Nanotechnologically assembled new generation of biologically active nano-complexes in acne and post-acne treatment

Transcription

1 A.Sepper, M.Danielov, N.Danielov (New York, USA) Nanotechnologically assembled new generation of biologically active nano-complexes in acne and post-acne treatment Abstract: The article provides results of nanotechnology anti-mycotic remedy treatment of Acne patients. The best results are manifested while using the new generation nanotechnologies. Keywords: New generation nanotechnology, pathogenetical treatment of Acne Introduction: Acne Vulgaris is one of the most serious dermatological problems, which under severe inflammation can manifest to serious septic process requiring critical care. It is also important to point out that Acne Vulgaris today is not only dermatological but serious social problem. Why having so many prescriptive Acne medications and OTC drugs in combination with skincare products the problem of Acne not only remains the same but gradually increases in population between 12 and 24 year old? The reason of low efficacy of available products is that treatment of Acne is symptomatic and not covers complex pathogenetical factors involved in Acne process. BIONOVA s technological achievement in area of Life Science Nanotechnology allows pathogenetical approach to treatment of the disease through normalization of physiological processes. The precise pathogenetical treatment of Acne is only possible by assembling specific [to the pathogenesis] composition of Biologically Active Substances [NANO-COMPLEXES ] to imitate physiological processes occurring in a living organism. BIONOVA s approach in treatment of Acne is based on usage of multiple proprietary NANO- COMPLEXES, including several primary [Anti-Bacterial, Keratolitic, Oil Skin Regulation, Anti- Inflammatory] and secondary NANO-COMPLEXES [Antioxidants, Amino-Acids, Vitamin- Coenzyme, Skin Barrier System, HDL]. The use of OTC Active Ingredients in combination with pathogenetical treatment [Acne targeted NANO-COMPLEXES ] allowed creation the first Acne Medication line containing unique product categories, such as: Intensive Acne Care System; Acne Scar Treatment with UV Chromophores; Post- Acne Bioactive Serum to Normalize Metabolism in Acne dysfunctional skin; specially developed product for Scalp Acne often accompanying Facial Acne. ACNE VULGARIS AND ITS MANAGEMENT Acne Vulgaris is one of the most serious and common skin diseases that affects about 90% of adolescents and 20-30% of adults aged 20 to 40 years. Acne affects all ages, races and genders. Of the 85% of teenagers (between the ages of 12 and 24) that suffer from acne, 25% will have permanent scars ranging from severe to light. According to American Dermatological Association 20% (60 millions) of adults have active Acne condition (1,2). Critical Care Medicine Isntitute / Page 91

2 Based on the mentioned above facts Acne is not only a dermatological problem but even more it is a big social problem - face covered with abounded pimples drives teenagers away from active social life and makes them less communicative to the society. Acne Vulgaris is a medical problem and that is why in multiple countries, including US and EU it is regulated by the local health organizations. According to the FDA s definition Acne is a disease involving the oil glands and hair follicles of the skin which is manifested by blackheads, whiteheads, acne pimples, and acne blemishes. For treatment of Acne Vulgaris in US only several Active Ingredients where approved as OTC drugs [Salicylic Acid, Benzoyl Peroxide, Sulfur (or their combinations with Resorcinol) in appropriate concentrations]. As prescription medications antibiotics, retinoids, oral contraceptives, corticosterois can be used. There is a great concern about the increase in the incidence of antibiotic resistance and their uncommon side effects (8,10). Oral isotretinoin is believed to cause teratogenic affects apart from other side effects like mucocutaneous symptoms (11). Why having so many prescriptive Acne medications and OTC drugs in combination with skincare products the problem of Acne not only remains the same but gradually increases in population between 12 and 24 year old? All available treatment products for Acne are symptomatic, and do not covers the pathogenesis of the disease itself. BIONOVA s technological achievement in area of Life Science Nanotechnology allows pathogenetical approach to the treatment of the disease through normalization of physiological processes. Such pathophysiological treatment can be achieved only by activation of Self-Healing processes utilizing set of bioactive substances involved in biological information transfer in the quantities normally existing in the living organism. The major reason of low efficacy of available products is that the treatment of Acne is symptomatic and basically all active ingredients Acne treatment intend to reduce skin inflammation and number of existing Acne blemishes. The substantial experience in the development of anti-acne products and monitoring of customers with Acne conditions brought us to the conclusion that treatment of Acne Vulgaris with one or combination of several antibacterial and anti-inflammatory active substances in not effective. We believe that the successful treatment of Acne should be based on the complex pathogenetical approach. The rationale for using this approach is based on the pathophysiology of Acne. None of the existing on the market products covers complex pathogenetical factors involved in Acne process. PATHOGENESIS OF ACNE VULGARIS Acne Vulgaris begins with abnormal follicular keratinization and the formation of a small keratin plug that precedes clinical comedones in the microcomedo stage. The comedo becomes enlarged when it retains cellular debris. Dilatation of the follicular opening occurs and a blackhead may form. Plugged sebaceous materials create the ideal condition for colonization of the follicle by the anaerobic organism Propionibacterium acnes, which promote inflammation. Diagram 1 bellow shows the principal pathogeneses of Acne Vulgaris. Critical Care Medicine Isntitute / Page 92

