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Home > Formulation, Characterization and Pharmacokinetic Evaluation of Statistically Optimized Solid Lipid Microparticles of Cardiovascular Drugs

Formulation, Characterization and Pharmacokinetic Evaluation of Statistically Optimized Solid Lipid Microparticles of Cardiovascular Drugs

Thesis Info

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Author

Khan, Hafeez Ullah

Program

PhD

Institute

Bahauddin Zakariya University

City

Multan

Province

KPK

Country

Pakistan

Thesis Completing Year

2019

Thesis Completion Status

Completed

Subject

Pharmaceutics

Language

English

Link

http://prr.hec.gov.pk/jspui/bitstream/123456789/11901/1/Hafeez%20Ullah%20Khan%20Pharmacy%202019%20bzu%20prr.pdf

Added

2021-02-17 19:49:13

Modified

2024-03-24 20:25:49

ARI ID

1676726235905

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The use of Ivabradine (IBH) and Nebivolol (NEB) are considered as being effective and safe but their short plasma half-life and decreased bioavailability in conventional formulations demand frequent dosing which ultimately reduce patient compliance. The purpose of this research was to prepare Solid lipid microparticles (SLMs) of IBH and NEB to overcome the inadequacies associated with conventional formulation and to release drugs in a sustained fashion. Preliminary studies were performed to identify the effect of independent variables like concentration of lipid polymer like beeswax (BW), carnaubawax (CW), stearic acid (St-A), Glyceryle monostearate (GMS) and surfactant like tween 20 (T-20) and tween 80 (T-80). IBH and NEB loaded SLMs were designed in five different batches with different concentrations of a single or combination of lipid polymer by simple melt emulsification technique and solvent evaporation method. Central composite Rotatable Design (CCRD) was applied on every batch of SLMs to study the impact of three independent variables on responses like percentage yield (Y1), entrapment efficiency-EE-(Y2) and drug release (Y3) at pH 6.8 for 12hr. In every batch of SLMs, the compatibility of drugs with lipid polymer was checked by Fourier transform infrared spectroscopy (FTIR), Differential scanning calorimetry (DSC) and X-ray powder Diffractometry (XRD). SLMs were further analyzed for rheological behavior, zeta potential, size and for morphology by scanning electron microscope (SEM).The drug release data was analyzed by different kinetic models. Numerical optimization techniques were applied and an optimized formulation (OF) from every batch (total 5 optimized formulations) were further prepared and then characterized for in-vitro and in-vivo pharmacokinetic behaviour in healthy male volunteers. Before performing in-vivo drug analysis, HPLC method for the simultaneous estimation of IBH and NEB was developed and validated for linearity and range, intra- and inter-day precision, accuracy, recovery, limit of detection and limit of quantification. The experimental conditions of HPLC method were optimized by using CCRD, in which, flow rate, pH of buffer and wavelength were used as independent factors in order to optimize three dependent factors like retention time, number of theoretical plates and tailing factor of NEB and IBH. Noncompartmental model approach was used to calculate the pharmacokinetic parameters including the area under the plasma concentration–time curve from zero to infinity (AUC0-∞), Tmax, Cmax, t1/2, MRT and kel. All data was expressed as mean ± SD (standard deviation). Spherical, smooth surface SLMs having good rheological behavior were obtained. The resultant data from FTIR, DSC and XRD concluded the absence of any interaction between formulation components. Zeta-potential study confirmed better stability of optimized SLMs because of presence of negative charge on OF1 (-30mV to 52mV), OF2 (-25mV to -60mV), OF3 (-20mV-40mV), OF4 (-20mV to -40mV) and OF5 (-40 to -60). The size of SLMs ranged from ranged from 300µm to 400µm (OF1), 20µm to 120µm (OF2), 80µm to 220µm (OF3), 20µm to 100µm (OF4) and from 05µm to 20µm (OF5). The SLMs prepared from solvent evaporation technique (OF2, OF4, OF5) were found to have smaller size with smoother spherical surface as compared to SLMs (OF1) produced by simple emulsion congealing technique. The dependent variables had followed quadratic, 2F1 and linear models. The obtained outcomes of Y1, Y2 and Y3 for all of the SLMs have shown a significant dependence on formulation conditions. The Y1 and Y2 were found to be varied from 38 to 90% and 29 to 78% indicating the effect of formulation variables. The drug release Y3 was found to be 46 -88% and was significantly (p˂0.05) affected by lipid polymer concentration. The release mechanism followed the zero order and Korsmeyer-Peppas (n˃0.85) kinetic models suggesting slow erosion alongwith diffusion mechanism. A highly precise, robust, economical, specific, sensitive, less time consuming and accurate HPLC method was successfully developed and validated in mobile phase and human plasma as evident from short retention time and run time. The mobile phase consisting of mixture of acetonitrile and phosphate buffer maintained at pH of 3.5 in the volumetric ratio of 1:1 led to achievement of the best resolution. The optimized HPLC experimental conditions involve a flow rate of 1 mL/min under which, a good retention time of 3.591 minutes for NEB and 2.21 minutes for IBH was obtained. The optimized SLMs OF3 (Group C), OF4 (Group D) and OF5 (Group E) have significantly higher (P˂0.005) Cmax, Tmax, AUC0-24, MRT0-24 and t1/2 than those obtained from OF1 (Group A) and OF2 (Group B) because of use of a combination of lipid polymers. However, OF1 and OF2 were found to be better as compared to marketed brands of IBH (Group F) and NEB (Group G).The difference in Tmax, AUC0-24, MRT0-24 for OF3, OF4, OF5 was found to be statistically insignificant, however these parameters were found to be higher for OF5. The marketed brands of IBH and NEB released the drugs immediately resulting in rapid drug absorption with lower Tmax and lower AUC values. Results of the study clearly depicted the suitability of lipids as carriers for designing a controlled release SLMs which would definitely increase the clinical utility of IBH and NEB to improve the patient compliance by decreasing dosing frequency and drugs associated side effects particularly in the cases of chronic illnesses like Hypertension. The results of pharmacokinetic analysis were quite suggestive of prominent effect of SLM formulations on in-vivo behavior of drugs and they can be considered a prospective administration system for once-a-day oral administration of a medicament. Key Words: Beeswax, Carnauba wax, Central composite rotatable design (CCRD), DSC, FTIR, Glyceryle monostearate, HPLC, Ivabradine, Melt Emulsion Congealing Technique, Nebivolol, Solid Lipid Microparticles, Solvent evaporation process, Stearic acid, XRD.
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عشقی الہاشمی

