CN107921284A - The therapeutical uses of barberry alkali preparation - Google Patents

The therapeutical uses of barberry alkali preparation Download PDF

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Publication number
CN107921284A
CN107921284A CN201680049200.3A CN201680049200A CN107921284A CN 107921284 A CN107921284 A CN 107921284A CN 201680049200 A CN201680049200 A CN 201680049200A CN 107921284 A CN107921284 A CN 107921284A
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inhibitor
jamaicin
method described
analog
preparation
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卡尔·奥斯卡·布朗三世
曾博远
林伊银
蔡陈恩
陈志光
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TWi Biotechnology Inc
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TWi Biotechnology Inc
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Priority claimed from US15/161,576 external-priority patent/US20160263092A1/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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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    • 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
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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
    • A—HUMAN NECESSITIES
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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
    • A—HUMAN NECESSITIES
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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
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • 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
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    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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Abstract

Pharmaceutical composition comprising jamaicin is used to treat dermal toxicity and the purposes of other skin disorders.

Description

The therapeutical uses of barberry alkali preparation
Background technology
Red face related dermal illness (red face with identical symptom similitude and possible causes for pathological Related skin disorder) include rosacea, acne vulgaris, seborrhea, photodermatitis and contact skin It is scorching.The scope of these red face related conditions can be from thermal sensation and sensitive to the scorching hot of flush or strong sensitivity.With red face The patient of related dermal illness usually reveals exquisite sensitivity to environment and local factor meter.The rosacea sample of steroids induction Dermatitis (or steroids rosacea) is papular or pustular lesion (lesion), has erythema and an edemous substrate, companion or Without telangiectasis, this is because topical steroids are applied to for a long time caused by face or topical steroids stop The rebound patient's condition afterwards.
Dermal toxicity is known and targeted therapies or the relevant skin adverse events of immunotherapy, and related to red face Skin disorder has similar symptom and possible causes for pathological.Targeted therapies such as EGF-R ELISA (EGFR) inhibitor, More tyrosine kinase (MTK) inhibitor, mek inhibitor, phosphoinositide 3-kinase (PI3K) inhibitor, protein kinase B (AKT) suppression It is preparation, BRAF inhibitor, HER2 inhibitor, more kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitor, more Kinases Abl inhibitor, BTK inhibitor, hdac inhibitor, proteasome inhibitor and Retinoid X Receptor (RXR) activator； Immunotherapy such as cancer vaccine, cell factor reagent are (for example, granulocyte-macrophage colony stimutaing factor (GM-CSF), interference Element and interleukin 2 (IL-2)), cell therapy is (for example, tumor infiltrating lymphocyte (TIL), φt cell receptor (TCR) work Journey peripheral blood lymphocytes (PBL) and Chimeric antigen receptor (CAR) engineering PBL), immunologic test point protein inhibitor (for example, PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT) and immunologic test point albumen stimulant (for example, CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40)；Or any of the above-described therapy Combination can induce toxic reaction, including papulopustular rash (papulopustular rash), plaque-like papule (maculopapular rash), erythema, telangiectasis flush, paronychia and cracking, hair change, axersis, mucous membrane Scorching, pruritus and hand-foot skin react, these can occur in the patient more than 90%, and be also possible to sense overlapping with bacterium Dye, the bacterium such as staphylococcus aureus (Wollenberg, Kroth et al., Cutaneous side effects of EGFR inhibitors--appearance and management,Dtsch Med Wochenschr 2010； Lacouture, Maitland et al., A proposed EGFR inhibitor dermatologic adverse event- specific grading scale from the MASCC skin toxicity study group,Support Care Cancer,2010；Curry, Torres-Cabala et al., Dermatologic toxicities to targeted cancer therapy:shared clinical and histologic adverse skin reactions, International Journal of Dermatology,2014；Jeffrey S.Weber et al., Toxicities of Immunotherapy for the Practitioner,Journal of Clinical Oncology,Vol.33,2015； Grace K.Dy and Alex A.Adjei,Understanding,Recognizing,and Managing Toxicities of Targeted Anticancer Therapies,CA Cancer J Clin,Vol.63,2013；Ahmad Tarhini, Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4Blockade Therapy:The Underlying Mechanisms and Clinical Management,Scientifica,2013；J Larkin et al., Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma,N.Engl.J.Med.,Vol.373,2015).The histopathology of this dermal toxicity finds that display frequently involves Inflammation simultaneously causes acneform eruptions.Papulopustular rash is in EGFR inhibitor such as Cetuximab (cetuximab) (83% trouble Person) and Afatinib (90% patient), and mek inhibitor as take charge of it is beautiful for Buddhist nun (selumetinib) (93% patient) and Sibutramine Hydrochloride is replaced in Buddhist nun (trametinib) (80% patient) therapy and reported frequently.Plaque-like papule more commonly with PI3K inhibitor Such as example anti-CTLA-4 suppressions of BKM-120 (37% patient), MK2206 (52% patient) therapy, immunologic test point protein inhibitor The easy Puli's nurse agate (ipilimumab) (33% patient) of preparation, anti-PD-1 inhibitor nivolumab (26% patient) or easy The combination (patient more than 40%) of Puli's nurse agate and nivolimumab are described together.
