Dual retard tablets of amlodipine besylate and atenolol

Transcription

1 10 Formulation, optimization and evaluation of dual retard tablet of amlodipine besylate and atenolol Hypertension, commonly referred to as high blood pressure, is a medical condition where the pressure is chronically elevated is one of the commonly found diseases, affecting most of the populations in the world. For treating hypertension, commonly used drugs include ACE inhibitors, alpha blockers, beta blockers, Angiotensin receptor blockers, calcium channel blocker, diuretics and combination of any of these categories. Combination drug therapy is recommended for treatment of hypertension to allow medications of different mechanism of action to complement each other and together effectively lower blood pressure at lower than maximum doses of each. The rational for combination therapy is to encourage the use of lower doses of drug to reduce the patient s blood pressure to goal to minimize dose dependent side effects and adverse reactions. When smaller doses of medication with different mechanism of action are combined synergistic or additive effects on blood pressure are achieved and dose dependent side effects are minimized. Amlodipine is a prototype second generation dihydropyridine calcium channel blocker (CCB). They have a longer duration of action and can be given once daily. Amlodipine is used in the treatment of mild to moderate hypertension, chronic stable angina pectoris or vasospastic angina (prinzmetal s or variant). In these conditions it may be employed as monotherapy or in combination with other antihypertensives or antianginals. Amlodipine can be safely combined with ß blockers, ACE inhibitors, thiazides and nitrates. It has a half life of 40 hr and the initial effects are cumulative over many days. Atenolol is a cardio selective beta-1 adrenoceptor blocker devoid of intrinsic sympathomimetic and membrane stabilizing activity. Atenolol is mainly absorbed in the stomach than in the lower gastrointestinal tract and the oral bioavailability has been reported to be 50%. Hence, it is ideally suited for the gastroretentive floating tablets. The human jejunal permeability to atenolol and the extent of absorption is low. Thus, it seems that an increase in gastric retention time may increase the extent of absorption and bioavailability of the drug. Aim to formulate and evaluate the formulation for hypertension and related disease to produce quick onset of action as well as longer duration of action. In research work amlodipine besylate was formulated in such a way that provides quick release of the drug to produce quick onset of action within 60 min. Theophylline was formulated in Modi Darshan A. 153 Ph.D Thesis

2 such a way that that provides sustained release of the drug action over an extended period of time i.e. for 12 hr Preparation of dual retard tablets of amlodipine besylate and atenolol 1, 2 Composition of dual retard gastro retentive tablet was formed using optimized immediate layer formula of amlodipine besylate and sustained release layer of atenolol and as well as gastro retentive portion. Optimized part of amlodipine besylate was containing 8% SSG and optimized part of theophylline sustained release part containing 25% HPMC K-100M with 12.5% sodium bicarbonate along with xanthan gum and citric acid. First, immediate release formulation placed on cavity of die and 2 kg/cm 2 pressure was applied then finally granules of sustained release layer (gastro retentive layer) were placed on previously filled layer and tablet was prepared having hardness of 6-7 kg/cm 2. Table 10.1: Formulation of dual retard floating tablet Ingredients (mg) Immediate release formulation batch (A4) Sustain release formulation batch (F5) Amlodipine besylate Atenolol - 50 Kyron T Lactose 50 - Talc 3 - Mg.stearate MCC HPMC K100M - 75 Xanthan gum Sod.bicarbonate Citric acid - 25 PVP K30 (5%) - 15 DCP - 55 Mg.stearate 5 IPA - Q.S. Total 450 mg Modi Darshan A. 154 Ph.D Thesis

