Development of a Model for Simultaneous Measurement of Rheology and Dissolution for In Situ Gel Forming Drug Delivery Systems

In situ gel forming drug delivery systems utilize the concept of undergoing sol-gel transitions on exposure to physiological fluids in response to changes in temperature, pH and/or ionic environment. Gelation in response to the changes in pH/ionic contents are particularly difficult to measure in a biorelevant manner as gelation is often too rapid for adequate mixing of physiological fluids with the polysaccharides prior to loading on to a rheometer. Although, several modifications have been applied to conventional rheometers to facilitate changing environmental conditions, modifications that can change the chemical environment of a sample and simultaneously measure release of active ingredients from in situ gelling formulations has yet to be developed. To address this problem a novel method has been demonstrated using a 3D printed rheo-dissolution cell to simultaneously measure the rheological behaviour and dissolution of drug from the in situ gelling systems on exposure to physiological fluids. The technique was validated and then used to understand the behaviour of a range of in situ gelling formulations. An in situ gel forming ophthalmic formulation of low acyl gellan gum (gellan) (0.4%) and timolol maleate (TM) (6.8 mg/ml) was prepared based on commercial Timoptol LA®. Rheological evaluation and a drug release study were performed separately using the rheo-dissolution device. This study also highlighted the importance of drug-polymer interaction by indicating electrostatic interactions between the positively charged TM and negatively charged gellan. The concept of rheo-dissolution was further explored with the full experimental set up of the rheo-dissolution cell integrated with a rheometer. An in situ gelling ophthalmic (gellan-TM) and an oral formulation (alginate- metronidazole) were prepared to evaluate the novel technique. The ophthalmic formulations of gellan-TM showed rapid onset of gelation on exposure to simulated lacrimal fluid (SLF) (pH 7.5) and release slowed down with increased gellan concentrations (0.6% to 0.8% w/v). Rheo-dissolution experiments performed on the oral formulation of revealed the formation of a strong gel with rapid gelation on exposure to simulated gastric fluid (pH 1.2). Rapid release was observed while the gel was structuring, which then slowed down (~53% in 7h) once gelation was complete. The pH of the media was increased to 8.0, which resulted in a dramatic increase of MNZ release (~96% in 7h) and degradation of the alginate gel. Finally, an in situ gelling ophthalmic formulation of gellan was prepared using flurbiprofen (FBP) (a poorly soluble drug) and 2-hydroxypropyl-β-cyclodextrin (HβCD) inclusion complex. This work highlighted the difficulties of incorporating the sodium salt form FBP in in situ gelling systems prepared using gellan because of the tendency of gellan to cross link with salts. Besides the rheo-dissolution study, ex-vivo permeation study was performed which showed higher percentage of FBP permeation (~55% in 6h) in the inclusion complex formulation compared with FBP sodium in the commercial product Ocufen® (~37% in 6h)

Gastro-retentive drug delivery systems and their in vivo success: A recent update

Gastro-retentive drug delivery system (GRDDS) has gained immense popularity in the field of oral drug delivery recently. It is a widely employed approach to retain the dosage form in the stomach for an extended period of time and release the drug slowly that can address many challenges associated with conventional oral delivery, including poor bioavailability. Different innovative approaches like magnetic field assisted gastro-retention, plug type swelling system, muco-adhesion technique, floating system with or without effervescence are being applied to fabricate GRDDS. Apart from in vitro characterization, successful GRDDS development demands well designed in vivo study to establish enhanced gastro-retention and prolonged drug release. Gama scintigraphy and MRI are popular techniques to evaluate in vivo gastric residence time. However, checking of their overall in-vivo efficacy still remains a major challenge for this kind of dosage form, especially in small animals like mice or rat. Reported in vivo studies with beagle dogs, rabbits, and human subjects are only a handful in spite of a large number of encouraging in vitro results. In spite of the many advantages, high subject variations in gastrointestinal physiological condition, effect of food, and variable rate of gastric emptying time are the challenges that limit the number of available GRDDS in the market. This review article highlights the in vivo works of GRDDS carried out in the recent past, including their limitations and challenges that need to be overcome in the near future

Formulation and in-vitro characterization of floating sustained-release tablets of metformin hydrochloride

