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WO2016210230A1 - Utilisations thérapeutiques de formulations de berbérine - Google Patents

Utilisations thérapeutiques de formulations de berbérine Download PDF

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Publication number
WO2016210230A1
WO2016210230A1 PCT/US2016/039180 US2016039180W WO2016210230A1 WO 2016210230 A1 WO2016210230 A1 WO 2016210230A1 US 2016039180 W US2016039180 W US 2016039180W WO 2016210230 A1 WO2016210230 A1 WO 2016210230A1
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WIPO (PCT)
Prior art keywords
inhibitors
berberine
biologically equivalent
group
equivalent analogue
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/US2016/039180
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English (en)
Inventor
Carl Oscar BROWN, III
Po-Yuan TSENG
I-Yin Lin
Chen-En Tsai
Chih-Kuang Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
TWi Biotechnology Inc
Original Assignee
TWi Biotechnology Inc
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 US15/161,576 external-priority patent/US20160263092A1/en
Priority to MX2018000262A priority Critical patent/MX2018000262A/es
Application filed by TWi Biotechnology Inc filed Critical TWi Biotechnology Inc
Priority to RU2018102700A priority patent/RU2733743C2/ru
Priority to EP16815356.7A priority patent/EP3313520A4/fr
Priority to KR1020187001673A priority patent/KR20180020229A/ko
Priority to HK18108954.7A priority patent/HK1249068A1/zh
Priority to AU2016282800A priority patent/AU2016282800A1/en
Priority to CN201680049200.3A priority patent/CN107921284A/zh
Priority to CA2990237A priority patent/CA2990237A1/fr
Priority to JP2017566661A priority patent/JP2018518507A/ja
Priority to BR112017027897A priority patent/BR112017027897A2/pt
Publication of WO2016210230A1 publication Critical patent/WO2016210230A1/fr
Priority to IL256400A priority patent/IL256400A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • 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
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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Definitions

  • Red face related skin disorders which share symptomatic similarities and probably pathological causes, include rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis and contact dermatitis. These red face related conditions may range from feelings of heat and sensitivity to flushing or burning with intense sensitivity. Patients with red face related skin disorders often exhibit extreme sensitivity to environmental and topical factors. Steroid-induced rosacea-like dermatitis (or steroid rosacea) is papular or pustular lesions with erythematous and edematous base with or without telangiectasia, which is caused by prolonged application of topical steroids to the face or as a rebound condition after discontinuation of topical steroids.
  • Dermatologic toxicities are known cutaneous adverse events associated with targeted therapies or immunotherapy and share similar symptoms and probable pathologic causes of the red face-related skin disorders.
  • Targeted therapies such as epidermal growth factor receptor
  • EGFR EGFR inhibitors
  • MTK multityrosine kinase
  • MEK MEK inhibitors
  • PI3K 3-kinase
  • protein kinase B (AKT) inhibitors protein kinase B (AKT) inhibitors
  • BRAF inhibitors BRAF inhibitors
  • HER2 inhibitor multikinase angiogenesis inhibitors
  • mTOR inhibitors ALK/c-met inhibitors
  • multikinase Abl inhibitors BTK inhibitors
  • HDAC inhibitors HDAC inhibitors
  • proteasome inhibitors and retinoid X receptor (RXR) agonists
  • immunotherapies such as cancer vaccines, cytokine agents (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons, and interleukin-2
  • cytokine agents e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF)
  • interferons interferons
  • interleukin-2 interleukin-2
  • IL-2 tumor-infiltrating lymphocytes
  • TILs tumor-infiltrating lymphocytes
  • TCR tumor necrosis factor receptor
  • PBL peripheral blood lymphocytes
  • CAR immune checkpoint protein inhibitors
  • PD-1 PD-1 , PD-L1 , CTLA-4
  • CTLA-4 immune checkpoint protein inhibitors
  • TIM-3 LAG-3, BTLA, VISTA, and TIGIT
  • immune checkpoint protein stimulators e.g., CD28, ICOS, 4-1 BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 , and CD-40
  • toxicities including papulopustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction, which may occur in more than 90% of patients and may also superinfected with bacteria, such as staphylococcus aureus (Wollenberg, Kroth et al., Cutaneous side effects of EGFR inhibitors-appearance and management, Dtsch Med Klischr 2010; Lacouture, Maitland et al., A proposed EGFR inhibitor dermatologic adverse event
  • a maculopapular rash was more commonly described with PI3K inhibitors like BKM-120 (37% of patients), MK2206 (52% of patients) therapy, immune checkpoint protein inhibitors like anti-CTLA-4 inhibitor ipilimumab (33% of patients), anti-PD-1 inhibitor nivolumab (26% of patients), or combination of ipilimumab and nivolimumab (more than 40% of patients).
