Optimization and characterization of gastroretentive floating drug delivery system using Box-Behnken design

Context: One among many strategies to prolong gastric residence time and improve local effect of the metronidazole in stomach to eradicate Helicobacter pylori in the treatment of peptic ulcer was floating drug delivery system particularly effervescent gastroretentive tablets.

Objective: The objective of this study was to prepare and evaluate, effervescent floating drug delivery system of a model drug, metronidazole.

Methods: Effervescent floating drug delivery tablets were prepared by wet granulation method. A three-factor, three levels Box-Behnken design was adopted for the optimization. The selected independent variables were amount of hydroxypropyl methylcellulose K 15M (X₁), sodium carboxy methylcellulose (X₂) and NaHCO₃ (X₃). The dependent variables were floating lag time (Y_FLT), cumulative percentage of metronidazole released at 6th h (Y₆) and cumulative percentage of metronidazole released at 12th h (Y₁₂). Physical properties, drug content, in vitro floating lag time, total floating time and drug release behavior were assessed.

Results: Y_FLT range was found to be from 1.02 to 12.07?min. The ranges of other responses, Y₆ and Y₁₂ were 25.72?±?2.85 to 77.14?±?3.42 % and 65.47?±?1.25 to 99.65?±?2.28 %, respectively. Stability studies revealed that no significant change in in vitro floating lag time, total floating time and drug release behavior before and after storage.

Conclusion: It can be concluded that a combination of hydroxypropyl methylcellulose K 15M, sodium carboxy methylcellulose and NaHCO₃ can be used to increase the gastric residence time of the dosage form to improve local effect of metronidazole.     

Formulation and evaluation of gastroretentive floating drug delivery system of dipyridamole

A multiple-unit floating alginate bead drug delivery system with prolonged stomach retention time was developed in this study. The floating alginate beads were prepared by ionic cross-linking method, using CaCO₃ as the gas-forming agent. Over 92% of the beads remained floating after 9?h. In order to prepare sustained-release dosage forms of dipyridamole, the solid dispersion technique was applied using a blend of Eudragit L100 and Eudragit RLPO. Afterwards, the solid dispersions of dipyridamole were incorporated into the floating alginate beads. The drug release was modified by changing the ratio of Eudragit RLPO and Eudragit L100 in the solid dispersions. The in vivo results showed that the relative bioavailability of alginate beads was enhanced by approximately 2.52-fold compared with that of the commercial tablet. Therefore, our study illustrated the potential use of floating alginate beads combined with the solid dispersion technique for the delivery of acid-soluble compounds, such as dipyridamole.     

Development of novel gastroretentive drug delivery system of gliclazide: hollow beads

Aim: The current communication deals with the development of hollow floating beads of gliclazide. The primary effect of this drug is to potentiate glucose-stimulated insulin release from pancreatic islet-β-cells by induction of a decrease in potassium efflux from these cells. Because of the poor aqueous solubility, its absorption is limited. Thus, an attempt was made to improve its release profile.

Methods: The hollow drug-loaded alginate beads in combination with low methoxyl pectin and hydroxypropylmethylcellulose (HPMC) were prepared by a simple ionotropic gelation method. The beads were evaluated for particle size and morphology using optical microscopy and scanning electron microscopy (SEM), respectively. Mucoadhesion test was done using goat stomach mucosal membrane. Release characteristics of the gliclazide-loaded hollow beads were studied in 0.1?N HCl (pH 1.2) and phosphate buffer (pH 5.8).

Results: The developed beads were spherical in shape with hollow internal structure and had a particle size in the range of 0.730?±?0.05 to 0.890?±?0.03?mm. The incorporation efficiency of alginate -pectin beads was higher than alginate -HPMC beads. The Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction analysis showed stable character of drug in the drug-loaded hollow beads and revealed the absence of any drug -polymer interactions. The beads remained buoyant for more than 12?h. The drug release from beads followed Fickian diffusion with swelling.

Conclusion: The preliminary results of this study suggest that the developed beads containing gliclazide could enhance drug entrapment efficiency, reduce the initial burst release and modulate the drug release.     