عشقی الہاشمی(۱۹۰۹ء ۔۱۹۸۳ء)کا اصل نام جعفر علی اور عشقیؔ تخلص کرتے تھے۔ عشقیؔ سیالکوٹ کے سادات نقوی خاندان میں ہوئے۔ آپ عربی فارسی میں خدا داد قابلیت رکھتے تھے اور علومِ شرقیہ کے بہترین اساتذہ میں شمار ہوتے تھے۔ عشقیؔ نے شاعری میں علی طالب الہٰ آباد ی اور لسان الہند مرزا ہادی عزیز لکھنوی سے فیض حاصل کیا۔ سیالکوٹ میں عشقیؔ کے بہت زیادہ شاگرد تھے۔ جنھوں نے اُردو شاعری میں اعلیٰ مقام حاصل کیا۔ اصغر سودائیؔ اور تابؔ اسلم جیسے کاملِ فن شعرا عشقیؔ کے تلمذ میں رہے۔(۴۵۶)

آپ نے مجلہ در’’نجف‘‘ میں بحیثیت مدیر معاون کام کیا۔ ’’شبابِ اردو‘‘ ،اور’’نوروز‘‘ کی ادارت بھی سنبھالی ۔اور امر تسر کے ہفت روزہ ’’مجلہ آرٹ‘‘ کے مدیر بھی رہے۔ (۴۵۷) ’’سر شک بہار‘‘ ،’’مطلع الانوار‘‘ ،’’سوزو ساز‘‘ ،’’سہا و سمن‘‘ اور ’’غزلستان‘‘ عشقیؔ کے چار شعری مجموعے ہیں۔’’العروض ‘‘تصنیف میں فنِ شاعری پر تنقید اور تبصرے شامل ہیں۔(۴۵۸)

عشقیؔ روایتی شاعر ہیں ان کے ہاں کوئی جدت نظر نہیں آتی۔ عشقی ؔ کے اسلوب پر دبستان دہلی اورلکھنو کے اثرات بھی دیکھے جا سکتے ہیں ۔ اُن کی غزلیات چھوٹی اور لمبی بحروں میں ہیں ۔شاعری میں قافیہ اور ردیف پر بہت زور دیتے ہیں ۔ان کی اکثر غزلیات کی طویل ردیفیں ہیں ایسا لگتا ہے جیسے وہ شاعری پر قافیہ اور ردیف کو فوقیت دیتے ہیں ۔ مذکورہ بالا خامیوں کے باوجود عشقیؔ کے ہاں آفاقی موضوعاتِ شاعری بھی موجود ہیں۔ اخلاقیات،رجائیت،قومیت،حقیقت پسندی،اصلاح ،عشقِ مجازی اور عشقِ حقیقی عشقیؔ کی شاعری کے اہم موضوعات ہیں اس حوالے سے نمونہ کلام ملاحظہ ہو:

قوم پر جب زوال آتا ہے

 

/نوجوان بے لگام ہوتے ہیں

 

1جن کو جینے کا...

