Thesis (Ph.D)-Cairo University, 2025.

Bibliography: pages 80-86.

The oral delivery system is the most used route of drug administration for systemic drug delivery due to its non-invasiveness, patient compliance, and convenience of drug administration. Despite the advantages of oral drug delivery, there are serious limitations to achieving the required goal. The drug's low permeability and low solubility characteristics in addition to gastric enzymes or acids degradation and first-pass metabolism of drugs could result in unacceptably low bioavailability. The IV biopharmaceutical classified drugs are a challenge to be orally delivered due to the low gastric absorption. Ticagrelor (TCG) is an IV biopharmaceutical classified antiplatelet drug. Although the potent antiplatelet activity of TCG compared to other antiplatelet therapeutics, the oral bioavailability is not more than 36%.
Hence, this research aimed to instruct an analytical procedure to be used in the determination of TCG during the study; prepare a lipid-based formulation to enhance the oral delivery of TCG and formulate a solid dosage form for TCG oral lipid-based formulation.
Chapter I:Development and Optimization of UPLC analysis method for ticagrelor determination
The analytical method was developed using UPLC to utilize the high separation efficiency, accuracy, and short run time. The development of the analytical procedure suggested using UPLC column C18 (2.1 x 100mm; 1.7µm) and a mobile phase composed of acidified solution mixed with acetonitrile in a ratio of 55:45. The detection wavelength was 254nm. The auto sampler temperature was 4°C.
The developed analytical method was optimized using a full factorial design. The design space includes four variable factors of acid type and acid concentration that are used in mobile preparation, flow rate, and elution temperature. The obtained responses were studied to investigate the efficiency of the chromatographic separation of TCG from the impurities TCG impurity I and TCG impurity II.
The responses including run time, resolution theoretical plate, and tailing factor were studied to optimize the chromatographic factors and understand the variable's effect. The correlation between separation responses was investigated using principal component analysis that detects the most dominant response and order of importance. The optimized analytical method achieved the separation and detection of TCG at 6.96 min with a tailing factor of 1.03 and theoretical plates of 13598, and the resolution of TCG from TCG imp II was 2.81.
The optimized analytical method was successfully validated according to ICH Q2R1 to be used to determine TCG in formulations, plasma, and liver tissue.
Chapter II: Development and Evaluation of lectin conjugated lipid nanocarrier for ticagrelor oral delivery.
Lipid-based nanocarriers are colloidal drug delivery systems emerging in the last decades as therapeutic carriers in favor of the offered advantages. Lipid nanocarriers (LNC) could enhance oral drugs bioavailability through multiple mechanisms including the small size that enables the nanoparticles to penetrate the mucosal layers in the gastric tract. LNC could protect the drugs from enzymatic and acidic degradation risks. LNC provides a controlled drug release behavior that enhances the drug therapeutic pattern and decreases the drug side effects.
Many lipids had been screened to choose the appropriate lipid base that TCG could solubilize the most. Different Hydrophilic lipophilic balance (HLB) surfactants have been used to formulate the LNCs. The choice of the surfactant was based on the most optimum ticagrelor-loaded lipid nanocarrier (TLN) physiochemical characteristics obtained.
The central composite design was employed as an optimization tool to study the effect of variable factors on formulation characterization results as responses. The design space consisted of three variables including lipid concentration, surfactant concentration, and sonication time. The responses to be studied were encapsulation efficiency percentage (EE%), particle size (PS), poly dispersion index (PDI), and zeta potential (ZP). The application of the formulation condition suggested from the CCD optimization with desirability 71.5% resulted in EE% (83.7±2.78%), PS (184.2±5.54 nm), and ZP (-31.8±1.83 mV).
