Pharmaceutical Sciences

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Preparation and Characterization of Carvedilol-Loaded Poly (D, L) Lactide Nanoparticles/Microparticles as a Sustained Release System
(2015) Majd Suleiman Mahmoud Bani-Odeh; Dr. Mohyeddin Assali; Prof. Abdel Naser Zaid
Background: Polymeric nano and micro particles are promising delivery systems for the enhancement of the bioavailability of highly lipophilic drugs prone to ﬁrst pass metabolism. Purpose: This study aims at preparing carvedilol polymeric nanoparticles and microparticles with high loading efficiency. Other objective was to study carvedilol release profile from the obtained particles at room and body temperatures. Method: Carvedilol PDLLA nanoparticles and microparticles were prepared using nano-precipitation method. PVA was used as emulsifying agent. The effect of the solvents (acetone, tetrahydrofuran, acetonitrile, ethanol and dichloromethane) and the polymer amount on the size, size distribution and morphology of the formed particles were studied using atomic force microscope (AFM). Results: Spherical polymeric particles were obtained in all solvents used. The used method is easy, rapid, reproducible, effective (high loading capacity of carvedilol) and consequently can be used as new strategy for the development of carvedilol controlled release dosage forms. The in vitro release profile of carvedilol has shown a sustained release pattern with a little rapid release rate at body temperature in comparison to that at room temperature. Conclusion: The carvedilol loaded PDLLA nanoparticles have been successfully prepared with high loading efficacy and small particle size when acetone was used as the organic solvent and 12.5 mg of PDLLA polymer was used. Microparticles obtained when dichloromethane was used. The Korsmeyer Peppas with T lag model was the best one to explain the sustained release behavior.Chapter One
Analytical and Dissolution Method Development and Validation for a Home Formulated Rutin Tablet
(2015) Jumana Saleh Mohamed Mansour; Dr. Murad Abualhasan; Dr. Nidal Jaradat
Rutin can be classified as flavone, colorant and vitamin. It is highly available in some foods, fruits, vegetables and plant-based beverages. Rutin is highly attracted to the researchers due to its variant beneficial medical effects making rutin used in the treatment of various ailments. Rutin is available in different oral dosage forms such as tablets or capsules either alone or in combination with other active ingredients. Rutin pharmaceutical preparations are widely available in international market as well as Palestinian market. In this study we formulated a 250mg rutin tablet and we developed an easy and simple validated analytical method to quantify rutin in our formulated tablet as well as the internationally marketed Rutin® tablet of Solgar. The method was validated in accordance to international guidelines of the ICH and USP. The dissolution profile of our formulated tablet was also inspected. The shelf and the accelerated stability of the locally formulate tablet was studied. The results clearly show that our developed method was a valid method with a good linearity, precision and accuracy. The validated method was sensitive with LOD and LOQ value of 4.34*10-3 and 0.013mg/ml respectively. The locally formulated rutin tablet was stable under accelerate as well as room temperature for 150 days, only with slight and tolerable drop in the %assay with no detrimental effect on the physical properties of the tablets. The dissolution profile of our locally formulated tablet show slightly better dissolution in phosphate buffer compared with the internationally marketed Rutin® tablet of Solgar. Our study encourages and helps companies that manufacture herbal products especially those present in Palestine to improve their formulated herbals and apply validation analytical methods to check their product quality. In conclusion we succeeded in developing a validated analytical method to quantify rutin in our locally formulated rutin tablet as well as the available rutin formulations present in the local and international markets. Our formulated tablet showed a slight improvement in the dissolution profile and was stable in normal as well as under stress condition
Biological and phytochemical screening of Erodium laciniatum and Lactuca orientalis
(An-Najah National University, 2017-01-12) Othman, Dua'a; Jaradat, Nidal
From ancient times, various herbal remedies and various medical agents containing flavonoids, tannins and phenols have been utilized for prevention and treatment of different diseases and disorders. Currently, such groups of bioactive compounds have become the subject of many antimicrobials researches, with possessed antiviral, antifungal and antibacterial activities. Moreover, many of high quality studies assessed the relationship between flavonoid's, tannin's and phenol's chemical structures and their antibacterial activities, and also studied their mechanisms of action on the microbial growth. These investigations approved that such classes of natural compounds can possess many therapeutic properties, including oestrogenic, antiinflammatory, enzyme inhibition and antimicrobial activities. In this study we aimed to screen Erodium laciniatum and Lactuca orientalis phytoconstituents and to evaluate their total flavonoids, tannins and phenols contents. An additional aim is to evaluate their antioxidant and antimicrobial activities. Phyto-constituents, total flavonoids, phenols and tannins were screened and evaluated by using standard analytical and phytochemical methods. Antioxidant activity was evaluated by using DPPH method meanwhile antibacterial activities were examined by using several reference bacterial strains obtained from the American Type Culture Collection (ATCC) and multidrug resistant clinical isolates. The tested strains included Staphylococcus aureus (ATCC 25923), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus (MRSA Positive), Enterococcus faecium (ATCC 700221), Shigella sonnei (ATCC 25931), Enterobacter cloacae (clinical) and Klebsiella pneumoniae (clinical). In addition to that anti-fungal activities of these extracts were also examined against two reference strains Candida albicans (ATCC 90028) and Epidermatophyton floccosum (ATCC 52066). Antibacterial and antifungal activity of all prepared Erodium laciniatum and Lactuca orientalis organic and aqueous extracts were determined by using several methods including agar diffusion well-variant method, agar diffusion disc-variant method and broth micro-dilution method. The results of the phytochemical screening showed that L. orientalis and E. laciniatum contain phenols, tannins, flavonoids, saponins, monosaccharides, reducing sugars, carbohydrates, cardiac glycosides, and steroids, while alkaloids were not detected in both of the studied species. However, proteins, starch and terpenoids were not detected in L. orientalis and detected in E. laciniatum which means that E. laciniatum had more phyto-constituents than L. orientalis. Moreover, total flavonoid, tannins and phenols content in E. laciniatum extract were higher than the L. orientalis extracts. The IC50 values of the antioxidant activity were almost the same in L. orientalis and E. laciniatum extracts. Additionally the lowest value of MIC was for organic extract of E. laciniatum against Staphylococcus aureus. The same organic extract also showed to have the largest diameter of inhibition against Enterococcus faecium. However, L. orientalis aqueous extract showed to have the largest diameter of inhibition against Staphylococcus aureus. Whereas, the antifungal activity which was tested by using agar dilution method against Epidermatophyton floccosum showed that the organic extract of E. laciniatum had the lowest MIC which was 0.391mg/ml. In conclusion, both of the studied species have a mixture of phytochemicals and rich in flavonoids, phenols and tannins and have potential antioxidant and antimicrobial activities which can be used as therapeutic agents or can be used in cosmeceutical and pharmaceutical industries.
