diluent
containing neutralizer) of this suspension are spread on at least 2
plates each. The number of surviving test organisms in the test
mixture is calculated for each sample and the reduction is
determined with respect to the corresponding test suspension No.
The experimental conditions (control A), the non-toxicity of the
neutralizer (control B) and the dilution-neutralization method
(control C) are validated.
[0197] The formulation in form of a solution used contains 0.1 g
PHMB, 1.0 g Poloxamer 188 and 98.9 g distilled water per 100 g.
[0198] The formulation in form of a gel used contains 0.1 g PHMB,
1.0 g poloxamer 188, 8.6 g glycerin, 1.8 g hydroxyethyl cellulose
and 88.5 g distilled water per 100 g.
[0199] The test with the solution according to the present
invention was performed under dirty conditions (0.3% albumin+0.3%
sheep erythrocytes) using C. albicans (ATCC 10231) as
test-organism. 80%, 50% and 25% test solutions of the formulation
containing 0.1% PHMB (CAS Nr.: 32289-58-0) and 1% Poloxamer (CAS
Nr: 9003-11-6) were used. The pH-values were 6.21 (100%), 7.36
(80%), 7.35 (50%) and 6.88 (WSH). As neutralizer, 4% Tween80+3%
Saponin+0.4% Lecithin+0.5% SDS (Neutralizer XXIII) were used.
Results are presented below.
[0200] The test with the gel according to the present invention was
performed under dirty conditions (0.3% albumin+0.3% sheep
erythrocytes) using C. albicans (ATCC 10231) as test-organism. 80%,
50%, 25% and 5% test solutions of the formulation containing 0.1%
PHMB (CAS Nr.: 32289-58-0) and 1% Poloxamer (CAS Nr.: 9003-11-6)
were used. The ph-values values were 6.20 (80%), 7.19 (50%), 7.22
(25%), 7.68 (5%) and 7.05 (WSH). As neutralizer, 4% Tween80 +3%
Saponin 0.4% Lecithin+0.5%) SDS (Neutralizer XXIII) were used.
Results are presented below.
Results for Yeasticidal Activity:
[0201] The solution according to the present invention possesses
bactericidal activity (log.sub.10 RF.gtoreq.4) at 20.degree. C.
under dirty conditions for reference strain C. albicans within a
contact time of 15 min at a product concentration starting at
50%.
[0202] The gel according to the present invention possesses
bactericidal activity (log.sub.10 RF.gtoreq.4) at 20.degree. C.
under dirty conditions for reference strain C. albicans within a
contact time of 15 min at a product concentration starting at
25%.
COMPARISON WITH OTHER FORMULATIONS
Bactericidal and Yeasticidal Activity
[0203] The formulations of the present invention have the same or
better bactericidal and/or yeasticidal activity as commonly used
formulations.
[0204] For instance, the solution according to the present
invention containing PHMB and poloxamer (e.g. poloxamer 188) has
the same or a better bactericidal and yeasticidal activity compared
to PHMB used alone.
[0205] Further, the solution according to the present invention
containing PHMB and poloxamer (e.g. poloxamer 188) has the same or
a better bactericidal and yeasticidal activity compared to PHMB in
combination with undecylenamidopropyl betaine.
[0206] Further, the solution according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188) and a co-surfactant
or a mixture of co-surfactants has the same or a better
bactericidal and yeasticidal activity compared to PHMB in
combination with undecylenamidopropyl betaine or poloxamer.
[0207] Further, the gel according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188), glycerin and
hydroxyethylcellulose has the same or a better bactericidal and
yeasticidal activity compared to PHMB used alone with glycerin and
hydroxyethyl cellulose.
[0208] Further, the gel according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188), glycerin and
hydroxyethyl cellulose has the same or a better bactericidal and
yeasticidal activity compared to PHMB used with glycerin and
hydroxyethyl cellulose and undecylenamidopropyl betaine.
[0209] Further, the gel according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188), glycerin,
hydroxyethyl cellulose and a co-surfactant or a mixture of
co-surfactants has the same or a better bactericidal and
yeasticidal activity compared to PHMB used with
undecylenamidopropyl betaine or poloxamer and glycerin and
hydroxyethyl cellulose.
