Purification and modification of neem gum for enhancement of its suspending property

Background The present study aimed to purify and modify the neem gum (NG) to evaluate its dispersing ability in a pharmaceutical suspension formulation. The modification was carried out to cross-link the sugars as carbamate in the presence of calcium chloride to improve the suspending property. Physiochemical properties such as pH, solubility, swelling index and ash value were performed before investigating the dispersing potential. The suspending potential of neem gum was studied in its different forms such as purified and modified gum in paracetamol suspension and was compared with sodium carboxymethylcellulose (CMC) being used as standard at a concentration range of 0.25–1% (w/v). The test suspensions were evaluated for the redispersibility, flowability, sedimentation volume (%) and stability study for 3 months. Result The redispersibility of modified neem gum (MNG) was found equal to CMC at a higher concentration. The flowability and apparent sedimentation of test suspending agents and CMC were found in the order of NG > MNG > CMC. It showed a positive correlation with the viscosity of suspension formulations. All the test paracetamol suspension formulations were found stable in the stability study. Conclusion The findings of the present study showed that as an alternate suspending agent, modified cross-linked neem gum could be used.

Selection of Rhizosphere Bacterial Isolates and Development of Antagonistic Bacterial-Based Formulation to Control Fusarium Wilt on Shallot

<p>Wilt disease caused by Fusarium spp. is a major disease in shallot-producing areas particularly in the North Coast of West Java. The research was aimed to select rhizosphere bacteria and develop an antagonistic bacterial-based formulation for its effectiveness to suppress wilt disease caused by Fusarium spp. on shallot plant under greenhouse and field trials. The field trials were carried out using randomized complete block design with four replications at the shallot farmer condition in Subang and Indramayu during the 2019 planting season. Antagonistic test of bacterial isolates from the rhizosphere showed that most of the bacterial isolates can be used as a biocontrol to Fusarium spp. pathogen. The result revealed that bacterial suspension formulation (E-76 + DBS-2 isolates) in combination with phytohormone (1:1 [v/v]) at Subang and Indramayu tended to suppress Fusarium wilt disease intensity with the disease inhibition ranging from 73.54–93.39% and 66.3–95.65%, respectively. The spraying application of formulation 2.5 ml/l was obtained as the best formula to suppress the disease. The growth and production of shallot were also affected by the application of antagonistic-bacterial formula.</p>

Characterization of cough evoked by inhaled treprostinil and treprostinil palmitil

Cough is induced by inhaled prostacyclin analogs including treprostinil (TRE), and, at higher doses, treprostinil palmitil (TP), a prodrug of TRE. In this report, we have investigated mechanisms involved with TRE- and TP-induced cough, using a dry powder formulation of TP (TPIP) to supplement previous data obtained with an aqueous suspension formulation of TP (TPIS).Experiments in guinea pigs and rats investigated the prostanoid receptor subtype producing cough and whether it involved activation of sensory nerves in the airways and vasculature. Experiments involved treatment with prostanoid, tachykinin and bradykinin receptor antagonists, a cyclooxygenase inhibitor and TRE administration to the isolated larynx or intravenously.In guinea pigs, cough with inhaled TRE (1.23 µg·kg−1) was not observed with an equivalent dose of TPIP and required higher inhaled doses (12.8 and 35.8 µg·kg) to induce cough. TRE cough was blocked with IP and tachykinin NK1 receptor antagonists but not with EP1, EP2, EP3, DP1 or bradykinin B2 antagonists or a cyclooxygenase inhibitor. TRE administered to the isolated larynx or intravenously in rats produced no apnea or swallowing, whereas citric acid, capsaicin and hypertonic saline had significant effects.The mechanisms inducing cough with inhaled TRE likely involves the activation of prostanoid IP receptors on jugular C-fibers in the tracheobronchial airways. Cough induced by inhaled dry powder and nebulised formulations of TP occurs at higher inhaled doses than TRE, presumably due to the slow, sustained release of TRE from the prodrug resulting in lower concentrations of TRE at the airway sensory nerves.

