BR102016001739A2 - PHARMACEUTICAL COMPOSITION COMPOSING LIPID NANOPARTICLES CONTAINING CLOBETASOL PROPIONATE FOR TOPICAL ADMINISTRATION IN THE TREATMENT OF ALOPECIA - Google Patents
PHARMACEUTICAL COMPOSITION COMPOSING LIPID NANOPARTICLES CONTAINING CLOBETASOL PROPIONATE FOR TOPICAL ADMINISTRATION IN THE TREATMENT OF ALOPECIA Download PDFInfo
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- BR102016001739A2 BR102016001739A2 BR102016001739A2 BR 102016001739 A2 BR102016001739 A2 BR 102016001739A2 BR 102016001739 A2 BR102016001739 A2 BR 102016001739A2
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- Brazil
- Prior art keywords
- acid
- alopecia
- propionate
- treatment
- fluoro
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- 231100000130 skin irritation / corrosion testing Toxicity 0.000 description 1
- 239000002047 solid lipid nanoparticle Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 210000000434 stratum corneum Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 231100001005 telangiectasia Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000003813 thin hair Effects 0.000 description 1
- 229940083878 topical for treatment of hemorrhoids and anal fissures Corticosteroids Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
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Description
COMPOSIÇÃO FARMACÊUTICA COMPREENDENDO NANOPARTÍCULAS LIPÍDICAS CONTENDO PROPIONATO DE CLOBETASOL PARA ADMINISTRAÇÃO TÓPICA NO TRATAMENTO DA ALOPECIA Campo da invenção [001] A presente invenção pertence ao campo farmacêutico, envolvendo preparações de uso tópico para permeação cutânea direcionada ao folículo piloso. Em especial, a presente invenção refere-se a uma formulação nanoparticulada para a prevenção ou o tratamento da alopecia de diferentes origens, em particular a alopecia areata, que contenha nanopartículas lipídicas, em particular, carreadores lipídicos nanoestruturados (CLN) de propionato de clobetasol (CLO), um glicocorticoide de uso tópico, que nessa forma de apresentação pode direcionar e controlar a liberação do CLO no folículo piloso, possibilitando a redução da frequência de aplicações necessárias, a redução da absorção sistêmica e a redução de efeitos adversos, além da promoção do crescimento dos cabelos de forma sustentada.PHARMACEUTICAL COMPOSITION UNDERSTANDING LIPID NANOParticles CONTAINING CLOBETASOL PROPIONATE FOR TOPICAL ADMINISTRATION Field of the invention [001] The present invention pertains to the pharmaceutical field, involving topical preparations for targeted follicular dermal permeation. In particular, the present invention relates to a nanoparticulate formulation for the prevention or treatment of alopecia of different origins, in particular alopecia areata, containing lipid nanoparticles, in particular clobetasol propionate nanostructured lipid carriers (CLN) ( CLO), a topical glucocorticoid that in this presentation can direct and control the release of CLO in the hair follicle, enabling the reduction of the frequency of necessary applications, the reduction of systemic absorption and the reduction of adverse effects, in addition to promoting sustained hair growth.
[002] Dessa forma, a formulação deve possibilitar a produção de um medicamento para alopecia que seja mais eficaz e mais seguro que os existentes atualmente. A presente invenção se situa no campo na medicina, biomedicina, química, farmácia e nanotecnologia.Thus, the formulation should make it possible to produce a drug for alopecia that is more effective and safer than currently available. The present invention is in the field of medicine, biomedicine, chemistry, pharmacy and nanotechnology.
Antecedentes da invenção Alopecia [003] Alopecia é a diminuição excessiva de pelos e atinge um grande percentual da população 1. Alguns estudos apontam que mais de 50 % dos homens na faixa de 30 a 50 anos apresentam diminuição dos cabelos 2 3. Essa condição também parece afetar entre 15 e 30 % das mulheres acima de 30 anos, chegando a mais de 80 % para mulheres na pré-menopausa 4. A queda de cabelos pode ter diversas causas, e entre elas podem-se citar questões genéticas 1’5’6, autoimunes 6~8, endócrinas 1·9, metabólicas 1, nutricionais 10, emocionais911, uso de drogas 1, traumas mecânicos e térmicos 8, infecções 12, cicatrizes 1, entre outras. Especificamente, a alopecia areata é uma patologia de etiologia complexa, que envolve um mecanismo autoimune e perda de cabelo desigual no couro cabeludo. Ela se manifesta como lesões não-cicatriciais, arredondadas ou ovais, com bordas bem definidas e perda de fios por tração. Esta patologia pode evoluir para perda de cabelo de todo o couro cabeludo (alopecia totalis) ou para a progressão extrema, resultando em ausência completa de pelos em todo corpo (alopecia universalis)6'8·13.BACKGROUND OF THE INVENTION Alopecia Alopecia is excessive hair loss and affects a large percentage of the population 1. Some studies show that over 50% of men in their 30s and 50s have hair loss. seems to affect between 15 and 30% of women over 30 years, reaching more than 80% for premenopausal women 4. Hair loss can have several causes, and among them genetic issues 1'5 ' 6, autoimmune 6 ~ 8, endocrine 1 · 9, metabolic 1, nutritional 10, emotional911, drug use 1, mechanical and thermal trauma 8, infections 12, scars 1, among others. Specifically, alopecia areata is a pathology of complex etiology that involves an autoimmune mechanism and uneven scalp hair loss. It manifests as non-scarring, rounded or oval lesions with well-defined edges and loss of traction wires. This condition may progress to hair loss of the entire scalp (alopecia totalis) or to extreme progression, resulting in complete absence of hair on the entire body (alopecia universalis) 6'8 · 13.
