RU2733743C2 - Therapeutic use of medicinal forms of berberine - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to treatment and/or prevention of skin toxicity caused by a targeted therapy. Method comprises administering to patient a pharmaceutical composition for local application containing 0.1 to 0.3 wt % berberine, and said targeted therapy is selected from a group consisting of MEK inhibitors, HER2 inhibitors and mTOR inhibitors.

EFFECT: invention provides a wider range of products, namely new effective methods of treating various skin diseases, accompanied by face redness, as well as skin toxicity caused by the targeted therapy.

6 cl, 2 tbl, 4 ex, 7 dwg

Description

THERAPEUTIC APPLICATION OF DOSAGE FORMS OF BERBERINE

BACKGROUND OF THE INVENTION

[001] Inflammations of the skin accompanied by facial flushing, having similar symptoms and possibly similar pathological causes, include rosacea, juvenile acne, seborrheic dermatitis, photodermatitis, and contact dermatitis. Such conditions associated with facial flushing can include sensations ranging from hot sensations and soreness to flushing or fever with great sensitivity. Patients with skin inflammation accompanied by facial flushing are often highly sensitive to environmental and topical factors. Steroid-induced rosacea-like dermatitis (or steroid rosacea) is a papular or pustular rash with an erythematous and edematous base with or without telangiectasia caused by prolonged use of topical steroids on the face or a recurrent condition after discontinuation of topical steroids.

[002] Cutaneous toxicity is a known side effect on the skin associated with targeted therapies or immunotherapy, having similar symptoms and possibly similar pathological causes of skin inflammation accompanied by facial flushing. Targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors, multityrosine kinase inhibitors (MTK, MEK inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, protein kinase B inhibitors (AKT), BRAF inhibitors, HER2 inhibitors, HER2 inhibitors, angiogenesis inhibitors, mTOR inhibitors, ALK / c-met inhibitors, multi-kinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and retinoid X receptor (RXR) agonists; immunotherapy, eg, cancer vaccines, cytokine agents (eg granrophagocytic colorectal macrostimulation factor (GM-CSF), interferons and interleukin-2 (IL-2)), cell therapy (for example, tumor-infiltrating lymphocytes (TILs), peripheral blood lymphocytes (PBL) derived from T-cell receptors (TCR), and PBLs derived from chimeric antigen receptors (CARs)), immune checkpoint protein inhibitors (e.g. PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VIS TA and TIGIT) and immune checkpoint protein stimulants (eg CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40); or a combination of any of the above treatments, may cause toxicity, including papular pustular rash, maculopapular rash, erythema, telangiectasia, paronychia and fissures, hair changes, xerosis, mucositis, pruritus, and skin reactions on the hands and feet, which can occur with more than 90% of patients, it is also possible to superinfect with bacteria, for example, 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-4 Blockade 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). Histopathological studies of such cutaneous toxicity have shown that inflammation is often present, leading to acne-like rash. Papular pustular rash was more common with EGFR inhibitors such as cetuximab (83% of patients) and afatinib (90% of patients), and MEK inhibitors such as selumetinib (93% of patients) and trametinib (80% of patients). Maculopapular rash was more common with PI3K inhibitors such as BKM-120 (37% of patients), MK2206 (52% of patients), immune checkpoint protein inhibitors such as the anti-CTLA-4 inhibitor ipilimumab (33% of patients), the anti-PD-1 inhibitor nivolumab (26% of patients) or a combination of ipilimumab and nivolumab (more than 40% of patients).

[003] Berberine (natural yellow 18,5,6-dihydro-9,10-dimethoxybenzo (g) -1,3-benzodixolo (5,6-a) quinolizinium) is an isoquinoline alkaloid found in herbal plants such as coptis (Coptidis rhizome), phellodendron, Baikal skullcap, holly mahonia and barberry. It was found that berberine and its derivatives have antimicrobial and antimalarial activity. It can act against various types of pathogens such as fungi, saccharomycetes, parasites, bacteria, and viruses.

[004] Berberine also has anti-inflammatory function, but the exact mechanism is not yet known.

[005] US Patent No. 6,440,465 relates to topical formulations of glucosamine with an emollient base containing berberine for the treatment of psoriasis. US Patent Publication No. 2005/0158404 relates to a nutritional product, dietary supplement, or pharmaceutical composition containing vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and a plant source of berberine for the treatment of acne via oral administration. US patent No. 6974799 relates to pharmaceutical compositions for topical use containing a tripeptide (N-palmitoyl-Gly-His-Lys) and a tetrapeptide (N-palmitoyl-Gly-Gln-Pro-Arg) for the elimination of visible signs of aging, including wrinkles, stretch marks , dark circles. The dosage form may contain additional ingredients, including berberine. In these inventions, berberine is included as one of many ingredients, and its concentration is not indicated.

