Fabrication, assessment, and optimization of alendronate sodium nanoemulsion-based injectable in-situ gel formulation for management of osteoporosis.

Low bone mass, degeneration of bone tissue, and disruption of bone microarchitecture are all symptoms of the disease osteoporosis, which can decrease bone strength and increase the risk of fractures. The main objective of the current study was to use a phospholipid-based phase separation in-situ gel (PPSG) in combination with an alendronate sodium nanoemulsion (ALS-NE) to help prevent bone resorption in rats. The effect of factors such as concentrations of the ALS aqueous solution, surfactant Plurol Oleique CC 497, and Maisine CC oil on nanoemulsion characteristics such as stability index and globular size was investigated using an l-optimal coordinate exchange statistical design. Injectable PPSG with the best nanoemulsion formulation was tested for viscosity, gel strength, water absorption, and in-vitro ALS release. ALS retention in the rats' muscles was measured after 30 days. The droplet size and stability index of the optimal nanoemulsion were 90 ± 2.0 nm and 85 ± 1.9%, respectively. When mixed with water, the optimal ALS-NE-loaded PPSG became viscous and achieved 36 seconds of gel strength, which was adequate for an injectable in-situ formulation. In comparison with the ALS solution-loaded in-situ gel, the newly created optimal ALS-NE-loaded PPSG produced the sustained and regulated release of ALS; hence, a higher percentage of ALS remained in rats' muscles after 30 days. PPSG that has been loaded with an ALS-NE may therefore be a more auspicious, productive, and effective platform for osteoporosis treatment than conventional oral forms.

Response Surface Methodology (RSM) Powered Formulation Development, Optimization and Evaluation of Thiolated Based Mucoadhesive Nanocrystals for Local Delivery of Simvastatin.

In oral administration systems, mucoadhesive polymers are crucial for drug localization and target-specific activities. The current work focuses on the application of thiolated xanthan gum (TXG) to develop and characterize a novel mucoadhesive nanocrystal (NC) system of simvastatin (SIM). Preparation of SIM-NC was optimized using response surface methodology (RSM) coupled with statistical applications. The concentration of Pluronic F-127 and vacuum pressure were optimized by central composite design. Based on this desirable approach, the prerequisites of the optimum formulation can be achieved by a formulation having 92.568 mg of F-127 and 77.85 mbar vacuum pressure to result in EE of 88.8747% and PS of 0.137.835 nm. An optimized formulation was prepared with the above conditions along with xanthan gum (XG) and TXG and various parameters were evaluated. A formulation containing TXG showed 98.25% of SIM at the end of 96 h. Regarding the mucoadhesion potential evaluated by measuring zeta potential, TXG-SIM-NC shoed the maximum zeta potential of 16,455.8 ± 869 mV at the end of 6 h. The cell viability percentage of TXG-SIM-NC (52.54 ± 3.4% with concentration of 50 µg/mL) was less than the plain SIM, with XG-SIM-NC showing the highest cytotoxicity on HSC-3 cells. In vivo pharmacokinetic studies confirm the enhanced bioavailability of formulated mucoadhesive systems of SIM-NC, with TXG-SIM-NC exhibiting the maximum.

Development and optimization of a tamsulosin nanostructured lipid carrier loaded with saw palmetto oil and pumpkin seed oil for treatment of benign prostatic hyperplasia.

Benign prostatic hyperplasia (BPH) is a nonmalignant growth of the prostate tissue and causes urinary tract symptoms. To provide effective treatment, tamsulosin (TM), saw palmetto oil (SP), and pumpkin seed oil (PSO) were combined and fabricated a nanostructured lipid carrier (NLC) as TM-S/P-NLC using experimental design. The purpose was to enhance the permeation and therapeutic activity of TM; combining TM with SP and PSO in an NLC generates a synergistic activity. An optimized TM-S/P-NLC was obtained after statistical analysis, and it had a particle size, percentage of entrapment efficiency, and steady-state flux of 102 nm, 65%, and 4.5 µg/cm2.min, respectively. Additionally, the optimized TM-S/P-NLC had spherical particles with a more or less uniform size and a stability score of 95%, indicating a high level of stability. The in vitro release studies exhibited the optimized TM-S/P-NLC had the maximum release profile for TM (81 ± 4%) as compared to the TM-NLCs prepared without the addition of S/P oil (59 ± 3%) or the TM aqueous suspension (30 ± 5%). The plasma TM concentration-time profile for the TM-S/P-NLC and the marketed TM tablets indicated that when TM was supplied in a TM-S/P-NLC, the pharmacokinetic profile of the drug was improved. Simultaneously, in vivo therapeutic efficacy studies also showed favorable results for the TM-S/P-NLC in terms of the prostate weight and prostate index following treatment of BPH. Based on the findings of present study, we suggest that in the future, the TM-S/P-NLC could be a novel drug delivery system for treating BPH.

