专利摘要:

公开号:BR112012031117B1
申请号:R112012031117-4
申请日:2011-06-08
公开日:2018-01-16
发明作者:Cebrian Puche Juan;Alminana Domenech Nuria;Delgado Gonzalez Raquel
申请人:Lipotec S.A.;
IPC主号:
专利说明:

(54) Title: METHOD FOR ANTI-AGING SKIN TREATMENT AND KIT FOR ANTI-AGING SKIN TREATMENT (51) lnt.CI .: A61K 8/64; A61Q 19/08; A61K 8/99 (30) Unionist Priority: 06/09/2010 US 12 / 797,222 (73) Holder (s): LIPOTEC S.A.
(72) Inventor (s): JUAN CEBRIAN PUCHE; NURIA ALMINANA DOMENECH; RAQUEL DELGADO GONZALEZ
1/66
METHOD FOR ANTI-AGING SKIN TREATMENT AND KIT FOR ANTI-AGING SKIN TREATMENT
FIELD OF THE INVENTION
The present invention relates to a method for treating skin anti-aging which comprises administering Botulinum toxin to an area of skin on the face and / or neck combined with administering a cosmetic or pharmaceutical composition comprising a cosmetic or pharmaceutically effective of at least one peptide derived from the SNAP-25 protein and / or at least one peptide derived from enkephalin, and at least one
excipient or adjuvant cosmetically or pharmaceutically acceptable. 0 combined treatment prolongs in time to efficiency anti-aging of injections in toxin Botulinum. BACKGROUND OF THE INVENTION
Expression wrinkles are the wrinkles that result from the stress exerted by the contractions of facial muscles responsible for causing facial expressions on the skin of the face. Expression wrinkles are commonly located on the forehead, in the space between the eyebrows, around the mouth and / or around the eyes. Depending on the shape of the face, the frequency of expression and the existence of tics (convulsive movements that are often repeated, caused by the involuntary contraction of one or several muscles, in this case facial muscles), expression wrinkles may even appear during adolescence. External factors, such as sun exposure, emphasize its depth and visibility.
The basis or mechanism for the formation of these facial wrinkles is the contraction of the muscles of the epidermis that drag the skin inward. This muscle contraction is the result of hyperactivity of the nerves that unnervate facial muscles. Nerve hyperactivity is characterized by the release
2/66 uncontrolled and excessive neurotransmitters that excite muscle fibers. For this reason, the molecules that control neuronal exocytosis contribute to the relaxation of muscle contraction, and consequently, to eliminate wrinkles.
Botulinum toxin injections have been widely used for such purposes, in particular serotype A (BOTOX® Cosmetic / Vistabel, Allergan Inc., Dysport ™, Ipsen Biopharm, Ltd. and Azzalure®, Galderma SA) [Carruthers, A., Kiene, K. and Carruthers, J. (1996) Botulinum Exotoxin use in clinicai dermatology J. Am. Acad. Dermatol. 34, 788 to 797; Cheng, C.M. (2007) Cosmetic use of botulinum toxin type A in the elderly Clin. Interv. Aging. 2.81 to 83; Ascher, B, Talarico, S., Cassuto, D., Escobar, S., Hexsel, D., Jaén, P., Monheit, G., Rzany, B., Viel, M. (2010) International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) part I: upper facial wrinkles J. Eur. Acad. Dermatol. Venereol.]. Such techniques deliver toxins to muscles to produce a local effect. Botulinum neurotoxins inhibit neuronal exocytosis at the neuromuscular junction (nerve-muscle synapse) by cleaving any of the proteins that form the SNARE complex that directs and controls the release of acetylcholine accumulated in the vesicles, thus causing weakness of the nearby muscle.
The paralytic effects of the toxin are reversible with an average duration of 3 to 4 months, depending on the severity of wrinkles and the resistance of the treated muscles [Rzany, B., Ascher, B., Monheit, GD (2010) Treatment of glabellar lines com botulinum toxin type A (Speywood Unit): a clinical overview J. Eur. Acad. Dermatol. Venereol. 24, Sl, 1 to 14]. Maximum effectiveness after toxin injection
Botulinum is obtained during the first month after
3/66 administration, with rapid deterioration over the next few months, that is, 2 months after the injection of Botulinum toxin, the average wrinkle reduction is approximately 40% of the maximum average wrinkle reduction, and approximately 20 % 4 months after the injection. Treatment therefore requires repeated injection of Botulinum toxin, which can trigger an immune response that will eventually cause a clear loss of treatment effectiveness. This loss of effectiveness of treatment with Botulinum toxin implies the need to increase the dose administered in subsequent treatments, which in turn causes a potentiation of the immune response. As an alternative to treatment with Botulinum toxin serotype A, the use of different Botulinum toxin serotypes, such as serotype B, serotype F and serotype E, was considered. However, the application of different serotypes cannot be considered a solution to the problem, since sooner or later, the immune reaction can occur again. Additionally, treatment with toxins
Botulinum for aesthetic improvement is not exempt from adverse side effects, with the most frequently reported (> 10% prevalence) reactions at the injection site and migraine, but also with a non-negligible prevalence (> 1 to <10%) of ptosis, facial paresis, increased lacrimation or dry eye, eyelid edema, asthenopia and muscle spasm around the eyes. Such side effects are transient and moderate in intensity, but can last for several weeks, and can discourage volunteers from reinjecting the toxin as soon as wrinkles reappear. The frequency of toxin reinjection must be agreed with the doctor who must between the benefit and the potential effects arising from the treatment. As a regular medical practice, doctors recommend injections every 6 months.
The cosmetic industry has made several efforts
Botulinum balance collaterals
4/66 to develop new molecules that mimic the paralytic effects of Botulinum toxins, but with simpler and more stable molecular structures, which do not induce immune responses, and whose cost of manufacture is economical. Peptide-type molecules agree with these properties and solve the problems presented by treatment with Botulinum toxin. Specifically, EP 1180524 BI and patent application WO 2008/049945 A1 to Lipotec, S.A. describe peptides derived from the amino terminating fragment of the SNAP-25 protein which inhibits neuronal exocytosis and thus has an anti-wrinkle effect. International patent application WO 97/34620 A1 also describes peptides derived from the amino acid sequence of the SNAP-25 protein, in particular its carboxy termination, or neuronal capable synaptobrevine or syntaxin.
A different approach to muscle is that achieved by acting at the postsynaptic level. This is the approach of some commercially available anti-expression wrinkle peptides such as Inyline ™ [INCI: Acetyl Hexapeptide-30] marketed by Lipotec that interferes with acetylcholine receptor agglomeration, or Vialox [INCI: Pentapeptide-3] and Syn e -Ake [INCI: Diaminobutyryl diacetate benzylamide dipeptide], marketed by
Pentapharm / DSM, which are acetylcholine receptor antagonists.
Other methods described for reducing and / or eliminating expression wrinkles involve the use of calcium channel antagonists, particularly salts of manganese (FR 2809005 Al), alverine (FR 2798590 Al) or magnesium gluconate (FR 2846885 Al), or the use of chloride channel agonists such as glycine (EP 0704210 A2) or extracts of iris pallida (FR 2746641 Al).
inhibit exocytosis inhibit contraction
5/66
A different mechanism of action to inhibit neuronal exocytosis is described in patent application EP 1892247 Al to Lipotec, SA The document describes a family of peptides derived from the enkephalin sequence that are effective in reducing and / or eliminating facial wrinkles, especially wrinkles of expression, which act by activating K + currents in neurons, causing a hyperpolarizing effect that results in a reduction in Ca 2+ dependent neuronal exocytosis.
In patent application EP 1892247 A1 with Lipotec, S.A., the effect of combining Peptides derived from SNAP-25 with peptides derived from enkephalin is also described. The combination of both complementary mechanisms to attenuate muscle contraction provides a marked and sustainable effectiveness in reducing expression wrinkles.
There is also a need for improvement in the performance of Botulinum toxin treatments, and it is especially necessary to prolong the benefits received from the treatment and / or minimize the need for multiple treatments for a cosmetically or pharmaceutically remarkable result.
Surprisingly, the inventors have found that administration to areas of the skin of the face and / or neck of a cosmetic or pharmaceutical composition comprising peptides derived from the SNAP-25 protein, which block neuronal exocytosis, and / or encephalin-derived peptides, which reduce Ca 2+ -dependent neuronal exocytosis, prolong the anti-aging efficacy of Botulinum toxin injections in time.
DESCRIPTION OF THE INVENTION
This invention provides a solution to the needs mentioned above. This invention provides a method for treating skin anti-aging which comprises the administration of Botulinum toxin to an area of
6/66 skin of the face and / or neck, combined with the administration of a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide derived from the SNAP-25 protein, and / or at least one peptide derived enkephalin, and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant. Anti-aging skin treatment is a treatment to reduce or eliminate skin wrinkles on the face and / or neck.
This invention provides a simple, effective and risk-free solution to prolong the temporary effects of treatment with Botulinum toxin injections in time. Administration of a cosmetic or pharmaceutical composition containing peptides derived from the SNAP-25 protein and / or peptides derived from enkephalin maintains the benefit of administering Botulinum toxin beyond the common average of three to four months, and allows for a reduction in the frequency of Botulinum toxin injections for two or less times a year. The anti-wrinkle effect of Botulinum toxin injections is best maintained until the next Botulinum toxin administration, and also the next Botulinum toxin administration can be delayed, thereby reducing the likelihood of a patient's immune response and loss of treatment effectiveness as a consequence of repeated administrations of Botulinum toxin. The treatment of this invention provides an average wrinkle reduction greater than 50% after 2 months in relation to the maximum average wrinkle reduction, greater than 25% after 4 months and greater than 10% after 6 months.
DEFINITIONS
In order to facilitate the understanding of this invention, the meanings of some terms and expressions as they are used within the context of the invention are included.
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Within the context of this invention, the terms aging and aging of the skin are used to describe the appearance of visible changes in the appearance of the skin, as well as those perceptible by touch, for example, and in a non-limiting sense wrinkles, fine lines, roughness , expression lines, stretch marks, discontinuities, ridges, sagging, loosening of the skin, such as loosening of cheeks, pockets in the eyes, double chin, increase in pore size, loss of elasticity, loss of resilience, loss of firmness, elastosis , anomalous differentiation, hyperkeratinization, keratosis, changes in skin color, such as marks, redness or bags under the eyes, formation of hyperpigmented areas such as age spots, melasma or freckles, loss of smoothness, orange peel skin, loss of skin structure collagen and other histological changes in the stratum corneum, dermis, epidermis, vascular system (for example, the formation of microvarices or telangiectasias) or those tissues close to the skin. Skin aging is a process with two main components: chronological, which is due to the passage of time, and photoinduction, which is due to the level of exposure to ultraviolet radiation (UV) and which is known as photoaging. The sum of several environmental factors, such as exposure to tobacco smoke, exposure to pollution, and climatic conditions, such as cold and / or wind, also contribute to skin aging.
Within the context of this invention, skin anti-aging treatment is a treatment to prevent, delay and / or reduce skin aging in humans.
In the present invention, the abbreviations used for amino acids follow the rules of the IUPAC-IUB Board Committee on Biochemical Nomenclature specified in Eur. J. Biochem., 1984, 138: 9 to 37 and in J. Biol. Chem., 1989, 264: 633
8/66 to 673. Thus, for example, Gly represents NH 2 -CH 2 -CO-OH, Glirepresenta NH 2 -CH 2 -CO-, Gly represents -NH-CH 2 -CO-OH and -NH -Glirepresenta -CH 2 -CO-. The hyphen, which represents the peptide bond, therefore eliminates the OH from the 1-carboxyl group of the amino acid (represented in this document in conventional non-ionized form) when it is placed to the right of the symbol, and eliminates the H from the group 2-amino of the amino acid when it is placed to the left of the symbol; both modifications can be applied to the same symbol.
The abbreviation Ac- is used in the present description to denote the acetyl group (CH 3 -CO-) and the abbreviation Palm is used to denote the palmitoyl group (CH 3 - (CH 2 ) 14-CO-).
Within the context of this invention, the term non-cyclic aliphatic group is used in this invention to encompass, for example, and not limited to, straight or branched alkyl, alkenyl and alkynyl groups.
The term alkyl group in this invention refers to a straight or branched saturated group, which has 1 to 24, preferably 1 to 16, more preferably 1 to 14, even more preferably 1 to 12, even more preferably 1, 2, 3, 4, 5 or 6 carbon atoms, and which is attached to the rest of the molecule via a single bond, including, for example, and not limited to, methyl, ethyl, isopropyl, isobutyl, tert-butyl, heptyl, octyl, decyl, dodecyl, lauryl, hexadecyl, octadecyl, amyl, 2-ethylhexyl, 2-methylbutyl, 5-methylhexyl and the like.
The term alkenyl group in this invention refers to a straight or branched unsaturated group that has between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, with even more preferably 2, 3, 4, 5 or 6 carbon atoms with one or more carbon-carbon double bonds, preferably with 1, 2
9/66 or 3 carbon-carbon double bonds, conjugated or unconjugated, which are linked to the rest of the molecule through a single bond, including, for example, and not limited to, the vinyl, oleyl, linoleyl group and the like.
The term alkynyl group in this invention refers to a straight or branched unsaturated group that has between 2 and 24, preferably between 2 and 16, more preferably between 2 and 14, even more preferably between 2 and 12, with even more preferably 2, 3, 4, 5 or 6 carbon atoms with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, which are attached to the rest of the molecule through a single bond, including, for example, and not limited to, the ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, pentynyl group, for example, 1pentinyl, and the like.
The term alicylyl group is used in this invention to encompass, for example, and not limited to, cycloalkyl or cycloalkenyl or cycloalkynyl groups.
The term cycloalkyl refers in this invention to a saturated mono- or polycyclic aliphatic group having between 3 and 24, preferably between 3 and 16, more preferably between 3 and 14, more preferably between 3 and 12, and with even more preferably 3, 4, 5 or 6 carbon atoms and which are attached to the rest of the molecule via a single bond, including, for example, and not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methyl cyclohexyl , dimethyl cyclohexyl, octahydroindene, decahydronaphthalene, dodecahydro phenalene and the like.
The term cycloalkenyl refers in this invention to a mono- or polycyclic non-aromatic aliphatic group having between 5 and 24, preferably between 5 and 16, with more
10/66 preferably between 5 and 14, even more preferably between 5 and 12, and even more preferably 5 or 6 carbon atoms with one or more carbon-carbon double bonds, preferably 1, 2 or 3 double bonds of carbon-carbon, conjugated or unconjugated, and which are linked to the rest of the molecule through a single bond, including for example, and not limited to, the cyclopent-l-en-1yl group and the like.
cycloalkynyl refers in this invention to a mono- or polycyclic non-aromatic aliphatic group having between 8 and 24, preferably between 8 and 16, more preferably between 8 and 14, even more preferably between 8 and 12, and with even more preferably 8 or 9 carbon atoms with one or more carbon-carbon triple bonds, preferably 1, 2 or 3 carbon-carbon triple bonds, conjugated or unconjugated, and which are linked to the rest of the molecule through a single bond, including for example, and not limited to, the cyclooct-4-en-2inyl group and the like.
