international journal of innovative pharmaceutical sciences ......1d.archana jyothi*, 2ch.s.vijaya...

RESEARCH ARTICLE Jyothi et.al / IJIPSR / 2 (11), 2014, 2669-2690

Department of Pharmaceutics ISSN (online) 2347-2154

Available online: www.ijipsr.com November Issue 2669

FORMULATION AND EVALUATION OF ORAL THIN FILMS

CONTATING SAXAGLIPTIN

1D.Archana Jyothi

*,

2Ch.S.Vijaya Vani,

3Dr.V.Uma Maheshwar Rao

Department of Pharmaceutics, CMR College of Pharmacy, Kandlakoya, Medchal Road,

Hyderabad-501401INDIA

Corresponding Author

D.Archana Jyothi

Department of Pharmaceutics

CMR College of Pharmacy, Kandlakoya, Medchal Road,

Hyderabad-501401, INDIA

Email: [email protected]

Mobile: +91 8125327241

International Journal of Innovative

Pharmaceutical Sciences and Research www.ijipsr.com

Abstract

The purpose of the present investigation was to formulate and develop RDF of Saxagliptin for oral use

and deliver maximum amount of the drug in shortest duration of time with most comfort to the patient.

Saxagliptin is an oral antidiabetic drug belongs to the class of gliptins and is a dipeptidyl peptidase

enzyme inhibitor. Various grades of HPMC(E3 LV,E5 LV,E15 LV) as film forming polymers, PEG 400

as plasticer, different flavours (lemon flavor ,passion fruit flavour) Aspartame as sweetening agent,

Citric acid as saliva stimulating agent were used in the formulation of rapidly dissolving films. FTIR

Studies show no incompatability among drug and excipients.15 different formulations were prepared by

using solvent casting method. The prepared formulations were evaluated for taste, in-vitro

disintergration and dissolution. Other parameters measured for evaluation of RDF include mechanical

properites % elongation and elastic modulus study. The optimized batch E9 contanting HPMC (E3 LV),

PEG 400, Aspartame had acceptable characteristics in-vitro disintergration time is 25 sec and in-vitro

dissolution drug realese in 2 min is 98% and taste masking properties. ESEM study was also carried out to study the surface morphology.

Keywords: Saxagliptin, HPMC, Flavours, PEG 400.




INTRODUCTION

Rapidly dissolving dosage forms (RDDF) have recently acquired great importance due to their

properties such as quick disintegration and dissolution, obviating need of water for disintegration

and especially suitable for pediatric and geriatric patients. Orally disintegrating tablets (also called

quick disintegrating tablets, mouth dissolve tablets) are the most common and widely used rapidly

dissolving dosage form [1]. Fast-dissolving drug delivery was pioneered by scientists at Wyeth

Laboratories in the UK during the late 1970s, which resulted in patenting of the “Zydis” drug

delivery system. Fast-dissolving drug delivery systems can be manufactured by a variety of

technologies, including direct compression, wet granulation, freeze drying, spray drying, vacuum

drying and use of super disintegrants [1]

Rapidly dissolving films (RDF)

Oral film strips have hit the mainstream in the last few years as a new way of freshening the

breath. The wafers are slipped into the mouth and dissolve quickly to release the mint flavour

(Pfister W,Ghosh T 2005).[2,3]. The product attributes that a patient today seeks in a dosage form

are-

Better portability

Ease and accuracy of dosing

Overall convenience

These films generally dissolve within seconds to release the active agents but can be modified to

release the drug more slowly depending upon film thickness and selection of the polymer matrix.

A film or strip can be defined as a dosage form that employs a water dissolving polymer which

allows the dosage form to quickly hydrate, adhere and dissolve when placed on the tongue or in

the oral cavity to provide rapid local or systemic drug delivery. Drug release may be either quick

or slow by varying the rate of dissolution of the films. The breath freshening strip was created by

Pfizer‟s Warner-Lambert‟s consumer healthcare division, which launched Listerine PocketPaks™

in 2001. Chloraseptic relief strips were the first oral thin film product to incorporate a drug and

were introduced in the United States in September, 2003 by Prestige Brands international for

relief of sore throat. Zengen Inc developed this new delivery technology, which is a medicated

oral strip structured as a proprietary bilayer system. These films typically contain water soluble

hydrocolloids such as HPMC, pullulan, pectin, carboxymethylcellulose, an effective dose of

active agent, other additives such as flavoring agents, plasticizers and preservatives. The




disintegration and dissolution characteristic of thin film is dependent on thickness and

combination of hydrocolloids. RDF are already being used in breath freshening product

introductions from Warner Lambert and Wrigley's in the USA and Europe, and Boots in the UK,

as well as vitamin products. Consumers have now been exposed to this concept through the

introduction of multiple breath-freshening products introduced over the past 2 years, and the trend

is now towards developing over the counter (OTC) and prescription products in this delivery

form. The delivery system is simply placed on a patient‟s tongue or any oral mucosal tissue.

