BR102022013489A2 - USE AND PHARMACEUTICAL COMPOSITIONS BASED ON EPIISOPILOTURIN IN THE TREATMENT OF PAIN AND INFLAMMATION - Google Patents
USE AND PHARMACEUTICAL COMPOSITIONS BASED ON EPIISOPILOTURIN IN THE TREATMENT OF PAIN AND INFLAMMATION Download PDFInfo
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- BR102022013489A2 BR102022013489A2 BR102022013489-8A BR102022013489A BR102022013489A2 BR 102022013489 A2 BR102022013489 A2 BR 102022013489A2 BR 102022013489 A BR102022013489 A BR 102022013489A BR 102022013489 A2 BR102022013489 A2 BR 102022013489A2
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- epiisopiloturin
- pharmaceutical compositions
- compositions based
- pain
- sodium
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- DZOVBAVEJYPSLL-UHFFFAOYSA-N Epiisopilosin Natural products CN1C=NC=C1CC1C(C(O)C=2C=CC=CC=2)C(=O)OC1 DZOVBAVEJYPSLL-UHFFFAOYSA-N 0.000 title claims abstract description 59
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
patente de invenção uso e composições farmacêuticas a base de epiisopiloturina no tratamento da dor e inflamação. uso e composições farmacêuticas a base de epiisopiloturina no tratamento da dor e inflamação a presente invenção refere-se ao uso e as composições e formas farmacêuticas contendo o alcaloide imidazólico epiisopiloturina, obtido de subproduto industrial do processamento de folhas de pilocarpus microphyllus, no tratamento da dor e inflamação. formulação líquida oral contendo epiisopiloturina mostrou efeito antinociceptivo e anti-inflamatório superior à ação farmacológica do insumo farmacêutico ativo (epiisopiloturina) em modelo experimental de dor inflamatória.invention patent use and pharmaceutical compositions based on epiisopiloturin in the treatment of pain and inflammation. use and pharmaceutical compositions based on epiisopiloturin in the treatment of pain and inflammation and inflammation. oral liquid formulation containing epiisopiloturin showed an antinociceptive and anti-inflammatory effect superior to the pharmacological action of the active pharmaceutical ingredient (epiisopiloturin) in an experimental model of inflammatory pain.
Description
[001] A presente invenção refere-se à aplicação de composições farmacêuticas a base de epiisopiloturina, nas formas farmacêuticas de solução oral, cápsulas moles, cápsulas duras, comprimidos, solução injetável, xarope e gel transdérmico no tratamento da dor e inflamação.[001] The present invention relates to the application of pharmaceutical compositions based on epiisopiloturin, in pharmaceutical forms of oral solution, soft capsules, hard capsules, tablets, injectable solution, syrup and transdermal gel in the treatment of pain and inflammation.
[002] A dor é definida pela Associação Internacional para o Estudo da Dor (IASP) como “experiência sensitiva e emocional desagradável associada, ou semelhante àquela associada, a uma lesão tecidual real ou potencial”. De acordo com a Sociedade Brasileira para o Estudo da Dor, a dor interfere significativamente na qualidade de vida do paciente, sendo a principal causa de sofrimento e incapacidade para o trabalho. Estudos apontam que no Brasil a prevalência de dor em serviços de emergência é de 45% dos atendimentos, o que indica a presença constante de casos de dor nos serviços de saúde. A dor crônica é considerada uma crise de saúde devido a sua prevalência, sendo uma das principais causas de incapacidade em muitas regiões do mundo, em países desenvolvidos ou em desenvolvimento, e pode inibir a capacidade das pessoas de realizar trabalho e atividades diárias, além de prejudicar sua mobilidade.[002] Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated, or similar to that associated, with actual or potential tissue injury”. According to the Brazilian Society for the Study of Pain, pain significantly interferes with the patient's quality of life, being the main cause of suffering and inability to work. Studies indicate that in Brazil the prevalence of pain in emergency services is 45% of visits, which indicates the constant presence of cases of pain in health services. Chronic pain is considered a health crisis due to its prevalence, being one of the main causes of disability in many regions of the world, in developed and developing countries, and can inhibit people's ability to carry out work and daily activities, in addition to impair your mobility.
[003] A dor é um fenômeno multidimensional com componentes sensoriais, fisiológicos, cognitivos, afetivos, comportamentais e espirituais. Assim existem formas diferentes para classificar a dor. Baseando-se no mecanismo fisiopatológico (dor nociceptiva, inflamatória ou neuropática), na duração (crônica ou aguda), na etiologia (maligna ou não maligna) e na localização anatômica. Geralmente, na dor inflamatória, o dano tecidual é responsável pela ativação de mediadores inflamatórios implicados na potencialização da dor. Esses mediadores refletem em mecanismos de sensibilização, cujas consequências são hiperalgesia, uma resposta dolorosa acentuada decorrente de um estímulo doloroso, e/ou alodinia, dor associada a um estímulo que normalmente não provocaria dor. A sensibilização pode ocorrer nos níveis periférico e central.[003] Pain is a multidimensional phenomenon with sensory, physiological, cognitive, affective, behavioral and spiritual components. So there are different ways to classify pain. Based on the pathophysiological mechanism (nociceptive, inflammatory or neuropathic pain), duration (chronic or acute), etiology (malignant or non-malignant) and anatomical location. Generally, in inflammatory pain, tissue damage is responsible for the activation of inflammatory mediators implicated in pain enhancement. These mediators reflect on sensitization mechanisms, the consequences of which are hyperalgesia, a pronounced painful response resulting from a painful stimulus, and/or allodynia, pain associated with a stimulus that would not normally cause pain. Sensitization can occur at peripheral and central levels.