Development and validation of a new HPLC method for the analysis of a novel oral suspension formulation of 50 mg/ml ursodeoxycholic acid for newborns

ObjectivesDrugs are developed for adults, making it difficult to find suitable treatments for children. Hospital pharmacy has developed alternatives to respond to this medical need. The objective of this study is to present a new liquid formulation of ursodeoxycholic acid (UDCA) at a concentration suitable for treatment of neonatal jaundice, and to introduce a novel high pressure liquid chromatography (HPLC) assay method.MethodsFour formulations have been developed using suspension vehicles due to the low solubility of the active ingredient, and different concentrations of excipient, xanthan gum, needed to facilitate resuspension. An HPLC method coupled to a diode array detector (DAD) has been developed. This method was used to analyze chemical and microbiologic stabilities, as well as physicochemical properties and palatability.ResultsAfter formulation was chosen, our new HPLC method assay was developed and validated for the quantification of chemical and microbiological stabilities of our product. Both parameters were stable over three months. Palatability has been improved thanks to the addition of universal suspension adjuvants. Odor, appearance and taste were judged pleasant despite a bitter aftertaste, with a persistence of the UDCA resuspension after one month.ConclusionsThree months after informing neonatal department about the availability of the drug, patients and caregivers are satisfied, and production campaigns are routinely planned.

Sustained absorption of delamanid from lipid-based formulations as a path to reduced frequency of administration

Delamanid is a poorly water-soluble drug currently being used for the treatment of tuberculosis. The high frequency of dosing leads to poor adherence for patients who live in lower economic and nomadic populations. Non-digestible self-assembling lipids as a formulation approach for poorly water-soluble drugs have previously been shown to extend the window of absorption through gastric retention. We hypothesise that this approach could lead to the reduction of dosing frequency for delamanid and thereby has potential to improve adherence. Formulations of delamanid were prepared in selachyl alcohol and phytantriol as non-digestible self-assembling lipid vehicles, and their behaviour was compared with reconstituted milk powder, as a digestible lipid-based formulation, and an aqueous suspension. The self-assembly of selachyl alcohol and phytantriol in aqueous media in the presence of delamanid was studied using small angle X-ray scattering and produced the inverse hexagonal (H2) and inverse bicontinuous cubic (V2) liquid crystal structures, respectively. The times at which maximum delamanid levels in plasma were observed (Tmax) after oral administration of the phytantriol, selachyl alcohol and reconstituted milk powder formulations of delamanid to rats were 27 ± 3, 20 ± 4 and 6.5 ± 1.0 h, respectively, compared with the aqueous suspension formulation with a Tmax of 3.4 ± 1 h, which confirms the hypothesis of an extended duration of absorption after administration in non-digestible self-assembling lipids. The digestion products of the triglycerides in the milk formulation increased the solubilisation of delamanid in the gastrointestinal tract, leading to an increase in exposure compared with the aqueous suspension formulation but did not significantly extend Tmax. Overall, the non-digestible nanostructured lipid formulations extended the duration of absorption of delamanid well beyond that from milk or suspension formulations.

Outdoor Transmission of Malaria

Recent assessments of controlling the vectors of malaria have shown that due to reliance of treatments inside houses, malaria transmission is still occurring as people are more active outdoors during the evening after sunset. During several visits to Cameroon, it was noticeable that, at least in the towns, there was considerable activity outdoors after sunset as people preferred to go shopping or socialise with friends when it was cooler. However, as in other countries in Africa, the emphasis has been put on the distribution of insecticide treated bednets while indoor residual spraying (IRS) has also been used. A pilot study in six villages in a malaria-endemic area examined different mosquito control interventions applied to entire villages to assess their impact on vectors, malaria incidence and the quality of life of the communities. One of the villages was left untreated during the year of the trial. One of the other villages which had been treated with IRS and bednets treated with ICON CS (lambda-cyhalothrin capsule suspension formulation) or another that had improved screening of houses combined with outdoor misting showed reduced numbers of mosquitoes collected from exit traps compared to the other treatments. More malaria sporozoites were detected in mosquitoes sampled in exit traps in the untreated village than in the treated villages. Malaria incidence several months after both IRS/ITN and screening/misting treatments was not significantly different from pre-treatment levels. In retrospect, the village with house improvement and outdoor misting was almost as effective as using both treated bed nets and IRS inside houses, indicating important transmission outdoors. A subsequent study showed that, as expected, the treated bed nets were of greater importance in protecting young children remaining under the nets throughout the night than adults.