[006] US Patent No. 2004/0146539 relates to topical nutraceutical pharmaceutical compositions with volume-reducing, toning and anti-aging properties that can be used to prevent skin aging, wrinkles, skin exfoliation, treat acne, rosacea and other problems. with skin. The present invention includes antimicrobial agents selected from several agents, including berberine. In these nutraceutical compositions, berberine is included as one of a variety of ingredients, and its concentration is not indicated. There was a cream with 10% Mahonia holly (Relieva ^TM , Apollo Pharmaceutical Canada Inc) containing 0.1% berberine for the treatment of psoriasis.

[007] US Patent No. 2012/0165357 discloses the use of berberine for the treatment of various skin inflammations accompanied by facial flushing, but does not disclose specific dosage forms of berberine that could be determined to be effective for the treatment of certain conditions.

[008] Thus, there is still a need for the development of new effective methods for the treatment of various skin diseases accompanied by facial flushing, as well as skin toxicity caused by targeted therapy and / or immunotherapy.

SUMMARY OF THE INVENTION

[009] The present invention provides pharmaceutical compositions for the treatment and / or prevention of various skin diseases accompanied by facial flushing and skin toxicity caused by targeted therapy and / or immunotherapy. The proposed dosage forms are cream (eg cream) or gel-like.

[010] In particular, this invention provides a pharmaceutical composition comprising berberine, said composition being a cream dosage form comprising an aqueous phase and an oil phase.

[011] In one embodiment, the concentration of berberine in said cream dosage form is from 0.01% to 10%, preferably from 0.01% to 0.3% by weight, more preferably from 0.1% to 0%, 2% by weight, even more preferably from 0.1% to 0.15% by weight, and most preferably 0.12% by weight.

[012] Unless expressly indicated otherwise, when the application indicates the amount or concentration in the format "by weight", the weight of each ingredient is determined based on the total weight of the dosage form.

[013] The pharmaceutical compositions of the invention may further comprise a penetration enhancer.

[014] In one embodiment, the penetration enhancer is an anionic penetration enhancer.

[015] In another embodiment, the penetration enhancer comprises Tween® 60 and glycerin.

[016] In one embodiment, berberine is the only pharmaceutically active ingredient in the present dosage forms.

[017] In one embodiment, the pharmaceutical compositions of the invention have a pH of from about 4 to about 7, more preferably about 5.5.

[018] In a preferred embodiment, the invention provides a pharmaceutical composition containing berberine as the sole pharmaceutically active ingredient, said berberine having a concentration of 0.1% to 0.2% by weight, said composition being a cream dosage form containing an aqueous 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 from about 4 to about 7.

[019] In a more preferred embodiment, the invention provides a pharmaceutical composition comprising berberine as the only pharmaceutically active ingredient, said berberine having a concentration of about 0.12 wt%, said composition being a cream dosage form comprising an aqueous phase and an oil phase, wherein said composition comprises a penetration enhancer, preservative and stabilizer, and wherein said composition has a pH of about 5.5.

[020] In another embodiment, the present invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel dosage form, wherein said composition comprises an anionic penetration enhancer.

[021] In a preferred embodiment, the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS).

[022] In one embodiment, the gelled pharmaceutical compositions of the invention have an average particle size of about 90% of the berberine particles less than 10 microns.

[023] In another embodiment, the gelled pharmaceutical compositions of the invention have an average particle size of about 50% of the berberine particle less than 4 microns.

[024] In one embodiment, the concentration of berberine in said gel dosage form is from 0.01% to 0.3% by weight, more preferably from 0.1% to 0.2% by weight, even more preferably from 0.1% to 0.15% by weight, and most preferably about 0.12% by weight.

[025] The invention also provides methods for treating skin inflammation accompanied by facial flushing, comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.

[026] In an embodiment, the flushing of the skin is selected from the group consisting of rosacea, juvenile acne, seborrheic dermatitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitor skin inflammation.

[027] The invention further provides methods for treating and / or preventing skin toxicity caused by targeted therapy and / or immunotherapy, comprising administering to a patient a pharmaceutically effective amount of berberine and / or a biologically equivalent analogue thereof.

[028] In a preferred embodiment, targeted therapy includes therapy with EGFR inhibitors, MTK inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, BRAF inhibitors, HER2 inhibitors, multikinase angiogenesis inhibitors, mTOR inhibitors, ALK / c-metase inhibitors Abl, BTK inhibitors, HDAC inhibitors, proteasome inhibitors and RXR agonists.