The term aryl group in this invention refers to an aromatic group having between 6 and 30, preferably between 6 and 18, more preferably between 6 and 10, and even more preferably 6 or 10 carbon atoms, composed of 1 , 2, 3 or 4 aromatic rings bonded via a carbon-carbon bond or fused, including, for example, and not limited to, phenyl, naphthyl, diphenyl, indenyl, phenanthryl or anthranyl, among others, or an aralkyl group .
The term aralkyl group in this invention refers to an alkyl group substituted by an aromatic group, which has between 7 and 24 carbon atoms, which is attached to the rest of the molecule through a single bond, and including, for example, and not limited thereto, - (CH 2 ) i- 6 -phenyl, - (CH 2 ) i- 6 (1-naphthyl), - (CH 2 ) i- 6 - (2-naphthyl), - (CH 2 ) i - 6 -CH (phenyl) 2 and
11/66 heterocyclyl completely not limited to triazolyl, similar.
The term heterocyclyl group refers in this invention to a 3 to 10-membered hydrocarbon ring in which one or more of the ring atoms, preferably 1, 2 or 3 ring atoms, is an element other than carbon, for example, nitrogen, oxygen or sulfur and that can be saturated or unsaturated. For the purposes of this invention, the heterocycle can be a cyclic, monocyclic, bicyclic or tricyclic system, which can include fused ring systems, and nitrogen, carbon or sulfur atoms can be optionally oxidized to the heterocyclyl radical; the nitrogen atom can be optionally quaternized and that of the radical can be partially or saturated or aromatic. More preferably, the term heterocyclyl refers to a 5- or 6-membered ring. Examples of saturated heterocyclyl groups are dioxane, piperidine, piperazine, pyrrolidine, morpholine and thiomorpholine. Examples of aromatic heterocyclyl groups, also known as heteroaromatic groups, are pyridine, pyrrole, furan, thiophene, benzofuran, imidazoline, quinoline, quinoline, pyridazine and naphthyridine.
The term heteroarylalkyl group in this invention refers to an alkyl group substituted by a substituted or unsubstituted aromatic heterocyclyl group, where the alkyl group has 1 to 3 carbon atoms and the aromatic heterocyclyl group between 2 and 24 carbon atoms and 1 to 3 atoms in addition to carbon, which is linked to the rest of the molecule through a single bond, and including, for example, and to the same, - (CH 2 ) i_ 6 -imidazolyl, - (CH 2 ) i- 6 - (CH 2 ) i-6-thienyl, - (CH 2 ) xg-furyl- (CH 2 ) χ_ 6 pyrrolidinyl and the like.
As is understood in this technical area, there may be a certain degree of substitution in the groups previously
12/66 defined. Thus, there can be a substitution in any of the groups of this invention. References in that document to substituted groups in the groups of this invention indicate that the specified radical can be substituted in one or more available positions by one or more substituents, preferably in 1, 2 or 3 positions, more preferably in 1 or 2 positions, and most preferably in 1 position. Such substituents include, for example, and are not limited to, C 1 -C 4 alkyl; hydroxyl; alkoxy C] .- C 4 ; amino; C 1 -C 4 aminoalkyl; C 1 -C 4 carbonyloxy; C 1-4 oxycarbonyloxy; halogen such as fluorine, chlorine, bromine and iodine; cyan; nitro; azido; C 1 -C 4 alkylsulfonyl; thiol; C 1 -C 4 alkylthio; aryloxy as phenoxy, -NR b (C = NR b ) NR b R c ; wherein R b and R c are independently selected from the group consisting of group H, Ci-C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 10 cycloalkyl, C 6 -C aryl 8 , C 7 -C 17 aralkyl, 3 to 10 membered heterocyclic or amino protector.
METHOD OF THE INVENTION
In a first aspect, this invention relates to a method for treating skin anti-aging which comprises:
The. The administration of an effective amount of Botulinum toxin to an area of skin on the face and / or neck,
B. and the administration, once a week to ten times a day, of a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide containing a sequence of 6 to 40 adjacent amino acids contained in the amino acid sequence of SNAP-25 protein, defined by SEQ ID No. 1, and according to general formula (I):
Ri-AA-Rs (I) their stereoisomers, mixtures thereof, and / or
13/66 their cosmetically or pharmaceutically acceptable salts thereof, in which AA is a sequence of 6 to 40 adjacent amino acids contained in the amino acid sequence SEQ ID No. 1;
and / or at least one enkephalin-derived peptide of the general formula (II):

their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, where:
X and Y are independently selected from the group consisting of natural and unnatural amino acids;
Ri and R ' x are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R 5 -C (O) -; and
R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 , -OR 3 and -SR 3 ; where R 3 and R 4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, aryl
14/66 substituted or unsubstituted and substituted or unsubstituted aralkyl;
where R 5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted heteroarialkyl or not replaced;
and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
The groups R lz R ' x and R 2 , R' 2 are linked at the amino termination (TV-terminal) and carboxy termination (C-terminal) ends of the peptide sequences, respectively.
In a particular embodiment, the anti-aging skin treatment is a treatment to reduce or eliminate skin wrinkles on the face and / or neck, preferably expression wrinkles.
In another particular embodiment, the preferred structures of the peptides represented in the general formula (II) are those in which X is -Gli-, -Ala- or -Ser-, and more preferably -D-Ala- or -D-Ser- ,
In another particular embodiment, the preferred structures of the peptides represented in the general formula (II) are those in which Y is -Leu- or -Met-, and more preferably -L-Leu- or -L-Met-.
In another particular embodiment, R x and R ' x are independently selected from the group consisting of H, a polymer of the general formula (III)
O O
(III)
15/66 where n is in the range 1 to 100, preferably between 1 and 5, and R 5 -CO-, where R 5 is selected from the group consisting of substituted C 1 -C 24 alkyl radical or unsubstituted, substituted or unsubstituted C 2 -C 2 alkenyl radical, substituted or unsubstituted C 2 -C 24 alkynyl radical, substituted or unsubstituted C 3 -C 24 cycloalkyl radical, substituted or unsubstituted C 5 -C 24 cycloalkyl radical substituted, substituted or unsubstituted C 8 -C 24 cycloalkynyl radical, substituted or unsubstituted C 6 -C 30 aryl radical, substituted or unsubstituted C 7 -C 24 aralkyl radical, a substituted or unsubstituted heterocyclyl radical that has 3 to 10 ring members, a substituted or unsubstituted heteroarylalkyl radical having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 carbon atoms. Preferably, R 3 and R'i are independently selected from the group consisting of H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroil, myristoyl, palmitoyl, stearoyl, behenyl, linoleyl . More preferably, Ri and independently selected from the group consisting of H, acetyl, hexanoyl, octanoyl, lauroyl, myristoil or palmitoyl.
In another particular embodiment, R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 , -OR 3 or -SR 3 where R 3 and R 4 are independently selected from the group consisting of H, alkyl C 3 C 24 substituted or unsubstituted C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 3 -C 24 substituted or unsubstituted cycloalkenyl C 5 - C 24 substituted or unsubstituted, C 8 -C 24 cicloalquinila or not substituted and R 'are oleoíla
16/66 substituted, substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted C 7 -C 24 aralkyl, substituted or unsubstituted heterocyclyl having 3 to 10 ring members, and substituted or unsubstituted heteroarylalkyl group which has 2 to 24 carbon atoms and which has 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 carbon atoms and a polymer of the general formula (III) where n is in the range between 1 and 100, preferably between 1 and 5. Optionally, R 3 and R 4 can be linked via a saturated or unsaturated carbon-carbon bond, which forms a cycle with the nitrogen atom. Preferably, R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 or -OR 3 , where R 3 and R 4 are independently selected from the group consisting of H, C 1 alkyl -C 24 substituted or unsubstituted C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 0 -C 3 substituted or unsubstituted, aryl C 6 -C 5 unsubstituted or substituted and the substituted or unsubstituted 3 to 10 membered heterocyclyl, a substituted or unsubstituted heteroarylalkyl group with a ring having 3 to 10 members and an alkyl chain of 1 to 6 carbon atoms and a polymer of the general formula (III ) where n is in the range between 1 and 100, preferably between 1 and 5. More preferably, R 3 and R 4 are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Most preferably, R 3 is H and R 4 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. According to an even more preferred embodiment, R 2 and R ' 2 are independently selected from the group consisting of -OH and -NH 2 .
Peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention may exist as
17/66 stereoisomers or mixtures of stereoisomers; for example, the amino acids that form them can have L-, D- configuration or be racemic independently of each other. Therefore, it is possible to obtain isomeric mixtures as well as racemates or diastereomeric mixtures or diastereomers or pure enantiomers, depending on the number of asymmetric carbons and which isomers or isomeric mixtures are present. The preferred structures of the peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention are pure isomers, i.e., enantiomers or diastereomers. For example, unless otherwise stated, it is understood that when it is indicated that an amino acid can be -Ala-, it is understood that it is selected from -L-Ala-, -DAla- or racemic mixtures or non-racemic of both. The methods described in this document allow the person skilled in the art to obtain each of the stereoisomers of the peptide derivative of the invention by choosing the amino acid with the appropriate configuration.
In the context of this invention amino acid sequence derived from the amino acid sequence of the SNAP-25 protein means any amino acid sequence or fragments of the amino acid sequence of the SNAP-25 protein, defined by SEQ ID No. 1, or any amino acid sequence that differs from the sequence SEQ ID No. 1 through mutation, insertion, deletion or substitution of at least one amino acid, or through degeneration of the genetic code, as long as it corresponds to a peptide that has the activity of the SNAP-25 protein.
Mutations, insertions or substitutions can occur through genetically encoded amino acids or non-encoded amino acids, natural or not, for example, and not limited to, citrulline, ornithine, sarcosine, desmosine, norvaline, 4-aminobutyric acid, 218/66 aminobutyric acid , 2-aminoisobutyric acid, 6aminohexanoic acid, 1-naphthylalanine, 2-naphthylalanine, 2aminobenzoic acid, 4-aminobenzoic acid, 4-chlorophenylalanine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, cycloserine, carnitine, cystine, cystine , pyroglutamic acid, thienylalanine, hydroxyproline, allo-isoleucine, allo-threonine, isonipecotic acid, isoserine, phenylglycine, statin, beta-alanine, norleucine, N-methylamino, beta- or gamma-amino acids, among others, and their derivatives. A list of unnatural amino acids can be found at
Unusual amino article acids in peptide synthesis by Roberts D.C. and Vellaccio F • r in The Peptides, Vol 5 (1983), Chapter VI, Gross, AND. and Meienhofer, J., Eds. , Academic Press, New York, USA or in catalogs commercials companies specialized nc > sector, how NeoMPS, Bachem,
Novabiochem, Sigma-Aldrich, Peptides International, Advanced ChemTech, Chem-Impex, Maybridge Chemical, Chirotech Technology, Peninsula Laboratories or RSP Amino Acid Analogues, among others.
Among the peptides derived from the SNAP-25 amino acid sequence defined by SEQ ID No. 1 included in the cosmetic or pharmaceutical composition of the method of this invention, preferred sequences are those that have an adjacent amino acid sequence contained in the sequence of the amino termination region of SNAP-25 protein defined by SEQ ID No.2 or the amino-terminal region of SNAP25 protein defined by SEQ ID No. 3, more preferably in the region between residues 10 to 22, defined by SEQ ID No.4, or contained in region between residues 25 to 40, defined by SEQ ID No. 5, or contained in the region between residues 65 to 81, defined by SEQ ID No.6, or contained in the region between residues 181 to 206, defined by SEQ ID No.7 , more precisely contained in the region between residues 12 to 19, defined by SEQ ID No.8, or contained
19/66 in the region between residues 26 to 38, defined by SEQ ID No.9 or contained in the region between residues 68 to 79, defined by SEQ ID No. 10 or specifically contained in the region between residues 12 to 17, defined by SEQ ID No. 11, and a sequence of 7 to 12 adjacent amino acids contained in SEQ ID No.4, wherein said sequence comprises the amino acid sequence of SEQ ID No.11.
In particular preferred, sequences of are preferably those amino acid sequences selected from the group consisting of SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 7, SEQ ID No. 8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11, SEQ ID No.12, SEQ ID No.13, SEQ ID No. 14, SEQ ID No. 15, SEQ ID No. 16, SEQ ID No. 17, SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20, SEQ ID No. 21, SEQ ID
15 No.22, SEQ ID No.23, SEQ ID NO.24, SEQ ID No. 25, SEQ ID No.2 6, SEQ ID No.2 7, SEQ ID No.28, SEQ ID No. 29, SEQ ID No.3 0, SEQ ID No.31 and SEQ ID No.32. With more preferably,
amino acid sequences are those sequences selected from the group consisting of SEQ ID No. 4, SEQ ID No. 5, 20 SEQ ID No.6, SEQ ID No.7, SEQ ID No.8, SEQ ID No.11 and SEQ ID
No.2 6.
In addition, the cosmetic or pharmaceutical composition of the method of this invention also comprises peptides substantially homologous to the peptides derived from the amino acid sequence of the SNAP-25 protein, irreversibly chemically modified. Substantially homologous peptides in this invention mean those amino acid sequences that are at least 60%, preferably 80% and more preferably 95% identical to any of the preceding sequences. The percentage of identity refers to the percentage of amino acids that is identical between two compared amino acid sequences, after an optimal alignment of these sequences, where this percentage is purely
20/66 statistics and the differences between the two amino acid sequences are randomly distributed throughout the sequence. The term optimal alignment means the alignment of the amino acid sequences that result in a higher percentage of identity. The percentage of identity is calculated by determining the number of identical positions where an amino acid is identical in the two compared sequences, dividing the number of identical positions by the number of compared positions and multiplying the result by 100 to obtain the percentage of identity between the two. sequences. Sequence comparisons between two amino acid sequences can be performed manually or through software such as the BLAST algorithm (Basic Local Alignment Search Tool - Basic Local Alignment Search Tool), available online at http: //blast.ncbi.nlm.nih .gov /.
In the context of this invention encephalin-derived peptides means pentapeptides of the general formula (II) with amino acid sequences that differ by 0, 1 or 2 amino acids from the amino acid sequences of the enkephalin pentapeptides defined by the sequences SEQ ID No.33 or SEQ ID No.34.
Among the peptides defined by the general formula (II) included in the cosmetic or pharmaceutical composition of the method of this invention, the preferred amino acid sequences are preferably those sequences selected from the group consisting of SEQ ID No.33, SEQ ID No.34 , SEQ ID No.35, SEQ ID No.36, SEQ ID No.37 and SEQ ID No.38. Most preferably, amino acid sequences are those sequences selected from the group consisting of SEQ ID No.33 and SEQ ID No.35.