Instantly wet by saliva, the film rapidly hydrates and adheres onto the site of application. It then

rapidly disintegrates and dissolves to release the medication for oramucosal absorption or, with

formula modifications, will maintain the quick-dissolving aspect but allow for gastrointestinal

absorption to be achieved when swallowed (Vollmer U,2006, Corniello CM,2006). [4-12]

The benefits of film over conventional delivery systems are numerous:

Faster absorption into the bloodstream;

More portable than syrups and tablets;

Easy to administer;

More cost-effective than conventional tablet solutions.

The key advantage for rapidly dissolving film is patient compliance and convenience.

The main drawback is with drug loading. Drug loading is generally limited to roughly 20mg. This

problem can be addressed by increasing the thickness of the strip, but that in turn may change the

dosage form to slowly dissolving film. But drug companies have been interested in this

technology as it provides fast, accurate dosing that is expected to increase compliance,

particularly among children. There is no need for water or measuring, and upon melting, the dose

of medicine is swallowed. The likely candidates for rapidly dissolving films or oral thin films are

nicotine replacing its transdermal delivery, antiulcer drug and antihistamine products. Prescription

products, antipsychotic and sleeping disorder drugs are the potential candidates [4-12].

The Aim of the Present study was to formulate and develop RDF of Saxagliptin for oral use and

deliver maximum amount of the drug in shortest duration of time with most comfort to the

patient. Saxagliptin is an oral antidiabetic drug belongs to the class of gliptins and is a dipeptidyl

peptidase enzyme inhibitor.

The RDF of Saxagliptin using various grades of HPMC E LV were prepared by solvent casting

method




MATERIALS AND METHOD

Materials used

Saxagliptin, HPMC E3 LV,HPMC E5 LV, HPMC E15 LV, Sucralose, Citric acid anhydrous,

Menthol, Polyethylene glycol 400, Aspartame, Passion fruit and lemon flavours

Methodology

Analytical Methods

Standard Graph of Saxagliptin

Preparation of calibration curve of Saxagliptin

Standard plot of Saxagliptin was prepared using pH phosphate buffer. 100 mg of Saxagliptin was

weighed and transferred into volumetric flask. To this add small quantity of pH 6.8 phosphate

buffer to dissolve the drug and then the solution was made up to 100 ml using pH phosphate

buffer. This is stock solution (A). From stock solution (A), 1 ml was transferred into 100 ml

volumetric flask and made up to the mark. This is stock solution (B). From stock solution (B),

appropriate dilutions 2, 4, 6, 8, 10 were made and absorbance was measured by using UV-

Spectrophotometer at 208 nm.

Preformulation studies:

Preformulation testing is the first step in the rational development of dosage forms of a drug

substance. It can be defined as „investigation of physical and chemical properties of the drug

substance alone and when combined with excipients. These studies should focus on those

physicochemical properties of the new compound that could affect drug performance and

development of an efficacious dosage form.(Solubility Analysis and Melting Point)

Drug-Excipient Compatibility Studies

FTIR interaction studies

Drug-excipient compatibility study was performed by Fourier transform infrared (FTIR)

Spectroscopy. In the preparation of formulation, the drug and polymers were in close contact

with each other, which could leads to instability of drug. Thus preformulation studies regarding

drug-polymer interaction is very important in selecting appropriate polymers.

Method of preparation of rapidly dissolving films and its evaluation

Preparation of rapidly dissolving films (RDF)

The RDF of Saxagliptin using various grades of HPMC E LV were prepared by solvent casting

method. An aqueous solution of the polymer HPMC E LV was prepared in distilled water.




Saxagliptin was added to the aqueous polymeric solution. This was followed by addition of

menthol which was previously dissolved in ethyl alcohol (95%) and plasticizers like PEG 400 or

glycerol. Sweeteners like aspartame and sucralose were also added to the above solution. Citric

acid and flavour were also mixed with it. The solution was casted on a glass petridish (diameter 9

cm) and dried at room temperature for 24 hr.

The film was carefully removed from the petridish, checked for any imperfections and cut into the

required size to deliver the equivalent dose (2 x 2 cm2) per strip. The samples were stored in a

desiccator at relative humidity 30-35 % until further analysis. Film samples with air bubbles, cuts

or imperfections were excluded from the study.

The calculation for the strips of RDF to be prepared is shown below-

Diameter of petridish = 8.97 cm, Surface area of petridish = 63.34 cm2, Number of strips

obtained =16

Table 1: Composition of Oral Thin Films Contating Saxagliptin

Ingredi

ents/Ba

tch

F

1

F

2

F

3

F

4

G

1

G

2

G

3

G

4

E

1

E

2

E

3

E

4

E

5

E

6

E

7

E

8

E

9

E

1

0

E

1

1

E

1

2

E

1

3

E

1

4

E

1

5

E1

6

Saxagli

ptin 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5

HPMC

E5 LV

2

0

0

2

0

0

4

0

0

4

0

0

- - - - - - - - - - - - - - - - - - - -

HPMC

E15 LV - - - -

2

0

0

2

0

0

4

0

0

4

0

0

- - - - - - - - - - - - - - - -

HPMC

E3 LV - - - - - - - -

2

0

0

2

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

4

0

0

40

0

Menthol -

7

.

