Ciprofloxacin as Ocular Liposomal Hydrogel

The purpose of this study was to prepare and characterize an ocular effective prolonged-release liposomal hydrogel formulation containing ciprofloxacin. Reverse-phase evaporation was used for preparation of liposomes consisting of soybean phosphatidylcholine (PC) and cholesterol (CH). The effect of PC/CH molar ratio on the percentage drug encapsulation was investigated. The effect of additives such as stearylamine (SA) or dicetyl phosphate (DP) as positive and negative charge inducers, respectively, were studied. Morphology, mean size, encapsulation efficiency, and in vitro release of ciprofloxacin from liposomes were evaluated. For hydrogel preparation, Carbopol 940 was applied. In vitro transcorneal permeation through excised albino rabbit cornea was also determined. Optimal encapsulation efficiency of 73.04 ± 3.06% was obtained from liposomes formulated with PC/CH at molar ratio of 5:3 and by increasing CH content above this limit, the encapsulation decreased. Positively charged liposomes showed superior entrapment efficiency (82.01 ± 0.52) over the negatively charged and the neutral liposomes. Hydrogel containing liposomes with lipid content PC, CH, and SA in molar ratio 5:3:1, respectively, showed the best release and transcorneal permeation with the percentage permeation of 30.6%. These results suggest that the degree of encapsulation of ciprofloxacin into liposomes and prolonged in vitro release depend on composition of the vesicles. In addition, the polymer hydrogel used in preparation ensure steady and prolonged transcorneal permeation. In conclusion, ciprofloxacin liposomal hydrogel is a suitable delivery system for improving the ocular bioavailability of ciprofloxacin.     

Effects of Formulation Variables on the Particle Size and Drug Encapsulation of Imatinib-Loaded Solid Lipid Nanoparticles

Imatinib (IMT), an anticancer agent, inhibits receptor tyrosine kinases and is characterized by poor aqueous solubility, extensive first-pass metabolism, and rapid clearance. The aims of the current study are to prepare imatinib-loaded solid lipid nanoparticles (IMT-SLN) and study the effects of associated formulation variables on particle size and drug encapsulation on IMT-SLN using an experimental design. IMT-SLN was optimized by use of a “combo” approach involving Plackett-Burman design (PBD) and Box-Behnken design (BBD). PBD screening resulted in the determination of organic-to-aqueous phase ratio (O/A), drug-to-lipid ratio (D/L), and amount of Tween® 20 (Tw20) as three significant variables for particle size (S _z), drug loading (DL), and encapsulation efficiency (EE) of IMT-SLN, which were used for optimization by BBD, yielding an optimized criteria of O/A?=?0.04, D/L?=?0.03, and Tw20?=?2.50%?w/v. The optimized IMT-SLN exhibited monodispersed particles with a size range of 69.0?±?0.9 nm, ζ-potential of ?24.2?±?1.2 mV, and DL and EE of 2.9?±?0.1 and 97.6?±?0.1%?w/w, respectively. Results of in vitro release study showed a sustained release pattern, presumably by diffusion and erosion, with a higher release rate at pH 5.0, compared to pH 7.4. In conclusion, use of the combo experimental design approach enabled clear understanding of the effects of various formulation variables on IMT-SLN and aided in the preparation of a system which exhibited desirable physicochemical and release characteristics.     

Liposomal hydrogel formulation for transdermal delivery of pirfenidone

Context: Pirfenidone (PFD) is an anti-fibrotic and anti-inflammatory agent indicated for the treatment of idiopathic pulmonary fibrosis (IPF). The current oral administration of PFD has several limitations including first pass metabolism and gastrointestinal irritation.

Objective: The aim of this study is to investigate the feasibility of transdermal delivery of PFD using liposomal carrier system.

Materials and methods: PFD-loaded liposomes were prepared using soy phosphatidylcholine (SPC) and sodium cholate (SC). Encapsulation efficiency (EE) of PFD in liposomes was optimized using different preparation techniques including thin film hydration (TFH) method, direct injection method (DIM) and drug encapsulation using freeze–thaw cycles. In vitro drug release study was performed using dialysis membrane method. The skin permeation studies were performed using excised porcine ear skin model in a Franz diffusion cell apparatus.

