Preparation of Tamsulosin Hydrochloride-Loaded Mucoadhesive In Situ Gelling Polymeric Formulation for Nasal Delivery in Geriatrics.

This study aimed to prepare tamsulosin hydrochloride (HCl)-loaded in situ gelling formulation by using hydroxypropyl methylcellulose (HPMC), gellan gum, poloxamer 188, and benzalkonium chloride. Physicochemical evaluation of formulations included determination of pH, viscosity, gelation time, gel strength, drug content, and sterility. In silico study was performed to analyze interactions between polymers, drug, and mucin glycoprotein. In vitro degradation time, drug release, ex vivo mucoadhesion time, permeation, in vivo pharmacokinetics, and stability studies were performed to assess the formulation. Formulations were transparent and displayed acceptable physicochemical attributes. Tamsulosin HCl and polymers interacted via non-covalent interactions. HPMC formed hydrogen bonds, hydrophobic and van der Waals interactions with mucin protein while the drug formed hydrogen bonds only. Gel formulation degraded in simulated nasal fluid within 24 h. In situ gelling formulation showed 83.8 ± 1.7% drug release and remained adhered to the mucosa for 24.5 ± 1 h. A higher (~ 1.85 times) drug permeation was recorded through mucosa within 6 h by in situ gelling formulation when compared to control counterparts (aqueous solution of drug and in situ gelling formulation without poloxamer 188). Nasal administration of tamsulosin HCl by using in situ gelling formulation led to a ~ 3.3 and ~ 3.5 times, respectively, higher Cmax (maximum plasma concentration) and AUCtotal (total area under the curve) than the orally administered aqueous solution. Relative bioavailability of drug delivered by nasal in situ gelling formulation was 3.5 times the oral counterpart. These results indicated that the prepared in situ gelling formulation can act as a promising candidate for systemic administration of tamsulosin HCl.

Improved Transdermal Delivery of Rabies Vaccine using Iontophoresis Coupled Microneedle Approach.

AIM: This study was aimed to develop rabies vaccine incorporated microneedle (MN) patches and evaluate the immunogenicity of prepared formulations in combination with iontophoresis. METHODS: Patches comprising of polyvinyl pyrrolidone, hyaluronic acid and polyethylene glycol 400 were engineered by vacuum micromolding technique. Physical evaluation of patches included determination of folding endurance, % swelling and morphological features. In vitro release study was performed in skin simulant agarose gel using model drug (methylene blue) loaded patches. In vitro insertion ability was assessed using stratum corneum simulant parafilm. In vivo insertion study was performed in rats. Immunogenicity was evaluated in dogs by determining immunoglobulin G (IgG) and rabies virus neutralizing antibodies (RVNA) titer. RESULTS: Patches displayed uniformly distributed microprojections with pointed tips and smooth surface, ~ 70% swelling, remained intact for ~ 200 foldings and successfully penetrated the parafilm. The area covered by model drug across agarose gel was almost double following treatment with MN-iontophoresis combination (MNdi) compared to MN alone (MNdo). Histological examination of rat skin treated with vaccine laden MN (MNvo) and MN-iontophoresis combination (MNvi) confirmed the formation of grooves in epidermis without any damage to the deep vasculature. A ~ 73% and ~ 206% increase (compared to untreated counterpart) was observed in the IgG titer of MNvo and MNvi treated dogs, respectively. The RVNA titer was increased by ~ 1.2 and ~ 2.2 times (compared to threshold value) after MNvo and MNvi treatment, respectively. CONCLUSION: MN-iontophoresis combination provided relatively potent immunogenic response over the conventional intramuscular injection, hence, can be used for administering vaccines transcutaneously.

Engineering of clarithromycin loaded stimulus responsive dissolving microneedle patches for the treatment of biofilms.