[029] In a preferred embodiment, immunotherapy includes therapy with cancer vaccines, cytokine agents (e.g., granulocyte macrophage colony stimulating factor (GM-CSF)), interferons and interleukin-2 (IL-2)), cell therapy (e.g. , tumor infiltrating lymphocytes (TILs), peripheral blood lymphocytes (PBL) derived from T cell receptors (TCR) and PBL derived from chimeric antigen receptors (CAR)), immune checkpoint protein inhibitors (e.g., PD -1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT) and immune checkpoint protein stimulants (e.g. CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40).

[030] In a preferred embodiment, berberine and / or its biologically equivalent analogue is administered to the patient in the dosage form of a pharmaceutical composition for topical use.

BRIEF DESCRIPTION OF THE GRAPHIC MATERIALS

[031] The patent or application contains at least one tone pattern. Copies of this patent or patent application with tone (s) drawing (s) will be provided by the Office upon request and upon payment of the required fees.

[032] Figure 1 is a graph of the total amount of permeated berberine (ng / cm ² ) versus time for six dosage forms of berberine tested.

[033] Figure 2 is a graph of total permeated berberine (ng / cm ² ) versus time for three gel suspension dosage forms of berberine (G22, G23 and G24).

[034] Figure 3 is an image of hematoxylin-eosin (H&E) staining of bilateral nasolabial skin biopsy of a patient taking afatinib and on one side of the face of which a gel formulation is applied (G23).

[035] Figure 4 is an image of hematoxylin-eosin (H&E) staining of bilateral skin biopsy from the nasolabial folds of a patient taking afatinib EGFR inhibitor and on the other side of his face applying a gel base (G23 without berberine).

[036] Figure 5 is a graph of the number of papules versus time for a patient taking afatinib who has a gel formulation applied to one side of his face (G23) and a gel base (G23 without berberine) applied to the other side of his face (* denoted by P <0.05 according to the Wilcoxon signed rank coefficient).

[037] Figure 6 is a graph of the number of pustules versus time for a patient taking afatinib who has a gel formulation applied to one side of his face (G23) and a gel base (G23 without berberine) applied to the other side of his face (* denoted by P <0.05 according to the Wilcoxon signed rank coefficient).

[038] Figure 7 is a graph of the cumulative amount (papules and pustules) versus time for a patient on afatinib who has a gel formulation applied to one side of his face (G23) and a gel base is applied to the other side of his face (G23 without berberine ) (* denoted P <0.05 according to the Wilcoxon signed rank coefficient).

DETAILED DESCRIPTION OF THE INVENTION

[039] Depending on the specific inflammation being treated, it is important that berberine is effectively absorbed into the skin. Berberine is a hydrophilic compound (partition coefficient 1.07 in the octanol-water system), which makes it difficult for berberine to penetrate through the stratum corneum to reach a given site, for example, the dermis or epidermis, where inflammation of the skin, accompanied by facial flushing, or skin toxicity caused by targeted therapy. In addition, berberine is quite soluble (solubility 1.57 mg / ml) and will be quickly released into the target cells, resulting in a temporary effect.

[040] The present invention thus provides pharmaceutical compositions with an increased rate of penetration of berberine for the treatment and / or prevention of various skin diseases associated with facial flushing and skin toxicity caused by targeted therapy and / or immunotherapy. The proposed dosage forms are cream dosage forms (eg, creams) or gel dosage forms.

[041] In particular, this invention provides a pharmaceutical composition comprising berberine, said composition being a cream dosage form comprising an aqueous phase and an oil phase.

[042] Since the cream dosage forms of the invention can facilitate the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve the desired treatment effect. In one embodiment, the concentration of berberine in said cream dosage form is from 0.01% to 10% by weight, preferably from 0.01% to 0.3% by weight, more preferably from 0.1% to 0.2 % by weight, even more preferably from 0.1% to 0.15% by weight, and most preferably 0.12% by weight, based on the total weight of the preparation.

[043] The pharmaceutical compositions of the invention may further comprise a penetration enhancer.

[044] In one embodiment, the penetration enhancer is an anionic penetration enhancer. For example, the anionic penetration enhancer may contain sodium dodecyl sulfate (SDS).

[045] In another embodiment, the penetration enhancer comprises Tween® 60 and glycerin. Cream dosage forms of the invention should preferably contain Tween® 60 and glycerin as penetration enhancers. When the same penetration enhancers are used in non-cream dosage forms, they do not increase the rate of penetration, suggesting that cream-based dosage forms have unique properties.

