Design of chondroitin sulphate coated proglycosomes for localized delivery of tofacitinib for the treatment of rheumatoid arthritis.

Long-term oral tofacitinib (TOF) administration has been linked to serious side effects majorly immunological suppression. The aim of this work was to enhance the therapeutic efficacy of TOF by chondroitin sulphate (CS) coated proglycosomes through the anchoring of high-affinity CS to CD44 receptors on immune cells in the inflammatory region. The CS was coated onto the TOF-loaded proglycosomes (CS-TOF-PG) formulations and they were evaluated for in vitro drug release, ex vivo (permeation, dermatokinetics) studies. In vivo efficacy studies were carried out in Freund's complete adjuvant (CFA) induced arthritis model. The optimized CS-TOF-PG showed particle sizes of 181.13 ± 7.21 nm with an entrapment efficiency of 78.85 ± 3.65 %. Ex-vivo studies of CS-TOF-PG gel exhibited 1.5-fold high flux and 1.4-fold dermal retention compared to FD-gel. The efficacy study revealed that CS-TOF-PG showed a significant (P < 0.001) reduction in inflammation in arthritic rat paws compared to the TOF oral and FD gel. The current study ensured that the CS-TOF-PG topical gel system would provide a safe and effective formulation for localization and site-specific delivery of TOF at the RA site and overcome the adverse effects associated with the TOF.

Hyaluronic acid-coated proglycosomes for topical delivery of tofacitinib in rheumatoid arthritis condition: Formulation design, in vitro, ex vivo characterization, and in vivo efficacy studies.

Tofacitinib (TF) is a selective oral jakanib approved by the USFDA for the treatment of rheumatoid arthritis (RA). To overcome the adverse effects of orally administered TF, topical delivery can be a suitable choice. The therapeutic efficacy of TF can be improved through the high affinity of natural ligands (hyaluronic acid and chondroitin sulphate) to CD44 receptors on the macrophages or other immune cells in the dermal region. Thus, the present research work was inspired by the possibility to develop and evaluate the potential of hyaluronic acid-coated proglycosomes (HA-TF-PG) as the carrier for site-specific dermal delivery. The normal-PG (N-TF-PG) and HA-TF-PG showed particle sizes of <250 nm. The HA-TF-PG demonstrated 3.15-fold higher retention of TF in the viable dermis layers than the conventional formulation. The in vivo pharmacodynamic study, cytokines, and radiographic study on Complete Freud's Adjuvant-induced arthritic rat model revealed that HA-TF-PG exhibited a significant (P < 0.001) reduction in inflammation in arthritic rat's paw compared to the conventional TF. The developed HA-TF-PG treated groups showed significantly lowered CD44 levels compared to FD-gel and N-TF-PG i.e. 2.28 and 1.32-fold respectively (p < 0.001). In conclusion, The HA-TF-PG can be developed as an effective carrier for the site-specific dermal drug delivery system of TF to treat RA.

Spectrophotometric method to quantify tofacitinib in lyotropic liquid crystalline nanoparticles and skin layers: Application in ex vivo dermal distribution studies.

Tofacitinib is an oral Janus kinase inhibitor used in the treatment of Rheumatoid arthritis. The topical delivery of novel Tofacitinib loaded liquid crystal nanoparticles (LCNPs) can provide a controlled release, and also targeted drug delivery to inflamed synovium. There is need of UV spectroscopic method which can determine Tofacitinib in designed nanocarriers like LCNPs, that can be applied to evaluate entrapment efficiency, in vitro drug release, and ex vivo skin studies. In the present study, we have developed and validated a simple and sensitive spectrophotometric method for the quantitative determination of Tofacitinib in methanol and phosphate buffer saline. The linearity range in both the media was 5-30 µg/mL (methanol) and 5-40 µg/ mL (phosphate buffer saline) with high correlation coefficient value (>0.9998). This indicates the clear correlation between Tofacitinib concentrations and their absorbance within the test ranges. The repeatability and intermediate precision articulated by the relative standard deviation were less than 2% in the developed method. The method specificity and applicability were also ascertained by performing recovery studies by spiking method, which was 95.85 ± 1.98% with % RSD 1.24 ± 0.045. The method developed in methanol was successfully applied to determine the entrapment efficiency of Tofacitinib in developed LCNPs formulation and skin retention (dermatokinetics). The method developed in pH 7.4 phosphate buffer saline was applied to quantify Tofacitinib from LCNPs in in vitro and ex vivo drug release samples. In conclusion, a simple, sensitive, accurate, and precise UV spectrophotometric method was established to determine Tofacitinib in in vitro and ex vivo skin studies.

