11 Chapter 4, Metformin Glimepiride floating tabletsshodhganga.inflibnet.ac.in/bitstream/10603/13928/11/11_chapter 4.p… · Glimepiride given simultenously it will give better pharmacological

Chapter 4 METFORMIN - GLIMEPIRIDE FLOATING TABLETS

JJT University, Rajasthan Page 62

4. METFORMIN - GLIMEPIRIDE FLOATING TABLETS

4.1 Aim of the Present Work

There are several types of gastro retentive system but among of all these system gastro

retentive floating drug delivery system had major advantages. In these system the active

content embedded in the dosage form and having a desired release mechanism with

buoyancy on to the gastric fluid. These type of dosage form float in the gastric

environment without effecting the gastric emptying rate and so the dosage form remain in

the gastric environment for longer period of time. During the floating stage the active

content release from the dosage form at specified time and rate in the gastric

environment.1

Orally delivered biguanide for example Metformin Hydrochloride vastly utilized in the

treatment of non insulin dependent diabetis mellitus. Metformin Hydrochloride improves

insulin sensitivity in liver and muscle and so enhance glycemic control. Orally delivered

biguanide has application on cardiac disease like insulin resistance, fibrinolytic

abnormalities, plasminogen activator inhibitor, dyslipidemia etc.2, 3

Metformin Hydrochloride have half life of four hours to six hours which incompletely

absorbed and excreted in the urine.4 Metformin Hydrochloride is protonated under strong

physiological condition its pKa is around 11.5 and is a strong base. The absorption

pattern of Metformin Hydrochloride had been affected by negatively charged intestinal

epithelium.5 Metformin Hydrochloride have saturable dose dependent mechanism and its

absorption is in the small intestine.6

A modified release dosage form generally release the active content in the colon. So as

per this the absorption window should be in colon or throughout the complete

gastrointestinal tract. Some scientist done research and concluded that absorption window

of Metformin Hydrochloride is low in the colon.6,7 So if the Metformin Hydrochloride

release in the small intestine have no pharmacological action and low therapeutic value.

After the research it had been concluded that if the dosage form like gastro retentive

tablets of Metformin Hydrochloride when administered there in sudden change in the

mean bioavailability of Metformin Hydrochloride increase to 115 % which is quite high

when compare to immediate release formulation of Metformin Hydrochloride.8



For the control of diabetes mellitus, type 2 third generation sulfonyl urea drug is useful

like Glimepiride. A drug substance like Glimepiride have several advantage when

compared to other sulfonyl urea.

Thus as per the discussion a drug i.e. Metformin Hydrochloride would be an ideal

candidate for the floating drug delivery system. It is also more suitable when its

pharmacokinetic and pharmacodynamic properties are discussed. In the current

formulation development an attempt was made to design, development and evaluate

Gastro retentive floating drug delivery system of metformin hydrochloride. Our aim

behind this formulation development is to development of delivery that release the drug

for longer period of time and at controlled rate and floating of the same for more than

eight hours.

When there is increase in the blood sugar level that is caused due to type two diabetes a

patient should be given dose of Glimepiride and Metformin Hydrochloride in

combination. The pancreas released the insulin after the meal so the body store the extra

sugar. When the human being is suffering from type two diabetes the human body does

not work properly to store the extra sugar and thus the sugar remains in the body for the

longer period of time. So by this when there is increase in the blood sugar level it leads to

the serious problem. When the combination of Metformin Hydrochloride and

Glimepiride given simultenously it will give better pharmacological effect and it will help

to the patient against high blood sugar level.9

In the immediate release layer Glimepiride is given for the immediate pharmacological

action for the control of the extra sugar. In the initial stage the blood sugar level is

controlled by Glimepiride and after that the blood sugar level is maintained by controlled

release layer of Metformin Hydrochloride. So if both the active content is given in single

dose it will improve patient compliance. So, efforts are made to prepare such modified

release dosage form.10

In the oral traditional dosage form most of the drug content from the dosage form at

colon, so an active content should have absorption window in the colon or the absorption

through out the gastrointestinal tract. When the Metformin Hydrochloride release after

the small intestine there is no pharmacological effect on the patient.11



Thus there is a strong need to develop gastro retentive formulation containing Metformin

Hydrochloride which is released in the gastric environment before passing the absorption

window.

4.1.1 Objectives of the present study

• By using the Hypromellose and carbopol as sustained release polymers it will

increase gastric resistande time and so resulting into the prolonged drug delivery

system.

• The effect of various process and formulation variable that effects the release of the

active content.

• Selection of polymer that has pronounced effect on the tablet properties and drug

release.

• Development and evaluation of bilayer floating tablets of Metformin Hydrochloride

and Glimepiride based on low density copolymer that keep the dosage form in the

gastrointestinal tract.



4.1.2 Principles to achieve goal

• Tablets should have satisfactory physical properties.

• Tablet release more than 90% of drug within 8 hours.

• Floating lag time of drug delivery system is reduced to minimum.

• Tablet remains buoyant for 8 hours in the gastrointestinal tract and also release the

active content in the modified manner.