In vitro and in vivo performance of a multiparticulate pulsatile drug delivery system

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

Effect of formulation variables on the floating properties of gastric floating drug delivery system

PURPOSE: To evaluate the contribution of formulation variables on the floating properties of a gastric floating drug delivery system (GFDDS) using a continuous floating monitoring system and statistical experimental design. METHODS: A modified continuous floating monitoring system, which consisted of an electric balance interfacing with a PC, was designed to perform the continuous monitoring of floating kinetics of GFDDS. Several formulation variables, such as different types of hydroxypropyl methylcellulose (HPMC), varying HPMC/Carbopol ratio, and addition of magnesium stearate, were evaluated using Taguchi design, and the effects of these variables were subjected to statistical analysis. RESULTS: The continuous floating monitoring system developed was validated, using capsules with different density, and a good correlation between theoretical and experimental values was obtained (R2 = 0.9998), indicating the validity of the setup. The statistical analysis indicated that magnesium stearate had a significant effect on the floating property of GFDDS (p < 0.05), and addition of magnesium stearate could significantly improve the floating capacity of the GFDDS. It was found that the HPMC of higher viscosity grade generally exhibited a greater floating capacity, but the effect was not statistically significant. For polymers with the same viscosity, i.e., K4M and E4M, the degree of substitution of the function group did not show any significant contribution. A better floating behavior was achieved at higher HPMC/Carbopol ratio. Carbopol appeared to have a negative effect on the floating behavior of GFDDS. CONCLUSIONS: It was concluded that by using a validated continuous floating monitoring system, the effect of formulation variables on the floating property of the delivery system and their ranges could be identified. Incorporation of hydrophobic agents, such as magnesium stearate, could significantly improve the floating capacity of the GFDDS.     

Application of ion exchange resin in floating drug delivery system

The purpose of this study was to explore the application of low-density ion exchange resin (IER) Tulsion(R) 344, for floating drug delivery system (FDDS), and study the effect of its particle size on rate of complexation, water uptake, drug release, and in situ complex formation. Batch method was used for the preparation of complexes, which were characterized by physical methods. Tablet containing resin with high degree of crosslinking showed buoyancy lag time (BLT) of 5-8 min. Decreasing the particle size of resin showed decrease in water uptake and drug release, with no significant effect on the rate of complexation and in situ complex formation for both preformed complexes (PCs) and physical mixtures (PMs). Thus, low-density and high degree of crosslinking of resin and water uptake may be the governing factor for controlling the initial release of tablet containing PMs but not in situ complex formation. However, further sustained release may be due to in situ complex formation.     

Preparation of multiparticulate systems for oral delivery of a micronized or nanosized poorly soluble drug

The purpose of the present work was to prepare multiparticulate drug delivery systems for oral administration of a poorly soluble drug such as itraconazole. Multiparticulate systems were prepared by extrusion/spheronization technique using a mix of crospovidone, low viscosity hypromellose, microcrystalline cellulose, micronized drug and water. In order to improve the release performance of the multiparticulate systems, the micronized drug was suspended in water with polysorbate 20 and nanonized by a high-pressure homogenization. The suspension of drug nanoparticles was then spray-dried for enabling an easy handling of the drug and for preventing the over-wetting of the powders during extrusion/spheronization processing. Both multiparticulate units prepared with micronized or nanonized drug showed acceptable disintegrating properties. The nanosizing of micronized drug powder provided a significant improvement of drug dissolution rates of the multiparticulates.     

Optimization of self nanoemulsifying drug delivery system for poorly water-soluble drug using response surface methodology

There is an increasing interest on self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of poorly water-soluble drugs. However, development of SNEDDS is often driven by empiric, pseudo-ternary diagrams and solubility of drugs, and it is lacking a systematic approach for evaluating impact of excipients on the performance of formulations as well as the fate of drug. The aim of this study was to rationalize the SNEDDS development procedure and to get a better understanding on the role of excipients on the SNEDDS. The formulations consist of soybean oil or rapeseed oil, Cremophor^® RH40, Maisine? 35-1 and ethanol. Response surface methodology (RSM) was used in the development of SNEDDS. Significant advantages of RSM were found in reducing the work load and determining the impact of excipients on formulation characteristics. The most significant factor in influencing droplet size was the co-surfactant Maisine? 35-1, the droplet size increased with increasing concentration of Maisine? 35-1. It suggests that Maisine? 35-1 has double functions in the SNEDDS; it functions as co-surfactant to improve the emulsification of oil, meanwhile it also works as the oil phase and results in larger droplets. A significant reduction in droplet size was interestingly observed when fenofibrate was loaded in the vehicles, probably due to the surface activity of fenofibrate, promoting the self-emulsifying process. It was evident that drug precipitation during lipolysis was not affected by the level of co-solvent ethanol in the formulation, while it had pronounced impact on drug solubilization during the initial dispersion stage.     

