Water-soluble Nonsteroidal Anti-inflammatory Drug Research Articles

ENHANCING TRANSDERMAL DELIVERY OF POORLY WATER-SOLUBLE NSAIDS: EFFECTIVE STRATEGIES

Transdermal drug delivery offers significant advantages for administering non-steroidal anti-inflammatory drugs (NSAIDs) and anti-complementary drugs, particularly those with poor water solubility. This delivery route bypasses first-pass metabolism and gastrointestinal degradation, enhancing bioavailability and patient compliance. However, the stratum corneum, the outermost layer of the skin, poses a formidable barrier to drug permeation. To address this challenge, several innovative strategies have been developed to improve the transdermal delivery of these poorly soluble drugs. Chemical enhancers, such as alcohols, fatty acids, and surfactants, can disrupt the lipid structure of the stratum corneum, increasing drug solubility and permeability. Nanoformulations, including liposomes, niosomes, solid lipid nanoparticles, and nanoemulsions, enhance drug solubility, provide protection against degradation, and facilitate controlled release with deeper skin penetration. Prodrugs, designed to convert into the active drug within the skin, can improve solubility and permeability. Physical methods like microneedles, iontophoresis, and phonophoresis create micropores or use electrical and ultrasound waves to enhance permeation without compromising skin integrity. Cyclodextrins form inclusion complexes with drugs, boosting solubility and stability. Hydrogels and polymer-based formulations create a moist environment for sustained drug release and better absorption. Co-solvents and surfactants, such as ethanol and DMSO, further enhance solubility and disrupt the stratum corneum to facilitate drug penetration. Electroporation and thermal ablation transiently disrupt the skin barrier, significantly improving drug permeation. These strategies, individually or in combination, hold promise for optimizing the transdermal delivery of poorly water-soluble NSAIDs and anticomplementary drugs, ensuring effective therapeutic outcomes and improved patient compliance.

Strategies to Improve the Transdermal Delivery of Poorly Water-Soluble Non-Steroidal Anti-Inflammatory Drugs.

The transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) has the potential to overcome some of the major disadvantages relating to oral NSAID usage, such as gastrointestinal adverse events and compliance. However, the poor solubility of many of the newer NSAIDs creates challenges in incorporating the drugs into formulations suitable for application to skin and may limit transdermal permeation, particularly if the goal is therapeutic systemic drug concentrations. This review is an overview of the various strategies used to increase the solubility of poorly soluble NSAIDs and enhance their permeation through skin, such as the modification of the vehicle, the modification of or bypassing the barrier function of the skin, and using advanced nano-sized formulations. Furthermore, the simple yet highly versatile microemulsion system has been found to be a cost-effective and highly successful technology to deliver poorly water-soluble NSAIDs.

Small is Powerful: Demonstration of the Impact of Nanoformed Piroxicam in a Controlled Clinical Study.

New solutions are needed to enable the efficient use of poorly water-soluble drugs. Therefore, we aimed to demonstrate that decreasing particle size with a solution-to-particle method known as nanoforming can improve dissolution and thus bioavailability. Piroxicam, a poorly water-soluble non-steroidal anti-inflammatory drug (NSAID), was used as a model compound. A Quality-by-Design (QbD) approach was used to nanoform piroxicam and a design space was established. The pharmacokinetics of piroxicam nanoparticles were compared to two marketed products in a clinical trial. Nanoformed tablets showed a 33% increase in exposure during the first hour after dosing (AUC0-1h) compared with an immediate release tablet and was similar to a fast absorbing tablet incorporating complexation of piroxicam with β-cyclodextrin. The results show that nanoforming enabled more rapid absorption in comparison to a typical marketed tablet and indicate that nanoforming is an alternative to complex formulation such as cyclodextrins based products. The study outcomes support the potential of nanoforming for producing fast-acting dosage forms of poorly soluble drugs.

Evaluation of Solubility, Physicochemical Properties, and Cytotoxicity of Naproxen-Based Ionic Liquids.