Synthesis, characterization & biological activity of Isopropyl Thiazole derivatives of the natural products Distamycin & Proximicin
(An-Najah National University, 2017-05-04) عبد الرحمن, امجد عبد الرحمن موسى; النيص, حسن
Minor groove binders (MGBs) are molecules which bind selectively to the minor groove of DNA. Distamycin and netropsin are naturally occurring MGBs, and are members of the polypyrrole class of compounds. They have potential antiviral, antibacterial, and anticancer properties. However, they also have toxic properties. These biological effects arise from the molecule binding to DNA in regions where there are short runs of A: T base pairs. Much work has been carried out in developing analogues of distamycin and netropsin which have improved their biological activities and reduced their toxicity profile. This project was concerned with developing a novel synthetic pathway of MGBs which allows for more varied substituents at the tail and head position of these molecules and replacing the N-methyl pyrrole with more lipophilic aromatic rings which, to date, has not been fully investigated. Aromatic rings such as benzene, pyridine, morpholine and indole were added to the structure of these compounds, in order to enhance the lipophilicity and membrane permeability to generate biologically active compounds. The tail group is significant as it plays a key role in both DNA binding, and transportation of these compounds to within cells. These structural variations will allow libraries of compounds with small molecular weight to be prepared. In this project, we developed simple and novel routes for the synthesis of potential minor groove binders. The outcome of such a study would be of great importance regarding the development of new analogues of distamycin and netropsin as potential antibacterial and anticancer agents. The synthetic pathway of the compounds started from the preparation of the isopropyl thiazole ring using the Darzen reaction and coupling the epoxide intermediate with thiourea. The second step was reacting the amine terminal of the isopropyl thiazole ring with various acid chlorides to give the second intermediate compounds in the synthetic pathway. After that the intermediate compounds where ether refluxed with an amine directly, or, where hydrolyzed and converted to acyl chlorides to be then reacted with various amines to give the final products. NMR spectroscopy was used to confirm the chemical structures of the investigated compounds, which were tested against different bacterial strains, and showed variable activities among the different compounds with the compound MGB 10 being the most active of the synthesized compounds.
Bio-Functionalization of SWCNTs with Combretastatin A4 for Targeted Cancer Therapy
(An-Najah National University, 2017-05-25) حمد, ديمه فهيم محمد رشدي; العسالي, محي الدين
Chemotherapy is a mainstay approach in the management of cancer. Unfortunately, it can affect not only the cancerous cells but also the healthy ones resulting in a number of severe side effects. Therefore, many researchers are keen to developing new Drug Delivery Systems (DDS) that may in one hand help reducing the used doses and on the other hand target the delivery of the chemotherapy to cancer cells. Some modern investigational DDS in this field are based on carbon nanotubes (CNTs) technology. The aim of this work is to covalently functionalize single walled carbon nanotubes (SWCNTs) with Combretastatin A4 (CA4) through click reaction in the presence of tetraethylene glycol linker to improve the solubility and dispersibility of the developed nano-drug. Moreover, in order to specifically target the cancer cells, a targeting agent folic acid was also loaded on the nano-system. The characterization of the developed nano-drug by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) showed good dispersibility of the functionalized SWCNTs with diameters of (5-15) nm. Moreover, the efficiency of functionalization was determined by thermogravometric analysis (TGA) showing 45% of functionalization in the case of CA4-SWCNTs (7) and 50% for CA4-FA-SWCNTs (13). The in vitro release profile of CA4 showed that approximately 90% of the loaded drug was released over 50 hrs at pH 7.4 and 37 ºC. MTS proliferation test was implemented to determine the suitable concentration for the CA4-SWCNTs (7), which was found to be 15 ng/ml. After that the cytotoxic activity of the nano-drug was evaluated by flow cytometry using Annexin V/Propidium iodide (PI) test. In comparison with free CA4, CA4-SWCNTs (7) treatment demonstrated a significant increase in necrotic cells (around 50%) at the expense of the proportion of the apoptotic cells. Moreover, cell cycle PI test demonstrated that free CA4 and CA4-SWCNTs (7) caused G2/M arrest. However with CA4 treatment higher proportion of cells were in the S-phase while with CA4-SWCNTs treatment greater proportion of cells appeared to be in the G1-phase. Taken together, the provided data suggest that the novel CA4-SWCNTs (7) has a significant anticancer activity that might be superior to that of free CA4. The anticancer activity of CA4-FA-SWCNTs (13) is under investigation.
Evaluation of Food Effect on the Absorption of Clarithromycin using Physiological Modeling
(جامعة النجاح الوطنية, 2017-08-08) جيوسي, رند خليل عبداللطيف; رضوان, أسماء
Background: Food may affect the oral absorption of drugs by inducing physiological changes in the gastrointestinal physiology, such as: gastrointestinal pH, gastric residence time, bile salt secretion and drug metabolism. Purpose: The aim of the present study was to investigate the influence of food on the oral absorption of Clarithromycin by evaluating the effect of media parameters such as; pH, bile secretions and food composition, on the release of the drug from immediate release tablet, using in vitro and in silico assessments Method: The solubility, disintegration and dissolution profiles of Clarithromycin 500 mg immediate release tablets in compendial media with/without the addition of homogenized FDA meal as well as in biorelevant simulated intestinal media mimicking fasting and fed conditions were determined. These in vitro data were input to GastroPlusTM to make computational simulation in order to anticipate the effect of food on Clarithromycin absorption profiles under fasted and fed states. In vivo plasma concentration curves were used for compartmental modeling of pharmacokinetic data. Level A in vitro – in vivo linear correlations were established using mechanistic absorption modeling based deconvolution approach. Gastroplus™ was used for developing a physiological absorption model for Clarithromycin, which is capable of predicting the in vivo performance Results: Media pH has a profound effect on drug solubility, tablet disintegration and drug release. Clarithromycin has lower solubility in the biologically biorelevant media compared to other media, due to complex formation with bile salts. Clarithromycin tablets exhibited prolonged disintegration times and reduced dissolution rates in the presence of the standard FDA meal. The simulation model predicted no significant food effect on the oral bioavailability of Clarithromycin. The developed IVIVC model considered SIF, acetate, and FaSSIF buffer media to be the most relevant from the physiological standpoint. Conclusion: the intake of standard FDA meal with Clarithromycin may have no significant effect on oral bioavailability of Clarithromycin from immediate release tablets. This may suggest that the dissolution conditions recommended by ICH are sufficient to demonstrate interchangeability between generic and brand Clarithromycin, a class II drug, especially during the developmental phase of the generic product.
