Inclusion of fenofibrate in a series of mesoporous silicas using microwave irradiation

A selection of porous silicas were combined with a model drug using a recently developed, controlled microwave heating process to determine if the application of microwave irradiation could enhance subsequent drug release. Five mesoporous silica types were investigated (core shell, core shell rehydrox, SBA-15, silica gel, SYLOID®) and, for comparison, one non-porous silica (stober). These were formulated using a tailored microwave heating method at drug/excipient ratios of 1:1, 1:3 and 1:5. In addition, all experiments were performed both in the presence and absence of water, used as a fluidising media to aid interaction between drug and support, and compared with results obtained using more traditional heating methods. All formulations were then characterised using differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and Fourier transformation infrared spectroscopy (FT-IR). Pharmaceutical performance was investigated using in vitro drug release studies. A significant enhancement in the release profile of fenofibrate was observed for formulations prepared using microwave heating in the absence of water for five of the six silica based formulations. Of all the formulations analysed, the greatest extent of drug release within the experimental 30 min was the 1:5 core shell rehydrox achieving a total of 86.6 ± 2.8%. The non-porous (stober) particles did not exhibit an increased release of the drug under any experimental conditions studied. This anomaly is thought to be a result of the comparatively small surface area of the silica particles, thus preventing the adsorption of drug molecules.     

Solid self-emulsifying nitrendipine pellets: Preparation and in vitro/in vivo evaluation

Objective of this study is to develop and evaluate the new solid self-emulsifying (SE) pellets of poorly soluble nitrendipine (NTD). These pellets were prepared via extrusion/spheronization technique, using liquid SEDDS (NTD, Miglyol^® 812, Cremophor^® RH 40, Tween 80, and Transcutol^® P), adsorbents (silicon dioxide and crospovidone), microcrystalline cellulose and lactose. The resulting SE pellets with 30% liquid SEDDS exhibited uniform size (800–1000 μm) and round shape, droplet size distribution following self-emulsification was nearly same to the liquid SEDDS (72 ± 16 nm and 64 ± 12 nm). The in vitro release was similar for the two SE formulations (over 80% within 30 min), both significantly higher than the conventional tablets (only 35% within 30 min). The oral bioavailability was evaluated for the SE pellets, liquid SEDDS and conventional tablets in fasted beagle dogs. AUC of NTD from the SE pellets showed 1.6-fold greater than the conventional tablets and no significant difference compared with the liquid SEDDS. In conclusion, our studies illustrated that extrusion/spheronization technique could be a useful large-scale producing method to prepare the solid SE pellets from liquid SEDDS, which can improve oral absorption of NTD, nearly equivalent to the liquid SEDDS, but better in the formulation stability, drugs leakage and precipitation, etc.     

A novel coating concept for ileo-colonic drug targeting: Proof of concept in humans using scintigraphy

The in vivo proof of concept of a novel double-coating system, based on enteric polymers, which accelerated drug release in the ileo-colonic region, was investigated in humans. Prednisolone tablets were coated with a double-coating formulation by applying an inner layer composed of EUDRAGIT® S neutralised to pH 8.0 and a buffer salt (10% KH₂PO₄), which was overcoated with layer of standard EUDRAGIT® S organic solution. For comparison, a single coating system was produced by applying the same amount of EUDRAGIT® S organic solution on the tablet cores. Dissolution tests on the tablets were carried out using USP II apparatus in 0.1 N HCl for 2 h and subsequently in pH 7.4 Krebs bicarbonate buffer. For comparison, tablets were also tested under the USP method established for modified release mesalamine formulations. Ten fasted volunteers received the double-coated and single-coated tablets in a two-way crossover study. The formulations were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. There was no drug release from the single-coated or double-coated tablets in 0.1 N HCl for 2 h. The single-coated tablets showed slow release in subsequent Krebs bicarbonate buffer with a lag time of 120 min, while in contrast drug release from the double-coated tablets was initiated at 60 min. In contrast, using the USP dissolution method, normally employed for modified release mesalamine products, no discrimination was attained. The in vivo disintegration of the single-coated EUDRAGIT® S tablets in the large intestine was erratic. Furthermore, in 2 volunteers, the single-coated tablet was voided intact. Double-coated tablets disintegrated in a more consistent way, mainly in the ileo-caecal junction or terminal ileum. The accelerated in vivo disintegration of the double-coating EUDRAGIT® S system can overcome the limitations of conventional enteric coatings targeting the colon and avoid the pass-through of intact tablets. Moreover, Krebs bicarbonate buffer has the ability to discriminate between formulations designed to target the ileo-colonic region.     

