Drug Release Profile Research Articles

Design and fabrication of 3D-printed gastric floating tablets of captopril: effect of geometry and thermal crosslinking of polymer on floating behavior and drug release

The present study aims to investigate the potential of the 3D printing technique to design gastroretentive floating tablets (GFTs) for modifying the drug release profile of an immediate-release tablet. A 3D-printed floating shell enclosing a captopril tablet was designed having varying number of drug-release windows. The impact of geometrical changes in the design of delivery system and thermal cross-linking of polymers were evaluated to observe the influence on floating ability and drug release. Water uptake, water insolubilization, Differential Scanning Calorimetry (DSC), and Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) were performed to assess the degree of thermal cross-linking of polyvinyl alcohol (PVA) filament. The 3D-printed GFT9 was considered the optimized gastric floating tablet that exhibited >12 h of total floating time with zero floating lag time and successfully accomplished modified-drug release by exhibiting >80% of drug release in 8 h. The zero-order release model, with an r2 value of 0.9923, best fitted the drug release kinetic data of the GFT9, which followed a super case II drug transport mechanism with an n value of 0.95. The optimized gastric floating device (GFT9) also exhibited the highest MDT values (238.55), representing slow drug release from the system due to thermal crosslinking and the presence of a single drug-releasing window in the device.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes “face-to-face” contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as ‘beneficial horse’ to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (−25.77 mV, −16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Precisely Programmable Degradation and Drug Release Profiles in Triblock Copolyether Hydrogels with Cleavable Acetal Pendants.

Hydrogels hold significant promise as drug delivery systems due to their distinct advantage of sustained localized drug release. However, the challenge of regulating the initial burst release while achieving precise control over degradation and drug-release kinetics persists. Herein, we present an ABA-type triblock copolymer-based hydrogel system with precisely programmable degradation and release kinetics. The resulting hydrogels were designed with a hydrophilic poly(ethylene oxide) midblock and a hydrophobic end-block composed of polyethers with varying ratios of ethoxyethyl glycidyl ether and tetrahydropyranyl glycidyl ether acetal pendant possessing different hydrolysis kinetics. This unique side-chain strategy enabled us to achieve a broad spectrum of precise degradation and drug-release profiles under mildly acidic conditions while maintaining the cross-linking density and viscoelastic modulus, which is unlike the conventional polyester-based backbone degradation system. Furthermore, programmable degradation of the hydrogels and release of active therapeutic agent paclitaxel loaded therein are demonstrated in an in vivo mouse model by suppressing tumor recurrence following surgical resection. Tuning of the fraction of two acetal pendants in the end-block provided delicate tailoring of hydrogel degradation and the drug release capability to achieve the desired therapeutic efficacy. This study not only affords a facile means to design hydrogels with precisely programmable degradation and release profiles but also highlights the critical importance of aligning the drug release profile with the target disease.

In Vitro In Vivo Extrapolation and Bioequivalence Prediction for Immediate-Release Capsules of Cefadroxil Based on a Physiologically-Based Pharmacokinetic ACAT Model.

Physiologically based pharmacokinetic (PBPK) modeling is a mechanistic concept, which helps to judge the effects of biopharmceutical properties of drug product such as in vitro dissolution on its pharmacokinetic and in vivo performance. With the application of virtual bioequivalence (VBE) study, the drug product development using model-based approach can help in evaluating the possibility of extending BCS-based biowaiver. Therefore, the current study was intended to develop PBPK model as well as in vitro in vivo extrapolation (IVIVE) for BCS class III drug i.e. cefadroxil.A PBPK model was created in GastroPlus™ 9.8.3 utilizing clinical data of immediate-release cefadroxil formulations. By the examination of simulated and observed plasma drug concentration profiles, the predictability of the proposed model was assessed for the prediction errors. Furthermore, mechanistic deconvolution was used to create IVIVE, and the plasma drug concentration profiles and pharmacokinetic parameters were predicted for different virtual formulations with variable cefadroxil in vitro release. Virtual bioequivalence study was also executed to assess the bioequivalence of the generic verses the reference drug product (Duricef®).The developed PBPK model satisfactorily predicted Cmax and AUC0-t after cefadroxil single and multiple oral dose administrations, with all individual prediction errors within the limits except in a few cases. Second order polynomial correlation function obtained accurately predict in vivo drug release and plasma concentration profile of cefadroxil test and reference (Duricef®) formulation. The VBE study also proved test formulation bioequivalent to reference formulation and the statistical analysis on pharmacokinetic parameters reported 90% confidence interval for Cmax and AUC0-t in the FDA acceptable limits.The analysis found that a validated and verified PBPK model with a mechanistic background is as a suitable approach to accelerate generic drug development.

