Oral drug delivery strategies for development of poorly water soluble drugs in paediatric patient population

Salunke, Smita; Brien, Fiona O; Tan, David Cheng Thiam; Harris, David R.; Math, Marie-Christine; Ariën, Tina; Klein, Sandra; Timpe, Carsten

doi:10.1016/j.addr.2022.114507

Cited by 30 publications

(9 citation statements)

References 118 publications

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“…The solubility of NRV in each buffer fell within a range of 950–1000 µg/mL. RTV is a weakly basic compound with pH-dependent solubility in various buffer systems [ 16 ]. The pKa values of RTV are 2.01 and 2.51, owing to the two weakly basic thiazole moieties [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

“…Typically, the poor aqueous solubility of a drug limits its oral bioavailability. There are currently several strategies applied to conquer the challenge of improving drug solubility, including particle size reduction, pre-drug administration, pH adjustment, salt formation, and the addition of surfactants and co-solvents [ 16 ]. The addition of co-solvents is one of the most widely used methods.…”

Section: Introductionmentioning

confidence: 99%

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The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability

Wang,

Ding,

Wang

et al. 2024

Pharmaceutics

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Paxlovid®, a co-packaged medication comprised of separate tablets containing two active ingredients, nirmatrelvir (NRV) and ritonavir (RTV), exhibits good effectiveness against coronavirus disease 2019 (COVID-19). However, the size of the NRV/RTV tablets makes them difficult for some patients to swallow, especially the elderly and those with dysphagia. Therefore, an oral liquid formulation that can overcome this shortcoming and improve patient compliance is required. In this study, we developed a liquid formulation containing NRV and RTV by adopting strategies that used co-solvents and surfactants to enhance the solubility and inhibit possible recrystallization. The in vitro release results showed that NRV and RTV could be maintained at high concentrations in solution for a certain period in the investigated media. In vivo studies in rats showed that the oral bioavailability of NRV/RTV solution was significantly enhanced. Compared to Paxlovid® tablets, the AUC(0–t) of NRV and RTV increased by 6.1 and 3.8 times, respectively, while the Cmax increased by 5.5 times for both. Furthermore, the promoting effect of the absorption of RTV on the bioavailability of NRV was confirmed. Experiments with a beagle showed a similar trend. Stability studies were also conducted at 4 °C, 25 °C, and 40 °C for 90 days, indicating that the oral liquid formulation was physically and chemically stable. This study can be used as a valuable resource for developing and applying oral liquid NRV/RTV formulations in a clinical context.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability

Wang,

Ding,

Wang

et al. 2024

Pharmaceutics

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“…The problem faced by the pharmacy today is drugs that are insoluble in water [1]. Obtaining a drug form that is assimilable by the patient's body is therefore a challenge.…”

Section: Introductionmentioning

confidence: 99%

The Use of Hot Melt Extrusion to Prepare a Solid Dispersion of Ibuprofen in a Polymer Matrix