[004] Os analgésicos atualmente mais utilizados na prática clínica, AINES e opioides juntamente com adjuvantes (por exemplo, relaxantes musculares, anticonvulsivantes), apresentam diferentes eventos adversos e diferentes graus de eficácia. Podem causar insuficiência hepática aguda e complicações graves que afetam os sistemas gastrointestinal, cardiovascular e renal. Os opioides, por exemplo, são considerados os analgésicos mais eficazes no tratamento da dor crônica ou situações em que as outras alternativas terapêuticas não forneçam alívio adequado da dor. No entanto, pode apresentar efeitos adversos graves, incluindo depressão respiratória, comprometimento motor e cognitivo, sedação e desenvolvimento de tolerância. Além disso, o uso sustentado de opioides pode resultar no desenvolvimento de uma sensibilidade aumentada à dor, conhecida como hiperalgesia induzida por opioides. Em virtude disso, é oportuno a pesquisa de novos fármacos para o tratamento da dor e inflamação, que apresentem vantagens sobre a farmacoterapia atual.[004] The analgesics currently most used in clinical practice, NSAIDs and opioids together with adjuvants (e.g., muscle relaxants, anticonvulsants), present different adverse events and different degrees of effectiveness. They can cause acute liver failure and serious complications that affect the gastrointestinal, cardiovascular and renal systems. Opioids, for example, are considered the most effective analgesics in the treatment of chronic pain or situations in which other therapeutic alternatives do not provide adequate pain relief. However, it can have serious adverse effects, including respiratory depression, motor and cognitive impairment, sedation and development of tolerance. Additionally, sustained opioid use can result in the development of increased sensitivity to pain, known as opioid-induced hyperalgesia. As a result, it is timely to research new drugs for the treatment of pain and inflammation, which have advantages over current pharmacotherapy.
[005] O alcaloide imidazólico epiisopiloturina (EPI) é isolado de um subproduto (resíduo) obtido durante o processo de isolamento da pilocarpina de Pilocarpus microphyllus, um produto comercial da empresa Phytobios (Grupo Centroflora) / Barueri, São Paulo. De acordo com a literatura, a epiisopiloturina possui atividade anti-inflamatória em modelo de edema de pata induzido por diferentes mediadores inflamatórios e antinociceptiva em modelos de contorção induzida por ácido acético, teste da placa quente, formalina e hipernocicepção mecânica. Também modula mecanismos pró-inflamatórios como a ativação de NF-KB e a produção de TNF-α e IL-6 em neutrófilos humanos. Além disso, foi demonstrado que a EPI apresenta efeito gastroprotetor em modelos de colite induzida por TNBS (ácido trinitrobenzenossulfônico), dano gástrico induzido por naproxeno e mucosite intestinal induzida por 5-FU (5-fluorouracil).[005] The imidazole alkaloid epiisopiloturine (EPI) is isolated from a byproduct (residue) obtained during the process of isolating pilocarpine from Pilocarpus microphyllus, a commercial product from the company Phytobios (Grupo Centroflora) / Barueri, São Paulo. According to the literature, epiisopiloturin has anti-inflammatory activity in a model of paw edema induced by different inflammatory mediators and antinociceptive activity in models of writhing induced by acetic acid, hot plate test, formalin and mechanical hypernociception. It also modulates pro-inflammatory mechanisms such as the activation of NF-KB and the production of TNF-α and IL-6 in human neutrophils. Furthermore, EPI has been shown to have a gastroprotective effect in models of TNBS (trinitrobenzenesulfonic acid)-induced colitis, naproxen-induced gastric damage, and 5-FU (5-fluorouracil)-induced intestinal mucositis.
[006] Tais estudos que demonstraram os efeitos anti-inflamatório e antinociceptivo foram realizados utilizando como forma de tratamento a via intraperitoneal, mais empregada em pesquisas pré-clínicas. Dessa forma, o desenvolvimento de formulações analgésicas e anti-inflamatórias com o maior número possível de opções quanto a via de administração do medicamento, observando o conforto do paciente, segurança e efetividade deve ser perseguido pela indústria farmacêutica. Estudo anterior indicou uma baixa biodisponibilidade da epiisopiloturina por via oral e levantou a hipótese que tal fato esteja relacionado a redução da polaridade no pH fisiológico, resultando na diminuição da absorção.[006] Such studies that demonstrated the anti-inflammatory and antinociceptive effects were carried out using the intraperitoneal route as a form of treatment, most commonly used in pre-clinical research. Therefore, the development of analgesic and anti-inflammatory formulations with the greatest possible number of options regarding the route of administration of the medication, taking into account patient comfort, safety and effectiveness should be pursued by the pharmaceutical industry. A previous study indicated a low bioavailability of epiisopiloturin orally and raised the hypothesis that this fact is related to a reduction in polarity in physiological pH, resulting in decreased absorption.
[007] Baseado nisso, buscou-se desenvolver uma formulação oral de epiisopiloturina (insumo farmacêutico ativo - IFA), que mostrou efeito farmacológico superior à IFA administrada por via oral, e eficácia comparável à IFA administrada por via intraperitoneal.[007] Based on this, we sought to develop an oral formulation of epiisopiloturin (active pharmaceutical ingredient - IFA), which showed a pharmacological effect superior to IFA administered orally, and efficacy comparable to IFA administered intraperitoneally.
[008] Sendo assim, esses dados nos motivaram a desenvolver composição contendo epiisopiloturina patenteável, diante do grande potencial desse alcaloide imidazólico no tratamento da dor aguda e crônica, e da inflamação.[008] Therefore, these data motivated us to develop a composition containing patentable epiisopiloturin, given the great potential of this imidazole alkaloid in the treatment of acute and chronic pain, and inflammation.
