WO2015199753A1 - Réparation de la peau atteinte de vieillissement prématuré - Google Patents

Réparation de la peau atteinte de vieillissement prématuré Download PDF

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Publication number
WO2015199753A1
WO2015199753A1 PCT/US2014/072239 US2014072239W WO2015199753A1 WO 2015199753 A1 WO2015199753 A1 WO 2015199753A1 US 2014072239 W US2014072239 W US 2014072239W WO 2015199753 A1 WO2015199753 A1 WO 2015199753A1
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WIPO (PCT)
Prior art keywords
composition according
topical composition
tissue
collagen
penetration
Prior art date
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PCT/US2014/072239
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English (en)
Inventor
Bruce J. Sand
Original Assignee
Sand Bruce J
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/US2014/043720 external-priority patent/WO2014209910A1/fr
Application filed by Sand Bruce J filed Critical Sand Bruce J
Priority to PCT/US2015/000229 priority Critical patent/WO2016105499A1/fr
Priority to JP2017534737A priority patent/JP6891118B2/ja
Priority to AU2015371308A priority patent/AU2015371308A1/en
Priority to EP23211322.5A priority patent/EP4349414A2/fr
Priority to KR1020177020413A priority patent/KR20170110083A/ko
Priority to EP21169395.7A priority patent/EP3915542B1/fr
Priority to CA2972065A priority patent/CA2972065A1/fr
Priority to EP15873783.3A priority patent/EP3236903B1/fr
Publication of WO2015199753A1 publication Critical patent/WO2015199753A1/fr
Priority to IL253123A priority patent/IL253123B/en
Priority to HK18105430.7A priority patent/HK1245625A1/zh
Priority to US15/994,927 priority patent/US20180271983A1/en
Priority to US16/119,178 priority patent/US10814003B2/en
Priority to US17/030,325 priority patent/US11052152B2/en
Priority to US17/361,158 priority patent/US11491225B2/en

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y116/00—Oxidoreductases oxidizing metal ions (1.16)
    • C12Y116/03—Oxidoreductases oxidizing metal ions (1.16) with oxygen as acceptor (1.16.3)
    • C12Y116/03001—Ferroxidase (1.16.3.1), i.e. ceruloplasmin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/26—Iron; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A61K38/1738—Calcium binding proteins, e.g. calmodulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • Premature skin aging, or solar aging is a manifestation of the sun's UV radiation in up-regulating three collagen and elastin-degrading enzymes, collagenase, 92 kD gelatinase and stromelysin-1.
  • collagen and elastin of the extracellular matrix are diminished in their roles of providing the structural integrity and elasticity of the skin, which, due to the forces of gravity, begins to deform under it's own weight. This results in the fine lines, wrinkles, furrows, skin laxity, and loss of volume, all of which are viewed as the common visual signs of aging.
  • the predominant functional cell in the dermal layer of skin is the fibroblast. It's primary functionality is that of manufacturing the protein components of the extracellular matrix (ECM).
  • ECM extracellular matrix
  • the two fibrillar proteins, which play the central role in the skin's structural integrity, tone and elasticity are collagen and elastin, respectively.
  • the fibroblast mirrors these requirements, as well.
  • An efficacious composition intended to restore these elements in premature skin aging must be both bioactive and nutritionally balanced.
  • This invention embodies the energy component, as well as the appropriate raw materials, in the same ratios as present in normal body fluids, for fibroblastic restoration of age-depleted collagen and elastin.
  • Glutaric anhydride (GA) in conjunction with a chemical penetration enhancing compound causes collagen matrices to bind water and, thereby increase tissue volume at selected sites.
  • the penetrant provides expeditious transepidermal delivery of the acylating agent (GA) to the ECM.
  • a preferred embodiment of this invention is the efficacious transepidermal delivery capability from topical application. All active agents in the formulation are delivered simultaneously requiring only minimal dosimetry.
  • the present invention is directed to methods, apparatus and comprehensive anti-aging compositions, which address the age-related degradation of the critical protein components and resultant visible signs of skin aging associated with the dermal extra-cellular matrix (ECM).
  • ECM dermal extra-cellular matrix
  • Synergism has been defined as the "interaction of two or more agents, which produce a combined effect greater than the sum of their separate effects.”
  • the critical agents as raw materials, energy sources and processes, driving the fibroblastic collagen and elastin remodeling are derived from the following formulation in a synergistic process.
