The present study was aimed at the development of gastroretentive floating pulsatile release tablets (FPRTs) of lercanidipine HCl to enhance the bioavailability and treat early morning surge in blood pressure. Immediate release core tablets containing lercanidipine HCl were prepared and optimized core tablets were compression-coated using buoyant layer containing polyethylene oxide (PEO) WSR coagulant, sodium bicarbonate, and directly compressible lactose. FPRTs were evaluated for various
The oral route is the common way for consumption of drugs among various routes of drug administration due to the patient compliance and cost involved in therapy. However, to know the detailed fate of drugs after oral administration in the body requires understanding of physiology of the gastrointestinal tract (GIT). Absorption of drugs from the GIT is a very complicated process as it is difficult to confine and locate the system within anticipated regions of the GIT and also absorption varies with the conditions of GIT [
For treating some diseases showing circadian rhythms in symptoms such as cardiovascular diseases, arthritis, bronchial asthma, cancer, duodenal ulcers, diabetes, and neurological disorders, it is essential to deliver the maximum drug at the time when symptoms are observed wherein release of drug can be controlled by lag time [
For drugs that have site specific action and need maximum concentrations at particular time, it is required to combine different approaches to obtain desired release. In the present study, the two concepts, that is, floating and pulsatile, are combined in order to get gastroretentive floating pulsatile delivery system of lercanidipine HCl, intended for chronotherapy of hypertension. Lercanidipine HCl is a calcium antagonist of the dihydropyridine group and has effective antihypertensive action [
Accordingly in the present study gastroretentive floating pulsatile release tablets (FPRTs) of lercanidipine HCl were prepared by compression/press-coating technology so that drug can be released in the stomach after specified lag time. Liquid based coatings offer disadvantages as it is time consuming process and drug instability may occur due to hydrolysis; hence, nonsolvent press-coating method was used [
Thus, the gastroretentive pulsatile composition of lercanidipine HCl can achieve prolonged gastric residence time and pulsatile release of the drug in a time-controlled manner following erosion of the coating. Rapid release in gastric region after lag time enhances the absorption of lercanidipine HCl and also can achieve the objective of chronotherapy. In order to accomplish these objectives, various parameters were varied such as the properties of the inner immediate release core and the coatings and were optimized.
Lercanidipine HCl was a gift sample from Cipla Limited, Mumbai. Valdecoxib, polyvinyl pyrrolidone (PVP K30), directly compressible lactose (DCL), Ac-Di-Sol (crosscarmellose sodium), sodium starch glycolate (SSG), crospovidone, talc, magnesium stearate, and sodium lauryl sulphate (SLS) were obtained as gift samples from Lupin Research Park, Pune, India. Polyethylene oxide (PEO) was obtained as gift sample from Colorcon Asia Pvt. Ltd., Goa. Sodium bicarbonate was purchased from Kem Light Laboratories Pvt. Ltd., Mumbai, India. Acetonitrile and methanol were purchased from Merck Specialties Ltd., Mumbai. Milli-Q water was produced in the lab using the Milli-Q water generator (Millipore (India) Pvt. Ltd., Bangalore). All other chemicals and reagents used are of analytical grade and are purchased from standard chemical manufacturers.
Analysis of lercanidipine HCl was done by HPLC (LC-2010CHT, Shimadzu, Kyoto, Japan). A Phenomenex Gemini C18 (250.0 × 4.6 mm, 5
For preparing FPRTs of lercanidipine HCl, initially the immediate release core tablets containing drug were prepared and optimized tablets were compression-coated using mixture of hydrophilic swellable polymer and lactose. To obtain buoyancy, sodium bicarbonate was included in the coating layer. Accordingly, various formulation parameters of the inner immediate release core and the coatings were varied and optimized.
The immediate release core tablets were prepared by weighing the drug, diluents along with superdisintegrants and PVP K30 (dry binder), and passing them through sieve #44 to break the lumps and also for proper blending of powder; to this powder blend magnesium stearate and talc were added and mixed. The powder mixtures were punched to 100 mg and 50 mg using flat-faced punches using a 10 station automatic rotary compression machine (Rimek Mini Tablet Press-1, Mumbai, India). The composition of the tablets is given in Table
Composition of immediate release core tablets of lercanidipine HCl.
