FORMULATION AND EVALUATION OF SUSTAINED RELEASE TABLETS OF VILDAGLIPTIN

Under the Guidance ofMr. P.VISHNU M.Pharm.Assistant Professor

Presented By CHAITANYA.B B.Pharm.

Department of Pharmaceutics

CMR COLLEGE OF PHARMACY(Approved by AICTE & PCI and affiliated to JNTU Hyderabad)

6/12/2012

SRF’s describes the slow release of a drug substance from a dosage form to maintain therapeutic response for extended period of time. Time depends on the dosage form. In oral form it is in hours, and in parenteral’s it is in days and months. Ex: Aspirin SR, Dextrim SR.

INTRODUCTION

ADVANTAGES:

Decreased local and systemic side effects

Better drug utilization

Improved efficiency in treatment

DISADVANTAGES:

Decreased systemic availability in comparison to immediate-release conventional

dosage forms

Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions.

Reduced potential for dosage adjustment of drugs normally administered in varying

strengths.

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Drug Selection For Oral Sustained Release Drug Delivery Systems:

Parameter CommentElimination half life Preferably between 0.5- 8 hElimination rate constant Required for designAbsolute bioavailability Should be 75% or moreIntrinsic absorption rate Must be greater than release rate

Biopharmaceutical parameters for drug selection

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Parameter Preferred value

Molecular weight/ size < 1000Solubility > 0.1 mg/ml for pH 1 to pH 7.8Apparent partition coefficient

High

Absorption mechanism DiffusionGeneral absorbability From all GI segmentsRelease Should not be influenced by pH and

enzymes

Pharmacokinetic parameters for drug selection

MATRIX TABLETS:

These are the type of controlled drug delivery systems, which release the drug in

continuous manner by both dissolution as well as diffusion controlled mechanisms. To

control the release of the drugs, which are having different solubility properties, the drug

is dispersed in swellable hydrophilic substances, an insoluble matrix of rigid non swellable

hydrophobic materials or plastic materials.

Advantages of matrix systems

•Very easy to fabricate in a wide range of sizes and shapes.

•Suitable for both non-degradable and degradable system.

•No danger of dose dumping in the case of rupture.

Disadvantages of matrix systems

•Not all the drugs can be blended with a given polymeric matrix.

•Water soluble drugs have a tendency to burst from the system.

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Drug Release Mechanism from Matrix Systems:

Drug Release from Hydrophilic Colloid Matrices:The classic description of the events following immersion of a matrix in aqueous media is as follows:Surface area (if water soluble) dissolves and gives a ‘burst effect’.The hydrophilic polymer hydrates and an outer gel layer is formed.The gel layer becomes a barrier to the uptake of further water and to the transfer of drug (if soluble) release occurs by diffusion through the gel layer, insoluble drug is released by erosion followed by dissolution.Following erosion the new surface becomes hydrated and forms a new gel layer.

Drug Release from Fat Matrices:

The drug embedded into a melt of fats and waxes is released by leaching and or hydrolysis as well as dissolution of fats under the influence of enzymes and pH chan-ges in the gastro intestinal tract. Fatty acids are more soluble in an alkaline rather than acidic medium. Fatty esters are more susceptible to alkali catalyzed hydrolysis than to acid catalyzed hydrolysis. Polyethylene, ethyl cellulose and glycerine esters of hydrogenated resins have been added to modify release pattern.

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Drug Release from Inert Matrices:

The release of drugs from insoluble matrices has been investigated and four

types of drug matrix systems can be considered:

•Drug molecularly dissolved in the matrix and drug diffusion occurs by a solution-diffusion

mechanism.

•Drug dispersed in the matrix and then, after dissolution of the drug, diffusion occurs via

a solution- diffusion mechanism.

•Drug dissolved in the matrix and diffusion occurs through water- filled pores in the matrix.

•Drug dispersed in the matrix and then, after dissolution, diffusion occurs through water

filled pores

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DIABETES MELLITUS

Diabetes mellitus is a metabolic disorder in which the body does not produce

or

properly use insulin. It causes disturbances in carbohydrate, protein, lipid

metabolism

and complications such as retinopathy, microangiopathy and nephropathy.

It is a group of metabolic disorders characterized by hyperglycemia. These

metabolic

disorders include alterations in the carbohydrate, protein and fat metabolisms

associated with absolute or relative deficiencies in insulin secretion or insulin

action.

