Amorphous solid dispersion formation via solvent granulation - A case study with ritonavir and lopinavir.
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ABSTRACT:
SUBMITTER: Trasi NS
PROVIDER: S-EPMC6880113 | biostudies-literature | 2019 Dec
REPOSITORIES: biostudies-literature
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Project description:Amorphous solid dispersions containing a polymeric component often impart improved stability against crystallization for a small molecule relative to the pure amorphous form. However, the relationship between side chain functionalities on a polymer and the ability of a polymer to stabilize against crystallization is not well understood. To shed light on this relationship, a series of polymers were functionalized from a parent batch of poly(chloromethylstyrene- co-styrene) to investigate the effect of functionality on the stability in amorphous solid dispersions without altering the physical parameters of polymers, such as the average molecular weight or backbone chain chemistry. The kinetics of the crystallization of the nonsteroidal anti-inflammatory drug nabumetone from amorphous solid dispersions containing each functionalized polymer were interpreted on the basis of two interactions: hydrogen bonding between the drug and the polymer and the solubility of the polymer in the amorphous drug. It was found that hydrogen bonding between functionalized polymers and nabumetone can impart stability against crystallization, but only if the polymer shows significant solubility in amorphous nabumetone. Methylation of a protic functionality can improve the ability of a polymer to inhibit nabumetone crystallization by increasing the solubility in the drug, even when the resulting polymer lacks hydrogen bonding functionalities to interact with the pharmaceutical. Furthermore, factors, such as the glass transition temperature of pure polymers, were uncorrelated with isothermal nucleation rates. These findings inform a framework relating polymer functionality and stability deconvoluted from the polymer chain length or backbone chemistry with the potential to aid in the design of polymers to inhibit the crystallization of hydrophobic drugs from amorphous solid dispersions.
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Project description:When developing an amorphous solid dispersion (ASD), a prudent choice of polymer is critical to several aspects of ASD performance including: processability, solid state stability and dissolution rate. However, there is little guidance available to formulators to aid judicious polymer selection and a "trial and error" approach is often taken. This study aims to facilitate rational polymer selection and formulation design by generating ASDs using a range of poly-vinyl polymers and ketoprofen as a model active pharmaceutical ingredient (API) and evaluating several aspects of their performance. The molecular weight of the polymer and the ratio of vinyl pyrrolidone to vinyl acetate in the polymer were found to influence the relative humidity at which the relative humidity induced glass transition occurred, as well as the extent of ketoprofen supersaturation achieved during dynamic solubility testing. Interestingly, ASD tablets containing polymers with the vinyl pyrrolidone functional group exhibited higher tensile strengths than those without. This points towards the binder functionality of vinyl pyrrolidone. In conclusion, the physicochemical properties of poly-vinyl polymers greatly influence ketoprofen ASD performance and due regard should be paid to these properties in order to develop an ASD with the desired attributes.
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Project description:BackgroundCOVID-19 infection is the most serious global public health crisis of the century. With no approved treatments against it, investigational treatments are being used despite limited safety data. Besides being at higher risk of complications of COVID-19 infection, patients with underlying cardiovascular disease are more likely to develop cardiac-related side effects of treatment. We present a case of sinus arrest with junctional escape related to lopinavir-ritonavir.Case summaryA 67-year-old man, with underlying stable ischaemic heart disease, acquired COVID-19 infection. He had a prolonged duration of fever and cough. He subsequently developed acute respiratory distress and required intensive care unit (ICU) care. Given his severe infection, he was started on lopinavir-ritonavir. Hydroxychloroquine was not used as he had a prolonged QTc interval. During observation in the ICU, the patient developed recurrent episodes of sinus arrest with junctional escape. Initial concerns were of myocarditis, but he had no ST-segment changes on ECG, with mild elevations of highly sensitive troponin I and a normal transthoracic echocardiogram. A multidisciplinary team discussion involving the intensivist, infectious disease physicians, and cardiologist; the decision was made to stop treatment with lopinavir-ritonavir. Within 48 h, the bradyarrhythmia resolved. The patient did not require transvenous and permanent pacemaker insertion.ConclusionCurrent efficacy and safety evidence of lopinavir-ritonavir as a treatment in COVID-19 patients is limited. Although uncommonly reported, those with underlying cardiovascular disease are at increased risk of bradyarrhythmia-related adverse effects of lopinavir-ritonavir. When initiating investigational therapies, especially in patients with cardiovascular conditions, adequate counselling and close monitoring are required.