Batch number | Ingredients (mg) | Total weight (mg) | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Drug | MCC | Lactose | PVP K30 | SSG | Cross PVP | Ac-Di-Sol | Magnesium stearate | Talc | ||
F 1 | 10.00 | 82.00 | — | 3.00 | — | 3.00 | — | 1.00 | 1.00 | 100 |
F 2 | 10.00 | 82.00 | — | 1.00 | 5.00 | — | — | 1.00 | 1.00 | 100 |
F 3 | 10.00 | 80.00 | — | 3.00 | 5.00 | — | — | 1.00 | 1.00 | 100 |
F 4 | 10.00 | 78.00 | — | 5.00 | 5.00 | — | — | 1.00 | 1.00 | 100 |
F 5 | 10.00 | 82.00 | — | 3.00 | 3.00 | — | — | 1.00 | 1.00 | 100 |
F 6 | 10.00 | 82.00 | — | 3.00 | — | — | 3.00 | 1.00 | 1.00 | 100 |
F 7 | 10.00 | — | 34.00 | 2.50 | 2.50 | — | — | 0.50 | 0.50 | 50 |
F 8 | 10.00 | — | 35.25 | 2.50 | 1.25 | — | — | 0.50 | 0.50 | 50 |
F 9 | 10.00 | — | 32.75 | 2.50 | 3.75 | — | — | 0.50 | 0.50 | 50 |
F 10 | 10.00 | — | 34.00 | 2.50 | — | 2.50 | — | 0.50 | 0.50 | 50 |
F 11 | 10.00 | — | 34.00 | 2.50 | — | — | 2.50 | 0.50 | 0.50 | 50 |
FPRTs were prepared by compression/press-coating method as per the composition given in Table
Composition of coat for floating pulsatile release tablets.
Batch number | Ingredients (mg) | Total weight | |||||
---|---|---|---|---|---|---|---|
PEO | Lactose | Sodium bicarbonate | Talc | Magnesium stearate | % of PEO | ||
FP 1 | 60 | 174 | 60 | 3 | 3 | 20 | 300 |
FP 2 | 80 | 232 | 80 | 4 | 4 | 20 | 400 |
FP 3 | 100 | 290 | 100 | 5 | 5 | 20 | 500 |
FP 4 | 90 | 144 | 60 | 3 | 3 | 30 | 300 |
FP 5 | 120 | 192 | 80 | 4 | 4 | 30 | 400 |
FP 6 | 150 | 240 | 100 | 5 | 5 | 30 | 500 |
FP 7 | 120 | 192 | 80 | 4 | 4 | 30 | 400 |
FP 8 | 120 | 192 | 80 | 4 | 4 | 30 | 400 |
FP 9 | 120 | 192 | 80 | 4 | 4 | 30 | 400 |
FP 10 | 120 | 192 | 80 | 4 | 4 | 30 | 400 |
FP 11 | 120 | 114 | 60 | 3 | 3 | 40 | 300 |
FP 12 | 160 | 152 | 80 | 4 | 4 | 40 | 400 |
FP 13 | 200 | 190 | 100 | 5 | 5 | 40 | 500 |
FP 14 | 96 | 278.4 | 96 | 4.8 | 4.8 | 20 | 480 |
Data obtained from all FPRT formulations were analyzed using Design-Expert software (version 8 trial, Stat-Ease, Inc., Minneapolis, MN) and used to generate the study design. The central composite design (CCD) is the commonly used RSM design. It indicates whether or not interaction occurs between the factors and thereby affects the magnitude of the response. CCD can be used to derive two or more factors (
Physicochemical characteristics of core tablets as well as FPRTs were studied. The diameter, thickness, and hardness of the tablets (
The buoyancy of the tablets was determined in triplicate [
For determining swelling behavior of the tablets, a tablet was weighed (
The
Pure drug and powdered tablet formulation were analysed for Fourier transform infrared spectroscopy (FTIR). FTIR spectra were recorded by using a Shimadzu FTIR 8300 Spectrophotometer (Shimadzu, Tokyo, Japan). The samples were mixed with dry potassium bromide and this mixture was taken in a diffuse reflectance sampler and IR spectra were recorded and compared.
The optimized tablet was studied for the surface morphology from the micrographs taken with the SEM (Zeiss, EVO 18, Carl Zeiss SMT Ltd., UK). Formulation was subjected to dissolution after 60 min and at the end of 5 h the tablet was taken out and dried at 40°C in an oven for 24 h and was analyzed for surface topography. The samples were placed on a double sided adhesive tape on copper stubs and then analyzed at accelerating voltage of 15 kV.