A comparative study between nanostructured lipid carriers and invasomes for the topical delivery of luteolin: Design, optimization and pre-clinical investigations for psoriasis treatment

Psoriasis is an inflammatory skin condition manifested by hyper-proliferation and reactive aberrant epidermal differentiation, in which genetic and environmental factors have a significant role. The current context is focused on designing novel nanovesicular systems (invasomes) incorporating terpenes with reported anti-inflammatory potential and loaded with a nutraceutical compound (luteolin/Lut) for treatment of psoriasis. Additionally, their topical efficacy in psoriasis treatment compared to lipid-based nanocarriers (nanostructured lipid carriers) was investigated. Invasomes were assessed regarding their particle size (PS), zeta potential (ζ-potential), drug entrapment (EE%), storage stability, in-vitro drug release profile and release kinetics. The optimized vesicles were investigated for their ex-vivo skin deposition and in-vitro anti-inflammatory potential in comparison with nanostructured lipid carriers (NLCs). The optimized formulation was selected to carry out the in-vivo study using rat model of imiquimod-induced psoriasis. Luteolin-invasomes were found to have spherical shape and promising colloidal properties. They possessed PS ranging from 277.80 to 812.91 nm, negative ζ-potential (−35.22–38.55 mV), and high EE% values, which ranged from 89.38 to 99.75 %. Furthermore, they exhibited good stability properties and significant sustainment of drug release in comparison to NLCs. In addition, they were able to enhance Lut deposition by 2.1-fold in the stratum corneum (SC) and 5.5-fold in epidermis and dermis compared to control suspension of Lut. Moreover, invasomes showed more potential to retain Lut into deep skin layers 1.5-fold higher than NLCs. They also displayed higher in-vitro anti-inflammatory activity compared to plain invasomes and control suspension, and comparable activity compared to NLCs. In the in-vivo animal study, the ability of Lut to alleviate psoriatic symptoms was significantly enhanced after its encapsulation in invasomal dispersions, where Lut-invasomes possessed a great inhibitory potential compared to the control Lut suspension, and even to Lut-NLCs. This suggests their efficiency in treating psoriasis, delineating them promising for further use in treating other inflammatory skin conditions.

Alginate/Carboxymethyl Chitosan Core-Shell Microspheres Coloaded with Doxorubicin/DocetaxelReverse Chemotherapy Resistance in Anaplastic Thyroid Carcinoma.

Drug resistance is a major obstacle in the treatment of anaplastic thyroid carcinoma (ATC) with the combination of docetaxel (DTX) and doxorubicin (DOX). Excessive intracellular drug efflux is considered a key factor contributing to drug resistance. Therefore, developing drug-loaded microspheres to enhance cellular uptake and inhibit efflux of docetaxel and doxorubicin may be an effective strategy to overcome chemoresistance. Alginate-Doxorubicin@carboxymethyl chitosan-Docetaxel (A-DOX@C-DTX) microspheres were prepared using an electrostatic spraying-assisted microfluidic device. The microspheres were characterized, and the in vitro drug release profiles and extracellular efflux rates were determined. The effects of A-DOX@C-DTX microspheres on drug-resistant ATC cells were evaluated in vitro. In vivo, a subcutaneous tumor model was established in mice to investigate the effects of A-DOX@C-DTX microspheres on tumor growth, as well as the accumulation and release of the materials at the tumor site. We successfully prepared ALG/CMC microspheres with a core-shell structure. These microspheres exhibited controllable size, good monodispersity, excellent biocompatibility, high encapsulation efficiency for doxorubicin and docetaxel, and high drug loading capacity. Moreover, the microspheres promoted cellular uptake of doxorubicin and docetaxel while inhibiting their efflux. A-DOX@C-DTX microspheres showed significant inhibition of viability, proliferation, migration, and invasion of drug-resistant ATC cells in vitro. In vivo, A-DOX@C-DTX microspheres suppressed tumor growth, induced tumor tissue necrosis, and promoted tumor cell apoptosis. Additionally, the microspheres facilitated the enrichment of active substances in the tumor and their sustained release. A-DOX@C-DTX microspheres exhibited superior anti-tumor effects compared to free drug treatment both in vitro and in vivo, particularly against drug-resistant ATC cells. This improved therapeutic efficacy may be attributed to the enhanced drug uptake and reduced drug efflux in drug-resistant ATC cells facilitated by ALG/CMC microspheres.

