Skin care compositions containing nano-elements of collagen synthesis stimulating compounds and methods for their preparation - Patents.com

Abstract

A skin composition is disclosed that includes a water-insoluble biodegradable compound (CSSC) capable of stimulating collagen synthesis, the CSSC being dispersed in a polar carrier as nanoelements having a molecular weight of 0.6 kDa or more and an average diameter of 200 nm or less. A method for preparing the skin composition and its use are also provided.

Description

[Technical field]

[0001] The present disclosure relates to compositions suitable for skin treatment, particularly for cosmetic skin treatment. Methods for preparing these dermatological compositions are also disclosed. [Background technology]

[0002] The skin plays an important role in protecting the body from the dangers of the external environment, and also exhibits the most visible signs of aging, ranging from fine lines to deep wrinkles, loss of elasticity, tonicity and firmness leading to sagging skin, as well as superficial blemishes or lesions.

[0003] Skin changes as a result of intrinsic and extrinsic factors. Intrinsic aging factors include genetics, cellular metabolism, hormones, and metabolic processes. Such factors can lead to a decrease in the production of collagen and elastin, which are ubiquitous proteins that ensure the structural integrity of the skin, and of glycosaminoglycans (GAGs), which are water-binding molecules that contribute to the dermal matrix along with elastin and collagen. Reduced functioning of sweat and sebaceous glands is another intrinsic process that can also contribute to the thinning and fragility of skin with age. Extrinsic factors include chronic light exposure, smoking, pollution, ionizing radiation, chemicals, toxins, etc. These usually result in thickening of the outermost layer of skin (stratum corneum), precancerous changes (which can lead to skin cancer), the formation of freckles and sun spots, and excessive loss of collagen, elastin, and GAGs. These processes, together or alone, give the skin its appearance of deep wrinkles, uneven skin tone, roughness, and thinness. Collagen, elastin and GAGs can be referred to as structural skin polymers and perform biological functions as well as providing the mechanical properties of skin in both healthy and pathological conditions.

[0004] There are many approaches to reduce or delay skin aging, ranging from mild topical treatments to more extreme surgical treatments. Early symptoms of aging can be treated with cosmetics, such as retinoids, vitamin C, and alpha-hydroxy acids. Chemical peels, dermabrasion, microneedling, ultrasonic energy devices, or laser resurfacing may be options for moderate to severe skin damage. Deeper facial wrinkles can be treated invasively, for example, by injecting skin proteins that are reduced by the aging process, such as botulinum toxin, dermal fillers, or collagen itself. Surgical interventions, such as facelifts, brow lifts, or eyelid cosmetic surgery, are more extreme measures taken against wrinkles and sagging skin.

[0005] One approach used in anti-aging treatment involves enhancing collagen synthesis in situ. There are many known agents to induce such synthesis and they can be administered orally, topically, or parenterally. Orally administered agents include food supplements such as vitamin C, ginseng, and dietary antioxidants (blueberries, cinnamon, certain herbs, etc.). Aloe vera and retinol are two agents known to promote collagen synthesis when applied topically to the skin. Hydroxyapatite, on the other hand, can only achieve such an effect when administered by injection.

[0006] Compared with parenteral (which entails pain and risk of infection) or oral (which needs to overcome first-pass metabolism to maintain efficacy) compositions, topical compositions are considered to be convenient to apply and safer.Therefore, while there is still a need for injectable compositions with improved efficacy, topical compositions are more desirable, especially for anti-aging treatments such as the above-mentioned treatments.

[0007] However, to allow penetration into the skin, the cosmetically active agents (i.e., cosmeceuticals) or medicamentally active agents (i.e., pharmaceuticals) of such topical compositions must be small enough (typically with a molecular weight of 500 g / mol) to penetrate the skin barrier and achieve satisfactory transdermal delivery. Such agents are preferably in the form of nanomaterials, such as nanofibers, nanoemulsions, nanospheres, nanocapsules, nanocrystals, dendrimers, liposomes, nanotubes, etc., as described, for example, in the review by Souto EB et al.; "Nanomaterials for Skin Delivery of Cosmeceuticals and Pharmaceuticals"; Applied Sciences, 2020, Vol. 10(5), 1594.

[0008] In addition to the above exemplary compounds known to enhance the synthesis of structural skin proteins, polymers (including proteins and their fragmented / truncated forms known as peptides) have also been reported to promote the production of collagen, elastin, GAGs, or other such molecules involved in maintaining the structural and functional integrity of skin. Other polymers (or the same polymers) can (alternatively or additionally) inhibit processes or enzymes (e.g., proteases) that lead to the degradation of natural skin proteins. For example, some peptides have been reported to enhance the neosynthesis of collagen, while other peptides have been reported to inhibit collagenase, the enzyme responsible for collagen degradation.

[0009] Regardless of the type of biological activity, such substances (polymeric or not) may positively stimulate the neosynthesis of structural skin proteins and / or negatively inhibit downregulators of such skin proteins, with the end result ranging from reducing or slowing the loss of the amount of skin proteins, maintaining their levels, or even increasing their presence. Such agents may be referred to herein as collagen-synthesis stimulating compounds (CSSCs) or, in particular, collagen-synthesis stimulating polymers (CSSPs), and the activity of such agents with respect to collagen includes not only the stimulation of its neosynthesis, but alternatively or additionally also the prevention of its degradation.

[0010] Dermal fillers, also called "volumizers," temporarily "soften" wrinkles by filling in the wrinkles, depressions, or depressions under or around the skin's surface creases or folds. Dermal fillers can rejuvenate the skin by replacing structural dermal polymers that disappear naturally, restoring their levels to a degree that delays the appearance of visible signs of aging. Because such dermal matrix components are relatively high molecular weight polymers, their replacement generally requires injections, a method that is relatively expensive and poses compliance issues. Take hyaluronic acid (HA) for example, which exists in the skin in the form of polymers with relatively high molecular weights, usually above 500 kilodaltons (kDa). Because of their size, these molecules are generally unable to cross the skin barrier, so cosmetic compositions aimed at delivering HA in transdermal applications generally refer to different classes of polymers with relatively low molecular weights. The potential physiological role of HA, or its relative efficacy, depends on the size of the polymer, with larger ones believed to have greater water retention and smaller ones more effective at enhancing neosynthesis of structural dermal polymers.

[0011] Thus, considering the molecular weight parameter among many other factors that will further affect the efficacy of the product, there is, simply put, a conflict between compliance (increasing low molecular weight (LMW) HA) and efficacy (increasing high molecular weight (HMW) HA). HA is far from being the only polymer of interest in the cosmetic field, which faces a similar problem of using a molecule with a molecular weight high enough to achieve sufficient or enhanced efficacy after transdermal penetration while at the same time ensuring a convenient delivery as achieved by topical application. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Souto EB et al.; “Nanomaterials for Skin Delivery of Cosmeceuticals and Pharmaceuticals”; Applied Sciences, 2020, 10(5), 1594 Summary of the Invention [Problem to be solved by the invention]

[0013] Since pharmaceutical or cosmetic products for the skin are always needed to maintain the integrity (function and / or structure) of the skin for as long as possible, to protect against environmental factors such as UV or toxic oxygen products, to reduce dryness of the skin or to combat the signs of skin aging, there remains a need to provide a dermatological composition that solves at least some of the above problems. [Means for solving the problem]

[0014] Advantageously, the novel compositions will allow for higher loadings of CSSCs, whether alone or in combination with additional ingredients having beneficial dermatological activity, and / or delivery of CSSCs (especially CSSPs) having relatively high average molecular weights.

[0015] BRIEF DESCRIPTION OF THE DRAWINGS Some embodiments of the present disclosure will now be further described, by way of example, with reference to the accompanying drawings, in which the same reference numerals or characters indicate corresponding or identical components. The specification, together with the drawings, will make clear to those skilled in the art how some embodiments of the present disclosure can be implemented. The drawings are for illustrative purposes and do not attempt to show the structural details of the more detailed embodiments, but are necessary for a basic understanding of the present disclosure. For the sake of clarity and convenience of illustration, some of the objects depicted in the drawings are not necessarily drawn to scale. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows a simplified schematic diagram of a method for preparing a dermatological composition according to an embodiment of the present teachings. [Diagram 2] FIG. 2 shows the size distribution of PCL nanoparticles by volume, as measured by DLS, in a nanodispersion prepared according to one embodiment of the method. [Diagram 3] FIG. 3 is a CryoTEM image of PCL nanoparticles in a nanodispersion prepared by one embodiment of the method, the PSD of which was previously shown in FIG. [Figure 4] FIG. 4 is a line graph showing the change over time in the number of facial wrinkles in a group treated with a skin composition according to an embodiment of the present teachings compared to a group treated with a placebo composition, shown as a percentage of baseline values. [Figure 5AB] Figure 5A is an image showing the level of collagen in the skin of a volunteer before application of a dermatological composition according to the present teachings (referred to as "baseline"), and Figure 5B is an image showing the level of collagen in the skin of the same volunteer as in Figure 5A as observed one month after application of a dermatological composition according to the present teachings. [Figure 6AB]Figure 6A is a photograph of a volunteer's face showing lines and wrinkles before application of a skin composition according to the present teachings (referred to as "baseline"), and Figure 6B is a schematic diagram of the lines and wrinkles shown in the photograph of Figure 6A. [Figure 7AB] Figure 7A is a photograph of the face of the same volunteer shown in Figure 6A three months after application of a skin composition according to an embodiment of the present teachings, showing a reduction in lines and wrinkles, and Figure 7B is a schematic diagram of the reduced lines and wrinkles shown in the photograph of Figure 7A. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] overview An embodiment of the present invention relates to a dermatological composition comprising a water-insoluble collagen synthesis stimulating compound (CSSC), such as a collagen synthesis stimulating polymer (CSSP), dispersed as nanoparticles or nanodroplets in a polar carrier. In particular, the molecular weight of the CSSC or CSSP molecule is 0.6 kDa or more. In general, the composition comprises at least one surfactant together with the CSSC, the carrier, or both, and may optionally contain, in addition to the CSSC or CSSP, at least one active agent as defined herein below.

[0018] These dermatological compositions have been developed in particular to overcome at least some of the drawbacks associated with the current delivery of CSSC(s) (e.g., CSSP(s)) and / or specific active agent(s) to the skin, preferably via transdermal delivery by topical application, although suitability for parenteral delivery by injection is not excluded. Methods for preparing such topical or injected dermatological compositions are also disclosed.

[0019] In a first aspect of the present disclosure, a dermatological composition is provided comprising nanoelements (i.e., nanoparticles or nanodroplets) of a water-insoluble biodegradable collagen synthesis stimulating compound (CSSC) having a molecular weight of 0.6 kDa or more, said nanoelements being dispersed in a polar carrier and having an average diameter (e.g., Dv50) of 200 nanometers (nm) or less.

[0020] In a second aspect of the present disclosure, a dermatological composition is provided comprising nanoelements of a water-insoluble biodegradable CSSC plasticized by a non-volatile liquid, said CSSC having an average molecular weight of 0.6 kDa or more, the plasticized nanoelements of CSSC being dispersed in a polar carrier and having an average diameter (e.g., Dv50) of 200 nm or less.

[0021] In some embodiments, the CSSC (and / or the plasticized CSSC) is characterized by at least one, at least two, or at least three of the following structural properties: i. CSSC and / or plasticized CSSC are insoluble in polar carriers; ii. the CSSC and / or the plasticized CSSC has at least one of a melting temperature (Tm), a softening temperature (Ts), or a glass transition temperature (Tg) of at most 300°C, at most 250°C, at most 200°C, at most 180°C, at most 150°C, or at most 120°C, said temperature being either a first (i.e. native) Tm, Ts, or Tg of the CSSC, or a second Tm, Ts, or Tg of the CSSC when plasticized, or both; iii. the CSSC has a first and / or second Tm or Ts of at least 20°C, at least 30°C, at least 40°C, at least 50°C, or at least 60°C; iv. the CSSC has a first and / or second Tg of -75°C or greater, -50°C or greater, -25°C or greater, 0°C or greater, 20°C or greater, 30°C or greater, 40°C or greater, 50°C or greater, or 60°C or greater; v. the CSSC has at least one of a first and / or second Tm, Ts, and Tg of 20°C to 300°C, 20°C to 250°C, 20°C to 200°C, 30°C to 180°C, 40°C to 180°C, or 50°C to 150°C; vi. the CSSC has a molecular weight of 0.7 kDa or more, 0.8 kDa or more, 0.9 kDa or more, 1 kDa or more, 2 kDa or more, or 5 kDa or more; vii. the CSSC has a molecular weight of 500 kDa or less, 300 kDa or less, 200 kDa or less, 100 kDa or less, 80 kDa or less, 50 kDa or less, 25 kDa or less, or 15 kDa or less; and viii. The CSSC has a molecular weight of 0.6 kDa to 500 kDa, 0.7 kDa to 300 kDa, 0.8 kDa to 200 kDa, 1 kDa to 100 kDa, or 2 kDa to 80 kDa.

[0022] In some embodiments, at least one structural property satisfied by at least one of the CSSC and plasticized CSSC is: property i) above, property ii) above, property iii) above, property iv) above, property v) above, property vi) above, property vii) above, or property viii) above.

[0023] In some embodiments, the at least two structural properties satisfied by at least one of the CSSC and the plasticized CSSC are properties i) and v), i) and viii), or v) and viii), of the above properties.

[0024] In some embodiments, the at least three structural properties satisfied by at least one of the CSSC and plasticized CSSC are properties i), ii) and v); properties i), ii) and viii); properties i), iii) and viii); properties i), iv) and viii); properties i), v) and vi); properties i), v) and vii); or properties i), v) and viii), among the properties above.

[0025] In a particular embodiment, the CSSC is a CSSP, a chemical compound that is a polymer formed from repeating structural units, where such monomers are either the same (homopolymer) or different (random or block copolymer). In another particular embodiment, the polymer of the CSSP is a thermoplastic polymer. The molecular weight of non-polymeric compounds is usually up to 2 kDa, and generally does not exceed 1 kDa, while CSSPs can be larger molecules of at least several kDa.

[0026] As used herein, the term "nanoelements", particularly as used with respect to structures containing CSSC (plasticized or unplasticized), refers to relatively solid nanoparticles or relatively liquid nanodroplets having an average diameter of 200 nm or less, 150 nm or less, 100 nm or less, 75 nm or less, or 50 nm or less, such structures being dispersed (e.g., as a result of nanosizing) in a homogeneous medium and forming a nanosuspension therein. Such nanoelements generally have an average diameter of 2 nm or more, 5 nm or more, 10 nm or more, 15 nm or more, or 20 nm or more. In some embodiments, the average diameter of the nanoelements of the compositions according to the present teachings is between 2 nm and 200 nm, between 5 nm and 150 nm, between 10 nm and 100 nm, between 15 nm and 75 nm, or between 20 nm and 50 nm. The average diameter of the nanoelements can be determined by any suitable method, including the hydrodynamic diameter (D) of the elements as measured by dynamic light scattering (DLS) and determined for 50% of the volume of the nanoelements. V 50).

[0027] Considering their intended use and / or preparation methods, CSSCs suitable for the present invention are advantageously relatively solid at room temperature (about 20° C.) and up to body temperature (e.g., about 37° C. for human subjects). Such preferences also extend to plasticized CSSCs, where the presence of non-volatile liquids and their relative amounts, or any other substances that affect the thermal behavior of the product, are further considered. As can be understood by those skilled in the art, since CSSCs can be thermoplastic polymers, the "relative solidity" of such substances, or that such substances are "relatively solid", at any particular temperature refers to the fact that they are not necessarily solid, but rather exhibit viscoelastic behavior. Without wishing to be bound by a particular theory, such characteristics of CSSCs should ensure, to the extent necessary, that nanoelements made therefrom are relatively non-sticky, thereby facilitating their uniform distribution in the compositions according to the present teachings.

[0028] In some embodiments, the first (native) viscosity of the CSSC is at 50° C. and a shear rate of 10 s -1 (sec -1 ) when measured at 10 7 Millipascal·second (mPa·s) or less, 10 6 mPa·s or less, 10 5 mPa·s or less, 10 4 mPa s or less, or 10 3 mPa s or less.

[0029] In another embodiment, the first (natural) viscosity of the CSSC, generally the CSSP, is 10 7 Higher than mPa s, e.g. up to 10 11 mPa·s, in which case the CSSC can be combined with a non-volatile liquid to plasticize or swell the CSSC to reduce the viscosity and facilitate its processing and incorporation as nanoelements into the dermatological composition. Thus, in such an embodiment, the composition is heated at 50° C. at a shear rate of 10 s -1 When measuring the viscosity of the first (natural) CSSC, 7It further contains a non-volatile liquid in an amount sufficient to at least reduce the viscosity to a second (plasticized) viscosity of no more than mPa·s.

[0030] In some embodiments, the CSSC plasticized with a non-volatile liquid (referred to herein as a "plasticized" or "swollen" CSSC) exhibits a reduced "second" viscosity compared to the first viscosity, and the second viscosity of the CSSC is measured at a temperature of 50° C. and 10 seconds. -1 When measured at a shear rate of 10 6 mPa·s or less, 10 5 mPa·s or less, 10 4 mPa s or less, or 10 3 mPa s or less.

[0031] The dermatological composition of the present invention is in the form of a nanosuspension. Depending on the Tm or Ts of the CSSC (either plasticized or naturally having the desired viscosity), the composition can be in the form of a nanodispersion at room temperature (i.e., when Tm or Ts is above 20° C., for example between 25° C. and 80° C.), in which the nanoelements are relatively solid nanoparticles, or in the form of a nanoemulsion (i.e., when Tm or Ts is below 20° C.), in which the nanoelements are relatively liquid nanodroplets.

[0032] In some embodiments, the CSSC is plasticized and exhibits at least one of a second Tm, Ts, or Tg that is lower than the first Tm, Ts, or Tg, respectively, of the unplasticized native CSSC (either alone or in combination with any substance added thereto as a mixture), and the at least one second Tm, Ts, or Tg is 20° C. or higher, 30° C. or higher, 40° C. or higher, 50° C. or higher, or 60° C. or higher. In other embodiments, at least one of the second Tm, Ts, or Tg of the plasticized or swollen CSSC is at most 300° C., at most 250° C., at most 200° C., at most 190° C., at most 180° C., or at most 170° C. In some embodiments, the plasticized or swollen CSSC, and / or mixtures comprising same, have at least one of a second Tm, Ts, or Tg in the range of 0°C to 290°C, 10°C to 250°C, 20°C to 200°C, 30°C to 190°C, 40°C to 180°C, or 50°C to 170°C.

