Pharmaceutical Sciences

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Design of Novel Gabapentin Prodrugs by Computational Methods
(AL-Quds University, 2021-01-05) هنادي عبد الكريم حسني سنقرط; Hanadi A H Sunoqrot; رفيق قرمان; صالح جبور; حاتم حجاز
التركيب الكيميائي والخصائص والقوى المحركة المخبرية لدوائيْن أوليّيْن جديديْن مبتكريْن من مضادات البكتيريا؛ الأموكسيلين والسيفالكسين
(AL-Quds University, 2014-02-22) غدير عبد مطر دقماق; GHADEER ABED MATAR DOKMAK; رفيق قرمان; د. أحمد عمرو; Nasr Shraim
Marketed antibacterial drugs suffer several problems, such as bitter taste and low stability which lead to patient incompliance. Prodrug technology for solving such problems is extremely exciting. Based on previously reported density functional theory calculations, amoxicillin ProD 1-2 and cephalexin ProD 1-2 were designed and synthesized. For the intraconversion of both antibacterial prodrugs the kobs and t1/2 values in different media were calculated from the linear regression equation obtained from the correlation of log concentration of the residual prodrug versus time. At constant temperature and pH the hydrolysis reaction for the above mentioned prodrugs displayed strict first order kinetics as the kobs was quite constant and a straight line was obtained. Kinetic studies in 1N HCl, pH 2.5 and pH 5 were selected to examine the intraconversion of both prodrugs to their parent drugs. The acid-catalyzed hydrolysis of the prodrugs was found to be much higher in 1N HCl than in pH 2.5 and pH 5. The experimental t1/2 values of amoxicillin ProD 1 in 1N HCl, pH 2.5 and pH 5 were 2.5, 7 and 81 hours respectively and for cephalexin ProD 1 in 1 N HCl and pH 2.5 were 2 and 14 hours respectively. In contrast, t1/2 values of amoxicillin ProD 2 in 1N HCl and pH 2.5 were 8 and 44 hours respectively and for cephalexin ProD 2 in 1 N HCl was 6 hours. On the other hand, at pH 7.4, the four prodrugs were quite stable and no release of the parent drugs was observed. At pH 5 the hydrolysis of the prodrugs was too slow. The four antibacterial prodrugs were found to be bitterless. The bitter taste masking by the prodrugs is believed to be via altering the ability of the drug to interact with bitter taste receptors.
السلوك القيادي للمديرين وعلاقته بالنمو المهني للمعلمين من وجهة نظر معلمي المدارس الحكومية في محافظة الخليل
(AL-Quds University, 2013-06-26) هناء سعيد سليم شاهين; hana said saleem shaheen; محمد شعيبات; د. محمد عابدين; د. أحمد فتيحة
This study aimed at identifying the degree of principals’ leadership behavior and its relationship to teachers' professional development at governmental schools from the point of view of teachers at Hebron governorate during the academic year 2012-2013. The population of the study consisted of all teachers in Hebron (7962); a stratified random sample of 5% was chosen (399). However, statistical analysis was applied on 381 teachers. To achieve the objectives of the study, a questionnaire consisted of (33) items was developed to measure the principals’ leadership behavior distributed on three domains namely: administrative, technical and humanitarian. Another questionnaire consisted of (29) items was developed to measure professional development of teachers distributed on three domains: methods of teaching, evaluation and scientific materials. Validity and reliability of the study were verified by appropriate statistical methods. The results revealed that the estimates of teachers about the degree of the principals’ leadership behavior is medium at a mean of (3.56) and of a standard deviation (0.511). The administrative domain was the highest while the humanitarian was the lowest, and there were no significant statistical differences due to the variables of gender and experience while there were significant statistical differences due to the variable of qualification in the domains of administrative and technical in favor of teachers holding a degree of less than BA and directorate in favor of the north Hebron. Also it revealed that the estimates of teachers about the degree of professional development for teachers in government schools, came with a high degree a mean of 3.87 and a standard deviation of 0.80, and there were no significant statistical differences due to the variable of gender and qualification and experience, while there were differences due to the variable of directorate in the domain of scientific material in favor of the north Hebron. There was a weak positive correlation-i.e., Berson correlation coefficient (0.20) -between the variables of principals’ leadership behavior and the degree of their professional development. the researcher recommend that setting up criteria for choosing principals based on their leadership characteristics, and the necessity of continuing the process of development forteacher, especially in the field of teacher Evaluation by doing training courses for teachers and the school principal together.