[046] In one embodiment, berberine is the only pharmaceutically active ingredient in the present medicaments. Even though an ingredient of the present dosage forms may be an active ingredient in prior art dosage forms for purposes other than dermal toxicity caused by targeted therapy or immunotherapy, it is still considered a pharmaceutical adjuvant for the purposes of these present dosage forms, since this ingredient is not present. in an amount sufficient to effectively treat cutaneous toxicity caused by targeted therapy or immunotherapy.

[047] In one embodiment, the pharmaceutical compositions of the invention have a pH of from about 4 to about 7, more preferably about 5.5.

[048] In a preferred embodiment, the invention provides a pharmaceutical composition containing berberine as the only pharmaceutically active ingredient, said berberine having a concentration of 0.1% to 0.2% by weight, said composition being a cream dosage form containing an aqueous 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 from about 4 to about 7.

[049] In a more preferred embodiment, the invention provides a pharmaceutical composition comprising berberine as the sole pharmaceutically active ingredient, said berberine having a concentration of about 0.12 wt%, said composition being a cream dosage form comprising an aqueous phase and an oil phase, wherein said composition comprises a penetration enhancer, preservative and stabilizer, and wherein said composition has a pH of about 5.5.

[050] Surprisingly and unexpectedly, it has been found that cream dosage forms of the invention have a better penetration rate compared to non-cream dosage forms of berberine.

[051] In another embodiment, the invention provides a pharmaceutical composition comprising berberine, wherein said composition is a gel dosage form, wherein said composition comprises an anionic penetration enhancer.

[052] In a preferred embodiment, the anionic penetration enhancer comprises sodium dodecyl sulfate (SDS). The inclusion of sodium dodecyl sulfate (SDS) as an anionic penetration enhancer results in gel-based dosage forms becoming hydrophobic (partition coefficient 50.1 in octanol-water system) and have a much lower solubility of about 0.011 mg / ml, which provides a slow release of berberine into targeted cells and results in an extended release curve.

[053] In the present invention, it has been found that at a pH of 4 to 7, the solubility of berberine in the presence of SDS is 0.01 to 0.06 mg / ml, i.e. 25–150 times less than the solubility of aqueous berberine (1.57 mg / ml), and relatively low at pH 5.5.

[054] Surprisingly, it was found that of all the penetration enhancers tested (SDS, glycerin, propylene glycol, PEG 400, ethanol and Tween®), the addition of SDS to gel-based dosage forms resulted in the highest penetration rate and increased local concentration berberine in the epidermis and dermis.

[055] In one embodiment, in the gelled pharmaceutical compositions of the invention, about an average size of about 90% of the berberine particles is less than 10 microns.

[056] In another embodiment, the gelled pharmaceutical compositions of the invention have an average particle size of about 50% of the berberine particles less than 4 microns.

[057] It was also surprisingly found that there was a direct relationship between the amount of SDS and the rate of penetration and an inverse relationship between the size of berberine and the rate of penetration in the gel-based dosage forms.

[058] Since the dosage forms of the invention on a gel basis can promote the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve the desired effect of treatment. In one embodiment, the concentration of berberine in said gel-based dosage form is from 0.01% to 0.3% by weight, more preferably from 0.1% to 0.2% by weight, even more preferably from 0, 1% to 0.15% by weight, and most preferably 0.12% by weight, based on the total weight of the dosage form.

[059] The invention also provides methods for treating skin inflammation accompanied by facial flushing, comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.

[060] In an embodiment, the skin inflammation accompanied by facial flushing is selected from the group consisting of rosacea, juvenile acne, seborrheic dermatitis, contact dermatitis, steroid-induced rosacea-like dermatitis, and epidermal growth factor receptor (EGFR) inhibitor skin inflammation.

[061] The invention further provides methods for treating and / or preventing cutaneous toxicity caused by targeted therapy and / or immunotherapy, comprising administering to a patient a pharmaceutically effective amount of a pharmaceutical composition of the invention.

[062] In one embodiment, said targeted therapy is selected from the group consisting of: epidermal growth factor receptor (EGFR) inhibitors, multityrosine kinase (MTK) inhibitors, MEK inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, protein kinase inhibitors B (AKT), BRAF inhibitors, HER2 inhibitors, multikinase angiogenesis inhibitors, mTOR inhibitors, ALK / c-met inhibitors, Abl multikinase inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and retinoid X receptor (RXR) agonists said immunotherapy is selected from the group consisting of: cancer vaccines, cytokine agents (e.g., granulocyte macrophage colony stimulating factor (GM-CSF), interferons and interleukin-2 (IL-2)), cell therapy (e.g., tumor infiltrating lymphocytes (TILs), peripheral blood lymphocytes (PBL) derived from T-cell receptors (TCR) and PBLs derived from chimeric antigen receptors (CAR)), immune checkpoint protein inhibitors (e.g. PD-1, PD- L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT) and immune checkpoint protein stimulants (e.g. CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40); and said cutaneous toxicity caused by targeted therapy and / or immunotherapy is selected from the group consisting of papular-pustular rash, maculopapular rash, erythema, telangiectasia, paronychia and fissures, hair changes, xerosis, mucositis reaction, pruritus and skin on arms and legs.