Analysis of Nifedipine Absorption from Soft Gelatin Capsules Using PBPK Modeling and Biorelevant Dissolution Testing

Delayed absorption of nifedipine when administered as a 20 mg immediate release soft gelatin capsule to fasted volunteers has been reported. Physiologically based pharmacokinetic (PBPK) modeling and in vitro dissolution data were used to explore our hypothesis that at high doses of nifedipine it precipitates in the stomach. Plasma concentration-time profiles following different doses of nifedipine were simulated using commercial PBPK software and compared to in vivo data. In vitro dissolution tests were performed with Adalat® 10 mg capsules in different volumes of fasted state simulated gastric fluid (FaSSGF). The discrepancy in plasma concentration-time profiles between the different nifedipine doses could be well simulated, assuming protracted dissolution for the 20 mg dose. Nifedipine release from one Adalat® 10 capsule in 250 or 500 mL FaSSGF was completed within 15 min whereas when release from two capsules, corresponding to 20 mg nifedipine, was studied in 250 mL FaSSGF, a maximum of about 75% drug dissolved was observed after 15 min followed by a decline in the % dissolved to a final value of approximately 40%. Based on the in silico and in vitro results it can be concluded that the observed prolongation in nifedipine absorption following the 20 mg dose was likely caused by nifedipine precipitation in human stomach.     

Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.     

Oseltamivir Phosphate–Amberlite™ IRP 64 Ionic Complex for Taste Masking: Preparation and Chemometric Evaluation

The objective of the present work was to evaluate and characterize a pediatric- friendly formulation of a bitter tasting drug, oseltamivir phosphate (drug). Amberlite IRP64 (resin) was used to make ionic complexes for masking its bitterness. Complexes of four drug-to-resin ratios, 1:1, 1:2, 1:4, and 1:6 (w/w), were prepared and characterized. At buccal pH of 6.8, drug–resin complexes of 1:1,1:2,1:4, and 1:6 ratios released 42.13%, 23.26%, 4.13%, and 14.94%, respectively, of loaded drug after 20 s. However, at stomach pH of 1.2 (0.1 N HCl), 61.96%, 70.18%, 85.88%, and 91.42% of drug was released from the same complexes in 6 min. Near-infrared (NIR) chemical imaging of the complexes showed homogeneous distribution of drug in the resin. Chemometric partial least squares model using NIR data of the drug showed a high correlation between calibration and predicted data(R² > 0.998). Overall, these results indicated the complex formation between drug and resin. The pH dependence of drug release from these complexes could minimize drug release in the mouth, whereas immediately releasing it in the stomach. Electronic tongue used to evaluate taste indicated that conductivity taste signals were different from control, suggesting taste masking of the drug.     