  • PI3K inhibitors like BKM-120 (37% of patients), MK2206 (52% of patients) therapy, immune checkpoint protein inhibitors like anti-CTLA-4 inhibitor ipilimumab (33% of patients), anti-PD-1 inhibitor nivolumab (26% of patients), or combination of ipilimumab and nivolimumab (more than 40% of patients).
  • Berberine Natural Yellow 18, 5,6-dihydro-9,10-dimethoxybenzo(g)-1 ,3-benzodioxolo (5,6-a) quinolizinium
  • Berberine and its derivatives have been found to have antimicrobial and antimalarial activities. It can act against various kinds of pathogens such as fungi, saccharomycete, parasite, bacterium and virus.
  • Berberine also has anti-inflammatory function, yet the exact mechanism is unknown.
  • U.S. Pat. No. 6,440,465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis.
  • U.S. Patent Publication No. 2005/0158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and an herbal source of berberine for the treatment of acne in oral administration.
  • 6,974,799 relates to topical compositions comprising a tripeptide (N-palmitoyl-Gly-His-Lys) and a tetrapeptide (N-palmitoyl-Gly-Gln-Pro-Arg) for the treatment of visible signs of aging including wrinkles, stretch marks, dark circles.
  • the formulation may contain additional ingredients, including berberine. In these inventions, berberine is included as one of the many ingredients and its concentration is not specified.
  • U.S. Patent Publication 2004/0146539 relates to topical nutraceutical compositions with body slimming and tone-firming anti-aging benefits that may be used to treat skin aging, skin wrinkle, skin exfoliating, acne, rosacea and other skin problems.
  • the composition of this invention includes antimicrobial agents selected from several agents including berberine.
  • berberine is included as one of the many ingredients and its concentration is not specified.
  • U.S. Patent Publication 2012/0165357 discloses the use of berberine to treat various red face related skin disorders but it does not disclose any specific formulations of berberine that would be found to be effective for the treatment of specific conditions.
  • the present invention provides pharmaceutical compositions for the treatment and/or prevention of red face related skin disorders and dermatologic toxicities induced by targeted therapy and/or immunotherapy.
  • the provided formulations are either cream-based (i.e., cream) formulations or gel-based formulations.
  • the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a cream formulation comprising a water phase and an oil phase.
  • the concentration of berberine in the provided cream formulations is between 0.01% and 10%, preferably between 0.01% and 0.3% w/w, more preferably between 0.1% and 0.2% w/w, even more preferably between 0.1% and 0.15% w/w, and most preferably about 0.12% w/w.
  • compositions of the invention may further comprise a penetration enhancer.
  • the penetration enhancer is an anionic penetration enhancer.
  • the penetration enhancer comprises Tween® 60 and glycerin.
  • berberine is the only pharmaceutically active component in the provided formulations.
  • the pharmaceutical compositions of the invention have a pH of between about 4 and about 7, and more preferably of about 5.5.
  • the invention provides a pharmaceutical composition comprising berberine as the only pharmaceutically active component, wherein said berberine is at a concentration of between 0.1% and 0.2% w/w, wherein said composition is a cream formulation comprising a water phase and an oil phase, wherein said composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein said composition has a pH of between about 4 and about 7.
  • the invention provides a pharmaceutical composition comprising berberine as the only pharmaceutically active component, wherein said berberine is at a concentration of about 0.12% w/w, wherein said composition is a cream formulation comprising a water phase and an oil phase, wherein said composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein said composition has a pH of about 5.5.