4.2 Preliminary Trials

When designing gastro-retentive solid oral dosage form care should be taken for the its

floating lag time. Floating lag time mainly depends on the density of the dosage form and

gas generation property of the dosage form. Usually low density polymer like

hypromellose utilized in the development of the floating drug delivery system. When the

hypromellose comes in contact with the media it dissolve and form the gelling surface. It

form gel boundry around the dosage form. By utilizing various grade of hypromellose

desired rate of release and desired floating lag time can be achieved.

Methodology

Metformin Hydrochloride were utilized in the modified release layer and Glimepiride is

taken in the immediate release layer for the gastro resistance bilayer tablets.

Immediate release layer blend preperation

Glimepiride, red iron oxide and sodium starch glycollate were sifted through 100 # and

blended in the blender for five minutes at 24 RPM. Lactose DCL 15, microcrystalline

cellulose pH 102 were sifted through 30 # and then these blend is added to the above

mixed blend and mix for five minutes at 24 RPM. Magnesium stearate were sifted

through 40 # and then add the magnesium stearate to the above blend in the blender for

five minutes at 24 RPM. By doing the mixing of the blend in above manner there is

minimizing in the deviation of content uniformity. The weight of immediate release

tablets were kept fix at 150 mg per tablet.



Sustained release layer preperation

For the preparation of sustained release layer various different polymer were used.

Different excipient like hypromellose K4M, Hypromellose K100M, sodium carbonate,

potassium carbonate, sodium bicarbonate, calcium carbonate, Guar gum, sodium carboxy

methyl cellulose, sodium alginate, stearic acid, various grade of carbopol were sifted

through 40 # and then mixed with metformin Hydrochloride and stated quantity of

previously sifted dibasic calcium phosphate dehydrate in blender for five minutes at 24

RPM. Sift talc through 40 # and mixed with above blend in the blender for five minutes

at 24 RPM. Sift magnesium stearate through 40 # and then mix the sifted magnesium

stearate to the above mixed blend for five minutes at 24 RPM.

Compression of Bilayer Tablets

Granules of both layer i.e. immediate layer and sustained release were compressed at 19.5

mm x 9.5 mm size caplet punches and corresponding dies on the bilayer compression

machine. (Cadmach, Ahmadabad).

Physical characterization of tablets

Weight variation

At the inprocess time during compression the tablets weight individually and average of

twenty tablets had also been weight. These had been performed on all the batches

compressed. From the resultant data average weight, relative standard deviation, standard

deviation had been calculated. The compression machine was adjusted in such a way that

it produce the tablets without weight variation.

Tablet thickness

During the inprocess stage in compression when the weight variation found in limit the

thickness was measured. Ten pre weighed tablets were taken and thickness were

measured by using dial hand micrometer. The average thickness, relative standard

deviation, standard deviation were reported.



Tablets hardness

In the measurement of hardness the crushing strength of the tablets is measured. It gives

the tablets breaking force and the strength of the physical tablets are represented by the

hardness. Hardness was measured using a Dr. Scheleuniger’s hardness tester. Hardness to

be measured of ten tablets. The harness were measured in newton. The average hardness,

relative standard deviation, standard deviation were reported. The hardness of the tablets

were measured during start and between the compression.

Friability

Friability were carried out to determine the loss of mass when the tablets were subjected

in the friability test apparatusat 25 RPM for four minutes i.e 100 RPM. The friability

Friability were conducted in van Kel tablet friabilitor. For the friability test twenty tablets

were selected from each batch and weighed and subjested to friability test. After the

completion of test the dust were removed and tablets were re weighed. The percent loss

mass were calculated.

Floating lag time

The floating behavior were studied to determine the floating lag time. The floating

behavior were studied by placing the tablets in approximately thousand ml beaker fill up

with five hundredml of 0.1 N Hydrochloric acid temperature of around 37.5 degree. The

floating lag time is the time between the placing of tablets in the medium and the time up

to which the tablets remain float in the media.

Dissolution

The dissolution was carried out to study the in vitro drug release of the prepared bilayer

gastro retentive solid oral dosage form. The dissolution was carried out in basket

apparatus i.e. type 1. The dissolution were carried out in acidic media with pH 1.2 0.1 N

HCl 900 ml with 0.1 % w/v of sodium lauryl sulphateand then followed by alkaline

media with pH 6.8 phosphate buffer at 100 RPM. Dissolution sample were analysed by

high performance liquid chromatography.



Chromatographic condition in HPLC ;

Mobile phase : 50: 50 of 10 Mol phosphate buffer pH 2.5 : Acetonitrile

Column : C8

Loop size : 20

Detector : UV detection

Wavelength : 228 nm

Solution of Glimepiride and metformin Hydrochloride were prepared in 0.1 N NaOH as 1

mg/ml. Calibration curve were prepared from each analyte. The regression of the

obtained curve were used to calculate the drug content and in vitro drug release.

Drug Content12

For the determination of drug content in each tablets twenty tablets were taken and

crushed to fine powder with pastel and mortal. The 1.15 gram of powder were taken and

diluted with alkali solution i.e 0.1 N NaOH up to 100 ml in the volumetric flask. The

solution were subjected to sonification for fifteen minutes. Then these sonicated solution

were filtrered through 0.45 micron filter paper. Then the solution were run to high

performance liquid chromatography and finally calculated drug content of Metformin and

Glimepiride.