[0033] In some embodiments, the CSSC is a quinone, particularly ubidecarenone, also known as 1,4-benzoquinone or coenzyme Q10 (CoQ10).

[0034] In another embodiment, the CSSC is a CSSP, the polymer being selected from the group of polymers including: aliphatic polyesters such as polycaprolactone (PCL), polylactic acid (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(D,L-lactide) (PDLLA), polyglycolic acid (PGA), poly(p-dioxanone) (PPDO), and poly(lactic-co-glycolic acid) (PLGA); polyhydroxybutyrate (PHB), poly-3-hydroxybutyrate (P3HB), poly-4-hydroxybutyrate (P4HB), polyhydroxyvalerate (PHV), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyhydroxyhexanoate (PHB ... polyhydroxy-alkanoates such as polyhydroxyoctanoate (PHO), polyhydroxyoctanoate (PHH), and polyhydroxyoctanoate (PHO); poly(alkene dicarboxylates) such as poly(butylene succinate) (PBS), poly(butylene succinate-co-adipate) (PBSA), and poly(ethylene succinate) (PES); polycarbonates such as poly(trimethylene carbonate) (PTMC), poly(propylene carbonate) (PPC), and poly[oligo-(tetramethylene succinate)-co(tetramethylene carbonate); aliphatic-aromatic copolyesters such as poly(ethylene terephthalate) (PET) and poly(butylene adipate-co-terephthalate) (PBAT); isomers thereof, copolymers thereof, and combinations thereof.

[0035] In certain embodiments, the CSSC is CoQ10 or a CSSP that is an aliphatic polyester. In further specific embodiments, the aliphatic polyester of the CSSP is selected from polycaprolactone, polylactic acid, isomers thereof, copolymers thereof, and combinations thereof.

[0036] In some embodiments, non-volatile liquids that may be added to the CSSC to reduce at least one of the first (native) viscosity, Tm, Tg, and Ts of the CSSC are selected from the group including mono- and polyfunctional aliphatic esters, fatty esters, cyclic organic esters, fatty acids, terpenes, aromatic alcohols, aromatic ethers, aldehydes, and combinations thereof. In certain embodiments, the non-volatile liquid is selected from the group including dibutyl adipate, C benzoate, 12 ~C 15 The alkyl and dicaprylyl carbonates are selected from the group consisting of aryl and dicaprylyl carbonates.

[0037] In some embodiments, the polar carrier in which the nanoelements, including CSSC, are dispersed includes water, glycols (e.g., propylene glycol, 1,3-butanediol, 1,4-butanediol, 2-ethyl-1,3-hexanediol, and 2-methyl-2-propyl-1,3-propanediol), glycerol, its precursors and derivatives, collectively referred to herein as "glycerol" (e.g., acrolein, dihydroxyacetone, glyceric acid, tartronic acid, epichlorohydrin, glycerol tert-butyl ether, polyglycerol, glycerol esters, and glycerol carbonate), and combinations thereof. In certain embodiments, the polar carrier comprises, consists of, or is water.

[0038] In some embodiments, the dermatological (e.g., topical) composition further comprises at least one surfactant selected from an emulsifier and a hydrotrope. The surfactant(s) can be present in the nanoelements containing the CSSC (e.g., if they are polar carrier-insoluble surfactants), in the liquid phase containing the polar carrier (e.g., if they are polar carrier-soluble surfactants), or both (e.g., if they are intermediate emulsifiers).

[0039] In some embodiments, the at least one surfactant is an emulsifier selected from the group including: alkyl sulfates, sulfosuccinates, alkylbenzenesulfonates, acylmethyltaurates, acylsarcosinates, isethionates, propyl peptide condensates, monoglyceride sulfates, ether sulfonates, ester carboxylates, fatty acid salts, quaternary ammonium compounds, betaines, alkylamphopropionates, alkyliminopropionates, alkylamphoacetates, fatty alcohols, ethoxylates, ethylaminopropionates ... silyl fatty alcohols, poly(ethylene glycol) block copolymers; ethylene oxide (EO) / propylene oxide (PO) copolymers, alkylphenol ethoxylates, alkyl glucosides and polyglucosides, fatty alkanolamides, ethoxylated alkanolamides, ethoxylated fatty acids, sorbitan derivatives, alkyl carbohydrate esters, amine oxides, ceteareths, oleths, alkyl amines, fatty esters, polyoxylglycerides, natural oil derivatives, carboxylic acid esters, and ureas.

[0040] In some embodiments, the at least one surfactant is a hydrotrope selected from the group including sodium dioctyl sulfosuccinate, urea, sodium tosylate, adenosine triphosphate, cumene sulfonate, and salts (e.g., sodium, potassium, calcium, ammonium) of toluene sulfonic acid, xylene sulfonic acid, and cumene sulfonic acid.

[0041] In some embodiments, the dermatological (e.g., topical) composition further comprises at least one skin penetration enhancer, which is typically found in the liquid phase in which the CSSC-containing nanoelements are dispersed.

[0042] In some embodiments, the dermatological (e.g., topical) composition further comprises at least one active agent within the nanoelements, which is substantially insoluble in the polar carrier in which the nanoelements are dispersed.

[0043] In some embodiments, the dermatological (eg, topical) composition further comprises at least one active agent in a liquid phase with the polar carrier, where the active agent is soluble in the polar carrier.

[0044] As used herein, a substance is considered to be insoluble in a liquid carrier, e.g., a "polar carrier insoluble active agent" (or "carrier insoluble active agent"), if it has a solubility (solubility) in the carrier of less than 5 wt.% (more typically, less than 4 wt.%, less than 3 wt.%, less than 2 wt.%, less than 1 wt.%, or less than 0.5 wt.%) by weight of the polar carrier at a temperature of 20°C.

[0045] Conversely, a substance is considered soluble in a liquid carrier, e.g., a "polar carrier soluble active" (or "carrier soluble active"), if it is soluble and immersed in the carrier at 5 wt% or more (more typically, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, or 10 wt% or more) based on the weight of the polar carrier at a temperature of 20° C. As will be appreciated by those of skill in the art, some substances having a desired activity may be polar carrier insoluble in one chemical form and polar carrier soluble in another, and a salt of the substance will generally increase its solubility.

[0046] In some embodiments, the dermatological (e.g., topical) composition comprises two or more active agents in addition to the CSSC, which are either in the same phase or in different phases. For example, a first active agent that is carrier insoluble can be contained within the nanoelements, and a second active agent that is carrier soluble can be contained within the polar carrier phase.

[0047] In some embodiments, the at least one carrier-insoluble active agent is selected from the group including benzoyl peroxide, erythromycin, macrolides, retinol, salicylic acid, tetracycline, tretinoin, vitamin A, vitamin D, vitamin K, and plant extracts insoluble in polar carriers, such active agents having anti-acne, antioxidant, anti-inflammatory, and / or anti-aging activity that is particularly beneficial for the skin. In a particular embodiment, the carrier-insoluble active agent that can be incorporated into the nanoelements of the CSSC is retinol.

[0048] In some embodiments, the at least one carrier-soluble active agent is selected from the group including azelaic acid, biotin, clindamycin, collagen, elastin, folacin, hyaluronic acid (HA), niacin, pantothenic acid, riboflavin, thiamine, vitamin B12, vitamin B6, vitamin C, and plant extracts soluble in polar carriers, such active agents having anti-acne, antioxidant, anti-inflammatory, and / or anti-aging activity beneficial to the skin. In a particular embodiment, the carrier-soluble active agent soluble in the polar carrier in which the nanoelements of the CSSC are dispersed is HA.

[0049] Advantageously, the dermatological (e.g., topical) compositions of the present invention may have a relatively high concentration (e.g., 1 wt% or more) of the CSSC (e.g., CSSP) and / or a relatively high concentration (e.g., 1 wt% or more) of any active agent (e.g., retinol or HA) and / or the CSSC(s) and / or any active agent(s) may have a relatively high molecular weight, compared to conventional topical compositions containing such ingredients. Without wishing to be bound by theory, it is expected that the relatively high loading and / or potency (if dependent on MW) of the CSSC and / or any active agent provides a high concentration gradient, favoring transdermal delivery and ultimately favoring cosmetic or pharmaceutical efficacy.

[0050] It is noted that nanoparticles or nanodroplets of CSSC with particle sizes within the size ranges disclosed herein have been unexpectedly discovered by the inventors, since such forms of CSSC, especially when plasticized CSSPs, would be expected to aggregate in light of the expected tackiness.

[0051] In a third aspect of the present disclosure, there is provided a method for preparing a dermatological composition comprising a water-insoluble CSSC, the method comprising the steps of: a) providing a water-insoluble CSSC, wherein: i. the CSSC is biodegradable; ii. the CSSC has a molecular weight of at least 0.6 kDa; iii. the CSSC has at least one of a first Tm, Ts, or Tg less than or equal to 300° C.; and iv. The CSSC is performed at 50°C and a shear rate of 10 seconds. -1 When measuring at 10 7 having a first viscosity higher than mPa s, The above steps; b) mixing the CSSC with a non-volatile liquid miscible therewith, and optionally with at least one surfactant, said mixing being carried out at 50° C. and a shear rate of 10 s -1 and a mixing temperature equal to or greater than at least one of a first Tm, Ts, or Tg of the CSSC, whereby a homogeneous plasticized CSSC is formed, the plasticized CSSC having a second Tm, Ts, or Tg lower than the first Tm, Ts, or Tg, respectively, and a second viscosity lower than the first viscosity, the second viscosity being greater than or equal to 10. 7 the step in which the temperature is equal to or lower than mPa·s; c) combining the plasticized CSSC (optionally containing at least one surfactant) with a polar carrier; and d) nanosizing the combination of step c) by applying shear at a shear temperature equal to or higher than at least one of a second Tm, Ts, or Tg of the plasticized CSSC to obtain a nanosuspension, thereby dispersing nanoelements of the plasticized CSSC in a polar carrier, the nanoelements having an average diameter (e.g., Dv50) of 200 nm or less.

[0052] In some embodiments of the third aspect, the mixing temperature in step b) is at least 5° C., at least 10° C., at least 20° C., at least 30° C., or at least 40° C. higher than at least one of the first Tm, Ts, or Tg of the CSSC, so long as the mixing is performed at a temperature at which only a small portion of the non-volatile liquid boils and evaporates. l In some embodiments, the mixing temperature is the boiling temperature Tb of the non-volatile liquid. l If the mixing time is short enough and / or there is a sufficient excess of non-volatile liquid, the mixing temperature may alternatively be lower than the boiling temperature Tb l It can be more than that.

[0053] In a fourth aspect of the present disclosure, there is provided a method for preparing a dermatological composition comprising a water-insoluble CSSC, the method comprising the steps of: a) providing a water-insoluble CSSC, i. the CSSC is biodegradable; ii. the CSSC has a molecular weight of at least 0.6 kDa; iii. the CSSC has at least one of a first Tm, Ts, or Tg less than or equal to 300° C.; and iv. The CSSC is 50°C and 10 seconds -1 When measured at a shear rate of 10 7 having a first viscosity of less than or equal to mPa s, The above steps; b) combining the CSSC with a polar carrier and, optionally, with at least one surfactant; and c) applying shear at a shear temperature equal to or higher than at least one of a first Tm, Ts, or Tg of the plasticized CSSC to obtain a nanosuspension, thereby dispersing nanoelements of the CSSC in the polar carrier, the nanoelements having an average diameter (e.g., Dv50) of 200 nm or less.

[0054] In some embodiments of each of the third and fourth aspects, the shear temperature is at least 5° C., at least 10° C., at least 20° C., at least 30° C., or at least 40° C. higher than the second Tm, Ts, or Tg of the plasticized CSSC (or the first Tm, Ts, or Tg, in the case of an unplasticized CSSC), so long as the nanosizing is carried out at a temperature at which only a small portion of the polar carrier boils and evaporates. c Assuming that, in some embodiments, under the pressure at which the nanosizing process is carried out, the shear temperature is equal to or greater than the boiling point Tb of the non-volatile liquid (if added). l and / or the boiling point Tb of the polar carrier c If the nanosizing time is sufficiently short and / or the polar carrier is in sufficient excess, the nanosizing temperature may alternatively be lower than the boiling temperature Tb. c It can be more than that.

[0055] In some embodiments of each of the third and fourth aspects, the resulting nanosuspension is a nanoemulsion, and the method includes the further step of cooling the resulting nanoemulsion to a temperature below at least one of the first or second Tm, Ts, or Tg of the CSSC. Such cooling can occur passively at the end of nanosizing, in some embodiments the temperature of the nanosuspension naturally decreases to room temperature over time, while cooling is performed by actively lowering the temperature of the nanoemulsion by any suitable cooling method. Additionally or alternatively, cooling is performed under continued shear or any other method that maintains agitation of the composition. The composition may remain a nanoemulsion after its active or passive cooling, although in some embodiments the composition may then be a nanodispersion.

[0056] In some embodiments of each of the third and fourth aspects, the method further comprises combining at least one polar carrier insoluble active agent with the CSSC(s) (and optionally the non-volatile liquid(s) and / or surfactant(s)), said combining being carried out a) while mixing the CSSC with the non-volatile liquid and / or at least one surfactant (optionally); b) by mixing the polar carrier insoluble active agent with the plasticized CSSC (optionally) prior to combining with the polar carrier; or c) while mixing the CSSC (optionally plasticized) with the polar carrier or while nanosizing the composition components to obtain nanoelements comprising CSSC, wherein the polar carrier insoluble active agent(s) is / are either included in the nanoelements (if added as in (a) or b)) or separately dispersed in the polar liquid phase (if added as in (c)).

[0057] In some embodiments of each of the third and fourth aspects, the method further comprises dissolving at least one polar carrier-soluble active agent in the polar carrier. Such dissolution of the active agent can be carried out at various stages during the preparation of the dermatological composition, depending on the resistance of the active agent to the temperature, mixing conditions or shear conditions applied in the envisaged process. A relatively resistant active agent can be added a) while combining the CSSC (or the plasticized CSSC) with the polar carrier; or b) while nanosizing the composition components to obtain nanoelements containing the CSSC. Alternatively, an active agent soluble in the polar carrier, especially in the case of a shear-sensitive active agent, can be dissolved in the obtained nanosuspension, and a relatively heat-sensitive active agent is preferably dissolved in the polar carrier of the nanoemulsion or nanodispersion after cooling.

[0058] In some embodiments of each of the third and fourth aspects, the method further comprises combining a first active agent that is insoluble in the polar carrier with the CSSC, the combining being carried out as described above, and dissolving a second active agent that is soluble in the carrier in the polar carrier as described above, thereby preparing a dermatological composition that comprises the first active agent in the nanoelements containing the CSSC and the second active agent in the polar carrier phase of the nanosuspension in which the nanoelements are dispersed.

[0059] In some embodiments of each of the third and fourth aspects, the method further comprises adding a skin penetration enhancer to the polar carrier phase of the nanosuspension. The addition of such skin penetration enhancer can be done at various stages during the preparation of the dermatological composition, and generally as described above for incorporating active agents that are soluble in the polar carrier.

[0060] In some embodiments of each of the third and fourth aspects, the CSSC, polar carrier, and, if desired for preparation of the dermatological composition, the non-volatile liquid, the surfactant, the skin penetration enhancer, the carrier-insoluble active agent, and the carrier-soluble active agent are substantially as detailed above and herein.

[0061] In this context, the compounds are classified for simplicity according to their primary role in the present invention, especially with regard to the preparation method, but it should be noted that such functions are not mutually exclusive. As an example, a non-volatile liquid that generally serves to plasticize the CSSC may also serve as a surfactant for the nanoelements; and a polar carrier (e.g., glycol) that serves as a liquid medium for the dispersed nanoelements, or a surfactant (e.g., urea) intended to enhance the dispersibility of the nanoelements, may additionally serve as a skin penetration enhancer when the composition is applied to the skin. The dominance of one role over the other may depend on the inherent efficacy of the material in the respective field, but also on the relative presence of the material in the composition. For example, a material that is considered a carrier when it constitutes a fairly abundant part of the liquid phase (e.g., more than 20 wt%) may be considered to serve a different function if its amount is relatively small, which is more suitable for its secondary role.

[0062] In some embodiments, the dermatological compositions of the present invention can be prepared according to the methods disclosed herein and can further contain any additives conventionally present in such compositions.

[0063] In a fifth aspect of the present disclosure, there is provided a use of the dermatological composition of the present invention, said use being for improving the appearance of the skin (in particular by stimulating the neosynthesis of skin structural proteins and / or preventing their degradation), which may have a cosmetic or pharmaceutical effect on the skin, generally, but not necessarily, of a mammalian subject (e.g., human).

[0064] Although the dermatological compositions of the present invention can be injected subcutaneously if necessary, their primary use is to be applied on the skin, allowing transdermal delivery of the CSSC (and any other active agents present in the composition). The compositions can be applied topically to the skin and can function as cosmetic compositions (e.g., to improve appearance, such as anti-aging treatments, skin protection treatments, skin filling treatments, skin smoothing treatments, etc.) or as pharmaceutical compositions (e.g., to alleviate or treat disorders).

[0065] For the sake of brevity, the effects of the present compositions when considered cosmetic will be termed "anti-aging" to delay, reduce or prevent skin aging, but this should not be interpreted as limiting, since similar processes that lead to natural time-dependent skin aging are encountered in further situations, such as degenerative disorders, or benign and malignant neoplasms, to name a few. Thus, for the sake of brevity, the present invention will be detailed with respect to its cosmetic role and improvement of the appearance of the skin (or postponement and / or reduction of the deterioration of the appearance), but the compositions and preparation methods disclosed herein may have a broader beneficial impact, at least in the area of ​​dermatological treatment of conditions in which one or more structural skin proteins are pathologically reduced, which may be restored by the present compositions.