The cosmetic or pharmaceutical composition of the method of the invention may further comprise a cosmetically or pharmaceutically effective amount of at least one peptide from the
21/66 general formula (IV):
R 1 -A p -B r -AA 1 -AA 2 -AA 3 -AA 4 -AA 5 -AA 6 - C s -D t -R 2 (IV) their stereoisomers, mixtures thereof, and / or their salts cosmetically or pharmaceutically acceptable, where:
AAi and selected The leave of group what It consists in -Asp-, -Glu- e -Pro-; AA 2 is -Asp-; AA 3 e selected The leave of group what It consists in -Remove -Arg-; AA 4 is selected The leave of group what It consists in -Fe- e -Tir-; AA5 and selected The leave of group what It consists in -Arg- e -Lis -; AAg is selected The leave of group what It consists in -Leu- and -Met-; A, B, C and D are independently selected The leave of the group consisting of amino acids natural and amino acids not natural; P, r, s and t are independently selected and if situate in the range between 0 and 1 / Laugh is selected The leave of group what It consists in H, aliphatic group not cyclic replaced or not
substituted, substituted or unsubstituted alicyclyl, substituted, substituted or unsubstituted heteroaryl or substituted heteroaryl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R ' 5 -C (O) -; and
R 2 is selected from the group consisting of -NR ' 3 R' 4 , -0R ' 3 and -SR'3; where R ' 3 and R' 4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group,
22/66 substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;
where R ' 5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and heteroarialkyl replaced or unsubstituted.
The groups R x and R 2 are linked at the amino terminating (N-terminal) and carboxy terminating (Cterminal) ends of the peptide sequences, respectively.
In another particular embodiment, Ri is selected from the group consisting of H, and R ' 5 -CO-, where R' 5 is selected from the group consisting of substituted or unsubstituted C 1 -C 2 alkyl radical , substituted or unsubstituted C 2 -C 2 4 alkenyl radical, C 2 -C 2 4 alkynyl radical
substituted or not substituted, radical cycloalkyl C 3 -C 24 substituted or not substituted, radical cycloalkenyl C5 - C 2 4 substituted or not substituted, radical cycloalkynyl Cg-C 2 4
substituted or unsubstituted, substituted or unsubstituted C 6 -C 30 aryl radical, substituted or unsubstituted C 7 -C 24 aralkyl radical, a substituted or unsubstituted heterocyclyl radical having 3 to 10 ring members, a substituted or heteroarylalkyl radical unsubstituted which has 2 to 24 carbon atoms and which has 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 carbon atoms. Preferably, Ri is selected from the group consisting of H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, stearoyl, behenyl, oleyl and linoleoyl. More preferably, Ri is H,
23/66 acetyl, hexanoyl, octanoyl, lauroyl, myristoil or palmitoyl.
In another particular embodiment, R 2 is -NR ' 3 R' 4 , OR ' 3 or -SR' 3 where R ' 3 and R' 4 are independently selected from the group consisting of H, C x C 24 alkyl substituted or unsubstituted C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted C 3 -C 24 cycloalkyl substituted or unsubstituted C 5 -C 24 cycloalkenyl unsubstituted or C 8 cicloalquinila -C 24 substituted or unsubstituted C 6 -C 30 substituted or unsubstituted, C 7 -C 24 substituted or unsubstituted, the substituted, substituted, substituted or unsubstituted heterocyclyl aralkyl having 3 to 10 ring members, and a group substituted or unsubstituted heteroarylalkyl having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 carbon atoms. Optionally, R ' 3 and R' 4 can be linked via a saturated or unsaturated carbon-carbon bond, which forms a cycle with the nitrogen atom. Preferably, R 2 is -NR ' 3 R' 4 or -OR ' 3 , where R' 3 and R ' 4 are independently selected from the group consisting of H, substituted or unsubstituted C x -C 24 alkyl , C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 3 -C x substituted or unsubstituted, aryl C 6 -C 15 substituted or unsubstituted heterocyclyl and substituted or non - substituted from 3 to 10 members, a heteroarylalkyl group substituted or unsubstituted with a ring having 3 to 10 members and an alkyl chain of 1 to 6 carbon atoms. More preferably, R ' 3 and R' 4 are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. More preferably, R ' 3 is H and R' 4 is selected from the group consisting of H, methyl, ethyl, hexyl,
24/66 dodecyl and hexadecyl. According to an even more preferred embodiment, R 2 is selected from -OH and -NH 2 .
In another particular modality, R x is selected from the group consisting of H, acetyl, lauryl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Leu-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauryl, myristoil and palmitoyl, AA X is -L-Pro-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Lis-, AA 6 is -L-Leu-, and R 2 is NR ' 3 R' 4 or -0R ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, Ri is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Arg- , AA 4 is -L-Fe-, AA 5 is -L-Arg-, AA 6 is -L-Met-, and R 2 is NR ' 3 R' 4 or -0R ' 3 where R' 3 and R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Met-, and R 2 is .25 / 66
NR ' 3 R' 4 or -OR ' 3 where R' 3 and R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl, preferably R 2 is OH or - NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauryl, myristoil and palmitoyl, AA X is -L-Pro-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Met-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, Ri is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, preferably Ri is selected from the group consisting of H, acetyl and palmitoyl, and R 2 is selected from of the group consisting of -OH or NH 2 .
In another particular embodiment, the peptide of the general formula (IV) is selected from the group consisting of Ac-L-Glu-L-Asp-L-Tir-L-Tir-L-Arg-L-Leu-NH 2 , PalmL-Glu-L-Asp-L-Tir-L-Tir-L-Arg-L-Leu-NH 2 , Ac-L-Pro-L-Asp-LTir-L-Tir-L-Lis-L- Leu-NH 2 , Palm-L-Pro-L-Asp-L-Tir-L-Tir-LLis-L-Leu-NH 2 , Ac -L-Glu-L-Asp-L-Arg-L-Fe- L-Arg-L-Met-NH 2 , Palm-L-Glu-L-Asp-L-Arg-L-Fe-L-Arg-L-Met-NH 2 , Ac-L-Glu-L-AspL- Tir-L-Tir-L-Arg-L-Met-NH 2 , Palm-L-Glu-L-Asp-L-Tir-L-Tir-LArg-L-Met-NH 2 , Ac-L-Pro- L-Asp-L-Tir-L-Tir-L-Arg-L-Met-NH 2 and Palm-L-Pro-L-Asp-L-Tir-L-Tir-L-Arg-L-Met-NH 2 .
The scope of this invention also includes cosmetically or pharmaceutically acceptable salts of the peptides of the cosmetic composition or
26/66 of the method of this invention. The term cosmetically or pharmaceutically acceptable salts in this invention means a salt generally recognized for use in animals and more particularly in humans, including the salts used to form base addition salts, whether inorganic, for example, but not limited to it , lithium, sodium, potassium, calcium, magnesium, manganese, copper, zinc or aluminum, among others, or organic, for example, and not limited to, ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, arginine, lysine, histidine or piperazine, among others, or acid addition salts, whether organic, for example, and without limitation, acetate, citrate, lactate, malonate, maleate, tartrate, fumarate, benzoate, aspartate, glutamate, succinate, oleate, trifluoroacetate, oxalate, pamoate or gluconate, among others, or inorganic, as, for example, and not limited to it, chloride, sulfate, borate or carbonate, among others. The nature of the salt is not critical, as long as it is cosmetically or pharmaceutically acceptable. The cosmetically or pharmaceutically acceptable salts of the peptides of the cosmetic or pharmaceutical composition of the method of this invention can be obtained by conventional methods, well known in the art [Berge, S.M., Bighley, L.D. , and Monkhouse, D.C. (1977) Pharmaceutical Salts J. Pharm. I know 66: 1 to 19].
Additionally, the peptides of the cosmetic or pharmaceutical composition of the method of this invention can be subjected to reversible chemical modifications to enhance their bioavailability and ease of crossing the blood-brain barrier or epithelial tissue.
The peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention can be administered through any means that produces contact of the peptides with their site of action in the body of a mammal, in
27/66 preference human beings. The cosmetic or pharmaceutical composition can be prepared using conventional methods known to a person skilled in the art [Harry's Cosmeticology, Eight [sic] edition (2000) Rieger M.M., ed. , New York Chemical Pub., NY, USA; Remington: The Science and Practice of Pharmacy, Twentieth Edition (2003) Genaro A.R., ed., Lippincott Williams & Wilkins, Philadelphia, USA].
The peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention have variable solubility in water, depending on the nature of their sequences or the possible changes in their amino and / or carboxy terminations that they have. Therefore, the peptides can be incorporated into the cosmetic or pharmaceutical composition by means of an aqueous solution, and those that are not soluble in water can be solubilized in conventional cosmetically or pharmaceutically acceptable solvents such as, but not limited to, ethanol, propanol, isopropanol, propylene glycol, glycerin, butylene glycol or polyethylene glycol or any combination thereof.
The effective amount of peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention, their stereoisomers, mixtures thereof or their cosmetically or pharmaceutically acceptable salts, as well as their dosage, will depend on some factors including age, condition of the individual, route, frequency of administration and the particular nature of the peptides used.
Effective amount means a non-toxic but sufficient amount of at least one peptide to provide the desired effect. Any peptide of the general formula (I) and / or (II) of the cosmetic or pharmaceutical composition of the method of this invention is used in concentrations effective to achieve the desired effect; preferably in
28/66 reference to the total weight of the composition, between 0.00000001% (by weight) and 20% (by weight); preferably between 0.000001% (by weight) and 20% (by weight), more preferably between 0.0001% (by weight) and 10% (by weight) and most preferably between 0.0001% (by weight) ) and 5% (by weight).
In another particular embodiment, the peptides of the general formula (I) and / or (II) comprised in the cosmetic or pharmaceutical composition of the method of this invention can also be incorporated into delivery systems and / or prolonged release systems.
The term delivery systems refers to a diluent, adjuvant, excipient or carrier with which the peptide derivative of the invention is administered. These carriers can be liquids such as water, oils and surfactants, including those of petroleum, animal, vegetable or synthetic origin, such as, and not limited to, peanut oil, soybean oil, mineral oil, oil sesame, castor oils, polysorbates, sorbitan esters, sulfate ether, sulphates, betaines, glucosides, maltosides, fatty alcohols, nonoxynol, poloxamer, polyoxyethylenes, polyethylene glycols, dextrose, glycerol, digitonin and the like. Remington's Pharmaceutical Sciences by E.W. Martin describes diluents, adjuvants or excipients as suitable carriers.
The term extended release is used in the conventional sense, referring to a delivery system for a compound that provides gradual release of said compound over a period of time and preferably, although not necessarily, with constant release levels of the compound over a period of time. period of time.
Examples of delivery or extended release systems are liposomes, mixed liposomes, oleosomes, niosomes, miniparticles, milliparticles, microparticles,
29/66 nanospheres, lipospheres, nanocapsules, as well as solid lipid nanoparticles and nanoparticles, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed surfactant micelles, mixed surfactant-phospholipid micelles, millispheres, microspheres, microcapsules and microscopes and microemulsions and nanoemulsions, which can be added to achieve greater penetration of the active ingredients and / or improve their pharmacokinetic and pharmacodynamic properties.
Extended release systems can be prepared by methods known in the prior art, and the compositions containing them can be administered, for example, by topical administration, including adhesive bandages, non-adhesive bandages and microelectric bandages, or by systemic administration , for example, subcutaneous implantation or injection, or direct implantation or injection into a specific part of the body, and should preferably release a relatively constant amount of the peptides of the invention. The amount of peptide contained in the extended release system will depend, for example, on where the composition will be administered, the kinetics and duration of the peptide release from the cosmetic or pharmaceutical composition of the method of this invention, as well as the frequency of administration and the nature particular of the peptides to be used.
In another particular embodiment, the peptides comprised in the cosmetic or pharmaceutical composition of the method of this invention can also be adsorbed on solid organic polymers, or solid mineral carriers such as, but not limited to, talc, bentonite, silica, starch or maltodextrin, among others.
In another particular modality, the composition
30/66 cosmetic or pharmaceutical of the method of this invention can also be incorporated into fabrics, nonwoven fabrics and medical devices that are in direct contact with the skin, so that they release the peptides through biodegradation of the anchoring system to the tissue , non-woven fabric or medical device or through their friction with the body, body hydration, skin pH or body temperature. Likewise, fabrics and nonwoven fabrics can be used to produce garments that are in direct contact with the body.
Examples of fabrics, nonwoven fabrics, clothing, medical devices and means of immobilizing the peptides to them, including the delivery systems and / or prolonged release systems described above can be found described in the literature and are known in the prior art [Schaab CK (1986) Impregnating Fabrics With Microcapsules, HAPPI May 1986; Nelson G. (2002) Application of microencapsulation in textiles Int. J. Pharm. 242: 55 to 62; Biofunctional Textiles and the Skin (2006) Curr. Probl. Dermatol. v.33, Hipler U.C. and Elsner P., eds. S. Karger AG, Basel, Switzerland; Malcom R.K., McCullagh S.D., Woolfson A.D., Gorman S.P., Jones D.S. and Cuddy J. (2004) Controlled release of a model antibacterial drug from a novel self-lubricating biomaterial silicone J. Cont. Release 97: 313 to 320]. The preferred fabrics, nonwoven fabrics, clothing and medical devices are bandages, gauze, scarves, adhesive bandages, non-adhesive bandages, microelectric bandages and / or face masks.
In another particular embodiment, the cosmetic or pharmaceutical composition of the method of this invention can be used in different types of formulations for topical or transdermal application that optionally will contain the acceptable excipients necessary for the formulation of the form.
31/66 of desired dosage [Faulí i Trillo C. (1993) in Treaty of Farmacia Galénica, Luzán 5, S.A. Ediciones, MadriJ.
The cosmetic or pharmaceutical composition can be produced in any solid, liquid or semi-solid formulation, such as and not restricted to, creams, multiple emulsions such as, and not restricted to, oil and / or silicone in water emulsions, water-in-emulsions. oil and / or silicone, water / oil / water or water / silicone / water emulsions, and oil / water / oil or silicone / water / silicone emulsions, anhydrous compositions, aqueous dispersions, oils, milks, balms, foams , lotions, gels, cream gels, hydroalcolic solutions, hydroglycolic solutions, hydrogels, liniments, serums, soaps, shampoos, conditioners, serum fluids, polysaccharide films, ointments, mousses, ointments, powders, bars, pencils and sprays or aerosols ( sprays), including formulations without the need for removal and rinsing. These formulations can be incorporated using techniques known to the person skilled in the art in different types of solid accessories such as, and not restricted to, capsules, vials, syringes, pre-filled syringes, tissues, adhesive bandages, non-adhesive bandages, bandages microelectric or facial masks, or they can be incorporated into different makeup products as a makeup base, such as fluid foundations and compact foundations, makeup removal lotions, makeup removal milks, concealers under the eye, eye shadows, lipsticks, lip balms, lip gloss and powders among others.
