FORMULATION AND EVALUATION OF GLIMIPERIDE AND METFORMIN

SUSTAINED RELEASE TABLETS

M. Pharm dissertation protocol submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

By

Mr. CH V S R HANUMAN PRASAD B. Pharm

Under the Guidance of

Dr. KALYANI PRAKASAM M. Pharm, PhD

Professor & HOD

Dept. of Pharmaceutics

Department of Industrial Pharmacy

Acharya & B.M.Reddy College of Pharmacy
Soldevanahalli, Chikkabanavara (Post)
Hesarghatta main road, Bangalore – 560 090
2010 – 2011

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 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.

ANNNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

1 Name and address of Mr. CH V S R HANUMAN PRASAD

candidate S/o CH V S kondalarao
H/no 2-32, Yadavula street,
Dwaraka Tirumala, West godavari Dt,
Andhra Pradesh 534426

2 Name of institution ACHARYA & B.M. REDDY COLLEGE OF

PHARMACY.
Soldevanahalli, Hesarghatta Main Road,
Chikkabanavara Post.
Bangalore-560090

3 Course of study and M. Pharm

subject (Pharmaceutics)

4 Date of admission 25-05-2010

Title of the project FORMULATION AND EVALUATION OF GLIMEPIRIDE

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AND METFORMIN SUSTAINED RELEASE TABLETS.

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6 BRIEF RESUME OF INTENDED WORK

6.1 NEED FOR THE STUDY:

Diabetes mellitus, often simply referred to as diabetes is a group of metabolic diseases in
which a person has high blood sugar, either because the body does not produce enough insulin, 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) and polyphagia
(increased hunger).
There are two main types of diabetes:
a) Type 1 diabetes: results from the body's failure to produce insulin, and presently requires
the person to inject insulin.
b) Type 2 diabetes: this type is characterized by insulin resistance which may be combined
with relatively reduced insulin secretion. The defective responsiveness of body tissues
to insulin is believed to involve the insulin receptor. Type 2 diabetes is the most
common type.
In the early stage of type 2 diabetes, the predominant abnormality is reduced insulin sensitivity. At
this stage hyperglycemia can be reversed by a variety of measures and medications that improve
insulin sensitivity or reduce glucose production by the livers insulin-dependent diabetes mellitus.
As of 2009[update], metformin and glibenclamide are the two oral anti-diabetics in the
World Health Organization Model List of Essential Medicines.
Metformin is an oral anti-diabetic drug in the biguanide class. It is the first-line drug of
choice for the treatment of type 2 diabetes, particularly in overweight and obese people and those
with normal kidney function. It is also used in the treatment of polycystic ovary syndrome and has
been investigated for other diseases where insulin resistance may be an important factor.
Metformin helps reduce LDL cholesterol and triglyceride levels and is not associated with weight
gain, and is the only anti-diabetic drug that has been conclusively shown to prevent the
cardiovascular complications of diabetes.
The side effects of Metformin are gastrointestinal upset—and are associated with a low risk
of hypoglycemia. Lactic acidosis (a buildup of lactate in the blood) can be a serious concern in
overdose and when it is prescribed to people with contraindications, but otherwise, there is no
significant risk.

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 Glimepiride is a medium-to-long acting sulfonylurea anti-diabetic drug. It is sometimes
classified as third-generation, and sometimes classified as second-generation Like all sulfonylureas
glimepiride acts as a secretagogue. It lowers blood sugar by stimulating the release of insulin by
pancreatic beta cells and by inducing increased activity of intracellular insulin receptors.
Oral administration of drugs has been the most common and preferred route for delivery of
most therapeutic agents. It remains the preferred route of administration investigated in the
discovery and development of new drug candidates and formulations. The popularity of the oral
route is attributed to patient acceptance, ease of administration, accurate dosing, cost-effective
manufacturing methods, and generally improved shelf-life of the product. For many drugs and
therapeutic indications, conventional multiple dosing of immediate release formulations provides
satisfactory clinical performance with an appropriate balance of efficacy and safety. The rationale
for development of an extended-release formulation of a drug is to enhance its therapeutic benefits,
minimizing its side effects while improving the management of the diseased condition. . Besides its
clinical advantages, an innovative extended-release formulation provides an opportunity for a
pharmaceutical company to manage its product life-cycle. The dearth of new chemical entities is
forcing many pharmaceutical companies to reformulate an existing conventional formulation into
sustained-release product as a strategy of life-cycle management and retaining market share.

