Indian Journal of Pharmaceutical and Biological Research (IJPBR)

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1 Indian J.Pharm.Biol.Res. 2014; 2(2):1-6 CODEN (USA): IJPB07 ISSN: Indian Journal of Pharmaceutical and Biological Research (IJPBR) Journal homepage: Original Research Article Comparative Evaluation of semisolid bases for transdermal use of Ketorolac tromethamine Ajay Aggarwal 1, Kamal Saroha* 1, Sanju Nanda 2 1 Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra, India. 2 Department of Pharmaceutical Sciences, Maharishi Dayanand University, Rohtak, India. ARTICLE INFO: Article history: Received: 20 March 2014 Received in revised form: 29 March 2014 Accepted: 3 April 2014 Available online: 15 June 2014 Keywords: Ketorolac tromethamine, Ointment, Formulations, Cream, Gel, Drug content. ABSTRACT Ketorolac tromethamine (KT) is a non-steroidal anti-inflammatory drug that belongs to class of heteroacetyl derivatives. An attempt has been made to make use of ointments, creams and gels as suitable vehicles for KT, which will released the drug effectively on surface when applied topically. Formulations belongs to ointment, cream and gel bases containing 1% KT were prepared and were evaluated for physiochemical parameters like physical appearance, ph, viscosity, spreadability, drug content. Drug release was also studied by in-vitro techniques. Viscosity was found highest in ointment formulation F3 Gel formulation showed better extrudability and spreadability as compared to ointment and creams. Gel formulation showed better release as compared to ointment and creams. Introduction Ketorolac tromethamine is a potent non narcotic analgesic with moderate anti-inflammatory activity. It has been investigated extensively for use in post-operative analgesia both as a sole agent and supplement opioid analgesics and excellent applicability in the emergency treatment of post operative cancer pain and in the treatment of migraine pain [1].Among various non-steroidal anti-inflammatory drugs (NSAIDS), Ketorolac tromethamine (KT) exhibit potent analgesic and antiinflammatory activities by inhibiting prostaglandin synthesis[2,3]. The analgesic activity of ketorolac tromethamine is comparable to morphine [4]. Although oral bioavailability of KT was reported to be 90% with a very low first pass metabolism, but it accompanies adverse effects like other NSAIDS including gastrointestinal irritation, ulcers, bleeding due to localized high concentration of drug in gastrointestinal lumen when administered orally. Topical administration of KT offers the advantage of enhanced drug delivery to the affected sites with a reduced incidence of GI side effects [5]. To avoid invasive drug therapy such as injections and to eliminate frequent dosing regimen with oral administration, a transdermal drug delivery system has been studied as an alternative dosage form. In addition to the noninvasive therapy and maintaining the drug blood levels for an extended period of time, the transdermal delivery system has several advantages: it avoids first-pass metabolism, it is easy to discontinue the administration, and it reduces side effects. The effectiveness of transdermal dermatological product is greatly influenced by the type of base used in formulating the product [8]. Various bases have been used for TDDS like ointments, lotions, creams, pastes and gels [6]. Bases consist of oleaginous substances which provide an emollient effect to dry irritated skin. Creams have good emollient properties with some degree of occlusion especially W/O type. The less hydrophobic films formed by O/W creams and water soluble bases don t provide an occlusive barrier to skin & thus allow moisture to escape from its surface. Gels facilitate greater drug permeation into the skin as compared to ointment and cream. Gels have higher aqueous component that permits high dissolution of drug & permit easier migration of the drug to the vehicle that is essentially a liquid compared with ointment and creams. Gels are superior in term of use & patient acceptability. In present study we formulated KT in different transdermal bases including ointment, creams and gels. All the formulations were compared I terms of various physical parameters like ph, * Corresponding Author: Kamal Saroha, Institute of Pharmaceutical Sciences, Kurukshetra University, Kuruksetra, India. kamal_kuk@rediffmail.com 1

2 viscosity, drug content, spreadability and extrudability. Drug release from bases and stability study was also studied. Materials and methods Ketorolac tromethamine was received as a gift sample from Ranbaxy laboratory ltd., Gurgaon, India. Carbopol, liquid paraffin, triethanolamine and other chemicals were of analytical grade and used without further purification. Formulation of ointment: KT Ointment (F1) KT Ointment (F2) Table 1: Composition of the KT Ointment (F1) 1 White Wax 5 2 White petroletum 95 Table 2: Composition of the KT Ointment (F2) KT Ointment (F3) S.No Ingredients Quantity(mg) 1 Cholesterol 3 2 Stearyl Alcohol 3 3 White Wax 8 4 White Petrolatum 86 Table 3: Composition of the KT Ointment: (F3) 1 PEG PEG Formulation of KT cream KT Cream (F4) Table 4: Composition of the KT Cream (F4) 1 White wax Cetyl Esters Wax (or Spermaceti) Mineral Oil (Sp Gr = 0.9) Sodium Borate Water 19.0 KT Cream (F5) Table 5: Composition of the KT Cream (F5) 1 Sodium lauryl sulfate 1 2 Propylene glycol 12 3 Stearyl alcohol 25 4 White petrolatum 25 5 Purified water 37 Original Research Article 2

