RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, KARNATAKA, BANGALORE.
M. PHARM SYNOPSIS YEAR OF ADMISSION-JUNE 2010
TITLE OF THE SYNOPSIS
“FORMULATION AND CHARACTERIZATION OF NANOSTRUCTURED LIPID MATRICES OF UBIQUINONE (COENZYME Q10)”
BY Mr. Vikrant T. Kadam (M. Pharm.) Department of Pharmaceutics
UNDER THE GUIDANCE OF
Dr. Basavaraj K. Nanjwade. M.Pharm., Ph.D.
Professor of Pharmaceutics
KLES’s COLLEGE OF PHARMACY Akkol Road, NIPANI KARNATAKA RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES KARNATAKA, BANGALORE.
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. NAME OF THE Mr. Vikrant Kadam CANDIDATE S/o.- Tanajirao Kadam AND ADDRESS A/P. - NIPANI DIST. - BELGAUM PIN CODE - 591237 STATE - KARNATAKA
2. NAME OF THE KLES’s COLLEGE OF PHARMACY INSTITUTION Akkol Road,NIPANI DIST:- BELGAUM KARNATAKA.
3. COURSE OF STUDY AND MASTER OF PHARMACY IN PHARMACEUTICS SUBJECT
4. DATE OF ADMISSION JUNE 2010
5. TITLE OF THE TOPIC
“FORMULATION AND CHARACTERIZATION OF NANOSTRUCTURED LIPID MATRICES OF UBIQUINONE (COENZYME Q10)”
2 6.0 BRIEF REVIEW OF THE INTENDED WORK
6.1 - Need for the study
The use of solid lipid matrices for the prolonged release of drugs is known in pharmacy for many years, i.e. drug release from lipid pellets. Based on this, consequently it was only a matter of time until the production of lipid microparticles. In the next step the first generation of lipid nanoparticles was produced, the so-called lipid nanopellets for oral administration. At the beginning of the nineties the second generation was developed, the solid lipid nanoparticles (SLN) either produced by high pressure homogenisation or alternatively using the microemulsion precipitation technique.1 There are also some potential limitations for SLN, especially like limitation in drug loading capacity, drug expulsion during storage, high water content of aqueous SLN dispersions (70–95%). This led to a new improved generation of lipid nanoparticles, NLC. The NLC are produced by the controlled mixing of the solid lipids with the spatially incompatible liquid lipids1. Nanostructured lipid carriers (NLC) are solid lipid nanoparticles (SLN) of the second generation, which are used for the delivery of lipophilic actives. Advantages over conventional delivery systems are the protection of chemically labile compounds against chemical degradation and an increased bioactivity.2 Besides, NLC remain their solid state by controlling the liquid lipid content added to the formulation, therefore, the controlled drug release properties for NLC can be achieved.3 It led to special nanostructures with improved properties for drug loading, modulation of the drug release profile and stable drug incorporation during storage. Depending on the productive method and the composition of lipid blend, different types of NLC were obtained, i.e., the imperfect, amorphous and multiple components.4 These types have low crystalline of SLN, thereby lead to ‘highest incompatibility’ and higher drug loading.5,6 To manufacture NLC and SLN, the hot high-pressure homogenization above the melting point of the lipid and subsequent recrystallization are recommended (melt- emulsification), but the cold high-pressure homogenization for thermo labile drugs exists too. Other production methods for NLC as production from micro emulsions, the precipitation and dispersing by ultrasound are published and differ normally in obtained particle size distribution.7
3 6.2 - Review of Literature
1. Veerawat Teeranachaideekul et al, prepared Nanostructured lipid carriers (NLC), composed of cetyl palmitate with caprylic/capric triacylglycerols (as liquid lipid) and Coenzyme Q10 (Q10) has been incorporated in such carriers due to its high lipophilic character. By photon correlation spectroscopy a mean particle size in the range of 180– 240 nm with a narrow polydispersity index (PI) lower than 0.2 was obtained for all developed formulations. The entrapment efficiency was 100% in all cases. Using static Franz diffusion cells, the in vitro release studies demonstrated that Q10-loaded NLC possessed a biphasic release pattern, in comparison to Q10-loaded nanoemulsions comprising similar composition of which a nearly constant release was observed.13