2

-

1

1

.

2

-

7

.

2

-

1

1.

2

- 7.

2 -

1

1.

2

-

1

1.

2

-

1

1.

2

-

1

1.

2

-

1

1.

2

- 2

8

2

8 28

Glycero

l - - - - - - - - - - - -

1

1

2

1

1

2

2

2

4

2

2

4

- - - - - - 5

6

11

2

PEG400 - - - - - - - - - - - - - - - -

1

1

2

1

1

2

2

2

4

2

2

4

5

6

5

6 - -

Asparta

me

(10%)

- - - - - - - - - - - - - - - - - - - - - 5

6

5

6 56

Distilled

Water

(ml)

1

0

1

0

2

0

2

0

1

0

1

0

2

0

2

0

1

0

1

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0

2

0 20




Evaluation of RDF

The RDF were evaluated for the following parameters-

1. Measurement of mechanical properties of the RDF

2. In-vitro disintegration studies

3. In-vitro dissolution studies

4. Environment Scanning electron microscopy (ESEM)

5. Taste evaluation

Measurement of mechanical properties of the film

Mechanical properties of the RDF were evaluated using Lloyd universal testing machine, UK

with load cell range 0-40 N. Films of dimension 10 x 2.5 cm2 and free from physical

imperfections were used for the study. The films were held between two clamps at distance of 5

cm. The RDF were pulled by the clamp at the rate 50 mm/min. Measurements were done in

triplicate for each batch.

The mechanical properties tensile strength, elastic modulus and % elongation were calculated for

the RDF from the above measurements.

Tensile strength is the ratio of maximum stress applied to a point at which the film specimen

breaks and can be computed from the applied force at rupture to the cross sectional area of the

fractured film as a mean of three measurements and described in the equation-

Tensile strength = Force at break (N)

Initial cross sectional area of the film (mm2)

Elastic modulus is the ratio of applied stress and corresponding strain in the region of

approximately linear proportion of elastic deformation on the load displacement profile and

calculated using the following equation-

Elastic modulus = Force at corresponding strain (N) x 1

Cross-sectional area of the film corresponding strain

Percentage elongation was calculated by the following equation-

= Increase in length x 100

Original length

Study of Physical properties:

Weight variation:

Three films each of 1 cmwas cut at three different places from the casted film were taken and




weighed individually on analytical electronic balance and weight of each film was noted and

weight variation was calculated. It was found to be in a range of 53.05±0.43 to 150.68 ± 0.33. The

weight of all the films was found to be uniform. From all the formulations it has been observed

that increase in concentration of polymer increases weight of the film. Weight variation is an

important parameter to consider as any variation in the weight of film leads to under medication or

over medication.

Thickness:

Thickness of films was measured by screw gauge at different locations. It is essential to

determine uniformity in the thickness of the thickness of the film as this is directly related to

accuracy of dose in films. The average thickness and standard deviation were reported.

Moisture Uptake:

The film sample was weighed and placed on a preweighed stainless steel wire mesh. The wire

mesh was then submerged in a Petri dish containing 20 ml distilled water. Increase in weight of

the film was determined at regular time intervals until a constant weight was obtained. The

hydration ratio of the film was calculated using following formula:

Where,

Wt = Weight of film at time„t‟

W0 = Weight of film at „zero‟ time.

Moisture Loss:

The percent moisture loss was determined by placing prepared film in desiccators containing

anhydrous calcium chloride. After three days, the film was taken and reweighed. The percent

moisture loss was calculated using following formula:

Where,

W0= Initial weight

Wt = Final weight.

In-vitro disintegration studies

Disintegration time study was slightly modified to mimic the in-vitro and in-vivo conditions. For

the study, film as per the dimensions (2 x 2 cm2) required for dose delivery were placed on a




stainless steel wire mesh containing 10 ml distilled water. Time required for the film to break and

disintegrate was noted as in- vitro disintegration time. Since, the film is expected to disintegrate in

the mouth in presence of saliva, only 10 ml of medium was used.