3 Formulation of KT gel Table 6: Composition of the KT gel (F6) S.No. Composition KT gel (g) 1 KT Carbopol Propylene glycol Polyethylene glycol Glycerin Peppermint oil Ethanol Triethanolamine Distil. Water 46.9 Evaluation of ointments, creams and gels [9-13] Physical appearance and Homogeneity The physical appearance and homogeneity of the prepared ointments, creams and gel were tested by visual observations after the formulations have been set in the container. They were tested for their appearance and presence of any aggregate. Measurement of ph The ph of various formulations was determined by using digital ph meter. One gram of formulation was dissolved in 100 ml distilled water and stored for two hours. The measurement of ph of each formulation was done in triplicate and average values are calculated. Viscosity study The measurement of viscosity of the formulations was done with Brookfield Viscometer.(Table 7) Spreadability The spreadability of the each formulation was determined using the following technique: 0.5g formulation was placed within a circle of 1 cm diameter pre-marked on a glass plate over which a second glass plate was placed. A weight of 500 g was allowed to rest on the upper glass plate for 5min. The increase in the diameter due to spreading of the formulation was noted. Extrudability The extrusion of the every formulation from the tube is an important during its and in patient acceptance. This study is useful in explaining whether the formulation is removing from the collapsible tube during in proper manner or not. Semisolid base with high consistency may not extrude from the tube whereas, low viscous may flow quickly, and hence suitable consistency is required in order to extrude from the tube. The formulations were filled into collapsible aluminium tubes. The tubes were pressed to extrude the 0.5 cm ribbon of the formulation in 10 second and the extrudability of formulations was checked. Drug content A specific quantity (10mg) of each formulation was taken and dissolved in 100ml of phosphate buffer of ph 7.4. The volumetric flask containing the solution was shaken for 2hr on mechanical shaker in order to get complete solubility of drug. This solution was filtered and estimated spectrophotometrically at 322 nm using phosphate buffer (ph 7.4) as blank. In-Vitro release study Dissolution study was carried out across egg membranes by using USP apparatus-ii, paddle type for 8 hr. The stirring rate was 50 rpm. Phosphate buffer ph 7.4 was used as medium (900 ml) and was maintained at 37 ± C. Samples (5ml) were collected periodically at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hr and assayed for dissolution spectrophotometrically at 322 nm. Each sample was replaced with equal volume of fresh dissolution medium, and dissolution rate test was repeated thrice and average values were reported. Result and Discussion The physical appearance of formulations was checked and compared visually and by physical. The gel formulation F6 was found translucent, smooth & non-greasy on, slightly glossy in nature and ointments formulations F1-F3 was greasy & opaque in appearance. The ph of all formulations was found to be suitability for on the skin. Results from extrudability indicated that gel F6 had better extrudability than other & marketed formulation when they were extruded from metallic collapsible tubes. Results of spreadability as shown in table showed that gel F6 gave better spreadability than ointments and creams. All the formulations were found to contain the labeled amount of KT. The viscosity of gel base F6 Original Research Article 3

4 was found to be least at 2.5 rpm. In-vitro diffusion studies were carried out and release profile is shown in table. The carbopol 940 gel showed better release compared with PEG ointment and cream base. The ointment bases like anhydrous and oleaginous base showed average release. Based on results, F3 and F6 were selected and compared with marketed preparation. The Rf value of 0.61 has been reported for KT using solvent toluene: ethyl acetate: acetic acid (6:2:1 v/v) as mobile phase. & pretreated silica gel as stationary phase. In present study, an Rf value of pure drug & all formulations was found to close to 0.61.These results prove the intact nature of drug and rule out the presence of any degraded product of KT. The results of stability studies are shown in table & there are no significant changes in drug content after 12 weeks in all tested formulations. In-vitro release study: Table 8: %Cumulative Drug Release for formulations F1-F7 S. No Formulation Code % CDR (in 12hr) F F F F F F F %CumulativeDrug Release F1 F2 F3 F4 F5 F6 Formulation Code F7 Fig 1: In-Vitro drug release of formulations (F1-F7) Original Research Article 4