Jamaicin (18,5,6- dihydro -9,10- dimethoxy benzo (g) -1,3- benzodioxoles of natural Huang (5,6-a) quinolizine) it is the morphinane alkaloid being present in herbaceous plant, the herbaceous plant such as Coptis (coptis root Stem), Cortex Phellodendri (phellodenron), radix scutellariae (Scutellaria baicalensis), leaf of Chinese ilex Chinese mahonia (Mahonia ) and berberis (berberis) aquifolium.It has been found that jamaicin and its derivative have antimicrobial and antimalarial Disease activity.It can act on various pathogen, such as fungi, saccharomycete, parasite, bacterium and virus.
Jamaicin also has anti-inflammatory effect, but precise mechanism is unclear.
U.S. Patent number 6,440,465 is related to the topical skin preparations of the aminoglucose in emollient matrix, it contains barberry Alkali, for treating psoriasis.U.S. Patent Publication No. 2005/0158404 is related to nutrition product, dietary supplements or drug regimen Thing, it contains the jamaicin of VitAVitE, selenium, vitamin B6, zinc, chromium and herbal medicine source, for orally administering treatment Acne.U.S. Patent number 6,974,799 be related to comprising tripeptides (n-palmitoyl-Gly-His-Lys) and tetrapeptide (N- palmityls- Gly-Gln-Pro-Arg topical composition), for treating the visible signs of aging, including wrinkle, vergeture (stretch Mark), livid ring around eye.Said preparation can contain other compositions, including jamaicin.In these inventions, jamaicin as it is numerous into / mono- by including and being not specified by its concentration.
U.S. Patent Publication 2004/0146539 is related to slim and toning Firm (tone-firming) anti-aging benefit The local Halth-care composition at place, it can be used for treatment skin aging, wrinkle of skin, skin exfoliative (skin Exfoliating), acne, rosacea and other skin problems.The composition of the invention includes antimicrobial, described anti- Microorganism agent is selected from several medicaments, including jamaicin.In these Halth-care compositions, jamaicin is as one of numerous compositions quilt Including, and it is not specified by its concentration.There is the 10% leaf of Chinese ilex Chinese mahonia emulsifiable paste containing 0.1% jamaicin (RelievaTM, Apollo Pharmaceutical Canada Inc) it is used to treat psoriasis.
U.S. Patent Publication 2012/0165357 discloses the use that jamaicin is used to treat various red face related dermal illnesss On the way, but without the specific preparation for disclosing any small bavin alkali that can effectively treat the specific patient's condition.
Therefore, there is still a need for exploitation is used to treating various red face related dermal illnesss and by targeted therapies and/or immune The new effective method of the dermal toxicity of therapy induction.
The content of the invention
The present invention provides for treating and/or preventing red face related dermal illness and by targeted therapies and/or immune treatment The pharmaceutical composition of the dermal toxicity of method induction.The preparation provided is based on emulsifiable paste (i.e. emulsifiable paste) preparation or based on gel Preparation.
Especially, the present invention provides the pharmaceutical composition comprising jamaicin, wherein the composition be bag aqueous phase and The cream preparation of oil phase.
In one embodiment, the concentration of the cream preparation Berberine provided is excellent between 0.01% to 10% 0.01% is selected between 0.3%w/w, more preferably 0.1% between 0.2%w/w, even more preferably 0.1% to 0.15%w/w it Between, most preferably from about 0.12%w/w.
Unless expressly stated otherwise, otherwise when the application is with w/w form description amounts or concentration, the weight of every kind of component With the gross weight meter of preparation.
The pharmaceutical composition of the present invention can also include penetration enhancer.
In one embodiment, penetration enhancer is anionic permeation enhancers.
In another embodiment, penetration enhancer includes60 and glycerine.
In one embodiment, jamaicin is unique pharmaceutical active in provided preparation.
In one embodiment, the pH of pharmaceutical composition of the invention is between about 4 to about 7, and more preferably from about 5.5.
In a preferred embodiment, the present invention provides include the jamaicin as unique pharmaceutical active Pharmaceutical composition, wherein the concentration of the jamaicin 0.1% between 0.2%w/w, wherein the composition is bag aqueous phase With the cream preparation of oil phase, wherein the composition includes penetration enhancer, preservative and stabilizer, and wherein described combination The pH of thing is between about 4 to about 7.
In even more preferably embodiment, the present invention provides include the jamaicin as unique pharmaceutical active Pharmaceutical composition, wherein the concentration of the jamaicin is about 0.12%w/w, wherein the composition is bag aqueous phase and oil phase Cream preparation, wherein the composition includes penetration enhancer, preservative and stabilizer, and the pH of wherein described composition It is about 5.5.
In another embodiment, the present invention provides the pharmaceutical composition comprising jamaicin, wherein the composition It is the preparation based on gel, wherein the composition includes anionic permeation enhancers.
In a preferred embodiment, anionic permeation enhancers include lauryl sodium sulfate (SDS).
In one embodiment, in the pharmaceutical composition provided by the invention based on gel, about 90% jamaicin Particle mean size be less than 10 μm.
In another embodiment, in the pharmaceutical composition provided by the invention based on gel, about 50% barberry The particle mean size of alkali is less than 4 μm.
In one embodiment, the concentration of the preparation Berberine based on gel provided is 0.01% to 0.3% Between w/w, more preferably 0.1% between 0.2%w/w, and even more preferably 0.1% between 0.15%w/w, and most preferably from about 0.12%w/w.
Present invention also offers the method for treating red face related dermal illness, it includes its patient to needs and applies pharmacy Upper a effective amount of pharmaceutical composition of the invention.