[0066] Thus, the use of a dermatological composition comprising nanoelements of water-insoluble CSSC dispersed in a polar carrier as disclosed herein (optionally prepared by the method of the present teachings) should be broadly understood as the use of a cosmetic or pharmaceutical composition to achieve any desired cosmetic or pharmaceutical improvement of the skin. Such effects for which the compositions of the present invention may be beneficial are generally indicated by the improvement of the appearance of the skin (e.g., the use of the composition to reduce the number of wrinkles and / or fine lines, improve skin elasticity, improve skin tonicity, combat sagging skin, combat loose skin, combat thinning skin, combat skin pigmentation, promote wound healing, promote skin integrity, relieve pain from skin lesions, etc.), regardless of the cause of the phenomenon treated by the composition.

[0067] In other embodiments, the dermatological compositions of the present invention may be used as pharmaceutical compositions for the topical treatment of skin lesions, open wounds, inflammation or pain.

[0068] Additional objects, features, and advantages of the present disclosure will be set forth in the following detailed description, and in part will become readily apparent to those skilled in the art from the specification or will be learned by the practice of the present disclosure as set forth in the written specification and claims, as well as the accompanying drawings. Various features and subcombinations of the embodiments of the present disclosure can be employed without reference to other features and subcombinations.

[0069] Detailed Description The present invention relates to a dermatological (e.g. topical) composition comprising nanoelements, such as nanoparticles or nanodroplets, of a water-insoluble compound (especially a polymer) capable of stimulating collagen neosynthesis and / or inhibiting processes leading to collagen degradation, said nanoelements comprising a CSSC (e.g. a CSSP) dispersed as a nanosuspension in a polar carrier. Advantageously, the CSSC has a molecular weight of 0.6 kDa or more and can be optionally plasticized or swollen by a non-volatile liquid, which can also be called a plasticizer or swelling agent. The optionally plasticized nanoelements comprising a CSSC can further comprise a surfactant and / or an active agent miscible therewith to enable or increase the dispersibility of the nanoelements in the composition and / or to further enhance or modify the biological activity of the composition, respectively. Alternatively or additionally, the surfactant(s), active agent(s) and / or skin permeation enhancer(s) can be present in the polar carrier, provided they are soluble in the polar carrier. Methods for preparing such dermatological compositions and their use for cosmetic or pharmaceutical benefits are also disclosed.

[0070] Before describing at least one embodiment in detail, it is to be understood that the disclosure is not necessarily limited in its application to the particulars of construction and arrangement of the components and / or methods set forth herein. The disclosure is capable of other embodiments or of being practiced or carried out in various ways. The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting.

[0071] It is to be understood that both the foregoing general description and the following detailed description, including materials, methods, and examples, are merely exemplary of the present disclosure and are intended to provide an overview or framework for understanding the nature and character of the invention as claimed, but are not intended to be necessarily limiting.

[0072] Bioactivity and biodegradability The CSSC that can be used in the present invention is selected for its ability to promote collagen formation in the skin and / or prevent its degradation.Without wishing to be bound by a particular theory, it is believed that such compounds, when applied to the skin and penetrated, can trigger biological signals that lead to the neosynthesis of skin structural proteins.If these compounds are biodegradable, for example biodegradable polymers, the CSSC can be degraded by certain biological mechanisms and cause local inflammation.This process can induce the formation of collagen aimed at healing this inflamed area, and this newly synthesized collagen also contributes to skin firmness.

[0073] Considering the intended use, CSSCs are generally biocompatible and biodegradable in physiological environments such as those found after transdermal delivery. Suitable CSSCs may also be referred to in the general literature as bioresorbable or bioabsorbable, depending on their biological fate and expected excretion from the body, but for simplicity, all such compounds are generally referred to herein as "biodegradable". A CSSC is said to be biodegradable if, after having served its purpose, it is relatively quickly degraded (e.g., by bacterial degradation processes in the environment or by enzymatic or metabolic processes in vivo) to naturally produce by-products. Biodegradable CSSCs are known and new ones are being developed. The relevant biodegradability in various environments can be assessed by a number of methods, which, depending on the conditions of interest, may be procedures based on standards such as ASTM F1635 or procedures modified from standards.

[0074] Regardless of its tendency to degrade naturally under suitable physiological conditions, a biodegradable CSSC suitable for the present invention must have sufficient stability and durability during storage and application for its intended use, which may be particularly difficult if the use involves conditions that promote biodegradation.For example, when a topical composition containing a CSSC is spread on the skin as a thin layer, a high surface area is expected to be formed, which may increase the exposure of the resulting layer to factors (e.g., light, chemicals, or microorganisms) that promote the degradation of the CSSC before it can penetrate the skin and reach its target, and therefore the selection of a suitable CSSC for the dermatological (e.g., topical) composition of the present invention must take these factors into account.

[0075] Insoluble In addition to being biodegradable, the CSSC is preferably substantially insoluble in the liquid phase of a composition that includes a polar carrier (eg, water) and is dispersed as nanoelements in the polar carrier.

[0076] As used herein, the solubility (solubility) of a substance (e.g., a CSSC, a non-volatile liquid, or an active agent) refers to the amount of such component that can be introduced into a liquid (e.g., a polar) carrier while maintaining the transparency of the liquid medium. The solubility of a particular component of a composition in any particular liquid is generally evaluated only in the polar carrier in the absence of other possible components of the composition, but may alternatively be determined with respect to the final composition of the liquid phase including the carrier.

[0077] A CSSC (or any other substance involved in the present invention) is considered insoluble if its solubility in a polar carrier or a liquid phase containing it is 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.5 wt% or less, or 0.1 wt% or less based on the weight of the carrier or liquid phase. For example, a substance that is insoluble in a polar carrier will dissolve no more than 5 g in 100 g of carrier. This substantial insolubility is generally measured at room temperature, but should preferably apply at any temperature at which the components are combined and processed, i.e., even at relatively high temperatures, and the solubility of these compounds in the polar carrier must remain within the required range. Substances that meet these conditions can be called "polar carrier insoluble" substances.

[0078] The insolubility of such materials is expected to prevent dissolution of one or more of the CSSC (or any other one of the nanoelement components of an optionally plasticized CSSC mixture, or a CSSC mixture further comprising a surfactant and / or a carrier insoluble active agent) into the surrounding medium, which, if the material is soluble in the polar carrier, may affect the relative proportions of the nanoelement components, their size, or other such parameters that may ultimately adversely affect the efficacy of the composition.

[0079] Regardless of the composition of the polar liquid phase, including the polar carrier in which the CSSC is dispersed as nanoelements, the CSSC can be primarily characterized as being water insoluble (i.e., having a generally established solubility in water of less than 5 wt % at room temperature).

[0080] molecular weight Advantageously, the present invention allows the delivery of CSSCs with relatively high molecular weights, compared to compounds that may conventionally penetrate the skin barrier sufficiently to show some efficacy.The CSSCs suitable for the compositions, methods and uses of the present invention can have a molecular weight (MW) of 0.6 kDa or more, 0.7 kDa or more, 0.8 kDa or more, 0.9 kDa or more, or 1 kDa or more, and CSSPs also exhibit a molecular weight (MW) of 2 kDa or more, 5 kDa or more, or 10 kDa or more.Generally, if the compound is not polymeric, its molecular weight does not exceed 2 kDa, and CSSPs reach a molecular weight of up to 500 kDa, and generally are 300 kDa or less, 200 kDa or less, 100 kDa or less, 80 kDa or less, 50 kDa or less, 25 kDa or less, or 15 kDa or less. In another embodiment, the molecular weight of the CSSC is between 0.6 kDa and 500 kDa, between 0.7 kDa and 300 kDa, between 0.8 kDa and 200 kDa, between 1 kDa and 100 kDa, or between 2 kDa and 80 kDa.

[0081] As used herein, the term "molecular weight" (or "MW") refers to the actual molecular weight that can be calculated for a non-polymeric CSSC, which can be expressed in grams / mole, or it refers to the weight average MW of a CSSP, which may be a mixture of polymers each containing slightly different numbers of repeat units, the weight average MW of a polymer being generally expressed in Daltons.

[0082] The molecular weight of the CSSC may be provided by its supplier or may be independently determined by standard methods including, for example, gel permeation chromatography, high pressure liquid chromatography (HPLC), size exclusion chromatography, light scattering or matrix-assisted laser desorption / ionization time-of-flight mass spectrometry MALDI-TOF MS, some of which are described in ASTM D4001 or ISO 16014-3.

[0083] Characterization Temperature While most non-polymeric compounds can be characterized by the melting temperature at which they change from a solid to a liquid phase, polymeric compounds can additionally or alternatively be defined by a glass transition temperature in the case of amorphous and purely amorphous polymers that have no Tm. Purely crystalline polymers can be characterized by their Tm, and semi-crystalline polymers often exhibit two characterization temperatures (e.g., Tg and Tm) that reflect the respective proportions of amorphous and crystalline parts in the molecule. Such polymers can also be defined by a softening temperature Ts midway through the log steps to melting. Since the glass transition temperature represents the transition from a glassy to a rubbery state and the softening temperature represents an intermediate inflection point in the thermal analysis of a material, these temperatures generally relate to the temperature range or temperature at which the process will first be observed.

[0084] Thus, depending on the chemical nature of the CSSC, the temperatures that may characterize its thermal behavior may be at least one of the melting temperature (Tm), the softening temperature (Ts) and the glass transition temperature (Tg). Thus, when a CSSC is defined as having at least one of a first and / or second Tm, Ts and Tg within a certain range, the temperatures considered are those related to the substance. Some compounds may be identified by two such characterizing temperatures, in which case carrying out a step of the method at a temperature above any of the two temperatures may be able to exceed the lowest of the two temperatures (which would prolong the step) or the highest of the two temperatures (which would accelerate the step). Conversely, carrying out a step of the method at a temperature below any of the two temperatures may be below the highest or below the lowest of the two temperatures. As an example, taking a semi-crystalline polymer characterized by all three temperatures, in decreasing order Tm, Ts, or Tg, heating above Tg (i.e., above at least one) may be insufficient to reach Ts or Tm, while heating above Ts (i.e., above at least two) may be insufficient to reach Tm. Only heating above Tm will ensure that the heating temperature is greater than all three temperatures that may characterize such an exemplary polymer.

[0085] In some embodiments, the CSSC suitable for the present composition is characterized by at least one of a melting temperature (Tm), a softening temperature (Ts), or a glass transition temperature (Tg) of at least 20° C., at least 30° C., at least 40° C., at least 50° C., or at least 60° C. In other embodiments, at least one of the Tm, Ts, and Tg of the CSSC is at most 300° C., at most 250° C., at most 200° C., at most 180° C., at most 150° C., or at most 120° C. In some embodiments, at least one of the Tm, Ts, and Tg of the CSSC is from 20° C. to 300° C., from 20° C. to 250° C., from 20° C. to 200° C., from 30° C. to 180° C., from 40° C. to 150° C., or from 50° C. to 120° C. Such thermal properties of a CSSC may be provided by its manufacturer or may be determined independently by standard methods, such as thermal analysis methods, such as differential scanning calorimetry (DSC) as described in ASTM 3418, ISO 3146, ASTM D1525, ISO 11357-3, or ASTM E1356. The characterization temperature (Tm, Ts, or Tg) of a CSSC may be referred to as the "first" Tm, Ts, or Tg when referring to a natural / unmodified compound, or as the "second" Tm, Ts, or Tg when referring to a CSSC that has been modified, for example by mixing with a non-volatile liquid resulting in a plasticized or swollen CSSC.

[0086] Polymer CSSC and non-polymer CSSC In some embodiments, the collagen synthesis stimulating compound (CSSC) used in the compositions, methods and uses is a collagen synthesis stimulating polymer (CSSP). Since it is desirable for CSSPs to be adapted for biodegradation once delivered to the physiological environment of the skin (e.g., under the skin), such polymers generally contain hydrolyzable functional groups.

[0087] Suitable CSSPs, which may be of natural or synthetic origin, are thermoplastic in nature and their shape can be reversibly changed by appropriate heating and cooling. Suitable CSSPs can also be plasticized with suitable non-volatile liquids, and optional processing of such CSSPs facilitates their nanosizing to an extent that facilitates transdermal delivery of dispersed nanocomponents.

[0088] The synthetic CSSPs can be selected from aliphatic polyesters, polyhydroxy-alkanoates, poly(alkene dicarboxylates), polycarbonates, aliphatic-aromatic copolyesters, enantiomers thereof, copolymers thereof, and combinations thereof.

[0089] As long as the monomers forming the CSSP have a chiral center, all enantiomers and stereoisomers are included. For example, lactic acid (2-hydroxypropionic acid, LA) has two enantiomers, L-lactic acid and D-lactic acid, so PLA has stereoisomers such as poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), and poly(DL-lactide) (PDLLA). Thus, CSSPs are mixtures of isomers of the same molecule, or specific stereoisomers (or stereocopolymers).

[0090] In some embodiments, the CSSP is selected from the group including: aliphatic polyesters such as polycaprolactone (PCL), polylactic acid (PLA), poly(L-lactide) (PLLA), poly(D-lactide) (PDLA), poly(D,L-lactide) (PDLLA), polyglycolic acid (PGA), poly(lactic-co-glycolic acid) (PLGA), and poly(p-dioxanone) (PPDO); polyhydroxybutyrate (PHB) (e.g., poly-3-hydroxybutyrate (P3HB), poly-4-hydroxybutyrate (P4HB), poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), polyhydroxyvalerate (PHV), polyhydroxyhexanoate (PHH), and polyhydrazine (DHA). polyhydroxyalkanoates (PHAs) including polyhydroxyoctanoate (PHO); poly(alkene dicarboxylates) such as poly(butylene succinate) (PBS), poly(butylene succinate-co-adipate) (PBSA), and poly(ethylene succinate) (PES); polycarbonates such as poly(trimethylene carbonate) (PTMC), poly(propylene carbonate) (PPC), and poly-[oligo(tetramethylene succinate)-co(tetramethylene carbonate)]; aliphatic-aromatic copolyesters such as poly(ethylene terephthalate) (PET) and poly(butylene adipate-co-terephthalate) (PBAT); isomers thereof, copolymers thereof, and combinations thereof.

[0091] In certain embodiments, the CSSP is or includes an aliphatic polyester, isomer, copolymer, and combinations thereof. In more specific embodiments, the CSSP is PCL. In yet other specific embodiments, the CSSP is PLA.

[0092] Such polymers can be identified by their respective characteristic functional groups detectable by standard methods known to those skilled in the art, such as Fourier transform infrared spectroscopy (FTIR).

[0093] Non-polymeric CSSCs suitable for the compositions, methods and uses of the present invention include quinones, hi certain embodiments, the non-polymeric CSSC is coenzyme Q10 (CoQ10).

[0094] Furthermore, the CSSC can be a mixture of different compounds, polymerizable or not, whose properties (e.g., characterizing temperature, viscosity, etc.) meet the ranges set for the appropriate individual compounds. For example, a CSSC or CSSP whose Tm, Ts or Tg are outside the ranges previously considered suitable (e.g., below 20° C. or above 300° C.) can be combined with a CSSC or CSSP whose Tm, Ts or Tg are adapted to "correct" the characterization temperature of the resulting mixture to be suitable for the purposes of the present invention. By way of example, the CSSC can be a mixture or copolymer of polymers comprising at least one of the aforementioned CSSPs, such copolymers can contribute to the biocompatibility, biodegradability, and mechanical and optical properties of the nanoelements.

[0095] viscosity Alternatively (or additionally), CSSCs can be selected for their viscosity to suit the shear in the method of the present invention for preparing a dermatological composition. CSSCs suitable for the method, composition and use of the present invention are generally selected for their viscosity at a temperature of 50° C. and a shear rate of 10 s -1 When measured at 10 11 Not exceeding 5×10 millipascal·seconds (mPa·s, equivalent to centipoise) 10 mPa·s or less, 10 10 mPa·s or less, 5×10 9 mPa·s or less, 10 9 mPa·s or less, 5×10 8 mPa·s or less, 10 8 mPa·s or less, 5×10 7 mPa·s or less, 10 7 mPa s or less, or 5×10 6 They can have viscosities that are often less than or equal to mPa·s.

[0096] For efficient shearing, the viscosity of the CSSC is preferably at a temperature of 50°C and a shear rate of 10 s -1 In 10 7 The viscosity should be less than or equal to mPa·s. Such a viscosity may be related to the natural properties of the isolated unmodified CSSC, in which case it may be called the "first viscosity", or it may refer to the viscosity of a CSSC modified by mixing it with a miscible substance, in which case it may be called the "second viscosity" of the CSSC. As an example, the second viscosity may be the viscosity of a CSSP plasticized with a suitable non-volatile liquid. The viscosity of a material (with or without modification by the presence of other substances) at any temperature of interest (or range) can be measured by conventional thermorheological analysis, such as those described in ASTM D3835 or ASTM D440.

[0097] Non-volatile liquids can be added to the CSSC or CSSP regardless of their natural viscosity, but such substances should be added at temperatures below 50°C and a shear rate of 10 s -1 At 10 7 Typically used in the present compositions or methods is a non-volatile liquid having a relatively high first viscosity, such as greater than mPa·s. A non-volatile liquid (sometimes called a plasticizing liquid or swelling liquid) is contained in the nanoelements comprising the plasticized or swollen CSSC, and the liquid is typically absorbed or retained by the CSSC.

[0098] Such "plasticization" or "swelling" generally results in an increase in weight and / or volume compared to the mass or volume of the CSSC itself in its native form. Such plasticization of the CSSC makes the plasticized CSSC softer and more malleable, as indicated by a decrease in its viscosity (i.e., the second viscosity is less than the first viscosity), facilitating subsequent nanosizing to an extent that facilitates transdermal delivery of the resulting nanoelements.

