INTRODUCTION for the treatment of local diseaseINTRODUCTION for the treatment of local disease

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).

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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).

 

 

 

 

 

DRUG PROFILE:-

METFORMIN (Drug)

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).

Structure:

 

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

 

Pharmacokinetic Pofile:-

Bioavailability                              : 50-60%

Protein
binding                             :
Minimal

Biological
half-life                       : 4-8.7
hours

Metabolism                                  : Not by
liver

Excretion                                      : Urine
(90%)

 

 

 

Pharmacodynamic Profile:-

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).

Use:-

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).

Side effect:-

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.

 

POLYMER PROFILE:-

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).

Ethyl
cellulose

 

 

 

 

 

 

 

 

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 :

 

 

 

 

MATERIALS:

DRUG: Anti-hyperglycemic agents such as
Metformin.

POLYMERS: Hydroxypropylmethyl cellulose,
Ethyl cellulose.

EXCIPIENTS: Excipients as required etc.,

 

METHODS:

?          
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

LITTRATURE REVIEW-

 

 

 

OBJECTIVE OF THE STUDY-

 

 

COATING OF TABLETS AND GRANULES –

 

References: