NATAL- RN 2019
UNIVERSIDADE FEDERAL DO RIO GRANDE DO NORTE CENTRO DE CIÊNCIAS DA SAÚDE
FACULDADE DE FARMÁCIA
GABRIELA RIBEIRO CAVALCANTI
FERULIC ACID ACTIVITY ON TOPICAL FORMULATIONS: A PATENT REVIEW (2008-2018)
NATAL- RN 2019
Gabriela Ribeiro Cavalcanti
FERULIC ACID ACTIVITY ON TOPICAL FORMULATIONS: A PATENT REVIEW (2008-2018)
Trabalho de Conclusão de Curso apresentado ao Curso de Farmácia da Universidade Federal do Rio Grande do Norte, como requisito parcial para obtenção do título de Bacharel em Farmácia. Orientador: Profª Dr. Ádley Antonini Neves de Lima
NATAL- RN 2019
Universidade Federal do Rio Grande do Norte - UFRN Sistema de Bibliotecas - SISBI
Catalogação de Publicação na Fonte. UFRN - Biblioteca Setorial do Centro Ciências da Saúde - CCS
Cavalcanti, Gabriela Ribeiro.
Ferulic acid activity on topical formulation: a patent review (2008-2018) / Gabriela Ribeiro Cavalcanti. - 2019.
33f.: il.
Trabalho de Conclusão de Curso - TCC (Graduação em Farmácia) - Universidade Federal do Rio Grande do Norte, Centro de Ciências da Saúde, Departamento de Farmácia. Natal, RN, 2019.
Orientador: Ádley Antonini Neves de Lima.
1. Acido ferúlico - TCC. 2. Antiinflamatório - TCC. 3. Formulações tópicas - TCC. I. Lima, Ádley Antonini Neves de. II. Título.
RN/UF/BS-CCS CDU 647.636.8
Elaborado por ANA CRISTINA DA SILVA LOPES - CRB-15/263
Gabriela Ribeiro Cavalcanti
FERULIC ACID ACTIVITY ON TOPICAL FORMULATIONS: A PATENT REVIEW (2008-2018)
Trabalho de Conclusão de Curso apresentado ao Curso de Farmácia da Universidade Federal do Rio Grande do Norte, como requisito parcial para obtenção do título de Bacharel em Farmácia. Orientador: Prof. Dr. Ádley Antonini Neves de Lima
Presidente: Prof. Dr. Ádley Antonini Neves de Lima - Orientador Universidade Federal do Rio Grande do Norte - UFRN
Membro Interno: Profª. Drª. Elissa Arantes Ostrosky Universidade Federal do Rio Grande do Norte -UFRN
Membro Externo: Prof. Dr. Eduardo Pereira de Azevedo Universidade Potiguar - UNP
Ferulic Acid Activity on Topical Formulations: A Patent Review
Gabriela Ribeiro Cavalcantia, Fernanda Illary Costa Duartea, Ádley Antonini Neves de
Limaa*.
aDepartment of Pharmacy, Laboratory Drug Development, Federal University of Rio Grande do Norte, Natal, RN 59012-570, Brazil; gabircavalcanti@gmail.com;
fernandailary@gmail.com; adleyantonini@yahoo.com.br
*corresponding author. Ádley Antonini Neves de Lima, Laboratory Drug Development, Department of Pharmacy, Federal University of Rio Grande do Norte – UFRN, Natal – RN. R. General Gustavo Cordeiro de Faria, S/N - Petrópolis, Natal - RN, 59012-570. Fone: +55 (84) 99928-8864 E-mail:
adleyantonini@yahoo.com.br
AGRADECIMENTOS
Agradeço primeiramente aos meus pais, Cavalcanti Júnior e Alessandra, que me apoiaram incondicionalmente durante essa caminhada e em todos os momentos da minha vida. Obrigada por todo incentivo, confiança e compreensão, por terem tornado os meus sonhos, seus sonhos.
A minha irmã, Manuela, por ser o momento de alegria e paz nos meus dias e me transmitir tanto amor, mesmo distante, te amo demais Xuxu.
Aos meus avós Sofia e Geraldo, por terem me acolhido em sua casa desde o início da graduação, agradeço pelo amor e carinho.
Aos meus avós Arthur e Jô pelo apoio incondicional, pela alegria que sempre me passaram e pelos abraços verdadeiros sempre que os visitava.
Aos meus tios Rosane, Aluízio e Renata e aos meus primos por todo o apoio e por acreditarem em mim, amo muito vocês
A tia Vera, tio Silva, Nathália e Jonathan por terem me acolhido em sua casa, por serem meu refúgio nesses anos de graduação e fazer eu me sentir sempre parte da família.
Ao meu orientador, Ádley Antonini pelas conversas, conselhos, direcionamento, por apoiar minhas idéias e acreditar sempre no meu potencial.
A Fernanda Ílary pelo apoio, pelas risadas, pelo incentivo e por tornar esse processo mais leve, sem você essa caminhada seria mil vezes mais difícil.
Pelos meus queridos professores, em especial a professora Naianne Klebis do Departamento de Morfologia e pelo professor Fernando Nogueira do Departamento de Farmácia. Agradeço pela convivência, pela oportunidade de aprendizado e pelo suporte na iniciação científica, vocês são verdadeiros exemplos de profissionais.
A Cápsula Jr que abriu meus olhos para o empreendedorismo, pelo acolhimento, pelos verdadeiros amigos que fiz e por ser um local aonde os inconformados podem se juntar para fazer a diferença na universidade e impactar o mercado.
Aos meus amigos que estiveram ao meu lado durante toda a graduação, pelos momentos de descontração, pelo aprendizado, pelos momentos de estudo e pela amizade verdadeira formada dentro da faculdade.
Por fim, a Universidade Federal do Rio Grande do Norte, pelo ensino de excelência e incentivo a pesquisa.
“Fazer o melhor nas condições que tem, enquanto não tem condições melhores de fazer melhor ainda.” Mário Sérgio Cortella
ABSTRACT
Introduction: Ferulic Acid is a phenolic compound widely found in monocotyledons with a
large application field, especially in pharmaceutical and cosmetic industries. It has proven antioxidant, anti-inflammatory and other activities especially due to its molecular structure. The main factor that can lead to more serious skin damages like inflammation, dryness, wrinkles, and cancer is the exposure to UV radiation increasing the radical oxygen species ratio. The aim of this review is to evaluate the application of Ferulic Acid in topical formulations and the technologies used to enhance its bioavailability and stability in the compositions.
Areas covered: This patent review covers the publications between 2008-2018 in four
different databases, analyzed the tendency and application of the Ferulic Acid by country and years of publication. Having a bigger picture of its effects by in vivo and in vitro studies specifically in topical formulations.
Expert opinion: The Ferulic Acid showed great activity in many formulations for topical
application and improved stability and bioavailability when combined to new technologies and techniques. Showing an open path to target the treatment of skin disorders.
SUMÁRIO
1. Introduction ... 9
1.1 Patent research and evaluation ... 10
2. Ferulic Acid in topical formulations... 13
2.1. Therapeutic activity in formulations ... 13
2.1.1 Antioxidant ... 13
2.1.2 Anti-aging ... 14
2.1.3 Antiinflammatory ... 15
2.1.4 Prevent adipose overload ... 16
2.1.5 Whitening ... 17
2.2. Improving the Ferulic Acid characterists ... 18
3. Expert opinion ... 18
9 1. Introduction
Phenolic compounds are attractive due to their antioxidant activity [1]. Ferulic acid (3-methoxy-4-hydroxycinnamic acid) is a phenolic compound, occurring in cell walls of seeds and leaves of monocotyledons and can be found in free form or conjugated to other substances like carbohydrate, proteins and fatty acids. This substance has proven results cites in cientific articles in the treatment of various diseases, such as cancer [2] and diabetes [3], as well as lipolytic [4], antimicrobial action, anti-inflammatory [5] and, mainly, antioxidant activity [6], responsible for its main benefits and applications [7].
The compound molecular structure and characteristics explain its main activity and interactions, these chemical aspects are: The benzene ring, the side chain, the COOH carboxyl group that protects against lipid peroxidation, the OH hydroxyl substituent that is connected directly to the benzene ring and fights the reactive oxygen species, inducing the resonance and stabilizing the molecule, and the OCH3 methoxyl group that can form hydrogen bonds in the molecule giving more stability. The Ferulic Acid has low water solubility mainly because of the aromatic ring and the carbonic side chain. Although it has polar groups in the structure that can interact by hydrogen bonds with the water molecules, the apolar aspect is predominant, because of the benzene ring and the side chain, making the Ferulic Acid a more apolar compound, less soluble in water. The characteristic leads to low oral bioavailability and makes the development of cosmetic and pharmaceutical compositions more challenging [8, 9,10,11].
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Conditions that affect the skin include physical such as ultraviolet rays, infrared rays, air pollution, internal causes, and stress. Among various factors, the skin is damaged by external causes such as ultraviolet rays and infrared rays, thereby causing trouble [11]. Exposure to solar ultraviolet (UV) rays initially causes sunburn, tanning, inflammation including erythema and later premature photoaging with mottled, darkened pigmentation, wrinkles, dryness, leathery texture, as well as the more serious consequences of immunosuppression, precancerous actinic keratoses and actual skin cancer [7]. It happens mainly by increasing cellular levels of reactive oxygen species (ROS), which damages lipids, proteins, and nucleic acids in both epidermal and dermal cells [12]. Ultraviolet irradiation is a potent generator of oxidative stress in the skin. It has been shown that in vitro and in vivo that both UVA and UVB spectra lead to Reactive oxygen spicies production, impaired antioxidant defense and thus to oxidative damage [13,14].
Because these consequences are mediated by ROS, delivering antioxidants (isolated or with other components acting synergically in the formulations) directly to the skin should prevent injuries, damages, relief skin irritation and smoothes the complexion aspect [1,15]. Along with the phenolic compound results in the treatment of various diseases and antioxidant activity, Ferulic acid has a wide range of applications on formulations to be explored, from and sèrum, cream and lotion, to oil and ointment compositions depending on the therapeutical target and application [16].
1.1 Patent research and evaluation
This review was developed using as a guide the main patent databases with the objective of understanding the evolution and tendency in the use of ferulic acid in topical formulations, between 2008-2018. The databases used for the research were the World Intellectual Property Organization (WIPO), European Patent Office (EPO), Instituto Nacional de Propriedade Industrial (INPI) e United States Patent and Trademark Office (USPTO).
The patent research was conducted between January and April 2019, utilizing the main words 'ácido ferúlico' in Portuguese, 'ferulic acid' in English and focusing in topical applications. Right after the wider search the patents were counted and separated initially by year of publication. From this scenario, they were filtered using the IPC classification code A61K which includes medical
11
preparations, dentistry, and hygiene. After the first phase, the patents that included topical applications were selected and organized by country of publication.
Based on this strategy 510 publications were found, 253 of them on EPO, 245 on WIPO, 10 on USPTO and 3 on INPI as shown in the figure 2.
Figure 2 - Overal steps of the patents research and selection
The strategy was finalized by removing the double-ups resulting in a total of 290 patents, only the ones that presented the Ferulic Acid as one of the main actives in the formulation were selected for the analyzies by year of publication and country. I was observed that most of the patents had only formulations or methods in their description, that’s why this review explored more the ones that presented in vivo or in vitro tests and the ones that were more inovative. After the removal of the double-ups the remaining patents were analyzed by the year of publication (Figure 3) showing a significant increase in the number of works published, the tendency can be observed especially looking to the number of publications in 2008 that were 4 and in 2018 that were the year of most publications with 38 patents publication.
12
Figure 3 - Patents publication per year
Related to the countries that the patents were published it was observed a significant statystic difference between the Asian countries (especially China) and the occidental countries following the tendency of using the Ferulic Acid on topical formulations. China has a larger percentage of publications with 69% of the patents, followed by the United States 10,9 %, Japan 6,1%, Korea 5,8% and Brazil as well as the Patent research and evaluation as shown in figure 4.
13 2. Ferulic Acid in topical formulations
It is known that the ferulic acid occurs naturally in plants, mainly in rice and maize bran. It has a strong antioxidant activity, a potential of application in various pharmaceutical formulations, and pharmaceutical porpuses. The versatility of this compound allows it to be present in formulations acting isolated or combined with other actives, having a synergic effect and giving a better result [8,17, 18].
This substance presents low water solubility, being soluble in ethanol and other organic solvents, low stability when exposed to light ant temperature higher than 80ºC. Characteristic that associated with its low toxicity and wide range of application in topic formulations, opened the space for patents and publications in this area of research that has the Ferulic Acid in preparations with the most diverse technologies with the goal to facilitate the incorporation in formulations and improve the stability [19, 20, 21].
2.1. Therapeutic and cosmetic activity in formulations
2.1.1 Antioxidant
Antioxidant substances protect cells from the damage of oxidative stress by scavenging free radicals, inhibiting superoxide and acting against the long term effects of the reactive oxygen species (ROS). The topical application of antioxidants is broadly used in skincare as actives to promote skin health, prevent aging and skin cancer [22].
The patent US20140107046 presents the combination of at least one flavonoid (baicalin and taxifolin) and ferulic acid effect in an aqueous formulation. The flavonoids ratio is about 0.01% to about 20% based on the total weight of the composition. It’s been reported that the combination of polyphenols and other antioxidants shows strong synergic effects in comparison to the individual compounds, increasing the antioxidant activity. One hydrotrope (caffeine or nicotinamide) or one diol was added to the increase in the solubility of the antioxidant in water.
14
absorption capacity assay (ORAC) of the single compound and the combinations, the synergistic effect is present when the ORAC result of the combination is more than 25% higher than the expected based in the value of the substance alone. The Ferulic Acid isolated showed an ORAC of almost 15000 μmolTE/g, while the vitamin C had less them 5000 μmolTE/g, the ferulic acid had an antioxidant property almost 3 times higher than the vitamin C, but when combined, the synergic effect shows an even stronger capacity.
In the first formulation which is a water-based solution, the synergic effect was observed when the baicalin and the Ferulic acid were combined with another antioxidant such as vitamin C or resveratrol when the baicalin or resveratrol was removed from the formulation the antioxidant effect from the formulation the effect wasn’t as strong. This shows that the Ferulic Acid has a great activity as an antioxidant, but combined with other actives, the benefit to the skin is considerably increased.
Still using the ascorbic acid, which is a well known antioxidant compound, the patent KR20180073305 used the antioxidant activity of vitamin C as a comparative with the ferulic acid. The Ferulic acid scavenging activity was confirmed with the FSC50 method that measures the necessary amount of the substance needed to reduce 50% of the free radicals of DPPH, confirmed by ELISA reader, which for the F.A. showed 4.5 ppm compared with 7.0 ppm for the Ascorbic Acid, attributing the ferulic acid an excellent antioxidant effect.
2.1.2 Anti-aging
It is well known that the natural production of collagen (responsible for the firmness and lift of the skin) and hyaluronic acid ( the main substance of water retention and skin hydration) decreases with aging due to internal and external factors like stress, pollution, and exposure to radiation [18]. With that in mind and focusing on improving skin wrinkles, the invention KR20110101727 shows a composition of Peonyflorin, Cardamonine and Ferulic Acid that acts inhibiting the collagenase activity, improving ferulic acid production and stimulating the collagen synthesis [23].
15
In the first test, the inhibition of the collagenase was tested using a sample with 1% of retinoic acid as the positive control, another with the actives and the negative control had only the base substracts with no other component. As it was a colorimetric reaction, the color absorbance was measured using a fluorometer. The results for the positive control was an inhibition rate of 40% and the three samples that had the ratios of peonyflorin, cardamonine and F.A. respectively between 1-3: 1-3: 8-4 presented an inhibition rate of 62 to 68%.
The collagen synthesis was confirmed with an in vitro test using a culture of fibroblasts and the same 3 ratios of the compounds showed and excellent synergetic action with a synthesis promoting effect 26% higher than the positive control that was 52.8 μg/ml of vitamin C. Evaluating the hyaluronic acid expression (done in a culture of mouse fibroblasts), comparing the results of the three substances isolated and combined in concentrations of 1 and 10 μg/ml, it was observed that the synergic effect was the most effective, but comparing the isolated compounds, Ferulic Acid was the one that had the best result.
Because of the studies that not only associate the Ferulic Acid with its antioxidant property but with the collagen production stimulation, the invention BR102017016356-3 proposed a composition of Ferulic Acid and Hyaluronic Acid associated with radiofrequency therapy that’s widely used in treatments improving the elasticity of the skin and increasing in this composition, the antiaging effect.
2.1.3 Antiinflammatory
The patent KR20110068258 showed the synergetic effect of Ferulic Acid in compositions with at least one of the following components Polydatin and 2- methoxycinnamaldehyde, variating the weight ratio from 1:0.1 to 1:20 between two components of the three cited before. The effect of 21 different compositions with various ratios was compared initially measuring the production amount of Prostaglandine 2 (PGE2), and the relative inhibition rate of the enzyme Phosphodiesterase 2 (PDE2) in cell culture, compared with alpha-bisabolol, which was used as the positive control. The same method was used in experiment 2, but only with the two compositions that had the best previous results, Composition 12 (that had 0.5% of Polydatin and 1.5% of 2-methoxycinnamaldehyde) and Composition 19 (with 0.5% of Ferulic Acid and 1.5% of 2-methoxycinnamaldehyde)
16
comparing their effects in four different concentrations from 0,0001% up to 0.1%. Showing that the combination of the anti-inflammatory component added with ferulic acid had an excellent synergic effect of inhibiting the production of very potent PGE 2 without being toxic at 0.1% concentration.
At last a third experiment was done with an in vivo method applying 2 mg of arachidonic acid in the right ear of each mouse once a day for four days, leaving de left one as the control. The anti-inflammatory effect was determined based on the group that was treated with the arachidonic acid, in comparison to the formulated topic treatments using the measurement of the edema and added to an equation that calculated the inhibition rate of the compositions. Showing that the combination of the 2-methoxycinnamaldehyde with the ferulic acid had an antiinflammatory effect 3 times higher them if it was used isolated, along with the antioxidant potential, this association can lead to great results and a wide variety of therapeutic applications.
2.1.4 Lipolytic activity
Adipose overload has become more common because of unhealthy habits especially in developed countries, with a high intake of processed foods and not enough practice of physical activities. A consequence of this lifestyle is the build-up of excess fat in the hypodermis that is intimately linked with a systemic inflammatory reaction on the body, a decrease in insulin sensibility leading do chronical and serious diseases. This topic has become more than an aesthetic subject, more importantly, a health issue.[24,25]
Studying the Ferulic Acid lipolytic effect, the patent FR2907338 presented in their first in vitro test that 0,2% of Ferulic Acid added to a culture of human adipocytes increased in 24% the release of glycerol into the culture, which shows a significant lipolytic action. Another test demonstrated the competing effect of the Ferulic acid in the insulin receptors of adipocytes, competing at a level of - 34% with the insulin. Acting like a mediator that inhibits lipogenesis after binding with the receptors instead of the insulin. In that way, the Ferulic Acid inhibits the insulin activity in lipogenesis that now reduced the synthesis and secretion of the lipoprotein lipase.
17 2.1.5 Whitening
Tyrosinase inhibition leads to a decrease in melanin production, increasing the brightness and inhibiting hyperpigmentation on the skin, especially when the skin is exposed to the sun. Invention CN105581919 presented a ferulic acid phospholipid complex that aimed to have a great whitening effect, especially by increasing the bioavailability of the F.A by improving its physicochemical properties. The patent showed great results in the inhibition rate of the tyrosinase and the inhibition in cell melanin synthesis, done by in vitro experimental methods. Added to the previous tests, the experiment run with 30 volunteers between 25-45 years showed an increase in skin brightening and reduced facial melanin spots on the skin. It even suggested three formulations being a cream, an emulsion, and a skincare oil.
Another method that had a skin whitening effect was in the publication US2013345307 that brought a system of skin rejuvenation including first a chemical pell and than a booster that should be applied after the exfoliation and removal of dead skin cells, what makes the booster have a better effect penetrating more effectively on the skin. When comparing the effect of ferulic acid, and other phenolic compounds isolated and in combinations, the one that had the F.A associated with the phloretin, vitamin C and E had the best result. Especially because both the F.A. and the phloretin have whitening effect with different mechanisms, both modulating the melanocyte and fibroblast. The disclosure products indicated had about 2% to 15% of ferulic acid in their formulations, the effect of the treatment could be seen in volunteers that had treated their face, hand, and V neck region showing great results in alleviating sun and acne spots as well as smoother skin texture.
The invention CN103637924 also showed a composition that focused on the synergic effect containing ginsenoside Rb1 and Ferulic Acid as the main actives in a face mask, the indicated ratio by weight was 18 parts of ginsenoside Rb1 and 15 parts of ferulic acid. Finally, the patent BR102015003242-0 A2 showed the whitening effect to treat melasma with a formulation that has no serious side effects as the traditional treatments, combining at least other two antioxidants with the F.A. The M.A.S.I. (Melasma Area and Severity Index) evaluation in 11 volunteers showed an average improvement in the aspect of the skin by 25.3% after 28 days of treatment.
18 2.2. Improving the Ferulic Acid characterists
Ferulic Acid has a wide range of activities, from antioxidant and antiinflammatory to preventing fat accumulation and inhibiting melanin, but its application in formulations is limited due to its low water solubility and molecule instability, leading into physicochemical limitations.
One of the main study areas that cover the F.A is the application of technologies and new methods to improve the interaction and stability of the compound molecule in formulations, with that in mind the invention CN101485447 explored the inclusion of F.A. in cyclodextrins, creating a compound that can be applied not only in pharmaceutical and cosmetic industry, but in the veterinary and food industry too. Similar to the patent BR 102016022392-0 that proposed a multi-component system, complexing the molecule into cyclodextrin and hydrophilic polymers witch provides a synergic effect increasing the molecule solubility, stability and the antioxidant activity when compared to the FA alone.
Another invention CN105581919 proposes a Ferulic Acid phospholipid complex to improve the compound bioavailability in formulations. The solubility and Free radical scavenging experiments showed great results in both tests, the first one increased the solubility of the F.A in water and the second one has a better scavenging effect than the Ferulic Acid alone. They also tested the permeability and the transdermal permeation of the combined F.A. with time. The accomplished results showed that the Ferulic Acid phospholipid complex has good permeation performance, better solubility and improved penetration in the skin.
