The Inclusion of Tolfenamic Acid into Cyclodextrins Stimulated by Microenvironmental pH Modification as a Way to Increase the Anti-Migraine Effect.

PURPOSE: The poorly soluble nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA), was studied to maximize its solubility, permeability through biological membranes, and pharmacological activity. METHODS: A mixture with magnesium stearate (MS) - microenvironment pH-modifier was prepared, as well as systems additionally containing incorporating substances methyl-ß-cyclodextrin (M-ß-CD) and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The identification of TA-MS-CD systems was confirmed using experimental methods: X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FT-IR) with the theoretical support. Apparent solubility study was performed using the paddle apparatus, while in vitro gastrointestinal tract (GIT) and blood-brain barrier (BBB) permeability were conducted by using PAMPA (Parallel Artificial Membrane Permeability Assay). The in vivo part of the study used the mouse nitroglycerin (NTG)-induced migraine pain model. RESULTS: From practically insoluble substance, TA in TA-MS-M-ß-CD system dissolved up to 80.13% ± 2.77%, and in TA-MS-HP-ß-CD up to 92.39% ± 3.25% in 180 minutes. An increase in TA permeability was also obtained in the TA-MS-M-ß-CD and TA-MS-HP-ß-CD systems through GIT membranes (Papp values 2.057 x 10-5 cm s-1 and 2.091 x 10-5 cm s-1, respectively) and through BBB (Papp values 3.658 x 10-5 cm s-1 and 3.629 x 10-5 cm s-1, respectively). The enlargement of the solubility and permeability impacted analgesia. The dose 25 mg/kg of both TA-MS-HP-ß-CD and TA-MS-M-ß-CD was almost equally effective and only slightly less effective than the dose 50 mg/kg of pure TA. Both TA-MS-HP-ß-CD and TA-MS-M-ß-CD used at 50 mg/kg more effectively attenuated tactile allodynia in NTG-treated mice than the same dose of pure TA. None of TA forms influenced heat hyperalgesia. CONCLUSION: Increasing solubility of TA caused an increase of its analgesic effect in an animal model of migraine pain.

Amine-Grafted Mesoporous Carbons as Benzocaine-Delivery Platforms.

Smart porous carriers with defined structure and physicochemical properties are required for releasing the therapeutic drug with precise control of delivery time and location in the body. Due to their non-toxicity, ordered structure, and chemical and thermal stability, mesoporous carbons can be considered modern carriers for active pharmaceutical ingredients whose effectiveness needs frequent dosing algorithms. Here, the novel benzocaine delivery systems based on ordered mesoporous carbons of the cubic structure were obtained with the use of a hard template method and functionalization with amine groups at 40 °C for 8 h. It has been shown that amine grafting strongly modifies the surface chemistry and textural parameters of carbons. All samples indicated good sorption ability towards benzocaine, with evident improvement following the functionalization with the amine groups. The sorption capacity and drug release kinetics were strongly affected by the porosity of carbon carriers and the surface functional groups. The smallest amount of benzocaine (~12%) was released from pristine mesoporous carbon, which could be correlated with strong API-carrier interactions. Faster and more efficient release of the drug was observed in the case of triethylenetetramine modified carbon (~62%). All benzocaine delivery platforms based on amine-grafted mesoporous carbons revealed high permeability through the artificial membrane.

Combinations of Piperine with Hydroxypropyl-ß-Cyclodextrin as a Multifunctional System.

Piperine is an alkaloid that has extensive pharmacological activity and impacts other active substances bioavailability due to inhibition of CYP450 enzymes, stimulation of amino acid transporters and P-glycoprotein inhibition. Low solubility and the associated low bioavailability of piperine limit its potential. The combination of piperine with 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) causes a significant increase in its solubility and, consequently, an increase in permeability through gastrointestinal tract membranes and the blood-brain barrier. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR) were used to characterize interactions between piperine and HP-ß-CD. The observed physicochemical changes should be combined with the process of piperine and CD system formation. Importantly, with an increase in solubility and permeability of piperine as a result of interaction with CD, it was proven to maintain its biological activity concerning the antioxidant potential (2,2-diphenyl-1-picryl-hydrazyl-hydrate assay), inhibition of enzymes essential for the inflammatory process and for neurodegenerative changes (hyaluronidase, acetylcholinesterase, butyrylcholinesterase).