Propionato de Clobetasol (CLO) [004] O propionato de clobetasol (C25H32CIFO5) (CLO) é um fármaco glicocorticoide análogo da prednisolona e tem como sinônimos: 9a-flúor-21-cloro-11 β-hidróxi-l 63-metilpregna-3,20-diona-1,4-dieno-17a-propionato; clobetasol 17-propanoato; clobetasol 17-propionato; 21-cloro-9-fluoro-1ip,17-dihidroxi-163-metilpregna-1,4-dieno-3,20-diona 17-propionato; pregna-1,4-dieno-3,20-diona, 21-cloro-9-fluoro-11-hidroxi-16-methil-17-(1-oxopropoxi)-,(11 β,16β)-; 21 -Cloro-9-fluoro-11 β,17-dihidroxi-16β-methilpregna-1,4-dieno- 3,20-diona 17-propionato [25122-46-7; 25122-41-2]; e (1 R,2S, 10S,11 S,13S, 14R,15S,17S)-14-(2-cloroacetil)-1 -fluoro-17-hidroxi-2,13,15-trimethil-5-oxotetraciclo [8.7.0.02,7 .O11,15 ] heptadeca-3,6-dien-14-il propanoato. Este fármaco vem sendo usado há décadas para o tratamento de dermatoses e está disponível no mercado em diferentes apresentações, tais como creme, xampu e spray tópico. O propionato de clobetasol (CLO) é um dos esteroides mais potentes, com altos níveis de efetividade em casos de eczema, psoríase, líquen, dermatite atópica, dermatite seborreica, entre outros 14_17. Atualmente ele vem sendo testado também no tratamento da alopecia após observação do efeito colateral de hipertricose 11.15.17-19.Clobetasol Propionate (CLO) Clobetasol Propionate (C25H32CIFO5) (CLO) is a prednisolone analog glucocorticoid drug and has synonyms: 9a-fluoro-21-chloro-11 β-hydroxy-l 63-methylpregna-3 , 20-dione-1,4-diene-17α-propionate; clobetasol 17-propanoate; clobetasol 17-propionate; 21-chloro-9-fluoro-1α, 17-dihydroxy-163-methylpregna-1,4-diene-3,20-dione 17-propionate; pregna-1,4-diene-3,20-dione, 21-chloro-9-fluoro-11-hydroxy-16-methyl-17- (1-oxopropoxy) -, (11 β, 16β) -; 21-Chloro-9-fluoro-11β, 17-dihydroxy-16β-methilpregna-1,4-diene-3,20-dione 17-propionate [25122-46-7; 25122-41-2]; and (1R, 2S, 10S, 11S, 13S, 14R, 15S, 17S) -14- (2-chloroacetyl) -1-fluoro-17-hydroxy-2,13,15-trimethyl-5-oxotetracyclo [8.7 0.02.7 .10.15] heptadeca-3,6-dien-14-yl propanoate. This drug has been used for decades to treat dermatoses and is available in the market in different presentations, such as cream, shampoo and topical spray. Clobetasol propionate (CLO) is one of the most potent steroids, with high levels of effectiveness in cases of eczema, psoriasis, lichen, atopic dermatitis, seborrheic dermatitis, among others 14_17. Currently it has also been tested in the treatment of alopecia after observing the side effect of hypertrichosis 11.15.17-19.
[005] A atividade dos corticosteroides junto à alopecia se dá devido aos seus efeitos imunossupressores. Eles agem combatendo reações autoimunes, em que as células do bulbo em anagênese são atacadas por linfócitos 1·19. Sua eficácia foi comprovada no tratamento de queda de cabelo, barba, bigode, sobrancelhas, cílios, no peito, nas costas e nas extremidades 19. Uma das grandes vantagens do CLO é a reposta mais rápida e prolongada em relação a outros esteroides tópicos 14.The activity of corticosteroids with alopecia is due to their immunosuppressive effects. They act by fighting autoimmune reactions, in which anagenized bulb cells are attacked by lymphocytes 1 · 19. Its effectiveness has been proven to treat thinning hair, beard, mustache, eyebrows, eyelashes, chest, back, and extremities 19. One of the great advantages of CLO is its faster and longer response over other topical steroids 14.
[006] Pesquisas indicam que o creme de CLO a 0,05% sob oclusão é eficaz em induzir o crescimento do cabelo em pacientes com alopecia 11·18. No entanto, mesmo nos casos em que foram realizadas aplicações tópicas, foram relatados efeitos adversos e entre os mais frequentes estão prurido, foliculite e telangiectasia 11-19. Além disso, estudos sugerem que a possibilidade de absorção sistêmica do clobetasol pode fazer com que a terapia a longo prazo seja associada a eventos adversos mais severos 11’20.Research indicates that 0.05% CLO cream under occlusion is effective in inducing hair growth in patients with alopecia 11 · 18. However, even where topical applications have been performed, adverse effects have been reported and among the most frequent are pruritus, folliculitis and telangiectasia 11-19. In addition, studies suggest that the possibility of systemic absorption of clobetasol may cause long-term therapy to be associated with more severe adverse events 11'20.
[007] A publicação internacional WO2013/028049 refere-se a uma composição líquida para aplicação percutânea, que inclui propionato de clobetasol, minoxidil, tretinoína e finasterida como princípios ativos para usuários com alopecia, especialmente alopecia androgenética. O pedido de patente US2011/0129546, por sua vez, descreve uma composição farmacêutica dermatológica que inclui pelo menos um corticoide (ex.: CLO) para o tratamento de várias doenças dermatológicas, incluindo a alopecia areata. O pedido PI 0510893-4 descreve uma emulsão inversa contendo CLO e calcitriol para uso cosmético e dermatológico, incluindo para a prevenção ou o tratamento da alopecia. Nenhum desses documentos, entretanto, descreve o uso de sistemas nanoparticulados contendo CLO capaz de possibilitar o acúmulo direcionado do fármaco no folículo piloso.International publication WO2013 / 028049 refers to a liquid composition for percutaneous application, which includes clobetasol propionate, minoxidil, tretinoin and finasteride as active ingredients for users with alopecia, especially androgenic alopecia. US2011 / 0129546, in turn, describes a dermatological pharmaceutical composition that includes at least one corticoid (e.g., CLO) for the treatment of various dermatological diseases, including alopecia areata. Application PI 0510893-4 describes a reverse emulsion containing CLO and calcitriol for cosmetic and dermatological use, including for the prevention or treatment of alopecia. None of these documents, however, describe the use of nanoparticulate systems containing CLO capable of enabling targeted accumulation of the drug in the hair follicle.
[008] Assim, o desenvolvimento de formulações com o potencial de direcionar a liberação do fármaco aos folículos pilosos é de extrema importância para diminuição dos efeitos adversos, além da possibilidade de redução da dose. Adicionalmente, é necessário que uma formulação inovadora, não apenas direcione o acúmulo de fármaco no folículo, mas que o faça de forma sustentada, de modo que o intervalo de administrações possa ser prolongado, resultando em aplicações menos frequentes e maior adesão dos pacientes. Nano/Microssistemas de aplicação tópica [009] A pesquisa na utilização de nano/micropartículas para a veiculação de fármacos para o tratamento de afecções cutâneas que envolvem os folículos pilosos tem se intensificado consideravelmente nos últimos anos 21~25. Esses sistemas podem resolver desafios diferentes ao mesmo tempo: direcionamento do fármaco ao folículo piloso, retenção no sítio-alvo e proteção contra a degradação no ambiente da pele 24.Thus, the development of formulations with the potential to direct drug release to hair follicles is of utmost importance for decreasing adverse effects, in addition to the possibility of dose reduction. Additionally, it is necessary that an innovative formulation not only directs drug accumulation in the follicle, but must do so in a sustained manner so that the administration interval can be prolonged, resulting in less frequent applications and increased patient compliance. Nano / Microsystems for topical application Research on the use of nano / microparticles for the delivery of drugs for the treatment of skin disorders involving hair follicles has intensified considerably in recent years 21 ~ 25. These systems can solve different challenges at the same time: targeting the drug to the hair follicle, retention at the target site and protection against degradation in the skin environment 24.
[010] Além disso, de acordo com as características das partículas, os folículos podem servir como compartimento de armazenamento, o que permite uma exposição prolongada do fármaco no sítio-alvo, além de atuar também como reservatório para liberação sustentada 24·26-28.In addition, according to the characteristics of the particles, the follicles can serve as a storage compartment, which allows prolonged exposure of the drug to the target site, and also acts as a reservoir for sustained release. 24 · 26-28 .
[011] A literatura científica reporta alguns estudos de nano/microssistemas de clobetasol para penetração cutânea, visando tratamento de desordens cutâneas tais como psoríase e dermatites 16>29~38. Em especial, o artigo de Silva et al. (2012) 30, cita as vantagens da nanoencapsulação do CLO em carreadores lipídicos nanoestruturados visando aumentar o acúmulo do fármaco nas camadas superiores da pele, diminuindo a absorção sistêmica e os efeitos colaterais. Entretanto, o artigo não cita ou indica seu uso para a prevenção ou tratamento da alopecia - uso reivindicado por esse invento.[011] The scientific literature reports some studies of clobetasol nano / microsystems for skin penetration aiming at treatment of skin disorders such as psoriasis and dermatitis 16> 29 ~ 38. In particular, the article by Silva et al. (2012) 30, cites the advantages of CLO nanoencapsulation in nanostructured lipid carriers in order to increase drug accumulation in the upper layers of the skin, reducing systemic absorption and side effects. However, the article does not cite or indicate its use for the prevention or treatment of alopecia - use claimed by this invention.
[012] No âmbito patentário, alguns documentos descrevem nanopartículas contendo CLO, contudo, nenhuma delas indica o uso para prevenção e tratamento da alopecia.[012] In the patent field, some documents describe CLO-containing nanoparticles, however, none of them indicate use for prevention and treatment of alopecia.
[013] O pedido de patente PI 0112553-2 descreve uma formulação lipossômica de CLO para aplicação tópica, para o tratamento de dermatite atópica, psoríase, eczemas e outras dermatoses. Nossa invenção difere tanto pelo tipo de partícula ser CLN, quanto pela aplicação na prevenção e o tratamento da alopecia areata.Patent Application PI 0112553-2 describes a liposomal formulation of CLO for topical application for the treatment of atopic dermatitis, psoriasis, eczema and other dermatoses. Our invention differs by both the particle type being CLN and its application in the prevention and treatment of alopecia areata.
[014] O pedido de patente CN102429913, descreve uma formulação lipossômica de CLO e vitamina A, para tratamento de doenças como psoríase, dermatite, eczema, e doenças afins. O presente invento difere deste pedido pelo tipo de partícula e pelo uso reivindicado.Patent application CN102429913 describes a liposomal formulation of CLO and vitamin A for treating conditions such as psoriasis, dermatitis, eczema, and related diseases. The present invention differs from this application in particle type and claimed use.
[015] Ainda, no âmbito patentário, alguns documentos descrevem nanopartículas para direcionamento de fármacos ao folículo piloso, entretanto nenhuma delas inclui o CLO como ativo.[015] Still, in the patent scope, some documents describe nanoparticles for targeting drugs to the hair follicle, however none of them include CLO as active.
[016] A patente US6733776 trata de uma formulação lipossômica para liberação específica de fármaco no folículo piloso para prevenção de alopecia, para estimular o crescimento do cabelo ou para agir na pigmentação do mesmo, porém esta não inclui CLO. Além disso, o nosso invento difere pelo tipo de partícula desenvolvida.[016] US6733776 deals with a liposome formulation for specific drug release into the hair follicle to prevent alopecia, to stimulate hair growth or to act on hair pigmentation, but it does not include CLO. Furthermore, our invention differs by the type of particle developed.