4.2.1 Optimization of drug: polymer ratio

In preliminary trial batches, Hypromellose K4M and Hypromellose K100 M were

selected. Viscosity of different polymer of Hypromellose K4M and Hypromellose

K100M are four thousand cp and one lac cp, respectively.

Table 4.1 Formulation of Metformin HCl and Glimepir ide

Excipients Batch No.#

A1 A2 A3 A4 Layer – 1 Metformin HCl 500.0 500.0 500.0 500.0 Hypreomellose K 100M 125.0 250.0 - - Hypromellose K4M - - 125.0 250.0 Dicalcium phosphate dihydrate

159.0 34.0 159.0 34.0

Avg. wt. of layer 1 800.0 800.0 800.0 800.0 Layer – 2 Glimepiride 1.0 1.0 1.0 1.0 Lactose DCL 15 48.0 48.0 48.0 48.0 Microcrystalline cellulose pH 102

90.0 90.0 90.0 90.0

Sodium starch glycollate 8.0 8.0 8.0 8.0 Iron oxide red 1.0 1.0 1.0 1.0 Avg. wt. of layer 2 150.0 150.0 150.0 150.0 Total wt. 950.0 950.0 950.0 950.0 Floating lag time No floating No floating No floating No floating

Layer -1: Talc 8.0 mg / tablet and Magnesium stearate 8.0 mg / tablet

Layer – 2: Magnesium stearate 2.0 mg / tablet



Table 4.2 Physical and chemical evaluation

Sr.No. Batch No. A1

A2 A3 A4

1 Description * * * *

2 Weight variation (mg)

944 mg to 954 mg

939 mg to 951 mg

938 mg to 957 mg

941 mg to 960 mg

3 Thickness (mm) 8.45 ± 0.2 8.45 ± 0.2 8.48 ± 0.2 8.45 ± 0.2 4 Hardness (N) 95 to 104 98 to 103 85 to 94 91 to 97 5 Friability (%w/w) 0.11 0.19 0.13 0.17

6 Assay - Glimepiride (%)

98.7 99.1 97.3 99.1

7 Assay - Metformin HCl (%)

99.6 98.9 99.5 97.3

8 Floating lag time (min)

No floating No floating No floating No floating

9 Dissolution -Glimepiride (%)

97 98 98 100

10

Dissolution -Metformin HCl (%) 1 Hour

27

27

37

35

4 Hours 69 60 78 63 8 Hours 85 78 95 87

* Capsule shape, Biconvex, Bilayer, uncoated tablet with White to off white one layer

and pink other layer.



Figure 8 Dissolution profile comparison for release of Metformin HCl from Bilayer

tablets using HPMC K4M and HPMC K100M as polymer

Results & discussion:

(1) Floating properties of delivery system:

Floating was not observed in any of the above batches.

(2) In vitro Release properties of delivery system:

The drug release profile of different formulation i.e. A1 to A4, formulated by utilizing

Hypromellose K4M and K100M, are illustrated in table: 4.2.

The dissolution profile shows biphasic release of active with rapid loading dose

followed by slower release in another phase which is controlled by polymer. Due to

different viscosity grade of polymer utilized there is difference in drug release

observed.

In the formulation where Hypromellose K4M utilized which is low viscosity polymer

shows a faster release at initial time points.

So by utilizing the Hypromellose polymer which is hydrophilic in nature and showing

fast hydration the dissolution profile can be controlled.

Dissolution profile comparision

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Conclusion:

Dissolution profile of batch: A1 and A2 having drug (Metformin HCl): polymer ratio

1:0.25 and 1:0.5 respectively in giving controlled drug delivery were nearly similar.

Hence, 1:0.25 drug (Metformin HCl) to HPMC K100M was used for further study.

Release of active content from the dosage form it had been observed that due to high

solubility of Metformin hydrochloride (BCS Class-III), HPMC K4M could not retard the

release rate sufficiently to get the active content release from the dosage form at regulated

rate but HPMC K100M could. Thus, high viscosity grade HPMC K100M was selected

for study.

It can be concluded that viscosity is playing the major role in active content release from

the tablets. The ingredientwith high viscosity when utilized it prevents the initial rapid

release of the drug but later on it does not have any effect on the release rate of the active

content.

4.2.2 Use of gas-generating agents

It is well known that gas-generating agents form CO2 gas in HCl that entrapped into the

polymeric gel network results in the decrease in the density of the dosage unit and so it it

floats on the medium. If the gas generating agent comes in the contact of acidic

environment of stomach it generates carbon dioxide and is protected and trapped in the

gel layer which is formed by polymer and due that the density of dosage form comes

below one. Due to these reason the dosage form remain buoyant in the media.

Thus, we decided to incorporate gas-generating agent in the above formulation and

optimize it for floating lag time using various gas-generating agent with different

concentration.

To study the effect of various gas-generating agents in the formulation of GRDDS,

sodium bicarbonate, potassium carbonate, calcium carbonate and sodium carbonate were

incorporated with 7.5 % w/w concentration of sustained release layer. Formulation of

batches B1-B4 are mentioned in table 4.3.