الفعالية المضادة للكائنات الدقيقه لدوائيْن أوليّيْن جديديْن مبتكريْن من مضادات البكتيريا؛ الأموكسيلين والسيفالكسين
(AL-Quds University, 2015-06-02) ساميه صلاح الدين عبد الغني كرد; samia salahaldeen abdalgani kord; رفيق قرمان; احمد عمرو; حاتم سلامة
The two novel prodrugs of amoxicillin and cephalexin were synthesized to improve the stability and bitter taste of their parent drugs. The in vitro susceptibility for both prodrugs was determined against Escherichia coli, staphylococcus epidermidis, staphylococcus aureus, Klebsiella pneumonia, streptococcus group A, streptococcus group B, and compared to that of their parents. The results revealed that both novel prodrugs have antibacterial activity on most bacterial strains with about the same potency as their parent drugs, In addition, Klebsiella pneumonia, and staphylococcus epidermidis showed resistance to both amoxicillin drug and its prodrug. Since klebsiella is gram negative bacteria and staphylococcus epidermidise is beta lactamase positive . It is worth noting that those two novel prodrugs are among a small number of prodrugs that have activity themselves before undergoing conversion via enzymatic or chemical processes to their corresponding parent drugs. The novel prodrugs exhibit their antibacterial activity against different types of bacterial strains due to the presence of beta lactam ring in their structures. In addition, it is expected that the novel two prodrugs will be much more stable in aqueous media than their corresponding parent drugs due to the fact that the sensitive amine group exists in the parent drugs was replaced with a more stable group, amide.
القوة العاملة الفلسطينية في الصيدلية :الممارسة والرضا الوظيفي والاتجاهات نحو دورهم كمختصين في الرعاية الصحية
(AL-Quds University, 2018-05-05) جوناء غسان عبد العزيز سرحان; Jawna Ghassan Abdul Aziz Sirhan; ماهر خضور; Hussein Hallak; Samah Jabi
المعرفة والمواقف والممارسات للنساء الفلسطينيات تجاه وسائل منع الحمل
(AL-Quds University, 2019-05-04) نعيمه مازن حمدي رجبي; naeema mazen hamdi rajabi; أحمد عمرو; rafik Karaman; saed Zyoud
تأثيرمركبات لتيولين، ميدستيورين (PKC-412) و PD173074 على مراحل حياة فيروس Cytomegalovirus (HCMV) المختلفة.
(AL-Quds University, 2016-04-25) عامر عزت محمد دوفش; Amer Izzat Mohammad Doufish; ميساء العزة; د. عماد معتوق; الدكتور رائد الكوني
The cytoplasmic assembly compartment (AC) in HCMV-infected human foreskin fibroblasts (HFF) is a unique juxtanuclear ―bulb‖-like structure. Morphology of the AC is dependent on the activity of the viral-encoded serine/threonine kinase, pUL97. The ―bulb‖-like structure morphology is also altered when wt-HCMV infected cells are treated with kinase inhibitors NGIC-I, a kinase C inhibitor, or Staurosporine, a wide range serine/threonine kinase inhibitor. Infection with a UL97 deletion mutant simulated the inhibition with NGIC-I or Staurosporine of wt-HCMV infection, resulting in a less compact and a vacuole-rich AC. In all three cases viral titers were reduced 2-3 logs. Cellular kinases play central roles in regulation of cell replication and differentiation, making cellular kinase inhibitors attractive antiviral targets. Different protein kinases were identified to affect different stages of HCMV life cycle and infectivity, which prompted us to explore yet not recognized kinase inhibitors for their activity against HCMV infection. In this study, we employed protein kinase inhibitors Luteolin, Midostaurin (PKC-412) and PD173074, and investigated their influence on the assembly compartment, early stages of HCMV infection and viral load. Luteolin at 20 μM did indeed reduce viral load without any detectable effects on the assembly complex. Midostaurin, PKC-412, did not affect viral load or the assembly compartment. The most striking result was observed with the tyrosine kinase inhibitor, PD173074, at 5 μM concentration. Although PD173074 did not affect early stages of HCMV infection, it reduced viral load and induced a specific structure of the assembly compartment we referred to as ―vesicles’-rich AC pattern. Hereby, the AC remained its ―bulb‖-like structure, but was remarkably accompanied withvesicles spread throughout the cytoplasm, which arose at 48 h p.i. and were remarkable by 72 h p.i. and 96 h p.i.. These vesicles stained for markers of the assembly complex; viral tegument proteins pp28 and pp65 as well as WGA Golgi marker and accumulated densely along the cytoplasmic membrane of the infected cells. Taken together, our data provide the first evidence for a role of tyrosine kinase in HCMV assembly.
