الفهرس 
Formulation and evaluation of sildenafil citrate sublingual tablets using Solid dispersion techniqueOnly 14 pages are availabe for public view
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Abstract
SILD was approved by FDA for pulmonary arterial hypertension treatment, however the available dosage forms are oral tablets, suspension and injection. Oral route suffers from poor bioavailability due to extensive liver metabolism and first-pass effect leading to nearly 40% bioavailability and GIT discomfort, moreover SILD suffers from decreased and delayed absorption in case of fatty meal, whereas the parenteral route is invasive and of low patient compliance, so our scope of work is the preparation of tablets overcoming the aforementioned drawbacks of oral and parenteral routes together with achieving rapid onset of action for acute attack treatment. The buccal route was chosen as an alternative route, where the sublingual absorption overcomes the first-pass effect and hence enhance SILD bioavailability, consequently allowing dose reduction and minimizing its oral side effects, moreover the sublingual route is noninvasive and facilitates rapid onset of action due to considerable surface area and high blood flow. Saliva is mainly composed of water (99.5%), this water rich environment of the oral cavity requires adequate drug solubility for transmucosal drug delivery. SILD suffers from poor aqueous solubility (3.5 mg/ml), which in turn requires solubility and dissolution enhancement for buccal absorption, hence this thesis aims to formulate SILD sublingual tablets after enhancement of SILD solubility and dissolution to ensure its solubility in the oral cavity and subsequent absorption from sublingual mucosa directly to blood stream thus
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bypassing liver metabolism and enhancing SILD bioavailability together with achieving rapid onset of action, this was planned to be achieved by two comparative techniques; solid dispersion and lyophilization technique. So the work in this thesis was divided into three chapters:
Chapter 1: Formulation and Evaluation of Sildenafil Citrate Sublingual Tablets using Solid Dispersion Technique.
Chapter 2: Formulation and Evaluation of Sildenafil Citrate Sublingual Tablets using Lyophilization Technique.
Chapter 3: Bioavailability and Pharmacokinetic Study of Sildenafil Citrate Sublingual Tablets in Human Volunteers.
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Chapter 1: Formulation and Evaluation of Sildenafil citrate Sublingual Tablets using Solid Dispersion Technique.
In this chapter the solubility and dissolution of SILD was enhanced by solid dispersion technique then the optimum SD was incorporated in sublingual tablets by direct compression. PEG 4000, 6000, 8000 and poloxamer 188 were used as solid polymers for preparation of SILD physical mixtures and SDs by fusion method. Solubility and dissolution studies were done and the results showed that SDs significantly increased the solubility of SILD up to 1.65 fold, except for PEG 6000 which showed a non-significant increase in solubility (P>0.05), in addition the solubility of SILD from SDs was significantly higher than their physical mixture counterparts, so physical mixtures were excluded from further testing. Moreover SDs prepared using poloxamer 188, PEG 4000 and PEG 8000 enhanced SILD dissolution compared to the plain drug. Bitterness evaluation revealed reduction in the bitterness score of the plain drug when incorporated in SDs. According to solubility, dissolution and bitterness evaluation results, SD1 (SILD-poloxamer 188) & SD10 (SILD-PEG 8000) were chosen for further physicochemical studies using DSC, XRPD and FTIR, where all explained and confirmed enhanced SD solubility and dissolution. Accordingly SD1 and SD10 were chosen for preparation of SILD STs by direct compression technique.
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In direct compression technique, various excipients were employed for tablets preparation, both SSG and pharmaburst were compared as superdisintegrants in achieving rapid disintegration. Formulations prepared using Pharmaburst (S5, S6, S7 and S8) gave higher release rate and extent of SILD much more than those prepared using SSG (S1, S2 and S4). This finding come in agreement with the results of wetting time, water absorption ratio and DT, where pharmaburst shortened in vivo and in vitro DT, wetting time and increased water absorption ratio. Moreover, tablets prepared using poloxamer SD (S1, S5 and S7) were superior than those prepared using PEG8000 (S2, S4, S6 and S8) as manifested by the higher dissolution rate. It was also observed that incorporation of SD of poloxamer188 in sublingual tablet together with Pharmaburst (S5 and S7) gave better extent and release rate than those prepared by SD of PEG8000 (S6 and S8) as evidenced by the higher dissolution rate. Moreover, it was observed that increasing concentration of Pharmaburst from 58 to 78 mg and SSG from 10 to 25 mg enhanced the dissolution rate. According to the obtained results S7 was proven to be superior when compared to other formulations and hence was subjected to further in vivo studies.