In-vitro dissolution studies

The in-vitro dissolution studies were conducted using three media namely distilled water(500 ml),

simulated gastric fluid (900 ml) and simulated saliva (500 ml). The dissolution studies were

carried out using USP dissolution apparatus XXIV (Electrolab, Mumbai, India) at 37 + 0.5°C and

at 50 rpm using specified dissolution media. Each film with dimension (2 x 2 cm2) was placed on

a stainless steel wire mesh with sieve opening 700μm. The film sample placed on the sieve was

submerged into dissolution media. Samples were withdrawn at 2, 5, 10, 15, 30, 60, 120 min time

intervals and filtered through 0.45μmWhatman filter paper and were analyzed

spectrophotometrically at 208 nm (UV 2450Shimadzu, Japan). To maintain the volume, an equal

volume of fresh dissolution medium maintained at same temperature was added after withdrawing

samples. The absorbance values were converted to concentration using standard calibration curve

previously obtained by experiment. The dissolution testing studies were performed in triplicate

for all the batches.

Environment scanning electron microscopy (ESEM)

The surface morphology of the film forming excipient, drug and the film was observed using

Environment scanning electron microscope (Philips, XL 30, The Netherlands). The film sample

was placed in the sample holder and the photomicrographs were taken using tungsten filament as

electron source and GSE detector at 65x and 350x magnification.

Taste evaluation

Taste acceptability was measured by a taste panel (n=6) with 10 mg drug and subsequently film

sample containing 10 mg drug held in mouth until disintegration, then spat out and the bitterness

level was then recorded. The volunteers were asked to gargle with distilled water between the

drug and film sample administration. The scale for the bitterness study was as follows:

+ = very bitter,

++ = moderate to bitter,

+++ = slightly bitter,

++++ = tasteless/taste masked

+++++ = excellent taste masking




RESULTS AND DISCUSSIONS

Analytical Methods

Determination of Saxagliptin:

It was performed in pH 6.8 phosphate buffer.

Fig. 1: λ max of Saxagliptin

The drug solution was subjected to scanning between 200 to 400nm and absorption maximum

was determined. The λ max of saxagliptin was found as 208nm and that was selected for analysis.

Standard graph for Saxagliptin in 6.8 pH phosphate buffer at 208nm.

The standard graph of Saxagliptin in pH 6.8 phosphate buffer showed a good linearity with r2 of

0.9997 in the concentration range of 0-10 µg/ml.

Table 2: Standard graph of Saxagliptin Fig.2: Standard graph of Saxagliptin

Concentration

(µg/m)

Absorbance

(nm)

0 0

2 0.146

4 0.297

6 0.449

8 0.599

10 0.736

Preformulation studies

Preformulation studies for the selected drug Saxagliptin include test for identification

(examination of physical appearance, melting point determination, and IR spectroscopy) and

solubility studies.

Tests for Identifications:




Physical appearance: Saxagliptin was found to be a white to off white crystalline powder, non-

hygroscopic in nature.

Melting point: Saxagliptin was found to be melting at 228°C

Solubility Analysis:

A definite quantity (5 mg) of drug was dissolved in 5 ml of each solvent at room temperature. The

solubility was observed only by the visual inspection.

Table 3

S.No Solvents Solubility

1 Distilled water Sparingly soluble

2 Ethyl acetate Slightly soluble

3 Methanol, ethanol, IPA, Acetonitrile; PEG 400 Soluble

Drug Compatibility Studies

FT-IR-spectra: The characteristic peaks were determined by FT-IR spectra, which identified the

purity of drug.

Compatibility Studies:

FTIR interaction studies.

As described in the methodology section, drug- polymer compatibility studies were carried out

using Fourier Transform Infrared Spectroscopy to establish any possible interaction of Saxagliptin

with the polymers used in the formulation. It was expected that the intermolecular hydrogen

bonding between hydroxyl groups of HPMC and amino (-NH) groups of Saxagliptin might be

involved. In order to have better understanding of type of interaction between the blended

polymers, FTIR spectra of all different combinations of polymers with the drug were studied.

The results indicated that the characteristic absorption peaks due to pure Saxagliptin have

appeared in the formulated FDF‟s, without any significant change in their position after

successful formulation, indicating no chemical interaction between Saxagliptin and polymers.

Fig. 3: FTIR Spectra Saxagliptin




Fig. 4: FTIR Spectra of optimized formulation

Preliminary trials

The preliminary trials were undertaken for designing the RDF wherein the effects of various

grades of HPMC namely E3, E5 and E15 LV on the characteristics of the films were assessed. All

the three grades were varied in a concentration range of 1 to 4% w/v. Initial trials were taken to

check the suitability of various grades of HPMC E LV for the formation of RDF without addition

of the drug. In-vitro disintegration time studies as shown in Table 7.3 suggested that films

prepared using all 3 grades of HPMC E LV had in-vitro disintegration time below 30 sec and was

thus, acceptable for further formulation.

Table 4: In-vitro disintegration time of blank preliminary batches

In-Vitro Disintegration Time (Sec)

Grade/Concentration 1% 2% 3% 4%

HPMC E3 LV 7.5 (1E) Very Thin, Brittle 12.5 (2E) 12.5 (3E) 22.5(4E)

HPMC E5 LV 7.5 (1F) Very Thin, Brittle 12.5 (2F) 25 (3F) 25(4F)

HPMC E15 LV 12.5 (1G) Very Thin, Brittle 17.5 (2G) 25 (3G) 30(4G)

Figures in bracket indicates batch number; n=3.

