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• • A—HUMAN NECESSITIES
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  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
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  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
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  • A61P37/02—Immunomodulators
• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2121/00—Preparations for use in therapy

Definitions

• Rosacea is a chronic skin disease that manifests redness and swelling, primarily on the face, especially on the central facial area. Other areas affected include the scalp, neck, ears, chest, back and the eyes. Rosacea is characterized by facial flushing, erythema, telangiectasia, and inflammatory episodes with papules and pustules and, in severe cases, rhinophyma. Comedones are notably absent 1 .
• the disease can be classified into 4 subtypes: (a) erythematotelangiectatic, (b) papulopustular, (c) phymatous, and (d) ocular, each with 3 grades of severity (mild, moderate, severe) 3 .
• the course of the disease is typically chronic, with recurrent remissions and relapses.
• Rosacea is the most common red face skin disorder.
• Other red face related skin disorders which share symptomatic similarities and probably pathological causes, include acne vulgaris, seborrheic dermatitis, photodermatitis and contact dermatitis. These red face related conditions may range from feelings of heat and sensitivity to flushing or burning with intense sensitivity . Patients with rosacea and other red face related skin disorders often exhibit extreme sensitivity to environmental and topical factors 5 .
• Steroid-induced rosacealike dermatitis is a papular or pustular lesions with erythematous and edematous base with or without telangiectasia., which is caused by prolonged application of topical steroids to the face or as a rebound condition after discontinuation of topical steroids 6 ' 7 (Chen AY Zirwas MJ, 2009; Lee DH, Li K, Suh DH 2008).
• EGFR inhibitors such as cetuximab, erlotinib, gei ⁇ tinib, cause acneiform dermatitis on face or other skin area, including papulopustular reaction, erythema, telangiectasias, and flushing in 30 to 90 % of patients and may also super-infected with bacteria, such as staphylococcus aureus 8 ' 9 (Wollenberg A, Kroth J et al, 2010; Lacouture ME, Maitland ML et al, 2010).
• inflammatory lesions become evident. Unlike acne vulgaris, inflammatory rosacea is not a bacterial disease of the pilosebaceous unit. Comedones are usually not present, and only normal bacterial flora is identified in skin samples taken from rosacea patients 12 . The inflammatory stage of rosacea can be regarded as a form of chronic sterile cellulitis 13 . While the presence of microorganisms has been examined as a potential contributing factor to rosacea, results have been inconclusive 1 . Demodex folliculorum mites are considered as commensal and do not play a significant pathogenic role in rosacea, although an inflammatory reaction to the mites may aggravate symptoms 14 .
• Yamasaki et al found an abnormally high level of cathelicidins by histopathological staining in skin lesions from patients with rosacea.
• Human epidermal keratinocytes stimulated by cathelicidin peptides were found to increase the release of IL-8.
• Injection of cathelicidin peptides into the skin of mice caused inflammatory changes with increased neutrophil infiltration and micro vessels characteristic of the skin disorder of rosacea in humans 15 .
• Cathelicdins possibly have dual roles in immunity because it can both kill microorganisms and stimulate host inflammatory responses such as inducing IL-8 release 16 .
• Other inflammatory cytokines found to be increased in rosacea include IL-I alpha and transforming growth factor beta-2 17 ' 18 .
• Inflammatory mediators may be responsible for the vasodilation seen in rosacea patients.
• substance P histamine, serotonin, bradykinin, or prostaglandins have been suggested 19 .
• Smith et al has reported an increased expression of vascular endothelial growth factor and its receptors in rosacea 20 .
• antibiotics such as tetracycline and doxycycline have been used in treating rosacea. It has been suggested that such antibiotics render anti-inflammatory rather than antimicrobacterial effects. However, other anti-inflammatory agents are not effective in treating rosacea. Immunosuppressive agents such as corticosteroids often worsen the inflammatory condition of rosacea .
• Topical metronidazole and certain systemic antibiotics are often used as first-line therapy for rosacea. Oral tetracycline, doxycycline, and minocycline are commonly used for treating rosacea. The efficacy of oral antibiotics is probably due more to anti-inflammatory rather than to antibiotic effects 21 . Azelaic acid 15% gel was approved by FDA of USA in 2002 for the topical treatment of mild to moderate rosacea 22 .
