Delivery Of Sodium Research Articles

Chloride-sensitive signaling turns the potassium switch on

The potassium switch refers to plasma potassium regulation of the sodium-chloride cotransporter (NCC), which controls distal sodium delivery and therefore potassium secretion. Low extracellular potassium activates NCC by relieving chloride inhibition of With-No-Lysine 4 (WNK4). A new mouse model carrying a chloride-insensitive WNK4 mutant still shows NCC activation on low potassium diet. These effects are mediated by WNK4 activation and kelch-like 3 (KLHL3) inhibition and reveal additional chloride-sensitive pathways for NCC activation.

Dual inhibition of SGLT2 and DPP-4 promotes natriuresis and improves glomerular hemodynamic abnormalities in KK/Ta-Ins2Akita mice with progressive diabetic kidney disease

Natriuresis is closely linked to glomerular hemodynamics in diabetic kidney disease (DKD), and is known to be influenced by inhibition of sodium-glucose cotransporter 2 (SGLT2) or dipeptidyl peptidase-4 (DPP-4). In the present study, we investigated whether dual inhibition of SGLT2 and DPP-4 exerts an additive effect on promoting natriuresis and how it ameliorates glomerular hemodynamic abnormalities via the natriuretic effect in DKD. Eight-week-old male KK/Ta-Ins2Akita (KK/Ta-Akita) mice which develop progressive DKD were orally once-daily given either SGLT2 inhibitor empagliflozin (30 mg/kg) alone, DPP-4 inhibitor linagliptin (5 mg/kg) alone or a combination of empagliflozin (30 mg/kg) plus linagliptin (5 mg/kg) for 6 weeks. In vehicle-treated control KK/Ta-Akita mouse group, markedly enhanced glomerular albumin filtration and glomerular filtration rate (GFR) were observed. These renal alterations were dramatically attenuated in KK/Ta-Akita mouse group treated with a combination of empagliflozin plus linagliptin. Notably, the combination therapy provided greater reduction in glomerular albumin filtration and GFR along with higher urinary excretion of sodium and a potential afferent arteriolar vasoconstrictor adenosine than the empagliflozin monotherapy. Significant reduction in urinary excretion levels of a potential afferent arteriolar vasodilator prostaglandin E2 (PGE2) relative to the baseline values was observed after the combination therapy but not the monotherapy. These results suggest that dual inhibition of SGLT2 and DPP-4 highly promotes a distal tubular sodium delivery and thereby contributes to the appropriate modulation of preglomerular arteriolar tone and intraglomerular pressure via an increase in adenosine release and a reduction in PGE2 secretion from macula densa in DKD.

Effect of compromised skin barrier on delivery of diclofenac sodium from brand and generic formulations via microneedles and iontophoresis

Application of drugs on skin with compromised barrier can significantly alter permeation of drugs with the possibility of increased adverse side effects or even toxicity. In this study, we tested in vitro delivery of diclofenac sodium from marketed brand and generic formulations across normal and compromised skin using microneedles and iontophoresis, alone and in combination. Ten tape strips on dermatomed human skin were used to create a compromised skin model, as demonstrated by changes in skin resistance and transepidermal water loss. Histology studies further confirmed creation of a compromised skin barrier. There was no significant difference between brand and generic formulations for delivery of diclofenac sodium into and across normal and compromised skin. Compromised skin showed higher total delivery (µg/sq.cm) of diclofenac sodium for all groups – microneedles (brand: 79.45 ± 8.81, generic: 92.15 ± 8.63), iontophoresis (brand: 233.13 ± 8.32, generic: 242.07 ± 11.17), combination (brand: 186.88 ± 6.76, generic: 193.8 ± 5.69) as compared to intact normal skin for same groups, microneedles (brand: 21.83 ± 1.96, generic: 20.38 ± 0.91), iontophoresis (brand: 149.78 ± 18.43, generic: 145.53 ± 12.61), and combination (brand: 80.97 ± 9.86, generic: 70.76 ± 6.56). These results indicate the effect of barrier integrity on delivery of diclofenac sodium which suggests increased absorption and systemic exposure of the drug across skin with compromised skin barrier.

