INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE

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1 INTERNATIONAL JOURNAL OF PHARMACEUTICAL RESEARCH AND BIO-SCIENCE FORMULATION AND EVALUATION OF SUBLINGUAL DOSAGE FORM OF LERCANIDIPINE HCL DIPTI S. MAHESHWARI 1, PANKAJ H. PRAJAPATI, 1 C. N. PATEL 1. Department of Pharmaceutics and Pharmaceutical Technology, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat.. Department of Pharma. chemistry, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat. Accepted Date: 19/0/01; Published Date: /0/01 Abstract: The aim of this study was to formulate and evaluate the effect of increasing Lercanidipine HCl on the characteristics of fast-disintegrating sublingual tablets by solubility enhancement as Lercanidipine HCl undergoes first pass metabolism in liver and gut wall which has oral bioavailability of approx 10-0%. Sublingual dosage form bypasses the metabolism of the Lercanidipine HCl in liver and offers a fast relieve from anginal pain and hypertension.the purpose of present work was a development of sublingual tablet of Lercanidipine HCL with solubility enhancement to overcome the limitation of current routes of administration, to provide faster dissolution rate and increase patient compliance especially for outpatient setting. The amount of drug was calculated same as available marketed immediate release formulation. For solubility enhancement screening of different polymers like Povidone k-0, PEG-000, Poloxamer and HPMC cps were done using phase solubility study and Povidone k-0 was selected. For screening of methods like kneading, solvent evaporation and spray drying method utilizing Povidone K-0 were done using phase solubility study and spray drying was selected. The effect of drug: polymer ratio and super disintegrant crospovidone concentration were optimized using design of experiment and tested for physico chemical properties of sublingual tablets. Aspartame and mannitol were used as a sweetener. The preformulation studies showed no interaction between drug and polymer or with other additives. Using experimental design, the prepared formulations were evaluated for in vitro dissolution characteristics, in vitro disintegration time and their physic chemical properties. The optimized formulation (batch F8) containing Drug: polymer ratio (1:) and crospovidone % showed greater drug dissolution (more than 9% within 0 min), satisfactory in vitro disintegration time ( sec) and physico chemical properties that were suitable for sublingual tablet. The stability study of optimized formulation for 1 month showed no appreciable change in drug content, in vitro drug release and in vitro disintegration time. Keywords: Sub lingual tablet, Lercanidipine HCL, Spray drying, Experimental design Corresponding Author: MS. DIPTI S. MAHESHWARI Access Online On: How to Cite This Article: PAPER-QR CODE 990

2 INTRODUCTION According to the World Health Organization, disease attributable to hypertension is the No. 1 cause of mortality in the world (). Hypertension is a major risk factor for cardiac disease and stroke, with an increase in risk for these ailments with progressively higher blood pressures (). High blood pressure is the second-leading cause of end-stage renal disease, and its presence increases the rate of progression of all kidney diseases (). Because of this, hypertension will be a central theme at the American Society for Biochemistry and Molecular Biology meeting in Anaheim, with a session titled, Hypertension: Treatment, Disparities and Molecular Mechanisms. Lercanidipine HCL is a calcium channel blocker of the dihydropyridine class. Effective in the treatment of hypertension, chronic stable angina pectoris, and Prinzmetal's variant angina. Oral bio availability is approx 10-0% only due to extensive hepatic first pass metabolism into inactive metabolites.indicated as 10-0 mg once a day.log P value is =., which indicates a highly lipophilic dug, ideal candidate for Sub lingual drug delivery system. Lercanidipine hydrochloride is available in conventional dosage forms such as film coated tablets administered as once a day dosage form. Conventional dosage forms have their own limitations like high first pass metabolism and poor solubility of drug. Thus a novel approach is required to design and develop an ideal dosage form for Lercanidipine HCl. Among the delivery routes, the sub lingual route is the most acceptable from patient compliance aspects as it avoids first pass metabolism and fast disintegration. Sub lingual tablet is formulated by preparation of solid dispersion and other excipients that rapidly dissolve below the tongue. Sublingual tablets offer fast, accurate dosing in a safe, efficacious approach that is both convenient and portable, without the need for water or measuring devices. These dosage devices offer many advantages like accurate dosing, no risk of choking, rapid release profile, enhanced stability, taste masking and improved patient compliance and convenience. In the present research work an attempt was made to formulate and evaluate sub lingual tablets of Lercanidipine hydrochloride using different ratio of drug: polymer and design of experiment (DOE) approach for optimization. MATERIALS AND METHODS Materials Lercanidipine HCl was recieved from Torrent pharmaceutical limited, Gandhinagar, India. Cross povidone, Mannitol, Polivinylpyrolidone K0, Poloxamer 188, Poloxamer 0, HPMC cps, PEG 991

