Morbidity Rates From The Multiple Organ Damage Biology Essay

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Hypertension is one of the most common worldwide diseases afflicting humans. Because of the associated morbidity and mortality and the cost to society, it is an important public health challenge. Over the past several decades, extensive research, widespread patient education, and a concerted effort on the part of health care professionals have led to decreased mortality and morbidity rates from the multiple organ damage arising from years of untreated hypertension. Hypertension or high blood pressure is a condition in which the blood pressure in the arteries is chronically elevated. Hypertension is the most important modifiable risk factor for coronary heart disease (the leading cause of death in North America), stroke (the third leading cause), congestive heart failure, end-stage renal disease, and peripheral vascular disease (Sharma, 2008).

Complications occuring in diabetes mellitus are retinopathy, neuropathy, nephropathy, 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 disturbance. (Poulsen, 1998, Choate, 1998 and Tiwari et al, 2002). Diabetes is one of the most serious challenge to health care worldwide; according to recent projections, it will affect 239 million people by 2010- almost doubling in prevalence since 1994.

Hypertension and Diabetes coexist more frequently than would be estimated from their relative prevalence in the general population. Hypertension in diabetic patients is usually essential and mild to moderate but rarely malignant, occuring twice as often in the diabetic as in the nondiabetic individual (Houston, 1989). Hypertension is a major contributor to the development and progression of macrovascular and microvascular complications in people with diabetes. Compared to the general population, people with diabetes face a two to four fold increased risk of cardiovascular disease (CVD) (Stults, 2006). Nearly 60% of people with Type 2 diabetes have hypertension and people with both hypertension and diabetes face a high risk of cardiovascular and kidney disease. Patients with diabetes should have blood pressure levels less than 120/80 mmHg and low-density lipoprotein cholesterol levels < 100 mg/dL (2.60 mmol/L). If left uncontrolled, diabetes and hypertension are a dangerous combination (http://www.arabia.msn.com/Women/HealthAndFitness/2008/august/DiabetesHypertension.aspx).

ORAL ROUTE

Oral delivery of drug is most versatile, convenient and commonly employed route of drug delivery for systemic action. Due to ease of administration, patient compliance and flexibility in formulation oral sustained release systems continues to be the most popular among all the drug delivery systems (Shargel, L., 2007). There are many methods by which we can formulate a dosage form which contain two drugs, one of which is multilayered tablet formulation.

Tablet is a solid dosage form of medicament which can be manufactured by compression or molding the medicament. It can be of any size, shape and colour. In general, tablet is a mixture of active substance and excipients, usually in powder form, pressed or compacted into a solid mass.

Extended release dosage form: A dosage form that allows at least a two fold reduction in dosage frequency as compared to that drug presented as an immediate release (conventional) dosage form. Examples of extended release dosage forms include controlled release, sustained-release and long acting drug products (Shargel, L., 2007).

Sustained release dosage form: Sustained release tablets are those which are formulated to dissolve slowly and release a drug over time. The advantages of sustained release tablets are that they are taken less frequently than instant release formulation of the same drug and they can maintain steady state concentration in blood stream. The safety margin of high-potency drugs can be increased, and the incidence of both local and systemic adverse side effects can be reduced in sensitive patients. Administration of sustained release form enables increased reliability of therapy (Shargel, L., 2007; Lachman, L., 2005).

Its disadvantages include:

Dose dumping of drug.

Expensive technology is required.

More complicated technology.

Administration of sustained release medication does not permit the prompt termination of therapy. Immediate changes in drug need during therapy cannot be accommodated.

TRILAYER TABLET

Tablet consists of three layers having different drugs with different release mechanisms and different drug release profiles.

Advantages of the 'Trilayer' tablet

• Combination of incompatible drugs.

• Patient convenience.

• Least probability of developing drug resistance.

• Delivery of two drugs having different release profiles and different release mechanisms from a single dosage form.

DRUGS SELECTED

1. Verapamil hydrochloride

2. Gliclazide

DRUG REVIEW

Verapamil hydrochloride

Verapamil hydrochloride is a slow calcium channel blocking agent which has antihypertensive, anti angina and anti-arrhythmic activity. It works by relaxing the muscles of heart and blood vessels. Calcium antagonists cause generalised arterial/arteriolar dilatation, there by reducing blood pressure. Verapamil hydrochloride is a white crystalline powder with no discernible odor. Chemical name of Verapamil hydrochloride is 5-[(3,4-dimethoxy phenethyl) iso propel valeronitrile. Solubility of Verapamil hydrochloride is 80-90mg/ml from pH 2.3 to 6.4 where the ionized species predominates, then decreases rapidly at high pH. The solubility of the base form of Verapamil hydrochloride is 0.025 mg/ml in 0.1N NaOH. Verapamil hydrochloride melts in the range of 140°C and 144°C (Florey, 2005., Jansen et.al., 1990).