3. Expert opinion
Ferulic Acid is widely used in the food industry, veterinary, pharmaceutical, and cosmetic fields [26]. It is a well-known compound that has been showing great responses in antiinflammatory, lipolytic, brightening, anti-wrinkle, and antioxidant activities as confirmed in the patent tests highlighted in table 1 of this review [27]. Wich opens doors to explore even more it's properties, especially in the field of topical formulations, extending to the dermo- cosmetic area. Chronical dermatological disorders like dermatitis, rosacea, psoríase, and acne could be a study target to Ferulic acid activity especially since these diseases have been increasing in the population [17, 29].
19
Through the selection of the patents it was observed that although China is the country with a higher percentage of patents published, most of them are methods and compositions of products using the ferulic acid. Overall only a few of the inventions published had tests in vitro and/or in vivo and these were the ones that were most explored in this review. This shows a necessity to have more deeply studied and tested formulations and compositions in order to develop further researches in the pharmaceutical field. But the topic that has been growing more lately and has the largest applicability is the development of new technologies and methods to improve the physicochemical properties of the Ferulic Acid, delivering a more stable active that has more efficacy, especially against Reactive Oxygen Species.
Code Tittle of the patents Activity Tests performed and cited in the patents
Year Country US2014
0107046
Cosmetic compositions containing at least one flavonoid and Ferulic Acid
Antioxid ant
Oxygen radical absorption capacity assay (ORAC)
2014 US
KR2018 0073305
Cosmetic composition for preventing skin aging by heating Antioxid ant and Antiagin g Scavenging activity FSC50, Production of MMP-1 (Matrix Metalloproteinase-1) and MMP-3 for Ferulic Acid Treatment in Heat Treatment Conditions and Production
2018
Korea
KR2011 0101727
Composition for improving skin wrinkle
Antiagin g
Inhibitory effect of collagenase activity, Confirmation of collagen synthesis promoting effect (quantified using a PICP EIA kit) and Evaluation of Increased HAS2 Expression in Mouse Fibroblast NIH3T3. Confirmation of skin wrinkle improvement through panel test.
2011 Korea
KR2011 0068258
Composition for anti- inflammatory
Antiinfla mmatory
Production of Prostaglandin 2 (PGE2), Relative inhibition rate of the enzyme
Phosphodiesterase 2 (PDE2) in cell culture
2011 Korea
FR2907 338
Use of ferulic acid, its salts and/or derivatives as lipolytic agent to prepare a cosmetic and/or pharmaceutical composition to prevent and/or treat the adipose overloads and/or cellulitis, by systemic and/or local administration
Lipolytic Enzymatic determination of glycerol in culture cells and Competition of the substance for insulin receptors in a co-culture system of keratinocytes and adipocytes
20 BR1020 1500324 2-0 A2 Composição cosmética e uso da mesma Whitenin g
The composition was tested in volunteers the M.A.S.I. (Melasma Area and Severity Index)
2016 Brazil
US2013 345307
Systems and methods for skin rejuvenation
Antiagin g and Whitenin g
The product was applied in the face, hand and neckline of the volunteers and compared the before and after
2013 US
CN1055 81919
Ferulic acid and phospholipid complex and application thereof to preparation of skin- whitening cosmetics
Whitenin g
In vitro tyrosinase inhibition test of ferulic acid phospholipid complex and Inhibition test of cell melanin
2016 China
Conflict of interest
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23. Varani, James, et al. "Decreased collagen production in chronologically aged skin: roles of age-dependent alteration in fibroblast function and defective mechanical stimulation." The American journal of pathology 168.6 (2006): 1861-1868.
24. Kim, Jong In, et al. "Lipid-overloaded enlarged adipocytes provoke insulin resistance independent of inflammation." Molecular and cellular biology 35.10 (2015): 1686-1699.
25. Unger, Roger H., et al. "Lipid homeostasis, lipotoxicity and the metabolic syndrome." Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1801.3 (2010): 209-214.
26. Saeed, M., et al. "Health promoting and pharmaceutical potential of ferulic acid for the poultry industry." World's Poultry Science Journal 75.1 (2019): 83-92.
27. Raab, Susana, et al. "Clinical evaluation of an antioxidant cream containing resveratrol, ferulic acid, and vitoptin on photodamaged skin." Journal of the
American Academy of Dermatology 64.2 (2011).
28. Fonacier, Luz S., Stephen C. Dreskin, and Donald YM Leung. "Allergic skin diseases." Journal of Allergy and Clinical Immunology 125.2 (2010): S138-S149.
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1. Overview
Expert Opinion on Therapeutic Patents: Author Guidelines
Expert Opinion on Therapeutic Patents is the leading review journal for pharmaceutical patent
information, providing a monthly, peer-reviewed guide to the technological advances and developments in pharmaceutical patents. The journal also provides timely reviews in medicinal chemistry.
The following document details the requirements for article submissions. Please refer to the
Submission Checklist at the end of this document, and ensure that all criteria are met before
submission. This will ensure the timely publication of your article.
2. Audience
The audience consists of scientists and managers in the healthcare and pharmaceutical industry, academic pharmaceutical scientists and related professionals. Reviews are intended to be concise updates on the field, both providing interest for the specialist reader as well as a clear introduction for those with less familiarity.
3. Peer-review
All articles are subject to double-blind, independent peer-review. When all comments have been submitted to the Editorial Office, they will be collated and forwarded to the author, along with any Editorial recommendations. Comments remain confidential and are shared only with the corresponding author or submitting party. For a detailed description of the journal’s peer review process, authors are referred to the journal’s website.
4. Manuscript content
Every article must contain:
5. Title
All article types should have a concise, informative title that contains no brand names (except in Technology Evaluations). Meeting Highlights titles should have the meeting name, date and location as the title.
