Tablets are solid dosage form of medicament which can be manufactured by compression or moulding of the medicament and they can be of any size, shape and colour. It can also be defined as a mixture of active substance and excipients, usually in powder form, pressed or compacted into a solid (Lachman et al, 2005).
To overcome the potential problems associated with conventional drug therapy, modified release systems were developed. These includes: -
Delayed release
Sustained release
Controlled release
Prolonged release
Site specific release (Shargel et al, 2005, U.S. F.D.A.).
Trilayer Dosage form
A trilayer oral dosage form has three different layers which includes a non-erodible core containing a pharmaceutically active compound and/or a nutritionally active compound and at least one release-modulating layer laminated to each side of the core layer. The dosage form can be prepared using simple, inexpensive tablet compression techniques (Zerbe et al, 2007).
Applications of Trilayer Tablet
Combination of drugs having different release profile.
Patient convenience.
Diabetes Mellitus is a syndrome in which homeostatis of carbohydrate and lipid metabolism is improperly regulated by insulin, leading to hyperglycemia. Diabetes is divided into two main categories: - Type I diabetes mellitus, also called insulin-dependent diabetes mellitus (IDDM) and Type 2 diabetes mellitus also called the noninsulin-dependent diabetes mellitus (NIDDM). Complications that occur in diabetes mellitus are retinopathy, neuropathy, nephropathy, and atherosclerosis and delayed healing. The symptoms of diabetes mellitus are frequent urination, excessive thirst, rapid weight loss, excessive hunger, fatigue, slow healing, skin infections and visual disturbances (Poulsen, 1998, Choate, 1998 and Tiwari et al, 2002).
Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-associated conditions, such as coronary heart disease (CHD), ischemic cerebrovascular disease and peripheral vascular disease (Brunton et al, 2008).
DRUG REVIEW:
Metformin hydrochloride
It is an oral antihyperglycemic agent used in the treatment of patients with non-insulin-dependent diabetes mellitus (NIDDM). It is not associated with weight gain and can also have a favourable effect on the dyslipidemia of type 2 diabetes mellitus. It has three different actions:
It slows the absorption of sugar in the small intestine.
It also stops the liver from converting stored sugar into blood sugar.
It helps our body to use natural insulin more efficiently (Mandal et al, 2007 and U.S F.D.A, 2008).
Advantages
It decreases the amount of glucose absorbed from the food.
It decreases the amount of glucose made by liver.
It may rarely cause low blood sugar levels or hypoglycaemia.
It does not cause increase in bodyweight (U.S F.D.A, 2008).
Adverse Effects
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Hypersensitivity.
Renal disease or renal dysfunction which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction and septicaemia (U.S F.D.A, 2008).
Marketed Formulation
Tablets--500, 850, 1,000 mg; extended-release tablets--500 mg
Brand names: - Glucophage, Glucophage XR, Glumetza, Fortamet, Riomet
Dosages
500-850 mg/day per oral (P.O.) in divided doses to a maximum of 2,550 mg/day. Dose should be adjusted based on response and blood glucose level.
ER tablet: Initially 500 mg/day P.O. with the evening meal; may be increased by 500 mg each week to a maximum of 2,550 mg once daily (U.S F.D.A, 2008).
Simvastatin
It is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. Its mechanism of action: -
It decreases the cholesterol synthesis by inhibition of rate limiting HMG-CoA reductase.
It raises the HDL-CH level (U.S.P, 2007, Triphati, 2008 and Rang et al, 2008).
Advantages
It decreases the LDL-CH, VLDL-CH very effectively.
It also increases the level of HDL-CH.
It also reduces the atherosclerosis, one of the complications of diabetes mellitus (Brunton et al, 2008, Triphati, K.D., 2008 and Rang et al, 2008).
Adverse Effects
Hypersensitivity.
Common adverse reactions are upper respiratory infection, headache, abdominal pain, constipation, and nausea (U.S.F.D.A., 1991).
Dosages
The recommended usual starting dose is 20 to 40 mg once a day. For patients at high risk for a CHD event due to existing coronary heart disease, diabetes, peripheral vessel disease, history of stroke or other cerebrovascular disease, the recommended starting dose is 40 mg/day (U.S. F.D.A., 1991).
