Efficient drug delivery to alveolar macrophages and lung epithelial lining fluid following pulmonary administration of liposomal ciprofloxacin in rats with pneumonia and estimation of its antibacterial effects

The efficacy of pulmonary administration of liposomal ciprofloxacin (CPFX) in pneumonia was evaluated. In brief, the pharmacokinetics following pulmonary administration of liposomal CPFX (particle size, 1,000 nm; dose, 200 microg/kg) were examined in rats with lipopolysaccharide-induced pneumonia as an experimental pneumonia model. Furthermore, the antibacterial effects of liposomal CPFX against the pneumonic causative organisms were estimated by pharmacokinetic/pharmacodynamic (PK/PD) analysis. The time-courses of the concentration of CPFX in alveolar macrophages (AMs) and lung epithelial lining fluid (ELF) following pulmonary administration of liposomal CPFX to rats with pneumonia were markedly higher than that following the administration of free CPFX (200 microg/kg). The time course of the concentrations of CPFX in plasma following pulmonary administration of liposomal CPFX was markedly lower than that in AMs and ELF. These results indicate that pulmonary administration of liposomal CPFX was more effective in delivering CPFX to AMs and ELF compared with free CPFX, and it avoids distribution of CPFX to the blood. According to PK/PD analysis, the liposomal CPFX exhibited potent antibacterial effects against the causative organisms of pneumonia. This study indicates that pulmonary administration of CPFX could be an effective technique for the treatment of pneumonia.     

Efficient drug delivery to lung epithelial lining fluid by aerosolization of ciprofloxacin incorporated into PEGylated liposomes for treatment of respiratory infections

Purpose: The efficacy of aerosolization of ciprofloxacin (CPFX) incorporated into PEGylated liposomes (PEGylated CPFX-liposomes) for the treatment of respiratory infections was evaluated. Method: PEGylated CPFX-liposomes with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] (particle size: 100 nm) were prepared, and the drug distribution characteristics in lung epithelial lining fluid (ELF) following aerosolization of PEGylated CPFX-liposomes were examined in rats. Furthermore, the antibacterial effects of PEGylated CPFX-liposomes in ELF were evaluated by pharmacokinetic/pharmacodynamic analysis. Results: The elimination rate of CPFX from ELF following aerosolization of PEGylated CPFX-liposomes was significantly slower than that of CPFX incorporated into unmodified liposomes (unmodified CPFX-liposomes; particle size: 100 nm). According to pharmacokinetic/pharmacodynamic analysis, the PEGylated CPFX-liposomes exhibited potent antibacterial effects against pathogenic microorganisms in ELF. Conclusion: This study shows that PEGylated CPFX-liposomes are a useful aerosol-based pulmonary drug delivery system for the treatment of respiratory infections.     

Design,characterization, and evaluation of intranasal delivery of ropinirole-loaded mucoadhesive nanoparticles for brain targeting

Context: Parkinson disease (PD) is a common, progressive neurodegenerative disorder, characterized by marked depletion of striatal dopamine and degeneration of dopaminergic neurons in the substantia nigra.

Objective: The purpose of the present study was to investigate the possibility of targeting an anti-Parkinson’s drug ropinirole (RH) to the brain using polymeric nanoparticles.

Materials and methods: Ropinirole hydrochloride (RH)-loaded chitosan nanoparticles (CSNPs) were prepared by an ionic gelation method. The RH-CSNPs were characterized for particle size, polydispersity index (PDI), zeta potential, loading capacity, entrapment efficiency in vitro release study, and in vivo distribution after intranasal administration.

Results and discussion: The RH-CSNPs showed sustained release profiles for up to 18?h. The RH concentrations (% Radioactivity/g) in the brain following intranasal administration (i.n.) of RH-CSNPs were found to be significantly higher at all the time points compared with RH solution. The concentration of RH was highest in the liver (7.210?±?0.52), followed by kidneys (6.862?±?0.62), intestine (4.862?±?0.45), and lungs (4.640?±?0.92) in rats following i.n. administration of RH-CSNPs. Gamma scintigraphy imaging in rats was performed to ascertain the localization of drug in the brain following intranasal administration of formulations. The brain/blood ratios obtained (0.251?±?0.09 and 0.386?±?0.57 of RH (i.n.) and RH-CSNPs (i.n.), respectively) at 0.5?h are indicative of direct nose to brain transport, bypassing the blood–brain barrier (BBB).