[063] The concentrations of berberine in the epidermis, dermis and receptacle (ie, container filled with phosphate buffer PBS in contact with the skin) are measured using the following approach. The Franz diffusion cell setup is essentially skin sandwiched between two clamps. The drug is applied to one side of the skin (top) and the concentration of the drug is measured in the resulting sample (bottom) of the unit.

[064] As used herein, the term "penetration rate" refers to the amount of berberine per gram of epidermal or dermal tissue, or the amount of berberine per cm ^{2 of} skin in the receptacle, after a certain period of time after application of the dosage form to the skin.

[065] The amount of drug measured in the receiver reflects the total amount that has penetrated through the stratum corneum, epidermis and dermis of the skin. The pharmaceutical composition of this invention increased the rate of penetration, and the preferred range of the rate of penetration is as follows:

Epidermis: 0.4 to 4000 mcg berberine per gram of tissue

Dermis: 0.003 to 30 mcg berberine per gram of tissue

Receiver: 0.0001 to 1 mcg of berberine per 1X1 cm ^{2 of} skin.

[066] Table 1 lists various ingredients that can be used in the invention. However, this list is presented for purposes of illustration only and is not limiting to the scope of this invention. In addition, various ingredients / excipients can act in more than one way, for example, function as a penetration enhancer, emulsifying agent, wetting agent, etc.

TABLE 1

Excipient Function Concentration range
walkie-talkies (%) Substitutes /
analogs Lauryl sulfate
sodium Anionic substance, method
penetrating 0.5-2.5 sulfate, sulfonate, phosphate, oleate, monostearate and carboxylates Carbopol 934P Geleobra-
calling agent 0.3-3 Carbopol 940, Carbopol 941, Carbopol 971, Carbopol 974, Carbopol 980, Carbopol 981, Carbopol 5984EP, Carbopol ETD 2020, Hydroxyethyl
methyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose (with a low degree of substitution), methyl cellulose, methyl hydroxypropyl cellulose Hydroxyethyl cellulose Gelling agent 0.5-8 Methylparaben Preservatives 0.02-0.3 Quaternary ammonium compounds, amino aryl acid ester, alkyl / aryl alcohols, alkyl / aryl acids, alkyl / aryl amides, organomercury compounds, formaldehyde donors, biguanides, phenols Propylparaben 0.01-0.8 EDTC Antioxidant 0.005-0.1 Dipotassium edetate, disodium edetate, edetate calcium disodium, sodium edetate, trisodium edetate

Glycerol Wetting agent 0.01-30 Propylene glycol, polyethylene glycol Tween® 80 Moisturizing agent 0.1-3 Polyethylene glycol, sorbitol ethers Citric acid monohydrate Buffer agent 0.1-2 Anhydrous citric acid, fumaric acid, malic acid, sodium citrate dihydrate, tartaric acid Sodium citrate dihydrate 0.3-2 Sodium citrate anhydrous; citric acid monohydrate Water Water - - Stearic acid Oil base 1-20 Calcium stearate, magnesium stearate, polyoxyethylene stearates, purified stearic acid, zinc stearate, lauric acid, myristic acid, palmitic acid, oleic acid Castor oil Oil base 5-12.5 Mineral oil, almond oil, cocoa butter, corn oil, coconut oil, cottonseed oil, linseed oil, olive oil, soybean oil White Vaseline Oil base 4-56 Yellow petrolatum, liquid paraffin, paraffin, ceresin, microcrystal
hair wax, Plastibase

Excipient Function Concentration range
walkie-talkies (%) Substitutes /
analogs SPAN 60 Emulsifying agent 1-15 Polyoxyethylene sorbitol fatty acid ester, Tween® 60 Emulsifying agent 1-15 Polyethylene glycol, sorbitol ethers

[067] As used herein, the term "berberine" refers to 5,6-dihydro-9,10-dimethoxybenzo (g) -1,3-benzodixolo (5,6-a) quinolysinium. This invention also contemplates the use of berberine analogs containing, but not limited to, jatrorizine, palmatine, coptisine, 9-demethylberberine, 9-demetypalmatine, 13-hydroxyberberine, berberrubin, palmatrubin, 9-O-ethylberberrubin, 9-O-ethyl-13 -ethylberberubine, 13-methyldihydroberberine N-methyl salt, terahydroproberberines and their N-methyl salts, 9-lauroylberrubin chlorine and pharmaceutically acceptable salts of all these compounds.

