FORMULATION AND EVALUATION OF SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM OF POORLY SOLUBLE ANTHELMINTICS
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560 041
By
Ms. SHRUTHI K.V, B.Pharm
Under the Guidance of
Dr. KALYANI PRAKASAM, M.Pharm,Ph.D
Professor
Department of Pharmaceutics,
Acharya & B.M. Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post)
Hesaraghatta Main Road, Bangalore – 560 090.
2009-2010
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA, BANGALORE.
ANNEXURE - II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION
1. / Name of the Candidateand Address / Ms. SHRUTHI K.V.
D/o K.Venkappa Gowda.
“Poorvadeepa”
J.P.Road,
Sullia D.K -574239.
2. /
Name of the Institution
/ ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara Post.
Bangalore-560090
3. / Course of Study and Subject / M. Pharm
(Pharmaceutics)
4. /
Date of Admission
/20th June 09
5. TITLE OF THE PROJECT:-FORMULATION AND EVALUATION OF SELF MICROEMULSIFYING DRUG DELIVERY SYSTEM OF POORLY SOLUBLE ANTHELMINTICS
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8.0 / BRIEF RESUME OF THE INTENDED WORK:
NEED FOR THE STUDY:
A new self-microemulsifying drug delivery system (SMEDDS) has been developed to increase the solubility, dissolution rate and oral bioavailability.
Up to 40% of new chemical entities discovered by the pharmaceutical industry are poorly soluble or lipophilic compounds, which leads to poor oral bioavailability, high intra- and inter-subject variability, and lack of dose proportionality.
SMEDDSs are isotropic mixtures of oils and surfactants, sometimes containing co-solvents, and can be used for the design of formulations in order to improve the oral absorption of highly lipophilic compounds. SMEDDSs emulsify spontaneously to produce fine oil-in-water emulsions when introduced into an aqueous phase under gentle agitation. Self-emulsifying formulations spread readily in the gastrointestinal (GI) tract, and the digestive motility of the stomach and the intestine provide the agitation necessary for self emulsification.
SMEDDSs are physically stable formulations that are easy to manufacture. Thus, for lipophilic drug compounds that exhibit dissolution rate-limited absorption, these systems may offer an improvement in the rate and extent of absorption and result in more reproducible blood-time profiles.1
Anthelmentics are drugs that act either locally to expel worms from the gastrointestinal tract or systematically to eradicate adult helminthes or developmental forms that invade organs and tissues. Some of the systemic infection caused by tissue- dwelling helminthes is cysticercosis, echinococcosis, filariasis and trichinosis. Anthelminticspertaining to a substance that destroys or prevents the development of parasitic worms, such as filariae, flukes, hookworms, pinworms, roundworms, schistosomes, tapeworms, trichinae, and whipworms.
An anthelmintic drug, may interfere with the parasites carbohydrate metabolism, inhibit their respiratory enzymes, block their neuromuscular action, or render them susceptible to destruction by the host's macrophages. Drugs used in treating specific helmintic infections include albendazole, pyrantel pamoate, mebendazole, niclosamide and ivermectin.2
REVIEW OF LITERATURE :
Ø A new self-microemulsifying drug delivery system (SMEDDS) was developed to increase the dissolution rate, solubility, and, ultimately, bioavailability of a poorly water soluble drug, idebenone. Pseudoternary phase diagrams were used to evaluate the self-microemulsification existence area, and the release rate of idebenone was investigated. The mixtures consisting of Labrafac hydro or Labrafil 2609 (HLB values > 4) with the surfactant (Labrasol containing 80% Transcutol) and cosurfactant (Plurol oleique WL 1173) were found to be optimum formulations. Using the SMEDDS formulations of 5% to 20% of Labrafac hydro or Labrafil 2609 in combination with the surfactant/cosurfactant mixing ratio of 3, the microemulsion existence field was wider compared to the other SMEDDS formulations due to high affinity for the continuous phase. The in vitro dissolution rate of idebenone from SMEDDS was more than twofold faster compared with that of tablets. The developed SMEDDS formulation can be used as a possible alternative to traditional oral formulations of idebenone to improve its bioavailability. 3