Indomethacin sustained release pellets prepared by extrusion-spheronization

Gastrointestinal side effects may interrupt essential therapy with indomethacin, a non-steroidal anti-inflammatory drug. Formulation of this drug into sustained release multiparticulate form may reduce some of these side effects by avoiding contact of drug crystals with gastrointestinal mucosa at high concentrations, as may happen with immediate release dosage forms. Indomethacin (IM) sustained release pellets containing 5 or 10 % w/w of the drug were prepared using an extrusion-spheronization technique. Different concentrations of hydrophilic polymers, polyethylene glycol 4000 (PEG 4000), hydroxypropyl methylcellulose E5 LV premium (HPMC) and polyvinyl pyrrolidone (PVP K30), were mixed at different concentrations (5,10 and 20 %) with Avicel PH 101 to prepare the sustained release formulae. Moreover, a mixer torque rheometer was used to quantitatively determine the suitable moisture content in the pastes before the extrusion process. The resulting pellets were characterized for content, particle size, shape and dissolution profile. The studies on the effect of the polymers used on Avicel rheological properties revealed that the magnitude of torque for the system was decreasing as the polymer concentration increased. The in vitro release of IM from the prepared Avicel pellets was found to be dependent upon the type and concentration of the added polymer. The rank order of IM release in the presence of the investigated polymers was as follows: PEG > HPMC > PVP. Furthermore, the magnitude of IM release rate from the pellet formulations was found to be dependent on the magnitude of the peak torque of the pellet forming paste, which in turn depends on the type and concentration of the added polymer. Increasing IM loading from 5 to 10 % has led to an increase in dissolution rates. At least two of the prepared pellet formulations showed dissolution profiles similar to the commercial product Bonidon 75 SR capsules. In conclusion, the formulation of IM sustained release pellets successfully controlled the drug release which might be beneficial in lowering the risk of side effects and improving patient convenience as an advantage of the pellets as a drug delivery system.     

Principles of rational design of thermally targeted liposomes for local drug delivery

Drug release from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes occurs close to the main transition temperature T_m = 41 °C. The exact release temperature can be adjusted by additional lipids, which shift T_m. A major issue is drug leakage at 37 °C. We here describe a novel approach with improved drug retention yet rapid release. To obtain spherical, smooth liposomes we included: i) 2 mol% cholesterol, to soften bilayers (Lemmich et al 1997), ii) lipids, which due to their spontaneous curvature stabilize the negative and positive curvatures of the inner and outer leaflets of unilamellar liposomes. In addition to differential scanning calorimetry (DSC) and fluorescence spectroscopy, the lipid mixtures were analyzed by a Langmuir balance for their elastic properties and lipid packing, aiming at high elasticity modulus C_S^− 1. Maxima in C_S^− 1 coincided with minima in the free energy of lateral mixing. These liposomes have reduced drug leakage, yet retain rapid release.From the Clinical EditorThis paper reports the development of optimized DPPC liposomes for drug delivery, with reduced drug leakage but maintained rapid release.     

A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs

The applicability of the semi-fluorinated alkane 1-perfluorohexyloctane (F6H8) as a novel excipient in lipid based drug delivery systems was studied. Solubility studies of 11 poorly water soluble drugs (cinnarizine, danazol, estradiol, fenofibrate, griseofulvin, halofantrine, lidocaine, prednisolone, probucol, rolipram and siramesine) showed significantly lower equilibrium solubility in F6H8 compared to soy bean oil (long chain triglyceride). F6H8 was miscible with medium chain triglycerides (MCT) but not miscible with long chain triglycerides, neither was pure F6H8 nor the mixture F6H8:MCT (1:1) miscible with 7 commonly used surfactants (Cremophor EL, Span 20, Span 80, Labrasol, Softigen 767 and Gelucire 44/14, polysorbate 80). In vitro lipolysis studies confirmed that F6H8 was non-digestible. F6H8:MCT (1:1) showed initially faster lipolysis compared to pure MCT. Thus, final phase lipolysis was lower indicating that F6H8 may affect the lipolysis of MCT. However, in vivo bioavailability studies in rats showed the same plasma concentration-time profiles when dosing 10 mg/kg halofantrine at two dose levels of F6H8, MCT or F6H8:MCT (1:1) (AUC ranged from 3058 to 3447 h ng/ml, T_max ～ 6.0 h, C_max ranged from 168 to 265 mg/ml). Generally, the addition of polysorbate 80 shortened the time to reach C_max (T_max ranged 1.3–4.5 h), but had limited effect on the bioavailability from F6H8 or MCT in combination with polysorbate 80 (4:1) (AUC ranged from 3807 to 4403 (h ng/ml)). Although a synergistic effect was obtained with halofantrine in F6H8:MCT:polysorbate 80 (2:2:1) (AUC 5574 ± 675 h ng/ml; mean ± SEM), it was not superior to dosing halofantrine in pure polysorbarte 80 (AUC 7370 ± 579 h ng/ml; mean ± SEM). The applicability of F6H8 as an excipient for future use in lipid based formulations for poorly water soluble drugs is therefore considered to be very limited.     

