CSDDS

4.1 PLAN OF WORK4.1.1. Literature Survey:Detailed literature survey of drugs suitable for treatment of colon,

formulation approaches to achieve colon specific release and detailed

evaluation parameters of such systems will be studied.

4.1.2. Selection of Drugs:Drugs selection was done from the list of therapeutic agents available for

treatment of irritable bowel disease and ulcerative colitis.

4.1.3. Preformulation Study: This includes development and validation

of analytical method. The IR spectroscopy and DSC for drug excipient

compatibility studies.

4.1.4. Formulations of Colon Specific Drug Delivery Systems:Different approaches will be exploited to develop suitable formulations

for targeting the colon, which includes

pH Responsive formulations

Enzyme Responsive formulations

Time controlled formulations

4.1.5. Evaluation of formulations:The prepared formulations will be evaluated for various parameters with

regards to

Coating quality -SEM

In vitro studies – drug release by changing pH method

In- vivo studies- X ray roentography in human volunteers

4.2. MATERIALS AND DRUG EXCIPIENT PROFILE

4.2.1; Materials

Table 4.1: List of chemicals

CSDDS

Sr. No. Materials Manufacturer/supplier

1. Diclofenac sodium Aarti Pharmaceuticals

2. Eudragit FS 30 D USP Degussa India Pvt. Ltd.

3. Eudragit S100 USP Degussa India Pvt. Ltd.

4. HPMC 15 cps USP Maxim Pharmaceuticals

5. HPMC K4M, K15M USP Colorcon Asia Pvt. Ltd., Goa.

6. Lactose Anhydrous IP Maxim Pharmaceuticals

7. Sodium starch glycolate IP Signet India Pvt. Ltd.

8. Microcrystalline cellulose IP Signet India Pvt. Ltd.

9. Magnesium Stearate IP Signet India Pvt. Ltd

10. Talc IP Signet India Pvt. Ltd

11. Glyceryl Monostearate Vijay chemicals

12. Tween 80 Vijay chemicals

13. Propylene Glycol USP Vijay chemicals

14. Ethyl alcohol Anand agency

15. Isopropyl alcohol Anand agency

16. MethanolAR grade Vijay chemicals

17. Hydrochloric acidAR grade Vijay chemicals

18. Tribasic sodium phosphate Loba chem. Pvt. Ltd.

19. HPMC Colorcon India Pvt. Ltd.

20. Eudragit FS30D Colorcon India Pvt. Ltd.

21. Eudragit S100 Colorcon India Pvt. Ltd.

CSDDS

22. Eudragit RSPO Colorcon India Pvt. Ltd.

23. Amylose National starch Institute

24. Pancreatin Omkar chemicals

4.2.2 DRUG PROFILE AND EXCIPINT PROFILE:

4.2.2.1. Diclofenac Sodium

Chemical Name 2-[2-(2, 6-dichlorophenyl) aminophenyl] ethanoic

acid

Chemical Formula C14H11Cl2NO2

Chemical

Structure

Molecular Weight 296.148 g/mol

Category Analgesic and anti – inflammatory

Solubility Freely soluble in methanol, soluble in ethanol

(95%), sparingly soluble in water and in glacial

acetic acid, practically in soluble in ether,

chloroform, and toluene.

Official in USP, IP.

Pharmacokinetics Completely absorbed from the gastrointestinal

tract. It is metabolized and excreted both in urine

CSDDS

and bile.

The plasma t1/2 is ~ 2 hrs.

Protein binding: It is 99% protein bound.

Mechanism of action The diclofenac sodium

inhibit the enzyme cyclooxygenase leading to the

inhibition synthesis of prostaglandin which is

responsible for pain sensitization.

Indications Diclofenac is one of the most extensively used

NSAID’s for the treatment of rheumatoid and

osteoarthritis, ankylosing spondylitis, toothache,

dysmenorrhoea, post traumatic and postoperative

inflammatory conditions.

Contraindications Diclofenac not suggested to patients suffering from

asthma, allergic-type or urticaria.

Dose Orally or by intra – muscular injection 25 - 75 mg

CSDDS

4.2.2.2. Sodium Starch Glycolate 98

Nonproprietary

Names

BP: Sodium starch glycolate

PhEur: Carboxymethylamylum natricum

USPNF: Sodium starch glycolate

Synonyms Carboxymethyl starch, sodium salt; Explosol;

starch carboxymethyl ether, sodium salt; Tablo;

Vivastar

Chemical Name

and CAS Registry

Number

Sodium carboxymethyl starch [9063-38-1]

Functional

Category

Tablet and Capsule disintegrant.

Applications Disintegrant in solid formulations. It is regularly

used in directly compressed tablet or tablet

prepared by wet-granulation processes. It is used

in concentration range of 2% to 8% and

disintegrate formulation by rapid uptake of water

followed by quick and vast swelling.

