Brinzolamide Dimethyl Sulfoxide In Situ Gelling Ophthalmic Solution: Formulation Optimisation and In Vitro and In Vivo Evaluation.

In the present work, a cost-effective, stable and sustained release ophthalmic solution formulation of brinzolamide (BRZ) was developed for the treatment of glaucoma. The prototype formulation undergoes 'in situ gelling' when administered in the eye, thereby providing longer residence (16-24 h). As a result, the same therapeutic endpoint is achieved with once daily dosing vis-à-vis the commercially available product Azopt® (brinzolamide 1.0% w/v, Alcon Laboratories, USA) that requires 3-4 times instillations per day. The prototype formulations were prepared using dimethyl sulfoxide, polyoxyl 35 castor oil and polysorbate 80. Gellan gum was used as the in situ gelling agent. Formulation variables like (i) concentration of the drug, dimethyl sulfoxide and in situ gelling agent and (ii) type and concentration of solubiliser showed a significant effect on the solubility of brinzolamide, in vitro gelling time, in vitro drug release and in situ gel stability. Prototype formulations were evaluated in New Zealand white rabbits for ocular toxicity and efficacy study. The tested formulations were well tolerated and reduced intraocular pressure (IOP) from 25-28 to 12-14 mmHg compared to saline and placebo control samples. Additionally, a significant increase in the area under change in IOP from baseline (ΔIOP) vs. time curve and a longer mean residence time (MRT) were also observed for the test formulations (7.4 to 17.7 h) compared to the commercially available suspension of Azopt® (4.9 h) (p < 0.0001). Thus, 'in situ gelling' formulation strategy described in this work can work as a viable option for ocular delivery of brinzolamide for the treatment of glaucoma.

Levofloxacin Hemihydrate In Situ Gelling Ophthalmic Solution: Formulation Optimization and In Vitro and In Vivo Evaluation.

Bacterial conjunctivitis is a leading cause of ocular infections requiring short-term therapeutic treatment with frequent administration of drugs on daily basis. Topical dosage forms available in the market for the treatment of bacterial conjunctivitis such as simple drug solutions and suspensions are rapidly eliminated from the precorneal space upon instillation due to tear turn over and nasolacrimal drainage, limiting intraocular bioavailability of drug to less than 10% of the administered dose. To overcome issues related to conventional drop, an effort was made to design and evaluate prolong release ophthalmic solution of levofloxacin hemihydrate (LFH) using ion-sensitive in situ gelling polymer. Gellan gum was used as the in situ gelling agent. Formulations were screened based on in vitro gelation time, in vitro drug release, and stability towards sol to gel conversion upon storage. The prototype formulations exhibiting quick in vitro gelling time (< 15 s), prolonged in vitro drug release (18-24 h), and stability for at least 6 months at 25°C/40% relative humidity (RH) and 40°C/25% RH were evaluated for pharmacokinetic studies using healthy New Zealand white rabbits. Tested formulations were found to be well-tolerated and showed significant increase in AUC0-24 (22,660.39 h ng/mL) and mean residence time (MRT 12 h) as compared with commercially available solution Levotop PF® (Ajanta Pharma Ltd., India)(AUC0-24 6414.63 h ng/mL and MRT 4 h). Thus, solution formulations containing in situ gelling polymer may serve as improved drug delivery system providing superior therapeutic efficacy and better patient compliance for the treatment of bacterial conjunctivitis.

Mechanistic modeling of ophthalmic, nasal, injectable, and implant generic drug products: A workshop summary report.

For approval, a proposed generic drug product must demonstrate it is bioequivalent (BE) to the reference listed drug product. For locally acting drug products, conventional BE approaches may not be feasible because measurements in local tissues at the sites of action are often impractical, unethical, or cost-prohibitive. Mechanistic modeling approaches, such as physiologically-based pharmacokinetic (PBPK) modeling, may integrate information from drug product properties and human physiology to predict drug concentrations in these local tissues. This may allow clinical relevance determination of critical drug product attributes for BE assessment during the development of generic drug products. In this regard, the Office of Generic Drugs of the US Food and Drug Administration has recently established scientific research programs to accelerate the development and assessment of generic products by utilizing model-integrated alternative BE approaches. This report summarizes the presentations and panel discussion from a public workshop that provided research updates and information on the current state of the use of PBPK modeling approaches to support generic product development for ophthalmic, injectable, nasal, and implant drug products.