Conclusion: The novel formulation showed the superiority of nose to brain delivery of RH using mucoadhesive nanoparticles compared with other delivery routes reported earlier.     

Nebulized oil-in-water nanoemulsion mists for pulmonary delivery: development,physico-chemical characterization and in vitro evaluation

Context: This study presents novel nanostructured oil-in-water (o/w) mists based on self-nanoemulsifying (SNE) mixtures capable of delivering poorly water-soluble drugs into the lungs.

Objective: Formulation development of an o/w nanoemulsion (NE) capable of being nebulized for pulmonary delivery of poorly water-soluble drugs.

Materials and methods: SNE mixtures were prepared and evaluated using Tween 80 and Cremophor RH 40 as surfactants; Transcutol P, Capryol 90 and PEG 400 as cosurfactants; and Labrafac Lipophile Wl 1349 (a medium-chain triglyceride) as an oil. Liquid NEs were analyzed by light scattering, zeta potential, transmission electron microscopy (TEM) and in vitro drug release studies. The aqueous NE was nebulized and assessed by light scattering and TEM. The formulation was aseptically filtered and the sterility validated. In vitro cytotoxicity of the formulations was tested in NIH 3T3 cells. The capability of the formulation to deliver a poorly water-soluble drug was determined using ibuprofen.

Results: Ibuprofen was found to be stable in the NEs. The formulations were neutrally charged with a droplet size of about 20?nm. TEM images displayed 100?nm oil droplets. The aseptic filtration method produced sterile NE. The nebulized mist revealed properties ideal for pulmonary delivery. The biocompatible aerosol has a nanostructure consisting of several oil nanodroplets enclosed within each water drop. Solubility and in vitro drug release studies showed successful incorporation and release of ibuprofen.

Conclusion: The developed formulation could be used as an inhalation for delivering material possessing poor water solubility into the lungs.     

Development and evaluation of nanosized niosomal dispersion for oral delivery of Ganciclovir

Encapsulation of Ganciclovir in lipophilic vesicular structure may be expected to enhance the oral absorption and prolong the existence of the drug in the systemic circulation. So the purpose of the present study was to improve the oral bioavailability of Ganciclovir by preparing nanosized niosomal dispersion. Niosomes were prepared from Span40, Span60, and Cholesterol in the molar ratio of 1:1, 2:1, 3:1, and 3:2 using reverse evaporation method. The developed niosomal dispersions were characterized for entrapment efficiency, size, shape, in vitro drug release, release kinetic study, and in vivo performance. Optimized formulation (NG8; Span60:Cholesterol 3:2 molar ratio) has shown a significantly high encapsulation of Ganciclovir (89?±?2.13%) with vesicle size of 144?±?3.47?nm (polydispersity index [PDI]?=?0.08). The in vitro release study signifies sustained release profile of niosomal dispersions. Release profile of prepared formulations have shown that more than 85.2?±?0.015% drug was released in 24?h with zero-order release kinetics. The results obtained also revealed that the types of surfactant and Cholesterol content ratio altered the entrapment efficiency, size, and drug release rate from niosomes. In vivo study on rats reveals five-time increment in bioavailability of Ganciclovir after oral administration of optimized formulation (NG8) as compared with tablet. The effective drug concentration (>0.69 µg/mL in plasma) was also maintained for at least 8?h on administration of the niosomal formulation. In conclusion, niosomes can be proposed as a potential oral delivery system for the effective delivery of Ganciclovir.     

Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization,ex-vivo permeation studies,and in-vivo evaluation

Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex-vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect.     

