TW201713334A - Therapeutic uses of berberine formulations - Google Patents

Abstract

Uses of pharmaceutical compositions comprising berberine for treatment of dermatologic toxicities and other skin disorders are provided.

Description

Therapeutic use of berberine preparations

Red-face related skin diseases, including rosacea, acne vulgaris, seborrheic dermatitis, photodermatitis, and contact dermatitis, all have similar Symptoms and common possible causes. These red-face related symptoms can include heat and sensitive sensations, and even intense sensitivity to flushing or burning sensations. Patients with red-faced skin diseases are often extremely sensitive to environmental and external factors. Steroid-like dermatitis (or rosacea) caused by steroids is a papular or pustular lesion with or without telangiectasia and edema, caused by prolonged external administration of steroids to the face, or The symptoms of recurrence after topical steroid administration were discontinued.

Dermatologic toxicities are skin adverse reactions known to be associated with target treatment or immunotherapy, and have similar symptoms and possible causes to red face related skin diseases. Targeted treatments such as epidermal growth factor receptor (EGFR) inhibitors, multiple tyrosine kinase (MTK) inhibitors, mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitor, protein kinase B (AKT) inhibitor, BRAF inhibitor, human epidermal growth factor receptor 2 (HER2) inhibitor, multi-kinase angiogenesis inhibitor, rapamycin in mammalian cells Inhibitors of (mTOR), anaplastic lymphoma kinase (ALK)/c-met inhibitors, multi-kinase Abl inhibitors, Bruton tyrosine kinase (BTK) inhibitors, histone deacetylase (HDAC) inhibition Agents, proteasome inhibitors, and retinoic X receptors (RXR) agonists; immunotherapies such as cancer vaccines, cytokine agents (eg, granular cell-macrophage colony-stimulating factor (GM-CSF) , interferon and interleukin-2 (IL-2), cell therapy (eg, tumor infiltrating lymphocytes (TILs), T cell-receptor modified peripheral blood lymphocytes (TCR-engineered PBL), and chimeric antigens Peripheral hemolymph CAR-engineered PBL), immunosuppressive protein inhibitors (such as PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA, and TIGIT), and protein stimulation at the immunological checkpoint Agents (eg, CD28, ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1, and CD-40); or a combination of any of the above treatments, can cause toxicity, including papulopustular rash , maculopapular rash, rash, capillary dilated flushing, paronychia and laceration, hair changes, xerosis, mucositis, scrapie, and hand-foot skin reaction, which can occur in more than 90% of patients On the body, and will be repeatedly infected by bacteria 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 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 t Herapy: 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 lpilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management, Scientifica , 2013; J Larkin et al., Combined Nivolumab and lpilimumab or Monotherapy in Untreated Melanoma, N. Engl. J. Med. , Vol. 373, 2015). Histopathological studies of such dermal toxicity have shown that inflammatory reactions often occur and cause acne-prone skin rashes. The pustular rash is more often treated with EGFR inhibitors such as cetuximab (83% of patients) and afatinib (90% of patients); and MEK inhibitor treatment Such as selumetinib (93% of patients) and trametinib (80% of patients). The maculopapular rash is more commonly treated with PI3K inhibitors, such as BKM-120 (37% of patients), MK2206 (52% of patients), immunological checkpoint protein inhibitors, such as the anti-CTLA-4 inhibitor ipilimumab ( 33% of patients), anti-PD-1 inhibitor nivolumab (26% of patients), or combination of ipilimumab and nivolimumab (over 40% of patients).

Berberine (natural yellow 18,5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolane (5,6-a) quinoline salt) It is an isoquinoline alkaloid present in medicinal plants such as coptidis rhizome, cork, scutellaria, holly leaf, Mahonia aquifolium, and genus. Berberine and its derivatives have been found to have antimicrobial and antimalarial activity. It is resistant to a variety of pathogens such as fungi, yeasts, parasites, bacteria and viruses.

Berberine also has anti-inflammatory effects, but the exact mechanism remains unknown.

U.S. Patent No. 6,440,465 is a topical skin formulation of a lubricant-based glucosamine containing berberine and used to treat psoriasis. US Patent Application No. 2005/0158404 relates to a nutraceutical, dietary supplement or pharmaceutical composition comprising vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and berberine derived from herbs. Oral administration to treat acne. U.S. Patent No. 6,974,799 is directed to a tripeptide (N-hexadecylidene-glycine-histidine-deaminic acid) and a tetrapeptide (N-hexadecanyl-glycine-glutamic acid) - A topical composition of valine-arginine which is used to treat the external symptoms of aging, including wrinkles, obesity, and dark circles. This formula may contain additional ingredients including berberine. In these inventions, berberine is included as one of many components, and the concentration thereof is not specifically specified.