In one embodiment, red face related dermal illness is selected from the group consisted of：Rosacea, common Cuo Sore, seborrhea, photodermatitis, contact dermatitis, the rosacea sample dermatitis and epidermal growth factor of steroids induction The skin disorder of acceptor (EGFR) inhibitor induction.
Present invention also offers treatment and/or prevent the side of dermal toxicity induced by targeted therapies and/or immunotherapy Method, it includes the jamaicin and/or its biology equivalence analog using pharmaceutical effective amount to its patient of needs.
In preferred embodiments, the targeted therapies include by EGFR inhibitor, MTK inhibitor, mek inhibitor, PI3K inhibitor, AKT inhibitor, BRAF inhibitor, HER2 inhibitor, more kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitor, more kinases Abl inhibitor, BTK inhibitor, hdac inhibitor, proteasome inhibitor and RXR excitements The therapy that agent carries out.
In preferred embodiments, immunotherapy include by cancer vaccine, cell factor reagent (such as granulocyte- Macrophage colony stimulatory factor (GM-CSF), interferon and interleukin 2 (IL-2)), cell therapy (such as tumour leaching Moisten lymphocyte (TIL), the peripheral blood lymphocytes (PBL) and Chimeric antigen receptor (CAR) of φt cell receptor (TCR) engineering The PBL of engineering), immunologic test point protein inhibitor (such as PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT) and immunologic test point albumen stimulant (such as CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40) carry out therapy.
In a preferred embodiment, in the form of local medicine composition to patient apply jamaicin and/or its Biology equivalence analog.
Brief description of the drawings
This patent or application documents contain an at least color drawings.This patent or patent application with color drawings are public The copy opened will provide as requested and under conditions of necessary expense is paid by Patent Office.
Fig. 1 is that small bavin alkali (ng/cm is permeated in the accumulation of the barberry alkali preparation of six kinds of tests2)-time diagram.
Fig. 2 is that small bavin alkali (ng/cm is permeated in the accumulation of three kinds of jamaicin gel mixed suspension preparations (G22, G23 and G24)2)-when Between scheme.
Fig. 3 is the figure of h and E (H＆E) dyeing for the bilateral skin biopsy for showing patient's nasolabial groove gauffer, described Patient receives Afatinib and in its facial side local application gel preparation (G23).
Fig. 4 is the figure of h and E (H＆E) dyeing for the bilateral skin biopsy for showing patient's nasolabial groove gauffer, described Patient receives EGFR inhibitor Afatinib and in its facial opposite side local application vehicle gel (G23 of no jamaicin).
Fig. 5 is papule counting-time diagram of patient, and the patient receives Afatinib and in its facial side local application Gel preparation (G23) and (* represents to pass through Weir in its facial opposite side local application vehicle gel (G23 of no jamaicin) The gloomy signed rank test in Cork (Wilcoxon Signed Rank test), P<0.05).
Fig. 6 is warts counting-time diagram of patient, and the patient receives Afatinib and in its facial side local application Gel preparation (G23) and (* represents to pass through Weir in its facial opposite side local application vehicle gel (G23 of no jamaicin) The gloomy signed rank test in Cork, P<0.05).
Fig. 7 is tale (papule and warts)-time diagram of patient, and the patient receives Afatinib and in its face one Side local application gel preparation (G23) and in its facial opposite side local application vehicle gel (G23 of no jamaicin) (* table Show by Wilcoxen signed rank test, P<0.05).
Embodiment
Depending on the particular condition treated, jamaicin can skin permeation be effectively important.Jamaicin is a kind of parent Aqueous compounds (distribution coefficient in octanol-water system is 1.07), this causes jamaicin to be difficult to penetrate through cuticula (SC) target site of the dermal toxicity of red face related dermal illness or targeted therapies induction, example may occur wherein with arrival Such as, corium or epidermis.In addition, jamaicin is quite solvable (solubility 1.57mg/ml), therefore target will be fast released In cell, cause interim effect.
Therefore, the present invention provides the pharmaceutical composition that jamaicin permeability improves, for treating and/or preventing red face phase Close skin disorder and the dermal toxicity induced by targeted therapies and/or immunotherapy.The preparation provided be based on emulsifiable paste (i.e. Emulsifiable paste) preparation or the preparation based on gel.
Especially, the present invention provides the pharmaceutical composition comprising jamaicin, wherein the composition be bag aqueous phase and The cream preparation of oil phase.
Because the cream preparation of the present invention can promote jamaicin to infiltrate into skin, the jamaicin of relatively small amount is just Sufficiently achieve expected therapeutic effect.In one embodiment, the gross weight based on preparation is small in the cream preparation provided The concentration of bark of a cork tree alkali 0.01% between 10%w/w, preferably 0.01% to 0.3%w/w, more preferably 0.1% to 0.2%w/w it Between, even more preferably 0.1% between 0.15%w/w, most preferably from about 0.12%w/w.
The pharmaceutical composition of the present invention can also include penetration enhancer.
In one embodiment, penetration enhancer is anionic permeation enhancers.For example, anionic permeation enhancers can To include lauryl sodium sulfate (SDS).
In another embodiment, penetration enhancer includes60 and glycerine.The cream preparation of the present invention is preferred Including60 and glycerine as penetration enhancer.When identical penetration enhancer is used in non-cream preparation, they Permeability will not be caused to improve, this shows on unique there are some based on the preparation of emulsifiable paste.
