Recent Patents on Drug Delivery and Formulation最新文献

{"title":"Pharmaceutical Cocrystal: A Novel Approach to Tailor the Biopharmaceutical Properties of a Poorly Water Soluble Drug.","authors":"Dipti Srivastava,&nbsp;Zeeshan Fatima,&nbsp;Chanchal D Kaur,&nbsp;Sachin L Tulsankar,&nbsp;Sanap S Nashik,&nbsp;Dilshad A Rizvi","doi":"10.2174/1872211313666190306160116","DOIUrl":"https://doi.org/10.2174/1872211313666190306160116","url":null,"abstract":"<p><strong>Background: </strong>The present study reports the formation of a cocrystal of candesartan with the coformer methyl paraben, its characterization and determination of its bioavailability. Candesartan is a poorly water-soluble drug having an anti-hypertensive activity. The recent patents on the cocrystals of the drugs Progesterone (US9982007B2), Epalrestat (EP2326632B1), Gefitinib (WO2015170345A1), and Valsartan (CN102702118B) for enhancement of solubility, helped in selection of the drug for this work.</p><p><strong>Methods: </strong>Candesartan cocrystal was prepared by solution crystallization method. The formation of a new crystalline phase was characterized by Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) and Powder X-ray Diffraction (PXRD) studies. Saturation solubility studies were carried out in ethanol: water (50:50 % v/v) mixture. The dissolution studies were conducted in 900 ml of phosphate buffer at pH 7.4(I.P.) with 0.7% w/w of Tween 20 at 50 rpm, maintained at a temperature of 37±0.5°C in a USP type II dissolution apparatus. The pharmacokinetic behavior of candesartan and its cocrystal was thereof investigated in male Wistar rats.</p><p><strong>Results: </strong>There was 6.94 fold enhancement in the solubility of candesartan after its cocrystallization. The dissolution profile of the cocrystal exhibited significant improvement in solubility at 60 and 120 minutes and it remained stable in ethanol: water (50:50%v/v) mixture for 48 h as confirmed by PXRD studies. The AUC0-24of the cocrystal was found to be increased by 2.9 fold in terms of bioavailability as compared to the pure drug.</p><p><strong>Conclusion: </strong>The prepared cocrystal was found to be relatively more soluble than the pure drug and also showed an enhanced oral bioavailability as compared to the pure drug.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 1","pages":"62-69"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1872211313666190306160116","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37036606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bilayer Tablet Based Chronotherapeutics in the Management of Nocturnal Asthma: An Overview.","authors":"Sourav Thakur,&nbsp;Bhupendra Singh,&nbsp;Vijay Mishra,&nbsp;Nishika Yadav,&nbsp;Namita Giri,&nbsp;Pardeep Sharma,&nbsp;Ankit Saini,&nbsp;Lavi K Garg","doi":"10.2174/1872211313666190227204127","DOIUrl":"https://doi.org/10.2174/1872211313666190227204127","url":null,"abstract":"<p><strong>Background: </strong>Asthma is a common ailment with a larger circadian difference. Nocturnal Asthma (NA) is an inconstant exacerbation of asthmatic condition related to the rise in warning sign during the night time and there is a need for its treatment addressing air route alertness and decline in lung functions. These symptoms are linked to sleep or known as circadian events. Chronotherapeutics is a management system based on an in-vivo drug accessibility programmed to check the rhythms of ailment in a direction to improve the therapeutic outcomes by suppressing the side effects. This review aims to provide an overview of NA, chronotherapeutics for the treatment of NA, bilayer tablets, and advanced techniques involved in the fabrication of bilayer tablets. The review also discusses some of the related patents.</p><p><strong>Methods: </strong>Relevant literature about the latest developments and updated information related to NA, chronotherapeutics and bilayer tablets has been very widely searched on different biomedical literature programs such as Google, Web of Science, PubMed portals, etc. Bilayer tablet mediated chronotherapy has gained significant attention and consideration as it is developed and fabricated based on the body's circadian rhythm. Bilayer tablets can deliver the bioactive compounds at an appropriate time, place as well as amount and site.</p><p><strong>Results: </strong>Available literature advocated that the bilayer matrix tablet containing a single drug in the sustained release film and fast releasing film, may be beneficial for the chronic diseases like asthma, migraine, diabetes, hypertension and inflammation which usually require immediate as well as maintained therapeutic effect.