IN VITRO EVALUATION OF TRAMADOL RECTAL SUPPOSITORIES
Sabin Raj Shakya11,*, Nattha Kaewnopparat 22, and Kamonthip Wiwattanawongsa31,#
1Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla Thailand 90112
2Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, Songkhla Thailand 90112
#, *
ABSTRACT
The objectives of this study were to formulate conventional and sustained release suppositories and examine the release characteristics of the prepared formulations.Tramadol conventional and sustained release suppositories were prepared by fusion method using polyethylene glycol (PEG) or Witepsol H15 base. In vitro release study revealed rapidrelease,i.e. 90% release of drug in 30 minutes, from both type of conventional suppositoriesindicating immediate release characteristics.By varying pH of dissolution medium, decreased amount of drug released at increase pH was observed Sustained release characteristics were studied using Eudragit L100 1.5 - 5% in PEG base, and 2.5-10 % in Witepsol H15 base. Delayed release of tramadol was more pronounced in Eudragit/PEG than Eudragit/Witepsol base. Drug release kinetics was best explained by first order model. In conclusion, PEG and Witepsol H15 bases are suitable for immediate release, whereas PEG/Eudragit suppository provided sustained release characteristics.
Keywords: Tramadol suppository; Sustained release; Eudragit L100; Release kinetic
INTRODUCTION
Tramadol is an effective analgesic commonly used for the management of chronic pain of malignant and non-malignant origin [1]. Gastrointestinal adverse effects, as well as respiratory depression, constipation, which can be associated with NSAIDs and opiates, were less likely with tramadol[1]. Adverse effect of tramadol includes nausea, vomiting, dizziness, fatigue, sweating, dry mouth, drowsiness and orthostatic hypotension. Nausea and vomiting, leading to discontinuation of tramadol[2], could be attributed to high peak plasma concentration of active moiety after oral and IV administration[3].
Tramadol can be administered orally or non-orally (i.e.subcutaneous, intramuscular, intravenous and rectal). Rectal administration can serve as an alternative in situations where oral administration was impractical, such as chemotherapy treated patients, or those with difficulty in swallowing. Beside conventional suppository, sustained release(SR) formulation was examined in this study. SR formulations normally provide constant plasma concentration, which might improve patient compliance from reduced frequency of administration and less side effects.
The objectives of this study were to formulate immediate and sustained release suppository and examine the release characteristic of the prepared formulations.
MATERIALS AND METHODS
Materials
Tramadol hydrochloride was kindly provided by Biolab Co. ltd. pharmaceutical Industry, Thailand. Witepsol H15waspurchased from Science lab Com, Inc, Texas, USA and PEG 400, PEG 4000 from S. Tong Chemicals Co. Ltd. Thailand. Eudragit L100 was kindly supplied Rohm pharma, Germany.
Methods
Preparation of suppository
Adult 2 g of suppositories containing 100 mg of tramadol were prepared by fusion method using fatty and hydrophilic bases. Drug displacement values were first determined and the amount of suppository base required was calculated [4]. The calculated weight of base for desired number of suppositories was melted in a hot water bath and then tramadol hydrochloride was added. The content was stirred until the homogenous mixture was obtained and poured into metal mold (2 g capacity). Then, it was allowed to coolat room temperature for 30-60 minutes. All suppositories were wrapped in aluminium foil and stored in 8-10ºC. The selected fatty base for formulation was Witepsol H15. Similarly, hydrophilic base composed of polyethylene glycol (PEG) mixture such as PEG 4000 and PEG 400 in equal amount.
Moreover, suppositories containing Eudragit L100 in different concentration; 1.5%, 2.5%, 3.5%, 5% for PEG base, and 2.5%, 5%, 7.5%, 10% for Witepsol H15 base, were used for preparing sustained release suppositories. The suppositories were prepared in similar as mentioned for conventional suppositories.
Evaluation of suppository
Disintegration test
USP tablet disintegration test apparatus was used to examine disintegration time of suppositories. Six suppositories were randomly chosen from each formulation and placed in the disintegration apparatus (Hanson Research, Chatsworth, USA, model no. 39-400-311). Distilled water maintained at 37±1ºC was used as a disintegration medium.The time for disintegration was recorded when the suppository completely melt (Witepsol H15 base) or dissolve (PEG) in the medium.
Content Uniformity
Determination of drug content was performed according to previously reported method with slight modification[5, 6]. The suppositories were meltedusing water bath heating in presence of distill water. The volume was adjusted to a final 100 ml with distilled water, and continuously shaken for 30 minutes. The content was filtered before UV absorption at 272 nm was measured. Concentration was calculated from calibration curve prepared at 20-125µg/ml. Content uniformity was determined as mean±SD of three determinations[7].