Excipient Batch No. #

B1 B2 B3 B4 Layer – 1 Metformin Hydrochloride

500.0 500.0 500.0 500

Hypromellose K100M 125.0 125.0 125.0 125.0 Sodium bicarbonate 60.0 - - - Sodium carbonate - 60.0 - - Potassium carbonate - - 60.0 - Calcium carbonate - - - 60.0 Dicalcium phosphate dihydrate

99.0 99.0 99.0 99.0

Avg. wt. of layer 1 800 800 800 800 Layer - 2 Glimepiride 1.0 1.0 1.0 1.0 Lactose 48.0 48.0 48.0 48.0 Microcrystalline cellulose pH 102

90.0 90.0 90.0 90.0

Sodium starch glycollate

8.0 8.0 8.0 8.0

Iron oxide red 1.0 1.0 1.0 1.0 Avg. wt. of layer 2 150.0 150.0 150.0 150.0 Total weight 950.0 950.0 950.0 950.0 Floating lag time 3 49 23 57 Layer 1 : Talc 8.0 mg / tablet and Magnesium stearate 8.0 mg / tablet Layer 2 : Magnesium stearate 2.0 mg / tablet



Table 4.4 Physical and chemical evaluation Sr.No. Batch No.

Test B1 B2 B3 B4

1 Description * * * *

2 Weight variation (mg)

950 mg to 957 mg

938 mg to 959 mg

948 mg to 960 mg

944 mg to 959 mg

3 Thickness (mm) 8.45 ± 0.2 8.42 ± 0.2 8.46 ± 0.2 8.45 ± 0.2 4 Hardness (N) 95 to 109 92 to 107 98 to 111 95 to 103 5 Friability (%w/w) 0.17 0.21 0.19 0.23

6 Assay – Glimepiride (%)

100.1 98.2 98.3 99.1

7 Assay – Metformin HCl (%)

100.6 101.0 100.6 98.6

8 Floating lag time (min)

3 49 23 57

9 Dissolution – Glimepiride (%)

100 99 97 99

10

Dissolution - Metformin HCl (%) 1 Hr.

26

20

19

21 4 Hrs. 54 75 70 63 8 Hrs. 95 100 100 100





Figure 9 : Dissolution profile comparision for release of Metformin HCl from Bilayer tablets using different gas generating agent

Result & discussion:

Sodium bicarbonate gave least floating lag time. It was not desirable to use other gas-

generating agents as they exhibited more floating lag time, while our aim was to prepare

dosage form with floating lag time less than 10-15 minutes.

Other gas-generating agents have slow reaction with hydrochloric acid hence; the

reaction for CO2 formation was slowed and results in higher floating lag time.

Conclusion:

Thus, it was concluded to use sodium bicarbonate which gave least floating lag time.

Thus, because of sodium bicarbonate is superior over other it was selected for further

studies.


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4.2.3 Optimization of gas generating agent

To optimize the concentration of sodium bicarbonate it has been used in varying

concentration from 5 %, 7.5 %, 10 % of the sustained release layer. Formulation of

batches C1, B1 and C3 is mentioned in Table 4.5:

Table 4.5 Formulation of Metformin hydrochloride and Glimepiride

Ingredients Batch No.#

B1 C1 C2 Layer – 1 Metformin Hydrochloride 500.0 500.0 500.0 Hypromellose K100 M 125.0 125.0 125.0 Sodium bicarbonate 60.0 40.0 80.0 Dicalcium phosphate dehydrate

99.0 119.0 79.0

Avg. wt. of layer 1 800.0 800.0 800.0 Layer – 2 Glimepiride 1.0 1.0 1.0 Lactose DCL 15 48.0 48.0 48.0 Microcrystalline cellulose pH 102

90.0 90.0 90.0

Sodium starch glycollate 8.0 8.0 8.0 Iron oxide red 1.0 1.0 1.0 Avg. wt. of layer 2 150.0 150.0 150.0 Total weight 950.0 950.0 950.0

Floating lag time 12 3 2

Layer 1 – Talc 8.0 mg /tablet and Magnesium stearate 8.0 mg / tablet Layer 2 – Magnesium stearate 2.0 mg / tablet




Test B1

C1 C2

1 Description * * *

2 Weight variation (mg) 950 mg to 957

mg 940 mg to 961 mg

935 mg to 954 mg

3 Thickness (mm) 8.45 ± 0.2 8.47 ± 0.2 8.45 ± 0.2 4 Hardness (N) 95 to 109 96 to 104 98 to 104 5 Friability (%w/w) 0.17 0.09 0.11 6 Assay – Glimepiride (%) 100.1 98.6 97.9


100.6 98.1 98.6

8 Floating lag time (min) 12 3 2


100 98 99

10


26

24

30 4 Hrs. 54 55 55 8 Hrs. 95 86 90





Figure 10 :- Drug release profile of Metformin Hydrochloride using sodium bicarbonate as gas generating with different concentration i.e 5 %, 7.5 %, 10 % .


By varying the concentration of gas generating agent there is change in the floating lag

time which is mentioned in Table: 5. If the concentaration of gas generating agent

increase there is decrease in lag time of the formulation. When there is introduction of

suitable gas generating agent then it exhibits reduction in the floating lag time of the

dosage unit.

