Selective detection of azelnidipine in pharmaceuticals via carbon dot mediated spectrofluorimetric method: A green approach.

A spectrofluorimetric method using fluorescent carbon dots (CDs) was developed for the selective detection of azelnidipine (AZEL) pharmaceutical in the presence of other drugs. In this study, N-doped CDs (N-CDs) were synthesized through a single-step hydrothermal process, using citric acid and urea as precursor materials. The prepared N-CDs showed a highly intense blue fluorescence emission at 447 nm, with a photoluminescence quantum yield of ~21.15% and a fluorescence lifetime of 0.47 ns. The N-CDs showed selective fluorescence quenching in the presence of all three antihypertensive drugs, which was used as a successful detection platform for the analysis of AZEL. The photophysical properties, UV-vis light absorbance, fluorescence emission, and lifetime measurements support the interaction between N-CDs and AZEL, leading to fluorescence quenching of N-CDs as a result of ground-state complex formation followed by a static fluorescence quenching phenomenon. The detection platform showed linearity in the range 10-200 µg/ml (R2 = 0.9837). The developed method was effectively utilized for the quantitative analysis of AZEL in commercially available pharmaceutical tablets, yielding results that closely align with those obtained from the standard method (UV spectroscopy). With a score of 0.76 on the 'Analytical GREEnness (AGREE)' scale, the developed analytical method, incorporating 12 distinct green analytical chemistry components, stands out as an important technique for estimating AZEL.

Intranasal delivery of doxepin: enhancing brain targeting efficiency utilizing nanostructured lipid carriers for a biopharmaceutics drug disposition classification system class-I drug.

Doxepin, a Class-I Biopharmaceutics Drug Disposition Classification System (BDDCS) drug, exhibits poor bioavailability due to extensive first-pass metabolism. This research focuses on enhancing the delivery of doxepin by formulating nanostructured lipid carriers (NLCs) through the utilization of the Box-Behnken Design methodology. These optimized NLCs are intended for intranasal administration, with the ultimate goal of improving nose-to-brain drug delivery. NLCs were formulated using a high-speed homogenization technique. The optimized batch had a small particle size (75.80 ± 5.48 nm, PDI = 0.286), high entrapment efficiency (94.10 ± 0.16%), and sustained ex vivo release (82.25 ± 4.61% at 24 h). Characterization studies confirmed the conversion of doxepin from a crystalline to an amorphous state with uniform distribution in the lipid matrix. In vivo pharmacokinetic studies in rats showed significantly higher doxepin concentration in the brain tissue (Cmax = 16.77 µg/g, tmax = 30 min) after intranasal administration compared to intravenous administration (Cmax = 2.53 µg/g, tmax = 6 h). High-drug targeting efficiency (DTE = 284.3%) and direct transport percentage (DTP = 64.8%) suggested direct penetration of NLCs in the brain via olfactory and trigeminal pathways. In conclusion, the study highlights the potential of NLCs to improve the bioavailability of doxepin through nose-to-brain delivery and thereby potentially enable the treatment of neurological disorders.

Clozapine-laden carbon dots delivered to the brain via an intranasal pathway: Synthesis, characterization, ex vivo, and in vivo studies.

Clozapine, which is widely used to treat schizophrenia, shows low bioavailability due to poor solubility and high first-pass metabolism. The study aimed to design clozapine-loaded carbon dots (CDs) to enhance availability of the clozapine to the brain via intranasal pathway. The CDs were synthesized by pyrolysis of citric acid and urea at 200 °C by hydrothermal technique and characterized by photoluminescence, transmission electron microscopy (TEM), X-ray Photoelectron Spectrometer (XPS), and Fourier transform infrared spectrum (FTIR). The optimized clozapine-loaded CDs (CLZ-CDs-1:3-200) showed a quasi-spherical shape (9-12 nm) with stable blue fluorescence. The CDs showed high drug solubilization capacity (1.5 mg drug in 1 mg/ml CDs) with strong electrostatic interaction with clozapine (drug loading efficiency = 94.74%). The ex vivo release study performed using nasal goat mucosa showed sustained release of clozapine (43.89%) from CLZ-CDs-1:3-200 for 30 h. The ciliotoxicity study (histopathology) confirmed no toxicity to the nasal mucosal tissues using CDs. In the rat model (in vivo pharmacokinetic study), when CDs were administrated by the intranasal route, a significantly higher concentration of clozapine in the brain tissue (Cmax = 58.07 ± 5.36 µg/g and AUCt (µg/h*g) = 105.76 ± 12.31) was noted within a short time (tmax = 1 h) compared to clozapine suspension administered by intravenous route (Cmax = 20.99 ± 3.91 µg/g, AUC t (µg/h*g) = 56.89 ± 12.31, and tmax = 4 h). The high value of drug targeting efficiency (DTE, 486%) index and direct transport percentage (DTP, 58%) indicates the direct entry of clozapine-CDs in the brain via the olfactory route. In conclusion, designed CDs demonstrated a promising dosage form for targeted nose-to-brain delivery of clozapine for the effective treatment of schizophrenia.