Pharmacokinetic parameters of both the drugs:
Parameters
Metformin Hydrochloride
Simvastatin
BCS class
3
2
Cmax
1.03±0.33µg/ml
4.52 ± 2.01 ng/mL
tmax
2.75±0.81hours
4.31 ± 1.73 hr
Bioavailability
50-60% (Fasting condition)
25-40% (After meal)
4-5%
Solubility
Freely soluble in Water
Freely soluble in methanol
T1/2
6.2 hours
3 hours
(U.S.F.D.A, 2008, Indian Pharmacopoeia, 2007, Tucker et al, 1981, U.S. Pharmacopoeia, 2007, Tseng et al, 2007)
REVIEW OF LITERATURE
Metformin hydrochloride is used to treat type 2 diabetes. The antihyperglycaemic properties of metformin are attributed to suppress hepatic glucose production, especially hepatic gluconeogenesis, and increased peripheral tissue insulin sensitivity. Although the precise mechanism of hypoglycaemic action of metformin remains unclear, it probably interrupts mitochondrial oxidative processes in the liver and corrects abnormalities of intracellular calcium metabolism in insulin-sensitive tissues and cardiovascular tissue (Kirpichnikov et al, 2002).
Metformin improves the serum glucose control and has beneficial cardiovascular effects but not to increase the risk of life-threatening postoperative lactic acidosis. Otherwise metformin decrease the mortality and morbidity compared with treatment with other hypoglycemic drugs in diabetes patients undergoing cardiac surgery (Duncan et al, 2007).
Patients with type 2 diabetes are often obese and require large doses of insulin to achieve glycemic control. Weight gain often accompanies insulin therapy and results in increasing insulin requirements. The addition of metformin to insulin therapy resulted in haemoglobin A1C concentrations that were 10% lower than those achieved by insulin therapy alone. This improvement in glycemic control occurred with the use of 29% less insulin and without significant weight gain. Metformin is an effective adjunct to insulin therapy in patients with type 2 diabetes (Santa et al, 1999).
Metformin monotherapy and combination therapy with metformin and sulfonylurea are well tolerated and improve glycemic control and lipid concentrations in patients with NIDDM whose diabetes is poorly controlled with diet or sulfonylurea therapy alone (Defronzo et al, 1995).
The efficacy and safety of a novel extended-release metformin in patients with type 2 diabetes. Once- or twice-daily extended-release metformin was as safe and effective as twice-daily immediate-release metformin and provided continued glycemic control for up to 24 weeks of treatment (Schwartz et al, 2006).
Metformin, a drug widely used to treat type 2 diabetes, was recently shown to activate the AMP-activated protein kinase (AMPK) in intact cells and in vivo. There results also show that AMPK can be activated by mechanisms other than changes in the cellular AMP-to-ATP ratio (Hawley et al, 2002).
Metformin is a guanidine derivative used for the treatment of NIDDM. As it is used for a long-term therapy, it may be co administered with other drugs. The metformin competes with histamine for H2 receptors and block gastric acid secretion and some cardiovascular effects of histamine. Decrease availability of metformin may result in delayed effect. On the other hand, increase in metformin concentration may result in hypoglycaemic effects (Sultana et al, 2006).
Poorly water-soluble drugs that do not show pH-dependent solubility, an approach to increase the dissolution rate is the addition of wetting agents, solubilizing agents or surfactants to the dissolution media. A biorelevant dissolution medium for simvastatin was developed with a lower concentration of surfactant (0.1% sodium lauryl sulfate, SLS) in the medium as compared with the 0.5% SLS concentration stated in the USP monograph (Singla et al, 2009).
Validate and compare simple, economic and fast analytical methods to be applied in quality control routine analysis for the determination of simvastatin in tablets, HPLC method can be considered as stability-indicating method because it can separate simvastatin from its degradation products. The proposed UVDS method is inexpensive and low-polluting, so it can be used as an excellent alternative method in routine analysis (Gomes et al, 2009).
20-30% of diabetic patients are hyperlipidemic and many have retinopathy. The effect of the HMG-CoA Reductase Inhibitor, simvastatin, in patients with DR and hypercholesterolemia, using a double-blind randomized placebo controlled design. The HMG-CoA reductase inhibitor simvastatin significantly retards the progression of retinopathy in diabetic patients with hypercholesterolemia (Sen et al, 2002).
A simple, accurate, precise, sensitive and a highly selective spectrophotometric method was developed for the simultaneous estimation of simvastatin and ezetimibe was carried out by dual wavelength method at 223 nm and 254.5 nm for simvastatin while ezetimibe was estimated as single component at 258.5 nm ( Jain et al, 2009).
Patients with coronary heart disease or higher risks for atherosclerosis, this postprandial hyperlipidemia are more apparent, and when an examination performs at overnight fasting, we may estimate their cardiovascular risks to be lower. Cholesterol concentration increased significantly during the afternoon and mid-night (Mondola et al, 1995).