6. Authors’ names and addresses
Including address, academic qualifications and job titles of all authors, as well as telephone number, fax number and email address of the author for correspondence on a separate cover
sheet as the peer reviewers will be blinded to the authors’ identity. Please note that only the address of the first author of the article will appear on Medline/PubMed, not necessarily the
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7. Abstract
The aim of the abstract is to draw in the interested reader and provide an accurate reflection of the content of the paper. We therefore request the following structure is followed for full-length review articles:
Introduction Authors are required to describe the significance of the topic under discussion. Areas covered Authors are required to describe the research discussed and the literature search
undertaken.
Expert opinion Authors are required to summarise briefly their Expert Opinion section.
For shorter article types, such as Editorials, the above sections are not required, but the abstract must describe the nature and objective of the paper.
References must not be included in the abstract. ©2007 Informa UK Ltd ISSN 1354-3776
8. Keywords
A brief list of keywords, in alphabetical order, is required to assist indexers in cross-referencing. The keywords will encompass the therapeutic area, mechanism(s) of action, key compounds and so on.
9. Body of the article
Depending on what type of article you are preparing, please refer to the relevant section from the list below, along with the appropriate row from the Guide Table:
GUIDE TABLE:
Article type Length (not includin g tables, figures and referenc es ) Number of figures (not including chemical structure s) Number of tables Length of Expert Opinion section Number of referenc es EDITORIAL 1000 – 1500 2 2 200 – 500 < 15 PATENT EVALUATIO N 1500 5 5 200 – 500 100 REVIEWS 4000 – 6000 5 5 500 – 1000 100 • Editorial:
The author should discuss the various therapeutic strategies which have been and are being explored
, providing the reader with an overview of the research field. • Patent
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information
disclosed, placing it in context with previous research in the same area, and indicating the relative importance of the present application. It is essential that a critical stand is taken when writing.
Chemistry - Briefly comment on any novel or particularly adroit chemical syntheses; draw a scheme if necessary to illustrate your point. Name, and draw, the most interesting
compound(s). You may prefer to use a generic structure to illustrate the range of compounds covered. Indicate how the compounds disclosed differ from other inventions patented by the same or competitor companies, i.e., in terms of novel chemistry or superior biological activity.
claims. Quote in vitro and in vivo data, the species used, route of administration, and so on, as appropriate.
Expert opinion - To conclude, give your opinion as to whether you think
the compounds described are likely to become lead candidates for development, or if any of the techniques disclosed will be of potential therapeutic use. If not, indicate why you think the patent is nevertheless of interest. Comparative assessment is encouraged. When evaluating the patent, the author should place emphasis on the therapeutic significance of the novel invention.
The evaluation should place the invention into the context of the ‘state-of-the-art’ in the relevant field, by comparing and contrasting the invention with those of other companies working in the same field, or with earlier inventions from the same company. The chemistry and biology covered in the patent should be examined. Evaluations must, above all, contain critical analyses of the invention, i.e., they should not just summarise the patent text. Comparative evaluations should highlight similarities and differences and identify the most interesting patents in the group.
• Review article:
Introduction - Incorporating basic background information on the area
under review.
Body - Body of the review paper covering the subject under review
Expert opinion - Should compare and contrast the patented
approaches/drugs reviewed in the article with the range of alternative patented approaches/drugs.
The above table includes specific requirements of each article type published by Expert Opinion on Therapeutic Patents. Please refer to the relevant row of this paper while preparing your article.
10. Conclusion
The conclusion for all articles should contain an analysis/summary of the data presented in the article. Please note that this section is meant to be distinct from, and appear before the ‘Expert opinion’ section.
11. . Expert opinion
To distinguish the articles published in the Expert Opinion series, authors must provide an additional section entitled ‘Expert Opinion’. This section affords authors the opportunity to go beyond the conclusion and provide their interpretation of the data presented in the article. In addition, there is the opportunity to discuss the developments that are likely to be important in the future and the avenues of research likely to become exciting as further studies yield more detailed
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• What are the key findings and weaknesses in the research done in this field so far? • What are the most innovative and promising compounds?
• What is the short-term clinical outlook for these compounds?
• What potential does this research hold? What is the ultimate goal in this field? • What research or knowledge is needed to achieve this goal and what is the biggest
challenge in this goal being achieved?
• Where do you see the field going in the coming years? What is going to happen? • Is there any particular area of the research you are finding of interest at present?
Please note that ‘opinions’ are encouraged in the Expert opinion section, and as such, referees are asked to keep this in mind when peer-reviewing the manuscript.
Please refer to section 2.5 for article-specific advice on how to frame the Expert opinion.
12. Article highlights box
Please provide, in the form of a bulleted list (five or six points), statements covering the key aspects of the paper.
13. Annotated bibliography
Important references should be highlighted with a one/two star system and brief annotations should be given (see ‘Section 4’ of these guidelines for examples and for a more detailed description of our referencing style).
14. House style
15. File formatting
Keep all formatting to a minimum. Do not assign ‘styles’ to headings, extracts or paragraphs. Make sure that the ‘normal’ style is used throughout the text. Turn off the automatic hyphenation feature.
16. Spacing and headings
Please use double line spacing throughout the manuscript. Headings, sub-headings and title paragraphs should be used to divide the text. Please use numbers (Arabic numerals) to indicate a hierarchy of headings/sub-headings (i.e., 1., 1.1, 2., 2.1, 2.1.1, 2.1.2 and so on).
17. Abbreviations and units
Abbreviations should be defined on their first appearance both in the abstract and in the text; commonly used abbreviations need not be defined. Authors are encouraged to submit a list of abbreviations used to the Editorial Office alongside the manuscript. Use SI units or quote SI equivalents where possible. To indicate atom positions in a molecule, use the convention C-1, C-2 and so on.