تحليل المركبات الثانوية لأوراق المريمية البرية/ المروية بواسطة GC-MS ودراسة تأثيراتها المضادة للأكسدة والميكروبات
(AL-Quds University, 2015-01-01) ريم نمر محمد سبوبه; Reem Nimer Mohammad Sabbobeh; صالح ابو لافي; خالد صولحة; عبد الناصر زايد
تصميم أدوية مساعدة مبتكرة من الفينيلفرين والباراسيتامول بالطرق الحسابية
(AL-Quds University, 2016-01-05) دنيا ابراهيم خالد قرمان; donia ibrahim khalid karaman; رفيق كرمان; Omer Deeb; Nasr Shraim
تصميم أدوية مساعدة مبتكرة من حمض امينو كابروك بالطرق الحسابية
(AL-Quds University, 2017-08-26) نداء مازن سالم لقيانية; neda mazen salem leqeanea; رفيق قرمان; Dr. Hatem Hejaz; : Dr. Naser Shraim
Background and objectives: Unraveling the mechanisms of a number of enzyme models has allowed for the design of efficient chemical devices having the potential to be utilized as prodrug linkers that can be covalently attached to commonly used drugs which can chemically, and not enzymatically, be converted to release the active drug in a programmable manner. For instance, exploring the mechanism for a proton transfer in Kirby‘s N-alkylmaleamic acids (enzyme model) has led to the design of a number of prodrugs such as tranexamic acid, acyclovir, atenolol. Method: Based on density functional theory (DFT) calculations for the acid-catalyzed hydrolysis of several N-alkylmaleamic acid derivatives five 6-aminocapproic acid prodrugs were designed, aiming to provide a drug with potentially to have higher bioavailability than its parent drug. Result and discussion: DFT calculations at B3LYP/6-31G(d,p) for intramolecular proton transfer in 1-7 and prodrugs of 6-aminocapproic acid, ProD1-ProD5, demonstrated that the reaction rate is dependent on the strain energy difference between the intermediate and the reactant (Es INT-GM). This suggests that the reaction is governed by strain effect. Additionally, no correlation was found between the proton transfer efficiency and the distance between the two reactive centers (rGM) and the attack angle (α). Conclusion: Hence, the rate by which the prodrug releases the 6-aminocapproic acid drug can be determined according to the structural features of the promoiety (Kirby’s enzyme model)
تصميم أدوية مساعدة مبتكرة من لأموكسيسلن بالطرق الحسابية
(AL-Quds University, 2017-07-26) وعد محمد صالح حوراني; waad mohammad saleh huorani; رفيق قرمان; Dr.Hatem Hejaz; Dr.naser shraim
تصميم طلائع أدوية مبتكرة من الدوبامين - النهج الحسابي
(AL-Quds University, 2017-12-04) إسراء تيسير محمد قطوش; رفيق قرمان; Dr. Hatem Hejaz; Dr. Naser Shraim
تصميم طلائع أدوية مبتكرة من الدوبامين - النهج الحسابي
(AL-Quds University, 2018-08-18) إسراء تيسير محمد قطوش; Essra tayseer mohammad qattoush; رفيق قرمان; Dr. Hatem Hejaz; Dr. Naser Shraim
Parkinson patients have insufficient dopamine in specific regions of the brain, so attempts have been made to replenish the deficiency in the dopamine. Dopamine itself doesn't cross blood brain barrier, but its precursor, levodopa (LD) is actively transported into the CNS and is converted to dopamine in the brain. The bioavailability of LD is less than 10% with only 1% of administered oral levodopa penetrates the brain. Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. To minimize the conversion to dopamine (DA) outside the central nervous system (CNS), LD is usually co-administered with peripheral inhibitors of amino acid decarboxylase (carbidopa or benserazide). In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain. In this project, a number of dopamine prodrugs were designed using DFT molecular orbital at B3LYP 6-31G (d, p) levels and molecular mechanics (MM2) calculations aiming to provide prodrugs that are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, the proposed prodrugs are believed to be more effective than L-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood–brain barrier. The DFT calculation results revealed that the rate of a proton transfer in processes dopamine ProD 1-ProD 5 is largely dependent on the geometric variations of thereactant (GM) mainly the distance between the two reactive centers, rGM, and the angle of attack α. It was found that systems with low rGM and high α values in their global minimum structures, such as ProD 1 and ProD 2, exhibit much higher rates (lower ∆G‡ ) than these with high rGM and low α values, such as ProD 3-ProD 5 and the rate of the reaction is linearly correlated with rGM and (1/α). Moreover, it was found that the intraconversion rate of the designed dopamine prodrugs is largely determined on the strain energies of the reaction ̓s tetrahedral intermediates(EsINT). Systems having strained tetrahedral intermediates were found to be with low rates and vice versa.
تصميم و تحضير مشتقات البيريميدين ثلاثية التفرع كمثبطات لبروتين مرافق المنشط لمستقبلات الاستروجين
(AL-Quds University, 2016-01-09) ميران محمد جمال طلال مسودى; Miran M.Jamal Talal Masswadeh; يوسف نجاجرة; Zaidoun Salah; Tawfeq Kaimari
Breast cancer (BC) is one of the most commonly diagnosed cancers in women. Estrogen signaling and the estrogen receptors (ERα, ERβ) are implicated in breast cancer progression. Majority of breast cancers start out as estrogen dependent as a result of overexpression of ER-regulated genes: Estrogen deprivation therapy using anti-estrogens (AEs) and aromatase inhibitors (AIs) to block ER activity and arrest the estrogen-dependent growth of BC still represents the primary treatment for breast cancer patients. This approach, however, frequently fails and patients develop resistant breast cancer, which is almost untreatable. In this project we focused on synthesizing a potent coactivator binding inhibitors (CBIs) molecules that block ER activity through a different mechanism that may arrest the estrogen-dependent growth of BC and offer a solution to the existing resistance. Coactivator binding inhibitors (CBIs) act by blocking the conformational change needed for DNA binding and gene expression. In this project set of compounds have been designed, synthesized through sequential substitution of the chlorine atoms of 2,4,6-trichloropyrimidine with amines or other nucleophiles. The synthesized compounds were purified using chromatography techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR and MS (ESI)) spectroscopy. Some of these compounds were screened for their inhibitory activity against the acute myeloid leukemia cells (Molm-13) cells. Two forms of Molm-13 had been used to evaluate the role of p53. In one case cells were transfected with empty vector and in the other the cells were tranfected with sh-p53 RNA(sh-p53). The viability of cells was determined using WST-1 assay. Initial results of the tested compounds demonstrated that MY12 (35) and MY3 (26) exhibited potent activities against the two forms of Molm-13 cell lines and have a dose dependent effect while the compound MY2 (25) showed no significant inhibitory action on the same cell lines.