[068] As used herein, the term "pharmaceutically acceptable salts" includes salts of an acidic or basic group. Examples of pharmaceutically acceptable salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarboxylic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogenic, hydroiodic, phosphoric acids, and the like. derived from relatively non-toxic organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, almond, phthalic, benzenesulfonic, toluenesulfonic, including p-toluenesulfonic, m-toluenesulfonic, toluene-toluenesulfonic wine, methanesulfonic, etc. Also included are amino acid salts such as arginate and the like, and organic acid salts such as glucuronic acid or galacturonic acid and the like.

[069] As used herein, the term "treatment" includes containing a disease or current condition, resulting in a decrease in the severity and / or frequency of symptoms and / or root causes, preventing symptoms and / or their root causes, and improving the patient's condition. Thus, "treating" a patient with said compositions of the invention comprises preventing certain inflammations in a predisposed individual, as well as controlling the course of treatment for an individual with clinical symptoms in order to slow or regress the inflammation or disease, and maintain the current state and / or prevent the progression of the inflammation or disease. ... Treatment may include prevention, therapy, or treatment.

[070] As used herein, the term "pharmaceutically effective amount" of compounds and / or for pharmaceutical compositions of this invention refers to a sufficient amount of a compound and / or composition to treat, control, improve or prevent various skin inflammations accompanied by facial flushing, including but not limited to targeted therapy-induced skin toxicity, with a reasonable risk / benefit ratio applied to any medical treatment. However, it should be understood that the total amount for daily use of the compounds and / or compositions of this invention should be determined by the attending physician following careful medical evaluation. The individual effective dose level for a particular patient will depend on various factors, including the inflammation being treated and the severity of the inflammation; the activity of the individual compound involved; individual involved composition; the age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of excretion of the individual compound involved; duration of treatment; drugs used in conjunction with or concurrently with the individual compound involved; and similar factors well known to those skilled in the art. For example, it is well known to those skilled in the art that it is necessary to start with doses of the composition at a lower level than required in order to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[071] The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier and be in solid or liquid form, including but not limited to tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, patches or suppositories, including rectal and urethral suppositories.

[072] 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. The pharmaceutically acceptable carrier is compatible with the other ingredients of the composition, with the route of administration, and is not harmful to the patient. The pharmaceutically acceptable carrier can be aqueous or non-aqueous. The pharmaceutically acceptable carrier contains gums, starch, sugars, cellulosic materials, and mixtures thereof. Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: (a) sugars such as lactose, glucose, and sucrose; (b) starch such as corn starch and potato starch; (c) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (d) tragacanth powder; (e) malt; (f) gelatin; (g) talc; (h) excipients such as cocoa butter and candle wax; (i) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; (j) glycols such as propylene glycol; (k) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (l) ethers 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 buffer; (o) alginic acid; (p) pyrogen-free water; (q) isotonic solution; (r) Ringer's solution; (s) ethyl alcohol; (t) phosphate buffer solutions; and (u) other non-toxic compatible substances suitable for use in pharmaceutical compositions.

[073] Compositions of the invention can be administered by any means known in the art, including, but not limited to, oral, nasal, parenteral, topical, transdermal, or rectal routes of administration. It is preferred that the compositions are adapted for oral or topical administration. For example, the active ingredient of the composition can be combined with auxiliaries for preparing tablets, capsules, pellets, lozenges, lozenges, solutions, powders or granules, suspensions, hard or soft capsules, patches, and any other suitable form.

[074] The invention also provides a method of treating and / or preventing skin toxicity caused by targeted therapy and / or immunotherapy, comprising administering to a patient a pharmaceutically effective amount of berberine or a biologically equivalent analogue thereof.

[075] The invention further provides a method of treating and / or preventing skin toxicity caused by targeted therapy and / or immunotherapy, comprising topically applying to the affected skin a pharmaceutically effective amount of a topical pharmaceutical composition containing berberine or a biologically equivalent analogue thereof.

[076] In another embodiment, the topical pharmaceutical composition is in the form of a lotion, cream, ointment, paste, gel, spray, suspension, emulsion, foam, patch, powder, and ointment.