[017] De acordo com os documentos citados no estado da técnica, até o momento, não foram encontrados relatos de desenvolvimento de sistemas nanoparticulados contendo CLO com características específicas para o estudo da penetração folicular ou para o tratamento da perda de cabelos. Dessa forma, concluímos que a presente invenção não é antecipada nem sequer sugerida pelos ensinamentos existentes.[017] According to the documents cited in the prior art, no reports of development of CLO-containing nanoparticulate systems with specific characteristics for the study of follicular penetration or for the treatment of hair loss have been found to date. Thus, we conclude that the present invention is not anticipated or even suggested by existing teachings.
Sumário da invenção [018] A presente invenção descreve a utilização de CLN contendo CLO para a prevenção ou o tratamento da alopecia de diferentes origens, em particular a alopecia areata. A presente invenção proporciona a possibilidade de promover uma liberação sítio-específica do fármaco CLO nos folículos pilosos, de forma a reduzir a dose e a toxicidade, além de promover o crescimento dos cabelos de forma sustentada.SUMMARY OF THE INVENTION The present invention describes the use of CLO containing CLN for the prevention or treatment of alopecia of different origins, in particular alopecia areata. The present invention provides the possibility of promoting site-specific release of the drug CLO into the hair follicles in order to reduce dose and toxicity, and to promote sustained hair growth.
Descrição Detalhada da Invenção [019] A presente invenção faz referência à utilização de CLN contendo CLO para a prevenção ou o tratamento da alopecia de diferentes origens, em particular a alopecia areata.Detailed Description of the Invention The present invention relates to the use of CLO containing CLN for the prevention or treatment of alopecia of different origins, in particular alopecia areata.
[020] Dentre os componentes lipídicos utilizados para produção de CLN da presente invenção, pode-se citar, mas não limitando-se a, ácido esteárico, ácido cetílico, ácido cetoestearílico, ácido láurico, ácido palmítico, ácido behênico, ácido oleico, monoglicerídeos, diglicerídeos, poliglicerídeos, fosfolipídeos, colesterol, ácido fosfatídico, estearilamina, óleos minerais, óleos fixos vegetais, óleos essenciais, cera de abelha, cera de carnaúba, cetilpalmitato, entre outros.[020] Among the lipid components used for CLN production of the present invention, mention may be made, but not limited to, stearic acid, cetyl acid, cetostearyl acid, lauric acid, palmitic acid, behenic acid, oleic acid, monoglycerides. , diglycerides, polyglycerides, phospholipids, cholesterol, phosphatidic acid, stearylamine, mineral oils, vegetable fixed oils, essential oils, beeswax, carnauba wax, cetylpalmitate, among others.
[021] Adicionalmente, os sistemas podem compreender tensoativos, entre os quais podem-se destacar, sem se restringira, lecitina, taurodeoxicolato de sódio, polissorbatos, polissorbatos (poli)etoxilados, ésteres de polietilenoglicol, monoestearato de sorbitol, poliglucosídios, alcoxilatos, docusato de sódio, dodecanoato de sódio, lauril sulfato de sódio, cetrimida, cloreto de cetilpiridínio, gliceril monooleato, alquil éteres de polioxietileno, derivados polioxietilênicos de óleo de castor, sorbitano, trietil citrato, N-alquil e C-alquil betaina e sultaina, álcool amino fosfatidil, ésteres de trietil citrato, cocoanfoacetato de sódio, ésteres de ácido graxo de sacarose, entre outros.Additionally, the systems may comprise surfactants, among which, without limitation, lecithin, sodium taurodeoxycholate, polysorbates, polysorbates (poly) ethoxylates, polyethylene glycol esters of sorbitol, polyglucosides, alkoxylates, docusate may be highlighted. sodium, sodium dodecanoate, sodium lauryl sulfate, cetrimide, cetylpyridinium chloride, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene derivatives of castor oil, sorbitan, triethyl citrate, N-alkyl and C-alkyl betaine and sultain, alcohol amino phosphatidyl, triethyl citrate esters, sodium cocoanfoacetate, sucrose fatty acid esters, among others.
[022] Em uma modalidade específica dessa invenção, foram utilizados como componentes lipídicos uma mistura de ácido esteárico e ácido oleico em uma proporção 3:1 (m/m), tensoativos lecitina de soja e taurodeoxicolato de sódio em uma proporção 4:1 e quantidades variadas de CLO para formação de um sistema de CLN em dispersão aquosa.[022] In a specific embodiment of this invention, a mixture of stearic acid and oleic acid in a 3: 1 ratio (w / w), soybean lecithin surfactants and sodium taurodeoxycholate in a ratio of 4: 1 were used as lipid components. varying amounts of CLO to form a CLN system in aqueous dispersion.
Exemplo 1. Realização Preferencial [023] O exemplo aqui mostrado tem o intuito somente de exemplificar uma das inúmeras maneiras de se realizar a invenção, contudo sem limitar, o escopo da mesma.Example 1. Preferred Embodiment The example shown herein is intended solely to exemplify one of the numerous ways of carrying out the invention, but without limiting the scope thereof.