</p><p><strong>Conclusion: </strong>The application of nanotechnology in the arena of medicine will transform the diagnosis and treatment strategies of a wide range of diseases in the upcoming years. The findings of this review confirm the importance of bilayer tablet based chronotherapy in nocturnal asthma.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 2","pages":"74-82"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37179174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Patents on Permeation Enhancers for Drug Delivery Through Nails.","authors":"Tainá Kreutz, Sheila Porto de Matos, Letícia Scherer Koester","doi":"10.2174/1872211313666191030155837","DOIUrl":"10.2174/1872211313666191030155837","url":null,"abstract":"<p><p>The human nail is a unique barrier with a keratinized constitution that favors protection and fine touch. However, many disorders can affect the nail, among them, are the onychomycosis and psoriasis. Systemic oral therapy has been applied to treat these diseases, even presenting disadvantages, including side effects, drug interactions, contraindications, toxicity, high cost and low patient compliance. A great option to succeed in dealing with the problems associated with oral therapy is the topical administration of drugs. However, nail composition, low diffusion through ungual route and reduced tissue bioavailability for topical treatments are limiting factors. These drawbacks can be overcome by promoting penetration through the nails by employing penetration enhancers. The review focuses on patents that highlight permeation enhancers applied to nail drug delivery for the treatment of onychomycosis and psoriasis. Literature and patent searches were conduced regarding the topic of interest. The substantial literature and patent search revealed that permeation enhancers, especially chemicals, are great strategies for promoting the ungual delivery of drugs. Nail topical therapy containing permeation enhancers is an attractive option for delivering localized treatments.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":" ","pages":"203-218"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1872211313666191030155837","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40452521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and Characterization of Valacyclovir HCl Hybrid Solid Lipid Nanoparticles by Using Natural Oils.","authors":"Archana Chacko,&nbsp;Amaldoss M J Newton","doi":"10.2174/1872211313666190304142129","DOIUrl":"https://doi.org/10.2174/1872211313666190304142129","url":null,"abstract":"<p><strong>Background: </strong>The Jojoba Simmondsia Chinensis oil is used as one of the main ingredients which has an antioxidant, moisturizing and stabilizing activity. Likewise, grape seed (Vitis vinifera) oil is also used in this preparation which also has some remarkable medicinal properties such as antioxidant, astringent and is also used as a moisturizer. The Valacyclovir Solid Lipid Nanoparticles (SLN) are prepared in combination.</p><p><strong>Objective: </strong>The prime objective of the study was to prepare a nanodispersion with good stability indicating zeta potential. The formulations were prepared by varying concentrations of jojoba oil and grape seed oil which form the hybrid nanoparticles with the drug.</p><p><strong>Methods: </strong>The high-pressure hot-homogenization technique was used to prepare the nanoparticles. The prepared nanoparticles were subjected to characterization analysis such as Mean particle size, Zaverage, and Zeta potential by using Dynamic Light Scattering (DLS) and Photon Correlation Spectroscopy (PCS). The best formulation was subjected to Transmission Electron Microscopy (TEM) technique for surface morphology and other characterizations. The crystalline pattern of the drug alone, drug-loaded nanoparticles and nanoparticles without the drug was studied by XRD. The drug excipients compatibility studies were performed by using Fourier-Transform Infrared Spectroscopy (FTIR) Differential Scanning Calorimetry and (DSC). The other factors such as in vitro drug release, and % drug entrapment efficiency were studied by using suitable methods.</p><p><strong>Results: </strong>The results demonstrated that the particles are in nano range with good stability with appreciable Zeta potential (-48.2±mV). The selected formulations were analyzed for MPS which demonstrated the value of 306.7±183.4 and 416.5±289.3. The best formulation VNP5 demonstrated the Bellshaped curve and confirmed the uniform distribution.</p><p><strong>Conclusion: </strong>Based on the patents, it was demonstrated that valacyclovir is widely used in the treatment and prophylaxis of viral infections in human, particularly infections caused by the herpes group of viruses. Valacyclovir is an effective drug for the treatment of cold sores.