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Assessing Hibiscus rosa-sinensis Linn as an Excipient in Sustained-Release Tablets
Making drug-embedded matrix tablets through the direct compression of a blend of drug, retardant material, and additives is one of the simplest formulation approaches. The inclusion of polymeric materials in a matrix system is a common method of modulating drug release (1). Drug-release retarding polymers are the key performers in matrix systems. Various polymers have been investigated as drug-retarding agents, each presenting a different approach to the matrix system. Based on the features of the retarding polymer, matrix systems are usually classified into three main groups: hydrophilic, hydrophobic, and plastic. Hydrophilic polymers are most suitable for retarding drug release, and interest is growing in using these polymers in sustained drug delivery (2–4).
In India, natural gums and mucilage are well known for their medicinal use. Natural gums and mucilage are preferred to semisynthetic and synthetic excipients because of their lack of toxicity, low cost, availability, soothing action, and nonirritant nature (5–8). Many natural materials are studied for use in sustained-release tablets. These materials include: guar gum (9), ispaghula husk (10), olibanum and its resins (11), cross-linked high amylose starch (12), Ulmus fulva (slippery elm mucilage) (13), pectin (14), Peumus boldus dry plant extract (15), galactomannon from Mimosa scabrella (16, 17), Gleditsia triacanthos Linn (honey locust gum) (18), Sesbania gum (19), mucilage from the pods of Hibiscus esculenta (20), Tamarind seed gums (21), and gum copal and dammar (22).
Hibiscus rosa-sinensis Linn has not been explored as a pharmaceutical excipient. Hibiscus rosa-sinensis Linn of the Malvaceae family is also known as the shoe-flower plant, China rose, and Chinese hibiscus. The plant is available in India in large quantities, and the leaves contain mucilage (23, 24). The leaves are used in traditional medicines as emollients and aperients to treat burning sensations, skin disease, and constipation (25). The plant contains cyclopropanoids, methyl sterculate, methyl-2-hydroxysterculate, 2-hydroxysterculate malvate, and β-rosasterol. Mucilage of Hibiscus rosa-sinensis contains L-rhamnose, D-galactose, D-galactouronic acid, and D-glucuronic acid (26). The leaves contain carotene (7.34 mg/100 g of fresh material) and are used as cattle feed (27). The leaves also contain moisture, protein, fat, carbohydrate, fibers, calcium, and phosphorus (28).
The objective of this study was to extract mucilage from the leaves of Hibiscus rosa-sinensis Linn and examine the various pharmaceutical properties of the dried mucilage to assess its functionality as an excipient. Specifically, the study evaluated the physicochemical properties and examined the effect of polymer blends on the rate and kinetics of diclofenac sodium released from matrix tablets.
Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug. Diclofenac sodium rapidly dissolves in intestinal fluid, reaches its maximum blood concentration (Cmax) within 30 min, and is metabolized mainly by hepatic hydroxylation and subsequent conjugation (29). In healthy human volunteers, the mean plasma clearance of diclofenac sodium was 16.0 L/h, and the mean elimination half-life of the terminal phase was 1.2–1.8 h (30). To reduce gastrointestinal irritation, a common problem with all nonsteroidal anti-inflammatory agents, effective enteric-coated dosage forms have been developed. Food delays the absorption of the drug, which causes a nonreproducible pharmacokinetic profile, and the drug has no immediate therapeutic effect (31).
Drug release from hydrophilic matrices is a complex interaction between dissolution, diffusion, and the erosion mechanism. In this study, the drug-release mechanism was evaluated for diclofenac sodium tablets prepared with highly hydrophilic mucilage from the leaves of Hibiscus rosasinensis Linn. A 32 full factorial design was carried out to evaluate the effect of certain variables such as the amount of mucilage and diluent. Further studies were performed using water uptake, the mass loss of pure mucilage, and the matrix tablet containing the drug and mucilage. A stability study for an optimized batch was performed for three months.