Adenosine Conjugated Docetaxel Nanoparticles-Proof of Concept Studies for Non-Small Cell Lung Cancer.

Non-small cell lung cancer, a molecularly diverse disease, is the most prevalent cause of cancer mortality globally. Increasing understanding of the clinicopathology of the disease and mechanisms of tumor progression has facilitated early detection and multimodal care. Despite the advancements, survival rates are extremely low due to non-targeted therapeutics and correspondingly increased risk of metastasis. At some phases of cancer, patients need to face the ghost of chemotherapy. It is a difficult decision near the end of life. Such treatments have the capability to prolong survival or reduce symptoms, but can cause serious adverse effects, affecting quality of life of the patient. It is evident that many patients do not die from burden of the disease alone, but they die due to the toxic effect of treatment. Thus, increasing the efficacy is one aspect and decreasing the toxicity is another critical aspect of cancer formulation design. Through our current research, we tried to uncover both mentioned potentials of the formulation. Therefore, we designed actively targeted nanoparticles for improved therapeutics considering the overexpression of adenosine (ADN) receptors on non-small cell lung cancer (NSCLC) cells. Docetaxel (DTX), an essential therapeutic as part of combination therapy or as monotherapy for the treatment of NSCLC, was encapsulated in biodegradable poly(lactic-co-glycolic acid) nanoparticles. ADN was conjugated on the surface of nanoparticles using EDC-NHS chemistry. The particles were characterized in vitro for physicochemical properties, cellular uptake, and biocompatibility. The size and zeta potential of DTX nanoparticles (DPLGA) were found to be 138.4 ± 5.45 nm and -16.7 ± 2.3 mV which were found to change after ADN conjugation. The size was increased to 158.2 ± 6.3 nm, whereas zeta potential was decreased to -11.7 ± 1.4 mV for ADN-conjugated DTX nanoparticles (ADN-DPLGA) indicative of surface conjugation. As observed from transmission electron microscopy (TEM), the nanoparticles were spherical and showed no significant change in encapsulation efficiency even after surface conjugation. Careful and systematic optimization leads to ADN-conjugated PLGA nanoparticles having distinctive characteristic features such as particle size, surface potential, encapsulation efficacy, etc., that may play crucial roles in the fate of nanoparticles (NPs). Consequently, higher cellular uptake in the A549 lung cancer cell line was exhibited by ADN-DPLGA compared to DPLGA, illustrating the role of ADN receptors (ARs) in facilitating the uptake of NPs. Further in vivo pharmacokinetics and tissue distribution experiments revealed prolonged circulation in plasma and significantly higher lung tissue distribution than in other organs, dictating the targeting potential of the developed formulation over naïve drug and unconjugated formulations. Further, in vivo acute toxicity was examined using multiple parameters for non-toxic attributes of the developed formulation compared to other non-targeted organs. Further, it also supports the selection of biocompatible polymers in the formulation. The current study presents a proof-of-concept for a multipronged formulation technology strategy that might be used to maximize anticancer therapeutic responses in the lungs in the treatment of NSCLC. An improved therapeutic and safety profile would help achieve maximum efficacy at a reduced dose that would eventually help reduce the toxicity.

Augmentation of Antidiabetic Activity of Glibenclamide Microspheres Using S-Protected Okra Powered by QbD: Scintigraphy and In Vivo Studies.