Functionalization of graphene sheets and their antibacterial activity
(An-Najah National University, 2017-08-08) Alsouqi, Deema Ghaleb; Assali, Mohyeddin
Graphene is a thin flat monolayer of carbon atoms tightly packed into a two-dimensional (2D) honeycomb lattice. It is one of the most studied materials nowadays because it has a high surface area and unique properties. However, graphene is considered a hydrophobic material (has a low solubility and dispersability in physiological solution), which leads to aggregation and precipitation in cell tissue and causing toxicity for different types of cells. For this purpose, functionalization of graphene has its purpose to improve its dispersability in water and its biocompatibility for various biomedical applications. The aim of this work is to covalently functionalize the graphene sheets with various charged groups (positive, negative and neutral) to improve its water dispersability, study its antibacterial activity and to determine the effect of charge on the activity. The graphene sheets had successfully functionalized covalently with three different groups (COOH, amine and tetraethylene glycol). The functionalization was confirmed by infrared spectroscopy and transmission electron microscope images. The functionalization demonstrates good dispersability in water and the degree of functionalization was quantified using the thermogravimetric analysis obtaining 32% of the functionalization in the case of graphene-TEG, 33% of graphene-amine and 47% of graphene-COOH. The antibacterial activity was determined primarily by agar diffusion disk- and well-variant method. Agar diffusion well-variant demonstrated the presence of the antibacterial activity for all graphene derivatives. In additional step, the antibacterial activity was detected and quantified through determining the MIC of the graphene derivatives by broth microdilution method. MIC was 250µg/ml for graphene-amine and graphene-TEG and 125µg/ml in the case of graphene-COOH. Moreover, the reduction of bacterial concentration after exposure to graphene derivatives was detected by the plate count method, the result shows that the bacterial reduction was increased in functionalized graphene nanomaterials with the complete growth inhibition in the case of graphene-COOH on both bacteria (E. coli and S. aureus). Graphene toxicity mechanism was investigated by in vitro graphene-mediated oxidation of glutathione, the loss of glutathione activity was the maximum for graphene-COOH with a reduction of 83%. Finally, graphene-COOH and graphene-TEG showed good hemo-compatibility, which supports their further in vivo studies.
Synthesis, Formulation and Analytical Method Validation of Rutin Prodrugs
(An-Najah National University, 2017-11-01) سرحان, تالا محمد أحمد; أبو الحسن, مراد
Background: Rutin is a plant extract that belongs to the flavonoid group of compounds. Many studies showed that Rutin has a potential pharmacological uses such as antioxidant, anti-inflammatory and antihypertensive activities. Rutin is widely used as medicinal product and food supplement and marketed in different pharmaceutical dosage formulations. However, rutin suffered from low systemic bioavailability due to its low absorption from the gastrointestinal tract and its low water solubility. In this study, we aimed to improve the water solubility and consequently its dissolution profile by synthesizing a more soluble derivative of rutin. Method: Decaacetylated ester of rutin was first synthesized. Then selective partial deacetylation was performed to produce the hexaacetylated ester of rutin. Water solubility of the new derivative as well as its dissolution was compared to rutin. An evaluation of the antioxidant activity of the hexaacetylated derivative was tested using 2,2-diphenyl-1-picrylhydrazyl reduction method. Moreover, A Ultraviolet/Visible spectrophotometric method was developed and validated for the analysis of a tablet formulation of the newly synthesized derivative. An ultraviolet spectrophotometric quantitative analytical method for rutin derivative as active particle ingredient and in a tablet dosage form was developed and validated according to the International Conference on Harmonization and international guidelines. Results: The hexaacetylated ester derivative of rutin was successfully synthesized and the derivative structure was confirmed by nuclear magnetic resonance. Moreover, the water solubility and the dissolution profile were improved by approximately two fold increase compared to that of the original rutin. Water solubility of the partially acetylated product has been increased from 0.07 to 0.15 mg/mL and its dissolution increased from 22% to 37.5% compared to the original rutin. Moreover, the antioxidant activity results showed that the newly synthesized derivative preserved the antioxidant activity of the original rutin. An easy and feasible analytical method was developed and validated. The developed method was found to be linear, precise, accurate and selective with a lowest limit of detection and lowest limit of quantification of 0.00854 and 0.0259 mg/mL respectively. The formulated tablets of hexaacetylated rutin in our research laboratory were found to be stable under accelerated conditions as well as long term conditions for three months. Conclusion: An improvement on the solubility of rutin was achieved by selective acetylation of some of the OH groups of rutin. The tablet formulation of the partially acetylated ester derivative of rutin gives a better dissolution over the already marketed rutin tablets.