[024] Os CLN foram obtidos pelo método da diluição de microemulsão. A microemulsão teve como fase externa água e a fase interna oleosa foi composta por uma mistura de 300 mg ácido esteárico e 100 mg de ácido oleico. Os tensoativos utilizados foram 200 mg de lecitina de soja e 50 mg de taurodeoxicolato de sódio. Os componentes da fase interna e os tensoativos foram misturados até total fusão. Em seguida, o CLO foi adicionado e homogeneizado por 10 minutos. Logo após, foram adicionados 250 pL de água, sob constante agitação magnética, para formação da microemulsão. A microemulsão formada foi então gotejada em uma solução tampão HEPES (pH 7,4) mantido em banho de gelo. A adição foi realizada sob agitação em ultra-turrax® a 13500 rpm por 10 minutos. A proporção microemulsão: tampão foi de 1:20. O volume da dispersão final foi de 20 mL.38 [025] A quantidade de CLO foi de 1,5% (p/p) em relação à massa lipídica para a formulação de CLN a 0,03% e 2,5% (p/p) para a formulação de CLN a 0,05%. Caracterização das nanopartículas [026] O tamanho de partícula e o potencial zeta foram analisados por espalhamento de luz dinâmico e mobilidade eletroforética, respectivamente, utilizando um aparelho Zetasizer Nano ZS. Para tanto, 20 pL de cada formulação foram suspensos em 990 pL de água e levados ao aparelho para análise.The CLNs were obtained by the microemulsion dilution method. The microemulsion had as external phase water and the internal oily phase was composed of a mixture of 300 mg stearic acid and 100 mg oleic acid. The surfactants used were soybean lecithin 200 mg and sodium taurodeoxycholate 50 mg. Internal phase components and surfactants were mixed until complete melting. Then, the CLO was added and homogenized for 10 minutes. Immediately thereafter, 250 µl of water was added under constant magnetic stirring to form the microemulsion. The formed microemulsion was then dripped into a HEPES buffer solution (pH 7.4) kept in an ice bath. The addition was performed under stirring in ultra-turrax® at 13500 rpm for 10 minutes. The microemulsion: buffer ratio was 1:20. The final dispersion volume was 20 mL.38 The amount of CLO was 1.5% (w / w) relative to the lipid mass for the 0.03% and 2.5% CLN formulation ( w / w) for the 0.05% CLN formulation. Nanoparticle Characterization [026] Particle size and zeta potential were analyzed by dynamic light scattering and electrophoretic mobility, respectively, using a Zetasizer Nano ZS apparatus. To this end, 20 µl of each formulation was suspended in 990 µl of water and taken to the apparatus for analysis.
[027] Os CLN contendo 0,03% e 0,05% de CLO apresentaram, respectivamente, tamanho médio de 173,6 (± 8,7) e 237,0 (± 6,1) nm; com pdl de 0,242 (± 0,013) e 0,234 (± 0,024). As partículas apresentaram uma distribuição de tamanho monomodal e tiveram suas dimensões na ordem de nanômetros, sendo, portanto, caracterizadas como nanopartículas.CLNs containing 0.03% and 0.05% CLO had, respectively, average size of 173.6 (± 8.7) and 237.0 (± 6.1) nm; with pdl of 0.242 (± 0.013) and 0.234 (± 0.024). The particles had a monomodal size distribution and had their dimensions in the order of nanometers, being therefore characterized as nanoparticles.
[028] Os CLN contendo 0,03% e 0,05% de CLO apresentaram, respectivamente, potencial zeta de -49.9 (± 11.5) e -49.1 (± 12.3) mV. Esta carga pode ser vantajosa, uma vez que evita a atração e posterior aglomeração das partículas formadas.[028] CLNs containing 0.03% and 0.05% CLO had, respectively, zeta potential of -49.9 (± 11.5) and -49.1 (± 12.3) mV. This charge can be advantageous as it avoids the attraction and further agglomeration of the formed particles.
Exemplo 1.1 - Estudo in vitro de permeação cutânea do CLO a partir dos CLNExample 1.1 - In vitro study of CLO skin permeation from CLNs
[029] Foram realizados experimentos de permeação in vitro por 6 horas, utilizando pele de orelha de porco em células de difusão tipo Franz modificadas. As células foram montadas de modo que a pele suína se localizou entre os compartimentos superior e inferior. As formulações desenvolvidas e a formulação de creme comercial foram dispostas no compartimento doador. O compartimento receptor foi preenchido com uma solução aquosa de SDS 0,5% a fim de garantir a condição "sink". A solução receptora foi mantida a 37°C e agitada a 350 rpm por 6 h.In vitro permeation experiments were performed for 6 hours using pigskin on modified Franz diffusion cells. The cells were assembled so that swine skin was located between the upper and lower compartments. The developed formulations and the commercial cream formulation were arranged in the donor compartment. The receptor compartment was filled with 0.5% aqueous SDS solution to ensure sink condition. The receptor solution was maintained at 37 ° C and stirred at 350 rpm for 6 h.
[030] Após o final do experimento, a pele de porco foi retirada e o CLO extraído de cada camada da pele. A metodologia para remoção diferencial, que permite estimar o acúmulo intrafolicular do fármaco. A pele foi presa em suporte (1). A fim de determinar a quantidade de fármaco que não penetrou pela via transdérmica, (2) o estrato córneo desta região foi removido com o auxílio de 10 fitas adesivas, com movimento rápido e com mudança de direção. Em seguida, para determinar o conteúdo acumulado no folículo, (3) uma gota de cianoacrilato foi aplicada sobre a superfície da pele remanescente e no infundíbulo folicular. Uma fita foi colocada sobre a cola e pressionada levemente até sua secagem. (4) Após polimerização do cianoacrilato, a fita foi retirada, removendo o conteúdo infundibular e o cabelo. Por fim, o fármaco foi extraído das fitas e da cola seca com metanol e quantificado por CLAE.[030] After the end of the experiment, pig skin was removed and CLO extracted from each skin layer. The methodology for differential removal, which allows to estimate the intrafolicular accumulation of the drug. The skin was held in support (1). In order to determine the amount of drug that did not penetrate the transdermal route, (2) the stratum corneum of this region was removed with the aid of 10 fast-moving, direction-changing tapes. Then, to determine the accumulated content in the follicle, (3) a drop of cyanoacrylate was applied to the remaining skin surface and to the follicular infundibulum. A tape was placed over the glue and lightly pressed until it dried. (4) After cyanoacrylate polymerization, the tape was removed, removing infundibular content and hair. Finally, the drug was extracted from the tapes and methanol dried glue and quantified by HPLC.
[031] As formulações de CLN contendo CLO a 0,03 e 0,05% aumentaram a retenção do fármaco no folículo piloso em torno de 5 e 10 vezes, respectivamente, em relação ao CLO em solução aquosa (SDS 0,5%). Em comparação ao creme comercial (CLO 0,05%), os valores aumentaram cerca de 19 e 40 vezes, respectivamente. Não foi observada penetração do CLO na solução receptora, o que representa dizer que, por extrapolação, as formulações não apresentarão absorção sistêmica do fármaco.[031] CLN formulations containing 0.03 and 0.05% CLO increased retention of drug in the hair follicle by 5 and 10 times, respectively, relative to CLO in aqueous solution (0.5% SDS). . Compared to commercial cream (CLO 0.05%), the values increased about 19 and 40 times, respectively. No penetration of CLO into the receptor solution was observed, which means that, by extrapolation, the formulations will not have systemic absorption of the drug.
