RESUMO
OBJECTIVES: To predict the substance's behaviour in vivo and determine the viability of the bioactive substance to become a drug, this work aimed to evaluate the biopharmaceutics characteristics of goyazensolide. METHODS: Differential scanning calorimetry (DSC) and thermogravimetry (TG) were applied for the characterization of goyazensolide. The biopharmaceutics characteristics were evaluated using in-silico and in-vitro (shake-flask and Parallel Artificial Membrane Permeability Assay) methods. KEY FINDINGS: DSC curve showed a single endothermic peak. According to the TG curve, goyazensolide has thermal stability close to 221.0°C and 210.0°C, under a nitrogen and oxygen atmosphere, respectively. In-silico data indicated that goyazensolide has high solubility and low permeability. The high solubility was confirmed by equilibrium solubility studies determined by the shake-flask method. The dose/solubility ratio values were 175.16 ml (pH 1.2), 194.99 ml (pH 4.5) and 222.07 ml (pH 6.8). The effective permeability of 0.03 × 10-6 cm/s was obtained for goyazensolide. This value is lower than furosemide (1.03 × 10-6 cm/s), confirming the low permeability of goyazensolide. CONCLUSIONS: Biopharmaceutics characteristics of goyazensolide are similar to drugs available on the market and attest to the feasibility of starting the process of developing a formulation containing this substance.
Assuntos
Asteraceae , Biofarmácia , Asteraceae/química , Biofarmácia/métodos , Hidrocarbonetos Aromáticos com Pontes , Furanos , Absorção Intestinal , Permeabilidade , Sesterterpenos , SolubilidadeRESUMO
BACKGROUND: Lychnophora trichocarpha (Spreng.) Spreng. ex Sch.Bip has been used in folk medicine to treat pain, inflammation, rheumatism and bruises. Eremantholide C, a sesquiterpene lactone, is one of the substances responsible for the anti-inflammatory and anti-hyperuricemic effects of L. trichocarpha. OBJECTIVES: Considering the potential to become a drug for the treatment of inflammation and gouty arthritis, this study evaluated the permeability of eremantholide C using in situ intestinal perfusion in rats. From the permeability data, it was possible to predict the fraction absorbed of eremantholide C in humans and elucidate its oral absorption process. METHODS: In situ intestinal perfusion studies were performed in the complete small intestine of rats using different concentrations of eremantholide C: 960 µg/ml, 96 µg/ml and 9.6 µg/ml (with and without sodium azide), in order to verify the lack of dependence on the measured permeability as a function of the substance concentration in the perfusion solutions. RESULTS: Eremantholide C showed Peff values, in rats, greater than 5 × 10-5 cm/s and fraction absorbed predicted for humans greater than 85%. These results indicated the high permeability for eremantholide C. Moreover, its permeation process occurs only by passive route, because there were no statistically significant differences between the Peff values for eremantholide C. CONCLUSION: The high permeability, in addition to the low solubility, indicated that eremantholide C is a biologically active substance BCS class II. The pharmacological activities, low toxicity and biopharmaceutics parameters demonstrate that eremantholide C has the necessary requirements for the development of a drug product, to be administered orally, with action on inflammation, hyperuricemia and gout.
Assuntos
Asteraceae , Sesquiterpenos/metabolismo , Animais , Biofarmácia , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Masculino , Permeabilidade , Componentes Aéreos da Planta , Ratos Wistar , Sesquiterpenos/química , Sesquiterpenos/classificaçãoRESUMO
Acyclovir is an antiviral drug poorly absorbed in the gastrointestinal tract due to its hydrophilicity, with low oral bioavailability (~20%). Although acyclovir is prescribed in the management of herpes simplex encephalitis (HSE), the disease has a poor prognosis, particularly if the treatment is delayed, reaching mortality rates of 70% if left untreated. Thus, high acyclovir doses are administered by intravenous (IV) infusion, usually at a dosage of 10 mg kg-1 8-hourly in adults with normal renal function. However, the mortality related to HSE treated with acyclovir remains high (~20%) and permanent sequelae are commonly reported after 1 year (~50%). This review analyzed clinical trials following IV acyclovir administration. Novel insights aiming to improve drug bioavailability were reviewed, including acyclovir or its prodrugs, leading to the systemic distribution of the drug or drug targeting. Much research effort has been made to improve antiviral therapy, searching for delivery systems increasing acyclovir bioavailability by non-invasive pathways, such as oral and nasal pathways, or parenterally administered nanotechnology-based systems leading to drug targeting. Nanocarriers administered by non-invasive pathways represent feasible alternatives to treat HSE, even though not be industrially manufactured yet.