In another particular embodiment, the cosmetic or pharmaceutical composition of the method of this invention may additionally include agents that enhance percutaneous absorption for topical or transdermal application of the peptides of the general formula (I) and / or (II), their stereoisomers, mixtures thereof and / or its salts
32/66 cosmetically or pharmaceutically acceptable, such as, but not limited to, dimethylsulfoxide, dimethylacetamide, dimethylformamide, surfactants, azone (1dodecylazacycloheptan-2-one), alcohol, acetone, propylene glycol or polyethylene glycol, among others. Additionally, the cosmetic or pharmaceutical composition of the method of this invention can be applied through topical or transdermal application to local areas to be treated by means of iontophoresis, sonophoresis, electroporation, microelectric bandages, mechanical pressure, osmotic pressure gradient, occlusive cure, microinjections or pressure-free needle injections, such as oxygen pressure injections, or any combination thereof, to achieve greater penetration of the peptides of the cosmetic or pharmaceutical composition of the method of this invention.
The composition of the method of this invention can also be administered, in addition to the topical or transdermal route, by any other appropriate means, for example, via the enteral or parenteral route, which will include the acceptable excipients necessary for the formulation in dosage form. desired. An analysis of the different dosage forms of the active ingredients and excipients needed to obtain them can be found, for example, in the Treaty of Farmacia Galénica, C. Faulí i Trillo, 1993, Luzán 5, S.A.
Ediciones, Madrid.
In the context of this invention, the terms enteral or parenteral include oral, nasal, inhalation, rectal, adhesive or non-adhesive bandages, subcutaneous, intradermal, intravascular injections, such as intravenous, intramuscular, intraarterial, intravitreal, spinal, intracranial, intraarticular , intrathecal and intraperitoneal, as well as any similar injection or infusion technique.
In another particular modality, the composition
The cosmetic or pharmaceutical method of the method of this invention further comprises a cosmetically or pharmaceutically effective amount of at least one additional active agent commonly used in compositions for the treatment and / or care of the skin such as, and not restricted to, cAMP (adenosine monophosphate) cyclic) agents that stimulate synthesis, elastase inhibiting agents, matrix metalloproteinase inhibiting agents, melanin synthesis inhibiting or stimulating agents, depigmentation or bleaching agents, propigmentation agents, self-tanning agents, anti-aging agents, anti-aging agents NO synthase, 5a-reductase inhibiting agents, lysyl- and / or prolyl hydroxylase inhibiting agents, antioxidants, free radical scavengers and / or agents against atmospheric pollution, scavengers of reactive carbonyl species, anti-glycating agents, antihistamines , antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents water, liquid propellants, skin and / or hair conditioners as humectants, substances that retain hydration,
0 alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermal hydrolytic enzymes, vitamins, pigments or dyes, dyes, gelling polymers, thickeners, surfactants, softening agents, anti-wrinkle agents, agents capable of reducing or treating bags under the eyes, exfoliating agents, antimicrobial agents , antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting or preventing their degradation, such as agents that stimulate collagen synthesis, agents that stimulate collagen synthesis elastin synthesis, agents that stimulate the synthesis of decorin, agents that stimulate the synthesis of laminin, agents that stimulate the synthesis of defensin, agents that
34/66 proliferation proliferation differentiation differentiation stimulate chaperone synthesis, agents that stimulate aquaporin synthesis, agents that stimulate hyaluronic acid synthesis, agents that stimulate fibronectin synthesis, agents that stimulate sirtuin synthesis , agents that stimulate the synthesis of lipids and components of the stratum corneum (ceramides, fatty acids, etc.), agents that inhibit collagen degradation, other agents that inhibit the degradation of elastin, agents that inhibit serine proteases such as cathepsin G, agents that stimulate fibroblast proliferation, agents that stimulate keratinocyte proliferation, agents that stimulate adipocyte, agents that stimulate melanocyte, agents that stimulate keratinocyte, agents that stimulate adipocyte, agents that inhibit acetylcholinesterase, agents that relax the skin, agents that inhibit skin aggregation of acetylcholine receptors, agents that inhibit muscle contraction, agents that and stimulate the synthesis of glycosaminoglycan, anti-hyperkeratosis agents, comedolytic agents, antipsoriasis agents, DNA repair agents, DNA protection agents, stabilizers, anti-itch agents, agents for the treatment and / or care of sensitive skin, firming agents, anti-stretch mark agents, binding agents, agents that regulate sebum production, lipolytic agents or agents that stimulate lipolysis, anti-cellulite agents, antiperspirants, agents that stimulate healing, supporting healing agents, agents that stimulate re-epithelialization, supporting re-epithelialization agents , cytokine proliferation factors, soothing agents, anti-inflammatory agents, anesthetic agents, agents that act in the circulation and / or capillary microcirculation, agents that stimulate angiogenesis, agents that inhibit vascular permeability, agents
35/66 venotonics, agents that act on cellular metabolism, agents to improve the dermal-epidermal junction, agents that induce hair growth, hair growth inhibiting or retarding agents, preservatives, perfumes, chelating agents, plant extracts, essential oils, marine extracts, agents obtained from a biofermentation process, mineral salts, cell extracts and sunscreens (organic photoprotective agents or minerals active against ultraviolet rays A and / or B), among others, as long as they are physically and chemically compatible with the other components of the composition and especially with the peptides of the general formulas (I) and (II) contained in the composition of this invention. In addition, the nature of these additional ingredients should not unacceptably alter the peptide benefits of the composition of the method of this invention. The nature of these additional ingredients can be synthetic or natural, such as plant extracts, or obtained through a biofermentation process. Additional examples can be found at CTFA
International Cosmetic Ingredient Dictionary & Handbook, 12th Edition (2008).
In a preferred embodiment, the cosmetic or pharmaceutical composition of the method of this invention additionally comprises a cosmetically or pharmaceutically effective amount of at least one extract that is an anti-wrinkle agent and / or an anti-aging agent such as, and not restricted to, Vi tis vinifera extracts , Rosa canina, Curcuma longa, iris pallida, Theobroma cacao, Ginkgo biloba, Leontopodium Alpinum or Dunaliella salina among others or, in addition, at least one synthetic compound or biofermentation product that is an anti-wrinkle agent and / or an anti-aging agent such as, and not restricted to, Matrixyl® [INCI:
Palmitoyl Pentapeptide-4], Matrixyl 3000® [INCI:
36/66
Palmitoyl Tetrapeptide-7, Palmitoyl Olipeptide],
Essenskin
TM [INCI: calcium hydroxyethionine], Renovage or Dermaxyl® [INCI: Olipeptide from
Palmitoíla] marketed by Sederma / Croda, Vialox® [INCI: 5 Pentapeptide-3], Syr ^ -Ake [INCI: Diaminobutyryl Diacetate Dipeptide Benzylamide], Syn®-Coll [INCI: Palmitoyl Tripeptide-5], Fitaluronate [ INCI: Carob Gum (Ceratonia Siliqua)] or Preregen ”[INCI: Soy Protein Glycine (Soybean), Oxido Reductases] sold by 10 Pentapharm / DSM, Myoxinol ™ [INCI: Hibiscus Extract
Esculentus Hydrolyzate], Syniorage ™ [INCI: Acetyl
Tetrapeptide-11], Dermican ™ [INCI: Acetyl Tetrapeptide-9] OR DN-AGE ™ LS [INCI marketed by 15 Algisum C® [INCI: Manuronate
Hydroxyprolisilane CN® [INCI: Methylsilanol aspartate of
Φ
Hydroxyproline] marketed by Exsymol, Aldenine [INCI: Hydrolyzed wheat protein, Hydrolyzed soy protein, Tripeptide-1], Preventhelia ™ [INCI: Diaminopropionoyl
Tripeptide-33], Decorinyl ™ [INCI:
Citrulline], Trylagen ™ [INCI: Extract
Pseudoalteromones, Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-10 Citrulline, Tripeptide-1], Eyeseryl® [INCI: Acetyl Tetrapeptide-5], Peptide AC29 25 [INCI: Acetyl Tripeptide-30 Citrulline], Lipochroman-6 [INCI: Dimethylmethoxy Cromanol], Chromabright ™ [INCI: Dimethylmethoxy Cromanyl Palmitate], Antarcticine [INCI: Pseudoalteromone Yeast Extract], Vilastene ™ [INCI: Lysine HC1, Lecithin, Tripeptide-10 Citrulline], Iny : 30 Acetyl Hexapeptide-30], Relistase ™ [INCI:
Acetilarginyltriptofil Diphenylglycine], Thermostressine ™ [INCI: Acetyl Tetrapeptide-22] marketed by Lipotec,
Kollaren ”[INCI: Tripeptide-1, Dextran] marketed by [INCI: teprenone]
Cassia Alata leaf extract] Laboratoires Sérobiologiques / Cognis, of Methylsilanol] or
Yeast Tripeptide-10
37/66
Vincience / ISP, Hexapeptide-19]
Deepaline
TM
PVB
Institut Europeen de Biologie Cellulaire / Unipex Group, Collaxyl® IS [INCI: Hexapeptide-9], Laminixyl IS ™ [INCI: Heptapeptide], Orsirtine ™ GL [INCI: Oryza Sativa Extract (Rice)], DOrientine ™ IS [INCI: Phoenix Dactylifera (Date) seed extract], Phytoquintescine ™ [INCI: Spelled Wheat Extract (Triticum Monococcum)] or Quintescine ™ IS [INCI: Dipeptide-4] marketed by BONT-L-Peptide [INCI: Palmitoyla marketed by Infinitec Assets, [INCI: Palmitoíla Wheat Protein
Hydrolyzed] or Sepilift® DPHP [INCI: Hydroxyproline of Dipalmitoíla] marketed by Seppic, Gatulme Expression [INCI: Extract of Acmella oleracea], Gatuline® In-Tense [INCI: Extract of Spilanthes Acmella] or Anti-aging Gatuline® 2 [INCI: Juglans Regia Seed Extract (Walnut)] marketed by Gattefossé, Thalassine ™ [INCI: Algae Extract] marketed by Biotechmarine, ChroNOline ™ [INCI: Capraoyl Tetrapeptide-3] or Timulen-4 [INCI: Acetyl
Tetrapeptide-2] sold by Atrium / Unipex
Innovations, EquiStat [INCI: Pyrus Malus Fruit Extract, Glycine Soybean Extract] or Juvenesce [INCI: Etoxidiglycol and Caprylic Triglyceride, Retinol, Ursolic Acid, Phytonadione, Ilomastat] marketed by Coletica, Ameliox [INCI: Carnol , Silybum Marianum Fruit Extract] or PhytoCellTec Malus Domestica [INCI: Malus Domestica Fruit Cell Culture] marketed by Mibelle Biochemistry, Bioxilift [INCI: Pimpinella Anisum Extract] or SMS Anti-Wrinkle® [INCI: Seed Extract of Annona Squamosa] marketed by Silab, calcium channel antagonists such as, and not restricted to, alverine, manganese or magnesium salts, magnesium gluconate, some secondary or tertiary amines, retinol and its derivatives, idebenone and its derivatives, Coenzyme Q10 and
38/66 its derivatives, boswellic acid and its derivatives, GHK and its derivatives, carnosine and its derivatives, DNA repair enzymes such as, and not restricted to, photoliase, T4 endonuclease V, or chloride channel agonists, among others.
In another particular embodiment, the cosmetic or pharmaceutical composition of the method of this invention additionally includes acceptable carriers and / or auxiliary agents necessary for administering the composition in the desired manner. Carriers and / or auxiliary agents include excipients, thickeners, diluents, solvents, dispersants or adjuvants known to the person skilled in the art. Thickeners include, but are not limited to, water-soluble polymers such as those selected from the group consisting of modified celluloses, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and dextrans, gelatines, collagen pyrrolidone. Diluents and solvents include, but are not limited to, those selected from the group consisting of ethanol, polyethylene glycol, glycofurol, N-methyl-2-pyrrolidone, glycerol, propanediol, polypropylene glycol, benzyl alcohol or dimethyl sulfoxide. Dispersants include, but are not limited to, surfactants selected from the group consisting of iox Φ polyoxyethylene sorbitan fatty acid monoesters (Tween, Emalex, Nikkol, Hodag, Dacol or Liposorb), sorbitan fatty acid monoesters (Span ), 15-hydroxystearate polyethylene glycol (Solutol® HS15), polyethylene glycol fatty acid (Crodet, ®, φ Φ, φ Φ
Kessco, Nikkol, Mapeg, Myrj, Tagat, Aldo, Glycerox, Lactomul®, or Emerest®), esters of Cithrol esters, Capmul 0 , of polyoxyethylene glycol (Emulphor), castor oils
39/66 polyoxyethylates (Cremophor, Emalex, Eumulgin, Nikkol or Simusol), polyglycerol fatty acid esters (Nikkol Decaglyn, Polymuls, Caprol®), polyethylene glycol ethers (Volpo or Brij®), poloxamer (Lutrol® or Pluronic® ), polyoxyethylene phenyl ethers (Triton® or Igepal®), or mixtures thereof. Preferably, the cosmetic or pharmaceutical composition of the method of this invention also contains one or more acceptable excipients such as humectants, pH buffers, preservatives, bactericidal and fungicidal agents, absorption retardants, absorption accelerators, or any other excipient known to the person skilled in the art .
The administration of the cosmetic or pharmaceutical composition of the method of this invention can be started before, as a pre-treatment, simultaneously, as a co-treatment, and / or soon after, as a post-treatment, performing injections of Botulinum toxin. The frequency of administration of the cosmetic or pharmaceutical composition of the method of this invention can vary widely, depending on the needs of each individual, with recommendation for a
The administration range from once a week to ten times a day, preferably twice a week to four times a day, more preferably three times a week up to three times a day, more preferably once or twice per day. In a most preferred embodiment, the method of this invention comprises the administration of Botulinum toxin, followed by the administration of the cosmetic or pharmaceutical composition of the method of this invention twice daily until the next administration of Botulinum toxin.
In a particular embodiment, the average wrinkle reduction obtained by the method of this invention after 2 months of treatment is greater than 50% in relation to the maximum average wrinkle reduction, particularly greater than 60%. The average wrinkle reduction after 4 months of treatment obtained by
40/66 method of this invention is greater than 25% in relation to the maximum of the average wrinkle reduction, particularly greater than 35%. The average wrinkle reduction after 6 months of treatment obtained by the method of this invention is greater than 10% in relation to the maximum of the average wrinkle reduction, particularly greater than 20%.
In a second aspect, this invention relates to a kit for the treatment of skin anti-aging, which comprises:
The. Botulinum toxin,
B. and at least one cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide that contains a sequence of 6 to 40 adjacent amino acids contained in the amino acid sequence of the SNAP-25 protein, defined by SEQ ID No. 1, and according to general formula (I):
Rx-AA-Rs (I) their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which AA is a sequence of 6 to 40 adjacent amino acids contained in the amino acid sequence SEQ ID No. 1;
and / or at least one enkephalin-derived peptide of the general formula (II):
stereoisomers, mixtures thereof, and / or
cosmetically or pharmaceutically acceptable salts of the
41/66 same, where:
X and Y are independently selected from the group consisting of natural and unnatural amino acids;
Ri and R'i are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R 5 -C (O) -; and
R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 , -OR 3 and -SR 3 ; wherein R 3 and R 4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted aryl substituted and substituted or unsubstituted aralkyl;
where R 5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted heteroarialkyl or not replaced;
and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
The groups R x , R ' x and R 2 , R' 2 are linked at the amino terminating (N-terminal) and carboxy terminating (C-terminal) ends of the peptide sequences, respectively.