Responses obtained from all the formulations were analyzed using Design-Expert 8 software and were used to generate a study design and the response surface plots. A numerical optimization technique was used to develop the optimized formulation, in which a minimum and a maximum level must be given for each parameter. The outputs were combined into an overall desirability function. The list of solutions was sorted with the highest desirability; solutions that meet the criteria are reported. The association between the independent and dependent variables was interpreted by response surface plots. The effects of different factors on regression coefficients were studied using analysis of variance (ANOVA).
The relative error (%) was calculated as part of validation of the selected experimental design by using the difference in the predicted and experimental values.
The
The study was carried out to compare the pharmacokinetics of optimized FPRTs of lercanidipine HCl and immediate release tablet (core). The overnight fasted rabbits were divided into 2 groups (
A sensitive validated HPLC method was used to analyze the lercanidipine HCl in plasma. Valdecoxib was used as internal standard (IS). Lercanidipine HCl was extracted from the rabbit plasma using 0.2% v/v HCl and chilled acetonitrile as protein precipitating agents. Chromatographic conditions were similar to analytical method as mentioned earlier. However, injection volume was 100
In order to improve the bioavailability, rapid absorption of the lercanidipine HCl is essential for the gastric region as soon as it gets released from the dosage form. Therefore, lercanidipine HCl immediate release formulations were developed and optimized. For chronotherapeutic drug delivery, it is essential to have lag time in drug release, and accordingly tablets were compression-coated for controlling the drug release.
The core tablets showed uniform thickness (2.26 ± 0.06 mm for 50 mg; 3.35 ± 0.02 mm for 100 mg tablets) and diameter (5.03 ± 0.002 mm for 50 mg; 5.30 ± 0.01 mm for 100 mg tablets). The hardness was found to be 103.9 ± 2.38 N. The friability and weight variations were within the official limits of Indian Pharmacopoeia 2007 [
For
Dissolution profiles showing (a) the effect of binder concentration and (b) effect of superdisintegrants on drug release.
The effect of superdisintegrants on release behavior was also observed; 3% of crospovidone, 3% of Ac-Di-Sol, and 3% of SSG were studied by keeping PVP K30 constant. Among all, SSG was found to have good release compared to others and increase in concentration of SSG from 3 to 5% has shown better release with initial 45% at 5 min and 86% at the end of 60 min. Although the formulations were prepared with MCC when processed for further steps, that is, dry coating, the floating behavior has not shown which might be attributed to the density of MCC and thus the diluent was replaced with DCL. Also, in order to get uniform coating in all sides of core tablet, tablet weight was reduced to 50 mg. The new formulations were tested for the effect of superdisintegrants again, and the release was observed using 2.5, 5, and 7.5% of SSG and 5% of CPVP and Ac-Di-Sol. There were no significant changes in the release profile between 100 mg and 50 mg tablets. Comparative release patterns of 50 mg tablets (F 7 to F 11) were shown in Figure
Controlled-release floating pulsatile lercanidipine HCl tablets were prepared by compression coating of the optimized immediate release tablet (F 7) using polymer mixture containing PEO, sodium bicarbonate, and DCL. Based on available literature, 20% sodium bicarbonate was incorporated into the polymer mixture which is sufficient to maintain the buoyancy of the tablet [
The tablets of different batches showed uniform thickness (4.19 ± 0.05 mm) and diameter (11.05 ± 0.03 mm). The hardness was found to be 155.9 ± 8.73 N. The friability and weight variations were within the official limits [
Floating lag time (FLT) and total floating time (TFT) of the formulations were observed visually and were in the range of 60–220 sec and 8 to >12 h (Table
Floating lag time and total floating time of floating pulsatile release formulations.