The prepared TLN was conjugated with lectin using carbodiimide chemistry. The conjugated lipid nanocarriers (C-LNC) with lectin were undergone to investigation for EE%, PS, PDI, and ZP. The drug release from TLN and C-TLN was studied and showed a controlled release of TCG from both formulations with a diffusion mechanism. The morphological characterization and crystallinity for TLN and C-TLN were examined. The cytotoxicity, bio-adhesive ability, binding ability, and platelet aggregation characterizations of TLN and C-TLN were investigated. Invivo TCG absorption and In-vivo thrombus targeting were evaluated. Results of the study showed that the surface-modified lipid nanocarriers had oral bioavailability 2.37 fold higher than free ticagrelor. Furthermore, Lectin-conjugated lipid nanocarriers accumulated more at the thrombus-modified site and less in the liver tissue compared to the non-conjugated nanocarriers and free ticagrelor.
Chapter III: Development and characterization of fast disintegrated tablets loaded with supersaturated ticagrelor for oral delivery.
A supersaturable formulation was developed depending on sodium oleate as a lipid base, chromophore El as a surfactant, and PEG 4000 as a stabilizer as a primary formulation for TCG oral delivery. Sodium oleate has a long carbon (C18) tail that enables the molecule to self-assemble in the presence of nonionic surfactants forming a vehicle-like structure. The dispersion medium of sodium oleate and surfactants enables TCG to be in a supersaturation form. HPMC was used as a viscosity-increasing agent to prevent TCG precipitation and increase the metastable TCG concentration.
A fast disintegration tablet was developed as s secondary formulation to be loaded with the primary TCG formulation. Due to the fast disintegration, the secondary formula did not affect TCG release and supersaturable condition. The sublimation process is an effective tool in favor of creating a capillary network in the tablet and forming pores in the tablet body that shortens the required time for tablet disintegration.
The compatibility of TCG with the formulation excipient was investigated. The interaction between TCG and formulation excipient was studied using differential scanning calorimetry and infrared spectroscopy. The pre-compression parameters including Hausner’s ratio, Carr’s index, and angle of repose were studied to characterize the powder flowability. The post-compression parameters including hardness test, friability test, weight variation, and TCG content were investigated to characterize the efficiency of blending and compression on the quality of the formulated tablets. Tablet disintegration behavior was studied through the investigation of disintegration time, wetting time, and water absorption to investigate the efficiency of the sublimation process in preparation for fast disintegrated tablets.
The super-saturation condition of TCG in the dispersion medium was studied to select the optimum precipitation inhibitor. The in vitro TCG dissolution from the tablets was studied to determine the mechanism of TCG release and the effect of formulation in controlling TCG release. TCG permeability through the intestinal tissue was investigated to study the effect of the supersaturation condition in increasing the permeated TCG concentration. The bioadhesive character of the tablet was investigated to study the effect of formed hydrogel in increasing the residencetime of supersaturated TCG on the intestinal tissue. The effect of the storage time was studied to investigate the stability of formulations' physical and chemical properties.
The study’s results showed that the primary and secondary formulation excipients are compatible with TCG. The obtained formulation powders had poor flowing properties. All the formulations showed acceptable quality control testing including hardness, friability, drug content, and weight variation. Formulation dependent on PVP showed faster disintegration time (31.7 sec) and less wetting time (28.3 sec). The HPMC-related formulation showed the highest soluble TCG concentration (88.07%). The invitro dissolution study of TCG indicated the diffusion mechanism in TCG release. TCG permeability from T6 was up to 83% after 24h. The bioadhesive study reported that formulation T6 had 53% of the components attached to the intestinal tissue. The formulation T6 was physically and chemically stable during 12 months in the storage time effect study.

