Self-microemulsifying Drug Delivery System Formulation Research Articles

Improved Therapeutic Efficacy of MT102, a New Anti-Inflammatory Agent, via a Self-Microemulsifying Drug Delivery System, in Ulcerative Colitis Mice.

MT-102 is a new anti-inflammatory agent derived from Juglans mandshurica and Isatis indigotica. Its therapeutic potential is hindered by low aqueous solubility, impacting its in vivo efficacy. Therefore, this study aimed to develop a self-microemulsifying drug delivery system (SMEDDS) for MT-102 to enhance its oral efficacy in treating ulcerative colitis. Solubility assessment in different oils, surfactants, and cosurfactants led to a SMEDDS formulation of MT-102 using Capmul MCM, Tween 80, and propylene glycol. Based on a pseudoternary phase diagram, the optimal SMEDDS composition was selected, which consisted of 15% Capmul MCM, 42.5% Tween 80, and 42.5% propylene glycol. The resulting optimized SMEDDS (SMEDDS-F1) exhibited a narrow size distribution (177.5 ± 2.80 nm) and high indirubin content (275 ± 5.58 µg/g, a biomarker). Across an acidic to neutral pH range, SMEDDS-F1 showed rapid and extensive indirubin release, with dissolution rates approximately 15-fold higher than pure MT-102. Furthermore, oral administration of SMEDDS-F1 effectively mitigated inflammatory progression and symptoms in a mouse model of ulcerative colitis, whereas pure MT-102 was ineffective. SMEDDS-F1 minimized body weight loss (less than 5%) without any significant change in colon length and the morphology of colonic tissues, compared to those of the healthy control group. In addition, oral administration of SMEDDS-F1 significantly inhibited the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α. In conclusion, the SMEDDS-F1 formulation employing Capmul MCM, Tween 80, and propylene glycol (15:42.5:42.5, w/w) enhances the solubility and therapeutic efficacy of MT-102.

NOVEL SELF-MICROEMULSIFYING DRUG DELIVERY SYSTEM FOR ENHANCED DIABETES MANAGEMENT: EVALUATING THE COMBINED EFFECTS OF GLIMEPIRIDE AND BOSWELLIA SERRATA EXTRACT

This study aimed to create and assess a novel self-microemulsifying drug delivery system (SMEDDS) for treating diabetes mellitus that contains glimepiride and Boswellia serrata extract. In the creation of SMEDDS formulations, Transcutol-P was employed as the base oil, while the surfactants Tween 80 and propylene glycol/polyethylene glycol 400 served as the co-surfactants. To improve the formulation, pseudoternary phase diagrams were created. While the SMEDDS of B. serrata extract showed a mean droplet size of 27.63 nm, 98.3% transmittance, a zeta potential of -0.11 mV, and a polydispersity index of 0.287, the glimepiride-optimized SMEDDS showed a mean droplet size of 14.8 nm, 98.5% transmittance, a zeta potential of -0.10 mV. In-vivo evaluation on diabetes-induced rats demonstrated significant reductions in SGOT and SGPT levels with the glimepiride and B. serrata extract SMEDDS compared to diabetic control rats and the marketed glimepiride formulation. The formulation showed promising results in controlling serum total protein, triglyceride, and cholesterol levels. The glimepiride and B. serrata extract SMEDDS also exhibited antioxidant activity, reducing malondialdehyde (MDA) absorbance. Histopathological assessment of kidney and pancreas tissues revealed the protective effects of the concomitant administration of glimepiride and B. serrata extract SMEDDS formulation against diabetes-induced damage. Overall, the developed SMEDDS formulation kit showed superior in-vitro and in-vivo performance, suggesting its potential as an effective therapeutic option for managing diabetes mellitus.

