RESUMO
A variety of in vitro dissolution and gastrointestinal transfer models have been developed aiming to predict drug supersaturation and precipitation. Further, biphasic, one-vessel in vitro systems are increasingly applied to simulate drug absorption in vitro. However, to date, there is a lack of combining the two approaches. Therefore, the first aim of this study was to develop a dissolution-transfer-partitioning system (DTPS) and, secondly, to assess its biopredictive power. In the DTPS, simulated gastric and intestinal dissolution vessels are connected via a peristaltic pump. An organic layer is added on top of the intestinal phase, serving as an absorptive compartment. The predictive power of the novel DTPS was assessed to a classical USP II transfer model using a BCS class II weak base with poor aqueous solubility, MSC-A. The classical USP II transfer model overestimated simulated intestinal drug precipitation, especially at higher doses. By applying the DTPS, a clearly improved estimation of drug supersaturation and precipitation and an accurate prediction of the in vivo dose linearity of MSC-A were observed. The DTPS provides a useful tool taking both dissolution and absorption into account. This advanced in vitro tool offers the advantage of streamlining the development process of challenging compounds.
RESUMO
The Biorelevant Gastrointestinal Transfer (BioGIT) system is a useful screening tool for assessing the impact of dose and/or formulation on early exposure after administration of immediate release or enabling drug products with a glass of water in the fasted state. The objective of this study was to investigate potential limitations. BioGIT experiments were performed with five low solubility active pharmaceutical ingredients with weakly alkaline characteristics: mebendazole (tablet and chewable tablet), Compound E (aqueous solutions, three doses), pazopanib-HCl (Votrient™ tablet, crushed Votrient™ tablet and aqueous suspension), Compound B-diHCl (hard gelatin capsule, three doses) and Compound C (hard gelatin capsule containing nanosized drug and hard gelatin capsule containing micronized drug). For all formulation or dose comparisons the ratio of mean BioGIT AUC0-50 min values was not predictive of the ratio of mean plasma AUC0-60 min values which became available after completion of BioGIT experiments. BioGIT experimental conditions have not been designed to simulate the gastrointestinal drug transfer process after administration of chewable tablets or aqueous solutions, therefore, BioGIT may not be useful for the assessment of intraluminal performance early after administration of such drug products. Also, based on this study, BioGIT may not be useful in investigating the impact of dose and/or formulation on early exposure when the dose is not administered with a glass of water to fasted healthy individuals or when BioGIT data are highly variable. Finally, the rapid dissolution of nanocrystals after administration of low solubility weak bases may require adjustment of the pH in the gastric compartment of BioGIT to slightly higher pH values. Limitations identified in this study for the BioGIT system may be also relevant to other in vitro systems proposed for similar evaluations.
Assuntos
Trato Gastrointestinal , Gelatina , Humanos , Administração Oral , Solubilidade , Suspensões , Comprimidos , ÁguaRESUMO
The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-ß-CD aqueous solution and tablet). Based on mean plasma AUC0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC0-50min values and log-transformed ratios of plasma AUC0-60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC0-60min ratios vs. log-transformed BioGIT AUC0-50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis.
Assuntos
Fenofibrato , Administração Oral , Diclofenaco , Jejum , Comprimidos , Estudos Cross-Over , Equivalência Terapêutica , Área Sob a CurvaRESUMO
This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.
Assuntos
Solubilidade , Cristalização , Liberação Controlada de FármacosRESUMO
Formulation of amorphous solid dispersions (ASD) is one possibility to improve poor aqueous drug solubility by creating supersaturation. In case of weakly basic drugs like ketoconazole (KTZ), supersaturation can also be generated during the gastrointestinal (GI) transfer from the stomach to the intestine due to pH-dependent solubility. In both cases, the supersaturation during dissolution can be stabilized by polymeric precipitation inhibitors. A small-scale GI transfer model was used to compare the dissolution performance of ASD versus crystalline KTZ with the polymeric precipitation inhibitor HPMCAS. Similar in vitro AUCs were found for the transfer from SGF pH2 into FaSSIF. Moreover, the impact of variability in gastric pH on drug dissolution was assessed. Here, the ASD performed significantly better at a simulated hypochlorhydric gastric pHof 4. Last, the importance of drug-polymer interactions for precipitation inhibition was evaluated. HPMCAS HF and LF grades with and without the basic polymer Eudragit EPO were used. However, EPO caused a faster precipitation probably due to competition for the interaction sites between KTZ and HPMCAS. Thus, the results are suited to assess the benefits of amorphous formulations vs. precipitation inhibitors under different gastrointestinal conditions to optimize the design of such drug delivery systems.
Assuntos
Trato Gastrointestinal/fisiologia , Preparações Farmacêuticas/química , Precipitação Química , Química Farmacêutica/métodos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Cetoconazol/química , Metilcelulose/análogos & derivados , Metilcelulose/química , Polímeros/química , Ácidos Polimetacrílicos/química , SolubilidadeRESUMO
The characterization of intestinal dissolution of poorly soluble drugs represents a key task during the development of both new drug candidates and drug products. The bicarbonate buffer is considered as the most biorelevant buffer for simulating intestinal conditions. However, because of its complex nature, being the volatility of CO2, it has only been rarely used in the past. The aim of this study was to investigate the effect of a biorelevant bicarbonate buffer on intestinal supersaturation and precipitation of poorly soluble drugs using a gastrointestinal (GI) transfer model. Therefore, the results of ketoconazole, pazopanib, and lapatinib transfer model experiments using FaSSIFbicarbonate were compared with the results obtained using standard FaSSIFphosphate. Additionally, the effect of hydroxypropyl methylcellulose acetate succinate (HPMCAS) as a precipitation inhibitor was investigated in both buffer systems and compared to rat pharmacokinetic (PK) studies with and without coadministration of HPMCAS as a precipitation inhibitor. While HPMCAS was found to be an effective precipitation inhibitor for all drugs in FaSSIFphosphate, the effect in FaSSIFbicarbonate was much less pronounced. The PK studies revealed that HPMCAS did not increase the exposure of any of the model compounds significantly, indicating that the transfer model employing bicarbonate-buffered FaSSIF has a better predictive power compared to the model using phosphate-buffered FaSSIF. Hence, the application of a bicarbonate buffer in a transfer model set-up represents a promising approach to increase the predictive power of this in vitrotool and to contribute to the development of drug substances and drug products in a more biorelevant way.