Brimonidine tartrate-eudragit long-acting nanoparticles: formulation, optimization, in vitro and in vivo evaluation.

In the present study, an effort was made to design prolonged release Eudragit nanoparticles of brimonidine tartrate by double emulsion-solvent evaporation technique for the treatment of open-angle glaucoma. The effect of various formulation variables like initial drug amount, lecithin proportion, phase volume and pH, secondary emulsifier and polymer proportion were studied. Various process variables like energy and duration of emulsification, lyophilization on the characteristics of nanoparticles and in vitro drug release profile were studied. The selected formulations were subjected to in vivo intraocular pressure-lowering efficacy studies by administering aqueous dispersion of nanoparticles into the lower cul de sac of glaucomatous rabbits. The prepared Eudragit-based nanoparticles were found to have narrow particle size range and improved drug loading. The investigated process and formulation variables found to have significant effect on the particle size, drug loading and entrapment efficiency, and in vitro drug release profile of nanoparticles. The selected formulations upon in vivo ocular irritability and tolerability tests were found to be well tolerated with no signs of irritation. In vivo pharmacodynamic efficacy studies revealed that the selected nanoparticle formulations significantly improved the therapy as area under the ∆IOP vs. time curve [AUC((∆IOP vs. t))] showed several fold increase in intensity and duration of intraocular pressure (IOP) decrease. All the selected nanoparticle formulations were found to prolong the drug release in vitro and prolong IOP reduction efficacy in vivo, thus rendering them as a potential carrier in developing improved drug delivery systems for the treatment of glaucoma.

Design, optimisation and evaluation of in situ gelling nanoemulsion formulations of brinzolamide.

The present research work summarises the development of an in situ gelling ophthalmic nanoemulsion of brinzolamide providing sustained release and prolonged therapeutic effect for the treatment of glaucoma. Nanoemulsions were prepared using castor oil, polyoxyl 35 castor oil and polysorbate 80 and with gellan gum as the in situ gelling agent. Formulations were screened based on globule size, Zeta potential, in vitro drug release and stability towards phase separation and sol to gel conversion upon storage. Selected formulations exhibiting a low mean globule diameter (< 160 nm), narrow size distribution (polydispersity index < 0.3), quick in vitro gelling time (< 15 s) and stability for at least 6 months at 25 °C/40% RH and 40 °C/25% RH were evaluated for intraocular pressure (IOP)-lowering efficacy studies using glaucomatous rabbits. Tested nanoemulsion formulations were well tolerated and significantly decreased IOP relative to saline and placebo controls (p < 0.005). Furthermore, an appreciable increase in the area under change in IOP from baseline (ΔIOP) vs. time curve and a longer mean residence time (MRT) was also observed for the test formulations compared with commercially available suspension of brinzolamide (Azopt, Alcon Laboratories, USA). Thus, nanoemulsion formulations containing in situ gelling polymer may serve as improved drug delivery system providing superior therapeutic efficacy and better patient compliance for the treatment of glaucoma. . Graphical abstract.

Microspheres with pH modulated release: design and characterization of formulation variables for colonic delivery.

The aim of this study was to design and develop microspheres of indomethacin with pH and transit time dependent release properties for achieving targeted delivery to the colon. Microspheres containing varying proportions of ethyl cellulose and Eudragit (L100 or S100) either alone or in combination were prepared using an oil-in-oil emulsion-based solvent evaporation technique. System comprising of acetone (internal phase) and liquid paraffin (external phase) in the ratio of 1 : 1 and 1 : 9 yielded microspheres with good physical properties (spherical and discrete), high drug loading (70-80%) and entrapment efficiency (70-85%). The lag time in the initial release depended on the proportion of pH-sensitive polymer Eudragit, while the duration of indomethacin release from microspheres was found to be directly proportional to proportion of the total polymer. Thus, a pH- and time-modulated sigmoidal release pattern could be observed in optimized formulations with less than 10% drug release in 4-6 h followed by controlled release extending up to 14-16 h.