In one embodiment, jamaicin is unique pharmaceutical active in provided preparation.Even if provided The component of preparation be probably for the purpose in addition to treating the dermal toxicity induced by targeted therapies or immunotherapy Active component in prior art preparation, but as long as the component is not induced with being enough effectively treatment by targeted therapies or immunotherapy Dermal toxicity amount exist, then for the purpose of the preparation provided, be still construed as drug excipient.
In one embodiment, the pH of pharmaceutical composition of the invention is about 4 to about 7, more preferably from about 5.5.
In a preferred embodiment, the present invention provides include medicine jamaicin as unique pharmaceutical active Compositions, wherein the concentration of the jamaicin 0.1% between 0.2%w/w, wherein the composition for bag aqueous phase and The cream preparation of oil phase, wherein the composition includes penetration enhancer, preservative and stabilizer, and wherein described composition PH be about 4 to about 7.
In even more preferably embodiment, the present invention provides comprising jamaicin as unique pharmaceutical active Pharmaceutical composition, wherein the concentration of the jamaicin is about 0.12%w/w, wherein the composition is bag aqueous phase and oil phase Cream preparation, wherein the composition includes penetration enhancer, preservative and stabilizer, and the pH of wherein described composition is About 5.5.
It is very astonishing and surprisingly it has been found that compared with non-emulsifiable paste barberry alkali preparation, cream preparation of the invention With excellent permeability.
In another embodiment, the present invention provides the pharmaceutical composition comprising jamaicin, wherein the composition It is the preparation based on gel, wherein the composition includes anionic permeation enhancers.
In a preferred embodiment, anionic permeation enhancers include lauryl sodium sulfate (SDS).Including SDS is hydrophobic (in octanol-water system point as the preparation based on gel that anionic permeation enhancers cause to be provided Distribution coefficient is 50.1), and to have significantly lower solubility, is about 0.011mg/ml, jamaicin is sustained to target cell In, cause release profiles to extend.
Find in the present invention, under the pH between 4 to 7, in the presence of SDS, jamaicin solubility range is certainly 0.01 to 0.06mg/ml, i.e. it is 25 to 150 times lower than water-based barberry alkali solubility (1.57mg/ml), and in 5.5 times phases of pH To relatively low.
It was surprisingly found that all tests penetration enhancer (SDS, glycerine, propane diols, PEG 400, ethanol and) in, added in the preparation based on gel in permeability promotion and maximum epidermis and corium that SDS causes maximum The local concentration increase of jamaicin.
In one embodiment, in the pharmaceutical composition provided by the invention based on gel, about 90% jamaicin Particle mean size be less than 10 μm.
In another embodiment, in the pharmaceutical composition provided by the invention based on gel, about 50% barberry The particle mean size of alkali is less than 4 μm.
It was also surprisingly found that in the preparation based on gel, it is proportionate between the amount and permeability of SDS, and It is negatively correlated between the size and permeability of jamaicin.
Because the present invention the preparation based on gel jamaicin can be promoted to infiltrate into skin, relatively small amount it is small Bark of a cork tree alkali just sufficiently achieves required therapeutic effect.In one embodiment, the gross weight based on preparation, provided based on solidifying The concentration of the preparation Berberine of glue is 0.01% to 0.3%w/w, more preferably 0.1% to 0.2%w/w, even more preferably 0.1% and 0.15%w/w, most preferably from about 0.12%w/w.
Present invention also offers the method for treating red face related dermal illness, it includes its patient to needs and applies pharmacy Upper a effective amount of pharmaceutical composition of the invention.
In one embodiment, red face related dermal illness is selected from the group consisted of：Rosacea, common Cuo Sore, seborrhea, photodermatitis, contact dermatitis, the rosacea sample dermatitis and epidermal growth factor of steroids induction The skin disorder of acceptor (EGFR) inhibitor induction.
Present invention also offers treatment and/or prevent the side of dermal toxicity induced by targeted therapies and/or immunotherapy Method, it includes the pharmaceutical composition of the invention using pharmaceutical effective amount to its patient of needs.
In one embodiment, the targeted therapies are selected from the group consisted of：EGFR, more tyrosine kinase (MTK), MEK, phosphoinositide 3-kinase (PI3K), protein kinase B (AKT), BRAF inhibitor, HER2 inhibitor, more kinases blood Pipe formation inhibitor, mTOR inhibitors, ALK/c-met inhibitor, more kinases Abl inhibitor, BTK inhibitor, hdac inhibitor, Proteasome inhibitor and rxr agonist；The immunotherapy is selected from the group consisted of：Cancer vaccine, cell factor examination Agent (such as granulocyte-macrophage colony stimutaing factor (GM-CSF), interferon and interleukin 2 (IL-2)), cell are treated Method (such as tumor infiltrating lymphocyte (TIL), φt cell receptor (TCR) engineering peripheral blood lymphocytes (PBL) and be fitted together to Antigen receptor (CAR) engineering PBL), immunologic test point protein inhibitor (such as PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT) and immunologic test point albumen stimulant (such as CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40)；And the dermal toxicity induced by targeted therapies and/or immunotherapy Selected from group consisting of：Papulopustular rash, plaque-like papule, erythema, telangiectasis flush, paronychia and cracking, hair Send out change, axersis, catarrh, pruritus and hand-foot skin reaction.