Films prepared at 1% w/v concentration using all the three grades were very thin, brittle and were

easily broken. Films with 2% to 4% w/v concentration for all three grades were clear, transparent

and easily separated. Therefore, further batches containing the drug were formulated using 2% to

4% w/v of HPMC E LV grades.

Table 5: Preliminary trials using HPMC E5 LV as a polymer

Ingredients*/Batch F1 F2 F3 F4

Saxagliptin 5 5 5 5

HPMC E5 LV 200 200 400 400

Menthol - 7.2 - 11.2

Distilled Water (ml) 10 10 20 20

In-Vitro Disintegration Time (Sec) - - 45 45

Film Property Brittle, Very Thin Brittle, Very Thin Good Good




*All quantities are in mg, Batch size 16 strips

The RDF containing 200 mg HPMC E5 LV formulated with Saxagliptin resulted in highly brittle

films compared to films containing 400 mg HPMC E5 LV which were separated easily. Thus,

films containing 400 mg HPMC E5 LV were further evaluated for various parameters. The reason

for the brittle film formation in the presence of the drug using 200 mg HPMC E5 LV might be

insufficient amount of sample required for film formation. The in-vitro disintegration time of

batches containing 400 mg HPMC E5 LV was acceptable i.e. 45 sec. Trials were also taken with

the same formulation in presence (containing 0.7 mg menthol per strip) and absence of menthol as

a cooling agent.

Table 6: In-vitro dissolution profile of batch F3 and F4 in distilled water

Time (min) Cumulative % Drug release

F3 F4

0 0 0

2 59.01 60.72

5 75.51 70.66

8 92.62 89.98

10 100 85.64

15 - 96.77

30 - 100

60 - -

In-vitro dissolution study of batch F3 and F4 was carried out in distilled water. It was observed

that complete drug released in 10 min and 30 min respectively for batch F3 and F4.

Table 7: Formulation trials containing HPMC E15 LV as a polymer

Ingredients*/Batch G1 G2 G3 G4

Saxagliptin 5 5 5 5

HPMC E15 LV 200 200 400 400

Menthol (2%) - 7.2 - 11.2


In-Vitro Disintegration Time (Sec) 45 45 95 95

Film seperation Good Good Good Good


G1 to G4 containing HPMC E 15 LV as a film forming polymer. The RDF containing 200 mg

HPMC E15 LV formulated with Saxagliptin resulted in films with good quality and acceptable in-

vitro disintegration time (45 sec). Films with 400 mg HPMC E15 LV resulted in higher in-vitro




disintegration time (95 sec). This might be due to delayed disintegration time with higher

viscosity grade of HPMC E LV at higher concentrations.

Table 8: In-vitro dissolution profile of batch G1, G2, G3 and G4

Time (min) Cumulative % drug release

G1 G2 G3 G4

0 0 0 0 0

2 67.63 69.26 63.95 71.78

5 76.95 73.3 69.36 77.93

8 86.02 81.8 75.55 85.98

10 91.57 90.44 82.34 89.34

15 96.24 93.86 83.06 94.96

30 100 96.53 83.17 95.93

60 99.89 100 89.51 98.52

120 - - 84.86 92.12

240 - - 100 100

Table shows in-vitro dissolution profile of batches G1 to G4. Batches G1 and G2 showed 67-69%

drug release in 2 min and 96% and 94% drug release in 15 min but as the amount of HPMC E15

LV was increased, drug release was retarded and complete drug release was observed in 4 hr.

Thus, HPMC E15 LV retarded the dissolution behaviour of rapidly dissolving films.

Table 9: Formulation trials containing HPMC E3 LV as a polymer

Ingredients*/Batch E1 E2 E3 E4

Saxagliptin 5 5 5 5

HPMC E3 LV 200 200 400 400

Menthol - 7.2 - 11.2


Total weight/Strip 22.5 22.95 35 35.7

Film separation No No No Partial


Saxagliptin when incorporated in 200 mg of HPMC E3 LV films resulted in formation of very

brittle and thin films. When Saxagliptin was incorporated in 400 mg of HPMC E3 LV, it resulted

in slightly brittle films. Thus, to improve the characteristics of the film addition of plasticizer was

found to be necessary. Various preliminary formulations E5 to E12 using 400 mg HPMC E3 LV

were prepared to check film separation property using glycerol and menthol as plasticizer.

Table 10: Formulation batches with HPMC E3 LV using glycerol


Saxagliptin 5 5 5 5

HPMC E3 LV 400 400 400 400

Menthol (2%) - 11.2 - 11.2

Glycerol 112(0.2:1) 112 224(0.4:1) 224




PEG400 - - - -


Total weight/Strip 42 42.7 42 42.7

Film seperation No No No Yes


None of the above batches resulted in good film separation property. So, further trials were

carried out using PEG 400 as plasticizer.