  • the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel-based formulation, wherein said composition comprises an anionic penetration enhancer.
  • the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS).
  • about 90% of an average particle size of the berberine is less than 10 ⁇ .
  • about 50% of an average particle size of the berberine is less than 4 ⁇ .
  • the concentration of berberine in the provided gel-based formulations is between 0.01% and 0.3% w/w, more preferably between 0.1% and 0.2% w/w, even more preferably between 0.1% and 0.15% w/w, and most preferably about 0.12% w/w.
  • the invention also provides methods of treating a red face related skin disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the invention.
  • red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitor-induced skin disorder.
  • EGFR epidermal growth factor receptor
  • the invention further provides methods of treating and/or preventing dermatologic toxicities induced by targeted therapy and/or immunotherapy comprising administering to a patient in need thereof a pharmaceutically effective amount of berberine and/or a biologically equivalent analogue thereof.
  • the targeted therapy comprises therapies by EGFR inhibitors, MTK inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, BRAF inhibitors, HER2 inhibitor, multikinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multikinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists.
  • the immunotherapy comprises therapies by cancer vaccines, cytokine agents (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons, and interleukin-2 (IL-2)), cell therapies (e.g., tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR)-engineered peripheral blood lymphocytes (PBL), and chimeric antigen receptor (CAR)-engineered PBL), immune checkpoint protein inhibitors (e.g., PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA, and TIGIT), and immuno checkpoint protein stimulators (e.g., CD28, ICOS, 4-1 BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1, and CD-40).
  • cytokine agents e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF),
  • berberine and/or the biologically equivalent analogue thereof is administered to the patient in form of a topical pharmaceutical composition.
  • Figure 1 is a plot of cumulative berberine penetrated (ng/cm 2 ) vs time for six tested formulations of berberine.
  • Figure 2 is a plot of cumulative berberine penetrated (ng/cm 2 ) vs time for three gel suspension formulations of berberine (G22, G23 and G24).
  • Figure 3 is a picture showing hematoxylin and eosin (H&E) staining of bilateral skin biopsies from nasolabial folds of a patient receiving afatinib and topically administered with a gel formulation (G23) on one side of his face.
  • H&E hematoxylin and eosin
  • Figure 4 is a picture showing H&E staining of bilateral skin biopsies from nasolabial folds of the patient receiving the EGFR inhibitor afatinib and topically administered with a vehicle gel (G23 without berberine) on the other side of his face.
  • Figure 5 is a plot of papule counts vs time for a patient receiving afatinib and topically administered with a gel formulation (G23) on one side of his face and a vehicle gel (G23 without berberine) on the other side of his face (* denotes P ⁇ 0.05 by Wilcoxon Signed Rank test).
  • Figure 6 is a plot of pustule counts vs time for the patient receiving afatinib and topically administered with the gel formulation (G23) on one side of his face and the vehicle gel (G23 without berberine) on the other side of his face (* denotes P ⁇ 0.05 by Wilcoxon Signed Rank test).
  • Figure 7 is a plot of total counts (papule plus pustule) vs time for the patient receiving afatinib and topically administered with the gel formulation (G23) on one side of his face and the vehicle gel (G23 without berberine) on the other side of his face (* denotes P ⁇ 0.05 by Wilcoxon Signed Rank test).
  • Berberine is a hydrophilic compound (a partition coefficient of 1.07 in an octanol-water system) which makes it hard for berberine to penetrate through the stratum corneum (SC) to reach the target site, e.g. dermis or epidermis, where red face related skin disorders or targeted therapy-induced dermatologic toxicities may occur.
  • SC stratum corneum
  • berberine is rather soluble (solubility of 1.57 mg/ml) and will therefore be quickly released into the target cells, leading to a temporary effect.
  • the present invention thus provides pharmaceutical compositions having an improved penetration rate of berberine for the treatment and/or prevention of red face related skin disorders and dermatological toxicities induced by targeted therapy and/or immunotherapy.
  • the provided formulations are either cream-based (i.e., cream) formulations or gel-based formulations.