  • This patent further embodies a non-interventional comprehensive treatment protocol with protracted aesthetic enhancements described as a topical volumizer.
  • This adjunctive topical process yields prompt tissue augmentation, which can be supplemented with the daily topical application of the ECM restoration composition.
  • Figure 1 depicts the effect of daily application of a cream containing antioxidants, essential amino acids, and a methionine supplement on collagen synthesis, evaluated by the uptake of C-proline into newly synthesized collagen during a short term organ culture
  • Figure 2 depicts the effects of lipoic acid (A) and proanthocyanidin (B) on collagen synthesis by fibroblasts determined by 3H-proline incorporation into collagen. Data were normalized to total DNA content.
  • Figure 3 illustrates the histology of rat dorsal skin at the site of application of the various creams at the end of the 2-week test period is demonstrated.
  • A placebo control
  • B basic formulation containing the amino acid supplements, only
  • C complete formulation : essential amino acids, methionine supplement, and proanthocyanidin.
  • Figure 4 is a relationship between cross-linking effectiveness (judged by melting temperature) and PA concentration.
  • Figure 5 shows cell proliferation rates and collagen synthesis of human fibroblasts cultured on PA- treated or non- treated pericardium tissue.
  • Figure 6 demonstrates changes in the shrinkage temperature of tissues stored in two different solutions, (a) PBS (solid line); (b) 40% ethanol/PBS (dashed line). Storage temp. 21°C .pericardium strips were treated with 0.5% PA for 24 hr before storage.
  • Figure 7 illustrates the role of dermal stem cells in maintenance and repair of the dermis.
  • Figure 8 illustrates the compact single barrel-dual chamber syringe containing the micronized GA powder in the proximal chamber and the buffered penetrant solution in the distal chamber.
  • Figure 9 demonstrates the solubilization of collagen threads by acetic anhydride in alkaline buffer.
  • Figure 10 shows the Concentration Mass of iron (Fe) in samples collected at four different time points. Samples were evaluated for elements by PIXI analysis. Donor sample at the concentration used had Fe at a concentration mass of 169.708 (straight line). Experimental samples (with Collagen Biosynthesis compound)started showing an increase in the concentration mass of Fe starting at 30 min and reached a peak value in 120 min. Fe was undetectable in wells incubated with base or PBS.
  • Figure 11 shows the Concentration Mass of copper (Cu) in samples collected at four different time points. Samples were evaluated for elements by PIXI analysis. Donor sample at the concentration used had Cu at a concentration mass of 3.132 (straight line). Experimental samples (with Collagen Biosynthesis compound) started showing an increase in the concentration mass of Cu starting at 30 min and reached a peak value in 120 min. Cu was undetectable in wells incubated with base or PBS.
  • Figure 12 illustrates the Amplification plot data using pro-collagen primers and probes. These results show that human dermal fibroblast cells began expressing pro-collagen within 30 min after exposure to Collagen Biosynthesis compound sample. Control samples exposed to base alone did not express pro-collagen at this time point.
  • compositions which comprise a nutritionally balanced bioactive formulation intended to intercede in the condition of pre-mature or solar skin aging.
  • Skin rejuvenation of this sort requires raw materials crucial to production of the protein components of the dermal extracellular matrix. If one assumes that the predominant functional dermal cell, the fibroblast, functions as a "factory cell", its productivity will depend upon not only the raw materials presented to it, but, it's sources of energy to drive this function, as well.
  • fibroblasts will reach and exceed their epigenic determined life-span. This results in replicative senescence.
  • Replicative senescence is defined as an inability to replicate the fibroblastic progenitor adult human dermal stem cells. Normally, the dermal stem cells differentiate into productive fibroblasts, thereby, restoring the age-depleted components of the extracellular matrix.
  • Another preferred embodiment of this invention is a biochemical process for re-vitalizing senescent adult human dermal stem cells, which predispose to restorative collagen and elastin biosynthesis.
  • This patent also embodies a composition, methods and apparatus directed to the immediate restoration of age-depleted tissue volumetric loss and reduction in wrinkles, furrows and skin laxity.
  • topical ECM restoration formulations and the topical volumizer will address the visible signs of premature skin aging synergistically in the most comprehensive treatment protocol.
  • the application of these separate but synergistic modalities might also be used effectively in stand-alone anti-aging rejuvenation procedures.