[0099] Advantageously, the reduced viscosity should be compatible with the shear process (e.g., shear device, shear temperature, etc.) selected to nanosize the plasticized CSSC (e.g., plasticized CSSP). For example, the non-volatile liquid and its ratio to the CSSC can be selected to reduce the viscosity of the CSSC by at least half a logarithm, or at least one logarithm, as appropriate. For example, at a temperature of 50° C. and a shear rate of 10 s -1 When measuring with CSSC, 8 mPa s, the CSSC plasticized in this way has a first viscosity of 5 × 10 7 mPa·s, or (if a higher amount or alternatively a stronger agent is selected) the plasticizing agent and its amount allow a half log reduction in the viscosity of the CSSC so plasticized. 7 This would allow for a one log reduction in the case of a second viscosity of 10 ...

[0100] In some embodiments, the second viscosity of the CSSC plasticized with a non-volatile liquid is greater than or equal to 10 s at 50° C. -1 When measured at a shear rate of 10 2 mPa s~10 7 mPa s, 5×10 2 mPa s~10 6 mPa s, 5×10 2 mPa s~10 5 mPa s, 10 3 mPa s~5×10 4 mPa s or 10 3 mPa s~10 4 Viscosity is measured in mPa·s. Viscosity can be measured with any suitable rheometer equipped with a spindle suited to the viscosity range of interest at the appropriate shear rate.

[0101] plasticization The effect on the viscosity of CSSCs has been described above, but to the extent that a reduction in viscosity is desired, non-volatile liquids that can be incorporated into CSSCs in nanoelements may perform an additional function. Swelling, and in particular the swelling of CSSPs, can be observed visually when the swollen polymer is at a temperature below its melt. At higher temperatures, the effect of non-volatile liquids can be detected through their plasticizing activity, which includes the ability to lower at least one of the temperatures that characterize native CSSCs.

[0102] The lowering of the characterization temperature of the CSSC allows the corresponding lowering of the processing temperature at which the dermatological composition can be prepared. For example, the CSSC may have a first (native) Tm, Ts or Tg of 200°C or less in the absence of a suitable non-volatile liquid, but the addition of such a plasticizing agent allows the formation of a plasticized CSSC having a second (modified) Tm, Ts or Tg lower than the first temperature, for example 95°C or less. The temperature reduction brought about by the presence of a non-volatile liquid does not have to be as dramatic as described and clearly depends on the first Tm, Ts or Tg value of the natural CSSC, the second Tm, Ts or Tg that may be desired to facilitate the preparation of the composition and / or subsequent infiltration of nanoelements, preferably on the boiling temperature (Tb) of the liquid remaining present in the composition (but not necessarily if the process is short enough and / or there is an excess of liquid in case some of it boils off and evaporates), and / or on the concentration of the plasticizing agent relative to the compound to be plasticized.

[0103] Thus, additionally and / or alternatively, if the mixture of CSSC(s) and non-volatile liquid(s) further comprises ingredients which, due to forming the nanoelements or being present within the nanoelements, may affect the softening properties of the resulting combination (e.g. rheology modifiers, surfactants, preservatives, or any similar substances which may have a plasticizing effect), the thermal properties considered suitable for the present invention will apply to the mixture as a whole.

[0104] Thus, in some embodiments, the plasticized CSSC, or mixture of components comprising same, has at least one of Tm, Ts, and Tg in the range of 0° C. to 290° C., 10° C. to 250° C., 20° C. to 200° C., 30° C. to 180° C., 40° C. to 150° C., or 50° C. to 120° C. Such thermal behavior and characterization temperatures can be assessed during the preparation of the plasticized CSSC or mixture comprising same, or upon completion of the process for preparing the composition.

[0105] Non-volatile plasticizing liquid Although the role that the presence of a non-volatile liquid may have in the effectiveness of the delivery of nanoelements, including CSSC, cannot be ignored, the selection of such a substance is primarily considered from the perspective of improving the processability of the CSSP so as to facilitate the preparation and dispersion of the nanoelements in the polar carrier phase. In particular, suitable non-volatile liquids are capable of both reducing the viscosity of the CSSC and reducing at least one of Tm, Ts, and Tg, as described elsewhere above. Advantageously, suitable non-volatile liquids improve the processability of the CSSC under conditions suitable for shearing into nanoparticles, the shear temperature of which initially causes the formation of nanodroplets.

[0106] First, as the name suggests, the agent suitable for plasticizing the CSSC according to the present teachings is liquid at the temperature at which the CSSC is processed, i.e., at least one of the mixing temperature with the CSSC and the shear temperature. Such liquid agents can also be liquid at room temperature.

[0107] To ensure their effect is permanent, the plasticizing liquid is preferably non-volatile. As used herein, the term "non-volatile" as may be used with respect to a liquid capable of plasticizing the CSSC refers to a liquid that exhibits a low vapor pressure, such as less than 40 Pascal (Newtons per square meter) at a temperature of about 20°C. Such vapor pressure values ​​are usually provided by the liquid manufacturer, but can be independently determined by standard methods such as those described in ASTM D2879, E1194, or E1782, depending on the range of vapor pressure. The low or substantially zero volatility of the non-volatile liquid that may be used to plasticize the CSSC must be maintained, if desired, at the highest temperature at which the plasticized CSSC is processed. The use of such a non-volatile liquid allows the CSSC to remain in a plasticized or swollen state without risk of evaporation or removal of this liquid, even at the high temperatures at which the dermatological composition is prepared by the method of the present invention.

[0108] Suitable non-volatile liquids are also characterized by having a boiling point above room temperature, above body temperature and above the elevated temperatures that may be desired for the preparation of the composition, since it is preferred that the liquid selected to plasticize the CSSC of the present invention does not substantially evaporate during or after the preparation of the dermatological composition. However, some boiling and evaporation may be acceptable if the mixing step in which the non-volatile liquid plasticizes the CSSC is short enough to ensure that it remains as desired and / or if a sufficient excess of the non-volatile liquid is added to compensate for the possibility that boiling and partial evaporation may occur.

[0109] For similar reasons that non-polar liquids are desired to be retained by the CSSC plasticized thereby and to be retained in the nanoelements containing them, they should preferably be unable to migrate into the polar carrier phase. Suitable non-volatile liquids are therefore essentially immiscible in such polar carriers (e.g., water) and have a solubility in the pure polar carrier or liquid phase containing it as detailed above for the CSSC, i.e. 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.5 wt% or less, or 0.1 wt% or less by weight of the carrier or phase containing it.

[0110] Such non-volatile liquids must be compatible with the CSSC of the composition (i.e., capable of plasticizing the composition: e.g., lowering its Tm, Ts or Tg and / or lowering its viscosity). Non-volatile liquids compatible with a particular CSSC can be selected by routine experimentation. For example, given a particular CSSC, various non-volatile liquids can be mixed with it in one or more relative concentrations, and their effect on the plasticized CSSC can be monitored by thermorheology (for their ability to lower the viscosity as a function of temperature) and thermal analysis (e.g., by DSC, for their ability to lower the Tm, Ts or Tg of the native CSSC). The most potent non-volatile liquids for a particular CSSC can be selected by routine experimentation.

[0111] Essentially, a substance or chemical composition is compatible with another substance or chemical composition if it does not interfere with its activity or reduce its activity to such an extent that it does not significantly affect its intended purpose. Such compatibility can be from a chemical standpoint, for example, by sharing similar chemical functional groups, or by each substance having respective moieties that may interact favorably with each other. This type of compatibility can be demonstrated by the combined substances forming a homogenous mixture rather than separating into different phases. The substance must also be compatible with the method used to prepare the composition, and not be adversely affected by any of the steps at which it will be processed, and not be a volatile substance (or otherwise excluded) at the temperature(s) at which it will be introduced into the composition. Of course, the substance must also be compatible with its intended use, which in this case may include, by way of example, being biocompatible, non-irritating, non-immunogenic, and any such properties that will obtain regulatory approval at concentrations compatible with an effective cosmetic or pharmaceutical composition as disclosed herein.

[0112] Non-volatile liquids suitable for the present invention can be selected from the following: mono- or polyfunctional aliphatic esters (e.g., ethyl acetate, butyl lactate, dimethyl glutarate, dimethyl maleate, dimethyl methyl glutarate, ethyl lactate and isoamyl lactate, etc.); fatty esters (e.g., 2-ethylhexyl lactate, acetyl tributyl citrate, acetyl triethyl citrate, acetyl triethylhexyl citrate, allyl hexanoate, benzyl benzoate, butyl butyryl lactate, C benzoate, etc.); 12 ~C 15Alkyl, Caprylyl Caprate and / or Caprylyl Caprylate Mixture, Decyl Oleate, Dibutyl Adipate, Dicaprylyl Carbonate, Dibutyl Maleate, Dibutyl Sebacate, Diethyl Succinate, Ethyl Oleate, Glyceryl Monooleate, Glyceryl Monocaprate, Glyceryl Tricaprylate, Glyceryl Trioctanoate, Isopropyl Myristate, Isopropyl Palmitate, L-Menthyl Lactate, Lauryl Lactate, n-Pentyl Benzoate, PEG-6 Caprylic / Capric Glyceride, Propylene Glycol Monolaurate, Propylene Glycol Monocaprylate, Triacetin, Triethyl Citrate, Triethyl O-Acetyl Citrate, Tris(2-ethylhexyl) O-Acetyl Citrate, O-Acetyl Citric Acid tributyl, and tributyl citrate); cyclic organic esters (e.g., decanoic acid lactone, gamma-decalactone, menthalactone, and undecanoic acid lactone); fatty acids (e.g., caprylic acid, cyclohexanecarboxylic acid, isostearic acid, lauric acid, linoleic acid, linolenic acid, myristic acid, oleic acid, palmitic acid, and stearic acid); terpenes (e.g., citronellol, eugenol, farnesol, hinokitiol, D-limonene, linalool, menthol, menthone, neridol, terpineol, and thymol); aromatic alcohols (e.g., benzyl alcohol); aromatic ethers (e.g., methoxybenzene); aldehydes (e.g., cinnamaldehyde); and combinations thereof.

[0113] In certain embodiments, non-volatile liquids that can be used to plasticize the CSSCs disclosed herein are polyfunctional aliphatic esters (PFAEs), which are diester derivatives of common dicarboxylic acids: adipic acid (C6), azelaic acid (C9), and sebacic acid (C10), which are diester derivatives of common dicarboxylic acids: adipic acid (C11), azelaic acid (C12), and sebacic acid (C13). 10 ), and the alcohol portion of the diester is generally a C3-C6 alcohol, including linear and branched chain, even and odd numbered alcohols. 20Dibutyl adipate (e.g., commercially available as Cetiol® B) is an example of a PFAE suitable for plasticizing CSSCs, particularly CSSPs, according to one embodiment. Another suitable example is C 12 ~C 15 Included are alkyl benzoates (commercially available, for example, as Pelemol® 256) and dicaprylyl carbonate (commercially available, for example, as Cetiol® CC).

[0114] Polar Medium The liquid medium forming the continuous phase in which the nanoelements, including the CSSC, are dispersed is polar. In some embodiments, the liquid phase consists essentially of the polar carrier, while in other cases additional components may be present in the polar carrier. Such additional components may be, for example, surfactants, carrier-soluble active agents, or skin penetration enhancers, or other additives conventionally provided in dermatological compositions, as detailed herein. Polar carriers suitable for the present invention may be selected from the group including water, glycols (e.g., propylene glycol, dipropylene glycol, and 1,2-butanediol, 1,3-butanediol, 1,4-butanediol, 2-ethyl-1,3-hexanediol, and 2-methyl-2-propyl-1,3-propanediol), glycerols, including glycerol, precursors and derivatives thereof (e.g., acrolein, dihydroxyacetone, glyceric acid, tartronic acid, epichlorohydrin, glycerol tertiary butyl ether, polyglycerol, glycerol esters, and glycerol carbonate), and combinations thereof.

[0115] The polar medium may be formed from one or more suitable polar carriers, and when water is the predominant polar carrier, the resulting liquid is often referred to as an aqueous solution (or aqueous phase). In some cases, liquids that are not sufficiently polar to form the entire polar liquid phase can be present in the liquid phase in addition to the polar carrier(s) provided that a) they are soluble in the predominant polar carrier (e.g., have a water solubility of 5 wt% or more), thereby forming a unique liquid phase, and b) the overall polarity of the liquid phase is maintained, as well as liquids that are not considered sufficiently polar by themselves (such as fatty alcohols). The polarity index of the resulting liquid phase may be 3 or more, 4 or more, or 5 or more, with water having a polarity index of 9-10 being cited as a reference.

[0116] The polarity index of a solvent refers to its relative ability to dissolve a test solute; additionally or alternatively, the liquid may be characterized by its dielectric constant (ε r ) of the liquid. In general, liquids with a dielectric constant below 15 are considered non-polar, liquids with a higher dielectric constant are considered polar, and the relative polarity of the liquid increases with the value of the dielectric constant. Preferably, polar carriers suitable for the compositions of the present invention have a dielectric constant established at room temperature of 20 or more, 30 or more, 40 or more, 50 or more, or 60 or more. For example, propylene glycol has a dielectric constant of 32, glycerol has a dielectric constant of 46, and water has a dielectric constant of 80. For simplicity, this guidance is provided for the net polar carrier, but in practice this should preferably be applied to the entire polar liquid phase (e.g., including additional polar soluble materials and / or consisting of a mixture of liquid carriers) prepared therewith. Obviously, polar liquid phases should be considered to be polar in nature, with each volume being considered to render the entire liquid phase polar (e.g., ε r ≧15) r ≥ 15) and formally nonpolar solvents (e.g., ε r <15). The dielectric constant of the liquid is typically provided by the manufacturer, but can be independently determined by any suitable method, such as those described in ASTM-D924.

[0117] As discussed, the composition of the polar liquid phase must be such that the nanoelements, including the CSSC, are essentially water insoluble and can remain stably dispersed therein, and the nanoelement contents do not significantly leach into the surrounding medium.

[0118] The polar medium may include additional liquids and / or substances dissolved therein, so that the polar carrier may constitute at least 50 wt%, at least 60 wt%, at least 70 wt%, at least 80 wt%, or at least 90 wt%, by weight of the liquid phase.

[0119] In certain embodiments, the polar carrier comprises water (e.g., 45 wt.% water, 45 wt.% propylene glycol, and 10 wt.% fatty alcohol), consists of water (e.g., comprises 51 wt.% to 80 wt.% water), consists essentially of water (e.g., comprises 81 wt.% to 99 wt.% water), or is water.

[0120] Surfactants Some CSSCs may remain nano-dispersed in the dermatological composition in view of their inherent chemical properties, for example the nanoelements have a sufficient charge to ensure particle repulsion, thus ensuring a stable dispersion. Other CSSCs may alternatively or additionally remain nano-dispersed in view of being plasticized to a sufficient extent by a non-volatile liquid that also functions as a surfactant. However, in some embodiments the composition may further comprise at least one surfactant in order for the nanoelements to remain dispersed (and therefore also within the intended size range).

[0121] Surfactants suitable for the purposes of the present invention reduce the surface tension between the nanoelements containing the CSSC and the environment they are immersed in. The surfactant, depending on its chemical formula (and depending on the CSSC and polar carrier considered), can be miscible with the CSSC or polar carrier to form a nanosuspension.

[0122] Surfactants suitable for the compositions and methods of the present invention are generally amphiphilic, containing a polar or hydrophilic portion and a non-polar or hydrophobic portion. Such surfactants may be characterized by a Hydrophilic-Lipophilic Balance (HLB) value ranging from 1 to 35, where the HLB value generally indicates the affinity for aqueous systems, and is generally provided on the Griffin scale.

[0123] Surfactants suitable for the purposes of the present invention may be anionic surfactants, cationic surfactants, amphoteric surfactants, or non-ionic surfactants.

[0124] The anionic surfactants may be selected from the group including: alkyl sulfates (such as sodium lauryl sulfate, ammonium lauryl sulfate, and ammonium laureth sulfate); sulfosuccinates (such as disodium lauryl sulfosuccinate, disodium laureth sulfosuccinate, sodium dioctyl sulfosuccinate, and mixtures thereof with sulfonic acids and lauramidopropyl betaine); alkyl benzene sulfonates (such as sodium tosylate, cumene sulfonate, toluene sulfonic acid, xylene sulfonic acid, cumene sulfonic acid and their salts (such as sodium, potassium, acyl methyl taurate salts (e.g., sodium methyl lauroyl taurate and sodium methyl cocoyl taurate); acyl sarcosinate salts (e.g., sodium lauroyl sarcosinate, sodium cocoyl sarcosinate, and sodium myristoyl sarcosinate); isethionate salts (e.g., sodium butyl isethionate, sodium capryloyl isethionate, and sodium lauroyl isethionate); propyl peptide condensates; monoglyceride sulfates; ether sulfonates, and fatty acid salts (e.g., sodium stearoyl lactylate).

[0125] The cationic surfactants can be selected from the group including: quaternary ammonium compounds (such as benzalkonium chloride, stearalkonium chloride, centrimonium chloride, and trimethylammonium methyl sulfate).

[0126] The amphoteric surfactant may be selected from the group including: betaines (e.g., cocamidopropyl betaine); alkyl amphopropionates (e.g., cocoamphopropionate); alkyl iminopropionates (e.g., sodium lauraminopropionate); and alkyl amphoacetates (e.g., cocoampho-carboxyglycinate).

[0127] The non-ionic surfactant may be selected from the group including: fatty alcohols (e.g., cetearyl alcohol); ethoxylated fatty alcohols (e.g., C8-C 18alcohol polyglycols, polyoxyl 6 stearate, and polyoxyl 32 stearate; poly(ethylene glycol) block copolymers (e.g., poloxamers); ethylene oxide (EO) / propylene oxide (PO) copolymers; alkylphenol ethoxylates (e.g., octylphenol polyglycol ether and nonylphenol polyglycol ether); alkyl glucosides and polyglucosides (e.g., lauryl glucoside); fatty alkanolamides (e.g., lauramide diethanolamine and cocamide diethanolamine); ethoxylated alkanolamides; ethoxylated fatty acids; sorbitan derivatives (e.g., polysorbates, sorbitan laurate, sorbitol, sorbitol esters ... tocopherol, 1,4-sorbitan, isosorbide, and 1,4-sorbitan triesters, PEG-80); alkyl carbohydrate esters (e.g., sucrose fatty acid monoesters); amine oxides; ceteareth; oleth; alkyl amines; fatty acid esters (e.g., ascorbyl palmitate, ethylene glycol stearate, polyglyceryl-6 esters, polyglyceryl-6 pentaoleate, polyglyceryl-10 pentaoleate, and polyglyceryl-10 pentaisostearate); polyoxylglycerides (e.g., oleyl polyoxyl-6 glyceride); natural oil derivatives; ester carboxylates (e.g., D-α-tocopherol polyethylene glycol succinate (vitamin E TPGS)); and urea.