42/66
In a particular embodiment, the anti-aging skin treatment is a treatment to reduce or eliminate skin wrinkles on the face and / or neck, preferably expression wrinkles.
In another particular embodiment, the preferred structures of the peptides represented in the general formula (II) are those in which X is -Gli-, -Ala- or -Ser-, and more preferably -D-Ala- or -D-Ser- .
In another particular embodiment, the preferred structures of the peptides represented in the general formula (II) are those in which Y is -Leu- or -Met-, and more preferably -L-Leu- or -L-Met-.
In another particular embodiment, R x and R'i are independently selected from the group consisting of H, a polymer of the general formula (III)
O O
(III) where n is in the range between 1 to 100, preferably between 1 and 5, and R 5 -CO-, where R 5 is selected from the group consisting of a substituted C3.-C24 alkyl radical. , C 2 -C alkenyl radical 2 4 substituted alkynyl radical C 2 -C 4 bstituído 2, cycloalkyl radical C 3 -C 24 stituído radical C 5 -C 24 cycloalkenyl stituído radical cicloalquinila 4 2 C8 substituted radical substituted C 6 -C 30 aryl, substituted C 7 -C 24 aralkyl radical, a substituted heterocyclyl radical that has 3 to 10 members of substituted or unsubstituted heteroarylalkyl radical
substituted or not substituted or not substituted or not substituted or no S substituted or no S substituted or not substituted or not substituted or not substituted or not ring one radical substituted what has :
43/66 oleoyl and R'i are no atoms other than carbon in which the alkyl chain is 1 to 6 carbon atoms. Preferably, R x and R ' x are independently selected from the group consisting of H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, myristoyl, palmitoyl, styroyl, behenyl, linoleoyl . More preferably, R x is independently selected from the group consisting of H, acetyl, hexanoyl, octanoyl, lauroyl, myristoil or palmitoyl.
In another particular embodiment, R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 , -0R 3 or -SR 3 in which R 3 and R 4 are independently selected from the group consisting of H, alkyl C x C 24 substituted or unsubstituted C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 3 -C 24 substituted or unsubstituted cycloalkenyl C 5 - Substituted or substituted C 24, substituted or substituted C 8 -C 24 cycloalkynyl, substituted or unsubstituted C 6 -C 30 aryl, substituted or unsubstituted C 7 -C 24 aralkyl, a substituted or unsubstituted heterocyclyl that has 3 to 10 members ring, and a substituted or unsubstituted heteroarylalkyl group having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 carbon atoms and a polymer of the general formula ( III) where n is in the range between 1 and 100, preferably between 1 and 5. Optionally, R 3 and R 4 can be linked via a saturated or unsaturated carbon-carbon bond, which forms a cycle with the nitrogen atom. Preferably, R 2 and R ' 2 are independently selected from the group consisting of -NR 3 R 4 or -OR 3 , where R 3 and R 4 are independently selected from the group consisting of
44/66 of H, alkyl Ci-C24 substituted or unsubstituted C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 0 -C 3 substituted or unsubstituted aryl C 6 -C 5 substituted or unsubstituted and a substituted or unsubstituted 3 to 10 membered heterocyclyl, a substituted or unsubstituted heteroarylalkyl group with a ring having 3 to 10 members and an alkyl chain of 1 to 6 carbon atoms and a polymer of general formula (III) in which n is in the range between 1 and 100, preferably between 1 and 5. More preferably, R 3 and R 4 are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Most preferably, R 3 is H and R 4 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. According to an even more preferred embodiment, R 2 and R ' 2 are independently selected from the group consisting of -OH and -NH 2 .
In the context of this invention amino acid sequence derived from the amino acid sequence of the SNAP-25 protein means any amino acid sequence or fragments of the amino acid sequence of the SNAP-25 protein, defined by SEQ ID No.1, or any amino acid sequence that differs from the sequence SEQ ID No. 1 by mutation, insertion, deletion or substitution of at least one amino acid, or by degeneration of the genetic code, provided that it corresponds to a peptide that has the activity of the SNAP-25 protein.
Among the peptides derived from the SNAP-25 amino acid sequence defined by SEQ ID No. 1 included in the cosmetic or pharmaceutical composition of the method of this invention, preferred sequences are those that have an adjacent amino acid sequence contained in the sequence of the amino termination region of SNAP-25 protein defined
45/66 by SEQ ID No.2 or the amino-terminal region of the SNAP25 protein defined by SEQ ID No. 3, more preferably in the region between residues 10 to 22, defined by SEQ ID No.4, or contained in the region between residues 25 to 40, defined by SEQ ID No. 5, or contained in the region between residues 65 to 81, defined by SEQ ID No.6, or contained in the region between residues 181 to 206, defined by SEQ ID No.7, more precisely contained in the region between residues 12 to 19, defined by SEQ ID No.8, or contained in the region between residues 26 to 38, defined by SEQ ID No.9 or contained in the region between residues 68 to 79, defined by SEQ ID No .10 or specifically contained in the region between residues 12 to 17, defined by SEQ ID No. 11, and a sequence of 7 to 12 adjacent amino acids contained in SEQ ID No.4, wherein said peptide comprises the amino acid sequence of SEQ ID No.11.
In particular preferred, sequences are preferably those amino acid sequences selected from the group consisting of SEQ ID No. 4, SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 7, SEQ ID No. 8, SEQ ID No.9, SEQ ID No.10, SEQ ID No.11, SEQ ID No.12, SEQ ID No.13, SEQ ID No. 14, SEQ ID No. 15, SEQ ID No. 16, SEQ ID No. 17, SEQ ID No. 18, SEQ ID No. 19, SEQ ID No. 20, SEQ ID No. 21, SEQ ID
No.22, SEQ ID No.23, SEQ ID No.24, SEQ ID No. 25, SEQ ID No.26, SEQ ID No.27, SEQ ID No.28, SEQ ID No. 29, SEQ ID No.3 0, SEQ ID No.31 and SEQ ID No.32. With more preferably,
amino acid sequences are those sequences selected from the group consisting of SEQ ID No.4, SEQ ID No. 5, SEQ ID No.6, SEQ ID No.7, SEQ ID No.8, SEQ ID No.11 and SEQ ID No.26.
Among the peptides defined by the general formula (II) included in the cosmetic or pharmaceutical composition of the kit of the method of this invention, preferred amino acid sequences are preferably those sequences
46/66 selected from the group consisting of SEQ ID No.33, SEQ ID No.34, SEQ ID No.35, SEQ ID No.36, SEQ ID No.37 and SEQ ID No.38. Most preferably, amino acid sequences are those sequences selected from the group consisting of SEQ ID No.33 and SEQ ID No.35.
The cosmetic or pharmaceutical composition of the kit of the method of the invention may further comprise a cosmetically or pharmaceutically effective amount of at least one peptide of the general formula (IV):
R iA p -B r -AA 1 -AA 2 -AA 3 - AA 4 - AA 5 - AA 6 - C s -D t -R 2 (IV) their stereoisomers, mixtures thereof, and / or their salts cosmetically or pharmaceutically acceptable products, where:
ΑΑχ is selected starting of group what consisting of -Asp-, -Glu- and -Pro-; aa 2 is -Asp-; aa 3 is selected starting of group what consisting of
-Take- and -Arg-;
aa 4 is selected starting of group what It consists in -Fe- and -Tir-; AA S is selected starting of group what It consists in -Arg- and -Lis- aa 6 is selected starting of group what It consists in -Leu- and -Met- t THE, B, C and D are independently selected The from the group consisting of amino acids natural and
unnatural amino acids;
p, r, s and t are independently selected and are in the range between 0 and 1;
Ri is selected from the group consisting of
H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl,
47/66 consists of substituted, substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R ' 5 -C (O) -; and
R 2 is selected from the group consisting of -NR ' 3 R'4, -OR z 3 and -SR'3; wherein R ' 3 and R' 4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted aryl or unsubstituted and substituted or unsubstituted aralkyl;
where R ' 5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and heteroarialkyl replaced or unsubstituted.
The Ri and R 2 groups are linked at the amino terminating (W-terminal) and carboxy terminating (Cterminal) ends of the peptide sequences, respectively.
In another particular embodiment, Ri is selected from the group consisting of H, preferably between 1 and 5, and R ' 5 -CO-, where R' 5 is selected from the group which radical C 1 -C 24 alkyl alkenyl moiety C 2 -C 24 alkynyl radical substituted C 2 -C 24, cycloalkyl radical C 3 -C 24 substituted or unsubstituted cycloalkenyl radical C 5 -C 24 substituted or unsubstituted radical cicloalquinila C8 substituted or unsubstituted 24 substituted, substituted or unsubstituted C 6 -C 30 aryl radical, substituted or unsubstituted C 7 -C 24 aralkyl radical, substituted or unsubstituted or unsubstituted or unsubstituted or unsubstituted
48/66 behenil, oleoíla and Ri is H, acetyl, miristoil, palmitoíla, linoleoíla. With more substituted which has 3 to 10 ring members, a substituted or unsubstituted heteroarylalkyl radical which has 2 to 24 carbon atoms and which has 1 to 3 atoms in addition to carbon in which the alkyl chain is 1 to 6 atoms of carbon. Preferably, R x is selected from the group consisting of H, acetyl, tert-butanoyl, hexanoyl, 2-methylhexanoyl, cyclohexanecarboxyl, octanoyl, decanoyl, lauroyl, stearroyl, preferably hexanoyl, octanoyl, lauryl, myeloyl or palmitoyl.
In another particular modality, R 2 is -NR ' 3 R' 4 ,
0R '3 or -SR 3 wherein R' 3 and R '4 are independently selected from the group consisting of H, alkyl CiC 24 substituted or unsubstituted alkenyl C 2 -C 24 substituted or unsubstituted alkynyl C 2 -C 24 substituted or unsubstituted, C 3 -C 24 cycloalkyl substituted or unsubstituted, substituted or unsubstituted C 5 -C 24 cycloalkenyl, substituted or unsubstituted C 8 -C 24 cycloalkenyl, substituted C 6 -C 30 aryl unsubstituted, substituted or unsubstituted C 7 -C 24 aralkyl, a substituted or unsubstituted heterocyclyl having 3 to 10 ring members, and a substituted or unsubstituted heteroarylalkyl group having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon where the alkyl chain is 1 to 6 carbon atoms. Optionally, R ' 3 and R' 4 can be linked via a saturated or unsaturated carbon-carbon bond, which forms a cycle with the nitrogen atom. Preferably, R 2 is -NR ' 3 R' 4 or -OR ' 3 , where R' 3 and R ' 4 are independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 24 alkyl, C 2 -C 24 alkenyl substituted or unsubstituted C 2 -C 24 alkynyl substituted or unsubstituted cycloalkyl C 0 -C 3 substituted or unsubstituted, aryl C 6 -C 15 substituted or
49/66 unsubstituted and a substituted or unsubstituted 3 to 10 membered heterocyclyl, a substituted or unsubstituted heteroarylalkyl group with a ring having 3 to 10 members and an alkyl chain of 1 to 6 carbon atoms. More preferably, R ' 3 and R' 4 are selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. Most preferably, R ' 3 is H and R' 4 is selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl. According to an even more preferred embodiment, R 2 is selected from -OH and -NH 2 .
In another particular modality, R x is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Leu-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, Ri is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, AA X is -L-Pro-, AA 2 is -L-Asp-, AA 3 is L-Tir- , AA 4 is -L-Tir-, AA 5 is -L-Lis-, AA 6 is -L-Leu-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 and R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, Ri is selected from the group consisting of H, acetyl, lauroyl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Arg- , AA 4 is -L-Fe-, AA 5 is -L-Arg-, AA S is -L-Met-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 and R ' 4 are independently
50/66 selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, Ri is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauryl, myristoil and palmitoyl, AA X is -L-Glu-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Met-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl or hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauryl, myristoil and palmitoyl, AA X is -L-Pro-, AA 2 is -L-Asp-, AA 3 is L-Tir -, AA 4 is -L-Tir-, AA 5 is -L-Arg-, AA 6 is -L-Met-, and R 2 is NR ' 3 R' 4 or -OR ' 3 where R' 3 is R ' 4 are independently selected from the group consisting of H, methyl, ethyl, hexyl, dodecyl and hexadecyl, preferably R 2 is OH or -NH 2 . More preferably, R x is acetyl or palmitoyl and R 2 is -NH 2 . More preferably, p, r, set are 0.
In another particular modality, R x is selected from the group consisting of H, acetyl, lauroil, miristoil and palmitoyl, preferably R x is selected from the group consisting of H, acetyl and palmitoyl, and R 2 is selected from the group consisting of -OH or NH 2 .
In another particular embodiment, the peptide of the general formula (IV) is selected from the group consisting of Ac-L-Glu-L-Asp-L-Tir-L-Tir-L-Arg-L-Leu-NH 2 , PalmL-Glu-L-Asp-L-Tir-L-Tir-L-Arg-L-Leu-NH 2 , Ac-L-Pro-L-Asp-LTir-L-Tir-L-Lis-L- Leu-NH 2 , Palm-L-Pro-L-Asp-L-Tir-L-Tir-L51 / 66
Lis-L-Leu-NH 2 , Ac-L-Glu-L-Asp-L-Arg-L-Fe-L-Arg-L-Met-NH 2 ,
Palm-L-Glu-L-Asp-L-Arg-L-Fe-L-Arg-L-Met-NH 2 , Ac-L-Glu-L-AspL-Tir-L-Tír-L-Arg-L -Met-NH 2 , Palm-L-Glu-L-Asp-L-Tir-L-Tir-LArg-L-Met-NH 2 , Ac-L-Pro-L-Asp-L-Tir-L-Tir -L-Arg-L-Met-NH 2 and
Palm-L-Pro-L-Asp-L-Tir-L-Tir-L-Arg-L-Met-NH 2 .
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows Ra values for the mean of the different regions studied as a function of time (total effect, average of the total effects in the periorbital and frontal region). It shows the comparison effect of control treatment (Botulinum toxin type A treatment and Example 1 placebo composition) versus Botulinum toxin type A treatment and Example 3 composition.
EXAMPLES
The specific examples given below are intended to illustrate the nature of this invention. These examples are for illustrative purposes only and are not to be construed as limiting the invention claimed herein.
EXAMPLE 1. Preparation of a placebo composition for in vivo studies.
INGREDIENT INCI Nomenclature) % by weight THE WATER (AQUA) q.s.p. 100 DISSODIC EDTA 0.3 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.7 B WATER (AQUA), POLYACRYLAMIDE, ISOPARAFINE C13-14, LAURET-7 1 Ç CYCLOPENTASILOXANE, DIMETHICONE / VINYLDIMETHYCONECROSSED POLYMER 4 PEG / PPG-18/18 DIMETHICONE 2.5 D ETILHEXIL METOXICINAMATO 3 BUTIL METOXIDIBENZOILMETANO 0.5 4-METHYLBENZYLIDENE CAMPHORUS 0.5 AND FRAGRANCE (PERFUME) 0.2 F TRIETHANOLAMINE q.s.