Verapamil hydrochloride is very stable under high stress thermal, photochemical degradative and neutral, acidic, basic aqueous reflux conditions. The mean elimination half life of Verapamil hydrochloride is ranged from 2.8 to 7.4 hrs. After repetitive dosing the half-life increased to a range from 4.5 to 12 Hours. Orally administered Verapamil hydrochloride undergoes extensive first-pass metabolism and its major metabolite is the N-demethylated metabolite nor-Verapamil hydrochloride, which is pharamacologically active and can accumulate to or greater than those of Verapamil hydrochloride itself. Because of its relatively short elimination half-life, Verapamil hydrochloride is normally prescribed in divided daily doses every 6 to 8 hours. For this reason a number of sustained release formulations of Verapamil hydrochloride have been developed to minimise dosage frequency (Jansen et.al., 1990).

Gliclazide

Gliclazide is a white or almost white powder, practically insoluble in water, freely soluble in dichloromethane, sparingly soluble in acetone and slightly soluble in ethanol 96%. The melting point of Gliclazide is approximately 168°C. Gliclazide is a sulphonylurea drug with half-life of around 11 hours. It is extensively metabolised in liver, and renal clearance accounts for only 4% of total drug clearance. The molecule contains an azabicyclo-octyl group which confers special properties on the basic sulphonylurea moiety. Gliclazide stimulates insulin secretion through the beta cell sulphonylurea receptor, and possibly through a direct effect on intracellular calcium transport. It specifically improves the abnormal first phase insulin release in type 2 diabetes, and also has an effect on the second phase (Camphbell et al., 1991). Gliclazide is metabolised by liver. Dosage should be initiated at 40mg daily and may be increased if necessary up to 320 mg daily (4 tablets). Doses up to 160mg daily may be taken in a single dose, preferably at the same time each morning. Doses in excess of 160mg should be taken in divided doses in the morning and the evening. The severity of glycaemia will determine the dosage, requiring adjustment to obtain the optimal

response at the lowest dosage. (http://www.medsafe.govt.nz/profs/Datasheet/d/DiamicronMRtab.htm, http://www.medsafe.govt.nz/profs/datasheet/g/Glizontab.htm).

LITERATURE REVIEW

Co-occurence of Diabetes and Hypertension

In 1989, Houston et al., studied that hypertension and diabetes mellitus commonly occur together. The coexistence of both disorders increases the risk of cardiovascular, cerebrovascular, renal, and retinal damage that results in earlier and more frequent morbid events as well as a higher mortality. In general,α-blockers, calcium channel blockers, central α agonists, and ACE inhibitors are recommended as firstline monotherapy.

In 1995, Gilbert et al., concluded that individuals with both hypertension and diabetes are at high risk for both vascular and renal disease. They should therefore be treated with the appropriate antihypertensive drugs and be carefully monitored to ensure satisfactory blood pressure control and prevention of end-organ complications.

In 2006, Howard et al., studied that hypertension is an important modifiable cardiovascular (CV) risk factor that, if controlled, reduces the risk of large and small vessel complications in diabetes; a decrease of 10 mmHg in mean systolic blood pressure (BP) corelates with a 12% reduction in diabetes related complications.

In 2009, D. Weyeker et al., studied that people with hypertension appear to be at high risk of diabetes, which in turn is an important predictor of cardiovascular disease. All the people with hypertension, irrespective of age, sex, and body mass index are at elevated risk of developing diabetes.

Verapamil hydrochloride

The in-vitro dissolution and in-vivo pharmacokinetics of two marketed sustained release formulations, Verelan and Isoptin SR, were compared by Devane et al. (1990). The effect of food on Verelan was also examined in a separate study with conventional Isoptin as a reference. Both sustained release preparations had extended dissolution profiles with 50% release times (T50%) of 4 hours for Isoptin and 8 hours for Verelan. The extended in-vitro profile of Verelan versus Isoptin was confirmed in-vivo with a Tmax of 7.3 hours compared to 5.0 hours, a Cmax of 114.3 compared to 171.0 and a peak to trough ratio of 3.8 compared to 10.1 for Verelan and Isoptin respectively. In a second pharmacokinetic study the rate and extent of absorption of Verapamil hydrochloride from Verelan was shown to be unaffected by food.

