|Year : 2017 | Volume
| Issue : 1 | Page : 50-56
Formulation and evaluation of gastroretentive-floating multiparticulate system of lisinopril
Manasa Moganti, HN Shivakumar
Department of Pharmaceutics, KLE University's College of Pharmacy, Bengaluru, Karnataka, India
|Date of Web Publication||18-Jan-2017|
Department of Pharmaceutics, KLE University's College of Pharmacy, 2nd Block, Rajaji Nagar, Bengaluru - 560 010, Karnataka
Source of Support: None, Conflict of Interest: None
Aim and Objective: The main objective of this research was to formulate and evaluate gastroretentive-floating multiparticulate system of lisinopril to prolong the gastric residence time.
Materials and Methods: Gastroretentive system of lisinopril was developed by ionotropic-gelation technique using isabgol (Plantago ovata F.) husk mucilage (IHM) as a floating agent, sodium alginate as a mucoadhesive polymer, and sodium bicarbonate as a gas-generating agent.
Results: The beads were evaluated for entrapment efficiency (EE), in vitro drug release, and ex vivo mucoadhesion. The beads of batch F-2 exhibited high-EE (96.04 ± 0.74%), complete drug release (95.27 ± 0.12%), and good mucoadhesion (50% in 8 h). The in vitro drug release from these beads exhibited first-order kinetics that followed Higuchi diffusion model.
Conclusion: The beads by virtue of the high EE, complete drug release, and good mucoadhesivity that exhibit prolonged gastric residence time are likely to improve the bioavailability of the drugs having the absorption window in proximal stomach.
Keywords: Gastroretentive drug delivery, lisinopril, mucoadhesivity
|How to cite this article:|
Moganti M, Shivakumar H N. Formulation and evaluation of gastroretentive-floating multiparticulate system of lisinopril. Indian J Health Sci Biomed Res 2017;10:50-6
|How to cite this URL:|
Moganti M, Shivakumar H N. Formulation and evaluation of gastroretentive-floating multiparticulate system of lisinopril. Indian J Health Sci Biomed Res [serial online] 2017 [cited 2019 Jul 16];10:50-6. Available from: http://www.ijournalhs.org/text.asp?2017/10/1/50/198589
| Introduction|| |
Oral route of drug administration is the most convenient and commonly used method of drug delivery. However, this route has several physiological problems such as unpredictable gastric emptying rate and the existence of an absorption window in the upper part of the stomach for several drugs. To overcome these difficulties, a novel approach has been proposed in which the dosage forms can be retained in the stomach known as gastroretentive drug delivery systems. These systems can prolong the gastric residence time by improving solubility and bioavailability of the drug.
Lisinopril, a angiotensin-converting enzyme-inhibitor, is mostly used in the treatment of hypertension, congestive heart failure, and renal diseases. Lisinopril has a narrow absorption window with an overall bioavailability of 25%. The half-life on multiple dosing is 12 h.
Therefore, in the present study, isabgol as gastroretentive carrier and sodium alginate (SA) as mucoadhesive polymer were used as excipients for the drug lisinopril to investigate a new formulation for gastroretentive drug delivery system and to prolong the residence time in the stomach.
| Materials and Methods|| |
Lisinopril was obtained as a generous gift sample from Aurobindo Pharma Ltd., Hyderabad. SA, hydroxy propylmethyl cellulose (HPMC-K4M), sodium bicarbonate, and hydrochloric acid (HCl) were supplied by SD Fine chemicals, Mumbai. Isabgol-husk was obtained from Sidhpur Sat-Isabgol Factory, Gujarat.
Determination of melting point
Melting point of the drug was determined by taking a small amount of the drug in a capillary tube closed at one end. The capillary tube was placed in a melting point apparatus and the temperature at which the drug melts was recorded.
Determination of solubility
An excess amount of drug was taken and dissolved in a measured volume of 0.1 N HCl (PH 1.2) in a glass vial to get a saturated solution. The solution was sonicated and kept at room temperature for attainment of equilibrium. Following this, it was filtered. The concentration of lisinopril in the filtrate was determined spectrophotometrically by measuring absorbance at 258 nm after 24 h.
Compatibility studies of drug with excipient
Infrared spectrophotometry is a useful analytical technique utilized to check the chemical interaction between the drug and the other excipients used in the formulations. The sample was powdered and intimately mixed with 10 mg of powdered potassium bromide (KBr). The powdered mixture was taken in a diffuse reflectance sampler and the spectrum was recorded by scanning in the wavelength region of 4000-400/cm in a Fourier transform infrared spectroscopy (FT-IR) spectrophotometer (Jasco 460 plus, Japan). The IR spectrum of the drug was compared with that of the physical mixture to check for any possible drug-excipients interaction.
