Enzymes in the dissolution testing of gelatin capsules.

Gelatin capsules are a widely used dosage form both for pharmaceutical drug products as well as dietary supplements. Gelatin in the presence of certain compounds, mainly aldehydes, or in high humidity and high temperature conditions can cross-link. Cross-linking involves covalent bonding of the amine group of a lysine side chain of one gelatin molecule to a similar amine group on another molecule. The covalent bonding is, for practical purposes, irreversible. Cross-linking results in the formation of a pellicle on the internal or external surface of the gelatin capsule shell that prevents the capsule fill from being released. In vitro dissolution testing of cross-linked gelatin capsules can result in slower release of the drug or no release at all. The data obtained by the Gelatin Capsule Working Group, created in the early 90s to investigate noncompliance of gelatin capsules, was used to establish the type and amounts of enzymes that can be added to the dissolution medium in the case of test failure to the presence of cross-linking in the gelatin. The two-tier dissolution testing was included in the US Pharmacopeia and it recommends the addition of pepsin (pH below 6.8) or pancreatin (pH above 6.8) to the medium depending on its pH. Pepsin shows good protease activity up to pH 4 and pancreatin above pH 6 leaving a gap where neither one has good activity. Possible proteolytic enzymes that could be used for the pH range 4-6.8 could be papain or bromelain.

Passive transdermal systems whitepaper incorporating current chemistry, manufacturing and controls (CMC) development principles.

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration's Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro-in vivo correlation considerations for transdermal systems.

Nanomedicines - Tiny particles and big challenges.

After decades of research, nanotechnology has been used in a broad array of biomedical products including medical devices, drug products, drug substances, and pharmaceutical-grade excipients. But like many great achievements in science, there is a fine balance between the risks and opportunities of this new technology. Some materials and surface structures in the nanosize range can exert unexpected toxicities and merit a more detailed safety assessment. Regulatory agencies such as the United States Food and Drug Administration or the European Medicines Agency have started dealing with the potential risks posed by nanomaterials. Considering that a thorough characterization is one of the key aspects of controlling such risks this review presents the regulatory background of nanosafety assessment and provides some practical advice on how to characterize nanomaterials and drug formulations. Further, the challenges of how to maintain and monitor pharmaceutical quality through a highly complex production processes will be discussed.

Enzymatic activity in the presence of surfactants commonly used in dissolution media, Part 1: Pepsin.

The United States Pharmacopeia (USP) General Chapters Dissolution 〈711〉 and Disintegration and Dissolution of Dietary Supplements 〈2040〉 allows the use of enzymes in dissolution media when gelatin capsules do not conform to dissolution specifications due to cross linking. Possible interactions between enzymes and surfactants when used together in dissolution media could result in loss of the enzymatic activity. Pepsin is an enzyme commonly used in dissolution media, and in this work, the activity of pepsin was determined in the presence of different surfactants as usually found in case of dissolution tests of certain gelatin capsule formulations. Pepsin enzymatic activity was determined according to the Ninth Edition of the Food Chemicals Codex (FCC) 9 method, in dissolution conditions: simulated gastric fluid, 37 °C and 50 rpm. Sodium dodecyl sulfate (SDS), cetyltrimethyl ammonium bromide (CTAB), polysorbate 80 (Tween 80) and octoxynol 9 (Triton X100) in concentrations above and below their critical micellar concentrations were selected. Results showed a significant reduction in the activity of pepsin at all the concentrations of SDS assayed. On the contrary, CTAB, Tween 80, and Triton X100 did not alter the enzymatic activity at of pepsin any of the concentration assayed. This data demonstrates a rational selection of the surfactant to be used when pepsin is required in dissolution test.

[Seroepidemiological survey of human cysticercosis in a municipality of Piauí State, Northeast Brazil]. / Estudo soroepidemiológico da cisticercose humana em um município do Estado do Piauí, Região Nordeste do Brasil.

As part of parasitological studies in the area surrounding the Serra da Capivara National Park, Piauí State, Northeast Brazil, from 1999 to 2001, the current study aimed to evaluate the epidemiological profile of human cysticercosis in the Municipality of João Costa. Clinical and epidemiological data were obtained, and blood samples were drawn for immunoenzymatic serological tests (ELISA and Western blot), using Taenia crassiceps as the antigen. The first stage, in 1999, investigated 169 individuals with a confirmed history or suspicion of infection/disease involving the teniasis/cysticercosis complex, along with the family members. Some 13.6% of the individuals were seroreactive for cysticercosis by the ELISA method. The second stage, in 2001, evaluated 92 serum samples of individuals who had been detected as reactive for cysticercosis in the first stage, along with their family members; 24% of the samples were reactive to cysticercosis by ELISA and 29% by Western blot. During this same stage a coprological survey was performed with 701 individuals, including volunteers. Prevalence of intestinal parasites was 51%, with a higher prevalence of protozoans (95%) than helminths (5%). The results indicate the endemicity of cysticercosis in the area, in addition to the high frequency of intestinal protozoan infections.

