Formulation and Evaluation of Transdermal Gel of Ibuprofen: Use of Penetration Enhancer and Microneedle

Iranian Journal of Pharmaceutical Sciences 2020: 16 (3):11-32 www.ijps.ir Original Article Formulation and Evaluation of Transdermal Gel of Ibuprofen: Use of Penetration Enhancer and Microneedle Rabinarayan Parhia*, Sahukara Venkata Sai Goutamb, Sumanta Mondalc aDepartment of Pharmaceutical Sciences, Assam University ( A Central University), Silchar-788011, Assam, India, bDepartment of Pharmaceutics, GITAM Institute of Pharmacy, GITAM (Deemed to be University), Gandhi Nagar Campus, Rushikonda, Visakhapatnam-530045, Andhra Pradesh, India, cDepartment of Pharmaceutical chemistry, GITAM Institute of Pharmacy, GITAM (Deemed to be University), Gandhi Nagar Campus, Rushikonda, Visakhapatnam-530045, Andhra Pradesh, India. Abstract The objective of the current study was to develop Ibuprofen (IBP) gel using different polymers individually and in combination and then to select best gel formulation based on various in-vitro evaluation parameters such as bioadhesive strength, gel strength, spreadability, viscosity and drug release study. The selected gel formulation was found to be composed of 1% (w/w) each of hydroxypropyl methylcellulose (HPMC K100M) and sodium carboxy methylcellulose (NaCMC). Two techniques such as chemical method using 1,8-cineole as chemical penetration enhancer (CPE) and physical technique using microneedle were employed to improve IBP permeation across the abdominal skin of rat. Out of the two techniques, the later technique showed higher (2.865-fold) permeation enhancement compared to control. Furthermore, a synergistic effect was also observed when both the techniques were used simultaneously with 3.307-fold increase in permeation enhancement. In- vivo anti-inflammatory study on rats induced with carrageenan paw oedema and analgesic activity investigation by tail flick method in rat model exhibited sustained effect up to 8 h compared to orally treated group. The stability study at room and accelerated conditions for three months did not show any sign of instability. Thus, the developed IBP gel is stable and have potential to illicit both anti-inflammatory and analgesic effect when administered transdermally. Keywords: Analgesic activity, Anti-inflammatory activity, Ibuprofen, Microneedle, Penetration enhancers, Stratum corneum, Transdermal. 1. Introduction day-by-day since the approval of Transderm The number of drugs and their Scop® in 1979 by FDA. Furthermore, formulations, which deliver the drug across the transdermal drug delivery (TDD) is skin into systemic circulation, are increasing increasingly important for drugs that need to Parhi R, et al. / IJPS 2020; 16 (3): 11-32 Corresponding Authors: Rabinarayan Parhi, two components i.e. gelling agent and solvent Department of Pharmaceutical Sciences, Assam component, (ii) show mechanical properties as University (A Central University), Silchar-788011, Assam, India. exhibited by solid state, and (iii) each Tel: (+91) 9052983544 component is continuous throughout the Email: [email protected] Cite this article as: Parhi R, Sai Goutam S. V., Mondal system. S, Formulation and Evaluation of Transdermal Gel of Ibuprofen: Use of Penetration Enhancer and Based on the solvent used in the Microneedle, 2020, 16 (3): 11-32. preparation, gels can be of two types; water be administered for disease of chronic nature based (aqueous gels or hydrogel) or organic such as cardiovascular agent [1], pain solvent based (organogels) [6]. Hydrogels can management in rheumatoid arthritis and be defined as three-dimensional polymeric osteoarthritis etc. It is reported that a network with the presence of a large number worldwide transdermal patch market of hydrophilic groups or domain capable of approaches £2 billion and is growing at a imbibing large amount of water within [7]. In faster rate than ever [2]. In addition, some this case, the polymers may be of either FDA approved transdermal formulations such natural or synthetic origin. Hydroxypropyl as AndroGel® (testosterone gel), EstroGel®, methylcellulose (HPMC) is widely used in and Gel-Andractim (Dihydrotestosterone gel) several pharmaceutical formulations because by Unimed Pharmaceuticals, Alprox-TD of its nontoxic nature, ability to accommodate (Alprostadil Gel) by Nexmed, and Estradiol- high levels of drugs and swelling properties MDTS (metered dose transdermal spray) by [8]. Carbopol 934 (C-934) was selected on the Acrux are widely used in clinical settings. basis of its good consistency [9]. Poly TDD can be defined as discrete and self- (ethylene oxide) (PEO) is a synthetic polymer contained dosage form, when applied on the which has FDA-approval for its negligible skin delivers the drug to the systemic immunogenicity, absence of residual elements, circulation through the skin at a controlled