When dissolution profile study conducted it was observed that the release rate remained

almost similar in all batches (table 6).

It was reported that higher proportion of gas-generating agent showed higher bursting

effect. To achieve least floating time and minimum bursting effect it is desirable to utilize

gas generating agent in the optimum concentration.

Conclusion:

Sodium bicarbonate in concentration range 7.5 – 10% was use in further trials to get least

floating lag time.

At the time of compression when there is increase in the compaction force of tablets there

will be decrease in the porosity of tablets and leads to penetration of water and alters the


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floating lag time. So, in such instances it is desirable to go with 10 % sodium bicarbonate

to get lower floating time in presence of the other ingredients.

4.2.4 Effects of other gel-forming agents Other gel-forming agents, such as sodium carboxymethylcellulose, guar gum and sodium

alginate were tried in place of HPMC for controlled drug delivery of Metformin

hydrochloride.

To study the effect of other gel-forming agents, guar gum, sodium alginate and sodium

carboxymethylcellulose was incorporated in place of HPMC K 100M in the formulation

as shown below in Table: 4.7.


Ingredients Batch No. # D1 D2 D3

Layer – 1 Metformin hydrochloride 500.0 500.0 500.0 Sodium bicarbonate 60.0 60.0 60.0

Guar gum 125.0 - - Sodium alginate - 125.0 - Sodium carboxy methyl cellulose - - 125.0

Dicalcium phosphate dihydrate 99.0 99.0 99.0

Avg. wt. of layer 1 800.0 800.0 800.0 Layer – 2 Glimepiride 1.0 1.0 1.0 Lactose DCL 15 48.0 48.0 48.0 Microcrystalline cellulose pH 102

90.0 90.0 90.0

Sodium starch glycollate 8.0 8.0 8.0 Iron oxide red 1.0 1.0 1.0 Avg. wt. of layer 2 150.0 150.0 150.0 Total weight 950.0 950.0 950.0 Floating lag time (min) 8 Erosion and

bursting Erosion and

bursting Layer 1 : Talc 8.0 mg / tablet and Magnesium stearate 8.0 mg / tablet Layer 2 : Magnesium stearate 2.0 mg / tablet




Test D1 D2 D3

1 Description * * *


mg 943 mg to 959

mg 934 mg to 951

mg 3 Thickness (mm) 8.45 ± 0.2 8.45 ± 0.2 8.51 ± 0.2 4 Hardness (N) 89 to 103 93 to 104 92 to 106 5 Friability (%w/w) 0.20 0.19 0.07 6 Assay – Glimepiride (%) 98.1 98.3 99.0


99.0 98.0 99.9

8 Floating lag time (min) 8 Erosion and

bursting Erosion and

bursting


99 -- --

10


37 -- --

4 Hrs. 75 -- -- 8 Hrs. 100 -- --





Figure 11: Dissolution profile for release of Metformin HCl from Bilayer tablets

using guar gum as release retarding agent .


Batch D1 showed least floating lag time with good controlled release of active content

from the matrix prepared using polymer guar gum.

Tablets of batch D2 and D3 disintegrated within 3 min. Formulation development using

release retarding agent as sodium carboxymethyl cellulose and sodium alginate could not

retard the release rate of drug and burst immediately.

Conclusion:

Guar gum in higher concentrations or incorporation of release retarding agents might

provide drug retaining property for longer period of time.

Sodium alginate and sodium carboxymethylcellulose could not give satisfactory result. It

may be due to less gel forming property and more hydrophilicity of these polymers.

Formulation with guar gum does not have sufficient strength when compared to

hypromellose, entrapment of carbondioxide and providing stable floating lag time.

Dissolution profile

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4.2.5 Addition of release retarding agent (stearic acid)

Stearic acid was used as hydrophobic agent and it was incorporated with drug using

chloroform solution. First make complex of drug with stearic acid by chloroform and

then add other ingredients, mix well and compressed it. Stearic acid was used for

sustaining the release of Metformin hydrochloride at 1, 2 and 3% of SR layer.

Formulation of batches E1-E3 is mentioned in table 4.9.


Excipients Batch No.# E1 E2 E3

Layer – 1 Metformin Hydrochloride 500.0 500.0 500.0 Hypromellose K 100 M 125.0 125.0 125.0 Sodium bicarbonate 60.0 60.0 60.0 Stearic acid 8.0 16.0 24.0 Dicalcium phosphate dihydrate 91.0 83.0 75.0 Avg. wt. of layer 1 800.0 800.0 800.0 Layer – 2 Glimepiride 1.0 1.0 1.0 Lactose DCL 15 48.0 48.0 48.0 Microcrystalline cellulose pH 102

90.0 90.0 90.0

Sodium starch glycollate 8.0 8.0 8.0 Iron oxide red 1.0 1.0 1.0 Average wt. of layer 2 150.0 150.0 150.0 Total wt. 950.0 950.0 950.0 Floating lag time (min) 2 3 3