Preparation of calibration curve
An accurately weighed quantity of lisinopril was dissolved and diluted in 0.1 N HCl in a volumetric flask to obtain a concentration of 1 mg/ml. From the standard solution, 1000 μg/ml was serially diluted with 0.1 N HCl to get working standard solution having a concentration of 10-50 μg/ml. The absorbance of the solutions was measured at 258 nm using ultraviolet (UV) spectrophotometer against 0.1 N HCl as a blank.
Preparation of the drug-loaded gastroretentive-floating beads
A solution was prepared by dissolving 5% w/v of SA and 3% w/v of isabgol husk in sufficient quantity of distilled water. To this solution, lisinopril and HPMC-K4 M were added. Then, gas-forming agent sodium bicarbonate was separately added to the solution. The resulting solution was dropped through a 24-gauge syringe into 2% (w/v) calcium chloride (CaCl2) solution at low rpm (200). Then, the beads formed were allowed to remain in the stirred solution for 10 min. The beads were filtered and dried at room temperature. Eight different formulations containing different concentrations of SA, Isabgol, and CaCl2 solution were prepared [Table 1].
Evaluation of gastroretentive-floating beads
Accurately weighed beads equivalent to 10 mg of lisinopril were taken and crushed using mortar and pestle. The crushed powder was placed in a 10 ml volumetric flask and the volume was made up to 10 ml by 0.1 N HCl and kept for 24 h with occasional shaking at 37 ± 0.5°C. The drug content in the filtrate was determined using a UV-spectrophotometer (Shimadzu, Japan) at 258 nm against appropriate blank. The entrapment efficiency (EE) (%) of these prepared beads was calculated by the following formula: and the resuts were recorded in [Table 2].
|Table 2: Entrapment efficiency, percentage of release, and floatation time |
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Bead size measurement
Particle size of 100 dried beads from each batch was measured by microscopic method to determine the average particle size using an optical microscope (Olympus). The ocular micrometer was previously calibrated by a stage micrometer.
Scanning electron microscope analysis
Samples were gold coated by mounting on a brass stub using double-sided adhesive tape under vacuum in an ion sputter. A thin layer of gold (3 ~ 5 nm) was coated in 75 s at 20 kV to render the beads electrically conductive. The morphology of the gold-coated beads was examined under scanning electron microscope (SEM).
The prepared gastroretentive beads were placed in a glass beaker containing 0.1 N HCl. Their time of floating was recorded.
In vitro drug release studies
The release of lisinopril from various beads was tested using a dissolution apparatus USP (Electrolab- TDT-08 L). The baskets were covered with a muslin cloth to prevent the escape of the beads. The dissolution rates were measured at 37°C ± 1°C under 100 rpm speed. Accurately weighed beads containing lisinopril equivalent to 10 mg were added to 900 ml of 0.1 N HCl. The test was carried out for 8 h. A volume of 5 ml of aliquots was collected at regular time intervals, and the same amount of fresh dissolution medium was replaced into dissolution vessel to maintain the sink condition throughout the experiment. The collected aliquots were filtered and suitably diluted to determine the absorbance using a UV-spectrophotometer (Shimadzu, Japan) at 258 nm against appropriate blank.
To analyze the in vitro release data, various kinetic models were used to describe the release kinetics. Zero-order equation (C = K0t, where K0 = zero-order rate constant, t = time), in which the drug release rate is independent of the drug concentration. First-order equation (log C = log C0-Kt/2.303, where C0 = drug's initial concentration, K = first-order constant), in which the release rate is concentration-dependent and Higuchi (Q = Kt1/2 , where K = constant reflecting the design variables of the system), in which the release of drug from insoluble matrix as a square root of time-dependent process based on Fickian diffusion equation. An attempt was made to determine the mechanism of drug release by fitting the dissolution data into a different equation such as Higuchi equation.
The mucoadhesive property of beads containing lisinopril was evaluated by ex vivo wash-off method. Freshly excised pieces of rat stomach mucosa (2 cm × 2 cm) were mounted on a glass slide (7.5 cm × 2.5 cm) using a thread. About fifty beads were spread onto the wet tissue specimen, and the prepared slide was hung onto a groove of disintegration test apparatus. The tissue specimen was given a regular up and down movement in a vessel containing 900 ml of 0.1 N HCl (pH 1.2) at 37°C ± 0.5°C. After regular time intervals, the apparatus was stopped and the number of beads still adhering to the tissue was counted.
| Results|| |
Calibration curve of lisinopril in 0.1 N HCl
The calibration curve of Lisinopril in 0.1N HCl was shown in [Figure 1].
