U.S. patent application number 17/302527 was filed with the patent office on 2021-08-19 for putrescine topical barrier formulation.
The applicant listed for this patent is VIVIER CANADA INC.. Invention is credited to GHISLAIN VIVIER.
Application Number | 20210251920 17/302527 |
Document ID | / |
Family ID | 1000005557176 |
Filed Date | 2021-08-19 |
United States Patent
Application |
20210251920 |
Kind Code |
A1 |
VIVIER; GHISLAIN |
August 19, 2021 |
PUTRESCINE TOPICAL BARRIER FORMULATION
Abstract
The present invention describes stable topical barrier
compositions comprising primary polyamines and uses thereof for
protecting the skin from external stressors, for improving skin's
moisture and fort stimulating healing of the skin. These
compositions may be used in a variety of cosmetic and therapeutic
applications including for promoting wound healing, for reducing or
preventing the formation of hypertrophic scar tissue, for reducing
or preventing skin irritation and inflammation, for increasing
skin's moisture and/or for reducing or preventing skin's signs of
aging.
Inventors: |
VIVIER; GHISLAIN;
(St-Lazare, CA) |
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Applicant: |
Name |
City |
State |
Country |
Type |
VIVIER CANADA INC. |
VAUDREUIL-DORION |
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CA |
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Family ID: |
1000005557176 |
Appl. No.: |
17/302527 |
Filed: |
May 5, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16883864 |
May 26, 2020 |
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17302527 |
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16349030 |
May 10, 2019 |
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PCT/CA2018/050008 |
Jan 5, 2018 |
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16883864 |
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62443158 |
Jan 6, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/205 20130101;
A61P 17/02 20180101; A61K 31/132 20130101; A61K 9/0014 20130101;
A61K 47/44 20130101 |
International
Class: |
A61K 31/132 20060101
A61K031/132; A61P 17/02 20060101 A61P017/02; A61K 9/00 20060101
A61K009/00; A61K 31/205 20060101 A61K031/205; A61K 47/44 20060101
A61K047/44 |
Claims
1. A topical water free barrier composition comprising: (i) a
polyamine; (ii) a phospholipid to encapsulate the primary
polyamine; (iii) petroleum jelly; and (iv) mineral oil.
2. The barrier composition of claim 1, wherein the polyamine is a
primary aliphatic lower-alkyl (C1-5) monoamine, preferably
aminoacetonitrile; a primary aliphatic alkylamine, preferably
spermine or spermidine; or a primary aliphatic lower-alkyl (C1-5)
polyamine, preferably putrescine or dansylcadaverine.
3. The barrier composition of claim 1, wherein the polyamine is
aminoacetonitrile; spermine or spermidine; or putrescine or
dansylcadaverine, preferably putrescine.
4. The barrier composition of claim 3, wherein the putrescine is in
a concentration of between about 0.1% w/w to about 1% w/w; about
0.4% w/w; or about 0.8% w/w.
5. The barrier composition of claim 1, wherein the petroleum jelly
is in a concentration of between about 25% w/w and 65% w/w; or
about 45% w/w.
6. The barrier composition of claim 1, wherein the mineral oil is
in a concentration of between about 30% w/w and about 45% w/w; or
of about 35% w/w.
7. The barrier composition of claim 1, wherein the phospholipid is
a quaternary ammonium salt.
8. The barrier composition of claim 7, wherein the quaternary
ammonium salt is cocamidopropyl PG-dimonium chloride phosphate.
9. The barrier composition of claim 8, wherein the cocamidopropyl
PG-dimonium chloride phosphate is in a concentration of between
about 3% w/w and about 6% w/w; or about 4% w/w.
10. The barrier composition of claim 1, further comprising (i)
paraffin; (ii) lanolin oil; (iii) a lipophilic Vitamin C
derivative; (iv) one or more humectants; and/or (v) bisabolol.
11. The barrier composition of claim 10, wherein the paraffin is in
a concentration of between about 3% w/w and 15% w/w; or about 8.5%
w/w.
12. The barrier composition of claim 10, wherein the lanolin oil is
in a concentration of between about 3% w/w and 6% w/w; or about 5%
w/w.
13. The barrier composition of claim 10, wherein the lipophilic
Vitamin C derivative is in a concentration of between about 0.1%
w/w and 10% w/w.
14. The barrier composition of claim 10, wherein the lipophilic
Vitamin C derivative comprises 3-O-Ethyl Ascorbic Acid
(3-O-EAA).
15. The barrier composition of claim 14, wherein the 3-O-EAA is in
a concentration of about 0.5% w/w.
16. The barrier composition of claim 10, wherein the one or more
humectants is(are) in a concentration of between about 0.5% w/w and
3% w/w.
17. The barrier composition of claim 10, wherein the one or more
humectants comprise(s) glycerin, vitamin B5 or a combination
thereof.
18. The barrier composition of claim 17, wherein the one or more
humectants comprise(s) about 1% w/w of the glycerin and about 1%
w/w of the Vitamin B5.
19. The barrier composition of claim 10, wherein the bisabolol is
in a concentration of between about 0.1% w/w and 1% w/w; or about
0.5% w/w.
20. A method of using the barrier composition defined in claim 1,
for (i) treating or preventing skin inflammation, skin's signs of
aging and/or skin irritation; (ii) promoting wound healing; or
(iii) preventing or reducing the formation of hypertrophic scar
tissue.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/883,864, now pending which is a continuation of U.S.
application Ser. No. 16/349,030, now abandoned, which is a National
Entry Application of PCT application no PCT/CA2018/050008 filed on
Jan. 5, 2018 and published in English under PCT Article 21(2),
which itself claims benefit of U.S. provisional application Ser.
No. 62/443,158, filed on Jan. 6, 2017. All documents above are
incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to stable, barrier and
multi-function, multi-layer topical formulations comprising primary
polyamines and uses thereof for stimulating wound healing,
improving moisturization (prevention of Trans Epidermal Water Loss)
and reducing skin inflammation, skin irritation and signs of aging.
The present invention also relates to a process for obtaining such
formulations.
BACKGROUND OF THE INVENTION
[0003] Skin is a physical barrier to the environment. In mammals,
it is composed of multiple layers of ectodermal tissue, and guards
the underlying muscles, bones, ligaments and internal organs. It is
the alteration (damage) of the barrier properties that causes skin
conditions.
[0004] The epidermis and the dermis, separated by the basal
membrane, EDJ (Epidermal--Dermal Junction) or Grenz Zone,
constitute the cutaneous covering on the hypoderm. The epidermis is
the most superficial layer of the skin and provides its resistance
and impermeability. Alteration of this layer will negatively affect
perceived quality of the skin and will eventually lead to cutaneous
aging. Lasers, retinoids, chemical peels, microdermabrasion,
microneedling, skin exfoliants (glycolic, salicylic acid,
AHAs///BHAs) cause thinning of the skin. The dermis (the internal
layer of the skin) is conjunctive tissue composed of cells
(essentially fibroblasts) dispersed in a complex medium called the
extracellular matrix (ECM). This matrix consists of collagen and
elastin fibers, glycoproteins (fibronectin and laminin) and
proteoglycans. The extracellular matrix serves as a structure for
the cells, allowing tissues and organs to cohere in pluricellular
organisms. The EDJ, which attaches the epidermis, and the dermis of
the skin is vitally important due to the roles it plays in cellular
communication, nutrient exchange and absorption, moisturization and
other skin functions. The layers of the epidermis are continually
moving upward, throwing their "contents" overboard, flattening,
building up at the surface and then eventually sloughing off to
make room for the cells right behind them. This natural movement or
"keratinization" of the skin is an integral part of skin renewal
and healing. It would not be possible without the Epidermal-Dermal
Junction (EDJ) maintaining the relationship between the two main
layers of skin, allowing for healthy communication from the top all
the way to the bottom.
[0005] The EDJ is also responsible for the exchange of nutrients
back and forth from the epidermis to the dermis. These nutrients
are carried in the blood from the food we eat and absorbed through
the pores from topical application. Vitamins, antioxidants, acids
and other nutrients are needed for DNA repair, new cell production,
protection from outside elements and oxidative stress and more. In
youth, this junction is a healthy, wavy terrain. The finger-like
waves in the junction, called rete ridges, form the interlocking
connection between the dermis and epidermis. They increase the
surface area of the epidermis that is exposed to these blood
vessels and the needed nutrients. Without this nutrient exchange,
skin would suffer premature aging and damage.
[0006] As we age or stress our skin, it tends to flatten out. If
the junction completely flat lines, no pun intended, the
communication and nutrient exchange comes to a halt. So, in order
to maintain skin healthy--and youthful--you want to keep the
communication open and the EDJ's rete waves as wavy as possible.
Maintaining EDJ functioning can be helped by proper diet and
topical skin supplementation as well as limiting over exfoliation,
over exposure to harsh elements and any other form of stress or
trauma.