  • This patent embodies the following active agents in restoration of age-depleted components of the ECM.
  • collagen The two critical fibrillar proteins of the dermal extracellular matrix are collagen and elastin.
  • Collagen the most abundant protein in the human body, accounts for over 90% of the protein in human dermis. It plays a major role in the strength, tone and structural integrity of the skin. As collagen is age-depleted, skin will deform under its own weight because gravity will be unopposed.
  • Collagen biosynthesis and remodeling is complex and involves several post-translational modifications.
  • the dermal fibroblasts synthesize the individual polypeptide chains of Types I and 111 collagen as precursor molecules, procollagen.
  • the individual chains which contain globular amino- and carboxy-terminal domains, assemble into trimeric procollagens.
  • procollagens are secreted into the extracellular space (ECM) as soluble proteins.
  • ECM extracellular space
  • Specific proteases cleave and, thereby remove the carboxy- and amino- terminal domains, which gives rise to pC and pN collagen.
  • telopeptides consist of a triple helical domain and small, non-helical portions called telopeptides on each end of the molecule. These telopeptide domains are involved in stabilizing the collagen fibers by forming intermolecular covalent cross-links. These cross-links connect C- or N- terminal telopeptide domains to central triple helical domains on adjacent collagen molecules.
  • Elastic fibers are essential extracellular matrix macromolecules comprising an elastic core surrounded by a mantle of fibrillin-rich microfibrils. They endow the skin with the critical properties of elasticity and resilience.
  • the keratinocyte of the epidermis participates with the fibroblast in elastin synthesis.
  • the cross-links between individual elastin molecules is very similar in mechanism to that of collagen. This allows elastin fibers to stretch 100% and still return to their original form.
  • Amino acids are the building blocks of peptides. In the restoration of age-depleted collagen and elastin, all ten of the essential amino acids must be bio-available to the dermal fibroblast. These amino acids are essential because the body doesn't produce them intrinsically. The University of Arizona Biology Project has reported that the "failure to obtain enough of even one of the essential amino acids has serious implications and can result in the degradation of the body's proteins. The body does not store excess amino acids for later use.”
  • This invention embodies the addition of sulfated amino acids, which function to restore the age-depleted GAGs.
  • tissue specific GAGs require a source of inorganic sulfur for their synthesis.
  • One suitable source of sulfur embodied in this invention, is the sulfur-containing amino acids (SAAs), cysteine and methionine. The importance of the addition of these active ingredients has been previously unrecognized in the synthesis of GAGs.
  • the GAGs are key components of the dermal extracellular matrix in facilitating the dermal reservoir, thus providing hydration, which aids in filling and plumping the overlying tissue. This aids in eliminating the appearance of rhytides (wrinkles), as well as imparting a youthful texture to the skin.
  • This proprietary skin restoration composition might well be one of the sole contributors of SAA to the restoration of health to solar-damaged skin.
  • Collagen and elastin cross-links are also degraded in pre-mature aging.
  • This invention embodies the utilization of remedial cross-linking agents to provide the molecular stability lost during the solar-aging process.
  • PA proanthocyanidin
  • Vitamin C is a co-factor for the synthesis of collagen, because it participates in an essential step of the biosynthetic process, that of the hydroxylation of proline to hydroxyproline, a key structural amino acid, which contributes to the helical configuration of the collagen molecule.
  • the ten essential amino acids are embodied in this invention in ratios as in human body fluids ( Figure 3).
  • the entire amino acid subgroup comprises about 0.50 % (w/w) of the total composition.
  • Cysteine is included with the methionine as sulfated amino acids (SAAs) at about 0.20% (w/w) of the total composition
  • Protein-rich proteins such as collagen have an extremely high affinity for proanthocyanidin (PA) and form especially strong hydrogen bonds with PA. Hydrogen bond formation stabilizes the helical structure of collagen fibers and increases the denaturation temperature of collagen.
  • PA proanthocyanidin
  • Proanthocyanidin is a bioflavanoid and a robust remedial collagen and elastin cross-linker derived from grape seed extract. It also acts as a natural antioxidant and free radical scavenger ( Figures 4,5 & 6).
  • This invention embodies PA in about a 1.0 % to 2.0% (w/w) concentration in the composition.
  • a-Lipoic acid is integrated in the formulation at about 1.0 % (w/w).