This study aimed to fabricate clarithromycin laden Eudragit S-100-based microfibers (MF), microfibers coated film (MB), clarithromycin loaded polyvinyl pyrollidone, hyaluronic acid and sorbitol-based dissolving microneedle patches (CP) and microfibers coated microneedle patches (MP). Morphological and phase analysis of formulations were carried out by scanning electron microscopy and differential scanning calorimetry, X-ray diffraction, respectively. Substrate liquefaction test, in vitro drug release, antimicrobial assay and in vivo antibiofilm studies were performed. MF exhibited a uniform surface and interconnected network. Morphological analysis of CP revealed sharp-tipped and uniform-surfaced microstructures. Clarithromycin was incorporated within MF and CP as amorphous solid. Liquefaction test indicated hyaluronate lyase enzyme responsiveness of hyaluronic acid. Fibers-based formulations (MF, MB and MP) provided an alkaline pH (7.4) responsive drug release; ∼79 %, ∼78 % and ∼81 %, respectively within 2 h. CP showed a drug release of ∼82 % within 2 h. MP showed ∼13 % larger inhibitory zone against Staphylococcus aureus (S. aureus) as compared to MB and CP. A relatively rapid eradication of S. aureus in infected wounds and subsequent skin regeneration was observed following MP application as compared to MB and CP indicating its usefulness for the management of microbial biofilms.

Fabrication and Characterization of Celecoxib-Loaded Chitosan/Guar Gum-Based Hydrogel Beads.

The aim of this study was to fabricate celecoxib-loaded chitosan/guar gum (CS/GG) single (SC) and dual (DC) crosslinked hydrogel beads using the ionotropic gelation approach. The prepared formulations were evaluated for entrapment efficiency (EE%), loading efficiency (LE%), particle size and swelling studies. The performance efficiency was assessed by in vitro drug release, ex-vivo mucoadhesion, permeability, ex-in vivo swelling and in vivo anti-inflammatory studies. The EE% was found to be ~55% and ~44% for SC5 and DC5 beads, respectively. The LE% was ~11% and ~7% for SC5 and DC5 beads, respectively. The beads showed a matrix-like network with thick fibers. The particle size of beads ranged from ~2.74 to 1.91 mm. About 74% and 24% celecoxib was released from SC and DC hydrogel beads, respectively, within 24 h. The SC formulation showed higher %swelling and permeability than the DC counterpart, while the %mucoadhesion was relatively higher for DC beads. During the in vivo study, a significant decrease in the inflammation of the rat paw and inflammatory markers including C-reactive proteins (CRP) and interleukin-6 (IL-6) was observed following treatment with the prepared hydrogel beads; however, the SC formulation showed better therapeutic efficiency. In conclusion, celecoxib-loaded crosslinked CS/GG hydrogel beads can provide sustained drug release and act as potential candidates for managing inflammatory conditions.

Engineering of tetanus toxoid-loaded polymeric microneedle patches.

This study is aimed to fabricate tetanus toxoid laden microneedle patches by using a polymeric blend comprising of polyvinyl pyrrolidone and sodium carboxymethyl cellulose as base materials and sorbitol as a plasticizer. The tetanus toxoid was mixed with polymeric blend and patches were prepared by using vacuum micromolding technique. Microneedle patches were evaluated for physical attributes such as uniformity of thickness, folding endurance, and swelling profile. Morphological features were assessed by optical and scanning electron microscopy. In vitro performance of fabricated patches was studied by using bicinchoninic acid assay (BCA). Insertion ability of microstructures was studied in vitro on model skin parafilm and in vivo in albino rat. In vivo immunogenic activity of the formulation was assessed by recording immunoglobulin G (IgG) levels, interferon gamma (IFN-γ) levels, and T-cell (CD4+ and CD8+) count following the application of dosage forms. Prepared patches, displaying sharp-tipped and smooth-surfaced microstructures, remained intact after 350 ± 36 foldings. Optimized microneedle patch formulation showed ~ 74% swelling and ~ 85.6% vaccine release within an hour. The microneedles successfully pierced parafilm. Histological examination of microneedle-treated rat skin confirmed disruption of epidermis without damaging the underneath vasculature. A significant increase in IgG levels (~ 21%), IFN-γ levels (~ 30%), CD4+ (~ 41.5%), and CD8+ (~ 48.5%) cell count was observed in tetanus vaccine-loaded microneedle patches treated albino rats with respect to control (untreated) group at 42nd day of immunization. In conclusion, tetanus toxoid-loaded microneedle patches can be considered as an efficient choice for transdermal delivery of vaccine without inducing pain commonly experienced with hypodermic needles.