Ø Celecoxib is a hydrophobic and highly permeable drug belonging to class II of biopharmaceutics classification system. Low aqueous solubility of celecoxib leads to high variability in absorption after oral administration. Cohesiveness, low bulk density and compressibility, and poor flow properties of celecoxib impart complications in it's processing into solid dosage forms. To improve the solubility and bioavailability and to get faster onset of action of celecoxib, the self-microemulsifying drug delivery system (SMEDDS) was developed. Composition of SMEDDS was optimized using simplex lattice mixture design. The SMEDDS formulation optimized via mixture design consisted of 49.5% PEG-8 caprylic/capric glycerides, 40.5% mixture of Tween20 and Propylene glycol monocaprylic ester (3:1) and 10% celecoxib, which showed significantly higher rate and extent of absorption than conventional capsule. The relative bioavailability of the SMEDDS formulation to the conventional capsule was 132%. The developed SMEDDS formulations have the potential to minimize the variability in absorption and to provide rapid onset of action of celecoxib.4
Ø A new self-emulsifying drug delivery system (SEDDS) and self-microemulsifying drug delivery system (SMEDDS) have been developed to increase the solubility, dissolution rate, and, ultimately, oral bioavailability of a poorly water soluble drug, carvedilol. The self-emulsification time following introduction into an aqueous medium under gentle agitation was evaluated. The minimum self-emulsification time was found at a Tween 80 content of 40%. The particle size distribution and zeta-potential were determined. Benzoic acid had a dual function, it improved the self-emulsification performance of SEDDS and SMEDDS in 0.1 N HCl and lead to a positively charged emulsion. The in vitro dissolution rate of carvedilol from SEDDS and SMEDDS was more than two-fold faster compared with that from tablets. The developed SEDDS formulations significantly improved the oral bioavailability of carvedilol significantly, and the relative oral bioavailability of SEDDS compared with commercially available tablets was 413%.5
Ø Atorvastatin is insoluble in aqueous solution and the bioavailability after oral administration is low. Self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin have been successfully prepared to improve its bioavailability. Droplet size, zeta-potential and long-term physical stability of the formulations were investigated. The release of atorvastatin from SMEDDS capsules was studied using the dialysis bag method in 0.1 M HCl and phosphate buffer (pH 7.4), compared with the release of atorvastatin from a conventional tablet. The bioavailability of atorvastatin SMEDDS capsules was significantly increased compared with that of the conventional tablet. SMEDDS capsules consisting of Labrafil, propylene glycol and Cremophor RH40 provided the greatest bioavailability.6
Ø Silymarin has been used to treat hepatobiliary diseases. It has a low bioavailability after being administered orally on account of its low solubility in water. To improve the dissolution rate, silymarin was formulated in the form of a self-microemulsifying drug delivery system (SMEDDS). The optimum formulation of SMEDDS containing silymarin was obtained based on the study of pseudo-ternary phase diagram. The SMEDDS consisted of 15% silymarin, 10% glyceryl monooleate as the oil phase, a mixture of polysorbate 20 and HCO-50 (1:1) as the surfactant, Transcutol as the cosurfactant with a surfactant/cosurfactant ratio of 1. The mean droplet size of the oil phase in the microemulsion formed from the SMEDDS was 67 nm. The % release of silybin from the SMEDDS after 6 hours was 2.5 times higher than that from the reference capsule. After its oral administration to rats, the bioavailability of the drug from the SMEDDS was 3.6 times higher than the reference capsule.7
Ø Acyclovir is a potent anti-viral agent useful in the treatment of Herpes Simplex Virus (HSV) infections. Oral bioavailability of acyclovir was enhanced by developing it into self-microemulsifying drug delivery system (SMEDDS). Solubility of acyclovir was determined in various vehicles. SMEDDS is mixture of oils, surfactants, and co-surfactants, which are emulsified in aqueous media under conditions of gentle agitation and digestive motility that would be encountered in the gastro-intestinal (GI) tract. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region dilution study was also performed for optimization of formulation. SMEDDS was evaluated for its percentage transmittance, Assay of SMEDDS, phase separation study, droplet size analysis, zeta potential, electrophoretic mobility, and viscosity. The developed SMEDDS formulation contained acyclovir (50 mg), Tween 60 (60%), glycerol (30%) and sunflower oil (9%) was compared with the pure drug solution by oral administrating to male albino rats. The absorption of acyclovir from SMEDDS form resulted about 3.5 fold increase in bioavailability compared with the pure drug solution.8
Ø Oral bioavailability of the poorly water-soluble drug, oridonin, was enhanced by developing it into a self-microemulsifying drug delivery system (SMEDDS). The influence of the oil, surfactant and co-surfactant types on the drug solubility and their ratios on forming efficient and stable SMEDDS were investigated in detail. The SMEDDS were characterized by morphological observation, droplet size and zeta-potential determination, cloud point measurement and in vitro release study. The optimum formulation consisted of 30% mixture of Maisine 35-1 and Labrafac CC (1:1), 46.7% Cremopher EL, and 23.3% Transcutol P. Invitro release test showed a complete release of oridonin from SMEDDS in an approximately 12h. The absorption of oridonin from SMEDDS showed a 2.2-fold increase in relative bioavailability compared with that of the suspension.9
