“FORMULATION AND DEVELOPMENT OF EMULSION OF
AN ANTIANXIETY DRUG”
SYNOPSIS FOR
M.PHARM DISSERTATION
SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA
BY
PREM KUMAR REDDY PALLE
I M.PHARM
DEPARTMENT OF PHARMACEUTICAL TECHNOLOGY
PES COLLEGE OF PHARMACY
BANGALORE-560 050
(2011-2013)
2
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the candidate and address / PREM KUMAR REDDY PALLE1st M. PHARM (PHARMACEUTICAL TECHNOLOGY)
PES COLLEGE OF PHARMACY
HANUMANTHANAGAR
BANGALORE-560 050
PERMANENT ADDRESS:
S/O P. VENKAT RAMA REDDY
ITIKYALAPADU (VILLAGE), MANOPADU(MANDAL),
MAHABOOBNAGAR (DIST), A.P. 509153
2. / Name of the institution / PES COLLEGE OF PHARMACY
HANUMANTHA NAGAR
B.S.K.1st STAGE
BANGALORE:-560 050
3. / Course of the study / MASTER OF PHARMACY
(PHARMACEUTICAL TECHNOLOGY)
4. / Date of Admission / 30th JULY 2011
5. / Title of the topic:
“FORMULATION AND DEVELOPMENT OF EMULSION OF
AN ANTIANXIETY DRUG”
6. / Brief resume of the intended work:
6.1 Need for the study:
The benzodiazepines are drugs used generally in the symptomatic relief of anxiety and tension states resulting in stressful environment or emotional factors. Moreover they do not induce a true “anesthetic effect” since awareness is still present and total muscle relaxation is not obtained even after long doses. Anterograde amnesia may take place and this creates the illusion that anesthesia has occurred1. Benzodiazepines exert their tranquilizing effect by potentiating the effects of gamma-aminobutyric acid (GABA), an inhibitory transmitter, by binding to the specific benzodiazepine receptor sites2. Many generic and parentral formulations are available for different benzodiazepines like alprazolam, clonazepam, diazepam etc. The preparation of emulsion of benzodiazepines is essential in maintaining the release and dosage; they also increase the solubility and bioavailability3.
Nanoemulsions, with a characteristic droplet size of 20-200 nm (generally less than 1 micrometer) were developed around 20 years ago. They are often referred to as mini, submicron, ultrafine or fine dispersed emulsions, and appear transparent to the naked eye due to the inability of nanoparticles to scatter light. Nanoemulsion formulations either involve oil droplets dispersed in aqueous medium (O/W) or the reverse (W/O) or both. The major routes for the administration of drugs using these vehicles, viz., oral, parentral, transdermal and intranasal channels. The drug administration usually adopted for actives with low bioavailability and narrow therapeutic index. Their capacity to dissolve large quantities of hydrophobic, along with their mutual compatibility and ability to protect the drugs from hydrolysis and enzymatic degradation makes them ideal vehicles for drug delivery3.
By formulation of nanoemulsion of benzodiazepine the frequency and dosage of injections can be reduced throughout the drug therapy period as these emulsions guarantee the release of drugs in a sustained and controlled mode over long periods of time and the lack of flocculation, sedimentation and creaming, combined with a large surface area and free energy, offer obvious advantages over emulsions of larger size4.
6.2 Review of the literature:
£ Catarina PR et al., they prepared insulin loaded alginate-dextran nanoemulsion. They prepared by employing the aqueous solution of low viscous sodium alginate (2%w/v) and dextran sulphate(2.75%w/v) and overnight stirring on orbital shaker(100 rpm) then insulin was added and allowed for deareation then suspension of calcium carbonate was added and sonicated, resulted was emulsified with paraffin oil aided by span 80 (1.5% v/v) by using mixing propeller at 1600 rpm and after 15 minutes 20 ml of paraffin oil was added to trigger the gelation and nanospheres were collected by centrifugation. Nanospheres were characterized for mean size and distribution by laser diffraction spectroscopy and for shape by transmission electronmicroscopy. Insulin encapsulation efficiency and in vitro release were determined by Bradford protein assay and bioactivity determined in vitro using a newly developed Western blot immunoassay and in vivo using Wistar diabetic rats. Nanospheres ranged from 267nm to 276nm in diameter demonstrated a unimodel size distribution, encapsulation efficiency was 82.5% and suppressed insulin release in acidic media and promoted a sustained release at near neutral conditions. Nanoencapsulated insulin bioactive was demonstrated through both in vivo and in vitro bioassays5.