3 000, Aerosil, Magnesium Stearate,citric acid and aspartame were supplied by Yarrow Chem. Products, Mumbai, India. All other materials used were of pharmaceutical or analytical grade Method of analysis Calibration curve of Lercanidipine HCl was taken in phosphate buffer ph.8. Accurately weighed drug (10 mg) was placed in 100 ml volumetric flask and the volume was made upto 100ml with Actonitrile: ph.8 phosphate buffer 0:0 ratio (100µg/ml). From the above solution 1ml was pipette out and volume was made 10ml (10µg/ml). The resultant solution obtained was 10µg/ml and was scanned in UV range of 00 to 00 nm. The drug showed maximum absorption at 0nm. Thus 0nm was taken λmax. Preliminary screening of polymer by Phase solubility study Drug and carrier as per specific drug-carrier ratio (1:1) were weighed accurately and added to 10 ml of ph.8 phosphate buffer in screw capped bottles, then shaken in a rotary shaker at 0 C for hrs. The container containing the pure drug and ph.8 phosphate buffer alone was used as a control. After hrs solution filtered, diluted and the absorbance levels were measured at 0nm Preliminary Screening and Selection of method of preparation of solid dispersion by Phase solubility study Drug and carrier as per specific drug-carrier ratio were weighed accurately and added to 10 ml of ph.8 phosphate buffer in screw capped bottles, then shaken in a rotary shaker at 0 C for hrs. the container containing the pure drug and ph.8 phosphate buffer alone was used as a control.after hrs solution filtered, diluted and the absorbance levels were measured at 0nm Preparation of solid dispersion by spray dryer Spray dried solid dispersion were prepared by dissolving ratio (1:1,1:,1:) of drug(lercanidipine HCL) and polymer ( PVP K 0) in sufficient amount of methanol to obtain clear solution and spray-dried to obtain amorphous Lercanidipine or solid dispersion of Lercanidipine HCL with PVP K 0. The solutions were prepared 10% W/V. The solutions were added slowly under stirring to obtained uniform solid dispersion. Spray Drying was carried out in spray dryer using following parameter.feed rate: 1 ml/min,inlet temp : 0 C, Outlet temp: 0 C, Aspirator: 100%, Pump: 1-1%, O content:.8% (should be < % )All the samples were kept in vacuum dryer for hours to remove residual solvent and stored in a dessicator until further study. Physical mixture of Lercanidipine HCL with PVPk0 in the ratio (1:1, 1:, and 1:) was prepared by mixing them gently. 99

4 Table 1: Spray drying technique composition Lercanidipine HCLwith PVP K 0 Ratio Drug (gm) Polymer (gm) PVP K 0 Solvent (10% W/V) (ml) % Yield 1:1 gm gm 80 % 1: gm 8gm 10 88% 1: gm 1gm 10 9% Optimization of Sub lingual tablet Formulation Using Full Factorial Design From the results of preliminary screening studies, the optimization was carried out using design of expert (DOE) approach. To study the effect of independent variables i.e. Drug:Polymer ratio (X 1 ) and amount super disintegrant (X) on responses full factorial design was used. In this design Drug:Povidone K-0 and Crospovidone were used as independent variables while disintegration time, and % drug release at,10,1,0 min. were selected as response variables. Trials were taken at all possible combinations. The equations relating independent variables and responses were obtained by subjecting the results to statistical evaluation. Design Expert was used to perform multiple linear regressions to determine the control factors that significantly affect the responses. Ingredients F 1 F F F F F F F 8 F 9 mg/tablet Lercanidipine HCL PVP k0(solid dispersion) Mannitol Aspartame Crospovidone Citric acid Aerosil Talc Magnesium Stearate Total weight 100 mg 99

