Home > Macromolecular Prodrugs of Some Antibiotics onto Polyglucans: Fabrication, Characterization, Applications and Studies of Nano-Assemblies in Solution
Macromolecular Prodrugs of Some Antibiotics onto Polyglucans: Fabrication, Characterization, Applications and Studies of Nano-Assemblies in Solution
Present study reports the synthesis and characterization of hydroxypropylcellulose (HPC) based macromolecular prodrugs (MPDs) of a broad spectrum class of antibacterial agents; fluoroquinolones. Prodrugs of some fluoroquinolones, i.e., moxifloxacin, ofloxacin, levofloxacin and ciprofloxacin were fabricated as ester conjugates of HPC in various mole ratios using p-toluenesulfonyl chloride as carboxylic acid activating agent. All prodrugs were found organo- as well as water-soluble. Structural characterization of HPC-fluoroquinolone conjugates 1-17 was carried out by FTIR, 1H, 13 C and 2D NMR spectroscopic techniques. Covalently loaded drug content (DC) of the conjugates was determined by UV/Vis spectrophotometry as well as by HPLC/UV method. Degree of substitution (DS) of the conjugates was derived from the respective DC of each conjugate. DS of all conjugates was also determined by acid-base titration after saponification and found to be 0.27-0.38, 0.53- 0.71, 0.57-0.64 and 0.87-1.15 per AGU for moxifloxacin, ofloxacin, levofloxacin and ciprofloxacin, respectively. Nano-assembly behavior of HPC-fluoroquinolone conjugates at solvent interface (DMSO/H2O) was assessed by transmission electron microscopy (TEM). TEM images showed that HPC-fluoroquinolone conjugates behaved differently; HPC- moxifloxacin conjugate 3 self-assembled into nanowires of 30 nm diameter, while HPC- ofloxacin conjugate 7, HPC-levofloxacin conjugate 11 and HPC-ciprofloxacin conjugate 15 self-assembled onto nanoparticles having diameter range of 200-270, 50-250 and 150-250 nm, respectively. In vitro drug release studies revealed higher release from prodrugs in simulated intestinal fluid (SIF) as compared to simulated gastric fluid (SGF). Conjugates 3, 7, 11 and 15 showed release of 49, 39, 44 and 43%, respectively, in SIF after first 6 h. While these conjugates showed only 12-15% release in SGF in the same time period. Higher release in SIF confirmed that the synthesized prodrugs could be used as devices for achieving colon targeted drug delivery. Pharmacokinetic studies of the conjugates in rabbit models indicated enhanced bioavailability of the respective drugs. Following single oral dose, conjugates 3, 7, 11 and 15 showed half-life of 25.20, 18.07, 18.08 and 10.87 h, respectively. These enhanced half-life values suggest the potential of the fabricated MPDs for once daily dosage formulation. Thermal analyses of the synthesized prodrugs were carried out to assess their pharmaceutical performance parameters. Thermal stability of HPC, drugs and prodrugs was compared in terms of thermal degradation temperatures (Tdi, Tdm,Tdf). Comparable Tdm values of drugs and conjugates suggested that no thermal stress was developed after the attachment of bulky drug molecules to polymer backbone. Thermal stability of conjugates was also evaluated in terms of integral procedure decomposition temperature (IPDT) and index of thermal stability (ITS). Conjugate 3, 7, 11 and 15 showed IPDT values of 450, 442, 464 and 486 °C, respectively. The ITS values were found to be 0.51, 0.52, 0.46 and 0.51, respectively, for these conjugates. Significantly higher IPDT and ITS values also confirmed the intrinsic thermal stability of these conjugates. Modulated differential scanning calorimetry was also performed to analyze glass-transition temperatures (Tg) imparted due to attachment with polymer. Tg values observed were 111.60, 84.16, 113.85 and 61.91 °C for conjugates 3, 7, 11 and 15, respectively. PXRD studies confirmed that some crystallinity was imparted to MPDs of fluoroquinolones. Powder X-ray analysis also confirmed the amorphous characteristics of the conjugates. Therefore, such MPDs can be used for colon targeted delivery of fluoroquinolones with enhanced bioavailability and reduced dosage frequency.
ریاضؔ حسین چودھری( ۱۹۴۱ء۔۲۰۱۷)کا اصل نام محمد ریاض حسین ہے۔ آپ محلہ خراساں مسلم بازار سیالکوٹ میں پیدا ہوئے ۔گورنمنٹ مرے کالج سے بی۔ا ے کیا۔ایل ایل بی اور ایم۔ اے اردو پنجاب یونیورسٹی سے کیا۔ آپ چھٹی کے طالب علم تھے جب آپ نے شعر و شاعری کا آغاز کیا۔(۱)شاعری میں ابتدائی رہنمائی آسی ضیائی رامپوری سے لی۔ آپ نے آغا صادق کے سامنے بھی زانوئے تلمذ طے کیے۔ ۱۹۵۹ء میں آپ نے بچوں کے لیے ایک نظم لکھی جو ماہنامہ ’’پھلواری‘‘ میں شائع ہوئی۔ ابتدا میں آپ نے نظم اور غزل میں شاعری کی لیکن نعتیہ شاعری ان کی پہچان ہے۔ ان کی پہلی نعت، ہفت روزہ ’’قندیل‘‘ لاہور میں شائع ہوئی۔ سید آفتاب احمد نقوی کی ترغیب پر ریاض حسین چودھری کا رجحان نعت کی طرف بڑھا پھر ایک وقت ایسا آیا کہ آپ نے اپنے آپ کو صرف نعت کے لیے وقف کر دیا ۔ بہترین نعت گو شاعر ہونے کی وجہ سے ۲۰۰۰ء میں آپ کو صدارتی ایوارڈ سے بھی نوازا گیا۔(۲) ریاضؔ حسین چودھری کا پہلا شعری مجموعہ ’’خونِ رگِ جاں‘‘ ہے۔ جو ملی نظموں پر مشتمل ہے۔ جو ۱۹۷۰ء میں شائع ہوا۔ دوسرا شعری مجموعہ زرِ معتبر ‘‘ نعتوں پر مشتمل ہے۔ یہ پہلی بار ۱۹۹۵ء میں اور دوسری بار۲۰۰۰ء میں شائع ہوا۔ یہ مجموعہ دو سو اٹھاسی صفحات پر مشتمل ہے۔حفیظ تائب نے اس کتاب کی نعتیہ شاعری کا تنقیدی جائزہ لیا ہے۔ ریاض حسین چودھری نے ’’تحدیث نعمت‘‘ کے عنوان سے اس کتاب پر تعارفی مضمون لکھا ہے۔ اس مجموعے کا فلیپ احمد ندیم قاسمی نے لکھا ہے۔ جس میں زرِ معتبر کی نعتیہ شاعری پر تبصرہ کیا گیا ہے۔ تیسرا شعری مجموعہ ’’رزقِ ثنا‘‘ہے جو پہلی بار ۱۹۹۹ء میں شائع ہوا۔ اور دوسری بار ۲۰۰۰ء میں شائع...