[009] Patentes relacionadas a epiisopiloturina, uma trata do processo de obtenção desse alcaloide e sua aplicação no combate a infecções parasitárias (PI 0904110-9) e outra relacionada ao emprego da epiisopiloturina em um complexo de inclusão liofilizado para o tratamento de doenças negligenciadas (BR 1020190089075). A busca de outros antecedentes desta patente mostra trabalhos que se referem a nanoformulações com aplicação antiparasitária, não apresentando assim qualquer similaridade dos objetivos da presente invenção.[009] Patents related to epiisopiloturin, one deals with the process of obtaining this alkaloid and its application in combating parasitic infections (PI 0904110-9) and another related to the use of epiisopiloturin in a lyophilized inclusion complex for the treatment of neglected diseases ( BR 1020190089075). The search for other antecedents of this patent shows works that refer to nanoformulations with antiparasitic application, thus not presenting any similarity to the objectives of the present invention.
[010] A Figura 1 apresenta a estrutura química do alcaloide imidazólico epiisopiloturina.[010] Figure 1 shows the chemical structure of the imidazole alkaloid epiisopiloturine.
[011] A Figura 2 apresenta o efeito do tratamento com a EPI e a formulação líquida à base de epiisopiloturina na hipernocicepção mecânica. Camundongos foram tratados com salina (v.o.), Gotas EPI (v.o.) ou EPI (1 mg/kg, v.o ou i.p.) 1h antes da injeção de Cg (300μg/pata). Δ Intensidade da hipernocicepção mecânica após 1h, 3h e 5h da administração do estímulo inflamatório, os animais foram desafiados no Von Frey eletrônico. A Cg causou uma hipernocicepção mecânica nos animais que foi significativamente reduzida pelas Gotas EPI em todos os intervalos de tempo investigados (1h, 3h e 5h) de maneira comparável ao grupo tratado com EPI administrado por via intraperitoneal e oral. Resultados estão expressos como a média ± E.P.M. # vs Salina; * vs Veículo; + EPI (1 mg/kg, v.o.) (p < 0,05 - ANOVA e teste de Tukey).[011] Figure 2 shows the effect of treatment with EPI and the liquid formulation based on epiisopiloturin on mechanical hypernociception. Mice were treated with saline (v.o.), EPI Drops (v.o.) or EPI (1 mg/kg, p.o or i.p.) 1h before Cg injection (300μg/paw). Δ Intensity of mechanical hypernociception after 1h, 3h and 5h of administration of the inflammatory stimulus, the animals were challenged in the electronic Von Frey. Cg caused mechanical hypernociception in the animals that was significantly reduced by EPI Drops at all time intervals investigated (1h, 3h and 5h) in a comparable way to the group treated with EPI administered intraperitoneally and orally. Results are expressed as the mean ± S.E.M. # vs Salina; * vs Vehicle; + EPI (1 mg/kg, p.o.) (p < 0.05 - ANOVA and Tukey test).
[012] A Figura 3 apresenta o efeito do tratamento com a formulação líquida à base de epiisopiloturina no aumento da atividade da enzima mieloperoxidase (MPO) pró-inflamatória induzida por carragenina. Camundongos foram tratados com salina (v.o. e i.pl.), Gotas EPI (v.o.) ou EPI (1 mg/kg, v.o ou i.p.) 1h antes da injeção de Cg (300μg/pata). Após 3h da administração da Cg, os animais foram eutanasiados e o tecido subplantar foi retirado para quantificação de MPO. As Gotas EPI (v.o.) reduziram significativamente a atividade da MPO em relação ao grupo tratado apenas com Cg. Esse resultado foi comparável à EPI administrada por via intraperitoneal. O tratamento com EPI por via oral reduziu a atividade MPO, porém em menor extensão em comparação com as Gotas EPI. Os resultados estão expressos como média ± E.P.M. # vs salina; * vs Veículo (p < 0,05 - ANOVA e Teste de Tukey).[012] Figure 3 shows the effect of treatment with the liquid formulation based on epiisopiloturin on the increase in the activity of the pro-inflammatory enzyme myeloperoxidase (MPO) induced by carrageenan. Mice were treated with saline (v.o. and i.pl.), EPI Drops (v.o.) or EPI (1 mg/kg, p.o. or i.p.) 1 h before Cg injection (300μg/paw). After 3h of Cg administration, the animals were euthanized and the subplantar tissue was removed for MPO quantification. EPI Drops (v.o.) significantly reduced MPO activity compared to the group treated with Cg alone. This result was comparable to EPI administered intraperitoneally. Oral EPI treatment reduced MPO activity, but to a lesser extent compared to EPI Drops. The results are expressed as mean ± S.E.M. # vs saline; * vs Vehicle (p < 0.05 - ANOVA and Tukey Test).
[013] A Figura 4 apresenta o efeito do tratamento com a formulação líquida à base de epiisopiloturina na concentração de citocinas alteradas pela Cg. Camundongos foram tratados com salina (v.o.), Gotas EPI (v.o.) ou EPI (1 mg/kg, v.o) 1h antes da injeção de Cg (300μg/pata).[013] Figure 4 shows the effect of treatment with the liquid formulation based on epiisopiloturin on the concentration of cytokines altered by Cg. Mice were treated with saline (v.o.), EPI Drops (v.o.) or EPI (1 mg/kg, p.o) 1h before Cg injection (300μg/paw).
