In vitro and in vivo techniques to assess the performance of gastro-retentive drug delivery systems: a review

Background: Interest in gastro-retentive drug delivery systems (GRDDS) can be attributed to the desire for increased patient convenience (once daily dosing) and to increase the therapeutic index (reduced C_max, increased C_min). A range of evaluation techniques for GRDDS exist for in vitro and in vivo evaluation. Objective: The aim of the present review is to describe the methodologies used for in vitro and in vivo evaluations of GRDDS. Methods: The proposed critical parameters for floating and swelling types of GRDDS are discussed. Modifications in dissolution testing and improved biorelevant testing methods are also described. The in vivo techniques for measuring gastro-retentive performance are also summarised. Conclusion: The described methods can be used as assessment techniques for the evaluation and development of GRDDS. With these techniques, it is possible (with appropriate controls) to determine if a GRDDS provides hope for advantages of extended residence time in the stomach.     

Polymeric nanofibers: targeted gastro-retentive drug delivery systems

Background: Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders.

Purpose: The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention.

Conclusion: Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system.     

In vivo and in vitro release of macromolecules from polymeric drug delivery systems

In vivo release rates of a macromolecule from an ethylene-vinyl acetate copolymer have been shown to be indistinguishable from those of identical implants tested in vitro. The studies were conducted for approximately 2 months, and two different techniques were used to assess release rates. One of these techniques, using [3H]inulin as a marker, may be particularly useful in future studies assessing in vivo release rates from drug delivery systems. The appearance of [3H]inulin in the urine of rats bearing implants allowed continuous monitoring of release. A histological evaluation of tissue sections surrounding polymer implanted for 7 months showed no inflammatory cell reaction.     

In vivo imaging of drug delivery systems in the gastrointestinal tract

An essential basis for the understanding of the complex interplay between oral drug delivery systems and gastrointestinal physiology is the ability to relate deposition of the dosage form to the plasma concentration time profile. The pharmaceutical scientist requires an array of methods that provide information on formulation disposition without influencing the physiological process, commonly termed "non-invasive" imaging modalities. In this paper, a short historical view on the suitability of different imaging modalities for the investigation of the fate of drug delivery systems in the GI tract is given. The focus of the review is the presentation of currently mostly used methodologies scintigraphy, magnetic tracking techniques like magnetic marker monitoring (MMM), magnetic moment imaging (MMI), AC biosusceptometry (ACB) and magnetic resonance imaging and the discussion of their strengths and weaknesses.     

In vitro/in vivo comparisons in pulmonary drug delivery

Establishing clear relationships between in vitro and in vivo data for inhaled drug products is an important goal. In vitro aerodynamic particle size distributions (APSDs) are expected to have some predictive power not only for drug deposition, but also for clinical effects. APSD data obtained by cascade impaction have been compared with lung deposition data measured in gamma scintigraphy studies. Whole-lung deposition correlated significantly with fine particle fraction (FPF) across a range of inhaler devices. FPF, defined in terms of aerosol <5.8 microm or <6.8 microm diameter, systematically overestimated lung deposition for virtually all inhalers. Lung deposition showed closer numerical equivalence to the percentage of the aerosol dose smaller than 3 microm diameter. Correlations exist between APSD data and whole-lung deposition, which may allow the greater use of APSD data for comparing inhaler devices. Agreement between in vitro and in vivo data may be improved by measuring APSD in ways that more closely mimic clinical use, including the use of impactor inlets that simulate the human upper airway anatomy. At the present time there are few published data that relate APSD to the clinical response of inhaled drugs in an unambiguous way.     

In vitro and in vivo techniques used in drug development for evaluation of dose delivery of inhaled corticosteroids

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered-dose inhaler (MDI) with an integrated spacer (Azmacort) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort has been reformulated with a non-CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic-pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort.     

