Aceclofenac, a Biopharmaceutical Classification System (BCS) class-II drug is a popularly used analgesic for the relief of rheumatoid arthritis which suffers from issues like poor bioavailability and gastric irritation on oral administration. Hence it was decided to formulate this drug as buccal tablets. Buccal route of drug delivery offer advantages like faster onset and improved bioavailability which make it an ideal route for drug delivery. However, the poor solubility of this drug presents a major hindrance in it being formulated as a buccal dosage form. Hence a novel solubilizer Sepitrap-80 was added to the formulation to enhance the solubility of the drug in the mucosal fluids. The objective of the present study was to evaluate the impact of the solubilizer on the drug release with various mucoadhesive polymers.
Solid dispersion of Aceclofenac was prepared with PEG (Polyethylene glycol) 6000 and the obtained granules along with Sepitrap-80 along with various mucoadhesive polymers and other tableting excipients were compressed to obtain the buccoadhesive tablets. The tablets were evaluated for the various physicochemical properties, drug content and in-vitro drug release in pH 6.8 buffer using an in-house dissolution apparatus.
Results show that Sepitrap-80 improves the compressibility property of certain tablet blends. On comparing the in-vitro drug release it was found that the solubilizer does not have any impact on the initial drug release, however it contributed in shortening the t90% of drug release. Among the various polymer studied, Hypromellose displayed the fastest initial drug release and hydroxypropyl cellulose (HPC) was the slowest (irrespective of presence of Sepitrap-80). However Sepitrap-80 shortened the t90% of HPC containing tablets from 91 minutes to 65 minutes and that of sodium alginate containing tablets from 80 minutes to 56 minutes.
The t90% of Hypromellose containing formulation was not affected by the presence of Sepitrap-80.
Sepitrap-80 contributes in improving the solubility of class-II drugs like Aceclofenac and can be used in a bioadhesive tablet formulation with Sodium alginate HPC as the mucoadhesive polymer.
Among the various routes of drug delivery, the oral route is perhaps the most preferred route for both patients and clinicians alike. However, the various disadvantages associated with per-oral route of drug delivery like hepatic first-pass metabolism and degradation within the gastrointestinal (GI) tract necessitates the investigation of other potential sites of drug administration. Transmucosal routes of drug delivery offer distinct advantages over per-oral route of drug delivery for systemic effects. Among the various transmucosal sites like nasal, vaginal, oral etc. oral route is the most commonly used route ]. The oral mucosa has two prominent sites for drug administration i.e. the buccal site for drug delivery (drug administration through the mucosal membrane lining the cheeks) and the sublingual route (floor of mouth, beneath the tongue). The sublingual mucosa is relatively permeable giving rapid absorption and acceptable bioavailability, is convenient and accessible and generally well accepted. However, the sublingual region lacks an expanse of smooth muscle or immobile mucosa and is constantly washed by a considerable amount of saliva making it difficult for device placement. On the other hand, the buccal mucosa is less permeable and is thus not able to give a rapid onset of absorption. This property however makes it more suitable for a sustained release formulation. Secondly, the buccal mucosa has an expanse of smooth muscle and relatively immobile mucosa which makes it a more desirable region for retentive systems used for oral transmucosal drug delivery. Thus the buccal mucosa is more fitted for sustained delivery applications, delivery of less permeable molecules, and perhaps peptide drugs .
Aceclofenac (ACE) is a non-steroidal anti-inflammatory drug (NSAID) belonging to the ‘phenyl acetic acid’ class. It is used as an analgesic in the treatment of rheumatoid arthritis, osteoarthritis, management of dental pain and post-operative pain. It is a BCS class II drug and possesses very slight solubility in water]. Oral bioavailability of Aceclofenac is 60-70% and half-life is 4-5 hours]. The main drawback of oral administration of Aceclofenac is its poor bioavailability due to first-pass metabolism and enzymatic degradation in the gut wall.
Hence, to avoid these side effects buccal tablets of Aceclofenac are prepared which deliver the drug directly into systemic circulation over a prolonged period of time. Since Aceclofenac is almost insoluble in water, it remains in the stomach wall for a prolonged period of time which may cause ulceration, gastric perforation and bleeding. Hence, to improve its solubility, a solid dispersion of Aceclofenac was prepared using a hydrophilic carrier like PEG 6000 in a specific ratio and a novel solubilizer, Sepitrap-80 was used for further improvement of solubility.
The present investigation deals with the study of effect of Sepitrap-80 on the performance of buccal tablets of Aceclofenac prepared using various mucoadhesive polymers like sodium alginate, carbopol,
Hypromellose (Hydroxypropylmethyl Cellulose- HPMC) and HPC. Sepitrap-80 is a physically modified solubilizer which comes in a free flowing powder form and designed for oral formulations. Chemically it is Polysorbate-80 and is hydrophilic in nature.
Materials and methods Materials
Aceclofenac was purchased from Life Sciences Ltd Sepitrap-80 was obtained as a gift sample from Seppic Air Liquide Healthcare Specialty Ingredients. All other materials were of analytical grade or pharmacopoeial grade and used as received.