Towards the bioequivalence of pressurised metered dose inhalers 1: Design and characterisation of aerodynamically equivalent beclomethasone dipropionate inhalers with and without glycerol as a non-volatile excipient

A series of semi-empirical equations were utilised to design two solution based pressurised metered dose inhaler (pMDI) formulations, with equivalent aerosol performance but different physicochemical properties. Both inhaler formulations contained the drug, beclomethasone dipropionate (BDP), a volatile mixture of ethanol co-solvent and propellant (hydrofluoroalkane-HFA). However, one formulation was designed such that the emitted aerosol particles contained BDP and glycerol, a common inhalation particle modifying excipient, in a 1:1 mass ratio. By modifying the formulation parameters, including actuator orifice, HFA and metering volumes, it was possible to produce two formulations (glycerol-free and glycerol-containing) which had identical mass median aerodynamic diameters (2.4 μm ± 0.1 and 2.5 μm ± 0.2), fine particle dose (⩽5 μm; 66 μg ± 6 and 68 μg ± 2) and fine particle fractions (28% ± 2% and 30% ± 1%), respectively. These observations demonstrate that it is possible to engineer formulations that generate aerosol particles with very different compositions to have similar emitted dose and in vitro deposition profiles, thus making them equivalent in terms of aerosol performance. Analysis of the physicochemical properties of each formulation identified significant differences in terms of morphology, thermal properties and drug dissolution of emitted particles. The particles produced from both formulations were amorphous; however, the formulation containing glycerol generated particles with a porous structure, while the glycerol-free formulation generated particles with a primarily spherical morphology. Furthermore, the glycerol-containing particles had a significantly lower dissolution rate (7.8% ± 2.1%, over 180 min) compared to the glycerol-free particles (58.0% ± 2.9%, over 60 min) when measured using a Franz diffusion cell. It is hypothesised that the presence of glycerol in the emitted aerosol particles altered solubility and drug transport, which may have implications for BDP pharmacokinetics after deposition in the respiratory tract.     

Reversal of propoxur-induced impairment of step-down passive avoidance,transfer latency and oxidative stress by piracetam and ascorbic acid in rats

Propoxur, a carbamate pesticide has been shown to adversely affect memory and induce oxidative stress. The present study was designed to correlate the effect of propoxur, piracetam (a nootropic drug) and ascorbic acid (an antioxidant) on oxidative stress and cognitive function. Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on elevated plus maze. Oxidative stress was assessed by examining brain malondialdehyde (MDA) and non-protein thiol (NP-SH) levels. A significant reduction in SDL and prolongation of TL was found for the propoxur-treated group at weeks 6 and 7 as compared with control (p < 0.001). One week treatment by piracetam (400 mg/kg/d, i.p.) or ascorbic acid (120 mg/kg/d, i.p.) antagonized the effect of propoxur on SDL as well as TL. Both piracetam and ascorbic acid attenuated the propoxur-induced increase in brain MDA levels and decrease in brain NP-SH levels. Results of the present study show that ascorbic acid and piracetam have the potential to reverse cognitive dysfunction and oxidative stress induced by propoxur in the brain.     