Results and discussion: The average particle size and zeta-potential of liposomes were 191?±?4.1?nm and ?40.4?±?4.5?mV, respectively. The liposomes prepared by TFH followed by 10 freeze–thaw cycles showed the greatest EE of 22.7?±?0.63%. The optimized liposome formulation was incorporated in hydroxypropyl methyl cellulose (HPMC) hydrogel containing different permeation enhancers including oleic acid (OA), isopropyl myristate (IPM) and propylene glycol (PG). PFD-loaded liposomes incorporated in hydrogel containing OA and IPM showed the greatest flux of 10.9?±?1.04?μg/cm²/h across skin, which was 5-fold greater compared with free PFD. The cumulative amount of PFD permeated was 344?±?28.8?μg/cm² with a lag time of 2.3?±?1.3?h.

Conclusion: The hydrogel formulation containing PFD-loaded liposomes can be developed as a potential transdermal delivery system.     

The Study on the Entrapment Efficiency and In Vitro Release of Puerarin Submicron Emulsion

The entrapment efficiency (EE) and release in vitro are very important physicochemical characteristics of puerarin submicron emulsion (SME). In this paper, the performance of ultrafiltration (UF), ultracentrifugation (UC), and microdialysis (MD) for determining the EE of SME were evaluated, respectively. The release study in vitro of puerarin from SME was studied by using MD and pressure UF technology. The EE of SME was 86.5%, 72.8%, and 55.8% as determined by MD, UF, and UC, respectively. MD was not suitable for EE measurements of puerarin submicron oil droplet, which could only determine the total EE of submicron oil droplet and liposomes micelles, but it could be applied to determine the amount of free drug in SMEs. Although UC was the fastest and simplest to use, its results were the least reliable. UF was still the relatively accurate method for EE determination of puerarin SME. The release of puerarin SME could be evaluated by using MD and pressure UF, but MD seemed to be more suitable for the release study of puerarin emulsion. The drug release from puerarin SME at three drug concentrations was initially rapid, but reached a plateau value within 30 min. Drug release of puerarin from the SME occurred via burst release.     

Topical delivery and in vivo antileishmanial activity of paromomycin-loaded liposomes for treatment of cutaneous leishmaniasis

The present study aimed to evaluate the potential of liposomes loaded with paromomycin (PA), an aminoglycoside antibiotic associated with poor skin penetration, for the topical treatment of cutaneous leishmaniasis (CL). Fluid liposomes were prepared and characterized for particle size, zeta potential, and drug entrapment. Permeation studies were performed with two in vitro models: intact and stripped skin. The antileishmanial activity of free and liposomal PA was evaluated in BALB/c mice infected by Leishmania (L.) major. Drug entrapment ranged from 10 to 14%, and the type of vesicle had little influence on this parameter. Particle size and polydispersity index of the vesicles composed by phosphatidylcholine (PC) and PC/cholesterol (Chol) ranged from of 516 to 362?nm and 0.7 to 0.4, respectively. PA permeation across intact skin was low, regardless of the formulation tested, while drug penetration into skin (percent of the applied dose) from PC (7.2?±?0.2%) and PC/Chol (4.8?±?0.2%) liposomes was higher than solution (1.9?±?0.1%). PA-loaded liposomes enhanced in vitro drug permeation across stripped skin and improved the in vivo antileishmanial activity in experimentally infected mice. Our findings suggest that the liposomes represent a promising alternative for the topical treatment of CL using PA.     

Development of egg PC/cholesterol/α-tocopherol liposomes with ionic gradients to deliver ropivacaine

Context: Ropivacaine (RVC) is an aminoamide local anesthetic widely used in surgical procedures. Studies with RVC encapsulated in liposomes and complexed in cyclodextrins have shown good results, but in order to use RVC for lengthy procedures and during the postoperative period, a still more prolonged anesthetic effect is required.

Objective: This study therefore aimed to provide extended RVC release and increased upload using modified liposomes.

Materials and methods: Three types of vesicles were studied: (i) large multilamellar vesicle (LMV), (ii) large multivesicular vesicle (LMVV) and (iii) large unilamellar vesicle (LUV), prepared with egg phosphatidylcholine/cholesterol/α-tocopherol (4:3:0.07?mol%) at pH 7.4. Ionic gradient liposomes (inside: pH 5.5, pH 5.5?+?(NH₄)₂SO₄ and pH 7.4?+?(NH₄)₂SO₄) were prepared and showed improved RVC loading, compared to conventional liposomes (inside: pH 7.4).