[0128] These surfactants are classified into emulsifiers and hydrotropes depending on their mechanism of action. Emulsifiers tend to form micelles (and are therefore characterized by a critical micelle concentration (CMC) value), which is believed to enhance the dispersibility of the CSSC (or plasticized CSSC) when it is subsequently combined with a polar carrier to obtain a nanosuspension. In principle, emulsifiers generally refer to surfactants that ensure the dispersion of one liquid in another liquid, the liquid having the opposite polarity, whereas dispersants refer to surfactants that ensure the dispersion of a solid in a liquid. Since the method can provide nanoemulsions and nanodispersions, surfactants that are called emulsifiers in the process where the nanosuspension is an emulsion can actually become dispersants to the extent that the initial nanoemulsion later produces a nanodispersion at low temperature. Thus, as used herein, the term "emulsifier" also includes surfactants otherwise known as dispersants.

[0129] Emulsifiers that are lipophilic in nature, i.e., contain a relatively large hydrophobic portion, are more suitable for combination with CSSCs (and any other substances that are not miscible in polar carriers, e.g., non-volatile liquids), and therefore may be referred to as polar carrier insoluble emulsifiers (or generally surfactants). Thus, such relatively hydrophobic emulsifiers are expected to be present in the nanoelements of the present compositions. These relatively hydrophobic emulsifiers generally have an HLB value of 9 or less, 8 or less, 7 or less, or 6 or less on the Griffin scale.

[0130] Emulsifiers that are more hydrophilic by nature have a relatively large hydrophilic portion and therefore have a higher affinity for the polar phase of the composition, and therefore may be referred to as polar carrier soluble emulsifiers (or generally surfactants). Such relatively hydrophilic emulsifiers generally have an HLB value of 11 or more, 13 or more, 15 or more, 17 or more, or 20 or more.

[0131] Emulsifiers with HLB values ​​in the range of 9-11 are considered "intermediate" and the hydrophobic and hydrophilic portions of such emulsifiers are very well balanced. Such intermediate emulsifiers can be added to either the CSSC or the polar carrier in the present method and can be found in the nanoelements or their medium accordingly, and the ability of some of such surfactants to migrate between the two phases is also envisaged.

[0132] In certain embodiments, the surfactant that functions as an emulsifier is selected from the following: vitamin E TPGS, poly(ethylene glycol) block copolymers; polyoxyl 6 stearate (type I), a mixture of ethylene glycol stearate and polyoxyl 32 stearate (type I) (e.g., commercially available as Tefose® 63, Gattefosse, France), a mixture containing an extract derived from olive oil (e.g., commercially available under the trademark Olivatis®, Medolla Iberia, Spain), ascorbyl palmitate, polyglyceryl-10 pentaoleate, polyglyceryl-10 pentaisostearate, oleoyl polyoxyl-6 glycerides (e.g., commercially available as Labrafil® M 1944 CS, Gattefosse, France), disodium laureth sulfosuccinate; disodium lauryl sulfosuccinate, C 14 ~C 16 Mixtures of sodium olefin sulfonate and lauramidopropyl betaine (for example, commercially available as Cola® Det EQ-154, Colonial Chemical, USA), and mixtures of olive oil and glutamic acid (for example, commercially available as Olivoil® glutamate, Kalichem, Italy).

[0133] While surfactants acting as emulsifiers are generally sufficient to stabilize the nanoelements of the compositions of the present invention, the inventors have found that when the CSSC is present in relatively high concentrations, as enabled by the present invention, the addition of another type of surfactant, i.e., a hydrotrope, helps to achieve satisfactory stability.

[0134] Hydrotropes are also amphiphilic molecules, but in contrast to emulsifiers, they contain relatively short lipophilic chains. Because the lipophilic portion of the hydrotrope is generally too short to allow micelle formation, the hydrotrope instead solubilizes hydrophobic compounds in the polar carrier, allowing co-emulsification with the emulsifier. In general, hydrotropes are characterized by being miscible primarily in the polar carrier phase (e.g., the aqueous phase) of the nanosuspension and having an HLB value of 10 or more, 12 or more, 15 or more, or 18 or more.

[0135] Suitable hydrotropes may be selected from the group including: sodium dioctyl sulfosuccinate, urea, sodium tosylate, adenosine triphosphate, cumene sulfonate, toluene sulfonic acid, xylene sulfonic acid, cumene sulfonic acid, and salts thereof.

[0136] In certain embodiments, the hydrotrope is selected from sodium dioctyl sulfosuccinate, urea, xylene sulfonates such as ammonium xylene sulfonate.

[0137] Activator While the dermatological compositions of the present invention may be biologically active by virtue of the presence of the CSSC per se, their use may be enhanced and / or modified by the inclusion of active agents with similar functions to enhance efficacy, and / or active agents with different functions to broaden the range of efficacy.

[0138] In some embodiments, the dermatological composition further comprises one or more polar carrier-insoluble active agent(s). Such carrier-insoluble active agents are generally contained within the nanoelements because they are miscible with the components contained therein, i.e., the CSSC, and any non-volatile liquids and emulsifiers. The components of the nanoelements are miscible with each other when forming a unique phase.

[0139] In some embodiments, as with the CSSC and non-volatile liquids described above, any carrier-insoluble active agent should have a solubility of 5 wt % or less, 4 wt % or less, 3 wt % or less, 2 wt % or less, 1 wt % or less, 0.5 wt % or less, or 0.1 wt % or less, based on the weight of the polar carrier or liquid phase containing it.

[0140] Carrier insoluble active agents incorporated into the nanoelements can include benzoyl peroxide, erythromycin, macrolides, retinol, salicylic acid, tetracycline, tretinoin, vitamin A, vitamin D, and vitamin K, and in a particular embodiment, the carrier insoluble active agent is retinol.

[0141] In some embodiments, the dermatological composition further comprises one or more polar carrier soluble active agents that will dissolve in the polar carrier.

[0142] Exemplary active agents that are carrier soluble and may be present in the polar liquid phase of the composition may be selected from the following: azelaic acid, biotin, clindamycin, collagen, elastin, folacin, hyaluronic acid (HA), niacin, pantothenic acid, riboflavin, thiamine, vitamin B12, vitamin B6, and vitamin C. In certain embodiments, the carrier soluble cosmetic active agent is HA.

[0143] In some embodiments, both low molecular weight (LMW) HA, i.e., HA with a MW less than 500 kDa, and high molecular weight (HMW) HA, i.e., HA with a MW greater than 500 kDa, can be used. In some embodiments, the HA is LMW HA with a MW of 400 kDa or less, 300 kDa or less, 200 kDa or less, or 100 kDa or less. In certain embodiments, the LMW HA has a molecular weight of 50 kDa or less, 25 kDa or less, or 10 kDa or less.

[0144] In some embodiments, the dermatological composition can include both carrier-insoluble and carrier-soluble active agents.

[0145] Plant extracts that function as active agents can also be added to the composition, and can be either carrier insoluble or carrier soluble. As used herein, the term "plant extract" refers to both natural fractions isolated from any relevant part of any suitable plant (e.g., flowers, fruits, herbs, leaves, skins, roots, seeds, stems, etc.) and synthetic forms of the active agents of natural extracts. Plants whose natural extracts are traditionally used to obtain cosmetic or therapeutic effects when applied to the skin are known to those skilled in the art and are too numerous to list comprehensively. By way of example, plant extracts containing active agents suitable for the present invention can be isolated from bergamot, coffee, curcumin, fennel, garden angelica, ginseng, grapefruit, mitsuba, red pine, orange, paprika, passion fruit, raspberry, rooibos, soybean, and tea. Such plant extracts are known to have anti-acne, antioxidant, anti-inflammatory, and / or anti-aging effects, among others.

[0146] The carrier-insoluble and / or carrier-soluble active agents optionally added to the dermatological composition may have a cosmetic function, for example, having a dermal filling effect, or may be capable of promoting collagen synthesis (and / or inhibiting its degradation) by itself. Considering the collagen synthesis stimulating ability of the CSSC or CSSP in the nanoelements by itself, the addition of such active agents that may serve a similar purpose may result in a combined activity leading to even higher collagen formation in the skin. Regardless of the exact cosmetic contribution of the active agent, the resulting dermatological composition may be considered "cosmetically active".

[0147] Alternatively, the active agent (either soluble or insoluble in the carrier) may serve a pharmaceutical role, thereby making the composition "pharmaceutical active."

[0148] Skin penetration enhancer The polar carrier may be sufficient to allow sufficient delivery of the CSSC nanoelements through the skin, and some surfactants, if present, may facilitate this, although in some embodiments the topical composition further comprises a skin penetration enhancer.

[0149] Suitable skin penetration enhancers may be selected from the group including: C1 to C 22 Alcohols (e.g., short chain alcohols: ethanol, isopropyl alcohol, and hexanol, and fatty alcohols: octanol, decanol, lauryl alcohol, myristyl alcohol, oleyl alcohol, and octyldodecanol); amides, such as 1-dodecylazacycloheptan-2-one (also known as laurocapram and commercially available as Azone®) and its analogs, N-alkyl-azacycloheptan-2-ones (wherein the alkyl is represented by the general formula C x H 2x+1 where X is an integer selected from 1, 3 to 10 and 14), branched and / or unsaturated N-substituted azacycloheptan-2-ones, N-acylaZepan-2-ones, substituted 2-(2-oxoazepan-1-yl)alkanoic acids and esters thereof, N-alkyl-aZacycloheptane-2-thiones, N-alkyl-aZacycloheptenones, 4-alkyl-1,4-oxaZepan-5,7-diones; x H 2x+1wherein X is an integer selected from 10 to 12, 14, 16 and 18; long chain N-acylate azepanes, dehydrogenated azacycloheptane derivatives, 6-membered ring analogues (e.g. azacycloheptadienes, N-substituted piperidin-2-ones, derivatives of 6-membered ring analogues of Azone®), esters of 2-(2-oxopiperidin-1-yl)acetic acid, N-substituted derivatives of 6-oxopiperidine-2-carboxylic acid, N-1-(2-alkylsulfanylethyl)-piperidine-3-carboxylic acid, (thio)morpholine, morpholine-dione derivatives, long chain N-acyl morpholines, long chain N-mol Morpholinylalkenones, five-membered ring analogues: long chain N-acylmorpholine and morpholinoethanol derivatives, 1-piperazin-1-yl-alkan-1-ones and 1-(4-methylpiperazin-1-yl)-alkan-1-ones; aromatic esters (such as octyl salicylate and 2-ethylhexyl 4-(dimethylamino)benzoate); ether alcohols (such as 2-(2-ethoxy-ethoxy)ethanol); glycols; pyrrolidones (such as 2-pyrrolidone, and N-methyl-2-pyrrolidone); and sulfoxides (such as dimethylsulfoxide (DMSO), and decylmethylsulfoxide).

[0150] It should be noted that some substances defined above as skin penetration enhancers may further function as part of the liquid phase, provided that combination with the primary polar carrier does not affect the overall polarity of the liquid and the lack of solubility of the nanoelements therein.

[0151] composition Having considered the various ingredients that may be used in the present skin composition, the appropriate concentrations or respective ratios are as follows. It should be noted that some of the components according to the present teachings can play multiple roles. For example, some non-volatile liquids, such as fatty esters (e.g., ethyl acetate); fatty acids (e.g., lauric acid, linoleic acid, linolenic acid, myristic acid, oleic acid, palmitic acid, stearic acid, and isostearic acid); fatty acid esters (e.g., ethyl oleate, glyceryl monooleate, glyceryl monocaprate, glyceryl tricaprylate, isopropyl myristate, isopropyl palmitate, propylene glycol monolaurate, and propylene glycol monocaprylate); and terpenes (e.g., eugenol, D-limonene, menthol, menthone, farnesol, and neridol); can also have skin penetration enhancing properties. In another example, polar carriers such as water and certain glycols and glycerol can also aid in skin penetration or even act as surfactants. Thus, for example, when referring to the concentration of a skin penetration enhancer in a composition, the information refers only to compounds specifically added to fulfill this role, and excludes compounds that have another primary role in the composition.

[0152] In some embodiments, the concentration of the CSSC (or combination thereof) in the nanoelements is in the range of 0.1 wt% to 100 wt% (where 100 wt% refers to nanoelements containing only the CSSC(s) without the need for the presence of a plasticizing liquid or surfactant) based on the total weight of the nanoelements. In some embodiments, the concentration of the CSSC(s) is in the range of 1 wt% to 90 wt%, 5 wt% to 80 wt%, 10 wt% to 50 wt%, or 15 wt% to 40 wt% based on the total weight of the nanoelements.

[0153] In some embodiments, the concentration of the CSSC(s) in the dermatological composition is in the range of 0.1 wt% to 30 wt%, preferably in the range of 0.5 wt% to 13 wt%, 1 wt% to 10 wt%, 2 wt% to 10 wt%, 3 wt% to 10 wt%, 4 wt% to 10 wt%, or 4 wt% to 8 wt%, relative to the total weight of the composition. In other embodiments, the concentration of the CSSC(s) is at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 3 wt%, or at least 4 wt%, relative to the total weight of the composition. In other embodiments, the concentration of the CSSC is at most 30 wt%, at most 25 wt%, at most 20 wt%, at most 15 wt%, at most 13 wt%, at most 10 wt%, or at most 8 wt%, based on the total weight of the composition.

[0154] In some embodiments, the polar carrier (e.g., water) is present in the dermatological composition in a range of 30 wt% to 90 wt%, 30 wt% to 80 wt%, 40 wt% to 70 wt%, or 30 wt% to 60 wt%, based on the total weight of the composition.

[0155] In some embodiments, the concentration of the non-volatile liquid(s), when present in the nanoelements, is at most 99 wt%, at most 90 wt%, at most 80 wt%, at most 70 wt%, or at most 60 wt%, based on the total weight of the nanoelements.

[0156] In some embodiments, the concentration of the non-volatile liquid(s), when present in the dermatological composition, is in the range of 0.1 wt% to 50 wt%, preferably in the range of 0.1 wt% to 45 wt%, 0.1 wt% to 40 wt%, 0.5 wt% to 35 wt%, 0.5 wt% to 30 wt%, 0.5 wt% to 25 wt%, 1 wt% to 22.5 wt%, or 5 wt% to 20 wt%, based on the total weight of the composition. In some embodiments, the concentration of the non-volatile liquid(s), when present in the dermatological composition, is at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, or at least 5 wt%, based on the weight of the dermatological composition. In other embodiments, the concentration of the non-volatile liquid(s) is at most 50 wt%, at most 45 wt%, at most 40 wt%, at most 35 wt%, at most 30 wt%, at most 25 wt%, at most 22.5 wt%, or at most 20 wt%, based on the weight of the dermatological composition. The non-volatile liquid (or combinations thereof) can be included for plasticization in a weight ratio of at least 1:200, at least 1:20, at least 1:10, at least 1:5, or at least 1:3, at least 1:1, at least 2:1, or at least 3:1, based on the weight of the CSSC(s) to be plasticized. In some embodiments, the weight ratio of the non-volatile liquid(s) to the CSSC(s) is at most 100:1, at most 50:1, at most 20:1, at most 10:1, or at most 5:1.

[0157] In some embodiments, the concentration of the surfactant(s), when present in the nanoelements, is in the range of 0.1 wt% to 50 wt%, in the range of 1 wt% to 50 wt%, in the range of 5 wt% to 50 wt%, in the range of 10 wt% to 50 wt%, in the range of 15 wt% to 45 wt%, or in the range of 20 wt% to 40 wt%, based on the total weight of the nanoelements.

[0158] In some embodiments, the combined concentration of surfactants (e.g., emulsifiers and / or hydrotropes, etc.), when present in the dermatological composition, is in the range of 0.1 wt% to 60 wt%, in the range of 0.5 wt% to 60 wt%, in the range of 1 wt% to 60 wt%, in the range of 5 wt% to 40 wt%, in the range of 6 wt% to 30 wt%, in the range of 7 wt% to 25 wt%, in the range of 8 wt% to 20 wt%, or in the range of 5 wt% to 15 wt%, based on the total weight of the dermatological composition. In some embodiments, the combined concentration of surfactants is at least 5 wt%, at least 6 wt%, at least 7 wt%, or at least 8 wt%, based on the total weight of the composition. In other embodiments, the combined concentration of surfactants is at most 40 wt%, at most 35 wt%, at most 30 wt%, at most 25 wt%, at most 20 wt%, or at most 15 wt%, based on the total weight of the composition.

[0159] In some embodiments, the concentration of the emulsifier(s), when present in the dermatological composition, is in the range of 0.01 wt% to 60 wt%, 0.1 wt% to 50 wt%, 0.5 wt% to 40 wt%, 1 wt% to 30 wt%, 3 wt% to 25 wt%, or 5 wt% to 20 wt%, based on the total weight of the composition. In some embodiments, the concentration of the emulsifier(s) in the composition is at least 0.01 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 3 wt%, or at least 5 wt%, based on the total weight of the composition. In other embodiments, the concentration of the emulsifier(s) in the composition is at most 60 wt%, at most 50 wt%, at most 40 wt%, at most 30 wt%, at most 25 wt%, or at most 20 wt%, based on the total weight of the composition.

[0160] In some embodiments, the concentration of the hydrotrope(s), when present in the dermatological composition, is in the range of 0.01 wt% to 60 wt%, 0.05 wt% to 50 wt%, 0.1 wt% to 40 wt%, 0.1 wt% to 30 wt%, 0.5 wt% to 25 wt%, 1 wt% to 20 wt%, or 1 wt% to 10 wt%, based on the total weight of the composition. In some embodiments, the concentration of the hydrotrope(s) in the composition is at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.5 wt%, or at least 1 wt%, based on the total weight of the composition. In other embodiments, the concentration of the hydrotrope(s) in the composition is at most 60 wt%, at most 50 wt%, at most 40 wt%, at most 30 wt%, at most 25 wt%, at most 20 wt%, at most 15 wt%, or at most 10 wt%, based on the total weight of the composition.