Nanostructured lipid carriers-based flurbiprofen gel after topical administration: acute skin irritation,pharmacodynamics, and percutaneous absorption mechanism

In order to assess the preliminary safety and effectiveness of nanostructured lipid carriers-based flurbiprofen gel (FP NLC-gel), the acute irritation test, in vivo pharmacodynamics evaluation and pharmacokinetic study were investigated after topical application. No dropsy and erythema were observed after continuous dosing 7?d of FP NLC-gel on the rabbit skin, and the xylene-induced ear drossy could be inhibited by FP NLC-gel at different dosages. The maximum concentration of FP in rats muscle was 2.03?μg/g and 1.55?μg/g after oral and topical administration, respectively. While the peak concentration in untreated muscle after topical administration was only 0.37?μg/mL. And at any time, following topical administration the mean muscle–plasma concentration ratio C_muscle/C_Plasma was obviously higher than that following oral administration. Results indicated that FP could directly penetrate into the subcutaneous muscle tissue from the administration site. Thus, the developed FP NLC-gel could be a safe and effective vehicle for topical delivery of FP.     

Novel oral amphotericin B formulation (iCo-010) remains highly effective against murine systemic candidiasis following exposure to tropical temperature

Purpose: To evaluate the antifungal activity of amphotericin B (AmB) in a mouse model of systemic candidiasis following administration of a novel oral AmB formulation (iCo-010) that has been pre-exposed to tropical temperatures.

Methods: Amphotericin B (AmB) was prepared as a 5?mg/mL dispersion in a mixture of Peceol, Gelucire 44/14 and VitE-TPGS 2,3 (iCo-010). The formulation was protected from light and incubated in a sealed container at 43?°C for 60 days. Mice infected with Candida albicans were treated with either iCo-010 formulation pre-incubated at 43?°C for 60 days or freshly prepared iCo-010 formulation at doses of 5, 10 and 20?mg/kg once daily for five consecutive days. Single intravenous 5?mg/kg dose of AmBisome® was used as a positive control group. Seven days following the last dose, the kidney, liver, spleen, lung, heart and brain were removed and the number of colony forming units (CFUs) was determined as a measure of tissue fungal load. In addition, the concentration of AmB within each tissue was determined using high performance liquid chromatography (HPLC).

Results: There were no significant differences in the reduction of CFUs and the concentration of AmB recovered in all organs at all iCo-010 doses tested between the freshly prepared iCo-010 formulation compared to the formulation that was incubated at 43?°C for 60 days.

Conclusions: A novel oral AmB formulation, iCo-010, incubated at 43?°C for 60 days to simulate the exposure of the formulation to tropical temperatures remained highly effective against murine systemic candidiasis.     

Preparation and evaluation of SEDDS of simvastatin by in vivo,in vitro and ex vivo technique

The objective of this work was to formulate a Self Emulsifying Drug Delivery System (SEDDS) of simvastatin, a poorly soluble drug and to evaluate by in vivo, in vitro and ex vivo techniques. Oils and surfactants were screened out depending upon their solubilizing capacity. Among all of the solvents, Capryol 90 showed good solubilizing capacity. It dissolved 105?mg/ml of simvastatin. Tween-80 also showed good solubilizing capacity which was 117?mg/ml. The two excipients were used to prepare simvastatin SEDDS. Formulations were initially checked for the color, clarity and sedimentation. The SEDDS formulations were transparent and clear. Formulation F2 containing 7:3 (m/m) mixture of Capryol 90/Tween-80 produced smallest micro-emulsion with particles size of 0.074?µm and drug release was higher than other formulation (102% within 20?min). Ex vivo study of the SEDDS formulation was evaluated using guinea pig intestinal sac. Drug diffused from F2 formulation was significantly higher than pure drug (p?In vivo study of SEDDS was performed in albino mice using plasma cholesterol level as a pharmacodynamic marker parameter. The test formulation (F2) appeared remarkable reduction in plasma cholesterol level, after oral administration which showed that SEDDS may be an effective technique for the oral administration of simvastatin.     