3 Diagram 1: Pathogenesis of Acne Vulgaris Heredity Family Background Overactive Phylocebaceous Unit Increased Systemic Androgen Level Increased Sebum Production Rate Increased Proliferation of Ductal Cells Clogged Pores with Sebum & Dead Cells Non-Inflammatory Acne Inflammatory Acne Microcomedo Initial Acne Lesion Propionibacterium Acnes Whitehead P. Acnes Lipases Neutrophils Chemotaxis Blackhead Cleavage of Triacylglycerols Neutr. Hydrolytic Enzymes Release of Fatty Acids Breakdown of Follicular Wall Proinflammatory Effect Camedonic Effect BIONOVA S APPROACH TO PATHOGENETIC TREATMENT OF ACNE VULGARIS Pathogenetical treatment of Acne Vulgaris is based on use of problem oriented NANO- COMPLEXES incorporated into NUCELL-DIRECT delivery system. For pathogenetical treatment of Acne Vulgaris eleven (11) NANO-COMPLEXES were used. They were divided into two groups: 1. Primary NANO-COMPLEXES acting on major pathogenetical pathways: Keratolytic NANO-COMPLEX Oily Skin NANO-COMPLEX Anti-Bacterial Bacto-Stat TM NANO-COMPLEX Anti-Inflammatory NANO-COMPLEX Critical Care Medicine Isntitute / Page 93

4 2. Secondary NANO-COMPLEXES supporting skin optimal metabolism and healthy function: Bioactive Sterols NANO-COMPLEX Antioxidants NANO-COMPLEX Amino-Acids NANO-COMPLEX High Density Lipoproteid NANO-COMPLEX Skin Barrier NANO-COMPLEX Vitamin-Coenzyme NANO-COMPLEX UV Chromophores NANO-COMPLEX In Diagram 2 presented BIONOVA s pathogenetical approach in construction of product composition for treatment Acne Vulgaris treatment. On this diagram pathogenetical steps of Acne Vulgaris presented by white boxes and the corresponding biologically active NANO-COMPLEX by gray boxes. Diagram 2: Pathogenetical Approach For Acne Vulgaris Treatment Oily Skin Nanocomplex Antioxidants Nanocomplex Hyperandrogenization and Increased Sebum Production Bioactive Sterols Nanocomplex Clogged Pores Non-Inflammatory Acne Vitamin-Coenzyme Nanocomplex Amino-Acids Nanocomplex Increased Proliferation of Ductal Epithelial Cells Keratolytic Nanocomplex Inflammatory Acne UV Chromofores Nanocomplex Change in Composition of Skin Lipids HDLNanocomplex Proliferation of Propionibacterium Acnes Bactostat TM Nanocomplex Skin Barrier Nanocomplex Proinflammatory Effect in Phylocebaceouse Unit Anti-Inflammatory Nanocomplex Efficacy of each NANO-COMPLEX was tested. Results of primary NANO COMPLEXES are following: Keratolytic NANO-COMPLEX - the Follicular Keratinization Nanocomplex containing hydrogel was administered to 20 panelists affected by Acne Vulgaris enrolled in the single-blind study. The formulation was applied daily as a solo treatment on the right side of the face for 60 days, while the hydrogel vehicle was applied to the left side of the face as a control. To objectively evaluate the results, a digital photographic database was used to collect images. The number and type of lesions were recorded for each panelist, to compare the Global Acne Grading System (GAGS) score before treatment with that obtained at the end of the study. Moreover, with the innovative technique of follicular biopsy, areas of acne skin were prepared for histopathology. The average area occupied by microcomedones at baseline was compared with that at the end of treatment. Critical Care Medicine Isntitute / Page 94

