+

WO2018195111A1 - Administration parentérale non systémique d'agents tampons pour inhiber la métastase de tumeurs solides, l'hyperpigmentation et la goutte - Google Patents

Administration parentérale non systémique d'agents tampons pour inhiber la métastase de tumeurs solides, l'hyperpigmentation et la goutte Download PDF

Info

Publication number
WO2018195111A1
WO2018195111A1 PCT/US2018/028017 US2018028017W WO2018195111A1 WO 2018195111 A1 WO2018195111 A1 WO 2018195111A1 US 2018028017 W US2018028017 W US 2018028017W WO 2018195111 A1 WO2018195111 A1 WO 2018195111A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
skin
subject
buffer
agent
Prior art date
Application number
PCT/US2018/028017
Other languages
English (en)
Inventor
Bruce J. Sand
Original Assignee
Ampersand Biopharmaceuticals, Llc
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
Application filed by Ampersand Biopharmaceuticals, Llc filed Critical Ampersand Biopharmaceuticals, Llc
Priority to MX2019012385A priority Critical patent/MX390709B/es
Priority to AU2018255294A priority patent/AU2018255294B2/en
Priority to KR1020197033931A priority patent/KR20200042440A/ko
Priority to CN201880040474.5A priority patent/CN111093774A/zh
Priority to EP18787621.4A priority patent/EP3612274A4/fr
Priority to JP2020506134A priority patent/JP2020516690A/ja
Priority to EP18856604.6A priority patent/EP3681479B1/fr
Priority to US16/132,358 priority patent/US20190083386A1/en
Priority to EP23195939.6A priority patent/EP4324460A3/fr
Priority to PCT/US2018/051250 priority patent/WO2019055880A2/fr
Priority to JP2020515698A priority patent/JP2020534285A/ja
Priority to US16/132,357 priority patent/US20190083527A1/en
Publication of WO2018195111A1 publication Critical patent/WO2018195111A1/fr
Priority to US16/546,260 priority patent/US10632146B2/en
Priority to US16/546,256 priority patent/US10639326B2/en
Priority to US16/866,466 priority patent/US10933088B2/en
Priority to US17/168,114 priority patent/US11730756B2/en
Priority to US17/168,111 priority patent/US20210228623A1/en
Priority to US17/488,154 priority patent/US20220016159A1/en
Priority to US17/488,132 priority patent/US11357792B2/en
Priority to US17/488,143 priority patent/US20220016158A1/en
Priority to US17/497,794 priority patent/US11793830B2/en
Priority to US17/497,799 priority patent/US11389472B2/en
Priority to US17/514,653 priority patent/US11744853B2/en
Priority to AU2022241559A priority patent/AU2022241559B2/en
Priority to US18/331,875 priority patent/US12310983B2/en
Priority to JP2023146344A priority patent/JP2023179467A/ja
Priority to AU2023254920A priority patent/AU2023254920A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K33/10—Carbonates; Bicarbonates
    • 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
    • A61K33/42—Phosphorus; Compounds thereof
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to the use of anti -metastatic agents, including buffering agents administered parenterally, non-systemically, in particular topically, to result in resistance of tumors to metastasis. Buffering agents that raise pH are also useful in treating hyperpigmentation and gout. Both topical and other parenteral administrations that are themselves non-systemic are contemplated as overcoming difficulties with oral
  • MMP-2 and MMP-9 matrix metalloproteinases-2 and -9
  • cathepsins in particular B, D and L.
  • MMP-2 and MMP-9 matrix metalloproteinases-2 and -9
  • cathepsin B as a cancer target is described by Gondi, C.S. and Rao, J.S. Expert Opin. Ther. Targets (2013) 17:281-291
  • cathepsins in general are described as such targets by Olson, O.C. and Joyce, J. A., Nat. Rev. Cancer (2015) 15:712-729.
  • MMPs play an extensive role in modeling the extracellular matrix, thus permitting cancer cells from solid tumors to escape.
  • cysteine protease inhibitors are naturally occurring endogenous cysteine protease inhibitors.
  • Endogenous CPIs constitute a single protein superfamiiy, the cystatins, such as type 1 cystatins; stefins A (or cystatins A) with a molecular mass of 11,775 Da and stefins B (or cystatins B) with a molecular weight of 1 1 ,006 Da.
  • Cysteine protease inhibitors are very tight binding, pseudo-irreversible inhibitors.
  • anti -metastatic agents include inhibitors of the src homology region 2- containing protein tyrosinase phosphatase (Shp2).
  • a multiplicity of inhibitors of this activity is known, including Fumosorine, PHPS (NSC-87877) and NSC-1 17199,
  • PHPS 1 phenylhydrazonopyrazolone sulfonate
  • DC A cryptotanshinone
  • cryptotanshinone 1 1-B08 and #220- 324.
  • Another anti -metastatic agent is based on the well-known role of epidermal growth factor receptor (EGFR) and/or integrins in driving tumor progression and it is well known that both of these classes of receptors stimulate NHEl activity.
  • EGFR epidermal growth factor receptor
  • integrins e.g. erlotinib
  • cilengitide an anti-integrin drug
  • Cariporide, eniporide and/or amiloride have passed all clinical phases.
  • phytochemicals with antioxidative and anti-inflammatory properties are thought to play important roles in the prevention and/or treatment of cancer.
  • numerous phytochemicals have been examined for their potential anticancer properties by using a diverse array of preclinical experimental models.
  • Withanolides are a group of naturally occurring C28-steroidal lactones. They contain four cycloalkane ring structures, three cyclohexane rings and one cyclopentane ring. WFA is a steroidal lactone, derived from Acnistus arboescens, Wiihania somnijera and other members of Solanaceae family. It has been traditionally used in ayurvedic medicine. It is the first member of the withanolide class of ergostane type product to have been discovered.
  • WFA Withaferin A
  • biocompatible buffers and other metastatic agents including topical administration of such buffers and agents has a positive effect on cancer, including inhibition of metastasis, inhibition of growth and in some cases, tumor shrinkage.
  • Such administration of pH-raising buffers is also useful to treat gout and melasma (hyperpigmentation).
  • Topical administration may employ penetrants that improve transdermal transit either locally or systemically. Suitable penetrants are described, for example, in PCX publications WO/2017/105499 and WO/2017/127834.
  • melasma There is a variety of agents that have been suggested for the treatment of melasma including the tyrosinase inhibitors hydroquinone, kojic acid, azelaic acid, various phenols and arbutin. These appear not to be completely successful and have undesirable side effects.
  • the causes of melasma are varied and the condition is characterized by a multiplicity of lesions of hyperpigmentation varying in size, shape and distribution. These lesions may suitably be treated by raising the local pH according to the methods of the invention described below.
  • Applicants have found that the drawbacks of intravenous and oral administration of buffers and other anti -metastatic agents can be overcome by administering these agents non-systemically parenterally, such as by intraperitoneal, subcutaneous or intramuscular injection and in particular by topical administration.