Multiparticulate drug delivery system of aceclofenac: development and in vitro studies

The aim of this study was to develop an enteric-coated multiunit dosage form containing aceclofenac, a nonsteroidal anti-inflammatory drug. The pellets were prepared by using extrusion/spheronization method, and the core pellets were coated with a pH-sensitive poly(meth) acrylate copolymer (Eudragit L100-55) to achieve site-specific drug release. The formulated pellets were characterized for percentage yield, size distribution, surface morphology studies, drug content, and flow properties. In vitro dissolution test was used for comparison of drug release profiles of various coated pellets. The practical yield was found to be 90-95%. The particle size of enteric-coated pellets was found to be in the range of 0.59-0.71 mm. The pellets were spherical in shape and surfaces of pellets were found to be rough and showing micropores. Enteric-coated pellets showed good flow properties and in vitro dissolution profile. Dissolution tests were carried out in a USP type II dissolution apparatus in media-simulating pH conditions of the gastrointestinal tract. The release of the aceclofenac from formulated pellets was established to be minimum in the pH 1.2 (<5%) for a period of 2 h, and at pH 6.8, it shows the maximum release (85 +/- 5% release within 1 h) which indicates gastric resistance of the formulated pellets. The 20% wt/wt enteric-coated pellets were compared to that of marketed product (tablets), it was observed that pellets showed better release profile. The study concluded that the formulated multiparticulate dosage forms can be used as an ideal drug delivery system for the aceclofenac.     

Bioavailability enhancement of baclofen by gastroretentive floating formulation: statistical optimization,in vitro and in vivo pharmacokinetic studies

Objectives: The study was aimed to improve bioavailability of baclofen by developing gastroretentive floating drug delivery system (GFDDS).

Methods: Preliminary optimization was done to select various release retardants to obtain minimum floating lag time, maximum floating duration and sustained release. Optimization by 3² factorial design was done using Polyox WSR 303 (X₁) and HPMC K₄M (X₂) as independent variables and cumulative percentage drug released at 6?h (Q6h) as dependent variable.

Results: Optimized formulation showed floating lag time of 4–5 s, floated for more than 12?h and released the drug in sustained manner. In vitro release followed zero ordered kinetics and when fitted to Korsemeyer Peppas model, indicated drug release by combination of diffusion as well as chain relaxation. In vivo floatability study confirmed floatation for more than 6?h. In vivo pharmacokinetic studies in rabbits showed C_max of 189.96?±?13.04?ng/mL and T_max of 4?±?0.35?h for GFDDS. The difference for AUC_(0–T) and AUC_(0–∞) between the test and reference formulation was statistically significant (p > 0.05). AUC_(0–T) and AUC_(0–∞) for GFDDS was 2.34 and 2.43 times greater than the marketed formulation respectively.

Conclusion: GFDDS provided prolonged gastric residence and showed significant increase in bi oavailability of baclofen.     

Porous carrier based floating granular delivery system of repaglinide

A floating granular delivery system consisting of calcium silicate (CS) as porous carrier; repaglinide (Rg), an oral hypoglycemic agent; and hydroxypropyl methylcellulose K4M (HPMC K4M), ethyl cellulose (EC) and carbopol 940 (CP940) as matrix forming polymers was prepared and evaluated for its gastro-retentive and controlled release properties. The effect of various formulation and process variables on the particle morphology, micromeritic properties, in vitro floating behavior, drug content (%) and in vitro drug release was studied. The transit of floating granules of optimized formulation in the gastrointestinal (GI) tract was monitored by gamma scintigraphy in albino rabbits. The optimized formulation was compared in vivo with lactose granules (RgSCLG) prepared from identical polymers with their optimized composition ratio. Repaglinide-loaded optimized formulation was orally administered to albino rabbits and blood samples collected were used to determine pharmacokinetic parameters of Rg from floating granular formulation. Results were compared with pharmacokinetic parameters of marketed tablet formulation of Rg. The optimized formulation (RgSCG4) demonstrated favorable in vitro floating and release characteristics. Prolonged gastric residence time (GRT) of over 6 hr was achieved in all subjects for calcium silicate based floating granules of Rg. The relative bioavailability of Rg-loaded floating granules increased 3.8-fold in comparison to that of its marketed capsule. The designed system, combining excellent buoyant ability and suitable drug release pattern, offered clear advantages in terms of increased bioavailability of repaglinide.     