U.S. Patent Application No. 2004/0146539, which relates to topical nutritional compositions, has the anti-aging benefits of slimming and firming skin and can be used to treat skin aging, skin wrinkles, skin peeling, acne, rose spots, and other skin problems. The compositions of the present invention comprise an antimicrobial agent selected from a variety of agents, including berberine. In this nutritional composition, berberine is included as one of many ingredients, and its concentration is not specifically indicated. 10% have been used for the treatment of holly leaves Mahonia cream psoriasis ^{(Relieva TM, Apollo Pharmaceutical Canada Inc} ), which contains 0.1% berberine.

U.S. Patent Application Serial No. 2012/0165357 discloses the use of berberine to treat various red face related skin disorders, but it does not disclose any particular berberine formulation effective to treat a particular condition.

Therefore, there is still a need to develop new and effective methods for treating various red face related skin diseases, as well as skin toxicity caused by target treatment and/or immunotherapy.

The present invention provides pharmaceutical compositions for treating and/or preventing red-face related skin diseases, as well as skin toxicity caused by target treatment and/or immunotherapy. The formulations provided are cream-based formulations (ie creams) or gel-based formulations.

In particular, the present invention provides a pharmaceutical composition comprising berberine, wherein the composition is a cream formulation comprising an aqueous phase and an oil phase.

In one embodiment, the concentration of berberine in the cream formulation provided is from 0.01 to 10% by weight (i.e., % w/w), preferably from 0.01 to 0.3% by weight, more preferably from 0.1 to 0.2. The % by weight is particularly preferably from 0.1 to 0.15% by weight, most preferably about 0.12% by weight.

Unless otherwise expressly defined, when the content or concentration is described herein as "% by weight", the weight of each component is based on the total weight of the formulation.

The pharmaceutical composition of the present invention may further comprise a penetration enhancer.

In one embodiment, the penetration enhancer is an anion penetration enhancer.

In another aspect of the embodiment, the penetration enhancer comprises glycerol and Tween ^® 60.

In one embodiment, berberine is the only pharmaceutically active ingredient in the formulation provided.

In one embodiment, the pharmaceutical composition of the present invention has a pH of from about 4 to about 7, preferably about 5.5.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising berberine as the sole pharmaceutically active ingredient, wherein the berberine is present in a concentration of from 0.1 to 0.2% by weight, wherein the composition comprises one An aqueous phase and an oil phase cream formulation wherein the composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein the composition has a pH of from about 4 to about 7.

In a further preferred embodiment, the present invention provides a pharmaceutical composition comprising berberine as the sole pharmaceutically active ingredient, wherein the berberine concentration is about 0.12% by weight, wherein the composition comprises one water And an oil phase cream formulation wherein the composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein the composition has a pH of about 5.5.

In another embodiment, the invention provides a pharmaceutical composition comprising berberine, wherein the composition is a gel-based formulation, wherein the composition comprises an anion penetration enhancer.

In a preferred embodiment, the anion penetration enhancer comprises sodium dodecyl sulfate (SDS).

In one embodiment, in the gel-based pharmaceutical composition provided by the present invention, about 90% of the berberine has an average particle size of less than 10 micrometers (μm).

In another embodiment, in the gel-based pharmaceutical composition provided by the present invention, about 50% of the berberine has an average particle size of less than 4 micrometers (μm).

In one embodiment, the concentration of berberine in the gel-based formulation is from 0.01 to 0.3% by weight, preferably from 0.1 to 0.2% by weight, more preferably from 0.1 to 0.15% by weight, most preferably. It is about 0.12% by weight.

The invention also provides the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment or prevention of a red face related skin disorder.

In one embodiment, the red face related skin disease is selected from the group consisting of rose plaque, acne, seborrheic dermatitis, photodermatitis, contact dermatitis, rosy-like erythematous dermatitis, And skin diseases caused by epidermal growth factor receptor (EGFR) inhibitors.

The invention also provides the use of berberine and/or biologically equivalent analogs thereof for the manufacture of a medicament for the treatment and/or prevention of dermal toxicity caused by target treatment and/or immunotherapy.

In a preferred embodiment, the target treatment comprises the following treatment modalities: EGFR inhibitor, MTK inhibitor, MEK inhibitor, PI3K inhibitor, AKT inhibitor, BRAF inhibitor, HER2 inhibitor, multi-kinase angiogenesis Inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multi-kinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists.

In a preferred embodiment, the immunotherapy comprises the following treatments: cancer vaccine, cytokine reagent (such as GM-CSF, interferon and IL-2), cell therapy (such as TILs, TCR modified PBL, and CAR). Modified PBL), immunological checkpoint protein inhibitors (eg PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT), and immunoassay protein stimulators (eg CD28) , ICOS, 4-1BB, OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40).

In a preferred embodiment, the patient is administered a berberine and/or a biologically equivalent analog thereof in the form of a pharmaceutical composition.