Measure epidermis, corium and receiver by the following method (it refers to the container filled with PBS with skin contact) The concentration of Berberine.Franz diffusion cells are substantially that one piece of skin is clipped between two fixtures.By medicinal application in skin The side (top) of skin, and measure drug concentration in the receiving portion (bottom) of device.
As used herein, term " permeability " refer to from by formulation application in skin for a period of time after, be present in every gram The amount of jamaicin in epidermis or dermal tissue, or the every cm being present in receiver2The amount of the jamaicin of skin.
The amount of the medicine measured in the receiver represents to penetrate through the total amount of the SC of skin, epidermis and dermal zone.This The pharmaceutical composition of invention has the permeability improved, and the preferred scope of permeability is as follows：
Epidermis：The μ g jamaicins of per gram of tissue 0.4 to 4000
Corium：The μ g jamaicins of per gram of tissue 0.003 to 30
Receiver：Every 1 × 1cm2The μ g jamaicins of skin 0.0001 to 1.
Table 1 below lists the various composition that may be used in the composition of the present invention.But, there is provided the list is only used for Improving eyesight, rather than limit the scope of the invention.In addition, different component/excipient can be worked in a manner of more than one, Such as it may be used as penetration enhancer, emulsifying agent, wetting agent etc..
Table 1
As used herein, term " jamaicin " refers to two between 5,6- dihydro -9,10- dimethoxy benzos (g) -1,3- benzo Oxole (5,6-a) quinolizine.Present invention also contemplates that the purposes of jamaicin analog, the jamaicin analog include but It is not limited to jateorrhizine (jatrorrhizine), palmatine (palmatine), coptisine, 9- demethyls jamaicin, 9- demethyls Palmatine, 13- hydroxyls jamaicin, berberrubine (berberrubine), the red alkali of palmatine (palmatrubine), 9-O- ethyls Berberrubine, 9-O- ethyl -13- ethyls berberrubine, 13- methyl dihydroberberine N- methyl salts, Tetrahydro-proto-berberines and its The pharmaceutically acceptable salt of N- methyl salts, 9- lauryl berberrubine chlorides and all these compounds.
As used herein, term " pharmaceutically acceptable salt " includes acid or basic group salt.It is pharmaceutically acceptable Salt example include derived from inorganic acid salt, the inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, a hydrogen carbonic acid, phosphorus Acid, a hydrogen phosphoric acid, dihydrogen phosphoric acid, sulfuric acid, a hydrosulphuric acid, hydroiodic acid or phosphorous acid etc., and derived from the organic of relative nontoxic The salt of acid, the organic acid such as acetic acid of the relative nontoxic；Propionic acid；Isobutyric acid；Maleic acid；Malonic acid；Benzoic acid；Butanedioic acid；It is pungent Diacid；Fumaric acid；Mandelic acid；Phthalic acid；Benzene sulfonic acid；Toluenesulfonic acid, including p-methyl benzenesulfonic acid, m-toluene sulfonic acid and adjacent first Benzene sulfonic acid；Citric acid；Tartaric acid；Methanesulfonic acid；Etc..Further include for example arginic salt of amino acid etc., and the salt of organic acid, institute State organic acid such as glucuronic acid or galacturonic acid etc..
As used herein, term " treatment " includes suppressing disease or the patient's condition, causes the order of severity and/or frequency drop of symptom It is low, symptom and/or potential cause are eliminated, prevents symptom and/or the generation of its potential cause, mitigates and/or improve the shape of patient Condition.Therefore, the particular condition in prevention susceptible individual is included with composition of the present invention " treatment " patient, and management has The individual of clinical symptoms is to suppress or cause the regression of conditions or diseases, and maintains current state and/or prevention illness or disease The progress of disease.Treatment can include prevention, treatment or cure.
As used herein, the term of compound of the invention and/or pharmaceutical composition " pharmaceutical effective amount " refers to be enough It is suitable for reasonable benefit/Hazard ratio of any therapeutic treatment to treat, suppress, mitigate or prevent various red face related dermal illnesss The compound of (dermal toxicity for including but not limited to targeted therapies induction) and/or the amount of composition.It will be understood, however, that The compound of the present invention and/or daily total dosage of composition will be determined within a reasonable range of medical judgment by attending doctor. Many factors will be depended on for the specific effective dose level of any specific patient, including the illness treated and illness is tight Weight degree；The activity of used particular compound；Used concrete composition；The age of patient, weight, general health shape Condition, gender and diet；The discharge rate of time of application, route of administration and used particular compound；The duration for the treatment of； Combine with used particular compound or medicine used at the same time；And well-known similar factor in medical domain.Example Such as, those skilled in the art are known, to start composition dosage less than the level needed for expected therapeutic effect of realizing, and gradually increase Add dosage until realizing Expected Results.
Pharmaceutical composition can also include pharmaceutically acceptable carrier, and can be solid or liquid form, including But it is not limited to tablet, pulvis, capsule, pill, solution, supensoid agent, elixir, emulsion, gelling agent, cream, patch or bolt Agent includes rectum and urethral suppositories.