5 All panelists were satisfied with the active treatment and none experienced adverse effects. Clinical evaluation showed a 65.5% mean reduction in the GAGS score on the Follicular Keratinization Nanocomplex-treated sides of the face compared with 6.1% on the vehicle-treated sides of the face. These data were supported by histologic analysis, which showed a 72.6% mean reduction in the average area of microcomedones on the Follicular Keratinization Nanocomplex - treated sides of the face. The comparison with the vehicle-treated side of the face (8.3% reduction) showed a clinically relevant and statistically significant decrease of lesions in areas treated with Keratolytic Nanocomplex - containing hydrogel. Oily Skin NANO-COMPLEX - Skin Oiliness Nanocomplex containing cream was administered to 30 female panelists with excessive oily skin who could meet the study schedule. Fifteen (15) panelists were selected for participation in the test phase of the study. Another fifteen (15) panelists were selected for participation in the placebo (control) phase of the study. The chin, left and right sides of the forehead and cheeks were chosen as test sides. Measurement Intervals: Baseline - evaluation of sebum production was made on Test Day 0, three weeks - post treatment and six weeks - post treatment AG - the amount of Active Gland Count was expressed as counts/cm 2 and SO (RSDR) - sebum output (Relative Sebum Delivery Rate) - volumetric sebum output was expressed as nanoliters/cm 2. The results of the study show that 100% of the test panelist who received the formula containing BIONOVA bioactive nanocomplexes for Oily Skin experienced positive improvement ranging from moderate to superior. The results indicated that at week six (6), Sebum Output (RSDR) and the Inherent Rate (IR) parameters for the group treated with BIONOVA bioactive cream for Oily Skin were significantly lower than baseline (p<0.006 and p< respectively), while there was no significant difference in either parameters for the control group. On the following charts, we can observe that in the group treated with bioactive cream for Oily Skin, the RSDR (relative sebum delivery rate) in three weeks reduced by ~ 14-20%, and in six weeks RSDR reduced by ~ 42-45%. At the same time IR (Inherent Rate) in the group treated with BIONOVA bioactive cream in three weeks reduced by ~ 14-18%, and in six weeks IR reduced by ~ 35%. This data illustrates that using BIONOVA s Cream for Oily Skin it is possible to reduce endogenous sebum production by ~ 40-45% after six weeks as compared to the control. Critical Care Medicine Isntitute / Page 95

6 It is important to note that the actual number of active glands remained the same. Only the sebum output per gland decreased at each concentration tested. Anti Bacterial Bacto-Stat TM NANO-COMPLEX - a nanocomplex designed for skin bacterial infection, fungal infections, and aseptic inflammation. The formula contains anti-bacterial substances acting simultaneously on three levels of microbial metabolism: destruction of microbial cell wall inhibition of microbial breathing, blockage of microbial replication 60 panelists with clinical symptoms of Skin Infections and Inflammations were included in study group. The hydrogel with Bacto-Stat TM NANO-COMPLEX was applied over the affected skin twice a day during 14 day period. Each clinical sign was graded from 0 to 5 depending to visual estimation of changes. Pain factor was also estimated by 0 5 scale according to panelist information. Critical Care Medicine Isntitute / Page 96

7 PERCENTAGE Edition of 2012 year Results of study see in Table 1 & Diagram 3 bellow: Table 1 SKIN INFECTION COMPLETE PARTIAL NO EFFECT RESTORATION EFFECT Pustules Crusted Oozing Patches Tender Red Spots Boil Vesicle Red Ulcer Swelling Pus Accumulation Pain Diagram 3 PERCENTAGE OF EFFECTIVENESS IN TWO-WEEK TREATMENT WITH QURSKIN COMPLETE RESTORATION PARTIAL EFFECT NO EFFECT 0 PUSTULS CRUSTING PATCHRS RED SPOTS CLINICAL SIGNS BOIL VESICLE RED ULCER SWELLING PUS ACCUMULATION PAIN Critical Care Medicine Isntitute / Page 97