Oral bioavailability improvement of felodipine using tailored microemulsion: Surface science, ex vivo and in vivo studies.

Felodipine is a calcium channel blocker, which shows low oral bioavailability (<15%) owing to poor water solubility and high first pass metabolism. The aim of the present investigation was to study the surface science (dynamic surface tension) and characteristics of microemulsion (Capmul MCM, Tween 20 and polyethylene glycol) to enhance the oral bioavailability of felodipine by improving permeability of the drug in the intestine. The paper is the first attempt to study the stability of oil-water interface of microemulsion using bubble tensiometer. The Smix at 2:1 ratio showed the maximum microemulsion area which did not alter in the presence of drug. The microemulsion batch coded Fe-O5-Smix45 (5% Capmul MCM and 45% Smix) was selected based on transmittance (>99%), dilution (stable after 100 times dilution with water), size (15.1 nm), dispersibility (grade A) and thermodynamic stability studies. The dynamic surface tension at newly created surface indicate the stability of surfactant film at the oil/water interface. The microemulsion was also stable in the presence of drug and in different buffer phases. The ex vivo intestinal permeability studies showed significant increase in the microemulsion permeation (74.1% after 1 h) in comparison to the felodipine suspension (16.9% after 1 h). The in vivo pharmacokinetic parameters in the rat model confirmed the improvement in oral bioavailability with microemulsion (relative bioavailability = 21.9) in comparison to the felodipine suspension, due to high surface area of oil droplets and its lymphatic uptake via transcellular route. In conclusion, the stable microemulsion offers a promising approach to improve the oral bioavailability of felodipine which can help to reduce the dose and its associated side effects.

Nose to brain delivery of tailored clozapine nanosuspension stabilized using (+)-alpha-tocopherol polyethylene glycol 1000 succinate: Optimization and in vivo pharmacokinetic studies.

Clozapine is widely used to treat schizophrenia as an atypical antipsychotic. Low solubility, poor dissolution rate, degradation in the gastrointestinal tract, high hepatic first-pass metabolism, and eventually less drug transfer in the brain are all issues with oral clozapine administration. On account of this poor pharmacokinetic parameters, the authors aimed to develop clozapine nanosuspension using (+)-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS) and polyvinylpyrrolidone K-30 (PVP K-30) and deliver it through the intranasal route. The nanosuspension was prepared by the high-speed homogenization method with 32 full factorial design for optimization of the product. Quality Target Product Profile (QTPP) was enlisted before the product development. The amount of TPGS and speed of homogenizer were selected as independent variables whereas, particle size and drug permeation profile after 24 h (Y2, %) were selected as dependent variables. As per the results of optimization, amount of TPGS and speed of homogenizer were chosen as 0.1% and 7000 rpm, respectively. The particle size of the optimized nanosuspension of clozapine was found to be 281 nm. The conversion of clozapine crystals to an amorphous form was verified by characterization studies (XRD and DSC). The drug permeability study showed 96.15% and 41.12% clozapine release after 24 h from nanosuspension and conventional suspension, respectively. The study of nasal cilio-toxicity (histopathological studies) demonstrated the appropriateness of nanosuspension for intranasal purposes. The single-dose in vivo pharmacokinetic analysis in the rat model showed a substantial increase in the therapeutic concentration of clozapine in the brain tissue in the case of intranasal nanosuspension (dose = 0.05 mg drug/0.1 mL, Cmax = 8.62 ± 0.45 µg/g, tmax = 1 h) compared to conventional oral clozapine suspension (dose = 26.43 mg drug/0.158 mL, Cmax = 1.14 ± 0.12 µg/g, tmax = 1 h).Ultimately, in the case of an intranasal route, a 3.56-fold increase in brain drug concentration was observed with a 528-fold lower drug dose compared with oral administration. The results suggest that clozapine nanosuspension may be used for successful nose-to-brain delivery.