  • Ascorbyl palmitate is integrated in the formulation at about 0.3% % (w/w).
  • Nucleotides from DNA & RNA are biological molecules that form the building blocks of nucleic acids (DNA & RNA) and serve to carry packets of energy within the cell (ATP). They play a central role in metabolism, participate in cell signaling and are incorporated into co-factors of enzyme reactions.
  • the invention embodies the provision in DNA and RNA powder from dry baker's yeast (saccharomyces cerevisiae) at about 0.1 % (w/w).
  • Calcium (Ca) is a co-factor of the matrix metallopproteinases (MMPs) and in the conversion of pro-collagen to tropo-collagen, which takes place due to two enzymes (N- and C- proease), cleaving the N- and the VC- terminal of the procollagen molecule.
  • MMPs matrix metallopproteinases
  • Ca is also involved in the general cell proliferation through in it's role in the Ca channels, used in the delivery of stimulant factors into the cells and through it's role in the action of cAMP (cyclic adenosine monophosphate). This is a messenger intracellular signal transducer.
  • Fe is involved in the proliferation of fibroblasts at the chromosomal and DNA replication steps. Fe is also a co-factor in cytochromal enzymes in the mitocondria, which mediates the metabolism of the cell. Fe is also active in defense against reactive oxygen species (ROS).
  • ROS reactive oxygen species
  • Copper (Cu) plays a role related to collagen cross-linking as a co-factor for the enzyme, lysyl oxidase. Remedial cross-linking aids in the stabilization of the collagen triple helical molecule, thus providing maturation of the collagen. Cu is also involved in the free radical-producing reactions known as Fenton-type reactions.
  • Ca might be added as Calmodulin at about 1.5% (w/w),
  • CTGF connective tissue growth factor
  • This invention embodies the use of the extract, PhytoCellTec ArganTM in a concentration of about 0.4% to about 0.8% (w/w) in combination with the Nutritionally Balanced Bio-Active Formulation to revitalize the senescent population of fibroblasts and to add to the synthesis of collagen and elastin of the extracellular matrix in pre-mature skin aging.
  • Collagen and elastin biosynthesis will partially restore the loss of structural integrity, tone and flexibility in the reversal of premature skin aging.
  • the current use of injectable dermal fillers and volumizers will temporarily augment the age-related loss of volume while treating wrinkles and skin laxity but all are biodegradable and require multiple tissue interventions.
  • This patent further embodies a non-interventional comprehensive treatment protocol with protracted aesthetic enhancements described as a topical volumizer.
  • This adjunctive topical process yields prompt tissue augmentation, which can be supplemented with the daily topical application of the ECM restoration composition.
  • This patent also embodies a topical formulation, which is composed of an acylating agent defined as an agent that transfers an acyl group to another nucleophile, examples of specific agents include, but are not limited to glutaric anhydride, succinic anhydride or malleic anhydride, since each of these anhydrides hydro lyze into rather innocuous compounds.
  • an acylating agent defined as an agent that transfers an acyl group to another nucleophile
  • specific agents include, but are not limited to glutaric anhydride, succinic anhydride or malleic anhydride, since each of these anhydrides hydro lyze into rather innocuous compounds.
  • the GA (C5H603) is obtained from SIGMA-ALDRICH of St. Louis, MO. It is supplied in a white to light yellow powder or crystals or chunks of a molecular weight of 114.1 g/mol. It has been determined that rapid solubility is desirable in the embodied process.
  • the GA is referred to a company, such as Powdersize, Inc. of Quakertown, PA for the purpose of particle size reduction and consistency. They employ processes, such as "high potency milling/micronization, jet milling, mechanical milling andmicropulverizing.” These technologies improve the solubility of poorly soluble chemical entities with average particle size ranges from 2 to 10 microns.
  • the present invention embodies a process for reacting specific acylation agents with collagen fibrils in intact tissue to alter the net charge and net charge density of the treated tissue.
  • the exposed tissue surface is pre-treated for 30 seconds to 2 minutes with a chemical penetration enhancer adjusted to alkaline pH to bring the pH of the tissue to between about 8.5 and about 9.5 resulting in deprotonation of ⁇ -amino groups of lysine residues on exposed proteins.
  • the multi-functional penetration enhancer is mixed with the acylating agent (micronized GA) for about 5 seconds bringing the GA to a concentration of between 10 mg/mL and 100 mg/mL, preferably between 10 mg/mL and 50 mg/mL in the buffered penetration enhancer.