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English used in the manuscript submitted to the Editor. All accepted manuscripts will be copyedited in house upon acceptance, but authors are advised to check their work for English spelling and grammar prior to submission. The Editorial Office can arrange an English language edit prior to
submission if required - please contact the editorial office for details of available services and costs.
19. Companies and drug brand names
• Companies are treated as single entities requiring a verb in the third person singular (e.g., GSK is developing an AII antagonist).
• Drug brand names should not appear in paper titles. In the body of the review, the generic name should be used in preference to brand names. Drug brand names are to be used only if absolutely necessary. In such a case, when referring to a lead compound (or compounds claimed in patents) for the first time, please ensure that the ® or TM symbols are used as required, and that the name of the relevant company is also stated. Generic names always take a lower case first letter unless they are beginning a new sentence.
20. References
Ensure that all key work relevant to the topic under discussion is cited in the text and listed in the bibliography. Reference to unpublished data should be kept to a minimum and authors must obtain a signed letter of permission from cited persons to use unpublished results or personal communications in the manuscript.
21. Numbering
References MUST be numbered consecutively, using Arabic numerals in square brackets, in the order in which they are first mentioned in the text. The reference list should appear in the same
sequence as the numbers in the text.
22. Annotations
Papers or patents of particular interest should be identified using one or two asterisk symbols (• = of interest, •• = of considerable interest), and annotated with a brief sentence explaining why the reference is considered to be of interest.
23. Bibliography
References can be formatted using EndNote or Reference Manager according to the style of
Current Medical Research and Opinion.
References use plain, unformatted text, as in the following examples:
Journals: Books:
24. Weissman P, Goldstein BJ, Rosenstock J, et al. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE
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25. Gottman J. Time Series Analysis. Cambridge: CUP, 1981 26. Working party reports and similar:
27. Clinical Disputes Forum Working Party. Pre-action protocol for the resolution of clinical disputes. London: Clinical Disputes Forum, 1998
Pre-publication articles assigned DOI numbers:
28. de Lau LM, Koudstaal PJ, Hofman A, Breteler MM. Subjective complaints precede Parkinson disease: the
Rotterdam study. Arch Neurol 2006: published online 9 January2006, doi:10.1001/archneur.63.3.noc50312 Internet articles and website information:
29. Suicidality in adults being treated with antidepressant medications. FDA Public Health Advisory.
Washington, DC: FDA/Center for Drug Evaluation and Research, 2005. Available at: www.fda.gov/cder/drug/advisory/SSRI200507.htm [Last accessed 3 January 2006] Patents:
30. Genzyme Corp. JAK/STAT pathway inhibitors and the use thereof for the treatment of osteoarthritis. EP1875900 (2008)
Use the following formats for patent numbers issued by the World, US (applications and granted patents) and European patent offices, respectively: WO2013001234; US20130066069 (applications); US6803189 (granted patents); EP1549318.
Note, for citations with four or fewer authors/assignees cite all names; for citations with more than four authors, cite three author names plus et al.
Full reference details must be provided in the bibliography (for example, for journal citations, author surnames and initials, article title, journal name, year, volume, page range). Failure to do so may lead to a delay in publication or a return of the paper by the Editor to the author.
31. Tables
Number tables consecutively in the order of their first citation in the text. Place explanatory matter in the footnotes, not in the header. Define in the footnotes all abbreviations that are used in the table. Be sure each table is cited in the text. If you are using data from another published or unpublished source, please obtain permission and acknowledge the source(s).
32. Illustrations
Do include illustrations (figures/diagrams/structures) as appropriate. Please ensure that the following recommendations are adhered to as closely as possible:
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two, please also provide their .gif or .jpg equivalent inserted in your manuscript). • Figures should use CMYK rather than RGB colour scheme.
• Small figures should be 300 dpi and large figures should be 72 dpi.
• Figures and structures original files should be in separate files to the text. It is however necessary to incorporate the figures in low resolution format into the body of the manuscript. If there are several figures, please submit these individually, rather than as one file (preferably the original source files). We cannot improve resolution beyond that of the file submitted.
• If these formats are not possible, figures can be submitted in PowerPoint or Word as a last resort.
• Figures should be numbered consecutively according to the order in which they have been first cited in the text. Define in the legend all abbreviations that are used in the figure. • If a figure has been previously published, acknowledge the original source and please
submit written permission from the copyright holder to reproduce the material.
The Editorial Office can arrange for figure re-drawing and medical illustration - please contact us for details of available services and costs.
Publication in colour will be charged at $575 per paper. 33. Chemical structures
Please submit structures drawn in ISISDraw or Chemdraw and ensure that you submit these in their original, editable format.Please also submit their jpeg or gif equivalent already inserted into the manuscript. Also, use the following conventions:
• Always indicate stereochemistry where necessary – use the wedge and hash bond convention for chiral centres and mark cis/trans bonds as such.
• Draw small peptides (up to five amino acids) in full; use amino acid abbreviations (Gly, Val, Leu and so on) for larger peptides.
• Refer to each structure with a number in the text and submit a separate file (i.e., not pasted throughout the text) containing these numbered structures in the original chemical drawing package that you used.
• Where structures do not appear as part of a figure, number each structure (using Arabic numerals only) and cite the compound number in the body of the article. Note that structures within figures can also be cited in this way.
34. Copyright
As the author of your manuscript, you are responsible for obtaining permissions to use material owned by others. As the permission-seeking process can be remarkably time-consuming, it is wise to begin writing for permission as soon as possible. A template permission letter is available on request. Please send us photocopies of letters or forms granting you permission for the use of copyrighted material so that we can see that any special requirements with regard to wording and placement of credits are fulfilled. Keep the originals for your files. You will be asked to transfer
copyright to Informa UK Ltd following acceptance for publication. If there are any problems with this, this should be raised with the Editor as soon as possible.