[032] Desse modo, as formulações desenvolvidas apresentam grande potencial para o direcionamento do CLO aos folículos pilosos, o que pode permitir a redução da dose e frequência de aplicações, reduzindo os efeitos adversos, além de promover o crescimento do cabelo de forma sustentada. As formulações podem, portanto, representar um impacto significativo na eficácia e segurança do tratamento da alopecia.[032] Thus, the formulations developed have great potential for directing CLO to hair follicles, which may allow dose reduction and frequency of applications, reducing adverse effects, and promoting sustained hair growth. The formulations may therefore have a significant impact on the efficacy and safety of alopecia treatment.
[033] Os versados na arte valorizarão os conhecimentos aqui apresentados e poderão reproduzir a invenção nas modalidades apresentadas e em outros variantes, abrangidos no escopo das reivindicações anexas.Those skilled in the art will enhance the knowledge presented herein and may reproduce the invention in the embodiments disclosed and in other embodiments within the scope of the appended claims.
[034] Embora a versão preferida da invenção tenha sido ilustrada e descrita, deve ser compreendido que a invenção não é limitada. Diversas modificações, mudanças, variações, substituições e equivalentes poderão ocorrer, sem que haja desvio do escopo da presente invenção.Although the preferred version of the invention has been illustrated and described, it should be understood that the invention is not limited. Various modifications, changes, variations, substitutions and equivalents may occur without departing from the scope of the present invention.
REFERÊNCIAS 1. Cotsarelis, G. & Millar, S. E. Towards a molecular understanding of hair loss and its treatment. Trends Mol. Med. 7, 293-301 (2001). 2. Rogers, N. E. & Avram, M. R. Medicai treatments for male and female pattern hair loss. J. Am. Acad. Dermatol. 59, 547-566 (2008). 3. Higgins, C. A. & Christiano, A. M. Regenerative medicine and hair loss: how hair follicle culture has advanced our understanding of treatment options for androgenetic alopecia. Regen. Med. 9,101-111 (2014). 4. Birch, Μ. P,, Messenger, J. F. & Messenger, A. G. Hair density, hair diameter and the prevalence of female pattern hair loss. Br. J. Dermatol. 144, 297-304 (2001). 5. Ludwig, E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br. J. Dermatol. 97,247-254 (1977). 6. Ahmad, W, Alopecia Universalis Associated with a Mutation in the Human hairless Gene. Science (80-. ). 279, 720-724 (1998). 7. Tarlow, J. K. et al. Severity of Alopecia Areata Is Associated with a Polymorphism in the lnterleukin-1 Receptor Antagonist Gene. J. Invest. Dermatol. 103, 387-390 (1994). 8. Lew, B.-L., Shin, M.-K. & Sim, W.-Y. Acute diffuse and total alopecia: A new subtype of alopecia areata with a favorable prognosis. J. Am. Acad. Dermatol. 60, 85-93 (2009). 9. Rook, A. Endocrine Influences on Hair Growth. Br. Med. J. 1, 609-614 (1965). 10. Trost, L. B., Bergfeld, W. F. & Calogeras, E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J. Am. Acad. Dermatol. 54, 824-44 (2006). 11. Lenane, P. et al. Clobetasol propionate, 0.05%, vs hydrocortisone, 1%, for alopecia areata in children: a randomized clinicai trial. JAMA Dermatology 150, 47-50 (2014). 12. Sakr, F. M., Gado, A. M., Mohammed, H. R. & Adam, A. N. I. Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology: a pilot study. Drug Des. Devei. Ther. 7, 413-423 (2013). 13. Abraham, L. S., Torres, F. N. & Azulay-Abulafia, L. Dermoscopic clues to distinguish trichotillomania from patchy alopecia areata. Images in Dermatology 85, 723-726 (2010). 14. Elise A. Olsen & Roger C. Cornell. Topical clobetasol-17-propionate: review of its clinicai efficacy and safety. J. Am. Acad. Dermatol. 15, 246-255(1986). 15. Feldman, S. R. Relative efficacy and interchangeability of various clobetasol propionate vehicles in the management of steroid-responsive dermatoses. Curr. Ther. Res. Clin. Exp. 66,154-171 (2005). 16. Fontana, M. C., Bastos, M. O. & Beck, R. C. R. Development and validation of a fast RP-HPLC method for the determination of clobetasol propionate in topical nanocapsule suspensions. J. Chromatogr. Sei. 48, 637-640 (2010). 17. Senyigit, T. & Ozer, O. in Glucocorticoids - New Recognition ofOur Familiar Friend (ed. Qian, X.) (InTech, 2012). doi: 10.5772/2915 18. Tosti, A., Piraccini, B. M., Pazzaglia, M. & Vincenzi, C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis/universalis. J. Am. Acad. Dermatol. 49, 96-98 (2003). 19. Ucak, H., Kandi, B., Cicek, D., Halisdemir, N. & Dertlioglu, S. B. The comparison of treatment with clobetasol propionate 0.05% and topical pimecrolimus 1% treatment in the treatment of alopecia areata. J. Dermatolog. Treat. 23, 410-420 (2012). 20. Carruthers, J. A., August, P. J. & Staughton, R. C. Observations on the systemíc effect of topical clobetasol propionate (Dermovate). Br. Med. J. 4, 203-204 (1975). 