Table 11: Formulation batches with HPMC E3 LV using PEG 400


Saxagliptin 5 5 5 5

HPMC E3 LV 400 400 400 400

Menthol (2%) - 11.2 - 11.2

Glycerol - - - -

PEG400 112 (0.2:1) 112 224(0.4:1) 224


Film seperation Yes Yes Yes, soft Partial

Invitro disintegration time (Sec) 60 60 - -


PEG 400 at (plasticizer: polymer) ratio of 0.2:1 resulted in better elasticity than glycerol. Thus, it

could be concluded that film separation could be improved in the presence of plasticizer PEG

400. In-vitro dissolution study of batch E9 was carried out in 3 different dissolution media as

shown in Table 7.10.

Table 12: In-vitro dissolution study of batch E9

The in-vitro disintegration time of batch E9 containing 400 mg HPMC E3 LV, Saxagliptin and

PEG 400 was 25 sec. The comparative drug release of batch E9 in different dissolution medium

Time (Min)

Cumulative % Drug Release

Batch E9

PH 6.8 Phosphate Buffer 0.1N HCl Simulated Saliva

0 0 0 0

2 85.3 80.61 78.22

5 100 83.35 82.23

8 - 82.89 88.96

10 - 86.65 93.12

15 - 100 100

30 - - -




indicated 85% drug release in 2 min in pH 6.8 Phosphate Buffer, 81% drug release in 2 min in

0.1N HCl and 78% drug release in 2 minutes in simulated saliva.

Fig. 5: Comparative in-vitro dissolution profile of batch E9

Thus, it can be concluded that the viscosity grades of HPMC E LV affected the mechanical

properties, disintegration and dissolution characteristics of the RDF. The higher the viscosity of

HPMC E LV grades, there was an increase in the in-vitro disintegration and dissolution time.

Although batches containing 400 mg HPMC E5 LV and 200 mg HPMC E15 LV in presence of

drug had an in-vitro disintegration time of 45 sec, the in-vitro dissolution time was 30 min and 45

min in distilled water respectively. Batch E9 had 98% drug release in 2 min in distilled water.

Therefore, further studies were carried out using HPMC E3 LV as a polymer for the RDF

formulation trials. RDF containing Saxagliptin prepared using HPMC E3 LV also possessed

satisfactory mechanical property, in-vitro disintegration and in-vitro dissolution time and were

used for further optimization.

Taste masking of Saxagliptin films

Saxagliptin being bitter in taste, the taste masking of the films was found to be essential to

improve the patient acceptability. To improve the taste of the films, flavours and sweeteners were

incorporated in the formulation. Various amount of menthol (5% w/w of drug and polymer

amount) and sucralose (10%w/w of drug and polymer amount) at various plasticizer ratios were

added to Saxagliptin containing films.

Table 13: Formulation batches with HPMC E3 LV

Ingredients/Batch E13 E14 E15 E16

Saxagliptin 5 5 5 5

HPMC E3 LV 400 400 400 400

Menthol (5%) - 28 28 28

Aspatame (10%) - 56 56 56

Flavour - - Yes Yes




Glycerol - - 56 112

PEG400 56 56 - -


Total Weight/Strip 38.5 42.7 42 42.7

Film Separation -- -- No, Film Too soft No, Film Too soft

None of the above batches resulted in taste masking of the film. Thus, further trial batches S1 to

S4 were taken with another sweetener sucralose. This too did not result in taste masking of

Saxagliptin. As none of the above excipients resulted in complete taste masking of the film

further trials were taken using combination of sweeteners i.e. aspartame and sucralose.

Table 14: Selection of sweetener for the taste masked films

Ingredients/Batch S1 S2 S3 S4

Aspartame - - - 112

Sucralose 84 84 56 84

PEG400 - 112 112 112

Film Separation No yes Partial Yes

Invitro disintegration time(sec) 25 25 25 50

Taste Masking ++ ++ ++ +++


All batches contained 400 mg HPMC E3 LV and 5 mg Saxagliptin. All batches were formulated

in 20 ml distilled water.

Table shows that batch S4 exhibited an in-vitro disintegration time of 50 sec. The batch S4

possessed good taste masking property but was followed by bitter aftertaste.

Table 15: In-vitro dissolution of batch S4 in pH6.8 phosphate buffer, 0.1N HCl and

simulated saliva

Time (Min)

Batch S4

Cumulative % release in different medium

pH 6.8 Phosphate buffer 0.1N HCl Simulated Saliva

0 0 0 0

2 77.24 90.65 79.25

5 82.57 90.89 83.43

8 83.09 92.03 89.24

10 84.89 100 95.45

15 86.48 -- 98.38

30 90.65 -- 100

60 100 -- --

In-vitro disintegration time of batch S4 was found to be 20 sec. In-vitro dissolution study of batch

S4 in 3 different dissolution media distilled water, 0.1N HCl and simulated saliva is shown in

Table. In-vitro dissolution study of batch S4 in 3 different dissolution media pH 6.8 phosphate

buffer , 0.1N HCl and simulated saliva is shown.