In 2001, David H.G Smith, findings led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension was to deliver the drug in higher concentrations during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. There were two antihypertensive agents, Verelan PM (Verapamil hydrochloride) and Covera HS (Verapamil hydrochloride) that provide chronotherapy for hypertension.

Siahi et al. (2005) performed a study to design oral controlled delivery systems for the water-soluble drug, Verapamil hydrochloride, using natural and semisynthetic polymers as carriers in the forms of 1 and 3 layer matrix tablets. Verapamil hydrochloride 1 layer matrix tablets containing hydroxyl propyl methyl cellulose, tragacanth, and acacia either alone or mixed were prepared by direct compression technique. 3 layer matrix tablets were prepared by compressing the polymers as release retardant layers on both sides of the core containing the drug. The prepared tablets were subjected to in vitro drug release studies. Tragacanth when used as the carrier in the formulation of 1 and 3 layer matrices produced satisfactory release prolongation. On the other hand, acacia did not show enough prolonging efficiency in 1 and 3 layer matrix tablets. The results also showed that the location of the polymers in the 3 layer tablets has a pronounced effect on the drug release.

Gliclazide

The safety and efficacy of Gliclazide, 80 mg twice daily was evaluated by kumar et al. in 2000. He studied on  patients with NIDDM who failed to respond to l0 mg or more of Glibenclamide. 227 patients were evaluated in eight centres. Fasting blood glucose was reduced by >20% in 36% and HbAIc by more than 12.5% in 74% of patients at the end of I2 weeks of treatment. There was a significant reduction in total serum cholesterol (p < 0.00 3 ), triglycerides (p <0.05) and LDL (p<0.01) at the end of 12 weeks. The incidence of side effects was 6.2%.

The immediate release Gliclazide tablet formulation was prepared by direct compression method and the dissolution profile of this formulation was compared with reference formulation (Diamicron® lot no:8A0799) by Demirturk et al., in 2005. In this study, three general approaches to compare dissolution profiles were examined, they were statistical methods, model dependent and model independent approaches.

In 2005, Wangnoo et al., suggested that in comparison to twice daily Gliclazide 80mg, once daily Gliclazide MR 60mg is more effective in achieving short term glycemic control with less hypoglycemic symptoms, both in monotherapy and in combination with other agents. Gliclazide MR is a useful once daily sulphonylurea formulation for the management of type 2 diabetes which will help in reducing the high frequency of uncontrolled patients in the Indian primary care setting.

AIM: Formulation and Evaluation of Trilayer tablet of Verapamil hydrochloride and Gliclazide.

OBJECTIVE

To prepare the Trilayer tablet containing Verapamil hydrochloride and Gliclazide.

To deliver the two different drugs with two different independent release profiles and two different release mechanisms from a single dosage form.

To increase patient compliance.

To prevent early morning hypertension.

.

RATIONALE FOR USING DIFFRENT RELEASE MECHANISM

Verapamil hydrochloride layer - swellable release mechanism:

Verapamil hydrochloride is water soluble and it requires strong matrix of swellable polymer for its sustained release.

Gliclazide layer - erodible release mechanism:

Gliclazide is insoluble in water therefore it requires erodible matrix for its sustain release.

EXPERIMENTAL WORK

Calibration curve of Verapamil hydrochloride in different media

Calibration curve of Verapamil hydrochloride in 0.1N HCl ( λmax.= 278nm)

Table No.1

S.No

Concentration (µg/ml)

Absorbance (%)

1

10

0.089

2

20

0.195

3

30

0.316

4

40

0.431

5

50

0.537

6

60

0.654

7

70

0.763

Graph 1

Calibration curve of Verapamil hydrochloride in Acetate buffer pH 4.5 ( λmax.= 278nm)

Table No.2

S .No

Concentration (µg/ml)

Absorbance (%)

1

10

0.101

2

20

0.226

3

30

0.347

4

40

0.437

5

50

0.539

6

60

0.658

7

70

0.777

Graph 2

Calibration curve of Verapamil hydrochloride in Phosphate buffer pH 6.8 ( λmax.= 278nm)