For specific diseases to be treated, it is important that berberine can effectively penetrate the skin. Berberine is a hydrophilic compound (with a partition coefficient of 1.07 in the octanol-water system), which makes it difficult for berberine to penetrate the stratum corneum (SC) to reach the target site, such as red-face related skin disease or target treatment. / dermatological or dermal layer caused by skin toxicity caused by immunotherapy. In addition, the solubility of berberine is quite good (solubility is 1.57 mg/ml), so it is rapidly released into the target cells, causing a transient effect.

Accordingly, the present invention provides a pharmaceutical composition having improved berberine penetration which is useful for treating and/or preventing red-face related skin diseases, as well as skin toxicity caused by target treatment and/or immunotherapy. The formulations provided are cream-based formulations (ie creams) or gel-based formulations.

In particular, the present invention provides a pharmaceutical composition comprising berberine, wherein the composition is a cream formulation comprising an aqueous phase and an oil phase.

Since the cream formulation of the present invention promotes the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve the desired therapeutic effect. In one embodiment, the concentration of berberine in the cream formulation provided 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, still more preferably 0.1. To 0.15 wt%, optimally about 0.12 wt%, based on the total weight of the formulation.

The pharmaceutical composition of the present invention may further comprise a penetration enhancer.

In one embodiment, the penetration enhancer is an anion penetration enhancer. For example, the anion penetration enhancer can comprise sodium dodecyl sulfate (SDS).

In another aspect of the embodiment, the penetration enhancer comprises glycerol and Tween ^® 60. Cream formulations of the present invention preferably comprises glycerin and Tween ^® 60 as penetration enhancer. When the same penetration enhancer is used in non-cream formulations, it does not improve penetration, so Tween ^® 60 and glycerin have a unique impact on cream-based formulations.

In one embodiment, berberine is the only pharmaceutically active ingredient in the formulation provided. Even if the ingredient in the formulation provided by the present invention is an active ingredient in a prior art formulation that is not used to treat dermal toxicity caused by target treatment or immunotherapy, if the amount of the ingredient is insufficient for effective treatment by the target treatment or immunization The dermal toxicity caused by the treatment should still be considered as a pharmaceutical excipient in the formulation of the present invention.

In one embodiment, the pharmaceutical composition of the present invention has a pH of from about 4 to about 7, preferably about 5.5.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising berberine as the sole pharmaceutically active ingredient, wherein the berberine has a concentration of 0.1 to 0.2% by weight, wherein the composition comprises one An aqueous phase and an oil phase cream formulation wherein the composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein the composition has a pH of from about 4 to about 7.

In a more preferred embodiment, the present invention provides a pharmaceutical composition comprising berberine as the sole pharmaceutically active ingredient, wherein the berberine concentration is about 0.12% by weight, wherein the composition comprises one water And an oil phase cream formulation wherein the composition comprises a penetration enhancer, a preservative, and a stabilizer, and wherein the composition has a pH of about 5.5.

Surprisingly and unexpectedly, the cream formulations of the present invention have superior penetration rates compared to non-cream berberine formulations.

In another embodiment, the present invention provides a pharmaceutical composition comprising berberine, wherein the composition is a gel-based formulation, wherein the composition comprises an anion penetration enhancer.

In a preferred embodiment, the anion penetration enhancer comprises sodium dodecyl sulfate (SDS). The addition of sodium lauryl sulfate as an anion penetration enhancer provides a gel-based formulation that is hydrophobic (50.1 partition coefficient in the octanol-water system) and greatly reduces solubility to about 0.011 mg/ In milliliters, berberine is slowly released to the target cells, resulting in an extended release profile.

It has been found in the present invention that the solubility of berberine in the presence of sodium lauryl sulfate is from 0.01 to 0.06 mg/ml at a pH of from 4 to 7, that is, the solubility in berberine water (1.57 mg/d). The milliliters are 25 to 150 times lower, and at a pH of 5.5, the solubility is relatively low.

Surprisingly found in all tested penetration enhancers (sodium lauryl sulfate, glycerol, propylene glycol, polyethylene glycol 400 (PEG 400), ethanol and Tween ^® ) on a gel-based basis The addition of sodium lauryl sulfate to the formulation produced the highest rate of penetration and increased the local concentration of berberine in the dermis and epidermal layers.

In one embodiment, in the gel-based pharmaceutical composition of the present invention, about 90% of the berberine has an average particle size of less than 10 microns.

In another embodiment, in the gel-based pharmaceutical composition of the present invention, about 50% of the berberine has an average particle size of less than 4 microns.

Surprisingly, it was found that in the gel-based formulation, there was a positive correlation between the amount of sodium lauryl sulfate and the penetration rate, and a negative correlation between the size and penetration of berberine.

Since the gel-based formulation of the present invention promotes the penetration of berberine into the skin, a relatively small amount of berberine is sufficient to achieve the desired therapeutic effect. In one embodiment, the concentration of berberine in the gel-based formulation is from 0.01 to 0.3% by weight, preferably from 0.1 to 0.2% by weight, more preferably from 0.1 to 0.15% by weight, most preferably. It is about 0.12% by weight based on the total weight of the formulation.

