IAJPS, 2014, Volume1, Issue (3), 191-195
A.Saritha
ISSN 2349-7750
ISSN 2349-7750 INDO AMERICAN JOURNAL OF
PHARMACEUTICAL SCIENCES Available online at: http://www.iajps.com
Research Article
FORMULATION AND EVALUATION OF FIXED COMBINATIONS OF ANTI HYPERTENSIVE DRUGS
DOSE
Alladi Saritha*, Vunnam Manoj 1. S S J College of Pharmacy, VN Pally, Hyderabad-500075. 2. Krupanidhi College of Pharmacy, Carmellaram, Bengaluru, Karnataka-560035. Abstract: Fixed-dose antihypertensive combinations may provide significant advantages over high-dose single drugs, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs. The research work was aimed to design, evaluate fixed dose combination of model cardiovascular drugs enalapril with diuretic hydrochlor thiazide . Different formulation were developed with different proportions of binding agents and disintegrants. The tablets manufactured by direct compression technique. All the formulations passed the evaluation tests as per the pharmacoepial limits. Key Words: enalapril, diuretic ,hydrochlor thiazide, fixed dose, anti hypertensives. Corresponding Author:
QR code
Alladi saritha, HOD, Dept. Of Pharmaceutics, S S J College of Pharmacy, VN Pally, Hyderabad-500075
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IAJPS, 2014, Volume1, Issue (3), 191-195
A.Saritha
ISSN 2349-7750
cardiovascular drugs hydrochlor thiazide .
INTRODUCTION Fixed dose drug combinations (FDCs), are combinations of two or more active drugs in a single dosage form. The Food and Drug Administration, USA defines a combination product as ‘a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product [1]. It is widely accepted that most drugs should be formulated as single compounds. Fixed ratio combination products are acceptable only when the dosage of each ingredient meets the requirement of a defined population group and when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety or compliance [2, 3]. FDCs are highly popular in the Indian pharmaceutical market and have been particularly flourishing in the treatment of hypertension, rhematoid arthritis, antibiotics, anti viral drugs etc [4,5]. Fixed-dose antihypertensive combinations may provide significant advantages over high-dose monotherapy, such as improved BP-lowering efficacy, reduced adverse event frequency, improved patient compliance, potentially lower treatment costs, and shorter time to BP control. Combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients, such as those with stage 2 hypertension. The combination of a reninangiotensin-aldosterone system-targeting agent, such as an ACE inhibitor or angiotensin II receptor antagonist and a diuretic or calcium channel antagonist appears to provide synergy with regard to BP lowering. In addition, ACE inhibitors and ARBs have demonstrated beneficial effects beyond BP reduction, reducing cardiovascular morbidity and mortality, inhibiting development and progression of type 2 diabetes mellitus and the progression of renal disease [6, 7]. The aim of this work would be to formulate, develop and evaluate fixed dose combination of model
enalapril
with
diuretic
MATERIAL AND METHODS The drugs enalapril and hydrochlorthiazide was obtained as gift sample from micro labs, Bangalore. Lactose, Micro crystalline cellulose, HPC are procured from sigma Aldrich. All the reagents were analytical grade. Experimental Preparation Fixed Dose Tablets Mix the pre-sifted enalapril, hydrochlorthiazide, HPC EXF, LHPC LH11 & Lactose monohydrate & mix for 10 min. Cross carmellose sodium was used as super disintegrant & PVP K-30 & HPMC E5 were used as binders in wet granulation process and HPC & LHPC were used as binder and disintegrant respectively in direct compression process shown in table-1. A typical concentration of HPC EXF to be used as a tablet binder is 2% to 6% that is 8.56mg to 25.68 mg according to the present tablet weight. similarly LHPC-LH-11 can be used as a disintegrant and antisticking agent in the range from 5% to 20% i.e. 21.4 to 85.6 mg according to the present tablet weight. Lubricate the blend with magnesium stearate in the for 5 min. Compress the lubricated blend of step 3 with 11.0mm*7.0mm oval standard concave punches with plain upper &lower punch [8, 9]. Evaluation of Blend Angle of Repose In order to determine the flow property, the Angle of repose was determined. It is the maximum angle that can be obtained between the free standing surface of the powder heap and the horizontal plane. Bulk Density and Tapped Density A quantity of 5g of the powder (W) from each formula was introduced into a 25 ml measuring cylinder. After the initial volume was observed, the cylinder was allowed to fall under its own weight onto a hard surface from the height of 2.5 cm at 2 sec intervals. The tapping was continued until no further change in volume was noted [10].
