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Chapter 2 Review of Literature CHAPTER-II REVIEW OF LITERATURE 2.1. REVIEW OF PATENTS AND RESEARCH LITERATURE RELATED TO SMEDDS / SNEDDS IN GENERAL Literature survey carried out for the present work includes reports on all previous work done by other workers in the field of SMEDDS. The level of interest in SMEDDS was increased substantially as is evident by the number of research activities done on this subject. The foregoing literature SMEDDS formulation and in vivo evaluation for the Isotretinoin drug reveals that the delivery of the drug in a solubilised SMEDDS form has not been investigated in detail. This lacuna is noticed and the present work is attempted to address these issues in order to further enhance the solubility of the molecule and hence the bioavailability. In order to overcome the problems associated with Isotretinoin and other poorly soluble compounds, and to develop a stable and robust oral dosage form for such active ingredients, several approaches have been adapted in patent publications and research literature as listed below; however, some of them may bare the issue of invalidity or impracticality in terms of commercialization. Holm et al. (2003) examines oral absorption and lymphatic transport of halofantrine in a triple-cannulated canine model after administration in selfmicroemulsifying drug delivery system (SMEDDS) containing structured triglycerides. O’Driscoll CM. (2002) reveals that the recent monitoring halofantrine (Hf), in a fed versus fasted dog study, have shown that a higher degree of Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 54 Chapter 2 Review of Literature lymphatic transport is possible (>50% dose) in the postprandial state, this study should result in stimulating renewed interest in the potential of achieving significant levels of lymphatic targeting. This review analyses the success and limitations of a formulation approach using lipid-based vehicles and highlights potential areas for further research. Hauss et al. (1998) reveals that Ontazolast is practically insoluble in water (0.14 microgram/mL) and previous studies in animals have demonstrated extensive presystemic drug clearance through hepatic first-pass metabolism. Bioavailability of a suspension formulation in rats was less than 1%, but increased to approximately 9% when administered as a 20% soybean oil-in-water emulsion. The bioavailability of ontazolast was significantly and substantially enhanced by all of the lipid-based formulations. Abu.T.M.Serajuddin et al. (2008) investigated the solution of a poorly water-soluble drug in a liquid lipid–surfactant mixture, which served as a microemulsion preconcentrate, was converted into a solid form by incorporating it in a solid polyethylene glycol (PEG) matrix. The solid microemulsion preconcentrates thus formed consisted of Capmul PG8 (propylene glycol monocaprylate) as oil, Cremophor EL (polyoxyl 35 castor oil) as surfactant, and hydrophilic polymer PEG 3350 as solid matrix. It was confirmed that a solid microemulsion preconcentrate is a two-phase system, where clusters of crystalline PEG 3350 formed the solid structure (m.p. 55–60°C) and the liquid microemulsion preconcentrate dispersed in between PEG 3350 crystals as a separate phase. The drug remained dissolved in the liquid phase. In vitro release testing showed that the preconcentrate dispersed readily in water forming a microemulsion with the drug dissolved in the oil particles (<150 nm) and the presence of PEG 3350 did not interfere with the process of selfmicroemulsification. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 55 Chapter 2 Review of Literature Uno et al. (1999) investigated an oleic acid oil-in-water (o/w)-type emulsion of a new tacrolimus formulation that presented an improvement in the delivery of the drug for oral absorption. This investigation was undertaken to assess a sustained release drug delivery system and selective drug transfer into the lymphatic system. The whole blood concentration profiles after oral administration at a dose of 2 mg/kg and bone marrow, spleen, liver, lung, small intestine, kidney, brain, and whole blood distribution after oral administration at a dose of 1 mg/kg of o/w emulsion formulation of tacrolimus (O/W group) were compared with those of commercially available formulation (T group) in the rat. The area under the whole blood concentration-time curve (AUC) in the O/W group was significantly higher (P<0.01) than that in the T group. In contrast, the values of constant elimination rate and total clearance in the O/W group were significantly