Table No.3

S.No

Concentration (µg/ml)

Absorbance (%)

1

10

0.114

2

20

0.216

3

30

0.329

4

40

0.431

5

50

0.543

6

60

0.638

7

70

0.736

Graph 3

Calibration curve of Verapamil hydrochloride in water ( λmax.= 278nm)

Table No.4

S .No

Concentration (µg/ml)

Absorbance (%)

1

10

0.108

2

20

0.231

3

30

0.346

4

40

0.448

5

50

0.578

6

60

0.673

7

70

0.794

Graph 4

Calibration curve of Verapamil hydrochloride in Phosphate buffer pH 8 ( λmax.= 278nm)

Table No.5

S.No

Concentration (µg/ml)

Absorbance (%)

1

10

0.101

2

20

0.228

3

30

0.337

4

40

0.450

5

50

0.567

6

60

0.681

7

70

0.792

Graph 5

CALIBRATION CURVE OF GLICLAZIDE IN DIFFERENT MEDIA

Calibration curve of Gliclazide in Phosphate buffer pH 6.8 (λmax.= 226nm)

Table No.6

S.No

Concentration (µg/ml)

Absorbance (%)

1

0

0

2

5

0.209

3

10

0.400

4

15

0.577

5

20

0.824

6

25

0.969

Graph 6

Calibration curve of Gliclazide in Phosphate buffer pH 7.4 (λmax.= 226nm)

Table No.7

S.No

Concentration (µg/ml)

Absorbance (%)

1

0

0

2

5

0.243

3

10

0.420

4

15

0.630

5

20

0.836

Graph 7

Calibration curve of Gliclazide in phosphate buffer pH 6.8 (λmax=216nm)

Table No.8

S.No

Concentration (µg/ml)

Absorbance (%)

1

0

0

2

5

0.174

3

10

0.348

4

15

0.529

5

20

0.695

6

25

.846

7

30

1.036

Graph 8

SIMULTANEOUS ESTIMATION OF VERAPAMIL HYDROCHLORIDE AND GLICLAZIDE

Preparation of standard stock solution

Standard stock solution of Verapamil hydrochloride was prepared by dissolving 10 mg of Verapamil hydrochloride in 100 ml of pH 6.8 phosphate buffer to make final concentration of 100µg/ml and standard stock solution of Gliclazide was prepared by dissolving 10 mg of Gliclazide in 50ml of methanol and volume was made up to 100ml with pH 6.8 phosphate buffer. Different aliquots were taken from the stock solution and diluted with pH 6.8 phosphate buffer. The wavelength taken for Verapamil hydrochloride was 278nm and for Gliclazide was 216nm.

Preparation of mixture of both the drugs

From the standard stock solutions, 1ml of both the solutions were taken and volume was made up to 10 ml with pH 6.8 phosphate buffer. Absorbance was measured at both the wavelengths (278nm and 216nm) by using pH 6.8 phosphate buffer as blank. The readings were taken in triplicate. Absorbance of both the drugs was recorded at both the wavelengths. From the absorbance values the absorptivity values (A1% 1cm) were calculated at both the wavelengths.

The concentration of each component was determined by using simultaneous equation method.

A1 = E1aC1 + E2aC2 ---------- (at - 216)

A2 = E1bC1 + E2bC2---------- (at - 278)

A1= absorbance values of the sample solution at 216nm

A2= absorbance values of the sample solution at 278 nm

E1a= absorptivity of Verapamil hydrochloride at 216 nm

E1b= absorptivity of Verapamil hydrochloride at 278 nm

E2a= absorptivity of Gliclazide at 216 nm

E2b= absorptivity of Gliclazide at 278nm

C1= concentration of the Verapamil hydrochloride in µg/ml

C2= concentration of Gliclazide in µg/ml

Values of all above has been summarized in Table No.9

METHOD VALIDATION

The method was validated with respect to accuracy, precision, linearity and range.

Accuracy

Accuracy was assessed by using 9 determinations covering the specified range under 3 different concentrations 3 replicates each. Accuracy was reported as percent recovery by the assay of known added amount of both the drugs in the sample solution. The percentage recoveries of three concentrations were calculated and results has been summarized in Table No.10.

Precision

Precision was done under two parameters:

1 Repeatability

2 Intermediate Precision

Repeatability

Repeatability was assessed by using 3 different concentrations of Verapamil hydrochloride and Gliclazide (5, 10, and 15 ) in 3 replicates each. The data evaluated has been summarized in Table No.11.