  • Topical administration is most conveniently transdermal, but further includes transmembrane administration for example by suppository or intranasal application.
  • the invention is directed to a method to inhibit metastasis and/or growth of a solid tumor contained in a subject which method comprises administering by a non-systemic, parenteral route to a subject in need of such inhibition an effective amount of an anti-metastasis agent.
  • the anti -metastasis agent may be buffer sufficient to increase the pH of the microenvironment of the solid tumor, or a protease inhibitor, an inhibitor of NaV ' HT exchanger activity, an inhibitor of epidermal growth factor receptor (EGFR), an inhibitor of src homology region 2-containing protein tyrosinase phosphatase (Shp2), withaferin A or combinations thereof.
  • the administration is by non- systemic parenteral route includes topical administration, especially transdermal.
  • a suitable formulation typically involves a penetrant that enhances penetration of the skin and is, in some embodiments, composed of chemical permeation enhancers (CPEs). In some cases it can also include peptides designed to penetrate cells i.e. cell penetrating peptides (CPPs) also known as skin penetrating peptides (SPPs).
  • CPEs chemical permeation enhancers
  • SPPs skin penetrating peptides
  • the formulation may be applied as such, or by means of occlusive devices such as patches.
  • the choice of buffer system is based on the criteria of capability of buffering at a suitable pH typically between 7 and 8, as well as
  • the formulation is chosen to be compatible with the buffer selected, amounts of penetrants are generally less than those advantageous for therapeutic agents in general.
  • Raising the pH in the vicinity of melasmas and gout is also an effective treatment.
  • the methods of the invention can usefully be applied to treatment of these conditions as well.
  • another aspect of the invention such methods of treatment directed to melasma and gout.
  • Figure J shows the time course of urine pH immediately following topical administration of sodium bicarbonate in various formulations and dosage regimes.
  • Figure 2 shows the mean daily urine pH of experimental subjects as a function of time after administration of a formulation of sodium bicarbonate in the formulations and dosages of Figure 1.
  • Figure 3 shows the time course of urine pH over a 3 -day period using alternative topi cal f ormul ati on s .
  • one aspect of the invention is a method to inhibit cancer growth and metastasis, including diminution of cancer mass by non-systemic parenteral, including topical administration of antimetastatic agents, including those agents that result in buffering the immediate environment of tumor cells, including solid tumors and melanomas.
  • non-systemic parenteral administration such as intramuscular, intraperitoneal or subcutaneous administration standard formulations are sufficient. These formulations include standard excipients and other ancillary ingredients such as antioxidants, suitable salt concentrations and the like. Such formulations can be found, for example, in the latest edition of
  • subjects of the invention method are, in addition to humans, veterinary subjects, formulations suitable for these subjects are also appropriate.
  • Such subjects include livestock and pets as well as sports animals such as horses and greyhounds.
  • One important aspect of the invention is based on the above-noted recognition that some tumors do not respond to buffer treatment as their microenvironment is not acidic and at least some of these tumors achieve metastasis by elevation of certain proteolytic enzymes that break down the extracellular matrix (ECM).
  • ECM extracellular matrix
  • tumor cells from the biopsy of a solid tumor in a subject are therefore preferably cultured and tested in advance of treatment to insure responsiveness to buffer.
  • Such evaluation can be carried out by any suitable means, including measurement of pH, assessment of the levels of relevant proteases, and invasion assays as impacted by buffer treatment as described in Bailey, K.M. et al (2014) supra.
  • One important such assay is a glycolytic stress assay as described therein.
  • the formulation will comprise penetrants including either or both chemical penetrants (CPEs) and peptide-based cellular penetrating agents (CPPs) that encourage transmission across the dermis and/or across membranes including cell membranes, as would be the case in particular for administration by suppository or intranasal administration, but for transdermal administration as well.
  • CPEs chemical penetrants
  • CPPs peptide-based cellular penetrating agents
  • Particularly suitable penetrants especially for those that contain at least one agent other than buffer include those that are described in the above-referenced WO2016/105499 and WO2017/127834.
  • transdermal delivery can be effected by mechanically disrupting the surface of the skin to encourage penetration, or simply by supplying the formulation applied to the skin under an occlusive patch,
  • the penetrants described in the above-referenced PCX applications are based on combinations of synergistically acting components.
  • Many such penetrants are based on combinations of an alcohol, such as benzyl alcohol to provide a concentration of 0.5-20% w/w of the final formulation with lecithin organogel present in the penetrant to provide 25-70% w/w of the formulation.
  • these formulations are either essentially polar e.g.
  • aqueous formulations that comprise sufficient nonionic surfactant in order to be present at 1-25% w/w of the final formulation and an excess of polar solvent or, alternatively anhydrous formulations wherein the additional components of the penetrant include sufficient bile salts to provide 1-15% w/w of the formulation and a surfactant present to provide 20- 60% w/w of the formulation.
  • the anti-metastasis agent is a buffer, but less lecithin organogel may be required - e.g. 1-50% by weight when the buffer is present at high concentration. While lecithins are exemplified, other zwitterions could also be used.
  • the penetrant is such that the resulting formulation comprises at approximately 1 : 1 : 1 equi molar mixture of bile saltlecithin and a completion component as well as one or more electrolytes sufficient to impart viscosity and
  • the completion component can be a polar liquid, a non-polar liquid or an amphiphilic substance; however an amphiphilic substance is highly preferred.
  • the penetrant may further comprise a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer.
  • a keratinolytic agent effective to reduce thiol linkages, disrupt hydrogen bonding and/or effect keratin lysis and/or a cell penetrating peptide (sometimes referred to as a skin-penetrating peptide) and/or a permeation enhancer.
  • the additional components as listed above can be included in both the penetrant that provides 0.5-20% benzyl alcohol and lecithin organogel at 25-70% w/w of the final formulation and the above penetrant that comprises sufficient bile salt:lecithin:completion component to provide a 1 : 1 : 1 equimolar ratio of these to the formulation.