Batch number | Formulation | FLT (sec) | TFT (h) | |
---|---|---|---|---|
FP 1 | PEO 20% | 300 mg | 64 | 8 |
FP 2 | 400 mg | 130 | 10 | |
FP 3 | 500 mg | 140 | >11 | |
FP 14 | 480 mg | 132 | 11 | |
|
||||
FP 4 | PEO 30% | 300 mg | 68 | 9 |
FP 5 | 400 mg | 164 | 11 | |
FP 6 | 500 mg | 181 | >12 | |
FP 7 | 400 mg | 160 | 11 | |
FP 8 | 400 mg | 166 | 11 | |
FP 9 | 400 mg | 163 | 11 | |
FP 10 | 400 mg | 164 | 11 | |
|
||||
FP 11 | PEO 40% | 300 mg | 70 | >10 |
FP 12 | 400 mg | 130 | >11 | |
FP 13 | 500 mg | 220 | >12 | |
|
||||
FP 14 | PEO 20% | 480.77 mg | 137 | >11 |
FLT: floating lag time; TFT: total floating time.
PEO is a nonionic, highly swelling hydrophilic polymer absorbing 7 times its initial weight of water. As it swells enormously independent of pH, this ability has been utilized in gastroretentive formulations [
Swelling indices of floating pulsatile release formulations at different time points.
The
Dissolution profile of various floating pulsatile release formulations.
From the results, it is evident that as the amount or concentration of the polymer PEO increased, time required for the drug to release also increased and the same effect was observed as the weight of the formulation was increased. As observed from the swelling study, after floating pulsatile release tablet has absorbed sufficient water, PEO layer started eroding and in the meantime lactose formed pores on the polymer layer allowing further erosion. Lactose being a nonswelling wicking agent is dispersed throughout the matrix along with PEO; it creates channels for incoming aqueous fluid and further enhances the erosion of the polymer [
The FTIR spectrum of lercanidipine HCl exhibited the characteristic absorption peaks at 3186 cm−1 (NH stretching), 3078.8 cm−1 (CH aromatic stretching), 3100–2800 cm−1 (alkyl and phenyl stretching), 2565 cm−1 (+H stretching), 1672.95 cm−1 (>C=0 stretching vibrations), 1347.03 cm−1 (–NO2), and 785–685 cm−1 (out-of-plane bending of 5 and 3 adjacent hydrogen’s on aromatic rings). The characteristic drug peaks in the IR spectrum (Figure
FTIR spectra of (a) lercanidipine HCl and (b) optimized tablet, FP 14.
The FP 14 formulation was subjected to SEM studies and resulting images are shown in Figure
SEM images of optimized formulation FP 14 at magnification of 200x.
Responses obtained from evaluation study of all 13 formulations were fed into Design-Expert software using 32 full factorial design and constrains are given in Table
Presentation of values and responses in central composite design.
Batch number | Factor 1 |
Factor 2 |
Response 1 |
Response 2 |
Response 3 |
---|---|---|---|---|---|
FP 1 | 20.00 | 300.00 | 3 | 103.66 | 101.70 |
FP 2 | 20.00 | 400.00 | 3 | 99.69 | 98.87 |
FP 3 | 20.00 | 500.00 | 6 | 72.37 | 100.54 |
FP 4 | 30.00 | 300.00 | 3 | 78.86 | 99.96 |
FP 5 | 30.00 | 400.00 | 6 | 39.84 | 101.34 |
FP 6 | 30.00 | 500.00 | 7 | 2.07 | 105.86 |
FP 7 | 30.00 | 400.00 | 6 | 37.52 | 98.13 |
FP 8 | 30.00 | 400.00 | 6 | 39.28 | 100.15 |
FP 9 | 30.00 | 400.00 | 6 | 38.36 | 99.84 |
FP 10 | 30.00 | 400.00 | 6 | 40.25 | 100.06 |
FP 11 | 40.00 | 300.00 | 3 | 105.79 | 109.46 |
FP 12 | 40.00 | 400.00 | 7 | 19.70 | 84.61 |
FP 13 | 40.00 | 500.00 | 8 | 0.57 | 81.08 |
A numerical optimization technique was used to produce the set of formulations with the anticipated responses, in which a minimum and a maximum level must be provided for each dependent variable. The Lag time in drug release = 5.38 + 1.00 Release at 7 h = 40.46 − 25.56 Release at 12 h = 101.05 − 4.31
Response plots and contour plots for the effect of PEO % and coat weight on responses related to lag time and drug release are shown in Figure
Solutions that meet the criteria required for floating pulsatile release tablets.