تصميم, تحضير وفحص النشاط السمي لمشتقات البيرازين ثنائية التفرع
(AL-Quds University, 2017-12-06) آلاء محمود ربيع فرعون; Ala Mahmoud Rabie Faroun; يوسف نجاجرة; imad odeh; Michel Hanania
Pyrazine derivatives possess numerous pharmacological effects including but not limited to antiviral, antibiotic, antifungal, diuretic, anticonvulsant, antidiabetic, analgesic and anti proliferative effect. Consequently, interest has been shown by researchers in the field of pyrazine-based drug synthesis and many of the synthesized derivatives succeeded to reach the clinical field. A promising research discipline was concerned in utilizing the antiproliferative and cytotoxic activity of pyrazine derivatives -that is attributed to various mechanisms one of which is protein kinase inhibition- in designing new anti-cancer agents. In this study a set of disubstituted pyrazine derivatives has been designed and synthesized through a sequential nucleophilic substitution of chlorine atoms of 2,3-dichloropyrazine with amines or other nucleophiles. The synthesized derivatives were purified using several chromatographic techniques, and characterized by (1H-NMR, 13C-NMR, FT-IR, and MS (ESI)) spectroscopy. The mono-substituted pyrazine derivative A-7 (7) and three of its disubstituted analogues (YAN1(18), YAN-2 (19), and YAN-3(20)) were in vitro screened for their biological activity against two forms of acute myeloid leukemia cells (Molm-13). The viability of the cells was determined using WST-1 assay. Initial results of the tested derivatives showed that A-7 (7) was more potent than its analogues with IC50 of 18 and 39 µM against Molm-13 (sh-p53) and Molm-13 (empty vector) respectivelyThe biological activity of mono and disubstituted pyrazine derivatives was predicted using PASS software. Initial results demonstrated that A13 (13), A14 (14), YAN-7 (24), and YAN-8 (25) exhibited predicted activities as antineoplastic agents and signal transduction pathway inhibitors with relatively high Pa values. The previously mentioned compounds shared also the same mechanism of action “protein kinase inhibitor” with Pa values larger than 0.8SAR derived from PASS and initial biological activity screening results proved that the activity of the synthesized derivative is highly affected by the site and type of the substituent on the pyrazine ring. 2,3-disubstituted derivatives showed better Pa values when compared to the corresponding 2,5-disubstituted ones. In addition, amine substituents at positions 2 and 3 of pyrazine ring were preferred over alkoxide substituents in terms of antineoplastic activity. It was noticed that 1-(5-trifluoromethylpyridin-2-yl)-piperazine and 2-aminopyridine pharmacophores were the most active amine substituents. In order to gain an insight into the binding mode of pyrazine derivatives with CDK-2, a series of sixteen derivatives were docked with inactive monomeric cyclin dependent kinase-2 using SwissDock software. Results were compared with ‘Aloisine B‟, a well-known CDK-2 inhibitor. In terms of binding mode, pyrazine derivatives occupied the CDK-2 ATP binding site and made hydrogen bonds to the kinase backbone within the hinge sequence that links the two lobes of the kinase. The docked derivatives exhibited different binding affinities to the target, YAN-8 (25) showed the highest full fitness value (-1422.14 kcal/mol) among the synthesized derivatives. Moreover, both the full fitness and energy values indicated that YAN-8 (25) has higher affinity to the target in comparison to the known inhibitor Aloisine B (-1406.92 kcal/mol). Finally, the concept of drug likeness of the synthesized derivatives was investigated using the rule of five. Results revealed that all of the tested derivatives successfully met the rule of 5requirements except YAN-9 (26) and YAN-10 (27) which possessed molecular weights larger than 500 Daltons..