The invention also provides the use of a pharmaceutical composition of the invention for the manufacture of a medicament for the treatment of a red face related skin disorder.

In one embodiment, the red face related skin disease is selected from the group consisting of rose plaque, acne, seborrheic dermatitis, photodermatitis, contact dermatitis, rosy-like erythematous dermatitis, And skin diseases caused by epidermal growth factor receptor (EGFR) inhibitors.

The invention further provides the use of a pharmaceutical composition of the invention for the preparation of a medicament for the treatment and/or prevention of dermal toxicity caused by target treatment and/or immunotherapy.

In one embodiment, the target treatment is selected from the group consisting of an EGFR inhibitor, an MTK inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a BRAF inhibitor, a HER2 inhibitor, a multi-kinase blood vessel Neonatal inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multi-kinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists. The immunotherapy is selected from the group consisting of cancer vaccines, cytokine agents (such as GM-CSF, interferon and IL-2), cell therapy (such as TILs, TCR-modified PBL, and CAR-modified PBL), immunization. Checkpoint protein inhibitors (eg PD-1, PD-L1, CTLA-4, TIM-3, LAG-3, BTLA, VISTA and TIGIT), as well as immunosuppressive protein stimulators (eg CD28, ICOS, 4-1BB) , OX40, BITR, CD27, TWEAKR, HVEM, TIM-1 and CD-40). The skin toxicity caused by the target treatment and/or immunotherapy is selected from the group consisting of: pustular rash, maculopapular rash, rash, telangiectasia, paronychia and laceration, hair change, xerosis, mucosa Inflammation, scrapie, and skin reactions in the hands and feet.

The concentration of berberine in the epidermis layer, the dermis layer and the receiving site (i.e., the phosphate buffered container in contact with the skin tissue in the following examples) was measured in the following manner. The Franz diffusion cell setup consists essentially of a piece of skin tissue sandwiched between two clips. The drug was applied to one end of the skin (above) and the drug concentration was measured at the receiving portion (below) of the device.

As used herein, the term "permeability" refers to the amount of berberine present in the perigram epidermis or dermis tissue from the time the formulation is applied to the skin, or present in the skin at the receiving site per square centimeter of skin. The amount of berberine.

The amount of drug measured at the receiving site represents the total amount of drug in the stratum corneum, epidermal layer, and dermal layer region of the skin. The pharmaceutical composition of the present invention has improved penetration, and the preferred range of penetration is as follows: Epidermal layer: 0.4 to 4000 micrograms of berberine per gram of tissue; dermal layer: 0.003 to 30 micrograms of berberine per gram of tissue Receiving: 0.0001 to 1 microgram of berberine per square centimeter of skin.

Table 1 below lists various ingredients that can be used in the compositions of the present invention, but the tables are for illustrative purposes only and are not intended to limit the scope of the invention. In addition, the different ingredients/excipients may have more than one function, for example, as a penetration enhancer, an emulsifier, a wetting agent, and the like. Table 1

The term "berberine" as used herein refers to 5,6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodiox (5,6-a)hydroquinone ( 5,6-dihydro-9, 10-dimethoxybenzo (g)-1, 3-benzodioxolo (5,6-a) quinolizium). The invention also uses analogs of berberine, including but not limited to: jatrorrhizine, palmatine, coptisine, 9-desmethylberberine, 9-desmethyl palmatine, 13- Hydroxyberberine, berber rubine, palmatrubine, 9-oxo-ethyl berberine, 9-oxo-ethyl-13-ethyl berberine, 13 - methyl dihydroberberine N-methyl salt, tetrahydroprotoberberine and its N-methyl salt, 9-lauroyl berberine chloride salt, and pharmaceutically acceptable salts of all of these compounds class.

The term "pharmaceutically acceptable salts" as used herein includes salts of acids or base groups. Examples of pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogenic acid, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfuric acid, hydrogen iodine. Acid, or phosphorous acid, etc.; and salts derived from relatively less toxic organic acids, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, phenylglycolic acid, phthalic acid, benzenesulfonic acid, toluenesulfonic acid (including p-toluenesulfonic acid, m-toluenesulfonic acid, and o-toluenesulfonic acid), citric acid, tartaric acid, and methanesulfonic acid Acid, etc. Also included are salts of amino acids (e.g., arginine, etc.), and salts of organic acids (e.g., glucuronic acid or galacturonic acid, etc.).

The term "treatment" as used herein includes inhibition of a disease or condition, reduction in the severity and/or frequency of the condition, elimination of signs and/or causes, prevention of symptoms and/or etiology, slowing and/or improvement of symptoms of the patient. Thus, "treating" a patient with a composition of the invention includes preventing a particular condition in a susceptible individual; managing a clinically symptomatic individual to inhibit or reduce the disorder or disease; maintaining an existing state; and/or preventing a disorder or The progress of the disease. Treatment can include prevention, treatment, or cure.