Nanocarriers for ocular drug delivery: current status and translational opportunity.

Ocular diseases have a significant effect on vision and quality of life. Drug delivery to ocular tissues is a challenge to formulation scientists. The major barriers to delivering drugs to the anterior and posterior segments include physiological barriers (nasolacrimal drainage, blinking), anatomical barriers (static and dynamic), efflux pumps and metabolic barriers. The static barriers comprise the different layers of the cornea, sclera, and blood-aqueous barriers whereas dynamic barriers involve conjunctival blood flow, lymphatic clearance and tear drainage. The tight junctions of the blood-retinal barrier (BRB) restrict systemically administered drugs from entering the retina. Nanocarriers have been found to be effective at overcoming the issues associated with conventional ophthalmic dosage forms. Various nanocarriers, including nanodispersion systems, nanomicelles, lipidic nanocarriers, polymeric nanoparticles, liposomes, niosomes, and dendrimers, have been investigated for improved permeation and effective targeted drug delivery to various ophthalmic sites. In this review, various nanomedicines and their application for ophthalmic delivery of therapeutics are discussed. Additionally, scale-up and clinical status are also addressed to understand the current scenario for ophthalmic drug delivery.

Nanostructured lipid carriers for site-specific drug delivery.

Nanostructured lipid carriers (NLC), comprises of a blend of solid and liquid lipids which results in a partially crystallized lipid system and imparts many advantages over solid lipid nanoparticles such as enhanced drug loading capacity, drug release modulation flexibility and improved stability. NLC have found numerous applications in both pharmaceutical and cosmetic industry due to ease of preparation, the feasibility of scale-up, biocompatibility, non-toxicity, enhanced targeting efficiency and the possibility of site-specific delivery via various routes of administration. This review highlights the NLC with focus on the structure, the various fabrication techniques used and the characterization techniques which are critical in the development of a suitable and stable formulation. The review also provides an insight into the potential of NLC as site-specific delivery systems and the therapeutic applications explored via various routes of administration.

Investigations on pharmacokinetics and biodistribution of polymeric and solid lipid nanoparticulate systems of atypical antipsychotic drug: effect of material used and surface modification.

The present study focuses on the effect of material used for the preparation of nanoparticulate (NP) systems and surface modification on the pharmacokinetics and biodistribution of atypical antipsychotic, olanzapine (OLN). NP carriers of OLN were prepared from two different materials such as polymer (polycaprolactone) and solid lipid (Glyceryl monostearate). These systems were further surface modified with surfactant, Polysorbate 80 and studied for pharmacokinetics-biodistribution in Wistar rats using in-house developed bioanalytical methods. The pharmacokinetics and biodistribution studies resulted in a modified and varied distribution of NP systems with higher area under curve (AUC) values along with prolonged residence time of OLN in the rat blood circulation. The distribution of OLN to the brain was significantly enhanced with surfactant surface-modified NP systems, followed by nonsurface-modified NP formulations as compared with pure OLN solution. Biodistribution study demonstrated a low uptake of obtained NP systems by kidney and heart, thereby decreasing the nephrotoxicity and adverse cardiovascular effects. By coating the NP with surfactant, uptake of macrophage was found to be reduced. Thus, our studies confirmed that the biodistribution OLN could be modified effectively by incorporating in NP drug delivery systems prepared from different materials and surface modifications. A judicious selection of materials used for the preparation of delivery carriers and surface modifications would help to design a most efficient drug delivery system with better therapeutic efficacy.