Materials. Diclofenac sodium was received as a gift from Beacon Pharmaceuticals (Ahmedabad, India). The leaves of Hibiscus rosa-sinensis Linn were collected from the medicinal garden of the C.K. Pithawala Institute of Pharmaceutical Science and Research in Surat, India. Guar gum Indian Pharmacopoeia (IP) grade, ispaghula husk, sodium carboxymethyl cellulose IP, lactose IP, talc IP, and magnesium stearate IP were received from Atul Chemicals (Anand, India). All other solvents and chemicals were of analytical-reagent grade. Deionized double distilled water was used throughout the study.
Methods. The fresh leaves of Hibiscus rosa-sinensis Linn were collected, washed with water to remove dirt and debris, and dried. The powdered leaves were soaked in water for 5–6 h, boiled for 30 min, and kept aside for 1 h for complete release of the mucilage into water. The material was squeezed from an eight-fold muslin cloth bag to remove the marc from the solution. Acetone was added to the filtrate to precipitate the mucilage in a quantity of three times the volume of the total filtrate. The mucilage was separated, dried in an oven at a temperature < 50 °C, collected, dried-powdered, passed through a sieve (number 80), and stored for further use in desiccators (32).
Physicochemical properties of dried powdered mucilage. Dried- powdered mucilage was studied for percentage yield, particle size, mass loss on drying, viscosity, swelling index, bulk density, angle of repose, and compressibility.
Particle size. The microscopic method was used (in triplicate) to determine the particle size of the dried mucilage.
Mass loss on drying. The mass loss on drying was determined for an appropriate quantity of dried mucilage at 105 °C for 2 h in a hot-air oven.
Swelling ratio. The study was carried out in a 100-mL stoppered graduated cylinder. The initial bulk volume of 1 g of dried mucilage was measured, and water was added in sufficient quantity to yield a 100-mL uniform dispersion. The sediment volume of the swollen mass was noted after 24 h in storage at room temperature. The swelling ratio was calculated by determining the ratio of the swollen volume to the initial bulk volume. The swelling ratio was evaluated in distilled water, simulated gastric fluid (0.1 N HCl), and phosphate buffer (pH 6.8) (33).
Viscosity. Rheological studies of dried mucilage were carried out using various concentrations of solution (0.1–0.5% weight/volume (w/v) in distilled water. The viscosity was measured using an Ostwald viscometer and compared with the viscosity of sodium carboxymethylcellulose.
Bulk and tapped density. A preweighed and presieved quantity of dried mucilage was poured into a graduated cylinder, and the volume recorded. The cylinder was tapped until the powder bed volume reached a minimum value, and the tapped volume was recorded. The bulk and tapped densities were calculated. Carr's index and Hausner ratio. Carr's index and Hausner ratio were calculated from the bulk and tapped densities.
in which h is the height of the powder heap and r is the radius of the powder heap. Comparisons were made between dried mucilage, guar gum, and ispaghula husk.
Preparation of diclofenac sodium tablets. The required quantities of diclofenac sodium and dried mucilage powder (sieve number 80) were physically admixed. Lactose was included in the nine batches of factorial design. The powder blend was lubricated with 1% w/w talc and 2% w/w magnesium stearate. Lubrication was performed in a glass jar for 2 min. Each tablet contained 100 mg of the drug. The tablets were prepared by direct compression on a rotary tablet press (Rimek II, Karnavati Engineering, Ahmedabad, India) and fitted with concave punches of 9 mm in diameter. The turret was rotated at a fixed speed of 30 rpm (34).
Hardness and friability test. Hardness was determined by using the Monsanto hardness tester, and friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (Model EF2, Electrolab, Mumbai, India) for 4 min at 25 rpm. The tablets were dedusted, and the loss in weight caused by the fracture or abrasion was recorded as the percentage friability.
Uniformity of weight. The weight-variation test was performed. Twenty tablets were weighed individually, and the average weight was calculated.