Chemical composition and pharmacological screening of Micromeria fruticosa serpyllifolia volatile oils collected from West Bank-Palestine
(An-Najah National University, 2018-02-26) سلامه, نهاية محمد يوسف; شريم, نصر
Background and Objectives Micromeria fruticosa subspecies serpyllifolia (M. Bieb.) is one of the Medicinal Aromatic Plants (MAP) which are dominated in the eastern Mediterranean regions including Palestine, has pleasant minty fragrance, in hot summer provide sensation of coolness. The objective of the current work was to screen and compare the chemical constituents and potential pharmacological properties of Micromeria fruticosa serpyllifolia volatile oils collected from three different regions in the West Bank -Palestine. Methods The volatile oils of three samples of Micromeria fruticosa serpyllifolia were extracted using Microwave - ultrasonic apparatus method. The volatile oils samples were analyzed for chemical constituents using GC-MS. The antioxidant activity of the volatile oils of the three samples were screened by the inhibition of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. The antilipase activity was evaluated using porcine pancreatic lipase (PL) and p-nitrophenyl butyrate (PNPB). The anti amylase activity was assessed using porcine pancreatic α- amylase, starch and 3,5-dinitrosalicylic (DNSA). The antimicrobial activity was examined using broth microdiltution method separate for antibacterial and then for antifungal and agar dilution method for fungal assessment. Nine bacterial strains were used four Gram-positive: Staphylococcus aureus, Staphylococcal enterotoxin B (SEB), Enterococcus faecium, "methicillin"-resistant Staphylococcus aureus (MRSA), and five Gram-negative strains; Proteus mirabilis, Pseudomonas aeruginosa, Escherichia coli, Shigella sonnie, Klebsilla pneumoniae and one fungus Epidermophyton floccosum and one yeast Candida albicans. Results Plant extracts yield range was (0.67 to 0.99%) (w/w%). GC-MS analysis showed the high percentages of oxygenetated components with the range of (86.1-89.88%), non oxygenated components in the range of (4.38-4.71%), the total identified compounds range was (90.48-94.44%). Seven components were observed, pulegone was the most abundant components in the three samples in the range of (74.43-86.04%), isomenthone was the second abundant components with the range of (3.16-14.41%).The sample from Ramallah (middle region) showed the potent antioxidant agent with IC50 0.45 µg/mL, the sample from Hebron (southern region) was the potent antilipase agent with IC50 85.00 µg/mL. The sample from Nablus (northern region) was the potent antiamylase agent with IC50 3.00 µg/mL. The three samples exhibited broad antimicrobial activity; the three samples showed potent antifungal activity at minimum inhibitory concentration (MIC) with the range of (0.206 to 0.781 mg/mL). The sample from Hebron (southern region) showed the highest potency against Shigella sonnie with lowest reported MIC value (1.56 mg/mL), the sample of Nablus (northern region) demonstrated the least potency against Staphylococcal enterotoxin B (SEB) and 'methicillin" resistance Staphylococcus Aureus (MRSA) with highest MIC value (6.250 mg/mL). However, the three samples showed broadspectrum antibactreial activity with MIC value (3.125 mg/mL). Conclusion The study showed that Micromeria fruticosa serpyllifolia volatile oils samples from different regions in Palestine contained different proportions of phytochemicals which provided different potential biological activities such as: antioxidant, antiobesity, antidiabetes and antimicrobial activities that were in line with traditional uses of the plant extracts. The plant extracts showed higher antioxidant, antilipase and antiamylase potency higher than that of the relative references and there were significant differences in these activities compared to each other. Further in vivo studies are required to evaluate the potential pharmacological activities, safety and toxicity of plant extract. Also further studies are needed to isolate, identify and characterize the main components responsible for potential pharmacological activities..
Dual functionalization of single-walled carbon nanotubes for targeted cancer therapy
(An-Najah National University, 2018-05-07) نعيم كتانة, محي الدين العسالي
Chemotherapy is a mainstay strategy in the management of cancer. Regrettably, they suffer from serious side effects due to their effect on healthy cells besides cancerous cells. Therefore, many researchers are eager to develop new drug delivery systems that may help to decrease the side effects and the effective dose of the drug in addition to target delivery of the chemotherapy to cancer cells. One of the epochal drug delivery systems in this field are based on carbon nanotubes technology. The aim of this work is the covalent functionalization of single walled carbon nanotubes with Doxorubicin in the presence of tetraethylene glycol linker to improve the solubility and dispersibility of the developed nano-drug. Moreover, in order to target the cancer cells, a targeting agent mannose was also loaded on the nano-system. The characterization of the developed nano-drug by transmission electron microscopy showed good dispersibility of the functionalized single walled carbon nanotubes with diameters (6-10) nm. Moreover, the percentage of functionalization was determined by thermogravometric analysis showing 25% of functionalization in the case of Dox-SWCNTs (7) and 51% for Dox-mannose-SWCNTs (11). The in vitro release profile of Dox from Dox-SWCNTs (7) showed 45% of the loaded drug was released over 18 hr at pH 7.4 and almost complete release at pH 5.5 at 37 ºC. However, the in vitro release profile of Dox from Dox-mannose-SWCNTs (11) showed 75% of the loaded drug was released over 5hr at pH 5.5 at 37 ºC. The cytotoxity effect of the compounds was studied at different concentrations and different pH conditions and compared with Dox alone. The maximum cytotoxity effect was observed at 4μg/ml and at pH 6.5. After that, the pre-incubation with any of the tested concentrations of mannose reduced the cytotoxicity of Dox-mannose-SWCNT by approximately 40-57%, suggesting that the entry of this complex might be dependent on mannose receptors, which imparts this complex a kind of selectivity for cancer cells that overexpress this type of receptors.
Extemporaneous Compounding and Physiological Modeling of Amlodipine/Valsartan Suspension
(An-Najah National University, 2018-05-13) عابد, وفاء جاسم محمود; رضوان, أسماء
Background: In case of absent liquid dosage form, crushing a tablet or dispersing a capsule would be the most convenient option for using these drugs in patients with dysphagia difficulties. However, no bioequivalence or stability studies are conducted for these extemporaneous preparations, which leads to confusion regarding its efficacy and safety. In silico and in vitro tools have proven to be useful in predicting the in vivo performance of drugs depending on its physicochemical properties and it’s in vitro dissolution profiles. No liquid formulation of combination Amlodipine and Valsartan is available in the pharmaceutical market for use in pediatric population with hypertension. Purpose: The aim of the present study was to prepare an extemporaneous suspension of Amlodipine and Valsartan from available commercial tablets, and to evaluate the stability and dissolution properties of the compounded suspension. Method: Amlodipine/Valsartan extemporaneous suspension was prepared from available commercial tablets Valzadepine®. The dissolution profiles for the extemporaneous preparation and the commercial tablet was determined in different pH media. The physical, chemical and microbial stability of the compounded formulation was evaluated over one month period at room temperature. Moreover, In silico modeling using GastroPlus TM software was used to build absorption models for both drugs based on the in vitro dissolution data. The simulated plasma profile for both active ingredients were compared with the in vivo plasma profile to examine the similarity of the extemporaneous suspension and the commercial tablets. Results: The Amlodipine/Valsartan extemporaneous suspension was successfully prepared with acceptable organoleptic properties. The suspension was stable for four weeks period preserving its physical and chemical features. The release profiles of valsartan and Amlodepine from the suspension were similar to that from source tablet Valzadepine®. In silico modeling predicted similarity of the extemporaneous suspension and the commercial tablets. Conclusion: Amlodipine/Valsartan extemporaneous suspension could be prepared from available commercial tablets. Moreover, GastroPlusTM can be applied along with the in vitro dissolution in order to affirm similarity in extemporaneous compounding situations.