Structural Polymorphism of Sorafenib Tosylate as a Key Factor in Its Solubility Differentiation.

The presence of active pharmaceutical ingredients (APIs) in the forms of different polymorphic states can induce differences in their physicochemical properties. In the case of poorly soluble APIs, like the oncological drug sorafenib tosylate, small variations in solubility may result in large bioavailability differences. The control of its therapeutic dose is crucial from the effective pharmacotherapy point of view and the reduction of side effects. Therefore, this study aimed to assess the influence of sorafenib tosylate polymorphic forms on its solubility and, consequently, permeability, based on passive diffusion through membranes simulating the gastrointestinal tract (GIT) conditions. In the first part of the work, two crystalline forms of sorafenib tosylate were identified using the X-ray powder diffraction, FT-IR, and Raman spectroscopy. Subsequently, solubility studies were carried out. Both forms of sorafenib tosylate were insoluble in 0.1 N hydrochloric acid (HCl), in acetate buffer (pH 4.5), and in phosphate buffer (pH 6.8). Solubility (mg/mL) of form I and III of sorafenib tosylate in 0.1 N HCl + 1.0% SDS was 0.314 ± 0.006 and 1.103 ± 0.014, respectively, in acetate buffer pH 4.5 + 1.0% SDS it was 2.404 ± 0.012 and 2.355 ± 0.009, respectively, and in phosphate buffer pH 6.8 + 1.0% SDS it was 0.051 ± 0.005 and 1.805 ± 0.023, respectively. The permeability study was assessed using the parallel artificial membrane permeability assay (PAMPA) model. The apparent permeability coefficient (Papp-cm s-1) of form I and III in pH 1.2 was 3.01 × 10-5 ± 4.14 × 10-7 and 3.15 × 10-5 ± 1.89 × 10-6, respectively, while in pH 6.8 it was 2.72 × 10-5 ± 1.56 × 10-6 and 2.81 × 10-5 ± 9.0 × 10-7, respectively. Changes in sorafenib tosylate concentrations were determined by chromatography using the high-performance liquid chromatography (HPLC)-DAD technique. As a result of the research on the structural polymorphism of sorafenib tosylate, its full spectral characteristics and the possibility of using FT-IR and Raman spectroscopy for the study of polymorphic varieties were determined for the first time, and the HPLC method was developed, which is appropriate for the assessment of sorafenib solubility in various media. The consequences of various physicochemical properties resulting from differences in the solubility of sorafenib tosylate polymorphs are important for pre-formulation and formulation studies conducted with its participation and for the safety of oncological sorafenib therapy.

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment.

Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes. The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson's disease, Tourette's syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors. The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.

Design of Paracetamol Delivery Systems Based on Functionalized Ordered Mesoporous Carbons.

The oxidized ordered mesoporous carbons of cubic and hexagonal structure obtained by two templating methods (soft and hard) were applied for the first time as delivery systems for paracetamol-the most common antipyretic and analgesic drug in the world. The process of carbon oxidation was performed using an acidic ammonium persulfate solution at 60 °C for 6 h. The functionalization was found to reduce the specific surface area and pore volume of carbon materials, but it also led to an increasing number of acidic oxygen-containing functional groups. The most important element and the novelty of the presented study was the evaluation of adsorption and release ability of carbon carriers towards paracetamol. It was revealed that the sorption capacity and the drug release rate were mainly affected by the materials' textural parameters and the total amount of surface functional groups, notably different in pristine and oxidized samples. The adsorption of paracetamol on the surface of ordered mesoporous carbons occurred according to different mechanisms: donor-acceptor complexes and hydrogen bond formation. The adsorption kinetics was assessed using pseudo-first- and pseudo-second-order models. The regression results indicated that the adsorption kinetics was more accurately represented by the pseudo-second-order model. Paracetamol was adsorbed onto the carbon materials studied following the Langmuir type isotherm. The presence of oxygen-containing functional groups on the surface of ordered mesoporous carbons enhanced the amount of paracetamol adsorbed and its release rate. The optimal drug loading capacity and expected release pattern exhibited oxidized ordered mesoporous carbon with a hexagonal structure obtained by the hard template method.