Omega-3 fatty acid-based self-microemulsifying drug delivery system (SMEDDS) of pioglitazone: Optimization, in vitro and in vivo studies

Pioglitazone (PGL) is an effective insulin sensitizer, however, side effects such as accumulation of subcutaneous fat, edema, and weight gain as well as poor oral bioavailability limit its therapeutic potential for oral delivery. Recent studies have shown that combination of both, PGL and fish oil significantly reduce fasting plasma glucose,improve insulin resistance, and mitigate pioglitazone-induced subcutaneous fat accumulation and weight gain. Nevertheless, developing an effective oral drug delivery system for administration of both medications have not been explored yet. Thus, this study aimed to develop a self-micro emulsifying drug delivery system (SMEDDS) for the simultaneous oral administration of PGL and fish oil. SMEDDS was developed using concentrated fish oil,Tween® 80, and Transcutol HP and optimized by central composite design (CCD). The reconstituted, optimized PGL-SMEDDS exhibited a globule size of 142 nm, a PDI of 0.232, and a zeta potential of −20.9 mV. The in-vitro drug release study of the PGL-SMEDDS showed a first-order model kinetic release and demonstrated remarkable 15-fold enhancement compared to PGL suspension. Additionally, following oral administration in fasting albino Wistar rats, PGL-SMEDDS exhibited 3.4-fold and 1.4-fold enhancements in the AUC0–24h compared to PGL suspension and PGL marketed product. The accelerated stability testing showed that the optimized SMEDDS formulation was stable over a three-month storage period. Taken together, our findings demonstrate that the developed fish oil-based SMEDDS for PGL could serve as effective nanoplatforms for the oral delivery of PGL, warranting future studies to explore its synergistic therapeutic potential in rats.

Formulation and Evaluation of a Self-Microemulsifying Drug Delivery System of Raloxifene with Improved Solubility and Oral Bioavailability.

Poor aqueous solubility and dissolution limit the oral bioavailability of Biopharmaceutics Classification System (BCS) class II drugs. In this study, we aimed to improve the aqueous solubility and oral bioavailability of raloxifene hydrochloride (RLX), a BCS class II drug, using a self-microemulsifying drug delivery system (SMEDDS). Based on the solubilities of RLX, Capryol 90, Tween 80/Labrasol ALF, and polyethylene glycol 400 (PEG-400) were selected as the oil, surfactant mixture, and cosurfactant, respectively. Pseudo-ternary phase diagrams were constructed to determine the optimal composition (Capryol 90/Tween 80/Labrasol ALF/PEG-400 in 150/478.1/159.4/212.5 volume ratio) for RLX-SMEDDS with a small droplet size (147.1 nm) and stable microemulsification (PDI: 0.227). Differential scanning calorimetry and powder X-ray diffraction of lyophilized RLX-SMEDDS revealed the loss of crystallinity, suggesting a molecularly dissolved or amorphous state of RLX in the SMEDDS formulation. Moreover, RLX-SMEDDS exhibited significantly higher saturation solubility and dissolution rate in water, simulated gastric fluid (pH 1.2), and simulated intestinal fluid (pH 6.8) than RLX powder. Additionally, oral administration of RLX-SMEDDS to female rats resulted in 1.94- and 1.80-fold higher area under the curve and maximum plasma concentration, respectively, than the RLX dispersion. Collectively, our findings suggest SMEDDS is a promising oral formulation to enhance the therapeutic efficacy of RLX.

Celecoxib Oral Solution and the Benefits of Self-Microemulsifying Drug Delivery Systems (SMEDDS) Technology: A Narrative Review.