lower (P<0.01) than those in the T group, with a comparative bioavailability of 115.9%. Preparation and in vitro characterization of self-nanoemulsified drug delivery system (SNEDDS) of all-trans-retinol acetate by Mansoor A. Khan et.al (2004) investigated the preparation of SNEDDS with All-trans-retinol acetate using different concentrations of soybean oil (solvent) Cremophor EL (surfactant) and Capmul MCM-C8 (co-surfactant). The results showed that that surfactant to co-surfactant ratio has the main impact on the physical characteristics of the emulsion formed. The optimum surfactant to co-surfactant ratio was reported to be 2:1 (37.5–50% for Cremophor EL, and 18.75–25% for Capmul MCM-C8). With this ratio, the resultant nanoemulsions obtained had a particle size range of 0.103– 0.051 μm, turbidity range of 18.12–2.18 NTU and t30 values (cumulative% alltrans-retinol acetate dissolved in 30 min) of 90.42–99.5. The study finally concluded that the self-nanoemulsified drug delivery system of all-trans-retinol acetate increased its dissolution rate and reports the potential to enhance its bioavailability without interaction or incompatibility between the ingredients. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 56 Chapter 2 Review of Literature Development of self-microemulsifying drug delivery systems (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs by Sun Hang Cho et al. (2004) investigated the preparation of self-microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of a poorly water soluble drug, simvastatin. The prepared SMEDDS was compared with the conventional tablet (Zocor®) by administering the prefilled hard capsules to fasted beagle dogs. The absorption of simvastatin acid from SMEDDS form resulted in about 1.5-fold increase in bioavailability compared with the conventional tablet. The studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as simvastatin by the oral route. Design and evaluation of self-nanoemulsifying drug delivery systems (SNEDDS) for cefpodoxime proxetil by Nagarsenker et al. (2006) investigated the development of Self-nanoemulsifying drug delivery systems (SNEDDS) with the objective to overcome problems associated with the delivery of cefpodoxime proxetil (CFP), a poorly bioavailable high dose antibiotic having pH dependant solubility. Solubility of CFP in oily phases and surfactants was determined to identify components of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify selected oily phases. Ternary phase diagrams were constructed to identify area of nanoemulsification for the selected systems. The influence of CFP and the pH of dilution medium on the phase behavior of selected system were assessed. The globule size of optimized CFP SNEDDS in various dissolution media was determined to check the effect of pH on its behavior. The optimized CFP SNEDDS needed surfactant content less than 40% and yielded nanoemulsion of mean globule size 170 nm, which was not affected by the pH of dilution medium. The optimized SNEDDS released CFP completely within 20 min irrespective of the pH of dissolution medium. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 57 Chapter 2 Review of Literature Ehab I Taha et.al. (2007) investigated to assess and compare the bioavailability of three different oral dosage forms of vitamin A in rats. The formulations included vitamin A self-nanoemulsified drug delivery (SNEDD) optimized formulation-filled capsule (F1), vitamin A SNEDD optimized formulation compressed tablet (F2) and vitamin A oily solution-filled capsules without any additives (control, F3). From the pharmacokinetic parameters, both F1 and F2 showed improved bioavailability compared to F3. The increase in AUC, Cmax and Tmax was significant (p < 0.05). The bioavailability increased almost twofold and 1.4 times for F1 and F2, respectively. The study showed that the newly developed vitamin A SNEDD formulations increased the rate and extent of drug absorption compared to the oily drug solution. The present investigation demonstrated that vitamin A SNEDD optimized formulations, either as filled capsules or as compressed tablets, were superior to its oily solution with regard to their biopharmaceutical characteristics. Ehab I Taha et.al. (2009) investigated the preparation Vitamin A selfnanoemulsifying drug delivery system (SNEDDS), which comprises soybean oil, Cremophor EL, and Capmul MCM-C8, prepared and mixed with different grades of Avicel to produce homogenized powders. The resultant powders were compressed into tablets. The prepared tablets were characterized for their thickness, hardness, friability, disintegration time, and dissolution rate. In addition, the relative bioavailability of the tablets in comparison to solid-state Vitamin A oily solution (SSVAOS) tablets was investigated in rats. Vitamin A dissolution rate was markedly different from one formulation to another. From the bioavailability data, it was observed that Vitamin A SNEDD tablets have higher bioavailability (relative bioavailability 143.68%) compared with SSVAOS tablets. The AUC and Cmax of Vitamin A SNEDD tablets were found to be significantly different from that of SSVAOS tablets. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 58 Chapter 2 Review of Literature U.S. Patent no. 5,965,160, Benita S, et al. described a Self-emulsifiable formulation producing an oil-in-water emulsion.The invention claims and discloses a pharmaceutical composition suitable for oral administration, in form of an emulsion pre-concentrate, comprising (i) one or more NO-releasing NSAID(s); (ii) one or more surfactants, of which at least one is phospholipid; said composition forming an in-situ oil-in-water emulsion upon contact with gastrointestinal fluids. The composition may optionally also comprise an additional oil or semi-solid fat. Further, one or more short-chain alcohols can optionally be included in the composition. Also within the scope of the invention is a combination with a proton pump inhibitor. The pharmaceutical composition is useful in the treatment of pain and inflammation. The U.S. Patent no. 5,716,928 describes a method for increasing bioavailability and for reducing inter and intra individual variability of an orally administered hydrophobic pharmaceutical compound, which comprises orally administering the pharmaceutical compound with an essential oil or essential oil component in an amount sufficient to provide greater bioavailability of the active ingredient. The U.S. Patent no. 6,028,054 relates to a method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound to human, which comprises orally administering the pharmaceutical compound concurrently with a bioenhancer comprising an inhibitor of e-cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein mediated membrane transport. The U.S. Patent no. 5,993,858 describes a self microemulsifying excipient formulation for increasing the bioavailability of a drug Nifedipine, which includes an emulsion including oil or other lipid material, a surfactant and an hydrophilic co-surfactant. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 59 Chapter 2 Review of Literature The U.S. Patent no. 7,867,517B2 describes a prompt-release oral pharmaceutical composition containing one or more active principle solubilised, suspended or embedded in a suitably formulated amphilic matrix for improving in vitro and in vivo bioavailability of medicaments sparingly absorbed through the oral route with problems of high variability of absorption in gastrointestinal tract. The said matrix system containing an amphiphilic compound which melts at below 60°C or forms a eutectic mixture melts at 35 -37°C. In this the active substance kept in the form of dispersion or partially solubilised or embedded, granulated with amphiphilic compound previously solubilised or suspended in solvent (preferably water). This system also contains a surfactant which is compatible with the amphiphilic matrix in a solubilised form to enhance the bio availability of the poorly soluble active substances. 2.2. REVIEW OF PATENTS AND RESEARCH LITERATURE RELATED TO ISOTRETINOIN Very few publications and/or patents about the pharmaceutical formulation of Isotretinoin are available. The drug is available on most markets under the form of a soft gelatine capsule containing a fatty liquid formulation of Isotretinoin. Vanderbrist et al., 2007, Application number: 11/892,363, Publication number: US 2008/0171084 A1Filing date: Aug 22, 2007 details about the method of enhancing the bioavailability of Isotretinoin through the usage of two lipidic agents in which one of them being hydrophilic and the other is lipophilic in nature. The SEDDS system containing soya bean oil to Gelucire 50/13 in various ratios from 3.2 to 0.54 were prepared. The prepared SEDDS system was subjected for in-vitro dissolution studies and in-vitro Caco-2 diffusion studies. The composition contains the lower oil to Gelucire 50/13 ratio, resulted in Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 60 Chapter 2 Review of Literature nanoemulsion during the dissolution studies. Based on the dissolution and diffusion studies, the two formulations were prepared and subjected for pilot study pharmacokinetic study in healthy human