Ethylene vinyl acetate as matrix for oral sustained release dosage forms produced via hot-melt extrusion

Different ethylene vinyl acetate grades (EVA9, EVA15, EVA28 and EVA40 having a VA content of 9%, 15%, 28% and 40%, respectively) were characterized via differential scanning calorimetry. Glass transition temperature (T_g), polymer crystallinity, melting point and polymer flexibility were positively influenced by the vinyl acetate content. The processability of EVA-based formulations produced by means of hot-melt extrusion (2 mm die) was evaluated in function of VA content, extrusion temperature (60–140 °C) and metoprolol tartrate (MPT, used as model drug) concentration (10–60%). Matrices containing 50% MPT resulted in smooth-surfaced extrudates, whereas at 60% drug content severe surface defects (shark skinning) were observed. Drug release from EVA/MPT matrices (50/50, w/w) was affected by the EVA grades: 90% after 24 h for EVA15 and 28, while EVA9 and EVA40 formulations released 80% and 60%, respectively. Drug release also depended on drug loading and extrusion temperature. For all systems, the total matrix porosity (measured by X-ray tomography) was decreased after dissolution due to elastic rearrangement of the polymer. However, the largest porosity reduction was observed for EVA40 matrices as partial melting of the structure (melt onset temperature: 34.7 °C) also contributed (thereby reducing the drug release pathway and yielding the lowest release rate from EVA40 formulations).The Simulator of the Human Intestinal Microbial Ecosystem (SHIME) used to evaluate the stability of EVA during gastrointestinal transit showed that EVA was not modified during GI transit, nor did it affect the GI ecosystem following oral administration.     

Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress

Cisplatin, a cancer chemotherapy drug, is nephrotoxic. The aim of this study was to investigate whether resveratrol (RES) reduced cisplatin cytotoxicity and oxidative stress. Rat renal cortical slices were pre-incubated 30 min with 0 (VEH, ethanol) or 30 μg/ml RES followed by 60, 90 or 120 min co-incubation with 0, 75, or 150 μg/ml cisplatin. Lactate dehydrogenase (LDH) leakage was unchanged at 60 and 90 min by cisplatin. Cisplatin increased (p < 0.05) LDH leakage at 120 min which was protected by RES. Cisplatin induced oxidative stress prior to LDH leakage as cisplatin depressed glutathione peroxidase and superoxide dismutase (SOD) activity, increased lipid peroxidation, protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins within 60 min. RES failed to reverse glutathione (GSH) depression by cisplatin. In order to eliminated an extracellular interaction between RES and cisplatin, additional studies (RINSE studies) allowed a 30 min RES uptake into slices, transfer of slices to buffer lacking RES, followed by 120 min cisplatin incubation. RES in the RINSE studies prevented LDH leakage by cisplatin indicating that RES protection was not via a physical interaction with cisplatin in the media. These findings indicate that RES diminished cisplatin in vitro renal toxicity and prevented the development of oxidative stress.     

Dry Powder Aerosols Generated by Standardized Entrainment Tubes From Drug Blends With Lactose Monohydrate: 1. Albuterol Sulfate and Disodium Cromoglycate

The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (τ_s), using a novel powder aerosol deaggregation equation (PADE). Drug particles were < 5 μm in volume diameter with narrow unimodal distribution (Span < 1). The lowest shear SET (τ_s = 0.624 N/m²) gave a higher emitted dose (ED ~ 84–93%) and lower FPF (FPF_6.4 ~ 7–25%). In contrast, the highest shear SET (τ_s = 13.143 N/m²) gave a lower ED (ED ~ 75–89%) and higher FPF (FPF_6.4 ~ 15–46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given τ_s, as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R² ~ 0.9804–0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction.     

Poly(dl:Lactic Acid-Castor Oil) 3:7-Bupivacaine Formulation: Reducing Burst Effect Prolongs Efficacy In Vivo

Prolonged analgesia may be achieved using a single injection of slow-release local anesthetic formulation. The study objective was to improve the efficacy of a previously reported formulation comprising 10% bupivacaine in poly(dl:lactic acid co castor oil) 3:7. The polymer was loaded with 15% bupivacaine and injected through a 22G needle close to the sciatic nerve of ICR mice. Sensory and motor nerve blockade were measured. The efficacy and toxicity of the polymer–drug combination were determined. Sixty percent of the incorporated bupivacaine was released during 1 week in vitro. During in vitro release no burst effect was seen, suggesting low toxicity of the formulation. Single injection of 0.1 mL of 15% polymer-bupivacaine formulation caused motor block that lasted 64 h and sensory block that lasted 96 h. The MTD of the polymer–drug formulation was established as 0.175 mL. Microscopic examination of the injection sites revealed reversible nerve inflammation and normal internal organs. The polymer poly(dl:lactic acid co castor oil) 3:7 is a safe carrier for prolonged activity of bupivacaine up to 96 h. The increase of drug load in the formulation reduces the drug release rates due to stronger polymer–drug interactions and higher overall hydrophobicity of the formulation     

Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin,and absorption studies in rats

This study describes the development and characterization of self-microemulsifying drug delivery systems (SMEDDS) in liquid and pellet forms that result in improved solubility, dissolution, and in vivo oral absorption of the poorly water-soluble compound curcumin. Solubility of curcumin was determined in various vehicles, including oils, surfactants and co-surfactants. Pseudo-ternary phase diagrams were constructed to identify the most efficient self-emulsification region. The optimized SMEDDS used for curcumin formulations in liquid and pellet forms contained 70% mixtures of two surfactants: Cremophor EL and Labrasol (1:1), and 30% mixtures of oil: Labrafac PG and Capryol 90 (1:1). The curcumin-SMEDDS in liquid and pellet formulations rapidly formed fine oil-in-water microemulsions, with particle size ranges of 25.8–28.8 nm and 29.6–32.8 nm, respectively. The in vitro rate and extent of release of curcumin from liquid SMEDDS and SMEDDS pellets was about 16-fold higher than that of unformulated curcumin. Plasma concentration–time profiles from pharmacokinetic studies in rats dosed with liquid and pelleted SMEDDS showed 14- and 10-fold increased absorption of curcumin, respectively, compared to the aqueous suspensions of curcumin. Curcumin-SMEDDS liquid and curcumin-SMEDDS pellets were found to be stable up to 6 months under intermediate and accelerated conditions. These studies demonstrate that the new self-microemulsifying systems in liquid and pellet forms are promising strategies for the formulation of poorly soluble lipophilic compounds with low oral bioavailability.     

Gastroretentive hydrodynamically balanced systems of ofloxacin: In vitro evaluation

Hydrodynamically balanced systems (HBSs) of ofloxacin were prepared using lactose, HPMC K4M, PVP K 30, and liquid paraffin, which may increase the mean residence time in the gastrointestinal tract, and may be able to provide maximum drug at the site of absorption to improve oral bioavailability. All these formulated HBS capsules were floated well over 6 h with no floating lag time. They also showed sustained drug release over 6 h. Time for 50% release of ofloxacin was within the range, 2.47 ± 0.02 to 3.07 ± 0.08 h. The in vitro drug release from these HBS capsules was dependent on HPMC K4M, PVP K 30, and liquid paraffin content. The drug release pattern of these HBS capsules containing ofloxacin followed the Higuchi model with the anomalous transport mechanism.     

Development and statistical optimization of nefopam hydrochloride loaded nanospheres for neuropathic pain using Box–Behnken design

Nefopam hydrochloride (NFH) is a non-opioid centrally acting analgesic drug used to treat chronic condition such as neuropathic pain. In current research, sustained release nefopam hydrochloride loaded nanospheres (NFH-NS) were auspiciously synthesized using binary mixture of eudragit RL 100 and RS 100 with sorbitan monooleate as surfactant by quasi solvent diffusion technique and optimized by 3⁵ Box–Behnken designs to evaluate the effects of process and formulation variables. Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetric (DSC) and X-ray diffraction (XRD) affirmed absence of drug–polymer incompatibility and confirmed formation of nanospheres. Desirability function scrutinized by design-expert software for optimized formulation was 0.920. Optimized batch of NFH-NS had mean particle size 328.36 nm ± 2.23, % entrapment efficiency (% EE) 84.97 ± 1.23, % process yield 83.60 ± 1.31 and % drug loading (% DL) 21.41 ± 0.89. Dynamic light scattering (DLS), zeta potential analysis and scanning electron microscopy (SEM) validated size, charge and shape of nanospheres, respectively. In-vitro drug release study revealed biphasic release pattern from optimized nanospheres. Korsmeyer Peppas found excellent kinetics model with release exponent less than 0.45. Chronic constricted injury (CCI) model of optimized NFH-NS in Wistar rats produced significant difference in neuropathic pain behavior (p < 0.05) as compared to free NFH over 10 h indicating sustained action. Long term and accelerated stability testing of optimized NFH-NS revealed degradation rate constant 1.695 × 10⁻⁴ and shelf-life 621 days at 25 ± 2 °C/60% ± 5% RH.     