Results and discussion: An high-performance liquid chromatography analytical method was validated for RVC quantification. The liposomes were characterized in terms of their size, zeta potential, polydispersion, morphology, RVC encapsulation efficiency (EE(%)) and in vitro RVC release. LMVV liposomes provided better performance than LMV or LUV. The best formulations were prepared using pH 5.5 (LMVV 5.5_in) or pH 7.4 with 250?mM (NH₄)₂SO₄ in the inner aqueous core (LMVV 7.4_in?+?ammonium sulfate), enabling encapsulation of as much as 2% RVC, with high uptake (EE(%) ～70%) and sustained release (～25?h).

Conclusion: The encapsulation of RVC in ionic gradient liposomes significantly extended the duration of release of the anesthetic, showing that this strategy could be a viable means of promoting longer-term anesthesia during surgical procedures and during the postoperative period.     

Mannosylated liposomes bearing Amphotericin B for effective management of visceral Leishmaniasis

The cationic and mannosylated liposomes were prepared using the cast film method and compared for their antileishmaniasis activity. The surface of the Amphotericin B (Amp B)-bearing cationic multilamellar liposomes was covalently coupled with p-aminophenyl-α-D-mannoside using glutaraldehyde as a coupling agent, which was confirmed by agglutination of the vesicles with concanavalin A. The prepared liposomes were characterized for shape, size, percent drug entrapment, vesicle count, zeta potential, and in vitro drug release. Vesicle sizes of cationic and mannosylated liposomes were found to be 2.32?±?0.23 and 2.69?±?0.13?µm, respectively. Zeta potential of cationic liposomes was higher (30.38?±?0.3 mV), as compared to mannosylated liposomes (17.7?±?0.8 mV). Percentage drug release from cationic and mannose-coupled liposomes was found to be 45.7%?±?3.1 and 41.9%?±?2.8, respectively, after 24 hours. The in vivo antileishmanial activity was performed on Leishmania donovani–infected golden hamster, and results revealed that Amp B solution was reduced by 42.5?±?1.8% in the parasite load, whereas the placebo cationic liposomes and drug-containing cationic liposomes showed a reduced parasite load (i.e., 28.1?±?1.5 and 61.2?±?3.2%, respectively). The mannose-coupled liposomes showed a maximum reduction in parasite load (i.e., 78.8?±?3.9%). The biodistribution study clearly showed the higher uptake of mannosylated liposomes in the liver and spleen and hence the active targeting to the reticular endothelial system, which, in turn, would provide a direct attack of the drug to the site where the pathogen resides, rendering the other organs free and safe from the toxic manifestations of the drug.     

A Novel Method for Preparing Surface-Modified Fluocinolone Acetonide Loaded PLGA Nanoparticles for Ocular Use: <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Evaluations

Our objective was to prepare nanoparticulate system using a simple yet attractive innovated method as an ophthalmic delivery system for fluocinolone acetonide to improve its ocular bioavailability. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles were prepared by adopting thin film hydration method using PLGA/poloxamer 407 in weight ratios of 1:5 and 1:10. PLGA was used in 75/25 and 50/50 copolymer molar ratio of DL-lactide/glycolide. Results revealed that using PLGA with lower glycolic acid monomer ratio exhibited high particle size (PS), zeta potential (ZP) and drug encapsulation efficiency (EE) values with slow drug release pattern. Also, doubling the drug concentration during nanoparticles preparation ameliorated its EE to reach almost 100%. Furthermore, studies for separating the un-entrapped drug in nanoparticles using centrifugation method at 20,000 rpm for 30 min showed that the separated clear supernatant contained nanoparticles encapsulating an important drug amount. Therefore, separation of un-entrapped drug was carried out by filtrating the preparation using 20–25 μm pore size filter paper to avoid drug loss. Aiming to increase the PLGA nanoparticles mucoadhesion ability, surface modification of selected formulation was done using different amount of stearylamine and chitosan HCl. Nanoparticles coated with 0.1% w/v chitosan HCl attained most suitable results of PS, ZP and EE values as well as high drug release properties. Transmission electron microphotographs illustrated the deposition of chitosan molecules on the nanoparticles surfaces. Pharmacokinetic studies on Albino rabbit’s eyes using HPLC indicated that the prepared novel chitosan-coated PLGA nanoparticles subjected to separation by filtration showed rapid and extended drug delivery to the eye.     