Dermal Delivery of Diclofenac Sodium-In Vitro and In Vivo Studies.

Previously, we reported the use of confocal Raman spectroscopy (CRS) as a novel non-invasive approach to determine drug disposition in the skin in vivo. Results obtained by CRS were found to correlate with data from the well-established in vitro permeation test (IVPT) model using human epidermis. However, these studies used simple vehicles comprising single solvents and binary or ternary solvent mixtures; to date, the utility of CRS for monitoring dermal absorption following application of complex marketed formulations has not been examined. In the present work, skin delivery of diclofenac sodium (DFNa) from two topical dermatological drug products, namely Diclac® Lipogel 10 mg/g and Primofenac® Emulsion gel 1%, was determined by IVPT and in vivo by both CRS and tape stripping (TS) methodologies under similar experimental conditions. The in vivo data were evaluated against the in vitro findings, and a direct comparison between CRS and TS was performed. Results from all methodologies showed that Diclac promoted significantly greater DFNa delivery to the skin (p < 0.05). The cumulative amounts of DFNa which permeated at 24 h in vitro for Diclac (86.5 ± 9.4 µg/cm2) were 3.6-fold greater than the corresponding amounts found for Primofenac (24.4 ± 2.7 µg/cm2). Additionally, total skin uptake of DFNa in vivo, estimated by the area under the depth profiles curves (AUC), or the signal intensity of the drug detected in the upper stratum corneum (SC) (4 µm) ranged from 3.5 to 3.6-fold greater for Diclac than for Primofenac. The shape of the distribution profiles and the depth of DFNa penetration to the SC estimated by CRS and TS were similar for the two methods. However, TS data indicated a 4.7-fold greater efficacy of Diclac relative to Primofenac, with corresponding total amounts of drug penetrated, 94.1 ± 22.6 µg and 20.2 ± 7.0 µg. The findings demonstrate that CRS is a methodology that is capable of distinguishing skin delivery of DFNa from different formulations. The results support the use of this approach for non-invasive evaluation of topical products in vivo. Future studies will examine additional formulations with more complex compositions and will use a wider range of drugs with different physicochemical properties. The non-invasive nature of CRS coupled with the ability to monitor drug permeation in real time offer significant advantages for testing and development of topical dermatological products.

Efficient lung-targeted delivery of risedronate sodium/vitamin D3 conjugated PAMAM-G5 dendrimers for managing osteoporosis: Pharmacodynamics, molecular pathways and metabolomics considerations

AimsThis study aims at formulating combined delivery of Risedronate sodium (RIS) and Vitamin D3 (VITD3) for augmented therapeutic outcome against osteoporosis (OP) using deep lung targeted PAMAM-G5-NH2 dendrimers to minimize RIS gastrointestinal side effects and enhance both drugs bioavailability through absorption from the alveoli directly to the blood. MethodsRIS-PAMAM-G5-NH2, VITD3-PAMAM-G5-NH2, and RIS/VITD3-PAMAM-G5-NH2 were prepared and evaluated in vitro for particle size (PS), zeta potential (ZP), %loading efficiency (%LE), morphology and FTIR. The efficacy of the RIS/VITD3-PAMAM-G5-NH2 compared to oral RIS was evaluated in OP-induced rats by comparing serum calcium, phosphorus, and computed bone mineral density (BMD) pre- and post-treatment. Additionally, a comprehensive metabolomics and molecular pathways approach was applied to find serum potential biomarkers for diagnosis and to evaluate the efficacy of inhaled RIS/VITD3-PAMAM-G5-NH2. Key findingsRIS/VITD3-PAMAM-G5-NH2 was successfully prepared with a %LE of 92.4 ± 6.7 % (RIS) and 83.2 ± 4.4 % (VIT-D3) and a PS of 252.8 ± 34.1 adequate deep lung delivery. RIS/VITD3-PAMAM-G5-NH2 inhalation therapy was able to restore serum calcium, phosphorus, and BMD close to normal levels after 21 days of treatment in OP-induced rats. The WNT-signalling pathway and changes in the metabolite levels recovered to approximately normal levels upon treatment. Moreover, histone acetylation of the WNT-1 gene and miR-148a-3p interference proved to play a role in the regulation of the WNT-signalling pathway during OP progression and treatment. SignificancePulmonary delivery of RIS/VITD3-PAMAM-G5-NH2 offers superior treatment for OP treatment compared to the oral route. Molecular and Metabolic pathways represents key indicators for OP diagnosis and progression.