  • the surface of the skin may also be disrupted mechanically by the use of spring sy stems, laser powered systems, systems propelled by Lorentz force or by gas or shock waves including ultrasound and may employ niicrodermabrasion such as by the use of sandpaper or its equivalent or using microneedles or electroporation devices.
  • Simple solutions of the agent(s) as well as the above-listed formulations that penetrate intact skin may be applied using occlusive patches, such as those in the form micro-patches.
  • External reservoirs of the formulations for extended administration may also be employed.
  • the active buffer component is any mildly basic compound or combination that will result in a pH of 7-8 in the microenvironment of the tumor ceils.
  • buffers in addition to or in lieu of bicarbonate salts, include lysine buffers, chloroacetate buffers, tris buffers (i.e., buffers employing tris (hydroxymethyl) aminoethane), phosphate buffers and buffers employing non-natural amino acids with similar pKa values to lysine.
  • lysine buffers i.e., buffers employing tris (hydroxymethyl) aminoethane
  • phosphate buffers i.e., phosphate buffers
  • buffers employing non-natural amino acids with similar pKa values to lysine may be, for example, the enantiomers of native forms of such amino acids or analogs of lysine with longer or shorter carbon chains or branched forms thereof.
  • Histidine buffers may also be used.
  • concentration of buffer in the compositions is in the range of 1-40% wt/wt. More typical ranges for sodium bicarbonate or sodium carbonate or both as pH adjusters are 5-35% by weight. The lack of inflammation side effects at these concentrations is surprising as it is noted in US 5, 176,918 that uses lower concentrations to treat other conditions such as arthritis,
  • chemotherapeutic agents such as irinotecan, floxuridine, daunorubicin, cytarabine, and the like may be used,
  • an additional active agent that is optionally included in the compositions of the invention is one or more appropriate protease inhibitor. Particularly important are inhibitors of cathepsins, for example of cathepsin B, and inhibitors of matrix metalloproteinases (MMPs). These components are active alone or augment the effect of buffer for tumors that are not resistant to buffer treatment.
  • Withaferin A Another active agent is Withaferin A.
  • Withaferin A inhibits tumor metastasis and manifests other anti-cancer activities, e.g., inhibition of the neovascularzation associated with carcinoma, as well as cell proliferation.
  • Withaferin A is also a leptin sensitizer with strong anti-diabetic properties that could induce healthy weight loss and beneficial effects on glucose metabolism.
  • NHE1 target DNA + HT exchanger 1
  • Other anti-metastatic agents include inhibitors of the src homology region 2-containing protein tyrosinase phosphatase (Shp2). A multiplicity of inhibitors of this activity is known, including Fumosorine, PUPS (N SC- 87877) and NSC-117199, phenyihydrazonopyrazolone sulfonate (PHPS1), DC A,
  • cryptotanshinone 11 -BOS and #220-324, metalioproteinases-2 and -9 (MMP-2 and MMP-9) and certain cathepsins, in particular B, D and L.
  • MMP-2 and MMP-9 metalioproteinases-2 and -9
  • cathepsins in particular B, D and L.
  • Other agents include inhibitors of E-cadherin and of epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • Known inhibitors include erlotinib, an anti-integrin drug (cilengitide), cariporide, eniporide and amiloride.
  • the formulations may include other components that act as excipients or serve purposes other than active anti-tumor effects.
  • preservatives like antioxidants e.g., ascorbic acid or a-lipoic acid and antibacterial agents may be included.
  • Other components apart from therapeutically active ingredients and components that are the primary effectors of dermal penetration may include those provided for aesthetic potposes such as menthol or other aromatics, and components that affect the physical state of the composition such as emulsifiers, for example, Durasoft® (which is a mixture of
  • thermoplastic polyurethane and polycarbonate typically, these ingredients are present in ven,' small percentages of the compositions. It is understood that these latter ancillary agents are neither therapeutically ingredients nor are they components that are primarily responsible for penetration of the skin. The components that primarily effect skin penetration have been detailed as described above. However, some of these substances have some capability for effecting skin penetration. See, for example, Kunta, J.R. et al, J. Pharm. Sci. (1997)
  • the final formulation for transdermal administration may be in the form of a micellular composition.
  • Typical micelle dimensions are in the range of !O-lOOnm, Methods for providing micellular forms are known in the art. Micelle formation is encouraged by appropriate levels of components that are capable of micellular formation, as well as exertion of mechanical agitation. (See Cheng, C-Y et al. (2014) supra). Various devices for encouraging micelle formation are available commercially.
  • formation of micelles is enhanced by milling.
  • the level of enhancement is determined by the pressure and speed at which milling occurs as well as the number of passes through the milling machine. As the number of passes and speed and pressure are increased, the level of micelle formulation is enhanced.
  • typical speeds include any variation between 1 to 100, where 1 is the slowest and 100 is the fastest.
  • the pressure is selected from I to 5, where 1 is the highest and 5 is the lowest.
  • micelle densities can be compared microscopically to assure equivalent results to those obtained with Dermamill 100.
  • the micelle density is at least 20% and in many cases at least 30%, or more.
  • the dimensions of the micelles are in the nanometer range - e.g., 10- 150nm, including intermediate values.
  • This form of the formulation is particularly significant in those formulations that contain bile salts.
  • a bile salt is added to the combination of benzyl alcohol and lecithin organogel in lieu of topping off with an aqueous medium
  • micelles that would have been relatively spherical may become elongated and worm-like thus permitting superior penetration of the stratum corneum of the epidermis.
  • the worm like formation of the micelles is particularly helpful in accommodating higher molecular weight therapeutic agents.
  • bile salts are facial amphiphiles and include salts of taurocholic acid, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, cholic acid, deoxycholic acid.
  • Detergents are also useful in lieu of bile salts, and include Tween® 80 and
  • bile salts thus facilitates the ultradeformability of micelles which, in turn, facilitate passage of low and high molecular weight daigs and other active agents, such as nucleic acids and proteins.
  • These compositions overcome the skin penetration barrier by squeezing themselves along the intercellular sealing lipid thereby following the natural gradient across the stratum corneum. This facilitates a change in membrane composition locally and reversibly when pressed against or attracted to a narrow pore.