[0007] Dry skin is one of the most common skin problems. It can be
treated by applying moisturizers. Moisturizers are oily substances
which are used to replace natural skin oils, to cover tiny fissures
and to provide a protective film. Four types of moisturizers have
been described according to their mechanism of action: Occlusive,
Humectants, Emollients, and Protein Rejuvenators. Occlusive
moisturizers (e.g., petroleum in a minimum concentration of 5%,
lanolin, mineral oil, silicones (such as dimethicone)) are
substances which physically block Trans-Epidermal Water Loss (TEWL)
in the stratum corneum. Humectants (e.g., glycerin, sorbitol, urea,
alpha-hydroxy acids, and other sugars) work by attracting
trans-epidermal water to the skin to improve hydration of the
stratum corneum. Emollients (e.g., Vitamin E, fatty acids,
cholesterol, squalene, structural lipids (e.g., ceramide), stearic,
linoleic, linolenic and lauric acids (found in palm oil and coconut
oil)) smooth skin by filling spaces between skin flakes and
droplets of oil. Some emollients (long chain fatty acids) act by
influencing skin's physiology and pathology through their action on
skin barrier function, eicosanoid production, cell signaling and
membrane fluidity. Moisturizers containing collagen and other large
proteins (e.g., elastin and keratin) are said to rejuvenate the
skin by providing essential proteins (however, efficient dermal
delivery of such proteins often remains a challenge due to their
large size). Moisturizers and their effects are reviewed in C. W.
Lynde. Moisturizers: What they are and how they work. Skin Therapy
Letter, 2001; www.skintherapyletter.com/2001/6.13/2.html.
[0008] Cutaneous aging is a complex phenomenon responsible for
progressive changes of the skin. Aging of the skin results from two
processes: (1) an intrinsic process, corresponding to chronological
aging, and (2) an extrinsic process resulting mainly from the
deleterious effect of exposure to environmental stresses. Genetic
background, UV exposure, climatic factors
(harshness/wind/cold/warm), pollution (chemical, free radicals,
contaminant, nitrogen oxide, metals), alcohol consumption and
smoking are factors involved in cutaneous aging.
[0009] Scar tissue is formed during healing of wounds following for
example traumatic injury, burn and surgery (including cosmetic
surgery). Often unpredictably, hypertrophy of the scar tissue
occurs. Hypertrophic scar formation is characterized by the
accumulation of collagen type III out of proportion to collagen
type I. During skin wound healing it appears that type III
procollagen amino peptide (PIIP) is cross-linked to other
components of the wound matrix, such as fibrin and fibronectin, by
tissue transglutaminase. Such cross-linking is thought to
contribute to tissue hypertrophy and disproportionate scarring.
Common treatment of hypertrophic scar tissue includes the use of
drugs with potentially serious side effects (e.g., corticosteroid
injection) and invasive procedures including surgical excision or
cryotherapy.
[0010] Human growth factors (HGFs) have been attributed to many
rejuvenating properties and are used as anti-aging agents and
alternative wound healers. Many growth factors such as EGF and
TGF-B are large proteins, which do not penetrate the skin well.
They are also very unstable and often lose their activity within
days in water or even as solids at normal temperatures.
Furthermore, there are more and more concerns that at certain
concentrations and over certain durations of application they can
cause cells to over-proliferate and increase the risk of developing
cancer and other health problems.
[0011] Primary polyamines (polyazaalkanes) have long been known as
antioxidants. Recently, these compounds are attracting more and
more interest as they have been shown to reduce skin inflammation
and irritation and to be highly effective wound healing agents.
Their effect on wound healing and hypertrophic scarring is thought
to be due, at least partly, to their transglutaminase inhibiting
activity which reduces type III pro-collagen cross-linking to
components of the wound extracellular matrix. In addition to their
effects on skin irritation, inflammation and on wound healing,
primary polyamines have also been identified as useful agents to
prevent and/or reduce the skin's signs of aging (see for example
U.S. Pat. No. 5,885,982, CA 2 706 630 and WO 2009/067799).
[0012] Examples of primary polyamines include aminoacetonitrile,
dansylcadaverine (1,5-diaminopentane), spermidine, and putrescine
(1,4-diaminobutane (1,4-DAB)). Putrescine is a natural compound
that is related to cadaverine; both are produced by the breakdown
of amino acids in living and dead organisms. The two compounds are
largely responsible for the foul odor of putrefying flesh but are
also found in other conditions (e.g., bad breath). They are also
found in semen and some microalgae, together with related molecules
like spermine and spermidine. Putrescine is synthesized in small
quantities by healthy living cells by the action of ornithine
decarboxylase.
[0013] U.S. Pat. No. 5,885,982 (Dolynchuk) describes a method of
preventing hypertrophic scarring in human dermal wounds by applying
a topical inhibitor of fibroblast tissue transglutaminase.
Putrescine was shown to reduce collagen cross-linking in vitro and
in vivo resulting in a softer and a more rapidly mature-looking
scar as compared to controls. The negative side effects, typical of
steroid injection, were not seen. Studies done on human harvested
scars revealed an increase in apoptosis of scar fibroblasts which
lead to a less active scar than seen with other methods of
treatment.
[0014] Canadian patent application CA 2,706,630 (Dolynchuk, K.)
further shows that putrescine provides beneficial effects on the
epidermis of eroded skin increasing its barrier function as well as
the thickness of the stratum lucidum in animals and the inner
strata of human epidermis. The presence of topical polyamines such
as putrescine enhances the cellular regenerative mechanisms and
creates a robust Grenz layer. These are typically reduced by
inflammation, steroids and aging effects, the recovery of which,
results in a more youthful looking and functionally stable
skin.
[0015] Vitamin C (also known as Ascorbic Acid) is another
well-known powerful antiaging and wound healing agent. Vitamin C
deficiency causes spontaneous breakdown of wounds in the absence of
infection in many surgery patients. Furthermore, evidence from the
scientific literature shows that Vitamin C can increase collagen
production in skin fibroblasts.sup.1, counter skin damage
associated with photo aging.sup.2 and reduce the inflammation and
erythema of sunburn.sup.3. Ultimately Vitamin C helps reduce the
expression of skin aging, translated into the appearance of fine
lines or wrinkles in the skin.
[0016] In mammals, Vitamin C is involved in all phases of wound
healing. It is necessary for a normal response to physiological
stressors, with this need increasing during times of injury. Events
that cause wounding, including trauma or surgery are physiological
stressors that have been associated with a decrease in blood plasma
Vitamin C levels. In the inflammatory phase it is required for
neutrophil apoptosis and clearance. During the proliferative phase,
Vitamin C has been shown to regulate synthesis, maturation,
secretion and degradation of collagen. Also, evidence suggests that
Vitamin C may improve wound healing by stimulating quiescent
fibroblasts to divide and by promoting their migration into the
wounded area. Furthermore, studies have shown that Vitamin C
protects the skin by increasing the capacity of fibroblasts to
repair potentially mutagenic DNA lesions and acts as a powerful
antioxidant and immune system modulator.
[0017] The numerous beneficial effects attributed to Vitamin C make
it a particularly remarkable active agent in cosmetic and wound
healing applications. Humans lack the ability to store Vitamin C,
so it is important to continually replenish this vitamin through
dietary means and/or other means such as topical supplementation
(MacKay, Douglas, N D, and Miller, Alan L., ND, 2003).
[0018] Although a variety of chemical forms of Vitamin C are
available commercially, not all forms are equally absorbed or
active. As an antioxidant, Vitamin C needs to remain in its
unoxidized form in order to be effective. However, it is
particularly subject to oxidative degradation. Vitamin C is not
lipophilic and is thus much less soluble in glycols such as
propylene glycol (50 mg/ml) and even in alcohols such as ethanol
(10 mg/ml in absolute ethanol), but liposoluble derivatives have
been identified (e.g., Ascorbyl palmitate, Tetra-isopalmitoyl
ascorbic acid (IPAA) 3-0 Ethyl Ascorbic Acid, MAP (Magnesium
Ascorbyl Phosphate), SAP (Sodium ascorbyl phosphate)). The problem
to be solved with Ascorbic Acid formulations has thus always been
to find a compromise between solubilization and stability.
Furthermore, because of its sensitivity, it can be a challenge to
combine Vitamin C (especially in high concentrations) with certain
active ingredients, while maintaining adequate stability,
solubility and activity of all components in the formulation.
[0019] The creation of stable topical skin care compositions thus
often presents many difficulties and challenges due to the nature
of the active ingredients and unpredictable interactions between
components in the final formulation. Another important challenge in
the field of topical formulations (cosmetic and therapeutic)
remains the ability to deliver active ingredients into the skin to
reach target cells and provide biological effects. Factors that
influence skin penetration of a given active ingredient are
numerous and include size of the molecule, its
lipophilic/hydrophilic nature, polarity, interactions with other
components in the composition and skin condition.
[0020] Despite the number of solutions that have been proposed,
there thus remains a need for novel skin care compositions and
methods of use thereof.
SUMMARY OF THE INVENTION
[0021] Provided herein is stable barrier formulation which place a
physical barrier between the skin and contaminants (e.g.,
microorganisms and chemical and/or allergenic substances) or
environmental stressors (pollution, sun, wind, etc.) which may
irritate the skin or compromise its structural integrity or the
healing process. In addition to its barrier protective function,
the formulation advantageously comprises active ingredients (e.g.,
primary polyamines such as putrescine and optionally other
ingredients) which stimulate skin's healing, help maintain and/or
increase skin's moisture and prevent and/or reduce the formation of
hypertrophic scar tissue. These formulations may be used in
therapeutic and cosmetic applications and are particularly useful
in preventing and reducing skin's signs of aging, skin irritation
and inflammation, promoting wound healing and/or reducing the
development of scar tissue, including hypertrophic scar tissue. The
barrier formulations are thus particularly useful on sensitive,
irritated, inflamed, cracked, chapped and/or wounded skin.
