ดีเฟนซิน constitute a family of natural antimicrobial peptides involved in non-specific, or innate, immunity. They are small เปปไทด์ต้านจุลชีพชนิดประจุบวก consisting of chains of 36 to 42 amino acids ซึ่งประกอบรวมด้วย intramolecular disulfide bridges. In man, they have a broad spectrum of very efficient antibacterial and
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antifungal activities, and are divided into two groups, namely a-ดีเฟนซิน and
p-ดีเฟนซิน. The latter are present on all epithelia, ที่รวมถึง the cutaneous
epithelium and the lachrymal and buccal mucosae, and in numerous organs, and
play an important rote in responses to infections. 13-ดีเฟนซิน are released
following the activation of specific รีเซปเตอร์, the โทลล์ไลค์รีเซปเตอร์ (TLRs).
Studies have shown that commensal bacterial flora and pathogenic flora
use different f3-ดีเฟนซิน induction routes. Thus, the skin has molecular means for differentiating and combating bacteria.
The "โทลล์ไลค์รีเซปเตอร์" (TLRs) are membrane รีเซปเตอร์ expressed by the
family of TLR genes which have a fundamental role in the recognition of
pathogenic microorganisms and the activation of innate immunity. They modulate
the production of cytokines necessary for efficient immunity. TLR4 and TLR2 are
active during the recognition of lipopolysaccharides (LPSs) present on Gram-
negative bacteria. LPS is a pro-inflammatory bacterial endotoxin. TLR2 more
particularly recognizes the peptidoglycan of Gram-positive bacteria and TLR4
recognizes the LPS of Gram-negative bacteria. In the skin, the proteins TLR2 and
TLR4 are expressed on the keratinocytes and TLR2 on the sebaceous glands.
ดีเฟนซิน play the unusual role of elicitors, i.e. of a molecule that is
capable of triggering a defence mechanism of the organism. Thus, naturally
present in the skin, they are stimulated to reinforce the protection of weakened
skin. In an environment that is often hostile, it is important to aid the biological
functions in order to maintain the quality and condition of a sound and healthy
skin. The notion of elicitor involves inciting the biological pathways present in the skin to react better in the face of external attack.
The antimicrobial properties of human B-ดีเฟนซิน (HBD-3) are described in patent application WO 01/92309.
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กรดไฮยาลูโรนิก is a natural disaccharide-based polymer ซึ่งประกอบรวมด้วย D-
glucuronic acid and N-acetylglucosamine units linked via glucoside bonds. Its properties are very variable, depending on its molecular weight. กรดไฮยาลูโรนิกs with a high molecular weight, of greater than 1000 kDa, are essentially used for promoting the moisturization of the skin by means of the hydrophilic carbohydrate network they constitute. กรดไฮยาลูโรนิกs of low molecular weight, of less than about 50 kDa, can cross the stratum corneum barrier and stimulate the CD44 รีเซปเตอร์ responsible for the neosynthesis of กรดไฮยาลูโรนิก in the dermis.
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กรดไฮยาลูโรนิก, like collagen, is one of the main constituents of the
extracellular matrix of the dermis and it plays an important role in cell growth
and in the maintenance of moisturization. In the course of skin ageing, a decrease
in its concentration in the dermis is observed. กรดไฮยาลูโรนิก is a
glycosaminoglycan that is often used in cosmetic and dermatological
compositions, generally in the form of sodium hyaluronate, especially for
promoting moisturization and for stimulating cicatrization and the natural
defences of the skin. It is also used in cosmetic surgery for filling wrinkles, in
medical treatments for combating arthrosis, and in ophthalmology. Various
crosslinked or non-crosslinked กรดไฮยาลูโรนิก derivatives, which may show good
resistance to enzymatic degradation, and which may be used in particular in
cosmetic compositions, are described, for example, in patent application
WO 2011/080 450. Various forms of กรดไฮยาลูโรนิก are well known and
commercially available.
It has been proposed to combine กรดไฮยาลูโรนิก or derivatives with
chondroitin sulfate, as in patent application WO 2009/073 437, or with a retinoid
and an oligosaccharide, as in patent FR 2 894 827. Heavy metal salts of กรดไฮยาลูโรนิกhave also been proposed in antimicrobial compositions, as described in
patent application WO 87/05517. Patent US 6 180 601 describes a pharmaceutical
composition using a กรดไฮยาลูโรนิก of tow molecular weight, i.e. 50 to 200 kDa,
forming a matrix incorporating a peptide or a protein, for example a growth
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hormone. Patent application WO 2006/130 974 relates to peptides preferably containing 15 to 40 amino acids, which can bind, on the one hand, to กรดไฮยาลูโรนิก, and, on the other hand, to the bacterial capsule containing กรดไฮยาลูโรนิก, and which may be used in the presence of a lipid to form liposomes. A
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pharmaceutical composition ซึ่งประกอบรวมด้วย a peptide derived from lactoferrin and
กรดไฮยาลูโรนิก is described in patent application WO 2010/081 800.
Studies carried out by the Applicant have demonstrated that it is possible
to obtain efficient antimicrobial activity, equivalent to that of local antiseptics
and antibiotics, by combining an เปปไทด์ต้านจุลชีพชนิดประจุบวก with a กรดไฮยาลูโรนิก of medium molecular weight, and that the antimicrobial activity of the
cationic peptide is potentiated by the combination with กรดไฮยาลูโรนิก which
stimulates the production of p-ดีเฟนซิน. The term "antimicrobial activity" means antibacterial and/or antiviral and/or antifungal activity.
The object of the การประดิษฐ์นี้ is to propose a novel topical
composition which has antimicrobial properties, making it possible to efficiently
treat cutaneous microbial infections and to reinforce the skin's natural defence ,
without resorting to chemical antiseptics or antibiotics.
A subject of the การประดิษฐ์นี้ is thus a dermatological composition
ซึ่งประกอบรวมด้วย in combination at least one cationic antimicrobial peptide and
กรดไฮยาลูโรนิก of medium molecular weight or a salt thereof.
A subject of the การประดิษฐ์นี้ is also an antimicrobial topical
dermatological composition ซึ่งประกอบรวมด้วย in combination at least one เปปไทด์ต้านจุลชีพชนิดประจุบวก coupled to a lipid, and กรดไฮยาลูโรนิก, or a salt thereof,
with a molecular weight of between 100 kDa and 800 kDa.
Finally, a subject of the การประดิษฐ์นี้ is a composition ซึ่งประกอบรวมด้วย at
least one เปปไทด์ต้านจุลชีพชนิดประจุบวก coupled to a lipid, and กรดไฮยาลูโรนิก of medium molecular weight or a salt thereof, in combination, for use in the
treatment of cutaneous, integumental or mucosal microbial infections.
Such a composition is useful in human dermatology for treating skin wounds by virtue of its antimicrobial properties.
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It is also useful in dermatology and in ophthalmology, more particularly for treating infections associated with chronic acute wounds, folliculitis, overinfections of dermatological inflammatory diseases, blepharitis, meibomitis and conjunctivitis.