[0210] Further, the solution according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188), a
substance/substances obtained from herbs and optionally a
co-surfactant or a mixture of co-surfactants has the same or a
better bactericidal and yeasticidal activity compared to a solution
not containing said substance/substances obtained from herbs,
[0211] Further, the gel according to the present invention
containing PHMB, poloxamer (e.g. poloxamer 188), glycerin,
hydroxyethyl cellulose, a substance/substances obtained from herbs
and optionally a co-surfactant or a mixture of co-surfactants has
the same or a better bactericidal and yeasticidal activity compared
to a solution not containing said substance substances obtained
from herbs.
TOXICITY
[0212] The composition with PHMB and poloxamer has improved
properties compared to other surfactants such as
betaine-derivatives. It has turned out that poloxamers and in
particular poloxamer 188 have a significantly lower toxicity than
most commonly used surfactants such as betaine-derivatives.
Classification information according to EU regulations and LD50
values of some commercial surfactants are given in table 5.
TABLE-US-00031 TABLE 5 Comparison of hazardous information of
Kolliphor .RTM. P 188 (Poloxamer) with various commercially
available unbranched fatty acid derivative surfactants. LD50 Acute
oral Chemical name Cas Number GHS Classification.sup.a (Rat)
Kolliphor .RTM. P 188 9003-11-6 No hazard warning >5.000 mg/kg
(Poloxamer 188) label required CRODATERIC .TM. CAB 30-LQ-(RB)
61789-40-0 Eye Irrit. 2; H319 no data available (Cocamidopropyl
Betaine) CRODATERIC .TM. CAB 30-LQ-(TH) 4292-10-8 Skin Irrit. 2;
H315 >4.900 mg/kg (Lauramidopropyl betaine) Eye Irrit. 2; H319
Rewoteric .RTM. AM B U 185 98510-75-9 Eye Dam. 1; H318 >2.000
mg/kg (Undecylenamidopropyl Betaine) .sup.aCLP-Regulation (EC) No
1272/2008
[0213] As mentioned above, the cytotoxicity is an important key in
wound recovery. Further the cytotoxicity reducing effect of an
ingredient is a desirable. It has been shown that poloxamer 188 has
membrane sealing and repairing properties on neurons, cardiac
myocytes, fibroblasts, and skeletal muscle cells [22-25]. Thus
poloxamer 188 prevents apoptosis and reduce cytotoxicity.
Additionally, it was reported that poloxamer 188 facilitates plasma
membrane repair in alveolus resident cells [26].
[0214] Thus, it is beneficial to use poloxamers instead of commonly
used surfactants in bactericidal or yeasticidal formulations.
Surface Tension
[0215] Furthermore, tri-blockcopolymers of the present invention,
in particular poloxamers, due to their non-ionic properties have
improved surface tension compared to surfactants such as
betaine-derivatives. For instance, in case the pH on a wound
changes, the charge of the betaines may change and thus have a
different surface tension than before. Therefore, with
betaine-derivatives, the desired bactericidal or yeasticidal effect
may not always be reproducibly ensured. Tri-blockcopolymers of the
present invention on the other hand have the same surface tension,
independent of the surrounding pH and ensure a constant and
reliable bactericidal or yeasticidal effect.
[0216] At the same time, the adhesion of microorganisms on wounds
is minimized better by said tri-blockcopolymers,
REFERENCES
[0217] 1. Dahlen, N. and A. P. Kramer. 2008, Wound treatment agent.
Prontomed GmbH, 32120 Hiddenhausen (DE). EP1404311 (B1).
[0218] 2. L. Dahlen, N. 2001, Stable aqueous gel containing
polyhexamethylene biguanide, glycerol and hydroxyethyl cellulose,
useful e.g. as washing or shower gel having decontaminant action or
for covering wounds. Prontomed Gmbh. DE10012026 A1.
DE2000112026.
[0219] 3. Jovanovic, A., et al., The Influence of Metal Salts,
Surfactants, and Wound Care Products on Enzymatic Activity of
Collagenase, the Wound Debriding Enzyme. Wounds--A Compendium of
Clinical Research and Practice, 2012. 24(9): p. 242-253.
[0220] 4. Gethin, G., The significance of surface pH in chronic
wounds. Wounds uk, 2007. 3(3): p. 52.
[0221] 5. Arndt, A., et al. 2013, Antimicrobial wound dressing, B.
Braun Melsungen Ag. UD20130231394 A1. U.S. Ser. No. 13/637,111.
[0222] 6. Birnie, C. R., D. Malamud, and R. L. Schnaare,
Antimicrobial Evaluation of N-Alkyl Betaines and
N-Alkyl-N,N-Dimethylamine Oxides with Variations in Chain Length.
Antimicrobial agents and chemotherapy, 2000. 44(9): p.