Assuntos
Bicarbonatos/química , Bicarbonatos/farmacologia , Precipitação Química/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Absorção Gastrointestinal/fisiologia , Modelos Biológicos , Administração Oral , Animais , Soluções Tampão , Feminino , Trato Gastrointestinal , Concentração de Íons de Hidrogênio , Indazóis , Cetoconazol/administração & dosagem , Cetoconazol/sangue , Cetoconazol/química , Cetoconazol/farmacocinética , Lapatinib/administração & dosagem , Lapatinib/sangue , Lapatinib/química , Lapatinib/farmacocinética , Metilcelulose/análogos & derivados , Metilcelulose/farmacologia , Fosfatos/química , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/química , Pirimidinas/farmacocinética , Ratos , Ratos Wistar , Solubilidade , Sulfonamidas/administração & dosagem , Sulfonamidas/sangue , Sulfonamidas/química , Sulfonamidas/farmacocinéticaRESUMO
The majority of NCEs are weakly basic drugs. Consequently, their solubility is highly pH-dependent, with higher solubility in the acidic stomach and poor solubility in the neutral intestinal environment. The gastric emptying of dissolved drug can lead to the intestinal precipitation of the drug. One option of reducing this process is to formulate the drug together with a precipitation inhibitor (PI). The aim of this study was to investigate the effects of different PIs on the intestinal concentrations of ketoconazole and five orally administered kinase inhibitors (i.e. pazopanib, gefitinib, lapatinib, vemurafenib, and a Merck KGaA research compound, MSC-A) with the aid of a predictive small-scale in vitro transfer model. This screening revealed that HPMCAS and Soluplus® were the most effective PIs. Whereas all other drugs precipitated within several minutes, gefitinib expressed highly variable amorphous precipitation which was confirmed by PXRD. During the transfer model experiments, this intermediate supersaturated state was stabilized using HPMCAS and Soluplus®. The PI screening protocol described herein allows to study the effect of PIs for solubility and potential bioavailability improvement of poorly soluble drugs to support formulation development already in early stages.
Assuntos
Precipitação Química , Intestinos/química , Cetoconazol/química , Modelos Biológicos , Inibidores de Proteínas Quinases/química , Disponibilidade Biológica , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Metilcelulose/análogos & derivados , Metilcelulose/química , Polietilenoglicóis/química , Polivinil/química , SolubilidadeRESUMO
Precipitation testing, especially for weakly basic APIs, represents a key parameter in drug substance characterization during early development stages, where the amount of API available is limited. Therefore, it was the aim of this study to develop an automated small-scale in vitro transfer model to characterize the supersaturation and precipitation behavior of two poorly water-soluble drugs. Following automation and scale-down of the standard transfer model, the developed small-scale model was used to assess the impact of gastrointestinal variability, i.e. gastric pH, gastric emptying, and gastrointestinal fluid volumes, on supersaturation and precipitation of two weakly basic model compounds, ketoconazole and a new chemical entity from the research laboratories of Merck KGaA, MSC-A. The experiments revealed that variations in gastrointestinal parameters affected the in vitro behavior of ketoconazole, but not of MSC-A. Elevated gastric pH, as it can result from co-medication with acid-reducing drugs, resulted in lower degrees of supersaturation for both substances. This result is in agreement with the observation that the oral bioavailability of ketoconazole is lowered when proton pump inhibitors are co-administered. The small-scale transfer model presented herein represents a valuable in vitro tool to assess the risk of drug precipitation, additionally covering a broad range of gastrointestinal parameters.
Assuntos
Química Farmacêutica/métodos , Cetoconazol/química , Preparações Farmacêuticas/química , Tecnologia Farmacêutica/métodos , Automação , Precipitação Química , Esvaziamento Gástrico , Suco Gástrico/metabolismo , Concentração de Íons de Hidrogênio , SolubilidadeRESUMO
OBJECTIVES: Dissolution testing of poorly soluble and precipitating drugs is of great importance for pharmaceutical industry. As offline HPLC analytics is time-consuming and labour-intensive, the development of suitable in-line analytics to measure drug concentration allows better predictions of drug dissolution and precipitation. The purpose of this study was to develop an in-line derivative spectroscopic method which facilitates drug concentration measurements in suspensions without additional sample preparation. METHODS: Solubility, dissolution and precipitation of ketoconazole were analysed using derivative spectroscopy and HPLC. KEY FINDINGS: Results of solubility and dissolution experiments were highly comparable. Due to higher sampling frequency and lack of sample preparations, supersaturation in a pH-shift experiment was more accurately captured by UV in-line analytics. The application of a prefiltration step and flow-through cuvettes facilitates implementation of in-line derivative spectroscopy into an in vitro transfer model with changing UV-active media and high supersaturation in highly turbid samples. CONCLUSIONS: Although the application of derivative spectroscopy has been described previously, the approach described herein is novel and well-suited for the application in an automated in vitro transfer model. Moreover, it represents a promising tool for drug substance characterisation, candidate selection and formulation development.