Novel drug delivery system for captopril

It is known that drug substances showing no difference in absorbance along the whole gastro-intestinal (GI) tract are suitable for SR-formulations with an extended release characteristic. However, a decrease in bioavailability from proximal to distal parts of the gut may be suited for a limited retard effect. In this investigation, attempts have been made to design a suitable delivery system for captopril which is poorly bio-available from the alkaline regions of the GI-tract. The principles of 'Bioadhesion' as well as 'Gastric Floating Systems' are utilized in this study.     

Novel drug delivery system for captopril

Abstract

It is known that drug substances showing no difference in absorbance along the whole gastro-intestinal (GI) tract are suitable for SR-formulations with an extended release characteristic. However, a decrease in bioavailability from proximal to distal parts of the gut may be suited for a limited retard effect. In this investigation, attempts have been made to design a suitable delivery system for captopril which is poorly bio-available from the alkaline regions of the GI-tract. The principles of ‘Bioadhesion’ as well as ‘Gastric Floating Systems’ are utilized in this study.     

Porous pellets as drug delivery system

Background: Multiparticulate drug delivery systems, such as pellets, are frequently used as they offer therapeutic advantages over single-unit dosage forms. Aim: Development of porous pellets followed by evaluation of potential drug loading techniques. Method: Porous microcrystalline pellets were manufactured and evaluated as drug delivery system. Pellets consisting of Avicel PH 101 and NaCl (70%, w/w) were prepared by extrusion/spheronization. The NaCl fraction was extracted with water and after drying porous pellets were obtained (33.2% porosity). Immersion of the porous pellets in a 15% and 30% (w/v) metoprolol tartrate solution, ibuprofen impregnation via supercritical fluids and paracetamol layering via fluidized bed coating were evaluated as drug loading techniques. Results: Raman spectroscopy revealed that immersion of the pellets in a drug solution and supercritical fluid impregnation allowed the drug to penetrate into the porous structure of the pellets. The amount of drug incorporated depended on the solubility of the drug in the solvent (water or supercritical CO₂). Drug release from the porous pellets was immediate and primarily controlled by pure diffusion. Conclusion: The technique described in this research work is suitable for the production of porous pellets. Drug loading via immersion the pellets in a drug solution and supercritical fluid impregnation resulted in a drug deposition in the entire pellet in contrast to fluid bed layering where drugs were only deposed on the pellet surface.     

Solid self-microemulsifying drug delivery system of ritonavir

Context: Ritonavir (RTV) is a human immunodeficiency virus (HIV) protease inhibitor (PI) with activity against HIV, practically insoluble in water and recommended to co-administer as a booster along with other HIV-PI to enhance their bioavailability. The present study is aimed to enhance the dissolution and oral bioavailability of water-insoluble RTV using the Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS).

Objective: To enhance the dissolution and oral bioavailability of water-insoluble RTV using the S-SMEDDS.

Material and methods: Liquid SMEDDS (L-SMEDDS) of RTV was formulated by the optimizing ratio of Imwitor 988 (Oil), Cremophor EL and Cremophor RH 40 (1:1) (surfactant) and Capmul GMS K-50 (cosurfactant). Optimized L-SMEDDS showed improved dissolution rate of RTV compared to pure RTV powder. Optimized L-SMEDDS of RTV was adsorbed on Neusilin US-2 using a simple wet granulation technique with selected excipients to convert it into S-SMEDDS.