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 1","pages":"46-61"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1872211313666190304142129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37187750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmaceutical Manipulations for Ocular Drug Delivery.","authors":"Ashok Kumar Tiwary","doi":"10.2174/187221131304200312163019","DOIUrl":"https://doi.org/10.2174/187221131304200312163019","url":null,"abstract":"<jats:sec>\u0000<jats:title />\u0000<jats:p />\u0000</jats:sec>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 4","pages":"244-245"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/187221131304200312163019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37927652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bio-Inspired Strategies against Diabetes and Associated Complications: A Review.","authors":"Shalki Choudhary,&nbsp;Vinni Kalra,&nbsp;Manoj Kumar,&nbsp;Ashok Kumar Tiwary,&nbsp;Jatin Sood,&nbsp;Om Silakari","doi":"10.2174/1872211314666191224120145","DOIUrl":"https://doi.org/10.2174/1872211314666191224120145","url":null,"abstract":"<p><p>Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 4","pages":"273-282"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37498599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanotherapies for the Treatment of Age-Related Macular Degeneration (AMD) Disease: Recent Advancements and Challenges.","authors":"Vamshi Krishna Rapalli,&nbsp;Srividya Gorantla,&nbsp;Tejashree Waghule,&nbsp;Arisha Mahmood,&nbsp;Prem Prakash Singh,&nbsp;Sunil Kumar Dubey,&nbsp;Ranendra Narayan Saha,&nbsp;Gautam Singhvi","doi":"10.2174/1872211314666200117095917","DOIUrl":"https://doi.org/10.2174/1872211314666200117095917","url":null,"abstract":"<p><p>Age-related Macular Degeneration (AMD) is one of the common diseases affecting the posterior part of the eye, of a large population above 45 years old. Anti-Vascular Endothelial Growth Factor- A (Anti-VEGF-A) agents have been considered and approved as therapeutic agents for the treatment of AMD. Due to the large molecular weight and poor permeability through various eye membranes, VEGF-A inhibitors are given through an intravitreal injection, even though the delivery of small therapeutic molecules by topical application to the posterior part of the eye exhibits challenges in the treatment. To overcome these limitations, nanocarrier based delivery systems have been utilized to a large extent for the delivery of therapeutics. Nanocarriers system offers prodigious benefits for the delivery of therapeutics to the posterior part of the eye in both invasive and non-invasive techniques. The nano size can improve the permeation of therapeutic agent across the biological membranes. They provide protection from enzymes present at the site, targeted delivery or binding with the disease site and extend the release of therapeutic agents with prolonged retention. This leads to improved therapeutic efficacy, patient compliance, and cost effectiveness of therapy with minimum dose associated side-effects. This review has summarized various nanocarriers explored for the treatment of AMD and challenges in translation.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 4","pages":"283-290"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37555206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of Optimization Technique to Develop Nano-Based Carrier of Nigella Sativa Essential Oil: Characterization and Assessment.","authors":"Aya M Dawaba, Hamdy M Dawaba","doi":"10.2174/1872211313666190516095309","DOIUrl":"10.2174/1872211313666190516095309","url":null,"abstract":"<p><strong>Background: </strong>Chitosan, a naturally occurring polymer, has interesting applications in the field of drug delivery due to its plentiful advantages as biodegradability, biocompatibility and nontoxic nature. Nigella sativa essential oil is unstable, volatile, and insoluble in water and these problems confine its usage in developing new medicines.</p><p><strong>Objective: </strong>This study focuses on developing a chitosan-based nanocarrier for the encapsulation of Nigella Sativa essential oil. By using Quality by design outline, the quality target product outline, critical quality attributes and critical material attributes were defined by knowledge and risk-based procedures.</p><p><strong>Methods: </strong>According to defined critical material attributes, Optimization software (Statgraphics XVII) was used to study the effect of the processing parameters. The processing parameters identified and fixed first with a \"One factor at a time\" approach. Various physicochemical characterization techniques were performed.