To solve the problems associated with poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs), naproxen-based ionic liquids (ILs) containing naproxen as an active pharmaceutical ingredient (API) anion were prepared with benzalkonium (tetradecyldimethylbenzyl ammonium), choline, and 1-octyl-3-methylimidazole as the cation. The structures and thermal properties were analyzed. Through the conductivity method, the solubility at 25 and 37 °C and the critical micelle concentration (CMC) at 25 °C were determined in water and ethanol. The octanol-water partition coefficients (K ow) at 25 °C were measured with the shake-flask method. The cytotoxicity was evaluated with the MTT method. The results showed that the conversion of naproxen into the API-ILs increased the API's solubility in water by more than 850 times compared with the original API, and the thermostability was satisfactory with a lower glass transition temperature (t g). Moreover, the variation trends of solubility, hydrophilicity, and K ow were consistent with the different structures of naproxen-based ILs, except for benzalkonium naproxen. The CMC (10-5-10-6 M) in water and ethanol demonstrated that the naproxen-based ILs were surface activite ILs. The IC50 values exhibited the low cytotoxicity of the naproxen-based ILs, which was better than 100 μM. The results provide essential information and a research basis for future topical and transdermal administration and oral administration of naproxen-based ILs.

A comprehensive analysis of meloxicam particles produced by nanosecond laser ablation as a wet milling technique

Recently, the number of water insoluble and poorly soluble drug compounds has increased significantly. Therefore, growing interest has been witnessed in different particle size reduction techniques to improve the dissolution rates, transport characteristics and bioavailability of drugs. Laser ablation has proven to be an alternative method to the production of nano- and micrometre-sized drug particles without considerable chemical damage. We present the nanosecond laser ablation of drug pastilles in distilled water, targeting meloxicam, a poorly water soluble nonsteroidal anti-inflammatory drug, at different laser wavelengths (248 nm, 532 nm and 1064 nm). Besides chemical characterization, crystallinity, morphology and particle size studies, the mechanism of the particle generation process was examined. The applicability of ablated particles in drug formulation was investigated by solubility, cytotoxicity and anti-inflammatory effect measurements. We showed that laser ablation is a clean, efficient and chemically non-damaging method to reduce the size of meloxicam particles to the sub-micrometre–few micrometre size range, which is optimal for pulmonary drug delivery. Complemented by the excellent solubility (four to nine times higher) and anti-inflammatory (four to five times better) properties of the particles compared to the initial drug, laser ablation is predicted to have wider applications in the development of drug formulations.

Carboxyl-functionalized mesoporous silica nanoparticles for the controlled delivery of poorly water-soluble non-steroidal anti-inflammatory drugs

The purpose of this study was to investigate the delivery of poorly water-soluble non-steroidal anti-inflammatory drugs (NSAIDs) by carboxyl-functionalized mesoporous silica nanoparticles (MSN-COOH) with high specific surface area (SBET). In this study, MSN-COOH was prepared by collaborative self-assembly using cetyltrimethylammonium bromide (CTAB) as template and hydrolysis (3-triethoxyl-propyl) succinic anhydride (TESPSA) as co-structure auxiliary directing agent (CSDA). The drug delivery systems were constructed with NSAIDs including Nimesulide (NMS) and Indomethacin (IMC) as model drugs. Moreover, the characterization techniques, hemolysis and bio-adsorption testes, in vitro drug release and in vivo biological studies of MSN-COOH were also carried out. The characterization results showed that MSN-COOH is spheres with clearly visible irregular honeycomb nanopores and rough surface (SBET: 1257 m2/g, pore volume (VP): 1.17 cm3/g). After loading NMS/IMC into MSN-COOH with high drug loading efficiency (NMS: 98.7 and IMC: 98.2%), most crystalline NMS and IMC converted to amorphous phase confirmed using differential scanning calorimeter (DSC) and X-ray power diffraction (XRD) analysis. Meanwhile, MSN-COOH significantly increased the dissolution of NMS and IMC compared with non-functionalized mesoporous silica nanoparticles (MSN), which was also confirmed by wettability experiments. The results of in vivo biological effects showed that MSN-COOH had higher bioavailability of NMS and IMC than MSN, and exerted strong anti-inflammatory effects by delivering more NMS and IMC in vivo. Statement of significanceThis study successfully prepared MSNs-COOH (mesoporous silica nanoparticles modified with negatively charged carboxyl groups on the surface and in the pores) with high specific surface area and pore volume by using the negatively charged carboxyl group (hyd-TESPSA) and the positively charged CTAB self-assembled through electrostatic attraction under alkaline conditions. The drug delivery systems were constructed with Nimesulide (NMS) and Indomethacin (IMC) as model drugs. The results showed MSNs-COOH had high drug loading capacity and also exhibited good in vitro drug release properties. Interestingly, NMS loaded MSNs-COOH also had a potential pH responsive release effect. In vivo biological studies revealed that NMS/IMC loaded MSNs-COOH could evidently improve the bioavailability and played the strong anti-inflammatory effects.