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Chapter 2: Formulation and Evaluation of Sildenafil Citrate Sublingual Tablets using Lyophilization Technique.
SILD lyophilized STs were prepared using a) sugar matrix former (Maltodextrin) together with X. gum, xylitol and PEG8000 (F1-F3), b) non sugar matrix former (gelatin) in three concentrations 1, 2 and 3 g/40ml, together with glycine, mannitol and PEG 8000 (F4-F9).
Tablets prepared with Maltodextrin were of inelegant appearance and of poor mechanical strength so they were excluded from further testing, which indicates that Maltodextrin and xanthan gum were not suitable for the preparation of SILD lyophilized tablets.
The prepared tablets (F4-F9) were evaluated for uniformity of weight, tablet friability, uniformity of SILD content, wetting time, in-vitro and in vivo DT, moisture content analysis and in-vitro dissolution studies. The optimum formula was selected for further physicochemical evaluation including DSC, XRD and FTIR. The previous evaluation results showed that gelatin is a suitable matrix former for the preparation of lyophilized STs that complies with the pharmacopoeial limits concerning the weight uniformity, friability, drug content uniformity, and disintegration time. Friability test showed that all the formulations conformed to pharmacopoeial limits except for F5 (containing 1 g/40ml gelatin and PEG 8000) that showed 2.2% friability and thus was excluded from further testing. Moreover, it was observed that increasing gelatin concentration increased wetting time, delayed DT, and decreased drug release, where F4 (1 g/40ml gelatin)
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showed the shortest wetting time, whereas F9 (3 g/40ml gelatin) showed the longest wetting time. Moreover F4 showed the least in vitro and in vivo DT and the highest dissolution rate and extent. Addition of PEG 8000 didn’t enhance dissolution of SILD STs. Accordingly F4 was proven to be superior when compared to other formulations and hence was subjected to further in vivo studies.
Lyophilization process was superior in enhancing dissolution compared to direct compression where 100% of SILD was dissolved after only one minute (F4) compared to 7 min in case of (S7) prepared by direct compression.
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Chapter 3: Bioavailability and Pharmacokinetic Study of SILD Sublingual Tablets in Human Volunteers.
An accurate LC-MS/MS method was developed and validated following international guidelines before the study for determination of SILD in human plasma. The Pharmacokinetic study was done on Six healthy volunteers by randomized, single dose, three-way crossover open-label study using three SILD formulations, the prepared F4 and S7 sublingual tablets and the conventional market product Revatio® 20 mg oral tablets. Plasma concentration-time data of SILD was analyzed for each subject. Cmax, Tmax were directly obtained from the concentration-time data and The AUC0–12 was calculated according to the linear trapezoidal rule. The terminal elimination rate constant (λz) was estimated by linear regression of the terminal portion of the ln concentration-time curve, and the elimination half-life was calculated. Relative bioavailability of SILD sublingual tablets compared to the commercial product was calculated.
The plasma concentration-time profiles as well as the calculated pharmacokinetic parameters showed that the prepared sublingual tablets improved the oral absorption of SILD, expressed by the significantly higher Cmax(1.5–2 fold), significantly shorter Tmax and the significantly higher AUC0–12 (nearly 1.5 fold) (p< 0.05) compared to the conventional oral tablet.
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Results showed that the method of sublingual tablet preparation had a significant effect on the bioavailability of SILD, as evidenced by the significantly shorter Tmax of lyophilized tablets (F4) compared to directly compressed tablets (S7), with values of 0.5 and 0.75 h, respectively. Moreover, the AUC0–12 of lyophilized tablets (F4) was significantly higher than that of the directly compressed tablets, with relative bioavailability values of 159.81 and 140.85 %, respectively