Preparation and evaluation of mucinated sodium alginate microparticles for oral delivery of insulin

Effective oral insulin delivery remains a challenge to the pharmaceutical industry. In this study, insulin-loaded microparticles for oral delivery were prepared with mucin and sodium alginate combined at different ratios using a novel method based on polymer coacervation and diffusion filling. Some physical characteristics of the various insulin-loaded microparticles such as particle size, morphology and compressibility indices were determined. The microparticles were filled into hard gelatin capsules and the in vitro insulin release as well as the blood glucose reduction after oral administration to diabetic rabbits were determined. The microparticles formed were generally multi-particulate, discrete and free flowing. Before insulin loading, microparticles were round and smooth, becoming fluffier, less spherical and larger with rough and pitted surface after insulin loading. The insulin content of the microparticles increased with increase in their sodium alginate content. The various insulin-loaded microparticles prepared with the mucinated sodium alginate when encapsulated exhibited lag time before insulin release. The time taken to reach maximum insulin release from the various formulations varied with the mucin–sodium alginate ratio mix. The mean dissolution time of insulin from the microparticles prepared with sodium alginate, mucin, sodium alginate: mucin ratios of 1:1, 3:1 and 1:3 was 11.21 ± 0.75, 3.3 ± 0.42, 6.69 ± 023, 8.52 ± 0.95 and 3.48 ± 0.65 (min.), respectively. The percentage blood glucose reduction for the subcutaneously administered insulin was significantly (p < 0.001) higher than for the formulations. The blood glucose reduction effect produced by the orally administered insulin-loaded microparticles prepared with three parts of sodium alginate and one part of mucin after 5 h was, however, equal to that produced by the subcutaneously administered insulin solution, an indication that it is an effective alternative for the delivery of insulin.     

Design of a novel bilayered gastric mucoadhesive system for localized and unidirectional release of lamotrigine

Lamotrigine is a BCS class II drug with pH dependent solubility. The bilayered gastric mucoadhesive tablets of lamotrigine were designed such that the drug and controlled release polymers were incorporated in the upper layer and the lower layer had the mucoadhesive polymers. The major ingredients selected for the upper layer were the drug and control release polymer (either HPMC K15M or polyox) while the lower MA layer predominantly comprised of Carbopol 974P. A 2³ full factorial design was constructed for this study and the tablets were optimized for parameters like tablet size, shape, ex vivo mucoadhesive properties and unidirectional drug release. Oval tablets with an average size of 14 mm diameter were set optimum. Maximum mucoadhesive bond strength of 79.3 ± 0.91 * 10³ dyn/cm² was achieved with carbopol when used in combination with a synergistic resin polymer. All the tested formulations presented a mucoadhesion time of greater than 12 h. The incorporation of methacrylic polymers in the lower layer ensured unidirectional drug release from the bilayered tablets. The unidirectional drug release was confirmed after comparing the dissolution results of paddle method with those of a modified basket method. Model independent similarity and dissimilarity factor methods were used for the comparison of dissolution results. Controlled drug release profiles with zero order kinetics were obtained with polyox and HPMC K15M which reported t_90% at 6th and 12th hours, respectively. The “n” value with polyox was 0.992 and that with HPMC K15M was 0.946 indicating an approximate case II transport. These two formulations showed the potential for oral administration of lamotrigine as bilayered gastric mucoadhesive tablets by yielding highest similarity factor values, 96.06 and 92.47, respectively, between the paddle and modified basket method dissolution release profiles apart from reporting the best tablet physical properties and maximum mucoadhesive strength.