Table 1: Formulation of Fixed Dose Combinations of Enalapril and Hydrochlorthiazide Ingredients
F001
F002
F003
F004
F005
F006
F007
F008
F009
ENALAPRIL
40
40
40
40
40
40
40
40
40
HYDRO CHLORTHIAZIDE Lactose monohydrate
25
25
25
25
25
25
25
25
25
249.4
258.4
267.4
252.4
261.4
270.4
255.4
264.4
273.4
HPC EXF
8
8
8
5
5
5
2
2
2
Purified water
q.s
q.s
q.s
q.s
q.s
q.s
q.s
q.s
q.s
MCCPH 102
83.6
83.6
83.6
83.6
83.6
83.6
83.6
83.6
83.6
LHPC LH11
20
11
2
20
11
2
20
11
2
Magnesium stearate
2
2
2
2
2
2
2
2
2
Core tablet weight
428
428
428
428
428
428
428
428
428
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IAJPS, 2014, Volume1, Issue (3), 191-195
A.Saritha
ISSN 2349-7750
sample from the dissolution vessel was withdrawn at Hausner’s Ratio It indicates the flow properties of the powder and is the sampling time, 10, 15, 20, 30, 45 and 60 minutes measured by the ratio of tapped density to the bulk through free flow filter (10 µm) attached to auto density. sampler of the dissolution instrument. aliquots withdrawn for analysis was withdrawn with Hausner’s Ratio = Tapped density / Bulk density equal volumes of dissolution medium which is Compressibility index (Carr’s indices) Compressibility index is an important measure that maintained at 37 ± 0.5°C.After suitable dilution the can be obtained from the bulk and tapped densities. In concentration of enalapril and hydrochlorthiazide theory, the less compressible a material the more was determined at 320 and 261nm respectively [11]. flowable it is. A material having values of less than 20 to 30% is defined as the free flowing material. RESULTS AND DISCUSSIONS CI = 100 X (VO – Vf) Evaluation of Blend V0 Angle of Repose Table no. 2 shows the results obtained for angle of Evaluation of Tablets repose for all the formulations prepared by Direct Hardness Tablet requires a certain amount of strength or compression & Wet granulation. hardness and resistance to friability to withstand Bulk Density and Tapped Density mechanical shakes of handling in manufacture, Both bulk density (BD) and tapped density(TD) packaging and shipping. Hardness generally measures results are shown in Table no.2 shows. The bulk the tablet crushing strength. density and tapped density for all the formulations varied from 0.425gm/cm3 to 0.624 gm/cm3 and 0.530 Friability Friability of a tablet can determine in laboratory by gm/cm3 to 0.755 gm/cm3 respectively. The values Roche friabilator. This consist of a plastic chamber obtained lies within the acceptable range and no large that revolves at 25 rpm, dropping the tablets through a differences found between bulk density and tapped Distance of Six inches in the friabilator, which is then bulk density. These results help in calculating the % operate for 100 revolutions. The tablets are compressibility of the powder. reweighed. Compressed tablets that lose less than 0.1 to 0.5 % of the tablet weight are considered Percentage Compressibility (Carr’s Consolidation acceptable. Index) The percentage friability was measured using the Table no.2 shows the results obtained for percentage formula compressibility. The percentage compressibility of powder mix was determined by the equation given for % F = {1-(W / Wo)} x 100 Carr’s Consolidation Index in methodology section. Weight Variation test Take 20 tablets and weigh individually. Calculate The percentage compressibility for all the average weight and compare the individual tablet formulations lies within the range of 16.1 to 20.3; weight to the average. The tablet pass the B.P. test if hence they are showing good compressibility. no more that 2 tablets are outside the percentage limit Hausner’s Ratio and if no tablet differs by more than 2 times the Table no. 2 shows the results obtained for hausner’s percentage limit. ratio. The hausner’s ratio of powder mix was determined by the equation given in methodology In vitro Dissolution Studies Transfer 900 mL pH 1.2 buffer of dissolution medium section using the data obtained from bulk density and into each dissolution vessel Drop the fixed dose tablet tapped bulk density. The hausner’s ratio for all the formulation in to the buffer. A suitable volume of formulations lies within the range of 1.19 to 2.25 . Table: 2 Blend Parameters of the prototype formulations and F001-F009 formulations Formula Angle of Bulk Density Tapped Percentage Hausner’s Repose (θ) (gm/cm3) Density Compressibility Ratio (gm/cm3) 20 0.564 0.672 16.1 1.19 F001 27 0.562 0.690 18.6 1.23 F002 24 0.553 0.684 19.2 1.24 F003 29 0.566 0.675 16.1 1.19 F004 F005 F006 F007
26 23 21
0.558 0.562 0.555
0.670 0.670 0.690
16.7 16.1 19.6
1.20 1.19 1.24
F008 F009
24 25
0.558 0.557
0.670 0.681
16.7 18.2
1.20 1.22
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IAJPS, 2014, Volume1, Issue (3), 191-195
A.Saritha
ISSN 2349-7750
wear and tear. The percentage friability for all the formulations lies in the range of 0.04% to 0.09%, which was found to be in limit (i.e. < 1%). Disintegration Time (DT) Disintegration Time of core and coated tablets was found to be between 50 sec to 1 min & 1.25 to 1.35 min for the formulation Prototype F001 respectively. The formulations F001–F009 core and coated tablets showed DT of 50 sec to 1 min and 1.25 to 1.35min respectively. Weight Variation Test Weight variation test for all the formulations was carried out using the procedure described in methodology section. All the formulations passed weight variation test as the % weight variation was within the pharmacopoeial limits of ± 5%. None of the formulations were exceeding the limit 7.3% specified by IP. Thus all the formulations were found to comply with the BP standard.