Dissolution-rate study. The drug-release study was carried out using an USP XXIII paddle apparatus at 37 ± 0.50 °C at 50 rpm using 900 mL of distilled water and phosphate buffer (pH 6.8) as the dissolution medium (n = 5). A 5-mL sample solution was withdrawn at predetermined time intervals, filtered through a 0.45-μm membrane filter, diluted suitably, and analyzed spectrophotometrically at 276 nm using a UV-visible double-beam spectrophotometer (Shimazdu-UV 1700, Shimazdu, Kyoto, Japan). Equal amounts of fresh dissolution medium were replaced immediately after withdrawing a test sample. The percentage of drug that dissolved at different time intervals was calculated using a regression equation generated from the standard curve. Drug release from the optimized batch (HL6) and a market preparation of the drug were studied in distilled water.
Full factorial design. A 32 randomized full factorial design was used. Two factors were evaluated, each at three levels, and experimental trials were performed at nine possible combinations. The ratio of mucilage (X 1) and amount of lactose (X2) were selected as independent variables. The time required for 80% drug dissolution (t80) and percentage drug released in 60 min (Y60) and 300 min (Y300) were selected as dependent variables.
Hydration capacities and erosion studies. Erosion and water uptake of the formulated tablets were determined under conditions identical to those previously described for dissolution testing. Water uptake and mass loss were determined gravimetrically according to the following equations (35):
Percent water uptake =
Three tablets were used per time point. At predetermined times, the ring-mesh assemblies supporting the partially hydrated tablets were carefully removed, and the tablets were lightly blotted with tissue paper to remove excess surface water. After determining the wet weight, the tablets were dried at 70 °C for one day before reweighing to determine the remaining dry weight. The test was performed at speeds of 50 and 100 rpm. Placebo tablets consisting of pure mucilage were tested in the same way. All studies were performed in triplicate.
in which Vtand Vo are volumes; Rt and Ro are radius at time t and zero, respectively; and It and Io are thickness at time t and zero, respectively (36).
Stability study. To study the effect of storage on an in vitro drug release, the stability study of the best formulation (HL6) was carried out at 40 °C and 75% relative humidity in a humidity oven. Samples were withdrawn after a three-month interval, and in vitro drug release was performed.
Results and discussion
Table III shows the composition of the preliminary batches (L1 to L3) and the results of their dissolution studies. Table
IV shows the composition of the nine batches of the factorial design and the results of their dissolution studies. When the
dissolution study of the preliminary batches was performed, the complete drug release was obtained within 9, 10, and 11 h
with different proportions of mucilage and 100 mg of diclofenac sodium (see Table III). The authors concluded that mucilage
is suitable as a sustained-release matrixing agent for a diclofenac sodium tablet. Four criteria were established for the
desired drug-release profile:
in which Y is the dependent variable, b0 is the arithmetic mean response of the nine runs, and bi is the estimated coefficient for the factor Xi. The main effects (X1 and X2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X1X2) show how the response changes when two factors are simultaneously changed.
The values of the correlation coefficient were 0.9879, 0.9831, and 0.9870, respectively, indicating a good fit. Equations 6 and 7 may be used to obtain a reasonable estimate of the response because a small error of variance was noticed in the replicates. The polynomial equation can be used to draw conclusions after considering the magnitude of the coefficient and the mathematical sign it carries (i.e., positive or negative). The data demonstrate that both factors (X1 and X2) affect the drug release Y60, Y300, and t80. The low value X1X2 of the coefficient also suggests that the interaction between X1 and X2 is not significant.
Batches HL3 and HL6 met the set criteria of Y60, (i.e., 20% < Y60, < 25%. Batches HL3, HL5, HL6, and HL9 met the set criteria of Y300 (i.e., 40% < Y300 < 60%. Batches HL6 and HL9 met the set criteria of t80 between 490 and 590 min. Among the entire batches, only HL6 fulfilled all the selection criteria, which included prolonged drug release of the remaining drug over 12 h. Batch HL6, therefore, was selected as the optimized batch.
The authors conclude that a novel hydrophilic excipient, such as mucilage extracted from Hibiscus rosa-sinensis Linn, can be used for the development of sustained-release tablets. The dried mucilage powder shows superior swelling capacity and is pH independent. The mucilage can be further explored as a disintegrating agent, gelling agent and modified-release dosage form.