Hydrotropy – A Solubility Enhancement Tool for the Estimation of Cefdinir in its Suspension Dosage Form by UVSpectroscopy

Present work describes development and validation of a simple, novel, accurate, precise, economical and reproducible spectrophotometric method in ultraviolet region for the assay of Cefdinir in suspension formulation using sodium bicarbonate and distilled water (1:9) as hydrotropic solvent. Cefdinir exhibits absorption maxima at 287nm in hydrotropic solvent. Beer’s law was found to be obeyed in the concentration range of 2.5-17.5μg/ml. The developed method was validated as per the ICH guidelines. The calibration plot was linear over the concentration range investigated (2.5–17.5µg/ml) for Cefdinir in hydrotropic solvent with correlation coefficient, r2 , 0.99903. The method is accurate, precise and economical. In this proposed method, there was no interference from common pharmaceutical excipients. The proposed method is therefore successfully used for the routine analysis of the Cefdinir in its suspension dosage form.

Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response Evaluation

Background: Venous thromboembolism (VTE) in children occurs with increasing frequency predominantly as a result of hospital-acquired thrombosis leading to a substantial rise in the use of anticoagulant medications in children. Only one anticoagulant (dalteparin, a subcutaneously administered agent) is licensed for use in children, but the evidence to support the use of anticoagulants in children is lacking. While several direct oral anticoagulants have been licensed and are in widespread use in adults, as of yet, none have been licensed for children and child-appropriate formulations are not commercially available. The EINSTEIN-Jr. program is a comprehensive clinical development program aimed at providing data to support the use (and eventual licensure) of rivaroxaban for children with VTE. The recently completed randomized EINSTEIN-Jr. phase 3 study showed similar efficacy and safety for rivaroxaban compared to standard anticoagulation for treatment of pediatric VTE. This abstract reports the results of the dose-exposure-response relationship of rivaroxaban from this study. The pediatric rivaroxaban dosing regimens were established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling and has been previously reported. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, 12-&lt;30, and &lt;12kg, respectively. In children weighing &lt;12kg, the lower range of the adult exposure range was targeted to avoid excessive concentrations at the end of the dosing interval. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those &lt;20kg. Based on sparse blood sampling, the 24-hour area under the plasma concentration-time curve [AUC(0-24)ss] and trough [Ctrough,ss] and maximum [Cmax,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, change in thrombus burden at repeat imaging, and bleeding or adverse events. A taste and texture questionnaire was collected from suspension recipients. Results: Between November, 2014 and September, 2018, a total of 365 children were allocated to receive rivaroxaban in the following age groups: birth-&lt;0.5 years (n=13); 0.5-&lt;2 years (n=21); 2-&lt;6 years (n=44); 6-&lt;12 years (n=65); and 12-&lt;18 years (n=173). Of these, 316 (94.3%) were evaluable for PK analyses. A total of 121 (38.3%) children received the rivaroxaban tablet formulation and 195 (61.7%) the suspension formulation. Symptomatic recurrent VTE occurred in 2 children (0.6%) during rivaroxaban treatment. Repeat imaging outcomes in the asymptomatic children were classified as normalized in 124 (39.2%), improved in 125 (39.6%), no relevant change in 16 (5.1%), and deteriorated in 1 (0.3%). In 48 children (15.2%) the result of repeat imaging was uncertain. No major bleeding events occurred with rivaroxaban treatment, whereas clinically relevant non-major bleeding and trivial bleeding were observed in 10 (3.2%) and 111 (35.1%) children, respectively. With respect to the dose-exposure relationship, the vast majority of the individual values were within the 5th-95th percentile for AUC(0-24)ss, Cmax,ss and Ctrough,ss (see figure below on the left). With respect to exposure-response relationship, no clustering was observed for any of the PK parameters with respect to efficacy, bleeding (shown in the figure below on the right), or adverse event outcomes. The results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Conclusion: Treatment of children with bodyweight-adjusted rivaroxaban regimens resulted in exposures similar to those previously observed in adults receiving 20 mg once daily dosing and the level of exposure was not related to the efficacy, bleeding, or adverse events. Based on this analysis and in conjunction with the previously demonstrated similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide a new alternative treatment option for VTE in children. Figure Disclosures Young: Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria. Lensing:Bayer: Employment. Male:Bristol Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Bayer: Consultancy. Kubitza:Bayer: Employment. OffLabel Disclosure: Pediatric treatment of VTE for a drug approved only in adults.