Colon specific delivery of indomethacin: effect of incorporating pH sensitive polymers in xanthan gum matrix bases.

In the present study, an attempt has been made to design controlled release colon-specific formulations of indomethacin by employing pH responsive polymers Eudragit (L100 or S100) in matrix bases comprised of xanthan gum. The prepared tablets were found to be of acceptable quality with low-weight variation and uniform drug content. In vitro release studies indicated rapid swelling and release of significant percentage of drug in the initial period from matrix tablets composed of xanthan gum alone. Addition of pH responsive polymers Eudragit (L100 or S100) to xanthan gum matrix resulted in negligible to very low drug release in the initial period in acidic to weakly acidic medium. Furthermore, with increase in pH of the dissolution medium due to dissolution of Eudragit L100/Eudragit S100 that resulted in the formation of a porous matrix, faster but controlled drug release pattern was observed. Thus, a sigmoidal release pattern was observed from the designed formulations suitable for colonic delivery. Drug release mechanism in all cases was found to be of super case II type, indicating erosion to be the primary cause of drug release. Since the drug release from almost all the matrix bases in the initial phase was negligibly low and followed with controlled release for about 14-16 h, it was concluded that a matrix design of this composition could have potential applications as a colon-specific drug delivery device with additional advantage of easy scale-up and avoidance of all-or-none phenomenon associated with coated colon-specific systems.

Multiparticulate formulation approach to colon specific drug delivery: current perspectives.

Colon specific drug delivery has gained increased importance not just for the delivery of drugs for the treatment of local diseases associated with the colon but also as potential site for the systemic delivery of therapeutic peptide and proteins. To achieve successful colon targeted drug delivery, a drug needs to be protected from degradation, release and/or absorption in the upper portion of the GI tract and then ensure abrupt or controlled release in the proximal colon. Drug modifications through covalent linkages with carrier or prodrug approach and formulation based approaches can be used for colonic delivery. Report suggests that drug carrier systems larger than 200 mm possess very low gastric transit time due to physiological condition of the bowel in colitis. And for this reason and considering the selective uptake of micron or sub-micron particles by cancerous and inflamed cells/ tissues a multiparticulate approach based on pellets, granules, microsphere or nanoparticle type formulation is expected to have better pharmacological effect in the colon. The review is aimed at understanding recent advancements made in multiparticulate formulation approach for colon specific delivery of medicaments.

Development and in vitro evaluation of oral controlled release formulations of celecoxib using optimization techniques.

The objective of this study was to develop controlled release matrix embedded formulations of celecoxib (CCX) as candidate drug using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC), either alone or in combination, using optimization techniques like polynomial method and composite design. This would enable development of controlled release formulations with predictable and better release characteristics in lesser number of trials. Controlled release matrix tablets of CCX were prepared by wet granulation method. The in vitro release rate studies were carried out in USP dissolution apparatus (paddle method) in 900 ml of sodium phosphate buffer (pH 7.4) with 1% v/v tween-80. The in vitro drug release data was suitably transformed and used to develop mathematical models using first order polynomial equation and composite design techniques of optimization. In the formulations prepared using HPMC alone, the release rate decreased as the polymer proportion in the matrix base was increased. Whereas in case of formulations prepared using EC alone, only marginal difference was observed in the release rate upon increasing the polymer proportion. In case of formulations containing combination of HPMC and EC, the release of the drug was found to be dependent on the relative proportions of HPMC and EC used in the tablet matrix. The release of the drug from these formulations was extended up to 21 h indicating they can serve as once daily controlled release formulations for CCX. Mathematical analysis of the release kinetics indicates a near approximate Fickian release character for most of the designed formulations. Mathematical equation developed by transforming the in vitro release data using composite design model showed better correlation between observed and predicted t(50%) (time required for 50% of the drug release) when compared to first order polynomial equation model. The equation thus developed can be used to predict the release characteristics of the drug from matrix embedded formulations depending upon the proportion of HPMC and EC used in the formulation.

Design and evaluation of matrix base with sigmoidal release profile for colon-specific delivery using a combination of Eudragit and non-ionic cellulose ether polymers.