Co-delivery of carboplatin and doxorubicin using ZIF-8 coated chitosan-poly(N-isopropyl acrylamide) nanoparticles through a dual pH/thermo responsive strategy to breast cancer cells

A dual pH/temperature sensitive core-shell nanoformulation has been developed based on ZIF-8 coated with chitosan-poly(N-isopropyl acrylamide) (CS-PNIPAAm) for co-delivery of doxorubicin (DOX) and carboplatin (CBP) in breast cancer cells. The resulting nanoparticles (NPs) had particle sizes around 200 nm and a zeta potential of about +30 mV. The CBP and DOX loading contents in the final NPs were 11.6 % and 55.54 %, respectively. NPs showed a pH and thermoresponsive drug release profile with a sustained prolonged release under physiological conditions. The in vitro cytotoxicity experiments showed a significant synergism of CBP and DOX to induce the IC50 of 1.96 μg/mL in MCF-7 cells and 4.54 μg/mL in MDA-MB-231 cells. Also, the final NPs were safer than free DOX and CBP on normal cells. The in vitro study confirmed the higher potency of the designed NPs in combination therapy against breast cancer cells with lower side effects than free drugs.

Development of a biodegradable polymer-based implant to release dual drugs for post-operative management of cataract surgery.

Cataract surgery is followed by post-operative eye drops for a duration of 4-6 weeks. The multitude of ocular barriers, coupled with the discomfort experienced by both the patient and their relatives in frequently administering eye drops, significantly undermines patient compliance, ultimately impeding the recovery of the patient. This study aimed to design and develop an ocular drug delivery system as an effort to achieve a drop-free post-operative care after cataract surgery. An implant was prepared containing a biodegradable polymer Poly-lactic-co-glycolic acid (PLGA), Dexamethasone (DEX) as an anti-inflammatory drug, and Moxifloxacin(MOX) as an antibiotic. Implant characterization and drug loading analysis were conducted. In vitro drug release profile showed that the release of the two drugs are correlated with the clinical prescription for post operative eye drops. In vivo study was conducted on New Zealand albino rabbits where one eye underwent cataract surgery, and the drug delivery implant was inserted into the capsular bag after placement of the synthetic intraocular lens (IOL). Borderline increase in the intraocular pressure (IOP) was noted in the test sample group. Slit-lamp observations revealed no significant anterior chamber reaction in all study groups. Histopathology study of the operated eye revealed no significant pathology in the test samples. This work aims at developing the intra ocular drug delivery implant which will replace the post-operative eye drops and help the patient with the post-operative hassle of eye drops.

Shifting from sustained to delayed drug delivery systems: Encapsulated mesoporous silica-chitosan grafted polylactic acid-based composite approach