Synthesis and characterization of a nanoemulsion system for solubility enhancement of poorly water soluble non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) are highly used for the management and treatment of chronic and acute inflammation and to get relief from pain. It consists of a group of organic compounds having anti-inflammatory, anti-pyretic, and analgesic properties. However, majority of these drugs are poorly-water soluble leading to compromised bioavailability and hence limited therapeutic activity. In order to overcome these issues, we have studied the formulation, characterization, and cytotoxicity of NSAIDs, entrapped inside nanoemulsion droplets. NSAIDs-loaded nanoemulsions have been prepared by spontaneous aqueous titration method after the screening of excipients. On the basis of drug solubility study, the mixture of clove oil and isopropyl myristate has been selected as oil phase, whereas Tween 80 and isopropyl alcohol have been used as surfactant and co-surfactant respectively. The hydrodynamic sizes of Diflunisal and Niflumic acid-loaded nanoemulsions obtained from Dynamic Light Scattering (DLS) have been found in the range of 8–22 nm with the polydispersity index (PDI) below 0.5, implying fairly homogenous populations. The transmission electron microscopic (TEM) data supported the DLS results. However, the low zeta potentials of these nanodroplets suggest the formation of metastable nanoemulsions which have been further evaluated by various stress-stability studies. The cytotoxicity assay of the nanoemulsions loaded with poorly water-soluble drugs such as Diflunisal and Niflumic acid holds the promise of improved efficacy when administered via different routes such as oral, transdermal, or local application.

Application of pulsed laser ablation (PLA) for the size reduction of non-steroidal anti-inflammatory drugs (NSAIDs)

We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ1 = 532 nm/λ2 = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30–80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration.

On-line dissolution analysis of multiple drugs encapsulated in electrospun nanofibers.

Electrospun nanofiber is a very attractive material which can be used as the support to form multiple-drug dosage. Understanding the dissolution process of different active drug ingredients released from electrospun fibers is of great importance to control and evaluate the quality of medicated nanofibers. Here we present the first study of on-line automatic analysis of dissolution of multiple drugs in electrospun fiber mats. Single-needle electrospinning technology is utilized to combine polymers, hydrophilic polyvinylpyrrolidone (PVP) and hydrophobic polycaprolactone (PCL) as carrier to load three poorly water-soluble non-steroidal anti-inflammatory drugs (paracetamol, nimesulide, and ibuprofen). The loading of the drugs in PVP/PCL electrospun fibers are characterized by various techniques, including scanning electron microscopy, X-ray diffraction, Fourier infrared spectroscopy and differential scanning calorimetry. The in vitro dissolution is investigated by our home-made portable analyzer, which can simultaneously on-line determine multiple drugs released from the nanofibers by a single step. The analysis shows a wide linear detection range of the drugs with limit-of-detection (LOD) down to μg/mL-level. The dissolution profiles of three ingredients in nanofibers can be monitored every thirty seconds from the beginning to the end in the entire dissolution process from only one HSCE run. The kinetic information of the dissolution, including the dissolution curve, characteristic dissolution time and dissolution efficiency, is obtained and evaluated for different dissolution media, drug loading content and the ratio of PVP/PCL. Our study provides a promising method for rapid and accurate dissolution testing of nanofiber-based drugs, and would extend the applications of separation techniques in pharmaceutical analysis.

Fast Dissolving Oral Drug Delivery System Based on Electrospun Nanofibrous Webs of Cyclodextrin/Ibuprofen Inclusion Complex Nanofibers.