[0022] The barrier formulations of the present invention are of the
"water-repellent" type (i.e., non-aqueous and do not have a pH) and
are generally provided as an ointment. More specifically, barrier
compositions of the present invention which contain at least one
polyamine (e.g., Polyamine-DAB.TM. or 1,4-Diaminobutane) and
optionally other active ingredients (e.g., Vitamin C, lanolin,
glycerin, bisabolol (e.g., (-)-alpha-bisabolol (CAS 23089-26-1) and
CAS 515-69-5 (+/-)-alpha-bisabolol)) encourages the natural
regenerating process, accelerate healing, promote new cell growth,
increase healthy blood flow, boost collagen and moisture levels in
the skin and importantly, provide a physical barrier against
chemical and environmental stressors.
[0023] In an aspect, compositions of the present invention focus on
reducing inflammation and promoting skin's healing, resulting in
beautiful and optimized skin results.
[0024] In a first aspect, the present invention thus provides a
topical barrier (protective) composition comprising at least one
primary polyamine (e.g., putrescine) in a water-repellent base
(petroleum jelly and mineral oil base). The primary polyamine is
preferably encapsulated in triglyceride phospholipids, similar to
phospholipids that occur naturally in the body. Non-limiting
examples of useful phospholipids for encapsulating the primary
polyamine include phospholipids derived from coconut oil (e.g.,
composed predominantly of diester and triester phosphatides e.g.,
Coco phosphatidyl PG-dimonium chloride and Cocamidopropyl
phosphatidyl PG-dimonium chloride), soy, rapeseed, eggs and borage.
More specific examples include Stearamidopropyl phosphatidyl
PG-dimonium chloride (from Palm oil), Linoleamidopropyl
phosphatidyl PG-dimonium chloride (Safflower),
.gamma.-Linolenamidopropyl phosphatidyl PG-dimonium chloride
(Borage), Sodium borageamidopropyl PG-dimonium chloride phosphate
(borage (e.g., ColaTM Lipid BP)). Preferably, phospholipids used to
encapsulate and stabilize the primary polyamine also has
antimicrobial activity (see for example, Biomimetic phospholipids:
Components for self-preservation (chapter 6, pp. 139-158) and Fatty
Acids and Esters as multifunctional Components (Chapter 5, pp.
119-138) in Preservative-free and self-preserving cosmetics and
drugs. Principles and Practice. Edited by Jon J. Kabara and Donald
S. Orth. Cosmetic science and technology series; v. 16 (1997).
[0025] In embodiments, the phospholipid is in a concentration of
between about 1% w/w and about 10% w/w. In embodiments, the
phospholipid is in a concentration of between about 1% w/w and
about 6% w/w. In embodiments, the phospholipid is in a
concentration of between about 3% w/w and about 6% w/w. In
embodiments, the phospholipid is in a concentration of about 4%
w/w. Of course, the concentration of phospholipid used depends on
the amount of primary polyamine to encapsulate and stabilize. The
more primary polyamine is included in the topical composition, the
more phospholipids are needed to solubilize, encapsulate and
stabilize the primary polyamine
[0026] In embodiments, the phospholipid is a quaternary ammonium
salt which encapsulates (solubilizes) the primary polyamine and
acts as a stabilizer. In embodiments, the quaternary ammonium salt
is cocamidopropyl PG-dimonium chloride phosphate. In embodiments,
the cocamidopropyl PG-dimonium chloride phosphate is in a
concentration of between about 1% w/w and about 6% w/w. In
embodiments, the cocamidopropyl PG-dimonium chloride phosphate is
in a concentration of between about 3% w/w and about 6% w/w. In
embodiments, the cocamidopropyl PG-dimonium chloride phosphate is
in a concentration of about 4% w/w. Of course, the concentration of
phospholipid used depends on the amount of primary polyamine to
encapsulate. The more primary polyamine is included in the topical
composition, the more phospholipids are needed to solubilize,
encapsulate and stabilize the primary polyamine.
[0027] In embodiments, the primary polyamine is a primary aliphatic
lower-alkyl (C1-5) monoamine; a primary aliphatic alkylamine; or a
primary aliphatic lower-alkyl (C1-5) polyamine. In embodiments, the
primary aliphatic lower-alkyl (C1-5) monoamine is
aminoacetonitrile, the primary aliphatic alkylamine is spermine or
spermidine and the primary aliphatic lower-alkyl (C1-5) polyamine
is putrescine or dansylcadaverine. In preferred embodiments, the
primary aliphatic lower-alkyl (C1-5) polyamine comprises or
consists of putrescine.
[0028] In embodiments, the putrescine is in a concentration of
between about 0.1% w/w to about 1% w/w. In embodiments, the
putrescine is in a concentration of about 0.4% w/w. In embodiments,
the putrescine is in a concentration of about 0.8% w/w.
[0029] In embodiments, the petroleum jelly in the barrier
composition of the present invention is in a concentration of
between about 25% w/w and 65% w/w, preferably between 35% w/w and
55% w/w. In embodiments, the petroleum jelly in the barrier
composition of the present invention is in a concentration of
between about 40% w/w and 50% w/w. In embodiments, the petroleum
jelly is in a concentration of about 45% w/w.
[0030] In embodiments, the mineral oil in the barrier composition
of the present invention is in a concentration of between about 30%
w/w and about 50% w/w. In embodiments, the mineral oil in the
barrier composition of the present invention is in a concentration
of between about 34% w/w and about 50% w/w. In embodiments, the
mineral oil in the barrier composition of the present invention is
in a concentration of between about 30% w/w and about 40% w/w. In
embodiments, the mineral oil is in a concentration of about 35%
w/w.
[0031] In embodiments, the barrier composition of the present
invention further comprises paraffin. In embodiments, the barrier
composition of the present invention further comprises paraffin. In
embodiments, the paraffin wax is in a concentration of between
about 0% w/w and 15% w/w, preferably between 0% w/w and up to 10%
w/w, In embodiments, the paraffin wax is in a concentration of
between about 3% w/w and 15% w/w. In embodiments, the paraffin wax
is in a concentration of between about 6% w/w and 9% w/w (6%, 7%,
8%, 9%). In embodiments, the paraffin wax is in a concentration of
about 8.5% w/w. In embodiments, the paraffin is ceresin wax.
[0032] In embodiments, the barrier composition of the present
invention further comprises lanolin oil. In embodiments, the
lanolin oil is in a concentration of between about 3% w/w and 6%
w/w (3%, 4%, 5% and 6%). In embodiments, the lanolin oil is in a
concentration of about 5% w/w.
[0033] In embodiments, the barrier composition of the present
invention further comprises a lipophilic Vitamin C derivative. In
embodiments, the lipophilic Vitamin C derivative is in a
concentration of between about 0.% w/w and 10% w/w (i.e., up to
10%). In embodiments, the lipophilic Vitamin C derivative is in a
concentration of between about 0.1% w/w and 10% w/w. In
embodiments, the lipophilic Vitamin C derivative comprises Ascorbyl
palmitate. In embodiments, the Ascorbyl palmitate is in a
concentration of about 0.5% w/w. In embodiments, the lipophilic
Vitamin C derivative comprises 3-O-Ethyl Ascorbic Acid (3-OEAA). In
embodiments, the 3-O-EAA is in a concentration of about 0.5% w/w.
In embodiments, the 3-O-EAA is in a concentration of about 1% w/w.
In embodiments, the 3-O-EAA is in a concentration of about 2% w/w.
In embodiments, the 3-O-EAA is in a concentration of about 5%
w/w.
[0034] In embodiments, the barrier composition of the present
invention further comprises one or more humectants. In embodiments,
the humectants are in a concentration of between about 0.5% w/w and
3% w/w. In embodiments, the humectants comprise glycerin, Vitamin
B5 or a combination thereof. In embodiments, the humectants
comprise about 1% w/w of said glycerin and about 1% w/w of said
Vitamin B5.
[0035] In embodiments, the barrier composition of the present
invention further comprises bisabolol. In embodiments, the
bisabolol is in a concentration of between about 0.1% w/w and 1%
w/w. In embodiments, the bisabolol is in a concentration of about
0.5% w/w.
[0036] In embodiments, the above-noted barrier compositions are for
treating or preventing skin inflammation, skin irritation and/or
skin's signs of aging. In embodiments, the barrier compositions of
the present invention are for promoting wound healing. In
embodiments, the barrier compositions of the present invention are
for preventing or reducing the formation of hypertrophic scar
tissue.
[0037] In a related aspect, the present invention concerns the use
of the above-noted barrier compositions (i) for treating or
preventing skin inflammation, skin irritation and/or skin's sign of
aging; (ii) for promoting wound healing; and/or (iii) for
preventing or reducing the formation of hypertrophic scar
tissue.
[0038] More specifically there are provided the following
items:
[0039] 1. A topical water free barrier composition comprising: (i)
a primary polyamine; (ii) a phospholipid to encapsulate the primary
polyamine; (iii) petroleum jelly; and (iv) mineral oil.
