WO2015095640A1 - Berberine formulations and uses thereof - Google Patents

Berberine formulations and uses thereof Download PDF

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Publication number
WO2015095640A1
WO2015095640A1 PCT/US2014/071364 US2014071364W WO2015095640A1 WO 2015095640 A1 WO2015095640 A1 WO 2015095640A1 US 2014071364 W US2014071364 W US 2014071364W WO 2015095640 A1 WO2015095640 A1 WO 2015095640A1
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WIPO (PCT)
Prior art keywords
berberine
pharmaceutical composition
composition according
penetration enhancer
skin
Prior art date
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PCT/US2014/071364
Other languages
French (fr)
Inventor
Way-Yu Lin
Pao-Li Wang
Chen-Mao Lin
Po-Yuan TSENG
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Twi Biotechnology, Inc.
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Publication date
Application filed by Twi Biotechnology, Inc. filed Critical Twi Biotechnology, Inc.
Priority to MX2016008150A priority Critical patent/MX2016008150A/en
Priority to CA2933606A priority patent/CA2933606A1/en
Priority to KR1020167019395A priority patent/KR20160098491A/en
Priority to RU2016129193A priority patent/RU2016129193A/en
Priority to CN201480069592.0A priority patent/CN106163280A/en
Priority to JP2016541637A priority patent/JP2017500347A/en
Priority to AU2014364357A priority patent/AU2014364357A1/en
Priority to EP14873045.0A priority patent/EP3082425A4/en
Publication of WO2015095640A1 publication Critical patent/WO2015095640A1/en
Priority to IL246167A priority patent/IL246167A0/en

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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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/20—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
    • 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
    • A61K47/26—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
    • 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
    • A61K47/30—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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • 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
    • A61P17/08—Antiseborrheics
    • 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
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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 a 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), rau!tityrosine kinase (MTK), IvIEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and BRAF inhibitors could induce 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.
  • 8-dihydro-9,10 ⁇ dimethoxybenzo(g)-1 l 3-benzodioxolo is an isoquinoline alkaloid present in herb plants, such as coptis (Coptidis rhizome), phellodenron, Scutellaria baicalensis, Mahonia aquifolium and berberis.
  • 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. 8,440,465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis.
  • U.S. Patent Application Publication No, 20050158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and a herbal source of berberine for the treatment of acne in oral administration.
  • compositions comprising a tripeptide (N-paimitoy
  • the formulation may contain additional ingredients, including berberine.
  • berberine is included as one of the many ingredients and its concentration is not specified.
  • US Patent Application Publication No. 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.
  • Mahonia aquifolium cream RelievaTM, Apollo Pharmaceutical Canada Inc
  • US Patent Application Publication No. 2012/0185357 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 conditlGns. Further, it is known that berberine cannot easily efficiently penetrate the skin, and therefore it is likely to be instantly released into the tissue resulting in a temporary effect.
  • the present invention provides pharmaceutical compositions for the treatment and/or prevention of red face related skin disorders.
  • 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 1% 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.
  • 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 m.
  • 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, photoder atitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitors-induced skin disorder.
  • EGFR epidermal growth factor receptor
  • 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 afatinib and topically administered with a vehicle gel (G23 without berberine) on the other side of his face.
  • Berberine is a hydrophilic compound (diffusion coefficient of 1.07) 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. Further, 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.
  • SC stratum corneum
  • 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.
  • 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.
  • said 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 between 0,01 % and 1% 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® 80 and glycerin.
  • the cream formulations of the invention preferably include Tween® 60 and glycerin as penetration enhancers.
  • Tween® 60 and glycerin as penetration enhancers.
  • 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.
  • 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 dodecyi sulfate (SDS).
  • SDS sodium dodecyi sulfate
  • Including SDS as an anionic penetration enhancer results in the provided gel-based formulations being hydrophobic (a partition coefficient of 50.1) and having a dramaticaily 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 pm.
  • about 50% of an average particle size of the berberine is less than 4 pm.
  • 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-!ike dermatitis, and epidermal growth factor receptor (EGFR) inhibitors-induced skin disorder.