[014] Após 3h da administração do estímulo inflamatório, os animais foram eutanasiados e o tecido subplantar foi retirado e processado para posterior quantificação de (A) TNF-α e (B) IL-10 por ELISA. Os resultados estão expressos como média ± E.P.M. # vs salina; * vs Veículo; + EPI (1 mg/kg, v.o.) (p < 0,05 - ANOVA e Teste de Tukey).[014] After 3 hours of administration of the inflammatory stimulus, the animals were euthanized and the subplantar tissue was removed and processed for subsequent quantification of (A) TNF-α and (B) IL-10 by ELISA. The results are expressed as mean ± S.E.M. # vs saline; * vs Vehicle; + EPI (1 mg/kg, p.o.) (p < 0.05 - ANOVA and Tukey test).
[015] A presente invenção descreve o uso e composições e formas farmacêuticas contendo o alcaloide imidazólico epiisopiloturina de Pilocarpus microphyllus, como a formulação líquida oral a base de epiisopiloturina (Gotas EPI) como agente terapêutico da dor e inflamação, e outras composições contendo o alcaloide na forma de cápsulas moles, cápsulas duras, comprimidos, solução injetável, xarope e gel transdérmico.[015] The present invention describes the use and compositions and pharmaceutical forms containing the imidazole alkaloid epiisopiloturin from Pilocarpus microphyllus, such as the oral liquid formulation based on epiisopiloturin (EPI Drops) as a therapeutic agent for pain and inflammation, and other compositions containing the alkaloid in the form of soft capsules, hard capsules, tablets, injectable solution, syrup and transdermal gel.
[016] A eficácia in vivo da epiisopiloturina e composição para utilização terapêutica na dor e na inflamação é demonstrada na presente invenção.[016] The in vivo efficacy of epiisopiloturin and composition for therapeutic use in pain and inflammation is demonstrated in the present invention.
[017] A presente invenção será adiante melhor exemplificada através de exemplos.[017] The present invention will be further exemplified by examples.
[018] Pesou-se a epiisopiloturina (Figura 1), o citrato de sódio e o ácido cítrico, transferiu-se para o cálice de vidro e, com auxílio de bastão de vidro, dissolveu em água destilada. Em seguida foi adicionado o glicerol e a solução de parabenos. Aferiu-se o volume final e foi acrescentado água destilada q.s.p. 100 mL (Tabela 1). Tabela 1. Composição farmacêutica da formulação líquida oral a base de epiisopiloturina [018] The epiisopiloturin (Figure 1), sodium citrate and citric acid were weighed, transferred to the glass cup and, with the help of a glass rod, dissolved in distilled water. Then the glycerol and paraben solution were added. The final volume was measured and distilled water was added qsp 100 mL (Table 1). Table 1. Pharmaceutical composition of the oral liquid formulation based on epiisopiloturin
[019] Caracterização físico-química da formulação líquida oral à base de epiisopiloturina[019] Physicochemical characterization of the oral liquid formulation based on epiisopiloturin
[020] Foram realizados testes organolépticos (aspecto, sabor e odor) e determinação do pH, densidade, teor de ativo e avaliação preliminar da estabilidade.[020] Organoleptic tests (appearance, flavor and odor) and determination of pH, density, active content and preliminary assessment of stability were carried out.
[021] Análise organoléptica: A amostra foi homogeneizada e a solução foi observada e avaliada quanto ao aspecto, sabor e odor.[021] Organoleptic analysis: The sample was homogenized and the solution was observed and evaluated for appearance, flavor and odor.
[022] Determinação do pH: O pH foi verificado com potenciômetro de bancada calibrado da Marca Gehaka, Modelo PG2000 acoplado a eletrodo de vidro e termorregulador. O eletrodo foi mergulhado diretamente nas amostras em solução.[022] pH determination: The pH was checked with a calibrated Gehaka bench potentiometer, Model PG2000 coupled to a glass electrode and thermoregulator. The electrode was dipped directly into the samples in solution.
[023] Determinação da densidade: O ensaio foi realizado em picnômetro limpo e seco com capacidade para 5 mL. A temperatura foi ajustada para 20°C, o excesso da solução foi removido, a seguir o conjunto foi pesado em balança analítica. O peso da amostra foi obtido através da diferença de massa do picnômetro cheio e vazio. A densidade relativa (drel) foi calculada pela razão entre a massa da amostra líquida e a massa da água, ambas a 20°C.[023] Density determination: The test was carried out in a clean and dry pycnometer with a capacity of 5 mL. The temperature was adjusted to 20°C, the excess solution was removed, then the whole was weighed on an analytical balance. The weight of the sample was obtained through the difference in mass of the full and empty pycnometer. The relative density (drel) was calculated by the ratio between the mass of the liquid sample and the mass of water, both at 20°C.
[024] Determinação do teor de ativo por CLAE-DAD: A determinação quantitativa da epiisopiloturina em solução utilizou um sistema de cromatografia líquida de alta eficiência (CLAE-DAD) Waters Alliance®, equipado com detector UV-VIS 2996, operando em 212 nm. Foi utilizada uma coluna analítica de fase reversa Lichrospher® RP-Select B, 5 μm, 250 mm x 4,6 mm (Phenomenex, EUA). A fase móvel foi constituída por 13,5 mL de ácido fosfórico, 3 mL de trietilamina, 111,2 mL de metanol e água para completar 1 L, em modo isocrático e um fluxo de 0,6 mL/min. O volume de cada injeção foi de 20μL.[024] Determination of active content by HPLC-DAD: The quantitative determination of epiisopiloturin in solution used a Waters Alliance® high-performance liquid chromatography system (HPLC-DAD), equipped with a UV-VIS 2996 detector, operating at 212 nm . A Lichrospher® RP-Select B, 5 μm, 250 mm x 4.6 mm reversed-phase analytical column (Phenomenex, USA) was used. The mobile phase consisted of 13.5 mL of phosphoric acid, 3 mL of triethylamine, 111.2 mL of methanol and water to complete 1 L, in isocratic mode and a flow of 0.6 mL/min. The volume of each injection was 20μL.
