FORMULATION AND IN VITRO EVALUATION OF SUSTAINED
RELEASE BILAYER TABLETS OF VALSARTAN AND MIGLITOL
M. Pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560041
By
Miss KANCHAN SINGH, B.Pharm
Under the Guidance of
Prof. G. PARTHASARATHY, M.Pharm
Department of Pharmaceutics
Department of Pharmaceutics
R. R. College of Pharmacy
Raja Reddy Layout, Hesaraghatta Main Road
Chikkabanwara Post, Bangalore
Pin Code – 560090
2012 – 2013
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name and address of candidate / Miss KANCHAN SINGHD/O
RAJENDRA PRASAD SINGH
VILL+P.O – MAJHARIA KISHUN
VIA – JAGDISHPUR
DISTT – WEST CHAMPARAN, BETTIAH
STATE – BIHAR
PIN CODE - 845459
2 / Name of institution / R.R. COLLEGE OF PHARMACY
RAJA REDDY LAYOUT
HESERAGHATTA MAIN ROAD
CHIKKABANWARA POST
BANGALORE, KARNATAKA
PIN CODE - 560090
3 / Course of study and subject / M. Pharm
(DEPT OF PHARMACEUTICS)
4 / Date of admission / 15thJANUARY, 2013
5 / Title of the project / FORMULATION AND INVITRO EVALUATION OF SUSTAINED RELEASE BILAYER TABLETS OF VALSARTAN AND MIGLITOL
6
6.1 / BRIEF RESUME OF INTENDED WORK
NEED FOR THE STUDY:
DIABETES:
Diabetes mellitus, or diabetes, is a group of metabolic diseases in which a person has highblood sugar, either because thepancreasdoes not produce enoughinsulin, or because cells do not respond to the insulin that is produced.This high blood sugar produces the classical symptoms of polyuria(frequent urination),polydipsia(increased thirst) andpolyphagia(increased hunger).
There are three main types of diabetes mellitus (DM).
· Type1 DMresults from the body's failure to produce insulin, and currently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".
· Type2 DMresults frominsulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes".
· The third main form,gestational diabetesoccurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type2 DM.
Diabetes is one of the most prevailing and advancing diseases in the world having affected 6.6% of the world population. Untreated, diabetes can cause many complications.Acutecomplications includediabetic ketoacidosisandnon ketotic hyperosmolar coma. Serious long-term complications includecardiovascular disease,chronic renal failure, anddiabetic retinopathy(retinal damage).
HYPERTENSION:
Hypertension(HTN) or high blood pressure, is achronicmedical conditionin which theblood pressurein the arteriesis elevated.This requires the heart to work harder than normal to circulate blood through the blood vessels. Blood pressure is summarized by two measurements,systolicanddiastolic, which depend on whether the heart muscle is contracting (systole) or relaxed between beats (diastole) and equate to a maximum and minimum pressure, respectively. Normal blood pressure at rest is within the range of 100-140mmHg systolic (top reading) and 60-90mmHg diastolic (bottom reading). High blood pressure is said to be present if it is persistently at or above 140/90mmHg.
Hypertension has emerged as a major public health problem worldwide. If hypertension is not controlled, it may lead to heart attack, brain stroke or kidney damage.
Diabetes mellitus and hypertension are interrelated diseases that strongly predispose an individual to atherosclerotic cardiovascular disease23.
The prevalence of co-existing hypertension and diabetes appears to be increasing in industrialized nations because populations are aging and both hypertension and NIDDM incidence increases with age23.
Data obtained from death certificates show that hypertensive disease has been implicated in 4.4% of deaths coded to diabetes, and diabetes was involved in 10% of deaths coded to hypertensive disease.Indeed, an estimated 35% to 75% of diabetic cardiovascular and renal complications can be attributed to hypertension. Hypertension also contributes to diabetic retinopathy, which is the leading cause of newly diagnosed blindness in the United States. For all these reasons, hypertension and diabetes should be recognized and treated early and aggressively23.
Data obtained from death certificates show that hypertensive disease has been implicated in 4.4% of deaths coded to diabetes, and diabetes was involved in 10% of deaths coded to hypertensive disease.Indeed, an estimated 35% to 75% of diabetic cardiovascular and renal complications can be attributed to hypertension.Hypertension also contributes to diabetic retinopathy, which is the leading cause of newly diagnosed blindness in the United States.For all these reasons, hypertension and diabetes should be recognized and treated early and aggressively23.