[0161] In some embodiments, the concentration of the carrier insoluble active agent, when present in the nanoelements, is in the range of 0.1 wt% to 99.9 wt%, in the range of 1 wt% to 85 wt%, in the range of 2 wt% to 70 wt%, in the range of 3 wt% to 55 wt%, in the range of 5 wt% to 45 wt%, in the range of 5 wt% to 35 wt%, in the range of 10 wt% to 30 wt%, or in the range of 15 wt% to 25 wt%, based on the total weight of the nanoelements.

[0162] In some embodiments, the concentration of any one of the active agents, either soluble in the carrier or insoluble in the carrier, in the dermatological composition, or all of them, if more than one, is in the range of 0.01 wt% to 30 wt%, preferably in the range of 0.05 wt% to 25 wt%, 0.1 wt% to 20 wt%, 0.5 wt% to 15 wt%, 1 wt% to 12.5 wt%, 2 wt% to 10 wt%, 3 wt% to 10 wt%, or 5 wt% to 10 wt%, based on the total weight of the composition. In some embodiments, the concentration of any one of the active agents is at least 0.01 wt%, at least 0.05 wt%, at least 0.1 wt%, at least 0.5 wt%, at least 1 wt%, at least 2 wt%, at least 3 wt%, or at least 5 wt%, based on the total weight of the composition. In other embodiments, the concentration of all or only the active agents is at most 30 wt%, at most 25 wt%, at most 20 wt%, at most 15 wt%, at most 12.5 wt%, or at most 10 wt%, based on the total weight of the composition.

[0163] In some embodiments, the concentration of the skin penetration enhancer(s), when present in the dermatological composition, is in the range of 0.01 wt% to 30 wt%, 0.1 wt% to 25 wt%, 1 wt% to 20 wt%, 3 wt% to 15 wt%, or 5 wt% to 15 wt%, based on the total weight of the composition.

[0164] Preferably, the aforementioned ingredients are approved for cosmetic use at the envisaged concentrations, e.g., they do not irritate the skin, cause allergic reactions, or cause acute or chronic adverse effects. Furthermore, all ingredients must be compatible with each other, such compatibility being as described above. As will be easily understood, this principle of compatibility, which may be influenced not only by the chemical identity of these substances, but also by their relative proportions depending on the intended use, should preferably guide the selection of all substances required for the compositions disclosed herein.

[0165] Adjustment method In another aspect of the present invention, a method is provided for preparing a dermatological composition comprising nanoelements of a water-insoluble collagen synthesis stimulating compound (CSSC), in particular a water-insoluble collagen synthesis stimulating polymer (CSSP), said nanoelements being dispersed as a nanosuspension in a polar liquid. The properties and characteristics of the substances used in the method are as described above for each substance. The steps of the method are shown in a simplified manner in Figure 1 and are further detailed below, with the steps outlined in dashed lines being optional.

[0166] In a first step (S01) of the method, at least one CSSC (eg, at least one CSSP) is provided.

[0167] In the second step (S02) of the method, the CSSC can be mixed with one or more non-volatile liquids, whereby the CSSC is plasticized or swollen by said liquids. This step is optional, since the viscosity of the CSSC provided in S01 may be low enough for further processing (e.g., at a temperature of 50° C. and a shear rate of 10 s -1 Measured at 10 7 mPa·s or less).

[0168] If plasticization of the CSSC is desired, mixing with the non-volatile liquid can be carried out at any mixing temperature and / or mixing pressure suitable for such compounding.

[0169] The temperature at which the plasticization is carried out is generally within the range of, for example, the Ts, Tm, and / or Tg that characterize the CSSC, and optionally the Tb of the non-volatile liquid (Tb lThe mixing temperature is selected according to the temperature characterizing the substances involved in the process, taking into account the temperature Tb (referred to as the temperature Tb). As detailed above, the mixing temperature will suitably be higher than at least one of the characterizing temperatures of the CSSC and lower than the boiling temperature of the plasticizing liquid at the pressure at which the mixing step is carried out, although this upper limit is not essential, as long as the selected mixing temperature does not significantly boil off the plasticizing liquid to vaporization. Thus, in some cases, the mixing temperature may be as high as Tb if the step is short enough and / or there is a sufficient excess of non-volatile liquid and / or the mixing is carried out in a sufficiently closed chamber to limit its evaporation / facilitate its condensation back into the mixture. l It may even be.

[0170] It can be easily understood that the changes in the properties of the materials reflected by the reduction of these temperatures from a first value to a second value can alternatively occur at lower or higher mixing temperatures, if the pressure in the closed chamber responsible for the mixing process ensuring the plasticization of the CSSC is appropriately reduced or increased. Thus, in the description of the methods suitable for the preparation of the compositions according to the present teachings, reference can be made to specific temperatures and durations, assuming that the steps are carried out under standard atmospheric pressure, but such guidance should not be considered limiting and encompasses all temperatures and durations that achieve similar results with respect to the behavior of the plasticized CSSC.

[0171] Note that when a CSSC is a CSSP, the Tm and / or Tg of a polymer can set relatively distinct temperatures below and above which the polymer can behave differently, but this is generally not true for the Ts. Given the viscoelastic properties, a polymer or plasticized polymer can remain "fully solid" at temperatures moderately above its nominal softening point.

[0172] Plasticization can be carried out under various conditions, for example, at elevated temperatures (i.e., 30° C. or higher, e.g., 40° C. or higher, 50° C. or higher, 60° C. or higher, 75° C. or higher, or 90° C. or higher) and / or elevated pressures (i.e., 100 kPa or higher, e.g., 125 kPa or higher, 150 kPa or higher, 175 kPa or higher, 200 kPa or higher, 250 kPa or higher, or 300 kPa or higher), which generally accelerates the plasticization process (i.e., shortens the duration of the plasticization period) or reduces the boiling temperature Tb at which the non-volatile liquid may evaporate. l Mixing at high pressure allows the desired modification of Tb l , the temperature range in which plasticization can be performed is correspondingly broadened. Conversely, if desired, the plasticization process can be lengthened by plasticizing the CSSC with a non-volatile liquid under less favorable conditions than those arbitrarily set for evaluating the ability of the CSSC to be plasticized by a particular agent, such as a temperature below 50° C. and / or a reduced pressure below 100 kPa. The ability of the CSSC to be plasticized or swelled by a particular non-volatile liquid can be evaluated at any one of the temperature or pressure conditions described above.

[0173] Mixing the CSSC with or in the non-volatile liquid by stirring the mixture can also shorten the plasticization period, and such stirring further ensures that all parts of the CSSC are plasticized in a relatively uniform manner, and the plasticized CSSC exhibits a fairly homogeneous behavior with respect to the subsequent steps of the method and the results expected therefrom. If excess non-volatile liquid is used during the plasticization process, it can be optionally removed before proceeding to the next step. If the material to be plasticized is relatively highly viscous, the mixing step is also called compounding, and the mixing equipment can be selected accordingly.

[0174] The duration of the plasticization depends, inter alia, on the CSSC to be plasticized, the non-volatile liquid used, the plasticization conditions (e.g., temperature, pressure, and / or agitation), and the desired degree of plasticization. The plasticization period can be at least 1 minute and up to 4 days.

[0175] In some embodiments, additional substances may be incorporated into the CSSC to be plasticized and added during the mixing step S02. These substances (which are generally insoluble in the polar carrier) may be at least one polar carrier-insoluble surfactant (the surfactant functions as an emulsifier), at least one polar carrier-insoluble active agent (the active agent enhances or modifies the biological activity of the composition), or any desired additive. The plasticization conditions can be adapted to the presence of such additional components.

[0176] Mixing can be carried out by any method known to those skilled in the art, such as ultrasonication, using a double-jacketed planetary mixer or extruder. When the material to be mixed has a relatively high viscosity, the mixing step can be carried out using a two-roll mill, a three-roll mill and such types of equipment. In certain embodiments, mixing is carried out by ultrasonication.

[0177] In the third step (S03) of the method, the CSSC (optionally plasticized and optionally further comprising at least one surfactant and / or at least one carrier insoluble active agent) is combined with at least one polar carrier. Optionally, at least one surfactant can be added in this step, which is a relatively polar emulsifier or hydrotrope. Additional substances soluble in the polar carrier can also be added in this step, but may also be introduced after the subsequent nanosizing step.

[0178] This mixture is nanosized in a fourth step (S04) to form a nanosuspension, whereby nanoelements of the CSSC, optionally containing other polar carrier insoluble substances, are dispersed in a polar liquid comprising a polar carrier, optionally in combination with other polar substances.

[0179] Since nanosizing is generally performed by applying shear at relatively high temperatures, the nanoelements, including the CSSC, generally become nanodroplets during the process, and the resulting nanosuspension is a nanoemulsion.

[0180] Nanoemulsions can be obtained by nanosizing a mixture of the desired substances by any method capable of shearing the CSSC (whether plasticized or not, or whether it contains additional compounds), the shearing method being selected from the group comprising sonication, grinding, attrition, high pressure homogenization, high shear mixing, and high shear microfluidization. In a particular embodiment, the nanosizing is performed by sonication.

[0181] Nanosizing is carried out at a shear temperature at least equal to at least one of the first Ts, Tm, and Tg of the CSSC, at least equal to at least one of the second Ts, Tm, and Tg of the CSSC if plasticized, and which in some embodiments can be at least 5° C. higher, at least 10° C. higher, or at least 15° C. higher than the highest characterization temperature of the CSSC mix to be sheared. However, this is not essential if the shearing step is sufficiently short and / or the polar liquid is in sufficient excess, but the shear temperature should preferably prevent a significant amount of the liquid phase from boiling off and evaporating. In some embodiments, the nanosizing temperature at which shearing is carried out does not exceed the boiling temperature of the liquid phase at which shearing is carried out, or the boiling temperature of any other liquid whose evaporation needs to be prevented. The shear temperature is therefore generally determined by the Tb (Tb c For example, if the polar carrier is water, the shear temperature can be selected to be below 95°C, below 90°C, below 85°C, or below 80°C, assuming that the nanosizing is carried out at atmospheric pressure. However, if the nanosizing is carried out at high pressure, the Tb cwill increase and with it the shear temperature. Illustrating further for water, its Tb is 100°C at about 100 kPa, but its boiling temperature rises to 120°C at about 200 kPa, in which case the nanosizing temperature that must not be exceeded may be up to 115°C. As mentioned before, these upper limits are preferred but not essential, and evaporation by boiling of part of the polar carrier could be prevented at even higher temperatures if the process is short enough and / or there is a sufficient excess of polar carrier and / or the nanosizing is carried out in a sufficiently closed chamber to limit evaporation / encourage condensation back into the nanosuspension.

[0182] This Ts, Tm, or Tg is higher than Tb c At lower range shear temperatures, CSSCs, especially CSSPs, melt completely and the nanosizing process can be regarded as "melt nanoemulsion".

[0183] In some embodiments, the total number of nanoelements (e.g., nanodroplets or nanoparticles) formed in this nanosizing process (D N 50) or volume (D V At least 50% of the nanoelements (50) have a hydrodynamic diameter of at most 200 nm, at most 150 nm, at most 100 nm, at most 90 nm, at most 80 nm, or at most 70 nm. In some embodiments, the median diameter of the nanoelements is at least 5 nm, at least 10 nm, at least 15 nm, or at least 20 nm. Advantageously, such values ​​are applicable as the values ​​determined by the volume of the nanoelements, the values ​​determined by the number are generally lower, and are usually measured at room temperature.

[0184] As will be readily appreciated, depending on the temperature at which the material of the nanoelements is characterized and / or measurements may be performed, the nanoelements may be either relatively liquid nanodroplets or relatively solid nanoparticles as the temperature decreases. The size of the nanoparticles at room temperature is comparable to or slightly more compact than the size of the nanodroplets, with a median diameter not exceeding 200 nm.

[0185] In some embodiments, the size of the nanoparticles or nanodroplets is determined by microscopy techniques (e.g., Cryo-TEM) as known in the art. In some embodiments, the size of the nanoelements is determined by dynamic light scattering (DLS). In DLS techniques, particles are approximated as spheres of equivalent behavior and sizes can be provided in terms of hydrodynamic diameters. DLS can also assess the size distribution of a population of nanoelements.

[0186] Distribution results can be expressed in terms of hydrodynamic diameter at a given percentage of the cumulative particle size distribution, either in terms of particle number or volume, and are typically provided for 10%, 50%, and 90% of the cumulative particle size distribution. For example, D50 refers to the maximum hydrodynamic diameter at which less than 50% of the volume or number of particles in the sample, as the case may be, resides, and is expressed as the median diameter per volume (D V 50) or median diameter per particle number (D N 50) without distinction of meaning, or more simply called the mean diameter.

[0187] In some embodiments, the nanoelements of the present disclosure have a cumulative particle size distribution in which D90 is 500 nm or less, or D95 is 500 nm or less, or D97.5 is 500 nm or less, or D99 is 500 nm or less, i.e., 90%, 95%, 97.5%, or 99% of the particles in a sample by volume or number, respectively, have a hydrodynamic diameter of 500 nm or less.

[0188] In some embodiments, the cumulative particle size distribution of a population of nanoelements (e.g., nanoparticles) is calculated by dividing the number of particles in a sample that contain particles having a given hydrodynamic diameter (D N ) or volume (D V The evaluation is performed based on the following criteria:

[0189] Any hydrodynamic diameter having 90% or 95% or 97.5% or 99% of the cumulative size distribution of the particle population, whether in terms of particle number or volume of the sample, may hereinafter be referred to as the "maximum diameter", i.e. the maximum hydrodynamic diameter of the particles present in the population at the respective cumulative size distribution.

[0190] It should be understood that the term "maximum diameter" is not intended to limit the scope of the present teachings to nanoparticles having a perfectly spherical shape. As used herein, the term encompasses any representative dimension of particles in a cumulative particle size distribution at least 90% of the population distribution, such as 90%, 95%, 97.5% or 99%, or any other intermediate value.

[0191] The nanoparticles or nanodroplets, in some embodiments, may be of uniform shape and / or within a symmetric distribution about a population median and / or within a relatively narrow size distribution.

[0192] A particle size distribution is said to be relatively narrow if at least one of the following conditions applies: A) the difference between the hydrodynamic diameter of 90% of the nanoelements and the hydrodynamic diameter of 10% of the nanoelements is 200 nm or less, 150 nm or less, or 100 nm or less, or 50 nm or less, which can be expressed mathematically as: (D90-D10)≦200 nm, etc.; B) the ratio between a) the difference between the hydrodynamic diameter of 90% of the nanoelements and the hydrodynamic diameter of 10% of the nanoelements; and b) the hydrodynamic diameter of 50% of the nanoelements is 2.0 or less, or 1.5 or less, or even 1.0 or less, and can be expressed mathematically as: (D90-D10) / D50≦2.0; C) the polydispersity index of the nanoelements is less than or equal to 0.4, or less than or equal to 0.3, or less than or equal to 0.2, mathematically: PDI=σ 2 / d 2 ≦0.4, where σ is the standard deviation of the particle distribution, d is the average particle size of the particles, and the PDI is optionally 0.01 or more, 0.05 or more, or 0.1 or more.

[0193] In a fifth step (S05) of the method, the nanoemulsion may optionally be actively cooled to a temperature below the Tm, Ts, or Tg of the CSSC (or plasticized CSSC) if desired in the preparation to promote relative solidification of the nanoelements. Such active cooling may be achieved by refrigerating the nanosuspension (e.g., by placing it in a coolant at the desired low temperature), by subjecting the nanosuspension to continuous stirring to promote heat dissipation (and maintain proper dispersion of the nanodroplets as they cool), or by a combination of both approaches. This cooling step is optional, and the nanoemulsion may be allowed to passively cool without any stirring at the end of nanosizing.

[0194] In a further optional sixth step (S06) of the method, a polar carrier soluble active agent and / or a skin penetration enhancer can be added and dissolved in the polar carrier by stirring. Although depicted in the figure as a separate step after cooling of the nanosuspension, whether actively (S05) or passively, the addition of any polar carrier soluble material may alternatively occur before or during cooling.

[0195] In the method detailed above, some ingredients are described as being introduced (or optionally introduced) into the composition at a particular step, but this should not be construed as limiting. For example, a skin penetration enhancer, depending on the substance selected, can be added to the non-volatile liquid during step S02, if implemented, to the polar carrier during step S03, or to the polar liquid phase of the nanoemulsion as described herein in step S06. Alternatively, such agents can be omitted, provided that the nanoelements formed by the CSSC are administered transdermally in an amount sufficient to be effective for the desired effect.

[0196] Thus, the above-mentioned steps can be modified or omitted (e.g. S02, S05 or S06) or additional steps can be included. For example, the dermatological composition may contain any additives customary for cosmetic or pharmaceutical compositions, such as moisturizers, emollients, humectants, UV protection agents, thickeners, preservatives, antioxidants, bactericides, fungicides, chelating agents, vitamins, and fragrances, the nature and concentrations of which need not be described in further detail herein. The additives may be added during the process steps already mentioned or via a new step. Furthermore, the composition may be further processed (e.g. sterilized, filtered, etc.) in accordance with health regulations so as to be suitable for dermatological use, in particular for use on human skin.

[0197] Advantageously, the method of the present invention does not seek to chemically modify the active ingredients, as would be required, for example, to link and bind the active ingredients when preparing implants. The absence of such modifications in the present compositions is expected to prevent the formation of large particles that would be unable to penetrate the skin barrier and / or to prevent an undesirable decrease in the biological activity that these ingredients may provide in their native (unmodified) form, if they are to successfully penetrate the skin.

[0198] In another aspect, the present skin composition is provided for cosmetic or therapeutic use, in particular for improving the appearance of the skin of a subject, which is enabled by the delivery of an effective amount of CSSC.These uses include all the activities that such CSSC is known to have or will be found to have when delivered to the skin, including via injection, and the present invention advantageously allows such uses to be additionally carried out by topical application of the composition.The preparation of the skin composition for such use and its application mode can be conventionally carried out and performed, and need not be described in detail here. EXAMPLES

[0199] material The materials used in the following examples are listed in Table 1 below. Reported properties were taken from product data sheets provided by the respective suppliers or estimated by standard methods. All materials were purchased at the highest purity available unless otherwise noted. N / A means that the specific information is not available.