The current study demonstrates a desired drug delivery-controlled system with a wide range of release parameters. It illustrates the feasibility of carriers in the systems for extended and short drug release. Herein, mesoporous silica nanoparticles (MSNs) coated with chitosan (Cs) grafted polylactic acid (PLA) composite were fabricated by a sol-gel method in the form of micrometric porous particles (∼270 nm) with ζ-potential of -17.7±1.7 mV and a specific surface area and total pore volume of 122700 cm2/g and 0.057 cm3/g, respectively. The prepared template of polymer-silica composite pores proved to be essential in the incorporation of Doxorubicin (Dox) drug molecules with adsorption capacity of 83.33 mg/g and encapsulation efficiency of 88%. Dox was incorporated via the solvent diffusion method into the polymer-silica composites at suitable pH and concentration, resulting in solid drug dispersions. The silica-Cs-g-PLA composites showed greater effectiveness in the delayed release of the Dox with complete release after 10 days as compared to pristine MSNs and silica-Cs, which were completed after 12 h and 24 h, respectively. The drug release profiles were studied at different pH (2, 7, and 8), with maximum results obtained at pH 2. Both pristine MSNs and silica-Cs suffered from the burst effect, which was overcome by the grafting of PLA. The functionalized silica-Cs with PLA shows a significant change in the drug release properties from a sustained release process for pristine MSNs and silica-Cs to an enhanced delayed process for the silica-Cs-g-PLA composite, which makes this composite attractive for oral multi-particulate formulations of modified release.

AI-driven design of customized 3D-printed multi-layer capsules with controlled drug release profiles for personalized medicine

Personalized medicine aims to effectively and efficiently provide customized drugs that cater to diverse populations, which is a significant yet challenging task. Recently, the integration of artificial intelligence (AI) and three-dimensional (3D) printing technology has transformed the medical field, and was expected to facilitate the efficient design and development of customized drugs through the synergy of their respective advantages. In this study, we present an innovative method that combines AI and 3D printing technology to design and fabricate customized capsules. Initially, we discretized and encoded the geometry of the capsule, simulated the dissolution process of the capsule with classical drug dissolution model, and verified it by experiments. Subsequently, we employed a genetic algorithm to explore the capsule geometric structure space and generate a complex multi-layer structure that satisfies the target drug release profiles, including stepwise release and zero-order release. Finally, Two model drugs, isoniazid and acetaminophen, were selected and fused deposition modeling (FDM) 3D printing technology was utilized to precisely print the AI-designed capsule. The reliability of the method was verified by comparing the in vitro release curve of the printed capsules with the target curve, and the f2 value was more than 50. Notably, accurate and autonomous design of the drug release curve was achieved mainly by changing the geometry of the capsule. This approach is expected to be applied to different drug needs and facilitate the development of customized oral dosage forms.

3D-printed short nanofibers/hydrogel-based vaginal films as a novel system for the delivery of anti-HIV microbicide drugs.

Acquired immunodeficiency syndrome (AIDS) is a global epidemic that affects the lives of millions of young women, particularly those who live in poverty-stricken regions and engage in unsafe sexual behaviors, forcing the development of unique pre-exposure anti-HIV prophylaxis tools. Using a combination of antiretroviral medications with various antiviral mechanisms significantly improves the prognosis for HIV patients. The integration of 3D printing technology, short nanofiber technology, and hydrogel into a single system known as "3D-printed nanocomposites" is an emerging approach that is gaining traction in tissue engineering, regenerative medicine, and biomedical applications. Based on these foundations, the current study aims to develop, for the first time, a 3D-printed short nanofiber/film for the vaginal delivery of ritonavir and efavirenz in a fixed-dose combination. To identify an optimal 3D-printable short nanofibers/hydrogel formulation, multiple formulations, and fragmentation methods were investigated. Following that, the generated vaginal films were evaluated using several physicochemical characterizations, mechanical properties measurements, and in vitro release studies. The findings revealed that only cryocutting is effective for polycaprolactone nanofiber fragmentation. The 3D-printed short nanofibers-loaded films had an ultimate tensile strength of 6.75 ± 1.27 MPa and elongation at break of 262.67 ± 44.32 MPa, suggesting their reliability for handling and vaginal application. Furthermore, the in vitro release study demonstrated that rapid EFZ release occurred during the first 45 minutes, whereas RIT release lasted more than 72 hours, indicating that the complex drug release profile was met. In summary, the study emphasizes that 3D printing of short nanofiber-based films is likely to be an effective platform for localized vaginal drug delivery, particularly anti-HIV therapies.

Engineered shapes using electrohydrodynamic atomization for an improved drug delivery.