A "pharmaceutically effective amount" of a compound and/or a pharmaceutical composition of the invention herein means that the compound and/or composition is sufficient to treat, inhibit, slow or prevent various red face related skin diseases (including but not limited to by target) The amount of dermal toxicity caused by treatment or immunotherapy (a reasonable benefit/risk ratio in any medical treatment). However, it is to be understood that the total daily dose of the compound and/or the composition of the invention is determined by the physician within the scope of sound medical judgment. The specific effective dosage level of any particular patient will depend on a number of factors, including the condition being treated and the severity of the disease, the activity of the particular compound employed, the particular composition employed, the age, weight, and general health of the patient. The condition, sex and eating habits, time of administration, route of administration, rate of excretion of the particular compound employed, duration of treatment, drugs used or consistent with the particular compound employed, and other similar factors well known in the medical arts. For example, those skilled in the art will appreciate that the initial dose of the composition is less than the desired effect to achieve the desired therapeutic effect, and that the dosage is gradually increased until the desired effect is achieved.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, and may be in solid or liquid form, including but not limited to: tablets, powders, capsules, microparticles, solutions, suspensions, elixirs, emulsions, gels, Creams, patches, or suppositories (including rectal suppositories and urethral suppositories).

The term "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or carrier 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 and is compatible with the mode of administration and does not cause harm to the patient. The pharmaceutically acceptable carrier can be either aqueous or non-aqueous. Pharmaceutically acceptable carriers include gums, starches, saccharides, cellulosic materials, and mixtures thereof. Examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to: (a) sugars such as lactose, glucose, and sucrose; (b) starches such as corn starch and potato starch; (c) cellulose and its derivatives Such as sodium carboxymethylcellulose, ethylcellulose, and oryzanol acetate; (d) powdered tragacanth; (e) malt; (f) gelatin; (g) talc; (h) shaping Agents such as cocoa butter and suppository wax; (i) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (j) glycols such as propylene glycol; (k) polyols Classes such as glycerol, sorbitol, mannitol, and polyethylene glycol; (1) esters such as ethyl oleate and ethyl laurate; (m) amaranth; (n) buffers such as magnesium hydroxide , aluminum hydroxide, boric acid, sodium borate, and phosphate buffer; (o) alginic acid; (p) pyrogen-free water; (q) isotonic salt; (r) Ringer's solution; Ethanol; (t) phosphate buffer solution; and (u) other non-toxic compatible substances suitable for use in pharmaceutical compositions.

Compositions of the invention may be administered by any means known in the art including, but not limited to, oral, nasal, injection, topical, transdermal, or rectal routes of administration. Preferably, the compositions of the invention are suitable for oral or external administration. For example, the active ingredient of the composition may be formulated with suitable excipients to prepare lozenges, capsules, granules, tablets, lozenges, solutions, powders or granules, suspensions, hard or soft capsules, Tablets, and any other suitable form.

The invention also provides the use of berberine or a biologically equivalent analog thereof for the manufacture of a medicament for the treatment and/or prevention of dermal toxicity caused by targeted and/or immunotherapeutic treatment.

The invention further provides a use of berberine or a biologically equivalent analogue thereof for the preparation of a medicament for the treatment and/or prevention of dermal toxicity caused by target treatment and/or immunotherapy, wherein the medicament comprises berberine or a living organism thereof A pharmaceutical composition is used in addition to the analog.

In one embodiment, the topical pharmaceutical composition is in the form of a lotion, cream, ointment, paste, gel, spray, suspension, lotion, foam, patch, powder or coating.

In one embodiment, the topical pharmaceutical composition comprises at least 0.02% by weight, preferably from about 0.1% to about 2% by weight, of berberine or a biologically equivalent analog thereof, based on the total weight of the composition.

In one embodiment, berberine or a biologically equivalent analog thereof is a predominantly pharmaceutically acceptable active ingredient.

In another embodiment, berberine or a biologically equivalent analog thereof is the only pharmaceutically acceptable active ingredient.

The following examples illustrate some aspects of the invention. However, the embodiments are not intended to limit the invention. Example 1 [Mice skin penetration test of berberine formula]

The following six berberine formulations were compared: C8, 0.125%, 0.3%, G22, G23 and G24. formula