8 Complete recovery from hydrogel containing Bacto-Stat TM NANO-COMPLEX was obtained in 76.9% in two-week usage. Partial effect was obtained in 18.2%. In 4.9% Bacto-Stat TM NANO- COMPLEX was ineffective. PANELIST AND MATERIAL FOR THIS STUDY The objective of this study is to evaluate safety and efficacy of BIONOVA s formulations for treatment of Acne Vulgaris [containing all used NANO-COMPLEXES ]. One hundred thirty five (135) panelists were examined. Age ranged from 14 to 40 years (median 24 years). Disease duration ranged from 1 month to 20 years (median 5 years). Seventeen (15% of the total cases) did not use any treatment for acne previously. 23 panelists had non-inflammatory (whiteheads, blackheads, milia) changes. 112 panelists had inflammatory acne symptomocomplex (papules, pustules, nodules, cysts). The severity of Acne Vulgaris was graded as mild if the GAGS score was 1 18, moderate with scores from 19 to 30, severe with scores from 31 to 38, and as very severe if the score is more than 38 (4). Most cases (82) were classified as mild acne (73.2% of cases), 28 were classified as moderate severity (25% of cases), 2 were classified as severe acne (1.8% of cases), and no cases were classified as very severe (see Table 2) Table 2: Distribution of tested panelists with Inflammatory Acne Grade of Acne Severity GAGS score Panelist # Mild Moderate Severe TOTAL 112 Specific criteria, like types of non-inflamed comedones, types of inflamed comedones, amount of breakout activity, severity of inflammation, areas affected by acne were analyzed before and after BIONOVA s treatment. The observation period lasted 8 weeks. Full grade check for each panelist was performed every week. 23 panelists with Non-Inflammatory Acne received sets of the following products: Cleanser for Oily Skin (twice a day morning-evening) Activator for Oily Skin (twice a day morning-evening) Mask for Oily Skin (once every week) Treatment Cream for Oily Skin (twice a day morning-evening) Critical Care Medicine Isntitute / Page 98

9 Grade of Sign Edition of 2012 year After 8-week period these panelists were recommended to use Anti-Stress Treatment Cream for additional 4 weeks. 112 nelists with Inflammatory Acne received sets of the following products: Antibacterial Cleanser for Acne (twice a day morning-evening) Activator for Acne (twice a day morning-evening) Mask for Acne (once every 2 days) Treatment Cream for Acne (twice a day morning-evening) Intensive Antibacterial Treatment for Acne Spots (once a day evening) After 8-week period these panelists were recommended to use Treatment Cream for Acne Scars or Post- Acne Treatment Serum for additional 6-8 weeks STUDY RESULTS AND ANALYSIS Non-Inflammatory Acne. In all 23 cases of Non-Inflammatory Acne the 8-week observation showed the positive treatment dynamics (see Table 3 & Diagram 4). Table 3: 8-week Dynamics of Non-Inflammatory Acne Signs Average Number of: Whiteheads Blackheads Milia Pimples Diagram week Dynamics of Non-Inflammatory Signs of observation 7 8 Whiteheads Blackheads Milia Pimples Critical Care Medicine Isntitute / Page 99

10 Grade of sign Edition of 2012 year Amount of Whiteheads reduced in 60%, amount of Blackheads in 62.5%, amount of Milia in 59.3% and amount of occasional Pimples in 100%. All panelists expressed high satisfaction with treatment results. It should be emphasized that majority of available treatment products for Acne containing Salicylic acid usually leave feeling of skin dryness and tightness (9). FDA requires emphasizing consumers attention to this issue on product labeling. Salicylic acid treatments help to reduce the appearance of acne-related pimples and bumps. When applied to the skin, salicylic acid helps to unplug the pores, freeing them from dirt and oil. While salicylic acid offers some benefits to those with acne, it also can cause skin dryness or irritation. BIONOVA s treatment preparations also contain the required amount of salicylic acid, but of 23 panelists with Non-Inflammatory Acne none of them complained about skin dryness after completion of 8-week period. In our opinion that is due to an effective combination of one of the primary Nanocomplexes (Oily Skin Nanocomplex) supported with group of secondary Nanocomplexes (HDL Nanocomplex Skin Barrier Nanocomplex) which provided balanced regulation of skin oiliness and optimal hydration to Stratum Corneum. Inflammatory Acne. In 112 cases of Inflammatory Acne the 8-week observation showed the following dynamics of visual signs (see Table 4 and Diagram 5) Table 4: 8-week Dynamics of Inflammatory Acne Signs Average Number of: Milia Papules Pustules Nodules Cysts Diagram week Dynamics of Inflammatory Signs Milia Papules Pustules Nodules Cysts of observation Critical Care Medicine Isntitute / Page 100