21. Meidan, V. M., Bonner, M. C. & Michniak, B. B. Transfollicular drug delivery-is it a reality? Int. J. Pharm. 306, 1-14 (2005). 22. Gelfuso, G. M„ Gratieri, T, Simão, P. S„ de Freitas, L. A. P. & Lopez, R. F. V. Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate. J. Microencapsul. 28, 650-658 (2011). 23. DeLouise, L. a. Applications of nanotechnology in dermatology. J. Invest. Dermatol. 132, 964-975 (2012). 24. Vogt, A. & Blume-Peytavi, U. Selective hairtherapy: bringing Science to the fiction. Exp. Dermatol. 23, 83-96 (2014). 25. Kim, B. Y. S., Rutka, J. T. & Chan, W. C. W. Nanomedicine. N. Engl. J. Med. 363, 2434-2443 (2010). 26. Ossadnik, M. et al. Investigation of differences in follicular penetration of particle-and nonparticle-containing emulsions by laser scanning microscopy. Laser Phys. 16, 747-750 (2006). 27. Patzelt, A. & Lademann, J. Drug delivery to hair follicles. Expert Opin. Drug Deliv. 10, 787-797 (2013). 28. Patzelt, A. et al. Selective follicular targeting by modification of the particle sizes. J. Control. Release 150, 45-48 (2011). 29. Patel, Η. K., Barot, B. S., Parejiya, P. B., Shelat, P. K. & Shukla, A. Topical delivery of clobetasol propionate loaded microemulsion based gel for effective treatment of vitiligo: ex vivo permeation and skin irritation studies. Colloids Surf. B. Biointerfaces 102, 86-94 (2013). 30. Silva, L. A. D., Taveira, S. F., Lima, E. M. & Marreto, R. N. In vitro skin penetration of clobetasol from lipid nanoparticles: drug extraction and quantitation in different skin layers. Brazilian J. Pharm. Sei. 48, 811-817 (2012). 31. Hu, F. Q., Yuan, H., Zhang, Η. H. & Fang, M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int. J. Pharm. 239, 121-8 (2002). 32. Lacarrubba, F., Nardone, B., Musumeci, M. L. & Micali, G. Ultrasound evaluation of clobetasol propionate 0.05% foam application in psoriatic and healthy skin: a pilot study. Dermatol. Ther. 22, S19-S21 (2009). 33. Ali, M. S., Alam, M. S., Alam, N., Anwer, T. & Safhi, Μ. Μ. A. Accelerated Stability Testing of a Clobetasol Propionate-Loaded Nanoemulsion as per ICH Guidelines. Sei. Pharm. 81, 1089-1100 (2013). 34. Senyigit, T. et al. Lecithin/chitosan nanoparticles of clobetasol-17-propionate capable of accumulation in pig skin. J. Control. Release 142, 368-373 (2010). 35. Schãfer-Korting, M., Mehnert, W. & Korting, H.-C. Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv. Drug Deliv. Rev. 59, 427-43 (2007). 36. Rother, M. Clobetasol solution, clobetasol in transfersome (IDEA-068) and the drug-free vehicle (TDT 068) all showed significant treatment effects in a randomised psoriasis plaque study. J. Invest. Dermatol. 133, S163 (2013). 37. Lingan, Μ. A., Sathali, A. A. asan, Kumar, M. R. V. & Gokila, A. Formulation and evaluation of topical drug delivery system containing clobetasol propionate niosomes. Sei. Rev. Chem. Commun. 1, 7-12 (2011). 38. Silva, L. A. D. Penetração passiva e iontoforética de propionato de clobetasol incorporado em carreadores lipídicos nanoestruturados. (Universidade Federal de Goiás, 2013).REFERENCES 1. Cotsarelis, G. & Millar, S.E. Towards a molecular understanding of hair loss and its treatment. Trends Mol. Med. 7, 293-301 (2001). 2. Rogers, N. E. & Avram, M. R. Medical treatments for male and female pattern hair loss. J. Am. Acad. Dermatol. 59, 547-566 (2008). 3. Higgins, C. A. & Christiano, A. M. Regenerative medicine and hair loss: how hair follicle culture has advanced our understanding of treatment options for androgenetic alopecia. Regen Med. 9,101-111 (2014). 4. Birch, Μ. P ,, Messenger, J.F. & Messenger, A. G. Hair density, hair diameter and the prevalence of female pattern hair loss. Br. J. Dermatol. 144, 297-304 (2001). 5. Ludwig, E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br. J. Dermatol. 97,247-254 (1977). 6. Ahmad, W, Alopecia Universalis Associated with a Mutation in the Human Hairless Gene. Science (80-). 279, 720-724 (1998). 7. Tarlow, J.K. et al. Severity of Alopecia Areata Is Associated with a Polymorphism in the Interleukin-1 Receptor Antagonist Gene. J. Invest. Dermatol. 103, 387-390 (1994). 8. Lew, B.-L., Shin, M.-K. & Yes, W.-Y. Acute diffuse and total alopecia: A new subtype of alopecia areata with a favorable prognosis. J. Am. Acad. Dermatol. 60, 85-93 (2009). 9. Rook, A. Endocrine Influences on Hair Growth. Br. Med. J. 1, 609-614 (1965). 10. Trost, L. B., Bergfeld, W. F. & Calogeras, E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J. Am. Acad. Dermatol. 54, 824-44 (2006). 11. Lenane, P. et al. Clobetasol propionate, 0.05% vs hydrocortisone, 1%, for alopecia areata in children: a randomized clinical trial. JAMA Dermatology 150, 47-50 (2014). 12. Sakr, F.M., Gado, A.M., Mohammed, H.R. & Adam, A.N. Preparation and evaluation of a multimodal minoxidil microemulsion versus minoxidil alone in the treatment of androgenic alopecia of mixed etiology: a pilot study. Drug Des. Owe. The R. 7, 413-423 (2013). 