  • EGFR epidermal growth factor receptor
  • the invention further provides methods of treating and/or preventing targeted therapy-induced dermatologic toxicities 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), and BRAF inhibitors; and said targeted therapy-induced dermatologic toxicity is selected from the group consisting of papu!opustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction.
  • 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.
  • the term "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 pg 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. Concentration
  • Carbopoi 981 Carbopol 5984EP, Carbopoi ETD 2020, Carbopoi 5984EP, Hydroxyethyi cellulose,
  • Hydroxypropyl cellulose Hydroxypropyl cellulose (Low-substituted), Methyl cellulose, Methylhydroxypropyi cellulose
  • Amino aryl acid esters Alkyl/Aryl alcohols, Alkyl/Aryl acids, Alkyl/Aryl
  • berbenne refers to 5,6-dihydro-9 i 10-d!methoxybenzo(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-demethyiberberine, 9 ⁇ demethylpalmatine, 13-hydroyberberine, berberrubine, palmatrubine, .9-O-ethylberberrubine, 9 ⁇ 0 ⁇ ethyl ⁇ 13-ethylberberrubine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberines and N ⁇ methyl salts thereof, 9-lauroyiberberrubine chloride, and pharmaceutically acceptable salts of all these compounds.
  • analogues of berberine which include but are not limited to jatrorrhizine, palmatine, coptisine, 9-demethyiberberine, 9 ⁇ demethylpalmatine, 13-hydroyberberine, berberrubine, palmatrubine, .
  • 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, monohydrogensuSfunc, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids, such as acetic; propionic; isobutyric; maieic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthaiic; benzenesulfonic; toluenesulfonic, including p-toluenesulfonic, m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric; methanesulfonic;
  • 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 hyperuricemia or metabolic disorders associated with hyperuricemia, 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.
  • a pharmaceutically acceptable carrier including but not limited, to, tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, patch, or suppositories, including rectal and urethral suppositories.
  • the term "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 pharmaceuticaily-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; (j) glycols, such as propylene glycol; (k) po!yols, such as glycerin, sorbitol, manmtoi and polyethylene glycol; (I) esters, such as ethyl oleate and ethyl
  • 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.
  • Example 1 demonstrate some aspects of the invention. The Examples are not meant to limit the invention in any way. Example 1
  • Oil Phase stearic acid (7.5%), castor oil (8%), white petroiatum (6%), and SPAN 60 (2%).
  • G23 (gel-based formulation): berberine (0.1%), SOS (0.086%), glycerol (10%), Tween® 80 (0.5%), methylparaben (0.1 %), propylparaben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), Carbomer 934P (0.3%), HEC 250 HHX (1.2%). Particle Size Distribution: 1.45/2.85/9.30.
  • G24 (gel-based formulation): berberine (0,1 %), SDS (0.043%), glycerol (10%), Tween® 80 (0.5%), methylparaben (0.1 %), propylparaben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), Carbomer 934P (.0,3%), HEC 250 HHX (1.2%). Particle Size Distribution: 1.55/2.86/5.44.
  • 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, 8, 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 pm have higher penetration rate than G22 with D90 higher than 10 pm.
  • SDS penetration enhancer
  • Pig skin was placed on the diffusion cell with derma! 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
  • Tabie 2 summarizes the results of this experiment.
  • 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 58 year old male who received afatinib, an EGFR! inhibitor, for treatment of non-small cell lung cancer (N.SCLC).
  • N.SCLC 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.

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Abstract

Pharmaceuticai compositions comprising berberine for treatment of skin disorders and methods of use thereof.

Description

BERBERINE FORMULATIONS AND USES THEREOF BACKGROUND OF THE INVENTION
[0001] 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 a 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.
[0002] 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), rau!tityrosine kinase (MTK), IvIEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and BRAF inhibitors could induce 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. ( ollenberg A, Kroth J et a!, 2010; Lacouture M. E, Maitiand L et al, 2010; Curry J.L., Torres-Cabala C.A., et al., 2014). Histopathologic findings of such skin toxicities showed that inflammation is frequently involved and leads to acneiform skin rash. A papulopustular rash was more frequently reported on EGFR inhibitors like cetuximab (83% of patients) and afatinib (90% of patients), and EK inhibitors like selumetinib (93% of patients) and trametinib (80% of patients) therapy. A maculopapujar rash was more commonly described with PI3 inhibitors like BKM-120 (37% of patients) and MK2208 (52% of patients) therapy.
