INTRODUCTION OF METFORMIN –
Metformin HCl (MTH), most frequently prescribed by doctors in the treatment of NIDDM, belongs to biguanide class of antidiabetic agent (5). Metformin hydrochloride (HCl) was used in the model formulation which was intended to contain the high amount of hydrophilic drug. Metformin HCl 1000 mg extended release tablet is selected as the model formulation (3).
BENEFITS OF SUSTAINED RELEASE TABLET(SR) –
Carika Pundir et al, 2013).
Amongst various sustained release delivery devices used to target particular site of diseases, Colon drug delivery system has gained increased importance for the treatment of local disease associated with the colon and also for its potential for the delivery of proteins and therapeutic peptides, for colonic delivery a drug needs to be protected from absorption and environment of the upper gastrointestinal tract and then abruptly released into the proximal colon (M. K. Chourasiya et al, 2003). Colon-specific drug delivery system offers the therapeutic benefits by reducing the adverse effects in the treatment of colonic diseases, producing the ‘friendlier’ environment for peptides and proteins when compared to upper gastrointestinal tract, minimizing extensive first pass metabolism of steroid, preventing the gastric irritation produced by oral administration of NSAID, delayed release of drugs to treat angina, asthma and rheumatoid arthritis (M. K. Chourasiya et al, 2003).
Metformin is very popular since its approval in the United States in December, 1994 and continued to be used as monotherapy or combination therapy with sulfonyl urea for the treatment and management of Type II diabetic patients. Its antidiabetic action is attributed to its ability to reduce glucose production from liver, reduce glucose uptake from gastro intestinal tract (GIT), and improve glucose utilization by skeletal muscle and adipocytes. It has been found from several studies that MTH is highly effective as well as safe in the treatment of Type II diabetes. MTH could be a better option than the existing immediate-release and conventional sustained-release counterpart. If the drug is designed to be released from its dosage form slowly over an extended period of time in the stomach, complete utilization of the drug might result in its enhanced bioavailability. This theory is supported by several studies which reported that the bioavailability of MTH improved when formulated as gastro-retentive drug delivery system (GRDDS)(5).
The biguanides metformin, phenformin and buformin are derived from the herb Galega officinalis (French lilac, also known as Goat’s Rue or Italian Fitch) and were originally developed for the treatment of hyperglycemia and type 2 diabetes. Metformin was approved for the treatment of hyperglycemia in Britain in 1958, Canada in 1972, and the US in 1995. In addition to its
use in diabetics, metformin is also effective in the treatment of polycystic ovary syndrome and is being explored as an antiviral and anticancer agent. The use of biguanides in oncology was originally initiated in a series of studies targeting altered metabolism
in non-diabetic cancer patients. Metformin has been associated with decreased cancer incidence and mortality in diabetic patients and the insulin-lowering effects of metformin may be integral to its anticancer properties. Use of metformin in oncology and its potential mechanisms of action in the inhibition of cancer(1M).
IUPAC : N,N-Dimethylimidodicarbonimidic diamide
Category : Antidiabetic (biguanides)
Molecular formula : C4H11N5
Molecular mass : 129.16364 g/mol
Melting point : 222ºC-226 ºC
Solubility : Highly water soluble(>300 mg/ml at 25ºC)
pKa : 2.8 and 11.5
pH : 6.8
Route of administration : By mouth
Bioavailability : 50-60%
Protein binding : Minimal
Biological half-life : 4-8.7 hours
Metabolism : Not by liver
Excretion : Urine (90%)
Mechanism of action: Its antidiabetic action is attributed to its ability to reduce glucose production from liver, reduce glucose uptake from gastro intestinal tract (GIT), and improve glucose utilization by skeletal muscle and adipocytes. It has been found from several studies that MTH is highly effective as well as safe in the treatment of Type II diabetes(5). At the cellular level, metformin activates AMP-activated protein kinase (AMPK), an energy sensor involved in regulating cellular metabolism that is activated by increases in the intracellular levels of AMP. Metformin indirectly activates AMPK by disrupting complex I of the mitochondrial respiratory chain, which leads to decreased ATP synthesis and a rise in the cellular AMP : ATP ratio. Increased association of AMPK with AMP under such conditions leads to stimulation of AMPK activity by three mechanisms. AMP allosterically activates AMPK and facilitates phosphorylation of its catalytic subunit on residue Thr172 by the upstream kinase liver kinase B1 (LKB1, also known as STK11), the protein product of the tumor suppressor gene mutated in the Peutz-Jeghers cancer predisposition syndrome. Binding of AMP to AMPK also prevents dephosphorylation of AMPK Thr172 by protein phosphatases. Activated AMPK phosphorylates a number of downstream targets leading to stimulation of catabolic processes that generate ATP, such as fatty acid b-oxidation and glycolysis, and suppression of many of the processes dependent on ample cellular ATP supply, including gluconeogenesis, protein and fatty acid synthesis and cholesterol biosynthesis.