Ijtihad is an invaluable secondary source of the Muslim jurisprudence. In Islamic law, ijtihad refers to the independent interpretation of problems not precisely covered by the sacred scripture of Islam, Qur’an, and Prophetic traditions. The savants who undertake ijtihad must be firmly rooted in knowledge and savvy what the demands of the contemporary era are. Since new challenges call for innovative solutions, the faithful cannot genuinely live by Islam without their jurists deriving the laws of sharia from its sources.
This doctoral research plan (2008 to 2010) included comprehensive studies on two commercial mango cultivars of Pakistan including Sindhri and Sufaid Chaunsa with overall objective of evaluating controlled atmosphere (CA) and modified atmosphere (MA) conditions for sea-freighting mangoes to distant markets. The targeted areas included: a) Benchmark studies to monitor and document sea freight supply chain from farm to market (Germany); b) Evaluating impact of controlled and modified atmosphere storage conditions; c) Comparing open top vs. closed top boxes for sea freighting mangoes; e) Testing new chemistry fungicides for postharvest disease management, especially Stem End Rot (SER) in mango cv. Sufaid Chaunsa during long term storage and f) effects of pre-cooling on mango cv. Sufaid Chaunsa. Moreover, effect of harvest maturity (mid and late season harvest) on fruit quality and shelf life of Sindhri and Sufaid Chaunsa was also evaluated. Benchmarking studies showed that mango export supply chain to Europe (Germany) using Maersk shipping line requires about 35 days (Farm to retailing). The results revealed that poor skin colour development, skin shriveling, firmness retention in cv. Sindhri while disease development, mainly SER, (caused by organism: Botryodiplodia theobromae and Phomopsis mangiferae) in both cultivars are main issues.. The static research trials were conducted side by side to address these issues and to optimize the sea shipment protocols. Controlled atmosphere storage had significant impact on physico-chemical fruit quality and improved market value and consumer acceptability of the two cvs. Exposure to ILOS (Initial low oxygen stress) for one week had no significant negative effect; however, a concentration of 10% CO2 was found to be too high and inhibited the fruit ripening completely. These studies indicated that 1-1.5% O2 and 4-5% CO2as better CA combination for cv. Sindhri and Sufaid Chaunsa mangoes, for 4 weeks shipping period, followed by 5-7 days for post arrival handling, ripening and retailing. Mid-season harvested fruit of both cultivars showed better response in terms of better fruit marketability, less disease development and retention of the firmness of stored fruit under CA and MA conditions. Modified atmosphere packaging (MAP) trials showed that X®-tend bagging can only suppress the disease development at ripening and can be used for sea shipping mangoes to short distance markets; however the fruit with skin bruises and damages must be avoided for bagging. The experiment on packing mangoes in different types of corrugated boxes concluded that open top boxes were better option for sea shipping of the two mango cvs. since fruit developed good colour in open top boxes. Moreover, cv. Sindhri showed better shipping potential with higher percentage of marketable fruit than cv. Sufaid Chaunsa, which is more prone to post harvest diseases during long term storage. Post-harvest disease study during long term storage in cv. Sufaid Chaunsa showed that the combined application of Thiabendazole @ 2000 ppm with Prochloraz @0.5ml/L (Tank mix; HWT-52°C; 5 min) had significant disease control (i.e. stem end rot, side rot and anthracnose). Concentrations of Thiabendazole alone (1000, 1500 and 2000 ppm) did not perform well in this regard. Postharvest application of new chemistry fungicides including Amistar (0.8 ml/L) (A.I. Azoxystrobin), Nativo (0.3 g/L) (A.I. Trifloxystrobin and Tebuconazole), Cabrio Top (3 g/L) (A.I. Pyraclostrobin and Metiram) and Scholar were also found to be effective against postharvest disease development in mango. Best control was achieved by Amistar against anthracnose and stem end rot. Moreover, immediate precooling after harvest and processing gave significantly improved disease control and less weight loss in cultivar Sufaid Chaunsa. Finally, during July 2012, an industry collaborated trial shipment of cv. Sindhri was made to a commercial importer in Netherlands in which learning outcomes of these studies were intergraded from harvest to maturity and to marketing. The shipment was overall success with positive comments from importer. Some incidence of pulp breakdown in mangoes at ripe stage was observed which needs future investigation.