[0200] [Table 1] JPEG2024518126000002.jpg198153JPEG2024518126000003.jpg209153JPEG2024518126000004.jpg158153

[0201] Device Cryo-TEM: Transmission Electron Microscope (TEM), Talos 200C, Thermo Fisher Scientific, USA, with lacey grid DSC: Differential scanning calorimeter DSC Q2000 (TA Instruments, USA) Oven: DFO-240, MRC, Israel Particle size analyzer (dynamic light scattering): Zen3600 Zetasizer (Malvern Instruments®, UK) Sonicator: VCX750, Sonics&Materials, USA Thermorheometer: Thermo Scientific (Germany) Haake Mars III, C20 / 1° spindle, gap 0.052 mm, and shear rate 10 s -1 .

[0202] Example 1: Screening of non-volatile liquids suitable for plasticizing polycaprolactone In this study, we tested various candidate non-volatile liquids (also called plasticizers or swelling agents) suitable for plasticizing collagen synthesis-stimulating compounds (CSSCs), particularly collagen synthesis-stimulating polymers (CSSPs).

[0203] Each of the various liquids was incubated with PCL having a molecular weight of 14 kDa (PCL-14) in a 1:1 weight / weight ratio at 80°C for 1 hour. That is, 2 g of the non-volatile liquid was added to 2 g of PCL-14 in a glass vial, and the sealed vial was placed in an oven preheated to the plasticization temperature. After incubation, the contents of the vial were mixed manually for about 30 seconds until a clear solution was obtained. The plasticized polymer samples were cooled overnight (i.e., at least 12 hours) at room temperature to allow solidification. None of the liquids tested in this way showed any leaching from the plasticized PCL-14, suggesting that even higher weight ratios may be satisfactorily used.

[0204] The solid samples were then transferred to a rheometer where the viscosity was measured as a function of temperature from 20 °C to 80 °C at a heating rate of 10 °C / min. A reference fluid made with unswollen PCL-14 was also included in the study, and this control showed a viscosity decrease of approximately 2 × 10 with increasing temperature. 5 mPa s (measured at 50°C) to approximately 2×10 4 mPa s (measured at 80 °C). For comparison, the higher molecular weight unplasticized PCLs, PCL-37, PCL-45, and PCL-80 (discussed in more detail below), showed a maximum viscosity of about 6.2 × 10 measured at 50 °C within the above temperature range. 6 The viscosity was mPa·s.

[0205] Additional viscosity measurements over this temperature range for similarly prepared samples at a 1:1 weight ratio showed that the following non-volatile liquids reduced the viscosity: For PCL-14, the first viscosity of this CSSC was 2×10 5 The second viscosity is all 10 mPa·s. 4 mPa·s or less (measured at 50°C), thus reducing by at least 1.5 logs. These non-volatile liquids include caprylic acid, dicaprylyl carbonate, C 12 ~C 15These include alkyl benzoates, triethyl citrate, citronellol, cyclohexane carboxylic acid, dibutyl adipate, hinokitiol, linalool, menthol, propylene carbonate, terpinol, tert-butyl acetate, and thymol, available, for example, from Sigma-Aldrich, BASF®, or Phoenix Chemical.

[0206] Based on the above screening results, an initial pair of CSSPs and non-volatile liquids was selected, namely PCL with a molecular weight of about 14 kDa (PCL-14) and dibutyl adipate. Additional combinations of CSSPs and non-volatile liquids were also tested and found to be suitable for the preparation of dermatological compositions, as detailed in Examples 2-4.

[0207] Example 2: Nanosuspension of CSSC in a polar aqueous phase An aqueous solution containing a surfactant mixture (including emulsifiers and hydrotropes) was prepared as follows: 6.6 g of distilled water, 0.3 g of ammonium xylene sulfonate, 0.1 g of adenosine triphosphate, and 1 g of vitamin E TPGS were placed in a 20 ml glass vial and sonicated for 10 min (40% power, 7 second pulses followed by a 1 second break) until a clear aqueous solution was obtained that is intended to serve as the polar liquid phase for the nanoelements of the CSSC.

[0208] A CSSC premix was prepared as follows: In a separate 20 ml glass vial, 3 g of PCL-14, which has a natural melting temperature of about 62° C. (determined by DSC), was combined with 7 g of Cetiol® B, and the vial was placed in an oven at a temperature of 70° C.-80° C. for 1 hour until the PCL-14 was completely melted. The vial was then mixed by hand for about 30 seconds until a clear homogenous solution of 30 wt. % molten PCL plasticized with 70 wt. % Cetiol® B was obtained. The melting temperature of the plasticized polymer was measured by DSC and found to be about 50° C., indicating that plasticization with Cetiol® B effectively lowered the Tm of the polymer by more than 10° C.

[0209] 2 g of the CSSC premix containing the molten solution of plasticized polymer was added to a vial containing 8 g of an aqueous solution with surfactant and sonicated for 20 min at a shear temperature of approximately 70° C. (as described above) to obtain a nanoemulsion containing nanodroplets of the liquid polymer in an aqueous solution.

[0210] This composition is reported in Table 2A as composition 2.1. Additional compositions were prepared according to a similar procedure, each containing different components in different amounts and under different conditions, as specified in Tables 2A-2E. Sonication, if any, was performed as described above. The values ​​reported in the tables correspond to the concentration of each component in weight percent (wt%) relative to the total weight of the composition, except for the values ​​in the CSSC premix section, which correspond to the weight percent of each component in that particular premix. The nanoemulsion thus produced was passively cooled to room temperature for 1 hour, which allowed the nanodroplets to relatively solidify and form a nanodispersion. The size of the nanoparticles thus produced was measured by dynamic light scattering (DLS) on a sample of the composition diluted 1:100 in water, with the measured median diameter per volume (D V 50) and the median diameter per number (D N 50), as well as the polydispersity index (PDI) are also given in the table below.

[0211] [Table 2A] JPEG2024518126000006.jpg87153

[0212] [Table 2B] JPEG2024518126000008.jpg117153

[0213] [Table 2C] JPEG2024518126000010.jpg119153

[0214] Additional compositions were similarly prepared in which PCL-14 was replaced with various CSSPs, such as polylactides and polycaprolactones of higher molecular weight, specifically 25 kDa, 37 kDa, 45 kDa, and 80 kDa. A non-polymeric CSSC, i.e., coenzyme Q10, was also used without plasticization. These compositions are reported in Table 2D, as previously described.

[0215] [Table 2D] JPEG2024518126000012.jpg196153

[0216] More compositions were prepared using other non-volatile liquids, namely Pelemol® 256 and Cetiol® CC, instead of Cetiol® B. These compositions are reported in Table 2E as above.

[0217] [Table 2E]

[0218] As can be seen from Tables 2A-2E, the method is suitable for preparing a nanosuspension of nanoelements containing CSSC, the nanoelements being D V 50 and D N 50 did not exceed 200 nm, and these values ​​were even less than 100 nm for some of the compositions reported above. The PDI of the nanoparticle population was at most about 0.4.

[0219] Samples corresponding to the premixes described above were additionally tested for viscosity at the end of the mixing step, where the CSSC is at least uniformly mixed with the polar carrier insoluble material and is in most cases plasticized by the non-volatile liquid, if present. Viscosity was measured over a temperature range of 20°C to 80°C for 10 seconds. -1For all samples thus tested, the viscosity measured at 50°C was generally 10 6 It was found that the values ​​were less than 10 mPa s. 3 mPa s~10 5 mPa s, often 5×10 4 mPa s, and most samples are 10 4 It was found to have a viscosity of less than mPa·s.

[0220] Example 3: Nanosuspension of polycaprolactone containing a polar carrier insoluble active agent In this example, an active agent was added to the CSSC: water-insoluble retinol palmitate was used to illustrate the incorporation of a polar carrier-insoluble active agent into nanoelements containing CSSC.

[0221] A CSSC / retinol premix was prepared in a 20 ml glass vial by combining 2 g of PCL-14, 1 g of retinol palmitate, 1 g of Olivatis® 12C as a surfactant, and 6 g of Cetiol® B as a plasticized non-volatile liquid. The vial was sonicated (as described above) for 2 minutes at a temperature of approximately 80° C. to obtain a clear homogenous solution of plasticized CSSC. The CSSC / retinol premix was kept in an oven at a temperature of 80° C. until mixed with the aqueous phase.

[0222] In a separate 20 ml glass vial, 7.5 g of distilled water and 0.5 g of dioctyl sodium sulfosuccinate as an additional surfactant, a hydrotrope, were sonicated for 1 minute at a temperature of about 60° C. until a clear aqueous solution was obtained, which was intended to function as the polar liquid phase.

[0223] Next, 2 g of the hot CSSC / retinol premix was added to the vial containing 8 g of the aqueous solution and sonicated for 1 min at a shear temperature of approximately 70-80 °C, thereby dispersing a nanoemulsion containing nanodroplets of liquid PCL and retinol palmitate into the aqueous polar phase.

[0224] This composition is reported in Table 3 as composition 3.1. Other compositions were prepared following a similar procedure, containing different components in different amounts, as described in the table. The values ​​reported in the table correspond to the concentration of each component in weight percent (wt%) relative to the total weight of the composition, except for the value in the section CSSC / retinol premix, which corresponds to the weight percent of each component in that particular premix. The nanoemulsion thus produced was passively cooled to room temperature for 1 hour, which allowed the relative solidification of the nanodroplets and the formation of a nanodispersion. The size and PDI values ​​of the nanoparticles thus produced were measured by DLS as described above, and are also shown in Table 3.

[0225] [Table 3]

[0226] As can be seen from Table 3, the method is suitable for preparing a nanosuspension of nanoelements containing CSSC and a carrier-insoluble active agent, and the D V 50 and D N 50 does not exceed 200 nm, and these values ​​are still less than 100 nm for some of the compositions reported above. The PDI of the nanoparticle population was at most about 0.3.

[0227] Example 4: Nanosuspension of polycaprolactone in a polar liquid phase with a polar carrier-soluble active agent An aqueous solution containing the surfactant mixture (including an emulsifier and a hydrotrope) was prepared as follows: 4.4 g of distilled water, 0.6 g of ammonium xylene sulfonate, and 1 g of Vitamin E TPGS were placed in a 20 ml glass vial and sonicated for 10 minutes until a clear aqueous solution containing the surfactants and intended to function as the polar liquid phase was obtained (as described above).

[0228] In a separate 20 ml glass vial, a CSSC premix was prepared as follows: 3 g of PCL-14 and 7 g of Cetiol® B were combined and the vial was placed in an oven at a temperature of 80° C. for 1 hour until the PCL was plasticized and completely melted. The vial was then mixed by hand for approximately 30 seconds until a clear, homogenized solution of 30 wt % molten PCL swollen with 70 wt % Cetiol® B was obtained.

[0229] 2 g of the molten solution of plasticized polymer was added to a vial containing 6 g of the aqueous solution with surfactant and sonicated (as described above) for 20 minutes at a shear temperature of about 70° C., thereby resulting in a nanoemulsion containing nanodroplets of liquid polymer in an aqueous polar phase.

[0230] The nanoemulsion was allowed to passively cool to room temperature over the course of 1 hour, at which point 1 g of propylene glycol was added and the contents of the vial were manually mixed for 10 seconds. Propylene glycol was added in relatively small amounts as a skin permeation enhancer, but its presence also contributed to the polarity of the liquid phase. 1 g of LMW hyaluronic acid was then added as a polar carrier-soluble active agent, and the contents of the vial were again manually mixed for approximately 10 seconds until the HA was completely dissolved in the polar liquid phase.

[0231] This composition is reported in Table 4 as composition 4.1. Additional compositions were similarly prepared, containing different amounts of different components. The values ​​reported in the table correspond to the concentration of each component in weight percent (wt%) relative to the total weight of the composition, except for the values ​​in the CSSC premix section, which correspond to the weight percent of each component in that particular premix. The size and PDI values ​​of the nanoparticles thus produced were measured by DLS as described above and are also shown in Table 4.

[0232] [Table 4]

[0233] As can be seen from Table 4, the method is suitable for preparing a nanosuspension of nanoelements containing CSSC and a carrier-soluble active agent, said nanoelements being D V 50 and D N 50 does not exceed 200 nm, and the PDI of the nanoparticle population is at most about 0.2.

[0234] Representative results of the particle size distribution of a sample of composition 4.1 showing the percentage (per volume) of nanoparticles with hydrodynamic diameters between 10 and 1,000 nm are shown in Figure 2.

[0235] The size of the nanoparticles of composition 4.1 was further confirmed by microscopic TEM measurements of images taken of cryosections of the nanodispersion, where the frozen nanoparticles observed had sizes consistent with the measurements obtained by DLS, an example image of which is shown in Figure 3, where the nanoparticles appear against the background as dark greyish spheres.

[0236] Example 5: Patch test procedure for skin irritation analysis The irritation effect, if any, of dermatological compositions according to the present teachings, such as those prepared in Examples 2, 3, and 4, can be tested on the skin of human volunteers by applying the formulation to be tested via a patch.

[0237] Each volunteer was fitted with a small plastic cavity (e.g., 0.64 cm ) of an occlusive patch with a filter tissue in contact with the volunteer's skin at a predefined body site (e.g., back). 2 A predetermined volume of the test composition (e.g., 0.02 ml) is applied to the patch. The patch is attached to the skin area with a hypoallergenic nonwoven adhesive tape, and the test formulation is kept in contact with the skin for 48 hours.

[0238] The appearance of the treatment is evaluated before application of the topical composition and 30 minutes after removal of the patch. A blank patch containing no composition can serve as a negative control.

[0239] Skin reactions (erythema, dryness, and oedema) will be scored throughout the study according to the following predefined scoring criteria: erythema 0=no evidence of erythema, 0.5=minimal or questionable erythema, 1=slight redness, patchy, and diffuse, 2=moderate uniform redness, 3=intense uniform redness, 4=burning redness. Drying (scaly) 0=no traces of scale, 0.5=dry with no scale; smooth and firm appearance, 1=fine / mild scale, 2=moderate scale, 3=severe scale with significant flaking edema - = no edema, + = edema

[0240] The results obtained with any test composition are compared to those obtained in a control zone (unmedicated skin surface under an empty patch) and the composition is classified as non-irritating, very slightly irritating, slightly irritating, moderately irritating, irritating, or very irritating according to the composite effect the composition has with respect to the anticipated skin reaction described above.

[0241] Example 6: Effect of the composition on facial skin appearance The cosmetic effect of the dermatological compositions according to the present teachings was tested on the skin of healthy human volunteers by applying the formulations to be tested to the facial skin. The parameters monitored in this study were the number of skin wrinkles and fine lines in response to the various treatments. The volunteers were free of dermatological problems, skin irritation, blemishes, or other marks at the test sites that could interfere with the study. The test samples included topical compositions containing the given concentrations of CSSPs and corresponding placebo compositions (prepared by the same process), but also those that did not contain at least CSSC (Placebo I) or the surfactant used in the preparation of the premix (Placebo II). The compositions tested are summarized in Table 5.

[0242] [Table 5]

[0243] The clinical trial was double-blind and 20 volunteers were randomly assigned to each arm of the study (i.e., 20 each to the CSSC composition and 20 each to each placebo composition). All groups applied 1 ml of each composition twice daily (morning and evening) by gently rubbing into the facial skin.

[0244] The effect of various compositions on facial skin wrinkles was measured using a Canlfield VISIA system (Canfield Scientific, USA), which consists of a VISIA imaging booth and VISIA software for capturing and storing facial images using standard illumination, cross-polarized flash, and UV flash.

[0245] Measurements of the areas of interest were taken before the first application (baseline) and after 1 month (T1), 2 months (T2) and 3 months (T3) of twice daily application of the topical composition being tested. The results at time points T1, T2 and T3 were compared with the baseline values ​​initially obtained for each volunteer and with the results of the placebo group at the same time points.

[0246] The software automatically isolates or "masks" specific areas of the face shown in the image and performs an extensive analysis of that area to evaluate skin features such as wrinkles. The data provided by the VISIA system is displayed as a "feature count," which counts the number of distinct instances of the feature being evaluated (e.g., wrinkles and wrinkle lines) regardless of the size or intensity of each instance. This value can be presented as the number of wrinkles counted on both the left and right sides of the face ("total wrinkles"), or the average number of wrinkles counted on each side of the face ("average wrinkles"). The results for all volunteers in the same group were averaged, and the results for the different groups at different time points are shown in Figure 4.

[0247] FIG. 4 shows the change over time in the average number of wrinkles on the facial skin of the group treated with composition 2.2 compared to the group treated with the corresponding placebo composition "Placebo I", calculated as a percentage of the average number of wrinkles measured at baseline, which was about 80. As can be seen, the group that applied the placebo composition surprisingly showed an increase in the average number of wrinkles of up to 20% when normalized to baseline, while the group that applied composition 2.2 gradually reduced the average number of wrinkles over the three months of the study, with a reduction of 1.5% after one month, 3.2% after two months, and 5.7% after three months compared to baseline. This trend is reasonable considering that it takes nearly three months for CSSC to induce collagen neosynthesis to a degree that can be detected by the naked eye.

[0248] The sharp increase in the average number of wrinkles in the control group treated with a placebo lacking CSSC may be due to the presence of free surfactant in the placebo composition (this surfactant has no nanoelements to disperse). Without wishing to be bound by theory, the presence of free surfactant may lead to unfavorable modifications of the lipid structure of the skin layers, with a concomitant increase in transepidermal water loss. Such modifications may be responsible for the changes in the appearance of the skin, the relative dryness detected in this study by an increase in the number of wrinkles.

[0249] In contrast, in composition 2.2, the amount of free surfactant is expected to be much less than in the placebo composition, since most of the surfactant is bound to the CSSC (PCL). Comparing the effect of composition 2.2 with the effect of the corresponding placebo composition, as can be seen in Figure 4, the CSSC of composition 2.2 not only reduced the number of naturally occurring wrinkles on the facial skin of the volunteers, but also overcame the drying effect of free surfactant that may be present in the composition applied to the skin. Thus, the true reducing effect of the CSSC nanocomponent on the number of wrinkles measured after, for example, 3 months, may be greater than 5.7% if the composition is substantially free of free surfactant that may have the opposite effect on the number of wrinkles.