[0003] Berberine (Natural Yellow 18,
8-dihydro-9,10~dimethoxybenzo(g)-1 l3-benzodioxolo (5,6-a) qusnolizinium) is an isoquinoline alkaloid present in herb plants, such as coptis (Coptidis rhizome), phellodenron, Scutellaria baicalensis, Mahonia aquifolium and berberis. 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.
[0004] Berberine also has anti-inflammatory function, yet the exact mechanism is unknown.
[0005] U.S. Pat. No. 8,440,465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis. U.S. Patent Application Publication No, 20050158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and a herbal source of berberine for the treatment of acne in oral administration. U.S. Pat. No. 6,974,799 relates to topical compositions comprising a tripeptide (N-paimitoy|-Giy-His-Lys) and a tetrapeptide (N-paimitoyl-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.
[0006] US Patent Application Publication No. 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. In these nutraceutical compositions, berberine is included as one of the many ingredients and its concentration is not specified. There has been a 10% Mahonia aquifolium cream (Relieva™, Apollo Pharmaceutical Canada Inc) containing 0,1% berberine for the treatment of psoriasis.
[0007] US Patent Application Publication No. 2012/0185357 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 conditlGns. Further, it is known that berberine cannot easily efficiently penetrate the skin, and therefore it is likely to be instantly released into the tissue resulting in a temporary effect.
[0008] Therefore, there is still a need to develop new effective formulations of berberine for the treatment of various red face related skin disorders. SUMARY OF THE INVENTION
[0009] The present invention provides pharmaceutical compositions for the treatment and/or prevention of red face related skin disorders. The provided formulations are either cream-based (i.e., cream) formulations or gel-based formulations.
[00010] In particular, the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a cream formulation comprising a water phase and an oil phase.
[00011] In one embodiment, the concentration of berberine in the provided cream formulations is between 0.01 % and 10%, preferably between 0.01 % and 1% 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.
[00012] Ali w/w amounts in this application refer to weight by total weight of the formulation.
[00013] The pharmaceutical compositions of the invention may further comprise a penetration enhancer.
[00014] In one embodiment, the penetration enhancer is an anionic penetration enhancer.
[00015] In another embodiment, the penetration enhancer comprises Tween® 60 and glycerin.
[00016] In one embodiment, berberine is the only pharmaceutically active component in the provided formulations. 00017] In one embodiment, the pharmaceutical compositions of the invention have a pH of between about 4 and about 7, and more preferably of about 5,5.
[00018] In a preferred embodiment, 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.
[00019] In an even more preferred embodiment, 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.
[ΟΘΘ20] In another embodiment the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel-based formulation, wherein said composition comprises an anionic penetration enhancer.
[00021] In a preferred embodiment, the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS).
[00022] In one embodiment, in the gel-based pharmaceutical compositions provided by the invention, about 90% of an average particle size of the berberine is less than 10 m. [00023] In another embodiment, in the gel-based pharmaceutical compositions provided by the invention, about 50% of an average particle size of the berberine is less than 4 μηι.
[00024] In one embodiment, 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.
[00025] 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.
[00026] In one embodiment, red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photoder atitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitors-induced skin disorder.
BRIEF DESCRIPTION OF THE DRAWINGS
[00027] Figure 1 is a plot of cumulative berberine penetrated (ng/cm2) vs time for six tested formulations of berberine.
[00028] Figure 2 is a plot of cumulative berberine penetrated (ng/cm2) vs time for three gel suspension formulations of berberine (G22, G23 and G24).
8 [00029] 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.
[00030] Figure 4 is a picture showing H&E staining of bilateral skin biopsies from nasolabial folds of the patient receiving afatinib and topically administered with a vehicle gel (G23 without berberine) on the other side of his face.
DETAILED DESCRIPTION OF THE INVENTIO
[00031] Depending on a particular disorder being treated, it is important that berberine can efficiently penetrate the skin. Berberine is a hydrophilic compound (diffusion coefficient of 1.07) 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. Further, 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.