Critical evaluation of permeation enhancers for oral mucosal drug delivery

Background: Drug delivery via oral mucosa is an alternative method of systemic administration for various classes of therapeutic agents. Among the oral mucosae, buccal and sublingual mucosae are the primary focus for drug delivery. Buccal delivery offers a clear advantage over the peroral route by avoidance of intestinal and hepatic first-pass metabolism. However, despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. To date, the information available on oral mucosal permeation enhancement is much less than transdermal enhancement, though oral mucosa is more resistant to damage than other mucosal membranes. This article reviews the various categories of permeation enhancers for oral mucosal drug delivery, their mechanism of action, their usefulness, and the limitations associated with their use. Conclusion: To optimize the concentration of enhancer to limit its toxicity while facilitating an enhancing effect reproducibly will be a big challenge for future developments. Advances in permeability modulation and formulation with appropriate enhancers can provide for effective and feasible buccal drug delivery for many drugs, which otherwise have to be injected or ingested with water.     

In situ gelling formulation based on methylcellulose/pectin system for oral-sustained drug delivery to dysphagic patients

Background: Oral-sustained release gel formulations with suitable rheological properties have been proposed as a means of improving the compliance of dysphagic and geriatric patients who have difficulties with handling and swallowing oral dosage forms. Aim: We have modified the rheological and release properties of thermally reversible methylcellulose solutions by admixture with pectin, the gelation of which is ion-responsive, with the aim of formulating an in situ gelling vehicle suitable for oral-sustained drug delivery. Method: Gels formed by solutions containing methylcellulose (1.0–2.0%) and pectin (0.5–2.0%) were assessed for suitable gel strength, and in vitro and in vivo release of paracetamol. Results: Addition of 1.5% pectin to a 2.0% methylcellulose formulation containing 20% d-sorbitol and calcium ions in complexed form increased the gel strength and provided a formulation with a suitable viscosity for ease of swallowing by dysphagic patients. Gels formed in situ after oral administration of this formulation retained their integrity in the rat stomach for sufficient time for sustained release to be achieved. In vitro release of paracetamol from methylcellulose, pectin, and methylcellulose/pectin gels was diffusion-controlled. Plasma levels of paracetamol after oral administration to rats (gastric pH 2.6 and 5.5) of a solution including 2.0% methylcellulose/1.5% pectin showed improved sustained release compared with that from both 2.0% methylcellulose and 1.5% pectin solutions. Conclusions: The addition of suitable concentrations of pectin to methylcellulose solutions produces in situ gelling formulations with suitable viscosity for administration to dysphagic patients and improved sustained release characteristics.     

Effect of surface-mannose modification on aerosolized liposomal delivery to alveolar macrophages

Purpose: The effect of surface-mannose modification on aerosolized liposomal delivery to alveolar macrophages (AMs) was evaluated in vitro and in vivo. Method: 4-Aminophenyl-α-D-mannopyranoside (Man) was used for surface-mannose modification, and mannosylated liposomes with various mannosylation rates (particle size: 1000 nm) were prepared. Results: In the in vitro uptake experiments, the uptake of mannosylated liposomes by AMs was increased with the increase in the mannosylation rate over the range 2.4–9.1 mol% Man and became constant at over 9.1%. Thus, the most efficient mannosylation rate was 9.1 mol% Man. Furthermore, free mannose inhibited the uptake of mannosylated liposomes by AMs. This indicates that the uptake mechanism of mannosylated liposomes by AMs is mannose receptor-mediated endocytosis. In the in vivo animal experiments, the mannosylated liposomes (mannosylation rate, 9.1 mol% Man) were more efficiently delivered to AMs after pulmonary aerosolization to rats than nonmodified liposomes and did not harm lung tissues. Conclusion: These results indicate that surface-mannose modification is useful for efficient aerosolized liposomal delivery to AMs.     

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20?min. Finally, the PK profile of SDG-T and a reference formulation Oraxol? (oral solution formulation used in Phase I clinical study) at a dose of 60?mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10?mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol? solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol? solution was 132.25% at a dose of 60?mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10–150?ng/mL for a period of 24?h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.     