Palestinian pharmacists’ knowledge, attitudes, and practice on influenza: expanding the scope of practice through vaccination
(جامعة النجاح الوطنية, 2018-05-22) فوزي احمد, سحر
الانفلونزا هو مرض فيروسي شديد العدوى ويسبب الكثير من الوفيات وخاصة كبار السن والأطفال والحوامل والمرضى المصابين بالأمراض المزمنة حيث تقدر عدد الوفيات حسب احصائيات منظمة الصحة العالمية حوالي 250000-500000 سنويا، وزاد الاهتمام بالإنفلونزا بشكل كبير في السنوات الأخيرة بسبب الازدياد الكبير في عدد الوفيات وظهور الأوبئة لا سيما فيروس الانفلونزا أ. يتم الوقاية من الانفلونزا باستخدام لقاحات الانفلونزا، هذه اللقاحات يمكن ان تتواجد بشكل عام في الصيدليات. ان صيادلة المجتمع ما زالوا هم أكثر مقدمي خدمات الرعاية الصحية وذلك لسهولة وصول المرضى وثقتهم الكبيرة في الصيادلة. هذه الدراسة عبارة عن دراسة وصفية تم تطبيقها على صيادلة المجتمع في الصيدليات العامة في مناطق مختلفة من الضفة الغربية في فلسطين حيث تم مشاركة 370 صيدلي في الدراسة اغلبهم من الصيادلة الخريجين حديثا، في فلسطين يوجد حوالي 1100 صيدلية حيث توظف اغلبها صيدلي واحد ع الأقل من الخريجين حديثا والذي بلغ عدد المشاركين منهم في الدراسة حوالي 285 صيدلي. وتم استخدام استبيان مكون من 12 سؤال يمكن للمشاركين في الدراسة اكمال الاستبيان خلال 15 دقيقة. تم تحليل البيانات بواسطة البرنامج الاحصائي spss. ارتبطت نسبة معرفة الصيادلة بلقاحات الانفلونزا مع العمر (p value = 0.066) , الجنس (p value = 0.064),عدد سنوات الخبرة (p value = 0.000),عدد اللقاحات التي صرفت خلال العام الماضي (p value = 0.000),تدريب /دورات بإعطاء لقاحات الانفلونزا خلال دراسة علم الصيدلة p value = 0.018/0.041)) ,المواقف الإيجابية تجاه السماح للصيادلة بإعطاء اللقاح داخل مبنى صيدلياتهم (p value = 0.001). عندما تم سؤال الصيادلة عن فترة حضانة المرض لفيروس الانفلونزا 38% من الصيادلة اجابوا إجابة صحيحة. وعند السؤال عن الفترة التي تحدث فيها العدوى 40% الذين اجابوا إجابة صحيحة .9.5% فقط من الصيادلة من عرفوا انه لا يوجد شكل صيدلاني للقاح الانفلونزا يمكن ان يسبب الانفلونزا. و13% فقط من عرفوا انه يجب إعطاء المضاد الفيروسي خلال 48 ساعة من ظهور الاعراض. أظهرت نتائج الدراسة وجود العديد من الفجوات المعرفية لدى الصيادلة والتي يجب سدها بالتدخلات التعليمية بشكل مناسب وتبين الدراسة الدعوات الى ادخال تحسينات وتوسيع دور الصيادلة في المجتمع من خلال إعطاء لقاح الانفلونزا.
Synthesis and Characterization of a Polymeric Nanoparticles of a Potent Anticancer Agent (Combretastatin)
(An-Najah National University, 2018-07-24) حسان, منى
Background: Pharmaceutical nanotechnology is an emerging technology that proved its effectiveness in decreasing the side effects and improving the therapeutic outcomes of chemotherapeutic drugs. Combretastatin (CA4) is natural and potent antitubuline chemotherapeutic agent but it showed cardiotoxicity. Purpose: The aim of this research was to formulate and characterizeCA4 polymeric nanoparticles (NPs), to assess its release kinetic, and to evaluate the in vitro cytotoxic activity of the obtained NPs. Method: CA4 was synthesized using Perkin reaction. Nano-precipitation and emulsion evaporation methods were used to produce the desired NPs. The obtained NPs were characterized for shape, particle size, zeta-potential, encapsulation efficiency% (EE%), drug loading% (DL%), and drug release. Cytotoxicity and IC50 of the free CA4and the loaded NPs were determined using two cancer cell lines Caco-2 and HeLa. Results: Emulsion evaporation method was capable to produce spherical shaped CA4 loaded NPs with EE% 50.84%, DL% 1.13%, mean average particle size 203.25 nm, and zeta-potential -38.50mV.The NPs showed sustained release pattern. Korsmeyer-Peppas was adopted to describe the release mechanism of CA4 from our NPs, with n value higher than 1, which indicates a Super case II transport. In vitro cytotoxicity on Caco-2 and HeLa cells demonstrated better cytotoxic and IC50 of CA4 loaded NPs than the free CA4. Conclusion:CA4 loaded polymeric NPs were successfully produced and showed satisfactory characteristics such as EE%, particle size and shape, zeta potential, and sustained release pattern. In addition, an improvement in the cytotoxic and IC50 of CA4 loaded NPs was demonstrated. This suggests that these NPs could be used to improve the safety, effectiveness, and patient compliance. However, in vivo studies should be conducted to prove these interesting findings.