As used herein, term " pharmaceutically acceptable carrier " refers to pharmaceutically acceptable material, composition or matchmaker Jie's thing, such as liquid or solid filler, diluent, excipient, solvent or encapsulating material.Pharmaceutically acceptable carrier and group Other compositions, the method for application of compound are compatible, without being damaged to patient.Pharmaceutically acceptable carrier can be water-based Or it is non-aqueous.Pharmaceutically acceptable carrier includes natural gum, starch, sugar, cellulosic material and its mixture.It can be used as medicine Some examples of the material of acceptable carrier include but not limited on：(a) it is sugared, such as lactose, dextrose and saccharose；(b) Starch, such as cornstarch and farina；(c) cellulose and its derivates, as sodium carboxymethylcellulose, ethyl cellulose and Cellulose acetate；(d) tragacanth gum powder；(e) malt；(f) gelatin；(g) talcum powder；(h) excipient, such as cocoa butter and suppository Wax；(i) it is oily, such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil；(g) glycol, such as the third two Alcohol；(k) polyalcohol, such as glycerine, sorbierite, mannitol and polyethylene glycol；(l) ester, such as ethyl oleate and ethyl laurate； (m) agar；(n) buffer, such as magnesium hydroxide, aluminium hydroxide, boric acid and Boratex and phosphate buffer；(o) alginic acid； (p) pyrogen-free water；(q) isotonic saline solution；(r) Ringer's solution；(s) ethanol；(t) phosphate buffer solution；And (u) is suitable for Other non-toxic compatible materials used in pharmaceutical composition.
Any-mode known in the art can be used to apply composition of the invention, including but not limited to oral, nasal cavity, Parenteral, local, transdermal or rectal administration approach.Preferably, composition is suitable for orally or topically applying.For example, composition Active ingredient can be formulated for preparing tablet, capsule, pill, lozenge (troche), sugar together with suitable excipient Lozenge (lozenge), solution, pulvis or granule, supensoid agent, hard or soft capsule, patch and other any suitable shapes Formula.
Present invention also offers treatment and/or prevent the side of dermal toxicity induced by targeted therapies and/or immunotherapy Method, it includes the jamaicin or its biology equivalence analog to its patient of needs using pharmaceutical effective amount.
Present invention also offers treatment and/or prevent the side of dermal toxicity induced by targeted therapies and/or immunotherapy Method, it includes the local medicine composition to infected local skin application pharmaceutical effective amount, topical remedy's combination Thing includes jamaicin or its biology equivalence analog.
In one embodiment, local medicine composition for lotion, cream, ointment, paste, gel, spray, Supensoid agent, emulsion, foaming agent, patch, the form of pulvis and liniment.
In one embodiment, local medicine composition includes at least 0.02%w/w, and preferably from about 0.1% to about 2%w/ The jamaicin of w or its biology equivalence analog, wherein the amount is with the gross weight meter of composition.
In one embodiment, the biology equivalence analog of jamaicin or jamaicin is main pharmaceutically acceptable Active component.
In one embodiment, the biology equivalence analog of jamaicin or jamaicin is unique pharmaceutically acceptable Active component.
Following example illustrate some aspects of the present invention.Embodiment is not meant to limit this hair in any way It is bright.
Embodiment 1
The mouse skin penetration study of barberry alkali preparation
Compare following six kinds of barberry alkali preparations：C8,0.125%, 0.3%, G22, G23 and G24.
Preparation
Preparation is as follows：
C8 (preparation based on emulsifiable paste)：
Water phase
Jamaicin (0.12%),60 (1%), glycerine (3%), methyl p-hydroxybenzoate (0.1%),
Propylparaben (0.02%), NaOH (adjust pH to 5.5) and EDTA (0.02%).
Oil phase
Stearic acid (7.5%), castor oil (8%), albolene (6%) and SPAN 60 (2%).
0.125% (preparation based on gel)：
Jamaicin (0.125%), ethanol (2.5%), glycerine (10%), Phenoxyethanol (0.3%), carbomer.
0.3% (preparation based on gel)：
Jamaicin (0.3%), propane diols (9.25%), PEG 400 (5.03%), methyl p-hydroxybenzoate (0.1%), Propylparaben (0.02%), NaOH (0.4%), EDTA (0.02%), carbomer940 (1%).
G22 (preparation based on gel)：
Jamaicin (0.1%), SDS (0.086%), glycerine (10%),80 (0.5%), P-hydroxybenzoic acid first Ester (0.1%), propylparaben (0.02%), citric acid (0.033%), Trisodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), carbomer940 (0.3%), HEC 250HHX (1.2%).Size distribution：3.83/11.34/ 27.24 (in the form of D10/D50/D90, wherein each value refers to the corresponding percentage for being less than the particle of the size, i.e., 10% Particle is less than 3.83, etc.).
G23 (preparation based on gel)：
Jamaicin (0.1%), SDS (0.086%), glycerine (10%),80 (0.5%), P-hydroxybenzoic acid first Ester (0.1%), propylparaben (0.02%), citric acid (0.033%), Trisodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), carbomer940 (0.3%), HEC 250HHX (1.2%).Size distribution：1.45/2.85/9.30
G24 (preparation based on gel)：
Jamaicin (0.1%), SDS (0.043%), glycerine (10%),80 (0.5%), P-hydroxybenzoic acid first Ester (0.1%), propylparaben (0.02%), citric acid (0.033%), Trisodium citrate dihydrate (0.115%), NaOH, EDTA (0.02%), carbomer940 (0.3%), HEC 250HHX (1.2%).Size distribution：1.55/2.86/5.44
The granularity of G22, G23 and G24 preparation is by following measure.
Prepare pure water, then add Berberine hydrochloride,80 and lauryl sodium sulfate (SDS).It is fully dispersed Afterwards, mixture is micronized.Afterwards, granularity is measured by diffraction analysis instrument.