volunteers. The formulation which contains 16 mg of Isotretinoin in 192 mg of Gelucire50/13, soya bean oil 104 mg and 16 mg of span 80 the exhibited pharmacokinetic response equivalent to that of commercially available Isotretinoin 20 mg composition (Roacuttane 20 mg). The author concluded that the developed SEDDS system could improve the bioavailability by 20%. The U.S. Patent no.4,464,394 describes for the first time the therapeutical use of Isotretinoin, also describes briefly some possibilities of compositions including it. It involves the use of one antioxidant agent and of one carrier like lactose, starches or polyethylene glycols. The U.S. Patent no. 4,545,977 relates to improved compositions of Isotretinoin wherein taurine is associated with Isotretinoin to reduce the side effects thereof. The EP Patent no. 0184942 describes more specific compositions of Isotretinoin involving the use of one antioxidant, one chelating agent, one pharmaceutical carrier and one suspending agent. The composition obtained is stable during time. WIPO Patent Application WO/2004/084883 describes the use of lowsolubility complexes of natural cyclodextrins (CDs) in order to improve the bioavailability of Isotretinoin after oral administration. The complexation of Isotretinoin with natural CDs increases the aqueous solubility and dissolution rate of Isotretinoin, which results in improved absorption of Isotretinoin. The present Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 61 Chapter 2 Review of Literature innovation can be used in various oral dosage forms (tablet, capsule, etc.) and it includes a novel method to prepare solid formulations (e. g. tablet) from Isotretinoin. Hai-Shu Lin et al. (2007) demonstrated Biopharmaceutics of 13-cisretinoic acid (Isotretinoin) formulated with modified β-cyclodextrins. Watersoluble formulations of 13-cis-RA have been attempted with 2-hydroxypropyl-βcyclodextrin (HP-β-CD) and randomly methylated-β-cyclodextrin (RM-β-CD). In this study, the pharmacokinetic profiles of these two formulations were assessed in Sprague–Dawley rats after single intravenous or oral administration. It was found that 13-cis-RA was eliminated from the body through a dose-independent process after intravenous injection of either sodium salt or the HP-β-CD formulation within the tested dosage range (2.0–7.5 mg/kg). Furthermore, HP-βCD did not alter the kinetic profile of 13-cis-RA after intravenous administration in comparison with 13-cis-RA sodium salt. It was also found that RM-β-CD dramatically enhanced the oral absorption of 13-cis-RA. At 10.0 mg/kg, the bioavailability of 13-cis-RA formulated with RM-β-CD was about three-fold higher than that of the control (13-cis-RA suspended in 0.5% carboxymethylcellulose (CMC)). Similarly, the oral absorption of 13-cis-RA was not saturated within tested range (2.5–10.0 mg/kg) and the bioavailability remained unchanged. These results demonstrated that HP-β-CD and RM-β-CD were suitable excipients for the delivery of 13-cis-RA. Yap KL et al. (2005) investigated the effects of the complexation of 13cis-RA with alpha-cyclodextrin (alpha-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on its phase solubility. HP-beta-CD was found to be more effective in increasing the aqueous solubility of 13-cis-RA compared to alpha-CD. Phase solubility studies indicated that the solubility of 13-cis-RA was increased Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 62 Chapter 2 Review of Literature dramatically by the formation of inclusion complex with HP-beta-CD. The solubility was further enhanced by pH adjustment. The photostability of the selected inclusion complex of 13-cis-RA:HP-beta-CD was then evaluated. Complexation with HP-beta-CD was found to delay the photo-degradation of 13cis-RA in aqueous solution. The physicochemical properties of the solid inclusion complex were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffractometry (XRD). Molecular modeling with MMFF94s force field (SYBYL V6.6) was utilized to predict the preferred orientation of 13-cis-RA in the CD cavity and the main structural features responsible for the enhancement of its solubility and photostability. The energy scores estimated from the computational analysis were found capable of reflecting the stability constants of the cyclodextrin complexes obtained in the phase solubility studies. The results showed that HP-beta-CD was a proper excipient for increasing solubility and stability of 13-cis-RA. Design and Development of a Self Nano Emulsifying Drug Delivery System (SNEDDS) for Isotretinoin with enhanced Oral Bioavailability and Improved Stability 63