Novel Bile Salt Stabilized Vesicles-Mediated Effective Topical Delivery of Diclofenac Sodium: A New Therapeutic Approach for Pain and Inflammation

The oral delivery of diclofenac sodium (DNa), a non-steroidal analgesic, anti-inflammatory drug, is associated with various gastrointestinal side effects. The aim of the research was to appraise the potential of transdermal delivery of DNa using bilosomes as a vesicular carrier (BSVC) in inflamed paw edema. DNa-BSVCs were elaborated using a thin-film hydration technique and optimized using a 31.22 multilevel categoric design with Design Expert® software 10 software (Stat-Ease, Inc., Minneapolis, MI, USA). The effect of formulation variables on the physicochemical properties of BSVC, as well as the optimal formulation selection, was investigated. The BSVCs were evaluated for various parameters including entrapment efficiency (EE%), vesicle size (VS), zeta potential (ZP) and permeation studies. The optimized BSVC was characterized for in vitro release, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and incorporated into hydrogel base. The optimized DNa-BSVC gel effectiveness was assessed in vivo using carrageenan-induced paw edema animal model via cyclooxygenase 2 (COX-2), interleukin 6 (IL-6), Hemooxygenase 1 (HO-1) and nuclear factor-erythroid factor2-related factor 2 (Nfr-2) that potentiate anti-inflammatory and anti-oxidant activity coupled with histopathological investigation. The resulting vesicles presented VS from 120.4 ± 0.65 to 780.4 ± 0.99 nm, EE% from 61.7 ± 3.44 to 93.2 ± 2.21%, ZP from −23.8 ± 2.65 to −82.1 ± 12.63 mV and permeation from 582.9 ± 32.14 to 1350.2 ± 45.41 µg/cm2. The optimized BSVCs were nano-scaled spherical vesicles with non-overlapped bands of their constituents in the FTIR. Optimized formulation has superior skin permeability ex vivo approximately 2.5 times greater than DNa solution. Furthermore, histological investigation discovered that the formed BSVC had no skin irritating properties. It was found that DNa-BSVC gel suppressed changes in oxidative inflammatory mediators (COX-2), IL-6 and consequently enhanced Nrf2 and HO-1 levels. Moreover, reduction of percent of paw edema by about three-folds confirmed histopathological alterations. The results revealed that the optimized DNa-BSVC could be a promising transdermal drug delivery system to boost anti-inflammatory efficacy of DNa by enhancing the skin permeation of DNa and suppressing the inflammation of rat paw edema.

Preparation and characterization of Sr-substituted hydroxyapatite/reduced graphene oxide 3D scaffold as drug carrier for alendronate sodium delivery

Due to the characteristics of bone metabolic microenvironment in the local area of osteoporotic bone defect, it is often difficult for ordinary bone repair materials to achieve satisfactory repair effect. In this study, a multifunctional Sr-substituted hydroxyapatite/reduced graphene oxide (Sr-HAp/RGO) 3D scaffold was fabricated by a one-step hydrothermal reduction method. Sr-HAp colloids with good dispersion stability were firstly prepared to prevent precipitation and aggregation during hydrothermal process. The Sr-HAp/RGO composite scaffold with porous structure has a high compressive strength due to the reinforcement of Sr-HAp nanoparticles. Alendronate sodium (ALN), a commonly used drug for the treatment of osteoporosis, can be effectively loaded on the Sr-HAp/RGO scaffold and released for a prolonged time. The as-prepared ALN-loaded Sr-HAp/RGO scaffold shows promising potential for osteoporotic bone defect repair.