Hardness The hardness of all the formulations was checked using Monsanto Hardness Tester, by the method described in methodology section and is reported in Table no.30 &31. The average hardness of all the batches of core tablets and coated tablets are in the range of 7.6 to14.1 kg/cm2 and 13.6 to 20.1 kg/cm2 The lower standard deviation values indicated that the hardness of all the formulations were almost uniform in specific method and possess good mechanical strength with sufficient hardness. Friability Test This is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling, and shipping. A number of tablets were weighed and placed in tumbling apparatus where they were exposed to rolling and repeated shocks resulting from free falls within the apparatus. After a given number of rotations the tablets were weighed, and the loss in weight indicates the ability of the tablet to withstand
Table 3: Post Compressional Parameters of the prototype formulations and F001-F009 formulations Formulation Weight variation* Hardness# % Friability Disintegration (mg ± %) (Kg/cm2) time@ (min) 428.98 ± 4.55 13.6±0.40 0.05 ± 0.02 1.00±0.02 F001 F002
428.08 ± 4.23
11.9 ± 0.20
0.06 ± 0.03
0.59±0.57
F003 F004 F005
428.06 ± 4.97 428.63 ± 2.65 428.34 ± 2.88
13.6 ± 0.20 14.08 ± 0.20 12.40 ± 0.20
0.04 ± 0.03 0.04 ± 0.02 0.08 ± 0.05
0.59±0.55 1.00±0.02 0.59±0.57
F006 F007
428.53 ± 2.57 428.2 ± 3.40
11.18 ± 0.20 14.1 ± 0.95
0.09 ± 0.02 0.08 ± 0.03
1.00±0.02 0.59±0.57
F008 F009
428±2.47 428±2.63
12.7±0.20 13.6±0.40
0.05 ± 0.02 0.09 ± 0.02
0.59±0.55 1.00±0.02
In-Vitro Dissolution Studies Comparision of diuretic dissolution profiles
Comparision of AHARB dissolution profiles 120
120 F001 F002
100
F001
80
F002
80
F003
60
F004
40
F005
40
F006
20
20
F007
0 0
10
20
30
40
F008 F008
Time in min
Fig1: Comparison of AHARB Dissolution Profile The dissolution studies of fixed dose tablets showed significant changes in dissolution profile. All the formulation showed more than 70% of drug release in 30 min. The formulation containing 2% showed a improved drug release. The drug release was found to
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%CDR
%CDR
100
F003 60
F004 F005 F006 F007
0
F008 0
10
20
30
40
F009
Time in min
Fig 2:Comparision of Diuretic Dissolution Profile be decreased with increase in the amount of HPC LFX where as the drug release was not altered in dissolution studies of hydrochlorthiazide.
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IAJPS, 2014, Volume1, Issue (3), 191-195 CONCLUSION The present research work can be employed as a simple commercially feasible formulation approach for the treatment of hypertensive patients with diabetes or the metabolic syndrome, in addition to other cardiovascular risk factors. REFERENCES 1. Chandler S Gautam, Lekha Saha. Fixed dose drug combinations (FDCs): rational or irrational: a view point. Br J Clin Pharmacology, 65(5): 795–796, 2008. 2. Sreedhar D, Subramanian G, Udupa N. Combination drugs: are they rational. Current Science in pharmacy, 91:406, 2005. 3. Amitava S. Indian market's fixation with fixed dose combinations (Editorial) Rational Drug Bulletin, 12:1, 2009. 4.Margaret AP, Samuel LS. Chemotherapy of protozoal infections. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 11. New York: McGraw-Hill; 2006.
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5. Alladi S, Shastri NR. Semi solid matrix formulations of meloxicam and tenoxicam: an in vitro and in vivo evaluation. Archives in Pharmaceutical Research.22;5, 2014 6. C.G. Egan, R. Pontremoli. Role of the fixed-dose combination lercanidipine–enalapril in renal protection. Journal of Nephrology. 24; 428–437, 2011. 7. Taddei S. Fixed-dose combination therapy in hypertension. Journal of Cardiovascular diseases. 19 (2); 55–57,2012. 8. M. Gorostidi, A. Sierra. Combination therapy in hypertension. Advances in Therapeutics, 30; 320– 336, 2003. 9. Benjamin J. Epstein, Niren K. Shah, Nancy L. Borja-Hart. Management of hypertension with fixeddose triple-combination treatments. Therapeutic Advances in Cardio vascular Diseases. 7; 246– 259,2013. 10. Chrysant SG. Using fixed-dose combination therapies to achieve blood pressure goals. Clin Drug Investigations. 28(11):713-34,2008. 11. Xinhuan Wan , Panqin Ma. A promising choice in hypertension treatment: Fixed-dose combinations . Asian Journal of Pharmaceutical Sciences. 9(1),1-7, 2014.
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