افتاء كے فضائل قرآن و حدیث كی روشنی میں

To derive and discover the hidden solution to problems regarding every walk of life, according to the teachings of Islam is called Ijtihad and to convey this solution (answer) to the people concerned is called Ifta. Answers to some queries have been directly given by ALLAH ALMIGHTY Himself Then Allah gave the responsibility to his beloved Prophet Muhammad (SA W) to explain & enlighten the people according to the will of ALMIGHTY ALLAH as Quran And then the same responsibility transfers to the eminent religious scholars (Muftis) who are the true inheritors of the Holy Prophet (SAW) Mufti acts as the deputy of the Holy Prophet (SA W) and holds a very high, important & sensitive position of guiding the people towards Islamic teachings. That is why it needs high care, piety & skill. In the given article the reality, importance and virtues of this highly important position have been enlightened

Identification of Genes and Mutations Involved in Primary Microcephaly and Inherited Limb Disorders in Pakistani Families

Numerous genetic conditions have been described clinically but the molecular etiology for most of them is still unknown. With the advancement in the field of molecular biology powerful techniques have been developed to localize these conditions in the human genome and subsequent identification of causative genes. Functional analysis of causative genes leads to the discovery and understanding of novel genetic processes and pathways underlying disease conditions including normal developmental pathways. Linkage analysis studies in Mendelian disorders to identify the causative genes and mutations are possible using large pedigrees with multiple affected individuals. Analysis of alleles using microsatellite markers and genome wide SNPs lead to the discovery of novel genes and loci for specific disorders. The main aim of this thesis was to analyze families with autosomal recessive primary microcephaly and families with inherited limb disorders particularly polydactyl, syndactyly and brachydactyly to identify the causative mutations or chromosomal loci. Autosomal recessive primary microcephaly (MCPH) is a neurogenic disorder characterized by reduced head circumference (≤4 SD) and variable degree of mental retardation without any other neurological manifestations. The normal brain architecture is preserved despite the fact that brain size is reduced to three folds. In the first part of this study, genetic analysis of eleven primary microcephaly families was carried out. Linkage analysis using highly polymorphic microsatellite markers confirmed linkage in six families to ASPM (MCPH5), two CENPJ (MCPH6), one MCPH2 locus and haplotype analysis in two families demonstrated compound heterozygosity for ASPM. Sequencing of ASPM in six potentially linked families (MCP3, MCP6, MCP7, MCP9, MCP11 and MCP17) revealed six homozygous mutations in the affected subjects (A1160fs1181X, Y2245fs2258X, R3233X, Y3164X, S3186X, and R3244X respectively) and two possible compound heterozygous families (MCP35 and MCP18) demonstrated compound heterozygous mutations (W1326X/R3107X and R1019X/Q2632X, respectively). Compound heterozygous patients (W1326X & R3107X) also have additional clinical symptoms of seizures. Two families linked to MCPH6 locus (MCP21, MCP22) demonstrate 1bp deletion mutation c.17_18delC (T6fsX3) in exon 2 of CENPJ leading to premature termination of protein. This mutation was previously reported in two Northern Pakistani families. XVIFamily MCP15 established linkage to MCPH2 locus on chromosome 19q (19q13.1-q13.2). MCPH2 locus was defined by markers D19S416 and D19S420 which was about 7.6 cM in two consanguineous families from Northern Pakistan. However, the region is significantly reduced in MCP15 which is defined by markers D19S416 and D19S47. This substantially decreases the minimum critical interval from 7.6 cM to about 4.4 cM containing 162 genes. Family MCP36 has only single affected child. Molecular analysis using microsatellite markers revealed that affected individual is homozygous for the MCPH1 locus. By sequencing I have identified a novel nonsense mutation in exon 4 of MCPH1/microcephalin. The mutant protein lacks both of the C-terminal BRCT domains required for the normal functioning of protein during cell cycle progression and DNA repair mechanism. The second part of thesis comprised of genetic analysis of inherited limb disorders. Inherited limb malformations are genetically heterogeneous group of conditions with wide range of phenotypic manifestations. Inherited limb disorders occur as an isolated entity or syndromic form and are of clinical significance due to their severity and overall frequency. Limb development is a cascade of complex pathways involving patterning, growth and differentiation. Molecular characterization of inherited limb disorders may lead to the identification