The solubllity of lisinopril in 0.1N HCl and phosphate buffers was recorded in [Table 3].
Fourier transform-infrared spectroscopy of drug and polymers
The FTIR spectrum showing lisinopril, lisinopril + sodium alginate, lisinopril + HPMC- K4M, lisinopril + isabgol husk and lisinopril + sodium bicarbonate was shown in [Figure 2].
|Figure 2: Fourier transform infrared spectroscopy spectrum showing lisinopril, lisinopril + sodium alginate, lisinopril + hydroxy propylmethyl cellulose - K4M, lisinopril + isabgol husk, and lisinopril + sodium bicarbonate|
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Particle size determination
Average size of beads in micrometer of all the formulations was graphically representated in [Figure 3].
Scanning electron microscope analysis
The morphology of the gold coated beads were examined under scanning electron microscope was shown in [Figure 4].
In vitro release studies
The percentage drug release over 8 hrs of all the batches from F1 - F8 was graphically representated in [Figure 5] and [Figure 6].
The Ex-vivo wash test of batch (F2) was graphically representated in [Figure 7].
| Discussion|| |
The absorption maximum of the drug was determined in a UV-visible spectrophotometer after dissolving the drug in 0.1 N HCl. The drug was scanned in the region 200-400 nm for maximum absorption. The absorption maxima of lisinopril in 0.1 N HCl was found to be close to the value cited earlier. The standard curves were linear in the concentration range of 10-50 μg/ml with a slope of 0.0177 and regression coefficient of 0.9992 as shown in [Figure 1].
The FT-IR data are helpful to confirm the identity of the drug and to detect the interaction of drug with the polymer. They include spectral analysis of lisinopril alone and physical mixture of lisinopril and SA, lisinopril and HPMC-K4 M, and lisinopril and isabgol husk. The spectral analysis indicated that lisinopril was not altered. These studies revealed that there was no significant interaction between drug and polymer as characteristic peaks of lisinopril were found to match well with the reported values.
The FT-IR analysis for formulated gastroretentive beads was done, the spectrum obtained is shown in [Figure 2]. The results suggest that the drug and polymers are compatible for the preparation of gastroretentive isabgol husk-alginate beads.
The % EE [Figure 8] of isabgol husk-alginate beads containing lisinopril ranged from 64.6% to 96.04% [Figure 8]. SA to isabgol husk ratio and concentration of CaCl2 as cross-linker were found to influence EE (%) significantly. It was also observed that the drug encapsulation in these beads increased with the decrease in the SA to isabgol husk ratio and concentration of CaCl2. The better % EE could be due to the increase in viscosity of the polymeric solution as the isabgol husk amount increased in the polymer-blend solution. This might have been prevented drug leaching to the cross-linking solution during ionotropically gelled bead preparation.
The size of ionotropically gelled isabgol husk-alginate beads containing lisinopril was within the range of 909-980 μm [Figure 3]. Increasing the size of these beads was observed with the increasing incorporation of isabgol husk in polymer-blend solution, which could be explained based on hydrodynamic viscosity concept. The viscosity increment of the polymer-blend solution with the addition of isabgol husk in increasing ratio might form larger droplets of polymer-blend solutions during passing through the needle to the cross-linking solution containing Ca2+ ions. Again, the decrease in bead size was observed when concentrated CaCl2 solution was used. This could be due to the formation of more rigid polymeric network by the high degree of cross-linking by the high concentration of cross-linker (i.e., CaCl2).
The surface morphological analysis of the ionotropically gelled isabgol husk-alginate beads containing lisinopril (F-2) was visualized by SEM and is presented in [Figure 4]. The surface of these beads was very rough with characteristic large wrinkles, which could have been caused by partly collapsing the polymeric gel network during drying. In addition, a large number of pores were seen on the bead surface, which could be due to the presence of sodium bicarbonate in the formulation.
The floating time of gastroretentive isabgol husk-alginate beads containing lisinopril was within the range of 256-539 min [Table 2]. Higher floating time was recorded with beads of higher isabgol husk concentration (3%-5%) and due to the presence of bicarbonate ions.
