Compounded drugs as an alternative to the therapeutical gaps of inborn errors of metabolism

Abstract Inborn errors of metabolism are rare disorders with few therapeutic options for their treatments, which can make patients suffer with complications. Therefore, compounded drugs might be a promising option given that they have the ability of meeting the patient's specific needs, (i) identification of the main drugs described in the literature; (ii) proposal of compounding systems and (iii) calculation of the budgetary addition for the inclusion of these drugs into the Brazilian Unified Health System. The research conducted a literature review and used management data as well as data obtained from official Federal District government websites. The study identified 31 drugs for the treatment of inborn errors of metabolism. Fifty eight percent (58%) (18) of the medicines had their current demand identified, which are currently unmet by the local Health System. The estimated budget for the production of compounded drugs was of R$363,16.98 per year for approximately 300 patients. This estimated cost represents a budgetary addition of only 0.17% from the total of expenditures planned for drug acquirement. There is a therapeutic gap for inborn errors of metabolism and compounding pharmacies show potential in ensuring access to medicine therapy with a low-cost investment.

Liquid chromatography-mass spectrometry for simultaneous determination of spironolactone and canrenone in plasma samples

Abstract n our study, we aimed to validate a method based on liquid chromatography-mass spectrometry (LC-MS) to quantify spironolactone (SPI) and its active metabolite canrenone (CAN) simultaneously in plasma samples to support in vivo experiments. Compounds were separated by using a C18 column with the isocratic elution of a mobile phase composed of 0.1% (v/v) formic acid in methanol-water (60:40 v/v) at a flow rate of 0.4 mL min−1. SPI and CAN were detected in na electrospray interface operating in a positive ionization mode and quantified using the selective ion mode monitoring of mass-charge ratios (m/z) of 439.0 for SPI and 363.1 for CAN. After calculating the matrix effect using theoretical equations, we observed the strong interference of plasma in the equipment-generated signal, which required creating analytical curves using the matrix as a solvent. The method was nevertheless linear (r 2 > 0.999) in a concentration range of 0.4-5.0 µg mL−1, as well as precise, with a coefficient of variation less than 5%. SPI's and CAN's recovery rates from the plasma ranged from 87.4% to 112.1%, while their limits of detection (i.e., 0.07 µg mL−1 and 0.03 µg mL−1, respectively) and quantification (i.e., 0.20 µg mL−1 and 0.08 µg mL−1, respectively) in the presence of plasma contaminants were low. Therefore, the bioanalytical method seems to be feasible for quantifying SPI and CAN in plasma

Compatibility and stability studies involving polymers used in fused deposition modeling 3D printing of medicines / 药物分析学报

One of the challenges in developing three-dimensional printed medicines is related to their stability due to the manufacturing conditions involving high temperatures.This work proposed a new pro-tocol for preformulation studies simulating thermal processing and aging of the printed medicines,tested regarding their morphology and thermal,crystallographic,and spectroscopic profiles.Gener-ally,despite the strong drug-polymer interactions observed,the chemical stability of the model drugs was preserved under such conditions.In fact,in the metoprolol and Soluplus? composition,the drug's solubilization in the polymer produced a delay in the drug decomposition,suggesting a pro-tective effect of the matrix.Paracetamol and polyvinyl alcohol mixture,in turn,showed unmistakable signs of thermal instability and chemical decomposition,in addition to physical changes.In the presented context,establishing protocols that simulate processing and storage conditions may be decisive for obtaining stable pharmaceutical dosage forms using three-dimensional printing technology.

Topical ophthalmic antimicrobials: unfulfilled demands and possibility of new investments in Brazil and in the United States

In general, topical ophthalmic drug products, especially those used for treating infections, present low effectiveness because of various reasons, from unfavorable drug physicochemical properties to physiological protective mechanisms of the eye. The fact is such group of products holds room for improvement, which could mean the development of better drugs or dosage forms. To achieve this, the knowledge of market composition is essential. The present work studied and compared the antimicrobial ophthalmic markets of Brazil and of the United States (US). Official databank of Brazilian Health Regulatory Agency and of US Food and Drug Administration were assessed for registered antimicrobial topical ophthalmic drug products. Brazilian market has registered greater number of drug products (119) than the US (94), but the latter involves more variety of substances and dosage forms. In both countries, non-innovative products registered as solutions of antibacterials, especially fluoroquinolones and aminoglycosides lead the market. Despite the clinical demand, the US has only one group of antimycotics (polyenes) registered, while in Brazil, there is not any ophthalmic antimycotic product marketed. This study evidences there is not only space for development of newer drugs and formulations but also a demand for already existing technologies and products in both countries.

Influence of monoolein on progesterone transdermal delivery

abstract This work aimed to investigate in vitro the influence of monoolein (MO) on progesterone (PG) transdermal delivery and skin retention. Information about the role of MO as an absorption enhancer for lipophilic molecules can help on innovative product development capable of delivering the hormone through the skin in a consistent manner, improving transdermal therapy of hormonal replacement. MO was dispersed in propylene glycol under heat at concentrations of 0% (control), 5% w/w, 10% w/w and 20% w/w. Then, 0.6% of PG (w/w) was added to each formulation. Permeation profile of the hormone was determined in vitro for 48 h using porcine skin in Franz diffusion cells. PG permeation doubled when 5% (w/w) of MO was present in formulation in comparison to both the control and higher MO concentrations (10% and 20% w/w). An equal trend was observed for PG retention in stratum corneum (SC) and reminiscent skin (E+D). PG release rates from the MO formulations, investigated using cellulose membranes, revealed that concentrations of MO higher than 5% (w/w) hindered PG release, which indeed negatively reflected on the hormone permeation through the skin. In conclusion, this work demonstrated the feasibility of MO addition (at 5% w/w) in formulations as a simple method to increase transdermal PG delivery for therapies of hormonal replacement. In contrast, higher MO concentrations (from 10% to 20% w/w) can control active release, and this approach could be extrapolated to other lipophilic, low-molecular-weight molecules.