2. Jana Pardeike et al, prepared Cutanvoa Nanorepair Q10 cream, was compared to an identical o/w cream without NLC with regards to particlesize, melting behaviour, rheological properties and the invivo effect on skin hydration. By laser diffraction (LD) and differential scanning calorimetry (DSC) measurements it could be shown that NLC are physically stablein Cutanova Nanorepair Q10 cream. The rheological properties of Cutanova Nanorepair Q10 cream contributed to a better subjective impression of consistency and spreadability on the skin than found for NLC negative control cream.14
3. Varaporn B. Junyapraserta et al, prepared Nanoemulsions (NE) of medium chain triacylglycerols (MCT) and nanostructured lipid carriers (NLC) of cetyl palmiate/MCT to load coenzyme Q10 (Q10). After storage at 4, 25 and 40 ◦C, the particles remained in the nanosize range for 12 months, with zeta potential higher than |40mV|. Similar results were found in xanthan gum-based hydrogels containing NE or NLC. The crystallinity index of Q10-loaded NLC increased after being incorporated into hydrogels. The Q10 entrapped in NLC and NE remained higher than 90% at all temperatures for 12 months but dramatically decreased when exposed to light. From in vitro permeation studies, it could be stated that the amount of Q10 released and occlusiveness were major keys to promote the deep penetration of Q10 into the skin.15
4. Wen-Chuan Leea et al, prepared a liposomal formulation composed of soybean phosphatidylcholine (SPC) and α-tocopherol (Vit E) was utilized to encapsulate CoQ10 for topical application. The liposomes were less than 200nm in diameter and had a 4 narrow size distribution. This study demonstrates that liposomal CoQ10 is a promising candidate for the topical application of CoQ10.16
5. Slavomíra Doktorovová et al, developed nanostructured lipid carriers (NLC) for topical delivery of fluticasone propionate (FP) with the aim to further improve the safety profile and decrease the adverse-side effects commonly reported in topical corticotherapy. NLC consisting of glyceryl palmito-stearate, and PEG-containing medium chain triglycerides mixture, stabilised by polysorbate 80 and soybean phosphatidylcholine were prepared. A mean particle size between 380 and 408nm and entrapment efficacy of 95% were obtained for FP-loaded NLC. Results revealed a low- crystalline structure and confirmed the incorporation of FP into the particles.17
6. Chun-Yang Zhuang et al, prepared Vinpocetine–loaded NLC (VIN–NLC) by a high pressure homogenization method. The average encapsulation efficiency was 94.9±0.4%. In the in vitro release study, VIN–NLC showed a sustained release profile of VIN and no obviously burst release was observed. The relative bioavailability of VIN–NLC was 322% compared with VIN suspension. In conclusion, the NLC formulation remarkably improved the oral bioavailability of VIN and demonstrated a promising perspective for oral delivery of poorly water-soluble drugs.18
7. E.B. Souto et al, prepared Clotrimazole-loaded SLN and NLC by the hot high pressure homogenization Technique. The particle size was analyzed by PCS and LD showing that the particles remained in their colloidal state during 3 months of storage at 4, 20 and 40oC. The obtained results also demonstrate the use of these lipid nanoparticles as modified release formulations for lipophilic drugs over a period of 10 h.19
6.3 - Objective of the Study
Following are the objectives of the present study
1) To carry out Preformulation study. 2) To formulate and characterization of Nanostructure Lipid Matrices of Ubiquinone. 5 3) To evaluate the formulated dosage form by official in vitro studies. 4) To carry out Pharmacokinetic and Pharmacodynemic studies (in vivo). 5) To carry out stability studies as per ICH guidelines.