Investigations on feasibility of in situ development of amphotericin B liposomes for industrial applications

Amphotericin B (AmB) liposome formulations are very successful in the treatment of fungal infections and leishmaniasis. But higher cost limits its widespread use among people in developing countries. Therefore, we have developed a modified ethanol-injection method for the preparation of AmB liposomes. Two liposomal formulations were developed with dimyristoyl phosphatidylcholine [F-1a] and soya phosphatidylcholine [F-2a], along with egg phosphatidyl glycerol and cholesterol. AmB was dissolved in acidified dimethyl acetamide and mixed with ethanolic lipid solution and rapidly injected in 5% dextrose to prepare liposomes. Liposomes were characterized on the basis of size (~100?nm), zeta (–43.3?±?2.8 mV) and percent entrapment efficiency (>95%). The in vitro release study showed an insignificant difference (P?≥?0.05) for 24-hour release between marketed AmB liposomes (AmBisome) and F-1a and F-2a. Proliposome concentrate, used for the preparation of in situ liposomes, was physically stable for more than 3 months at experimental conditions. Similarly, AmB showed no sign of degradation in reconstituted liposomes stored at 2–8°C for more than 3 months. IC₅₀ value of Ambisome (0.18 µg/mL) was comparatively similar to F-1a (0.17 µg/mL) and F-2a (0.16 µg/mL) against intramacrophagic amastigotes. Under experimental conditions, a novel modified method for AmB liposomes is a great success and generates interest for development as a platform technology for many therapeutic drug products.     

Modulation of Tramadol Release from a Hydrophobic Matrix: Implications of Formulations and Processing Variables

In the present investigation, hydrogenated cottonseed oil (HCSO) was evaluated as a sustained release matrix for a freely soluble drug, tramadol. Hydrophobic matrix tablets of tramadol, was evaluated by compression of physical mixture of drug and wax, dispersion of drug in HCSO by hot fusion or solubilisation techniques. The method of preparation of tablet had a significant effect on drug release with higher release observed from direct compression matrices and slower release from matrix prepared by dispersion (hot-fused matrices). Influence of addition of hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and surfactants like sodium lauryl sulphate and polysorbate 20 to HCSO matrix on drug release was investigated. The added excipients exhibited a propensity to enhance drug release from the HCSO matrix. NaCMC was effective at a lower ratio (<10% w/w) and when incorporated at higher level made HCSO matrix to erode and disintegrate in a short period.     

Studies on Transdermal Delivery Enhancement of Zidovudine

The purpose of this study was to investigate physicochemical characteristics and in vitro release of zidovudine from monolithic film of Eudragit RL 100 and ethyl cellulose. Films included 2.5% or 5% (w/w) zidovudine of the dry polymer weight were prepared in various ratios of polymers by solvent evaporation method from methanol/acetone solvent mixture. The release studies were carried out by vertical Franz cells (2.2 cm² area, 20 ml receptor fluid). Ex vivo studies were done on Wistar rat skin within the films F6 (Eudragit RL100) and F7 (Eudragit RL100/Ethylcellulose, 1:1) consisting 5% (w/w) zidovudine in comparison with the same amount of free drug. Either iontophoresis (0.1 and 0.5 mA/cm² direct currents, Ag/AgCl electrodes) or dimethyl sulfoxide (pretreatment of 1% and 5%, w/w, solutions) were used as enhancers. Films consisting of ethyl cellulose under the ratio of 50% (w/w) gave similar release profiles, and the highest in vitro cumulative released amount was achieved with F6 film which gave the closest results with the free drug. This result could be due to the high swelling capacity and re-crystallization inhibition effect of RL 100 polymer which also influenced the film homogenization. All the films were fitted to Higuchi release kinetics. It was also observed that both 0.5-mA/cm² current and 5% (w/w) dimethyl sulfoxide applications significantly increased the cumulative permeated amount of zidovudine after 8 h; however, the flux enhancement ratio was higher for 0.5-mA/cm² current application, especially within F6 film. Thus, it was concluded that Eudragit RL100 film (F6) could be further evaluated for the transdermal application of zidovudine.     