[0040] 2. The barrier composition of item 1, wherein the primary
polyamine is a primary aliphatic lower-alkyl (C1-5) monoamine; a
primary aliphatic alkylamine; or a primary aliphatic lower-alkyl
(C1-5) polyamine.
[0041] 3. The barrier composition of item 2, wherein the primary
aliphatic lower-alkyl (C1-5) monoamine is aminoacetonitrile, the
primary aliphatic alkylamine is spermine or spermidine and the
primary aliphatic lower-alkyl (C1-5) polyamine is putrescine or
dansylcadaverine.
[0042] 4. The barrier composition of item 1 or 2, wherein the
primary polyamine is aminoacetonitrile.
[0043] 5. The barrier composition of item 1 or 2, wherein the
primary polyamine is spermine or spermidine.
[0044] 6. The barrier composition of item 1 or 2, wherein the
primary polyamine is putrescine or dansylcadaverine.
[0045] 7. The barrier composition of item 1 or 2, wherein the
primary polyamine is putrescine.
[0046] 8. The barrier composition of item 7, wherein the putrescine
is in a concentration of between about 0.1% w/w to about 1%
w/w.
[0047] 9. The barrier composition of item 8, wherein the putrescine
is in a concentration of about 0.4% w/w.
[0048] 10. The barrier composition of item 8, wherein the
putrescine is in a concentration of about 0.8% w/w.
[0049] 11. The barrier composition of any one of items 1 to 10,
wherein the petroleum jelly is in a concentration of between about
25% w/w and 65% w/w.
[0050] 12. The barrier composition of item 11, wherein the
petroleum jelly is in a concentration of about 45% w/w.
[0051] 13. The barrier composition of any one of items 1 to 12,
wherein the mineral oil is in a concentration of between about 30%
w/w and about 45% w/w.
[0052] 14. The composition of item 13, wherein the mineral oil is
in a concentration of about 35% w/w.
[0053] 15. The barrier composition of any one of items 1 to 14,
wherein the phospholipid is a quaternary ammonium salt.
[0054] 16. The barrier composition of item 15, wherein the
quaternary ammonium salt is cocamidopropyl PG-dimonium chloride
phosphate.
[0055] 17. The barrier composition of item 16, wherein the
cocamidopropyl PG-dimonium chloride phosphate is in a concentration
of between about 3% w/w and about 6% w/w.
[0056] 18. The barrier composition of item 17, wherein the
cocamidopropyl PG-dimonium chloride phosphate is in a concentration
of about 4% w/w.
[0057] 19. The barrier composition of any one of items 1 to 18,
further comprising paraffin.
[0058] 20. The barrier composition of item 19, wherein the paraffin
is in a concentration of between about 3% w/w and 15% w/w.
[0059] 21. The barrier composition of item 20, wherein the paraffin
is ceresin wax and is in a concentration of about 8.5% w/w.
[0060] 22. The barrier composition of any one of items 1 to 21,
further comprising lanolin oil.
[0061] 23. The barrier composition of item 22, wherein the lanolin
oil is in a concentration of between about 3% w/w and 6% w/w.
[0062] 24. The barrier composition of item 23, wherein the lanolin
oil is in a concentration of about 5% w/w.
[0063] 25. The barrier composition of any one of items 1 to 24,
further comprising a lipophilic Vitamin C derivative.
[0064] 26. The composition of item 25, wherein the lipophilic
Vitamin C derivative is in a concentration of between about 0.1%
w/w and 10% w/w.
[0065] 27. The composition of item 25 or 26, wherein the lipophilic
Vitamin C derivative comprises 3-O-Ethyl Ascorbic Acid
(3-O-EAA).
[0066] 28. The composition of item 27, wherein the 3-O-EAA is in a
concentration of about 0.5% w/w.
[0067] 29. The barrier composition of any one of items 1 to 28,
further comprising one or more humectants.
[0068] 30. The barrier composition of item 29, wherein the
humectants is in a concentration of between about 0.5% w/w and 3%
w/w.
[0069] 31. The barrier composition of item 29 or 30, wherein the
humectants comprise glycerin, Vitamin B5 or a combination
thereof.
[0070] 32. The barrier composition of item 31, wherein the
humectants comprise about 1% w/w of the glycerin and about 1% w/w
of the Vitamin B5.
[0071] 33. The barrier composition of any one of items 1 to 32,
further comprising bisabolol.
[0072] 34. The barrier composition of item 33, wherein the
bisabolol is in a concentration of between about 0.1% w/w and 1%
w/w.
[0073] 35. The barrier composition of item 34, wherein the
bisabolol is in a concentration of about 0.5% w/w.
[0074] 36. The barrier composition of any one of items 1 to 35, for
treating or preventing skin inflammation, skin irritation.
[0075] 37. The barrier composition of any one of items 1 to 36, for
promoting wound healing.
[0076] 38. The barrier composition of any one of items 1 to 36, for
preventing or reducing the formation of hypertrophic scar
tissue.
[0077] 39. Use of the barrier composition defined in any one of
items 1 to 36, for treating or preventing skin inflammation, skin's
signs of aging and/or skin irritation.
[0078] 40. Use of the barrier composition defined in any one of
items 1 to 36, for promoting wound healing.
[0079] 41. Use of the barrier composition as defined in any one of
items 1 to 36, for preventing or reducing the formation of
hypertrophic scar tissue.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0080] Not all cosmetic products are alike. Important factors
affecting cosmetic and therapeutic results include the stability of
the active ingredient(s) in the compositions, their solubility in
the desired carrier and their ability to penetrate the skin and
reach its targeted layer(s). Applicants have developed new
non-aqueous (substantially water free) topical barrier compositions
in which the active ingredients (e.g., putrescine and derivatives
thereof) are stable and soluble in an ointment-like base, thereby
protecting the skin from external irritants and contaminants and
enabling the active ingredients to reach the cells and provide the
desired effect.
[0081] A key ingredient of the composition of the present invention
is a polyamine such as 1,4-Diaminobutane Dihydrochloride (also
called Putrescine Dihydrochloride, or 1,4-DAB). The 1,4-DAB
molecule has unique cellular properties. It promotes healing and
repair at the cellular level, preserves skin elasticity and
enhances skin smoothness. 1,4-DAB may lengthen the lifespan of a
skin cell and thicken cellular matrix to rejuvenate skin, and
therefore may reduce downtime for patients after skin treatment
such as laser or peeling, or after cosmetic surgery intervention
(ex. Eyelift, breast augmentation).
[0082] 1,4-DAB, is a highly reactive basic amine salt. It reacts
easily with acidic compounds and is thus not very stable. Due to
their polar nature, salts such as 1,4-DAB do not usually dissolve
in ointment because they need water, which ointment base lacks.
Even when they do, they generally become unstable.
[0083] Applicants have found that by encapsulating the primary
polyamine (e.g., 1,4-DAB) in a phospholipid such as PG-Dimonium
Chloride Phosphate, a stable ointment could be prepared. The
encapsulation allows to dissolve the polyamine in an ointment base
to provide a homogenous, stable composition.
[0084] Encapsulation in phospholipids such as PG-Dimonium Chloride
Phosphate stabilizes the primary polyamine and prevents it from
reacting with other ingredients in the ointment, thereby avoiding
discoloration of the composition and preserving therapeutic and
cosmetic activity. Encapsulation further facilitates delivery of
the primary polyamine into the skin.
[0085] Applicants have further found that stability of the ointment
composition comprising a primary polyamine and Vitamin C could be
further improved by using certain forms of Vitamin C derivatives
over others. Indeed, L-Ascorbic Acid was difficult to combine with
a primary polyamine, even when encapsulated. Moreover, even when
liposoluble forms of vitamin C were used, it was found that the
stability of the composition could be significantly improved by
using 3-O-Ethyl Ascorbic Acid (3-O-EAA) instead of other forms of
liposoluble vitamin C derivatives such as ascorbyl palmitate.
Compositions comprising a combination of a primary polyamine (e.g.,
1,4-DAB) and 3-O-EAA in an ointment base were found to be most
stable.
[0086] Topical barrier compositions of the present invention were
found to allow proper dissolution of active ingredients (e.g.,
polyamines) and to be stable thereby enabling the effective
penetration and delivery of active ingredients into the skin.
[0087] In a first aspect, the present invention provides a topical
barrier composition comprising (i) at least one primary polyamine
(e.g., putrescine) in an ointment-like base comprising (ii)
petroleum jelly; and (iii) mineral oil. The primary polyamine is
encapsulated in phospholipids (e.g., cocamidopropyl PG-dimomium
chloride phosphate). In embodiments, the active ingredient further
comprises lanolin, glycerin, bisabolol, panthenol and/or a
liposoluble Vitamin C derivative.