COVID-19 Continuous-EEG Case Series: A Descriptive Study.

PURPOSE: Corona virus disease 2019 (COVID-19) refers to coronavirus disease secondary to SARS-CoV2 infection mainly affecting the human respiratory system. The SARS-CoV2 has been reported to have neurotropic and neuroinvasive features and neurological sequalae with wide range of reported neurological manifestations, including cerebrovascular disease, skeletal muscle injury, meningitis, encephalitis, and demyelination, as well as seizures and focal status epilepticus. In this case series, we analyzed the continuous video-EEGs of patients with COVID-19 infection to determine the presence of specific EEG features or epileptogenicity. METHODS: All continuous video-EEG tracings done on SARS-CoV2-positive patients during a 2-week period from April 5, 2020, to April 19, 2020, were reviewed. The demographics, clinical characteristics, imaging, and EEG features were analyzed and presented. RESULTS: Of 23 patients undergoing continuous video-EEG, 16 were COVID positive and were included. Continuous video-EEG monitoring was ordered for "altered mental status" in 11 of 16 patients and for "clinical seizure" in 5 of 16 patients. None of the patients had seizures or status epilepticus as a presenting symptom of COVID-19 infection. Instead, witnessed clinical seizures developed as results of COVID-19-related medical illness(es): anoxic brain injury, stroke/hemorrhage, lithium (Li) toxicity (because of kidney failure), hypertension, and renal disease. Three patients required therapeutic burst suppression because of focal nonconvulsive status epilepticus, status epilepticus/myoclonus secondary to anoxic injury from cardiac arrest, and one for sedation (and with concomitant EEG abnormalities secondary to Li toxicity). CONCLUSIONS: In this observational case series of 16 patients with COVID-19 who were monitored with continuous video-EEG, most patients experienced a nonspecific encephalopathy. Clinical seizures and electrographic status epilepticus were the second most commonly observed neurological problem.

Microneedle based transcutaneous delivery of low molecular weight heparin.

This study aimed to fabricate and characterize polymeric microneedle patches for rapid and non-invasive administration of enoxaparin across skin layers. The patches comprising of PVA, sorbitol and enoxaparin sodium were prepared by employing micromolding technique. Formulated patches were characterized physicochemically by folding endurance, dimensional analysis and swelling study, morphologically by optical and scanning electron microscopy and thermally by thermogravimetric analysis. Moreover, performance efficiency of prepared polymeric device was analyzed by in-vitro drug release study and piercing ability. Prepared patches showed appropriate dimensions and folding endurance (i.e., ~1100) indicating satisfactory integrity of polymeric device. Patches exhibited appropriately distanced needles with pointed tips in optical and scanning electron microscopy analysis. Thermogravimetric analysis proved thermal stability of formulation ingredients and prepared patches. Swelling percentage was >110 % suggesting that prepared formulation would allow penetration of physiological fluids in its polymeric network. Maximum (~89%) drug was released within ~2 hours during in-vitro release study. In-vitro piercing ability experiments suggested that prepared patches successfully breached skin barrier stratum corneum. It is concluded that prepared microneedle device can serve as a potential alternative of currently employed invasive parenteral route for rapid and efficient administration of enoxaparin sodium in the systemic circulation.

A review of emerging technologies enabling improved solid oral dosage form manufacturing and processing.