Ø Poorly water soluble immunosuppressant, tacrolimus (FK 506) was formulated as self-microemulsifying drug delivery system (SMEDDS), as it exhibited low and erratic bioavailability. Solubility of FK 506 in various oils, surfactants cosurfactants and buffers was determined. Phase diagrams were constructed at different ratios of surfactant/cosurfactant (K(m)) to determine microemulsion existence region. The effect of oil content, pH of aqueous phase, dilution, and incorporation of drug on mean globule size of resulting microemulsions was studied. The optimized SMEDDS formulation was evaluated for in vitro dissolution profile in comparison to pure drug and marketed formulation (Pangraf capsules). The in vivo immunosuppressant activity of FK 506 SMEDDS was evaluated in comparison to Pangraf capsules. The SMEDDS yielded microemulsion with globule size less than 25 nm which was not affected by the pH of dilution medium. The SMEDDS was robust to dilution and did not show any phase separation and drug precipitation even after 24 h. Optimized SMEDDS exhibited superior in vitro dissolution profile as compared to pure drug and Pangraf capsules. Furthermore, FK 506 SMEDDS exhibited significantly higher immunosuppressant activity in mice as compared to Pangraf capsules.10
Ø Self-microemulsifying drug delivery system (SMEDDS) was formulated using a novel, indigenous natural lipophile (N-LCT) as an oily phase. SMEDDS based on N-LCT and commercially available modified oil (Capryol 90) were formulated and their application in improving the delivery of a lipophilic anti-malarial drug, beta-Artemether (BAM) was evaluated. BAM-loaded SMEDDS were characterized with respect to mean globule size and in vitro drug release profile in comparison to the marketed formulation (Larither). The parameters studied were percent parasitemia, activity against time and animal survival period. Both the BAM-SMEDDS showed excellent self-microemulsification efficiency and released >98% of the drug in just 15 min whereas (Larither) showed only 46% drug release at the end of 1h. The mean globule size for optimized BAM-SMEDDS was <100 nm. The anti-malarial studies revealed that BAM-SMEDDS resulted in significant improvement in the anti-malarial activity (P<0.05) as compared to that of (Larither) and BAM solubilized in the oily phases and surfactant.11
Ø Self-microemulsifying drug delivery systems (SMEDDS) were developed to overcome the problems of delivery and administration of piroxicam, a drug with low bioavailability and gastrointestinal irritation. The solubility of piroxicam in several oils and surfactants was determined, and the compatibility of various oils and surfactants was investigated. Ternary phase diagrams were constructed to optimal area of microemulsion, and the influence of different oily phases, surfactants and co-surfactants was studied. The droplet size and dissolution of optimal formulation were determined to prove that the dosage form is a useful delivery system for piroxicam. In the optimized piroxicam SMEDDS, cinnamic alcohol was selected that gave the maximal solubility to piroxicam. Labrafil M 1944CS, Cremophor EL and Transcotol P were used as oils, surfactant and co-surfactant, respectively. And the releasing of piroxicam was rapid and complete. The optimized SMEDDS for piroxicam was obtained.12
Ø Curcumin is a poorly water-soluble drug and its oral bioavailability is very low. A new self-microemulsifying drug delivery system (SMEDDS) has been successfully developed to improve the solubility and oral absorption of curcumin. The formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. The optimal formulation of SMEDDS was comprised of 57.5% surfactant (emulsifier OP:Cremorphor EL = 1:1), 30.0% co-surfactant (PEG 400) and 12.5% oil (ethyl oleate). The solubility of curcumin (21 mg/g) significantly increased in SMEDDS. The average particle size of SMEDDS-containing curcumin was about 21 nm when diluted in water. The dissolution study in vitro showed that more than 95% of curcumin in SMEDDS could be dissolved in pH 1.2 or pH 6.8 buffer solutions in 20 min, however, less than 2% for crude curcumin in 60 min.The in situ absorption property of curcumin-loaded SMEDDS was evaluated in intestines of rats. The results showed the absorption of curcumin in SMEDDS was via passive transfer by diffusion across the lipid membranes. The results of oral absorption experiment in mice showed that SMEDDS could significantly increase the oral absorption of curcumin compared with its suspension.13