Hydroxypropyl-ß-cyclodextrin as an effective carrier of curcumin - piperine nutraceutical system with improved enzyme inhibition properties.

The nutraceutical system of curcumin-piperine in 2-hydroxypropyl-ß-cyclodextrin was prepared by using the kneading technique. Interactions between the components of the system were defined by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR). Application of hydroxypropyl-ß-cyclodextrin as a carrier-solubiliser improved solubility of the curcumin-piperine system, its permeability through biological membranes (gastrointestinal tract, blood-brain barrier) as well as the antioxidant, antimicrobial and enzyme inhibitory activities against acetylcholinesterase and butyrylcholinesterase.

Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates.

Epilepsy is a chronic neurological disorder affecting nearly 65-70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30-40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy.

Computer-Aided Design of Cefuroxime Axetil/Cyclodextrin System with Enhanced Solubility and Antimicrobial Activity.

This study aimed to investigate changes in the solubility and antimicrobial efficacy of cefuroxime axetil (CA) when incorporated into cyclodextrin (CD). While choosing the CD, the validated in silico model was used. A theoretical model based on docking and molecular mechanics/generalized born surface area was validated using a curated dataset of API (active pharmaceutical ingredient)-CD stability constants. The library of commonly used cyclodextrins was virtually screened, indicating CA -hydroxypropyl-ßCD (HPßCD) as the most thermodynamically favored system. Solid-state CA-HPßCD system was prepared and characterized by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR), and X-ray diffraction (XRPD) methods. The dissolution profiles of the CA and its cyclodextrin system were evaluated. Microbiological activity of the CA-HPßCD inclusion system was studied based on changes in minimal inhibitory concentration (MIC) values and related to ones of the pure CA. The theoretical model was successfully validated, obtaining an average correlation with experimental data R = 0.7. The dissolution study showed significantly improved dissolution profiles of CA-HPßCD compared to CA. HPßCD increases the antimicrobial efficacy of CA up to 4-fold compared to pure CA.

The Radiostability of Meropenem Trihydrate in Solid State.

The influence of ionising radiation on the physicochemical properties of meropenem trihydrate in solid state was studied for doses of e-beam radiation: 25 kGy and 400 kGy. In the first part of our studies, we evaluated the possibility of applying radiosterilization to obtain sterile meropenem. No changes for meropenem irradiated with a dose of 25 kGy, the dose required to attain sterility, was confirmed in the results of spectroscopic (FT-IR), thermal (DSC, TGA) and X-ray powder diffraction (XRPD) studies. The radiation dose of 25 kGy produces no more than about 1500 ppm of radical defects. The chromatographic studies of irradiated meropenem in solutions did not show any chemical degradation. Moreover, the antimicrobial activity of meropenem irradiated with the dose of 25 kGy was unchanged. Based on the received results, we can conclude that radiostelization is a promising, alternative method for obtaining sterile meropenem. In the second part of the research, meropenem was exposed to e-beam radiation at the 400 kGy dose rate. It was confirmed, that reducing of antimicrobial activity could be connected with the degradation of ß-lactam ring and changes in the trans-hydroxyethyl group. Apart from chemical changes, changes in the physical stability of irradiated meropenem (400 kGy) was also observed.