Rationale of Trilayer Tablet
To treat diabetes mellitus as well as hyperlipidemia.
To control the cholesterol level when it is maximum.
AIM:-
Formulation and Evaluation of Trilayer Tablet of Metformin Hydrochloride and Simvastatin.
OBJECTIVES:-
Formulation of trilayer tablet of Metformin Hydrochloride and Simvastatin.
Increased patience compliance by reducing dosage regimen and dosing frequency.
Method development and validation.
Stability Studies.
Formation of Trilayered Tablet
The tablet has three different layer in which inner core is simvastatin, the upper layer is the inert polymer and the lower layer is the metformin hydrochloride.
Inert polymer
Low hardness +
Simvastatin core
Compress
Low hardness + Trilayer Tablet
Metformin hydrochloride core
METHODOLOGY
1. Preformulation studies
Compatibility syudies
Differential scanning calorimetry (if required)
IR of active pharmaceutical ingredient (if required)
Solubility analysis
2. Development of Formulation
3. Formulation of Trilayer Tablet
4. Evaluation parameters
Hardness
Friability
Weight variation
Drug content
Dissolution
5. Validation
6. Stability study
EXPERIMENT PERFORMED:
1. Calibration Graphs
Standard stock and sub stock solution
UV analysis was done by using the standard stock solution of 1000 μg/ml of each simvastatin and metformin hydrochloride by dissolving 100mg of each standard drug separately in methanol and water respectively. Aliquots of 5, 7, 9, 11, 13, 15 μg/ml of simvastatin was prepared by using pH 6.8 phosphate buffer, 10, 15, 20, 25, 30, 35, 40 μg/ml of metformin hydrochloride was prepared by using 0.1 N HCl and 2, 4, 6, 8, 10 μg/ml of metformin hydrochloride were prepared by using pH 4.5 acetate buffer, pH 6.8 phosphate buffer, water, pH 8 phosphate buffer, for the preparation of calibration curve.
2. Simultaneous estimation and Validation: - Estimation was carried out of metformin hydrochloride and simvastatin in pH 6.8 phosphate buffer.
The absorbances of sample solutions were measured at 232.2 and 247 nm using solvent as blank. The results were calculated by the formula,
A1 = ax1 Cx + ax2 Cy at 232.2 nm
A2 = ay1 Cx + ay2 Cy at 247 nm
Where, A1 and A2 are absorbance of diluted mixture at 232.2 and 247 nm respectively, Cx and Cy are the concentration of metformin hydrochloride and simvastatin respectively (μg/ml), ax1 and ax2 are absorptivities of metformin hydrochloride at 232.2 and 247 nm respectively, ay1 and ay2 are absorptivities of simvastatin at 232.2 and 247 nm respectively.
Accuracy and Precision
Accuracy and precision were investigated by analyzing three concentrations of simvastatin and metformin hydrochloride mixtures in three independent replicates on the same day (Intra-day accuracy and precision) and on three consecutive days (Inter-day accuracy and precision). Intra-day and Inter-day relative standard deviation were calculated.
Linearity and Range
The prepared aliquots for simvastatin (5-15 μg/ml) were scanned for absorbance at wavelength 247 nm. The absorbance range was found to be 0.140-0.440. These aliquots obeyed Beer-Lambert's law with regression of 0.9982 and for metformin hydrochloride the aliquots (2-10 μg/ml) were prepared and scanned for absorbance at wavelength 232.2nm. Absorbance range was found to be 0.155-0.790 with regression of 0.9998.
The limit of quantitation (LOQ) and limit of detection (LOD)
The limit of detection (LOD) and quantification (LOQ) were evaluated from calibration curves plotted in concentration ranges of 5-15 μg/ml for simvastatin and 2-10 μg/ml for metformin hydrochloride, with formula LOD = 3.3 S.D./S and LOQ = 10 S.D./S (where S.D. = Standard Deviation and S= slope of the calibration curve). The LOD and LOQ for each drug were thus obtained.
Recovery Studies
To study the accuracy of the proposed methods, recovery studies were carried out by standard addition. A known amount of drug was added to preanalyzed powder and percentage recoveries were calculated. The results of recovery studies were satisfactory.
Compatibility Study was under process but stopped due to stability chamber was not working properly.
Dummy Tablets were prepared.