Assuntos
Encefalite por Herpes Simples , Herpes Simples , Pró-Fármacos , Aciclovir , Adulto , Antivirais/uso terapêutico , Encefalite por Herpes Simples/tratamento farmacológico , Herpes Simples/tratamento farmacológico , Humanos , Infusões Intravenosas , Pró-Fármacos/uso terapêuticoRESUMO
Vitamin K antagonists (VKA) and direct oral anticoagulants (DOACs) have been clinically used in the treatment of coagulation disorders. There are four DOACs approved since 2010 (dabigatran etexilate, rivaroxaban, apixaban, and edoxaban), and they were designed to overcome the practical limitations of VKA. This review summarized biopharmaceutics considerations about DOACs, which are critically discussed, applying risk analyses to subside the further classification of these drugs according to the Biopharmaceutics Classification System (BCS). These discussions included data compiled about physicochemical properties, equilibrium solubility, permeability, and drug dissolution of DOACs. From the biopharmaceutics characteristics is possible to identify critical variables related to the absorption process, which can help in the design of new formulations. The data were compared with the criteria recommended by regulatory agencies for the biopharmaceutics classification according to the BCS. From that, these data may be used to discuss the approval of generic medicines by the BCS-based biowaiver, and the clinical risks arising from novel formulations with DOACs. However, although there are indications of biopharmaceutics classifications for DOACs, conclusive information to classify these compounds according to the BCS is lacking, requiring more experimental studies to achieve this aim. Conclusive information is essential for a safe decision about the biowaiver, as well as to guide the development of new formulations containing the DOACs.
Assuntos
Anticoagulantes , Biofarmácia , Administração Oral , Dabigatrana , RivaroxabanaRESUMO
Among the methods described for determining the solubility, shake-flask is suitable to evaluate the equilibrium solubility according to the BCS. Nevertheless, experimental conditions related to the shake-flask method are not well described. Evaluating the effects of experimental conditions on solubility measurements by shake-flask method is important and contributes in biowaiver decision. For this work, propranolol hydrochloride and nimesulide were used as model compound of high and low solubility, respectively. Equilibrium solubility was evaluated at 37 ºC, 100 rpm during 48 hours in buffer media. Effects of the rotation speed, temperature, substance in excess and aliquot withdrawn were evaluated. Small variations of temperature caused significant differences in the solubility and then this parameter must be controlled. Excess of raw material influenced the results of the nimesulide, then, little excess is recommended. Rotation speed did not cause differences in the equilibrium solubilities, but at 150 rpm the equilibrium was reached faster. Aliquot did not present significant differences, but excessive withdrawn should be avoided. Therefore, the evaluation of equilibrium solubility using shake-flask method must be performed in physiological pH conditions, 37 ± 1 ºC, substance in excess 10% above saturation, 50, 100 or 150 rpm and aliquot withdrawn not more than 10% of the media volume.
Assuntos
Solubilidade , Técnicas de Cultura Celular por Lotes/métodos , Preparações Farmacêuticas/administração & dosagemRESUMO
BACKGROUND: Solubility, intestinal permeability and dissolution are the main factors that govern the rate and extent of drugs absorption and are directly related to bioavailability. Biopharmaceutics Classification System (BCS) is an important tool which uses in vitro results for comparison with bioavailability in vivo (biowaiver). Valsartan is widely used in the treatment of hypertension and shows different BCS classification in the literature (BCS class II or III). OBJECTIVE: This work proposes the study of valsartan biopharmaceutics properties and its BCS classification. METHODS: High Performance Liquid Chromatography (HPLC) method was developed and validated to quantify the drug in buffers pH 1.2, 4.5 and 6.8 respectively. Valsartan solubility was determined in these three different media using shake flask method and intrinsic dissolution rate. Evaluation of dissolution profile from coated tablets was conducted. RESULTS: The low solubility (pH 1.2 and 4.5) and high solubility (pH 6.8) were observed for both solubility methods. Permeability data reported from the literature showed that valsartan is a low permeability drug. Valsartan presented the rapid release profile only in pH 6.8. CONCLUSION: We defined that valsartan is a class IV drug, in disagreement with what has been published so far. It is important to emphasize that the conditions considered here are indicated to define the biopharmaceutics classification by regulatory agencies.
Assuntos
Anti-Hipertensivos/química , Valsartana/química , Anti-Hipertensivos/classificação , Anti-Hipertensivos/farmacocinética , Disponibilidade Biológica , Biofarmácia , Cromatografia Líquida de Alta Pressão/métodos , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Absorção Intestinal , Solubilidade , Comprimidos , Valsartana/classificação , Valsartana/farmacocinéticaRESUMO
The purpose of this work was to describe the closed loop in situ perfusion method in rats and to compare the difficulties and advantages with other methods proposed by regulatory agencies for BCS classification and finally to illustrate its application to evaluate the permeability of digoxin at relevant clinical concentrations. Digoxin was evaluated at two concentration levels: 1.0⯵g/ml (with and without sodium azide 65.0⯵g/ml) and 6.0⯵g/ml. These concentrations correspond to the ratio of the highest dose strength (0.25â¯mg) and the highest single dose administered (1.5â¯mg) and the 250â¯ml of water. In situ closed loop perfusion studies in rats were performed in the whole small intestine and also in duodenum, jejunum and ileum segments to evaluate the relevance of P-gp secretion in the overall permeability. A kinetic modelling approach involving passive permeation and efflux transport mechanism allowed the estimation of the passive diffusional component and the Michaelis-menten parameters. The estimated Km value demonstrated that at clinical luminal concentrations the efflux process is not saturated and then it could be inhibited by other drugs, excipients or food components leading to the already reported clinical drug-drug and drug-food interations. The present data confirms from a mechanistic point of view these interactions.