The characteristics symptoms of diabetes are polyurea , polydypsia ,

polyphagia,

pruritis, unexpected weight loss..etc.

Classification of Diabetes Mellitus:

1. Insulin dependent diabetes mellitus (IDDM)

2. Non Insulin dependent diabetes mellitus (NIDDM)

3. Maturity onset diabetes of youth (MODY)

4. Gestational Diabetes

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CLASIFICATION OF ANTI-DIABETIC DRUGS

Insulin

Secretagogues

Sulfonyl ureas E.g : Tolbutamide (Orinase), Glipizide (Glucotrol)..

Meglitanides E.g. : Repaglinide ( Prandin)..

Sensitizers

Biguanides E.g. : Metformin (Glucophage)…

Thiazolidinediones E.g. : Rosiglitazone ( Avavdia)..

Alpha Glucosidase inhibitor E.g. : Acarbose ( Glucobay)..

Peptide analogues

I. Incretin mimetics

Glucagon like peptides (GLP) analogs and agonist E.g. Exenatide..

Gastric inhibitory peptide (GIP)analogs

II. DPP-4inhibitots E.g. : Vildagliptin ( Galvus)

III. Amylin analogs E.g. : Pramlinitide

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LITERATURE REVIEW

Hindustan Abdul Ahad et al., (2012) reported to prepare the Formulation of Glimepiride SR

Matrix Tablets Using Hibiscus Rosa-Sinensis Leaves Mucilage and Povidone. Various

formulations of Glimepiride tablets were prepared. The tablets were evaluated and the

optimized formulation was tested for accelerated stability studies. The in vitro dissolution

data was fitting to zero order and the release of drug followed Higuchi's release. The stability

studies revealed that the tablets retain their characteristics even after stressed storage

conditions. it was concluded that the dried Hibiscus mucilage and Povidone combination can

be used as an effective matrix forming material for making SR matrix tablets of Glimepiride.

Mohd Azharuddin et al.,(2011) reported to prepare Formulation And Evaluation of CR Matrix

Tablets of Antihypertensive Drug Using Natural And Synthetic Hydrophilic Polymers. Tablets

were prepared by direct compression method using different drug: polymer concentration.

FT-IR and DSC study revealed no chemical interaction between drug and polymers. Pre and

post compression parameters complied with pharmacopoeial limit for the tablets. In-vitro

release studies was performed and the results indicates that matrix tablet (F9) containing

50% w/w blend of natural and synthetic polymer has better CR for a period of 24 hr.6/12/2012

DRK.L.Senthilkumar et al.,(2011) reported to prepare the Metformin Hcl tablets by using different

polymers like HPMC K 100M,HPMC K15 with different ratios. Tablets were prepared by wet

granulation technique. Finally It is concluded that formulation of sustained release tablet of

Metformin containing 13 % HPMC K100 with binder PVP K30 as an optimized formulation of

sustained release tablets for 10 hour release as it fulfils all the requirements for sustained release

tablets.

Harsha V. Patel et al., (2009) reported to prepare the sustained release matrix tablets of

Metformin Hcl. The tablets were prepared by the non-aqueous wet granulation method. Isopropyl

alcohol solution of polyvinylpyrrolidone (PVPK30) was used as granulating agents along with

hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC-K15) and locust bean

gum (LBG). The results of dissolution studies indicated that formulation of (HPMC: LBG, 200:30 mg)

could extend the drug release up to 8 hours. The successful formulation of the study, exhibited

satisfactory drug release was compared with the marketed formulation (Obimet SR™) and showed

very close to release profile which suggests sustained release profile.

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AIM

To prepare and evaluate the Sustained release matrix tablets of an anti diabetic drug of Vildagliptin(50mg)

OBJECTIVES

• To study the preformulation factors such as melting point, compatibility studies, etc.• To formulate a sustained release composition which releases drug over a time period of about 24 hours. • To develop a physicochemical stable dosage form.• To develop a in vitro dissolution profile of all formulations.• To evaluate the optimized formulation by establishing drug release kinetics using various dissolution models.

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PLAN OF WORK

Selection of the drug

Selection of excipients

Drug- excipient compatibility by FT-IR

Pre-compression evaluation

compression

Angle of repose

Bulk density

Tapped density

Hausner’ ratio

Carr’s index

Post compression evaluation

Thickness of Tablet

Hardness

Weight Variation

Friability

Drug Content

Dissolution time

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S. No. NameCategory Suppliers of

Material

1Vildagliptin Hypoglycaemic agent Affine Chemicals

Ltd.