Metformin HCl, a drug from biguanide class, is the most commonly used first-line antihyperglycemic agent in the treatment of NIDDM [1]. The major problems associated with the drug are high dose (1.5-2.0 g/day), frequent dosing due to its shorter biological half-life (1.5-4.9 hr), and low bioavailability (60%) [2]. Low bioavailability of metformin results from incomplete absorption of the drug as metformin is majorly absorbed from the stomach and lower part of GIT [3]. An oral sustained-release floating tablets of metformin HCl based on gas formation and swelling was developed to prolong gastric residence time and increase drug bioavailability. Sustained-release floating tablets of metformin was fabricated with Polyethylene oxide (PEO) and HPMC as polymers, SSG as swelling enhancer, NaHCO3 as effervescent component, PVPK as binder, Magnesium stearate as lubricant and Talc as glidant. Thirteen trial formulations (Table 1) were investigated according to Box-behnkhen experimental design taking various composition of SSG, NaHCO3 and combination of HPMC and PEO at three levels in order to find out the best formulation depending on floating lag time and in-vitro release profile. 12 mm circular bi-convex floating tablets were prepared by wet granulation method using a 10-station Rotary tablet press machine (Mini press II, Remek). Pre-compression parameters of the granules like bulk density (BD), tapped density (TD), compressibility index, angle of repose etc were tested as part of pre-formulation study. Drug-excipient compatibility was confirmed by DSC (DSC 821e, Mettler Toledo, Switzerland) and X-ray diffraction (Perkin Elmer RX-1) study. Tablets were evaluated for weight variation, hardness, thickness, friability, moisture content, assay, in-vitro floating lag time, % swelling etc. In vitro drug release for trial formulations and market formulation (Glucophase® XR by Merck Sante S.A.S.) was studied for 12 hr using a USP Type I dissolution apparatus (basket) with 100 rpm and 900 ml 0.1 N HCl as dissolution medium maintained at 37 ± 0.5 0C. Released metformin HCl amounts were determined UV-spectrophotometrically by measuring the absorption at 232 nm and calculated using calibration curves of the drug (Fig. 1). In vitro release mechanism was evaluated by linear regression analysis. The SEM images of the tablet were taken before and after in vitro dissolution study for both outer and inner cross-sectional surface. Tablets from the optimized formulation determined by response surface methodology (RSM) were stored at accelerated stability condition (40 °C and 75% RH) for 3 months. Content of metformin, drug release profile and buoyancy in 0.1N HCl of stored tablets were compared with the initial data. All pre-formulation parameters were found to be within acceptable range. Fabricated tablets showed acceptable weight variation, hardness, thickness, friability and uniformity of drug content. Melting peaks of metformin was visible in DSC thermogram of drug-excipients mixture (Fig. 2), indicating that metformin was compatible with the rest of the excipients of formulation. FTIR graphs (Fig. 3) also confirmed the same finding. Floating lag time and duration of floating were found to be dependent on amount of gas effervescent agent (NaHCO3), swelling of polymers (HPMC and PEO) and swelling enhancer (SSG). The optimized formulation was found to provide average floating lag time less than 4 minutes with a floating duration of more than 24 hours. Swelling rate of the combination of polymers was found to be rapid and linear for initial 2 hr, however it decreased thereafter and maintained the linearity until 8 hours (Fig. 4). Combination of HPMC and PEO allowed efficient control of drug release for 12 hr which was similar (f2 value 68) to that of market sample (Fig. 5). SEM figure (Fig. 6) showed the non-porous nature of tablet outer surface and little bit porous structure of inner surface before dissolution study. However, after dissolution of 2 hr and 8 hr, both surfaces turned into porous structure which allows the drug to diffuse to the surrounding medium. This also proves that the drug release occurs by diffusion. Based on accelerated stability study optimized formulation was found to be stable for three months without any major changes in assay, dissolution profile, floating lag time and other physical properties

Fabrication and optimization of gastro retentive drug delivery system with HPMC and polyethylene oxide (PEO) matrix

Gastro retentive tablets of metformin HCl were prepared based on polymer swelling and gas formation. Combination of HPMC and polyethylene oxide was used as both matrix forming agent and swelling agent, while sodium bicarbonate as gas forming agent. Fabricated tablets were optimized by response surface methodology (RSM) utilizing Box Behnken experimental design. The optimized tablets were further characterized by surface morphology, drug release kinetics, accelerated stability study etc. The optimized tablets enabled to float for more than 24 h and sustained the drug release for 12 h

Design and in-vitro evaluation of sustained release floating tablets of metformin HCl based on effervescence and swelling

An oral sustained-release floating tablet formulation of metformin HCl was designed and developed. Effervescence and swelling properties were attributed on the developed tablets by sodium bicarbonate and HPMC-PEO polymer combination, respectively. Tablet composition was optimized by response surface methodology (RSM). Seventeen (17) trial formulations were analyzed according to Box-Behnken design of experiment where polymer content of HPMC and PEO at 1: 4 ratio (A), amount of sodium bi-carbonate (B), and amount of SSG (C) were adopted as independent variables. Floating lag time in sec (Y1), cumulative percent drug released at 1 h (Y2) and 12 h (Y3) were chosen as response variables. Tablets from the optimized formulation were also stored at accelerated stability condition (40°C and 75% RH) for 3 months to assess their stability profile. RSM could efficiently optimize the tablet composition with excellent prediction ability. In-vitro drug release until 12 h, floating lag time, and duration of floating were dependent on the amount of three selected independent variables. Optimized tablets remained floating for more than 24 h with a floating lag time of less than 4 min. Based on best fitting method, optimized formulation was found to follow Korsmeyer-Peppas release kinetic. Accelerated stability study revealed that optimized formulation was stable for three months without any major changes in assay, dissolution profile, floating lag time and other physical properties