Is there any robust evidence showing that SGLT2 inhibitor use predisposes to acute kidney injury?

A novel class of oral glucose lowering drugs, sodium-glucose co-transporter type 2 inhibitors (SGLT2is), has shown additional beneficial effects on body weight, serum uric acid levels, blood pressure, and cardiac and renal function. Conflicting data have been published regarding the potential risk of acute kidney injury (AKI) when using SGLT2is. Aim of this manuscript was to review the current literature on this issue. SGLT2isinduce a mild acute decline in estimated glomerular filtration rate, attributed to the effect of proximal tubular natriuresis on tubuloglomerular feedback through increased macula densa sodium delivery, leading to afferent arteriole vasoconstriction and reduced intraglomerular pressure. This functional effect with a subsequent rise in serum creatinine fulfills the creatinine-basedcriteria for AKI,as defined in clinical practice and trial settings. Other proposed potential mechanisms as tohow SGLT2islead to AKI include osmotic diuresis leading to volume depletion, increased urinary uric acid levels, intratubular oxidative stress, local inflammation and tubular injury. Despite the warning published by the US Food and Drug Administration in 2016 about a potential risk of AKI and the report of some clinical cases of AKI after treatment with SGLT2is, large observational real-life retrospective studies, randomized controlled trials and propensity-matched analyses of data from clinical practice unambiguously demonstrate that SGLT2is are safe for the kidney and do not predispose to AKI. In conclusion, while we can probably stop worrying about AKI risk when using SGLT2is, the question whether these agents should be withheld in the presence of clinical situations at high risk for AKIremains unaddressed.

Development and evaluation of reservoir transdermal polymeric patches for controlled delivery of diclofenac sodium

Development and evaluation of reservoir transdermal polymeric patches for controlled delivery of diclofenac sodium

Penetration Enhancement Strategies for Intradermal Delivery of Cromolyn Sodium.

This study aimed to explore the use of chemical and physical enhancement strategies for the intradermal delivery of cromolyn sodium (CS) for treatment of atopic dermatitis. CS gels were formulated to individually contain 2.5 and 9% salcaprozate sodium (SNAC) as a potential chemical enhancer. The effect of microneedles, alone and in combination with SNAC, was investigated via in vitro permeation studies. Skin impedance and FTIR evaluation of SNAC-treated stratum corneum (SC) was done and compared to the control. The amount of drug delivered in the dermis after 24h by the 2.5% and 9% SNAC gels was 23.29 ± 1.89µg/cm2 and 35.87 ± 2.23µg/cm2, respectively, which were significantly higher than the control (p < 0.05) but were not remarkably different from each other (p > 0.05). Microneedles enhanced permeation in both the control and 2.5% SNAC groups (p < 0.05); however, no synergistic enhancement was observed when microneedle and SNAC treatments were combined (p > 0.05). Over 24h of treating the SC with 2.5% SNAC, FTIR evaluation showed stretches on the CH2 asymmetric and symmetric stretching vibrations observed at 2920.23cm-1 and 2850.79cm-1 respectively in untreated SC, which shifted to higher wavenumbers and indicated some lipid fluidizing effect. However, no significant drop in skin impedance was seen with SNAC as compared to the control (p > 0.05). SNAC was concluded to have skin permeation enhancement effect on CS, while microneedles effectively enhanced CS permeation even in the absence of SNAC.

Levothyroxine sodium loaded dissolving microneedle arrays for transdermal delivery.