  • the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a cream formulation comprising a water phase and an oil phase.
  • the cream formulations of the invention may promote the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve desired treating effects.
  • the concentration of berberine in the provided cream formulations is between 0.01% and 10% w/w, preferably 0.01% and 0.3% w/w, more preferably between 0.1% and 0.2% w/w, even more preferably between 0.1% and 0.15% w/w, and most preferably about 0.12% w/w, on the basis of the total weight of the formulation.
  • compositions of the invention may further comprise a penetration enhancer.
  • the penetration enhancer is an anionic penetration enhancer.
  • the anionic penetration enhancer may comprise sodium dodecyl sulfate (SDS).
  • the penetration enhancer comprises Tween® 60 and glycerin.
  • the cream formulations of the invention preferably include Tween® 60 and glycerin as penetration enhancers. When the same penetration enhancers are used in non-cream formulations, they do not result in an improved penetration rate, suggesting that there is something unique about the cream-based formulations.
  • berberine is the only pharmaceutically active component in the provided formulations. Even if an ingredient of the provided formulations may be an active component in prior art formulations for purposes other than treatment of dermatologic toxicities induced by targeted therapy or immunotherapy, it is still considered a pharmaceutical excipient for the purposes of the provided formulations as long as this ingredient is not present at an amount sufficient to effectively treat dermatologic toxicities induced by targeted therapy or immunotherapy.
  • the pharmaceutical compositions of the invention have a pH of between about 4 and about 7, and more preferably of about 5.5.
  • the invention provides a pharmaceutical composition comprising berberine as the only pharmaceutically active component, wherein said berberine is at a concentration of between 0.1% and 0.2% w/w, wherein said composition is a cream formulation comprising a water phase and an oil phase, wherein said composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein said composition has a pH of between about 4 and about 7.
  • the invention provides a pharmaceutical composition comprising berberine as the only pharmaceutically active component, wherein said berberine is at a concentration of about 0.12% w/w, wherein said composition is a cream formulation comprising a water phase and an oil phase, wherein said composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein said composition has a pH of about 5.5.
  • cream formulations of the invention have a superior penetration rate compared to non-cream berberine formulations.
  • the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel-based formulation, wherein said composition comprises an anionic penetration enhancer.
  • the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS).
  • SDS sodium dodecyl sulfate
  • Including SDS as an anionic penetration enhancer results in the provided gel-based formulations being hydrophobic (a partition coefficient of 50.1 in an octanol-water system) and having a dramatically lower solubility of about 0.011 mg/ml, allowing for a slow release of berberine into the target cells, resulting in an extended release profile.
  • berberine solubility in the presence of SDS ranges from 0.01 to 0.06 mg/mL, i.e., 25 to 150 times lower than aqueous berberine solubility (1.57 mg/mL), and is relatively low at pH 5.5.
  • about 90% of an average particle size of the berberine is less than 10 ⁇ m.
  • about 50% of an average particle size of the berberine is less than 4 ⁇ .
  • the gel-based formulations of the invention may promote the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve desired treating effects.
  • the concentration of berberine in the provided gel-based formulations is between 0.01% and 0.3% w/w, more preferably between 0.1% and 0.2% w/w, even more preferably between 0.1% and 0.15% w/w, and most preferably about 0.12% w/w, on the basis of the total weight of the formulation.
  • the invention also provides methods of treating a red face related skin disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the invention.
  • red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitor-induced skin disorder.
  • EGFR epidermal growth factor receptor
  • the invention further provides methods of treating and/or preventing dermatologic toxicities induced by targeted therapy and/or immunotherapy comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the invention.
  • said targeted therapy is selected from the group consisting of EGFR, multityrosine kinase (MTK), MEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), BRAF inhibitors, HER2 inhibitor, multikinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multikinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists;
  • said immunotherapy is selected from the group consisting of cancer vaccines, cytokine agents (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF), interferons, and interleukin-2 (IL-2)
  • the concentrations of berberine in epidermis, dermis, and receiver are measured by the following approach.
