Improvement Of Drug Absorption Research Articles

Enhancing the bioavailability of clozapine through microwave-assisted formulation of a stable β-cyclodextrin inclusion complex

The low oral bioavailability of clozapine due to its poor aqueous solubility, poor dissolution rate, and extensive hepatic first-pass metabolism poses a challenge to the effective treatment of psychiatric disorders. The objective of the current research was to address the above issues by developing a clozapine inclusion complex (CLZ-IC) using the microwave irradiation method. To optimize the formulation and processing variables, namely the molar ratio of CLZ to β-CD (X1) and the irritation reaction time (X2), a 32 factorial design was performed. The phase solubility study revealed the formation of a stable inclusion complex with a stoichiometry of 1:1, suggesting that β-cyclodextrin could effectively solubilize clozapine. The characterization data confirmed the formation of the inclusion complex of clozapine in β-cyclodextrin. The optimized inclusion complex showed a solubility of 342 ± 26 µg/ml and a percentage dissolution of 91.1 ± 3.4% after four hours. The inclusion-complex tablets exhibited excellent physical properties and showed an improved in vitro dissolution profile, with 80% of the drug being released within 100 minutes, compared to marketed tablets (80% release in 300 min). In vivo pharmacokinetic studies conducted in a rat model demonstrated an increase in Cmax, area under the curve (AUC), and relative bioavailability by a factor of 2.26 with the optimized formulation, indicating a significant improvement in drug absorption compared to the marketed tablet. The techno-economic analysis suggests a cost-benefit ratio of 25.08 after 7 years, indicating the suitability for large-scale production. Overall, using Design of Experiment, in silico, and in vivo studies proved effective in optimizing the inclusion-complex formation and enhancing the bioavailability of clozapine. In conclusion, the optimized clozapine-β-cyclodextrin inclusion complex prepared using a time-saving (90 sec) and cost-effective microwave irradiation method exhibited excellent physical properties and demonstrated significant improvements in the drug's solubility, dissolution rate, and pharmacokinetic performance.

Mucoadhesion: mucin-polymer molecular interactions

Mucoadhesion, adhesion of a material to a mucous membrane or a mucus-covered surface, has been employed in drug delivery to prolong contact with adsorption sites and consequently a likely improvement of drug absorption. Mucoadhesion in the oral cavity also provides additional effects on tactile mouthfeel and extended flavor delivery, which impact consumer perception. The mechanisms behind mucoadhesion have not been well understood and there are contradictory literature results on the ranking of mucoadhesive properties of different polymers based on what in-vitro methods that are used. We herein examine the molecular interactions of different polymers with mucin from bovine submaxillary glands at pH 6.6 by using 1H NMR (Nuclear Magnetic Resonance) that provides atomically resolved information on conformational mobility of the mucin. Studying different types of polymers with different chemical structures and degrees of polymerization (DP), we can via the NMR linewidths and the signal intensities distinguish if the polymers interact with specific segments of the mucin or if they have a universal effect on the mobility of all the molecular segments of the mucin. The specific interaction sites on the mucin for positively charged polymer poly(ethyleneimine) are shown to be different from those for negatively and neutrally charged polymers. In addition, the interactions are also driven by the DP, the concentration of the polymers, and the dehydration. Deepened understanding of molecular effects of the different polymers on the mucin can therefore have strong impact on the development of mucoadhesive products in pharmaceutical and food applications. Finally, we raise awareness of the interpretation of rheological data in terms of mucoadhesion.

QbD-Based Development of Cationic Self-nanoemulsifying Drug Delivery Systems of Paclitaxel with Improved Biopharmaceutical Attributes

The present studies describe quality-by-design-based design and characterization of cationic self-nanoemulsifying formulations of paclitaxel for improving its biopharmaceutical attributes. Solubility and phase titration experiments were designed to select the lipidic and emulsifying excipients. Two different types of lipidic nanoformulations were developed using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). The nanoformulations were optimized by mixture designs and subjected to evaluation for globule size, zeta potential, drug release, and intestinal permeability. Following apt mathematical modeling, the optimum nanoformulation was earmarked using numerical optimization. Further, cationic formulations were developed for both LCT- and MCT-containing formulations and subjected to performance evaluation. The optimized formulations were extensively evaluated, where an in vitro drug release study indicated 2.7-fold improvement in dissolution rate from optimized cationic nanoformulations over powder pure drug. Ex vivo and in situ evaluation performed on Wistar rats exhibited nearly six- to eightfold enhancement in permeation and absorption parameters of the drug for the optimized cationic nanoformulation as compared to the pure paclitaxel. Pharmacokinetic studies indicated nearly 13.4-fold improvement in AUC and Cmax, along with 1.8-fold reduction in Tmax of the drug from cationic nanoformulations as compared to the pure drug suspension. Moreover, nanoformulation containing long-chain lipids exhibited superior performance (1.18-fold improvement in drug absorption) over medium-chain lipids. Cytotoxicity evaluation of cationic nanoformulations on MCF-7 cells revealed significant reduction in growth vis-à-vis the pure drug. Overall, the current paper reports successful systematic development of paclitaxel-loaded cationic self-nanoemulsifying systems with distinctly improved biopharmaceutical performance.

Current Designs of Polymer Blends in Solid Dispersions for Improving Drug Bioavailability

Ternary solid dispersions have been demonstrated to be an effective strategy in the improvement of drug absorption and bioavailability. The applications of the combination of hydrophilic polymers with the potential of hydrophobic polymer incorporation at moderate concentrations have been discussed in recent publications. In this paper, the general review of this specific type of solid dispersion will be provided with comprehensive understanding of polymer blends of either hydrophilic or hydrophobic polymers. A detailed description of miscible polymers has been developed in recent studies. In addition to dissolution rate improvement, the role of second polymers in crystal growth inhibition and in maintaining the amorphous state will be mentioned. We also present a summary of characterization techniques commonly used to evaluate solid dispersion and polymer miscibility.