resumo Este trabalho teve como objetivo investigar in vitro a influência de monooleína (MO) na permeação transdérmica de progesterona (PG), bem como sobre a retenção cutânea desse hormônio a fim de (i) liberar de maneira mais consistente hormônio através da pele para melhorar a terapia transdérmica de reposição hormonal e (ii) trazer mais informações sobre o papel da MO como promotor da absorção cutânea de moléculas lipofílicas, tema ainda pouco explorado na literatura. MO foi dispersa em propilenoglicol, a concentrações de 0% (controle), 5%, 10% e 20% (p/p). Adicionou-se, em seguida, 0,6% (p/p) de PG a cada uma das formulações. O perfil de permeação do hormônio foi então determinado in vitro durante 48 h, utilizando pele de porco em células de difusão do tipo Franz. MO a 5% (p/p) foi capaz de duplicar a permeação de PG em comparação ao controle e às concentrações mais elevadas de MO, assim como a retenção de PG no estrato córneo (SC) e epiderme e derme remanescentes (E+D). A velocidade de liberação de PG a partir das formulações foi investigada usando membranas de celulose e este estudo revelou que concentrações de MO superiores a 5% (p/p) impediram a liberacão de PG, o que de fato refletiu de forma negativa na permeação cutânea do hormônio. Concluindo, este trabalho demonstrou a viabilidade da adição de MO a uma formulação como um método simples para aumentar a permeação transdérmica de PG para uso em terapias de reposição hormonal. Por outro lado, altas concentrações de MO (de 10% a 20% p/p) controlam a liberação de PG e este efeito pode ser extrapolado para outras moléculas lipofílicas de baixa massa molecular.

Bioequivalência de medicamentos tópicos dermatológicos: o cenário brasileiro e os desafios para a vigilância sanitária / Bioequivalence of dermatological topical medicines: the Brazilian scenario and the challenges for health surveillance

A avaliação comparativa exigida para registro das formulações tópicas genéricas no Brasil é feita por meio do estudo de equivalência farmacêutica que avalia apenas os parâmetros físico-químicos e microbiológicos dos medicamentos. Internacionalmente, estudos clínicos ou farmacodinâmicos vêm sendo exigidos para comprovar a eficácia e a segurança das formulações genéricas tópicas semissólidas. Este trabalho apresenta uma comparação entre os diferentes requerimentos para registro de uma formulação tópica, considerando diferentes autoridades regulatórias, e faz um levantamento dos produtos tópicos dermatológicos registrados no Brasil até 2013. Tal levantamento demonstrou haver uma grande quantidade de cópias desse tipo de formulação no Brasil em comparação com os EUA. Este fato, associado à grande quantidade de estudos encontrados na literatura demonstrando bioinequivalência de medicamentos tópicos, evidencia a grande importância de uma readequação da legislação brasileira no que se refere aos requisitos técnicos para o registro de medicamentos genéricos e similares de aplicação tópica dermatológica no Brasil.

The comparative evaluation required for the registration of generic topical medicines in Brazil is conducted by means of a pharmaceutical equivalence study, which merely assesses the physical/chemical and microbiological parameters of the formulations. At the international level, clinical or pharmacodynamic studies are now being required to prove the efficacy and safety of semisolid topical generic formulations. This work presents a comparison of the different requirements for the registration of topical formulations, taking into consideration the various regulatory authorities, and presents a survey of topical medicines registered in Brazil prior to 2013. The survey revealed that in comparison with the USA there were many more copies of these formulations registered in Brazil. This fact, together with the large number of studies in the literature showing the lack of bioequivalence of topical medication, is clear proof of the major importance of the need to realign Brazilian legislation with respect to the technical requirements for the registration of generic and similar medication for dermatological topical application in Brazil.

Injeção sem agulhas: aplicações médicas e perspectivas futuras / Needle-free injection: medical applications and future perspectives

Numerosos inconvenientes da administração de formulações farmacêuticas empregando agulhas e seringas têm impulsionado enorme investimento na pesquisa de novos mecanismos de administração. Uma das opções tecnológicas mais promissoras são os sistemas de injeção sem agulha, e alguns modelos são disponíveis no mercado. Esses sistemas, que incluem injetores de jato de formulações líquidas e injetores de pó, são dispositivos adaptados para a administração de diferentes tipos de fármacos e vacinas através da pele de maneira minimamente invasiva. A administração cutânea de vacinas é vantajosa, pois aumenta a resposta imunitária, elimina riscos de contaminação cruzada, facilita o ato da vacinação, o processo de descarte e, portanto, reduz os custos. Esta revisão se dedica a abordar as vantagens do uso dos sistemas semagulha em terapêutica, discutindo-se mecanismos de ação, vantagens e obstáculos para seu uso, diferenças entre os tipos de injetores, bem como aplicações e perspectivas futuras.

The various disadvantages of administering pharmaceutical formulations using needles and syringes have led to a huge investment in researchabout new delivery mechanisms. One of the most promising technological alternatives is the needlefree injection system. In fact, some models are already available in the market. These systems, which include liquid and powder jet injectors, are devices adapted for drug and vaccine administration through the skin in a minimally invasive manner. Topical vaccine administration is advantageous because it increases the immune response and eliminates cross-contamination risks. It also facilitates vaccination and the disposal process, thus reducing costs. This review aims at addressing the advantages of needle-free systems in therapy by discussing their mechanisms of action, the advantages of and obstacles to their use, differences between the types of injectors, and their applicationsand future perspectives.