Layer 1 : Talc 8.0 mg / tablet and Magnesium stearate 8.0 mg / tablet

Layer 2 : Magnesium stearate 2.0 mg / tablet




Sr.No. Batch No. Test

E1 E2 E3

1 Description * * *


mg 941 mg to 956

mg 939 mg to 951

mg 3 Thickness (mm) 8.45 ± 0.2 8.45 ± 0.2 8.43 ± 0.2 4 Hardness (N) 90 to 111 92 to 114 88 to 100 5 Friability (%w/w) 0.13 0.14 0.22 6 Assay – Glimepiride (%) 98.1 98.3 99.0


99.0 98.0 99.9

8 Floating lag time (min) 2 3 3


98.8 98.5 99.4

10


29.0 28.6 27.3

4 Hrs. 45.5 45.3 44.3 8 Hrs. 76.0 67.3 67.2





Figure 12: Dissolution profile comparision for release of Metformin HCl from Bilayer tablets using stearic acid as release retarding agent with different concentration i.e 1 %, 2 %, 3 % .


It appears that the incorporation of stearic acid had not much effect on release of

Metformin hydrochloride (end point not achieved) from the GFDDS compared with

batch B1 containing same composition without stearic acid.

Conclusion:

By addition of stearic acid it showed incomplete release in dissolution. Thus, it was

concluded that incorporation of stearic acid had not much benefit and hence; it was

decide to use Carbopol 940 P with HPMC to obtain desired drug release.


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4.2.6 Addition of release retarding agent (carbopol)

To overcome the burst effect and to improve the retardation in the drug release, release

retarding agents were added to the formulation.

When hypromellose and Carbopol utilized simultaneously in a mucoadhesive drug

delivery system it improves the mucoadhesive property of the dosage form.13,14

The total amount of the media imbibed in the Carbopol is much lower when the same is

compared with Hypromellose. It was investigated using model drug propranolol

hydrochloride.15

In the formulation the polymer hypromellose and carbopol can be utilized extragranular

to avoid contact with granulating fluid for the aid in compaction force.16

Carbopol 934P and Carbopol 940P were used with HPMC. The formulation of these

batches E4-E5 is mentioned in Table 4.11:



Table 4.11 Formulation of Metformin HCl and Glimepiride

Excipients Batch No. E4 E5

Layer – 1 Metformin Hydrochloride 500.0 500.0 Hypromellose K100M 125.0 125.0 Hypromellose K4M - - Sodium bicarbonate 60.0 60.0 Carbopol 934 40.0 - Carbopol 940 - 40.0 Di calcium phosphate dihydrate 59.0 59.0 Avg. wt. of layer 1 800.0 800.0 Layer – 2 Glimepiride 1.0 1.0 Lacvtose DCL 15 48.0 48.0 Microcrystalline cellulose pH 102 90 90

Sodium starch glycollate 8.0 8.0 Iron oxide red 1.0 1.0 Magnesium stearate 2 2 Avg. wt. of layer 2 150 150 Total weight 950 950 Floating lag time (min) 2 3

Layer 1 : Talc 8.0 mg / tablet and Magnesium stearate 8.0 mg tablet




Sr.No. Batch No. Test

E4 E5

1 Description * * 2 Weight variation (mg) 948 mg to 959 mg 943 mg to 957 mg 3 Thickness (mm) 8.49 ± 0.2 8.42 ± 0.2 4 Hardness (N) 91 to 101 96 to 109 5 Friability (%w/w) 0.15 0.18 6 Assay – Glimepiride (%) 97.1 98.3 7 Assay – Metformin HCl (%) 99.6 97.5 8 Floating lag time (min) 2 3 9 Dissolution – Glimepiride (%) 100 98

10


23

28 4 Hrs. 35 51 8 Hrs. 84 98



Figure 13: Dissolution profile comparision for release of Metformin HCl from Bilayer tablets using Carbopol 934 P and Carbopol 940 P as release retarding agent.


0

20

40

60

80

100

120

0 2 4 6 8 10

times in minutes

% c

um

ula

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dru

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isso

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B.No. E4

B.No. E5




From the conducted experimental trial it had been reveals that by utilizing the different

grade of carbopol there is change in drug release profile of Metformin Hydrochloride in

the dosage unit when compared with dosage unit without carbopol i.e. Batch B1.

Carbopol is not soluble in simulated gastric fluid and purified water at normal testing

condition. 17

In the trial where carbopol not utilized it exhibit rapid release at the initial time points

that might be due to crosslinking. When the formulation comes in direct contact with the

media or water the polymer swells and retain in the micro gelling network.

Thus there is deliver of active content at specific rate in the intestine and would enhance

absorption.

Presence of Carbopol 940 gave good release retarding of metformin hydrochloride

compared to Carbopol 934 (Batch-E5) and without Carbopol (Batch-B1).

Conclusion:

The usage of carbopol in the formulation development provide specific release and

buoyancy of tablets. It also provide another property like gastric retention to maintainthe

dosage form in the gastrointestinal tract.

Thus, the approach of combination of Carbopol 940 with HPMC was used.



4.3.1 Accelerated Stability Study of The Optimized Batch :

As per the regulatory requirement there is a need of performing the stability study of the

finalized formulation which is to be meant for marketing and consumer drug product. So

there is need of sound stability schedule for the dosage form which give the effect of

temperature and humidity. The product should be safe and efficacious through the shelf

life provided. All the different countries have different geographical condition and

different environmental condition. So they have their own regulatory agency.