  • bile salts in combination with lecithin organogel facilitate the factors of micellar stability, enhanced viscosity and visco-elasticity that are critical in transdermal drug deliver ⁇ -. Both thermodynamic and kinetic stability are enhanced by the addition of background electrolytes, such as sodium chloride and sodium citrate. These electrolytes can more effectively increase viscosity and visco-elasticity of micelles and screen the repulsion between bile salt anions at a minimal concentration.
  • the molar ratio of bile salt to lecithin is 1 : 1, and the concentration of electrolyte is determined by titration of the solution to transparency and enhanced viscosity as determined when the solution container is inverted.
  • Formulations designed for transdermal administration of the active ingredients specifically buffering agents and other therapeutically effective compounds and any ancillary components can be tested in a variety of known protocols for their nature and for their effectiveness in effecting transit across the skin.
  • the level of miceliular formation can be determined by rheological study on a commercially available rheometrics RDA-3 strain controlled rheometer.
  • Levels of collagen and proteoglycan components of the extracellular matrix in skin from subjects exposed to the penetrating composition can be measured histologically, for instance with H & E and Alician blue.
  • Skin models have been prepared as three dimensional constructs using human derived epidermal keratinocytes and cultured on normal human derived dermal fibroblasts to create a multi-layered highly differentiated model of human dermis and epidermis.
  • Water loss measurements may also be pertinent and these can be measured using the commercially available dermalab evaporimetry system marketed by Cortex Technology, Hadsun, Denmark.
  • Collagen message levels may also be measured using standard techniques and the permeability of the human epidermis may be measured by determining the electrical conductivity. Monitoring electrical conductivity of skin exposed to various formulations will identify the most efficient formulations in increasing permeability. Tracer elements such as copper and iron can also be used to ascertain the effectiveness of penetration as can chromatographic analysis of components that transit skin layers,
  • TGA Thioglycoiic Acid
  • the aspect of the invention that includes administering buffers so as to raise the pH locally at the environment of a solid tumor or in the vicinity of gout or melasma, expands the indications to which the methods of the invention are applicable. It has been found, generally, that the requirements for effective penetration of the skin in the case of buffers as active agents are less restrictive than those required for alternative agents useful in preventing cancer metastasis. While the penetrants described above in detail are useful, a wider range of concentrations of, for example, lecithin organogel is effective in these cases. In some cases, extra lecithin in addition to that in an organogel is included. In addition, although for these indications delivery to the locus of the solid tumor, including melanoma, or melasma or gout is desirable, effective systemic pH alteration can be used as a way to diagnose the
  • elevation of the pH of urine in a model system such as a mouse can be used to verify the effectiveness of the penetrants in the formulation although the effect on pH is desirably local to the tumor, melasma or gout.
  • LIP lecithin organogel comprised of a 1 : 1 molar mixture of soy lecithin containing 96% phosphatidyl choline and isopropyl palmitate
  • BA benzyl alcohol
  • PLU-F127 represents the detergent poloxamer F127 granules
  • PLU-Water represents PLU-F127 dissolved in deionized water.
  • Pluronic F127 30% gel could be used
  • Durasoft® is a commercially available form of emulsifier.
  • Pluronic Granules 4,20% 4,20% 4,20% 5.40% 2.10% 3.60%
  • cetiol ultimate (mixture of tndecane and
  • mice 24 NCR nude 5 week old male mice were used in this study, divided into four groups of six mice each. Topical compositions were applied to the back of each mouse from hip to shoulder three times per day for 8 successive days for a total of 24 applications.
  • a control group was administered sodium bicarbonate in water by mouth. The groups are as follows:
  • the transdermal formulations comprise penetrants to result in the formulations as follows: LIP-30.0%, EtOH-1.5%, BA-1.0%, menthol-0.5%, sodium bicarbonate-33.5%,
  • concentration of sodium bicarbonate in the control group was 200 mM and the consumption was ad libidum.
  • concentration of sodium bicarbonate in the transdermal formulations was 33.5% wt/wt.
  • Urine samples were collected at one hour, three hours and six hours after the first drag application and stored at 4°C for subsequent pH determination. On days 2-12 urine was collected twice daily— prior to the first application and 15 minutes after the last application. The mice were sacrificed one hour after the last drug application on day 8 and the back skin was harvested and placed on bibulous paper.
  • Table 8 Mean urine pH at two collection time points on day one and overall.
  • Healthy human Subjects Aged 18-60 were enrolled in a double-blinded, placebo controlled, randomized and cross-over in designed study.
  • the subjects applied 0.6g/kg of body weight of formulation of Table 9, per randomi zati on group, as follows: legs from ankle to top of thighs; arms from wrist to shoulder (including the deltoids) or drank 0.13 ounces of water per kg body weight (equates to about 8 ounces for a 140 pound subject) at 15 min, 1 hr 15 min, 2 hours and 15 min, 3 hours and 15 mins to control for dilution of urine.
  • a randomized, double-blinded, placebo controlled study of the efficacy and safety of a topical alkaiinizing treatment for reducing pain associated with an acute gout flare was conducted to determine if topical application of sodium bicarbonate and menthol in a transdermal delivery system can effectively and safely reduce pain associated with an acute gout flare and if time to resolution is shortened.
  • the subjects reported joint pain as measured using a 11 -point scale (0-10, with 0 as “no pain” and 10 as “worst possible pain”).
  • the reduction in pain in the target joints for the Active group was -3.0 points both after 30 minutes and 24 hours and -3.5 points at 4 days and 6 days
  • Subjects in the Control Group showed no reduction at 30 minutes and 2 days and only -1 point after 24 hours and at 4 and 6 days.
  • the maximum reduction in pain in a secondary joint for the Active group was -2 points, versus less or no reduction in pain for the Control group.
  • TA tranexamic acid
  • GA glycolic acid
  • RA retinoic acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne le dosage parentéral (autre que le dosage systémique direct) de l'augmentation du pH et d'autres agents anti-métastases seuls ou combiné, qui est efficace et permet de surmonter les inconvénients de l'administration intraveineuse et orale dans le traitement de tumeurs solides, du mélasma et de la goutte.
PCT/US2018/028017 2017-04-17 2018-04-17 Administration parentérale non systémique d'agents tampons pour inhiber la métastase de tumeurs solides, l'hyperpigmentation et la goutte WO2018195111A1 (fr)