Formulation and Stability Evaluation of Ciprofloxacin Topical Preparation
(An-Najah National University, 2018-08-16) احمد عيد, محي الدين العسالي
With increment the number of infections resistance to antibiotics and life threatening causes many researchers work on developing alternative approaches and manufacturing new drug delivery systems to traverse the disadvantages of the conventional antibiotics. The aim of this study was to encapsulate the ciprofloxacin HCl in three different surfactants such as anionic surfactant (Sodium Lauryl Sulfate), cationic surfactant (Cetrimide) and nonionic surfactant (Tween 20). The encapsulation may in one hand help improving penetration behavior of the ciprofloxacin and on the other hand reduce the used doses. The other vital role of this research was the formulation of three stable encapsulated topical dosage forms (ciprofloxacin HCl gels) in order to treat topical infections. The encapsulation of ciprofloxacin HCl lead to successful conspicuous increasing in ciprofloxacin loading with potentially more soluble pattern. Fortunately, the in vitro release results revealed that about almost 90% of the loaded ciprofloxacin HCl was released at pH 5.5 in the first 2 hours. The prepared three gels differentiated as stable, clear and homogeneous formulation with good rheology characteristics. Moreover, improvement in the results of the antibacterial activity manifest that the newly encapsulated ciprofloxacin had better antibacterial activity against S. aureus and P. aeruginosa than ciprofloxacin alone.
Pharmaceutical Dosage Form Preparation of a Synthesized Celecoxib Salt and Development of a Validated Method for its Analysis
(An-Najah National University, 2018-08-16) أبو شهاب, كفاح رسمي محفوظ; نضال زعتر, مراد أبو الحسن
Background: Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) and cyclooxygenase-2 (COX-2) inhibitor. It is used in the treatment of rheumatoid arthritis, osteoarthritis, juvenile arthritis, and acute pain. Celecoxib suffer of low systemic bioavailability due to its low water solubility. This study aimed to improve water solubility and dissolution profile by synthesizing a suitable celecoxib salt. Method: A library of celecoxib salts was synthesized, and it is water solubility was determined using UV/Visible spectrophotometric. One of the synthesized salts was chosen for tablet formulation. A simple and feasible reverse phase high performance liquid chromatography (HPLC) method was developed for the analysis of the tablet formulation. The developed method was then validated according to international guidelines. The dissolution profile, the shelf life and accelerated stability studies were performed on the formulated tablet. Results: Celecoxib-K salt showed an increase in water solubility by more than 140 folds (0.464mg/ml) compare to celecoxib. This salt was chosen to be formulated in tablet dosage form. The in vitro dissolution profile of the formulated celecoxib-K salt tablet was totally dissolved and reached plateau after 10 minutes. The developed analytical HPLC method was reliable and valid method with good linearity, accuracy and precision. Also the validated method was sensitive, the LOD and LOQ value of 0.001mg/L and 0.1mg/L respectively. The formulated celecoxib-K salt tablet was stable under room temperature and accelerated condition for 60 days. Conclusion: The solubility of celecoxib was improved by converting it to potassium salt form. The formulated tablet of celecoxib-K salt showeda good dissolution profile in water. The developed HPLC method was valid and reliable for analysis and quantification of the formulated tablet.The formulated tablet was stable at both room temperature and stress conditions.
“Multi-functionalization of single walled carbon nanotubes for antibacterial activity”
(جامعة النجاح الوطنية, 2018-10-30) عصام أبوالرب, خلود
تعتبر الأمراض المعدية أكبر مشكلة يعاني منها الناس في جميع أنحاء العالم. وأدى الاستخدام الواسع للمضادات الحيوية إلى زيادة المقاومة لهذه الأدوية. ولذلك، طور العديد من الباحثين أنظمة جديدة لتوصيل الدواء قد تدعم تقليل الآثار الجانبية والجرعة الفعالة للدواء. وتعتمد أحد أنظمة إيصال الدواء في هذا المجال على تكنولوجيا أنابيب الكربون النانوية. بالاضافة الى ذلك، استخدمت المركبات الكاتيونية كمرشحات واعدة لتقليل تطور المقاومة. الهدف من هذا البحث هو تطوير نظام نانوني جديد مضاد للبكتيريا يعتمد على التفعيل المتعدد لأنانيب الكربون النانونية أحادية الجدران من خلال ربط دواء السيبروفلوكسيسين ومركب متعدد الأمينات مع انابيب الكربون النانوية أحادية الجدار من خلال رابطة تساهمية وبالإضافة الى ربط دواء الكلاريثروميسن من خلال رابطة غير تساهمية على سطح انابيب الكربون النانوية أحادية الجدار. وقد تم تحديد التحميل الأميني من خلال تطبيق اختبار كايزر. وأظهر تحليل الدواء النانوني بواسطة المجهر الالكتروني النافذ فصل وتوزع جيد للأنابيب النانونية التي تشير إلى النجاح الوظيفي. بالإضافة الى ذلك، تم تحديد كفاءة التفعيل لأنابيب الكربون النانونية بواسطة جهاز التحليل الحراري الذي أظهر بنسبة 62 % لأنابيب الكربونية في حالة f-SWCNTs (16). النشاط البكتيري تم تحديده من خلال استخدام تقنية التخفيف المتسلسل عن طريق تحديد تركيز الحد الأدنى للتثبيط البكتيري لأربعة سلالات من البكتيريا. و قد أظهرت النتائج أن التفعيل المتعدد لأنانبيب الكربونية أحادية الجدار له أكبر تحسن في النشاط البكتيري بحوالي 64 ضعف بالنسبة لثلاثة أنواع بكتيريا(Staphylococcus aureus, Methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa) و بحوالي 16 ضعف ل faecalis Enterococcus بالمقارنة مع السيبروفلوكسيسين وذلك بسبب اضافة رابط متعدد الأمينات في حالة f-SWCNTs (16). بالاضافة الى ذلك أظهر التفعيل الثنائي والمتعدد للأنابيب الكربونية في كل من f-SWCNTs (15) و f-SWCNTs (16) على قدرة عالية من التوافق مع خلايا الدم على مدى واسع من التركيز.