[00032] 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. The provided formulations are either cream-based (i.e., cream) formulations or gel-based formulations.
[00033] In particular, the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a cream formulation comprising a water phase and an oil phase. [00034] Because 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. In one embodiment, the concentration of berberine in the provided cream formulations is between 0.01% and 10% w/w, preferably between 0,01 % and 1% 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.
[0G03SJ The pharmaceutical compositions of the invention may further comprise a penetration enhancer.
[00036] In one embodiment, the penetration enhancer is an anionic penetration enhancer. For example, the anionic penetration enhancer may comprise sodium dodecyl sulfate (SDS).
[00037] in another embodiment, the penetration enhancer comprises Tween® 80 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. 00038| In one embodiment, berberine is the only pharmaceutically active component in the provided formulations.
[00039] In one embodiment, the pharmaceutical compositions of the invention have a pH of between about 4 and about 7, and more preferably of about 5.5. [00040] in a preferred embodiment, 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.
[00041] In an even more preferred embodiment, 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.
[00Q42J If was very surprisingly and unexpectedly found that the cream formulations of the invention have a superior penetration rate compared to non-cream berberine formulations.
[00043] In another embodiment, the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel-based formulation, wherein said composition comprises an anionic penetration enhancer.
[00044] In a preferred embodiment, the anionic penetration enhancer comprises sodium dodecyi sulfate (SDS). Including SDS as an anionic penetration enhancer results in the provided gel-based formulations being hydrophobic (a partition coefficient of 50.1) and having a dramaticaily 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.
[00045] It was found in the present invention that, in a pH of between 4 and 7, 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.
[OO04S] it was surprisingly found that out of all tested penetration enhancers (SDS, glycerol, propylene glycol, PEG 400, ethanol, and Tween®}, the addition of SDS in the gel-based formulations resulted in the most enhanced penetration rate and increased local concentration of berberine in epidermis and dermis.
[00047] In one embodiment, in the gel-based pharmaceutical compositions provided by the invention, about 90% of an average particle size of the berberine is less than 10 pm.
[00048] in another embodiment, in the gel-based pharmaceutical compositions provided by the invention, about 50% of an average particle size of the berberine is less than 4 pm.
[00049] It was also surprisingly found that in the gel-based formulations there was a positive correlation between the amount of SDS and the penetration rate, and negative correlation between the size of berberine and the penetration rate.
[00050] Because 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. In one embodiment, 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.
[00051] 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.
[00052] In one embodiment, red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, contact dermatitis, steroid-induced rosacea-!ike dermatitis, and epidermal growth factor receptor (EGFR) inhibitors-induced skin disorder.
[00063] The invention further provides methods of treating and/or preventing targeted therapy-induced dermatologic toxicities comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition of the invention.
[00054] In one embodiment, said targeted therapy is selected from the group consisting of EGFR, multityrosine kinase (MTK), MEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and BRAF inhibitors; and said targeted therapy-induced dermatologic toxicity is selected from the group consisting of papu!opustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction.
[00055] The concentrations of berberine in epidermis, dermis, and receiver (which refers to a container filled with PBS that in contact wit the skin) 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.
[OO0S8] As used herein, the term "penetration rate" refers to an amount of berberine that presents in per gram of epidermis or dermis tissue, or an amount of berberine per cm2 of skin that presents in the receiver, after a certain time period from the application of a formulation to the skin.
£00057] 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 pg of berberine per gram of tissue
Dennis: 0.003 to 30 pg of berberine per gram of tissue
Receiver: 0.0001 to 1 pg of berberine per 1X1 cm2 of skin.