Dissolution test
The release of tramadol from suppositories was studied using rotating basket dissolution apparatus (USP dissolution apparatus I). Since human rectum could exhibit pH between 7-8, the study was performed dissolution media at pH 7.2, 7.5, 8, and in distilled water. The release was performed at 37±0.5ºC,50 rpm. Five ml aliquot of the medium was withdrawn at 10 and 30 min interval for 2 and 6 hours for immediate and sustained release suppositories respectively. The sample was filtered and the amount of tramadol was determined by measuring ultraviolet absorption at 272 nm, using appropriate blank solutions. The concentration of tramadol was calculated from the standard curve, prepared at 20-125 µg/ml. Percent release of the suppository was reported as mean ± SD of six determinations.
Kinetic analysis of the release data
The type of drug release kinetics applicable for the suppository base was determined by the evaluation of different kinetic models. The kinetic models are zero order (Q0-Qt=K0t), first order (lnQt = lnQ0-K1t) and Higuchi (Qt=KHt1/2) model, where Qt is the amount of drug released at time t, Q0 is the initial amount of the drug. K0, K1, KH are release rate constants for zero order, first order and Higuchi model respectively. The model that consistently produced the highest coefficient of determination (r2) among the suppository preparations was used for the assessment of drug release model, and a slope obtained from linear regression analysis of plot was determined as the drug release rate constant.[8, 9].
Statistical analysis
Results were expressed as the mean±SD. Analysis of variance (ANOVA) was used to test the statistical significance of differences among groups. Differences were considered statistically significant at P<0.05.
RESULTS
Disintegration time of the suppository was within 15 minutes using PEG or Witepsol (Tab.1). Disintegration time of suppository in Witepsol H15base, either with or without Eudragit L, was faster than those formulated in PEG formula. All of the formulation studied agreed British Pharmacopoeia 2011 requirements[17], except one formulated with 5% Eudragit L100 (Tab. 1). As shown in Tab. 2, tramadol content in either IR or SR formulations complied the requirement of BP with the test if not more than one individual content is outside the limits of 85 percent to 115 percent of the average content and none is outside the limits of 75 percent to 125 percent of the average content[10].
Table 1 Disintegration time (mean ± SD) of tramadol suppository with varying concentrationof Eudragit L 100 in PEG and Witepsol H15 bases
PEG baseEudragit L 100 (%) / 0 / 1.5 / 2.5 / 3.5 / 5
Disintegration time (min) / 12.39± 1.65 / 11.47±0.85 / 13.97 ± 1.98 / 29.76 ± 9.72 / No disintegration
Witepsol H15
Eudragit L 100 (%) / 0 / 2.5 / 5 / 7.5 / 10
Disintegration time (min) / 4.35± 0.12 / 4.02 ± 0.26 / 5.13 ± 0.05 / 5.31 ± 0.69 / 5.22 ± 0.50
Table 2Content uniformity of tramadol suppositories in Eudragit L100 –containing bases
PEG base (mean ± SD)Eudragit L 100 (%) / 0 / 1.5 / 2.5 / 3.5 / 5
Percent analyzed / 108.5 ± 1.01 / 109.6 ± 3.05 / 100.6 ± 4.32 / 101.6 ± 2.59 / 103.9 ± 2.11
Witepsol H15 (mean ± SD)
Eudragit L 100 (%) / 0 / 2.5 / 5 / 7.5 / 10
Percent analyzed / 93.4 ± 1.58 / 104.3 ± 4.34 / 107.7 ± 5.59 / 105.4 ± 7.21 / 100.0 ± 3.57
Figure 1 Release profile of tramadol suppositories formulated in PEG and Witepsol H15 base in distilled
water, buffer pH 7.2, 7.5 and 8
As shown in Fig. 1, tramadol suppositories formulated in Witepsol H15 base showed rapid release of tramadol (88.62%) in 10 minutes compared to polyethylene glycol (PEG) base (68.74%). Both show complete release of tramadol (about 98%) in 20 minutes in distilled water. Percent released from Witepsol based suppository (64-82% at 10 min) was greater than those from PEG base (40-49% at 10 minutes) in all pH studied (pH 7.2, 7.5 and 8). Release rates in the dissolution medium and distilled water were found to be statistically different (p < 0.5).
Delayed release obtained from Eudragit L100 depended on Eudragit concentration (Fig. 2). For example, approximately 90% of tramadol released from PEG base was observed at 3 and 5 hours with 3.5% and 5% Eudragit L100, respectively (Fig. 2A). In case of Witepsol H15, the same extent of release was observed at 0.5 and 1.5 hours with 2.5% and 10 % Eudragit L100, respectively (Fig.2B).
Figure 2 Release profile of tramadolin Eudragit L containing suppository. (A) in PEG base; (B) in Witepsol
H15 base
Release kinetics of tramadol suppositories, examined by fitting to zero order, first order, and Higuchi models, revealed high coefficient of correlation (r2) in all models (Tab. 3). However, first order was potentially the best model describing release characteristics of the formulation (r2 >0.99; Table 3).