[077] In another embodiment, the pharmaceutical composition for topical use contains at least 0.02% by weight, preferably from 0.1% to 2% by weight. berberine or its biologically equivalent analogue, this amount being the total weight of the composition.

[078] In another embodiment, berberine or a biologically equivalent analogue of berberine is the primary pharmaceutically acceptable active ingredient.

[079] In another embodiment, berberine or a biologically equivalent analogue of berberine is the only pharmaceutically acceptable active ingredient.

[080] The following examples show some aspects of the present invention. The examples are not limiting to the invention.

Example 1

Study of the penetration of dosage forms of berberine

into the skin of mice

[081] The following six dosage forms of berberine were compared: C8, 0.125%, 0.3%, G22, G23 and G24.

Dosage forms

[082] The following dosage forms were considered:

C8 (cream-based dosage form):

Water phase

Berberine (0.12%), Tween® 60 (1%), Glycerin (3%), Methylparaben (0.1%), Propylparaben (0.02%), NaOH (to adjust the pH to 5.5) and Ethylenediaminetetraacetic acid (EDTA) (0.02%).

Oil phase

stearic acid (7.5%), castor oil (8%), white petrolatum (6%) and SPAN 60 (2%).

0.125% (gel-based dosage form):

berberine (0.125%), ethanol (2.5%), glycerin (10%), phenoxyethanol (0.3%), carbomer.

0.3% (gel-based dosage form):

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 dosage form):

berberine (0.1%), SDS (0.086%), glycerin (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: 3.83 / 11.34 / 27.24 (in D10 / D50 / D90 format, where each value refers to the corresponding percentage of particles smaller than the specified size, i.e. 10% of particles smaller than 3.83, etc.) etc.).

G23 (gel-based dosage form):

berberine (0.1%), SDS (0.086%), glycerin (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 dosage form):

berberine (0.1%), SDS (0.043%), glycerin (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

[083] The particle size of the dosage forms G22, G23 and G24 was determined as follows.

[084] Purified water was prepared, then berberine chloride, Tween® 80 and sodium lauryl sulfate (SDS) were added. After the mixture was well mixed, it was ground finely. The particle size was then measured with a diffraction analyzer.

Experimental conditions

[085] Mice were withdrawn from the experiment by cervical dislocation. A full-thickness skin sample from the side was removed and placed on a diffusion cell in contact with the receptor phase, which was 0.01M PBS (pH 7.4 at 37 ℃). The buffers were pumped through the receiver compartment at a rate of 3-4 ml / h. In the donor chamber, 300 μl of dosage forms were added to the skin surface. The solutions from the receiver were withdrawn for HPLC analysis at hours 0, 1, 2, 3, 4, 6, 8, 10, and 12. The percutaneous penetration rate was calculated from the slope of the linear part of the total amount of berberine chloride permeated against the time graph. Results

[086] Figure 1 shows a graph of the total amount of penetrated berberine (ng / cm ² ) versus time for all six dosage forms tested. As can be seen, C8 (cream formulation) and G23 (gel-based formulation) penetrated better than the other formulations. This was unexpected since, in theory, all six dosage forms should penetrate at the same rate due to the physical properties of berberine in the aqueous phase.

[087] Figure 2 depicts a graph of total permeated berberine (ng / cm ² ) versus time for three gel suspension dosage forms (G22, G23 and G24). As can be seen, the permeation rate has a direct relationship with the penetration enhancer (SDS) and an inverse relationship with the size of berberine. G23 and G24 with berberine size less than 10 µm (D90) have a lower penetration rate than G22 with more than 10 µm (D90).

Example 2

Study of the penetration of dosage forms of berberine

into the skin of mini pigs

[088] The following dosage forms of berberine were compared: 1) C8, G22 and G23; and 2) 0.125%, 0.30% and G23.

[089] Skin: The skin of a mini-pig (Lanyu mumps or Lee sung mumps) is dermatomized to 700 μm with an electrical resistance> 10 kΩ (Millicell-ERS, Millipore).

Penetration experiments

[090] The skin of the guinea pig was placed on a diffusion cell so that the side of the dermis was in contact with the receptor phase, which was filled with PBS (pH 7.4 at 37 ℃). In the donor chamber, 20 μl dosage forms were added to the skin surface. After 8 hours, the remains of the dosage form on the skin surface were removed with three dry cotton swabs. After 12 and 24 hours of treatment with dosage forms, the skin was removed from the diffusion cell, and the skin surface was again gently cleaned with three cotton swabs soaked in water. 10 scrapes were made with adhesive tape to remove the stratum corneum. The skin was then placed on a glass disc and separated by heating into epidermis and dermis in a water bath at 60 ° C for 90 seconds. The separated epidermis and dermis were weighed, crushed and extracted with 0.5 ml of solvent (1% H ₃ PO ₄ : CH ₃ OH (1: 1)). The skin extracts were centrifuged at 14,500 rpm for 20 minutes. Berberine chloride concentrations in receiver solutions and supernatants from skin extracts were determined by HPLC. The recovery of berberine chloride from the skin was determined by adding a known amount of the drug to the skin tissue and processing as above.

results

[091] Table 2 summarizes the results of this experiment.