The shapes of micro- and nano-products have profound influences on their functional performances, which has not received sufficient attention during the past several decades. Electrohydrodynamic atomization (EHDA) techniques, mainly include electrospinning and electrospraying, are facile in manipulate their products' shapes. In this review, the shapes generated using EHDA for modifying drug release profiles are reviewed. These shapes include linear nanofibers, round micro-/nano-particles, and beads-on-a-string hybrids. They can be further divided into different kinds of sub-shapes, and can be explored for providing the desired pulsatile release, sustained release, biphasic release, delayed release, and pH-sensitive release. Additionally, the shapes resulted from the organizations of electrospun nanofibers are discussed for drug delivery, and the shapes and inner structures can be considered together for developing novel drug delivery systems. In future, the shapes and the related shape-performance relationships at nanoscale, besides the size, inner structure and the related structure-performance relationships, would further play their important roles in promoting the further developments of drug delivery field. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Nanoparticle-functionalized acrylic bone cement for local therapeutic delivery to spine metastases

Aim: Polymethylmethacrylate bone cement is often used to reconstruct critical-sized defects generated by the surgical resection of spinal metastases. Residual tumor cells after a resection can drive recurrence and destabilization. Doxorubicin (DOX) is a common chemotherapeutic drug with unwanted side-effects when administered systemically. Mesoporous silica nanoparticles (NPs) are gaining attention for targeted drug delivery to bypass the negative side effects associated with systemic drug administration. An NP-functionalized cement was developed for the local release of DOX and its ability to suppress cancer cells was tested. Methods: DOX was loaded onto NPs which were then mixed into the cement. Static contact angles were measured. Drug release profiles were obtained over a period of 4 weeks. Cement constructs were incubated with two-dimensional (2D) cultures of human bone-marrow derived mesenchymal stem cells and human osteoblasts, as well as 2D and three-dimensional (3D) cultures of breast and prostate cancer cell lines. Cell metabolic activity and viability were evaluated. Cell migration and spheroid growth of cancer cell lines were assessed in collagen-coated spheroid cultures. Results: NPs were homogenously dispersed and did not alter the mechanical strength nor the wettability of the cement. A sustained DOX release profile was achieved with the addition of NPs to the bone cement. The release profile of DOX from NP cement may be modified by varying the amount of the drug loaded onto the NPs and the proportion of NPs in the cement. Cancer cells treated with the cement constructs showed a dose- and time-dependent inhibition, with minimal toxicity against healthy cells. Cancer cell migration and spheroid growth were impaired in 3D culture. Conclusions: NPs were shown to be essential for sustained DOX release from bone cement. DOX-loaded NP cement can inhibit cancer cells and impair their migration, with strong potential for in vivo translation studies.

DEVELOPMENT AND EVALUATION OF DOMPERIDONE ORAL FILM USING MIXED SOLVENCY CONCEPT

a *, a and a a * For Correspondence: E-mail: kirtitomarmip@gmail.com https://doi.org/ ABSTRACT This study aimed to develop and evaluate oral film of antiemetic drug-using mixed solvency concept. The mixed-solvency concept was used in the solubility enhancement of domperidone, an antiemetic drug that is practically insoluble in water. Different types of solubilizers have been used for solubility improvement of domperidone and poly ethylene glycol, niacinamide, caffeine were found to be effective. Five formulations were prepared by using HPMC E15 a film-forming polymer. The prepared oral films were subjected to evaluation for thickness, pH, drug content, folding endurance, stability and in vitro drug release profile. The % in vitro drug release of the best two formulations F3 and F5 were 90.70% and 96.62 % respectively. From the above study, it was concluded that the solubility of the practically insoluble drug, domperidone could be improved successfully by using different water-soluble solubilizers in different ratios under the mixed-solvency concept.