• Other traditional topical agents that have been used in a "off label" fashion include clindamycin, sulfacetamide and sulfur, but their mechanism is not well understood.
• Berberine Natural Yellow 18, 6-dihydro-9,10-dimethoxybenzo(g)-l,3-benzodioxolo (5,6-a) quinolizinium
• Berberine and its derivatives have been found to have antimicrobial and antimalarial activities. It can act against various kinds of pathogens such as fungi, saccharomycete, parasite, bacterium and virus 24 .
• Berberine has been found to have other potential benefits. For example, it may have potential to treat high blood cholesterol, cardiovascular disease, diabetes, and tumor 25 .
• Berberine also has anti-inflammatory function, yet the exact mechanism is unknown. Recently, some researcher reported that the anti-inflammatory mechanism of berberine is mediated through cyclooxygenase-2 (COX-2) pathway, since COX-2 plays a key role in the synthesis of prostaglandins, which is elevated in inflammation 26 . Berberine is used as an ingredient in some eye drop solution or eye ointment for the treatment of tracoma 27 .
• COX-2 cyclooxygenase-2
• US patent #6440465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis 28 .
• Patent application #20050158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and a herbal source of berberine for the treatment of acne in oral administration 29 .
• US patent #691 Al 99 relates to topical compositions comprising a tripeptide (N-palmitoyl-Gly-His-Lys) and a tetrapeptide (N-palmitoyl-Gly-Gln-Pro-Arg) for the treatment of visible signs of aging including wrinkles, stretch marks, dark circles 30 .
• the formulation may contain additional ingredients, including berberine. In these inventions, berberine is included as one of the many ingredients and its concentration is not specified.
• Patent application #20040146539 relates to topical neutraceutical compositions with body slimming and tone-firming anti-aging benefits that may be used to treat skin aging, skin wrinkle, skin exfoliating, acne, rosacea and other skin problems 31 .
• the composition of this invention includes antimicrobial agents selected from several agents including berberine.
• berberine is included as one of the many ingredients and its concentration is not specified.
• Mahonia aquifolium cream Relieva , Apollo Pharmaceutical Canada Inc
• 0.1% berberine for the treatment of psoriasis 32 .
• the present invention pertains to topical pharmaceutical formulations that are effective and safe in treating rosacea and other red face related skin disorders, such as acne, seborrheic dermatitis, contact dermatitis and photodermatitis .
• This invention recognizes the deficiency in currently available topical pharmaceutical formulations or experimented formulations that contain berberine as a component, and improves over this deficiency.
• berberine is a drug active ingredient in animal studies and human clinical trials of berberine, either with purified berberine or formulations containing berberine herbal extract.
• disease indications such as in the treatment of bacterial and fungal infections and cardiovascular diseases
• efficacious results were also obtained, although the efficacy of berberine in psoriasis has not been accepted.
• a herbal pharmaceutical preparation fails to cause a therapeutic effect in a treated subject, it is likely that an otherwise pharmacologically active compound contained therein is present at too low a concentration in the treated subject and that the compound by itself or in combination with compounds in the preparation fail to cause a meaningful biological and pharmacological effect.
• many important drug compounds single chemical entities
• therapeutic efficacy often exceed that is achievable with the herbal preparations that contain the compounds.
• Topical herbal pharmaceutical formulations that include berberine-rich plant extracts have been used for centuries in the treatment of various ailments, including a variety of skin disorders, such as psoriasis, acne, eczema, etc. These topical herbal preparations have achieved variable results.
• berberine -containing extract consists of about 10% of the various components used to constitute the formulation. It has been estimated that the berberine compound in those topical total preparations accounts approximately 0.1 % (w/w) of the finished formulations 32 .
• protoberberine alkaloids can be prepared with variable biological activity similar to berberine, such as: jatrorrhizine, palmatine, coptisine , 9-demethylberberine, 9-demethylpalmatine, 13-hydroyberberine, berberrubine, palmatrubine, 9-O-ethylberberrubine , 9-O-ethyl-13- ethylberberrubine, 13-methyldihydroberberine N-methyl salt, tetrahydroprotoberberines, and their N-methyl salts, 13-Hexylberberine, 13-hexylpalmatine and 9-lauroylberberrubine chloride 33 ' 34 .