[00058] The following 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. Concentration
Excipient Function Replacemenis/Analogs
range (%)
Anionic
Sodium Lauryl Sulfate, Sulfonate, Phosphate, Oleate, penetration 0.5-2,5
Sulfate monostearate and Carboxylates enhancer
Carbopoi Carbopol 940, Carbopol 941 , Carbopol
Gelling agent 0.3-3
934P 971 , Carbopol 974, Carbopol 980,
Carbopoi 981 , Carbopol 5984EP, Carbopoi ETD 2020, Carbopoi 5984EP, Hydroxyethyi cellulose,
Hydroxyethyi
Gelling agent 0.5-8 Hydroxyethylmethyl cellulose, Cellulose
Hydroxypropyl cellulose, Hydroxypropyl cellulose (Low-substituted), Methyl cellulose, Methylhydroxypropyi cellulose
Quaternary ammonium compounds,
Methylparaben 0.02-0.3
Amino aryl acid esters, Alkyl/Aryl alcohols, Alkyl/Aryl acids, Alkyl/Aryl
Preservatives
amides, Organomercuria!s,
Propylparaben 0.01-0.8
Formaldehyde donators, Biguanides,
Phenols
Dipotassium edetate, Disodium edetate,
EDTA Antioxidant 0,005-0.1 Edetate calcium disodium, Sodium edetate, Trisodium edetate
Glycerin Humectant 0.01-30 Propylene glycol, Polyethylene glycol
Tween© 80 Wetting agent 0.1-3 Polyethylene glycol, Sorbitan esters
Anhydrous citric acid, Fumaric acid,
Citric acid
0.1-2 Malic acid, Sodium citrate dehydrate, monohydraie
Buffering agent Tartaric acid
Sodium citrate Anhydrous sodium citrate; citric acid
0.3-2
dihydrate monohydraie
Water Water - -
Stearic acid Oil base 1-20 Calcium stearate, Magnesium stearate, Concentration
Excipient Function Replacements/ Anaiogs
range (%}
Po!yoxyethylene stearates, Purified stearic acid, Zinc stearate, Laurie acid, Myristic acid. Palmitic acid, Oleic acid
Mineral oil, Castor oil, Almond oil, Cocao oil, Corn oil, Coconut oil, Cotton
Castor oil Oil base 5-12.5
seed oil, Linseed oil, Olive oil, Soybean oil
Yellow petrolatum, Liquid petrolatum,
White
Oil base 4-56 Paraffin, Ceresin, Microcrystalline wax, petrolatum
Plasiibase
Poiyoxyethylene sorbs'tan fatty acid
SPAN 60 Emulsifying agent 1-15
esters,
Tween® 60 Emulsifying agent 1-15 Polyethylene glycol, Sorbitan esters
[000S9] As used herein, the term "berbenne" refers to 5,6-dihydro-9i 10-d!methoxybenzo(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-demethyiberberine, 9~demethylpalmatine, 13-hydroyberberine, berberrubine, palmatrubine, .9-O-ethylberberrubine, 9~0~ethyl~13-ethylberberrubine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberines and N~methyl salts thereof, 9-lauroyiberberrubine chloride, and pharmaceutically acceptable salts of all these compounds.
[00060] As used herein, the term "pharmaceutically acceptable salts" includes salts of acidic or basic groups. Examples of pharmaceutically acceptable salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensuSfunc, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids, such as acetic; propionic; isobutyric; maieic; malonic; benzoic; succinic; suberic; fumaric; mandelic; phthaiic; benzenesulfonic; toluenesulfonic, including p-toluenesulfonic, m-toluenesulfonic, and o-toluenesulfonic; citric; tartaric; methanesulfonic; and the like. Also included are salts of amino acids such as arginat and the like, and salts of organic acids, such as glucuronic or galacturonic acids and the like.
[0D081] As used herein, the terms "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. Thus, "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.
[00862] As used herein, 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 hyperuricemia or metabolic disorders associated with hyperuricemia, 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.
[00003] 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.
[00084] As used herein, the term "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. Some examples of materials which can serve as pharmaceuticaily-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; (j) glycols, such as propylene glycol; (k) po!yols, such as glycerin, sorbitol, manmtoi and polyethylene glycol; (I) esters, such as ethyl oleate and ethyl laurate; (m) agar; (n) buffering agents, such as magnesium hydroxide, aluminum hydroxide, boric acid and sodium borate, and phosphate buffers; (o) alginic acid; (p) pyrogen-free wafer; (q) isotonic saline; (r) Ringer's solution; (s) ethyl alcohol; (t) phosphate buffer solutions; and (u) other non-toxic compatible substances suitable for use in pharmaceutical compositions.
[00065] The 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. Preferably, the compositions are adapted for oral or topical administration. For example, 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.