Levothyroxine (LT-4) sodium has shown variable bioavailability following oral administration. This can be assigned to the significant influence of gastrointestinal conditions, food and drugs administered concomitantly on the rate and extent of absorption from the gastrointestinal tract. Thus, the aim of this research study was to establish an efficient transdermal delivery system of LT-4 sodium via the application of hyaluronic acid dissolving microneedles. Microneedles-based drug delivery system consists of sharp-tip needles that puncture the top layers of the skin in a minimally invasive manner to create physical channels through which therapeutic molecules can easily diffuse into/across the skin. Hyaluronic acid polymer at different ratios (5-60 %) was used to prepare microneedle arrays (100 needles per array) using a micromoulding technique. Characterisation tests were carried out to select the optimum formulation. F11 formula containing 50% w/v hyaluronic acid and 1% v/v Tween 80 formula showed an appropriate needle shape with dimensions of 432 ± 6.4 μm in height and a tip diameter of 9.8 ± 1.3 μm. The microneedle arrays demonstrated a suitable mechanical strength after applying a force of 32 N per array and an excellent insertion ability both in Parafilm M® and human skin. The in vivo dissolution of microneedles was started rapidly within 5 minutes following the insertion in the skin and completed at 1 hour. Ex vivo permeation study using human skin has shown a significant improvement in LT-4 sodium delivery across the skin compared to control preparations (drug solution and microneedle free film). The microneedle array F11 has significantly (P ≤ 0.05) increased LT-4 sodium permeation through the skin (cumulative permeated amount of 32 ± 2 μg/cm2) in comparison to the control solution (cumulative permeated amount of 0.7 ± 0.07 μg/cm2) and the microneedle free film (cumulative permeated amount of 0.1 ± 0.02 μg/cm2) over 7 hours. The findings from the irritation test revealed that mild erythema was produced from the application of microneedle arrays which disappeared within 24 hours. Accordingly, dissolving hyaluronic acid microneedles could be a feasible and effective approach to delivering LT-4 sodium transdermally without causing significant skin damage.

Fast dissolving nanofibrous mats for diclofenac sodium delivery: Effects of electrospinning polymer and addition of super-disintegrant

Fast dissolving oral preparations have unique advantages such as rapid dissolution, fast onset of action, convenient administration, and enhanced bioavailability. Therefore, these formulations are proper choices for pain management. The aim of this study was to design and characterize nanofiber (NF) based fast dissolving oral preparations for diclofenac sodium (DS). Different NF-forming hydrophilic polymers were used for the preparation of fast dissolving oral mats and their disintegration time and dissolution rate were compared. DS was incorporated with high loading percentage (25%). The disintegration time showed the following order: PEO NFs > PVP NFs > PVA NFs. To further decrease disintegration time, a super-disintegrant was incorporated into the nanoformulations. The sodium starch glycolate (SSG) enriched NFs showed very rapid disintegration (0.4 s) and complete dissolution within 120 s. The XRD results confirmed the poorly crystalline nature of DS in NFs. FTIR indicated DS incorporation into NFs without any interaction with formulation components. The pH of NF solutions was around neutral and the system showed appropriate biocompatibility evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. Higher permeability of DS by incorporation into NFs was proved by permeation study through sheep buccal mucosa. The optimum formulation has great potential as a fast-dissolving mat for pain management.

In Vitro Evaluation of a Foamable Microemulsion Towards an Improved Topical Delivery of Diclofenac Sodium.

