scholarly journals Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 15
Author(s):  
Steven Dunne ◽  
Andrew R. Willmer ◽  
Rosemary Swanson ◽  
Deepak Almeida ◽  
Nicole C. Ammerman ◽  
...  
Keyword(s):  
Phase Transition ◽  
Self Assembly ◽  
Half Life ◽  
Drug Loading ◽  
Model Organism ◽  
Compartment Model ◽  
Multiple Dosing ◽  
Transition Mechanism ◽  
Long Term Treatment ◽  
Context Dependent

Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.

Simultaneous Analysis of the Single and Multiple Dose Pharmacokinetics of the Non-Steroidal Anti-Inflammatory, Alclofenac

1979 ◽  
Vol 7 (4) ◽  
pp. 253-262
Author(s):  
Lawrence T Sennello ◽  
Robert C Sonders ◽  
William G Jochimsen ◽  
Nadav Friedmann
Keyword(s):  
Half Life ◽  
Absorption Rate ◽  
Study Drug ◽  
Compartment Model ◽  
Multiple Dosing ◽  
Healthy Adult Male ◽  
Dosing Regimens ◽  
Rate Of Absorption ◽  
Multiple Dose Pharmacokinetics ◽  
Single Set

Two clinical studies were conducted to study the pharmacokinetics of alclofenac in healthy adult male volunteers when the drug was administered in both single and multiple dosing regimens. The first study involved the participation of thirty-two subjects, each of whom received single 500 mg and 1000 mg oral doses of alclofenac, using a complete crossover experimental design. The second study involved the participation of sixteen subjects, eight of whom received a 500 mg dose, and eight of whom received a 1000 mg dose of alclofenac every eight hours for ninety-six consecutive hours (four days) with no crossover. In the first study, plasma alclofenac levels were monitored for ten hours post-dosing, while in the second study, drug levels were monitored for four and one-half days (i.e. through twelve hours after the last dose). Initially, using the programme NONLIN, single dose data were fit to a bi-exponential equation, with output from these fits serving as initial estimates for a second fit to the same equation. The results of these second fits were then used as initial estimates to fit the multiple dosing data to a multiple dosing one-compartment model with first order absorption and elimination. Finally, all sets of data were simultaneously fit to the one-compartment open model, with both single and multiple dosing, in an attempt to obtain a uniform interpretation, with a single set of parameters that would adequately describe the plasma alclofenac levels to be expected with a variety of dosing regimens. It was found that the kinetics did not significantly change upon going from single to multiple dosing, and that with the exception of the apparent absorption rate constant, a single set of parameters adequately described all the data collected. The rate of absorption seemed to be somewhat dose-dependent at these levels, being slower after 1000 mg doses than after 500 mg doses. For this reason, the simultaneous fitting program was allowed to estimate different absorption rate constants for the 500 mg and 1000 mg doses. The results of these simultaneous analyses were: Vol Distribution/Fraction Abs = 6.56 Litres Absorption Half-Life (500 mg) = 14 Minutes Absorption Half-Life (1000 mg) = 30 Minutes Elimination Half-Life = 2.1 Hours Absorption Lag Time = 14 Minutes

Reversible microscale assembly of nanoparticles driven by the phase transition of a thermotropic liquid crystal

2017 ◽  
Author(s):  
Niamh Mac Fhionnlaoich ◽  
Stephen Schrettl ◽  
Nicholas B. Tito ◽  
Ye Yang ◽  
Malavika Nair ◽  
...  
Keyword(s):  
Phase Transition ◽  
Liquid Crystal ◽  
Self Assembly ◽  
Nematic Phase ◽  
Hierarchical Control ◽  
Building Blocks ◽  
Model System ◽  
Microscopic Level ◽  
Reversible Process ◽  
Thermotropic Liquid Crystal

The arrangement of nanoscale building blocks into patterns with microscale periodicity is challenging to achieve via self-assembly processes. Here, we report on the phase transition-driven collective assembly of gold nanoparticles in a thermotropic liquid crystal. A temperature-induced transition from the isotropic to the nematic phase leads to the assembly of individual nanometre-sized particles into arrays of micrometre-sized aggregates, whose size and characteristic spacing can be tuned by varying the cooling rate. This fully reversible process offers hierarchical control over structural order on the molecular, nanoscopic, and microscopic level and is an interesting model system for the programmable patterning of nanocomposites with access to micrometre-sized periodicities.

scholarly journals Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo

Pharmaceutics ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1210
Author(s):  
Xieguo Yan ◽  
Shiqiang Wang ◽  
Kaoxiang Sun
Keyword(s):  
Drug Loading ◽  
Entrapment Efficiency ◽  
In Vitro Dissolution ◽  
Dissolution Behavior ◽  
In Vivo Evaluation ◽  
Long Term Treatment ◽  
Long Acting

Schizophrenia, a psychiatric disorder, requires long-term treatment; however, large fluctuations in blood drug concentration increase the risk of adverse reactions. We prepared a long-term risperidone (RIS) implantation system that can stabilize RIS release and established in-vitro and in-vivo evaluation systems. Cumulative release, drug loading, and entrapment efficiency were used as evaluation indicators to evaluate the effects of different pore formers, polymer ratios, porogen concentrations, and oil–water ratios on a RIS implant (RIS-IM). We also built a mathematical model to identify the optimized formulation by stepwise regression. We also assessed the crystalline changes, residual solvents, solubility and stability after sterilization, in-vivo polymer degradation, pharmacokinetics, and tissue inflammation in the case of the optimized formulation. The surface of the optimized RIS microspheres was small and hollow with 134.4 ± 3.5 µm particle size, 1.60 SPAN, 46.7% ± 2.3% implant drug loading, and 93.4% entrapment efficiency. The in-vitro dissolution behavior of RIS-IM had zero-order kinetics and stable blood concentration; no lag time was released for over three months. Furthermore, the RIS-IM was not only non-irritating to tissues but also had good biocompatibility and product stability. Long-acting RIS-IMs with microspheres and film coatings can provide a new avenue for treating schizophrenia.