of novel genes and signalling pathways important for normal limb development during organogenesis. Family PD1 with preaxial polydactyly and triphalangeal thumb revealed autosomal dominant inheritance. Linkage analysis using microsatellite markers D7S550, D7S559 and D7S2423 was performed and maximum multipoint LOD score of 1.93 at recombination frequency θ= 0.1 was obtained. This region spans SHH and its cis-acting regulatory element (ZRS), which is well conserved among various species lying in intron 5 of LMBR1. Direct Sequencing of ZRS identified a novel point mutation (T>G) in ZRS element at base position 4976 in intron 5 of LMBR1. Many point mutations have been identified in ZRS leading to disruption of SHH expression during limb development leading to preaxial duplication in upper limbs. Electrophoretical mobility shift assay (EMSA) demonstrated a marked difference between wild and the mutant probe which uniquely bound a specific subset of nuclear transcription factors extracted from Caco-2 cells. It is suggested that altered transcription factor affinity may be important for our understanding of how single nucleotide substitutions in long distance regulatory elements changes cis-regulation of its target gene. XVIIGreig cephalopolysyndactyly syndrome (GCPS) is an autosomal dominant disorder which affects limb and craniofacial development. GCPS was mapped to chromosome 7p13. Mutations in GLI3 had been described in GCPS patients. In the present study four novel GLI3 mutations in four distinct families have been identified. In family PD2, a single nucleotide substitution mutation [c.1702A>T (p.R568X)] leading to immediate stop codon in exon 13 is identified. Two base pairs deletion mutation [c.1853_1854delAC (p.Y618fs)] leading to frameshift and premature terminated protein product of 673 amino acids is identified in family PD316 in a family from Denmark. Both the mutations R568X and Y618fs lie in zinc finger domain in the first third of GLI3 producing truncated protein product which may affect the DNA binding property of zinc finger domain leading to possibly haploinsufficiency of GLI3. In family PD7, a novel C to T substitution at coding nucleotide 4574 (p.P1525L) in exon 15 of GLI3 is identified. The third mutation which is a missense (c.4574C>T (p.P1525L) lies in the last third of GLI3. Missense mutation P1525L lies in the C terminal region of GLI3 protein in the transactivation domain. In family PD16, at coding nucleotide position 3557, C to T substitution leading to missense incorporation of amino acid (p.P1186L) is identified. The variability in phenotype with respect to mutation in the affected family members may help to understand the phenotypic spectrum of GLI3 mutation. Brachydactyly is a rare and genetically heterogeneous disorder. In the present study a novel locus in a large consanguineous family with recessive form of brachydactyly type E is localized on chromosome 6p22.3 by homozygosity mapping using 10K SNP analysis. The physical linkage interval lies between 15,837,143 to 16,579,402 bp which is about 742 Kb. Maximum two point LOD score (Zmax) of 5.00 at recombination fraction (θ=0.0) was calculated at marker locus D6S18xAG. This region spans only seven genes including four pseudogenes. Sequencing of protein coding genes which include MYLIP, GMPR and ATXN1 did not reveal any mutation. Analysis using SNP6 array also did not identify any homozygous deletion or duplication in the region. However, smaller deletions or duplication (≤30 kb) cannot be excluded. Family PD14A shows cutaneous syndactyly of 3 rd and 4 th digit in hands. After exclusion using microsatellite markers on chromosome 2q34-q36 (syndactyly type I), 3p21.31 (zygodactyly), 2q31 (SPD1 locus, HOXD13), 6q22.31 (GJA1, syndactyly type III), 22q13.31 (SPD2), 14q11.2- q12 (SPD3) and 17p13.3 (syndactyly type IX) genome wide 10K SNP analysis was performed. XVIIIAfter fine mapping using microsatellite markers a single homozygous region on chromosome 9 flanked by markers, SNP_A-1518820 and D9S21AT (marker not available in Marshfield genetic map) was identified. The physical positions of flanking markers are 12018387 bp to 15340449 bp on chromosome 9 with maximum LOD score (Zmax) of 2.35 for given locus (θ=0.00). The region spans only 22 genes. A novel single nucleotide G to A substitution at coding nucleotide position 1289 (c.1289G>A) in exon eight leading to missense incorporation of glutamine instead of arginine at amino acid position 430 of Frem1 (p.R430Q) is identified. Arginine at 430 amino acid position of Frem1 is not only conserved among different vertebrate species but also conserved among Frem family of genes. However, possibility of missense mutation in Frem1 producing a defect in digit separation requires more families to study in addition to the functional studies in experimental models to prove the pathogenic nature of this mutation." xml:lang="en_US