Results and discussion: Optimized L-SMEDDS showed an improved dissolution rate of RTV compared to pure RTV powder. Droplet size of resultant microemulsion of L-SMEDDS of RTV was observed between 16 and 22 nm and independent of pH (i.e. 0.1 N HCl and water). Conversion of the crystalline form of RTV to amorphous form was observed when RTV formulated into SMEDDS form as per X-ray diffraction study. In vitro dissolution study, stability study of optimized S-SMEDDS confirmed the formulation of stable and improved dissolution of RTV. Relative bioavailability of RTV was determined in male Wistar rats and pharmacokinetic parameters were calculated by the comparison of optimized S-SMEDDS versus aqueous suspension of RTV. S-SMEDDS improved the plasma profile in terms of maximum plasma concentration (C_max), and area under curve (AUC_0–24h), which is almost twofolds higher than the aqueous suspension of RTV.

Conclusion: S-SMEDDS tablet of RTV was formulated successfully by adsorbing optimized L-SMEDDS of RTV on Neusilin-US2® as a potential carrier with enhanced solubility and relative oral bioavailability compared to pure RTV by twofolds.     

Optimization and evaluation of microwave-assisted synthesis of magnetite as a carrier for targeted drug delivery system

ABSTRACT

The present research work is a novel cost-effective method for synthesis of magnetite. Magnetite is a carrier which is used in the targeted drug delivery system. The conventional methods of preparation of magnetite take around 6–7 h for the completion of reaction; moreover, the particle size of magnetite which we get by the conventional methods is above 5 µm, so the present work aims at preparing magnetite with microwave assistance which has found to reduce reaction time with particle size obtained below 5 µm. The aim of this study was to optimize magnetite synthesis using 2³ factorial design by Design-Expert software. Magnetites were synthesized using oxidation of ferrous sulfate. In the next step, the effects of different variables on particle size are studied, including the stirring speed, microwave power (W), and stirring time. Based on the type and the variables studied, eight formulations were designed using factorial design method, and were then prepared, and their particle size was determined. Finally, selected magnetite syntheses were evaluated from the viewpoints of scanning electron microscopy (SEM) and x-ray diffraction (XRD). Results revealed that magnetite obtained from the solutions generated Design-Expert software could be selected as the best and optimized formulations due to their lowest particle size.     

Comparative permeability studies with radioactive and nonradioactive risedronate sodium from self-microemulsifying drug delivery system and solution

The purpose of this work is to prepare a self-microemulsifying drug delivery system (SMEDDS) for risedronate sodium (RSD) and to compare the permeability with RSD solution. The solubility of RSD was determined in different vehicles. Phase diagrams were constructed to determine the optimum concentration of oil, surfactant, and cosurfactant. RSD SMEDDS was prepared by using a mixture of soybean oil, cremophor EL, span 80, and transcutol (2.02:7.72:23.27:61.74, w/w, respectively). The prepared RSD SMEDDS was characterized by droplet size value. In vitro Caco-2 cell permeability studies were performed for SMEDDS and solution of radioactive (^99?mTc-labeled RSD) and nonradioactive RSD. The experimental results indicated that RSD SMEDDS has good stability and its droplet size is between 216.68?±?3.79 and 225.26?±?7.65 during stability time. In addition, RSD SMEDDS has higher permeability value than the RSD solution for both radioactive and nonradioactive experiments. The results illustrated the potential use of SMEDDS for delivery of poorly absorbed RSD.     

High-throughput formulation screening system for self-microemulsifying drug delivery

Purpose: To develop a high-throughput formulation screening (HTFS) system for self-microemulsifying drug delivery system (SMEDDS) formulations. Methods: Formulations were prepared by dispensing surfactants and a model compound (Nilvadipine) dissolved in ethanol and oil with a robotic liquid dispenser. Screenings of emulsion particle size and phase stability were conducted for selecting SMEDDS formulations by a turbidity assay. Results: Formulations were prepared at 40 minute/96-formulation. Both the screenings were conducted at 1 minute/96-formulation. SMEDDS formulations and the most suitable hydrophilic surfactant (HS)/lipophilic surfactant (LS) combination, which formed the largest SMEDDS area on its corresponding phase diagram, were selected by SMEDDS–HTFS system with minimal manpower (one person) and compound consumption (0.2 mg/formulation). Conclusions: SMEDDS–HTFS system enabled rapid and efficient selections of SMEDDS formulations and the most suitable HS/LS combination for SMEDDS.