Spectroscopic In-Vitro Drug-Drug Interaction Studies of Amoxicillin and Paracetamol Solid Dosage Forms

Potential drug-drug interactions (DDIs) are a public health concern in clinical therapy and drug development because of their contribution to actual adverse drug reactions (ADRs) or events. The study aimed to quantify the in-vitro drug-drug interaction of amoxicillin (AMX) and paracetamol (PCM) formulations which are commonly co-administered. Determinations were carried out by spectroscopic methods – zero-order and derivative spectroscopy. The data were analyzed using Microsoft Excel, 2016. The UV-Spectra of AMX and PCM showed two distinctive peaks at 240 nm and 260 nm were observed for AMX, while for PCM at 290nm and 340 nm, with maxima at 240 nm and 340 nm for AMX and PCM respectively. Absorption measurements were taken at the maximum wavelength of 290 nm and 240 nm for PCM and AMX respectively. The content of both drugs and potential DDIs of AMX and PCM were assayed by zero- and 3rd-derivative spectroscopy. The calibration curves for AMX and PCM standards showed good linearity at concentrations, with corresponding correlation coefficients (R) being 0.999 and 0.998. The intercept and slope for AMX were -0.0148 and 0.0732 respectively, while for PCM values were 0.0071 and 0.148. The content of PCM and AMX in the formulations was 98.40 ± 0.44% and 96.04 ± 0.29% respectively. The joint-drug-dissolution studies for AMX and PCM interaction (DDI) were obtained with the 3rd-order derivative spectroscopy at 210 nm (zero-crossing for PCM) and 290 nm (zero-line crossing for AMX) respectively - which showed overlapping spectra for their zero-order derivative spectra. No significant difference was observed in the in-vitro drug release profiles for AMX and PCM, while comparative profiles were observed to have a very strong correlation between individual-release and joint-release profiles.

PLGA-based nanocarriers for combined delivery of colchicine and purpurin 18 in cancer therapy: Multimodal approach employing cancer cell spheroids

Improving the anticancer efficacy of chemotherapeutic drugs and photosensitizers requires innovative multifunctional nanoplatforms. This study introduces a chemo- and phototherapeutic drug delivery system (DDS) based on poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), both PEGylated and non-PEGylated, with a mean size of 200 ± 75 nm. Colchicine (Colch) and purpurin18 (P18) were co-encapsulated into these NPs, and their in vitro drug release profiles were investigated. The anticancer potential of these systems was evaluated across various cell lines (i.e., CaCo-2, PC-3, MCF-7, and MRC-5 cells), demonstrating enhanced NP uptake by cancer cells compared to free drugs. Co-administration of Colch and P18 in 2D and 3D cell line models exhibited a synergistic effect, harnessing both chemotherapeutic and photodynamic effects, leading to higher cancer cell elimination efficacy. This newly developed multifunctional DDS presents a promising platform for combined chemo- and photodynamic therapy in cancer treatment.

Fabrication and in vitro–in vivo evaluation of ligand appended isoniazid loaded nanoparticulate systems for the treatment of tuberculosis

Isoniazid (INH) is amongst the first-line antibiotics that have been employed for the treatment of Tuberculosis (TB). Despite its potent anti-tubercular action, susceptibility to rapid hepatic first-pass metabolism and elimination largely limits its oral bioavailability, and has been associated with the induction of drug resistance and adverse effects. This presents study aims at the development and evaluation of unique mannosylated INH loaded solid lipid nanoparticles (Mn-INH-SLNs) for the treatment of TB. The Mn-INH-SLNs demonstrated a particle size of 466 ± 11 nm, which was acceptable for macrophage targeting and had % entrapment efficiency of 80.41 ± 1.37% (n = 6). The dissolution studies depicted a dual-phase drug release profile, i.e., burst release followed by a sustained release, revealing the best fit with the Korsmeyer-Peppas model. The MTT assay (cytotoxicity study) performed utilizing J774A.1 cells with optimized Mn-INH-SLNs deemed them to be safe and nontoxic. Mannosylated SLNs tagged with coumarin-6 (C6 – an established fluorescent marker) showed a substantially high intracellular internalization (1.11-folds) when analyzed through flow cytometric analysis (FACS). The in vivo pharmacokinetic evaluation following per-oral administration in rats demonstrated a significant rise in relative bioavailability (∼5.5-folds) with Mn-INH-SLNs compared to pure drug solution. The bio-distribution (drug disposition) studies exhibited greater lung accumulation of Mn-INH-SLNs (2.13-folds) in comparison to the unconjugated INH-SLNs (Un-INH-SLNs). The promising results of the study depict that the targeted-optimized Mn-INH-SLNs may be a propitious and potent tool to fight TB.