Identification and prioritization of barriers to implement quality by design (QbD) by the local pharmaceutical industry in Palestine: a consensual analytic hierarchy process approach
(جامعة النجاح الوطنية, 2019-01-24) نشأت عبد الفتاح منصور, عبد الفتاح
الخلفية: على الرغم من الفوائد المحتملة لتطبيق مفهوم جودة التصميم (QbD) التي تم توضيحها من قبل خبراء الجودة والهيئات التنظيمية ، إلا أن هذه الفوائد ليست سهلة التنفيذ عمليًا. حيث وجدت العديد من المنشآت الصناعية الصيدلانية صعوبة في تنفيذ هذا المفهوم بنجاح. الأهداف: تبحث هذه الدراسة وتصنف العوائق التي تحول دون نجاح تنفيذ مفهوم جودة التصميم (QbD) في صناعة الأدوية المحلية في فلسطين. الغرض من هذه الدراسة هو فهم حواجز تطبيق مفهوم جودة التصميم (QbD) وتحديد أولوياتها النسبية من خلال تصنيفها في صناعة المستحضرات الصيدلانية. الطرق: استخدم جولة استفتاء الرأي لتقنية دلفي لتحديد العوائق التي تحول دون تطبيق مفهوم جودة التصميم (QbD) من قبل الصناعة الدوائية الفلسطينية المحلية. بالإضافة إلى ذلك ، تم إجراء جولتين من دلفي لتحقيق إجماع حول العوائق المحتملة ، وأجريت جولات دلفي المتتالية لتحديد الأولويات وتصنيفها باستخدام نهج عملية تحليل هرمي توافقي (Analytic hierarchy process approach ). الجودة والقيمة: إن قوة هذه الدراسة هي تطوير نموذج شامل للتحقيق وتحديد الأولويات من العوائق التي تواجهها صناعة الأدوية في فلسطين عند تنفيذ برنامج جودة التصميم (QbD). الموافقة الأخلاقية: الموافقة الأخلاقية التي تم الحصول عليها من مجلس المراجعة المؤسسية (IRB) من جامعة النجاح الوطنية. حيث يقدم المشاركون موافقة مستنيرة لفظية قبل المشاركة في هذه الدراسة. النتيجة: من ال 34 عائق المحتملة التي عرضت على المشاركين في الدراسة في الجولة الأولى من استفتاء الرأي (Delphi) تم التوصل إلى توافق في الآراء بشأن 15 من هذه العوائق أي بنسبة (44.1٪) حيث تمثل هذه الحواجز عوائق في تنفيذ مفهوم جودة التصميم (QbD) في الصناعة الدوائية المحلية في فلسطين من وجهة نظر المشاركين في الدراسة وكانت النتائج في جولة استفتاء الرأي الثانية (Delphi) حيث تم الاتفاق على 14 من العوائق أي بنسبة (41.2٪) تمثل عوائق تعيق في تنفيذ مفهوم جودة التصميم (QbD) في التطوير العام من قبل الصناعة الدوائية المحلية في فلسطين. وتم استبعاد 5 عوائق حيث تم الإجماع على أنها لا تعيق تطبيق مفهوم جودة التصميم (QbD) في الصناعة الدوائية المحلية في فلسطين من وجهة نظر المشاركين في الدراسة. صنفت العوائق التي تم الإجماع عليها في الجولتين إلي 15 عائق يتعلق بالموارد والأدوات والموظفين و5 عوائق متعلقة بالعملية التنظيمية و 9 عوائق تتعلق باتخاذ القرارات في صناعة المستحضرات الصيدلانية المحلية. ثم تم تصنيف هذه العوائق من الأكثر إلي الأقل باستخدام نهج تحليلي توافقي هرمي (Analytic hierarchy process approach). في هذه الدراسة ، كان حوالي 62٪ من المشاركين من الذكور ، ونحو 64٪ 40 سنة وأكثر ، وحوالي10٪ لديهم درجة الدكتوراه ، وحوالي 59٪ حصلوا على درجة جامعية قبل عام 2000 ، حوالي 85٪ يعملون حاليا في الصناعة الدوائية و حوالي 69٪ من المشاركين يحتلون مناصب مختلفة في مصانع الادويه كمراقبة الجودة وضمان الجودة و ممارسة التصنيع الجيد ( (GMP والبحث والتطوير ((R&D ، حوالي 80٪ لديهم خبرة عملية لمدة تزيد عن 10 سنوات ، وبنسبة 69٪ حصلوا على تدريب على مفهوم QbD خلال حياتهم العملية. 97٪ بأغلبية المشاركين صوتوا على أهمية تطبيق مفهوم QbD في الصناعة الدوائية المحلية في فلسطين ومع ذلك عندما سئل المشاركين في الدراسة إلى أي مدى اعتقدوا أن تنفيذ QbD من قبل الشركات المصنعة للأدوية الفلسطينية يمثل أولوية حاليًا، اعتقد 51٪ من المشاركين أن أولوية تطبيقه ذو أهمية كبيره . الخلاصة: يمكن استخدام التقنيات التوافقية أو الإجماع في تحديد وإعطاء الأولوية للعوائق التي تحول دون تطبيق مفهوم جودة التصميم من قبل الصناعة الدوائية المحلية. هناك حاجة إلى مزيد من الدراسات لدراسة سبل القضاء على هذه العوائق وتعزيز تنفيذ مفهوم جودة التصميم في تصنيع المنتجات الصيدلانية في فلسطين.