Re-evaluation of in vitro dissolution techniques for supersaturating drug delivery systems

Conventional dissolution testing using high-performance liquid chromatography (HPLC) analysis was evaluated against fiber optic dissolution method for studying supersaturable drug delivery systems. Two self-microemulsifying (SME) formulations of albendazole (ABZ) (15 mg/capsule and 5 mg/capsule) were prepared. Dissolution study was performed in medium with pH 1.2, 4.5, 6.8 and 7.4. Samples were analyzed simultaneously by HPLC and online fiber optic dissolution system. For 15 mg/capsule formulation, the profiles obtained using HPLC data showed almost 80-100% releases at pH 4.5, 6.8 and 7.4, whereas fiber optic data showed less than 40% release at the end of 60 min. The observed precipitation was due to pH-dependent solubility of ABZ in water and data analysis revealed a supersaturation phenomenon. This difference in release profiles was due to the presence of oil and water phase in the dissolution sample that upon dilution with high organic mobile phase resulted in quantification of the total drug and not the dissolved drug. The 5 mg/capsule formulation showed no difference in release profiles between methods as the concentration was under the saturation solubility. These results pointed out a considerable error in the development of a complex SME formulation, and use of fiber optic dissolution method was found beneficial.     

In vitro and in vivo evaluation of a novel capsule for colon-specific drug delivery

The aim of this study was to estimate colon-specific drug delivery of a novel capsule (CS capsule). Theophylline was used as model drug and little was released from the CS capsules in the release medium mimicking physiological environment of stomach to small intestine. However, 66.7 ± 8.8% theophylline was released from the capsules in the phosphate buffer (pH 6.8) mimicking the physiological environment of colon in the next 4 h, while the addition of galactomannanase (39.3 U/L) accelerated the disintegration of the CS capsule and enhanced the release rate to 92.6 ± 6.0%. Rats in vivo pharmacokinetics demonstrated that the relative bioavailability of theophylline after intragastric administration of CS capsules was 76.72% with delayed T_max of 8 h comparing to that of theophylline solution with T_max of 1.5 h. Radiolabeled with technetium-99m, the CS capsule could keep intact from stomach to small intestine while disintegration of the CS capsule was observed in the proximal colon or the joint between the distal small intestine and right colon. A great quantity of radiolabeled marker was released as well as distributed in the whole colon at 10 h after administration. As a whole, the CS capsule prepared could provide an alternative carrier for the colon-specific drug delivery. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2626–2635, 2009     

Transdermal drug delivery systems of albuterol: in vitro and in vivo studies.

In vitro and in vivo experiments were conducted with double- and single-layer albuterol transdermal pads designed for once-a-day application. In the in vitro experiments, dissolution of albuterol from pads and permeation of albuterol through hairless mouse skin were monitored. In the in vivo experiments, pads were applied to the chest area of four female rhesus monkeys (Macaca mulata), and an albuterol aqueous solution was injected into the saphenous vein of the same animals in a crossover design. The amount lost from pads applied to monkeys was monitored by analysis of pad residue. Blood samples were withdrawn at regular intervals and analyzed by a high-performance liquid chromatography-fluorescence method. Skin irritation due to the pad was measured by a modified Draize score test. The amounts released from the two formulations were similar. The amount released was, however, dependent on the technique used and decreased in the following manner: pad dissolution greater than in vivo amount lost from pads applied to monkeys greater than in vitro permeation through hairless mouse skin. The pharmacokinetic parameters determined after intravenous and transdermal administration were as follows: terminal half-life, 2.26 +/- 0.45 h; apparent volume of distribution, 1935 +/- 37.2 mL.kg-1; and total body clearance, 612.0 +/- 118 mL.h-1.kg-1. The average concentrations in serum after application of single- and double-layer pads were 44.60 +/- 16.40 and 62.50 +/- 8.00 ng/mL, respectively. Further, the amount lost from pads applied to monkeys correlated with the respective amount absorbed in monkeys, as calculated from the average concentration in serum and clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amylose formulations for drug delivery to the colon: a comparison of two fermentation models to assess colonic targeting performance in vitro

The purpose of this study was to develop an enzyme-based fermentation system for the in vitro assessment of colonic digestion of amylose films and coatings, and to compare its performance with a conventional fermentation model inoculated with human faecal bacteria. Amylose and ethylcellulose were mixed in different ratios and cast as isolated films, as well as spray coated onto drug-(5-aminosalicylic acid) loaded pellets. Four commercial amylase enzymes were individually screened for their ability to digest amylose cast films. The enzyme from the bacterium Bacillus licheniformis was found to be the most active against this substrate. Digestion of mixed amylose and ethylcellulose films was also observed, with the extent of digestion being proportional to the quantity of amylose present in the film. In terms of product performance, drug release from coated pellets was accelerated in the presence of the enzyme. The results with the enzyme system were comparable to those obtained from a faecal-based fermentation model, thereby suggesting that such a system has practical potential for in vitro screening of putative amylose formulations for colonic drug delivery.     