Girish K. Jani, PhD,* is a principal at K.B. Raval College of Pharmacy at Sheratha Post Kasturinagar, Gandhinagar, Gujarat, India 382423, tel.+
91 793 252 9996, fax +91 792 928 9767, firstname.lastname@example.org
* To whom correspondence should be addressed.
Submitted: Apr. 6, 2007. Accepted May 24, 2007.
1. A. Boza et al., "Evaluation of Eudrajit RS-PO and Ethocel 100 Matrices for Controlled Released of Lobenzarit Disodium," Drug Dev. Ind. Pharm. 25 (2), 229–233 (1999).
2. S.A. Bravo, M.C. Lamas, and C.J. Salomon, "Swellable Matrices for the Controlled Release of Diclofenac Dodium: Formulation and In-vitro Studies, " Pharm. Dev. Technol. 9 (1), 75–83 (2004).
3. G.M. Khan and Z. Jiabi, "Formulation and In-vitro Evaluation of Ibuprofen-Carbopol 974P-NF Controlled Release Matrix Tablets III: Influence of Co-Excipients on Release Rate of the Drug." J. Controlled Release 54 (2), 185–190 (1998).
4. L. Genc, H. Bilac, and E. Guler, "Studies on Controlled Release Dimenhydrinate from Matrix Tablet Formulations," Pharm. Acta Helv. 74 (1), 43–49 (1999).
5. G.T. Kulkarni et al., "Evaluation of Binding Properties of Plantago ovata and Trigonella foenum graecum Mucilage," Indian Drugs 39 (8), 422–425 (2002).
6. B. Anroop et al.,"Studies on Ocimum gratissimum Seed Mucilage: Evaluation of Suspending Properties," Indian J. Pharm. Sci. 67 (2), 206–209 (2005).
7. P.D. Bharadia et al., "A Preliminary Investigation on Sesbania Gum as a Pharmaceutical Excipient," Int. J. Pharm. Excipients 1(4), 102–105 (2004).
8. H. Pawar, and P.M. D'mello, "Isolation of Seed Gum from Cassia Tora and Preliminary Studies of its Application as a Binder for Tablets," Indian Drugs 41 (8), 465–468 (2004).
9. D. Thomas and R. Fassihi, "Guar Based Monolithic Matrix Systems: Effect of Ionizable and Non-ionizable Substances and Excipients on Gel Dynamics and Release Kinetics," J. Controlled Release 80 (1–3), 45–56 (2003).
10. M.C. Gohel and K.V. Patel, "Formulation Optimization of Dilitazem-HCl Matrix Tablets Containing Modified Ispaghula Husk using Factorial Design," Drug Dev. Ind. Pharm. 23 (11), 1055–1061 (1997).
11. K.P. R. Chowdary, P. Mohapatra, and M.N. Murali Krishna, "Evaluation of Olibanum and its Resin as Rate Controlling Matrix for Controlled Release of Diclofenac," Indian J. Pharm. Sci. 68 (4), 497–500 (2006).
12. J. Mulhbacher, P. Ispas-Szabo, and M.A. Mateeseu, "Cross-linked High Amylase Starch Derivatives for Drug Release II. Swelling Properties and Mechanistic Study," Int. J. Pharm. 278 (2), 231–238 (2004).
13. R.J. Beveridge et al., "Some Structural Features of the Mucilage from the Bark of Ulmus fulva (Slippery Elm Mucilage)," Carbohydrate Res. 9 (4), 429–439 (1969).
14. S. Nurjaya and T.W. Wong, "Effects of Microwave on Drug Release Properties of Matrices of Pectin," Carbohydrate Polym. 62 (3), 245–257 (2005).
15. P. Santiago et al. "Design of Peumus boldus Tablets by Direct Compression Using a Novel Dry Plant Extract," Int. J. Pharm. 233 (1–2), 191–198 (2002).
16. C.W. Vendruscolo et al, "Xanthan and Galactomannan (from M. scabrella) Matrix Tablets for Oral Controlled Delivery of Theophylline," Int. J. Pharm. 296 (1–2), 1–11 (2005).
17. F. Ughini et al., "Evaluation of Xanthan and Highly Substituted Galactomannan from M. scabrella as a Sustained Release Matrix," Int. J. Pharm. 271 (1–2), 197–205 (2004).