تصنيع ودراسة المواصفات ل الأدوية المساعده المصممة ل حمض ترانزاميك و براسيتامول
(AL-Quds University, 2014-02-22) هبه نعيم خميس غريب; hiba naeem khamees ghareeb; رفيق قرمان; د. صالح أبو لافي; د. وليد صويلح
Prodrug is a chemical devise in which the drug is covalently linked to a chemical moiety; this linked moiety will temporarily affect the physicochemical properties of the drug for increasing their usefulness or decreasing their toxicity. The prodrug should be converted to its active form by metabolic or/and chemical processes, conversion process involves metabolism by enzymes distributed throughout the body. These enzymes might either decrease the drug’s bioavailability, or a genetic polymorphisms might lead to variability in prodrug activation and thus affect the efficacy and safety of designed prodrug. In the past few decades computational chemistry methods have been utilized in calculating physicochemical and molecular properties of compounds. This tool can be used to design prodrugs that chemically (intramolecular processes) interconvert to their parent drugs without any involvement of enzyme catalysis. The release of the active drug is solely dependent on the rate limiting step of the intramolecular process. Based on DFT calculations four different tranexamic acid prodrugs and three different bitter less paracetamol prodrugs were designed, synthesized and characterized using FT-IR, 1H-NMR LCMS and their in vitro intra-conversion to their parent drugs revealed that the t1/2 was largely affected by the pH of the medium. For tranexamic acid ProD 1 the experimental t1/2 values in 1N HCl, buffer pH 2 and buffer pH 5 were 54 minutes, 23.9 hours and 270 hours, respectively. Tranexamic acid ProD 2 was readily converted in 1 N HCl and pH 2 while it was entirely stable at pH 5 and pH 7.4. On the other hand, tranexamic acid ProD 3 and Prod 4 were stable in all media studied. The experimental t1/2 values for paracetamol ProD 2 in pH 3 and pH 7.4 were 3 hours and 18 minutes respectively and for paracetamol ProD 3 it was 27 hours in pH 3 and 12 hours in pH 7.4. In vitro binding for paracetamol ProD 2 to bitter taste receptors revealed that this prodrug lacks any binding affinity and it was found not to have any bitter sensation. This suggests, that paracetamol ProD 2 can replace its parent drug, paracetamol, for the use asbitterless antipyretic drug for geriatrics and pediatrics.
تصنيع ودراسة المواصفات والقوى المحركة المخبرية للأدوية المساعدة للدوبامين
(AL-Quds University, 2016-12-21) يحيى فؤاد رشيد خواجا; yahya fuad rasheed khawaja; رفيق قرمان; د. حاتم حجازي; Dr. Nasr Shraim
Parkinson patients have insufficient dopamine in specific regions of the brain, so attempts have been made to replenish the deficiency in the dopamine. Dopamine itself doesn't cross blood brain barrier, but its precursor, levodopa (LD) is actively transported into the CNS and is converted to dopamine in the brain. The bioavailability of LD is less than 10% with only 1% of administered oral levodopa penetrates the brain. Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. To minimize the conversion to dopamine (DA) outside the central nervous system (CNS), LD is usually co- administered with peripheral inhibitors of amino acid decarboxylase (carbidopa and benserazide). In spite of that, other central nervous side effects such as dyskinesia, on-off phenomenon and end-of-dose deterioration still remain.Based on DFT calculations a novel dopamine prodrugs for the treatment of Parkinson’s disease that can improve the overall biopharmaceutical profile of the current medications to enhance effectiveness and to ease the use of the medications were synthesized, characterized, in vitro intra-conversion to their parent drugs and in silico pharmacokinetics and toxicity prediction were also studied. The synthesized dopamine prodrugs have a carboxylic group as a hydrophilic moiety and a hydrocarbon skeleton as a lipophilic moiety, where the combination of both groups ensures a moderate hydrophilic lipophilc balance value. The potential prodrugs are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, these prodrugs are believed to be more effective than L-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood– brain barrier. Additionally, the synthesized prodrugs can be used in different dosage forms (I.V., S.C., tablets, and others) because of their potential solubility in organic and aqueous media. For dopamine ProD 1 the experimental t½ values in 0.1N HCl, buffer pH 2.2, buffer pH 5.5 and buffer pH 7.4 were 60.3 hours, 54.66 hours, 99.93 hours and 138.13 hours, respectively. Dopamine ProD 2 was readily converted in 0.1N HCl, buffer pH 2.2, pH 5.5 and pH 7.4 with half -life time (t½) of 48.34 hours, 54.22 hours, 131.98 hours and 193.42 hours, respectively. Finally, in silico predicting of physiochemical parameters, ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties, oral bioavailability and BBB permeability for the synthesized prodrugs were studied. The results revealed that no prodrug had a high risk of toxicity, and all the prodrugs showed good pharmacokinetic properties. Moreover, all synthesized dopamine prodrugs were found to obey Lipinski’s rule of five.