The oral route of drug delivery is the most widespread and preferred route of administration, but it has several limitations, including variable pharmacokinetics (PK), reduced dissolution and absorption, and gastrointestinal irritation. Further, many compounds have low aqueous solubility, which also limits intestinal absorption. For this narrative review, we conducted a literature search of PubMed until August 2022, focusing on emulsions, microemulsions, nanoemulsions, and self-emulsifying drug delivery systems. The self-microemulsifying drug delivery system (SMEDDS) overcomes these limitations of hydrophobic compounds to enhance their bioavailability. A SMEDDS formulation is a clear, thermodynamically stable, oil-in-water emulsion of lipid, solubilized drug, and two surfactants, which spontaneously forms droplets < 100nm in diameter. These components help deliver presolubilized drugs to the gastrointestinal tract, while protecting them from degradation in gastric acid or first-pass hepatic metabolism. SMEDDS formulations have improved oral drug delivery in the treatment of cancer (paclitaxel), viral infections (ritonavir), and migraine headache (ibuprofen and celecoxib oral solution). The American Headache Society recently updated their consensus statement for the acute treatment of migraine and included a selective cyclo-oxygenase-2 selective inhibitor formulated in SMEDDS, celecoxib oral solution. This SMEDDS formulation showed pronounced improvement in bioavailability compared with celecoxib capsules, allowing for a low dose of celecoxib in the oral solution to provide safe and effective acute migraine treatment. Here, we will focus on SMEDDS formulations, what differentiates them from other analogous emulsions as vehicles for poorly soluble drugs, and their clinical application in the acute treatment of migraine. Oral drugs reformulated in SMEDDS have shown accelerated times to peak plasma drug concentrations and increased maximum plasma concentrations, compared with capsules, tablets, or suspensions. SMEDDS technology increases both drug absorption and bioavailability of lipophilic drugs, compared with other formulations. Clinically, this allows the use of lower doses with improved PK profiles without compromising efficacy, as shown with celecoxib oral solution for the acute treatment of migraine.

Self-micro Emulsifying Drug Delivery via Intestinal Lymphatics: A Lucrative Approach to Drug Targeting.

The intestinal lymphatics are considered one of the most specialized pathways, which promote the absorption of various agents such as vitamins, lipids, xenobiotics, and lipophilic substances. The intestinal lymphatics have provided various advantages like bypassing first-pass effects, and improved bioavailability. The oral delivery of poor hydrophilic drugs can be improved by employing a lipid-based formulation strategy. Self-micro emulsifying drug delivery systems (SMEDDS) are one of the vivacious strategies based on lipid-based drug delivery that have shown their effects by improving the solubility and bioavailability of the therapeutic agents. This review is an insight into the functions, targets, mechanisms, and carriers involved in intestinal lymphatics. Also, the review illustrates the types, formulation requirements, and mechanism of action of SMEDDS in detail. In addition, it describes the targeting, types, physicochemical properties, biological barriers, and benefits of lymphatic targeting in therapy. Finally, the marketed formulations and future aspects of SMEDDS formulations are addressed.

Improved oral bioavailability of febuxostat by liquid self-micro emulsifying drug delivery system in capsule shells

Febuxostat is a non-purine xanthine oxidase inhibitor which belongs to the BCS class II. Main aim of this study is to enhance dissolution and bioavailability of a drug by formulating a liquid self-micro emulsifying drug delivery system (SMEDDS) in different capsule shells. Compatability of gelatin and cellulose capsule shells was checked with different oils, surfactants and co-surfactants. Solubility studies were then carried out in selected excipients. Capryol 90, labrasol, and PEG 400 were used in a liquid SMEDDS formulation based on phase diagram and the drug loading. Further SMEDDS was characterized for zeta potential, globule size and shape, thermal stability and in vitro release. Based on the in vitro release, pharmacokinetic study was carried out using SMEDDS in gelatin capsule shells. The diluted SMEDDS had globule size of 157.9±1.5d.nm, zeta potential of -16.2±0.4mV and they were thermodynamically stable. The formulation was found stable for 12 months in capsule shells. When tested in different media (0.1N HCl and pH 4.5 acetate buffer), the in vitro release of newly produced formulations differed substantially from that of commercially available tablets, while the release rate in alkaline medium (pH 6.8) was comparable and the highest. According to in vivo findings in rats, a threefold increase in plasma concentration, a fourfold increase in AUC0-t, and a reduction in oral clearance increased fuxostat's oral bioavailability. This investigation revealed that the novel liquid SMEDDS formulation sealed in capsules has considerable potential as a vehicle for enhancing the bioavailability of febuxostat.