Topical microemulsion (ME) might provide a novel and advanced transdermal delivery system due to the enhances of drug solubility and permeability across the stratum corneum. Foams are topical delivery systems that have excellent patient compliance, acceptability, and preference. Therefore, this study aimed to investigate a foamable microemulsion as an alternative topical and transdermal dosage form for diclofenac sodium (DS). The physicochemical properties (optical clarity, percentage transmittance, homogeneity, consistency of formulation, particle size, zeta potential, conductivity, viscosity, and morphology, etc.) of the DS-loaded ME were investigated. The foam stability of both drug-free ME and DS-loaded ME was measured. The foam quality was evaluated, and the chemical stability over 90days was determined. Franz diffusion cells were employed to assess the in vitro drug release of a foamed DS-loaded ME and compared with a commercial topical product. A foamable and stable DS-loaded ME that maintained small particle sizes and constant zeta potential and was transparent and translucent in appearance after 90days was successfully produced. The foam of the DS-loaded ME was physically more stable compared to the drug-free foam. The foam had an increased drug release rate compared to the commercial product. The foamable DS-loaded ME has a great potential to enhance the transdermal delivery of DS after topical administration. Foamed DS-loaded ME is a promising alternative to the current topical formulation of DS.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

Pattern Recognition versus Pathogenesis: Electrolytes in a Patient with Adrenal Insufficiency.

THE EFFICACY AND SAFETY OF PENTOSAN POLYSULFATE SODIUM FOR IMPROVING DYSLIPIDAEMIA AND SYMPTOMATIC RELIEF IN PEOPLE WITH KNEE OSTEOARTHRITIS: A PILOT STUDY

Purpose: To evaluate the efficacy and safety of oral delivery of Pentosan polysulfate sodium (PPS, Elmiron®) on the improvement of dyslipidemia and symptomatic relief in people with knee osteoarthritis (OA).

Low Salt Delivery Triggers Autocrine Release of Prostaglandin E2 From the Aldosterone-Sensitive Distal Nephron in Familial Hyperkalemic Hypertension Mice.

Aberrant activation of with-no-lysine kinase (WNK)-STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) kinase signaling in the distal convoluted tubule (DCT) causes unbridled activation of the thiazide-sensitive sodium chloride cotransporter (NCC), leading to familial hyperkalemic hypertension (FHHt) in humans. Studies in FHHt mice engineered to constitutively activate SPAK specifically in the DCT (CA-SPAK mice) revealed maladaptive remodeling of the aldosterone sensitive distal nephron (ASDN), characterized by decrease in the potassium excretory channel, renal outer medullary potassium (ROMK), and epithelial sodium channel (ENaC), that contributes to the hyperkalemia. The mechanisms by which NCC activation in DCT promotes remodeling of connecting tubule (CNT) are unknown, but paracrine communication and reduced salt delivery to the ASDN have been suspected. Here, we explore the involvement of prostaglandin E2 (PGE2). We found that PGE2 and the terminal PGE2 synthase, mPGES1, are increased in kidney cortex of CA-SPAK mice, compared to control or SPAK KO mice. Hydrochlorothiazide (HCTZ) reduced PGE2 to control levels, indicating increased PGE2 synthesis is dependent on increased NCC activity. Immunolocalization studies revealed mPGES1 is selectively increased in the CNT of CA-SPAK mice, implicating low salt-delivery to ASDN as the trigger. Salt titration studies in an in vitro ASDN cell model, mouse CCD cell (mCCD-CL1), confirmed PGE2 synthesis is activated by low salt, and revealed that response is paralleled by induction of mPGES1 gene expression. Finally, inhibition of the PGE2 receptor, EP1, in CA-SPAK mice partially restored potassium homeostasis as it partially rescued ROMK protein abundance, but not ENaC. Together, these data indicate low sodium delivery to the ASDN activates PGE2 synthesis and this inhibits ROMK through autocrine activation of the EP1 receptor. These findings provide new insights into the mechanism by which activation of sodium transport in the DCT causes remodeling of the ASDN.

Efficacy and Safety of Dapagliflozin in Children With Inherited Proteinuric Kidney Disease: A Pilot Study

Efficacy and Safety of Dapagliflozin in Children With Inherited Proteinuric Kidney Disease: A Pilot Study

Renoprotective mechanisms of sodium-glucose co-transporter 2 (SGLT2) inhibitors against the progression of diabetic kidney disease.