Advantages of a drug formulated into an sustained release (SR)

Clinical advantages:
 Reduction in frequency of drug administration
 Improved patient compliance
 Reduction in drug level fluctuation in blood
 Reduction in total drug usage when compared with conventional therapy
 Reduction in drug accumulation with chronic therapy
 Reduction in drug toxicity (local/systemic)
 Stabilization of medical condition (because of more uniform drug levels)
 Improvement in bioavailability of some drugs because of spatial control
 Economical to the health care providers and the patient
Commercial/industrial advantages
 Illustration of innovative/technological leadership
 Product life-cycle extension

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  Product differentiation
 Market expansion
 Patent extension
The preparation contains two oral anti-hyperglycemic drugs glimepiride and metformin
hydrochloride as sustained release formulations used in the management of type 2 diabetes
(NIDDM). The primary mechanism of action of glimepiride in lowering blood glucose appears to
be dependent on stimulating the release of insulin from functioning pancreatic beta cells.
Metformin hydrochloride increases hepatic glucose production, decreases intestinal absorption of
glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Hence, the combination of glimepiride and Metformin as a sustained release formulation
complement each other and provide better glycaemic control in management of type 2 diabetes and
probably in the prevention of its associated macro vascular and micro vascular complications.

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6.2 REVIEW OF LITERATURE:-
 Metformin hydrochloride is an orally administered antihyperglycemic agent, used in the
management of non-insulin-dependent (type-2) diabetes mellitus. Difficulty in swallowing
(dysphagia) is common among all age groups, especially in elderly and pediatrics.
Unfortunately, a high percentage of patients suffering from type-2 diabetes are elderly
people showing dysphagia. The above problem becomes even more severe due to high dose
(500-1000 mg) and need for daily intake of metformin. Hence, Ashutosh et al., undertook
the work to provide patient friendly dosage form. Not only metformin is poorly
compressible (Carr's index 37), but effervescent ingredients are also poorly compressible
so, method of wet granulation was used for preparation of tablets using absolute alcohol as
binder. Metformin effervescent tablets were prepared using citric acid (CA), tartaric acid
(TA), and treated sodium bicarbonate (heating at 120°C for 30 min), glycine, talc,
sucralose, and mango flavor. Controlled heating of sodium bicarbonate formed a sheath or
desiccant skin of sodium carbonate on bicarbonate nucleus leading to surface passivation
which prevents onset effervescent reaction in presence of moisture leading to stability. Of
all combinations, CA and TA in the molar ratio 1:2 was found to be most stable as higher
amount of least hygroscopic TA protects hygroscopic CA from the attack of moisture. Also,
it was found that using treated sodium bicarbonate in stoichiometric ratio gave substantially
stable effervescent tablets on short term stability study (room temperature and humidity and
75% relative humidity (RH) and room temperature) as sodium carbonate preferentially
absorbs moisture. All the ingredients selected were water soluble1.
 Lian D H et al., prepared metformin hydrochloride (MH) sustained-release pellets by
centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating
of polymeric suspensions were carried out in a centrifugal granulator. Talc modification
was performed before coating in order to overcome the high water solubility of metformin.
The influence of surface modification by talc, the effects of Eudragit® types and ratios, as
well as the correlation between in vitro release and in vivo absorption were investigated in
detail. Experimental results indicated that talc modification made a decisive contribution to
controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M
HCL, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro
release behaviors of the above metformin hydrochloride pellets. The relative bioavailability
of the sustained-release pellets was studied in 12 healthy volunteers after oral