  • the acylating agent micronized GA
  • the resultant formulation is then applied to the exposed targeted tissue site such that the chemical composition immediately reacts with the exposed pre-treated tissue surface resulting in co-valent bonding of the pendant chemical moiety to the deprotonated ⁇ -amino groups of lysine residues on exposed proteins.
  • Acylation agents are applied to skin in order to obtain an increase in tissue hydration producing a thicker dermal skin layer with increased pliability.
  • the chemical binding of water to the dermal collagen fibers will result in 3-D volumetric enhancement, thereby, correcting the deficits from facial fat loss, fat movement and skeletal remodeling associated with pre-mature skin aging.
  • the first syringe is a single chamber syringe, which contains the multi-functional penetration enhancer buffered with an alkaline solution, such as sodium hydroxide or disodium phosphate to apH of about 10.
  • an alkaline solution such as sodium hydroxide or disodium phosphate to apH of about 10.
  • the targeted skin site is pre-treated for 1 to 2 minutes with the composition from within this syringe, with or without slight skin abrasive action to effectively to bring the treated tissue to a pH range from about 7.5 to about 10.0.
  • a second single-barrel syringe is a highly customized dual-chambered system fabricated by Unilife Corporation This novel device is pre-filled with the dry-micornized powdered acylating agent (GA) in the proximal chamber, which is sealed from inadvertent fluid contamination.
  • the distal chamber is pre-filled with the liquid multi-functional penetration enhancer.
  • This agent is buffered with an alkaline solution, such as sodium hydroxide, to a pH of about 10. (Figure 8).
  • the liquid-to-dry micronized drug reconstitution takes place as the syringe plunger is pulled forth resulting in a negative pressure, thereby, aspirating the liquid (penetrant) compound into the proximal chamber and instantaneously admixing and blending the two drugs in solution.
  • the pre-buffered liquid maintains the final mixture at an alkaline pH bringing the GA to a concentration of between 10 mg/rnL and 100 mg/mL, preferably between 10 mg/rnL and 50 mg/mL
  • the plunger is compressed, the resultant formulation is then rapidly applied to the exposed tissue site such that the chemical composition promptly reacts with the exposed pre-treated tissue.
  • the penetrant enables expeditious transepidermal delivery and bio-availability of the GA resulting in co-valent bonding of the pendant chemical moiety to the deprotonated ⁇ -amino groups of lysine residues on exposed proteins.
  • the third syringe in the system provides a buffer solution facilitating rinsing and neutralizing of the total tissue surface, thereby, removing un-reacted chemical agents.
  • a preferred embodiment of this invention is a multi-functional biochemical penetration enhancing formulation working in synergism with the bioactive compositions to synthesize the age-depleted components of the dermal extracellular matrix.
  • This invention further embodies a method and composition, which significantly enhances the transepidermal delivery of drugs, medicines, agents, formulations and other compositions that are applied topically to the skin surface, such as the embodied GA/penetrant mixture.
  • the following detailed description is of the best currently contemplated modes of carrying out the invention. The description should not be taken in a limiting sense, but is made merely for the purpose of illustrating the general principles of the invention, since the scope of the invention is best defined by the appended claims.
  • a multiphasic approach to transepidermal drug delivery is embodied in this invention.
  • This formulation which is integrated with the bioactive composition in a topical cream, lotion or serum, is based upon the hypothesis that two or more proven penetrants, which function in a synergistic manner by disparate biochemical pathways to breach the functional stratum corneal-induced epidermal barrier, and that have been demonstrated to be efficacious individually, might provide enhanced capability in the transport of topically applied compositions.
  • an alternative approach is to enhance the efficacy of standard enhancers by inhibiting the repair metabolic) response in-vivo.
  • a metabolic response could be used in conjunction with another method to further increase efficacy.
  • This patent embodies a transepidermal drug delivery system, whereby, the concentrations of biochemical penetration enhancers is determined by the molecular mass of the proposed penetrating agents.
  • this formulation enables the bioactive composition to become bio-available to the dermal target site within minutes of topical administration. Further embodiments permit the use of minimal concentrations, as little as 1/1000th of concentrations of previous alternative processes, while hosting all topical agents simultaneously.