BILAYER TABLETS:
This type of system is used primarily when maximum relief needs to be achieved quickly, and it is followed by a sustained release phase to avoid repeated administration. Oral route is the most commonly employed route of drug administration. Although different route of administration are used for delivery of drugs, oral route remain the preferred mode. The popularity of the oral route is attributed patient acceptance, ease of administration, accurate dosing, cost effective manufacturing and generally improved shelf life of the product. Even for sustained release system the oral route of administration has been investigated the most, because of flexibility in dosage forms design that the oral route offers2.
The bilayer tablet is innovative drug delivery system. This is novel type of dosage form for oral administration which is composed of one fast release layer and one sustain release layer.
Layered tablet concept is utilized to develop controlled and sustained release formulations. Such tablet is considered as biphasic delivery system that is designed to release the drug at two different rates and is usually composed of a fast release layer and sustain release layer. Conventional sustain release dosage form delay the release of drugs and do not provide the rapid onset of action after oral administration. Hence this layer tablet offer a pharmacokinetic advantage over conventional dosage forms as the drug is released quickly from the fast layer leading to the rapid raise in drug plasma concentration followed by continuation of drug release from the sustain-release layer. This release
pattern is required for successful treatment in many therapies, Primarily when maximum relief needs to be achieved as soon as possible and is followed by a sustained released phase to avoid repeated drug administrated. The term bilayer tablet refers to tablet containing subunits that may either the same or different. Bilayer tablets allow for designing and modulating dissolution and release characteristics and they are prepared with one layer of drug for immediate release. The second layer designed to release drug later3.
MIGLITOL:
Miglitol is an oral anti-diabetic drug that acts by inhibiting the ability of the patient to breakdown complex carbohydrates into glucose. It is primarily used in diabetes mellitus type 2 for establishing greater glycemic control by preventing the digestion of carbohydrates (such as disaccharides, oligosaccharides, and polysaccharides) into monosaccharides which can be absorbed by the body. Miglitol inhibits glycoside hydrolase enzymes called alpha-glucosidases. Since miglitol works by preventing digestion of carbohydrates, it lowers the degree of postprandial hyperglycemia.
VALSARTAN:
Valsartan is an angiotensin-receptor blocker (ARB) that may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure. Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system(RAAS); it competes with angiotensin II for binding to the type-1 angiotensin II receptor (AT1) subtype and prevents the blood pressure increasing effects of angiotensin II.
ADVANTAGES OF SUSTAINED RELEASE DRUG:
1. Improved patient compliance.
2. Reduction in frequency of drug administration.
3. Reduction in drug toxicity.
4. Decreases drug level fluctuation in blood.
6. Decreases drug accumulation with chronic therapy.
7. Stabilization of medical condition, since plasma drug level is uniform.
8. Economical to health care providers and patient.
IMPORTANCE OF THIS STUDY:
Immediate after oral administration, the upper layer of the bilayer tablets, disintegrates first to release valsartan in stomach and gets absorbed thereby reduces hypertension. Simultaneously, the sustained release layer will start to release miglitol, which gets absorbed hence it maintains normal blood glucose level in severe hyperglycemia for longer duration. Shorter half-life of miglitol (antidiabetic) and multiple dosing frequencies, the present study is aimed to formulate and evaluate bilayer sustained release tablets of valsartan and miglitol which is used for the treatment of diabetic hypertensive patients.
6.2
/ REVIEW OF LITERATURE:
· Astmakar and his co-workers worked on miglitol control release tablets. They used various polymers like HPMC, PVA to carry out dissolution studies. Finally they concluded that combination of PVA & HPMC gave desired controlled release of drug.
· Bilayer sustained release tablets of Isosorbide- mononitrate were developed by Ashish A and others. Tablets were prepared by wet granulation method. Various hydrophilic and hydrophobic matrix materials such as hydroxy propyl methylcellulose and polyox were used to release the drug up to 24 hrs in predetermined rate. Finally they reported the influence of hydrophilic and hydrophobic polymer and granulation technique on their research work7.
· A research work was done by Nagaraju R and his co-workers on Salbutamol and theophylline which are available in conventional dosage forms, administered four times a day, leading to saw tooth kinetics and resulting in ineffective therapy. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong bronchodilation. They studied about various polymers, such as HPMC- K4M, HPMC- K100M, xanthan gum, ethyl cellulose and HPMC-P and finally it was found that HPMC-P and HPMC- K4M were best polymer in controlling the release of the drug8.