A pH- and time-controlled drug delivery system with sigmoidal release profile was developed using Eudragit (L100 or S100) in combination with hydroxy ethyl cellulose (HEC) or hydroxy propyl cellulose (HPC) for sigmoidal release of indomethacin in the potential treatment of colon cancer. The effect of varying proportions of polymer type on sigmoidal release was evaluated. The prepared tablets were also characterized for physical characteristics, in vitro drug release, release kinetics, and stability on storage. The gastrointestinal transit of formulations was also investigated in human subjects. Results from in vitro release studies indicated that due to the presence of pH-responsive polymers, a pH- and time-dependent release pattern was observed, which was characterized by negligible drug release in first 4-6 h followed by controlled release for 14-16 h in alkaline pH. In vivo studies indicated that HPC-based formulations had satisfactory matrix strength to withstand gastric and colonic transit, while HEC-based tablets disintegrated during transit through the small intestine. All the formulations were stable on storage. It was concluded that such a matrix design has good potential for drug delivery to colon with controlled release.

Sustained release ocular inserts of brimonidine tartrate for better treatment in open-angle glaucoma.

Pathology of eye, especially in the case of glaucoma, requires optimal therapeutically effective concentration of the drug in the ocular tissues for prolonged period of time with decreased dosing frequency and improved patient compliance. In the present study, brimonidine tartrate (BRT) ocular inserts were designed based on hydrophilic and/or inert/zwitterionic polymer matrix to design mucoadhesive and extended release ocular inserts. Designed inserts were evaluated for their physicochemical properties such as crushing strength/hardness, friability, drug content and mucoadhesion, and erosion and in vitro drug release characteristics. The selected optimised formulations were compared with marketed preparation for in vivo ocular irritation in healthy rabbits and for in vivo pharmacodynamic efficacy on alpha-chymotrypsin-induced glaucomatous rabbits. The developed formulations showed good physicochemical properties and mucoadhesive strength, and a good correlation was seen between rate of erosion or swelling with drug release rate in case of formulations with higher proportion of polyethylene oxide (PEO). Modulation of drug release was achieved by incorporating Eudragit in PEO matrix. Addition of Eudragit resulted in shifting of drug release mechanism from erosion-controlled to diffusion-controlled mechanism. In vivo ocular irritation studies confirmed the absence of any irritation upon administration in rabbits. Intraocular pressure (IOP) measurement studies showed an improved IOP-lowering ability of ocular insert of BRT in comparison to eye drops.

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery.

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0-6 h) followed by controlled release for 14-16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery.

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH-sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible-to-very low drug release in the initial phase (0-6 h) followed by controlled release for 14-16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s), while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

Design and evaluation of matrices of Eudragit with polycarbophil and carbopol for colon-specific delivery.

The purpose of the present study was to investigate the effect of incorporating pH-responsive polymers Eudragit (L100 or S100) in matrix bases composed of hydrophilic polymers polycarbophil and carbopol to design oral controlled release formulations with sigmoidal release profile for colon-specific delivery. Matrix tablets were prepared by wet granulation technique using indomethacin as model drug and were characterized for physical parameters, in vitro drug release, release kinetics, and stability on storage. The gastrointestinal (GI) transit of selected formulations was also investigated in human subjects using gamma scintigraphy. In vitro release studies indicated that the presence of pH-sensitive polymers in hydrophilic polymer base retarded the initial release significantly (10-15% release in 6 h) followed with controlled release for the next 8-10 h in simulated GI fluid pH (without enzymes). The presence of Eudragit in hydrophilic matrix base retarded the swelling of the matrix base in acidic to weakly acidic pH, but in alkaline pH, enhancement in drug release rate was observed due to the dissolution of Eudragit from the base resulting in a porous matrix structure, resulting in around 80-90% release in 14 h of study. In vivo gamma scintigraphy studies in healthy human subjects proved that the formulations had acceptable matrix strength to withstand gastric and colonic transit. The mean colonic residence time of selected designed formulations varied between 15 and 19 h. Such a matrix design could have potential application as colon-specific drug delivery systems with pH- and time-dependent drug release profile.