The mechanism of metformin action in the treatment of diabetes involves the inhibition of hepatic gluconeogenesis and the stimulation of glucose uptake in muscle. These effects are achieved by AMPK-mediated transcriptional regulation of genes involved in gluconeogenesis in the liver and those encoding glucose transporters in the muscle, such as peroxisome proliferator- activated receptor-g coactivator 1a (PGC-1a) and glucose transporter type 4 (GLUT4), respectively. Consequently, metformin enhances insulin sensitivity and lowers fasting blood glucose and insulin in diabetics(1M).
Metfomin (1,1-dimethylbuguanide hydrochloride) is a biguanide currently used as an oral antihyperglycemic agent(2M).
Metformin could be used to treat and to prevent progression to impaired glucose tolerance (IGT) in PCOS patients(3M).
The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients(3M).
Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease(3M).
Metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence.
Health benefits of HPMC (Hydroxypropylmethyl cellulose)
Hydroxypropyl methylcellulose (HPMC) is the most important hydrophilic carrier material used for the preparation of oral controlled drug delivery. One of its most important characteris tics is the high swellability, which has a significant effect on the release kinetics of an incorporated drug.
In controlled drug delivery systems which are based on HPMC and aimed at providing particular, pre-determined release profiles it is highly desirable:
(i) To know the exact mass transport mechanisms involved in drug release
(ii) To be able to predict quantitatively the resulting drug release kinetics.
The practical benefit of an adequate mathematical model is the possibility to simulate the effect of the design parameters of HPMC-based drug delivery systems on the release profiles(4H).
PLAN OF WORK:
A summarized plan of works is proposed is below:
? Preformulation study
? Pre-compression characterization by the parameters as-
? angle of repose
? bulk density
? tapped density
? Carr’s index
? Hausner ratio
? Preparation of the formulation
? Evaluation of formulations for assessing different parameters
? Comparative release of developed dosage forms with marketed formulations of the drug
? Drug-polymer compatibility study
STUDY METHODOLOGY :
DRUG: Anti-hyperglycemic agents such as Metformin.
POLYMERS: Hydroxypropylmethyl cellulose, Ethyl cellulose.
EXCIPIENTS: Excipients as required etc.,
? Preformulation studies of drug & selected polymer
a. Formulation design using various polymers
b. Physico-chemical characterization of drug and excipients
c. Compatibility studies amongst the formulations ingredients by FTIR/DSC/TGA/DTA.
? Evaluation of powders and particulate properties
? Evaluation of formulations for following parameters
? Drug content uniformity
? Drug loading
? Size estimation
a) In-vitro dissolution studies using simulated gastric fluid, simulated intestinal fluid and simulated colonic fluid.
b) Drug release characterization by fitting into various kinetic models.
c) Short term stability studies for the best optimized formulation
d) Drug-polymer compatibility by various instrumental techniques
OBJECTIVE OF THE STUDY-
COATING OF TABLETS AND GRANULES –