Current Drug Therapy - Volume 13, Issue 1, 2018

Brain targeting has always been challenging due to the presence of various physiological barriers resulting in low bioavailability via the oral and parenteral route. Altering the integrity of these barriers so as to permit the drugs to enter into the brain could severely damage the Central Nervous System by also allowing the entrance of toxic substances, bacteria and viruses into the brain. This problem can be tackled by delivering drugs via the intranasal route which bypasses the blood brain barrier and reaches different parts of the brain primarily via the olfactory and trigeminal neural pathways. This route offers several advantages over the oral and parenteral route and has shown potential for targeting drugs to the brain for treating various central nervous system disorders such as Psychosis, Parkinson's and Alzheimer's disease. In spite of several advantages, the intranasal route faces many challenges. Hence, a complete understanding of every aspect related to nose to brain delivery is of utmost importance. This article reviews the mechanism of nose to brain drug transport, challenges and approaches for nose to brain drug delivery, a few specialized olfactory delivery devices and some applications of this novel route of brain targeting.

Background: Multiple sclerosis (MS) is an immune-mediated inflammatory disease that attacks myelinated axons in the central nervous system, destroying the myelin and the axon in variable degrees and causing significant disability in many patients. Neuro-Myelitis Optica Spectrum Disorder (NMOSD) is a rare disorder that was considered a subtype of MS but is now recognized as a distinct demyelinating disorder that affects mainly the spine and optic nerves. Objective: The present paper is a review of the recent knowledge regarding present and new drugs that have been recently added to the therapeutic arsenal for MS as well as those which seem to be beneficial for patients with NMOSD. Methods: A step-by-step description of the evolving drug arsenal is presented for both MS and Neuro-Myelitis Optica Spectrum Disorder (NMOSD). Results: Modern drug therapy for MS started with the introduction of ACTH (Adrenocorticotropic hormone) and somewhat later was followed by high dose corticosteroids for treatment of the neurological deficits during an acute relapse. This mode of treatment, which became popular during the years 1970-1980 failed to reduce the number of relapses or to affect the outcome of the disease. Only during the last two decades, the field of MS drug therapy underwent a remarkable change from simple amelioration of symptoms of an acute attack to the development of numerous Disease Modifying Treatments (DMTs). The formulation of DMTs evolved from the older inconvenient subcutaneous or intramuscular route of administration to oral preparations or periodic intravenous infusions of biological drugs. A new treatment was approved in 2017 for reducing disease progression rate for the first time in primary progressive MS. Besides MS, progress was made in delineating the pathophysiology of NMOSD, a devastating demyelinating disorder that is still frequently confused with MS. Although beneficial, the new treatment modalities carry with them adverse effects that may be serious and even life threatening. With the increase in the usage of those drugs, the spectrum of the reported adverse effects is expanding and calls for additional research in regard to the safest way of their utilization. Conclusion: Targeting the immune system in general in RRMS and NMOSD and even PPMS has proven successful, with efficacy varying based on the specific treatment. There are still unmet needs for medications that will address safety and efficacy altogether and prevent disability even more. Areas Covered: The mode of action and main characteristics and side effects of current DMTs for both MS and NMOSD and their place in the therapeutic algorithm of both diseases based on updated evidence from clinical trials.

Objective: This research work aimed to develop bucco-adhesive patches, which release curcumin in the oral cavity for an extended duration thereby assisting in the cure of oral thrush (candidiasis). Fluconazole containing patches were also developed in order to compare the effectiveness of curcumin patches against Candida albicans. Method: After suitable preformulation studies, five formulations of curcumin were prepared using Eudragit S100 and polyvinyl alcohol (PVA) in varying ratios. Three batches of fluconazole formulations were prepared without PVA. Patches were evaluated for their physical properties and chemical integrity. Newer techniques were developed to determine their bioadhesion and tensile strength. Sterile formulations of P3 and F2 were prepared and compared for the antifungal activity against C. albicans, by zone of inhibition method. Results: All formulations exhibited satisfactory tensile strength ranging from 0.282 to 0.411 Kg/m2 with good folding endurance. Formulations containing higher amount of PVP exhibited better bioadhesive strength. P3 formulation containing curcumin and F2 formulation of fluconazole were found to sustain the drug release upto 5 hours. An increasing amount of PVA retarded the drug release. In antifungal studies, the zone of inhibition for P3 patches was 19mm, and for F2 patches, it was 13mm, indicating a better in vitro antifungal activity for curcumin against fluconazole. SEM analysis of P3 formulations revealed continuous, non-porous but non homogenous structure of the polymer film. Conclusion: The effectiveness of curcumin buccal patches in superior to fluconazole patches was well demonstrated. Mathematical modelling of drug release data indicated a first order anomalous transport causing the drug release. Kinetic modelling with zero, first order, Higuchi and Korsmeyer- peppas are explained in this article.