The finalized formulation were packed in the blister pack. Which should be intended

marketing pack. Packed tablets were charged for accelerated stability condition at

400C/75% RH. There should not be any change in physical attributes and chemical

attributes of the dosage form. There should not be any change in floating lag time

throughout the shelf life and neither change in the dissolution profile of drug release.

Dose dumping and failure of floating of dosage form are probable effect for such types of

dosage form. Packed sample were evaluated after three month of accelerated stability

condition. Buoyancy study and drug release from dosage form were carried out.

Stability study data of formulation is mentioned in table 4.13

Table 4.13 Accelerated stability study data

Time in minutes Cumulative % Drug release

Initial After 3 months

Floating lag time (min) 3 4

Dissolution – Glimepiride (%) 98 98

Dissolution - Metformin HCl (%) - 1 Hr. 27 25

4 Hrs. 51 47

8 Hrs. 98 98

F2 77.2



Figure 14: Dissolution profile comparision for release of Metformin HCl from Bilayer tablets of optimized batch with initial and 40/75 – 3M.

The dissolution profile of optimized formulation had been carried out and compared. It

had been compared by mathematical equation called similarity and dissimilarity factor.

The similarity factor represented by F2 represent the similarity of the formulation. If the

F2 is more then 50 then the formulations are considered to be similar. The performed

dissolution shows the similarity 77.2 which is indicating the good similarity of the

formulation. There is also no change in the buoyancy study lag time of the dosage form.

So, the finalized formulation reveals good stability.


0

20

40

60

80

100

120

0 2 4 6 8 10

times in hours

% c

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B.No. E5 (Initial)

B.No. E5 (40/75 - 3M)



4.4.1 Result and discussion:

The dosage form with different formulation were analysed with different physical and

chemical parameters. Physical parameters include uniformity of weight, thickness, tablets

breaking force, friability etc. and chemical parameters include dissolution and drug

content. Uniformity of weight found well within the limit. Thickness and hardness of the

tablets were found to be uniform. Friability of the evaluated batches were found bellow 1

% w/w. Drug content of all the are also found well within the limit.

In Batch No. A1, A2, A3, A4 no floating observed. In Batch No. D2 and D3 erosion and

bursting observed. Floating lag time is more than 20 minutes in Batch No. B2, B3 and

B4. No complete release in dissolution was observed in Batch No. E1, E2, E3. For the

optimization of sodium bicarbonate Batch No. C1 and C2. Carbopol 934 is evaluated in

Batch No. E4. In Batch No. E5 Carbopol 940 is used.

4.4.2 Conclusion:

In the present investigation development is carried out for Bilayer floating tablets using

Glimepiride and Metfromin Hydrochloride. Glimepiride is used in immediate release

layer and Sustained release layer of Metformin Hydrochloride is prepared. In the

immediate release layer sodium starch glycolate is taken as super disintegrant.

In the preparation of bilayer floating tablets Sodium bicarbonate is finalized for gas

generating agent as its floating lag time is less compare to other salt and the qty. of

sodium bicarbonate is also optimized to 60.0 mg. Hypromellose is used as rate

controlling agent.

From all the above developed formulation it had been concluded that Batch No. E5 has

less floating lag time and sustained release of Metformin Hydrochloride and Glimepiride

as immediate release component.

Batch No. E5 shows better stability in accelerated condition.



4.5.1 In Vivo buoyancy study

In Vivo studies of gastro retentive floating dosage form

In vivo study was performed to optimized formulation of one of the batch: E5 by further

modifying formulation to incorporate X-ray grade Barium sulphate as X-Ray opaque

substance. Initial formulation trials were made by replacing metformin hydrochloride

with X-ray grade Barium sulphate. Relative high density, aqueous insolubility and poor

buoyancy properties were the limiting factor to achieve desired floating lag time of

prepared formulation. Part of metformin hydrochloride was replaced by Barium sulphate.

The composition of optimized formulation is mentioned in table 4.14.

Table 4.14 Formulation of Metformin Hydrochloride and Glimepir ide

Excipients Batch No.# E6

Layer – 1 Metformin hydrochloride 400.0 HPMC K 100M 125.0 Barium sulphate 100.0 Sodium bicarbonate 60.0 Carbopol 940 40.0 Dicalcium phosphate dihydrate 59.0 Avg. wt. of layer 1 800.0 Layer – 2 Glimepiride 1.0 Lactose DCL 15 48.0 Microcrystalline cellulose pH 102 90.0

Sodium starch glycolate 8.0 Iron oxide red 1.0 Avg. wt. of layer 2 150.0 Total weight 950.0 Floating lag time (min) 4



Table 4.15 Physical evaluation Sr.No. Batch No.

Test E6

1 Description * 2 Weight variation (mg) 940 mg to 960 mg 3 Thickness (mm) 8.39 mm ± 0.2 mm 4 Hardness (N) 95 to 120 5 Friability (%w/w) 0.18 % w/w 8 Floating lag time (min) 4



The amount of X-Ray opaque material was determined experimentally so that it is visible

in X-Ray screening technique but it does not show its effect to buoyancy of the dosage

form. At the same time the amount of BaSO4 should not be high enough to cause sinking

of tablets in stomach.