Tablets are the most widely utilized solid oral dosage forms because of the advantages of self-administration, stability, ease of handling, transportation, and good patient compliance. Over time, extensive advances have been made in tableting technology. This review aims to provide an insight about the advances in tablet excipients, manufacturing, analytical techniques and deployment of Quality by Design (QbD). Various excipients offering novel functionalities such as solubility enhancement, super-disintegration, taste masking and drug release modifications have been developed. Furthermore, co-processed multifunctional ready-to-use excipients, particularly for tablet dosage forms, have benefitted manufacturing with shorter processing times. Advances in granulation methods, including moist, thermal adhesion, steam, melt, freeze, foam, reverse wet and pneumatic dry granulation, have been proposed to improve product and process performance. Furthermore, methods for particle engineering including hot melt extrusion, extrusion-spheronization, injection molding, spray drying / congealing, co-precipitation and nanotechnology-based approaches have been employed to produce robust tablet formulations. A wide range of tableting technologies including rapidly disintegrating, matrix, tablet-in-tablet, tablet-in-capsule, multilayer tablets and multiparticulate systems have been developed to achieve customized formulation performance. In addition to conventional invasive characterization methods, novel techniques based on laser, tomography, fluorescence, spectroscopy and acoustic approaches have been developed to assess the physical-mechanical attributes of tablet formulations in a non- or minimally invasive manner. Conventional UV-Visible spectroscopy method has been improved (e.g. fiber-optic probes and UV imaging-based approaches) to efficiently record the dissolution profile of tablet formulations. Numerous modifications in tableting presses have also been made to aid machine product changeover, cleaning, and enhance efficiency and productivity. Various process analytical technologies have been employed to track the formulation properties and critical process parameters. These advances will contribute to a strategy for robust tablet dosage forms with excellent performance attributes.

Antibiofilm Effects of Macrolide Loaded Microneedle Patches: Prospects in Healing Infected Wounds.

AIM: The aim of this study was to fabricate polymeric microneedles, loaded with macrolides (erythromycin, azithromycin), using hyaluronic acid and polyvinyl pyrollidone. METHODS: These microneedles were fabricated using a vacuum micromolding technique. The integrity of the microneedle patches was studied by recording their morphologic features, folding endurance, swelling and micro-piercing. Physicochemical characteristics were studied by differential scanning calorimetry, thermogravimetric analysis and fourier transform infrared spectroscopy. In-vitro drug release, antibiofilm and effect of microneedle patch on wound healing were also studied to confirm the efficacy of the formulations. RESULTS: Formulated patches displayed acceptable folding endurance (>100) and uniform distribution of microneedles (10 × 10) that can penetrate parafilm. Differential scanning calorimetry results depict a decrease in the crystallinity of macrolides following their incorporation in to a polymer matrix. Percentage release of azithromycin and erythromycin from the polymeric patch formulations (over 30 min) was 90% and 63% respectively. Broadly, the zone of bacterial growth inhibition follows the same order for Staphylococcus aureus, Escherichia coli and Salmonella enterica. After 5 days of treatment with azithromycin patches, the wound healing was complete and skin structure (e.g. hair follicles and dermis) was regenerated. CONCLUSION: It was concluded that azithromycin loaded microneedle patches can be used to treat biofilms in the infected wounds.

Fabrication and characterisation of self-applicating heparin sodium microneedle patches.

The aim of this study was to develop heparin sodium loaded microneedle patches using different compositions of polyvinyl alcohol polymer and sorbitol. A vacuum micromolding technique was used to fabricate microneedle patches while heparin sodium was loaded into needle tips. Physical features of patches were evaluated by measuring thickness, width, folding endurance and swelling percentage. Patches were also characterised by optical microscopy and scanning electron microscopy to determine the microneedle length and surface morphologies. A preliminary assessment of the microneedle performance was studied by examining the in-vitro insertion to the parafilm and recording the in-vitro drug release profile. In-vivo activity of patches was confirmed by measuring activated partial thromboplastin time and histological examination of the micropierced skin tissues. Prepared patches were clear, smooth; uniform in appearance; with sharp pointed microprojections and remained intact after 1000 folding. The microneedles were stiffer in nature, as they reproduce microcavities in the parafilm membrane following hand pushing without any structural loss. Insertion study results showed successful insertion of microneedles into the parafilm. Disrupted stratum corneum evident from histological examination confirmed successful insertion of the microneedle without affecting the vasculature. In-vitro release study confirmed ∼92% release of the loaded drug within 120 min. A significant prolongation of activated partial thromboplastin time (4 folds as compared to negative control) was recorded following the application of heparin sodium loaded microneedle patch onto rabbit skin. In conclusion microneedles are a valuable drug delivery system, benefiting the patients with minimal skin invasion and also allowing self-administration of heparin sodium in a sustained release manner for the management of chronic ailments.