  • This multi-functional biochemical penetration enhancing formulation is comprised of at least two or more different biochemical agents, which function synergistically by disparate biochemical pathways to effectively and expeditiously deliver the topically administered composition directly to the target site in the dermis.
  • One active penetrant consists of a micro-emulsion-based organic gel defined as a semi-solid formation having an external solvent phase immobilized within the spaces available of a three-dimensional networked structure.
  • This micro-emulsion-based organic gel in liquid phase is characterized by 1 ,2-diacyl-sn-glycero-3 -phosphatidyl choline, an organic solvent, selected from a group consisting of:
  • anti-oxidants selected from the following group:
  • This permeation enhancer is a bipolar molecule with the intended drug molecule present in the micelle of this agent, such that the non-polar end is towards the center and the polar end is towards the outside.
  • the interaction between the lipid layer of the skin and the polar end of the phosphatidyl choline+ organic solvent formulation makes it possible for this bipolar molecule to enter the skin layers.
  • micro-emulsion-based organic gel is dissolved in isopropyl palmitate or other organic solvents. It is a microemulsion consisting of reversed polymer-like micelles and are readily obtained by adding a minimal amount of water to a solution of phosphatidyl choline in organic solvents. These gels have the ability to host various guest molecules.
  • lipids can be dissolved in the gels. They are visco-elastic, bicompatible and isotropic gels consisting of a 3 -dimensional network of entangled reverse cylindrical, polymer-like) micelles, which have no restrictions on the chemical structure on the drug to be transported.
  • This penetration enhancer has the advantages of ease of preparation and scale-up, easier quality monitoring, thermodynamic stability, and enhanced topical perforation qualities.
  • Template vehicle provides opportunities for incorporation of a wide range of substances with diverse physiochemical properties (e.g., chemical nature, solubility, molecular weight, size)
  • poloxamers which are nonionic triblock coploymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene.
  • Poloxamers are known by several trade names and a drug delivery agent known as Pluronic ® Lecithin Organogel is formulated with a BASF product of which there are some 49 types available.
  • Pluronic ® originally thought to be a inert carrier molecule, has a very real effect on biological systems independently of the drug they are transporting.
  • Pluronic ® Lecithin Organogel also creates a greasy, tacky and thermally unstable composition. Therefore, Pluronic ® is not embodied in the formulation of this invention.
  • another embodied penetrant of the formulation is selected from a group of lower alkyl diols, C10-C20 fatty acids and esters, thereof, and C4-C20 optionally substituted aliphatic alcohols.
  • the transepidermal delivery agent is a optionally substituted aliphatic alcohol. More preferably, the optionally substituted aliphatic alcohols is substituted with an aromatic substituent.
  • This permeation enhancer functions by transiently dissolving the lipids in the bilayer membrane of the epidermis.
  • the drug or compound dissolved in the penetrant can have a preferable access to the dermal layer of skin. It also has an advantage over other simple alcohols, such as methanol or ethanol, by virtue of the bipolar nature of the multi-functional biochemical penetration enhancing formulation.
  • the molecule Due to the aromatic group (i.e., benzene) present in the penetrant, the molecule has a polar end (the alcohol end) and a non-polar end (the benzene end). This enables this penetrant to dissolve a wider variety of drugs and agents, which are non-polar, in general, and carry then into the skin layers by lipid dissolving action of the alcohol end of the molecule.
  • aromatic group i.e., benzene
  • This penetration enhancer is provided to the formulation in a range from about a 0.5 % (w/w) to about 15% (w/w) concentration.
  • fatty acids (linoleic acid, oleic acid, valeric acid, and lauric acid),
  • alcohols and organic solvents acetone, ethanol, pentanol, lauryl alcohol, propylene glycol and glycerol
  • esters isopropyl palmitate isopropyl myristate and ethyl acetate
  • surfactants sodium laureate, cetylmethylammonium bromide and sodium cholate
  • EpiDermFT Series 200 System consists of normal, human-derived epidermal keratinocytes and normal, human-derived dermal fibroblasts which have been cultured to form a multilayered, highly differentiated model of human dermis and epidermis.
  • the tissues are cultured on specially prepared cell culture inserts using serum free medium, attain levels of differentiation on the cutting edge of in- vitro skin technology.
  • the EpiDermFT Skin Model closely parallels human skin, thus providing a useful in-vitro means to assess percutaneous absorption or permeability.