Biedrzycka

Marcinkowska

2023

Polymers

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In this work, we report the use of the hot melt extrusion method in harsh extrusion conditions, i.e., screw rotation speed of 250 rpm, temperature above 100 °C, and two mixing zones, in order to obtain an amorphous dispersion of an active pharmaceutical ingredient (API) that is sparingly soluble in water. As a polymer matrix Eudragit EPO (E-EPO) and as an API ibuprofen (IBU) were used in the research. In addition, the plasticizer Compritol 888 ATO (COM) was tested as a factor potentially improving processing parameters and modifying the IBU release profile. In studies, 25% by weight of IBU, 10% of COM and various extrusion temperatures, i.e., 90, 100, 120, 130, and 140 °C, were used. Hot melt extrusion (HME) temperatures were selected based on the glass transition temperature of the polymer matrix (Tg = 42 °C) and the melting points of IBU (Tm = 76 °C) and COM (Tm = 73 °C), which were tested by differential scanning calorimetry (DSC). The thermal stability of the tested compounds, determined on the basis of measurements carried out by thermogravimetric analysis (TGA), was also taken into account. HME resulted in amorphous E-EPO/IBU solid dispersions and solid dispersions containing a partially crystalline plasticizer in the case of E-EPO/IBU/COM extrudates. Interactions between the components of the extrudate were also studied using infrared spectroscopy (FTIR-ATR). The occurrence of such interactions in the studied system, which improve the stability of the obtained solid polymer dispersions, was confirmed. On the basis of DSC thermograms and XRPD diffractograms, it was found that amorphous solid dispersions were obtained. In addition, their stability was confirmed in accelerated conditions (40 °C, 75% RH) for 28 days and 3 months. The release profiles of prepared tablets showed the release of 40% to 63% of IBU from the tablets within 180 min in artificial gastric juice solution, with the best results obtained for tablets with E-EPO/IBU extrudate prepared at a processing temperature of 140 °C.

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“…The problem of water solubility is typical for 40% of drugs on the market and for more than 70% of new molecules approved by the Food and Drug Administration (FDA) [4][5][6]. According to the biopharmaceutics classification system (BCS), this can negatively affect bioavailability, and as a result, researchers have now developed many approaches to improve the solubilization and dissolution rates of molecules in water.…”

Section: Introductionmentioning

confidence: 99%

Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer

Markeev,

Tishkov,

Vorobei

et al. 2023

Polymers

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N-butyl-N-methyl-1-phenylpyrrole[1,2-a] pyrazine-3-carboxamide (GML-3) is a potential candidate for combination drug therapy due to its anxiolytic and antidepressant activity. The anxiolytic activity of GML-3 is comparable to diazepam. The antidepressant activity of GML-3 is comparable to amitriptyline. GML-3 is an 18 kDa mitochondrial translocator protein (TSPO) ligand and is devoid of most of the side effects of diazepam, which makes the research on the creation of drugs based on it promising. However, its low water solubility and tendency to agglomerate prevented its release. This research aimed to study the effect of dry grinding, the rapid expansion of a supercritical solution (RESS), and the eutectic mixture (composite) of GML-3 with polyvinylpyrrolidone (PVP) on the particle size, dissolution rate, and lattice retention of GML-3. The use of supercritical CO2 in the RESS method was promising in terms of particle size reduction, resulting in a reduction in the particle size of GML-3 to 20–40 nm with a 430-fold increase in dissolution rate. However, in addition to particle size reduction after RESS, GML-3 began to show signs of a polymorphism phenomenon, which was also studied in this article. It was found that coarse grinding reduced particle size by a factor of 2 but did not significantly affect solubility or crystal structure. Co-milling with the polymer made it possible to level the effect of the appearance of a residual electrostatic charge on the particles, as in the case of grinding, and the increased solubility in the resulting mechanical mixtures of GML-3 with the polymer may also indicate the dissolving properties of polymers (an increase in 400–800 times). The best result in terms of GML-3 solubility was demonstrated by the resulting GML-3:PVP composite at a ratio of 1:4, which made it possible to achieve a solubility of about 80% active pharmaceutical ingredient (API) within an hour with an increase in the dissolution rate by 1600 times. Thus, the creation of composites is the most effective method for improving the solubility of GML-3, superior to micronization.

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Oral drug delivery strategies for development of poorly water soluble drugs in paediatric patient population

Cited by 30 publications

References 118 publications

The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability

The Development of an Oral Solution Containing Nirmatrelvir and Ritonavir and Assessment of Its Pharmacokinetics and Stability

The Use of Hot Melt Extrusion to Prepare a Solid Dispersion of Ibuprofen in a Polymer Matrix

Modeling of the Aqueous Solubility of N-butyl-N-methyl-1-phenylpyrrolo[1,2-a] pyrazine-3-carboxamide: From Micronization to Creation of Amorphous–Crystalline Composites with a Polymer

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