Intermediate Precision

Intermediate Precision was investigated by analyzing one concentration (10µg/ml) of Verapamil hydrochloride and Gliclazide mixture in six independent replicates on the same day in morning and evening (Intra-day accuracy and precision) and on three consecutive days (Inter-day accuracy and precision). Intra-day and Inter-day relative standard deviation was calculated. The data evaluated has been summarized in Table No.12 and Table No.13.

Linearity

Aliquots for Verapamil hydrochloride were prepared from concentration 10-70 μg/ml and absorbance values were recorded at wavelength 278nm and for Gliclazide the aliquots were prepared from concentration 5-30 μg/ml, then absorbance values were recorded at 216nm.

Range

Aliquots for Verapamil hydrochloride from concentration 10-70 μg/ml obeyed Beer-Lambert's law with regression of 0.9991. The absorbance range was found to be 0.118- 0.736 and for Gliclazide the aliquots from concentration 5-30 μg/ml obeyed Beer-Lambert's law with regression of 0.9994 and the absorbance range was found to be 0.174-1.036.

RESULT AND DISCUSSIONS

The concentration of each component was determined by using simultaneous equation method.

A1 = E1aC1 + E2aC2 ---------- (at - 216)

A2 = E1bC1 + E2bC2---------- (at - 278)

Table No.9

A1

0.555

A2

0.117

E1a

0.0224

E1b

0.0112

E2a

0.0342

E2b

0.0008

By putting all these above values in simultaneous equation, C1 and C2 were calculated.

C1= 9.74µg/ml

C2= 9.84µg/ml

Accuracy

The data obtained from the proposed method showed accuracy of method. The values of standard deviation were satisfactorily low. The percent recovery of 99% was indicative of accuracy of method.

Table No. 10

Results for accuracy

Amount of drug taken (µg)

Average amount of drug found (µg) ± SD

%Recovery

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

40

10

39.76±0.176

9.94±0.020

99.4

99.4

41.6

10

41.26±0.521

9.67±0.132

99.18

96.7

50

10

50.19±0.453

10.03±0.06

100.3

100.3

*Every reading is average of three replicates

Vrp (Verapamil hydrochloride)

Glicla (Gliclazide)

Precision (Repeatability)

The data obtained from repeatability indicates precision of method. The values of standard deviation and %RSD were satisfactorily low.

Table No.11

Results for repeatability

Amount of drug taken (µg)

Average amount of drug found (µg) ± SD

%RSD

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

5

5

5.0±0.023

4.74±0.075

0.46

1.58

10

10

9.92±0.295

9.74±0.262

2.97

2.68

15

15

14.93±0.055

14.87±0.075

0.36

0.50

*Every reading is average of three replicates

Precision (Intermediate Precision)

Intra-day and Inter-day relative standard deviation values and the low RSD value obtained indicated good precision of the method.

Table No.12

Results for Intermediate Precision ( Inter day study)

Amount of drug ( µg)

Average amount found±SD

Average amount found in inter day study (µg)±SD

%RSD

Day 1

Day 2

Day 3

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

10

10

9.92±0.295

9.74±0.262

10.16±0.523

9.91±0.081

9.77±0.110

10.51±0.115

9.95±0.192

10.05±0.262

1.92

2.60

Table No.13

Result for Intermediate precision ( Intra day study)

Amount of drug ( µg)

Average amount found in inter day study (µg)±SD

%RSD

Vrp

Glicla

Vrp

Glicla

Vrp

Glicla

Morning

Evening

Morning

Evening

10

10

9.91±0.004

10±0.004

10.17±0.001

10.2±0.001

1.79

1.38

*Every reading is average of six replicate

METHODOLOGY

1. PREFORMULATION STUDIES

Compatibility studies

Melting point

Differential scanning calorimetry (if required)

Hygroscopicity

Bulk density

Powder flow property

Solubility analysis

Partition coefficient

IR of active pharmaceutical ingredient (if required)

2. DEVELPOMENT OF FORMULATION

3. ANALYTICAL METHOD DEVELOPMENT

4. FORMULATION OF TRILAYER TABLET

5. EVALUATION PARAMETERS:

Thickness of the tablet

Weight variation test

Hardness test

Friability test

Drug content

Dissolution

6. VALIDATION

7. STABILITY STUDIES

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