Nanomedicine I: In vitro and in vivo evaluation of paclitaxel loaded poly-(ε-caprolactone), poly (DL-lactide-co-glycolide) and poly (DL-lactic acid) matrix nanoparticles in wistar rats.

Progress in nanoscience and nanotechnology laid foundation for nanotherapy-based approach in cancer drug delivery for improved therapy and quality of life. The prepared polymeric nanoparticles (PNPs), PCL, PLGA and PLA NPs help in delivering paclitaxel (TAX) in vivo by avoiding the use of unsafe excipient, Cremophore EL. The classy microscopic examination SEM, TEM and AFM analysis revealed the spherical and smooth structure of the NPs as well as their homogeneous solid matrix without any amorphous arrangements. The FTIR analysis of PNPs exposed that there was no chemical interaction between polymer, stabilizer and TAX. The (1)H NMR and XRD analyses illustrate molecular dispersion of TAX in the polymeric matrix and no evidence was observed for the presence of crystalline TAX. The outcome of in vivo acute toxicity study endorses residual solvent free PNPs. The PNPs demonstrate excellent control in delivering TAX up to 48 h with best fitted to First-order, Baker-Lonsdale, Higuchi and Korsmeyer-Peppas model. The log plasma concentration-time profile shows that the prepared PNPs were safe and have much less side-effects. The pharmacokinetic study results illustrate increase in mean residence time as result of long circulating nature of the prepared nanoparticles, which helps them to reach target area. The estimated pharmacokinetic parameters AUC0-∞ (ng h)/mL, AUMC0-∞ (ng h(2))/mL, C max (ng/mL), t 1/2 (h), MRT (h), Cl (L/h/kg), V ss (L/kg) and V z (L/kg) shows improved therapeutic efficacy when compared with TAX solution.

Prediction of in vivo plasma concentration-time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method.

The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50 mg and IR 100 mg) and matrix based controlled release (CR 100 mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (Cmax and AUC) predicted from convolution method were found to be 106.90 ng/mL, 1138.96 ng/mL h for IR 50 mg and 209.80 ng/mL, 2280.61 ng/mL h for IR 100 mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for Cmax and AUC were found to be 7.04 and -7.35 for IR 50 mg and 11.10 and -8.21 for IR 100 mg formulations. The Cmax, Tmax, and AUC for CR 100 mg were found to be 120 ng/mL, 10 h and 2112.60 ng/mL h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24 h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies.

Study the effect of formulation variables on drug release from hydrophilic matrix tablets of milnacipran and prediction of in-vivo plasma profile.

The objective of this study was to design oral controlled release (CR) matrix tablets of Milnacipran using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, compression force and also the pH of dissolution medium on the in-vitro release of drug. Two viscosity grade of HPMC (15 K and 100 K) were used in the proportion of 50, 100, 150 and 200 mg per CR tablet. In-vitro release rate was characterized using various model dependent approaches and model independent dissolution parameters [T50% and T80% dissolution time, mean dissolution time (MDT), mean residence time (MRT), dissolution efficiency (DE)]. The statistical analysis was performed on all the model independent approaches using student t test and ANOVA. Results were found that as polymer concentration (50 mg to 200 mg) and viscosity (15 K to 100 K) increases, the MDT, MRT, T50% and T80% extended significantly. Drug release rate was found to be significantly different at different hardness. In-vivo human plasma concentration--time profile was predicted from in-vitro release data using convolution method. Predicted human pharmacokinetic parameters shows that the design CR formulation has capability to sustained the plasma drug level of milnacipran.

A simple and rapid 3D view method for selective and sensitive determination of paclitaxel in micro volume rat plasma by LC-diode array UV and its application to a pharmacokinetic study.