rate forming strong solid gel and available in [3]. These dosage forms are generally applied various grades [10]. Sodium carboxy topically with systemic circulation as target methylcellulose (NaCMC) has wide range of and include gels, creams, sprays and patch pharmaceutical properties such as thickening, systems. Among all, gels with bioadhesive binding and stabilizing [11]. property are widely used as they are capable of Ibuprofen (IBP), the most commonly used delivering the drug in controlled manner in NSAID in the United States, is a propionic addition to their excellent accessibility, and acid derivatives approved for the use in the can easily be localized and terminated in the symptomatic relief of pain related to various situation of adverse effect [3, 4]. A system can elements such as rheumatoid arthritis, be called as gel when it surely satisfies osteoarthritis, ankylosing spondylitis etc [12]. following three criteria [5]: (i) have at least IBP is a non-selective inhibitor of enzyme cyclooxygenase (COX), but its 12 Formulation and Evaluation of Transdermal Gel of Ibuprofen pharmacological effects are believed to be due due to their non-toxic, non-irritating effect to to inhibition of COX-2. This resulted in the the skin at low concentration (1-5%). In decrease of prostaglandins synthesis involved addition, US-FDA categorized them in in the mediation of inflammation, pain, fever generally recognized as safe (GRAS) category and swelling. However, IBP undergoes and also possesses transdermal favourable extensive hepatic metabolism (90% of the properties such as low melting point and low administered dose metabolized to hydroxilate molecular weight [9]. In the present study we or carboxylate derivatives), which made it a have used 1,8-cineole at 5% level as CPEs to poor choice for oral administration. In enhance the permeation of IBP across skin. In addition, like other NSAID it causes recent year’s physical technique like gastrointestinal adverse effect such as gastric microneedles are successfully used to deliver irritation [12]. Molecular weight and log P not only drug molecules [17-19] but also values of IBP were 206.29 g/mol and 3.97, vaccines [20-22] and toxoid [23] for respectively. Furthermore, IBP has a half-life immunization because of their ease of of 2 h and melting point of 76°C which make administration, well tolerability in the skin and it suitable candidate for controlled release great acceptance by the patient [24]. dosage form for transdermal delivery [13]. Therefore, microneedle technique is also used It is always a challenge to develop a in this study with an intention to improve transdermal dosage form with appropriate drug penetration of IBP across the skin. penetration rate [14]. This is mainly due to The goal of the present study is to prepare formidable barrier nature of stratum corneum IBP transdermal gel and to evaluate it for (SC), the outer most layer of epidermis [14]. various parameters such as bioadhesive This barrier must be reversibly altered to strength, gel strength, diffusion, in-vitro deliver drugs at a desired rate across the skin permeation and in-vivo analgesic and anti- without permanent damage. In addition, inflammatory activity in rat model. 1,8-cineole penetration across skin is much more essential as CPE and microneedle technique as physical when a poorly penetrating drug is being method were used to improve permeation of selected for TDD. To create a reversible IBP across rat skin. Finally, stability study was modification in the skin, various techniques performed on selected gel formulation for are employed under either chemical or three months at room condition and at physical approaches. Various classes of accelerated condition. chemical penetration enhancers (CPEs) are used in chemical approach. Among all, 2. Materials and Methods terpenes were widely used in number of 2.1. Materials studies and found to enhance percutaneous IBP and polymers such as C-934, HPMC permeation of many drugs [15, 16], which is K100M, PEO and NaCMC were procured 13 Parhi R, et al. / IJPS 2020; 16 (3): 11-32 from Loba Chemi Lab, Mumbai. Dialysis system was kept for 24 h with intermittent membrane was obtained from Himedia shaking. Finally, the aqueous layer was Laboratories Pvt. Ltd, Mumbai. 1, 8-cineole separated, clarified by centrifugation and was procured from Merck Specialties Pvt. Ltd, assayed [26]. Mumbai and MNR Microneedle roller system was obtained from Amazon, India. Other 2.3. Preparation of the IBP Gel Using Various chemicals used in the experiment were of Polymers analytical grade and used as received from Appropriate amount of polymers as suppliers. specified in the Table 1 were soaked in 40 mL DW overnight and then, the swelled polymers 2.2. Pre-formulation Studies were stirred using

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