[025] Foi construída uma curva analítica e a faixa de concentração de leitura foi de 5 μg/mL; 10 μg/mL; 20 μg/mL; 30 μg/mL; 40 μg/mL; 50 μg/mL, do padrão de epiisopiloturina em fase móvel. Foram determinados o coeficiente angular, o linear e o de correlação por regressão linear, utilizando-se os dados para determinação do teor de epiisopiloturina na Gotas EPI. O procedimento foi realizado em triplicata, obtendo-se a seguir a média, o desvio padrão relativo.[025] An analytical curve was constructed and the reading concentration range was 5 μg/mL; 10 μg/mL; 20 μg/mL; 30 μg/mL; 40 μg/mL; 50 μg/mL of epiisopiloturin standard in mobile phase. The angular, linear and correlation coefficients were determined by linear regression, using the data to determine the epiisopiloturin content in EPI Drops. The procedure was carried out in triplicate, then obtaining the mean and relative standard deviation.
[026] Avaliação preliminar da estabilidade: As Gotas EPI foram avaliadas nos tempos 0, 15 e 90 dias quanto ao seu perfil de qualidade físico-químico. A avaliação física das formulações contempla verificação do pH, densidade e as características organolépticas da formulação. Na avaliação química, foi realizada a determinação do teor de epiisopiloturina. Os dados obtidos em cada um dos parâmetros analíticos foram tabulados em planilha eletrônica e os resultados expressos em média (DPR).[026] Preliminary stability assessment: EPI Drops were evaluated at times 0, 15 and 90 days regarding their physicochemical quality profile. The physical evaluation of the formulations includes checking the pH, density and organoleptic characteristics of the formulation. In the chemical evaluation, the epiisopiloturin content was determined. The data obtained for each of the analytical parameters were tabulated in an electronic spreadsheet and the results were expressed as a mean (DPR).
[027] As Gotas EPI nos períodos investigados (até 90 dias) apresentaram-se inodoras, límpidas, transparentes e isentas de partículas estranhas em suspensão. O pH das Gotas EPI ficou na faixa ácida, o que significa que a EPI está em sua maioria na forma ionizada, podendo promover uma melhor dissolução. Na análise da densidade, não houve variação desse parâmetro até 90 dias (Tabela 2).[027] The EPI Drops in the periods investigated (up to 90 days) were odorless, clear, transparent and free of foreign particles in suspension. The pH of the EPI Drops was in the acidic range, which means that the EPI is mostly in ionized form, which can promote better dissolution. In the density analysis, there was no variation in this parameter up to 90 days (Table 2).
[028] Quanto ao sabor, apesar da característica marcante dos alcaloides de apresentar sabor amargo, o uso do glicerol promoveu um sabor adocicado à formulação. Essa estratégia é bastante utilizada na formulação de medicamentos líquidos orais.[028] As for flavor, despite the notable characteristic of alkaloids of having a bitter taste, the use of glycerol promoted a sweet flavor to the formulation. This strategy is widely used in the formulation of oral liquid medications.
[029] Os teores de epiisopiloturina na formulação avaliados até 90 dias apresentaram desvio padrão relativo abaixo do limite preconizado pela Farmacopeia Brasileira 6a edição, que estabelece um desvio padrão máximo de 5%, no qual variou entre 0,9% a 1,7% (Tabela 2). Tabela 2. Avaliação da estabilidade da formulação líquida à base de epiisopiloturina [029] The levels of epiisopiloturin in the formulation evaluated up to 90 days showed relative standard deviation below the limit recommended by the Brazilian Pharmacopoeia 6th edition, which establishes a maximum standard deviation of 5%, which ranged between 0.9% and 1.7% (Table 2). Table 2. Evaluation of the stability of the epiisopiloturin-based liquid formulation
[030] Assim, a formulação mostrou-se estável, considerando aspectos tais como cor, turbidez, pH e teor de ativo, quando armazenada em frascos de vidro de paredes na cor âmbar, por até 90 dias à temperatura ambiente (25°C).[030] Thus, the formulation proved to be stable, considering aspects such as color, turbidity, pH and active content, when stored in glass bottles with amber walls, for up to 90 days at room temperature (25°C) .
[031] Foram utilizados camundongos Swiss fêmeas pesando aproximadamente 20-30 g provenientes do Biotério Central da Universidade Federal do Ceará (UFC) e mantidos no Biotério do Departamento de Fisiologia e Farmacologia da Faculdade de Medicina - UFC, alojados em gaiolas com água e ração ad libitum e aclimatados com ciclos naturais dia/noite de 12/12h. A manipulação dos animais antes e durante os experimentos obedeceu às normas de manipulação de animais de laboratório preconizadas pelo Conselho Nacional de Controle de Experimentação Animal (CONCEA). Todos os procedimentos experimentais foram analisados e previamente aprovados pelo Comitê de Ética em Pesquisa Animal da Universidade Federal do Ceará (n° protocolo: 9862070619).[031] Female Swiss mice weighing approximately 20-30 g were used from the Central Animal Facility of the Federal University of Ceará (UFC) and maintained in the Animal Facility of the Department of Physiology and Pharmacology of the Faculty of Medicine - UFC, housed in cages with water and food. ad libitum and acclimatized to natural day/night cycles of 12/12h. Animal handling before and during the experiments followed the standards for handling laboratory animals recommended by the National Council for Animal Experimentation Control (CONCEA). All experimental procedures were analyzed and previously approved by the Animal Research Ethics Committee of the Federal University of Ceará (protocol number: 9862070619).
