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Natural gums and mucilage have been widely explored as pharmaceutical excipients. The goal of this study was to extract mucilage from the leaves of Aloe barbadensis Miller and to study its functionality as an excipient in pharmaceutical sustained-release tablet formulations.
Sustained-release dosage forms are prepared to achieve a desirable and predictable phamacodynamic response within appropriate pharmacokinetic parameters, improve patient compliance, reduce side effects, and maximize drug efficacy (1). Creating drug-embedded matrix tablets using direct compression of a blend of drug, retardant material, and additives is one of the simplest approaches for a formulation. One of the most commonly used methods of modulating drug release is including polymeric material within a matrix system. Matrix systems are important because of their simplicity, low cost, the small influence of physiological variables on their release behavior, and their suitability for manufacture on modern high-speed equipment. (2)
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 the most suitable for retarding drug release, and there is growing interest in using these polymers in sustained drug delivery (3–5).
In India, natural gums and mucilage are well known for their medicinal use. They are widely used in the pharmaceutical industry as thickeners, water-retention agents, emulsion stabilizers, gelling agents, suspending agents, binders, film formers, and sustained-release agents. They also are used in cosmetics, textiles, paints, and paper-making. Demand for these substances is increasing, and new sources are being developed. India, because of its geographical and environmental position, has traditionally been a good source for such products among the Asian countries. Still, large quantities are imported from Europe to meet increasing demand. 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. (6–9).
Mucilages are normal plant-cell constituents that exist in specialized histological formations such as cells or canals that are common in the external tegument of seeds. Many plants contain mucilage, which provides high concentration of complex polysaccharides. Mucilages are hydrophilic polymers (10).
The mucilage from Aloe barbadensis Miller (A. barbadensis), also known as curacao aloes (liliaceae), is obtained from the dried juice of the leaves. It is commonly known as aloe, musabbar, and kumari (gujarati). The principal active component is aloin, which is a mixture of barbaloin, isobarbaloin, aloe emodin, and resins. It also contains aloetic acid, galactouronic acid, glucosamine, monosaccharides, and polysaccharides. It is used as a purgative and is also used to heal wounds, burns, and to treat eczema and disturbed menstruation. In cosmetics, it is used to manufacture shampoos and conditioners. (11, 12).
Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug that has anti-inflammatory, analgesic, and antipyretic properties. It is used to treat degenerative joint diseases such as rheumatoid arthritis, osteoarthritis, and ankylosing spondilitis. Diclofenac sodium is rapidly dissolved in intestinal fluid and reaches its maximum blood concentration (Cmax) within 30 min. It is metabolized mainly by hepatic hydroxylation and subsequent conjugation (13). In healthy human volunteers, mean plasma clearance of diclofenac sodium was 16 L/h, and the mean elimination half-life of the terminal phase was 1.2–1.8 h (14). To diminish diclofenac sodium gastrointestinal irritation, which is a common problem with all nonsteroidal anti-inflammatory agents, effective enteric-coated dosage forms are used. Food, however, effectively delays the absorption of the drug, which causes a nonreproducible pharmacokinetic profile, and the drug has no immediate therapeutic effect (15).
A. barbadensis is available locally in India in large quantities and has not been explored as a pharmaceutical excipient. The goal of this research was to extract mucilage from the leaves of A. barbadensis and to study the various pharmaceutical properties of the mucilage to assess its functionality as an excipient in pharmaceutical sustained-release formulations.
Materials. Diclofenac sodium was obtained as a gift sample from Beacon Pharmaceuticals (Ahmedabad, India). The leaves of A. barbadensis were taken from the medicinal garden of C.K. Pithawala Institute of Pharmaceutical Science and Research in Surat, India. The plant was authenticated at the Bioscience Department of Veer Narmad South Gujarat University in Surat, India. Guar gum, isapgulla husk, Aerosil (colloidal silica), lactose IP, and sodium carboxymethylcellulose (sodium CMC) were procured from CDH (Mumbai, India). All other chemicals used were analytical-reagent grade.
Methods.Extraction of mucilage. The fresh leaves of A. barbadensis were taken and washed with water to remove dirt and debris. Incisions were made on the leaves, which were hung overnight. The leaves were crushed and soaked in water for 5–6 h, boiled for 30 min, and left to stand for 1 h to allow complete release of the mucilage into the water. The mucilage was extracted using an eight-layer muslin cloth bag to remove the marc from the solution. Acetone (three times the volume of filtrate) was added to precipitate the mucilage. The mucilage was separated, dried in an oven at a temperature of less than 500 °C, collected, ground, passed through a Number 80 sieve (nominal aperture size is 180 μm) and stored in desiccators at 300 °C and 40% relative humidity before use (16).