[0088] The primary polyamines used in accordance with the present
invention are preferably amine group terminated linear structures
such as unbranched aliphatic compounds (e.g., lower C1-C10,
preferably, C1-C5 alkyls). Such compounds include, but are not
limited to naturally occurring putrescine (1,4-diaminobutane (Cas
#333-93-7), H.sub.2N(CH.sub.2).sub.4NH.sub.2), cadaverine (Cas
#462-94-2, 1,5-pentanediamine, H.sub.2N(CH.sub.2).sub.5NH.sub.2),
spermidine (Cas #124-20-9, 1,4-butanediamine, N1-(3-aminopropyl,
H.sub.2N(CH.sub.2).sub.3NH(CH.sub.2).sub.4NH.sub.2), spermine (Cas
#71-44-3, 1,4-Butanediamine, N,N'-bis(3-aminopropyl),
H.sub.2N(CH.sub.2).sub.3NH(CH.sub.2).sub.4NH(CH.sub.2).sub.3NH.sub.2)
and their functional derivatives. The polyamines preferably have
(CH.sub.2), groups linking the nitrogen atoms where n is 2 to 10,
preferably 2 to 6, more preferably 2 to 5 and particularly ones
comprising 2 to 6 nitrogen atoms, particularly 2, 3 or 4 nitrogen
atoms. These polyamines are available from natural sources, e.g.,
mammalian semen or fermentation products (for example from soy or
anchovies), or may be manufactured by conventional techniques,
e.g., solid state polypeptide production followed by amidation and
reduction. Polyamines useful in accordance with the present
invention are described for example in WO2006/048671, U.S. Pat. No.
5,885,982 and CA 2,706,630. The polyamine(s) used in accordance
with the invention may conveniently be in salt form with a
physiologically tolerable counterion, (e.g., inorganic/mineral
acid, an organic acid such as an alpha-hydroxyacid or a fatty
acid). Such salts may be prepared by reaction of the polyamine and
the acid, e.g., in solution in approximately equimolar amounts.
[0089] Under certain aspects, the total polyamine content in the
compositions of the present invention is between about 0.0005 and
about 5% w/w (e.g., between about 0.001% w/w and about 1% w/w,
between about 0.005% w/w and about 1% w/w, between about 0.1% w/w
and about 1% w/w.). Preferably, in compositions for use in
stimulating wound healing (e.g., reducing the appearance of scar
tissue, including hypertrophic scar tissue), the concentration of
putrescine is preferably between about 0.1% w/w and about 1% w/w,
more preferably between about 0.4% w/w and about 0.8% w/w.
[0090] Advantageously, the barrier compositions of the present
invention comprise phospholipids (e.g., a quaternary ammonium salt)
which encapsulates and helps to stabilize and solubilize the
primary polymamine. Non-limiting examples of solubilizers for
primary polyamines which may be used in the barrier composition of
the present invention include cocamidopropyl PG-dimonium chloride
phosphate. In embodiments, for a concentration of putrescine of
about 0.8% w/w, compositions of the present invention comprise
between about 1% and about 6%, preferably between about 3% w/w and
about 6% w/w of phospholipids (e.g., quaternary ammonium salt
acting as a solubilizer/stabilizer). In embodiments, the
phospholipid (solubilizer/stabilizer) is cocamidopropyl PG-dimonium
chloride phosphate. In particular embodiments, the barrier
compositions of the present invention comprise about 4% of
cocamidopropyl PG-dimonium chloride phosphate.
[0091] In the barrier compositions of the present invention, active
ingredients are solubilized in a non-aqueous (water-insoluble)
"barrier" base which comprises petroleum jelly, and/or mineral oil.
In addition to its film-forming properties, which avoid contact
with exterior irritants and contaminants, the base also contributes
to healing and moisturization the skin. For example, a verified
medicinal use of petroleum jelly is to protect and prevent moisture
loss of the skin of patients in the initial post-operative period
following laser skin resurfacing (Khan, Jemshed A. (2008). "CO2
Laser Resurfacing Immediate Postoperative Care Prior to Complete
Epithelialization". In Hartstein, Morris E.; Holds, John B.;
Massry, Guy G. Pearls and Pitfalls in Cosmetic Oculoplastic
Surgery. p. 417. doi:10.1007/978-0-387-69007-0_136. ISBN
978-0-387-25389-3 and Jeong, Jeung-Tae; Kye, Young-Chul (2001).
"Resurfacing of Pitted Facial Acne Scars with a Long-Pulsed Er:YAG
Laser". Dermatologic Surgery. 27 (2): 107-10.
doi:10.1046/j.1524-4725.2001.00201.x. PMID 11207680). It is also
largely used to moisturize skin and combat cracking of the skin
(e.g., chapped skin). Mineral oil is also one of the safest, most
non-sensitizing moisturization ingredients found. Both ingredients
are among the most effective and inert moisturization ingredients
available.
[0092] In embodiments, the barrier compositions of the present
invention comprise between about 25% w/w and about 65% w/w of
petroleum jelly (25%, 26%, 27%, 28%, 29%, 30%, 31%, 31%, 33%, 34%,
35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%,
48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%,
61%, 62%, 63%, 64%, or 65%). In embodiments, the barrier
compositions comprise between about 40% w/w and 50% w/w of
petroleum jelly. In particular embodiments, the barrier
compositions comprise about 45% w/w of petroleum jelly.
[0093] In embodiments, the barrier compositions of the present
invention comprise between about 25% w/w and about 45% w/w of
mineral oil. In embodiments, the barrier composition comprises
between about 30% w/w and 50% w/w of mineral oil. In embodiments,
the barrier composition comprises about 35% w/w of mineral oil. In
particular embodiments, the barrier composition comprises about 34%
w/w of mineral oil.
[0094] In addition to petroleum jelly and mineral oil, the barrier
composition of the present invention may also comprise a wax (e.g.,
paraffin such as ceresin wax). The wax is used as a thickener and
stabilizer. In embodiments, the barrier compositions of the present
invention comprise between about 3% w/w and about 15% w/w of wax.
In embodiments, the barrier composition comprises between about 7%
w/w and about 10% w/w of wax. In particular embodiments, the
barrier composition of the present invention comprises about 8.5%
w/w of wax. In embodiments, the wax is paraffin. In embodiments,
the paraffin is cerasin. In embodiments, the barrier composition of
the present invention comprises about 8.6% of paraffin.
[0095] In embodiments, the barrier compositions of the present
invention further advantageously comprise Lanolin. Lanolin's
beneficial effects on the human skin and hair have been known and
valued by humans for thousands of years. This natural emollient is
absorbed by the skin, and is said to help restore its correct
moisture balance and softness without impairing natural skin
functions. To prevent the intercellular water from evaporation,
lanolin lipids form a semi-occlusive film on the skin and create a
protective barrier. Accordingly, in embodiments, the barrier
composition of the present invention comprise between about 2% w/w
and about 10% w/w of lanolin, preferably between 3% w/w and 6% w/w.
In particular embodiments, barrier compositions of the present
invention comprise between 4% w/w and 5% w/w of lanolin.
[0096] In embodiments, the barrier composition of the present
invention preferably further comprises one or more humectants
(moisturization ingredients). Preferably, the one or more
humectants comprise glycerin and/or Vitamin B5 (panthenol).
Humectants such as glycerin and panthenol have the ability to draw
water from the environment and the dermis (the lower layers of the
skin) into the outer (surface) layer of the skin. They also help to
keep the skin barrier intact. Thus, in embodiments, the barrier
compositions of the present invention comprise between 0.25% and
15% w/w of an humectant. In embodiments, between zero and 5% w/w,
preferably between and 3% w/w of humectants (e.g., glycerin and/or
panthenol). In particular embodiments, the barrier compositions of
the present invention comprise about 1% w/w of glycerin and about
1% w/w of panthenol.
[0097] Compositions of the present invention may also
advantageously include bisabolol. Bisabolol is a scent ingredient
naturally occurring in camomile. It is known to have anti-irritant,
anti-inflammatory and anti-microbial properties. Bisabolol was also
demonstrated to enhance the percutaneous absorption of certain
molecules (J Am Oil Chem. Soc. (2010) 87; 1-7). In embodiments,
barrier compositions of the present invention comprise between
about 0.01 and 2% w/w of bisabolol. In particular embodiments,
about 0.5% w/w of bisabolol.
[0098] In certain aspects, compositions of the present invention
additionally comprise a liposoluble Vitamin C derivative. As used
herein, the expression "liposoluble Vitamin C derivative" refers to
an Ascorbic Acid derivative which is liposoluble (e.g., soluble in
the non-aqueous barrier composition of the present invention which
comprises petroleum jelly and mineral oil). Non-limiting examples
of suitable liposoluble Vitamin C derivatives include: Ascorbyl
palmitate (AA-PAL), Ascorbyl-6-caprylate, ascorbyl-6-laurate and
Ascorbyl tetra-isopalmitate (VC-IP), 3-O-Ethyl Ascorbic Acid
(3-O-EAA). In an embodiment, such liposoluble Vitamin C derivative
is Ascorbyl palmitate and/or Tetra-isopalmitoyl Ascorbic acid
(IPAA). In particular embodiments, compositions of the present
invention comprise more than zero and up to about 10% w/w of a
liposoluble Vitamin C derivative. In embodiments, about 10% w/w,
about 5% w/w, about 2% w/w, about 1% w/w or about 0.5% w/w of a
liposoluble Vitamin C derivative. Preferably, compositions of the
present invention comprise at least about 0.5% w/w of a liposoluble
Vitamin C derivative. In embodiments, the compositions comprise
about 0.5% w/w of Ascorbyl palmitate.