In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate

Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self-microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs.     

Topical drug delivery systems: a patent review

Introduction: Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration.

Areas covered: This review summarizes innovations from the past 3 years (2012–2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically.

Expert opinion: Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.     

Polyethyleneimine-modified pectin beads for colon-specific drug delivery: In vitro and in vivo implications

Calcium-pectinate (Ca-pectinate) beads have shown immense potential as colon-specific drug carrier. However, Ca-pectinate itself is unable to prevent its swelling/degradation in the upper gastro-intestinal (GI) conditions. Hence, polyethyleneimine (PEI) was added in the cross-linking solution to strengthen the Ca-pectinate network. Resveratrol was used as a model drug due to its promising therapeutic activity towards several colonic diseases. Beads were prepared by varying cross-linking solution pH and other formulation variables. The effects of these formulation variables were investigated on the bead's characteristics. Furthermore, surface morphology, drug–polymer interaction, stability, and in vivo pharmacokinetic study of the optimized formulation were performed. The optimized PEI-modified beads prevented drug release in the upper GI conditions, while released the drug in simulated colonic fluid. Furthermore, in vivo pharmacokinetics studies in rats demonstrated delayed appearance of drug in blood after oral administration. The optimized Ca-pectinate beads demonstrated both in vitro and in vivo colon-specific drug release.     

In vitro–in vivo correlations of self-emulsifying drug delivery systems combining the dynamic lipolysis model and neuro-fuzzy networks

The aim of the current study was to evaluate the potential of the dynamic lipolysis model to simulate the absorption of a poorly soluble model drug compound, probucol, from three lipid-based formulations and to predict the in vitro–in vivo correlation (IVIVC) using neuro-fuzzy networks. An oil solution and two self-micro and nano-emulsifying drug delivery systems were tested in the lipolysis model. The release of probucol to the aqueous (micellar) phase was monitored during the progress of lipolysis. These release profiles compared with plasma profiles obtained in a previous bioavailability study conducted in mini-pigs at the same conditions. The release rate and extent of release from the oil formulation were found to be significantly lower than from SMEDDS and SNEDDS. The rank order of probucol released (SMEDDS ∼ SNEDDS > oil formulation) was similar to the rank order of bioavailability from the in vivo study. The employed neuro-fuzzy model (AFM-IVIVC) achieved significantly high prediction ability for different data formations (correlation greater than 0.91 and prediction error close to zero), without employing complex configurations. These preliminary results suggest that the dynamic lipolysis model combined with the AFM-IVIVC can be a useful tool in the prediction of the in vivo behavior of lipid-based formulations.     

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery

Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of molecules warrants additional study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was observed at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chemistry work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-week intervals. No mortality was observed. Forty-eight hours following the last administration, blood chemistry revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathological data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.     

Montmorillonite Poly-L-Lactide Microcomposites of Procainamide for controlled drug delivery: In vitro and In vivo evaluation

The research work reported in this paper is extension of our previous findings related to intercalation of procainamide hydrochloride, an antiarrythmia drug in interlayer gallery of Na⁺-clay (montmorillonite). The microcomposite particles prepared from procainamide-montmorillonite hybrid and poly L-lactide were characterised by scanning electron microscope and atomic force microscopy analysis. In vitro drug release study in simulated intestinal fluid showed controlled release pattern up to ~72 h and significant reduction in the drug release in gastric environment. In vivo pharmacokinetics and biodistribution in rats showed that the plasma/tissue drug levels were within therapeutic window as compared with free drug. The data from toxicity biomarker estimations and clinical biochemistry/haematological parameters showed significant reduction in drug toxicity when formulated in montmorillonite/poly L-lactide as compared with free drug, which is of considerable value in achieving improved therapy with reduced side effects.