Formulation of self-microemulsifying drug delivery system (SMEDDS) of ibuprofen for oral delivery

Background: In the Biopharmaceutical Classification System (BCS), ibuprofen (IBU) belongs to Class II (poorly soluble, well-absorbed), which limits its therapeutic effectiveness due to low bioavailability. Currently, self-microemulsifying drug delivery systems (SMEDDS) are used to stabilize drug compounds and enhance solubility and absorption of poorly soluble and poorly absorbable drugs. Therefore, the objective of this study was to develop and characterize a SMEDDS formulation containing IBU for oral administration. Materials and methods: The study utilized IBU (from China), various oils (such as oleic acid, Peceol, etc.), surfactants (such as Acrysol EL-135, Acrysol K-140, etc.), and co-surfactants (such as propylene glycol, Lauroglycol 90). The study investigated and selected the appropriate excipients and their ratios to optimize the formulation, and evaluated various aspects such as appearance, emulsification capacity, droplet size, size distribution, and drug content. Results: The results showed that the IBU-containing SMEDDS consisted of IBU 8.7%, Capryol 8.7%, Acrysol EL-135 66.08%, and propylene glycol 16.52%, with a droplet size of 16.33 ± 0.124 nm and a PDI of 0.185 ± 0.003. It is capable of rapid self-emulsification within 30 seconds of gentle stirring with distilled water (with a volume ratio of 1:500, v/v) to form a clear microemulsion. Conclusion: In conclusion, this study successfully developed a SMEDDS formulation containing IBU, which shows promise for the development of an oral dosage form. Key words: Ibuprofen, Self-microemulsifying drug delivery system, oral delivery.

Application of Design of Experiments in the Development of Self-Microemulsifying Drug Delivery Systems.

Oral delivery has become the route of choice among all other types of drug administrations. However, typical chronic disease drugs are often poorly water-soluble, have low dissolution rates, and undergo first-pass metabolism, ultimately leading to low bioavailability and lack of efficacy. The lipid-based formulation offers tremendous benefits of using versatile excipients and has great compatibility with all types of dosage forms. Self-microemulsifying drug delivery system (SMEDDS) promotes drug self-emulsification in a combination of oil, surfactant, and co-surfactant, thereby facilitating better drug solubility and absorption. The feasible preparation of SMEDDS creates a promising strategy to improve the drawbacks of lipophilic drugs administered orally. Selecting a decent mixing among these components is, therefore, of importance for successful SMEDDS. Quality by Design (QbD) brings a systematic approach to drug development, and it offers promise to significantly improve the manufacturing quality performance of SMEDDS. Furthermore, it could be benefited efficiently by conducting pre-formulation studies integrated with the statistical design of experiment (DoE). In this review, we highlight the recent findings for the development of microemulsions and SMEDDS by using DoE methods to optimize the formulations for drugs in different excipients with controllable ratios. A brief overview of DoE concepts is discussed, along with its technical benefits in improving SMEDDS formulations.

Self-microemulsifying Drug Delivery System for Solubility and Bioavailability Enhancement of Eprosartan Mesylate: Preparation, In-vitro, and In-vivo Evaluation.

Formulations of eprosartan mesylate with a surfactant, like Kolliphor HS 15, an oil phase like Labrafil M 1944 CS, and a cosurfactant Transcutol HP by employing a liquid self-microemulsifying drug delivery system (SMEDDS) after screening several vehicles have been studied. This study aimed to prepare a liquid self-microemulsifying drug delivery system for increasing the solubility and bioavailability of a poorly water-soluble eprosartan mesylate. The micro-emulsion unit, achieved through the phase diagram and augmented with the central-composite design (CCD) surface response process, was adjusted into SMEDDS by lyophilization using sucrose as a cryoprotective agent. Particle size, self-emulsification time, polydispersion index (PDI), zeta potential, differential scanning calorimeter (DSC) screening, in-vitro drug release, and in-vivo pharmacokinetics were the essential features of the formulations. The subsequent DSC experimentation indicated that the drug was integrated into S-SMEDDS. Eprosartan mesylate loaded SMEDDS formulation showed greater in-vitro and in-vivo drug release than conventional solid doses. SMEDDS has reported effectiveness in reducing the impact of pH of eprosartan mesylate, thereby improving its release efficiency. The HPLC method was successfully implemented to assess eprosartan mesylate concentration in Wister rat plasma after oral administration of commercial tablet EM, SMEDDS, and eprosartan mesylate. The pharmacokinetics parameters for rats were Cmax 1064.91 ± 225 and 1856.22 ± 749 ngmL-1, Tmax 1.9 ± 0.3 hr, and 1.2 ± 0.4 hr and AUC0~t were 5314.36 ± 322.61 and 7760.09 ± 249 ng/ml hr for marketed tablets and prepared SSMEDDS, respectively. When determined by AUC0~1, the relative bioavailability of eprosartan mesylate S-SMEDDC was 152.09 ± 14.33%. The present study reports the formulation of a self-microemulsifying drug delivery system for enhancing the solubility and bioavailability of a poorly water-soluble eprosartan mesylate in an appropriate solid dosage form.