The following formulation was prepared: C8 (cream recipe in the substrate) berberine aqueous phase ^{(0.12%), Tween ® 60} (1%), glycerol (3%), methylparaben (0.1%), paraben Propyl formate (0.02%), sodium hydroxide (adjusted to pH 5.5), and ethylenediaminetetraacetic acid (0.02%). Oil phase stearic acid (7.5%), castor oil (8%), white soft paraffin (6%), and SPAN 60 (2%). 0.125% (gel-based formulation) Berberine (0.125%), ethanol (2.5%), glycerol (10%), phenoxyethanol (0.3%), carbomer. 0.3% (gel-based formulation) Berberine (0.3%), propylene glycol (9.25%), PEG 400 (5.03%), methyl paraben (0.1%), propyl paraben (0.02%) Sodium hydroxide (0.4%), ethylenediaminetetraacetic acid (0.02%), carbomer 934P (1%). G22 (gel-based formulation) Berberine (0.1%), sodium lauryl sulfate (0.086%), glycerol (10%), Tween ^® 80 (0.5%), methyl paraben (0.1%) ), propyl paraben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), sodium hydroxide, ethylenediaminetetraacetic acid (0.02%), carbomer 934P (0.3 %), HEC 250 HHX (1.2%). Particle size distribution: 3.83/11.34/27.24 (D10/D50/D90 format, where each value represents the percentage of individual particles below the size of the contained size, ie 10% of the particle system is less than 3.83, and so on) . G23 (gel-based formulation) Berberine (0.1%), sodium lauryl sulfate (0.086%), glycerol (10%), Tween ^® 80 (0.5%), methyl paraben (0.1%) ), propyl paraben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), sodium hydroxide, ethylenediaminetetraacetic acid (0.02%), carbomer 934P (0.3 %), HEC 250 HHX (1.2%). Particle size distribution: 1.45/2.85/9.30. G24 (gel-based formulation) Berberine (0.1%), sodium lauryl sulfate (0.043%), glycerol (10%), Tween ^® 80 (0.5%), methyl paraben (0.1%) ), propyl paraben (0.02%), citric acid (0.033%), sodium citrate dihydrate (0.115%), sodium hydroxide, ethylenediaminetetraacetic acid (0.02%), carbomer 934P (0.3 %), HEC 250 HHX (1.2%). Particle size distribution: 1.55/2.86/5.44.

The particle sizes of the G22, G23 and G24 formulations were determined in the following manner.

Preparation of purified water, followed by addition of berberine chloride, Tween ^® 80, and sodium dodecyl sulfate (SDS). After the dispersion is uniform, the mixture is micronized. Thereafter, the particle size was measured with a diffraction analyzer. Test conditions

Mice were sacrificed via cervical dislocation. The full thickness of the flank skin was removed and placed on a diffusion unit that was in contact with the receiving surface (0.01 molar phosphate buffer, pH 7.4, 37 ^o C). The buffer is aspirated through the receiving compartment at a flow rate of 3 to 4 ml/hr. A 300 microliter formula was added to the skin surface in the supply compartment. At the 0, 1, 2, 3, 4, 6, 8, 10, and 12 hours, the receiving solution was collected for high performance liquid chromatography (HPLC) analysis. The skin flux is calculated from the slope of the cumulative amount of berberine chloride salt versus the linear portion of the time curve. result

Figure 1 shows the berberine penetration cumulative amount (NEK/cm 2 ) versus time for all six tested formulations. As shown, C8 (cream formula) and G23 (gel-based formula) have the highest penetration rate compared to other formulations. This result is unpredictable because in theory all six formulations should penetrate the skin at a similar rate due to the same physical properties of berberine in the aqueous phase.

Figure 2 shows the berberine penetration cumulative amount (NEK/cm 2 ) versus time for three colloidal suspension formulations (G22, G23 and G24). As shown, the penetration is proportional to the amount of penetration enhancer (SDS), but inversely proportional to the size of berberine. Compared to G22 with D90 greater than 10 microns, the berberine D90 of G23 and G24 is less than 10 microns in size and has a high transmittance. Example 2 [Small pig skin penetration test of berberine formula]

The following berberine formulations were compared: 1) C8, G22 and G23; and 2) 0.125%, 0.30%, and G23.

Skin: The skin of a mini pig (Lanyu pig or Li Song pig) was dermatome to 700 microns with a resistance greater than 10 kilohms (Millicell-ERS, Millipore). Penetration test

The pig's skin was placed on a percutaneous absorption diffusion channel, and the skin side was in contact with the receiving surface, which was filled with phosphate buffer (pH 7.4, 37 ^o C). A 20 microliter formula was added to the skin surface in the supply compartment. After 8 hours, the dry formula was removed using a dry cotton swab. At the end of the 12th and 24th hours of the formulation treatment, the skin was removed from the percutaneous absorption diffusion tank and the skin surface was carefully cleaned again with a water-soaked cotton swab. The stratum corneum is removed using tape-stripping. The skin was then placed on a glass dish and heated in a 60 ^o C water bath for 90 seconds to separate into a skin layer and a dermis layer. The separated epidermal and dermal layers were weighed and chopped and extracted with 0.5 ml of diluent (1% H ₃ PO ₄ :CH ₃ OH (1:1)). The skin extract was centrifuged at 14,500 rpm for 20 minutes. The concentration of berberine chloride salt in the skin extract and the supernatant extract in the supernatant was determined by high performance liquid chromatography. The recovery of berberine chloride salt from the skin is determined by adding a known amount of berberine to the skin tissue and treating it in the manner described above. result