Table 3 Drug release kinetic study of tramadol in PEG and Witepsol base at varying concentration of
Eudragit L 100
Formulation(% Eudragit) / Zero order / First order / Higuchi
r2 / k0(mg/min) / r2 / k1 (min-1) / r2 / KH
(mg/min-1/2)
PEG base
3.5 / 0.893 / 0.237 / 0.999 / 0.003 / 0.976 / 5.635
5 / 0.915 / 0.225 / 0.994 / 0.003 / 0.986 / 5.32
Witepsol H15 base
7.5 / 0.876 / 0.507 / 0.996 / 0.013 / 0.959 / 7.618
10 / 0.887 / 0.614 / 0.99 / 0.015 / 0.963 / 9.189
r2 : Co-efficient of Determination, k: Release rate constant for respective models, n: release exponent value
DISCUSSION AND CONCLUSION
Almost 90% of tramadol is released in 30 minutes in both types of suppository bases. Since release of drug content from suppository could be determined by the affinity of drug with suppository base. Tramadol (logP 1.35 at pH 7) could exhibit high affinity to PEG base compared to Witepsol H15 base. Due to the ease of Witepsol melting at body temperature, fast release could be obtained [11], whereas quite different mechanism (i.e. erosion) was postulated in case of PEG[11]. The release properties of these conventional suppositories, however, indicated immediate release characteristics according to FDA guideline[12].
Dissolution of tramadol seems to be affected by pH of the dissolution medium. Decreasedsolubility of tramadol at increased pH can cause slow release of the drug at higher pH. Slightly slower release of tramadol in PEG compared to Witepsol H15 base at each pH was observed. This may be due to the differentaffinity of the drug to hydrophilic PEG base and lipophilic Witepsol base, as well as rapid melting characteristic of Witepsol in dissolution temperature compared to PEG.
With the addition of Eudragit L100, delayed release of tramadol from Eudragit/Witepsol base was less pronounced than those from Eudragit/PEG base. Trapping of tramadol in a postulated cage like surface, resulting from slowly dissolving PEG in Eudragit/PEG base, could be a reason of the retarded release[9]. Lipophilic Witepsol, however, has high affinity and can be easily dissolved with Eudragit. Thus, the drug can be readily released in Eudragit/Witepsol base. Release kinetics in either PEG or Witepsol base with Eudragit L100 at varying percentage was best explained by first order equation. This suggested that release of tramadol depended upon concentration of the drug.
In conclusion, tramadol suppository, prepared in PEG base and Witepsol H15 base, showed immediate release properties. Sustained release characteristics could be obtained from including Eudragit L100 in PEG base, in which release kinetics were best fitted by first order model.
ACKNOWLEDGEMENT
We would like to thank National Research Council of Thailand (NRCT) and Graduate School, Prince of Songkla University.
REFERENCE
1.Grond S ,Sablotzki A. Clinical Pharmacology of Tramadol.Clin Pharmacokinet, 2004. 43(13): p. 879-923.
2.Petrone D, Kamin M,Olson W. Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double blind randomized trial.J Clin Pharm Ther, 1999. 24: p. 114-123.
3.Zwaveling J, Bubbers S, Meurs AHJ, et al. Pharmacokinetics of rectal tramadol in post-operative paediatric patients.Br J Anaesth, 2004. 93(2): p. 224-227.
4.Allen LV, Popovich NG,Ansel HW, Ansel's pharmaceutical dosage forms and drug delivery systems. 9 ed. 2011, Philadelphia: Lippincott Willliams & Wilkins, a Wolters Kluwer business.
5.Ghorab D, Refai H,Ranada T. Preparation and evaluation of fenoterol hydrobromide suppositories.Drug Discov Ther, 2011. 5(6): p. 311-318.
6.Saleem MA, Taher M, Sanaullah S, et al. Formulation and evaluation of tramadol hydrochloride rectal suppositories.Indian J Pharm Sci, 2008. 70(5): p. 640-644.
7.Guneri T, Arici M,Ertan G. Preparation and diffusional evaluation of sustained release suppositories containing ibuprofen microsphere.FABAD J Pharm Sci, 2004. 29: p. 177-184.
8.Aamir MN, Ahmad M, Akhtar N, et al. Drug release kinetics and stability studies of tablets of tramadol HCl microspheres.Journal of Chemical Society of Pakistan, 2010. 32(2): p. 180-188.
9.Tarimci N ,Ermis D. Preparation and in vitro evaluation of sustained release suppositories of indomethacine.J Fac Pharm Ankara, 1998. 27(1): p. 11-21.
10.British Pharmacopoea. 2011: British Pharmacopoeia Convention Laboratory, United Kingdom.
11.Reanmongkol W, Kaewnopparat N,Ratanajamit C. Physicochemical properties, in vitro release and in vivo evaluation of tramadol hydrochloride rectal suppositories and rectal gel.Asian Biomed, 2011. 5(2): p. 269-275.
12.Guidance for Industry: Dissolution testing of immediate release solid oral dosage forms. 1997: US Department of Health and Human Service, Food and Drug Administration, Center of Drug Evaluation and Research (CDER).