3 The immediate layer as well as sustain layer were prepared by the same method as prepared individually i.e immediate layer was prepared using direct compression method and sustained release layer was prepared by organic wet granulation. After sifting (20#) of accurately weighed amlodipine besylate, MCCP and lactose, they all were mixed for 15 min. To this mixer, super disintegrating agents, talcum and mg. stearate were added and mixed for 5 min. The prepared blend was passed through 20# sieve. Accurately weighed atenolol, polymers and DCP were passed through 20 # sieve. Slurry of PVP K-30 IP (5% w/w) was prepared in IPA by gentle stirring. All the above ingredients were mixed for 15 min. The paste was added slowly in above mixer and made the lumpy mass. The prepared mass was passed with sieve # 12 and dried it at 40 o C for 1 h in oven. Then passed this dried mass through sieve # 20. After mixing, mg. stearate (20#) was added and mixed for 5 min Evaluation parameters of dual retard tablet of amlodipine besylate and atenolol 3, Physical parameters of dual retard tablets of amlodipine besylate and atenolol As per I.P, prepared dual retard tablets of amlodipine and atenolol were evaluated for various parameters like weight variation test, hardness and friability as per procedure described in sections 5.3. Results are shown in table Floating property study Floating properties like floating lag time and total floating time were evaluated for dual retard tablets of amlodipine besylate and atenolol as per section Dissolution studies for sustain release layer In-vitro dissolution tests were carried out using USP apparatus type II (ELECROLAB TDT 06T, Bombay). The dissolution medium consisted of 900 ml 0.1N HCl for first two h and then replaced with phosphate buffer 6.8 for rest of the period maintained at 37± 0.5 o C and stirred at 50 RPM. Samples (10 ml) were withdrawn at predetermined time intervals of 1, 2, 4, 6, 8, 10 and 12 hr. Equal amount fresh dissolution medium, maintained at same temperature, was replaced immediately In vitro drug release study was performed by simultaneous method. Samples were analyzed using UV spectrophotometer at both the λ max i.e. 239 nm and 224 nm respectively for amlodipine besylte and atenolol. The drug content was calculated using the simultaneous equation. Modi Darshan A. 155 Ph.D Thesis

4 Figure 10.1: Overlain spectra of amlodipine besylate and atenolol C x = A 2 ay 1 -A 1 ay 2 / Ax 2 ay 1 *ax 1 ay 2 and, C y = A 1 ax 2 -A 2 ax 1 / Ax 2 ay 1 *ax 1 ay 2 Where, C x and C y is the concentrations of atenolol and amlodipine besylae respectively in diluted sample. ax 1 and ax 2 are absorptivities of atenolol at λ 1 (224 nm) and λ 2 (239 nm) respectively. ay 1 and ay 2 are absorptivities of amlodipine besylae at λ 1 and λ 2 respectively. A 1 and A 2 are the absorbances of diluted sample at λ 1 and λ 2 respectively Stability studies The sample formulation was packed in strips of 0.04 mm thick aluminum foil laminated with PVC. In order to determine the change in in-vitro release profile on storage, stability study was carried out at 40 o C in a humidity chamber having 75% RH according to ICH guideline. Sample were withdrawn after one month interval and evaluated for change in-vitro drug release pattern. The similarity factor (f 2 ) and dissimilarity factor (f 1 ) were applied to study the effect of storage on formulation. The formulation was also evaluated for drug content after one month. Modi Darshan A. 156 Ph.D Thesis

5 10.3 Results and discussion Physical parameters of dual retard tablet of amlodipine besylate and atenolol The average weight of tablet formulation was 452 mg. All tablets passed weight variation test as the % weight variation was within the pharmacopoeial limits of 5% of the weight. The weight of all the tablets was found to be uniform with low standard deviation values. The mean tablet thickness (n=5) were uniform, indicated uniformity within batch and batch to batch. The measured hardness of tablets was 5.3 kg/cm 2. This ensures good handling characteristics of all batches. The friability was less than 1% ensuring that the tablets were mechanically stable. Floating property was studied and found FLT of 99 sec with TFT of 12 hr. The percentage drug content of amlodipine besylate and atenolol was within acceptable limits indicating dose uniformity in tablet. Table 10.2: Evaluation parameter of dual retard tablet Parameter DRT Thickness ± S.D. (mm) (n = 5) 4.9 ± 0.04 Hardness ± S.D. (kg/cm 2 ) (n = 5) 5.3 ± 0.5 Friability (%) Weight variation (mg) (n=20) 452 ±6 Drug content (amlodipine besylate) (%) Drug content (atenolol) (%) Floating lag time (sec) (n=3) 99±3 Total floating time (min) In-vitro drug release of dual retard tablet of amlodipine besylate and atenolol In vitro drug release data and profile of prepared tablets are shown in Table Invitro drug release study was performed as per procedure. Samples were analyzed using UV spectrophotometer at both the λ max i.e. 239 nm and 224 nm respectively for amlodipine besylte and atenolol. In-vitro dissolution was performed and it was found that amlodipine besylate released more than 90% of drug within 10 min which confirmed the specification of immediate Modi Darshan A. 157 Ph.D Thesis

6 release drug delivery. Atenolol was remained sustained for 12 hr and confirmed desired time duration. Table 10.3: Release profile of amlodipine besylate from dual release tablet Time (min) Cumulative drug release (%) ± ± ± ± ± ± ± ± ± Cumulative Drug Release (%) Time (min) Figure 10.2: Dissolution profile of amlodipine besylate in dual retard tablet Modi Darshan A. 158 Ph.D Thesis