  • Franz diffusion cell setup is essentially a piece of skin clamped between two clamps. The drug is applied on one side of the skin (top) and drug concentration is measured in the received portion (bottom) of the setup.
  • penetration rate refers to an amount of berberine that presents in per gram of epidermis or dermis tissue, or an amount of berberine per cm 2 of skin that presents in the receiver, after a certain time period from the application of a formulation to the skin.
  • Amount of the drug measured in the receiver indicates the total amount that penetrated through SC, epidermis and dermis region of the skin.
  • the pharmaceutical composition of the present invention has improved penetration rate, and the preferred range of the penetration rate is as follows:
  • Epidermis 0.4 to 4000 ⁇ g of berberine per gram of tissue
  • Receiver 0.0001 to 1 pg of berberine per 1X1 cm 2 of skin.
  • Table 1 lists various ingredients that may be used in the compositions of the invention. This list, however, is only provided for illustration purpose, but not to limit the scope of the present invention. Further, different ingredients/excipients can act in more than one way, e.g. can function as a penetration enhancer, an emulsifying agent, a wetting agent, etc.
  • berine refers to 5,6-lihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo (5,6-a) quinolizinium.
  • the invention also contemplates the use of analogues of berberine which include but are not limited to jatrorrhizine, palmatine, coptisine, 9-demethllberberine, 9-demethylpalmatine, 13-hydroxyberberine, berberrubine, palmatrubine, 9-O-ethylberberrubine, 9-0-ethyl-13-ethylberberrubine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberines and N-methyl salts thereof, 9-lauroylberberrubine chloride, and pharmaceutically acceptable salts of all these compounds.
  • analogues of berberine which include but are not limited to jatrorrhizine, palmatine, coptisine, 9-demethllberberine, 9-demethylpalmatine, 13-hydroxyberberine, berberrubine, palmatrubine, 9-O-ethylberberrubine
  • salts include salts of acidic or basic groups.
  • pharmaceutically acceptable salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids, such as acetic; propionic; isobutyric; maleic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthalic; benzenesulfonic; toluenesulfonic, including p-toluenesulfonic, m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric; methanesulfonic; and the like.
  • inorganic acids such as hydrochloric, hydrobromic,
  • treatment and “treating” include inhibiting the disease or condition, causing a reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, ameliorating and/or improving a patient's condition.
  • "treating" a patient with said compositions of the invention includes prevention of a particular disorder in a susceptible individual, as well as management of a clinically symptomatic individual to inhibit or cause regression of a disorder or disease, and maintenance of the current state and/or prevention of a progression of a disorder or disease.
  • Treatment can include prophylaxis, therapy, or cure, ;
  • the term "pharmaceutically effective amount" of the compounds and/or pharmaceutical compositions of the invention refers to a sufficient amount of the compound and/or composition to treat, inhibit, ameliorate or prevent various red face related skin disorders, including but not limited to, targeted therapy-induced dermatologic toxicities, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and/or compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the composition at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the pharmaceutical composition can further include a pharmaceutically acceptable carrier, and can be in solid or liquid form, including but not limited to, tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, patch, or suppositories, including rectal and urethral suppositories.
  • pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • a pharmaceutically acceptable carrier is compatible with the other ingredients of the composition, with the mode of administration, and not injurious to the patient.
  • a pharmaceutically acceptable carrier may be either aqueous or non-aqueous.
  • Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof.
  • materials which can serve as pharmaceutically-acceptable carriers include, but are not limited to: (a) sugars, such as lactose, glucose and sucrose; (b) starches, such as corn starch and potato starch; (c) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (d) powdered tragacanth; (e) malt; (f) gelatin; (g) talc; (h) excipients, such as cocoa butter and suppository waxes; (i) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; 0) glycols, such as propylene glycol; (k) polyols, such as glycer
  • compositions of the invention may be administered using any means known in the art, including but not limited to oral, nasal, parenteral, topical, transdermal, or rectal routes of administration.
  • the compositions are adapted for oral or topical administration.
  • the active ingredient of the composition can be formulated with suitable excipients for the preparation of tablets, capsules, pellets, troches, lozenges, solutions, powders or granules, suspensions, hard or soft capsules, patches and any other suitable forms.