In this study, the polymer-free electrospinning was performed in order to produce cyclodextrin/ibuprofen inclusion complex nanofibers, which could have potential as the fast dissolving oral drug delivery system. Ibuprofen is a poorly water-soluble nonsteroidal anti-inflammatory drug; however, the water solubility of ibuprofen can be significantly enhanced by inclusion complexation with cyclodextrins. Here, hydroxypropyl-beta-cyclodextrin (HPβCyD) was chosen both as a nanofiber matrix and host molecule for inclusion complexation in order to enhance water solubility and fast dissolution of ibuprofen. Ibuprofen was inclusion-complexed with HPβCyD in highly concentrated aqueous solutions of HPβCyD (200%, w/v) having two different molar ratios: 1:1 and 2:1 (HPβCyD/ibuprofen). The HPβCyD/ibuprofen-IC (1:1) aqueous solution was turbid having some undissolved/uncomplexed ibuprofen, whereas HPβCyD/ibuprofen-IC (2:1) aqueous solution was homogeneous and clear, indicating that ibuprofen was totally complexed with HPβCyD and becomes water soluble. Then, both HPβCyD/ibuprofen-IC solutions (1:1 and 2:1) were electrospun into bead-free and uniform nanofibers having ∼200 nm fiber diameter. The electrospun HPβCyD/ibuprofen-IC nanofibers were obtained as nanofibrous webs having self-standing and flexible character, which is appropriate for fast dissolving oral drug delivery systems. Ibuprofen was completely preserved during the electrospinning process, and the resulting electrospun HPβCyD/ibuprofen-IC nanofibers were produced without any loss of ibuprofen by preserving the initial molar ratio of 1:1 and 2:1 (HPβCyD/ibuprofen). X-ray diffraction and differential scanning calorimetry measurements indicated the presence of some crystalline ibuprofen in HPβCyD/ibuprofen-IC (1:1) nanofibers, whereas ibuprofen was totally in the amorphous state in HPβCyD/ibuprofen-IC (2:1) nanofibers. Nonetheless, both HPβCyD/ibuprofen-IC (1:1 and 2:1) nanofibrous webs have shown very fast dissolving character when contacted with water or when wetted with artificial saliva. In brief, our results revealed that electrospun HPβCyD/ibuprofen-IC nanofibrous webs have potential as fast dissolving oral drug delivery systems.

Preparation and characterization of N-benzyl-N,O-succinyl chitosan polymeric micelles for solubilization of poorly soluble non-steroidal anti-inflammatory drugs

Purpose: To investigate the solubilization of poorly water-soluble non-steroidal anti-inflammatory drugs (NSAIDs) in N-benzyl-N,O-succinyl chitosan (BSCS) polymeric micellesMethods: BSCS was synthesized by reductive amination and succinylation, respectively. NSAIDs; meloxicam (MX), piroxicam (PRX), ketoprofen (KP) and indomethacin (IND) were entrapped in the hydrophobic inner cores by evaporation method. The effects of drug structure on loading efficiency, particle size and surface charge of micelles were investigated.Results: The critical micelle concentration of BSCS micelles was 0.0385 mg/mL and cytotoxicity on Caco-2 cells depends on the polymer concentration (IC50 = 3.23 ± 0.08 mg/mL). BSCS micelles were able to entrap MX, PRX, KP and IND and also improve the solubility of drugs. Drug loading efficiency was highly dependent on the drug molecules. The drug loading capacity of these BSCS micelles was in the following rank order: KP (282.9 μg/mg) > PRX (200.8 μg/mg) > MX (73.7 μg/mg) > IND (41.2 μg/mg). The highest loading efficiency was observed in KP-loaded BSCS micelles due to the attractive force between phenyl groups of KP and benzyl groups of the polymer. Particle size and surface charge were in the range of 312 - 433 nm and -38 to -41 mV, respectively.Conclusion: BSCS copolymer presents desirable attributes for enhancing the solubility of hydrophobic drugs. Moreover, BSCS polymeric micelles might be beneficial carrier in a drug delivery system.Keywords: BSCS, polymeric micelles, solubilization, non-steroidal anti-inflammatory drugs

Preparation and characterization of N-benzyl-N,O-succinyl chitosan polymeric micelles for solubilization of poorly soluble non-steroidal anti-inflammatory drugs

Purpose: To investigate the solubilization of poorly water-soluble non-steroidal anti-inflammatory drugs (NSAIDs) in N-benzyl-N,O-succinyl chitosan (BSCS) polymeric micellesMethods: BSCS was synthesized by reductive amination and succinylation, respectively. NSAIDs; meloxicam (MX), piroxicam (PRX), ketoprofen (KP) and indomethacin (IND) were entrapped in the hydrophobic inner cores by evaporation method. The effects of drug structure on loading efficiency, particle size and surface charge of micelles were investigated.Results: The critical micelle concentration of BSCS micelles was 0.0385 mg/mL and cytotoxicity on Caco-2 cells depends on the polymer concentration (IC50 = 3.23 ± 0.08 mg/mL). BSCS micelles were able to entrap MX, PRX, KP and IND and also improve the solubility of drugs. Drug loading efficiency was highly dependent on the drug molecules. The drug loading capacity of these BSCS micelles was in the following rank order: KP (282.9 μg/mg) > PRX (200.8 μg/mg) > MX (73.7 μg/mg) > IND (41.2 μg/mg). The highest loading efficiency was observed in KP-loaded BSCS micelles due to the attractive force between phenyl groups of KP and benzyl groups of the polymer. Particle size and surface charge were in the range of 312 - 433 nm and -38 to -41 mV, respectively.Conclusion: BSCS copolymer presents desirable attributes for enhancing the solubility of hydrophobic drugs. Moreover, BSCS polymeric micelles might be beneficial carrier in a drug delivery system.Keywords: BSCS, polymeric micelles, solubilization, non-steroidal anti-inflammatory drugs