7 Table 10.4: Release profile of atenolol from dual release tablet Time (h) Cumulative drug release (%) ± ± ± ± ± ± ± Cumulative Drug Release (%) Time (h) Figure 10.3: Dissolution profile of atenolol in dual retard tablet Fitting data of dual retard tablet in mathematical kinetic models Table 10.5: Mathematical model data analysis of dual retard tablets of amlodipine besylate and atenolol Model Higuichi Zero- Korsmeyr Hixon First- plot order R 2 n-value Crowell order R Modi Darshan A. 159 Ph.D Thesis

8 From the result shown in the table 10.5, the release profile of the best dual retard floating tablet, was fitted to zero-order which having highest R 2 value (0.9981). So, the drug release from the bi-layer tablet of amlodipine besylate and atenolol was best explained by Zero-order reaction. Diffussional constant n-value was found to be less than 0.5, indicated drug release mechanism was diffusion Stability study of dual retard tablet of amlodipine besylate and atenolol 5 An ethical drug manufacturer is committed to provide his consumers with drug products that are both efficacious and safe. This can only be ensured by instituting a program to study the stability of a product during its various stages of development ant to use proper storage conditions comply with the expiry period under those conditions. This is requirement in most countries and is stipulated by the regulatory agencies of those countries. Table 10.6: Results of the stability studies of optimized formulation DRT Time (Week) Hardness (kg/cm 2 ) Drug content (%) Amlodipine Atenolol besylate Cumulative drug release (%) Amlodipine Atenolol besylate (After 12 h) (after 30 min) ± ± ± ± These studies will very quickly identify the need, if any, to stabilize the active substance or the formulation and save any waste of time an effort on an unmarketable formulation. With the recent trends towards globalization of manufacturing operations, it is imperative that the final product is sufficiently robust for marketing worldwide under a variety of climate conditions, including tropical, subtropical and temperate. The accelerated stability study was carried out as per the ICH guideline. The physicochemical parameters like physical appearance, weight variation, hardness, thickness, assay and in-vitro dissolution were performed initially and after 3 months. Optimized formulation of dual retard tablet was packed in strips of 0.04 mm thick aluminum foil laminated with PVC. In order to determine the change in in-vitro Modi Darshan A. 160 Ph.D Thesis

9 release profile on storage, stability study of formulation was carried out at 40 0 C in a humidity chamber having 75% RH according to ICH guideline. Sample were withdrawn after one month interval and evaluated for change in-vitro drug release pattern. The formulation was also evaluated for drug content after one month. The results of accelerated stability studies are shown in table. The data values found after 30 min for amlodipine was not deviating significantly as well for atenolol after 12 hr Conclusion The aim of the present study was to develop an optimized formula for dual retard tablet containing amlodipine besylate and atenolol for the management of hypertension. Atenolol planned to design as the sustained release part and amlodipine besylate as the immediate release part. After preformulation studies it was decided to prepare amlodipine besylate part by direct compression and atenolol by wet granulation method. For sustained release portion optimized concentration of HPMC K100M (25%) polymer and gas generating agent sodium bicarbonate (12.5%) were used intragranularly. In the formulation of immediate release amlodipine besylate, optimized concentration of kyron T-314 (4%) was used as super disintegrant. Prior to compression the granules were evaluated for angle of repose, bulk density, tapped density, compressibility index, and hausner s ratio. The compressed dual retard tablets were also evaluated for weight variation, dimension, hardness, friability, drug content and in-vitro drug release. In the above studies DRT formulation showed promising results as it took only 10 min to release amlodipine besylate and also gave sustained action of atenolol for 12 hr. It was further supported by DSC analysis which showed that DRT had no interaction with excipients. The stability studies were carried out for the optimized batch DRT for three months and it showed acceptable results. The kinetic studies of the formulations revealed that diffusion is the predominant mechanism of drug release followed by zero order pattern References 1. Patel G, Patel D Formulation and evaluation of once a day regioselective dual component tablet of atorvastatin calcium and metoprolol tartrate. Int J Pharm Tech Res 2: Doddayya H, Goudanavar P, Mohmmad A Design and characterization of bilayer controlled release matrix tablets of losartan potassium. Int J Pharm Res 2: Modi Darshan A. 161 Ph.D Thesis

10 3. Rajendran N, Natarajan R Formulation and Evaluation of sustained release bilayer tablets of metformin and pioglitazone. Int J Current Pharm Res 3: Kumar B, Prasad G, Ganesh B Development and evaluation of guaifenesin bilayer tablet. Int J Pharm Sci Nano 3: Aryal S, Skalko-Basnet N Stability of amlodipine besylate and atenolol in multi-component tablets of mono-layer and bi-layer types. Acta Pharm. 58: Modi Darshan A. 162 Ph.D Thesis