يستخدم مستخلص الهيكسان من ثمار نبات سيرينوا ريبنس في علاج تضخم البروستاتا الحميد. ومؤخرًا، حَظي هذا المستخلص باهتمام متزايد لدوره المحتمل في علاج أمراض أخرى مرتبطة بإضطرابات الأندروجين، مثل الصلع الوراثي، وزيادة نمو الشعر في الوجه، وحَب الشباب، ومتلازمة المبيض متعدد الكيسات .و على الرغم من أن استخدام ثمار سيرينوا ريبنس لعلاج متلازمة المبيض المتعدد الكيسات معروف في الطب التقليدي، إلا أن الأدلة العلمية لا تزال محدودة، مع وجود عدد قليل من الدراسات التي استهدفت استكشاف فعاليته في علاج هذه المتلازمة.
نبات سيرينوا ريبنس يمتلك خصائص مضادة للاندروجين، و مضادة للالتهابات، ومضادة للأكسدة مما يجعله علاجًا عشبيًا واعدًا لمتلازمة المبيض المتعدد الكيسات. وتُعتبر الفيتوستيرولات (خصوصًا بيتا سيتوستيرول) والأحماض الدهنية (لاسيما حمض اللوريك وحمض الأوليك) هي المكونات النشطة الرئيسية المسؤولة عن هذه التأثيرات.
استهدفت هذه الدراسة تقييم الفعالية في علاج متلازمة المبيض المتعدد الكيسات للمكمل الغذائي الذي يحتوي على مستخلص الهيكسان لثمار سيرينوا ريبنس و المصرح به في السوق المصري كعلاج لتضخم البروستاتا الحميد، و ذلك من خلال دراسة متكاملة تشمل تقنيات الفصل الكروماتوجرافي، والنمذجة الدوائية الشبكية، والتقييم البيولوجي على فئران التجارب.
لتقييم النشاط البيولوجي لمستخلص الهيكسان لثمار سيرينوا ريبنس في علاج متلازمة المبيض المتعدد الكيسات، تم توزيع 42 فأرة أنثى عشوائيًا على ست مجموعات، تضم كل مجموعة سبعة فئران. تم تحفيز متلازمة المبيض المتعدد الكيسات عن طريق إعطاء عقار ليتروزول بجرعة 1 مجم/كجم فمويًا يوميًا لمدة 21 يومًا متتاليًا. وبعد تحفيز المرض، تم تطبيق العلاجات المختلفة لمدة 28 يومًا، والتي شملت: كلوميفين سيترات (1 مجم/كجم/يوم)، مكمل غذائي تجاري مصري يحتوي على مستخلص سيرينوا ريبنس (مودرن سو بالميتو®) (320 مجم/كجم/يوم)، ومستخلص الهيكسان لثمار سيرينوا ريبنس بتركيزين (160 و320 مجم/كجم/يوم).
شملت التقييمات قياس المؤشرات التالية: وزن الجسم، الملف الدهني، الملف الهرموني، مؤشرات الإجهاد التأكسدي، والتقييم المورفولوجي للمبيض.
أدى تحفيز متلازمة المبيض المتعدد الكيسات بواسطة عقار ليتروزول إلى زيادة وزن الجسم، وارتفاع مستويات الدهون الثلاثية والتستوستيرون، وانخفاض مستويات الإستروجين، واضطرابات في التركيب النسيجي للمبيض، و زيادة الإجهاد التأكسدي. في حين أدى العلاج بعقار كلوميفين سيترات و مستخلص الهيكسان لثمار سيرينوا ريبنس إلى تحسين هذه الاضطرابات بشكل ملحوظ، مما أظهر تحسنًا في المؤشرات الأيضية، والهرمونية، والمورفولوجية. وتشير هذه النتائج إلى فعالية مستخلص الهيكسان لثمار سيرينوا ريبنس في مواجهة متلازمة المبيض متعدد الكيسات.
بالإضافة إلى ذلك، تم إجراء تحليل كيميائي تفصيلي لثمار سيرينوا ريبنس باستخدام تقنية الكروماتوجرافيا السائل فائق الأداء المزود بمطياف الكتلة لتحليل مستخلص الإيثانول، وتقنية كروماتوغرافيا الغاز باستخدام مطياف الكتلة لتحليل مستخلص الهيكسان، مما ساعد في توضيح التركيب الكيميائي لهذا النبات بشكل أكبر.

Issues also as CD.

Text in English and abstract in Arabic & English.