Result
Calibration graph of Metformin Hydrochloride in 0.1N HCl (performed in triplicate) λmax= 232.2 nm
Table No. 1
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0.0
2
10
0.183
3
15
0.276
4
20
0.373
5
25
0.473
6
30
0.570
7
35
0.656
8
40
0.745
Graph No. 1
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Calibration graph of Metformin Hydrochloride in pH 4.5 acetate buffer (performed in triplicate) λmax = 232.2 nm
Table No. 2
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0
2
2
0.151
3
4
0.306
4
6
0.457
5
8
0.625
6
10
0.761
Graph No. 2
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Calibration Graph of Metformin Hydrochloride in pH 6.8 phosphate buffer (performed in triplicate) λmax=232.2 nm
Table No. 3
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0.0
2
2
0.155
3
4
0.313
4
6
0.464
5
8
0.623
6
10
0.790
Graph No. 3
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Calibration graph of Metformin Hydrochloride in water (performed in triplicate) λmax= 232.2 nm
Table No. 4
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0
2
2
0.131
3
4
0.280
4
6
0.431
5
8
0.573
6
10
0.741
Graph No. 4
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Calibration graph of Metformin Hydrochloride in pH 8 phosphate buffer (performed in triplicate) λmax = 232.2 nm
Table No. 5
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0
2
2
0.149
3
4
0.291
4
6
0.435
5
8
0.587
6
10
0.721
Graph No. 5
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Calibration graph of Simvastatin in pH 6.8 phosphate buffer (performed in triplicate) λmax = 247 nm
Table No. 6
Sr. No.
Concentration
(µg/ml)
Absorbance
(%)
1
0
0
2
5
0.140
3
7
0.194
4
9
0.261
5
11
0.308
6
13
0.369
7
15
0.440
Graph No. 6
Observation: Plot obtained is linear and R2 value is within the acceptance limit.
Polymers used did not show the desired result.
Simultaneous estimation and validation of metformin hydrochloride and simvastatin was completed.
Table No. 7 Optical characterstics for simvastatin and metformin hydrochloride in pH 6.8 phosphate buffer
Parameters
Simvastatin
Metformin Hydrochloride
Absorbance maximum (λmax)
247nm
232.2nm
Beer's law limit (μg/ml)
5-15
2-10
Correlation coefficient (r2)
0.9982
0.9998
Slope
0.0286
0.0783
Intercept
0
0
Table No. 8 Results of simultaneous estimation of metformin hydrochloride
Sr. No.
Concentration taken (μg/ml)
Concentration of simvastatin added (μg/ml)
Concentration observed
(μg/ml)
% Recovery
1
10
5
10.492
104.92
2
10
10
9.81
98.1
3
10
15
9.775
97.749
Mean of triplicate determinations
S.D. = 0.005131601
R.S.D. = 0.416864455
L.O.D. = 0.216271
L.O.Q. = 0.65538
Table No. 9 Results of simultaneous estimation of simvastatin
Sr. No.
Concentration taken (μg/ml)
Concentration of metformin hydrochloride added (μg/ml)
Concentration observed
(μg/ml)
% Recovery
1
10
5
9.597
95.97
2
10
10
9.72
97.2
3
10
15
10.048
100.48
Mean of triplicate determinations
S.D. = 0.002886751
R.S.D. = 0.499437949
L.O.D. = 0.333086
L.O.Q. = 1.00935
Table No. 10 Results of Repeatability of metformin Hydrochloride and simvastatin
Sr. No.
Concentration of metformin hydrochloride taken (μg/ml)
Concentration of simvastatin taken (μg/ml)
Concentration of metformin hydrochloride observed (μg/ml)
Concentration of simvastatin observed (μg/ml)
% Recovery of metformin hydrochloride
% Recovery of simvastatin
1
5
5
4.83
5.109
96.6
102.18
2
10
10
9.81
9.72
98.1
97.2
3
15
15
14.67
14.8299
97.8
98.866
Mean of triplicate determinations
S.D. of metformin hydrochloride = 0.02081 (R.S.D. = 0.213)
S.D. of simvastatin = 0.028249 (R.S.D. = 0.2857)
Table No. 11 Results of Intermediate Precision of metformin hydrochloride and simvastatin
Drug
Concentration of drug taken (μg/ml)
Average concentration found in Intra days studies (μg/ml)
Average concentration found in Inter days studies (μg/ml)
Metformin Hydrochloride
10
9.58
9.65
Simvastatin
10
10.47
10.39
Mean of triplicate determinations
S.D. of metformin hydrochloride = 0.1061 (Intra days) and 0.155027 (Inter days)
S.D. of simvastatin = 0.02121 (Intra days) and 0.147986 (Inter days)
R.S.D. of metformin hydrochloride = 1.1072 (Intra days) and 1.4243 (Inter days)
R.S.D. of simvastatin = 0.20261 (Intra days) and 1.606496 (Inter days)