5 FULL FACTORIAL DESIGN FORMULAS AND EVALUATION Polynomial equation for full factorial design: Y = b 0 + b 1 X 1 + b X + b 11 X 1 + b X + b 1 X 1 X was used. In this equation, Y is the dependent variable, b 0 is the arithmetic mean response of the 9 runs, and bi is the estimated coefficient for the factor Xi. The significant factors in the equations were selected using a stepwise forward and backward elimination for the calculation of regression analysis. The terms of full model having non-significant p value (p > 0.0) have negligible contribution hence they were neglected. The tablets were evaluated for Hardness(kg/cm), Diameter(mm), Thickness(mm), Assay, Friability(%),Wetting time, and dissolution test. Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using monsanto tester. It is expressed in kg/cm. Three tablets were randomly picked and hardness of the tablets was determined. The thickness of the tablets was determined by using micrometer screw. Five tablets were used, and average values were calculated. The friability of tablets was determined using Roche Friabilator. It is expressed in percentage (%). Ten tablets were initially weighed (W0) and transferred into friabilator. The friabilator was operated at rpm for minutes or run up to 100 revolutions. The tablets were weighed again (W). The % friability was then calculated by %F = 100 (1-W0/W),% Friability of tablets less than 1% are considered acceptable. Disintegration time was determined using the disintegration apparatus USP in water maintaining the temperature at ± 0. C. In vitro drug release study carrid out with apparatus with paddle stirrer Type-II. The dissolution rate was studied in 00 ml of ph.8 phosphate buffer maintained at a temperature of ±1ºC with a speed of 0 rpm for 0 min minutes. Samples of ml were withdrawn after every interval, filtered (through 0. μm) and replaced with ml of fresh dissolution medium. The samples were suitably diluted if necessary and estimated spectrophotometrically at 0 nm by using UV/Visible spectrophotometer and cumulative percentage drug release was calculated. In order to determine the change in evaluation parameters and in-vitro release profile on storage. stability study of optimized batch was carried out at accelerated storage condition at temperature 0± C and ±% RH in a humidity chamber for months. Sample were 99

6 withdrawn after one month interval and evaluated for change in in vitro drug release pattern, physical appearance thickness, and hardness and disintegration time. RESULTS AND DISCUSSION Sr. No. Concentration (µg/ml) Average (λ max =0nm) Absorbance ± SD (n=) Absorbance (y) = 0.0 * Concentration (x) Correlation coefficients (R²) = y = 0.0x R² = Series1 Linear (Series1) Calibration curve in ph.8 buffer 99

7 Drug excipient compatibility study DSC Data Drug Drug+ excipient FTIR of drug 99

8 Sample name Lercanidipine HCl OH N-H CH C=O C=C C=N stretch stretch stretch stretch stretch stretch All evaluation parameters like Melting point from DSC ad IR matches with literature.drug is compatible with excipient. Preliminary screening of polymer and method for solid dispersion Phase solubility studies were carried out to choose a suitable polymer and method of solid dispersion to identify maximum increase in solubility. Povidone k-0 ad spray dying method resulted in highest solubility compare to other polymers and methods. As a result an attempt was made to prepare sublingual tablet using combination of Povidone k-0 and spray drying method for the further studies, using DOE approach. Evaluation of Factorial Batches F1 to F9 Method concentration in µg/ml Drug. Spray drying 9.8 Solvent evaporation 1.9 Kneading 1.81 The factorial batches were evaluated for various parameters by the methods described in methodology section. 1:1 ratio concentration in µg/ml DRUG. PVP K-0 1. PEG POLOXAMER POLOXAMER 0.91 HPMC cps.9 99