Solid lipid nanoparticles for the controlled delivery of poorly water soluble non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (IBP) are among the most prescribed drugs across the globe. However, most NSAIDs are insoluble in water leading them to have poor bioavailability and erratic absorption. Moreover, NSAIDs such as IBP and ketoprofen (KP) have to be administered very frequently due to their short plasma half-life leading to side effects. Controlled release formulations of IBP, KP and nabumetone (NBT) based on solid lipid nanoparticles (SLNs) were successfully synthesised in the present study to solve the above-mentioned challenges that are associated with NSAIDs. SLNs were prepared in two steps; hot-melt homogenization followed by sonication to formulate SLNs with spherical morphology. While capmul® GMS-50K (capmul) was used as the lipid due to the high solubility of the studied drugs in it, gelucire® 50/13 (gelucire) was used as the surfactant. It was found that particle size was directly proportional to drug concentration and inversely proportional to surfactant concentration, volume of water added and temperature of water. Ultrasonication in a pulse mode with optimum duration of 15min was essential to obtain smaller nanoparticles through the formation of a nanoemulsion. Drug loaded SLNs with small particle size and narrow size distribution with good solid loading, encapsulation efficiency and drug loading percentage could be prepared using the optimised conditions. SLNs prepared at the optimised condition were characterized thoroughly by using different techniques such as dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR). The cytotoxicity results showed that the prepared SLNs are non-toxic to Raw cell line. The drugs IBP, KP and NBT showed 53, 74 and 69% of percentage entrapment efficiency with drug loading of 6, 2 and 7% respectively. Slow, steady and sustained drug release was observed from the SLNs for over 6days.

Ultrafiltration-Based Extraction and HPLC Analysis of Naproxen Sodium in Human Plasma Samples: an Innovative Approach to Pharmaceutical Analysis

The purpose of this study was to assess the possibility of using ultrafiltration-based extraction for pharmaceutical analysis and develop an innovative, rapid and simple analysis technique for determination of naproxen sodium in human plasma. The proposed extraction technique can be adapted for wide range of active pharmaceutical ingredients including water-soluble nonsteroidal anti-inflammatory drugs. Naproxen sodium was isolated from human plasma by ultrafiltration-based extraction and analyzed by HPLC. Proteins in the plasma samples were precipitated with methanol and the supernatant was filtered through commercial centrifugal filters (<3 kDa). The filtered part was vacuum centrifuged, dried, and then dissolved in water and centrifuged again. The supernatant was injected into the HPLC system where an ACE 5 μm C18 100 A LC column (150 × 4.6 mm) was used. The mobile phase was acetonitrile – phosphate buffer (pH 3.0, 20 mM) 55 : 45 v/v mixture, the injection volume was 20 μL, and the UV detection was performed at 240 nm. Using the developed extraction technique combined with HPLC method, plasma samples containing naproxen sodium were successfully analyzed (RSD 1.04–6.47, bias 2.33–6.00).

Analgesic Effects of 1st Generation Anti-histamines in Mice.

Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a well-known mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia.

Rheological and textural properties of microemulsion-based polymer gels with indomethacin

In this paper, we present novel microemulsion (ME)-based semisolid polymer gels designed for topical administration of poorly water soluble non-steroidal anti-inflammatory drugs. Indomethacin (IND) was used as a model compound. The ME consisted of castor oil, water, Tween®80 as a surfactant and ethanol as cosurfactant. To obtain the desired consistency of the formulations Carbopol®960 was applied as a thickening agent. The aim of the study was to analyze in detail the mechanical properties of the obtained systems, with special attention paid to the features crucial for topical application. The rheological and textural experiments performed for samples with and without the incorporated drug clearly indicate that flow characteristics, viscoelastic properties and texture profiles were affected by the presence of IND. Novel semisolid formulations with IND described for the first time in this paper can be considered as an alternative for commercially available conventional topical dosage forms.