18. U. Melike and A. Turan, "Evaluation of Honey Locust (Gleditsia triacanthos Linn) Gum as a Sustaining Material in Tablet Dosage Form," IL Farmaco 59 (7), 567–573 (2004).
19. P.D. Bharadia et al., "A Preliminary Investigation on Sesbania Gum as a Pharmaceutical Excipient," Int. J. Pharma. Excip. 1 (4) 99–102 (2004).
20. S.K. Baveja, K.V. Rao, and J. Arora, "Examination of Natural Gums and Mucilage as Sustaining Agents in Tablet Dosage Forms," Indian J. Pharm. Sci. 50 (2), 89–92 (1988).
21. S. Sumathi and A.R. Ray, "Release Behavior of Drugs from Tamarind Seed Polysaccharide Tablets," J. Pharm. Sci. 5 (1), 12–18 (2002).
22. D.M. Morkhade et al., "Gum Copal and Gum Damar: Novel Matrix Forming Material for Sustained Drug Delivery," Ind. J. Pharm. Sci. 68 (1), 53–58 (2006).
23. J. Anjaria, M. Parabia, and S. Dwivedi, Ethnovet Heritage–Indian Ethnoveterinary Medicine an Overview. (Pathik Enterprise, Ahmedabad, India, 1st ed., 2002), p. 382.
24. I.A. Ross, Medicinal Plants of the World—Chemical Constituents, Traditional and Modern Medicine Uses (Humana Press, Totowa, NJ 1999), pp. 155-163.
25. K.R. Kirtikar and B. D. Basu, Indian Medicinal Plants (International Book Distributors, Dehradun, India, 1999), p. 335.
26. The Wealth of India, First Supplement Series (Raw Materials) (National Institute of Science and Communication, CSIR, New Delhi, India, Volume 3: D–I, 2002), pp. 386–387.
27. The Wealth of India, First Supplement Series (Raw Materials) (National Institute of Science and Communication, CSIR, New Delhi, India, Volume V: H–K, 2002), pp. 91–92.
28. J.A. Duke, and E. S. Ayensu, Medicinal Plants of China. (Reference Publication Inc., Algonac, MI 1985).
29. J.G. Hardman and L.E. Limbrid. Goodman's and Gilman's The Pharmacological Basis of Therapeutics (McGraw Hill, New York, 9th ed., 1995).
30. P.D. Fowler et al., "Plasma and Synovial Fluid Concentration of Diclofenac Sodium and its Major Hydroxylated Metabolites During Long-term Treatment of Rheumatoid Arthritis," Eur. J. Clin. Pharmacol. 25 (3), 389–394 (1983).
31. J.V. Willis, M.J. Kendall, and D.B. Jack, "The Influence of Food on the Absorption of Diclofenac After Single and Multiple Oral Doses," Eur. J. Clin. Pharmacol. 19 (1), 33–37 (1981).
32. S.P. Wahi et al. "Studies on Suspending Property of Mucilage of Hygrophila Spinosa T. Anders and Hibiscus Esculentus Linn," Indian Drug. 22 (9), 500–502 (1985).
33. F.E. Bowen and W.A. Vadino, "A Simple Method for Differentiating Starches," Drug Dev. Ind. Pharm. 10, 505–511 (1984).
34. L. Lachman, H.A. Libermann, and J.L. Kanig, The Theory and Practice of Industrial Pharmacy (Varghese Publishing House, Bombay, India, 3d ed., 1987), p. 318.
35. D. Thomas and F. Reza, "Guar Based Monolithic Matrix Systems: Effect of Ionizable and Non-ionizable Substances and Excipients on Gel Dynamics and Release Kinetics," J. Controlled Release 80 (1–3), 45–56 (2002).
36. P. Colombo et al., "Drug Release Modulation by Physical Restriction of Matrix Swelling," Int. J. Pharm. 63 (1), 43–48 (1990).
37. M. Bamba and F. Puisieux, "Release Mechanisms in Gel Forming Sustained Release Preparations" Int. J. Pharm. 2, 307-315 (1979).