Sodium-glucose co-transporter 2 inhibitors (SGLT2-Is) have emerged as a promising class of antidiabetic drugs with cardioprotective and renoprotective effects in patients with type 2 diabetes (T2D). The sodium-glucose co-transporters 1 and 2 (SGLT 1 and SGLT2) located in the renal proximal tubules are responsible for glucose reabsorption from the glomerular filtrate back into the systemic circulation. Inhibition of SGLT2, which accounts for about 90% of the glucose reabsorption, leads to a significant reduction in blood glucose levels and a concomitant increase in the urinary excretion of glucose (glycosuria). Multiple mechanisms contribute to the nephroprotective effects of SGLT2-Is in T2D patients. These include: (1) Restoration of the tubuloglomerular feedback by increasing sodium delivery at macula densa, leading to afferent arteriolar constriction and reduced glomerular hyperfiltration, (2) Decreased activation of the intra-renal renin-angiotensin-aldosterone system, which also contributes to reducing glomerular hyperfiltration, (3) Increased production of ketone bodies, which serves as an alternate fuel for adenosine triphosphate production in mitochondria, which helps in attenuating inflammation, and (4) Protection against hypoxia, oxidative stress, and fibrosis. This review elaborates on the key mechanisms that underlie the nephroprotective effects and the adverse effects of SGLT2-Is in T2D patients with progressive diabetic kidney disease.

Peroral delivery of risedronate sodium for treatment of osteoporosis

Oral route of administration is considered as most widely accepted route which is a potential site for drug delivery, direct access to systemic circulation and site of action. Bisphosphonates are the class of drugs which have been approved for clinical use in osteoporosis and other bone diseases. Bisphosphonates are very poorly absorbed from the GI tract and have limited bioavailability of less than 1% with adverse gastrointestinal effects in humans. The present work aimed to develop sublingual spray formulation using Risedronate sodium with combination of Pullulan gum and HPMC E5. Formulation of sublingual spray was developed by employing optimization technique. The optimized formulation was selected and evaluated for various pharmaco-technical parameters such as viscosity, spray angle, drug content per actuation, In-vitro drug diffusion study, Ex-vivo permeation study and In-vivo pharmacodynamics study by glucocorticoid induced model in rats. Pharmaco-technical parameter results of optimized formulation showed satisfactory results. Comparative In-vitro drug permeation and ex-vivo permeation studies showed maximum drug release of 85% for optimized formulation incorporated with permeation enhance transcutol. In-vivo pharmacodynamic study showed better efficacy in treatment animals with optimized formulation and thus newly developed risedronate sodium sublingual spray proved to be effective used in treatment of osteoporosis.

Nose to Brain Delivery of Phenytoin Sodium Loaded Nano Lipid Carriers: Formulation, Drug Release, Permeation and In Vivo Pharmacokinetic Studies.

An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic agent for the immediate treatment of status epilepticus. Phenytoin sodium formulated as nanolipid carriers (NLCs) seems to be promising as an intranasal delivery system for controlling acute seizures. Three different nanosized phenytoin sodium loaded NLCs (<50 nm, 50–100 nm and >100 nm) were prepared by melt emulsification and was further characterised. In vitro drug release studies showed immediate drug release from phenytoin sodium loaded NLCs of <50 nm size, which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation from <50 nm sized NLC through the olfactory epithelium compared to thecontrol drug solution. Invivo pharmacokinetic studies revealed higher drug concentration in CSF/brain within 5 min upon intranasal administration of <50 nm sized phenytoin sodium NLCs than the control drug solution and marketed IV phenytoin sodium, indicating direct and rapid nose to brain drug transport through the olfactory epithelium. The study has shown that formulation strategies can enhance olfactory uptake, and phenytoin sodium NLCs of desired particle sizes (<50 nm) offer promising potential for nose to brain direct delivery of phenytoin sodium in treating acute epileptic seizures.