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Project description:Fused deposition modelling-based 3D printing of pharmaceutical products is facing challenges like brittleness and printability of the drug-loaded hot-melt extruded filament feedstock and stabilization of the solid-state form of the drug in the final product. The aim of this study was to investigate the influence of the drug load on printability and physical stability. The poor glass former naproxen (NAP) was hot-melt extruded with Kollidon® VA 64 at 10-30% w/w drug load. The extrudates (filaments) were characterised using differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermogravimetric analysis (TGA). It was confirmed that an amorphous solid dispersion was formed. A temperature profile was developed based on the results from TGA, DSC, and DMA and temperatures used for 3D printing were selected from the profile. The 3D-printed tablets were characterised using DSC, X-ray computer microtomography (XµCT), and X-ray powder diffraction (XRPD). From the DSC and XRPD analysis, it was found that the drug in the 3D-printed tablets (20 and 30% NAP) was amorphous and remained amorphous after 23 weeks of storage (room temperature (RT), 37% relative humidity (RH)). This shows that adjusting the drug ratio can modulate the brittleness and improve printability without compromising the physical stability of the amorphous solid dispersion.
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Project description:Zoonotic intestinal pathogens threaten human health and cause huge economic losses in farming. Enrofloxacin (ENR) shows high antibacterial activity against common intestinal bacteria. However, its poor palatability and low aqueous solubility limit the clinical application of ENR. To obtain an ENR oral preparation with good palatability and high solubility, a granule containing an amorphous ENR solid dispersion (ENR-SD) was prepared. Meanwhile, a PBPK model of ENR in pigs was built based on the physiological parameters of pigs and the chemical-specific parameters of ENR to simulate the pharmacokinetics (PK) of ENR-SD granules in the intestinal contents. According to the results of parameter sensitivity analysis (PSA) and the predicted PK parameters at different doses of the model, formulation strategies and potential dose regimens against common intestinal infections were provided. The DSC and XRD results showed that no specific interactions existed between the excipients and ENR during the compatibility tests, and ENR presented as an amorphous form in ENR-SD. Based on the similar PK performance of ENR-SD granules and the commercial ENR soluble powder suggesting continued enhancement of the solubility of ENR, a higher drug concentration in intestinal contents could not be obtained. Therefore, a 1:5 ratio of ENR and stearic acid possessing a saturated aqueous solubility of 1190 ± 7.71 µg/mL was selected. The predictive AUC24h/MIC90 ratios against Campylobacter jejuni, Salmonella, and Escherichia coli were 133, 266 and 8520 (>100), respectively, suggesting that satisfactory efficacy against common intestinal infections would be achieved at a dose of 10 mg/kg b.w. once daily. The PSA results indicated that the intestinal absorption rate constant (Ka) was negatively correlated with the Cmax of ENR in the intestine, suggesting that we could obtain higher intestinal Cmax using P-gp inducers to reduce Ka, thus obtaining a higher Cmax. Our studies suggested that the PBPK model is an excellent tool for formulation and dose design.
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Project description:BackgroundNevirapine-based antiretroviral therapy is the predominant (and often the only) regimen available for children in resource-limited settings. Nevirapine resistance after exposure to the drug for prevention of maternal-to-child human immunodeficiency virus (HIV) transmission is common, a problem that has led to the recommendation of ritonavir-boosted lopinavir in such settings. Regardless of whether there has been prior exposure to nevirapine, the performance of nevirapine versus ritonavir-boosted lopinavir in young children has not been rigorously established.MethodsIn a randomized trial conducted in six African countries and India, we compared the initiation of HIV treatment with zidovudine, lamivudine, and either nevirapine or ritonavir-boosted lopinavir in HIV-infected children 2 to 36 months of age who had no prior exposure to nevirapine. The primary end point was virologic failure or discontinuation of treatment by study week 24.ResultsA total of 288 children were enrolled; the median percentage of CD4+ T cells was 15%, and the median plasma HIV type 1 (HIV-1) RNA level was 5.7 log(10) copies per milliliter. The percentage of children who reached the primary end point was significantly higher in the nevirapine group than in the ritonavir-boosted lopinavir group (40.8% vs. 19.3%; P<0.001). Among the nevirapine-treated children with virologic failure for whom data on resistance were available, more than half (19 of 32) had resistance at the time of virologic failure. In addition, the time to a protocol-defined toxicity end point was shorter in the nevirapine group (P=0.04), as was the time to death (P=0.06).ConclusionsOutcomes were superior with ritonavir-boosted lopinavir among young children with no prior exposure to nevirapine. Factors that may have contributed to the suboptimal results with nevirapine include elevated viral load at baseline, selection for nevirapine resistance, background regimen of nucleoside reverse-transcriptase inhibitors, and the standard ramp-up dosing strategy. The results of this trial present policymakers with difficult choices. (Funded by the National Institute of Allergy and Infectious Diseases and others; P1060 ClinicalTrials.gov number, NCT00307151.).
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