  • the invention also provides a method of treating and/or preventing dermatologic toxicities induced by targeted therapy and/or immunotherapy comprising administering to a patient in need thereof a pharmaceutically effective amount of berberine or a biologically equivalent analogue thereof.
  • the invention further provides a method of treating and/or preventing dermatologic toxicities induced by targeted therapy and/or immunotherapy comprising topically applying to affected skin a pharmaceutically effective amount of a topical pharmaceutical composition comprising berberine or a biologically equivalent analogue thereof.
  • the topical pharmaceutical composition is in the form of a lotion, cream, ointment, paste, gel, spray, suspension, emulsion, foam, patch, powder and liniment.
  • the topical pharmaceutical composition comprises at least 0.02% w/w, preferably about 0.1% to about 2% w/w of berberine or a biologically equivalent analogue thereof, wherein the amounts are by the total weight of the composition.
  • berberine or the biologically equivalent analogue of berberine is the primary pharmaceutically acceptable active component.
  • berberine or the biologically equivalent analogue of berberine is the only pharmaceutically acceptable active component.
  • berberine (0.12%), Tween® 60 (1%), Glycerin (3%), methylparaben (0.1%), propylparaben (0.02%), NaOH (to adjust pH to 5.5), and EDTA (0.02%).
  • Purified water was prepared, then berberine chloride, Tween® 80 and sodium lauryl sulfate (SDS) were added. After well dispersed, the mixture was micronized. After that, the particle size was measured by a diffraction analyzer.
  • mice were sacrificed by cervical dislocation. The full-thickness flank skin was removed and placed on the diffusion cell in contact with receptor phase, which was 0.01 M PBS (pH 7.4 at 37°C). Buffers were pumped through the receiver compartment at a flow rate of 3 - 4 mL/h. 300 ⁇ of formulations were added onto the skin surface in the donor compartment. Receiver solutions were collected at hour 0, 1, 2, 3, 4, 6, 8, 10, and 12 for HPLC analysis. Skin flux was calculated from slope of the linear part of the cumulative amount berberine chloride penetrated versus time curve. Results
  • Figure 1 demonstrates a plot of cumulative berberine penetrated (ng/cm 2 ) vs time for all 6 tested formulations. As one can see, C8 (cream formulation) and G23 (gel-based formulation) penetrated the best as compared to the other formulations. This was unexpected because theoretically, all six formulations should penetrate with a similar rate due to physical properties of berberine in water phase.
  • Figure 2 demonstrates a plot of cumulative berberine penetrated (ng/cm 2 ) vs time for three gel suspension formulations (G22, G23 and G24). As one can see, penetration rate is positively correlated to the penetration enhancer (SDS) but is negatively correlated to berberine size. G23 and G24 with berberine size of D90 less than 10 ⁇ m have higher penetration rate than G22 with D90 higher than 10 ⁇ m.
  • SDS penetration enhancer
  • Pig skin was placed on the diffusion cell with dermal side in contact with receptor phase, which was filled with PBS (pH 7.4 at 37°C). 20 ⁇ of formulations were added onto the skin surface in the donor compartment. After 8 hours, the residual formulation on the skin surface was removed using three dry cotton swabs. At the end of 12 and 24 hours of treatment with formulations, skin was dismounted from the diffusion cell, again skin surface was cleaned carefully with three water-soaked cotton swabs. 10 tape-strippings were employed to remove stratum corneum. The skin was then placed on glass disc and heat-separated into epidermis and dermis at 60° C water bath for 90 seconds.
  • PBS pH 7.4 at 37°C
  • the mini-pig skin penetration results indicate that: a) C8 (cream formulation) penetrates surprisingly well; b) formulations containing berberine particles continuously released over the 24 hours (G22, G23 vs C8, 0.125% and 0.3%); c) G22 & G23 (formulations containing berberine particles) retained more berberine in the epidermis and dermis after 24 hours as compared to C8 (cream formulation); d) formulations containing berberine particles penetrated better than formulations with berberine in solution (G23 vs 0.3%); e) G23 retained approximately the same amount of berberine in the epidermis and more berberine in the dermis after 24 hours as compared to the 0.3% formulation even though G23 contained only 0.1% berberine; and f) compared with other penetration enhancers (ethanol and glycerol in the 0.125% formulation and propylene glycol and PEG 400 in the 0.3% formulation), the addition of SDS in G23
  • the subject tested was a 56 year old male who received afatinib, an EGFR inhibitor, for treatment of non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • the subject Upon receiving afatinib, the subject started applying topical gel of G23 formulation on one side of his face and vehicle gel (G23 with no berberine) on the other side once daily.