The influence of bile salts on the response of liposomes to ultrasound

Context: Triggering drug release from delivery vehicles with ultrasound has potential applications in targeted drug delivery. It was hypothesized that the addition of bile salts would increase the sensitivity of liposomes to ultrasound through creation of defects.

Objective: The aim of this study was to investigate whether incorporating bile salts into liposomes would lead to differential effects on their response to low and high frequency ultrasound.

Materials and methods: Cholate, chenodeoxycholate, ursodeoxycholate, glycocholate and taurocholate were the selected bile salts. Response to ultrasound was characterized by measuring the release of carboxyfluorescein (CF).

Results: At 30?kHz ultrasound, taurocholate containing liposomes were most responsive and released 70% (±2) CF after 30 seconds of sonication. Compared to this, liposomes that did not contain bile salts released just 7% (±2). At 1.1?MHz ultrasound, all liposome formulations were unresponsive. To increase the response of liposomes at 1.1?MHz ultrasound, a combination of membrane destabilizers were added to DSPC liposomes. DOPE, a hexagonal phase lipid was used in combination with taurocholate. Surprisingly, liposomes containing DOPE and taurocholate were more resistant to 1.1?MHz ultrasound than ones containing only DOPE.

Discussion: This suggests that the sensitivity of liposomes towards ultrasound may not simply be defined by a single membrane component but instead depends on the interaction between constituting lipid components. Furthermore, strategies other than membrane destabilization may be required to sensitize liposomes towards high frequency ultrasound.

Conclusion: Bile salts may be used to increase or decrease the sensitivity of liposomes to low frequency ultrasound.     

Microfluidic preparation of drug-loaded PEGylated liposomes,and the impact of liposome size on tumour retention and penetration

Understanding the effect of liposome size on tendency for accumulation in tumour tissue requires preparation of defined populations of different sized particles. However, controlling the size distributions without changing the lipid composition is difficult, and differences in compositions itself modify distribution behaviour. Here, a commercial microfluidic format as well as traditional methods was used to prepare doxorubicin-loaded liposomes of different size distributions but with the same lipid composition, and drug retention, biodistribution and localization in tumour tissues were evaluated. The small (～50?nm diameter) liposomes prepared by microfluidics and large (～75?nm diameter) liposomes displayed similar drug retention in in vitro release studies, and similar biodistribution patterns in tumour-bearing mice. However, the extent of extravasation was clearly dependent on size of the liposomes, with the small liposomes showing tissue distribution beyond the vascular area compared to the large liposomes. The use of microfluidics to prepare smaller size distribution liposomes compared to sonication methods is demonstrated, and allowed preparation of different size distribution drug carriers from the same lipid composition to enable new understanding of tissue distribution in compositionally consistent materials is demonstrated.     

Entrapment efficiency of pyridoxine hydrochloride in unilamellar liposomes: experimental versus model-generated data

The present study investigates the effect of the preparation method (four methods) and formulation additives (propylene glycol (PG) and cholesterol (CH)) on the entrapment efficiency (EE) of pyridoxine hydrochloride (vitamin B6 (VB6)), representing hydrophilic water-soluble low permeable vitamins, in unilamellar liposomes. The main aim is to compare determined EE with predicted values generated using a web-published, computational model. Results showed that among the different preparation methods, modified film hydration showed significantly higher EE (p?). With regard to formulation additives, PG (5% w/v) produced smaller vesicles size with narrow size distribution. Agreement between determined and model-generated EE values was more evident in formulae with narrow size distribution (polydispersity index (PdI) below 0.23). Formulae containing PG showed slightly higher determined than predicted EE values indicating vitamin–phospholipid bilayer interaction. Meanwhile, agreement between determined and predicted EE was limited to VB6-to-phospholipid ratio below (1.2:2). The comparison provided further insight into the usefulness of the prediction model factors affecting agreement between determined and predicted EE data.     