13. Abraham, L. S., Torres, F. N. & Azulay-Abulafia, L. Dermoscopic clues to distinguish trichotillomania from patchy alopecia areata. Images in Dermatology 85, 723-726 (2010). 14. Elise A. Olsen & Roger C. Cornell. Topical clobetasol-17-propionate: review of its clinical efficacy and safety. J. Am. Acad. Dermatol. 15, 246-255 (1986). 15. Feldman, S. R. Relative efficacy and interchangeability of various clobetasol propionate vehicles in the management of steroid-responsive dermatoses. Curr. The R. Res. Clin. Exp. 66,154-171 (2005). 16. Fontana, M.C., Bastos, M.O. & Beck, R.C. R. Development and validation of a fast RP-HPLC method for the determination of clobetasol propionate in topical nanocapsule suspensions. J. Chromatogr. Know. 48, 637-640 (2010). 17. Senyigit, T. & Ozer, O. in Glucocorticoids - New Recognition of Our Family Friend (ed. Qian, X.) (InTech, 2012). doi: 10.5772 / 2915 18. Tosti, A., Piraccini, B.M., Pazzaglia, M. & Vincenzi, C. Clobetasol propionate 0.05% under occlusion in the treatment of alopecia totalis / universalis. J. Am. Acad. Dermatol. 49, 96-98 (2003). 19. Ucak, H., Kandi, B., Cicek, D., Halisdemir, N. & Dertlioglu, S. B. The comparison of treatment with clobetasol propionate 0.05% and topical pimecrolimus 1% treatment in the treatment of alopecia areata. J. Dermatolog. Treat 23, 410-420 (2012). 20. Carruthers, J.A., August, P.J. & Staughton, R.C. Observations on the systemic effect of topical clobetasol propionate (Dermovate). Br. Med. J. 4, 203-204 (1975). 21. Meidan, V. M., Bonner, M. C. & Michniak, B. B. Transfollicular drug delivery-is it a reality? Int. J. Pharm. 306, 1-14 (2005). 22. Gelfuso, G. M. Gratieri, T. Simão, P. S. de Freitas, L. A. P. & Lopez, R. F. V. Chitosan microparticles for sustaining the topical delivery of minoxidyl sulphate. J. Microencapsul. 28, 650-658 (2011). 23. DeLouise, L. a. Applications of nanotechnology in dermatology. J. Invest. Dermatol. 132, 964-975 (2012). 24. Vogt, A. & Blume-Peytavi, U. Selective hairtherapy: Bringing Science to the Fiction. Dermatol Exp. 23, 83-96 (2014). 25. Kim, B.Y. S., Rutka, J.T. & Chan, W.C. W. Nanomedicine. N. Engl. J. Med. 363, 2434-2443 (2010). 26. Ossadnik, M. et al. Investigation of differences in follicular penetration of particle-and nonparticle-containing emulsions by laser scanning microscopy. Laser Phys. 16, 747-750 (2006). 27. Patzelt, A. & Lademann, J. Drug delivery to hair follicles. Expert Opin. Drug Deliv. 10, 787-797 (2013). 28. Patzelt, A. et al. Selective follicular targeting by modification of the particle sizes. J. Control. Release 150, 45-48 (2011). 29. Patel, Η. K., Barot, B.S., Parejiya, P.B., Shelat, P.K. & Shukla, A. Topical delivery of clobetasol propionate loaded gel based microemulsion for effective treatment of vitiligo: ex vivo permeation and skin irritation studies. Colloids Surf. B. Biointerfaces 102, 86-94 (2013). Silva, L.A.D., Taveira, S.F., Lima, E.M. & Marreto, R.N. In vitro skin penetration of clobetasol from lipid nanoparticles: drug extraction and quantitation in different skin layers. Brazilian J. Pharm. Know. 48, 811-817 (2012). 31. Hu, F. Q., Yuan, H., Zhang, Η. H. & Fang, M. Preparation of solid lipid nanoparticles with clobetasol propionate by a novel solvent diffusion method in aqueous system and physicochemical characterization. Int. J. Pharm. 239, 121-8 (2002). 32. Lacarrubba, F., Nardone, B., Musumeci, M.L. & Micali, G. Ultrasound evaluation of clobetasol propionate 0.05% foam application in psoriatic and healthy skin: a pilot study. Dermatol. The R. 22, S19-S21 (2009). 33. Ali, M.S., Alam, M.S., Alam, N., Anwer, T. & Safhi, Μ. Μ A. Accelerated Stability Testing of a Clobetasol Propionate-Loaded Nanoemulsion as per ICH Guidelines. Know. Pharm. 81, 1089-1100 (2013). 34. Senyigit, T. et al. Lecithin / chitosan nanoparticles of clobetasol-17-propionate capable of accumulation in pig skin. J. Control. Release 142, 368-373 (2010). 35. Schäfer-Korting, M., Mehnert, W. & Korting, H.-C. Lipid nanoparticles for improved topical application of drugs for skin diseases. Adv. Drug Deliv. Rev. 59, 427-43 (2007). 36. Rother, M. Clobetasol solution, clobetasol in transfersome (IDEA-068) and drug-free vehicle (DTT 068) all showed significant treatment effects in a randomized psoriasis plaque study. J. Invest. Dermatol. 133, S163 (2013). 37. Lingan, Μ. A., Sathali, A. A. asan, Kumar, M. R. V. & Gokila, A. Formulation and evaluation of topical drug delivery system containing clobetasol propionate niosomes. Know. Rev. Chem. Commun. 1, 7-12 (2011). 38. Silva, L. A. D. Passive and iontophoretic penetration of clobetasol propionate incorporated into nanostructured lipid carriers. (Federal University of Goiás, 2013).
REIVINDICAÇÕES
COMPOSIÇÃO FARMACÊUTICA COMPREENDENDO NANOPARTÍCULASPHARMACEUTICAL COMPOSITION UNDERSTANDING NANOParticles
LIPÍDICAS CONTENDO PROPIONATO DE CLOBETASOL PARALIPIDS CONTAINING CLOBETASOL PROPIONATE FOR
ADMINISTRAÇÃO TÓPICA NO TRATAMENTO DA ALOPECIATOPIC ADMINISTRATION IN TREATMENT OF ALOPECY
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