Physicochemical and microbial properties of A. barbadensis mucilage. The dried mucilage was studied for percentage yield, chemical test, particle size, weight loss on drying, solubility, viscosity, pH, swelling index, bulk and tapped density, angle of repose, compression properties, and microbial load.
Chemical test. The dried powder of mucilage was treated with Molisch's reagent and ruthenium red.
Weight loss on drying. Weight loss on drying was determined for an appropriate quantity of mucilage at 105 °C for 2 h (17).
Particle size. The particle size of the dried-powder mucilage was determined by the microscopic method, and the study was carried out in triplicate.
pH of solution. The pH of the 1% solution was measured with a pH meter.
Density. A 0.5% weight/volume (w/v) solution of dried mucilage was prepared and transferred to a density-measurement bottle. An empty bottle with distilled water was weighed. The density of the dried mucilage was calculated.
Charring. A few milligrams of dried mucilage were placed in a melting-point apparatus. The temperature was taken and recorded when the material started to char.
Swelling ratio. The study was carried out using a 100-mL stoppered graduated cylinder. The initial bulk volume of 1 g of dried mucilage was recorded. Water was added in sufficient quantity to yield 100 mL of a uniform dispersion. The sediment volume of the swollen mass was measured after 24 h, stored at room temperature. The swelling ratio was calculated by taking the ratio of the swollen volume to the initial bulk volume (18).
Bulk and tapped density. A preweighed, 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 (19).
Carr's index and Hausner ratio. Carr's index and Hausner ratio were calculated from the bulk and tapped densities (20).
Viscosity. Rheological studies of dried mucilage were carried out using varying concentrations (0.1–0.5% w/v) prepared in distilled water. The viscosities were measured using an Ostwald viscometer and compared with those of solutions of sodium CMC at the same range of concentrations.
Angle of repose. The angle of repose was determined by the fixed-height funnel method and calculated using the following equation:
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.
Microbial count. The microbial count of the dried mucilage was performed as outlined in the Indian Pharmacopoeia for total aerobic microbial count of bacteria and fungi using the plate count method (21).
Preparation and characterization of matrix tablets.To study the matrix-forming properties of the mucilage, tablets were prepared using diclofenac sodium as a model drug and different ratios of dried mucilage powder (see Table I). Different batches of tablets were prepared (A1 to A4). The tablets containing 100 mg of diclofenac sodium were prepared by direct compression on a rotary tablet machine. The batch size was 50 g. The turret was rotated at a fixed speed of 30 rpm. Tablets were prepared using a 10-station rotary tablet machine (Minipress II, Karnavati Engineering, Ahmedabad, India) and evaluated for the following parameters: hardness, friability, and uniformity of weight (22).
Hardness and friability test. Hardness and friability were determined using a Monsanto hardness tester and Roche friability tester, respectively.
Table I: Formulation of diclofenac sodium matrix tablets by the direct-compression method.
Uniformity of weight. Twenty tablets were weighed individually, and the average weight was calculated.
Tablet swelling index. Tablets of equal weight were immersed in 50 mL of distilled water on a watch glass. At specific time intervals, tablets were carefully removed from the watch glass and blotted with filter paper to remove the water present on their surface and weighed accurately. The experiment was performed for 5 h. The swelling index was calculated using the following formula (23):
Radial and axial swelling of the tablet. The initial diameter and height of the tablet were measured, and the tablet was stored in distilled water. The increase in diameter and height were measured at selected time intervals up to 5 h. The equilibrium degree of swelling (Q) was calculated from the radial and axial swelling ratio using the following equation:
in which Vt and Vo are the tablet volumes, Rt and Ro are the radii, and It and Io are the heights at time t and zero, respectively (24).
Dissolution-rate study.In vitro drug-dissolution studies were conducted using the USP Type II apparatus (Model TDL-08, Electrolab India, Mumbai) at 50 rpm in distilled water at 37 ± 0.5 °C. At specified intervals, 5-mL samples were withdrawn and replaced with fresh medium to keep a constant volume. After appropriate dilution, the sample solutions were analyzed using a UV-visible spectrophotometer (Shimadzu, Kyoto, Japan, Shimadzu-1700) at 276 nm.The amount of drug released was determined by reference to a calibration curve constructed in the three sets of same dissolution media. The mean of the three determinations was used for the data analysis (25).