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35. NIH/Wellcome-funded research
For NIH/Wellcome-funded manuscripts Informa Pharmaceutical Science will deliver to PMC/UKPMC the final peer-reviewed manuscript, which was accepted for publication and that reflects any author-
agreed changes made in response to the peer review. We will also authorize the author manuscript’s public access posting 12 months (NIH) or 6 months (Wellcome Trust) after final publication. Following the deposit, authors will receive further communications from the NIH Manuscript Submission System/UK Manuscript Submission System with respect to the submission. It is the author’s responsibility to make the Editor aware of this funding as early as possible.
36. Conflict of interest
We require all authors to complete and return the Disclosure Statement found at the end of these guidelines on submission of their work. It is the responsibility of authors to disclose any affiliation with any organisation with a financial interest, direct or indirect, in the subject matter or materials d iscussed in the manuscript (such as consultancies, employment, expert testimony, honoraria, speakers bureaus, retainers, stock options or ownership) that may affect the conduct or reporting of the work submitted. If uncertain as to what might be considered a potential conflict of interest, authors should err on the side of full disclosure. Information about potential conflict of interest may be made available to reviewers and may be published with the manuscript at the discretion of the Editors. The declaration of interest statement must be returned to the Editor upon submission (see end of this document).
For a detailed description of all the journal’s editorial policies, including plagiarism, authorship, patient privacy, and redundant publication, authors are referred to the editorial policy document on the journal’s website.
37. Submission
All material should be prepared as detailed below. Please refer to the Submission Checklist at the end of this document and ensure that all criteria are met before submission. This will ensure timely publication of your article.
Submissions should conform to the latest version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals, prepared by the International Committee of Medical Journal Editors (ICMJE:
http://www.icmje.org/). Although it is recommended that authors read the entire Uniform Requirements document, in particular, authors and contributors are referred to the following sections/paragraphs of this document:
II A.1 and II A.2. – Notes defining and distinguishing authorship and contributorship. II .D.1. – Peer review
I. E.1. – Patients and study participants II.F – Protection of human subjects in research
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Please submit manuscripts in Microsoft Word (double spaced, Times New Roman, 12 pt) using the Manuscript Central online submission system (http://mc.manuscriptcentral.com/eotp). As the peer reviewers will be blinded to the identity of the authors, contributors MUST provide a copy of the manuscript containing no author names or affiliations. These details should be provided on a separate cover sheet. Pages must be numbered. Authors sending incomplete submissions may be asked to rectify and resubmit the paper in case of any omissions or serious failures to follow the journal style.
Contributors are required, wherever possible and appropriate, to obtain content from any patient, client or participant in any research or clinical experiment or study who is mentioned in the Article for the inclusion of material pertaining to themselves. Such an individual should not be identifiable via the Article.
Where applicable, contributors are required to follow the procedures in force in their countries which govern the ethics of work done with human or animal subjects. The Code of Ethics of the World Medical Association (Declaration of Helsinki) represents a minimal requirement. In particular: When experimental animals are used, state the species, strain, number used, and other pertinent descriptive characteristics.
When describing surgical procedures on animals, identify the pre anaesthetic and anaesthetic agents used and state the amount of concentration and the route and frequency of administration for each. The use of paralytic agents, such as curare or succinylcholine, is not an acceptable substitute for anaesthetics. For other invasive procedures on animals, report the analgesic or tranquilizing drugs used; if none were used, provide justification for such exclusion.
When reporting studies on unanaesthetized animals or on humans, indicate that the procedures followed were in accordance with institutional guidelines.
38. Deadlines and what happens after you submit
• Please ensure that manuscripts are submitted on or before the deadline issued by the Editors.
• Please provide an outline of your article 1 month prior to the submission deadline. This will enable us to advise you on any problems with scope etc.
• Once the manuscript has been received in-house, it will be peer-reviewed (this usually takes ~ 3 weeks). A further 2 weeks is then allowed for any revisions (suggested by the
Referees/Editor) to be made.
• The final version is then typeset and edited. Page proofs are sent to the author for final approval before the journal is printed.
Note: If a manuscript requires company authorisation before submission, please remember to take
this into account when working towards these deadlines.
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required, we can also arrange for professional medical writing and illustration assistance, including: • Pre-submission language editing
• Comprehensive re-formatting • Detailed technical editing • Figure redrawing
• Medical illustration
If you are interested in the above services, please contact the Editorial Office for further details and costs. Please note, these services are independent of the peer review process and undertaking such work does not guarantee final acceptance of the manuscript.
Contributors are required, wherever possible and appropriate, to obtain content from any patient, client or participant in any research or clinical experiment or study who is mentioned in the Article for the inclusion of material pertaining to themselves. Such an individual should not be identifiable via the Article.
Where applicable, contributors are required to follow the procedures in force in their countries which govern the ethics of work done with human or animal subjects. The Code of Ethics of the World Medical Association (Declaration of Helsinki) represents a minimal requirement. In particular: When experimental animals are used, state the species, strain, number used, and other pertinent descriptive characteristics.
When describing surgical procedures on animals, identify the pre anaesthetic and anaesthetic agents used and state the amount of concentration and the route and frequency of administration for each. The use of paralytic agents, such as curare or succinylcholine, is not an acceptable substitute for anaesthetics. For other invasive procedures on animals, report the analgesic or tranquilizing drugs used; if none were used, provide justification for such exclusion.
When reporting studies on unanaesthetized animals or on humans, indicate that the procedures followed were in accordance with institutional guidelines.