2MCC IP(Avicel PH

101) Diluent

Ran Q Remedies

3HPMC K 100LV Drug release retarding

polymer Dow Chemicals

4HPMC K 15M Drug release retarding

polymer Dow Chemicals

5HPMC K 100 M Drug release retarding

polymer Dow Chemicals

6HPMC K4M Drug release retarding

polymer Dow Chemicals7 Povidone K 30 Binding agent Basf8 MCC IP(PH 102) Diluent Ran Q Remedies9 Talc Glidant Aravelli pvt.Ltd.

10Magnesium

Stearate Lubricant Amshi Drug and

Chemicals11 Water Vehicle

List of materials used

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DRUG PROFILE

Chemical name: (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine- 2-carbonitrile

Molecular Formula : C17H25N3O2

Molecular Weight : 303.399

Chemical structure :

6/12/2012

Description : A white or slightly yellow colour powder.

Melting Point : 150oC.

Solubility : freely soluble in water and organic solvents.

Therapeutic Category : dipeptidyl peptidase-4(DPP-4),

anti diabetic agent.

Mechanism of Action : Vildagliptin inhibits dipeptidyl peptidase-4 (DPP-4). This in

turn inhibits the inactivation of GLP-1 by DPP-4, allowing GLP-1 to potentiate the

secretion of insulin in the beta cells.

It inhibits the inactivation of GLP-1 and GIP by DPP-4,allowing GLP-1 and

GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon

release by the alpha cells of the islets of Langerhans in the pancreas.

GIP - glucose dependent insulinotropic polypeptide

GLP-1 -glucagon like peptide1

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Absorption:

The absolute bioavailability is 85%.

Distribution :

The plasma protein binding of vildagliptin is low (9.3%).Metabolism:

The major metabolite (LAY 151) is pharmacologically inactive and is the

hydrolysis product of the cyano moiety, accounting for 57% of the dose,

followed by the amide hydrolysis product (4% of dose).

Elimination :

The half-life after i.v administration is - 2 hours.

The half-life after oral administration is -3hours.

Dose: 50-100 mg daily once

6/12/2012

LIST OF EQUIPMENTS USED

Compression Machine Cadmach

Electronic BalanceSartorius

Fluidized Bed Dryer Betochem

Multi Mill Betochem

Vernier Caliper Mitutoyo Corps

Tablet Friability TesterLabindia-Ft1020

Tablet Hardness Tester

Monsanto type

Karl Fischer Apparatus Labindia

Dissolution Test Apparatus Labindia-Ds 8000

Uv-Visible Spectrophotometer Labindia-Uv 3200 Double Beam Spectrophotometer

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S.No Properties Description

1. Color White to slightly yellowish crystalline powder2. Odor Characteristic 3. Taste Metallic

Organoleptic characteristics

4. Melting point 150⁰C

PRE FORMULATION STUDIES

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Drug- excipient compatibility studies by FT-IR:

2mg drug+ 200mg KBr

Mix well

Pellet preparation

Sample cellspectra were recorded over the wave number of 4000 to 400cm-1.

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Drug-Excipient compatibility studies by FT-IR

Drug-Excipient compatibility studies by FT-IR

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MANUFACTURING PROCEDURE:Weigh accurate amounts of Vildagliptin+pH101+polymers HPMC(K15M,K100M,K4M& K100LV) mix for 5 min and sieved through 40 mesh preparation of binding solution(PVP K-30+water) preparation of wet mass(binding solution +mixed ingredients) sieved through 16 mesh Dry the wet granules at 60⁰C until LOD is 1-3 % w/w add pH102 to the granules dried granules were mixed with talc, magnesium stearate (sieved through 60 mesh) finally compress the tablet.