52/66
Phase A ingredients were mixed, phase B was added and the mixture was homogenized. Phase C was added to phase A + B during stirring until complete incorporation. The phase D ingredients were melted at 65 ° C and added to the pre-mix by stirring. Finally, the perfume (phase E) was added and the mixture was homogenized. The pH of the mixture was adjusted with triethanolamine (phase F) when necessary (final pH: 5.5 to
6.5).
EXAMPLE 2. Preparation of a composition comprising peptide Acetyl-SEQ ID No. 11-NH 2 .
INGREDIENT (INCI Nomenclature) % by weight WATER (AQUA) q.s.p.100 DISSODIC EDTAPHENOXYETHANOL, METHYLPARABEN,ETHYLPARABEN, BUTYLPARABEN, 0.3 PROPILPARABEN, ISOBUTILPARABEN 0.7 B WATER (AQUA), POLYACRYLAMIDE, ISOPARAFINE C13-14, LAURET-7 3.5 C CYCLOPENTASILOXAN,DIMETHICONE / VINYLDIMETHYCONE CROSSED POLYMER 4 PEG / PPG-18/18 DIMETHICONE 2.5 D ETILHEXIL METOXICINAMATO 3 BUTIL METOXIDIBENZOILMETANO 0.5 4-METHYLBENZYLIDENE CAMPHORUS 0.5 E Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L-Arg-NH 2(Acetyl-SEQ ID No.ll-NH 2 ) PHENOXYETHANOL, METHYLPARABEN, ETHYL PARABEN, BUTYL PARABEN, 0.005 PROPILPARABEN, ISOBUTILPARABEN 0.03 WATER (AQUA) 9.97 F FRAGRANCE (PERFUME) 0.2 G TRIETHANOLAMINE q.s.
Phase A ingredients were mixed, phase B was added and the mixture was homogenized. Phase C was added to phase A + B during stirring until complete incorporation. Phase D ingredients were melted at 65 ° C and added to the pre-mix by stirring. Phase E was added and the mixture was homogenized. Finally, the
53/66 perfume (phase F) was added and the mixture was homogenized. The pH of the mixture was adjusted with triethanolamine (phase G) when necessary (final pH: 5.5 to
6.5).
EXAMPLE 3. Preparation of a composition which comprises peptide Acetyl-SEQ ID No. 11-NH 2 and HL-Tir-D-AlaL-Gly-L-Fe-L-Leu-OH (SEQ ID No.35) of peptide.
INGREDIENT (INCI Nomenclature) _% by weight
THE WATER (AQUA) q.s.p.100 DISSODIC EDTA 0.3 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.7 B WATER (AQUA), POLYACRYLAMIDE, ISOPARAFINE C13-14, LAURET-7 1 Ç CYCLOPENTASILOXANE, DIMETHICONE / VINYLDIMETHYCONE CROSSED POLYMER 4 PEG / PPG-18/18 DIMETHICONE 2.5 D ETILHEXIL METOXICINAMATO 3 BUTIL METOXIDIBENZOILMETANO 0.5 4-METHYLBENZYLIDENE CAMPHORUS 0.5 AND Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L · (Acetyl-SEQ ID No.ll-NH 2 ) -Arg-NH 2 0.005 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.03 WATER (AQUA) 9.97 F H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH No.35) (SEQ ID 0.0025 GLYCERIN 0.5 CAPRYLYL GLYCOL 0.025 WATER (AQUA) 4.47 G FRAGRANCE (PERFUME) 0.2 H TRIETHANOLAMINE q.s.
Phase A ingredients were mixed, phase B was added and the mixture was homogenized. Phase C was added to phase A + B during stirring until complete incorporation. Phase D ingredients were melted at 65 ° C and added to the pre-mix by stirring. Phases E and F were added and the mixture was homogenized.
54/66
Finally, the perfume (phase G) was added and the mixture was homogenized. The pH of the mixture was adjusted with triethanolamine (phase H) when necessary (final pH: 5.5 to
6.5).
EXAMPLE 4. Preparation of a composition comprising peptide Acetyl-SEQ ID No. 11-NH 2 and HL-Tir-D-AlaL-Gly-L-Fe-L-Leu-OH (SEQ ID No.35) of peptide.
INGREDIENT (INCI Nomenclature)% by weight
THE LECITHIN 0.40 B Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L (Acetyl-SEQ ID No.ll-NH 2 ) -Arg-NH 2 0.0025 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.015 WATER (AQUA) 4.98 Ç H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH No.35) (SEQ ID 0.0025 GLYCERIN 0.5 CAPRILIL GLICOL 0.025 WATER (AQUA) 4.47 D WATER (AQUA) q.s.p.100 GLYCERIN 2.38 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.47 CARBOMER 0.15 AND MINERAL OIL 7.96 STEREARIC ACID, PALMITIC ACID 2.38 CETEARYL ALCOHOL 1.59 DIMETHICONE 0.15 BEE WAX (CERA ALBA) 0.79 F TRIETHANOLAMINE 0.88
Ingredients from phases A, B and C were dissolved by stirring. In a separate container, ingredients from phase D 10 were heated until melted. So phase ingredients
And they were added and mixed with phase D. The whole mixture was stirred with a turbine and ingredients from phases A + B + C were added. The pH of the mixture was adjusted to 6.0 to 7.0 with triethanolamine (phase F) when necessary.
EXAMPLE 5. Preparation of a composition that
55/66 comprises peptide Acetyl-SEQ ID No. 11-NH 2 and SEQ ID No. 33 peptide.
INGREDIENT (INCI Nomenclature)% by weight
THE LECITHINLECITHIN, GLYCOLIPIDS 1.50.012 ALKYL METICONE C24-28 1.9 PHENOXYETHANOL, METHYLPARABEN,ETHYLPARABEN, BUTYLPARABEN,PROPILPARABEN, ISOBUTILPARABEN 0.23 ETHYL HEXY COCOATE 15.1 B Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L-Arg-NH 2 (Acetyl-SEQ ID No.ll-NH 2 ) 0.0024 H-L-Tir-L-Gly-L-Gly-L-Fe-L-Leu-OH (SEQ ID 0.0024 No.33)WATER (AQUA) 0.24 Ç CYCLOPENTASILOXAN,DIMETICONE CROSSED POLYMERCYCLOPENTASILOXAN 5228.9 D FRAGRANCE (PERFUME) 0.1 AND Cl 17200 (RED 33) 0.03
Phase A ingredients were heated to about 80 ° C. In a separate container, ingredients from phase B 5 were mixed, stirred until completely dissolved and then added to phase A and mixed together. The mixture was maintained at 60 ° C.
Separately, phase C ingredients were mixed and stirred until the dispersion of the silicones was complete. Then phase A + B was added to the mixture of phase C ingredients. Finally, the fragrance and dye (phases D and E) were added.
EXAMPLE 6. Preparation of a composition comprising peptide Acetyl-SEQ ID No. 11-NH 2 and SEQ ID No. 33 of peptide.
INGREDIENT (INCI Nomenclature) _% by weight
THE ETHYL HEXYL COCOATE 15.10
LECITHIN 1.52
ALKYL METICONE C24-28 1.9
LECITHIN, GLYCOLIPIDS 0.0114
PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN,
PROPILPARABENO, ISOBUTILPARABENO_0.23
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B Ac-L-Glu-L-Glu-L-Met-L-Gin-L-Arg-L-Arg-NH 2 (Acetyl-SEQ ID No.ll-NH 2 ) 0.0024 H-L-Tir-L-Gly-L-Gly-L-Fe-L-Leu-OH (SEQNo.33) TD 0.0024 WATER (AQUA) 0.228 Ç CYCLOPENTASILOXAN, DIMETICONE CROSSED POLYMER 45.9 D CYCLOPENTASILOXAN 35 AND FRAGRANCE (PERFUME) 0.1 F Cl 17200 (RED 33) 0.0003
Phase A ingredients were heated to about 80 ° C until melted. In a separate container, ingredients from phase B were dissolved at a temperature of about 75 to 80 ° C. Phase B was added to phase A by stirring, and the mixture was maintained at 60 ° C.
Separately, phases C and D were mixed and added to the heated mixture of phases A + B. Finally, the fragrance and dye (phases E and F) were added.
EXAMPLE 7. Preparation of a composition comprising peptide Acetyl-SEQ ID No.8-NH 2 and HL-Tir-D-Ala-LGli-L-Fe-L-Leu-OH (SEQ ID No.35).
INGREDIENT (INCI Nomenclature) ~~% by weight
THE WATER (AQUA) q.s.p.100 DISSODIC EDTA 0.3 PHENOXYETHANOL, METHYLPARABEN,ETHYLPARABEN, BUTYLPARABEN, - PROPILPARABEN, ISOBUTILPARABEN 0.7 B WATER (AQUA), POLYACRYLAMIDE,ISOPARAFINE C13-14, LAURET-7 1 Ç CYCLOPENTASILOXANE, DIMETHICONE / VINYLDIMETHYCONE CROSSED POLYMER 4 PEG / PPG-18/18 DIMETHICONE 2.5 D ETILHEXIL ΜΕΤΟΧΙCINAMATO 3 BUTIL METOXIDIBENZOILMETANO 0.5 4-METHYLBENZYLIDENE CAMPHORUS 0.5 AND Ac-L-Glu-L-Glu-L-Met-L-Gin-L-Arg-L-Arg-LAla-L-Asp-NH 2 (Acetyl-SEQ ID No.8-NH 2 ) PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN, 0.005 PROPILPARABEN, ISOBUTILPARABEN 0.03
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WATER (AQUA) 9.97 F H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH No.35) (SEQ ID 0.0025 GLYCERIN 0.5 CAPRILIL GLICOL 0.025 WATER (AQUA) 4.47 G FRAGRANCE (PERFUME) 0.2 H TRIETHANOLAMINEq.s.
Phase A ingredients were mixed, phase B was added and the mixture was homogenized. Phase C was added to phase A + B during stirring until complete incorporation. Phase D ingredients were melted at 65 ° C and added to the pre-mix by stirring. Phases E and F were added and the mixture was homogenized. Finally, the perfume (phase G) was added and the mixture was homogenized. The pH of the mixture was adjusted with triethanolamine (phase H) when necessary (final pH: 5.5 to
6.5).
EXAMPLE 8. Preparation of a composition comprising peptide Acetyl-SEQ ID No. 11-NH 2 and HL-Tir-D-AlaL-Gly-L-Fe-L-Leu-OH (SEQ ID No.35) of peptide.
INGREDIENT (INCI Nomenclature)% by weight
THE WATER (AQUA) q.s.p.100 GLYCERINPHENOXYETHANOL, METHYLPARABEN, 5 ETHYLPARABEN, BUTYLPARABEN, PROPILPARABEN, ISOBUTILPARABEN 0.32 DISSODIC EDTA 0.15 GLYPOL PROPYLENE 5 B Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L-Arg-NH 2 (Acetyl-SEQ ID No.11-NH 2 ) PHENOXYETHANOL, METHYLPARABEN, ETHYL PARABEN, BUTYL PARABEN, 0.0025 PROPILPARABEN, ISOBUTILPARABEN 0.015 WATER (AQUA) 4.98 Ç H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH (SEQNo.35) ID 0.0025 GLYCERIN 0.5 CAPRILIL GLICOL 0.025 WATER (AQUA) 4.47 D POLYACRYLAMIDE, C13-14
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ISOPARAFINA, LAURET-7 1
MINERAL OIL (PARAFFINUM LIQUIDUM) 4
ALKYL METICONE C24-28 0.5
AND FRAGRANCE (PERFUME) 0.1
F WATER (AQUA) 19.3
PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN,
PROPILPARABEN, ISOBUTILPARABEN 0.1
ACRYLATES / ALKYLA CIO-30
ACRYLATE CROSSED POLYMER 0.6
G TRIETHANOLAMINE 0.625
Ingredients from phases A, B and C were dissolved. In a separate container, the phase D ingredients were heated to about 80 ° C and then added to phases A + B + C and mixed together. Phases E and F were added by stirring. Finally, the pH of the mixture was adjusted to 6.0 to 7.0 with phase G.
EXAMPLE 9. Preparation of a composition comprising peptide Acetyl-SEQ ID No.8-NH 2 and HL-Tir-D-Ala-LGli-L-Fe-L-Leu-OH (SEQ ID Mo.35) of peptide.
INGREDIENT (INCI Nomenclature)% by weight
THE WATER (AQUA) q.s.p.100 GLYPOL PROPYLENE 5 GLYCERIN 5 SORBITOL 2 ClCLOPENTASILOXANO 2 HYDROXYETHYLCELLULOSE 1 XANTAN GUM 0.4 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.3 GOMA GUAR 0.1 DISSODIC EDTA 0.15 B Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-LAla-L-Asp-NH 2 (Acetyl-SEQ ID No.8-NH 2 ) PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, -Arg-L- 0.0025 PROPILPARABEN, ISOBUTILPARABEN 0.015 WATER (AQUA) 4.98 Ç H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH No.35) (SEQ ID 0.0005 GLYCERIN 0.1
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CAPRILIL GLICOLWATER (AQUA) 0.0050.89 D WATER (AQUA) 4.821 XANTAN GUM 0.0852 PECTIN 0.0053 HYDROLYSED VEGETABLE PROTEIN 0.0405 SERINA 0.0025 ARGININE 0.0025 PROLINE 0.0025 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.0252 DISSODIC EDTA 0.0153 AND WATER (AQUA) 2.3420 TOCOPHERYL ACETATE 0.18 RETINYL PALMITATE 0.18 Phospholipids 0.12 HYDROGENED LECITHIN 0.12 CARRAGENS (CHONDRUS CRISPUS) 0.0015 CARBOMER 0.0086 TRIETHANOLAMINE 0.0067 DENAT ALCOHOL 0.015 TOCOPHEROL 0.0022 DISSODIC EDTA 0.009 PHENOXYETHANOL, METHYLPARABEN, ETYLPARABEN, BUTYL PARABEN, PROPYL PARABEN, ISOBUTYL PARABEN 0.015 F WATER (AQUA) 1.7919 GLYCERILE LINOLEATE, LINOLENATE IN 0.1 GLYCERILEPhospholipids 0.08 CARRAGENS (CHONDRUS CRISPUS) 0.001 CARBOMER 0.0061 TRIETHANOLAMINE 0.0048 DISSODIC EDTA 0.0061 PHENOXYETHANOL, METHYLPARABEN, ETHYLPARABEN, BUTYLPARABEN PROPILPARABEN, ISOBUTYLPARABEN 0.0101 G FRAGRANCE (PERFUME) 0.15 H CI 17200 (RED 33) 0.0007 AND TRIETHANOLAMINE 0.08 Phases A, B and C were mixed
homogenized. Phases D, E and F have been successfully added to Phases A + B + C and mixed together. Phases G and H were added by stirring. Finally, the pH of the mixture was adjusted to 6.0 to 7.0 with phase E.
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EXAMPLE 10. Preparation of a composition comprising Peptide Acetyl-SEQ ID No. 11-NH 2 , HL-Tir-D-Ala-LGli-L-Fe-L-Leu-OH (SEQ ID No. 35) peptide
Acetyl-SEQ ID No.39-NH 2 .