  • Bilateral skin biopsies from nasolabial folds both sides of the nose) were collected from the subject completing two-week topical treatment. Skin specimens were obtained by incisional biopsy measuring 1.0cm x 0.5cm, then histologically processed using hematoxylin and eosin (H&E) staining. Evaluation was performed by a trained dermatopathologist.
  • H&E hematoxylin and eosin
  • Subjects initiating afatinib inhibitors were enrolled to receive half face for G23 and the other half for vehicle gel (G23 with no berberine) during the 4-week treatment period. Subjects were assigned at a 1:1 ratio to determine the side of face for application of study medications. Subjects initiated study medications within 1 day before or after initiation of EGFRI therapy. Study medication was administered once daily (QD) at bedtime (HS) to the designated half of the face.

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Abstract

L'invention concerne des utilisations de compositions pharmaceutiques comprenant de la berbérine pour le traitement de toxicités dermatologiques et d'autres affections cutanées.
PCT/US2016/039180 2015-06-24 2016-06-24 Utilisations thérapeutiques de formulations de berbérine Ceased WO2016210230A1 (fr)

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CN201680049200.3A CN107921284A (zh) 2015-06-24 2016-06-24 小檗碱制剂的治疗用途
AU2016282800A AU2016282800A1 (en) 2015-06-24 2016-06-24 Therapeutic uses of berberine formulations
RU2018102700A RU2733743C2 (ru) 2015-06-24 2016-06-24 Терапевтическое применение лекарственных форм берберина
EP16815356.7A EP3313520A4 (fr) 2015-06-24 2016-06-24 Utilisations thérapeutiques de formulations de berbérine
KR1020187001673A KR20180020229A (ko) 2015-06-24 2016-06-24 베르베린 제형의 치료적 용도
HK18108954.7A HK1249068A1 (zh) 2015-06-24 2016-06-24 小檗碱制剂的治疗用途
CA2990237A CA2990237A1 (fr) 2015-06-24 2016-06-24 Utilisations therapeutiques de formulations de berberine
MX2018000262A MX2018000262A (es) 2015-06-24 2016-06-24 Usos terapeuticos de formulaciones de berberina.
BR112017027897A BR112017027897A2 (pt) 2015-06-24 2016-06-24 usos terapêuticos das formulações de berberina
JP2017566661A JP2018518507A (ja) 2015-06-24 2016-06-24 ベルベリン製剤の治療的使用
IL256400A IL256400A (en) 2015-06-24 2017-12-18 Therapeutic uses of berberine formulations

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US10583111B2 (en) 2017-12-13 2020-03-10 Onquality Pharmaceuticals China Ltd. Method for preventing or treating diseases associated with the inhibition of EGFR
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CN109999034A (zh) * 2019-02-11 2019-07-12 浙江理工大学 肿瘤蛋白tnik激酶靶向天然小分子抑制剂及其应用
CN109806264B (zh) * 2019-04-10 2021-04-02 江苏海钥医药科技有限公司 药物组合物及其应用
CN116370469A (zh) * 2023-04-27 2023-07-04 常州大学 四氢小檗碱类化合物对trpv3的抑制应用
KR20240159428A (ko) 2023-04-28 2024-11-05 경북대학교 산학협력단 아미노글리코시드계열 항생제에 의한 이독성 난청 치료용 조성물
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US10987336B2 (en) 2018-04-16 2021-04-27 Onquality Pharmaceuticals China Ltd. Method of preventing or treating side effect of tumor therapy

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EP3313520A4 (fr) 2019-01-02

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