Methods of formulation
Preparation of solid dispersion of Aceclofenac:
Aceclofenac being a BCS Class II drug is insoluble in water. Hence to increase the aqueous solubility, solid dispersion of Aceclofenac was prepared using PEG 6000 as a carrier by melt fusion method. Aceclofenac and PEG 6000 were used in the ratio of 1:0.25.
In melt fusion method, PEG 6000 was allowed to melt and form a solid dispersion with the drug. This dispersion was cooled to room temperature with constant stirring. The solid mass thus obtained was sieved through 60# to obtain a uniform and free flowing powder.
Formulation of buccoadhesive tablets of Aceclofenac:
Buccoadhesive tablets containing Aceclofenac (Dose: 50mg) and other standard excipients were prepared by direct compression method and the different formulae are listed in Table No. 1 and 2. The novel solubilizer Sepitrap-80 was used to improve the drug solubility. Sepitrap-80 along with the dispersion prepared, a mucoadhesive polymer and other standard tablet excipients constituted the formula. The powder blend was then compressed into tablets of 100 mg weight on Single Stroke Single Punch machine using 8 mm concave punch. The mucoadhesive polymers under study included Hypromellose, HPC, Carbopol and Sodium alginate.
Methods of evaluation Determination of physicochemical parameters:
All the tablet formulations were evaluated for compressibility, weight variation and drug content. Friability was determined using Roche friabilator while hardness was determined using Monsanto hardness tester.
Weight variation:
Twenty tablets were weighed individually and the average weight was determined. Percentage deviation was calculated and checked for weight variation.
Drug content:
Three tablets from each formulation were taken and crushed. Weight equivalent to 100 mg was weighed and dissolved in phosphate buffer pH 6.8. Volume was made up to 100 ml with the same buffer. The solution was filtered, diluted and analyzed using UV spectrophotometer at 275 nm.
In vitro drug release:
The influence of technologically defined condition and difficulty in simulating in vivo conditions has led to the development of a number of in vitro release methods for buccal formulations; however no standard in vitro method has yet been developed. In vitro drug release study was carried out using an in-house developed dissolution apparatus at 37±0.50C and 120 rpm. Volume of dissolution medium was 200mL and medium used was phosphate buffer pH 6.8. Study was conducted in triplicate.
Results and discussions:
Evaluation of physicochemical properties:
All the batches of Aceclofenac buccal tablets were found to be satisfactory in terms of its physicochemical parameters. The drug content was also found to be within the desired limits.
Preparation and compressibility of tablets with and without Sepitrap-80:
Tablets containing Sodium alginate, HPC and Hypromellose did not pose any compressibility problems in the absence of Sepitrap-80. Tablets comprising of carbopol as mucoadhesive polymer, but devoid of Sepitrap-80 gave processing problems and thus hence could not be prepared by direct compression method. (Refer Table no. 3) Hence, it can be concluded that Sepitrap-80 improves the compressibility property of the blend (processing) and tablets could be punched.
Initial drug release:
As seen from Table no. 4, tablets with and without Sepitrap-80 did not show any considerable difference in initial drug release. Hence, it can be concluded that the solubilizer does not show any significant impact on the initial drug release from a matrix system. Tablets with HPMC as mucoadhesive polymer showed the most rapid initial drug release. Initial drug release of tablets with sodium alginate was almost twice than that of tablets containing HPC.
Sustaining effect:
Tablets containing Sepitrap-80 and HPC as the mucoadhesive polymer and gave the maximum sustaining effect. The t90% with HPC was found to be 91 minutes which came down to 65 minutes after the incorporation of Sepitrap-80. The t90% was found to be minimum with tablets having HPMC. There was not a considerable difference in t90% of tablets containing with HPMC with and without Sepitrap-80. The t90% of sodium alginate containing tablets also reduced from 80 minutes to 56 minutes after inclusion of Sepitrap-80 in the formulation.
Conclusion
Tablets with carbopol cannot be prepared by direct compression method without using Sepitrap-80. Thus, along with a solubility enhancing effect, Sepitrap-80 is also useful in improving compressibility of poorly compressible tablet blends.
Sepitrap-80 and HPMC combination in tablets gave a rapid initial drug release as compared to other polymer-Sepitrap combinations but at the same time this combination fails to give a sustaining effect with t90% being only 19-20 minutes. It can also be concluded that the presence of Sepitrap-80 does not have an impact on the initial drug release from either of the mucoadhesive polymers studied.
Sustaining effect of Sepitrap-80 with HPC is more as compared to Sepitrap-80 with the other polymers. While Sepitrap-80 reduced the t90% of drug release from other polymers, it had no impact on the drug release from Hypromellose containing tablets.
Hence Sepitrap-80 can be used as a solubility enhancer in the formulation of buccal tablets of a BCS class-II drug like Aceclofenac.
(The authors are faculty, Department of Pharmaceutics, Vivekanand Education Society’s College of Pharmacy, Chembur, Mumbai.)