Successful drug delivery by mucoadhesive systems depends on the polymer type, which usually gets adherent on hydration. The intended polymers must sustain the association with biomembranes and preserve or accommodate the drug for an extended time. The majority of hydrophilic polymers tend to make weak interactions like noncovalent bonds, which hampers the positioning of dosage forms at the required target sites, leading to inefficient therapeutic outcomes. It is possible to overcome this by functionalizing the natural polymers with thiol moiety. Further, considering that S-protected thiomers can benefit by improving thiol stability at a broad range of pH and enhancing the residence period at the required target, 2-mercapto-nicotinic acid (MA) was utilized in this present study to shield the free thiol groups on thiolated okra (TO). S-protected TO (STO) was synthesized and characterized for various parameters. Glibenclamide-loaded microspheres were formulated using STO (G-STO-M), and the process was optimized. The optimized formulation has shown complete and controlled release of the loaded drug at the end of the dissolution study. Cell viability assay indicated that the thiolated S-protected polymers gelated very well, and the formulated microspheres were safe. Further, G-STO-M showed considerable in vivo mucoadhesion strength. The glucose tolerance test confirmed the efficacy of STO formulation in minimizing the plasma glucose level. These results favor S-protection as an encouraging tool for improving the absorption of poorly aqueous soluble drugs like glibenclamide.

Wasp venom peptide improves the proapoptotic activity of alendronate sodium in A549 lung cancer cells.

BACKGROUND: Lung cancer in men and women is considered the leading cause for cancer-related mortality worldwide. Anti-cancer peptides represent a potential untapped reservoir of effective cancer therapy. METHODOLOGY: Box-Behnken response surface design was applied for formulating Alendronate sodium (ALS)-mastoparan peptide (MP) nanoconjugates using Design-Expert software. The optimization process aimed at minimizing the size of the prepared ALS-MP nanoconjugates. ALS-MP nanoconjugates' particle size, encapsulation efficiency and the release profile were determined. Cytotoxicity, cell cycle, annexin V staining and caspase 3 analyses on A549 cells were carried out for the optimized formula. RESULTS: The results revealed that the optimized formula was of 134.91±5.1 nm particle size. The novel ALS-MP demonstrated the lowest IC50 (1.3 ± 0.34 µM) in comparison to ALS-Raw (37.6 ± 1.79 µM). Thus, the results indicated that when optimized ALS-MP nanoconjugate was used, the IC50 of ALS was also reduced by half. Cell cycle analysis demonstrated a significantly higher percentage of cells in the G2-M phase following the treatment with optimized ALS-MP nanoconjugates. CONCLUSION: The optimized ALS-MP formula had significantly improved the parameters related to the cytotoxic activity towards A549 cells, compared to control, MP and ALS-Raw.

Development, optimization, and evaluation of a nanostructured lipid carrier of sesame oil loaded with miconazole for the treatment of oral candidiasis.

Candida albicans is the fungus responsible for oral candidiasis, a prevalent disease. The development of antifungal-based delivery systems has always been a major challenge for researchers. This study was designed to develop a nanostructured lipid carrier (NLC) of sesame oil (SO) loaded with miconazole (MZ) that could overcome the solubility problems of MZ and enhance its antifungal activity against oral candidiasis. In the formulation of this study, SO was used as a component of a liquid lipid that showed an improved antifungal effect of MZ. An optimized MZ-loaded NLC of SO (MZ-SO NLC) was used, based on a central composite design-based experimental design; the particle size, dissolution efficiency, and inhibition zone against oral candidiasis were chosen as dependent variables. A software analysis provided an optimized MZ-SO NLC with a particle size of 92 nm, dissolution efficiency of 88%, and inhibition zone of 29 mm. Concurrently, the ex vivo permeation rate of the sheep buccal mucosa was shown to be significantly (p < .05) higher for MZ-SO NLC (1472 µg/cm2) as compared with a marketed MZ formulation (1215 µg/cm2) and an aqueous MZ suspension (470 µg/cm2). Additionally, an in vivo efficacy study in terms of the ulcer index against C. albicans found a superior result for the optimized MZ-SO NLC (0.5 ± 0.50) in a treated group of animals. Hence, it can be concluded that MZ, through an optimized NLC of SO, can treat candidiasis effectively by inhibiting the growth of C. albicans.

Carbopol emulgel loaded with ebastine for urticaria: development, characterization, in vitro and in vivo evaluation.