Liposomes for (trans)dermal drug delivery: the skin-PVPA as a novel in vitro stratum corneum model in formulation development

Penetration potential of vesicles destined for trans(dermal) administration remains to be of great interests both in respect to drug therapy and cosmetic treatment. This study investigated the applicability of the phospholipid vesicle-based permeation assay (PVPA) as a novel in vitro skin barrier model for screening purposes in preformulation studies. Various classes of liposomes containing hydrophilic model drug were examined, including conventional liposomes (CLs), deformable liposomes (DLs) and propylene glycol liposomes (PGLs). The size, surface charge, membrane deformability and entrapment efficiency were found to be affected by the vesicle lipid concentration, the presence of the surfactant and propylene glycol. All liposomes exhibited prolonged drug release profiles with an initial burst effect followed by a slower release phase. The permeation of the drug from all of the tested liposomes, as assessed with the mimicked stratum corneum – PVPA model, was significantly enhanced as compared to the permeability of the drug in solution form. Although the DLs and the PGLs exhibited almost the same membrane elasticity, the permeability of the drug delivered by PGLs was higher (6.2?×?10^?6?cm/s) than DLs (5.5?×?10^?6?cm/s). Therefore, this study confirmed both the potential of liposomes as vesicles in trans(dermal) delivery and potential of the newly developed skin-PVPA for the screening and optimization of liposomes at the early preformulation stage.     

Encapsulation of Ketoprofen and Ketoprofen Lysinate by Prilling for Controlled Drug Release

In this paper, ketoprofen and ketoprofen lysinate were used as model drugs in order to investigate release profiles of poorly soluble and very soluble drug from sodium alginate beads manufactured by prilling. The effect of polymer concentration, viscosity, and drug/polymer ratio on bead micromeritics and drug release rate was studied. Ketoprofen and ketoprofen lysinate loaded alginate beads were obtained in a very narrow dimensional range when the Cross model was used to set prilling operative conditions. Size distribution of alginate beads in the hydrated state was strongly dependent on viscosity of drug/polymer solutions and frequency of the vibration. The release kinetics of the drugs showed that drug release rate was related with alginate concentration and solubility of the drug. Alginate solutions with concentration higher than 0.50% (w/w) were suitable to prepare ketoprofen gastro-resistant formulation, while for ketoprofen lysinate alginate, concentration should be increased to 1.50% (w/w) in order to retain the drug in gastric environment. Differential scanning calorimetry thermograms and Fourier transform infrared analyses of drug-loaded alginate beads indicated complex chemical interactions between carboxyl groups of the drug and polymer matrix in drug-loaded beads that contribute to the differences in release profile between ketoprofen and ketoprofen lysinate. Total release of the drugs in intestinal medium was dependent on the solubility of the drug and was achieved between 4 and 6 h.     

Chitosan/Polyethylene Glycol Beads Crosslinked with Tripolyphosphate and Glutaraldehyde for Gastrointestinal Drug Delivery

This study reports on the preparation of chitosan (CS)/polyethylene glycol (PEG) hydrogel beads using sodium diclofenac (DFNa) as a model drug. Following the optimization of the polymer to drug ratio, the chitosan beads were modified by ionic crosslinking with sodium tripolyphosphate (TPP). The CS/PEG/DFNa beads obtained from a (w/w/w) ratio of 1/0.5/0.5 with crosslinking in 10% (w/v) TPP at pH 6.0 for 30 min yielded excellent DFNa encapsulation levels with over 90% loading efficiency. The dissolution profile of DFNa from CS/PEG/DFNa beads demonstrated that this formulation was able to maintain a prolonged drug release for approximately 8 h. Among the formulations tested, the CS/PEG/DFNa (1/0.5/1 (w/w/w)) beads crosslinked with a combination of TPP (10% (w/v) for 30 min) and glutaraldehyde (GD) (5% (w/v)) were able to provide minimal DFNa release in the gastric and duodenal simulated fluids (pH 1.2 and 6.8, respectively) allowing for a principally gradual drug release over 24 h in the intestinal (jejunum and ileum) simulated fluid (pH 7.4). Thus, overall the CS/PEG beads crosslinked with TPP and GD look to be a promising and novel alternative gastrointestinal drug release system.     