· Bilayer tablets of propanolol hydrochloride were formed by Prasanthi N.L. and others by using xanthan gum, locust bean gum and guar gum with different drug: gum ratios of 1:0.25 and 1:0.5 by wet granulation method. Sodium starch glycolate was for immediate release layer. Sustained release layer was prepared by using gums in different drug to gum ratio. It was found the drug content of the formulations within 98.9‐101.7%. The release of propanolol HCl was extended up to 12 hours and was dependent upon the concentration of the gum. Finally they concluded that the release was better sustained with xanthan gum at the concentration of 1:110.
· Maheswara Reddy A. et al., patented on the pharmaceutical tablets comprising a first layer formulated for immediate release of telmisartan from a dissolving matrix and a second layer formulated for immediate release of hydrochlorthiazide from a dissolving matrix to treat hypertension12.
· Nagori S.A. and his research team conducted immidiate release of paracetamol and slower release of diclofenac sodium from bilayer tablets. They adopted a factorial design by using the polyethylene glycol, microcrystalline cellulose and cross povidone as independent variables for fabricating paracetamol tablets. Diclofenac sodium tablets were prepared using hydroxypropyl methylcellulose as a matrixing agent. The results of analysis of variance showed that the friability of paracetamol was distinctly influenced by the formulation variables. The in vitrodrug release behaviour of diclofenac tablets was compared with a marketed formulation. The optimized formulations of paracetamol and diclofenac sodium were used for manufacturing of bilayer tablets. They finally concluded that bilayer tablets showed immediate release of paracetamol and modified release of diclofenac13.
· Sustained release matrix tablets of flutamide were developed by Jaber and hisco-workers. These were prepared by direct compression method using different polymers. Various polymers were used such as, cellulose ethers (HPMC and Na CMC), natural gums (guar and xanthan gums), compressible Eudragits (RSPO and RLPO) and their combinations in different
ratios to examine their influence on tablet properties and drug release profile. A suitable sustained release dosage form should release its content within 8-10 h. In this series, formulation containing 25% of HPMC, released about 70% of flutamide in 8 h and this could be considered as a sustained release formulation. This formulation could release more than 90% of its content within 10 hrs. They concluded that the rate and amount of drug release is inversely proportional to the HPMC percentage in formulations14.
· Namath ulla et al., formulated and evaluated sustained release matrix tablets of Lornoxicam. Lornoxicam has a shorter half life. Due to its acidic nature, its release from sustained release delivery system is limited to the lower gastro intestinal tract, consequently leads to a delayed onset of analgesic action. So they developed Lornaxicam sustained release matrix tablets to provide complete drug release that starts in stomach and maintains its analgesic effect15.
· Arunachalam A. and his co-workers worked on Metoprolol Succinate and Telmisartan which are available in conventional dosage forms, administered in a day, leading to saw tooth kinetics and resulting in ineffective therapy. The combination of these two drugs in a single dosage form will enhance the patient compliance and prolong cardiovascular system. They studied about various polymers, such as HPMC- K4M, HPMC- K100M, Lactose DCL 11, Bronopol and they found that the HPMC- K4M was best in controlling the release. They carried out in vitro dissolution studies for all the bi-layered tablets. The tablets were prepared by Direct Compression method16.
· Shyani B and others worked on bilayer tablet of Metoclopramide Hydrochloride and Ibuprofen for the effective treatment of migraine. They formulated MTH and IB for immediate and sustained release layer respectively. Various disintegrants like Polyplasdone XL, Explotab, Agar and Guar gum for immediate release of MTH. Treated form of Gellan gum and agar were prepared and compared their disintegrant efficiency with other disintegrants. HPMC K4M was used to form sustained release layer of ibuprofen. They studied the effect of concentration of hydrophilic matrix HPMC K4M, binder PVP K30 and buffer(sodium bicarbonate) on the release rate of ibuprofen. The dissolution study of sustained release layer showed that an increasing amount of HPMC or PVP K30 results in reduced ibuprofen release17.
· Chinam NP et al., researched on sustained release bilayer tablets of propranolol hydrochloride. They developed a bilayer tablet of propranolol hydrochloride using superdisintegrant sodium starch glycolate for the fast release layer. Various polymers such as ethylcellulose, Eudragit RLPO and Eudragit RSPO were for the sustaining layer and finally they concluded that there was no significant difference in the cumulative amount of drug release after 15 min, but significant difference (p < 0.05) in the amount of drug released after 12 h from optimized formulations was observed18.