• Palmatine is present in plants of various families, most notably in the rhizomes of Fibrarurea Tinctoria Lour. Palmatine is an isoquinoline alkaloid and formulations containing palmitine have been broadly used in China for the treatment of gynecological inflammation, bacillary dysentery, enteritis, respiratory tract infection, urinary infection. Additionally, palmatine has the function of anti- arrhythmia, antisepticise, bacteriostasis, and anti- viral activities. Palmatine can be also used as a compound in anti-tumor drug screening 5 . There has been a palmatine-containing pharmaceutical as topical hair growth inhibitor (Keramene, Meaning Skin Solutions D S Laboratories Keramene Body Hair Minimizer).
• Coptisine is an alkaloid found in Chinese goldthread ⁇ Coptis chinensis). It is used in Chinese herbal medicine along with the related compound berberine for treating digestive disorders caused by bacterial infections. Coptisine also exhibits some significant inhibition on tumor growth. Coptisine has been shown in vitro to be cytotoxic on human tumor colon cell line , human hepatoma and leukaemia cell lines 37 .
• Example 1 Effects of berberine on inhibiting cathelicdin peptides-induced cytokine secretion by human keratinocytes (in vitro assay)
• berberine Sigma, St. Louis, MO, USA
• DMSO dimethyl sulfoxide
• Normal human keratinocytes Invitrogen, CA, USA
• EpiLife medium Invitrogen, CA, USA
• penicillin/streptomycin Invitrogen, CA, USA
• Cells were grown at 37 °C in a humidified atmosphere of 5% CO 2 and 95% air.
• the human keratinocytes were cultured to confluence and treated with synthetic cathelicidin peptides (LL-37) (6.4 ⁇ M) for 16 h to induce inflammatory response similar to that observed in rosacea.
• Some of the cathelicidin-treated keratinocyte cultures were co-incubated with berberine of concentrations from 1.25 ⁇ g/ml to 12.5 ⁇ g/ml.
• the keratinocytes cultures treated with cathrlicidin or cathrlicidin with 1% ethanol and without berberine were used as negative controls.
• IL-8 interleukin-8
• IL-I alpha interleukin-1 alpha
• VEGF venous epithelial cell growth factor
• Example 2 Preparation of topical pharmaceutical formulations containing purified berberine and palmatine at defined percentages
• the topical berberine-containing pharmaceutical formulations of this invention have one key feature: it contains purified berberine at defined percentages that are higher than can be obtained in previous formulations using extracts of berberine-rich plants.
• the ranges of concentrations were subjected to tests in animal model studies and human clinical studies.
• berberine or a biologically equivalent analog of berberine is the only or primary active drug compound.
• the purified palmatine used for our studies is dissolved in 100% water, and then diluted to reach in the final solution or gel formulation with defined palmatine concentrations, for example, 0.02%, 0.1%, or 0.2% of palmitine.
• improved or modified formulations may include additional ingredients for increased solubility of berberine or its analogue, emulsification, lubrication, antibiotic activity, or hydration.
• One preferred embodiment of our invention to increase the solubility of berberine or a biological equivalent analog of berberine is to add glycerol into the formulation.
• One embodiment of our invention to increase the antibiotic activity of the formulation is to add plant extract that has been shown to have antibiotic activity.
• One embodiment to enhance the hydration property of the topical formulation of our invention is to add hyaluronic acid.
• Example 3 The effects of the topical pharmaceutical preparation of this invention on a mouse model of rosacea
• the animal model of rosacea was adopted from previous reported 18 . Briefly, BALB/c and C57BL/6 mice, shaved 24 h before treatments, were injected subcutaneously on the back with 40 ⁇ l of cathelicdin peptide (320 ⁇ M) twice a day. Forty-eight hours after the initial injection (four injections in total), erythema and edema were observed on the injected site mimicking the clinical features of rosacea.
• cathelicidin-injected mice were treated with or without topical berberine twice a day to observe the effect of berberine on reducing inflammation.
• the results showed that mice given subcutaneous injections of cathelicidin peptides induced erythema and vascular dilatation in the skin, which resembled clinical features of rosacea after 48 h.
• the topical formulation containing 0.1% berberine was applied on the cathelicidin-induced lesions twice a day.
• the erythematous or inflammatory lesions lasted for more than 7 days in the control group. At the 4 th day, erythema and vascular dilatation were significant reduced in the berberine treated group comparing to controls. These results indicate that topical berberine can reduce the inflammatory reaction induced by cathelicidin in vivo.