[0250] To verify that the above-mentioned apparently moderate effect of composition 2.2 can be attributed to the presence of free surfactant in the liquid phase, compositions 2.21, 2.28 and 2.29 were likewise tested on new groups of volunteers and compared with placebo II lacking surfactant applied by the corresponding control group. The results obtained after one month of application of the compositions, in terms of percentage reduction compared to the baseline values ​​of each group, are summarized in Table 6.

[0251] [Table 6]

[0252] As can be seen, after one month, the group that applied the test therapeutic composition showed at least a 7.8% reduction in the average number of wrinkles, whereas the group that applied the corresponding placebo II showed only a non-significant reduction of only 0.06%. Of note, this study demonstrated that CSSC with a molecular weight as high as 80 kDa reduces the average number of wrinkles compared to the placebo. This confirms that such molecules can be administered transdermally in sufficient effective amounts. As known and shown in composition 2.2, CSSC may exhibit a time lag between the time it is applied to the skin and the time when visible effects such as wrinkles are detected after sufficient neosynthesis of skin structural proteins, this trend of reducing the number of wrinkles is expected to continue over time with continued application of the therapeutic composition. An increase in the effectiveness of such compositions is expected (depending on the dose of CSSC in the composition) at least until collagen reaches a plateau level due to the stimulatory activity of the CSSC.

[0253] A reduction in wrinkles of at least 5%, at least 10%, at least 15%, or at least 20% in the characteristic number of the group to which the composition of the present invention is applied at a given time point compared to a group receiving a placebo composition at the same time point, or compared to the respective baseline before application of the composition, is considered satisfactory.

[0254] Example 7: Effect of the composition on facial skin elasticity The effect of the compositions of the present invention on skin elasticity was tested using a Dermal TorqueMeter® (DTM310) (Dia-Stron, UK), whereby a mechanical probe exerts a predetermined torque on a selected area of ​​the subject's facial skin surface for a predetermined length of time ("torque on"), followed by a "torque off" period, during which the force is rapidly released and the skin attempts to return to its original state after the strain caused by the torsional force. The rotation angle of the torque disc is measured throughout this process and provided as a ratio between the "torque on" period and the "torque off" period. Such measurements were performed on volunteers in a clinical trial conducted as described in Example 6, using composition 2.21 as the test composition and placebo II as the control.

[0255] After only one month of treatment, the group that applied composition 2.21 showed a statistically significant increase in elasticity of 23% compared to baseline, while the volunteers that applied placebo II showed no change in the initial elasticity of the skin.As shown in Example 6, composition 2.21 was a relatively ineffective sample in terms of reducing the average number of wrinkles in the group compared to placebo II.Nevertheless, this composition caused a significant increase in skin elasticity.This trend of increasing elasticity over time is expected to continue with continued application of the treatment composition, at least until the activity of CSSC reaches a plateau.

[0256] Example 8: Effect of the composition on moisturizing the facial skin The effect of the compositions of the present invention on skin hydration was measured to confirm that the changes in wrinkle number and / or elasticity reported in the previous examples are indeed due to the specific collagen stimulating activity of the compositions and not due to changes in hydration levels at the skin surface.

[0257] Skin hydration analysis was performed using a Corneometer® CM 825 (Courage+Khazaka electronic GmbH, Germany) which measures the capacitance of the stratum corneum using a probe capacitor that applies an electric scattering field penetrating the first layer of the stratum corneum (10-20 μm). Results are reported in arbitrary units.

[0258] Composition 2.21 was used as the CSSC-containing test composition and Placebo II was used as a control to measure the change in capacitance due to moisturization of the skin surface before application of the composition (baseline) and after one month of application as described in Example 6. Volunteers who applied Composition 2.21 showed a slight decrease in moisturization levels of about 5%, while volunteers who applied Placebo II showed a slight increase of about 3.9%.

[0259] These results show that neither the CSSC-containing composition nor the control composition significantly affects the moisturizing level of skin.The moisturizing level is expected to remain unchanged after continued application of the present composition, and such value reaches saturation relatively quickly and only fluctuates as a result of climatic conditions.More importantly, these results support that the effect of the present composition in reducing the number of wrinkles and / or increasing skin elasticity can be attributed specifically to the nano-elements containing CSSC, and does not result from the effect of the liquid phase on skin properties.

[0260] Example 9: Effect of the composition on in vivo collagen production in facial skin To confirm that the effectiveness of the composition is derived from the nano-elements of CSSC, their ability to be delivered transdermally, and their ability to play a biological role in stimulating neosynthesis, the collagen level of facial skin was measured before and after application of the composition.The measurement was performed using a DermaLab Combo (Cortex Technology, Denmark).The DermaLab Combo is a skin analyzer that uses an ultrasound probe that allows high frequency and high resolution analysis by passing it over target areas on the face.The output includes an image that changes color and intensity, showing spots where collagen is present, and the intensity of the spots corresponding to collagen is recorded in arbitrary units.

[0261] The evaluation was carried out following application by volunteers according to the method described in Example 6 of composition 2.21 in comparison with the corresponding placebo composition, Placebo II.

[0262] An increase in collagen formation of up to 37% was observed after one month of application of composition 2.21 to the volunteer group, compared to a slight decrease of 1.6% after one month of application of the corresponding Placebo II composition to the control volunteer group.

[0263] The change in collagen level can also be visually observed in the images obtained after the above measurements. Figure 5A shows the output of the measuring device, showing the collagen level of the skin of an example subject before application of the test composition. The collagen reservoirs present in the skin can be seen as small white rounded areas in Figure 5A. Figure 5B shows the output of the measuring device, showing the collagen level of the same subject measured one month after application of composition 2.21. The dramatic increase in collagen level of this subject can be easily seen, as evidenced by the increase in the number and area occupied by the white areas in Figure 5B, which indicate the presence of collagen (resulting from the collagen synthesis stimulating activity of CSSC).

[0264] Example 10: Appearance of the facial skin after application of the composition To visually demonstrate the effect of Composition 2.2 compared to baseline, photographs taken on selected volunteers are shown in Figures 6A and 7A and are shown diagrammatically in Figures 6B and 7B.

[0265] FIG. 6A shows a facial image of a volunteer before application of any composition ("baseline"), in which wrinkles are clearly visible on the volunteer's forehead (indicated by the dashed arrow in FIG. 6A and depicted diagrammatically with a dashed line in the upper part of FIG. 6B) and deep wrinkles are clearly visible bordering the sagging area under the eyes (indicated by the full arrow in the lower part of FIG. 6A and depicted diagrammatically with a full line in the lower part of FIG. 6B).

[0266] An image of the face of the same volunteer taken after three months of applying composition 2.2 twice daily as described above is shown in Figure 7A. The wrinkles on the forehead were no longer visible after three months, and the wrinkles bordering the sagging areas under the eyes had become less deep and flatter (schematically depicted at the bottom of Figure 7B).

[0267] It is understood that certain features of the disclosure that are described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the disclosure that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination or in any other described embodiment of the disclosure, as appropriate. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment does not function without those elements.

[0268] Although the present disclosure has been described with respect to various specific embodiments presented for illustrative purposes only, such specific disclosed embodiments should not be considered as limiting. Based on the applicant's disclosure herein, many other alternatives, modifications, and variations of such embodiments will occur to those skilled in the art. Therefore, it is intended to embrace all such alternatives, modifications, and variations, and to be bound only by any changes that fall within the spirit and scope of the present disclosure and the meaning and equivalent range of the present disclosure.

[0269] In the description and claims of this disclosure, the verbs "comprise," "include," and "have" and their conjugations are used to indicate that the object or objects of the verb are not necessarily an exhaustive list of features, materials, steps, components, elements, or moieties of the subject or subjects of the verb. However, it is contemplated that the compositions of the present teachings also consist essentially of or consist of the recited ingredients, and that the methods of the present teachings also consist essentially of or consist of the recited steps.

[0270] As used herein, the singular forms "a", "an" and "the" include plural references and mean "at least one" or "one or more", unless the context clearly indicates otherwise. At least one of A and B is intended to mean either A or B, and in some embodiments may mean A and B. A "substance" that may be present in the composition alone or in combination with other substances of the same type may be referred to as "substance(s)"; CSSC(s), CSSP(s), polar carrier(s), non-volatile liquid(s), surfactant(s), activator(s), etc., each referring to at least one CSSC, at least one CSSP, at least one polar carrier, at least one non-volatile liquid, at least one surfactant, at least one activator, etc., that may be used in the methods of the invention or may be included in the composition, or may meet the recited parameters or appropriate ranges thereof.

[0271] Unless otherwise stated, the use of the word "and / or" between the last two elements of a list of alternatives for selection indicates that the selection of one or more of the listed alternatives is appropriate and can be made.

[0272] Unless otherwise stated, when outer limits of ranges for features of embodiments of the present technology are noted in this disclosure, it should be understood that in embodiments, possible values ​​of that feature can include the noted outer limits, as well as values ​​between the noted outer limits.

[0273] As used herein, unless otherwise stated, adjectives such as "substantially," "approximately," and "about" modifying a condition or relationship of one or more features of an embodiment of the present technology are understood to mean that the condition or feature is defined relative to within acceptable tolerances that will allow the embodiment to function for its intended use, or within expected variations from the measurements made and / or the measurement equipment used. When a numerical value is preceded by the terms "about" and "approximately," it is intended to indicate the exact numerical value by ±15%, ±10%, or even ±5%, as the case may be. Moreover, unless otherwise stated, the conditions (e.g., numbers) used in this disclosure should be interpreted as having tolerances that, even in the absence of such adjectives, may deviate from the exact meaning of the associated condition and that are believed to enable the present invention or its relevant portions to operate and function as described and understood by one of ordinary skill in the art.

[0274] While the present disclosure has been described in terms of specific embodiments and generally associated methods, modifications and permutations of the embodiments and methods will be apparent to those skilled in the art, and it is to be understood that the present disclosure is not limited by the specific embodiments described herein.

[0275] Certain marks referenced herein may be common law trademarks or registered trademarks of third parties. Use of these marks is exemplary and should not be construed as descriptive or as limiting the scope of this disclosure to material relating solely to these marks.

Claims

1. A skin composition comprising single-phase nanoelements of at least one biodegradable, water-insoluble collagen-synthesis stimulating compound (CSSC) having a molecular weight of 0.6 kilodaltons (kDa) or greater, said nanoelements being dispersed in a polar carrier and having an average diameter Dv50 of 200 nm or less.

2. The or each CSSC has the following properties: i. the CSSC is insoluble in a polar support; ii. the CSSC has at least one of a first melting temperature (Tm), a first softening temperature (Ts), and a first glass transition temperature (Tg) of at most 300° C.; iii. the CSSC has a first Tm or Ts of at least 20° C.; iv. the CSSC has a first Tg of -75°C or greater; v. the CSSC has at least one of a first Tm, Ts, and Tg between 20° C. and 300° C.; vi. the CSSC has a molecular weight of 0.7 kDa or greater; vii. the CSSC has a molecular weight of 500 kDa or less; and viii. the CSSC has a molecular weight of 0.6 kDa to 500 kDa; The dermatological composition of claim 1 , characterized by at least one, at least two, or at least three of:

3. A skin composition as described in claim 1, wherein the or each CSSC is a thermoplastic collagen synthesis stimulating polymer (CSSP) of natural or synthetic origin.

4. The or each CSSC may comprise:

4. The dermatological composition of claim 3, selected from the group of polymers including aliphatic polyesters, polyhydroxy-alkanoates, poly(alkene dicarboxylates), polycarbonates, aliphatic-aromatic copolyesters, isomers thereof, copolymers thereof, and combinations thereof.

5. The dermatological composition of claim 1 , wherein said at least one CSSC is plasticized by a non-volatile liquid.

6. 6. The dermatological composition of claim 5, wherein the non-volatile liquid is selected from the group comprising mono- or polyfunctional aliphatic esters, fatty esters, cyclic organic esters, fatty acids, terpenes, aromatic alcohols, aromatic ethers, aldehydes, and combinations thereof.

7. 6. The dermatological composition of claim 5, wherein the at least one CSSC plasticized by the non-volatile liquid has at least one of a second Tm, Tg, or Ts that is lower than a respective first Tm, Tg, or Ts of the CSSC, and at least one of the second Tm, Tg, and Ts of the plasticized CSSC is in the range of 0° C. to 290° C.

8. The CSSC has a first viscosity, and the CSSC plasticized with a non-volatile liquid has a second viscosity lower than the first viscosity, and at least one of the first viscosity and the second viscosity is measured at a temperature of 50° C. and a shear rate of 10 s －１ When measured at 10 ７ The composition for skin according to any one of claims 1 to 7, having a viscosity of not more than mPa·s.

9. i. A surfactant that is an emulsifier or a hydrotrope; ii. a polar carrier insoluble active agent; iii. a polar carrier soluble active agent, and iv. Skin penetration enhancers The skin composition according to any one of claims 1 to 7, further comprising at least one of the following:

10. A method for preparing a dermatological composition comprising one or more single-phase nano-elements of a collagen synthesis stimulating compound (CSSC), the method comprising the steps of: a) providing at least one CSSC, wherein: i. the or each CSSC is biodegradable; ii. the or each CSSC is water-insoluble; iii. the or each CSSC has a molecular weight of at least 0.6 kDa; iv. the or each CSSC has at least one of a first melting temperature (Tm), a first softening temperature (Ts), and a first glass transition temperature (Tg) less than or equal to 300° C.; and v. The or each CSSC is heated to 50° C. and a shear rate of 10 s －１ When measuring at 10 ７ having a first viscosity greater than mPa·s; The process b) optionally mixing the CSSC(s) with a miscible non-volatile liquid, said mixing being performed at a mixing temperature equal to or greater than at least one of a first Tm, Ts, and Tg of the CSSC(s), thereby forming homogeneous plasticized CSSC(s), said plasticized CSSC(s) having a second Tm, Ts, or Tg lower than the first Tm, Ts, or Tg, respectively, and a second viscosity lower than the first viscosity, at least one of the first and second viscosities being greater than or equal to 50° C. and a shear rate of 10 s －１ When measured at 10 ７ the viscosity of the solution is equal to or less than mPa·s; c) 50°C temperature and 10 seconds －１ When measured at a shear rate of 10 ７ combining said CSSC(s) or optionally plasticized CSSC(s) having a first or second viscosity of no more than 1000 MPa s with a polar carrier; and d) nanosizing the combination of step c) by applying shear at a shear temperature equal to or higher than at least one of the first Tm, Ts and Tg of said CSSC(s) or at least one of the second Tm, Ts and Tg of said optionally plasticized CSSC(s) to obtain a nanosuspension, whereby nanoelements of the (optionally plasticized) CSSC(s) are dispersed in said polar carrier, said nanoelements having an average diameter Dv50 of 200 nm or less, The method comprising:

11. The CSSC has the following characteristics: i. the CSSC is insoluble in a polar support; ii. the CSSC has at least one of a first Tm, Ts, or Tg of at most 250° C.; iii. the CSSC has a first Tm or Ts of at least 20° C.; iv. the CSSC has a first Tg of -75°C or greater; v. the CSSC has at least one of a first Tm, Ts, and Tg between 20° C. and 300° C.; vi. the CSSC has a molecular weight of 0.7 kDa or greater; vii. the CSSC has a molecular weight of 500 kDa or less; and viii. the CSSC has a molecular weight of 0.6 kDa to 500 kDa; 11. The method of claim 10, further characterized by at least one, at least two, or at least three of:

12. 12. The method of claim 10 or 11, comprising step b) and wherein the non-volatile liquid is mixed with the CSSC(s) in a weight ratio of at least 1:200 relative to the weight of the CSSC(s).

13. 12. The method of claim 10 or 11, comprising step b) and wherein at least one of the second Tm, Ts, or Tg of the plasticized CSSC(s) is in the range of 0°C to 290°C.

14. step b), and wherein at least one of the first viscosity of the CSSC(s) and the second viscosity of the plasticized CSSC(s) is / are at 50° C. and a shear rate of 10 s －１ When measuring with ６ The method according to claim 10 or 11, wherein the viscosity is less than or equal to mPa·s.

15. The method comprises the step b), during which: i. a polar carrier insoluble surfactant; ii. an intermediate emulsifier; and iii. Polar carrier insoluble activators further comprising combining at least one of 12. The method according to claim 10 or 11.

16. During or after step c) or step d), in said polar support: i. a polar carrier soluble surfactant; ii. intermediate emulsifier; iii. a skin penetration enhancer; and iv. Polar Carrier Soluble Active Agents 12. The method of claim 10 or 11, further comprising dissolving at least one of:

17. The polar carrier has a boiling temperature Tb at the pressure for nanosizing. ｃ and the optional non-volatile liquid has a boiling temperature Tb at the pressure of mixing. ｌ and the nanosizing temperature is Tb ｃ Lower and any mixing temperature is Tb ｌ The method of claim 10 or 11, wherein the

18. 1. Use of a skin composition for improving the appearance of skin, said skin composition comprising single-phase nanoelements of a biodegradable, water-insoluble collagen synthesis stimulating compound (CSSC) having a molecular weight of 0.6 kilodaltons (kDa) or more, said nanoelements being dispersed in a polar carrier and having an average diameter Dv50 of 200 nm or less.

19. The use according to claim 18, wherein the dermatological composition is a dermatological composition according to any one of claims 1 to 7.

20. 19. The use according to claim 18, wherein the skin composition is a cosmetic composition and improving the appearance of the skin includes at least one of combating collagen degradation, treating signs of skin aging, combating wrinkles and fine lines, combating sagging skin, combating loose skin, combating thinning skin, combating dull and lifeless skin, and combating lack of elasticity and / or tonicity of the skin.

21. 20. The use of claim 18, wherein the dermatological composition is a pharmaceutical composition and improving the appearance of the skin includes at least one of treating skin lesions, restoring skin integrity, promoting wound healing, relieving local inflammation and / or local pain caused by skin lesions.

Images