£ Hiroshi F et al., A low dose therapeutic system with lipid emulsions for amphotericin B (AmB) an antifungal drug as LNS (lipid nano spheres) and conventional LM(lipid microspheres) and observed LNS as suitable candidate. They prepared emulsion by using egg lecithin, soya bean oil and by using solvent chloroform and methanol(2:1 V/V) and the organic solvent was removed by using pressure to form paste to which 5% dextrose was added and emulsified by sonification in an ice water bath for 60 min for LNS and 30 min for LM and the final dispersion was filtered using 2 micron filter for LNS and 4 micron filter for LM and plasma concentrations were taken and fitted in two compartment model and concluded LNS as a good candidate6.
£ Letecia SK et al., Carbamazepine (CBZ), a widely used anticonvulsant drug, is a poorly soluble drug with no parenteral treatment available for. The spontaneous emulsification method was used to prepare different formulations containing 2 mg/mL CBZ. The nanoemulsions were evaluated concerning droplet size, zeta potential, viscosity, drug content and association to oily phase.
The formulation, which presented the best characteristics required of intravenous administration, was selected. This formulation was characterized and kept its properties in a satisfactory range over the evaluated period (3 months), i.e. droplet size around 150nm photon correlation spectroscopy, drug content around 95% and zeta potential around −40mVelectrophoretic mobility technique. The transmission electron microscopy revealed emulsion droplets almost spherical in shape with an amorphous core, whereas the in vitro release profile assessed by dialysis bags demonstrated with 95% of Carbamazepine having been released within 11h7.
£ Koester LS et al., They developed nanoemulsions intended for intravenous administration of thalidomide (THD). The formulations were prepared by spontaneous emulsification method and optimized with respect to thalidomide (0.01–0.05%, w/w), and hydrophilic emulsifier (polysorbate 80; 0.5–4.0%,w/w) content. The formulations were evaluated concerning physical appearance and drug crystallization; droplet size; zeta potential and drug assay. Only the formulation containing 0.01% THD and 0.5% polysorbate kept its properties in a satisfactory range over the evaluated period (60 days), i.e. droplet size around 200 nm by photon correlation spectroscopy (PCS), drug content around 95% and zeta potential around −30 mV electrophoretic mobility using. The transmission electronmicroscopy revealed emulsion droplets almost spherical in shape confirming the results obtained by photon correlation spectroscopy8.
£ Santo MNS et al., They formulated benzathine penicillin G nanoemulsion and nanocapsules, to evaluate their physicochemical and stabilizing characteristics, and to determine their antimicrobial activity and
penicillin invitro release kinetics. Nanoemulsions were produced by the spontaneous emulsification approach and nanocapsules of poly (D,L-lactic acid-co-glycolic acid) polymer (PLGA) were prepared by the method of interfacial deposition of a pre-formed polymer. A 20798 nm mean diameter nanoemulsion formulation maintained stability for more than 5 months at 4°C. Stable nanocapsules with 224958 nm mean diameter were obtained, which remained stabilized over 120 days at 4°C. The penicillin encapsulation ratio in the nanocapsules was 85%. The in vitro release profiles indicated that penicillin released from the nanoemulsion was similar to the one observed from Nanocapsules9.
£ Daftary et al., they prepared a stable oil in water injection of docetaxel having high concentration 20mg/ml, devoid of hypersensitivity reactions and fluid retention. It is prepared by dissolving the drug in synthetic triglyceride oil as oil phase and polyhydric alcohol in water for injection as aqueous phase. The N-(carbonyl-methoxypolyethyleneglycol2000)-1,2-distearoyl-sn-gleroyl-3-phosphoethnolamine (DSPE PEG-2000) is dispersed in oil phase or aqueous phase or partially in both. Then oil phase is added to aqueous phase and homogenized to get average globule size less than 200 micrometers. Then acidified to PH 4 and filtered aseptically from 2 micron filter and filled in vials10.
£ Karen IW et al., they prepared nanoparticles of haloperidol a hydrophobic drug encapsulated in PLGA and PLA polymers by two process like emulsification by homogenization solvent evaporation and sonication-solvent evaporation to get nanoparticles with 200–1000 nm diameters and 0.2–2.5% drug content. Then the three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating as the increasing the polymer hydrophobicity reduces the initial burst and extends the period of release, increasing the particle size reduces the initial burst and increases the rate of release. Experimental in vitro drug release data were fitted with available mathematical models in literature to establish that the mechanism of drug
release is predominantly diffusion controlled11.
£ ZhiYong Q et al., they developed, a novel local hydrophobic drug delivery system: nanoparticles in thermo-sensitive hydrogel, was demonstrated. First, honokiol, as a model hydrophobic drug, loaded poly (є-caprolactone)-poly (ethylene glycol)-poly (є-caprolactone) (PCEC) nanoparticles were prepared by emulsion solvent evaporation method, and then were incorporated into thermo-sensitive F127 hydrous matrix. T. Honokiol release profile in vitro was studied, and the results showed that honokiol could be sustained released from the system have great potential application for local delivery of hydrophobic drugs such as honokiol12.