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 administration in a fast state using a commercially available immediate release tablet
(Glucophage) as a reference. Following coating with a blend of Eudragit ® L30D-55 and
Eudragit® NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3),
the pellets acquired perfect sustained-release properties and good relative bioavailability.
The Cmax, Tmax and relative bioavailability for F-2 and F-3 coated pellets were 1.21 μg/ml,
6 h, 97.6% and 1.65 μg/ml, 8 h, 165%, respectively. Combined use of two Eudragit®
polymers with different features as coating materials produced the desired results.
Restricted delivery of metformin hydrochloride to the small intestine from differently
coated pellets resulted in increased relative bioavailability and a sustained release effect.
The adoption of several different pH dissolution media established a better relationship
between the in vitro release and in vivo absorption of the sustained-release pellets2.
 Reven S et al., studied the feasibility of using hyperbranched polymers with highly
branched structure and a large number of functional groups as solubilization enhancers for
poorly water-soluble drugs. Antidiabetic drug glimepiride was used as a model drug and
commercially available hyperbranched poly (esteramide)s as drug carriers. The results of in
vitro dissolution studies showed significantly enhanced aqueous-solubility of glimepiride in
the form of solid dispersions with hyperbranched poly(esteramide)s as compared to pure
glimepiride in crystalline or amorphous form. The results of IR spectroscopic
measurements revealed that improved solubility is a consequence of a complex formation
between glimepiride and hyperbranched polymer. HB poly(esteramide)s with carbonyls of
ester (O)–C O and amide (N)–C O groups serve mainly as a source of proton acceptor
groups to which NH groups of establish hydrogen bonds. Due to complex formation,
glimepiride is within solid dispersions with HB polymers amorphous up to concentration of
5% (w/w) as revealed by X-ray powder diffraction measurements. Above this limit,
glimepiride crystallizes as a separate phase during solvent evaporation3.
 Llic I et al., prepared drug-free microparticles using a spray congealing process. The
influence of processing parameters were studied on the formulation by varying the
atomizing pressure and liquid feed rate, microparticles with median sizes (d(0.5)) from 58 to
278 μm were produced, with total process yields ranging from 81% to 96%. It was
observed that an increased liquid feed rate was found to increase microparticle size, and
higher atomizing pressures were found to decrease microparticle size. Greater change in
microparticle size was achieved by varying atomizing pressure, which can be considered a
dominant process parameter regarding microparticle size. In addition, microparticles with

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 glimepiride, a model poorly water-soluble drug, were prepared by spray congealing using
three different hydrophilic meltable carriers: Gelucire® 50/13, poloxamer 188, and PEG
6000. Spherical microparticles with relatively smooth surfaces were obtained, with no drug
crystals evident on the surfaces of drug-loaded microparticles. XRPD studies showed no
change in crystallinity of the drug due to the technological process of microparticle
production. All glimepiride-loaded microparticles showed enhanced solubility compared to
pure drug; however, Gelucire® 50/13 as a carrier represented the most promising approach
to the dissolution rate enhancement of glimepiride4.
 Patil SA et al., formulated and characterized solid dispersion (SD) of metformin
hydrochloride using methocel K100M as the carrier by the solvent evaporation and
cogrinding method. The influence of drug polymer ratio on drug release was studied by
dissolution tests. Characterization was performed by Fourier transform spectroscopy
(FTIR), ultraviolet, differential scanning calorimetry and X-ray powder diffractometry.
Release data were examined kinetically. SD with 1:4 and 1:5 ratio of drug to polymer
obtained by solvent evaporation and cogrinding were selected as the best candidates
suitable for prolonged-release oral dosage form of metformin5.
 Corti G et al., developed a Metformin hydrochloride (MH) sustained-release formulation in
order to improve its low bioavailabilty and short half life. Direct-compressed matrix tablets
were prepared by the combination of MH with the hydrophobic triacetyl-β-cyclodextrin
(TAβCD), dispersed in a polymeric material. Different polymers were tested as excipients,
i.e. HPMC, xanthan gum, chitosan, ethylcellulose, Eudragit®L100-55, and Precirol®.
Compatibility among the formulation components was assessed by DSC analysis. All the
tablets were examined for drug release pattern in simulated gastric and jejunal fluids used
in sequence to mimic the GI transit. Release studies demonstrated that blends of a
hydrophobic swelling polymer (HPMC or chitosan) with a pH-dependent one
(Eudragit®L100-55) were more useful than single polymers in controlling drug release.
Sustained-release effects were obtained by varying the relative amounts of MH–TAβCD as
ground or spray-dried product. 1:1 (w/w) blend of Eudragit–chitosan polymeric matrix,
fully achieved the prefixed goal, giving about 30% released drug after 2 h at gastric pH, and
overcoming 90% released drug within the subsequent 3 h in jejunal fluid6.
 Vidon N et al., carried out two sets of experiments on metformin, a drug of the biguanide
class. After ingestion there are gastrointestinal side effects in the form of nausea and
vomiting, and about 30% of the drug is recovered in feces. The purpose of this work was to