Self-micro emulsifying drug delivery systems: State-of-art a technology to enhance the solubility of poorly water-soluble drug

As new technologies are invented, research in the discovery of new active pharmaceutical moieties is reverberating now a day. Drug solubility is an extensive challenge for formulation scientists as approximately 35-40% of newly discovered drugs show lipophilicity. Low solubility is a rate limiting step for drug dissolution and extends of drug absorption to the systemic circulation. Poor dissolution results in low bioavailability, leading to difficulty to achieve desired therapeutic effect. Drug solubility can be increased by different methods like micronization, solid dispersion, salt formation, complexation etc. Self-micro emulsifying Drug Delivery System (SMEDDS) is in fame for enhancing solubility of poorly aqueous soluble drugs. Self-emulsifying drug delivery system, Self-micro emulsifying drug delivery system (SMEDDS) are isotropic mixers of oil, surfactant, drug and co-solvent which spontaneously form transparent micro-emulsions. When SMEDDS formulation administered orally, the solution disperses in GI fluid and instantly forms a fine emulsion by which drug gets a larger surface area which leads to quick dissolution of the drug. Objective of the present review is to update about advancements associated with SMEDDS preparation. It elaborates the evaluation tests required to analyse selfmicro emulsifying drug delivery systems. This review article also highlights on recent patents on SEDDS, SMEDDS and SNEDDS formulations.

Formulation and Evaluation of Self-Micro Emulsifying Drug Delivery System (SMEDDS) of Ticagrelor

The present work mainly emphasized on the enhancement of solubility of Ticagrelor by developing Self- Micro emulsifying drug delivery system. Ticagrelor is a BCS class IV drug with poor aqueous solubility and permeability. The saturated solubility of Ticagrelor in various oils, surfactants and co-surfactants was determined by using UV-spectroscopy. The excipients were selected based on their maximum solubility and compatibility for Ticagrelor. SMEDDS formulations od Ticagrelor were developed using different oils, surfactants and co-surfactant combinations (4:1 and 3:1). Pseudo ternary phase diagrams were constructed and based on pseudo ternary phase diagrams, Nano emulsification area was evaluated .Formulations were designed based on the pseudo ternary phase diagram using various proportions of oil (Capmul MCM E8 EP), surfactant (Labrasol), co-surfactant (PEG-400). The prepared formulations were selected among them F1 was optimized and carried out for further evaluations like dispersibility test, self-emulsification time ,phase separation and stability test, thermodynamic stability studies, droplet size and zeta potential, invitro drug release studies. The results of present study demonstrate that Ticagrelor SMEDDS can be used as a potential means for improving the solubility of Ticagrelor.

Improved oral bioavailability of poorly water-soluble vorinostat by self-microemulsifying drug delivery system

BackgroundVorinostat is a histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) with anticancer properties. However, it is plagued by low water solubility, low permeability (BCS class IV drug), and suboptimal pharmacokinetics. The purpose of the present study was to develop a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vorinostat. Capryol 90, labrasol, and polyethylene glycol (PEG 400) were selected as oil phase, surfactant, and co-surfactant, respectively. The vorinostat self-microemulsifying drug delivery systems were tested for self-microemulsifying time, phase separation, effect of pH, droplet size, zeta potential, dilution study, Fourier-transform infrared (FT-IR) spectroscopy analysis, and field emission scanning electron microscopy (FESEM). A rat model in vivo pharmacokinetic study was conducted for the optimized formulation against vorinostat pure drug powder.ResultsThe results from the characterization studies showed that the optimized formulation (F7) self-microemulsification time was 1.4 ± 0.05 min and no precipitation or phase separation was observed. The mean droplet size, polydispersity index (PDI), and zeta potential of the optimized formulation (F7) were found to be 272.9 ± 82.7 nm, 0.415, and − 57.2 mV, respectively. The pharmacokinetic parameters of the optimized formulation (F7) showed a 1.6-fold increase in maximum concentration (Cmax) and a 3.6-fold increase in area under the curve (AUC(0−∞)), in comparison with pure drug in suspension.ConclusionsThe findings suggest that SMEDDS formulation could be an effective method for increasing the oral bioavailability of vorinostat, which is poorly water soluble.

