Versatile Nanoparticulate Systems as a Prosperous Platform for Targeted Nose-Brain Drug Delivery.

The intranasal route has proven to be a reliable and promising route for delivering therapeutics to the central nervous system (CNS), averting the blood-brain barrier (BBB) and avoiding extensive first-pass metabolism of some drugs, with minimal systemic exposure. This is considered to be the main problem associated with other routes of drug delivery such as oral, parenteral, and transdermal, among other administration methods. The intranasal route maximizes drug bioavailability, particularly those susceptible to enzymatic degradation such as peptides and proteins. This review will stipulate an overview of the intranasal route as a channel for drug delivery, including its benefits and drawbacks, as well as different mechanisms of CNS drug targeting using nanoparticulate drug delivery systems devices; it also focuses on pharmaceutical dosage forms such as drops, sprays, or gels via the nasal route comprising different polymers, absorption promoters, CNS ligands, and permeation enhancers.

Combined site-specific release retardant mini-matrix tablets (C-SSRRMT) for extended oral delivery of dexketoprofen trometamol: in vitro evaluation and single versus multiple doses pharmacokinetic study in human volunteers.

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.

Investigating the potential of highly porous zopiclone-loaded 3D electrospun nanofibers for brain targeting via the intranasal route.

Nanofibers (NFs) have proven to be very attractive tool as drug delivery plateform among the different plethora of nanosystems, owing to their unique features. They exhibit two- and three-dimensional structures some of which mimic structural environment of the body tissues, in addition to being safe, efficacious, and biocompatible drug delivery platform. Thus, this study embarked on fabricating polyvinyl alcohol/chitosan (PVA/CS) electrospun NFs encapsulating zopiclone (ZP) drug for intranasal brain targeted drug delivery. Electrospun NFs were optimized by adopting a three factor-two level full factorial design. The independent variables were: PVA/CS ratio (X1), flow rate (X2), and applied voltage (X3). The measured responses were: fiber diameter (Y1,nm), pore size (Y2,nm) and ultimate tensile strength (UTS,Y3,MPa). The selected optimum formula had resulted in NFs diameter of 215.90 ± 15.46 nm, pore size 7.12 ± 0.27 nm, and tensile strength around 6.64 ± 0.95 MPa. In-vitro biodegradability testing confirmed proper degradation of the NFs within 8 h. Moreover, swellability and breathability assessment revealed good hydrophilicity and permeability of the prepared NFs. Ex-vivo permeability study declared boosted ex-vivo permeation with an enhancement factor of 2.73 compared to ZP suspension. In addition, optimized NFs formula significantly reduced sleep latency and prolonged sleep duration in rats compared to IV ZP drug solution. These findings demonstrate the feasibility of employing the designed NFs as an effective safe platform for intranasal delivery of ZP for insomnia management.

Cod liver oil nano-structured lipid carriers (Cod-NLCs) as a promising platform for nose to brain delivery: Preparation, in vitro optimization, ex vivo cytotoxicity & in vivo biodistribution utilizing radioiodinated zopiclone.

Nano-structured lipid carriers containing zopiclone were prepared as a targeted drug delivery system to convey zopiclone directly to brain via nasal route. Nano-structured lipid carriers were constructed adopting hot emulsification-ultrasonication method using palmitic acid in place of the solid lipid, cod liver oil as liquid lipid, and poloxamer 407 as a surfactant. A three-factor three-level central composite face-centered design was used to optimize the formulated nano-structured lipid carriers. The independent factors were lipid amount (X1), surfactant amount (X2), and sonication time (X3). The examined responses were entrapment efficiency (EE,Y1,%), particle size (PS,Y2,nm), zeta potential(mV), polydispersity index(PDI,Y3), in vitro release(Q8h,Y4,%) and dissolution efficiency (DE,Y5,%). The optimum formula showed high entrapment efficiency of 94.31% ± 2.44, in vitro drug release of 83.89% ± 1.77 with dissolution efficiency equals 88.63% ± 2.01, small particle size of 71.27 nm ± 13.57 and low polydispersity index 0.097 ± 0.15. In vivo biodistribution in mice was evaluated by a radiobiological technique using radioiodinated zopiclone([131I]iodo-ZP). Results revealed the superiority of the intranasal route to deliver zopiclone directly to brain faster and higher brain uptake (6.9 ± 1.02%ID/g at 5 min post-administration). The current study confirmed that intranasal administration of nano-structured lipid carriers had great potential as an effective tool for targeted brain zopiclone delivery for insomnia treatment.

Preparation and evaluation of microemulsion systems containing salicylic acid.

Microemulsions (MEs) are clear, thermodynamically stable systems. They were used to solubilize drugs and to improve topical drug availability. Salicylic acid (SA) is a keratolytic agent used in topical products with antimicrobial actions. The objective of this work was to prepare and evaluate SA ME systems. Different concentrations of SA were incorporated in an ME base composed of isopropyl myristate, water, and Tween 80: propylene glycol in the ratio of 15:1. Three ME systems were prepared: S2%, S5%, and S10% which contain 2%, 5%, and 10% of SA, respectively. Evaluation by examination under cross-polarizing microscope, measuring of percent transmittance, pH measurement, determination of the specific gravity, assessment of rheological properties, and accelerated stability study were carried out. The data showed that the addition of SA markedly affected the physical properties of the base. All systems were not affected by accelerated stability tests. Stability study for 6 months under ambient conditions was carried out for S10%. No remarkable changes were recorded except a decrease in the viscosity value after 1 month. The results suggested that ME could be a suitable vehicle for topical application of different concentrations of SA.

Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies.

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99mTc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE = 242.3%), drug targeting index (DTI = 144.25), and nose-to-brain direct transport percentage (DTP = 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

Bumadizone calcium dihydrate microspheres compressed tablets for colon targeting: formulation, optimization and in vivo evaluation in rabbits.

The objective of this study was the development of a colon-targeted microspheres which were compressed into tablets containing the non-steroidal anti-inflammatory bumadizone calcium hemihydrate. [corrected]. A 3(2) full factorial design was adopted for the evaluation of the prepared microspheres. The effect of two independent variables namely polymer type (Eudragit RS100, ethyl cellulose and cellulose acetate butyrate), and drug: polymer ratio (1:1, 9:1 and 18:1) was studied on the entrapment efficiency and in vitro drug release for 12 h. Colon targeting aims to minimize the release of the drug off target area (pH 1.2 and 6.8) and to maximize the release of the drug in target area (pH 7.4). Candidate formulae were compressed into core tablets and colon targeting was achieved using the enzyme-dependent polymer (pectin) as coat in three different concentrations 50, 75 and 90%. Candidate formula F15 (microspheres prepared using BDZ:CAB in a ratio of 18:1 and compressed into tablets using 50% pectin and 50% Avicel in the coat) was able to adequately modulate drug release avoiding drug release in the gastric ambient, and reaching the colonic targeting where 99.7% release was achieved within 12 h following zero-order model. In vivo studies showed that F15 achieved significant decrease in myeloperoxidase activity and inflammation with delayed Tmax (4 h) and lower Cmax (2700 ng/ml) when compared to marketed product.

Feasibility of optimizing trimetazidine dihydrochloride release from controlled porosity osmotic pump tablets of directly compressed cores.

The aim of this study was to develop and optimize Trimetazidine dihydrochloride (TM) controlled porosity osmotic pump (CPOP) tablets of directly compressed cores. A 2(3) full factorial design was used to study the influence of three factors namely: PEG400 (10% and 25% based on coating polymer weight), coating level (10% and 20% of tablet core weight) and hole diameter (0 "no hole" and 1 mm). Other variables such as tablet cores, coating mixture of ethylcellulose (4%) and dibutylphthalate (2%) in 95% ethanol and pan coating conditions were kept constant. The responses studied (Yi ) were cumulative percentage released after 2 h (Q%2h), 6 h (Q%6h), 12 h (Q%12h) and regression coefficient of release data fitted to zero order equation (RSQzero), for Y 1, Y 2, Y 3, and Y 4, respectively. Polynomial equations were used to study the influence of different factors on each response individually. Response surface methodology and multiple response optimization were used to search for an optimized formula. Response variables for the optimized formula were restricted to 10% â©½ Y 1 â©½ 20%, 40% â©½ Y 2 â©½ 60%, 80% â©½ Y 3 â©½ 100%, and Y 4 > 0.9. The statistical analysis of the results revealed that PEG400 had positive effects on Q%2h, Q%6h and Q%12h, hole diameter had positive effects on all responses and coating level had positive effect on Q%6h, Q%12h and negative effect on RSQzero. Full three factor interaction (3FI) equations were used for representation of all responses except Q%2h which was represented by reduced (3FI) equation. Upon exploring the experimental space, no formula in the tested range could satisfy the required constraints. Thus, direct compression of TM cores was not suitable for formation of CPOP tablets. Preliminary trials of CPOP tablets with wet granulated cores were promising with an intact membrane for 12 h and high RSQzero. Further improvement of these formulations to optimize TM release will be done in further studies.

Preparation, in vitro and in vivo evaluation of stomach-specific metronidazole-loaded alginate beads as local anti-Helicobacter pylori therapy.

Metronidazole (MZ), a common antibacterial drug used in treatment of H. pylori, was prepared in chitosan-treated alginate beads by the ionotropic gelation method. A (3x2x2) factorially designed experiment was used in which 3 viscosity-imparting polymers namely, methyl cellulose, carbopol 934P and kappa-carrageenan, 2 concentrations (0.2 and 0.4% w/v) of chitosan as encapsulating polymer and 2 concentrations (2.5 and 5% w/w) of the low density magnesium stearate as a floating aid were tested. The drug entrapment efficiency (%), the percent of floating beads and the time for 80% of the drug to be released (T(80%)) were the responses evaluated. The bead formula containing 0.5% kappa-carrageenan, 0.4% chitosan and 5% magnesium stearate showed immediate buoyancy, optimum drug entrapment efficiency and extended drug release. The histopathological examination of mice stomachs and in vivo H. pylori clearance tests were carried out by orally administering MZ floating alginate beads or MZ suspension, to H. pylori infected mice under fed conditions as a single daily dose for 3 successive days in different doses 5, 10, 15 and 20 mg/kg. The histopathological examination showed that groups receiving MZ in the form of floating alginate beads at doses 10, 15 and 20 mg/kg were better than the corresponding suspension form, regarding eradication of H. pylori infection. The in vivo H. pylori clearance tests showed that MZ floating beads with a dose of 15 mg/kg provided 100% clearance rate whereas the MZ suspension with a dose of 20 mg/kg gave only 33.33%.