Injectable Testosterone PLGA Microsphere with Different Characteristics: Effect of Preparation Method (Paddle Mixing versus Microfluidic Device)

The purpose of this study was to compare the characteristics of testosterone polylactic-co-glycolic (PLGA) microspheres prepared by a paddle mixer or microfluidics device. The comparison was conducted by not only in vitro evaluation but also in vivo evaluation which has not been reported up to date. We discovered that, among the steps in microsphere preparation, the solvent removal process strongly impacted drug content, particle size and surface morphology. Spectroscopic measurements suggested that molecular interactions and crystallinity of the drug incorporated in the microspheres differed. For the drug release profile, although both mixer- and microfluidics-prepared samples showed similar sustained release of the incorporated drug for approximately one month in vitro, they exhibited different plasma concentration profiles in vivo. Together, our findings show that the preparation process, especially the solvent removal process, may affect the physicochemical characteristics of testosterone PLGA microspheres, leading to different in vivo performance.

Synthesis and In vitro Evaluation of Doxorubicin loaded Polymeric Nanoparticles on Cancer Cells

Cancer is the second biggest mortality rate globally. Most of anti-cancer drugs are hydrophobic and when they are administered in the body, they get clear from the blood. That’s why polymeric nanoparticles (NPs) have been used for delivering anti-cancer drugs to targeted sites. Biodegradable and self-assembled nature, PEG-PLGA has been used as a nanocarrier for biomedical applications. We developed PEG-PLGA NP for the doxorubicin (DOX) delivery to cancerous cells. The successful PEG-PLGA synthesis was confirmed by its 1 H NMR spectrum. All NPs displayed individual spherical morphology and 100 nm size range with -18.5mV zeta potential. Drug release profile showed DOX had sustained release pattern from DOX@NPs. In vitro, MTT assay and apoptosis analysis revealed that low-dose DOX@NPs exhibited more toxic effects on cancerous cells as compared to DOX alone. Overall results demonstrate that polymeric-based nanosystems increase the efficacy of DOX on cancer cells.

Development of Analytical Quality by Design RP-HPLC Method and Its Validation for Estimation of Gefitinib from Bulk, Tablet Dosage Form and Complex Nanoformulation.

Estimation of the drug and development of the method is a critical aspect of formulation development and a critical factor for analytical scientists. Gefitinib is a poorly soluble anticancer drug. The present research enlightens the topic of the development of innovative quality by design methods for the estimation of Gefitinib (GF) from bulk, pharmaceutical tablet formulation and complex nanoformulations. To simplify the estimation of poorly soluble drugs like GF, Response Surface Methodology (RSM) was adopted with effective leverages to obtain precise computation design space using the Box-Behnken Design (BBD) model. The major 3 mixed effect independent factors (Percentage of Buffer, pH of buffer and flow rate) were screened with 3 prominent dependent responses (viz., Theoretical Plate, Retention Time, and Tailing Factor) selected for optimal analysis. Furthermore, co-processed steps were employed for the estimation of the analyte from the complex formulation. The RP-HPLC method utilizes the quality by design (QbD) approach can effectively estimate the analyte concentration of less than 4.5 min. The developed method was economically robust, and sensitive and shows a % relative standard deviation (%RSD) of less than 2% for all the selected validation parameters. The estimated design space suggests the highest desirability (R2-0.998) at 60% of buffer in the mobile phase, pH 4.25, and flow rate of 0.7 mL/min. The QbD approach was used to design and develop the method by understanding the interaction between dependent and independent variables to get the optimum values. The developed method was validated successfully and can be useful for formulation scientists to estimate drug concentration and drug release profiles from complex nanoformulations. The analytical approach was designed and quantified using a quality-by-design approach to make the RP-HPLC method more robust and efficient for the estimation of analytes from complex nanoformulations. The method is also useful to eliminate the interfering molecule during estimation by employing co-processing steps. The developed method saves time, and cost of solvent and employs QbD as a requirement of recent regulatory concern.