Table 2 Summary Results of this test Table 2, Round 1 (Comparative C8 , G22 , G23 ) 12-hour epidermal dermal layer receiving (μg/g) (μg/g) (μg/cm 2 ) C8 6.15 0.22 0.069 G22 7.55 0.14 0.0625 G23 11.99 0.09 0.0025 24 hour epidermal dermal layer receiving area (μg/g) (μg/g) (μg/cm 2 ) C8 14.675 0.2 0.029 G22 30.95 0.43 0.1905 G23 100.315 0.64 0.0285 Round 2 (Comparative 0.125% , 0.30% , G23 ) 12 hours Epidermal layer Dermal layer Receiving area (μg/g) (μg/g) (micrograms per square centimeter) 0.125% 11.67 0.14 0 0.30% 22.09 0.41 0 G23 16.68 0.1 0 24-hour epidermal dermal layer receiving area (μg/g) (μg/g) (μg/cm 2 ) 0.125% 18.74 0.19 0.01 0.30 % 39.83 0.15 0 G23 35.75 0.27 0.009

Mini pig skin penetration test results showed that: a) C8 (cream formula) penetration rate was unexpectedly high; b) formulation containing berberine particles was continuously released for more than 24 hours (G22 and G23 vs. C8, 0.125%) And 0.3%); c) compared to C8 (cream formula), G22 and G23 (forms containing berberine particles) retain more berberine in the epidermis and dermis after 24 hours; d) Compared to the formulation of berberine in solution, the formulation containing berberine particles has a higher penetration rate (G23 vs. 0.3%); e) compared to the 0.3% formulation, although G23 contains only 0.1% berberine, However, after 24 hours, it retained approximately equal amounts of berberine in the epidermal layer, while retaining more berberine in the dermis; f) compared to other penetration enhancers (ethanol and glycerol at 0.125) In the % formulation; propylene glycol and PEG 400 in a 0.3% formulation), the addition of sodium lauryl sulfate to G23 produced enhanced penetration and increased the local concentration of berberine in the epidermal and dermal layers. Example 3 [Skin biopsy of a patient treated with a formula other than berberine]

The subject was a 56-year-old man who received a refractory drug (afatinib, an epidermal growth factor receptor (EGFR) inhibitor) to treat non-small cell lung cancer (NSCLC). After taking the appropriate gram, the topical gel of the G23 formula was applied once a day to one side of the subject's cheek, and the other cheek was coated with a colloidal carrier (ie, the G23 formulation without berberine).

After the subject completed two weeks of external application treatment, two skin biopsies of the nasolabial fold (both sides of the nose) were collected. Skin samples of 1.0 cm x 0.5 cm were obtained via incisional biopsy and tissue treated with hematoxylin-eosin (H&E) staining. Assessed by a trained dermatologist.

The results of hematoxylin-eosin staining (Figs. 3 and 4) show that the follicular structure remains intact in the skin area treated with G23, and there is no infiltration of inflammatory cells (Fig. 3), but in the skin treated with the colloidal carrier. The hair follicle structure is damaged, and a large number of inflammatory cells infiltrate into the dermis layer of the hair follicle epithelium - the perifollicular region vacuolar change (Fig. 4), showing the potential of G23 to have anti-inflammatory effects, which can be used for Treatment of dermal toxicity associated with epidermal growth factor receptor inhibitors. Example 4 [Face lesion of a patient treated with a formula other than berberine]

During the 4-week treatment period, patients who received treatment with ecto Plus (EGFR inhibitor) were tested with G23 on one side of the face and a colloidal carrier on the other side (without berberine) G23 formula). G23 formula and colloidal carrier were applied to the side of the subject's face and distributed in a ratio of 1:1. Half of the subjects were administered G23 to the left side of the face (the colloidal carrier was applied to the right side of the face) and the other half was tested. The G23 formulation was applied to the right side of the face (the colloidal carrier was applied to the left side of the face). Subjects received the test drug either before or after the start of EGFR inhibitor treatment. The test drug was administered to the side of the subject's face once a day at bedtime.

The number of facial lesions (papules and pustules) was assessed weekly for 4 weeks. As shown in Figures 5 through 7, it can be clearly observed that the number of lesions on the side treated with the G23 formula is significantly lower than the other side of the face, indicating that berberine has treatment for EGFR inhibitors or other target treatments or The potential for skin toxicity caused by immunotherapy.

no.

Figure 1 is a graph showing the cumulative penetration of berberine (NEK/cm 2 ) versus time for the six tested berberine formulations.

Figure 2 is a graph showing the cumulative penetration of berberine (NEK/cm 2 ) versus time for the berberine formulations (G22, G23 and G24) of the three colloidal suspensions.

Figure 3 shows the hematoxylin and eosin (H&E) staining of bilateral skin biopsies from the nasolabial folds of the patient receiving the EGFR inhibitor afatinib. Treatment and application of the G23 colloid formulation externally on one side of the face.

Figure 4 shows the hematoxylin and eosin staining of bilateral skin biopsies from the nasolabial part of the patient, which was treated with the EGFR inhibitor Tock and on the other side of the face. A colloidal carrier (G23 formulation without berberine) was applied externally.