Production, physicochemical investigations, antioxidant effect, and cellular uptake in Caco-2 cells of the supersaturable astaxanthin self-microemulsifying tablets

The purpose of this study was to develop astaxanthin (AST)-loaded self-microemulsifying drug delivery system (SMEDDS) tablets and evaluate their physicochemical and biological properties. The optimized liquid (L)-AST SMEDDS formulation was composed of rice bran oil (33.67%), Kolliphor® RH 40 (34.70%), and Span® 20 (31.63%). Two types of hydrophilic polymers (hydroxypropyl methylcellulose, HPMC, and polyvinyl alcohol, PVA) solutions were selected as a precipitation inhibitor for AST and incorporated into L-AST SMEDDS to obtain supersaturation and enhance dissolution of AST. The formulation was then mixed with microcrystalline cellulose and subsequently transformed to solid S-AST SMEDDS particles using a spray dryer prior to direct compression into tablets. The HPMC AST SMEDDS tablet and PVA AST SMEDDS tablet were characterized for their physicochemical properties, dissolution, AST release, and stabilities. Moreover, the cellular uptake and antioxidant effect of AST SMEDDS tablets were evaluated in Caco-2 cells. With good tablet characters, both HPMC AST SMEDDS tablet and PVA AST SMEDDS tablet dissolution profiles were improved compared to that of raw AST. While initially less than 50% of AST released from HPMC AST SMEDDS tablet and PVA AST SMEDDS tablet in pH 1.2 medium, after 6 h more than 98% of AST releases in pH 6.8 were achieved which was similar to L-AST SMEDDS profile. Cellular antioxidant activities of L-AST SMEDDS and HPMC AST SMEDDS tablet & PVA AST SMEDDS tablet were significantly greater than pure AST powder. HPMC AST SMEDDS tablet showed better uptake and deeper penetration through Caco-2 cells than that in PVA AST SMEDDS tablet and pure powder. Our successfully developed AST SMEDDS tablets were demonstrated to be a potential platform to deliver highly lipophilic AST and improve permeation and bioavailability.

Development and Evaluation of Self Micro Emulsifying Drug Delivery System (SMEDDS) for Nebivolol Hydrochloride

The present investigation aimed to prepare a self micro emulsifying drug delivery system (SMEDDS) for the dissolution enhancement of nebivolol hydrochloride. The main objective of this work was to develop, characterize, and evaluate a solid SMEDDS prepared by using the adsorption technique of a liquid SMEDDS to improve the solubility and dissolution rate of nebivolol hydrochloride. The excipients were chosen based on the high solubility of nebivolol hydrochloride, and their concentrations were optimized by constructing ternary phase diagrams. Thirty-two combinations were prepared using oil (Labrafac Lipophile WL 1349), surfactant (Kolliphor RH 40), and co-surfactant (Gelucire 44/14). Self-emulsification time, dilution studies, and thermodynamic stability studies were satisfactory. The in vitro nebivolol release profile showed a faster rate of dissolution compared with the pure nebivolol hydrochloride suspension and marketed formulation. The droplet size was in the range of 132.8±22.1 to 955.7±15.5 nm and zeta potential in the range -7.2±0.53 mV to -46.4±0.32 mV for the selected formulations. Formulation N17 (Labrafac Lipophile WL 1349 -10%w/w, Kolliphor RH40-72%w/w, Gelucire 44/14- 18%w/w) was considered as optimized formulation and showed drug release of 97.26 ± 1.16% in 0.1 N HCl in 120 minutes, the particle size of 132.8±22.1 nm and zeta potential of -46.4±0.32 mV. Thus, the present studies ratify that the bioavailability was improved by nebivolol SMEDDS formulation. The optimized liquid SMEDDS was further used for the preparation of Solid SMEDDS (S-SMEDDS) formulations by using adsorption carriers. The optimized Solid SMEDDS formulation exhibited 95.38 ± 0.76% in vitro drug releases, which was significantly higher than that of the drug solution. The optimized formulation of nebivolol-loaded S-SMEDDS exhibited complete in vitro drug release in 120 min as a compared pure drug solution. The present result confirmed the potential use of SMEDDS to improve the dissolution and oral bioavailability of poorly water-soluble nebivolol.&#x0D;