A simple, highly repeatable and reproducible method for the estimation of Paclitaxel (TAX) in micro volume amounts of rat plasma is successfully developed and validated. The extraction procedure using 800 µL of ice-cold acetonitrile is very simple and economical with high sensitivity. The rectangular ratiograms and purity curve demonstrate the selectivity of the method. The validation and stability results show that propylparaben (PP) is a suitable internal standard (resolution 7.70 ± 0.15 min) for the estimation of TAX in micro volume rat plasma. TAX and PP are separated by isocratic reversed-phase high-performance liquid chromatography with diode array UV method with a retention time of 8.0 ± 0.25 and 5.3 ± 0.15 min, respectively, with a total run time of 10 min. The system suitability results show that the method has good reproducibility. The stability of TAX is well studied in rat plasma, and the % RSD of all stability studies of TAX are well within the acceptable range of ± 20 % at the lower limit of quantitation (LLOQ) and ± 15% at all quality control levels. The limit of detection (LOD) and LLOQ of the method are 5 and 10 ng/mL, respectively. This rapid method is successfully used to study the i.v pharmacokinetic of TAX at 10 mg/kg in wistar rats, and drug concentration is detected up to 24 h.

Nanoparticulate drug delivery systems for cancer chemotherapy.

Nanoparticles (NPs) are, in general, colloidal particles, less than 1000 nm, that can be used for better drug delivery and prepared either by encapsulating the drug within a vesicle and or by dispersing the drug molecules within a matrix. Nanoparticulate drug delivery systems have been extensively studied in recent years for spatial and temporal delivery, especially in tumour and brain targeting. NPs have great promise for better drug delivery as found in both pharmaceutical and clinical research. As a drug carrier, NPs have significant advantages like better bioavailability, systemic stability, high drug loading, long blood circulation time and selective distribution in the organs/tissues with longer half life. The selective targeting of NPs can be achieved by the enhanced permeability and retention effect (EPR-effect), attaching specific ligands, or by making selective distribution due to change of the physiological conditions of specific systems like nature, pH, temperature, etc. It has been observed that drug-loaded NPs can have selective distribution to organs/tissues using different types of and proportions of polymers. The current aim of researchers is to prepare NPs that are long-lived with and that demonstrate the appropriate selective distribution for better therapy and thus improved clinical outcomes. Nanoparticulate drug delivery systems have the potential to deliver a drug to the target site with specificity and to maintain the desired concentration at the site for the intended time without untoward effects. In this review article, the methods for the preparation of NPs, their characterization, biodistribution, and pharmacokinetic characteristics are discussed.

Controlled release hydrophilic matrix tablet formulations of isoniazid: design and in vitro studies.

The aim of the present investigation was to develop oral controlled release matrix tablet formulations of isoniazid using hydroxypropyl methylcellulose (HPMC) as a hydrophilic release retardant polymer and to study the influence of various formulation factors like proportion of the polymer, polymer viscosity grade, compression force, and release media on the in vitro release characteristics of the drug. The formulations were developed using wet granulation technology. The in vitro release studies were performed using US Pharmacopoeia type 1 apparatus (basket method) in 900 ml of pH 7.4 phosphate buffer at 100 rpm. The release kinetics was analyzed using Korsmeyer-Peppas model. The release profiles were also analyzed using statistical method (one-way analysis of variance) and f (2) metric values. The release profiles found to follow Higuchi's square root kinetics model irrespective of the polymer ratio and the viscosity grade used. The results in the present investigation confirm that the release rate of the drug from the HPMC matrices is highly influenced by the drug/HPMC ratio and viscosity grade of the HPMC. Also, the effect of compression force and release media was found to be significant on the release profiles of isoniazid from HPMC matrix tablets. The release mechanism was found to be anomalous non-Fickian diffusion in all the cases. In the present investigation, a series of controlled release formulations of isoniazid were developed with different release rates and duration so that these formulations could further be assessed from the in vivo bioavailability studies. The formulations were found to be stable and reproducible.

Etoposide loaded PLGA and PCL nanoparticles II: biodistribution and pharmacokinetics after radiolabeling with Tc-99m.