Improvement of solubility of celecoxib by inclusion in MCM-41 mesoporous silica: drug loading and release

Celecoxib is a poorly water-soluble nonsteroidal anti-inflammatory drug. Here we report four ordered mesoporous silica MCM-41 supports with different particle size, pore volume, and surface properties to investigate their loading capacity with celecoxib and their release abilities. Spherical MCM-41 mesoporous supports less than 50 nm in diameter were prepared and to compare the effect of the template removal process on morphology of samples, acid extraction and calcination methods were used. Moreover, nearly 500 nm sized rod-shaped MCM-41 mesoporous silica was obtained by changing the template concentration in preparation. Boron doping was performed to determine the effect of a heteroatom on the surface of mesoporous silica and adsorbance of drug molecules and release. In order to investigate the effect of polarity of solvent during drug loading, two different solvents were used: ethanol as polar solvent and hexane as nonpolar solvent. All bare and drug-loaded samples' physicochemical characterizations were performed. The release experiments were conducted in phosphate buffer solution of pH 7.4 at 37 °C. Celecoxib solubility was highly improved compared to the pure drug. The morphology and surface property differences of MCM-41 and the solvent effect in adsorption of celecoxib have been discussed, including its delivery.

Experimental and Computational Studies of Physicochemical Properties Influence NSAID-Cyclodextrin Complexation

The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.

Lipid vesicular systems: Formulation optimization and ex vivo comparative study

Lornoxicam, is a poorly water soluble non-steroidal anti-inflammatory drug, it provides effective analgesia in patients with acute and sever pain and after surgery. In this study, the effect of formulation ingredients composition and process on the physical properties, in vitro release and ex vivo permeation of lornoxicam traditional and elastic liposomes was investigated. A three-factor, two-level Box–Behnken design was used for optimizing two main ingredients and one process variable in lornoxicam liposomal formulations. The factors were cholesterol quantities, Tween 80 percentages and sonication time. The investigated responses were liposomes particle size and lornoxicam entrapment efficiency percentage. The results in this study revealed that sonication time has the main effect in determining both particle size and entrapment efficiency of liposomal formulations. After evaluating the main and interaction effects of experimental variables on the responses, an optimized formulation was theoretically obtained from Box–Behnken design that has the smallest particle size as well as the highest entrapment efficiency percent when cholesterol quantities, Tween 80 percentage and sonication time were 7.74mg, 2.5% and 3.7min respectively. A novel ex vivo comparison was conducted between lornoxicam traditional liposomes, elastic liposomes and the optimized formulation which generated from Box–Behnken design. The ex vivo results clearly showed that both elastic and optimized formulations have the ability to enhance lornoxicam permeation through rabbit skin over traditional liposomes.

Insights into Atomic-Level Interaction between Mefenamic Acid and Eudragit EPO in a Supersaturated Solution by High-Resolution Magic-Angle Spinning NMR Spectroscopy

The intermolecular interaction between mefenamic acid (MFA), a poorly water-soluble nonsteroidal anti-inflammatory drug, and Eudragit EPO (EPO), a water-soluble polymer, is investigated in their supersaturated solution using high-resolution magic-angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy. The stable supersaturated solution with a high MFA concentration of 3.0 mg/mL is prepared by dispersing the amorphous solid dispersion into a d-acetate buffer at pH 5.5 and 37 °C. By virtue of MAS at 2.7 kHz, the extremely broad and unresolved (1)H resonances of MFA in one-dimensional (1)H NMR spectrum of the supersaturated solution are well-resolved, thus enabling the complete assignment of MFA (1)H resonances in the aqueous solution. Two-dimensional (2D) (1)H/(1)H nuclear Overhauser effect spectroscopy (NOESY) and radio frequency-driven recoupling (RFDR) under MAS conditions reveal the interaction of MFA with EPO in the supersaturated solution at an atomic level. The strong cross-correlations observed in the 2D (1)H/(1)H NMR spectra indicate a hydrophobic interaction between the aromatic group of MFA and the backbone of EPO. Furthermore, the aminoalkyl group in the side chain of EPO forms a hydrophilic interaction, which can be either electrostatic or hydrogen bonding, with the carboxyl group of MFA. We believe these hydrophobic and hydrophilic interactions between MFA and EPO molecules play a key role in the formation of this extremely stable supersaturated solution. In addition, 2D (1)H/(1)H RFDR demonstrates that the molecular MFA-EPO interaction is quite flexible and dynamic.