Fig. 6: In-vitro dissolution study of batch S4 in 3 different dissolution media pH 6.8

Phosphate Buffer, 0.1N HCl and simulated saliva

Thus, formulation trials were carried out by using flavouring agents such as lemon and passion

fruit flavour and sour ingredients like citric acid.

Table 16: Selection of flavour for the taste masked films

Ingredients/Batch T1 T2 T3 T4

Flavour Passion fruit Lemon Passion fruit Lemon

PEG400 56 56 112 112

Citric acid 140 140 140 140

Film Separation Partial Yes Yes Yes

In-vitro disintegration time(sec) 50 50 50 50

Elasticity Good Good Very good Very good

Taste masking +++ ++ ++++ ++


All batches were formulated contained 400 mg HPMC E3 LV, 5 mg Saxagliptin, 112 mg

aspartame and 84 mg sucralose in 20 ml distilled water. Table indicates that further addition of

flavouring agents like citric acid and passion fruit flavour (T1 to T4) resulted in completely taste

masked film of batch T3. The in-vitro disintegration time was 50 sec. In-vivo disintegration time

of batch T3 was 20 sec. Addition of lemon flavour (T2 and T4) resulted in highly acidic taste of

the film which was unacceptable. Batch T3 showed good elasticity and taste masking properties.

In-vitro dissolution profile of batch T3 in different dissolution media i.e. Phosphate buffer

6.8pH,0.1N HCl and simulated saliva is shown Table 7.15.

Table 17: In-vitro dissolution profile of batch T3 in pH6.8 Phosphate buffer , 0.1 N HCl and

simulated saliva

Time (min)

Batch T3

Cumulative % release in different medium

Phosphate buffer 6.8pH 0.1N HCl Simulated saliva

0 0 0 0

2 100 95 80.31

5 - 98 86.27

8 - 98.5 91.16

10 - 100 95.86

15 - - 100

30 - - -




Fig.7: Comparative in-vitro dissolution study profiles of batch T3

Figure indicates the comparative in-vitro dissolution profile of batch T3 in different dissolution

medium. It can be concluded from the Figure that in 2 min batch T3 showed 100% drug release in

pH 6.8 Phosphate Buffer, 98% in 0.1N HCl and 80% in simulated saliva.

Environment scanning electron microscopy (ESEM)

The ESEM of HPMC E3 LV shown in Figure7.8 indicated irregular cylindrical to spherical

shaped particles at 150x magnification. Saxagliptin particles could not be seen distinct as such.

On dispersing it in acetone as shown in Figure7.9 cylindrical distinct particles could be observed

at 350x magnification. Figure 7.10 indicates optimized film at 350x magnification which was

uniform with few pores and solid particles without any striations.

Fig. 8: ESEM of HPMC E3 LV powder Fig.9: ESEM of Saxagliptin powder

at 150x magnification at 350x magnification

Fig. 10: ESEM of T3 film at 350x magnification




Study of mechanical properties

A suitable RDF requires moderate tensile strength, good percentage elongation and low elastic

modulus.

Table 18: Comparative mechanical properties of various batches

Batch Tensile Strength (N/mm2) % Elongation Elastic Modulus (N/mm2)

2E 19.49 1.82 654.6

4E 23.38 2.81 406.6

E9 9.07 8.55 162

S4 8.65 21.64 163

T3 4.22 27.69 38

Table shows the comparative mechanical properties of various formulations prepared during the

study. It can be observed that RDF containing 2% and 4% HPMC E3 LV alone i.e. batches 2E

and 4E showed extremely high tensile strength, poor % elongation values and very high elastic

modulus. The same formulation in the presence of drug and plasticizer (E9) demonstrated lower

tensile strength compared to batch 2E and 4E. The % elongation values increased and elastic

modulus values decreased. The taste masked batches S4 and T3 were found to possess acceptable

mechanical properties. The tensile strength values were in moderate range (4-9 N/m2). The %

elongation (21-28) and elastic modulus (35-165) were also satisfactory. These changes in the

mechanical properties can be attributed to the presence of plasticizer in the batches E9, S4 and T3.

Compared to films containing pullulan, HPMC E3 LV films possessed higher % elongation and

lower elastic modulus. The low % elongation value indicates brittle nature of the pullulan film.

Higher elastic modulus values indicate more toughness of pullulan containing films compared to

HPMC E3 LV films. Batch T3 showed most acceptable mechanical properties along with

complete taste masking which might be due to presence of suitable plasticizers and flavours.

Batch T3 showed most acceptable mechanical properties along with complete taste masking

which might be due to presence of suitable plasticizers and flavours.