Priority Applications (27)

Application Number Priority Date Filing Date Title
MX2019012385A MX390709B (es) 2017-04-17 2018-04-17 Administración parenteral no sistémica de agentes amortiguadores para inhibir la metástasis de tumores sólidos, hiperpigmentación y gota.
AU2018255294A AU2018255294B2 (en) 2017-04-17 2018-04-17 Parenteral non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout
KR1020197033931A KR20200042440A (ko) 2017-04-17 2018-04-17 고형종양, 과다색소침착 및 통풍의 전이를 억제하기 위한 완충제의 비경구 비전신적 투여
CN201880040474.5A CN111093774A (zh) 2017-04-17 2018-04-17 用于抑制实体瘤的转移、色素沉着过度和痛风的缓冲剂的肠胃外非全身性施用
EP18787621.4A EP3612274A4 (fr) 2017-04-17 2018-04-17 Administration parentérale non systémique d'agents tampons pour inhiber la métastase de tumeurs solides, l'hyperpigmentation et la goutte
JP2020506134A JP2020516690A (ja) 2017-04-17 2018-04-17 固形腫瘍の転移、色素沈着過剰および痛風を阻害する緩衝剤の非経口非全身投与
EP18856604.6A EP3681479B1 (fr) 2017-09-15 2018-09-14 Bicarbonate de sodium pour utilisation dans le traitement de la goutte et de troubles associés
US16/132,358 US20190083386A1 (en) 2017-09-15 2018-09-14 Methods and formulations for transdermal administration of buffering agents
EP23195939.6A EP4324460A3 (fr) 2017-09-15 2018-09-14 Bicarbonate de sodium pour utilisation dans le traitement de la goutte et de troubles associés
PCT/US2018/051250 WO2019055880A2 (fr) 2017-09-15 2018-09-14 Méthode d'administration et de traitement
JP2020515698A JP2020534285A (ja) 2017-09-15 2018-09-14 投与および処置の方法
US16/132,357 US20190083527A1 (en) 2017-09-15 2018-09-14 Method of administration and treatment
US16/546,256 US10639326B2 (en) 2017-09-15 2019-08-20 Method of administration and treatment
US16/546,260 US10632146B2 (en) 2017-09-15 2019-08-20 Method of administration and treatment
US16/866,466 US10933088B2 (en) 2017-09-15 2020-05-04 Method of administration and treatment
US17/168,114 US11730756B2 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/168,111 US20210228623A1 (en) 2017-09-15 2021-02-04 Method of administration and treatment
US17/488,154 US20220016159A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,132 US11357792B2 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/488,143 US20220016158A1 (en) 2017-09-15 2021-09-28 Method of administration and treatment
US17/497,794 US11793830B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
US17/497,799 US11389472B2 (en) 2017-09-15 2021-10-08 Method of administration and treatment
US17/514,653 US11744853B2 (en) 2017-09-15 2021-10-29 Method of administration and treatment
AU2022241559A AU2022241559B2 (en) 2017-04-17 2022-09-29 Parenteral non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout
US18/331,875 US12310983B2 (en) 2023-06-08 Method of administration and treatment
JP2023146344A JP2023179467A (ja) 2017-09-15 2023-09-08 投与および処置の方法
AU2023254920A AU2023254920A1 (en) 2017-04-17 2023-10-25 Parenteral non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout

Applications Claiming Priority (16)

Application Number Priority Date Filing Date Title
US201762602227P 2017-04-17 2017-04-17
US62/602,227 2017-04-17
US201762602358P 2017-04-20 2017-04-20
US201762602359P 2017-04-20 2017-04-20
US62/602,358 2017-04-20
US62/602,359 2017-04-20
US201762559360P 2017-09-15 2017-09-15
US62/559,360 2017-09-15
US201762559947P 2017-09-18 2017-09-18
US62/559,947 2017-09-18
US201762562725P 2017-09-25 2017-09-25
US62/562,725 2017-09-25
US201762609982P 2017-12-22 2017-12-22
US62/609,982 2017-12-22
US201862639904P 2018-03-07 2018-03-07
US62/639,904 2018-03-07

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US16/132,257 Continuation-In-Part US10952630B2 (en) 2013-07-23 2018-09-14 Device for electrophysiological recording from the eye
US16/132,357 Continuation-In-Part US20190083527A1 (en) 2017-09-15 2018-09-14 Method of administration and treatment
US16/132,358 Continuation-In-Part US20190083386A1 (en) 2017-09-15 2018-09-14 Methods and formulations for transdermal administration of buffering agents

Publications (1)

Publication Number Publication Date
WO2018195111A1 true WO2018195111A1 (fr) 2018-10-25

Family

ID=63856054

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/028017 WO2018195111A1 (fr) 2017-04-17 2018-04-17 Administration parentérale non systémique d'agents tampons pour inhiber la métastase de tumeurs solides, l'hyperpigmentation et la goutte

Country Status (7)