£ Calum JD et al., They presented a nanostructured nanoparticle system that can be prepared and characterized in a high-throughput fashion. They used phytantriol and MyverolTM to prepare inverse bicontinuous cubic and inverse hexagonal liquid crystalline nanoparticles loaded with 10 commonly used therapeutic agents at increasing concentration. The dispersions are prepared using automated apparatus to create different concentrations and phases using novel protocols. They characterized each stabilized nanoparticle dispersion using a range of methodologies including small angle X-ray scattering, particle sizing and drug partitioning13.
£ Maria JGC et al., The formation of O/W nano-emulsions suitable for pharmaceutical application and the solubilisation of a practically non-water-soluble drug, lidocaine, have been studied in water/non-ionic surfactant/oil systems. Nano-emulsions were prepared by using low-energy emulsification methods, changing the composition at constant temperature. Kinetic stability was assessed by measuring droplet diameter as a function of time. Lidocaine solubilisation was studied in nano-emulsions with high water content. In the water/Cremophor EL/Miglyol 812 system the lowest droplet sizes, from 14 to 39 nm at 10/90 and 40/60 oil/surfactant ratios, respectively, and 90% of water content, were obtained with an emulsification method consisting of stepwise addition of water to oil/surfactant mixtures at 70◦C resulted in maximum
Lidocaine solubilisation14.
£ Sierakowski MR et al., Enalaprilate (Enal), an active pharmaceutical component, was intercalated into a layered double hydroxide (Mg/Al-LDH) by an ion exchange reaction. The use of a layered double hydroxide (LDH) to release active drugs is limited by the low pH of the stomach (pH ∼1.2), in whose condition it is readily dissolved. To overcome this limitation, xyloglucan(XG) extracted from Hymenaea courbaril seeds, Brazilian species, was used to protect the LDH and allow the drug to pass through the gastrointestinal tract The resulting hybrid system containing HDL–Enal–XG(3) slowly released the Enalaprilate15.
£ Vanessa CFM et al., They worked in preparation, characterization and the investigation of the release profiles of radiolabeled fluconazole nanocapsules (NC). The size, homogeneity and zeta potential of NC preparations were determined. The preparation and invitro release of two radiolabeled forms the conventional and the surface modified NC was done and suggest that surface-modified nanocapsules could constitute a long-circulating intravenous formulation of fluconazole for treating sepsis caused by disseminated form of candidiasis16.
£ Lee CH et al., The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. ES nanoparticles containing a model compound (sodium fluorescein (FNa) or nile red (NR)) were prepared. Both hydrophilic and hydrophobic model drugs remained stable in nanoparticles at acidic pH, whereas they are quickly released from nanoparticles upon exposure at physiological pH. The study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release, with no cytotoxic activities. The pH-sensitive nanoparticles would be a promising carrier for the vaginal-specific deliver17.
£ Chong KK et al., Flurbiprofen microemulsion composed of ethyl oleate, lecithin and distearoylphosphatidyl-ethanolamine-N-poly (ethyleneglycol) 2000 (DSPE-PEG) were prepared using ethanol as a cosolvent by spontaneous emulsification method. The effect of formulation variables on the particle size of the microemulsion was investigated. Flurbiprofen concentrations in plasma
and various organs, biodistribution and reticuloendothelial uptake of Flurbiprofen loaded in this microemulsion was quite different compared with that in solution or Lipfen®. It is concluded that the current microemulsion system might be applicable to formulate the parenteral dosage form of poorly water-soluble flurbiprofen without chemical modification18.
6.3 Main objectives of the study:
1. To carry out the preformulation studies.
2. To formulate emulsion of an antianxiety drug.
3. To characterize the properties of emulsion.
4. To perform the in vitro release studies of emulsion.
5. To carry out the stability studies of the optimized formulation.
7 / 7.1 Source of data
· The data will be obtained from the literature survey, internet source and experimental work. The data will be obtained from the experimental work, which includes formulation and optimization of nanoemulsion, scale up techniques and stability studies of optimized formulation.
7.2 Method of collection of data (including sampling procedures if any)
· The pharmacological details of the drug will be collected from various standard books, journals and other sources like research literature databases such as Medline, Pubmed, Science direct, etc.
· Experimental data will be collected from the designed formulation and then subjecting the formulation to different evaluation techniques and stability studies obtained from Strides Arcolabs FDA approved facility in Bengaluru.
7.3 Does the study require any investigation or interventions to be
Conducted on patients or other humans or animals?