Mothball ingestion as a manifestation of pica, leading to paradichlorobenzene CNS toxicity.

BACKGROUND: Pica is a poorly understood psychiatric disorder that presents with the ingestion of non-nutritious substances for unclear reasons. A high index of suspicion for unusual toxin exposure aids in the diagnosis of pica patients presenting with unexplained neurodegenerative features. METHODS: We present a 47-year-old female with worsening gait over the past year. Prior to this, she was fully independent with activities of daily living, but is now mostly housebound due to frequent falls. Past medical history is significant for menorrhagia, iron deficiency anemia and pica. CBC and iron studies revealed iron deficiency with microcytic hypochromic anemia. MRI brain demonstrated symmetrical T2 hyperintensities within the middle cerebellar peduncles. RESULTS: Differential diagnoses for her clinical deficits and imaging, including Spinocerebellar Ataxia, Multiple System Atrophy and Fragile X Tremor-Ataxia Syndrome, were excluded based on neurological assessment, family history and genetic PCR testing. Collateral history revealed a regular habit of mothball ingestion and serum paradichlorobenzene levels were elevated to 15mcg/mL. The patient was treated with iron replacement therapy and her symptoms gradually improved over several months. CONCLUSION: Iron deficiency anemia is commonly associated with pica, which can lead to toxin ingestion. A high index of suspicion for toxin ingestion in pica patients can immensely aid in the diagnosis. Mothball abuse secondary to pica may affect the CNS and can present with nonspecific neurodegenerative changes. To our knowledge, there have been no reported cases in the literature with paradichlorobenzene neurotoxicity predominantly affecting the middle cerebellar peduncles.

COVID-19: Current Developments and Further Opportunities in Drug Delivery and Therapeutics.

SARS-CoV-2 has affected people from all age groups, races and ethnicities. Given that many infected individuals are asymptomatic, they transmit the disease to others unknowingly, which has resulted in the spread of infection at an alarming rate. This review aims to provide an overview of the pathophysiology, preventive measures to reduce the disease spread, therapies currently in use, an update on vaccine development and opportunities for vaccine delivery. The World Health Organization has advised several precautions including social distancing, hand washing and the use of PPE including gloves and face masks for minimizing the spread of SARS-CoV-2 infection. At present, several antiviral therapies previously approved for other infections are being repositioned to study their efficacy against SARS-CoV-2. In addition, some medicines (i.e., remdesivir, chloroquine, hydroxychloroquine) have received emergency use authorisation from the FDA. Plasma therapy has also been authorised for emergency use for the treatment of COVID-19 on a smaller scale. However, no vaccine has been approved so far against this virus. Nevertheless, several potential vaccine targets have been reported, and development of different types of vaccines including DNA, mRNA, viral vector, inactivated, subunit and vaccine-like particles is in process. It is concluded that a suitable candidate delivered through an advanced drug delivery approach would effectively boost the immune system against this coronavirus.

Opinion and Special Articles: Amateur fundus photography with various new devices: Our experience as neurology residents.