Country Link
EP (1) EP3612274A4 (fr)
JP (1) JP2020516690A (fr)
KR (1) KR20200042440A (fr)
CN (1) CN111093774A (fr)
AU (3) AU2018255294B2 (fr)
MX (1) MX390709B (fr)
WO (1) WO2018195111A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019075492A1 (fr) * 2017-09-25 2019-04-18 Ampersand Biopharmaceuticals, Inc. Applications topiques de withaférine a
WO2020086766A1 (fr) * 2018-10-23 2020-04-30 Ampersand Biopharmaceuticals, Inc. Méthodes et formulations pour l'administration transdermique d'agents de remodelage dermique
WO2020093069A1 (fr) * 2018-11-02 2020-05-07 Ampersand Biopharmaceuticals, Inc. Gestion du risque de surcharge cationique et de déséquilibre électrolytique avec des agents tampons appliqués par voie topique
US20210059955A1 (en) * 2019-08-26 2021-03-04 RL Patents, LLC Systems and methods for decrystallization of uric acid
US11357792B2 (en) 2017-09-15 2022-06-14 Dyvve Biosciences, Inc. Method of administration and treatment
US11491225B2 (en) 2014-12-23 2022-11-08 Dyve Biosciences, Inc. Transdermal carrier
CN116284814A (zh) * 2023-01-17 2023-06-23 杭州三式化妆品有限公司 超分子传明酸甘醇酸离子盐及其制备方法和应用
CN116539880A (zh) * 2022-12-05 2023-08-04 四川大学华西医院 检测代谢物和/或组织蛋白的试剂在制备痛风性关节炎筛查试剂盒中的用途
US12310983B2 (en) 2023-06-08 2025-05-27 Dyve Biosciences, Inc. Method of administration and treatment

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113181149A (zh) * 2021-06-11 2021-07-30 北京畅盛医药科技有限公司 一种治疗痛风性关节炎的皮肤外用药物制剂
US20230330041A1 (en) * 2020-08-27 2023-10-19 Beijing Changsheng Pharmaceutical Technology Co., Ltd. Application of tris (hydroxymethyl) aminomethane pharmaceutically acceptable salt to drugs for treating hyperuricemia

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069150A (en) * 1996-04-04 2000-05-30 F. Hoffman-La Roche Ag Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
CN101897784A (zh) * 2009-05-27 2010-12-01 北京因科瑞斯医药科技有限公司 一种用于痛风的中药组合物及其制备方法
US20110064828A1 (en) * 2009-09-11 2011-03-17 Novelos Therapeutics, Incorporated Treatment of metastatic tumors and other conditions
US20110230551A1 (en) * 2008-09-15 2011-09-22 Leslie Gunatilaka Withaferin a analogs and uses thereof
US20120277245A1 (en) * 2009-11-24 2012-11-01 H. Lee Moffitt Cancer Center And Research Institute, Inc. Method of Increasing Intratumoral pHe and Reducing Acid-Mediated Invasion
US20150057361A1 (en) * 2012-03-28 2015-02-26 University Of Central Florida Research Foundation, Inc. Anti-metastatic agents predicated upon polyamine macrocyclic conjugates
WO2016105499A1 (fr) * 2014-12-23 2016-06-30 Intellectual Property Associates, Llc Méthodes et formulations pour l'administration transdermique

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5176918A (en) * 1990-12-20 1993-01-05 Jones Jeffry L Topical medicament
US20030129251A1 (en) * 2000-03-10 2003-07-10 Gary Van Nest Biodegradable immunomodulatory formulations and methods for use thereof
US20030228374A1 (en) * 2002-06-07 2003-12-11 Pesacreta Thomas C. Topical treatment for skin irritation
AU2002950308A0 (en) * 2002-07-23 2002-09-12 Phoenix Eagle Company Pty Ltd Topically applied composition
WO2007103555A2 (fr) * 2006-03-08 2007-09-13 Nuviance, Inc. Composition de médicament à libération transdermique et compositions topiques pour application cutanée
WO2012064429A2 (fr) * 2010-11-09 2012-05-18 The Regents Of The University Of California Peptides entrant dans les cellules et traversant la peau (space) et leurs procédés d'utilisation
EP2692348A4 (fr) * 2011-03-29 2014-09-03 Neochemir Inc Agent antitumoral contenant du dioxyde de carbone en tant que principe actif
CN106236937A (zh) * 2016-08-31 2016-12-21 腾冲恒益东山休闲度假有限责任公司 能缓解痛风性关节炎的泡浴液

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6069150A (en) * 1996-04-04 2000-05-30 F. Hoffman-La Roche Ag Use of derivatives of tetrahydro-beta-carbolines as antimetastatic agents
US20110230551A1 (en) * 2008-09-15 2011-09-22 Leslie Gunatilaka Withaferin a analogs and uses thereof
CN101897784A (zh) * 2009-05-27 2010-12-01 北京因科瑞斯医药科技有限公司 一种用于痛风的中药组合物及其制备方法
US20110064828A1 (en) * 2009-09-11 2011-03-17 Novelos Therapeutics, Incorporated Treatment of metastatic tumors and other conditions
US20120277245A1 (en) * 2009-11-24 2012-11-01 H. Lee Moffitt Cancer Center And Research Institute, Inc. Method of Increasing Intratumoral pHe and Reducing Acid-Mediated Invasion
US20150057361A1 (en) * 2012-03-28 2015-02-26 University Of Central Florida Research Foundation, Inc. Anti-metastatic agents predicated upon polyamine macrocyclic conjugates
WO2016105499A1 (fr) * 2014-12-23 2016-06-30 Intellectual Property Associates, Llc Méthodes et formulations pour l'administration transdermique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BAILEY K. M. ET AL.: "Mechanisms of buffer therapy resistance", NEOPLASIA, vol. 16, no. 4, 2014, pages 354 - 364, XP055544145 *

Cited By (17)