6
7.0 MATERIALS AND METHODS Materials Drug : Ubiquinone (Coenzyme Q10) Lipids : Monostearin, Compritol 888 ATO, Cetyl Palmitate, Medium Chain Triglyceride(MCT), Oleic acid, Miglyol 812, etc Surfactant : Solutol, Cremophor EL, Tween80, etc. Solvent : Ethanol, Chloroform, Acetone, Ether, etc.
Method Development of nanostructured lipid carrier by hot pressure homogenization or any other suitable / Developed method using different lipid amounts.
7.1 - Source of Data
a) Journals such as, 1) Indian Drug. 2) Indian Journal of Pharmaceutical Sciences. 3) Indian Journal of Pharmaceutical Education and research. 4) European Journal of Pharmaceutical Sciences. 5) International Journal of Pharmaceuticals. 6) Drug Development & Industrial Pharmacy. 7) Journal of Controlled Release. b) Review articles c) World Wide Web. d) J-gate@Helinet. e) Science Direct, Pub med. f) Library: KLES’s College of Pharmacy. g) E-library: KLES’s College of Pharmacy.
7 7.2 - Method of collection of data
1) Preformulation studies for possible drug or Surfactant interaction. 2) Preparation of Nanostructured Lipid Matrices by Hot Pressure Homogenizer method or any suitable / developed method. 3) Evaluation of the various properties of Nanostructured Lipid Matrices. Particle size Analysis. Polydispersity Index. Physicochemical evaluation /TEM. HPLC IR Spectroscopy. Scanning Electron Microscopy X-ray Diffraction DSC/TGA 4) Carry out stability studies as per ICH guidelines. 5) To carry out Pharmacokinetic and Pharmacokinetic studies (in vivo).
7.3 - Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.
“YES” (Animal Studies.)
7.4 - Has ethical clearance been obtained from your institution in case of 7.3?
“APPLIED” (Awaiting)
8 8.0 REFERENCES
1. R.H. Müller, M. Radtke, S.A. Wissing, Nanostructured lipid matrices for improved microencapsulation of drugs, Int. J. Pharm. 242 (1–2) (2002) 121– 128.
2. Wasfy M. Obeidat, Kay Schwabe, Rainer H. Müller, Cornelia M. Keck, Preservation of nanostructured lipid carriers (NLC), Eur. J. Pharm. Biopharm. 76 (2010) 56–67.
3. Fu-Qiang Hu, Sai-Ping Jiang, Yong-Zhong Du, Hong Yuan, Yi-Qing Ye 1, Su Zeng, Preparation and characteristics of monostearin nanostructured lipid carriers, Int. J. Pharm. 314 (2006) 83–89.
4. Hong Yuan, Lei-Lei Wang, Yong-Zhong Du, Jian You, Fu-Qiang Hu, Su Zeng, Preparation and characteristics of nanostructured lipid carriers for control-releasing progesterone by melt-emulsification, Colloids Surf. B-Biointerf. 60 (2007) 174–179.
5. Volkhard Jenning, Andreas F. Thunemann, Sven H. Gohla, Characterisation of a novel solid lipid nanoparticle carrier system based on binary mixtures of liquid and solid lipids, Int. J. Pharm. 199 (2000) 167–177.
6. E.B. Souto, S.A. Wissing, C.M. Barbosa, R.H. Müller, Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery, Int. J. Pharm. 278 (2004) 71–77.
7. Fei Han, Sanming Li, Ran Yin, Hongzhuo Liu, Lu Xu, Effect of surfactants on the formation and characterization of a new type of colloidal drug delivery system:Nanostructured lipid carriers, Colloids and Surfaces A: Physicochem. Eng. Aspects 315 (2008) 210–216.
8. Rainer H. Muller, Cornelia M. Keck, Challenges and solutions for the delivery of biotech drugs – a review of drug nanocrystal technology and lipid nanoparticles, J. Biotech. 113 (2004) 151–170.
9 9. David J. Begley, Delivery of therapeutic agents to the central nervous system: the problems and the possibilities, Pharmacology & Therapeutics 104 (2004) 29– 45.