Formulation, Optimization and Evaluation of Ticagrelor Loaded Self Microemulsifying Chewable Tablets

Abstract: Ticagrelor is a new generation Adenosine diphosphate receptor inhibitor drug which is highly lipohilic having poor aqueous solubility used in the treatment of Acute Coronary Syndrome and prevention of Thrombotic events like Stroke and Heart Attack. An approach has been made to develop Chewable tablets of drug loaded on Self-microemulsifying drug delivery systems (SMEDDS), screen suitable adsorbent for solidification of formulated SMEDDS and to study the effect of superdisintegrants in chewable tablets. Methods: On basis of Pseudoternary diagrams constructed for selected oil, surfactant and cosurfactant, SMEDDS formulation was formulated using Capmul MCM EP oil with surfactant (Cremophor RH 40) and co-surfactant (PEG 400) which was solidified using selected adsorbent. Chewable tablets were compressed by direct compression method using superdisintegrants. Results: IR Studies and DSC studies revealed compatibility and stability of drug in formulation. Compression blend containing Solidified SMEDDS possessed good flow and compressibility. Chewable tablets compressed using Soy Polysaccharides as super disintegrant showed least wetting and disintegration time, drug release of 97.68% within 30 min. Short term stability studies revealed no significant change in physical and chemical properties. Conclusion: These results suggest that the Ticagrelor loaded self microemulsifying chewable tablets can be a promising oral drug delivery system to improve the solubility and dissolution profile of Ticagrelor. Key words: Ticagrelor, SMEDDS, Adsorbents, Chewable tablets, Acute coronary syndrome.

Enhancement of solubility and permeability of cefpodoxime proxetil by self-micro-emulsifying drug delivery system

The goal of this study was to design Cefpodoxime Proxetil SMEDDS (self-microemulsifying drug delivery system), to improve solubility and permeability which could improve therapeutic performance and drug loading capacity. Castor oil, Tween 80, PEG 400 were used as the oil, surfactant, and, co-surfactant respectively. A ternary phase diagram was used to choose the best formulations. Selected formulations were evaluated for various parameters. According to the findings, all SMEDDS formulations had nano-sized globules, good stability, and rapid dispersibility of microemulsions, which were clear and slightly bluish in colour, and no symptoms of phase separation, creaming or, cracking Intestinal permeability studies of SMEDDS formulations show that the drug diffused through a biological membrane is more when given in form of SMEDDS. The present investigation has shown that it is possible to enhance the solubility and permeability of poorly soluble drugs.

Formulation Approaches for Improving the Dissolution Behavior and Bioavailability of Tolvaptan Using SMEDDS.

Tolvaptan, a selective vasopressin receptor antagonist, is a Class IV agent of Biopharmaceutical Classification System (BCS). To improve bioavailability after oral administration, the new tolvaptan-loaded self-microemulsifying drug delivery system (SMEDDS) was further optimized using a “design of the experiment (DoE)” including components of D-optional mixture design. Based on a solubility study of tolvaptan in various oils, surfactants, and cosurfactants, Capryol® 90, Tween 20, and Transcutol® HP [or polyethylene glycol 200 (PEG 200)] were finally selected for optimization of tolvaptan-loaded SMEDDS formulations. The fitting models of, and poly-nominal equations for, all response variables were acceptable, as revealed by analysis of variance (ANOVA, R2 > 0.900, p < 0.0001). The optimized formulations A-1 (Capryol® 90/Tween 20/Transcutol® HP = 10%/70%/20% w/w) and B-1 (Capryol® 90/Tween 20/PEG 200 = 10%/70%/20% w/w) with desirabilities of 0.905 and 1.000, respectively, showed low droplet size and the dissolution rate exceeded 95% at 15 and 60 min. The tolvaptan-loaded SMEDDS remained stable for 3 months under accelerated conditions, thus with no change in any of content, color, particle size, or dissolution rate. In a rat pharmacokinetic study, the bioavailability of formulations A-1 (16.6%) and B-1 (11.5%) were 23–33-fold higher than that of raw tolvaptan powder (0.5%). Thus, the use of “quality by design (QbD)” during development of tolvaptan-loaded SMEDDS improved the dissolution rate and oral drug bioavailability.