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 explain these two phenomena. Study 1 evaluated the gastro duodenal (GD) absorption in
six healthy volunteers by means of an intubation method, employing a twin-lumen tube
introduced into the intestine and another into the stomach. Metformin 1 g was introduced
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into the stomach with a homogenized meal containing a non-absorbable marker, C-PEG
4000; another marker, PEG 4000, was perfused continuously into the duodenum at the
ampulla of Vater. Samples of GD contents were collected every 15 min during 4 h.
Metformin was poorly absorbed from the stomach, about 10% over a 4-h period. It did not
modify the gastric emptying of a meal but induced a duodeno-gastric reflux in five out of
six subjects. About 20% of the amount of drug emptied from the stomach was absorbed
from the duodenum. The delivery process was the rate-limiting factor for metformin
absorption from the duodenum. The AUC/24 h increased as the absorption rate from the
duodenum increased. Study 2 investigated in six healthy volunteers, using another intestinal
perfusion technique, the jejunal and ileal absorption of metformin. Metformin 400 mg in
saline solution was perfused, over a 2-h period, below an inflated balloon, directly into
either the jejunum or the ileum. The mean amount of drug absorbed along a 25-cm segment
was low, and similar from the jejunum and ileum: 10.8% and 8.8% respectively. When the
drug was perfused into the jejunum, the AUC values were about 2.5 times higher than the
values when the drug was perfused into the ileum. These results suggest that the whole
intestine is necessary for a sufficient absorption of the drug7.
 Glimepiride is poorly water soluble drug, so solubility is the main constraint for oral its
bioavailability. Hence Gupta GD et al., made an attempt to increase the solubility of
Glimepiride by formulating solid dispersion (SD) using Poloxamer 188 (PXM 188) as
polymer and then formulating SDs into tablets. Tablet formulations were prepared by direct
compression technique using superdisintegrant croscarmellose sodium in different
concentrations. SDs were evaluated for XRD, SEM, in vitro dissolution profiles, and
dissolution efficiency, and developed tablet formulations were evaluated for various
pharmaceutical characteristics viz. hardness, % friability, weight variation, drug content,
disintegration time, in vitro dissolution profiles, and dissolution efficiency. Among
different formulations of SDs, SD containing drug and polymer ratio 1 : 4 gives best
dissolution profile and dissolution efficiency and among tablet formulations, formulations
containing 5% croscarmellose sodium gave best disintegration and dissolution profiles
compared with other formulations. Results showed that poloxamer is a promising polymer
for enhancing the solubility of Glimepiride8.

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 Pentakinen PJ studied the bioavailability of metformin from aqueous solution (A), a rapidly
dissolving tablet (B) and three sustained release products (D, C, E) with a single oral dose
(1.0 g) by administering these products to six healthy volunteers in a randomized cross-
over study. Plasma levels of metformin were followed up to 10 h and excretion into urine
up to 48 h after the dose. The peak plasma levels after A and B were similar and
significantly (p less than 0.05) higher than after C, D and E. The AUC was significantly (p
less than 0.05) higher with A than with other products. The recovery of metformin in urine
was 37%, 33%, 25%, 28% and 29% of the dose after A, B, C, D and E, respectively. The
values of A and B were significantly (p less than 0.05) higher than those of C, D and E. The
renal clearance of metformin was similar after all the products, averaging 518 ±16 (SE)
ml/min. The terminal elimination half-life on the basis of urinary excretion rate data
averaged 12.6 ± 0.6 h with no significant difference between the products. The
bioavailability on the basis of urinary excretion of metformin showed a significant (p less
than 0.05) positive correlation to the dissolution rate of the products in vitro. Thus, the
bioavailability of metformin even from aqueous solution and rapidly dissolving tablets is
relatively low and further deteriorates when metformin is administered as sustained release
products. The bioavailability of the three sustained release products studied was similar9.
 Fliszar KA et al., examined a continuous dissolution/absorption system using a hexadecane
membrane (HDM) as the permeation measurement for three distinct formulations of
metformin hydrochloride. This system was used to correlate the absorption rate of
metformin through the membrane after release from the dosage form to rate of appearance
of metformin in the plasma from the same formulations. These correlations were then used
to make predictions of the in vivo plasma profile for each formulation. Successful
predictions of AUC were accomplished for both immediate release and extended release
formulations of metformin hydrochloride10.
 Altinoz S et al., analyzed Glimepiride (Amaryl®), which is a new oral antidiabetic drug in
the sulfonylurea class using second order derivative UV spectrophotometry. The
quantification of glimepiride in dimethylformamide was performed in the wavelength range
of 245–290 nm. The second order derivative spectra was calculated using peak to peak
(λDMF=263.3–268.2 nm), peak to zero (λDMF=268.2 nm) and tangent (λDMF=263.3–271.8
nm) method for calibration curves, the linearity range of 1.00–500.00 μg ml−1 by using the
second order derivative UV spectrophotometric method. R.S.D. were found to be
4.18%.The developed method was applied to directly and easily to the analysis of the

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pharmaceutical tablet preparations. The method was completely validated and proven to be
rugged. The limit of quantitation and the limit of detection were found as 1.00 and 0.4 μg
ml−1, respectively. This validated derivative UV spectrophotometric method is potentially
useful for a routine laboratory because of its simplicity, rapidity, sensitivity, precision and
accuracy11.