INGREDIENT (INCI Nomenclature) _% by weight
THE ETHYL HEXY COCOATELECITHINALKYL METICONE C24-28LECITHIN, GLYCOLIPIDSPHENOXYETHANOL, METHYLPARABEN,ETHYLPARABEN, BUTYLPARABEN,PROPILPARABEN, ISOBUTILPARABEN 15.101.521.90.01140.23 B Ac-L-Glu-L-Glu-L-Met-L-Gln-L-Arg-L-Arg-NH 2 (Acetyl-SEQ ID No. 11-NH 2 ) 0.0024 H-L-Tir-D-Ala-L-Gly-L-Fe-L-Leu-OH {SEQ ID 0.0024 No.35) Ac-L-Glu-L-Asp-L-Tir-L-Tir-L-Arg-L-Leu-NH 2 (Acetyl-SEQ ID No.39-NH 2 ) 0.0024 WATER (AQUA) 0.328 Ç CYCLOPENTASILOXAN,DIMETICONE CROSSED POLYMER 45.9 D CYCLOPENTASILOXAN 34.9 AND FRAGRANCE (PERFUME) 0.1 F Cl 17200 (RED 33) 0.0003
Phase A ingredients were heated to about 80 ° C until melted. In a separate container, phase B ingredients were dissolved at a temperature of about 80 ° C. Phase B was added to phase A by stirring, and the mixture was maintained at 60 ° C.
Separately, phases C and D were mixed and added to the heated mixture of phases A + B. Finally, the fragrance and dye (phases E and F) were added.
EXAMPLE 11. Preparation of a composition comprising peptide Acetyl-SEQ ID No.4-NH 2 and SEQ ID No. 33.
INGREDIENT (INCI Nomenclature)% by weight
LECITHIN 1.5
LECITHIN, GLYCOLIPIDS 0.012
ALKYL METICONE C24-28 1.9
PHENOXYETHANOL, METHYLPARABEN,
ETHYLPARABEN, BUTYLPARABEN,
PROPILPARABEN, ISOBUTILPARABEN 0.23
ETHYL HEXYL COCOATE 15.1
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B Ac-L-Glu-L-Leu-L-Glu-L-Glu-L-Met-L-Gln-L-Arg- -L-Arg-L-Ala-L-Asp-L-Gln-L-Leu -L-Wing-NH 2 (Acetyl - SEQ ID No. 4 -NH 2 ) 0.005 H-L-Tir-L-Gly-L-Gly-L-Fe-L-Leu-OH (SEQ IDNo.33) 0.0025 WATER (AQUA) 0.34 Ç ClCLOPENTASILOXANO, DIMETICONE CROSSED POLYMER 51.9 ClCLOPENTASILOXANO 28.9 D FRAGRANCE (PERFUME) 0.1 AND Cl 17200 (RED 33) 0.01 Phase A ingredients have been heated about
at 80 ° C. In a separate container, ingredients from phase B were mixed, stirred until completely dissolved and then added to phase A and mixed together. The mixture was maintained at 60 ° C.
Separately, phase C ingredients were mixed and stirred until the dispersion of the silicones was complete. Then phase A + B was added to the mixture of the ingredients of phase C. Finally, the fragrance and dye (phases D and E) were added.
EXAMPLE 12. Efficacy of in vivo combined treatment anti-wrinkles: Botulinum toxin type A and composition comprising peptide Acetyl-SEQ ID No.ll-NH 2 and HL-Tir-D-Ala-L-Gly-L-Fe-L -Leu-OH (SEQ ID No.35) of peptide.
A monocentric study was carried out under double-blind conditions to assess the anti-wrinkle effect of the compositions of Examples 2 and 3 after the Botulinum toxin type A injection. Botulinum toxin type A treatment and the composition of Example 1 (placebo) was used as the control treatment. Profile analysis of silicon replica impressions was performed to analyze the wrinkle depth 2, 4 and 6 months (2M, 4M and 6M) after the injection of type A of Botulinum toxin.
The study was conducted on 30 Caucasian women with an average age of 51 years old. All individuals
62/66 received type A injections of Botulinum toxin (Vistabel®, Allergan) in each periorbital region (crow's feet, 12.5 Units, U) and frontal region (25 U), receiving a total of 50 U toxin.
After the injections, a group of 8 volunteers started applying the composition of Example 2, another group of 9 volunteers received the composition of Example 3, and a final group of 13 volunteers received the placebo composition of Example 1. All volunteers applied compositions of
Examples 1, 2 or 3 twice a day.
Replicas of skin silicon from the periorbital ocular region (crow's feet) and frontal region of 30 volunteers exposed to the treatments described above were obtained before the injection of type A Botulinum toxin (TO) and after 2, 4 and 6 months ( 2M, 4M and 6M) of applying the placebo composition of Example 1 or the composition of Example 2 or Example 3. In summary, in a clean Petri dish, the silicon rubber material (Silflo) was mixed with a catalyst in a about 3 drops of catalyst / 2 ml of paste. The two ingredients were carefully mixed together for 1 minute and were finally spread over the skin area in the periorbital and frontal regions, covering an area of 6 x 3 cm. After 12 to 15 minutes of drying, the silicone replica was stripped of the skin.
The number of replicates per region obtained at each point in time is shown in Table 1:
Number in Treatment Regionstudy in Individuals / total region replicas / time TO 2 M 4M 6M Front 7 7 7 Example 2 Periorbital 8 8 8 - - Front 9 9 9 9 4 Example 3 Periorbital 9 9 9 9 4
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Front 13 13 10 10 4
Control
Periorbital 12 12 9 9 4
Table 1
The analysis of the study replicas was performed using confocal profilometry. A common area between replicas obtained before treatment (T0 replica) and replicas at different sample times, from the same volunteer and study region (frontal or periorbital region) were selected for analysis. A confocal profilometer (PLp, Eclipse L150A industrial microscope, Nikon) mechanically scanned the replica surface by direct illumination and the reflected signal was observed with a CCD (Charged-Coupled Device) matrix and analyzed with different data processing algorithms. Image.
From each volunteer and each study region (frontal or periorbital), two independent areas previously selected (two wrinkles) were analyzed. The area analyzed was exactly the same area at all times sampled for the same study region and the same volunteer.
From the profileometric analysis of each macrorrugosity (or wrinkle) the profilometer software calculated the roughness parameters (Ra, mean surface roughness, the deviation from the arithmetic mean of the evaluated relief; RMS, mean roughness of the quadratic mean root of the assessed relief and PV, Distance between Pico-e-Vale, distance between the values of the point of the maximum height and the point of the minimum height) and processed the three-dimensional image. The mean of Ra is understood as the mean of wrinkle reduction when it is related to the wrinkle at T0. Ra max is understood as the maximum of the average wrinkle reduction.
Results
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CONTROL TREATMENT EFFECTS
The percentages of the average reduction in the roughness parameters at 2, 4, and 6 months (2M, 4M and 6M) after the Botulinum toxin type A injection and the application of the Example 1 placebo composition treatment in relation to the base (TO) are shown in Table 2:
% roughness reduction: total periorbital and frontal effect) (effect in the region Sampled times N Lime. PV RMS Frog 2M versus TO 11 Average 10.52 15.24 15.42 4M versus TO 11 Average 5.56 7.82 7.72 6M versus TO 4 Average 0.24 -2.93 -3.76
Table 2
Figure 1 shows the Ra values for the mean of the different regions studied as a function of time (total effect, mean of the effects in the periorbital and frontal region). For the control treatment, the anti-wrinkle effect after 4 months was only 7.72% and the anti-wrinkle effect was completely lost 6 months after the Botulinum toxin type A injection. The maximum mean wrinkle reduction (Ra max 38.57%) for the control group was observed during the first month after administration of Botulinum toxin type A and application of the placebo composition of Example 1.
EFFECTS OF TREATMENT OF THE COMPOSITION OF EXAMPLE 2 The percentages of mean reduction of the roughness parameters in 2 months (2M) after the injection of type A of Botulinum toxin and the application of the composition of Example 2 in relation to the baseline (TO) are shown in Table 3:
% roughness reduction: total periorbital and frontal effect) (effect in the region Sampled times N Lime. PV RMS Frog 2M versus TO 9 Average 20.28 27.68 27.87
Table 3
When the type A injection of Botulinum toxin was
65/66 combined with the treatment with the composition of Example 2, the anti-wrinkle effect after 2 months was 27.87% (almost double that obtained with the control treatment at the same time). The average wrinkle reduction (Ra) after 2 months for the treatment group comprising the composition of Example 2 was 72.3% of the maximum wrinkle reduction average (Ra max) of the control treatment, that is, type A injection of Botulinum toxin and placebo composition.
EFFECTS OF TREATMENT OF THE COMPOSITION OF EXAMPLE 3 The percentages of mean reduction of the roughness parameters at 2, 4, and 6 months (2M, 4M and 6M) after the injection of type A of Botulinum toxin and the application of the composition of Example 3 versus baseline (TO) are shown in Table 4:
% roughness reduction: total periorbital and frontal effect) (It is made in the region Sampled times N Cal. PV RMS Frog
2 M versus TO 10 Average 20, 38 24.76 25.31 4M versus TO 10 Average 11, 07 16.36 17.11 6M versus TO 4 Average 18, 08 17.41 16.77
Table 4
When the type A injection of Botulinum toxin was combined with the application of the composition of Example 3, the anti-wrinkle effect was 16.77% even 6 months after the type A injection of Botulinum toxin and application of the composition of Example 3.
The average wrinkle reduction (Ra) after 2 months for the treatment group comprising the composition of Example 3 was 65.6% of the maximum wrinkle reduction mean (Ra max) of the control treatment, 44.4 % of Ra max after 4 months and 43.5% of Ra max after 6 months.
TREATMENT THAT UNDERSTANDS THE COMPOSITION OF EXAMPLE 3
VERSUS CONTROL TREATMENT
66/66 treatment of the Example in both
Botulinum anti-wrinkle treatment
Figure 1 shows the comparison effect of the control versus the treatment with composition 3, after the injection of type A of Botulinum toxin in the cases. The treatment with toxin type A and the composition of Example 3 had a better effect than the effect observed in the case of the control.
1/15
权利要求:
Claims (18)
[1]
1. METHOD FOR ANTI-AGING TREATMENT OF
SKIN, characterized by comprising:
The. administering an effective amount of Botulinum toxin to an area of skin on the face and / or neck,
B. and administering, once a week to ten times a day, a cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide selected from the group consisting of SEQ ID
No.11, SEQ ID No. 4, or a sequence in 7 a 12 amino acids adj acentes contained in SEQ ID No. 4, in what said sequence understands the sequence of amino acids in SEQ ID No.11, and
according to general formula (I):
R1-AA-R2 (I) their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which AA is a sequence selected from the group consisting of SEQ ID No. 11, SEQ ID No 4, or a sequence of 7 to 12 adjacent amino acids contained in SEQ ID No.4, wherein said sequence comprises the amino acid sequence SEQ ID No. 11;
on what:
Ri is independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl substituted and R5-C (O) -; and
R2 is selected from the group consisting of -NR3R4, -OR3 and -SR 3 ; where R 3 and R4 are independently
Petition 870170061322, of 08/22/2017, p. 5/21
[2]
2/15 selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl replaced;
wherein R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or heteroarialkyl not replaced;
and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
2. METHOD, according to claim 1, characterized by the anti-aging skin treatment being a treatment to reduce or eliminate skin wrinkles on the face and / or neck.
[3]
METHOD, according to claim 1, characterized in that Ri is selected from the group consisting of H, a polymer of the general formula (III)
OO (III) where n is in the range between 1 and 100, and R5-CO-, where R5 is selected from the group consisting of substituted or unsubstituted C1-C24 alkyl radical, substituted C2-C24 alkenyl radical or unsubstituted, substituted or unsubstituted C2-C24 alkynyl radical, substituted or unsubstituted C3-C24 cycloalkyl radical, substituted or unsubstituted C5-C24 cycloalkenyl radical, substituted or unsubstituted C8-C24 cycloalkyl radical
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3/15 substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C7-C24 aralkyl radical, a substituted or unsubstituted heterocyclyl radical having 3 to 10 ring members, a substituted or unsubstituted heteroarylalkyl radical having 2 to 24 carbon atoms and which has 1 to 3 atoms in addition to carbon where the alkyl chain is 1 to 6 carbon atoms.
[4]
4. METHOD, characterized by according
R3 and R4 according to claim 1, are independently selected from the group consisting of H, substituted or unsubstituted CC24 alkyl, substituted or unsubstituted C2-C24 alkenyl, substituted or unsubstituted C2-C24 alkynyl, substituted C3-C24 cycloalkyl or unsubstituted, substituted or unsubstituted C5-C24 cycloalkenyl, substituted or unsubstituted C8-C24 cycloalkynyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C7-C24 aralkyl, a substituted or unsubstituted heterocyclyl that has 3 to 10 ring members, and a substituted or unsubstituted heteroarylalkyl group having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon where the alkyl chain is 1 to 6 carbon atoms and a polymer of the formula general (III) where n is in the range between 1 and 100.
[5]
5. METHOD according to claim 1, characterized in that AA is a sequence of adjacent amino acids selected from the group consisting of SEQ
ID No. 4, SEQ ID No. 8, SEQ ID No.11, SEQ ID No.14, SEQ ID No.15, SEQ ID No.16, SEQ ID No.17, SEQ ID No.18, SEQ ID No.19, SEQ ID No.20, SEQ ID No.21, SEQ ID No.22, SEQ ID
No.23, SEQ ID No.24, SEQ ID No.25, and SEQ ID No.26.
[6]
6. METHOD, according to claim 1, characterized in that the cosmetic or pharmaceutical composition also contains a quantity cosmetically or
Petition 870170061322, of 08/22/2017, p. 7/21
4/15 pharmaceutically effective of at least one encephalin-derived peptide of the general formula (II):
Their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which:
X and Y are independently selected from
10 from the group consisting of natural and unnatural amino acids;
R 'i is independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl
15 substituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-C (O) -; and
R'z is selected from the group consisting of
20 -NR3R4, -OR3 and -SR3; where R3 and R4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted heterocyclyl, substituted heteroaryl alkyl
25 or unsubstituted, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;
where R5 is selected from the group consisting of H, non-cyclic aliphatic group substituted or not
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5/15 substituted, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylkyl.
7. METHOD, according to claim 6, characterized in that the structures of the peptides represented in the general formula (II) are those in which X is -Gli-, -Alaou -Ser-.
METHOD, according to claim 6, 10 characterized in that the structures of the peptides represented in the general formula (II) are those in which Y is -Leu- or Met-.
9. METHOD according to claim 6, characterized by the sequence of adjacent amino acids
15 contained in the general formula (II) is a sequence selected from the group consisting of SEQ ID No. 33, SEQ ID No. 34, SEQ ID No.35, SEQ ID No.36, SEQ ID No.37 and SEQ ID No.38.