Experiment condition
Mouse is put to death by cervical dislocation.Complete thick flank skin is removed, and is placed on the diffusion cell being in contact with acceptor In, the acceptor is mutually 0.01M PBS (pH 7.4 at 37 DEG C).Buffer solution is pumped across reception with the flow velocity of 3-4mL/h Device compartment.300 μ l preparations are added on the skin surface in donor compartment.Collect and connect when 0,1,2,3,4,6,8,10 and 12 are small Device solution is received to analyze for HPLC.Calculated by the slope of the linear segment of accumulation infiltration capacity-time graph of Berberine hydrochloride Skin flux.
As a result
Fig. 1 shows that small bavin alkali (ng/cm is permeated in the accumulation of all 6 kinds of test formulations2)-time diagram.As can see , compared with other preparations, C8 (cream preparation) and G23 (preparation based on gel) infiltrations are best.This be it is unexpected, because For in theory, due to physical property of the jamaicin in water phase, all six kinds of preparations should be with similar rate penetration.
Fig. 2 shows that small bavin alkali (ng/cm is permeated in the accumulation of three kinds of gel mixed suspension preparations (G22, G23 and G24)2)-the time Figure.As appears, permeability is proportionate with penetration enhancer (SDS), but negatively correlated with jamaicin size.D90 Permeability ratio D90 G22 higher than 10 μm of the jamaicin size less than 10 μm of G23 and G24 height.
Embodiment 2
The minipig penetration study of barberry alkali preparation
Compare following barberry alkali preparation：1) C8, G22 and G23；With 2) 0.125%, 0.30% and G23.
Skin：The skin-grafting of minipig (Lanyu pigs or Lee sung pigs) skin is up to 700 μm, resistance>10kΩ(Millicell- ERS, Millipore).
Permeability test：
Porcine skin is placed on diffusion cell, corium side is in contact with acceptor, and the acceptor is mutually filled with PBS (at 37 DEG C pH 7.4).The preparation of 20 μ l is added on skin surface into donor compartment.8 it is small when after, use three dry cotton swabs to remove skin tables Residual preparation on face.At the end of when small with preparation processing 12 and when 24 is small, skin is removed from diffusion cell, then with three leachings Water cotton swab carefully cleaning skin surface.Cuticula is removed using 10 adhesive tape stripping methods (tap-stripping).Then by skin Skin is placed on glass dish, and in 60 DEG C of water-baths thermal release 90 seconds into epidermis and corium.Weigh and shred separated epidermis and true Skin, and with 0.5ml diluents (1%H3PO4：CH3OH(1：1)) extract.Skin extract is centrifuged into 20min with 14,500rpm. Berberine hydrochloride concentration in receiver solution and supernatant from skin extract is measured by HPLC.By by known quantity Medicine be added in skin histology and handled as described above to determine Berberine hydrochloride from the recycling in skin.
As a result
Table 2 summarizes the result of the experiment.
Table 2
Ran for 1 (comparing C8, G22, G23)
Operation 2 (compare 0.125%, 0.30%, G23)
Minipig skin penetration results show：A) C8 (cream preparation) infiltrations are unexpectedly good；B) it is interior when 24 is small, contain The preparation for having jamaicin particle continuously discharges (G22, G23 are to C8,0.125% and 0.3%)；C) compared with C8 (cream preparation), G22 and G23 (preparation containing jamaicin particle) remain more jamaicins in the epidermis and dermis after 24 hours；D) contain The preparation for having jamaicin particle permeates more preferably (G23 is to 0.3%) than the preparation containing barberry aqueous slkali；Even if e) G23 containing only Have 0.1% jamaicin, but compared with 0.3% preparation, 24 it is small when after G23 the jamaicin of nearly identical amounts is remained in epidermis simultaneously And more jamaicins are remained in the dermis；And f) with other penetration enhancer (ethanol and glycerine in 0.125% preparation And 0.3% propane diols and PEG 400 in preparation) compare, added in G23 SDS cause permeability increase and epidermis and The increase of corium Berberine local concentration.
Embodiment 3：
Skin biopsy result of the patient after the topical formulations treatment containing jamaicin
The subject of test is 56 years old male, it receives EGFR inhibitor Afatinib, for treating non-small cell lung Cancer (NSCLC).After Afatinib is received, subject starts to coagulate using the part of G23 preparations in its facial side once a day Glue, and at opposite side application vehicle gel (G23 for being free of jamaicin).
The bilateral skin biopsy of subject's nasolabial groove gauffer (both sides of nose) is collected, completes the local treatment of two weeks.It is logical The incisional biopsy for crossing 1.0cm × 0.5cm obtains skin sample, is then dyed and carried out using h and E (H＆E) Histology processing.Assessed by well-trained dermal pathology scholar.
H＆E coloration results (Fig. 3 and 4) are shown, are kept with hair follicle (follicular) structure of the G23 skin areas handled It is complete and there is no inflammatory cell infiltration (Fig. 3), and the hair follicle structure of the skin handled with vehicle gel is destroyed, in hair follicle There is massive inflammatory cells infiltrated in all regions, vacuole change (Fig. 4) occurs in the dermal-epidermal junction of follicular epithelium, show barberry Alkali (G23) is used to treat the potential antiphlogistic effects with the relevant dermal toxicity of EGFR inhibitor.