Lidocaine tripotassium phosphate complex laden microemulsion for prolonged local anaesthesia: In vitro and in vivo studies.

Lidocaine is widely used as a local anaesthetic in the clinical practice to manage pre- and post-operative pain, skin burns, etc. However, the short duration of action (< 2 h) of marketed dosage forms limit their ability to meet clinical needs. Herein, we prepared a lidocaine-tPP(tri potassium phosphate)-complex loaded microemulsion to achieve greater penetration, followed by destabilization of microemulsion in the skin layer to precipitate oil-complex to produce a depot effect in the skin for prolonging the effects of anaesthesia. The lidocaine-tPP-complex-microemulsion was compared with lidocaine base loaded microemulsion, marketed ointment USP and lidocaine HCl. The pseudo ternary phase diagrams at three Smix ratios (1:2, 1:3 and 1:4; Pluronic F127: PEG 400) were constructed using Capmul MCM C8 EP as oil phase. The Smix at 1:4 ratio showed large microemulsion area in comparison to 1:2 and 1:6 ratio. The lidocaine base (LD-1:4-ME10O45SM and LD-1:4-ME20O45SM) and lidocaine-tPP-complex (LDC-1:4-ME10O45SM and LDC-1:4-ME20O45SM) loaded microemulsion batches (1:4 ratio) were thermodynamically stable. The ex vivo diffusion study showed sustained release up to 12 h with microemulsion batches, in comparison to lidocaine HCl (4 h) and ointment base (7 h). The selected LDC-1:4-ME20O45SM batch was non-irritating on the rabbit skin. In drug retention studies, LD-1:4-ME20O45SM and LDC-1:4-ME20O45SM batches showed 2.68- and 3.93-fold greater lidocaine retention in comparison to ointment USP. The radiant heat tail-flick test showed prolong local anaesthesia using LDC-1:4-ME20O45SM in comparison to ointment USP. The findings suggest that lidocaine-tPP-complex loaded microemulsion could be a potential strategy for providing prolong local anaesthesia.

Development of controlled release osmotic pump tablet of glipizide solid dispersion.

PURPOSE: To develop controlled release osmotic pump tablets (COPT) of glipizide (GZ) solid dispersion (SD). METHODS: In elementary osmotic pump (EOP) tablets, an osmotic core with the drug is surrounded by a semi-permeable membrane which is drilled with a delivery orifice. COPT tablets eliminate the need of drilling process as controlled release can be achieved by the presence of osmogen in the coating. Poorly water soluble drug molecule cannot give satisfactory drug release hence GZ solid dispersion was prepared in the present study. The SDs having different ratio of drug to Poloxamer (PXM) 188 were prepared by hot melt method and optimized by solubility study, drug content estimation and in vitro dissolution study. Effect of two independent variables, amount of osmogen (potassium chloride) and hydrophilic polymer (polyethylene oxide WSR 303), were investigated using 3(2) factorial design. Core and coated tablets were evaluated for pharmacotechnical parameters. In-vitro drug release profiles of COPT tablets were compared with marketed with push-pull osmotic pump tablet, Glucotrol XL. RESULTS: Prepared core and coated tablets showed acceptable pharmacotechnical parameters. Drug release was directly proportional to initial level of hydrophilic polymer, but inversely related to the osmogen, confirming osmotic mechanism. Zero order drug release pattern was achieved which was comparable to marketed product. CONCLUSION: Novel oral controlled release of glipizide was successfully achieved by incorporating glipizide solid dispersion into osmotic system.

Formulation and in vivo hypoglycemic effect of glipizide solid dispersion.

The present study was carried out with a view to enhance dissolution rate of poorly water-soluble drug glipizide (GZ) (BCS class II) using polyethylene glycol (PEG) 6000, PEG 8000 and poloxamer (PXM) 188 as carriers. Solid dispersions (SDs) were prepared by melting method using different ratios of glipizide to carriers. Phase solubility study was conducted to evaluate the effect of carrier on aqueous solubility of glipizide. SD was optimized by drug content estimation and in vitro dissolution study and optimised SD was subjected to bulk characterization, Scanning electron microscopy (SEM), Fourier transformation infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray diffraction study (XRD). Preclinical study was performed in mice to study the decrease in blood glucose level from prepared SD compared with pure drug. Due to high solubility and drug release, PXM 188 in weight ratio of 1:2 was optimized. Decrease in blood glucose level in mice from SD was significantly higher (p < 0.05) compared to pure glipizide. Thus, solid dispersion technique can be successfully used for the improvement of the dissolution profile of GZ.