Biorelevant Media Slows the Solution-Mediated Phase Transformation of Amorphous Spironolactone

Solution-mediated phase transformation (SMPT) can reduce the high drug concentration expected from amorphous formulations, eliminating the improvement in drug absorption one hoped to gain from this high energy drug state. The differences in SMPT of a supersaturating system were compared in biorelevant media (fasted state simulated intestinal fluid and fed state simulated intestinal fluid) and United States Pharmacopeia compendial medium, simulated intestinal fluid without pancreatin. Amorphous spironolactone underwent SMPT to the same hydrate of spironolactone in all 3 media which was confirmed by the decrease in dissolution rates assessed in a flow-through dissolution apparatus, as well as by the appearance of crystals on the amorphous solid surface detected by polarized light microscopy. Longer duration of supersaturation which may lead to greater in vivo oral drug absorption was found in both biorelevant media, compared to compendial (average > 90 vs. 20 min), indicating that the presence of surfactants in biorelevant media delays crystal growth. Surface profiles and polarized light micrographs suggest that (1) a significant increase in surface area due to 3D crystal formation, (2) amorphous areas remaining exposed on the surface, and (3) a lower nucleation rate are potential reasons for an elevated dissolution rate even after SMPT.

Competence of raloxifene hydrochloride loaded liquisolid compacts for improved dissolution and intestinal permeation

The primary purpose of this research is to formulate raloxifene hydrochloride (RXH) loaded liquisolid compacts for improved dissolution behavior and intestinal permeation. Owing to their higher drug solubility, Cremophor® EL, Capmul PG-8 and Transcutol P were selected as suitable non-volatile liquid vehicles to develop desired formulations. The liquisolid formulations were obtained by allowing liquid vehicles with varying drug concentrations to get absorbed onto carrier and coating material taken at different ratios (R = 5; R = 10). Avicel PH 102 and Aerosil PH 200 displayed good liquid retention potential values confirming appropriate load factor and thus, resulting in liquisolid powders with good flow properties exemplifying their caliber as efficient solid carrier and coating materials in developing liquisolid compacts. FT-IR spectra illustrated no significant interaction between drug and carrier. The DSC and PXRD studies demonstrated the absence of crystalline form of drug in liquisolid powders. Further, the enhanced dissolution performance of RXH from liquisolid systems suggested the transformation of the drug to molecular/amorphous state. Ex vivo rat intestinal permeation studies revealed an improvement in drug absorption from formulation unraveling the ability of non-volatile liquid vehicles of liquisolid systems in enhancing the intestinal permeation of dissolution rate limited RXH.

A systematic review on drugs absorption modifications after eradication in Helicobacter pylori positive patients undergoing replacement therapy.

Helicobacter pylori (H. pylori) infection has been suggested as a cause of impaired drug absorption. This infection leads to alteration of the gastric acid secretion that may change the conformational characteristics of drugs and their intestinal absorption leading to uncertainties about the dose to administer and the therapeutic results. A systematic review was undertaken to clarify the implications of drug absorption during the administration of replacement therapies. Electronic databases such as MEDLINE/Pubmed, EMBASE and The Cochrane Library [which includes Cochrane Database of Systematic Review (CDSR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Database of Abstract of Reviews of Effect (DARE)] were searched. Grey literature databases (e.g. the International clinical trials registry platform, Trials Register, Clinical Trials.gov, Controlled Trials and TrialsCentral), Theses database, Government publication and LILACS database were also searched. No language restriction was applied. Infection and altered drug absorption were evaluated in patients under replacement therapies with iron, thyroxin and L-dopa. In all, seven studies included an improvement in drug absorption after eradication and an existing inverse correlation between the grade of gastric inflammation and indices of drug absorption were noticed. This systematic review confirmed the presence of an interaction between infection and drug absorption of orally administered replacement therapies. Gastric acid reduction and subsequent alteration of drug composition seem to lead this mechanism. Clinicians should be aware of this possible interaction when starting a replacement therapy in patients and when evaluating poor clinical response.

Novel nanoemulsion for minimizing variations in bioavailability of ezetimibe

The objectives of the present study were to develop an optimal nanoemulsion of ezetimibe and evaluate its stability, lipid lowering and pharmacokinetic potential. Solubility of ezetimibe was determined in various vehicles. Pseudoternary phase diagrams were constructed to determine the existence of nanoemulsion region. Formulations were selected from the oil/water nanoemulsion region and subjected to various thermodynamic stability and dispersibility tests. Release rate of optimized formulations was determined using in vitro dissolution test. The formulation used for evaluation contained Capryol 90 (10% v/v), Tween 80 (15% v/v), Transcutol® P (30% v/v), double distilled water (45% v/v). The release of drug from the nanoemulsion was highly significant (P <0.001) when compared to the drug suspension. The value of total cholesterol in the group administered with the formulation TF1 was highly significant (P <0.001) with respect to the group administered with the suspension of the drug. The plasma concentration time profile of ezetimibe from nanoemulsion represented greater improvement of drug absorption than the marketed formulation and drug suspension. The shelf life of the nanoemulsion was found to be 5.94 years at room temperature. The present study established nanoemulsion to be a possible alternative for minimizing variation in bioavailability of ezetimibe.

Improvement of drug absorption through enhancers

The application of enhancers for improvement of drug absorption via the nasal, transdermal and rectal route are outlined. The importance of the relation between the time course of the enhancing effect and the desired plasma - concentration - time profile of the drug is stressed as well as the need to pay more attention to the safety aspects of absorption enhancers.