Oral dosage form performance tests: new dissolution approaches.

The performance test is one of a series of tests that compose the specification in a United States Pharmacopeia (USP) dosage form monograph. For an orally administered, nonsolution dosage form, it is usually satisfied by either a dissolution or disintegration procedure. Dissolution acceptance criteria are usually set in private negotiations between an applicant and a regulatory agency. With information about this private agreement and other information provided in a sponsor's Request for Revision to USP, the USP's Council of Experts elaborates a public dosage form monograph. Based on the relationship between the regulatory decisions and the Request for Revision, the USP dissolution procedure links to a regulatory judgment about bioavailability and bioequivalence and, ultimately, to a judgment about safety and efficacy. The current dissolution procedure and acceptance criteria are perceived as having worked well over the years and are generally accepted. This article discusses new approaches that merit consideration. These approaches focus on a) explicit use of hypothesis testing, b) use of parametric tolerance intervals, c) improved ways to set dissolution acceptance criteria, and d) a more flexible protocol to assess conformity. Application of the proposed approaches may better assess, manage, and communicate both manufacturer and consumer risk for dissolution testing.

Nasal secretions of Neisseria lactamica carriers have an inhibitory effect on Neisseria meningitidis attachment to human oroepithelial cells

As secreçöes nasais de voluntários colonizados por N. lactamica inibem a aderência de N. Lactamica e de meningococos dos grupos A e B à células oroepiteliais humanas, "in vitro". A aderência, nas amostras de Neisseria testadas, decorre da presença de adesinas näo-fimbriais que parecem possuir antígenos comuns. A despeito do surgimento de marcante atividade antiadesiva nas secreçöes nasais os voluntários persistiram como portadores de N. lactamica. A erradicaçäo do estado de portador parece assim ser dependente da açäo de diferentes fatores

Estudo soroepidemiológico da cisticercose humana em um município do Estado do Piauí, Região Nordeste do Brasil / Seroepidemiological survey of human cysticercosis in a municipality of Piaui State, Northeast Brazil

Integrando as pesquisas sobre parasitoses na região do entorno do Parque Nacional Serra da Capivara, Piauí, Brasil, realizadas entre 1999 e 2001, o presente estudo tem como objetivo avaliar a situação epidemiológica da cisticercose humana no Município de João Costa, no Nordeste do Brasil. Foram obtidas informações clínico-epidemiológicas e coletadas amostras de sangue para testes sorológicos imunoenzimáticos (ELISA e Western blot), empregando cisticercos de Taenia crassiceps como antígeno. Na primeira etapa, em 1999, foram investigadas 169 pessoas com história confirmada ou suspeita de infecção/doença pelo complexo teníase-cisticercose, e seus familiares. Na análise, 13,6 por cento das pessoas apresentaram soros reagentes para cisticercose pelo método ELISA. Na segunda etapa, em 2001, foram avaliadas 92 amostras de soro de indivíduos reativos para cisticercose detectados no primeiro momento e seus familiares, sendo que 24,0 por cento das amostras de soro foram reagentes para cisticercose pelo ELISA, e 29,0 por cento, pelo WB. Nessa mesma etapa, realizou-se inquérito coprológico em 701 pessoas, incluindo voluntários. A prevalência de parasitoses intestinais foi de 51,0 por cento, tendo sido observada uma maior prevalência de protozoários (95,0 por cento) em relação aos helmintos (5,0 por cento). Os resultados do estudo indicam o caráter endêmico da cisticercose na área, além da elevada freqüência de protozooses intestinais.

Doseamento microbiológico de neomicina: influência do volume de meio de cultura / Microbiological assay of neomycin: influence of the nutrient medium volume

As condiçöes experimentais do método oficial de difusäo em ágar, para a determinaçäo de neomicina, foram modificadas a fim de aumentar sua sensibilidade e simplificar sua execuçäo. O volume de meio de cultura base foi reduzido de 20 ml para 10 ml, mantendo-se 5 ml de meio superfície. Também foi utilizada monocamada inoculada, de 10 ml de meio cultura. Os melhores resultados foram obtidos reduzindo-se o volume de meio de cultura base para 10 ml, conseguindo-se, assim, determinaçöes no intervalo de 2 a 32 microng/ml de neomicina base

Comercializaçäo no Brasil de medicamentos contendo neomicina / Commercialization in Brazil of drugs containing neomycin

É feito um alerta sobre o grande número de especialidades farmacêuticas contendo neomicina à venda no Brasil. Estas, embora devessem ser comercializadas através de prescriçäo médica, podem ser adquiridas livremente. Uma vez que a neomicina apresenta efeitos colaterais muito significativos, é extremamente importante o acompanhamento durante o tratamento do paciente, ainda que seguindo o esquema posológico recomendado. Além desses fatores, esta diversificaçäo de fórmulas e os muitos fármacos associados à neomicina dificultam o estabelecimento de método analítico universal que possibilite controle de qualidade adequado dos medicamentos, impondo a necessidade de adaptaçäo metodológica para cada especialidade em particular