The in vitro release of lisinopril from the ionotropically gelled beads showed prolonged lisinopril release over 8 h in acidic dissolution medium, i.e., 0.1 N HCl [Figure 5] and [Figure 6]. The trace amount of drug release from these beads at the initial stage of the study could probably be due to the surface-adhered drug. The cumulative drug release from isabgol husk-alginate beads containing lisinopril after 8 h (% R8h ) was within the range of 61.26%-95.26%. The release was found to decrease with decrease in the SA to isabgol ratio and increasing CaCl2 . Isabgol husk might be responsible to produce the more viscous gel, which may block the pores on the surface of beads and thus, sustain the drug release profile. Drug release from SA-isabgol husk beads containing lisinopril prepared using higher CaCl2 concentration was comparatively sustained than the beads formulated with that of lower concentration of CaCl2. The higher concentration of CaCl2 (i.e., cross-linker) can produce a high degree of cross-linking and thereby slow down the drug release from highly cross-linked isabgol husk-SA beads containing lisinopril. The release increased in the following order: f2> f6> f7> f3> f5> f8> f1> f4. In vitro drug dissolution data results are shown in [Table 2].
The result of the curve fitting into various mathematical models such as zero-order, first-order, and Higuchi models is shown in [Table 4]. When the respective squared correlation coefficients (R2) of these ionotropically gelled isabgol husk-SA beads containing lisinopril were compared using various mathematical models, it was found that the drug release followed the Higuchi which is the best fit model over a period of 8 h of in vitro drug release (R2 = 0.9396-0.9961).
The results of the ex vivo wash-off test confirmed good mucoadhesive potential of isabgol husk-SA beads containing lisinopril, which could lead to higher bioavailability of the encapsulated drug due to increased gastric residence time and a closer contact between the absorptive membrane and these beads. This would enable sustained drug release of lisinopril in the stomach that represents the site proximal to the absorption window of the drug. The mucoadhesive property of these beads could be attributed to the presence of hydroxyl groups of both the hydrophilic polymers used as polymer blend, which have the ability to form hydrogen bonds with the mucous membranes. It has to be noted that hydrophilic polymers such as SA and HPMC-K4 M also have the ability to form noncovalent bonds such as Vanderwaals forces or ionic interactions, resulting in mucoadhesion.
The results of the present investigation have proved that the gastroretentive beads of SA in combination with isabgol husk (5%) and HPMC-K4 M as a mucoadhesive agent were found to be suitable for formulating a gastroretentive drug delivery system for lisinopril for clinically treating hypertension.
From the results of in vitro drug dissolution data, formulation (F2) was found to give the best results.
The results obtained so far have revealed that the formulations have satisfied all the physical parameters required for an ideal multiparticulate system for their utilization for oral route used for the chosen drug as it exhibited maximum floating time, extended mucoadhesion, and complete drug release in 8 h.
| Conclusion|| |
Lisinopril is an anti-hypertensive agent which is selected for the preparation of the gastroretentive drug delivery system as it has narrow absorption window in proximal part of the stomach.
The gastroretentive drug delivery system of lisinopril was prepared by ionotropic gelation method and the prepared beads were found to possess high EE %, complete drug release in 8 h, and good mucoadhesivity that are likely to exhibit prolonged gastric residence time and improve the bioavailability of the drug having the absorption window in proximal stomach.
From the above studies, it is revealed that the present work was a satisfactory preliminary study of lisinopril by the development of gastroretentive drug delivery system using isabgol husk as a natural floating agent.
However, the efficacy of the floating beads needs to be assessed in a suitable animal model to determine the bioavailability.
The authors thank Dr. H. N. Shivakumar, Professor and HOD, Department of Pharmaceutics, KLE University's College of Pharmacy, Bengaluru, for his unparalleled, constant encouragement, constructive criticism, and excellent guidance. The authors also thank Dr. S. M. Hipparagi, Principal, KLE University's College of Pharmacy, Bengaluru, Dr. Vanitha S, Mr. Y. D. Satyanarayana, Mrs. Preethi, Dr. Anasuyapatil, and Mr. Sujeet Kumar for their moral support, suggestions, and involvement in this research work. The authors would also like to thank nonteaching staff Mr. Suresh, Mr. Ramachandra, Mr. Biradar, etc., of KLE University's College of Pharmacy, Bengaluru, for their valuable help and guidance during the course of research work.
Financial support and sponsorship
This study was financially supported by KLE University's College of Pharmacy (Bengaluru).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2], [Table 3], [Table 4]