  • MPD MelTek Permeation Device
  • the cell culture insert which contains the EpiDermTM tissue, is inserted between the two pieces of the MPD and four screws are tightened to create a seal between the bottom rim of the device's inner annulus and stratum corneum. Donor solution with no samples added served as negative controls.
  • Donor solution containing four different concentrations (0.25g/ml, 0.5g/ml, lg/ml and 2g/ml) of the Collagen Biosynthesis Compound or control base was prepared. Neutral Red (0.001%) was added to give a red tinge to the donor solution. [142]The donor solution was then added to the center core of the MPD device containing the Skin tissue and the whole assembly was then placed into the wells of a 6 well plate containing 3 ml of PBS.
  • Control Base 15 min, 30 min, 60 min and 120 min
  • Human Dermal fibroblast cell line purchased from Cambrex Bio Sciences Walkersville, Inc. 8830 Biggs Ford Road, Walkersville, MD, 21793
  • cDNA was prepared from the fibroblasts using a retroscript RT-PCR kit purchased from Ambion Inc. RT reactions without reverse transcriptase served as negative control. Ten nanograms of cDNA were used as template for the RT-PCR reaction. Forward primers, reverse primers and TaqMan probes were purchased from Applied Biosystems (Foster City, CA). Collagen type 1 alpha 1 probe was labeled with the reporter dye FAM (6-carboxyfiuorescein) at the 5' end and a non-fluorescent quencher dye at the 3' end. Primers remained unlabeled.
  • FAM 6-carboxyfiuorescein
  • Master mix for PCR reaction consisted of 10 ⁇ of universal master mix (Applied Biosystems), 900 nM of each primer and 250 nM of probe in a final volume of 20 ⁇ . All PCR reactions were carried out in triplicate wells of a 96-well microamp optical plate (Applied Biosystems). Thermal cycling and data analyses were performed in an ABI Prism 7300 instrument (Applied Biosystems). A standard curve generated using different concentrations (10 ng, lng, 0. lng, 0.0 lng and 0.00 lng) of collagen plasmid was used for quantitative determination of collagen mRNA in the samples.
  • compositions which would benefit from the biochemical penetration enhancing compound herein described, such as retinoids, skin lightening agents, anti-fungal agents, non-steroidal anti-inflammatory drugs, optical clearing compounds, anti-bruising compounds, hair restoration formulations, topical vaccines, and other agents, wherein effective and expeditious transepidermal bio-availability would be advantageous.
  • biochemical penetration enhancing compound herein described, such as retinoids, skin lightening agents, anti-fungal agents, non-steroidal anti-inflammatory drugs, optical clearing compounds, anti-bruising compounds, hair restoration formulations, topical vaccines, and other agents, wherein effective and expeditious transepidermal bio-availability would be advantageous.
  • compositions, devices, and methods according to the present invention provide an enhanced transepidermal drug delivery method to a patient with increased efficiency and without pain or discomfort normally associated with penetrating injections.
  • Other possible complications of injections include localized swelling or edema, capillary hemorrhage, and inflammation.
  • the present invention discloses a composition comprising an appropriate dosage of drug and a transepidermal delivery system comprised of two or more penetrants working synergistically.
  • the topical application of the composition by means of ointment, cream, or saturated absorbent cotton pledget permits direct application over target site, thus avoiding inadvertent diffusion into an unwanted site, as well as previously indicated risks and complications.

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Abstract

L'invention concerne une composition à application locale, équilibrée d'un point de vue nourrissant et biologiquement active, destinée à intervenir de façon efficace dans les processus biologiques liés au vieillissement prématuré de la peau. Dans ce traitement anti-vieillissement complet sont inclus des agents dont le rôle est de revitaliser les cellules souches humaines adultes sénescentes de la peau. L'invention concerne également des méthodes, appareils et compositions ciblant la perte de volume en tissu associée au vieillissement prématuré de la peau. La biodisponibilité efficace des compositions anti-vieillissement qui font l'objet de l'invention est facilitée grâce à un composé chimique multi-fonctionnel améliorant la pénétration, lequel est intégré à la formulation complète qui fait l'objet de l'invention.