scholarly journals Development of In Situ Self-Assembly Nanoparticles to Encapsulate Lopinavir and Ritonavir for Long-Acting Subcutaneous Injection

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 904
Author(s):  
Irin Tanaudommongkon ◽  
Asama Tanaudommongkon ◽  
Xiaowei Dong
Keyword(s):  
Sustained Release ◽  
Trough Concentration ◽  
Self Assembly ◽  
Subcutaneous Injection ◽  
Drug Loading ◽  
Entrapment Efficiency ◽  
Long Acting

Most antiretroviral medications for human immunodeficiency virus treatment and prevention require high levels of patient adherence, such that medications need to be administered daily without missing doses. Here, a long-acting subcutaneous injection of lopinavir (LPV) in combination with ritonavir (RTV) using in situ self-assembly nanoparticles (ISNPs) was developed to potentially overcome adherence barriers. The ISNP approach can improve the pharmacokinetic profiles of the drugs. The ISNPs were characterized in terms of particle size, drug entrapment efficiency, drug loading, in vitro release study, and in vivo pharmacokinetic study. LPV/RTV ISNPs were 167.8 nm in size, with a polydispersity index of less than 0.35. The entrapment efficiency was over 98% for both LPV and RTV, with drug loadings of 25% LPV and 6.3% RTV. A slow release rate of LPV was observed at about 20% on day 5, followed by a sustained release beyond 14 days. RTV released faster than LPV in the first 5 days and slower than LPV thereafter. LPV trough concentration remained above 160 ng/mL and RTV trough concentration was above 50 ng/mL after 6 days with one subcutaneous injection. Overall, the ISNP-based LPV/RTV injection showed sustained release profiles in both in vitro and in vivo studies.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows – prospective and retrospective analysis

2017 ◽  
Vol 20 (2) ◽  
pp. 261-268
Author(s):  
A. Burmańczuk ◽  
T. Grabowski ◽  
T. Błądek ◽  
C. Kowalski ◽  
P. Dębiak
Keyword(s):  
Dairy Cows ◽  
Half Life ◽  
Drug Distribution ◽  
Compartment Model ◽  
Clinical Mastitis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Lactation Period ◽  
Milk Samples ◽  
Drug Concentrations

Abstract The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Pharmacokinetics and Tissue Residues of Sulfathiazole and Sulfamethazine in Pigs

1994 ◽  
Vol 57 (9) ◽  
pp. 796-801 ◽  
Author(s):  
LIEVE S. G. VAN POUCKE ◽  
CARLOS H. VAN PETEGHEM
Keyword(s):  
Intravenous Injection ◽  
Half Life ◽  
Intramuscular Injection ◽  
Compartment Model ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Parameters ◽  
Tissue Concentrations ◽  
Single Intravenous Injection ◽  
The Individual ◽  
Residue Study

The plasma pharmacokinetics and tissue penetration of sulfathiazole (ST) and sulfamethazine (SM) after intravenous and intramuscular injection in pigs were studied. Following a single intravenous dose of 40 mg ST/kg of bodyweight or 80 mg SM/kg of bodyweight, the plasma ST and SM concentrations were best fitted to a two-compartment model. The areas under the curve were 447 ± 39 and 1485 ± 41 mg/h/L, clearances were 0.090 ± 0.007 and 0.054 ± 0.001 L/kg/h, volumes of distribution were 1.16 ± 0.16 and 0.77 ± 0.06 L/kg, half-lifes in distribution phase were l.18 ± 0.57 and 0.23 ± 0.16 h and half-lifes in eliminations phase were 9.0 ± l.6 and 9.8 ± 0.6 h. When the two compounds were administered simultaneously as a single intravenous injection, the pharmacokinetic parameters for ST were not significantly different. The values for SM show statistical differences for some important parameters: α, β and the AUC0–>∞ were significantly decreased and t1/2α, Vd and CIB were significantly increased. It can be concluded that after a single intravenous injection of 40 mg/kg, sulfathiazole has a high tl/2β resulting in higher tissue concentrations. This half-life, which is higher than what is reported in the literature, is not influenced by the simultaneous presence of sulfamethazine. The tl/2β for sulfamethazine after a single intravenous injection of 80 mg/kg is comparable to the data from the literature and is not influenced by the presence of sulfathiazole. Sulfathiazole and SM were also administered simultaneously as an intramuscular injection to healthy pigs at a dosage of 40 and 80 mg/kg bodyweight. Pharmacokinetic experiments were conducted on three pigs. From this pharmacokinetic study it can be concluded that upon a single intramuscular administration of 40 mg/kg of ST and 80 mg/kg of SM the absolute bioavailability in pigs is 0.92 ± 0.04 for ST and l.01 ± 0.07 for SM. Six pigs received five intramuscular im) injections as a single dose of ST and SM every 24 h for five consecutive days for the residue study. The pigs were slaughtered at different times after the last dose was given and samples were taken from various tissues and organs. Concentrations were determined by a microbiological method and a HPTLC method. No edible tissue contained more than 100 μg/kg of the individual sulfonamides after 10 days of withdrawal. It means that adult animals which have a shorter half-life and thus lower tissue concentrations will certainly meet the economic community EC) maximum residue limits after a 10 days withdrawal period.

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