[00066] The following Examples demonstrate some aspects of the invention. The Examples are not meant to limit the invention in any way. Example 1
fVfouse Skin Penetration Study of Serberin© Formulations
[00067] The following six berberine formulations were compared: C8, 0,125%, 0.3%, G22, G23 and G24.
Formulations
[00088] The formulations were as follows: C8 (a cream-based formulation):
Water Phase 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%).
Oil Phase stearic acid (7.5%), castor oil (8%), white petroiatum (6%), and SPAN 60 (2%).
0.125% (gel-based formulation): berberine (0.125%), ethanoi (2.5%), glycerol (10%), phenoxyethanoi (0.3%), carbomer. 0,3% (gel-based formulation): berberine (0.3%), propylene glycol (9.25%), PEG 400 (5.03%), methylparaben (0.1%), propylparaben (0.02%), NaOH (0.4%), EDTA (0.02%), Carbomer 934P (1 %).
G22 (gel-based formulation); berberine (0.1%), SDS (0.086%), glycerol (10%), Tween® SO (0.5%), methylparaben (0.1%), propylparaben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), Carbomer 934P (0.3%), HEC 250 HHX (1.2%). Particle Size Distribution: 3.83/11.34/27.24 (in the format D10/D50/D90, where each value refers to the respective percentage of particles below the stated size, i.e. 10% of the particles are less than 3.83, and so on).
G23 (gel-based formulation): berberine (0.1%), SOS (0.086%), glycerol (10%), Tween® 80 (0.5%), methylparaben (0.1 %), propylparaben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), Carbomer 934P (0.3%), HEC 250 HHX (1.2%). Particle Size Distribution: 1.45/2.85/9.30. G24 (gel-based formulation): berberine (0,1 %), SDS (0.043%), glycerol (10%), Tween® 80 (0.5%), methylparaben (0.1 %), propylparaben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), Carbomer 934P (.0,3%), HEC 250 HHX (1.2%). Particle Size Distribution: 1.55/2.86/5.44.
[00069] The particle size of G22, G23 and G24 formulations were determined as follows.
[00070] 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.
Experimental Conditions
[00071] 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 μΙ of formulations were added onto the skin surface in the donor compartment. Receiver solutions were collected at hour 0, 1 , 2, 3, 4, 8, 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
[00072] Figure 1 demonstrates a plot of cumulative berberine penetrated (ng/cm2) 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.
[00073] Figure 2 demonstrates a plot of cumulative berberine penetrated (ng/cm2) 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 pm have higher penetration rate than G22 with D90 higher than 10 pm.
Example 2
fjmi-piia Penetration Study of Berberine Formulations
[00074] The following berberine formulations were compared: 1) C8, G22, and G23; and 2) 0.125%, 0.30%, and G23.
[00075] Skin: Mini-pig ( Lanyu pig or Lee sung pig) skin dermatomed to 700 μηι with electrical resistance > 10 kQ (IVliijicell-ERS, illipore).
Penetration experiments:
[00076] Pig skin was placed on the diffusion cell with derma! side in contact with receptor phase, which was filled with PBS (pH 7.4 at 37°C). 20 μΙ 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. Both the separated epidermis and dermis were weighed and minced, and extracted with 0.5 ml diluent (Ί%Η3ΡΟ4:0Η3θΗ (1 :1)). The skin extracts were centrifuged at 14,500 rpm for 20 min. Berberine chloride concentrations in the receiver soiutions and supernatants from skin extracts were determined by HPLC. Recovery of berberine chloride from skin was determined by spiking known amounts of the drug into skin tissues and processed as described above.
Results
[00077] Tabie 2 summarizes the results of this experiment.
