RESUMO
Though oral drug delivery is the most preferred route of administration, there is high drug pharmacokinetic variability associated with the oral route. Change in drug substance particle size distribution, formulation composition, or manufacturing process may impact the dissolution and, hence, the systemic drug absorption in biopharmaceutics classification system class II compounds. In the present research, using a Boehringer Ingelheim investigational drug substance as the model compound, the tiny-TIM in vitro data and in silico pharmacokinetic model were used to establish in vitro-in vivo correlation and to predict the oral bioavailability. The level C in vitro-in vivo correlation between in vivo AUC and in vitro amount dissolved in both fasted and fed states could be established. Furthermore, level A in vitro-in vivo correlation was established between in vivo fraction absorbed and bioaccessibility from tiny-TIM dissolution in both fasted and fed states. Prediction of positive food effect from tiny-TIM dissolution was consistent with conclusion from clinical studies. Such predictive models developed using the minimum clinical data and the in vitro tiny-TIM data have the potential to reduce the animal and human experiments and to expedite the overall drug development process.
Assuntos
Biofarmácia , Modelos Biológicos , Animais , Simulação por Computador , Preparações Farmacêuticas , SolubilidadeRESUMO
This study examined the use of focused beam reflectance measurement (FBRM) for qualitative and quantitative analysis of pharmaceutical suspensions with particular application to toxicology supply preparations for use in preclinical studies. Aqueous suspensions of ibuprofen were used as prototype formulations. Initial experiments were conducted to examine the effects of operational conditions including FBRM probe angle, probe location, and mixing (method and rate of mixing) on the FBRM analysis. Once experimental conditions were optimized, the homogeneity and sedimentation-redispersion of particles in the suspensions were assessed. Ibuprofen suspension under continuous agitation was monitored using FBRM for 60 h to study particle size change over time. Another study was performed to determine if particle count rates obtained by FBRM could be correlated to suspension concentration. The location and the angle of the FBRM probe relative to the beaker contents, and the rate and the method of mixing the suspension were found to be sensitive parameters during FBRM analysis. FBRM was able to monitor the process of particle sedimentation in the suspension. The attrition of ibuprofen particles was detectable by FBRM during prolonged stirring with an increase in the number of smaller particles and decrease in the number of larger particles. A strong correlation was observed between particle count rate by FBRM and ibuprofen concentration in the suspension. Also, change in content uniformity in the suspension at different locations of the beaker was represented by FBRM particle count. Overall, FBRM has potential to be a useful tool for qualitative and quantitative analysis of pharmaceutical suspensions.
Assuntos
Tecnologia Farmacêutica/métodos , Estudos de Viabilidade , Ibuprofeno/química , Tamanho da Partícula , SuspensõesRESUMO
Over the past decade, there has been an increase in accelerated drug development with successful regulatory approval that has provided rapid access of novel medicines to patients world-wide. This has created the opportunity for the pharmaceutical industry to continuously improve the process of quickly bringing new medicines to patients with unmet medical needs. This can be accomplished through sharing the learnings and advancements in drug development, enhancing regulatory interactions, and collaborating with academics on developing the underlying science to reduce drug development timelines. In this paper, the IQ Consortium - Accelerated Drug Development working group members intend to share recommendations for optimizing strategies that build efficiencies in accelerated pathways for regulatory approval. Information was obtained by surveying member pharmaceutical companies with respect to recent expedited submissions within the past 5 years to gain insights as to which development strategies were successful. The learnings from this analysis are provided, which includes shared learnings in formulation development, stability, analytical methods, manufacturing, and importation testing as well as regulatory considerations. Each of these sections provide a summary illustrating the key data collected as well as a discussion that is aimed to guide pharmaceutical companies on strategies to consider streamlining development activities and expedite the drug to market.
RESUMO
This review focuses on options available to a pharmaceutical scientist to predict in vivo supersaturation and precipitation of poorly water-soluble drugs. As no single device or system can simulate the complex gastrointestinal environment, a combination of appropriate in vitro tools may be utilized to get optimal predictive information. To address the empirical issues encountered during small-scale and full-scale in vitro predictive testing, theoretical background and relevant case studies are discussed. The practical considerations for selection of appropriate tools at various stages of drug development are recommended. Upcoming technologies that have potential to further reduce in vivo studies and expedite the drug development process are also discussed.
Assuntos
Preparações Farmacêuticas , Água , Precipitação Química , SolubilidadeRESUMO
A novel class of lymphocyte function-associated antigen-1 (LFA-1) inhibitors is described. Discovered during the process to improve the physicochemical and metabolic properties of BIRT377 (1, Figure 1), a previously reported hydantoin-based LFA-1 inhibitor, these compounds are characterized by an imidazole-based 5,5-bicyclic scaffold, the 1,3,3-trisubstituted 1H-imidazo[1,2-alpha]imidazol-2-one (i.e. structure 3). The structure-activity relationship (SAR) shows that electron-withdrawing groups at C5 on the imidazole ring benefit potency and that oxygen-containing functional groups attached to a C5-sulfonyl or sulfonamide group further improve potency. This latter gain in potency is attributed to the interaction(s) of the functionalized sulfonyl/sulfonamide groups with the protein, likely polar-polar in nature, as suggested by SAR data. X-ray studies revealed that these bicyclic inhibitors bind to the I-domain of LFA-1 in a pattern similar to that of compound 1.
Assuntos
Imidazóis/síntese química , Antígeno-1 Associado à Função Linfocitária/química , Cristalografia por Raios X , Imidazóis/química , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
This report describes the solubility properties of a poorly soluble drug-excipient complex in a lipid based formulation. Tipranavir (TPV) was used as the model drug and 1,3-dioctanoylglycerol (DOG) as the excipient. The TPV-DOG complex was prepared by dissolving TPV and DOG in ethanol at 60 degrees C followed by evaporation of ethanol. The formation of the complex with a 4:1 TPV-to-DOG molar ratio was confirmed by XRPD, DSC, and NMR. At 25 degrees C, total solubility of TPV decreased with increasing DOG concentration. The solubility properties of the TPV-DOG complex can be described by two simultaneous equilibria: a liquid-solid phase equilibrium of the complex and a species equilibrium among the various species in the liquid phase. A model equation was derived accordingly with two parameters, the intrinsic solubility of the complex (S(o)), and the solution complex constant (K(41)). The model was in good agreement with experimental results. The values of S(o) and K(41) are 0.0186 +/- 0.0025 (M) and 21.97 +/- 7.19 (1/M(4)), respectively. The equation can successfully predict the concentrations of total and free TPV as a function of DOG in the formulation. The approach developed provides a useful tool for rationale selection of excipients and their levels to avoid drug precipitation in lipid based formulations.