Pharmacological and Phytochemical Screening of Ephedra Alata Fruit Extracts
(جامعة النجاح الوطنية, 2019-05-22) Dacca, Hanaa
Background: During the latest year’s variety of scientific studies focusing all the time on developing new medications to fight diseases that are continuously increasing; in order to maintain the human genus and other living organisms. Discovering and screening for potential anti-obesity, anti-diabetic and antioxidant treatments from natural products still in the recent time the main goal for many of the pharmaceutical scientists. Methods: Different extract fractions have been prepared by using four solvents with several polarities for extraction of Ephedra alata fruits, then determination of natural active ingredients was followed. Finally, assessment protocols for antioxidant, anti-obesity, anti-diabetes and anti-cancer were applied to evaluate the pharmacological effects of these fruits’ extracts. Results: A high content of flavonoids and phenols were observed in the methanol fraction, which reached to 98.95 ± 2.3 mg of RU/g and 33.22 ± 1.56 mg of GAE/g, respectively. As a result, the methanol fraction had significant in vitro effects, such as potent antioxidant activity, with an IC50 value of 3.09 ± 0.25 µg/mL compared to Trolox (reference compound) that had an IC50 value of 3.16 ± 0.74 µg/mL. Also, methanol fraction showed moderate activity against lipase enzyme with an IC50 value of 61.65 ± 0.50 µg/mL compared with the IC50 of orlistat (reference compound), 12.3 ± 0.35 µg/mL. In addition, the methanol fraction seemed to be the most effective one against α-amylase with an IC50 of 16.22 ± 0.6 µg/mL compared to acarbose (reference compound) which had an IC50 value of 28.2 ± 1.29 µg/mL. Finally, in the α-glucosidase inhibition assay, the methanol fraction again seemed to be the most potent fraction with an IC50 of 32.36 ± 0.63 µg/mL, which was more effective than acarbose its self with an IC50 value equal to 37.15 ± 0.33 µg/mL. In addition, the methanol extract derived from Ephedra alata fruits induced significant cytotoxicity (0.0001 ≤ p < 0.05) by approximately 94%. Conclusion: Ephedra alata fruits methanol extract fraction was rich in reducing sugars, flavonoids, phenols, alkaloids. The DPPH assay and digestive enzymes assay showed that this fraction has potent antioxidant, anti-diabetic, and anti-lipase activities, which can be an excellent candidate for biological and chemical analysis and can be further subjected for isolation of the therapeutically active compounds with anticancer potency.
Multifunctional SWCNTs-based co delivery of silencing gene and Doxorubicin for synergistic anticancer activity
(ِAn-Najah National University, 2019-07-10) Ghazal, Noura
العلاج الكيميائي هو استراتيجية أساسية في علاج السرطان. لكنها تؤثر على الخلايا السليمة مثل الخلايا السرطانية مما يؤدي إلى عدد من الآثار الجانبية الشديدة. لذلك، يتوق العديد من الباحثين إلى تطوير أنظمة جديدة لتوصيل الأدوية قد تساعد في تقليل الجرعات المستخدمة وتقليل الآثار الجانبية. لذلك تم تطبيق العديد من الجهود لتطوير أنظمة توصيل الأدوية القائمة على أنابيب الكربون النانوية. الهدف من هذا البحث هو تطوير نظام نانوني جديد مضاد للسرطان يعتمد على التفعيل المتعدد لأنانيب الكربون النانونية أحادية الجدران من خلال ربط مركب متعدد الأمينات وعامل استهداف وهو سكر المنوز مع انابيب الكربون النانوية أحادية الجدار من خلال رابطة تساهمية و بالاضافة الى ربط دواء الدوكسوروبيسن من خلال رابطة غير تساهمية على سطح انابيب الكربون النانوية أحادية الجدار. وأظهر تحليل الدواء النانوني بواسطة المجهر الالكتروني النافذ فصل وتوزع جيد للأنابيب النانونية التي تشير إلى النجاح الوظيفي . بالاضافة الى ذلك، تم تحديد كفاءة التفعيل لانابيب الكربون النانونية بواسطة جهاز التحليل الحراري الذي أظهر 77.5% نسبة التحميل الكامل لأنابيب الكربونية النانونية. وشحنة السطح المفعل كانت +28 ملفولت لمركب 13 و+47 ملفولت لمركب 14 كما تم تأكيده بجهاز تحليل جهد زيتا. أما فيما يخص دراسة تأثير السمية والنشاط المضاد للسرطان، تمت الدراسة للمركبات المذكورة أعلاه، بتراكيز وظروف مختلفة. ولوحظ انه يسبب تسممًا خلويًا أكبر عند درجات الحموضه الذي تم اختباره عليها، مع وجود أعلى سمية عند تركيز 4 ميكروغرام / مل عند درجة الحموضة 6.5 لمركب 14. أما بالنسبة لدراسة الانتقائية لمستقبل المنوز، فقد قلت نسبة السمية بحوالي 96-98% بعد الاحتضان المسبق للمنوز بتراكيز مختلفة، مما يشير أن دخول هذا المركب يعتمد على نسبة مستقبلات المنوز الفعالة، مما يضفي نوعا من الانتقائية للخلايا السرطانية مقارنه بالخلايا الطبيعية. في حاله خلايا (caco2)، توضح ان عملية تثبيط جين β-catenin لها اثر ايجابي في اضعاف الخلايا السرطانية بالاعتماد على β-actin كقيمه مرجعيه، بحيث تظهر النتائج انه تم تثبيطه بنسبه 20% مقارنه مع β-actin. اخيرا، أظهر الجل ارتباطا ناجحا بين المركب 14 والجين المثبط عند جميع نسب (N/P) التي تم العمل عليها.
“Selective Cyclooxygenase 2 inhibitors: synthesis and biological evaluation”
(An-Najah National University, 2019-12-12) Sawaftah, Hadeel
Derivatives of diaryl pyrazoles and triazoles were synthesized to produce series of selective COX-2 inhibitors. In order to synthesize the series of these derivatives, Vilsmeier-Haack reaction and click reaction were followed in the synthesis of pyrzoles and triazoles based derivatives respectively. All produced compounds were In vitro evaluated by inhibition studies on COX-1 and COX-2 isozymes. Eleven compounds were successfully synthesized. Five compounds were the most potent and selective on COX-2 isozyme with IC50 values in 0.551–0.002 μM range. In diarylpyrazole derivatives best inhibition was showed by compound 4b with IC50 = 0.017 µM as the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, Compound 4d showed the best selectivity onCOX-2 (IC50 = 0.098 µM, SI = 54.847) as the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone. In the diaryltriazole based derivatives, compound 15a was the most potent among the entire synthesized library including the reference compound (Celecoxib) with IC50 = 0.002 µM and SI = 162.5 as the presence of spacer could facilitate binding with extra hydrophobic pocket of COX-2 enzyme. Compounds with a variety of substitutions on pyrazole and triazole cores and different linker lengths are recommended to be synthesized in further studies to evaluate their COX-2 inhibitory activity and selectivity. Moreover, an in vivo anti-inflammatory and cardiotoxicity studies will be managed to support the obtained in vitro results.

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