9 EVALUATION PARAMETERS OF FACTORIAL BATCHES F1 F F F F F F F8 F9 Hardness(kg/cm ) Diameter(mm) Thikness(mm) Assay(mg) Friability(%) Wetting time 9.1 ± ± ±0.9. ±0..00 ±0.10 Thickness was found in the range of.0 to. mm. Diameter were observed in ranges of. to. mm. Assay of tablets observed in range of 98 ad 10.In vitro dissolution study in phosphate buffer ph.8 was conducted as per method described earlier. The data for in vitro release are shown in below table. IN VITRO DRUG RELEASE STUDY IN PHOSPHATE BUFFER PH ± ± ± ±0.8 %Dissolution * F 1 F F F F F F F 8 F 9 min. ±0.. ± ± ± ±1. 10 min ±0.9 ±1.0 ±0.8 ±0.9 ± min ±0.9 ±0. ±1.9 ±1.9 ±1. 0 min ±1. ±1.01 ±0.8 ±0. ±1. Disintegration time(sec)* 9 1 ±0. ±0. ±0.8 ±0.0 ±0.11 * Values are expressed as mean ± S.D for six determinations. ± ± ± ±0.9 ±0.98. ±0. 8. ±0. 8. ± ±.8 ±0.1.1 ± ± ±0. 9. ±.9 ±0.9. ± ±0. 9. ± ± ± F F1 F F F F F F8 FIGURE : DRUG RELEASE COMPARISION OF BATCHES F1 TO F9 998

10 FACTORIAL DESIGN DATA (USING DESIGN EXPERT VERSION)..1 DF SS MS F P-value Prob > F Regression Residual Total Significant Response Y 1 : Disintegration Time in Sec. Coefficient b 0 b 1 b b 11 b b 1 Coefficient value P-value Full Model Y1= X 1 8. X. X X +.0X 1 X Reduced Model: Y 1 = X 1 8. X +.0X 1 X DF SS MS F P-value Prob > F Regression < Residual Total 1.9 significant Response Y : Dissolution Time in min Coefficient b 0 b 1 b b 11 b b 1 Coefficient value P-value < < < Full Model Y = X X +0.8 X 1 +.X -0.X 1 X Reduced Model: Y = X X +.X DF SS MS F P-value Prob > F Regression < Residual Total Significant Response Y : Dissolution Time in 1 min Coefficient b 0 b 1 b b 11 b b 1 Coefficient value P-value < < < < < Full Model Y =. +.0 X X +1. X 1 +.9X +0.1X 1 X Reduced Model: Y =. +.0 X X +1. X 1 +.9X +0.1X 1 X 999

11 DF SS MS F P-value Prob > F Regression < Residual Total 1 9. Significant Response Y : Dissolution Time in 1 min Coefficient b 0 b 1 b b 11 b b 1 Coefficient value P-value < < < < < Full Model Y = X X +0.0X 1 +.9X -0.0X 1 X Reduced Model: Y = X X +0.0X 1 +.9X DF SS MS F P-value Prob > F Regression < Residual Total 1.9 Response Y : Dissolution Time in 0 min Coefficient b 0 b 1 b b 11 b b 1 Coefficient value P-value < < < Full Model Y = X X Reduced Model: Y = X X Statistical Analysis of Factorial Design Batches Full and reduced model for disintegration time From the above equation it was found that, variable X 1 i.e. concentration of drug: polymer ratio shows positive effect on the disintegration time. As its concentration increases, disintegration time of tablet increases. Variable X i.e. concentration of Disintegrant also shows positive effect on the disintegration time. It can be qualitatively concluded that X 1 and X both had significant effect on the response. Full and reduced model for dissolution From the above equation it was found that, variable X 1 i.e. concentration of drug: polymer ratio shows positive effect on the dissolution. As its concentration increases, dissolution of tablet increases. Variable X i.e. concentration of Disintegrant also shows positive effect on the 1000

12 dissolution. It can be qualitatively concluded that X 1 and X both had significant effect on the response. disintegration time Design Points X1 = X = disintegration time Counter plot of Response 1(Disintegration Time in sec.) disintegration time Design points above predicted value Design points below predicted value X1 = X = disintegration time surface plot of Response 1(Disintegration Time in sec.) 1001

13 dissolution min Design Points.. dissolution min X1 = X = Counter plot of Response (%Dissolution min) dissolution min Design points above predicted value Design points below predicted value.. X1 = X = 80 dissolution min D surface plot of Response 1(%dissolution in min.) 100