Figure 5 is a graph showing the relationship between the number of papules and the time of the patients receiving the treatment. The patient applied a G23 colloidal formulation to the outside of the face and applied a colloid to the outside of the other side of the face. Carrier (G23 formulation without berberine). The "*" sign indicates P < 0.05 (according to Wilcoxon Signed Rank test).

Figure 6 is a graph showing the relationship between the number of pustules and the time of patients receiving Topotherapy. The patient applied G23 colloid on the outside of the face and applied a colloid to the outside of the other side of the face. Carrier (G23 formulation without berberine). The "*" sign indicates P < 0.05 (according to Wilcoxon Signed Rank test).

Figure 7 is a graph showing the relationship between the total number of papules and pustules in patients receiving Togo treatment, and the external application of G23 colloid on the outside of the face and on the other side of the face. A colloidal carrier (G23 formulation without berberine) was applied. The "*" sign indicates P < 0.05 (according to Wilcoxon Signed Rank test).

Claims (17)

A use of berberine or a biologically equivalent analog thereof for the manufacture of a medicament for the treatment and/or prevention of dermal toxicity caused by target treatment and/or immunotherapy. The use of the first aspect of the patent application, wherein the target treatment is selected from the group consisting of an EGFR inhibitor, an MTK inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a BRAF inhibitor, a HER2 inhibitor, Multi-kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multi-kinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists. The use of the first aspect of the patent application, wherein the immunotherapy is selected from the group consisting of a cancer vaccine, a cytokine reagent, a cell therapy, an immunological checkpoint protein inhibitor, and an immunological checkpoint protein stimulator. The use of the first aspect of the patent application, wherein the dermal toxicity is selected from the group consisting of: pustular rash, maculopapular rash, rash, telangiectasia, paronychia and laceration, hair change, xerosis, mucosa Inflammation, scrapie, and hand-foot skin reaction. The use of the biological equivalent of the berberine is selected from the group consisting of jatrorrhizine, palmatine, coptisine, 9-desmethylberberine, 9-desmethyl palmatine, 13-hydroxyberberine, berberrubine, palmatrubine, 9-oxo-ethyl berberine, 9-oxo-ethyl -13-ethyl berberine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberine and its N-methyl salt, and 9-lauroquinone berberine chloride salt. The use of the first aspect of the patent application, wherein the berberine bio-equivalent analog is palmatine or coptisine. Use of berberine or a biologically equivalent analog thereof for the preparation of a medicament for the treatment and/or prevention of dermal toxicity caused by target treatment and/or immunotherapy, wherein the medicament comprises berberine or a biologically equivalent analogue thereof External pharmaceutical composition. The use of the scope of claim 7 wherein the target treatment is selected from the group consisting of an EGFR inhibitor, an MTK inhibitor, a MEK inhibitor, a PI3K inhibitor, an AKT inhibitor, a BRAF inhibitor, a HER2 inhibitor, Multi-kinase angiogenesis inhibitors, mTOR inhibitors, ALK/c-met inhibitors, multi-kinase Abl inhibitors, BTK inhibitors, HDAC inhibitors, proteasome inhibitors, and RXR agonists. The use of claim 7, wherein the immunotherapy is selected from the group consisting of a cancer vaccine, a cytokine reagent, a cell therapy, an immunological checkpoint protein inhibitor, and an immunological checkpoint protein stimulating agent. The use of the scope of claim 7 wherein the dermal toxicity is selected from the group consisting of: pustular rash, maculopapular rash, rash, telangiectasia, paronychia and laceration, hair change, xerosis, mucosa Inflammation, scrapie, and skin reactions in the hands and feet. For the use of the seventh aspect of the patent application, wherein the biological equivalent of the berberine is selected from the group consisting of jatrorrhizine, palmatine, coptisine, 9-desmethylberberine, 9- go Methyl palmatine, 13-hydroxyberberine, berberine, scutellarin, 9-oxo-ethyl berberine, 9-oxo-ethyl-13-ethyl berberine , 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberine and its N-methyl salt, and 9-lauroyl berberine chloride salt. For example, the use of the berberine bio-equivalent is palmatine or coptisine. The use according to claim 7, wherein the external pharmaceutical composition comprises at least 0.02% by weight of berberine or a biologically equivalent analogue thereof. The use according to claim 7, wherein the external pharmaceutical composition comprises from about 0.1 to about 2% by weight of berberine or a biologically equivalent analogue thereof. The use of claim 7, wherein the berberine or a biologically equivalent analog thereof is a major pharmaceutically acceptable active ingredient. The use of claim 7, wherein the berberine or a biologically equivalent analog thereof is the sole pharmaceutically acceptable active ingredient. The use of the pharmaceutical composition of claim 7, wherein the external pharmaceutical composition is in the form of a lotion, a cream, an ointment, a paste, a gel, a spray, a suspension, an emulsion, a foam, a patch, a powder or a coating. Agent.