NO
7.4 Has ethical clearance been obtained from your institution in case of in vivo study?
Not Applicable
8. /
List of References
1. Remington. The Science and Practice of Pharmacy. Vol II. 21st ed.2. Lippincott. The Essentials of pharmacology. 5thed. 2007.
3. Reza A. Nanometric-scaled emulsions (Nanoemulsions). Iran J Pharm Res. 2010;9(4):325-6.
4. Marie G, Angelica V, Robert G, Florence D. Nanoparticles for drug delivery:The need for precision in reporting particle size parameters. Eur J Pharm Biopharm. 2008;69:1–9.
5. Catarina PR, Antonio JR, Simone H, Francisco V, Ronald JNC. Nanoparticulate delivery system for insulin:Design, characterization and in vitro/in vivo bioactivity. Eur J Pharm Biopharm. 2007;30:392–7.
6. Hiroshi F, Tomohiro K, Akira S, Satoru S, Junzo S. A novel delivery system for amphotericin B with lipid nano-sphere (LNS®). Int J Pharm. 2003;265:37–45.
7. Regina GK, Gislaine K, Helder FT, Leticia SK. Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process. Int J Pharm Pharm Nanotechnol. 2007;342:231–9.
8. Araujo FA, Kelmann RG, Araujo BV, Finatto RB, Teixeira HF, Koester L. Development and characterization of parenteral nanoemulsions containing Thalidomide. Eur J Pharm Biopharm. 2011;42:238–45.
9. Santos MNS, Pontes A, Pereira VMW, Caetano MNP. Colloidal carriers for benzathine penicillin G:Nanoemulsions and nanocapsules. Int J Pharm. 2000;208:71–80.
10. Daftary. US patent publication. 2011;0275705A1.
11. Avinash B, Steven JS, Karen IW. Controlling the in vitro release profiles for a system of haloperidol-loaded PLGA nanoparticles. Int J Pharm Pharm Nanotechnol. 2008;346:151–9.
12. Goua M, Li X, Daia M, Gonga C, Wanga X, Yao X, et al. A novel injectable local hydrophobic drug delivery system:Biodegradable nanoparticles in thermo-sensitive hydrogel. Int J Pharm Pharm Nanotechnol. 2008;359: 228–33.
13. Muleta X, Danielle FK, Charlotte EC, Adrian H, Calum JD. High throughput preparation and characterisation of amphiphilic nanostructured nanoparticulate drug delivery vehicles. Int J Pharm Pharm Nanotechnol. 2010;395:290–7.
14. Nuria S, Conxita S, Nuria A, Maria JGC. Studies on the formation of O/W nano-emulsions, by low-energy emulsification methods, suitable for pharmaceutical applications. Eur J Pharm Biopharm. 2005;26:438–45.
15. Ribeiroa c, Arizagab GGC, Wypychb F, Sierakowski MR. Int J Pharm Pharm Nanotechnol. 2009;367:204-10.
16. Danielle NDA, Vanessa CFM, Jose MCV, Margareth SA, Valbert NC. Release profiles and morphological characterization by atomic force microscopy and photon correlation spectroscopy of 99mTechnetium-fluconazole nanocapsules. Int J Pharm. 2008;349:152–60.
17. Jin WY, Namita G, Chi HL. pH-sensitive Eudragit nanoparticles for mucosal drug delivery. Int J Pharm Pharm Nanotechnol. 2011;403:262–7.
18. Kyung MP, Mi KL, Ki JH, Chong KK. Phospholipid-based microemulsions of flurbiprofen by the spontaneous emulsification process. Int J Pharm. 1999;183:145–54.
9.
10.
11.
12. /
Signature of the candidate:
(PREM KUMAR REDDY PALLE)
Remarks of Guide: RECOMMENDED
Name And Designation of: Dr. S.J. SHANKAR. M. Pharm, Ph.D.
11.1 Guide Professor Head,
Department of Pharmaceutical Technology,
P.E.S College of Pharmacy,
Banglore-50.
11.2 Signature
11.3 Co-Guide Dr. M. S. Vijay Kanth,
Group Leader, FDD-NDDS,
Strides Specialties Private Limited,
Bilekalli, Bannerghatta Road,
Bangalore - 560 076.
+91 80 66580252 (D)/ 99 00 054912,
11.4 Signature
11.5 Head of the department Dr. S. J. SHANKAR. M. Pharm, Ph.D.
Professor Head,
Department of Pharmaceutical Technology,
P.E.S College of Pharmacy,
Banglore-50.
11.6 Signature
12.1 Remarks of the Chairman and Principal:
Prof. Dr. S. Mohan
Principal & director,
P.E.S College of Pharmacy,
Bangalore-50.
12.2 Signature
14