Enhanced colonic delivery of ciclosporin A self-emulsifying drug delivery system encapsulated in coated minispheres

Objectives: Investigate the potential of coated minispheres (SmPill®) to enhance localized Ciclosporin A (CsA) delivery to the colon.

Methods: CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill® minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill® minispheres was compared to Neoral® po and Sandimmun® iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV.

Results: In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r²?=?0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill®, compared to Neoral® po and Sandimmun® iv (p?p?Conclusions: Modulating E:P coating thickness controls release of CsA from SmPill® minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.     

Formulation and evaluation of ubidecarenone transdermal delivery systems

Purpose: This study is aimed to examine the feasibility of developing ubidecarenone (coenzyme Q₁₀, CoQ₁₀) transdermal delivery systems (TDS). Method: In vitro permeation study using solution formulation and pressure-sensitive adhesive (PSA) TDS and in vivo pharmacokinetic study were conducted. Results: When using solution formulations, isopropyl alcohol (103.39 ± 1.61), ethyl alcohol (81.55 ± 7.27), and the mixture of diethylene glycol monoethyl ether (DGME)/propylene glycol monolaurate (PGML) at the ratio of 60:40 (91.08 ± 26.07) showed high flux (μg/cm²/hour). The addition of fatty acids to DGME-PGML failed to show profound enhancing effects; only unsaturated fatty acids such as linoleic acid and oleic acid at 3% and caprylic acid at 3% and 10% slightly increased permeation flux. CoQ₁₀ from the acrylic PSA TDS showed biphasic permeation profile that was permeated very rapidly up to the first 12 hours, and after that, permeation rate became slower. Overall, 6% fatty acids showed high permeation rates and the highest maximum flux of 9.3 μg/cm²/hour was obtained with a formulation containing 6% lauric acid in DGME-PGML (60:40). The in vivo pharmacokinetic study using TDS with 6% fatty acids in DGME-PGML (60:40) showed that the absorption of CoQ₁₀ decreased in the following order: TDS containing linoleic acid > oral dosage form > TDS with oleic acid > TDS with lauric acid > TDS with caprylic acid > TDS with capric acid. TDS containing oleic acid showed preferable pharmacokinetic profile with respect to lower C_max, comparable AUC, and prolonged t_1/2 and T_max compared to oral administration of drug. Conclusions: For effective transdermal delivery system of CoQ₁₀, 6% linoleic acid or oleic acid in DGME-PGML (60:40) could be employed.     

Multi-breath dry powder inhaler for delivery of cohesive powders in the treatment of bronchiectasis

A series of co-engineered macrolide–mannitol particles were successfully prepared using azithromycin (AZ) as a model drug. The formulation was designed to target local inflammation and bacterial colonization, via the macrolide component, while the mannitol acted as mucolytic and taste-masking agent. The engineered particles were evaluated in terms of their physico-chemical properties and aerosol performance when delivered via a novel high-payload dry powder Orbital^? inhaler device that operates via multiple inhalation manoeuvres. All formulations prepared were of suitable size for inhalation drug delivery and contained a mixture of amorphous AZ with crystalline mannitol. A co-spray dried formulation containing 200?mg of 50:50?w/w AZ: mannitol had 57.6%?±?7.6% delivery efficiency with a fine particle fraction (≤6.8?µm) of the emitted aerosol cloud being 80.4%?±?1.1%, with minimal throat deposition (5.3?±?0.9%). Subsequently, it can be concluded that the use of this device in combination with the co-engineered macrolide–mannitol therapy may provide a means of treating bronchiectasis.     

Preparation,optimization, characterization and in vivo pharmacokinetic study of asiatic acid tromethamine salt-loaded solid lipid nanoparticles

Purpose: To enhance the oral bioavailability of asiatic acid tromethamine salt (AAS) by encapsulation in solid lipid nanoparticles (SLN).