Urticaria affects all age groups of a population. It is triggered by allergens in foods, insect bites, medications, and environmental conditions. Urticaria is characterized by itching, a burning sensation, wheals and flares, erythema, and localized edema. The aim of this study was to develop a polymeric dosage form of ebastine using Carbopol 940 and mixture of span and tween. The emulsion was prepared, the gelling agent was added and the desired emulgel loaded with active drug was formulated. The formulations were subjected to physical stability, pH, viscosity, spreadability, drug content analysis, thermal analysis, in vitro drug release, and in vivo anti-allergic activity in animal model. The formulated emulgel exhibited good physical stability. The pH of the formulation was in the range of 5.2 ± 0.17 to 5.5 ± 0.20 which is suitable for topical application. Insignificant changes (p > .05) were observed in viscosity and spreadability of stored emulgels. The drug content was in the official limit of Pharmacopeia (i.e. 100 ± 10%). DSC measurements predicted that there is no interaction between the active moiety and excipients in emulgel formulation. The optimized formulation (ES3) released 74.25 ± 1.8% of ebastine after 12 h. The ebastine emulgel showed significant (p < .05; ANOVA) in vivo anti-allergic activity as compared to commercial product Benadryl® in histamine-induced allergy in rabbits. This study concluded that a topical drug delivery of ebastine-loaded emulgel could be well tolerated and safe for the treatment of urticaria/hives.

Gum Acacia Functionalized Colloidal Gold Nanoparticles of Letrozole as Biocompatible Drug Delivery Carrier for Treatment of Breast Cancer.

The most prevalent malignancy among postmenopausal women is breast cancer. It is one of the leading causes of cancer-related mortality among women. Letrozole (LTZ) is a clinically approved inhibitor for breast cancer in postmenopausal women. However, due to poor aqueous solubility, non-specific binding, unwanted toxicity, and poor blood circulation hampered its clinical applications. To maximize the pharmacological effects and minimize the side effects, inorganic nanoparticles are a good alternative. Due to excellent biocompatibility and minimum cytotoxicity, gold nanoparticles (AuNPs) offer distinct benefits over other metal nanoparticles. Emerging as attractive components, AuNPs and Gum acacia (GA) have been extensively studied as biologically safe nanomaterials for the treatment of cancers. This study reports the synthesis and characterization of GA stabilized gold nanoparticles (GA-AuNPs) of LTZ for breast cancer treatment. The observed particle size of optimized LTZ @ GA-AuNPs was 81.81 ± 4.24 nm in size, 0.286 ± 0.143 of polydispersity index (PDI) and -14.6 ± -0.73 mV zeta potential. The biologically synthesized LTZ @ GA-AuNPs also demonstrated dose-dependent cytotoxicity against the human breast cancer cell line MCF-7, with an inhibitory concentration (IC50) of 3.217 ± 0.247. We determined the hemolytic properties of the LTZ @ GA-AuNPs to evaluate the interaction between the nanoparticles and blood components. Results showed that there is no interaction between LTZ @ GA-AuNPs and blood. In conclusion, the findings indicate that LTZ @ GA-AuNPs has significant potential as a promising drug delivery carrier for treating breast cancer in postmenopausal women.

Formulation, optimization, and nephrotoxicity evaluation of an antifungal in situ nasal gel loaded with voriconazole‒clove oil transferosomal nanoparticles.

Fungal infections of the paranasal cavity are among the most widely spread illnesses nowadays. The aim of the current study was to estimate the effectiveness of an in situ gel loaded with voriconazole‒clove oil nano-transferosomes (VRC-CO-NT) in enhancing the activity of voriconazole against Aspergillus flavus, which causes rhinosinusitis. The nephrotoxic side effects of voriconazole may be reduced through the incorporation of the clove oil, which has antioxidant activity that protects tissue. The Box‒Behnken design was applied to formulate the VRC-CO-NT. The particle size, entrapment efficiency, antifungal inhibition zone, and serum creatinine concentration were considered dependent variables, and the soybean lecithin, VRC, and CO concentrations were considered independent ones. The final optimized formulation was loaded into a deacetylated gellan gum base and evaluated for its gelation, rheological properties, drug release profile, permeation capabilities, and in vivo nephrotoxicity. The optimum formulation was determined to be composed of 50 mg/mL lecithin, 18 mg/mL VRC, and 75 mg/mL CO, with a minimum particle size of 102.96 nm, an entrapment efficiency of 71.70%, an inhibition zone of 21.76 mm, and a serum creatinine level of 0.119 mmol/L. The optimized loaded in situ gel released 82.5% VRC after 12 hours and resulted in a 5.4-fold increase in drug permeation. The in vivo results obtained using rabbits resulted in a nonsignificant differentiation among the renal function parameters compared with the negative control group. In conclusion, nasal in situ gel loaded with VRC-CO-NT is considered an efficient novel carrier with enhanced antifungal properties with no signs of nephrotoxicity.