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 6.3 OBJECTIVE OF THE STUDY:
The objectives of the present study are following:-

1. To carry out pre-formulation studies such as angle of repose, bulk density, Carr’s index
whichever are required.

2. To design and develop SR tablet by wet granulation method/dry granulation/direct

compression whichever is suitable.

3. To carry out in-vitro release studies using suitable testing apparatus.

4. To carry out stability studies on the most satisfactory formulation as per ICH guidelines.

7 MATERIALS AND METHODS :

7.1 SOURCE OF DATA:-

1) Review of literature from:
a. Journals – such as
 Indian Journal of Pharmaceutical Sciences
 Journal of young Pharmacists.
 Asian Journal of Pharmaceutics
 International Journal of Pharmaceutical sciences
b. World Wide Web
c. J-Gate@Helinet

7.2 METHOD OF COLLECTION OF DATA:

 Compatibility studies for selected drugs and polymers by FTIR etc.
 Carrying out pre-formulation studies such as angle of repose, bulk density, Carr’s index, etc
 Designing and developing SR tablet by wet granulation method/dry granulation/direct
compression whichever is suitable.
 Carrying out post formulation studies such as hardness, friability, weight variation etc.
 Carrying out in-vitro release studies using suitable testing apparatus.
 Carrying out stability studies on the most satisfactory formulation as per ICH guidelines.

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7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION TO BE CONDUCTED ON
PATIENT OR OTHER HUMANS OR ANIMALS?

“ NO”

7.4
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN

CASE OF 7.3?

“ NOT APPLICABLE”

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8 LIST OF REFERENCES:-
1. Ashutosh M, Rajesh K P , Mukesh C G. Formulation, development and evaluation of
patient friendly dosage forms of metformin, Part – III: Soluble effervescent tablets. Asian J
Pharm. 2008;2(3):177-81.
2. Lian D H, Liu Y, Xing T, Qian Z. Preparation and invitro/invivo evaluation of sustained –
release metformin hydrochloride pellets. Eur J Pharm Biopharm 2006;64(2):185-92.
3. Reven S, Grdadolnik J, Kristi J, Zagar E. Hyperbranched poly(estramides) as solubility
enhancers for poorly water – soluble drug glimepiride. Int J Pharm 2010;396:119-26.
4. Llic I, Dreu R, Burjak M, Homar M, Kerc J, Srcic S. Microparticle size control and
glimepride microencapsulation using spray congealing technology. Int J Pharm
2009;381(2):176-83.
5. Patil SA, Kuchekar BS, Chabukswar AR, Jagdale SC. Formulation and evaluation of
extended solid dispersion of metformin hydrochloride .J Young Pharm 2010;2(2):121-9.
6. Corti G, Cirri M, Maestrelli F, Mennini N, Mura P. Sustained – release matrix tablets of
metformin hydrochloride in combination with triacetyl-β-cyclodextrin. Eur J Pharm
Biopharm 2008;68(2):303-9.
7. Vidon N, Chaussage S, Noel M, Franchisseur C, Huchet B, Beiner J J. Metformin in the
digestive tract. Diabetes Res Clin Pract 1988;4(3):223-9.
8. Gill B, Kaur T, Sandeep K, Gupta G D. Formulation and evaluation of glimepiride solid
dispersion tablets. Asian J Pharm. 2010;4(3):212-8.
9. Pentikainen PJ. Bioavailability of metformin. Comparison of solution, rapidly dissolving
tablet and three sustained release products. Int J Clin Pharmacol Ther Toxicol
1986;24(4):213-20.
10. Fliszar K, Foster N. Examination of metformin hydrochloride in continuous
dissolution/HDM system. Int J Pharm 2008;351(1-2):127-32.
11. Altinoz S,Tekeli D. Analysis of glimepride by using derivative UV spectrophotometric
method. J Pharm Bio Anal. 2001;24(3):507-15.

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9 Signature of the candidate:

10 Remarks of the Guide:

11 Name and Designation of:

11.1 Institutional Guide: Dr. KALYANI PRAKASAM M.Pharm ph.D

Professor
Dept. of Pharmaceutics.

11.2 Signature:

11.3 Co-Guide:

11.4 Signature:

11.5 Head of the Department: Dr. KALYANI PRAKASAM M.Pharm ph.D

Professor
Dept. of Pharmaceutics.

11.6 Signature

12 12.1 Remarks of the Principal

12.2 Signature

Dr. Goli Divakar

Principal
Acharya & B.M.Reddy college of pharmacy.

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