PCT/US2014/072239 2014-06-23 2014-12-23 Réparation de la peau atteinte de vieillissement prématuré WO2015199753A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
EP15873783.3A EP3236903B1 (fr) 2014-12-23 2015-12-23 Méthodes et formulations pour l'administration transdermique
EP21169395.7A EP3915542B1 (fr) 2014-12-23 2015-12-23 Formulations pour l'administration transdermique
CA2972065A CA2972065A1 (fr) 2014-12-23 2015-12-23 Methodes et formulations pour l'administration transdermique
JP2017534737A JP6891118B2 (ja) 2014-12-23 2015-12-23 経皮投与のための方法及び製剤
AU2015371308A AU2015371308A1 (en) 2014-12-23 2015-12-23 Methods and formulations for transdermal administration
EP23211322.5A EP4349414A2 (fr) 2014-12-23 2015-12-23 Méthodes et formulations pour l'administration transdermique
KR1020177020413A KR20170110083A (ko) 2014-12-23 2015-12-23 경피 투여를 위한 방법 및 제형
PCT/US2015/000229 WO2016105499A1 (fr) 2014-12-23 2015-12-23 Méthodes et formulations pour l'administration transdermique
IL253123A IL253123B (en) 2014-12-23 2017-06-22 Preparations for administration through the skin and their uses
HK18105430.7A HK1245625A1 (zh) 2014-12-23 2018-04-25 用於經皮施用的方法和製劑
US15/994,927 US20180271983A1 (en) 2014-12-23 2018-05-31 Transdermal carrier
US16/119,178 US10814003B2 (en) 2014-12-23 2018-08-31 Transdermal carrier
US17/030,325 US11052152B2 (en) 2014-12-23 2020-09-23 Transdermal carrier
US17/361,158 US11491225B2 (en) 2014-12-23 2021-06-28 Transdermal carrier

Applications Claiming Priority (2)

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USPCT/US2014/043720 2014-06-23
PCT/US2014/043720 WO2014209910A1 (fr) 2013-06-24 2014-06-23 Composition transépidermique pour régénérer les peaux vieillissant prématurément

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190358136A1 (en) * 2018-05-22 2019-11-28 HSP Technologies LLC Hair care compositions and methods of making and using same
US11491225B2 (en) 2014-12-23 2022-11-08 Dyve Biosciences, Inc. Transdermal carrier
CN117653716A (zh) * 2023-12-08 2024-03-08 东莞胶原生物科技有限公司 一种能够抑制皮肤光老化所致铁死亡的琥珀酰缺端胶原蛋白的应用

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US20050287182A1 (en) * 2003-05-24 2005-12-29 Beiersdorf Ag Cosmetic or dermatological preparation comprising a nutrient medium phase
US20060286406A1 (en) * 2005-04-25 2006-12-21 Fuji Photo Film Co., Ltd. Organic electroluminescent device
US20090053290A1 (en) * 2006-03-08 2009-02-26 Sand Bruce J Transdermal drug delivery compositions and topical compositions for application on the skin
US20090068255A1 (en) * 2007-04-30 2009-03-12 Betty Yu Use of matrix metalloproteinase inhibitors in skin care
US20130108603A1 (en) * 2011-11-02 2013-05-02 Mark K. Bennett Collagen production compound

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Publication number Priority date Publication date Assignee Title
US20050287182A1 (en) * 2003-05-24 2005-12-29 Beiersdorf Ag Cosmetic or dermatological preparation comprising a nutrient medium phase
US20060286406A1 (en) * 2005-04-25 2006-12-21 Fuji Photo Film Co., Ltd. Organic electroluminescent device
US20090053290A1 (en) * 2006-03-08 2009-02-26 Sand Bruce J Transdermal drug delivery compositions and topical compositions for application on the skin
US20090068255A1 (en) * 2007-04-30 2009-03-12 Betty Yu Use of matrix metalloproteinase inhibitors in skin care
US20130108603A1 (en) * 2011-11-02 2013-05-02 Mark K. Bennett Collagen production compound

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11491225B2 (en) 2014-12-23 2022-11-08 Dyve Biosciences, Inc. Transdermal carrier
US20190358136A1 (en) * 2018-05-22 2019-11-28 HSP Technologies LLC Hair care compositions and methods of making and using same
US11766391B2 (en) * 2018-05-22 2023-09-26 HSP Technologies LLC Hair care compositions and methods of making and using same
CN117653716A (zh) * 2023-12-08 2024-03-08 东莞胶原生物科技有限公司 一种能够抑制皮肤光老化所致铁死亡的琥珀酰缺端胶原蛋白的应用

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