11 % of Panelists Edition of 2012 year Amount of Milia reduced in 93.75%, amount of papules in 92.86%, amount of Pustules in 89.29%. There were only 2 panelists who had skin nodules and cysts. These signs disappeared at the end of fifth week of treatment, but because of small number of observations we can not consider them as a statistically verified. All panelists expressed satisfaction with treatment results. The size of inflamed comedones (papules and pustules) decreased in average from 5-6 mm in the beginning of treatment to 1-2 mm at the end of treatment. The breakout activity reported by panelists as every 2-3 week issue did not exacerbated during the 8-week treatment period. The grade of skin inflammation reduced significantly (~70-75%). In general the Pathogenetic treatment of Acne Vulgaris was completely effective in 69.9% of panelists, partially effective in 22.7% of panelists and ineffective in 7.4% of panelists (see Diagram 6) Diagram Effectiveness of Pathogenetical Treatment of Acne Completely Effective Partially Effective Ineffective CONCLUSION For treatment of Acne Vulgaris we do need to develop new Singular Active Substances. Acne Vulgaris requires complex pathogenetical treatment approach, where multiple chains of pathophysiological processes will be covered in complex composition of newly developed formulations. BIONOVA developed the first treatment line against Severe & Moderate Acne Skin conditions utilizing proprietary technologies based on achievements in Life Science Nanotechnology. The products biological activity are adjusted to Gender + Skin Type + Skin Problems, specifically Acne Vulgaris + Acne Scars + Scalp Acne + Post-Acne Condition. Critical Care Medicine Isntitute / Page 101

12 Developed Acne system are formulated from multiple Hyper-Natural substances incorporated into Nu- Cell Direct Delivery System [comprising specific NANO-COMPLEXES ] providing long term and effective treatment of Acne Vulgaris ands Acne Scars. This is the first treatment line offering specific products to treat and maintain Post-Acute Acne condition, which is not less important for healthy skin functioning than treatment of Acne condition itself; after calming acute Acne attack it is very important to reduce recurrence of Acne breakouts. This is the first system containing specific treatment Shampoo for Scalp Acne. Acne is not a skin dysfunction itself, but it is a systemic diseases and Scalp Acne is often exists together with Skin Acne. Usually Scalp Acne is camouflaged under hair and often goes neglected until it turns severe. The problem can be annoying, painful, and often lead to hair loss. Developed system contains the most effective special treatment product minimizing Acne Scar formation and helps reduce appearance of the already formed Acne Scars. REFFERENCES 1. David c. Liao, Management of acne, The Journal of Family Practice, 2003, vol. 52, No Berson D S, Chalker D K, Harper J C, Leyden J J, Shalita A R and Webster GF, Current concepts in the treatment of acne: Report from a clinical roundtable, Cutis. (2003), 72: pp Epidemiology of acne vulgaris. Rzany B, Kahl C, J Dtsch Dermatol Ges Jan; 4(1): A comparison of current acne grading systems and proposal of a novel system. 5. Doshi A, Zaheer A, Stiller MJ, Int J Dermatol Jun; 36(6): Thiboutot DM. An overview of acne and its treatment. Cutis 1996 ; 57 : Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51: Leuden JJ. Therapy for acne vulgaris. N.Engl. J. Med 1997; 336: Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7: Eady E A, Burke B M at al. The benefit of 2% salicylic acid lotion in acne A placebo cotrolled study. J. Dermattol Treat. 1996; 7: Thiboutot DM, Fleischer AB Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7: Akhyani M, Ehsani AH, Ghiasi M, et al. Comparison of efficacy of azithromycin versus doxycycline in the treatment of rosacea: a randomized open clinical trial. Int J Dermatol. 2008;47: Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21: Critical Care Medicine Isntitute / Page 102

13 a.sepperi, m.danielovi, n.danielova (niu-iorki, ass) axali Taobis biologiurad aqtiuri nanokompleqsebi aknesa da aknes Semdgom mdgomareobata mkurnalobasi akne micneulia ert ert seriozul dermatologiur problemad, romelic rig SenTxvevaSi gamoixateba septiur procesi da moitxovs kritikul movlas. mnisvnelovania agretve is, rom akne sadreisod ganixileba ara marto rogorc dermatologiuro, aramed rogorc socialuri problema. miuxedavad aknes mkurnalobis sagrznobi raodenobisa, daavadebis sixsire ara Tu ar klebulobs, aramed matulobs wlis axalgardebs Soris. baionovas teqnologiuri mirwevebi sicocxlis mecnierebis nanoteqnologiasi izleva aknes patogenetikuri mkurnalobis sasualebas specialuri biologiurad aqtivuri nanopompleqsebis gamoyenebit. amisatvis pirveladi keratolitikuri, antibakteriuli, antebis sawinaarmdego, kanis cximianobis da meoradi antioqsidantebi, amino mjavebi, vitamin kofaqtorebi, kanis barieruli sistemis nanokompleqsebia gamoyenebuli. aknes mkurnalobis patogenetikuri midgoma safuzvlad Caedo rig unikalur produqtebis SeqmnaSi rogoricaa aknes intensiuri mkurnalobis sistema, aknes Semdgomi nawiburebi mkurnaloba, aknes samkurnalo sirumi, specialuri skalpis samkurnalo sasualeba da sxva. Critical Care Medicine Isntitute / Page 103