Background: Tuberculosis is a threat to humankind due to the development of resistance against the existing drugs, so new drugs are an absolute necessity. Neuroleptic phenothiazines were reported for antitubercular activity, but the associated antipsychotic effect restricted their antitubercular use. Objective: Novel mycobacterial ATP synthase inhibitors having structural similarity with phenothiazines were designed in an attempt to develop potent antitubercular agents with no or less side effects. Methods: The designed molecules were synthesized and screened against Mycobacterium tuberculosis H37Rv (Mtb). The compounds with strongest growth inhibition of whole Mtb (S3, S4, S9, S10, and S16) were screened for ATP synthesis inhibition using inverted membrane vesicles from Mycobacterium smegmatis, and were also screened for bloodbrain barrier (BBB) permeability and mammalian cell cytotoxicity to assess the possible side effects. Results: Among all the compounds, S9 and S10 were found to be the most active (6.25 μg/mL) against Mtb and were comparable to chlorpromazine (12.5 μg/mL). Moreover, the compounds inhibited ATP synthesis at IC50 of 14 and 10.4 μM, respectively. A better correlation between MIC and IC50 observed, indicated that the compounds acted through mycobacterial ATP synthase inhibition. The blood-brain barrier (BBB) crossing ability of the compounds (S9, S10) was found to be less, indicating diminished CNS side effects. The compounds (S3, S4, S9, S10, and S16) were also marked safe against mammalian VERO cells, as CC50 was > 102 μg/mL. Conclusion: The enhanced antitubercular activity with reduced BBB permeability exhibited by the compounds has good prospect to develop them as antitubercular drugs.

Background: Monensin is a broad spectrum polyether antibiotic produced by Streptomyces cinnamonensis. It is widely used as veterinary medicine in the treatment of coccidiosis. Objective: The goal of this study was to assess the antimalarial efficacy of monensin in liposomal form in combination with potent antimalarial drugs like chloroquine, piperaquine, or FR900098 in free form under in vitro and in vivo condition. Method: In vitro drug sensitivity assay for different drug combinations against blood stages of chloroquine susceptible (3D7) and chloroquine resistant (INDO) strains of Plasmodium falciparum in culture was assessed by [³H]-hypoxanthine incorporation assay. In vivo efficacy was evaluated using the standard 4-day Peters' test in established mice models of both Plasmodium berghei NK65 and lethal strain of P. berghei ANKA. Results: Our results indicate that monensin exhibits superior efficacy than partner antimalarial drugs tested. The drug combinations between monensin/chloroquine, monensin/ piperaquine, and monensin/FR900098 showed synergistic to additive action, at their 50- percent inhibitory concentrations (IC50s) against P. falciparum strains in culture. Monensin in liposomal formulations in combination with subcurative doses of partner antimalarial drugs effectively reduced parasitic burden in P. berghei infected mice than comparable doses of antimalarial drugs used alone. Conclusion: Our results demonstrate that liposomal monensin in combination with partner antimalarials (chloroquine, piperaquine or FR900098) showed positive interactions with enhanced parasite killing on P. falciparum strains and P. berghei infection in murine model. This approach may provide a promising chemotherapeutic regimen at lower doses for treating human malarial infections.

Background: Hydrochlorothiazide (HCTZ) is a thiazide diuretic and also possesses an anti-hypertensive effect. It is BCS class IV drug with very poor aqueous solubility and permeability. Objective: The objective of the present work was to enhance the solubility and permeability of hydrochlorothiazide via self microemulsifying drug delivery system (SMEDDS) and to optimize gastro-retentive floating delivery for Solid-SMEDD. Method: T Solubility of drug was determined in the oil, surfactant and co-surfactant. Pseudo ternary phase diagram was constructed to identify efficient self emulsifying region. SMEDDS was transformed into a free flowing powder. Non-effervescent floating capsules containing Solid SMEDDS of HCTZ was prepared. Factorial design was used to optimize gastro-retentive delivery of HCTZ using polymer HPMC K4M and HEC HX 250 as independent variables. Results: SMEDDS consists of HCTZ, isopropyl myristate, tween 80 and PEG 400 as drug, oil, surfactant and co-surfactant. 1:1 ratio of the surfactant to co-surfactant gave larger transparent region for microemulsion. Ex-vivo drug release from SMEDDS was higher than plain drug at the end of 4 hrs. Magnesium hydroxide was used to convert SMEDDS to S-SMEDDS. ANOVA indicated that the drug release and swelling index were the most significant factors affecting gastro retentive drug delivery. Optimized batch F5 followed Zero order release model kinetics. Conclusion: The study concluded enhanced solubility of drug by SMEDD. Floating capsules gave controlled drug release in the stomach for longer period of time which reduced the dosing frequency and improved the patient compliance.

Background: Colorectal cancer is a major public health problem in the developed world. Capsaicin, a spicy component of hot pepper that preferentially induces certain cancer cells to undergo apoptosis including colon cancer cells. Objective: The aim of the present investigation was to entrap nanoemulsome containing capsaicin in gellan gum hydrogel beads and further coated with Eudragit S100 for site specific delivery to the colon. Method: Nanoemulsomes were prepared by thin film hydration method. Then the prepared nanoliposomes were entrapped in gellan gum hydrogel beads and coated with Eudragit S 100. Physical state of the drug in nanoemulsome was determined by X-ray diffraction and differential scanning calorimetry technique. Nanoemusomes were characterized for size, drug entrapment, and in vitro drug release. Results: The entrapment efficiency and average particle size of nanoemulsome were 33.75% and 174.4 nm respectively. In vitro drug release studies were carried out using dialysis bag technique in simulated fluids at different pH (1.2, 4.5, 7.4, and 6.8) to mimic the gastrointestinal tract. Eudragit S 100 coated hydrogel beads has shown complete drug release for 24 h in a controlled manner in comparison to the un-coated hydrogel beads, which released about 50% of the drug before entering the colonic region. Conclusion: The results clearly demonstrated that coated hydrogel beads can be used as a potential carrier for delivery of capsaicin to colon.