* 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
US12070503B2 (en) 2014-12-23 2024-08-27 Dyve Biosciences, Inc. Transdermal carrier
US11357792B2 (en) 2017-09-15 2022-06-14 Dyvve Biosciences, Inc. Method of administration and treatment
US11744853B2 (en) 2017-09-15 2023-09-05 Dyve Biosciences, Inc. Method of administration and treatment
US11793830B2 (en) 2017-09-15 2023-10-24 Dyve Biosciences, Inc. Method of administration and treatment
US11730756B2 (en) 2017-09-15 2023-08-22 Dyve Biosciences, Inc. Method of administration and treatment
US11389472B2 (en) 2017-09-15 2022-07-19 Dyve Biosciences, Inc. Method of administration and treatment
WO2019075492A1 (fr) * 2017-09-25 2019-04-18 Ampersand Biopharmaceuticals, Inc. Applications topiques de withaférine a
WO2020086766A1 (fr) * 2018-10-23 2020-04-30 Ampersand Biopharmaceuticals, Inc. Méthodes et formulations pour l'administration transdermique d'agents de remodelage dermique
JP2022536222A (ja) * 2018-11-02 2022-08-15 アンパサンド バイオファーマシューティカルズ インコーポレイテッド 局所的に施用される緩衝液によるカチオン過負荷および電解質平衡異常のリスクの管理
WO2020093069A1 (fr) * 2018-11-02 2020-05-07 Ampersand Biopharmaceuticals, Inc. Gestion du risque de surcharge cationique et de déséquilibre électrolytique avec des agents tampons appliqués par voie topique
EP3906059A4 (fr) * 2018-11-02 2022-06-22 Ampersand Biopharmaceuticals, Inc. Gestion du risque de surcharge cationique et de déséquilibre électrolytique avec des agents tampons appliqués par voie topique
US20210059955A1 (en) * 2019-08-26 2021-03-04 RL Patents, LLC Systems and methods for decrystallization of uric acid
CN116539880A (zh) * 2022-12-05 2023-08-04 四川大学华西医院 检测代谢物和/或组织蛋白的试剂在制备痛风性关节炎筛查试剂盒中的用途
CN116539880B (zh) * 2022-12-05 2023-12-08 四川大学华西医院 检测代谢物和/或组织蛋白的试剂在制备痛风性关节炎筛查试剂盒中的用途
CN116284814A (zh) * 2023-01-17 2023-06-23 杭州三式化妆品有限公司 超分子传明酸甘醇酸离子盐及其制备方法和应用
US12310983B2 (en) 2023-06-08 2025-05-27 Dyve Biosciences, Inc. Method of administration and treatment

Also Published As

Publication number Publication date
CN111093774A (zh) 2020-05-01
AU2022241559A1 (en) 2022-10-27
AU2018255294A1 (en) 2019-12-05
JP2020516690A (ja) 2020-06-11
KR20200042440A (ko) 2020-04-23
EP3612274A4 (fr) 2021-05-26
AU2023254920A1 (en) 2023-11-16
AU2022241559B2 (en) 2023-07-27
MX2019012385A (es) 2022-03-15
EP3612274A1 (fr) 2020-02-26
MX390709B (es) 2025-03-21
AU2018255294B2 (en) 2022-07-28

Similar Documents

Publication Publication Date Title
AU2018255294B2 (en) Parenteral non-systemic administration of buffering agents for inhibiting metastasis of solid tumors, hyperpigmentation and gout
ES2819148T3 (es) Reducción de tejido adiposo
JP2023179467A (ja) 投与および処置の方法
JP5047782B2 (ja) フィコトキシン及びその使用
WO2012131734A1 (fr) Composition topique destinée au traitement du vitiligo
EP2431031A2 (fr) Composition pour prévenir la perte de cheveux ou stimuler la pousse des cheveux
CN103108640B (zh) 包含烟酸腺嘌呤二核苷酸磷酸或该烟酸腺嘌呤二核苷酸磷酸的衍生物的药学或者化妆料组合物
CN101123967A (zh) 藻毒素的经皮给药
US20210268122A1 (en) Inhibition of spontaneous metastasis via protein inhibitors of cysteine proteases
JP2025011085A (ja) プラスミノーゲンアクチベーターインヒビター１（ｐｌａｓｍｉｎｏｇｅｎ ａｃｔｉｖａｔｏｒ ｉｎｈｉｂｉｔｏｒ １）（ＰＡＩ－１）阻害剤（ｉｎｈｉｂｉｔｏｒ）およびその使用
JP2012077083A (ja) Ｓｚｅｔｏ−Ｓｃｈｉｌｌｅｒペプチドの局所麻酔的使用
EP2907520B1 (fr) Composition pour favoriser la cicatrisation des plaies
CN112979762B (zh) 环肽piz及其用途
KR20110060529A (ko) 시클로헥산 디카르복실산 유도체를 함유하는 피부 외용제 조성물
US12310983B2 (en) Method of administration and treatment
WO2024184889A1 (fr) Méthodes de traitement

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18787621

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020506134

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2018787621

Country of ref document: EP

Effective date: 20191118

ENP Entry into the national phase

Ref document number: 2018255294

Country of ref document: AU

Date of ref document: 20180417

Kind code of ref document: A

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载