5 Characterization of formulations by thin layer chromatography Aggarwal et al. / Indian J. Pharm. Biol. Res., 2014; 2(2):1-6 Formulation code Distance travelled in cm Rf value F F F F F F Pure drug 6.1cm 0.61 Stability Study of Formulations Formulations Initial 2 nd week 4 th week 6 th week 8thweek 10 th week 12 th week F F F F F F Table 7: Value of appearance, ph, percent drug content, viscosity, spreadability and extrudability of formulations Formulation Code F1 F2 F3 F4 F5 F6 Appearance ph* Spreadibility (cm) White,non-greasy in White,non-greasy in White,non-greasy in White,smooth on White,smooth on anslucent,white smooth on Drug Content analysis* *each reading is an average of three determinations. +++Excellent,++good,+satisfactory Extrudability Viscosity Measurement (Cps) 6.9± ± ,832± ± ± ,928± ± ± ,219± ± ± ,676± ± ± ,704± ± ± ,675±21.54 Conclusion When semisolid preparations of drugs are used for the external to the skin, the choice of suitable base plays an important role in delivering the drug to the skin. We have formulated different types of dermatological semisolids incorporating 1% Ketorolac tromethamine in each. The preparations include ointments, creams and gel. It has been concluded that the gel formulation showed better release compared to other ointment and cream formulations.it has been observed that PEG base also play a significant role in enhancing the release of drug, which could be due to their Original Research Article 5

6 ability in solubilising KT. Anhydrous & oleaginous bases showed poor release. Among all the formulations, F6 (36.69% release) showed best result & suitable for local delivery of KT. Permeation enhancers can be used for enhance further release of drug from gel base. Conflict of interest statement We declare that we have no conflict of interest. References 1. Andrade JR., Maslanka M., Maneatis T., Bynum L., Burchomore M., The use of Ketorolac tromethamine in the management of post operative pain, Orthopedics. 1994; 17: Buckley MM, Brogden RN: Ketorolac: A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990; 39 (1): Rooks WH,: The analgesic and anti-inflammatory profile of ketorolac and its tromethamine salt. Drugs Exp. Clin. Res. 1985; 11 (8): Dubey R, Bommagani M, Venkateswarlu V, Mullangi R, Karnati, Thammera RK and Menon VCA. Ketorolac Tromethamine Transdermal Gel, Development, In Vitro and In Vivo Evaluation. Journal of Pain & Palliative Care Pharmacotherapy, 2009;23(1): Reinhart DI: Minimizing the adverse effects of ketorolac. Drug Safety 2000; 22: Howard C. Ansel, In: Introduction to pharmaceutical dosageforms,4 th edn., Lea & Febiger, Philadelphia,1985, Panda P and Ghosh A. Formulation and Evaluation of Topical Dosage Form of Eupatorium Odoratum Linn. and Their Wound Healing Activity. International Journal of Pharma and Bio Sciences. 2010;1(2): Suwanpidokkul N, Thongnopnua P, Umprayn K. Trans-dermal delivery of zidovudine: The effects of vehicles, enhancers, and polymer membranes on permeation across cadaver pig skin. AAPS Pharm. Sci.Tech. 2004;5(3): Rashmi. Topical Gel: A Review. Pharmainfo.net Gupta A, Mishra AK, Singh AK, Gupta V and Bansal P. Formulation and evaluation of topical gel of diclofenac sodium using different polymers. Drug Invention Today 2010; 2 (5): Nair R, Sevukarajan M, Mohammed B, Kumar J. Formulation of microemulsion based vaginal gel-in vitro and in vivo evaluation. Der Pharmacia Lettre 2010; 2(6): Hobart.H, Willard and Lynnel, Merrit J.R., Instrumental methods of analysis, Hobart.H, Willard and Lynnel, Merrit J.R. 7 th edn, Hobert.H, Vogel, G.H,Jeffery.J, Mendham and R.C.Denney., Text book of Quantitative chemical analysis 5th edn, Cite this article as: Ajay Aggarwal, Kamal Saroha, Sanju Nanda. Comparative Evaluation of semisolid bases for transdermal use of Ketorolac tromethamine. Indian J. Pharm. Biol. Res.2014; 2(2):1-6. All 2014 are reserved by Indian Journal of Pharmaceutical and Biological Research This Journal is licensed under a Creative Commons Attribution-Non Commercial -Share Alike 3.0 Unported License. This article can be downloaded to ANDROID OS based mobile. Original Research Article 6