OBJECTIVE OF THE STUDY:-
The objectives of the present study are following:-
1. To carry out pre-formulation studies.
2. To design and develop SMEDDS.
3. To carry out in-vitro release studies using U.S.P. II dissolution test apparatus.
4. To carry out stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).
MATERIALS AND METHODS:
SOURCE OF DATA:-
1) Review of literature from:
a. Journals – such as
· Indian Journal of Pharmaceutical Sciences
· European Journal of Pharmaceutical Sciences
· Asian Journal of Pharmaceutics
· International Journal of Pharmaceutics
· Journal of Pharmaceutical Research
· Study through research articles.
· The data related to details of the drug will be collected from pharma periodicals, various standard books, and other sources like literature databases such as science direct, pubmed, informa healthcare etc.
b. World Wide Web.
MethodS:-
1. A suitable poorly water soluble drug under the class of anthelmintics will be chosen for the formulation of SMEDDS.
2. The solubility of the compound will be determined in various oils (long and medium chain).
3. The best performing excipients will be selected for SMEDDS formulation.
4. The droplet size will be measured.
5. Zeta potential of SMEDDS will be measured in the absence and the presence of drug.
6. In vitropharmaceutical performance of the SMEDDS formulations will be investigated using the dialysis bag method in reverse mode using USP dissolution apparatus in the pH range 6.8 the values will be compared with the conventional dosage forms available in the market with respect to bioavailability.
7. Stability studies.
DOSE THE STUDY REQUIRES ANY INVESTIGATION TO BE CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“NO”
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3?
“NOT APPLICABLE”
REFERENCES:
1. Patel PA, Chaulang GM, Akolkotkar A, Mutha SS, Hardikar SR, Bhosale AV. Self Emulsifying Drug Delivery System: A Review. Research J.Pharm Tech.2008;1(4):313-23.
2. Wikipedia, The free Encyclopedia. Anthelmintics.[Online]. [Cited 2009 5 Dec];[screen 1]. Available from URL; http://medical-dictionary.thefreedictionary.com/Anthelmintics.
3. Kim HJ, Yoon KA, Hahn M, Park ES, Chi SC. Preparation and in vitro evaluationof self-microemulsifying drug delivery systems containing idebenone. Drug Dev Ind Pharm 2000 May;26(5):523-9.
4. Subramanian N, Ray S, Ghosal SK, Bhadra R, Moulik SP. Formulation design of self-microemulsifying drug delivery systems for improved oral bioavailability of celecoxib. Biol Pharm Bull. 2004 Dec;27(12):1993-9.
5. Wei L, Sun P, Nie S, Pan W. Preparation and evaluation of SEDDS and SMEDDS containing carvedilol. Drug Dev Ind Pharm. 2005 Sep;31(8):785-94.
6. Shen H, Zhong M. Preparation and evaluation of self-microemulsifying drug delivery systems (SMEDDS) containing atorvastatin. J Pharm Pharmacol. 2006 Sep;58(9):1183-91.
7. Woo JS, Kim TS, Park JH, Chi SC. Formulation and biopharmaceutical evaluation of silymarin using SMEDDS. Arch Pharm Res. 2007 Jan;30(1):82-9.
8. Patel D, Sawant KK. Oral bioavailability enhancement of acyclovir by self- microemulsifying drug delivery systems (SMEDDS). Drug Dev Ind Pharm. 2007 Dec;33(12):1318-26.