4.5.2 In-Vivo Study In – Vivo study had been carried out by taking the bilayer floating dosage form to a

human volunteer (Male 31 years, 67 kg weight). The study was conducted in fasting

state. The subject was swallowed the bilayer floating tablets containing barium sulphate

with 250 ml of purified water. Afterwards subject was not allowed to eat during the entire

study. After the swallowing of the dosage form the subject allowed to drunk the water

after four hours.

At the time of study conduction the subject remained in sitting or upright posture. The

position of the bilayer floating tablets had been monitored by X-Ray screening technique.

To view the position of the tablets after two hours and eight hours the radiography was

conducted. Figure 15 and 16 represent the photograph of X-Ray screening technique of

the formulation.



Figure 15: X ray indicating photo of tablets after 2 hrs.



Figure 16: X ray indicating photo of tablets after 7 hrs.

Results and discussion:

The results showed that tablet remained in floated condition in gastric content up to 7 hrs.

A tablet without Barium sulphate is expected to float for longer duration of time than the

test condition shown above since the density of Barium sulphate containing tablet will be

higher than the tablet without it. Even if tablet crossed stomach area after 8 hours, the

remaining drug will continuously absorbed from upper part of small intestine up to 12

hours without losing of drugs to waste.



4.6 Referances :-

1) Prescott LC, Nimma WS., “In rate control In Drug Therapy”, 1985; 59.

2) Shinde AJ., Gastro retentive Drug Delivery System: An Overview, Pharmaceutical

information, 2008; 6(1), 01-08.

3) Peters DH, Dunn CJ.,“Metformin. A review of its pharmacological properties and

therapeutic use in non-insulin dependent diabetes mellitus”, Drugs 1995; 49 (5), 721-

749.

4) Scheen CJ., “Clinical pharmacokinetics of Metformin”, Clinical Pharmacokinitic,

1996, 30 (5), 359-371.

5) Stepensky D., Hoffman A., Stepensky D., Ftiedman., “Preclinical evaluation of

pharmacokinetic- pharmacodynamic rationale for oral CR metformin formulation”,

Journal of Control Release, 2001; 71, 107-115.

6) Vidon N., Chaussade S., Noel M., Franchisseur C., Huchet B., Bernier JJ.,

“Metformin in the digestive tract”, Diabetes Research and Clinical Practice. , 1998; 4,

223-229.

7) Marathe PH., Wen Y., Norton J., Greene DS., Barbhaiya RH., Wilding IR., “Effect of

altered gastric emptying and gastrointestinal motility on metformin absorption”,

British Journal of Clinical Pharmacology; 2009, 50, 325-332.

8) Gusler G., Gorsline J., “Pharmacokinetic of Metoformin in gastric retentive tablets in

healthy volunteers”, The Journal of Clinical Pharmacology, 2001; 41, 655-661.

9) Charpentier G., Fleury F., Kabir M., Vaur L., Halimi S. “Improved glycaemic control

by addition of Glimepride to Metformin monotherapy in Type 2 diabetic patients”,

Diabetic Medicine.2001; 18, 823-834.

10) Package Insert, Bristol Myers Squibb, GLUCOPHAGE/ GLUCOPHAGE XR June

2001.



11) Stepensky D, Friedman M. “Preclinical evaluation of Pharmacokinetic

Pharmacodynamic rational for oral CR Metformin Formulation”, Journal of

Controlled Release 2001; 71, 107-115.

12) Bhaskar LK, Rant BB, Deo AA, Baqool MA, Shinde BR. “Simultaneous

determination of Metformin and Glimepride in pharmaceutical dosage form by

reverse phase liquid chromatography”, Journal of Separation Science October 2005;

Volume 28, Issue 16, pages 2076–2079.

13) Khanna R., Agarwal SP., Ahuja A., “Muco-adhesive buccal tablets of clotrimazole

for oral candidiasis”, Drug Development and Industrial Pharmacy., 1997; 23, 831–

837.

14) Anlar S., Capan Y., Guven O., Gogus A., Hincal AA., “Formulation and in vitro-in

vivo evaluation of buccoadhesive morphine sulfate tablets”, Pharm. Res. 1993; 231–

236.

15) Perez MB., Ford JL., Armstrong DJ., Elliott PN., Hogan JE., “Release of propranolol

hydrochloride from matrix tablets containing HPMC K4M and Carbopol 974”,

International Journal of Pharmaceutical Science., 1994; 111, 251–259.

16) Durrani MJ., Whitaker RF., Manji PA., “Novel wet granulation method for

Carbopol resin. Part 1. Extragranular addition”, Drug Development of Industrial

Pharmacy 1997; 23, 1201–1205.

17) Li S., Lin S., Daggy BP., Mirchandani HL., Chien YW., “Effect of HPMC and

carbopol on the release and floating properties of gastric drug delivery sytem using

factorial design”, International Journal of Pharmaceutical Science. 2003; 253, 13-22.

Documents

11 Chapter 4, Metformin Glimepiride floating tabletsshodhganga.inflibnet.ac.in/bitstream/10603/13928/11/11_chapter 4.p… · Glimepiride given simultenously it will give better pharmacological