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INGREDIENTS

(mg/tab)

F1 F2 F3 F4 F5 F6 F7 F8

Vildagliptin 50 50 50 50 50 50 50 50

MCCpH101 130 130 130 130 130 130 130 ―HPMC K 100LV ― ― ― 120 ― ― 50 148

HPMC K 15M ― 120 ― ― 50 ― ― 100HPMC K 100 M ― ― 120 ― ― 50 ― ―

HPMC K4M 120 ― ― ― 90 90 90 32Povidone K 30 12 12 12 12 12 12 12 12

MCCpH 102 20 20 20 20 20 20 20 20Talc 4 4 4 4 4 4 4 4

MagnesiumStearate

4 4 4 4 4 4 4 4

Water q.s q.s q.s q.s q.s q.s q.s q.s

340 340 340 340 360 360 360 370

Formulations of Vildagliptin matrix tablets (50mg tablet)

Total wt (mg)

6/12/2012

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PRE COMPRESSION PARAMETERS

Angle of repose

Bulk density

Tapped density

Compressibility index

Hausner’s ratio

S. No

Formulation code

Bulk Density (g/ml)

Tapped Density (g/ml)

Compressibility Index

(%)

Hausner’s Ratio

Angle of repose

(⁰)

1 F-1 0.48±0.02 0.625±0.1 21.23±0.21 1.32±0.14 38.5±0.23

2 F-2 0.583±0.15 0.745±0.21 23.60±0.16 1.27±0.05 38.5±0.15

3 F-3 0.490±0.12 0.635±0.31 22.45±0.31 1.33±0.08 37.2±0.26

4 F-4 0.581±0.01 0.714±0.14 16.67±0.25 1.2±0.16 36.5±0.09

5 F-5 0.654±0.21 0.802±0.26 15.07±0.31 1.19±0.21 35.4 ±0.21

6 F-6 0.694±0.09 0.834±0.09 16.09±0.16 1.21±0.18 34.5±0.19

7 F-7 0.510±0.06 0.641±0.28 17.74±0.17 1.22±0.22 35±0.17

8 F-8 0.582±0.01 0.714±0.13 12.45±0.13 1.15±0.24 32.5±0.14

Pre compression parameters

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Compression parameters

Description White, Round biconvex tablets debossed with R on one side and F8 on other side

Tooling 13.10*6.50 mm,Round shape biconcave punches

Weight of 10 tablets (g) 3.7

Weight of individual tablet (mg) 370.000±5% (340.00-370.000)

Hardness(k p) NLT 3 (6-7)

Thickness (mm) 5.50±0.2 (5.48-5.52)

Friability % NMT 1%

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Post compression parameters:

Thickness of Tablet

Weight variation test

Hardness

Friability

Water content

Assay

Dissolution studies

Batch code

WeightVariation(mg)

n=20

Thickness(mm)n=10

Hardness(Kg/cm²)

n=5

Friability(%w/w)

n=10

Assay(%)n=5 Water

content(%)

F1 340±3.01 5.52±0.2 6.5±0.02 0.15±0.01 96.5±0.9 6.39±0.01F2 340±2.89 5.48±0.2 7.0±0.2 0.18±0.01 96.0±1.8

6.35±0.21

F3 340±3.05 5.5±0.2 6.5±0.2 0.21±0.01 95.5±1.56.45±0.15

F4 340±2.98 5.52±0.2 6.8±0.2 0.19±0.01 105±2.16.58±0.21

F5 360±3.00 5.48±0.2 6.9±0.02 0.34±0.01 97.5±1.46.15±0.18

F6 360±2.95 5.52±0.2 6.9±0.2 0.19±0.02 96±0.9 6.38±0.24F7 360±2.99 5.48±0.2 7.0±0.01 0.22±0.01 98±0.51 6.55±0.09

F8 370±2.97 5.52±0.2 7.1±0.2 0.21±0.01 99.8±0.84 6.13±0.16

Physical properties of sustained release matrix tablets of vildagliptin

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The λmax of vildagliptin was 245 nm.

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Calibration curve with pH 6.8 phosphate buffer

S.No Concentration (μg/ml)

Absorbance

1. 0 0

2. 2 0.189

3. 4 0.375

4. 6 0.539

5. 8 0.756

6. 10 0.923

Results of calibration curve

0 2 4 6 8 10 120

0.2

0.4

0.6

0.8

1R² = 0.999086499271371

concentration(μg/ml)

abso

rban

ce

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Apparatus USP type II (Paddle)

Type of medium Phosphate buffer pH 6.8

Sampling

time intervals(hr)

1, 4, 8, 12, 16, 20 & 24

λmax245nm

In-vitro Dissolution studies:

Bowl Temperature - 37°C

Bath Temperature - 40°C

Stir speed - 50 rpm

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S.No Time(hr)