10. METHOD, according to claim 1, characterized by cosmetic or pharmaceutical composition
20 further contain a cosmetically or pharmaceutically effective amount of at least one peptide of the general formula (IV):
Ri-Ap-Br-AAi-AA2-AA3-AA4-AA 5 -AA6-Cs-Dt-R2 (IV)
25 their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which:
AAi is selected The leave of group what It consists in -Asp-, -Glu- e -Pro-; 30 AA 2 is -Asp-; AA 3 is selected The leave of group what It consists in -Take- and -Arg-; AA 4 is selected The leave of group what It consists in
Petition 870170061322, of 08/22/2017, p. 9/21
6/15
-Phe- and -Tir-;
AA5 is selected from the group consisting of -Arg- and -Lis-;
AAô is selected from the group consisting of 5 -Leu- and -Met-;
A, B, C and D are independently selected from the group consisting of natural and unnatural amino acids;
p, r, s and t are independently selected and 10 are in the range between 0 and 1;
Ri is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl,
15 substituted or unsubstituted heteroarialkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R'5-0 (0) -; and
R2 is selected from the group consisting of -NR'3R'4, -OR'3 and -SR'3; where R'3 and R '4 are independently
20 selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl alkyl, substituted or unsubstituted aryl and
25 substituted or unsubstituted aralkyl;
where R'5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl
30 substituted, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarialkyl.
11. METHOD, according to claim 10, characterized in that Ri is selected from the group that
Petition 870170061322, of 08/22/2017, p. 10/21
[7]
7/15 consists of H, and R'5-CO-, where R'5 is selected from the group consisting of substituted or unsubstituted C1-C24 alkyl radical, substituted or unsubstituted C2-C24 alkenyl radical, radical C2-C24 alkynyl substituted or not
substituted, radical cycloalkyl C3-C24 substituted or not substituted, radical cycloalkenyl C5-C24 substituted or not substituted, radical cycloalkynyl C8-C24 substituted or not
substituted, substituted or unsubstituted C6-C30 aryl radical, substituted or unsubstituted C7-C24 aralkyl radical
10 substituted, a substituted or unsubstituted heterocyclyl radical having 3 to 10 ring members, a substituted or unsubstituted heteroarylalkyl radical having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon in which the chain alkyl is 1 to 6 carbon atoms.
12. METHOD according to claim 10, characterized in that R '3 and R'4 are independently selected from the group consisting of H, substituted or unsubstituted C 1 -C 24 alkyl, substituted or unsubstituted C 2 -C 24 alkenyl, alkynyl C2-C24 replaced
20 or unsubstituted, substituted or unsubstituted C3-C24 cycloalkyl, substituted or unsubstituted C5-C24 cycloalkenyl, substituted or unsubstituted C8-C24 cycloalkynyl, substituted or unsubstituted C6-C30 aryl, substituted or unsubstituted C7-C24 aralkyl The
25 substituted or unsubstituted heterocyclyl which has 3 to 10 ring members, and substituted or unsubstituted heteroarylalkyl group having 2 to 24 carbon atoms and having 1 to 3 atoms in addition to carbon where the alkyl chain is 1 to 6 carbon atoms.
13. METHOD, according to claim 1, characterized in that any of the peptides of the general formula (I) and / or (II) are found in a concentration between
0.000001% to 20% by weight, relative to the total weight of the
Petition 870170061322, of 08/22/2017, p. 11/21
[8]
8/15 composition.
14. METHOD, according to claim 1, characterized in that the cosmetic or pharmaceutical composition is administered via topical, transdermal, enteral or parenteral route.
15. METHOD, according to claim 14, characterized in that the cosmetic or pharmaceutical composition is administered through topical, transdermal, adhesive or non-adhesive bandages, oral, nasal or inhalation route or through intradermal, intramuscular, intravenous, intraperitoneal or subcutaneous.
16. METHOD, according to claim 15, characterized by topical or transdermal administration through iontophoresis, sonophoresis, electroporation, mechanical pressure, osmotic pressure gradient, occlusive treatment, microinjections, pressure injections without needles, microelectric bandages, or any combination of them.
17. METHOD, according to claim 1, characterized in that the peptides of the general formula (I) and / or (II) are incorporated in a delivery or an extended release system selected from the group consisting of liposomes, mixed liposomes, oleosomes, niosomes, miniparticles, milliparticles, microparticles, nanoparticles and nanoparticles of solid lipid, nanostructured lipid carriers, sponges, cyclodextrins, vesicles, micelles, mixed micelles of surfactants, mixed micelles of surfactants, microspheres, spheres, millipedes, milies, milies millicapsules, microcapsules, nanocapsules, microemulsions and nanoemulsions.
18.
characterized to present a
METHOD, according to claim 1, by the cosmetic or pharmaceutical composition formulation selected from the group that
Petition 870170061322, of 08/22/2017, p. 12/21
[9]
9/15 consists of anhydrous, foams, in creams, multiple emulsions, aqueous dispersion compositions, oils, milks, balms, lotions, gels, hydrogel, hydroalcolic solutions, gels in cream, hydroglycolic solutions, liniments, serums, soaps, shampoos, conditioners, serum fluids, ointments, mousses, ointments, powders, bars, pencils, sprays and aerosols.
19. METHOD, according to claim 1, characterized in that the cosmetic or pharmaceutical composition is found incorporated in a product selected from the group consisting of capsules, vials, syringes, pre-loaded syringes, concealers under the eye, makeup base , makeup removal lotions, makeup removal milks, eye shadows, lipsticks, lip gloss, lip balms and powders.
20. METHOD according to claim 1, characterized in that the cosmetic or pharmaceutical composition is incorporated into a fabric, a nonwoven fabric, clothing or a medical device.
21. METHOD, according to claim 20, characterized in that the nonwoven fabric, clothing or medical device is selected from the group consisting of bandages, gauze, scarves, adhesive bandages, non-adhesive bandages, microelectric bandages and / or facial masks .
22. METHOD according to claim 1, characterized in that the cosmetic or pharmaceutical composition further comprises a cosmetically or pharmaceutically effective amount of at least one active agent selected from the group of stimulating agents for cyclic adenosine monophosphate synthesis, elastase inhibiting agents , matrix metalloproteinase inhibiting agents, inhibitors or stimulants for the synthesis of
Petition 870170061322, of 08/22/2017, p. 13/21
[10]
10/15 melanin, depigmentation or lightening agents, propigmentation agents, self-tanning agents, anti-aging agents, NO synthase inhibiting agents, 5a-reductase inhibiting agents, lysyl- and / or prolyl hydroxylase inhibiting agents, antioxidants , free radical scavengers and / or agents against atmospheric pollution, scavengers of reactive carbonyl species, anti-glycation agents, antihistamines, antiviral agents, antiparasitic agents, emulsifiers, emollients, organic solvents, liquid propellants, skin conditioners and / or hair, humectants, substances that retain hydration, alpha hydroxy acids, beta hydroxy acids, moisturizers, epidermal hydrolytic enzymes, vitamins, pigments or dyes, dyes, gelling polymers, thickeners, surfactants, softening agents, anti-wrinkle agents, agents capable of reducing or treating bags under the eyes, exfoliating agents, antimicrobial agents, antifungal agents, fungistatic agents, bactericidal agents, bacteriostatic agents, agents that stimulate the synthesis of dermal or epidermal macromolecules and / or capable of inhibiting or preventing their degradation, agents that stimulate collagen synthesis, agents that stimulate the synthesis of elastin, agents that stimulate the synthesis of decorin synthesis, agents that stimulate laminin synthesis, agents that stimulate defensin synthesis, agents that stimulate chaperone synthesis, agents that stimulate aquaporin synthesis, agents that stimulate hyaluronic acid synthesis, agents that stimulate synthesis fibronectin, agents that stimulate the synthesis of sirtuin, agents that stimulate the synthesis of lipids and components of the stratum corneum, agents that stimulate the synthesis of ceramides, agents that inhibit the collagen degradation, agents that inhibit the elastin degradation, agents that inhibit serine proteases like cathepsin
Petition 870170061322, of 08/22/2017, p. 14/21
[11]
11/15
G, agents that stimulate the proliferation of fibroblasts, agents that stimulate the proliferation of keratinocytes, agents that stimulate the proliferation of adipocytes, agents that stimulate the proliferation of melanocytes, agents that
5 stimulate keratinocyte differentiation, agents that stimulate adipocyte differentiation, agents that inhibit acetylcholinesterase, agents that relax the skin, agents that inhibit the aggregation of acetylcholine receptors, agents that inhibit muscle contraction, agents that stimulate
10 synthesis of glycosaminoglycan, anti-hyperkeratosis agents, comedolytic agents, antipsoriasis agents, DNA repair agents, DNA protection agents, stabilizers, anti-itch agents, agents for the treatment and / or care of sensitive skin, firming agents, agents anti-brand
15 stretch marks, binding agents, agents that regulate sebum production, lipolytic agents or agents that stimulate lipolysis, anti-cellulite agents, antiperspirants, agents that stimulate healing, supporting healing agents, agents that stimulate re-epithelialization, agents of
20 coadjuvant reepithelization, cytokine proliferation factors, soothing agents, anti-inflammatory agents, anesthetic agents, agents that act in circulation and / or capillary microcirculation, agents that stimulate angiogenesis, agents that inhibit vascular permeability, agents
25 venotonics, agents that act on cellular metabolism, agents to improve dermal-epidermal junction, agents that induce hair growth, hair growth inhibiting or retarding agents, preservatives, perfumes, chelating agents, plant extracts, essential oils, extracts
30 marine, agents obtained from a biofermentation process, mineral salts, cell extracts and sunscreens, organic photoprotective agents or minerals active against ultraviolet rays A and / or B, and / or
Petition 870170061322, of 08/22/2017, p. 15/21
[12]
12/15 mixtures thereof.
23. KIT FOR ANTI-AGING SKIN TREATMENT, as defined in claim 1, characterized by comprising:
The. botulinum toxin,
B. and at least one cosmetic or pharmaceutical composition comprising a cosmetically or pharmaceutically effective amount of at least one peptide selected from the group consisting of SEQ ID No. 11, SEQ ID No.4, or a sequence of 7 to 12 adjacent amino acids contained in SEQ ID No. 4, wherein said sequence comprises the amino acid sequence of SEQ ID No. 11, and according to general formula (I):
R1-AA-R2 (I) their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which AA is a sequence selected from the group consisting of SEQ ID No. 11, SEQ ID No 4, or a sequence of 7 to 12 adjacent amino acids contained in SEQ ID No.4, wherein said sequence comprises the amino acid sequence SEQ ID No. 11;
on what:
Ri is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R5-C (O) -; and
R 2 is selected from the group consisting of
-NR3R4, -OR3 and -SR3; where R3 and R4 are independently selected from the group consisting of H, group
Petition 870170061322, of 08/22/2017, p. 16/21
[13]
13/15 non-cyclic substituted or unsubstituted aliphatic, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;
wherein R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or heteroarialkyl not replaced;
and at least one cosmetically or pharmaceutically acceptable excipient or adjuvant.
24. KIT according to claim 23, characterized in that the cosmetic or pharmaceutical composition further contains a cosmetically or pharmaceutically effective amount of at least one encephalin-derived peptide of the general formula (II):
Their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which:
X and Y are independently selected from the group consisting of natural and unnatural amino acids;
R '1 is independently selected from the
Petition 870170061322, of 08/22/2017, p. 17/21
[14]
14/15 group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, aryl
5 substituted or unsubstituted, substituted or unsubstituted aralkyl and R.5-C (O) -; and
R'z is selected from the group consisting of -NR3R4, -OR3 and -SR3; where R3 and R4 are independently selected from the group consisting of H, group
10 non-cyclic substituted or unsubstituted aliphatic, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;
[15]
15 where R5 is selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and
[16]
20 substituted or unsubstituted heteroarialquila.
[17]
25. KIT according to claim 23, characterized in that the cosmetic or pharmaceutical composition contains a cosmetically or pharmaceutically effective amount of at least one peptide of the general formula (IV):
2 5 Ri-Ap-Br-AAi-AA2-AA3-AA4-AA 5 -AA6-Cs-Dt-R2 (IV) their stereoisomers, mixtures thereof, and / or their cosmetically or pharmaceutically acceptable salts thereof, in which :
30 AAi is selected starting of group what consisting of -Asp-, -Glu- e -Pro-; AA 2 is -Asp-; AA 3 is selected starting of group what consisting of
Petition 870170061322, of 08/22/2017, p. 18/21
15/15
-Take- and -Arg-;
AA4 is selected from the group consisting of -Phe- and -Tir-;
AA5 is selected from the group consisting of 5 -Arg- and -Lis-;
AAô is selected from the group consisting of -Leu- and -Met-;
A, B, C and D are independently selected from the group consisting of natural amino acids and
10 unnatural amino acids;
p, r, s and t are independently selected and are in the range between 0 and 1;
Ri is selected from the group consisting of
H, non-cyclic aliphatic group substituted or not
15 substituted, substituted or unsubstituted alicyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroarylkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl and R'5-C (O) -; and
20 R2 is selected from the group consisting of
-NR'3R ' 4 , -OR'3 and -SR'3; where R'3 and R'4 are independently selected from the group consisting of H, substituted or unsubstituted non-cyclic aliphatic group, substituted or unsubstituted alicyclic, heterocyclyl
25 substituted or unsubstituted, substituted or unsubstituted heteroarialkyl, substituted or unsubstituted aryl and substituted or unsubstituted aralkyl;
where R'5 is selected from the group consisting of H, non-cyclic aliphatic group substituted or not
[18]
30 substituted, substituted or unsubstituted alicyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heterocyclyl and substituted or unsubstituted heteroarylkyl.
Petition 870170061322, of 08/22/2017, p. 19/21
1/1
Ra parameter (total effect)
-A-Control treatment - «- Example 3% reduction of skin roughness
Time (weeks)
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同族专利:
公开号 | 公开日
CN103096980B|2018-02-09|
KR20190135555A|2019-12-06|
JP6306885B2|2018-04-04|
WO2011154126A2|2011-12-15|
CN103096980A|2013-05-08|
ES2654342T3|2018-02-13|
AU2011264125B2|2015-03-19|
KR20130135819A|2013-12-11|
ZA201209484B|2014-02-26|
KR20210090731A|2021-07-20|
CA2801961A1|2011-12-15|
KR20180083958A|2018-07-23|
EP2579952A2|2013-04-17|
MX2012014389A|2013-01-29|
WO2011154126A3|2012-07-26|
US20110305735A1|2011-12-15|
EP2579952B1|2017-11-08|
JP2013533226A|2013-08-22|
MX342853B|2016-10-14|
AU2011264125A1|2012-12-20|
BR112012031117A2|2016-08-23|
CO6640331A2|2013-03-22|
CA2801961C|2018-11-20|
JP2018058842A|2018-04-12|
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法律状态:
2017-06-27| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
2017-09-12| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
2018-01-16| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|
优先权:
申请号 | 申请日 | 专利标题
US12/797,222|US20110305735A1|2010-06-09|2010-06-09|Skin antiaging treatment|
US12/797,222|2010-06-09|
PCT/EP2011/002799|WO2011154126A2|2010-06-09|2011-06-08|Skin antiaging treatment|
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