[0099] Compositions of the present invention may additionally
comprise one or more further active ingredients (e.g., useful for
reducing or preventing skin aging, skin irritation and
inflammation, for improving skin texture, skin tone and/or skin
healing). As used herein, the term "active ingredient" refers to
various types of optional additional active ingredients that may be
used in compositions of the present invention. Actives are defined
as skin benefit agents other than emollients and ingredients that
merely improve the physical characteristics of the composition.
Although not limited to this category, common examples include
talcs and silicas, zinc salts, and sunscreens.
[0100] Non-limiting examples of active ingredients that may be
added in compositions of the present invention include: retinol,
resveratrol, polyphenol, Pseudoalteromonas ferment extract,
hydrolyzed wheat protein, hydrolyzed soy protein, glycine soja
(soybean) protein, citrulline, tripeptide-1
(glycine-histidine-lysine), tripeptide-5, palmitoyl tripeptide-5,
tripeptide-8, tripeptide-10, glycine, Butyrospermum parkii (shea)
butter, argania spinosa kernel oil, jojoba esters, glucose,
hydrolyzed rice protein, superoxide dismutase, Rosmarinus
officinalis (rosemary) leaf extract, cetearyl olivate, sorbitan
olivate, Ruscus aculeatus root extract, Centella asiatica extract,
hydrolyzed yeast protein, hydrolyzed casein, Calendula officinalis
flower extract, acetyl hexapeptide-3, allantoin, citrus grandis
(grapefruit) extract, hydrolyzed glycosaminoglycans, hyaluronic
acid, acetylated hyaluronic acid, sodium hyaluronate, Persea
gratissima (avocado) oil, tropolone, lysine HCII, Porphyridium
cruentum extract, dimethiconol, caprylic/capric triglyceride,
Cytokinol.TM., phytonadione (Vitamin K), Vitamin E (tocopherols
(e.g., .gamma.-tocopherol) and tocotrienols), escin, panthenol,
Argireline, Kinetine, CE ferulic Acid, skin growth factors,
Petrolatum/Canolin, dimethyl sulphoxide, coconut oil, keratolytic
agents, unsaturated fatty acids (e.g., omega-3, omega-6 and omega-9
unsaturated fatty acids, especially omega-3 acids, for example EPA,
DHA and ALA) and derivatives (particularly esters) thereof, HMG-CoA
reductase inhibitors, natural triterpenes, Coenzyme Q10
(ubiquinone), Vitamin B3, hydroquinone (tocopheryl acetate), Aloe,
Mallotus japonicus extract, hydroxyacids (e.g., alpha hydroxy acids
such as glycolic acid), beta-(I,3) glucans, extract of unpolished
rice, urea, pine seed oil, marine collagens, plant cell extracts,
ceramides, cholesterol, glutathione, carnitine, caffeine, Rosa
mosqueta oil, cystein derivatives, acid and alpha-amino acids, and
salts of any of these.
[0101] In embodiments, compositions of the present invention
comprise one or more further antioxidants. As used herein, the term
"antioxidant" refers to compounds, natural or synthetic, capable of
neutralizing reactive oxygen species (ROS). Commonly used
antioxidants in compositions (dermatological compositions) include,
for example, Ascorbic Acid (Vitamin C), tocopherol (Vitamin E),
isoflavones, polyphenols, and retinoids, (including retinoic acid
(0.25% to 0.1%), tretinoin, retinal, retinol (0.1% to 5%),
Adapalene, tazorotene and retinyl esters. Reviewed in Sheri L.
Rolewski. Dermatology Nursing. 2003; 15(5), Jannetti Publications,
Inc.), alpha lipoic acid, beta-glucan, coenzyme Q10, grape seed
extract, amino acids, green tea, soybean sterols, ergothioneine
(EGT, a thiourea derivative of histidine), Resorcinol, Carcinine
and mixtures thereof. In embodiments, compositions of the present
invention comprise Vitamin C and at least one further antioxidant.
In embodiments, compositions of the present invention further
comprise (in addition to putrescine and/or Vitamin C) one or more
of the following active ingredients: an antioxidant (e.g., a
retinoid such as retinol), grapefruit extract, Vitamin E and/or
hydroquinone. Generally, the concentration of retinoids (such as
retinol) that may be used in accordance with the present invention
is between about 0.01% and 5%.
[0102] Generally the total amount of active ingredients in
compositions of the present invention may be up to 40% w/w of the
composition. In embodiments, the total amount of active ingredients
in compositions of the present invention is between about 0.1% w/w
and about 35% w/w. In embodiments, the total amount of active
ingredients is between about 0.1% and about 30% w/w. In
embodiments, the total amount of active ingredients is up to 25%
w/w of the composition. In embodiments, the total amount of active
ingredients is up to 20% w/w of the composition.
[0103] The barrier compositions according to the invention may be
in any form suitable for topical application, e.g., creams,
ointments, balm, emulsions etc. and may if desired include a
carrier substrate, e.g., a woven or nonwoven web. The compositions
may contain conventional topical composition components, such as
for example, solvents, oils (e.g., plant oils), aromas, sunscreens,
colorants, viscosity modifiers, binders, diluents, emollients,
thickeners, preservatives, stabilizers, humidifiers, skin
penetration enhancers, vesicle wall formers, etc. Preferably,
barrier compositions of the present invention are topical
ointments.
[0104] Sunscreens include those materials commonly employed to
block ultra-violet radiation. Illustrative compounds are the
derivatives of para-aminobenzoic acid (PABA), cinnamate and
salicylate. For example, avobenzophenone (Parsol 1789.RTM.), octyl
methoxycinnamate and 2-hydroxy-4-methoxy benzophenone (also known
as oxybenzone) can be used.
2-ethylhexyl-3-(4-methoxyphenyl)-2-propenoate,
2-phenyl-benzimidazole-5 sulphonic acid, and 2-hydroxy-4-methoxy
benzophenone are commercially available under the trade-marks,
Parsol MCX.TM., Parsol HS.TM. and Benzophenone-3.TM., respectively.
The exact amount of sunscreen employed in the compositions can vary
depending upon the degree of protection desired from the sun's
ultra-violet radiation. Additives that reflect or scatter the sun
rays may also be employed. These additives include oxides like zinc
oxide and titanium dioxide.
[0105] Non-limiting examples of conventional topical composition
components that may be included in barrier compositions of the
present invention include lecithin, xanthan gum, carbomer,
triethanolamine, phenoxyethanol, butylene glycol, caprylyl glycol,
glyceryl stearate, PEG-100 stearate, PEG-75 stearate, PEG 40,
dimethicone, glycerin, behenyl alcohol, cetyl palmitate,
cyclopentasiloxane, dimethiconol, acrylates/acrylamide copolymer,
magnesium aluminum silicate, methylparaben, ethylparaben,
propylparaben, butylparaben, stearic acid, caprylic/capric
triglyceride, titanium dioxide, triethoxycaprylylsilane, castor oil
phosphate, tocopheryl acetate, tetrasodium edta, butylated hydroxy
toluene, allyl methacrylates crosspolymer, polysorbate 20,
carrageenan (chondrus crispus), ethylhexylglycerin, cetyl alcohol,
ceteth-20, steareth-20, pentylene glycol, sodium benzoate, sodium
dextran sulfate, potassium sorbate, ammonium glycyrrhizate,
ethoxydiglycol, propylene glycol, betaine, saccharide isomerate,
trimethylolpropane, tricaprylate/tricaprate, cetyl alcohol, dmdm
hydantoin, isobutylparaben, 1,2-hexanediol, 1,2-octanediol,
hydrogenated palm glycerides, glyceryl polyacrylate, mineral oil,
allyl methacrylate crosspolymer, polysorbate-85, glyceryl
dilaurate, C13-14 isoparaffin, laureth-7, C12-13 pareth-23,
hexamidine diisethionate, or benzoyl peroxide.
[0106] Many compositions may be protected against the growth of
potentially harmful microorganisms. However, microorganisms
generally don't grow or grow poorly in barrier compositions which
comprise of no or only very small amounts of water. Nevertheless,
anti-microbial compounds may be included in the compositions of the
present invention. Suitable preservatives include alkyl esters of
p-hydroxybenzoic acid (parabens), hydantoin derivatives, hexamidine
diisethionate, propionate salts, parabens and a variety of
quaternary ammonium compounds as well as chelating agents such as
EDTA and well known antimicrobial non-parabens of all kinds.
[0107] Uses
[0108] Compositions of the present invention are intended to be
used as is, or through the making of a composition or a medication,
to prevent or to treat any skin condition that involves skin
irritation or skin inflammation and to stimulate healing of wounded
skin. The skin condition includes but is not limited to dermatitis,
skin allergy, psoriasis, acne, eczema, rosacea, radiations exposure
including U.V. or sun exposure, laser exposure, skin aging (e.g.,
reduction of wrinkles), dry skin, cracked or chapped skin, skin
surgery and wound healing. Barrier compositions comprising
putrescine are particularly useful for promoting wound healing and
preventing and/or treating scars including hypertrophic scar
tissue.
[0109] General Manufacturing Procedures
[0110] Compositions of the invention may be produced by standard
cosmetic or pharmaceutical composition production techniques.
[0111] However, the process described in Examples 1 and 3 below,
has been found particularly useful in preparing compositions of the
present invention.
[0112] Other objects, advantages and features of the present
invention will become more apparent upon reading the following
non-restrictive description of specific embodiments thereof, given
by way of example only.