Novel Self-micro Emulsifying Drug Delivery System for Safe Intramuscular Delivery with Improved Pharmacodynamics and Pharmacokinetics.

Diclofenac Sodium (DS) injection is widely used in the management of acute or chronic pain and inflammatory diseases. It incorporates 20% w/v Transcutol-P as a solubilizer to make the stable injectable formulation. However, the use of Transcutol-P in high concentration leads to adverse effects such as severe nephrotoxicity, etc. Some advancements have resulted in the formulation of an aqueous-based injectable but that too used benzyl alcohol which is reported to be toxic for human use. This study aimed to develop an injectable Self-Micro Emulsifying Drug Delivery System (SMEDDS) as a novel carrier of DS for prompt release with better safety and efficacy. A solubility study was performed with different surfactants and co-surfactants. The conventional stirring method was employed for the formulation of SMEDDS. Detailed in vitro characterization was done for different quality control parameters. In vivo studies were performed using Wistar rats for pharmacokinetic evaluation, toxicological analysis, and analgesic activity. The optimized formulation exhibited good physical stability, ideal globule size (156±0.4 nm), quick release, better therapeutics, and safety, increase in LD50 (221.9 mg/kg) to that of the commercial counterpart (109.9 mg/kg). Furthermore, pre-treatment with optimized formulation reduced the carrageenan-induced rat paw oedema by 88±1.2% after 4 h, compared to 77±1.6% inhibition with commercial DS formulation. Moreover, optimized formulation significantly (p<0.05) inhibited the pain sensation in the acetic-acid induced writhing test in mice compared to its commercial equivalent with a better pharmacokinetic profile. The above findings confirmed that liquid SMEDDS can be a successful carrier for the safe and effective delivery of DS.

HLD-NAC design and evaluation of a fully dilutable lecithin-linker SMEDDS for ibuprofen

Lecithin-linker microemulsions have been previously proposed as a platform for designing a fully dilutable self-microemulsifying drug delivery system (SMEDDS). This SMEDDS formulation, composed of ethyl caprate (oil), lecithin (Le), glycerol monooleate (lipophilic linker, LL) and polyglycerol caprylate (hydrophilic linker, HL), produced a ternary phase diagram (TPD) that had a fully dilutable path suitable for oral drug delivery. However, introducing ibuprofen as an active pharmaceutical ingredient (API) resulted in TPD phase boundaries that eliminated the fully dilutable path. The purpose of this work was to understand the origin of the changes in the TPD, use that understanding to restore the fully dilutable path with an ibuprofen-loaded SMEDDS, and finally to evaluate the absorption of ibuprofen in vivo. The effect of ibuprofen on the HLD (hydrophilic-lipophilic difference, interpreted as normalized net interfacial curvature) of the system was evaluated via a polar oil model, showing that ibuprofen played a surfactant-like role, having a characteristic curvature (Cc) value of +5 (highly hydrophobic). The net-average curvature (NAC) framework used the HLD calculated with Le, LL, HL and ibuprofen Cc to generate TPDs in ibuprofen lecithin-linker systems. The HLD-NAC simulations show that restoring full dilutability required a highly hydrophilic linker (HL−) with a Cc of −5 or more negative. The fully dilutable path was restored after introducing a hexaglycerol caprylate as HL- (Cc = −6). Plasma concentration profiles obtained with this ibuprofen-loaded SMEDDS showed a more than three-fold increase in the area under the curve (AUC) of rat plasma concentration profiles compared to the same 25 mg/kg ibuprofen dose in suspension.