Embodiment 4：
Facial lesion result after the topical formulations treatment of the included jamaicin of patient
During the treatment of 4 weeks, the half side face of subject for starting to receive Afatinib inhibitor (EGFRI therapies) receives G23, the other half receives vehicle gel (G23 of no jamaicin).Subject presses 1：1 pro rate determines application study medicine The facing side of thing.Before or after EGFRI treatments are started in 1 day, subject begins to use research medicine.In the bedtime (HS) once a day (QD) will study medicament administration to it is facial specify it is half side.
The quantity of facial lesion (papule and warts) is assessed when accessing weekly, schedules to last surrounding.As illustrated in figs. 5-7, find Following obvious trend：The quantity of the upper lesion of half side face handled with G23 is substantially less than the quantity on the other half, shows small Bark of a cork tree alkali be used for treat EGFR inhibitor or other targeted therapies induction or immunotherapy induction dermal toxicity potential treatment Effect.

Claims (17)

1. a kind of method for treating and/or preventing the dermal toxicity induced by targeted therapies and/or immunotherapy, it is included to need Its patient is wanted to apply the jamaicin or its biology equivalence analog of pharmaceutical effective amount.
2. according to the method described in claim 1, wherein described targeted therapies are selected from the group consisted of：EGFR inhibitor, More tyrosine kinase (MTK) inhibitor, mek inhibitor, phosphoinositide 3-kinase (PI3K) inhibitor, protein kinase B (AKT) suppression It is preparation, BRAF inhibitor, HER2 inhibitor, more kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitor, more Kinases Abl inhibitor, BTK inhibitor, hdac inhibitor, proteasome inhibitor and rxr agonist.
3. according to the method described in claim 1, wherein described immunotherapy is selected from the group consisted of：It is cancer vaccine, thin Intracellular cytokine reagent, cell therapy, immunologic test point protein inhibitor and immunologic test point albumen stimulant.
4. according to the method described in claim 1, wherein described dermal toxicity is selected from group consisting of：Papulopustular rash, Plaque-like papule, erythema, telangiectasis flush, paronychia and cracking, hair change, axersis, catarrh, pruritus and hand Skin of foot reacts.
5. according to the method described in claim 1, the bioequivalence analog of wherein described jamaicin is selected from what is consisted of Group：Jateorrhizine, palmatine, coptisine, 9- demethyls jamaicin, 9- demethyls palmatine, 13- hydroxyls jamaicin, berberrubine, The red alkali of palmatine, 9-O- ethyls berberrubine, 9-O- ethyl -13- ethyls berberrubine, 13- methyl dihydroberberine N- methyl Salt, Tetrahydro-proto-berberines and its N- methyl salts and 9- lauryl berberrubine chlorides.
6. according to the method described in claim 1, the bioequivalence analog of wherein described jamaicin is palmatine or coptisine.
Treated and/or the method for dermal toxicity that prevention is induced by targeted therapies and/or immunotherapy 7. a kind of, it include to by The local medicine composition of the local skin application pharmaceutical effective amount of infection, the local medicine composition include jamaicin or Its biology equivalence analog.
8. according to the method described in claim 7, wherein described targeted therapies are selected from the group consisted of：EGFR inhibitor, More tyrosine kinase (MTK) inhibitor, mek inhibitor, phosphoinositide 3-kinase (PI3K) inhibitor, protein kinase B (AKT) suppression It is preparation, BRAF inhibitor, HER2 inhibitor, more kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitor, more Kinases Abl inhibitor, BTK inhibitor, hdac inhibitor, proteasome inhibitor and rxr agonist.
9. according to the method described in claim 7, wherein described immunotherapy is selected from the group consisted of：It is cancer vaccine, thin Intracellular cytokine reagent, interferon, interleukin 2, cell therapy, immunologic test point protein inhibitor and immunologic test point albumen thorn Swash thing.
10. according to the method described in claim 7, wherein described dermal toxicity is selected from group consisting of：Papulopustular rash, Plaque-like papule, erythema, telangiectasis flush, paronychia and cracking, hair change, axersis, catarrh, pruritus and hand Skin of foot reacts.
11. according to the method described in claim 7, the bioequivalence analog of wherein described jamaicin is selected from what is consisted of Group：Jateorrhizine, palmatine, coptisine, 9- demethyls jamaicin, 9- demethyls palmatine, 13- hydroxyls jamaicin, berberrubine, The red alkali of palmatine, 9-O- ethyls berberrubine, 9-O- ethyl -13- ethyls berberrubine, 13- methyl dihydroberberine N- methyl Salt, Tetrahydro-proto-berberines and its N- methyl salts and 9- lauryl berberrubine chlorides.
12. according to the method described in claim 7, the bioequivalence analog of wherein described jamaicin is palmatine or the coptis Alkali.
13. according to the method described in claim 7, wherein described local medicine composition includes at least barberry of 0.02%w/w Alkali or its biology equivalence analog.
14. according to the method described in claim 7, wherein described local medicine composition includes about 0.1% to about 2%w/w's Jamaicin or its biology equivalence analog.
15. according to the method described in claim 7, wherein described jamaicin or its biology equivalence analog are main pharmacy Upper acceptable active component.
16. according to the method described in claim 7, wherein described jamaicin or its biology equivalence analog are unique pharmacy Upper acceptable active component.
17. according to the method described in claim 7, wherein described local medicine composition is lotion, cream, ointment, paste Agent, gel, spray, supensoid agent, emulsion, foaming agent, patch, the form of pulvis and liniment.
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