[032] Os animais (n = 5) foram tratados com veículo, Gotas EPI (0,1 mg/mL, v.o) ou EPI (1 mg/mL, i.p. ou v.o) 1 hora antes da administração da carragenina (Cg) (300 μg/50 μL de salina) na pata traseira direita de cada camundongo. O grupo controle negativo foi formado por animais tratados com salina por via i.pl e v.o. A hipernocicepção mecânica foi avaliada nos tempos 1 (T1), 3 (T3) e 5 (T5) horas após a administração intraplantar (i.pl.) de Cg e calculada pela subtração das medidas (pressão/g) coletadas (Δ1= T0-T1; Δ2= T0-T3 e Δ3=T0- T5) (Figura 2).[032] Animals (n = 5) were treated with vehicle, EPI Drops (0.1 mg/mL, p.o.) or EPI (1 mg/mL, i.p. or p.o.) 1 hour before administration of carrageenan (Cg) ( 300 μg/50 μL saline) in the right hind paw of each mouse. The negative control group was formed by animals treated with saline i.pl and p.o. Mechanical hypernociception was assessed at times 1 (T1), 3 (T3) and 5 (T5) hours after intraplantar (i.pl.) administration of Cg and calculated by subtracting the measurements (pressure/g) collected (Δ1= T0 -T1; Δ2= T0-T3 and Δ3=T0- T5) (Figure 2).
[033] Os resultados apresentados demonstram que a formulação líquida à base de epiisopiloturina (Gotas EPI) reduziu significativamente (p<0,001) a hipernocicepção mecânica induzida por carragenina. Esse efeito foi superior ao tratamento com o alcaloide por via oral e estatisticamente semelhante ao tratamento por via intraperitoneal (Figura 2).[033] The results presented demonstrate that the liquid formulation based on epiisopiloturin (EPI Drops) significantly reduced (p<0.001) the mechanical hypernociception induced by carrageenan. This effect was superior to treatment with the alkaloid orally and statistically similar to treatment intraperitoneally (Figure 2).
[034] Os animais (n = 5) foram tratados com veículo, Gotas EPI (0,1 mg/mL, v.o) ou EPI (1 mg/mL, i.p. ou v.o) 1 hora antes da administração da carragenina (Cg) (300 μg/50 μL de salina) na pata traseira direita de cada camundongo.[034] Animals (n = 5) were treated with vehicle, EPI Drops (0.1 mg/mL, p.o.) or EPI (1 mg/mL, i.p. or p.o.) 1 hour before administration of carrageenan (Cg) ( 300 μg/50 μL saline) in the right hind paw of each mouse.
[035] Três horas após a administração da Cg, os animais foram eutanasiados e o tecido subcutâneo plantar das patas foi coletado a quantificação da atividade MPO. As amostras de tecido subcutâneo plantar foram homogeneizadas a 10% (peso/volume) em homogeneizador com solução de HTAB 0,5% e o material foi centrifugado a 1500 g por 15 minutos a 4°C. O sobrenadante foi submetido ao choque térmico em 3 etapas (10 minutos cada) de congelamento (-20 °C) e descongelamento. O sobrenadante foi novamente centrifugado (1500 g, 15 minutos, 4°C). Em seguida, as amostras foram plaqueadas em placas de 96 poços e adicionada a solução de leitura (tampão fosfato, H2O2 0,017% e tetrametil benzidina - TMB 18,4 mM), após 3 minutos, a reação foi parada com H2SO4 4M. A leitura da absorbância foi obtida a 450nm em leitora de microplacas e o resultado foi expresso em atividade de MPO (U/L) (Figura 3).[035] Three hours after Cg administration, the animals were euthanized and the plantar subcutaneous tissue of the paws was collected to quantify MPO activity. Plantar subcutaneous tissue samples were homogenized at 10% (weight/volume) in a homogenizer with 0.5% HTAB solution and the material was centrifuged at 1500 g for 15 minutes at 4°C. The supernatant was subjected to thermal shock in 3 stages (10 minutes each) of freezing (-20 °C) and thawing. The supernatant was centrifuged again (1500 g, 15 minutes, 4°C). Then, the samples were plated in 96-well plates and the reading solution was added (phosphate buffer, 0.017% H2O2 and tetramethyl benzidine - 18.4 mM TMB), after 3 minutes, the reaction was stopped with 4M H2SO4. The absorbance reading was obtained at 450nm on a microplate reader and the result was expressed as MPO activity (U/L) (Figure 3).
[036] Os resultados apresentados demonstram que a formulação líquida à base de epiisopiloturina (Gotas EPI) reduziu significativamente (p<0,001) a atividade da enzima mieloperoxidase induzida por carragenina. Não houve diferença estatística entre os tratamentos com Gotas EPI e EPI por via intraperitoneal e oral.[036] The results presented demonstrate that the liquid formulation based on epiisopiloturin (EPI Drops) significantly reduced (p<0.001) the activity of the myeloperoxidase enzyme induced by carrageenan. There was no statistical difference between treatments with EPI Drops and EPI intraperitoneally and orally.
[037] Os animais (n = 5) foram tratados com veículo, Gotas EPI (0,1 mg/mL, v.o), ou EPI (1 mg/mL, v.o) 1 hora antes da administração da carragenina (Cg) (300 μg/50 μL de salina) na pata traseira direita de cada camundongo.[037] Animals (n = 5) were treated with vehicle, EPI Drops (0.1 mg/mL, p.o.), or EPI (1 mg/mL, p.o.) 1 hour before the administration of carrageenan (Cg) (300 μg/50 μL saline) in the right hind paw of each mouse.