Study of Physical properties:

Weight variation:

Three films each of 1 cmwas cut at three different places from the casted film were taken and

weighed individually on analytical electronic balance and weight of each film was noted and

weight variation was calculated. It was found to be in a range of 53.05±0.43 to 150.68 ± 0.33. The

weight of all the films was found to be uniform. From all the formulations it has been observed

that increase in concentration of polymer increases weight of the film. Weight variation is an




important parameter to consider as any variation in the weight of film leads to under medication or

over medication.

Table 19: Comparative Physical properties of various batches

Batch Thickness (µm)* Mean Weight (1*1 Film)

(mg)*

% Moisture

Uptake

% Moisture

Loss

2E 0.3±0.01 53.05 ± 0.43 12.87 0.90

4E 0.5±0.01 104.89 ± 0.12 25.7 0.33

E9 0.8±0.02 101.5 ± 0.53 21.58 0.28

S4 1.1±0.01 150.68 ± 0.33 21.79 0.74

T3 1.3±0.01 136.22±0.14 19.57 0.75

* Mean ± SD; n = 3

Moisture absorption:

Moisture absorption study was performed to check the physical integrity of films. The films were

weighed accurately and placed on a preweighed stainless steel wire mesh. The wire mesh was

then submerged in a Petri dish containing 20 ml distilled water. Increase in weight of the film was

determined at regular time intervals until a constant weight was obtained.

Moisture absorption study is an important parameter to be performed, as the presence of

moisture possesses a critical challenge on drug stability. Moisture accelerates the hydrolysis of

drug as well as facilitates reaction with other excipients, thereby affecting stability and shelf life of

the final dosage form. All the reported values were shown. And it has been observed that all the

film forming polymers HPMC E3LV, E5LVand E15LV were of hydrophilic in nature and the

obtained values were in a range of 12.87 to 25.7%.

Moisture loss:

Moisture loss study was performed to check physical stability of films at dry environment. Film

was weighed accurately and kept in desiccator containing anhydrous calcium chloride for 3 days

and films were removed and reweighed and moisture loss was calculated. The moisture loss study

gives an idea about films stability nature and ability of films to withstand its physicochemical

properties under normal conditions. It also gives an idea about hydrophilicity of film

formulations.

All the obtained values were reported. The obtained values were in a range of 0.28to 0.90.

Stability studies

The stability studies of the optimized batch T3 was carried out at 40°C/75%RH, 25°C/60%RH

and 25°C/40%RH. These films were found to be unacceptable. Films stored at 40°C/75%RH were




highly unstable within 1 month storage. Films stored at 25°C/60%RH were unstable after 2

months period by developing colour change (yellow) and becoming sticky in appearance. Films

stored at 25°C/40%RH were found to be stable for one year period. The batch was found be

acceptable visually, mechanically, with slight change in in-vitro and in-vivo disintegration time

55 sec, 22 sec respectively. The above observations indicate that temperature and humidity plays

a critical role in the stability of the rapidly dissolving films containing HPMC E3 LV as the film

forming polymer. Therefore, precautions would be required during packaging and selection of

packaging container would play a crucial role for stability of the RDF.

Table 20: Stability studies of optimized batch

Time

% of drug

dissolved in 2 min

(Distilled water)

In vitro

disintegration

time (sec)

In vivo

disintegration

time (sec)

Appearance

Initial 100 50 20 Transparent, white,

Acceptable

1Month 100 50 21 Transparent, white,

Acceptable

2Months 99 48 20 Transparent, white,

Acceptable

3Months 99 49 21 Transparent, white,

Acceptable

CONCLUSION

Rapidly dissolving films using different grades of HPMC E LV were formulated using

Saxagliptin. It was formulated especially suitable for pediatric and geriatric patients. An ideal

rapidly dissolving drug delivery system should have following properties Transportability, Ease

of handling and administration, No special packaging material and/or processing requirements,

No water necessary for application and pleasant taste. It was prepared by solvent casting

method.It was observed that type of grade of HPMC E 3 LV significantly contributed to in-vitro

disintegration and in-vivo dissolution. Higher viscosity grade of HPMC E increased in-vitro

disintegration and in-vitro dissolution. HPMC E 3 LV was found to be suitable polymer for the

formation of rapidly dissolving films. As Saxagliptin is being bitter in taste, taste masking using

combination of sweeteners, flavours and citric acid was used. The optimized batch had acceptable

characteristics which include mechanical properties, in-vitro disintegration time is 25 sec, in-vitro

dissolution drug release 100% in 2 min and taste masking properties. ESEM study was also

carried out to study the surface morphology. These present findings suggest that the formulation

contaning Saxagliptin developed disintegrate within a minute hence is potentially useful for




pediatric and geriatric patients who show unwillingness to take tablets. It can be concluded that

the RDF of Saxagliptin which can be a promising drug delivery system.

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international journal of innovative pharmaceutical sciences ......1d.archana jyothi*, 2ch.s.vijaya...

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