Nanocubosomal based in situ gel loaded with natamycin for ocular fungal diseases: development, optimization, in-vitro, and in-vivo assessment.

Natamycin (NT) is a synthetic broad-spectrum antifungal used in eye drops. However, it has low solubility and high molecular weight, limiting its permeation, and generally causes eye discomfort or irritation when administered. Therefore, the present study aimed to develop an ophthalmic in situ gel formulation with NT-loaded cubosomes to enhance ocular permeation, improve antifungal activity, and prolong the retention time within the eye. The NT-loaded cubosome (NT-Cub) formula was first optimized using an I-optimal design utilizing phytantriol, PolyMulse, and NT as the independent formulation factors and particle size, entrapment efficiency %, and inhibition zone as responses. Phytantriol was found to increase particle size and entrapment efficiency %. Higher levels of PolyMulse slightly increased the inhibition zone whereas a decrease in particle size and EE% was observed. Increasing the NT level initially increased the entrapment efficiency % and inhibition zone. The optimized NT-Cub formulation was converted into an in situ gel system using 1.5% Carbopol 934. The optimum formula showed a pH-sensitive increase in viscosity, favoring prolonged retention in the eye. The in vitro release of NT was found to be 71 ± 4% in simulated tear fluid. The optimum formulation enhanced the ex vivo permeation of NT by 3.3 times compared to a commercial formulation and 5.2 times compared to the NT suspension. The in vivo ocular irritation test proved that the optimum formulation is less irritating than a commercial formulation of NT. This further implies that the developed formulation produces less ocular irritation and can reduce the required frequency of administration.

Development and Optimization of Cinnamon Oil Nanoemulgel for Enhancement of Solubility and Evaluation of Antibacterial, Antifungal and Analgesic Effects against Oral Microbiota.

Oral health is a key contributor to a person's overall health and well-being. Oral microbiota can pose a serious threat to oral health. Thus, the present study aimed to develop a cinnamon oil (CO)-loaded nanoemulsion gel (NEG1) to enhance the solubilization of oil within the oral cavity, which will enhance its antibacterial, antifungal, and analgesic actions against oral microbiota. For this purpose, the CO-loaded nanoemulsion (CO-NE) was optimized using I-optimal response surface design. A mixture of Pluracare L44 and PlurolOleique CC 497 was used as the surfactant and Capryol was used as the co-surfactant. The optimized CO-NE had a globule size of 92 ± 3 nm, stability index of 95% ± 2%, and a zone of inhibition of 23 ± 1.5 mm. This optimized CO-NE formulation was converted into NEG1 using 2.5% hydroxypropyl cellulose as the gelling agent. The rheological characterizations revealed that the NEG1 formulation exhibited pseudoplastic behavior. The in vitro release of eugenol (the marker molecule for CO) from NEG1 showed an enhanced release compared with that of pure CO. The ex vivo mucosal permeation was found to be highest for NEG1 compared to the aqueous dispersion of CO-NE and pure cinnamon oil. The latency reaction time during the hot-plate test in rats was highest (45 min) for the NEG1 sample at all-time points compared with those of the other tested formulations. The results showed that the CO-NEG formulation could be beneficial in enhancing the actions of CO against oral microbiota, as well as relieving pain and improving overall oral health.

Oral gel loaded with penciclovir-lavender oil nanoemulsion to enhance bioavailability and alleviate pain associated with herpes labialis.