14 dissolution 10 min Design Points dissolution 10 min X1 = X = Counter plot of Response (%Dissolution 10 min) dissolution 10 min Design points above predicted value Design points below predicted value X1 = X = 90 8 dissolution 10 min D surface plot of Response (%dissolution in 10 min.) 100

15 dissolution 1 min Design Points 9..8 dissolution 1 min X1 = X = Counter plot of Response (%Dissolution 1 min) dissolution 1 min Design points above predicted value Design points below predicted value 9..8 X1 = X = 9 90 dissolution 1 min

16 dissolution 0 Design Points 9.8 dissolution X1 = X = Counter plot of Response (%Dissolution 0 min) dissolution 0 Design points above predicted value Design points below predicted value X1 = X = dissolution D surface plot of Response (%dissolution in 0 min.) VERIFICATION OF MODEL BY COMPARING PREDICTED RESPONSE TO ACTUAL RESPONSE Table.18: Predicted response and actual response of checkpoint batch Batches Predicted response Actual response DT %Dissolution in minutes DT %Dissolution in minutes (Sec) (Sec) C C

17 Actual response of C1 and C batch was measured and compare with the predicted response of check point batch. All the values of responses were within the upper and lower predicted interval. Hence, this model is valid and optimized batch can be selected from the overlay plot of this model C C Comparison of c1 and c batch of in vitro drug release in ph.8 buffer Optimization of Batch from Overlay Plot From the overlay plot it was seen that batch F8, F9 fall under the optimized area. So, the batch with the minimum amount of drug: polymer ratio 1: and disintegrant i.e. % was selected as the optimized batch. The batch F8 was selected as the optimized batch. STABILITY STUDY OF OPTIMIZED BATCH (F8): After one month of Accelerated stability study (0ºC ± ºC and % RH ± %) of optimized batch i.e. F8, all evaluation parameters and dissolution test were performed. Results were shown no more drastically change in In-vitro drug release profile. Results of the Accelerated stability study had shown no remarkable change in the release profile of the Lercanidipine hcl. Table : Evaluation of optimized batch F8 (After Accelerated stability study 0 o C ± o C and %RH ± %) Evaluation parameters 0 days 0 days Disintegration time Hardness.0.9 Drug content% Wetting time(sec) Friability

18 Dissolution min min min min CONCLUSION The quality attributes of product like release profile and disintegration are dependent on type of polymer, amount of polymer and Disintegrant. A combination of Drug: Povidone K-0 in 1: ratio with %Crospovidone results in immediate release of drug from tablet. Similarly, ex vivo permeation studies showed 90.% drug release of the immediate release tablet, this can be used in once a day tablet. The prepared formulation is stable at0 ± C / ± % for 1 month. From this research study, it was concluded that formulation of Sublingual tablet of Lercanidipine HCl is one of the novel approach and alternatives routes of administration to avoid gastrointestinal side effects and also first pass metabolism and provide immediate release. In addition, these formulations give immediate action after administration and enhance patient compliance due to its solubility enhancement. REFERENCE: 1. Tripathi K.D., Cardiovascular Drugs, Essentials of medical pharmacology, th edition, Jaypee brothers, Delhi, 00, Neha Narang, Jyoti Sharma, Sublingual Mucosa As A Route For Systemic Drug Delivery, International Journal of Pharmacy and Pharmaceutical Sciences,011,(), Bhanja SB, Ellaiah P, Roy HK, Samal BK, Tiwari S And Murthy KVR Formulation And Evaluation Of Perindopril Sublingual Tablets International Journal Of Research In Pharmaceutical And Biomedical Sciences,011,(), K. Patel Nibha and SS. Pancholi, An Overview on: Sublingual Route for Systemic Drug Delivery, International Journal of Research in Pharmaceutical and Biomedical Sciences, 01, (), Shrikant Charde, Madri Mudgal, Lajwinder Kumar and Ranendra Saha, Development and Evaluation of Buccoadhesive Controlled Release Tablets of Lercanidipine, AAPS PharmSciTech, 008, 9(1),

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