</p><p><strong>Results: </strong>As a result, the ratio of chitosan to benzoic acid (2:1) along with the stirring rate (4000 rpm) produced minimum-sized particles (341 nm) with good stability. The anti-bacterial activity study using Staph. Aureus strain proved that the optimized nanoparticles were more efficacious than the pure oil based on the diameter of inhibition zone obtained (diameter =5.5 cm for optimized formula vs diameter = 3.6 cm for pure oil). Furthermore, MTT (methyl thiazolyl-diphenyl-tetrazolium bromide) assay was performed to compare the in vitro cytotoxicity using two different cell lines (i.e. HCT 116 for colorectal carcinoma and PC3 for prostatic cancer). It was found that in both cell lines, the optimized nanoparticles had noteworthy antiproliferative properties illustrated by determining the concentration at which 50% of growth is inhibited (IC50). The optimized nanoparticles showed lower IC50 (17.95 ±0.82 and 4.02 ±0.12μg/ml) than the bare oil IC50 (43.56 ±1.95 and 29.72 ±1.41μg/ml).</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 3","pages":"228-240"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/88/89/RPDDF-13-228.PMC7011686.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37249620","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Unprecedented Role of Gold Nanomaterial in Diabetes Management.","authors":"Simpal Kumari,&nbsp;Vipan Kumar Kamboj,&nbsp;Diksha Rajpoot,&nbsp;Anil Kumar Teotia,&nbsp;Prabhakar Kumar Verma,&nbsp;Gyanendra Nath Singh","doi":"10.2174/1871526518666181114165352","DOIUrl":"https://doi.org/10.2174/1871526518666181114165352","url":null,"abstract":"<p><p>Gold nanoparticles possess unique mechanical, chemical, photo-optical and biological properties and have been an interesting field of research on life sciences. The research studies produced new nanodevices and nanotechnology-based biosensing, diagnostics therapeutics, and targeted drug delivery systems. In this review, the unique potential aspects of gold nanoparticles/ nanoformulations/ or devices related to diabetes management have been discussed together with the recent patent on the gold nanoparticles developed for diabetes management. The first part of this review will focus on recent strategies for the treatment of hyperglycemia and its management with the help of gold nanoparticles and the second part of the review focused on recent patents on gold nanoparticles useful in the diabetes management. Gold nanoparticles have proved themselves useful in diabetes therapeutics and diagnostics. Due to the high surface area, and low toxicity, gold nanoparticles have become a unique aspect of the delivery approach. The main issues that need to be covered are the biopharmaceutics, biocompatibility, and potential clinical applications.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 3","pages":"219-227"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2174/1871526518666181114165352","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36678989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanosuspension Technology: Recent Patents on Drug Delivery and their Characterizations.","authors":"Surya Goel, Monika Sachdeva, Vijay Agarwal","doi":"10.2174/1872211313666190614151615","DOIUrl":"10.2174/1872211313666190614151615","url":null,"abstract":"<p><strong>Background: </strong>Nanosuspension has arisen as a remunerative, lucrative as well as a potent approach to improve the solubility and bioavailability of poorly aqueous soluble drug entities. Several challenges are still present in this approach which need more research. The prime aim of this review is to identify such challenges that can be rectified in the future.</p><p><strong>Methods: </strong>Through this review, we enlighten the recent patents and advancement in nanosuspension technology that utilize the different drug moieties, instruments and characterization parameters.</p><p><strong>Results: </strong>Nanosuspension has been found to possess great potential to rectify the several issues related to poor bioavailability, site-specific drug delivery, dosing frequency, etc. In the past decade, nanosuspension approach has been complementarily utilized to solve the developed grievances, arisen from poorly soluble drugs. But this field still needs more attention to new discoveries.</p><p><strong>Conclusion: </strong>Nanosuspension contributes a crucial role in administering the different drug entities through a variety of routes involving oral, transdermal, ocular, parenteral, pulmonary, etc. with solving the different issues. This review also confirms the significance of nanosuspension in safety, efficacy, and communal as well as the economic expense associated with healthcare.</p>","PeriodicalId":40024,"journal":{"name":"Recent Patents on Drug Delivery and Formulation","volume":"13 2","pages":"91-104"},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cd/71/RPDDF-13-91.PMC6806604.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37059585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}