Etoposide and nanoparticle formulations were labeled with Tc-99m and their biodistribution and pharmacokinetics were studied after intravenous administration in healthy mice and rabbits respectively. Etoposide was rapidly cleared from the body, while the disposition of nanoparticles was slower. A higher proportion of nanoparticles compared with etoposide was observed in different organs of mice. Scintigraphic images of rabbits concluded that the radioactivity shown by formulations is significantly higher after 4 and 24 h, as compared with etoposide administered in rabbits. AUC(0 - infinity), clearance and MRT are better than those obtained with etoposide administration. The overall high residence of nanoparticles, compared with etoposide, signifies the advantage of PLGA and PCL nanoparticles as drug carriers for etoposide in enhancing the bioavailability and reducing the etoposide-associated toxicity.

Oral matrix tablet formulations for concomitant controlled release of anti-tubercular drugs: design and in vitro evaluations.

The aim of the present investigation was to develop controlled release (C.R.) matrix tablet formulations of rifampicin and isoniazid combination, to study the design parameters and to evaluate in vitro release characteristics. In the present study, a series of formulations were developed with different release rates and duration using hydrophilic polymers hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). The duration of rifampicin and isoniazid release could be tailored by varying the polymer type, polymer ratio and processing techniques. Further, Eudragit L100-55 was incorporated in the matrix tablets to compensate for the pH-dependent release of rifampicin. Rifampicin was found to follow linear release profile with time from HPMC formulations. In case of formulations with HPC, there was an initial higher release in simulated gastric fluid (SGF) followed by zero order release profiles in simulated intestinal fluid (SIFsp) for rifampicin. The release of isoniazid was found to be predominantly by diffusion mechanism in case of HPMC formulations, and with HPC formulations release was due to combination of diffusion and erosion. The initial release was sufficiently higher for rifampicin from HPC thus ruling out the need to incorporate a separate loading dose. The initial release was sufficiently higher for isoniazid in all formulations. Thus, with the use of suitable polymer or polymer combinations and with the proper optimization of the processing techniques it was possible to design the C.R. formulations of rifampicin and isoniazid combination that could provide the sufficient initial release and release extension up to 24h for both the drugs despite of the wide variations in their physicochemical properties.

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.

New, simple and validated UV-spectrophotometric methods for the estimation of gatifloxacin in bulk and formulations.

New, simple and cost effective UV-spectrophotometric methods were developed for the estimation of gatifloxacin in bulk and pharmaceutical formulations. Gatifloxacin was estimated at 286 nm in 100 mM phosphate buffer (pH 7.4) and 292 nm in 100 mM hydrochloric acid (pH 1.2). Linearity range was found to be 1-18 mug ml(-1) (regression equation: absorbance=0.0684 x Concentration in microg ml(-1) + 0.0050; r2 = 0.9998) in the phosphate buffer (pH 7.4) and 1-14 microg ml(-1) (regression equation: absorbance = 0.0864 x Concentration in microg ml(-1) + 0.0027; r2 = 0.9999) in hydrochloric acid medium (pH 1.2). The apparent molar absorptivity was found to be 2.62 x 10(4) l mol(-1) cm(-1) in the phosphate buffer and 3.25 x 10(4) l mol(-1) cm(-1) in hydrochloric acid media. In both the proposed methods sandell's sensitivity was found to be about 0.01 microg cm(-2)/0.001A. These methods were tested and validated for various parameters according to ICH guidelines and USP. The quantitation limits were found to be 0.312 and 0.3 microg ml(-1) in the phosphate buffer and hydrochloric acid medium, respectively. The proposed methods were successfully applied for the determination of gatifloxacin in pharmaceutical formulations (tablets, injection and ophthalmic solution). The results demonstrated that the procedure is accurate, precise and reproducible (relative standard deviation <2%), while being simple, cheap and less time consuming and can be suitably applied for the estimation of gatifloxacin in different dosage forms and dissolution studies.