• Example 4 A human clinical study investigating the efficacy of the topical pharmaceutical formulation of this invention on patients with rosacea
• the standard grading system for rosacea developed by the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea was used 3 . Additionally, the investigator's global assessment (IGA) and overall erythema severity of the patients were scored at week 0, week 2, and week 6 of berberine therapy. The IGA was expressed according to a 7-point scoring system with a range of 0 (clear) to 6 (severe). The severity of overall facial erythema and telangiectasia, respectively, was graded as 'none', 'mild', 'moderate', or 'severe' with scores from 0 to 3. The grading system used to assess overall facial erythema severity was described previously 38 .
• Results a total of 20 patients with rosacea (18 females and 2 males) were enrolled in this study.
• the mean age of the study population was 43.3 (19-85) years.
• the mean duration of rosacea prior to berberine treatment was 4 (1-24) years.
• 13 cases were of erythematotelangiectatic type (65%), 7 cases papulopustular type (35%), and 5 cases (25%) phymatous type.
• IGA score of rosacea at baseline was 4.1 ⁇ 1.3. This score decreased to 2.6 ⁇ 0.9 at week 2, then 1.6 ⁇ 0.8 at week 6.
• the difference of IGA scores between week 0, week 2, and week 6 was statistically significant (W2 vs WO: paired t test P ⁇ 0.0001; W6 vs WO: paired t test P ⁇ 0.0001).
• W6 vs WO paired t test P ⁇ 0.0001
• the majority of patients had grading from mild to moderate (3) to severe (6).
• 19 of the 20 patients (95%) had a mild (2) to clear (0) rating.
• the overall erythema severity evaluated by the investigator was 2.35 ⁇ 0.6 at the beginning of treatment, 1.5 ⁇ 0.5 at week 2, and 0.95 ⁇ 0.4 at week 6.
• the improvement at week 2 or week 6 was statistically significant (W2 vs WO: paired t test P ⁇ 0.0001; W6 vs WO: paired t test P ⁇ 0.0001).
• W6 vs WO paired t test P ⁇ 0.0001
• At the beginning of treatment the majority of patients (95%) had erythema rating from moderate (2) to severe (3).
• 19 of the 20 patients (95%) had a mild (1) to none (0) erythema rating.
• Example 5 Topical berberine was effective for the treatment of steroid-induced rosacea-like dermatitis and EGFR inhibitors-induced acneiform dermatitis
• Palmitine showed efficacy for the treatment of rosacea or red face disorders:
• berberine exhibits anti-inflammatory effects by inhibiting cathelicidin-induced IL-8, IL-I alpha and VEGF production by human keratinocytes. Since inflammation is involved in the pathogenesis of rosacea and related skin disorders, the anti-inflammatory effects of berberine may account for its clinically beneficial effect in rosacea and related inflammatory skin disorders.
• topical pharmaceutical formulations of this invention containing purified berbreine at concentrations higher than 0.1% or palmatine at concentrations higher than 0.02% can be efficacious, safe and well tolerable for the treatment of rosacea and red skin related disorders, such as acne, contact dermatitis, seborrheic dermatitis and photodermatitis, steroid-induced rosacealike dermatitis, and EGFR inhibitors inducedacneiform dermatitis..
• FIG. 1 Berberine inhibited cathelicidin peptide (LL-37)-induced IL-8, IL-I alpha and VEGF release from human keratinocytes. Keratinocytes were stimulated by cathelicidin peptide (LL-37), and the release of IL-8 (Figure IA), IL-I alpha (Figure IB) and VEGF ( Figure 1C) by the keratinocytes was evaluated by ELISA assay.
• Figure 2 A. Investigator's global assessment scores at the beginning of berberine treatment and at 2 weeks and 6 weeks of treatment. B. Overall erythema severity scores at the beginning of topical berberine treatment and at week 2 and week 6 of treatment.
• Draelos ZD Assessment of skin barrier function in rosacea patients with a novel 1% metronidazole gel.J Drugs Dermatol. 2005; 4:557-562.
• RNA specific molecules Cytotoxic plant alkaloid palmatine binds strongly to poly(A). Bioorganic & Medicinal Chemistry Letters. 2006; 16:2364-2368 .

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