Times are changing in the way we secure and share patient fundus photographs to enhance our diagnostic skills in neurology. At the recent American Academy of Neurology meeting, the use of a fundus camera and smartphones to secure good-quality fundus photographs of patients presenting with headache to the emergency department (ED) was presented. We were enthusiastic to replicate the success of the Fundus Photography vs Ophthalmoscopy Trial Outcomes in the Emergency Department (FOTO-ED) study in our neurology department, but encountered problems in terms of cost, setup, feasibility, and portability of the device. As neurology residents, we came up with 3 easier options. We present these 3 options as our personal experience, and hope to reignite enthusiasm among neurology trainees to find their own means of performing ophthalmoscopy routinely in the hospital, as it appears that the Internet market is now thriving with many other devices to make this examination easier and more rewarding. Of the options explored above, the Handheld Fundus Camera was a clear favorite among the residents, and we have placed one in our call room for routine use. It travels to the clinic, floor, intensive care unit, and ED when needed. It has enhanced the way we approach the fundus examination and been a fun skill to acquire. We look forward to further advances that will make it possible to carry such a device in a physician's pocket.

Acute Left Internal Carotid Artery and Right Popliteal Artery Occlusion Related to Cisplatin-Gemcitabine Based Chemotherapy.

OBJECTIVES: The increased risk of thromboembolic complications with active cancer is well known. We present this case to highlight that chemotherapy may increase the risk of thromboembolic events even further in cancer patients. METHODS: We report a case of a 64-year-old male with Diffuse Large B-Cell Non-Hodgkin's Lymphoma who presented with left-sided headache and right calf pain two weeks after starting Rituximab/Gemcitabine/Cisplatin/Dexamethasone chemotherapy. Neurological examination was normal, but there was an absent right dorsalis pedis pulse. He subsequently developed left vision loss. CT angiogram of the head and neck revealed occlusion of his left internal carotid artery and poor opacification of the left ophthalmic artery. An angiogram of the right leg further revealed acute occlusion of the popliteal artery. RESULTS: The patient underwent intra-arterial Tissue Plasminogen Activator injection to his lower limb and was started on Low Molecular Weight Heparin. His vision gradually recovered with time. His chemotherapy regimen was changed to RICE (Rituximab, Ifosfamide, Carboplatin, Etoposide). CONCLUSION: Based on literature review, there are numerous similar presentations of arterial thromboembolism in patients on Cisplatin-based chemotherapy. A high index of suspicion for such events should be maintained for patients on chemotherapy presenting with unusual symptoms.

Rhino-orbito-cerebral mucormycosis: recovery against the odds.

A 22-year-old woman presented with diabetic ketoacidosis, acute right eye blindness and complete ophthalmoplegia. Despite early suspicion and treatment for rhino-orbito-cerebral mucormycosis, her extensive spread of infection led to right internal carotid artery occlusion and cavernous sinus thrombosis, right-sided cerebral watershed infarctions and large abscesses in her right cerebellum, temporal lobe and pons. She underwent surgical removal of her right eye, paranasal sinuses, maxilla and palate, suboccipital craniectomy and shunting for hydrocephalus. Despite the grave prognosis, she has gradually improved and has remained on antifungal treatment for the 18 months since presentation. We discuss the factors that may have influenced her recovery. The case highlights the aggressive nature of rhino-orbito-cerebral mucormycosis, the need for multiple surgeries and the ethical issues in managing such patients.

Plasma levels of B-type natriuretic Peptide in patients with unstable angina pectoris or acute myocardial infarction: prognostic significance and therapeutic implications.

Plasma B-type natriuretic peptide (BNP) levels were obtained from 146 patients with unstable angina pectoris, non-ST-segment elevation myocardial infarction (MI), or ST-segment elevation MI to determine their value in predicting the presence of new heart failure, recurrent MI or ischemia, or death 1 month after the index event. Patients with elevated plasma BNP levels (>80 pg/mL) had a significantly higher incidence of new heart failure and all-cause mortality than those with a normal plasma BNP level (

Valproate-induced encephalopathy.

Valproate-induced encephalopathy is a rare syndrome that may manifest in otherwise normal epileptic individuals. It may even present in patients who have tolerated this medicine well in the past. It is usually but not necessarily associated with hyperammonemia. The EEG shows characteristic triphasic waves in most patients with this complication. A case of valproate-induced encephalopathy is presented. The problems in diagnosing this condition are subsequently discussed.