تصنيع ودراسة لمواصفات الأدوية المساعدة المصممة لمادة الغايفينيسين
(AL-Quds University, 2014-02-25) أمين محمود عبد المنعم ثوابته; Amin Mahd A. Thawabteh; رفيق قرمان; د. عماد عودة; Abdel Naser Zaid
Guaifenesin is an extremely bitter taste substance which affects its usage in pediatric and geriatric formulations. In this thesis we aimed to mask the bitter taste of guaifenesin by converting it to a potential tasteless prodrugs using different linkers. The prodrugs were synthesized by esterification of carboxylic acid anhydrides and guaifenesin. Maleic anhydride, succinic anhydride, and glutaric anhydride, respectively, were used to synthesize guaifenesin ester prodrugs (guaifenesin maleate, guaifenesin succinate, guaifenesin glutarate), 1 H-NMR, LC-MS, and FT-IR have confirmed the identity and purity of the new prodrugs. In vitro kinetic studies for the above mentioned prodrugs were done in four different aqueous media: 1 N HCl and buffers pH 3.3, pH 5.5 and pH 7.4. Under the experimental conditions the target prodrug was hydrolyzed to release the parent drug, guaifenesin, as was confirmed by HPLC determination. The kobs and the corresponding t1/2 values for guaifenesin prodrugs in 1N HCl were calculated from the linear regression equation correlating the log concentration of the prodrug versus time. The rate constant (kobs) was found to be 7.2x10-4 for guaifenesin maleate prodrug, 2.54x10-4 guaifenesin succinate prodrug, and 2.36x10-4 guaifenesin glutarate prodrug. Half-lives values (t1/2) were 2.01 hours for guaifenesin maleate prodrug, 7.03 hours for guaifenesin succinate prodrugs, and 7.17 hours for guaifenesin glutarate prodrug. On the other hand, at pH 3.3, 5.5 and 7.4, guaifenesin maleate, guaifenesin succinate, and guaifenesin glutarate prodrugs were entirely stable and no release of the parent drug, guaifenesin, was observed.
تطوير دواء اولي مبتكر للاتوفاكوون? الدواء المضاد للملاريا: تصنيع كيميائي, تشخيص و تقييم القوى المحركه المخبريه
(AL-Quds University, 2016-01-05) بيسان وضاح امين الفتاش; Beesan Waddah Amin Alfattash; رفيق قرمان; د أحمد عمرو; Dr. Nasr Shraim
Malaria is a global public health problem, resulting in tow million deaths per year .The majority of death cases are due to the most severe form of malaria caused by Plasmodium falciparum. As a result, efforts were directed toward the development of new effective medications intended for the treatment of this endemic disease. Atovaqoune is a new treatment option, showed an improvement in malaria treatment. Although Atovaqoune is an effective medication, it has its own limitations. Atovaqoune is highly lipophilic compound (water solubility < 0.2 µg/ mL), has low water solubility and low absorption, hence low bioavailability (< 10% in the fasted state). Accordingly, increasing atovaqoune aqueous solubility will improve its pharmacokinetic profile in particular bioavailability, thus improving its effectiveness and ability to administer the drug through different routs of administration. So that, our goal was to develop atovaqoune prod rug that possesses increased aqueous solubility by linking water soluble moiety to the 3- hydroxyl group, via chemical synthesis. Purification techniques including extraction, re-crystallization and column chromatography were used. Identity confirmation was done using, IR, NMR and LC/MS. Based on purity and identity results; in vitro kinetic studies using the HPLC instrument were performed at pH 2.2, 5.5 and 7.4. ATQ succinate (ProD1) has been successfully synthesized, purified and evaluated. T1/2 of ProD1 at pH 2.2, 5.5 and 7.4 is 28.8 days, 2.2 days, 3.2 days, respectively. It can be concluded from these data, that ProD1 is converted into ATQ in pH dependentmanner, and the hydrolysis of the prodrug follows first order kinetics, as the data plotted gives a straight line, and the Kobs is nearly constant. Concisely, modifying atovaqoune structure may result in enhancing its pharmacokinetic profile mainly absorption into body tissues, consequently increasing efficacy and ability to formulate atovaqoune in different dosage forms. Keywords: Malaria, drug resistance, atovaquone, bioavailability, prodrugs .