Batch number | PEO % | Coat weight | Lag time (h) | Release at 7 h (%) | Release at 12 h (%) | Desirability |
---|---|---|---|---|---|---|
1 | 20 | 480.77 | 6.00 | 75.71 | 101.81 | 0.795 |
2 | 40 | 300.00 | 4.38 | 74.15 | 105.20 | 0.751 |
3 | 40 | 306.71 | 4.52 | 78.76 | 103.71 | 0.741 |
(a) Response plot and (b) contour plots for the effect of PEO % and coat weight on lag time and drug release.
The set criteria were as follows: 6 h of drug release lag time, more than 60% release at the end of 7 h, and more than 90% release at 12 h which was the goal of optimized formulation. PEO 20% with 480.77% coat weight showed desirability close to 1.0, and accordingly F 14 was considered as optimum formulation. Desirability and overlay plot for optimization of floating and pulsatile release tablets of lercanidipine HCl with PEO % and coat weight are shown in Figure
Desirability and overlay plots for optimization of floating pulsatile release tablets of lercanidipine HCl with PEO % and coat weight (mg).
The FP 14 was selected based on the drug release lag time of 6 h, 75.71% drug release at 7 h, and maximum drug release at 12 h, and satisfying these parameters the optimized formulation was chosen with a desirability of 0.795. Thus, obtained optimum formulation was evaluated for all the physicochemical evaluation parameters to verify the theoretical prediction. The observed values for the optimized formulation were compared with the predicted values. The results were found to be close to the predicted values, which confirm the practicability of the model. The relative errors for drug release lag time (
Comparison of predicted and observed responses for the statistically optimized formulation FP 14.
Formulation | Response | Observed | Predicted | Relative error (%) |
---|---|---|---|---|
FP 14 | Drug release lag time ( |
5.5 | 6.00 | 8.3 |
% drug release at 7 h ( |
77.07 | 75.71 | 1.71 | |
% drug release at 12 h ( |
98.95 | 101.81 | 2.80 |
This study aimed to confirm that the tablet would remain floating in the gastric region and after lag time release the core tablet. As the core tablet comes in contact with the gastric content, it gets disintegrated to release the drug. The radiographic images were taken after administering the developed barium sulphate-loaded floating pulsatile tablet to the rabbits under fasting conditions. Figure
X-ray radiograms showing the presence of floating tablet in rabbit gastric region.
The FPRT FP 14 was selected for
Pharmacokinetic parameters from the plasma concentration-time curves.
Parameters | Immediate release core tablet (F 7) | Floating pulsatile release tablet (FP 14) |
---|---|---|
|
168.58 ± 19.25 | 176.55 ± 22.14 |
|
1.00 ± 0.25 | 6.00 ± |
|
2709.62 ± 184.29 | 3346.55 ± 273.37 |
|
3016.47 ± 206.13 | 3785.32 ± 228.24 |
MRT (h) | 15.60 ± 1.94 | 20.1 ± 2.41 |
|
17.01 ± 1.16 | 13.70 ± 0.82 |
CL (L/h) | 1.35 ± 0.12 | 1.07 ± 0.09 |
|
8.70 ± 0.52 | 8.80 ± 0.46 |
|
0.079 ± 0.01 | 0.078 ± 0.01 |
Plasma drug concentration-time curves for pharmacokinetic study in rabbits. All points are presented as mean ± SEM,
In the present study, floating pulsatile release tablets of lercanidipine were developed. They were remained in the stomach condition for sufficient time period, and after specified lag time drug was released rapidly from the immediate release core tablet. Presence of sodium bicarbonate helped in gastric retention of the tablet. Amount of highly swellable polymer PEO and lactose and the coat weight were the key parameters that controlled the lag time in drug release. Sodium starch glycolate played an important role in immediate release of lercanidipine HCl. Thus, nighttime administration of designed floating pulsatile controlled-release tablets of lercanidipine HCl can be used in treating early morning surge in hypertension. However, while applying the developed dosage form to humans, adverse effects such as stomach distress due to gas formation and polymeric swelling should be considered which are very important with respect to patient compliance.
The authors declare that they have no conflict of interests.
The authors are grateful to Dr. Keerthilatha M. Pai, Professor and Head of the Department of Oral Medicine & Radiology, and Mr. Bhaskar H., Radiologist, Manipal College of Dental Sciences, Manipal University, Manipal, for their kind help and cooperation in X-ray imaging studies, and Mr. Sreedhar Prabhu, In-charge, Central Animal Facility, Manipal University, for helping in animal experimentation.