Cogrinding as a Tool to Produce Sustained Release Behavior for Theophylline Particles Containing Magnesium Stearate

The aim of the present study was to explore the cogrinding technique as a tool to slow down the drug release from capsule formulations. To this end, the physical mixtures of theophylline–magnesium stearate were prepared and subjected to different milling times (1, 15, 30, 120 min). In order to investigate the effect of magnesium stearate concentration on drug release, various concentrations of magnesium stearate (1%, 3%, 5%, and 10%, w/w) were used. The dissolution rate of the drug from coground samples and physical mixtures were determined at pH 6.5 according to USP. The results showed that all coground formulations showed slower release rates than their physical mixture counterparts. The effect of cogrinding time on the drug release was complex. Cogrinding time had no significant effect on drug release when the amount of magnesium stearate was 1% (w/w). When the amount of magnesium stearate was increased from 1% to 3% and cogrinding time increased from 1 to 5 min, there was a significant reduction in drug release. Beyond 5-min cogrinding, the drug release increased again. For coground samples containing 5% or 10% (w/w) magnesium stearate, generally, the highest drug release was obtained at higher cogrinding time. This was due to a significant increase in surface area of particles available for dissolution as proven by scanning electron microscopy results. Fourier transform infrared and differential scanning calorimetry results ruled out any significant interaction between theophylline and magnesium stearate in solid state.     

Liposomes as an ocular delivery system for acetazolamide: In vitro and in vivo studies

The purpose of this study was to formulate topically effective controlled release ophthalmic acetazolamide liposomal formulations. Reverse-phase evaporation and lipid film hydration methods were used for the preparation of reversephase evaporation (REVs) and multilamellar (MLVs) acetazolamide liposomes consisting of egg phosphatidylcholine (PC) and cholesterol (CH) in the molar ratios of (7∶2), (7∶4), (7∶6), and (7∶7) with or without stearylamine (SA) or dicetyl phosphate (DP) as positive and negative charge inducers, respectively. The prepared liposomes were evaluated for their entrapment efficiency and in vitro release. Multilamellar liposomes entrapped greater amounts of drug than REVs liposomes. Drug loading was increased by increasing CH content as well as by inclusion of SA. Drug release rate showed an order of negatively charged > neutral > positively charged liposomes, which is the reverse of the data of drug loading efficiency. Physical stability study indicated that approximately 89%, 77%, and 69% of acetazolamide was retained in positive, negative, and neutral MLVs liposomal formulations up to a period of 3 months at 4°C. The intraocular pressure (IOP)-lowering activity of selected acetazolamide liposomal formulations was determined and compared with that of plain liposomes and acetazolamide solution. Multilamellar acetazolamide liposomes revealed more prolonged effect than REVs liposomes. The positively charged and neutral liposomes exhibited greater lowering in IOP and a more prolonged effect than the negatively charged ones. The positive multilamellar liposomes composed of PC:CH:SA (7:4:1) molar ratio showed the maximal response, which reached a value of −7.8±1.04 mmHg after 3 hours of topical administration. Published: January 5, 2007     

Evaluation of mucoadhesive hydrogels loaded with diclofenac sodium-chitosan microspheres for rectal administration

Considering the advantageous for the rectal administration of non-steroidal anti-inflammatory drugs, the objective of this study was to formulate and evaluate rectal mucoadhesive hydrogels loaded with diclofenac-sodium chitosan (DFS-CS) microspheres. Hydroxypropyl methylcellulose (HPMC; 5%, 6%, and 7% w/w) and Carbopol 934 (1% w/w) hydrogels containing DFS-CS microspheres equivalent to 1% w/w active drug were prepared. The physicochemical characterization revealed that all hydrogels had a suitable pH for rectal application (6.5–7.4). The consistency of HPMC hydrogels showed direct proportionality to the concentration of the gelling agent, while carbopol 934 gel showed its difficulty for rectal administration. Farrow’s constant for all hydrogels were greater than one indicating pseudoplastic flow. In vitro drug release from the mucoadhesive hydrogel formulations showed a controlled drug release pattern, reaching 34.6–39.7% after 6 h. The kinetic analysis of the release data revealed that zero-order was the prominent release mechanism. The mucoadhesion time of 7% w/w HPMC hydrogel was 330 min, allowing the loaded microspheres to be attached to the surface of rectal mucosa. Histopathological examination demonstrated the lowest irritant response to the hydrogel loaded with DFS-CS microspheres in response to other forms of the drug.