Definitions
[0113] In order to provide clear and consistent understanding of
the terms in the instant application, the following definitions are
provided.
[0114] The articles "a," "an" and "the" are used herein to refer to
one or to more than one (i.e., to at least one) of the grammatical
object of the article.
[0115] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, un-recited elements or method steps and are
used interchangeably with, the phrases "including but not limited
to" and "comprising but not limited to".
[0116] For the recitation of numeric ranges herein, each
intervening number there between with the same degree of precision
is explicitly contemplated. For example, for the range of 18-20,
the numbers 18, 19 and 20 are explicitly contemplated, and for the
range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7,
6.8, 6.9, and 7.0 are explicitly contemplated. The terms "such as"
are used herein to mean, and is used interchangeably with, the
phrase "such as but not limited to".
[0117] Unless otherwise defined herein, scientific and technical
terms used in connection with the present disclosure shall have the
meanings that are commonly understood by those of ordinary skill in
the art. For example, any nomenclature used in connection with, and
techniques of biochemistry, microbiology, chemistry and cosmetics
described herein are those that are well known and commonly used in
the art. The meaning and scope of the terms should be clear; in the
event however of any latent ambiguity, definitions provided herein
take precedent over any dictionary or extrinsic definition.
Further, unless otherwise required by context, singular terms shall
include pluralities and plural terms shall include the
singular.
[0118] Practice of the methods, as well as preparation and use of
the products and compositions disclosed herein employ, unless
otherwise indicated, conventional techniques in chemistry and
related fields as are within the skill of the art. These techniques
are fully explained in the literature. See, for example The
Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association, Washington (Editors Raymond C Rowe, Paul J. Sheskey
and Sian C. Owen, 2006).
[0119] The term "substantially water-free" means very small amounts
of water that are usually introduced into the composition along
with the components and manufacturing process, such as less than
3%, preferably less than 2%, more preferably less than 1% by weight
based on the weight of the total composition. For example,
propyleneglycol may contain small amount of water (e.g., 0.2%
water), and thus a small amount of water will usually be introduced
into the composition along with certain ingredients such as
propyleneglycol. Water may also be introduced into the composition
by precipitation during the cooling phase of manufacturing.
Preferably, the amount of water should be maintained below 2% and
preferably less than 1%. Most preferably, no water is intentionally
added to the composition.
[0120] An important excipient in the formulation is petrolatum,
also commonly referred to as petroleum jelly. Petroleum jelly is
usually obtained as the semisolid residue from petroleum after the
lighter and more volatile components have been boiled off. The
Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association, Washington (Editors Ainley Wade and Paul J Weller)
Second Edition 1994, defines petroleum jelly as a purified mixture
of semisolid saturated hydrocarbons having the general formula
C(n)H(2n+2) obtained from petroleum. The hydrocarbons comprise
mainly branched and unbranched chains, although some cyclic alkanes
and aromatic molecules with paraffin side chains may also be
present. The term petroleum also includes other mixtures of
petroleum based semisolid hydrocarbons that are commonly referred
to in the art or commercially sold as "petroleum" or "petroleum
jelly" that are suitable for application to skin. A common
petroleum is sold under the trademark Vaseline. In the examples
disclosed herein, a white petrolatum from Calumet has been
utilized. If petrolatum from other manufacturers is used in the
inventive formulation, the amounts disclosed herein may have to be
slightly altered in order to achieve the desired properties of the
formulation, which is well within the skill of one of ordinary
skill in the art. Examples of other commercially available
petrolatum include, but are not limited to, those from Ultra
Chemical, Carolina Medical Products, Witco (Germany), and Amco
Chemical.
[0121] The present invention is illustrated in further details by
the following non-limiting examples.
Example 1
Barrier Composition Comprising 0.4% Putrescine
[0122] The following barrier composition was prepared as described
below.
TABLE-US-00001 TABLE 1 Barrier composition Formula A1 comprising
0.4% Putrescine. Amount Ingredients CAS# Grade (% W/W) 1 Petroleum
Jelly 8009-03-8 USP 47.00 (perfecta Petrolatum) 2 Mineral oil
(white) 8042-47-5 USP 35.30 3 Paraffin (ceresin wax 8001-75-0 MFR
9.00 130/135) 4 Lanolin oil 70321-63-0 / MFR 4.80 8038-43-5 5
Bisabolol 23089-26-1 USP 0.50 6 Putrescine (1,4- 110-60-1 or MFR
0.40 diaminobutane) 333-93-7 7 Cocamidopropyl PG- 83682-78-4 MFR
1.00 Dimonium Chloride Phosphate 8 Glycerin 56-81-5 USP 1.00 9
Panthenol (DL) 16485-10-2 MFR 1.00 100%
[0123] The above composition was prepared by adding and mixing the
ingredients as follows in a stainless steel tank equipped with a
lightening-type propeller mixer.
TABLE-US-00002 TABLE 2 Manufacturing procedure of Formula A1. Step#
Manufacturing Procedure 1 In a double jacketed stainless steel tank
equipped with a lightening type propeller add ingredients
indentified as 1 to 5 (PART A). Start heating to allow melting of
items 1 and 3 2 Heat ingredients in Part A to 80-85.degree. C.
while mixing gently until liquid and all of item 3 has melted and a
homogeneous mixture is obtained. It is important that all of the
paraffin (item 3) is melted. A clear, golden solution is obtained.
3 Gently cool to about 50-55.degree. C., scraping the sides and
bottom before adding PART B 4 In second double jacketed stainless
steel tank add ingredients identified as 6-9 (PART B). 5 Mix items
of Part B together until all of Cocamidopropyl PG-Dimonium Chloride
Phosphate (item 8) has dissolved. Do not heat. 6 Add Part B to Part
A while mixing and mix batch until homogeneous. 7 Slowly cool while
mixing batch (preferably using sweep mixing) until room
temperature. The formula will start thickening between
40-50.degree. C. and solidify around 35.degree. C.
Example 2
Barrier Composition Comprising 0.8% Putrescine
[0124] The following barrier composition was prepared as described
below.
TABLE-US-00003 TABLE 3 Barrier composition Formula A2 comprising
0.8% Putrescine. Amount Ingredients CAS# Grade (% W/W) 1 Petroleum
Jelly 8009-03-8 USP 45.50 (perfecta Petrolatum) 2 Mineral oil
(white) 8042-47-5 USP 34.00 3 Paraffin (ceresin wax 8001-75-0 MFR
8.62 130/135) 4 Lanolin oil 70321-63-0 / MFR 4.60 8038-43-5 5
Bisabolol 23089-26-1 USP 0.48 6 Putrescine (1,4- 110-60-1 or MFR
0.80 diaminobutane) 333-93-7 7 Cocamidopropyl PG- 83682-78-4 MFR
4.00 Dimonium Chloride Phosphate 8 Glycerin 56-81-5 USP 1.00 9
Panthenol (DL) 16485-10-2 MFR 1.00 100%
[0125] The above composition was prepared by adding and mixing the
ingredients as described in Example 1 in a stainless steel tank
equipped with a lightening-type propeller mixer.
Example 3
Barrier Composition Comprising 0.8% Putrescine and 0.5% 3-O-Ethyl
Ascorbic Acid
[0126] The following barrier composition was prepared as described
below.
TABLE-US-00004 TABLE 4 Barrier composition Formula B comprising
0.8% Putrescine and 0.5% 3-O-ethyl Ascorbic Acid. Amount
Ingredients CAS# Grade (% W/W) 1 Petroleum Jelly 8009-03-8 USP
45.00 (Perfecta Petrolatum) 2 White Mineral oil 8042-47-5 USP 34.00
3 Paraffin (ceresin wax 8001-75-0 MFR 8.60 130/135) 4 Lanolin oil
70321-63-0 / MFR 4.60 8038-43-5 5 Bisabolol 23089-26-1 USP 0.50 6
Cocamidopropyl PG- 83682-78-4 MFR 4.00 Dimonium Chloride Phosphate
7 Putrescine (1,4- 110-60-1 or MFR 0.80 diaminobutane 333-93-7 8
Glycerin 56-81-5 USP 1.00 9 Panthenol (DL) 16485-10-2 MFR 1.00 10
3-O-Ethyl Ascorbic 86404-04-8 MFR 0.50 Acid (3-O-EAA, ET- VC .TM.)
100%
[0127] The above composition was prepared by adding and mixing the
ingredients as follows:
TABLE-US-00005 TABLE 5 Manufacturing procedure of Formula B. Step#
Manufacturing Procedure 1 In a double jacketed stainless steel tank
equipped with a lightening type propeller add ingredients
identified as 1 to 5 (PART A). 2 Heat ingredients to 80-85.degree.
C. while mixing gently until liquid and all of item 3 has melted
and a homogeneous mixture is obtained. 3 In second double jacketed
stainless steel tank add ingredients identified as 6-10 in the
order listed (PART B). 4 Mix items of Part B one item at a time,
mix until items 6, 7, 8, 9 & 10 have dissolved well and a white
frothy lather is obtained. 5 At 50-55 degrees Celsius, add Part B
to Part A while mixing and mix batch until homogeneous. 6 Slowly
cool while mixing batch to desired consistency.