2514-2517.
[0223] 7. Fraud, S., et al., Activity of amine oxide against
biofilms of Streptococcus mutans: a potential biocide for oral care
formulations. Journal of Antimicrobial Chemotherapy, 2005. 56(4):
p. 672-677.
[0224] 8. Kanjilal, S., et al., Synthesis and evaluation of
miceliar properties and antimicrobial activities of imidazole-based
surfactants. European Journal of Lipid Science and Technology,
2009. 111(9): p. 941-948.
[0225] 9. Barel, A. O., M. Paye, and H. I. Maibach, Handbook of
Cosmetic Science and Technology. 2001, New York, Marcel Dekker,
ISBN: 0-8247-0292-1
[0226] 10. Logan, A. and D. Hill, Bioavailability: Is this a key
event in regulating the actions of peptide growth factors?Journal
of endocrinology, 1992. 134(2): p. 157-161.
[0227] 11. Agren, M., An amorphous hydrogel enhances
epithelialisation of wounds. ACTA DERMATOVENEREOLOGICA-STOCKHOLM-,
1998. 78: p. 119-122.
[0228] 12. Muetterlein, R. and C.-G. Arnold, Investigations
Concerning the Content and the Pattern of Pyrrolizidine Alkaloids
in Symphytum officinale L. PZ WISSENSCHAFT, 1993. 138: p.
119-119.
[0229] 13. EMA/HMPC/572844/2009, Assessment report on Symphytum
officinale L., radix, 12 Jul. 2011, Committee on Herbal Medicinal
Products (HMPC).
[0230] 14. Comfrey herb and leaf (Symphyti herba/-folium), List of
German Commission E Monographs (Phytotherapy), Phytotherapeutic
Monographs (BGA, Commission E, Germany). Jul. 27, 1990.
[0231] 15. Symphyti radix, 2009; E/S/C/O/P Monographs: The
Scientific Foundation for Herbal Medicinal Products. Supplement
2009, European Scientific Cooperative on Phytotherapy, Thieme. p.
249-254. ISBN: 1901964086
[0232] 16. Staiger, C., Symphytum, 2009; HagerROM 2009: Hagers
Enzyklopadie der Arzneistoffe und Drogen, W. Blaschek, S. Ebel, and
E. Hackenthal, Editors., Springer-Verlag: Berlin. ISBN:
978-3-642-16227-5
[0233] 17. Steiger, C., Comfrey: a clinical overview. Phytotherapy
Research, 2012, 26(10): p. 1441-1448.
[0234] 18. Andres, R., R. Brenneisen, and J. Clerc, Relating
antiphlogistic efficacy of dermatics containing extracts of
Symphytum officinale to chemical profiles Pl. Med, 1989. 55: p.
643-644.
[0235] 19. EMA/HMPC/96910/2010, Assessment report on Commiphora
molmol Engler, gummi-resina, 15 Sep. 2010, Committee on Herbal
Medicinal Products (HMPC)
[0236] 20. Myrrha, 2003; E/S/C/O/P Monographs: The Scientific
Foundation for Herbal Medicinal Products. Supplement 2003, European
Scientific Cooperative on Phytotherapy, Thieme, p. 340-344. ISBN:
1588902331
[0237] 21. Verhelst, G., Groot handboek geneeskrachtige planten.
2004, Welvergem: BVBA Mannavita. ISBN: 9080778427
[0238] 22. Marks, J. D., et al., Amphiphilic, tri-block copolymers
provide potent membrane-targeted neuroprotection. The FASEB
Journal, 2001. 15(6): p. 1107-1109.
[0239] 23. Yasuda, S., et al., Dystrophic heart failure blocked by
membrane sealant poloxamer. Nature, 2005, 436(7053): p.
1025-1029.
[0240] 24. Merchant, F., et al., Poloxamer 188 enhances functional
recovery of lethally heat-shocked fibroblasts. Journal of Surgical
Research, 1998. 74(2): p. 131-140.
[0241] 25. Collins, J. M., F. Despa, and R. C. Lee, Structural and
functional recovery of electropermeabilized skeletal muscle in-vivo
after treatment with surfactant poloxamer 188. Biochimica et
Biophysica Acta (BBA)--Biomembranes, 2007. 1768(5): p.
1238-1246.
[0242] 26. Piataki, M., et al., Poloxamer 188 facilitates the
repair of alveolus resident cells in ventilator-injured lungs.
American journal of respiratory and critical care medicine, 2011.
184(8): p. 939-947.
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