Methods: The AAS-loaded SLN (AASLN) was prepared by the modified solvent injection method with glycerin monostearate (GMS) as lipid and poloxamer 188 as surfactant. A Box–Behnken design was used to optimize the formulations. Physicochemical characterization was carried out by using dynamic light scattering, scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Stabilities at 4?°C and pH 1.2 were investigated by particle size or/and entrapment efficiency (EE%). The in vivo pharmacokinetics was evaluated by HPLC-MS/MS.

Results: The optimal formulation of AASLN had an average size of 237?nm with zeta potential of ?35.9?mV, and EE% of 64.4%. SEM showed that the AASLN had spherical shape with smooth surface. Furthermore, DSC and X-ray analyses indicated that AAS was amorphous state and the crystal degree of GMS was significantly decreased in the formulation. AASLN showed excellent stability at 4?°C for 1 month and no coacervation at pH 1.2. The bioavailability of AAS in SLN was found to be 2.5-fold higher than that of AAS alone after a single oral administration in rats.

Conclusions: This study reveals that SLN is developed as a promising oral delivery system of AAS with significantly enhanced bioavailability and good storage stability.     

Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: formulation,design and in vivo evaluation

The present work was aimed at developing an optimized oral nanostructured lipid carrier (NLC) formulation of poorly soluble atorvastatin Ca (AT Ca) and assessing its in vitro release, oral bioavailability and pharmacodynamic activity. In this study, chlorogenic acid, a novel excipient having synergistic cholesterol lowering activity was utilized and explored in NLC formulation development. The drug-loaded NLC formulations were prepared using a high pressure homogenization technique and optimized by the Box-Behnken statistical design using the Design-Expert software. The optimized NLC formulation was composed of oleic acid and stearic acid as lipid phase (0.9% w/v), poloxamer 188 as surfactant (1% w/v) and chlorogenic acid (0.05% w/v). The mean particle size, polydispersity index (PDI) and % drug entrapment efficiency of optimized NLC were 203.56?±?8.57?nm, 0.27?±?0.028 and 83.66?±?5.69, respectively. In vitro release studies showed that the release of drug from optimized NLC formulations were markedly enhanced as compared to solid lipid nanoparticles (SLN) and drug suspension. The plasma concentration time profile of AT Ca in rats showed 3.08- and 4.89-fold increase in relative bioavailability of developed NLC with respect to marketed preparation (ATORVA® tablet) and drug suspension, respectively. Pharmacodynamic study suggested highly significant (**p?0.01) reduction in the cholesterol and triglyceride values by NLC in comparison with ATORVA® tablet. Therefore, the results of in vivo studies demonstrated promising prospects for successful oral delivery of AT Ca by means of its chlorogenic acid integrated NLC.     

The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs

Abstract

Context: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation.

Objective: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development.

Materials and methods: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal.

Results: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ～68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model.

Discussion: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds.

Conclusions: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.     

A Study of the Effects of Sucrose Concentration,Lacquer Concentration and Coating Time on the Formulation of Stable and Effective Carbenicillin Indanyl Sodium Microcapsules

Abstract

Carbenicillin indanyl sodium, commonly known as Geocillin (GC), is an orally effective derivative of carbenicillin employed in the treatment of gram negative infections of the urinary tract. GC exhibits an extremely bitter taste which affects patient compliance upon oral dosing (1). A novel coating approach allows Geocillin to be prepared as a suspension for oral administration. GC is available only as a tablet.

Eudragit E100^R [EE] is a tasteless, acid soluble cationic polymer. Encapsulation of GC with [EE] inhibited its release in the mouth, thus overcoming its bitter taste. Dissolution studies were carried out in simulated gastric fluid and simulated intestinal fluid. Three factors, viz. sucrose concentration, lacquer concentration and coating time were evaluated to arrive at an optimally acceptable formulation.

The formulation containing GC and sucrose in the ratio of 1:3, suspension coated using a 5% w/w lacquer solution for 40 mins. yielded taste free microcapsules with optimal release characteristics.