Example 4
Barrier Composition Comprising 0.4% Putrescine and 0.5% 3-O-Ethyl
Ascorbic Acid
[0128] The following barrier composition was prepared as described
below.
TABLE-US-00006 TABLE 6 Barrier composition Formula C comprising
0.4% Putrescine and 0.5% 3-O-ethyl Ascorbic Acid. Amount
Ingredients CAS# Grade (% W/W) 1 Petroleum Jelly 8009-03-8 USP
46.20 (Perfecta Petrolatum) 2 White Mineral oil 8042-47-5 USP 34.90
3 Paraffin (ceresin wax 8001-75-0 MFR 8.8.00 130/135) 4 Lanolin oil
70321-63-0 / MFR 4.70 8038-43-5 5 Bisabolol 23089-26-1 USP 0.50 6
Cocamidopropyl PG- 83682-78-4 MFR 2.00 Dimonium Chloride Phosphate
7 Putrescine (1,4- 110-60-1 or MFR 0.40 diaminobutane 333-93-7 8
Glycerin 56-81-5 USP 1.00 9 Panthenol (DL) 16485-10-2 MFR 1.00 10
3-O-Ethyl Ascorbic 86404-04-8 MFR 0.5 Acid (3-O-EAA, ET- VC .TM.)
100%
[0129] The above composition was prepared as described in Example
3.
Example 5
Barrier Composition Comprising 0.8% Putrescine and 0.5% Ascorbyl
Palmitate
[0130] The following barrier composition was prepared as described
below.
TABLE-US-00007 TABLE 7 Barrier composition Formula D comprising
0.8% Putrescine and 0.5% Ascorbyl Palmitate. Amount Ingredients
CAS# Grade (% W/W) 1 Petroleum Jelly 8009-03-8 USP 45.00 2 Mineral
oil (white) 8042-47-5 USP 34.00 3 Paraffin (ceresin wax) 8001-75-0
MFR 8.62 4 Lanolin oil 70321-63-0 / MFR 4.60 8038-43-5 5 Bisabolol
23089-26-1 USP 0.48 6 Putrescine (1,4- 110-60-1 or MFR 0.80
diaminobutane) 333-93-7 7 Glycerin 56-81-5 USP 1.00 8
Cocamidopropyl PG- 83682-78-4 MFR 4.00 Dimonium Chloride Phosphate
(Cola Lipid C) 9 Panthenol 16485-10-2 MFR 1.00 10 Ascorbyl
palmitate 137-66-6 MFR 0.5 100%
[0131] Another composition lacking Ascorbyl palmitate was also
prepared. In such case, the absence of Ascorbyl palmitate was
compensated by Petroleum Jelly.
[0132] The above composition was prepared by adding and mixing the
ingredients as follows in a stainless steel tank equipped with a
lightening-type propeller mixer.
TABLE-US-00008 TABLE 8 Manufacturing procedure of Formula D. Step
Manufacturing Procedure 1 Add ingredients of items 1-5 in a first
stainless steel tank (Part A) 2 Heat ingredients to 80-85.degree.
C. while mixing gently until liquid and all of item 3 has melted
and a homogenous mixture is obtained. 3 In a second double jacketed
stainless steel tank add ingredients listed under items 6-10 (Part
B). 4 Mix items 6-10 together until putrescine and panthenol have
dissolved. 5 At 50-55.degree. C., add Part B to Part A with mixing
and mix batch until homogeneous. 6 Slowly cool while mixing batch
until room temperature.
Example 6
Effect of the Barrier Composition Comprising 0.8% Putrescine
[0133] A clinical study was performed on 10 subjects having
undergone laser treatment for mole removal. Subjects applied a thin
layer of the composition of Example 2 twice a day (morning and
night) on the treated area for 12 weeks. Application of the
composition decreased healing time as compared to untreated
subjects having undergone the same type of laser treatment.
Example 7
Stability of Compositions of the Present Invention
[0134] Preliminary stability tests of compositions of the present
invention comprising putrescine (from 0.4% or 0.8%) and optionally
0.5% Vitamin C (Ascorbyl palmitate or 3-O-Ethyl Ascorbic Acid) show
that the compositions are stable. Indeed, no significant change in
color, odor and texture (including absence of multiple phases, and
precipitate) were observed after about 12 months. Further stability
tests are underway and are conducted as follows.
TABLE-US-00009 TABLE 9 Stability program design for putrescine
barrier formulations. Stability Program Design 25.degree. C./~2 to
75% RH Time Points (months) 0 3 6 9 12 18 24 30 36 42 48 1)
Organoleptic C C C* C C* C C* C C* C C* 2) Viscosity: USP
<912>:.sup.(1) 3) Assay Vitamin C: HPLC Method.sup.(2) 4)
Assays Putrescine: HPLC Method.sup.(3) C = Anticipated results must
be conform to all testing specifications C* = only time point 0, 6,
12, 24, 36 & 48 will be tested for viscosity since not enough
samples .sup.(1)The Viscosity must be similar to the initial one
over time .+-. 10% (Just on the slow release formula: Barrier
composition Formula A2 comprising 0.8% Putrescine.) .sup.(2)The
Vitamin C must be .+-. 10% of the initial concentration of the
formula, if present .sup.(3)The Putrescine must be .+-. 10% of the
initial concentration of the formula Quantity of unit needed:
Viscosity: 300 mL min: 15 tubes of 30 mL Essays: 1 g: 1 tube of 30
mL Total: 16 tubes
[0135] Preliminary Stability Results
[0136] Compositions comprising Ascorbyl Palmitate, were much less
stable than compositions comprising 3-O-ethyl Ascorbic Acid, when
combined with putrescine. Indeed, formula comprising Ascorbyl
Palmitate changed color (turned to brown) much more rapidly than
compositions comprising 3-O-ethyl Ascorbic Acid in combination with
putrescine in the ointment base.
[0137] Results obtained thus far from ongoing stability assays for
formula A1, A2, B and C are provided in Tables 10-13 below.
TABLE-US-00010 TABLE 10 Formula A1 (Example 1). Finished Product
Testing Specification RD-12-00 RD-12-00 RD-12-00 RD-12-00 Method or
Initial 3 6 9 Test Specification Reference Testing Mth Mth Mth
Appearance Beige to pale Organoleptic Pale Beige to Yellow gel Pale
yellow yellow pale yellow gel yellow gel 1,4-Diaminobutane Target:
0.4% QIN-10-205 0.4 0.3 0.4 0.4 Dihydrochloride (%)
concentration
TABLE-US-00011 TABLE 11 Formula A2 (Example 2). Finished Product
Testing Specification SK-38-00 SK-38-00 SK-38-00 Method or Initial
3 6 Test Specification Reference Testing Mth Mth Appearance Beige
to pale Organoleptic Pale yellow Beige gel Pale yellow yellow*gel)
gel gel (*Product becomes pale yellow with time) Viscosity
variation USP <912> 212 400 NT 243 600 cP 1,4-Diaminobutane
Target: 0.8% QIN-10-205 0.7 0.9 0.7 Dihydrochloride (%)
concentration
TABLE-US-00012 TABLE 12 Formula B (Example 3). Finished Product
Testing Specification RD-13-00 Method or Initial RD-13-00 RD-13-00
RD-13-00 Test Specification Reference Testing 3 Mth 6 Mth 9 Mth
Appearance Beige to pale Organoleptic Pale yellow Beige to Yellow
Pale yellow gel pale gel yellow yellow gel gel 1,4-Diaminobutane
Target: 0.8% QIN-10-205 0.9 0.7 0.8 0.7 Dihydrochloride (%)
concentration 3-O Ethyl Ascorbic Target: 0.5% QIN-10-145 0.5 0.4
0.3 0.1 Acid (%) concentration
TABLE-US-00013 TABLE 13 Formula C (Example 4). Finished Product
Testing Specification RD-13-00 Method or Initial RD-13-00 RD-13-00
RD-13-00 Test Specification Reference Testing 3 Mth 6 Mth 9 Mth
Appearance Beige to pale yellow Organoleptic Pale Beige to Yellow
gel Pale yellow yellow gel pale yellow gel 1,4-Diaminobutane
Target: 0.4% QIN-10-205 0.5 0.3 0.4 0.4 Dihydrochloride (%)
concentration 3-O Ethyl Ascorbic Target: 0.5% QIN-10-145 0.4 0.4
0.1 0.2 Acid (%) concentration
[0138] The scope of the claims should not be limited by the
preferred embodiments set forth in the examples, but should be
given the broadest interpretation consistent with the description
as a whole.
REFERENCES
[0139] 1. Tajima S, Pinnell S R, Ascorbic acid preferentially
enhances type I and III collagen transcription in human skin
fibroblasts. J. Derm Science. 11:250-53, 1996. 2Traikovich S S.
[0140] 2. Use of topical ascorbic acid and its effects on photo
damaged skin topography. Arch Otolaryngol Head Neck Surg
125:1091-98, 1999. [0141] 3. Murray J, Darr D, Reich J. Pinnell S.
Topical vitamin C treatment reduces ultraviolet B
radiation-included erythema in human skin. J. Invest Dermatol
1991:96:587 (abstract). [0142] 4. C. W. Lynde. Moisturizers: What
they are and how they work. Skin Therapy Letter, 2001;
http://www.skintherapyletter.com/2001/6.13/2.html
* * * * *
References