تطوير وتقييم شكل صيدلاني جديد بخاصية التحرر الفوري (أقراص بريغابالين)
(AL-Quds University, 2016-05-21) محمد سميح شفيق شناعة; MOHAMMED SAMIH SHAFIQ SHANAA; نعمان مالكية; إبراهيم كيالي; هاني اشتيه
Pregabalin is an anticonvulsant agent used for the peripheral and central neuropathic pain treatment, marketed as Capsule and Solution dosage forms. The purpose of this study is to develop an immediate release Pregabalin Tablet, as a new dosage form in the Palestinian market that is bioequivalent to the FDA approved Reference Pregabalin Capsules (Lyrica). Pregabalin drug substance and the finished product during the time of development were not described in either the British or US pharmacopoeia. The chemical and physical evaluation of bulk drug substance (Pregabalin) was accomplished following the manufacturer`s analytical method and specification. A new reversed-phase, isocratic LC method was developed and validated according to USP validation parameters, for the qualitative and quantitative determination of Pregabalin in pharmaceutical dosage forms using HPLC (LaChrome Elite) equipped with photodiode array UV detector. Mobile Phase is a mixture of Phosphate Buffer pH 6.9, and acetonitrile (94:6). Chromatographic System is Column: C-18 ODS 5 to 10µm in diameter (25cm X 4.6 mm id), detector: UV set at wavelength 210 nm, Flowrate: 1.5 ml / min and Injection Volume: 20 μL. Formula development was accomplished through a series of steps: Selection of excipients through compatibility studies, selection of manufacturing process and in-vitro comparison studies versus the reference product. Excipients compatibilities were studied by preparing a binary mixture of Pregabalin and excipient (1:1) then sealed in neutral glass vials and incubated at 40±2 °C/75 ±5% RH for 30 days. The mixtures were tested by means of FTIR for any possible interactions. The following excipients (Microcrystalline Cellulose, Pregelatinized Starch, Talc and Mg Stearate) were found to be compatible with Pregabalin.A series of pre formulation trials were composed and processed by direct compression method. Selection of formula was based on: Powder characteristics: (such as compressibility ratio, flowability, bulk density and tapped density), which would allow for a simplified method of manufacture, friability, hardness and disintegration of compressed tablets. The selected formulation was applied to prepare Pregabalin Tablets in two strengths, i.e. tablets containing 75mg/tablet and 300mg/tablet. They are prepared as dose weight proportional. The compressed tablets were film-coated with PVA based polymer by using water as solvent.The stability of film coated Pregabalin tablets were tested by incubating the finished products in their final package (PVC-Alum) at different storage conditions i.e. 25 ± 2 °C / 60 % ± 5% RH, 30 C ± 2 °C / 60% ± 5% RH and 40 C ± 2 °C / 75% ± 5% RH. Samples were tested biweekly for content of Pregabalin (assay), physical appearance, dissolution rate, and degradation products. Pregabalin Tablets proved to be stable in all aspects for the period tested (1 month) at all storage conditions. Biowavier study was performed between Pregabalin Tablets (75mg and 300mg) and the Reference Pregabalin Capsules (Lyrica 75 and 300mg Capsules) using paddle method rotated at 50 rpm in different dissolution media (0.06N Hydrochloric acid solution, Acetate buffer pH 4.5 and phosphate buffer pH 6.8. It was found that either Reference or Test products release more than 85% of their Pregabalin content in 15 minutes. As Pregabalin API, according to BCS is Class I drug and the dissolution profiles of Pregabalin Tablets is similar to that of Reference Pregabalin Capsules (Lyrica) under the same test conditions, and all excipients used are not suspect of having any relevant impact on bioavailability it is strongly believed that the developed Pregabalin Tablets are bioequivalent to the marketed Lyrica Capsules.

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