Herpes labialis, caused by herpes simplex virus type 1, is usually characterized by painful skin or mucosal lesions. Penciclovir (PV) tablets are found to be effective against herpes labialis but suffer from poor oral bioavailability. This study aimed to combine the benefits of PV and lavender oil (LO), which exhibits anesthetic activity, in the form of a self-nanoemulsifying drug delivery system (SNEDDS) for the treatment of herpes labialis. Toward this purpose, LO (oil), Labrasol:Labrafil M1944 CS in the ratio of 6:4 (surfactant mixture), and Lauroglycol-FCC (co-surfactant, selected based on the solubility of PV) were evaluated as the independent factors using a distance quadratic mixture design. The formulation was optimized for the minimum globule size and maximum stability index and was determined to contain 14% LO, 40.5% Labrasol:Labrafil 1944 (6:4), and 45.5% Lauroglycol-FCC. The optimized PV-LO-SNEDDS was embedded in chitosan hydrogel and the resulting formulations coded by (O3) were prepared and evaluated. The rheological studies demonstrated a combined pseudoplastic and thixotropic behavior with the highest flux of PV permeation across sheep buccal mucosa. Compared to a marketed 1% PV cream, the O3 formulation exhibited a significantly higher and sustained PV release, nearly twice the PV permeability, and a relative bioavailability of 180%. Overall, results confirm that the O3 formulation can provide an efficient delivery system for PV to reach oral mucosa and subsequent prolonged PV release. Thus, the PV-LO-SNEDDS embedded oral gel is promising and can be further evaluated in clinical settings to establish its therapeutic use in herpes labialis.

Development of omega-3 loxoprofen-loaded nanoemulsion to limit the side effect associated with NSAIDs in treatment of tooth pain.

The majority of newly developed drugs need to be incorporated with delivery systems to maximize their effect and minimize side effects. Nanoemulsions (NEs) are one type of delivery system that helps to improve the solubility and dissolution of drugs, attempting to enhance their bioavailability and onset of action. The objective of this investigation was to develop an omega-3 oil-based NE loaded with loxoprofen (LXP) to enhance its dissolution, in vitro release, and mucosal penetration and decrease its mucosal ulcerative effects when applied in an oral treatment. LXP-loaded NEs were formulated with varying levels of omega-3 oil (10-30%), surfactant polyoxyethylene-C21-ethers (laureth-21) (40-60%), and co-surfactant polyethylene glycol-40 hydrogenated castor oil (HCO-40) (30-50%) using an extreme vertices mixture design. The developed NEs were characterized for globule size and drug loading capacity. The optimal formulation was tested for in vitro drug release, ex vivo permeation, and ulcer index value. The developed NE acquired a globule size ranging 71-195 nm and drug loading capacity of 43-87%. Considering the results of the in vitro release study, the optimized NE formulation achieved 2.45-fold and 2-fold increases in drug permeation across tested mucosa compared to a marketed tablet and drug aqueous dispersion, respectively. Moreover, the optimum NE exhibited the best ulcer index in comparison to drug aqueous suspension and different formulations when tested in rats. Overall, this research highlights the capacity of NEs to deliver LXP with enhanced solubility, drug release, and permeation while effectively protecting the application site from side effects of the model drug.

Recent Trends in Assessment of Cellulose Derivatives in Designing Novel and Nanoparticulate-Based Drug Delivery Systems for Improvement of Oral Health.

Natural polymers are revolutionizing current pharmaceutical dosage forms design as excipient and gained huge importance because of significant influence in formulation development and drug delivery. Oral health refers to the health of the teeth, gums, and the entire oral-facial system that allows us to smile, speak, and chew. Since years, biopolymers stand out due to their biocompatibility, biodegradability, low toxicity, and stability. Polysaccharides such as cellulose and their derivatives possess properties like novel mechanical robustness and hydrophilicity that can be easily fabricated into controlled-release dosage forms. Cellulose attracts the dosage design attention because of constant drug release rate from the precursor nanoparticles. This review discusses the origin, extraction, preparation of cellulose derivatives and their use in formulation development of nanoparticles having multidisciplinary applications as pharmaceutical excipient and in drug delivery, as bacterial and plant cellulose have great potential for application in the biomedical area, including dentistry, protein and peptide delivery, colorectal cancer treatment, and in 3D printable dosage forms.