F1 F2 F3 F4 F5 F6 F7 F8

1. 1 5.6±0.5 6.7±0.4 3.5±0.3 30.5±1 5.8±0.4 4.9±0.4 5.5±0.5 6.9±0.5

2. 4 32.2±1.3 28±1.1 19.9±0.8 65.1±1.2 30.1±1.4 23.9±1.1 30.7±1.4 28.4±1.1

3. 8 46.3±1.6 36.6±1.5 35.2±1.8 86.9±1.9 38.4±1.1 31.5±0.7 52.5±1.2 44.6±1.5

4. 12 55.2±0.8 49.6±1.9 42.4±1.3 95.4±0.6 49.3±1.1 38.9±1.2 69.1±1.8 58.9±1.1

5. 16 72.4±0.5 58±0.7 46.7±1.5 99±1.1 57±1 43.6±1.5 81.5±0.8 72.9±0.9

6. 20 80.8±2 67.2±0.8 50.1±1 - 66.7±1.9 57.5±0.8 99.4±0.8 87.5±0.6

7. 24 85.3±1.3 73.2±2.3 55.6±1.3 - 71.1±0.4 62.2±1.3 - 98.6±1

Cumulative percentage drug release profile of all formulations

6/12/2012 n=3 , ±=S.D

Graphs of Cumulative percentage drug release of all formulations

6/12/2012

0

10

20

30

40

50

60

70

80

90

0 5 10 15 20 25 30

%C

DR

Time(hrs)

Cumulative drug release of F1,F2,F3

F1

F2

F3

%CDR of F4,F5,F6

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time(hrs)

Series1

Series2

Series3

%CDR of F7, F8

0

20

40

60

80

100

120

0 5 10 15 20 25 30

Time (hrs)

F7

F8

Order of drug release:

Zero order

First order

0 5 10 15 20 25 300

20406080

100120

R² = 0.985095866985192

TIME(Hr)

% O

F D

RUG

REL

EASE

0 5 10 15 20 25 300

0.5

1

1.5

2

2.5

R² = 0.81583215381611

TIME(Hr)

Log

% D

RUG

REM

AIN

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Mechanism of drug release:

Higuchi Plot of Diffusion Kinetics :

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.50

20

40

60

80

100

120

R² = 0.994041623661288

SQUARE ROOT OF TIME(Hr)

DRU

G RE

LEA

SE%

0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.60

0.5

1

1.5

2

2.5

R² = 0.990472440763282

LOG TIME (Hr)

LOG

% C

DR

0 5 10 15 20 25 300

1

2

3

4

5R² = 0.873756160886899

TIME(Hr)

CUBE

RO

OT

OF

%D

RUG

REL

EASE

Korsemeyer peppas Diffusion kinetics

Hixon-crowell Diffusion kinetics

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SUMMARY

• Eight formulations were developed by different grades of HPMC (K100 LV,

K15M,K4M and K100M) by wet granulation technique.

• The preformulation studies like organoleptic properties, melting point were carried

out.

• The drug-excipients compatibility studies were conducted by using FTIR, there was

no interaction between drug and excipients.

• The calibration curve was prepared in pH 6.8 phosphate buffer, the λmax was found to

be 245nm.

• The developed formulations were evaluated for various pre-compression and post-

compression parameters.

• The invitro dissolution profile was conducted to all formulations.

• Among all formulations,F8 was found to be the most suitable sustained release

formulation.

• The best linearity was found in zero order release and mechanism of release was

fitted to Higuchi diffusion.6/12/2012

CONCLUSION

Vildagliptin is used for the treatment and relief of diabetes mellitus-type II.

Drug release from the matrix was found to depend on the combination of

polymer concentration, where as the polymer concentration was employed from

20-50%w/w of the average tablet weight.

HPMC K100LV, HPMC K15M, HPMC K4M required to channelize the drug release

was optimized to 95 to 99%.

In conclusion, a stable sustained release matrix tablet formulation of

Vildagliptin was successfully developed and in vitro drug release pattern

up to 24 hours.

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Dekker, (2nded) INC, and New York. 1987:29.

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6. Ho WH and Lee HLV. Controlled Drug Delivery Fundamentals and Applications: Design

and fabrication of oral controlled release drug delivery system, (2nded) MarcelDekker,

INC, New York. 1987:373-420.

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THANK YOU