[038] Três horas após a administração da Cg, os animais foram eutanasiados e o tecido subcutâneo plantar das patas foi coletado para quantificação das citocinas por ELISA (TNF-α e IL-10) conforme metodologias descritas pelo fabricante (Figura 4).[038] Three hours after Cg administration, the animals were euthanized and the plantar subcutaneous tissue of the paws was collected for quantification of cytokines by ELISA (TNF-α and IL-10) according to methodologies described by the manufacturer (Figure 4).
[039] Os resultados apresentados demonstram que a formulação líquida à base de epiisopiloturina (Gotas EPI) reduziu significativamente (p<0,001) a liberação da citocina pró-inflamatória TNF-α e aumentou significativamente (p<0,001) a citocina anti-inflamatória IL-10 após indução por carragenina. Entre as Gotas EPI e a EPI por via oral houve diferença estatística (p<0,001) na quantificação do TNF-α, enquanto que para IL-10, o efeito foi comparável.[039] The results presented demonstrate that the liquid formulation based on epiisopiloturin (EPI Drops) significantly reduced (p<0.001) the release of the pro-inflammatory cytokine TNF-α and significantly increased (p<0.001) the anti-inflammatory cytokine IL -10 after carrageenan induction. Between EPI Drops and oral EPI there was a statistical difference (p<0.001) in the quantification of TNF-α, while for IL-10, the effect was comparable.
[040] Cápsulas moles do tipo softgel, produzidas pela injeção do alcaloide no interior do envoltório de gelatina, o qual é selado hermeticamente formando as cápsulas finais, contendo: i. 1- 5 mg de epiisopiloturina; ii. envoltório de gelatina q.s.p. 1 cápsula; iii. diluentes. Tabela 3. Exemplo de formulação de cápsulas gelatinosas moles [040] Soft gel-type capsules, produced by injecting the alkaloid into the gelatin envelope, which is hermetically sealed forming the final capsules, containing: i. 1- 5 mg of epiisopiloturin; ii. gelatin wrap qsp 1 capsule; iii. diluents. Table 3. Example of soft gelatin capsule formulation
[041] Homogeneizar os constituintes da formulação até obtenção de um preparado homogêneo, e proceder o envase do líquido em cápsulas gelatinosas moles de 300 mg.[041] Homogenize the constituents of the formulation until obtaining a homogeneous preparation, and fill the liquid into 300 mg soft gelatin capsules.
[042] A epiisopiloturina é inserida em uma das partes do envoltório de gelatina (corpo), de forma a preencher seu volume total, adicionando-se em seguida uma segunda parte do envoltório de gelatina (tampa). As cápsulas possuem os seguintes ingredientes: i. 1 - 5 mg de epiisopiloturina; ii. diluente (o qual pode ser constituído de um ou mais dos seguintes componentes: celulose microcristalina, lactose, amido, maltodextrina, glicolato de amido sódico, manitol, laurilsulfato de sódio, dióxido de silício coloidal, entre outros) q.s.p. 1 cápsula iii. envoltório de gelatina q.s.p. 1 cápsula. Tabela 4. Exemplo de formulação de cápsulas gelatinosas duras [042] Epiisopiloturin is inserted into one of the parts of the gelatin envelope (body), in order to fill its total volume, then adding a second part of the gelatin envelope (lid). The capsules have the following ingredients: i. 1 - 5 mg of epiisopiloturin; ii. diluent (which may consist of one or more of the following components: microcrystalline cellulose, lactose, starch, maltodextrin, sodium starch glycolate, mannitol, sodium lauryl sulfate, colloidal silicon dioxide, among others) qsp 1 capsule iii. gelatin wrap qsp 1 capsule. Table 4. Example of hard gelatin capsule formulation
[043] Homogeneizar os constituintes da formulação que estão em menor quantidade com a celulose microcristalina até obter um pó homogêneo. Adicionar a lactose à preparação, mantendo a homogeneização do pó por 30 minutos em equipamento destinado a mistura de pós para preparações farmacêuticas.[043] Homogenize the constituents of the formulation that are in smaller quantities with the microcrystalline cellulose until obtaining a homogeneous powder. Add lactose to the preparation, maintaining the homogenization of the powder for 30 minutes in equipment designed to mix powders for pharmaceutical preparations.
[044] Comprimidos obtidos por compressão direta de forma a obter comprimidos com as doses desejadas do ativo. Os comprimidos resultantes possuem os seguintes ingredientes: i. 1 - 5 mg de epiisopiloturina; ii. Pó para compressão direta (lactose monohidratada, laurilsulfato de sódio, estearato de sódio, dióxido de silício coloidal, lauril sulfato de sódio, amido de milho) q.s.p. 1 comprimido iii. opcionalmente, agentes corantes; iv. opcionalmente, acidulantes; Tabela 5. Exemplo de formulação de comprimidos [044] Tablets obtained by direct compression in order to obtain tablets with the desired doses of the active ingredient. The resulting tablets have the following ingredients: i. 1 - 5 mg of epiisopiloturin; ii. Powder for direct compression (lactose monohydrate, sodium lauryl sulfate, sodium stearate, colloidal silicon dioxide, sodium lauryl sulfate, corn starch) qsp 1 tablet iii. optionally, coloring agents; iv. optionally, acidulants; Table 5. Example of tablet formulation
[045] Homogeneizar os constituintes da formulação questão em menor quantidade com 10 % do volume final de lactose até obter um pó homogêneo, completar o volume e manter a homogeneização do pó por 30 minutos em equipamento destinado a mistura de pós para preparações farmacêuticas. Esta preparação é destinada a compressão direta.[045] Homogenize the constituents of the formulation in question in smaller quantities with 10% of the final volume of lactose until obtaining a homogeneous powder, complete the volume and maintain the homogenization of the powder for 30 minutes in equipment intended for mixing powders for pharmaceutical preparations. This preparation is intended for direct compression.