[092] The results of the study of penetration into the skin of minipigs showed that: a) C8 (cream dosage form) penetrates surprisingly well; b) dosage forms containing particles of berberine were continuously released for 24 hours (G22, G23 versus C8, 0.125% and 0.3%); c) G22 and G23 (dosage forms containing particles of berberine) retained more berberine in the epidermis and dermis after 24 hours compared to C8 (cream dosage form); d) dosage forms containing berberine particles penetrated better than dosage forms with berberine solution (G23 versus 0.3%); f) G23 retained approximately the same amount of berberine in the epidermis and more berberine in the dermis after 24 hours compared to the 0.3% dosage form, despite the fact that G23 contained only 0.1% berberine; and f) compared to other penetration enhancers (ethanol and glycerol in 0.125% dosage form and propylene glycol and PEG 400 in 0.3% dosage form), the addition of SDS in G23 resulted in an increase in the rate of penetration and increased the local concentration of berberine in the epidermis and dermis.

Example 3

Results of a skin biopsy of a patient treated with a topical dosage form containing berberine

[093] The test subject was a 56-year-old male who was taking afatinib, an EGFR inhibitor, for the treatment of non-small cell lung cancer (NSCLC). After taking afatinib, the subject began applying topical formulation gel G23 to one side of the face and a gel base (G23 without berberine) to the other side of the face daily.

[094] A bilateral skin biopsy of the nasolabial folds (on both sides of the nose) was taken from the subject at the end of the two-week topical application. Skin samples of 1.0 cm x 0.5 cm were obtained by incisional biopsy and then histologically processed using hematoxylin-eosin staining. The assessment was performed by a trained dermatologist.

[095] The results of hematoxylin-eosin staining (Figures 3 and 4) show that the follicular structure remains unchanged, and the area of skin treated with G23 (Figure 3), there is no infiltration of inflammatory cells, while destruction of the follicular structure was observed, profuse infiltration inflammatory cells in the perifollicular region, vacuolar changes in the dermis-epidermis junction of the follicular epithelium for skin treated with a gel base (Figure 4), reflecting the potential anti-inflammatory effect of berberine (G23) for the treatment of skin toxicity associated with an EGFR inhibitor.

Example 4

Results of facial skin lesions of a patient treated with a topical dosage form containing berberine

[096] Subjects taking an afatinib inhibitor (EGFRI therapy) were registered to apply G23 to one half of the face and a gel base (G23 without berberine) to the other half of the face over a four week treatment period. Subjects were assigned to determine the side of the face to apply study drugs in a 1: 1 ratio. Subjects started study drugs 1 day before or after starting EGFRI therapy. The study drug was applied once daily (QD) at bedtime (HS) to the corresponding half of the face.

[097] The number of facial lesions (papules and pustules) was assessed at weekly visits for four weeks. As shown in Figures 5 to 7, a clear trend was found that the number of lesions in the G23-treated half of the face was significantly less than in the other half, reflecting the potential therapeutic effect of berberine in treating EGFR inhibitor-induced cutaneous toxicity. other targeted therapy or immunotherapy.

Claims (6)

1. A method of treatment and / or prevention of skin toxicity caused by targeted therapy, containing the introduction to the patient of a pharmaceutical composition for topical use, containing from 0.1 to 0.3% of the mass. berberine, and said targeted therapy is selected from the group consisting of MEK inhibitors, HER2 inhibitors, and mTOR inhibitors. 2. The method of claim 1, wherein said cutaneous toxicity is selected from the group consisting of papular pustular rash, maculopapular rash, erythema, telangiectasia, paronychia and fissures, hair changes, xerosis, mucositis and pruritus. 3. The method according to p. 1, in which the pharmaceutical composition for topical use contains 0.1% of the mass. berberine. 4. The method according to claim 1, wherein berberine is the preferred pharmaceutically acceptable active ingredient. 5. The method of claim 1, wherein berberine is the only pharmaceutically acceptable active ingredient. 6. The method of claim 1, wherein the topical pharmaceutical composition is in the form of a lotion, cream, ointment, paste, gel, spray, suspension, emulsion, foam, patch, powder, and liquid ointment.

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