Results and discussion
Various physiochemical and microbial characteristics of the extracted mucilage from A. barbadensis were investigated. The presence of mucilage in extracted material was confirmed using Molisch's test and by treatment with ruthenium red. Both tests were positive for the presence of mucilage. The results of other investigations (percentage yield, particle size, pH of solution, density, and charring) are shown in Table II. The weight loss on drying indicates the amount of moisture present in the material available to interact with other material. For dried mucilage, the loss on drying was 4.89%. The result of microbial testing of the mucilage was within official limits [less than 100 colony-forming units (cfg)/g]. The swelling ratio of mucilage, determined in distilled water, was 40. There was a significant change in swelling by the end of the study, which indicated that the mucilage had excellent swelling properties.
Table II: Physicochemical and microbial properties of dried powdered mucilage.
The viscosity of the extracted dried mucilage was compared with a semisynthetic polymer (sodium CMC). The range of viscosities over the concentration range studied was 5.03 to 9.96 mPa s for dried mucilage and 2.79 to 12.15 mPa s for sodium CMC (see Table III). It can be concluded that the dried mucilage has viscosity comparable with sodium CMC.
Table III: Rheological data of Aloe barbadensis mucilage and sodium carboxymethylcellulose (CMC).
The flow properties and compressibility of the dried mucilage, including bulk and tapped density, Carr's index, the Hausner ratio, and the angle of repose, were assessed. Comparison was made with guar gum and ispaghula, two other natural materials (see Table IV). The dried mucilage has excellent flow properties compared with guar gum and ispaghula. It can be concluded that the dried mucilage has flow properties suitable for a direct-compression formulation.
Table IV: Flow properties of dried Aloe barbadensis mucilage and other gums.
The physical tests (hardness test, friability, and weight variation) were performed for all formulations. Mean hardness for all formulations was about 4 kg/cm2 , friability was less than 1%, and the weight-variation results for the matrix tablets complied with pharmacopeial limits. From this work, it was shown that dried mucilage possesses good tablet-forming properties.
The study of dimensional changes in the tablets was carried out for 5 h in distilled water (see Table V). As the proportion of dried mucilage increased, the radial and axial swelling of the tablet increased. When the drug–mucilage ratio was at its lowest (1:0.5), the swelling of the tablet was at its lowest. As the ratio increased, the radial and axial swelling increased proportionally. There was more swelling of the tablet in the axial direction compared with the radial direction.
Table V: Radial and axial swelling of tablets in distilled water.
The dried mucilage was evaluated as a matrix-forming material for oral sustained-released tablets using diclofenac sodium as a model drug. Matrix tablets, each containing 100 mg of diclofenac sodium, were prepared using dried mucilage in various drug–mucilage ratios (1:0.5, 1:1, 1:1.5, and 1:2). An ideal modified-release dosage form should release a loading dose (20–25%) in the first hour. Later, the remaining drug should be released at a constant rate over an extended period. An ideal release pattern was calculated according to these criteria. The in vitro dissolution profiles are shown in Figure 1. Batches A1 and A2, at lower the ratios (1:0.5 and 1:1), released 35.45 and 30.70% of the drug in the first hour, and the remaining drug was released within 6 h. This result occurred probably because insufficient polymer was in the formulation. In batch A4 , where the drug-mucilage ratio was 1:2, 23.25% of the drug was released in the first hour, and the remaining drug was released during 8 h. The rate of release was faster in batch A1 and slower in batch A4. This result showed that as the proportion of mucilage increased, the overall time of release of the drug from the matrix tablet increased. Drug release from swellable and erodible hydrophilic matrices can be attributed to polymer dissolution, drug diffusion through gel layer, or a combination of both.
FIGURE1: C.K.Pithawala Institute of Pharmaceutical Science and Research
From this preliminary study, the mucilage extracted from Aloe barbadensisMiller appears suitable for use as a pharmaceutical excipient in the formulation and manufacture of sustained-release matrix tablets because of its good swelling, good flow, and suitability for direct-compression formulations. From the dissolution study, it was concluded that the dried mucilage can be used as an excipient for sustained-release, modified-release, and fast-release tablets with suitable modifications.
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