[046] Solução injetável desenvolvida a partir da mistura da epiisopiloturina aos demais componentes da fórmula, caracterizado por compreender: i. 0,5 - 2 mg de epiisopiloturina; ii. Diluente (glicerol, lecitina de ovo, hidróxido de sódio, oleato de sódio, glicerina e água para injetáveis) Tabela 6. Exemplo de formulação de solução injetável [046] Injectable solution developed from mixing epiisopiloturin with the other components of the formula, characterized by comprising: i. 0.5 - 2 mg of epiisopiloturin; ii. Diluent (glycerol, egg lecithin, sodium hydroxide, sodium oleate, glycerin and water for injections) Table 6. Example of injectable solution formulation
[047] Homogeneizar os constituintes da formulação sob alta tensão de cisalhamento utilizando equipamento como homogeneizador a alta pressão até obtenção de um preparado homogêneo.[047] Homogenize the constituents of the formulation under high shear stress using equipment such as a high pressure homogenizer until obtaining a homogeneous preparation.
[048] Xarope, desenvolvido através da dissolução de sacarose em água a 60°C, seguida da dissolução dos demais componentes da fórmula, contendo os seguintes ingredientes: i. 1 - 5 mg de epiisopiloturina; ii. Diluentes (glicerina, sorbitol, sacarose, carboximetilcelulose, goma xantana, entre outros) iii. Acidulante (ácido cítrico, ácido ascórbico) iv. Preservante (metilparabeno, benzoato de sódio, ácido benzóico, sorbato de sódio, ácido sórbico) v. Água purificada q.s.p. 100 mL; vi. opcionalmente, agentes corantes; vii. opcionalmente, agentes aromatizantes e flavorizantes Tabela 7. Exemplo de formulação de xarope obs: cada 5 mL deste xarope contém 2 mg do princípio ativo Epiisopiloturina[048] Syrup, developed by dissolving sucrose in water at 60°C, followed by dissolving the other components of the formula, containing the following ingredients: i. 1 - 5 mg of epiisopiloturin; ii. Diluents (glycerin, sorbitol, sucrose, carboxymethyl cellulose, xanthan gum, among others) iii. Acidulant (citric acid, ascorbic acid) iv. Preservative (methylparaben, sodium benzoate, benzoic acid, sodium sorbate, sorbic acid) v. Purified water qsp 100 mL; saw. optionally, coloring agents; viii. optionally, flavoring and flavoring agents Table 7. Example of syrup formulation Note: each 5 mL of this syrup contains 2 mg of the active ingredient Epiisopiloturin
[049] Diluir o ácido cítrico na água e adicionar o benzoato de sódio, misturar até homogeneização. Dispersar a epiisopiloturina na glicerina e esta na solução de água acidificada, adicionar os demais componentes e homogeneizar.[049] Dilute the citric acid in water and add sodium benzoate, mix until homogenized. Disperse the epiisopiloturin in the glycerin and the acidified water solution, add the other components and homogenize.
[050] Gel transdérmico obtido pela técnica de força de extrusão para a formação de micelas lipossomais e consequentemente a encapsulação do fármaco. O gel é caracterizado por compreender: i. 1 - 5 mg de epiisopiloturina; ii. Diluentes: álcool, solução de lecitina e palmitato de isopropila e gel de Polaxamer 407 (Pluronic® F127); iv. Água purificada q.s.p. 60 mL Tabela 8. Exemplo de formulação de gel transdérmico [050] Transdermal gel obtained by the extrusion force technique for the formation of liposomal micelles and consequently the encapsulation of the drug. The gel is characterized by comprising: i. 1 - 5 mg of epiisopiloturin; ii. Diluents: alcohol, lecithin and isopropyl palmitate solution and Polaxamer 407 gel (Pluronic® F127); iv. Purified water qsp 60 mL Table 8. Example of transdermal gel formulation
[051] Preparar a solução de lecitina e palmitato de isopropila e o gel de polaxamer e deixá-los em repouso de um dia para outro. Para preparar o gel transdérmico, triturar o ativo e dissolver em q.s. de álcool. Com a utilização de duas seringas do tipo luer lock obter uma mistura homogênea do ativo com a solução de lecitina. Após a obtenção da mistura, adicionar em uma das seringas, o gel polaxamer em q.s.p. 60 mL. O conteúdo é misturado empurrando os êmbolos das duas seringas pela técnica de extrusão até que esteja visualmente homogênea.[051] Prepare the lecithin and isopropyl palmitate solution and the polaxamer gel and leave them to rest overnight. To prepare the transdermal gel, grind the active ingredient and dissolve in q.s. of alcohol. Using two luer lock syringes, obtain a homogeneous mixture of the active ingredient with the lecithin solution. After obtaining the mixture, add the polaxamer gel in q.s.p. to one of the syringes. 60 mL. The content is mixed by pushing the plungers of the two syringes using the extrusion technique until it is visually homogeneous.
[052] Para dispensação de acordo com a dose diária a ser usada pelo paciente, pode ser dispensado na própria seringa de 60mL, em seringas menores que permitem a leitura precisa do gel em quantidades menores que 1mL ou envasar o gel em sachês aluminizados.[052] For dispensing according to the daily dose to be used by the patient, it can be dispensed in the 60mL syringe itself, in smaller syringes that allow accurate reading of the gel in quantities smaller than 1mL or bottled the gel in aluminized sachets.
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