10. Jian-Xin Wang, Xun Sun, Zhi-Rong Zhang, Enhanced brain targeting by synthesis of 30,50-dioctanoyl-5-fluoro-20-deoxyuridine and incorporation into solid lipid nanoparticles, Eur. J. Pharm. Biopharm. 54 (2002) 285–290.
11. Kenjiro Ono a, Kazuhiro Hasegawa b, Hironobu Naiki b, Masahito Yamada, Preformed b-amyloid fibrils are destabilized by coenzyme Q10 in vitro, Biochemical and Biophysical Research Communications 330 (2005) 111–116.
12. Makoto Sohmiya, Makoto Tanaka, Nyou Wei Tak, Makoto Yanagisawa, Yutaka Tanino,Yoko Suzuki, Koichi Okamoto, Yorihiro Yamamoto, Redox status of plasma coenzyme Q10 indicates elevated systemic oxidative stress in Parkinson’s disease, Journal of the Neurological Sciences 223 (2004) 161– 166.
13. Veerawat Teeranachaideekul, Eliana B. Souto, Varaporn B. Junyaprasert, Rainer H. Muller, Cetyl palmitate-based NLC for topical delivery of Coenzyme Q10 – Development, physicochemical characterization and in vitro release studiesCetyl palmitate-based NLC for topical delivery of Coenzyme Q10 – Development, physicochemical characterization and in vitro release studies, Euro. J. Pharm. Biopharm. 67 (2007) 141–148.
14. Jana Pardeike, Kay Schwabe, Rainer H. Müller, Influence of nanostructured lipid carriers (NLC) on the physical properties of the Cutanova Nanorepair Q10 cream and the in vivo skin hydration effect, Int. J. Pharm. 396 (2010) 166–173.
15. Varaporn B. Junyapraserta, Veerawat Teeranachaideekul, Eliana B. Soutoc, Prapaporn Boonmed, Rainer H. Müller, Q10-loaded NLC versus nanoemulsions: Stability, rheology and in vitro skin permeation, Int. J. Pharm. 377 (2009) 207–214.
16. Wen-Chuan Leea, Tung-Hu Tsai, Preparation and characterization of liposomal coenzyme Q10 for in vivo topical application, Int. J. Pharm. 395 (2010) 78–83.
10 17. Slavomíra Doktorovová, Joana Araújo, Marisa L. Garcia, Erik Rakovsky, Eliana B. Souto, Formulating fluticasone propionate in novel PEG-containing nanostructured lipid carriers (PEG-NLC), Colloids Surf. B-Biointerf. 75 (2010) 538–542.
18. Chun-Yang Zhuang, Ning Li, Mi Wang, Xiao-Ning Zhang, Wei-San Pan, Jun-Jie Peng, Yu-Sheng Pan, Xin Tang, Preparation and characterization of vinpocetine loaded nanostructured lipid carriers (NLC) for improved oral bioavailability, Int. J. Pharm. 394 (2010) 179–185.
19. E.B. Souto, S.A. Wissing, C.M. Barbosa, R.H. Müller, Development of a controlled release formulation based on SLN and NLC for topical clotrimazole delivery, Int. J. Pharm. 278 (2004) 71–77.
11 9. SIGNATURE OF THE CANDIDATE
10. REMARKS OF THE GUIDE Recommended
11. NAME AND DESIGNATION OF
11.1 Guide Dr. Basavaraj K. Nanjwade. M. Pharm. Ph.D Professor of Pharmaceutics
11.2 Signature
11.3 Co-Guide ( If any) ------
11.4 Signature
11.5 Head of the Department Prof. J K. Saboji, M.Pharm Professor & Head Department of Pharmaceutics
11.6 Signature
12. 12.1 Remarks of the Chairman Forwarded to the University for approval Principal
12.2 Signature
Principal Prof. J K. Saboji, M.Pharm KLES’s College of Pharmacy Akkol road, Nipani, 591 237.
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