Table 2
Run 1 (Comparing C8, GZZ, G23)
12hr Epidermis (pg/g) Dermis (pg/g) Receiver (pg/cnr)
C8 6.15 0.22 0.069
G22 7.55 0.14 0.Q625
G23 11.99 0.09 0.0025
24hr Epidermis (isg/g) Dermis (ug/g) Receiver (yg/cm2)
C8 14.675 0.2 0.029
G22 30.95 0.43 0.1905
G23 100.315 0.64 0.0285 Run 2 (Comparing 0.125%, 0.30%,. G23)
12hr Epidermis (MQ/g) Dermis (Mg/g) Receiver ( g/cm2)
0.125% 11.67 0.14 0
0.30% 22.09 0.41 0
G23 16.68 0.1 0
24hr Epidermis (pg/g) Dermis (pg/g) Receiver (Mg/cm2)
0.125% 18.74 0.19 0.01
0.30% 39.83 0.15 0
G23 35.75 0.27 0.009
[00078] 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 resulted in enhanced penetration rate and increased local concentration of berberine in epidermis and dermis. Example 3
Skin Biopsy Results from a Patient Treated by Topical
Formulation Comprising Berberine
[00079] The subject tested was a 58 year old male who received afatinib, an EGFR! inhibitor, for treatment of non-small cell lung cancer (N.SCLC). 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.
[000SO] 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.
[00081] The H&E staining results (Figures 3 & 4) show that follicular structure remains intact and there was no inflammatory ceil infiltrate for skin area treated with G23 (Figure 3) while there was destruction of the follicular structure, profuse infiltration of inflammatory cells at the perifollicular region vacuolar change of the dermal-epidermal junction of follicular epithelium for skin treated with vehicle gel (Figure 4), indicating potential anti-inflammatory effect of G23 for treating EGFR inhibitor-associated skin toxicity.

Claims

WHAT !S CLAIMED IS:
1. A pharmaceutical composition comprising berberine, wherein said composition is a cream formulation comprising a water phase and an oil phase, wherein said berberine is at a concentration between 0.01 % and 10% w/w, and wherein said composition comprises a penetration enhancer.
2. The pharmaceutical composition according to claim 1 , wherein the concentration of berberine is between 0.01% and 0.3% w/w.
3. The pharmaceutical composition according to claim 1 , wherein the penetration enhancer is an anionic penetration enhancer.
4. The pharmaceutical composition according to claim 3, wherein the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS).
5. The pharmaceutical composition according to claim 1 , wherein the penetration enhancer comprises Tween® 60 and glycerin.
6. The pharmaceutical composition according to claim 1 , wherein said berberine is the onl pharmaceutically active component.
7. A pharmaceutical composition comprising berberine as the only pharmaceutically active component, wherein said berberin 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.
8. A pharmaceutical composition comprising berberine, wherein said composition is a gei-based formulation, wherein said composition comprises an anionic penetration enhancer.
9. The pharmaceutical composition according to claim 8, wherein said anionic penetration enhancer comprises sodium dodecy! sulfate (SOS).
10. The pharmaceutical composition according to claim 8, wherein about 90% of an average particle size of said berberine is less than 10 pm.
11. The pharmaceutical composition according to claim 8, wherein the concentration of berberine is between 0.01 % and 0.3% w/w.
12. The pharmaceutical composition according to claim 8, wherein said berberine is the only pharmaceutically active component.
13. A method of treating a red face related skin disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition according to claim 1. 4. A method of treating a red face related skin disorder comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition according to claim 8.
15. A method of treating and/or preventing targeted therapy-induced dermatoiogic toxicities comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition according to claim 1.
16. A method of treating and/or preventing therapy-induced dermatologic toxicities comprising administering to a patient in need thereof a pharmaceutically effective amount of the pharmaceutical composition according to claim 8.
1 . The method according to claim 13, wherein said red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, contact dermatitis, and steroid-induced rosacea-like dermatitis.
18. The method according to claim 14, wherein said red face related skin disorder is selected from the group consisting of rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, contact dermatitis, and steroid-induced rosacea-like dermatitis.
19. The method according to claim 15, wherein said targeted therapy is selected from the group consisting of EGFR, multjtyrosine kinase (MTK), MEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and BRAF inhibitors, and wherein said targeted therapy-induced dermatologic toxicity is selected from the group consisting of papuiopustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction.
20. The method according to claim 18, wherein said targeted therapy is selected from the group consisting of EGFR, multityrosine kinase (MTK), EK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), and BRAF inhibitors, and wherein said targeted therapy-Induced dermatologic toxicity is selected from the group consisting of papuiopustular rash, maculopapular rash, erythema, telangiectasias flushing, paronychia and fissure, hair changes, xerosis, mucositis, pruritus, and hand-foot skin reaction.
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