Description Sodium starch glycolate is a white to off-white,

odorless, tasteless, free-flowing powder

4.2.2.3. Microcrystalline Cellulose 98

Nonproprietary

Names

BP: Microcrystalline cellulose

JP: Microcrystalline cellulos

CSDDS

Synonyms Avicel; Celex; Cellulose gel; Celphere; Crystalline

cellulose; E460; Emcocel; Ethispheres; Fibrocel;

Pharmacel; Tabulose;Vivapur

Empirical Formula

and Molecular

Weight

(C6H10O5)n ≈36 000, where n ≈ 220.

Functional

Category

Adsorbent, suspending agent, tablet and capsule

diluents, tablet disintegrant

Applications A binder/diluent in formulations. It also has slight

lubricant and disintegrating propertie.

Description It is partially depolymerized cellulose white,

tasteless, crystalline.

4.2.2.4.Lactoseanhydrous 98

Nonproprietary

Names

BP: Anhydrous lactose

JP: Anhydrous lactose

Synonyms Anhydrous LactoseNF 60M; Anhydrous LactoseNF

Direct Tableting

Chemical Name O-β-D-galactopyranosyl-(1→4)-β-D-glucopyranose

CSDDS

Empirical Formula

and Molecular

Weight

C12H22O11, 342.30

Functional

Category

Binding agent in directly compressible

lyophilization aid, filler.

Applications Anhydrous lactose is widely used in direct

compression tableting applications and as a tablet

and capsule filler and binder. Anhydrous lactose

can be used with moisture-sensitive drugs due to

its low moisture content.

Description Lactose occurs as white to off-white crystalline

particles or powder. Several different brands of

anhydrous lactose are commercially available

which contain anhydrous β-lactose and anhydrous

α-lactose. Anhydrous lactose typically contains

70–80% anhydrous β-lactose and 20–30%

anhydrous α-lactose.

4.2.2.5. Hydroxy Propyl Methylcellulose98

Nonproprietary

Names

BP- Hypromellose, USP – Hypromellose

JP- Hydroxypropyl methylcellulose

CSDDS

Synonyms Methocel, Cellulose, Hydroxypropyl methyl ether,

Hypromellose

Functional

Category

Coating agent, Film former, Stabilizing agent,

Suspending agent

4.2.2.6. Eudragit® FS 30 D99

Commercial form Aqueous dispersion with 30 % dry substance. The

dispersion contains 0.3 % Sodium Lauryl sulfate

and 1.2 % Polysorbate 80 as emulsifiers.

Chemical It is the aqueous dispersion of an anionic

copolymer methyl acrylate, methyl methacrylate

and methacrylic acid.

Structure

Description Milky-white liquid of low viscosity with a faint

characteristic odour. Above pH 6.5 the carboxylic

groups are converted into the carboxylate groups

and the polymer dissolves.

Applications It is used as an enteric coating film former for

solid-dosage forms. This polymer has a similar

CSDDS

threshold dissolution pH as Eudragit® S i.e. pH 7-

8, but dissolves in a slower and more controlled

manner

4.2.2.7. Eudragit® S-100 99

Chemical name Poly (methacrylic acid, methyl methacrylate) 1: 2

CAS Registry

Number

25086-15-1

Structure

Description EudragitS anionic copolymerization product of

methacrylic acid methyl methacrylate. The of free

carboxyl groups to the ester ratio is approximately

1: 2 in Eudragit S. This polymer is readily

dissolve in neutral to weakly alkaline conditions

(pH 6–7)

Applications It is used as an enteric coating for solid-dosage

forms. The coating is resistant to acidic pH but

CSDDS

4.3 ANALYTICAL METHOD DEVELOPMENT AND VALIDATION

4.3.1. Linearity:

i. Accurately weighed diclofenac Na was dissolved and diluted with

distilled water to make stock solution (50 μg/ ml).

ii.The solution was diluted up to 20 μg/ ml, which was scanned

spectrophotometrically in the range of 200 nm – 400 nm for

determination of λmax.

iii.The stock solution (50 μg/ ml) was diluted with distilled water to make

solutions of concentration of 5 to 30 μg/ ml.

iv.The UV absorbance’s were recorded at λmax and equation for

regression was obtained by plotting the graph of concentrations on X –

axis vs. absorbance’s on Y - axis.

4.3.2 Precision

i. The 50 μg/ ml standard stock solution was suitably diluted with

distilled water, to get the final concentration of 15 μg/ ml.

ii. The six replicates of 15 μg/ ml were prepared and absorbance

recorded at 276 nm.

iii. From the data standard deviation and % relative standard deviation

was calculated.

4.3.3 Accuracy using recovery method:

dissolves rapidly at and above pH 7.0

CSDDS

Procedure:

Recovery studies were carried out at three different levels 80 %, 100 %

and 120 % to study the accuracy of the method

A. Preparation of sample solution (A)

i. Tablet blend of 5 tablets each containing 50 mg of diclofenac Na

was prepared

ii. The quantity equivalent to 50 mg of diclofenac Na was weighed

accurately, dissolved in distilled water and volume was made upto

100 ml.

iii. From this solution 5ml was diluted upto 50 ml with distilled water

so as to get the final concentration of 50 µg / ml.

B. Preparation of standard solution (B)

i. Diclofenac sodium (50 mg) was weighed accurately and dissolved

in distilled water to make volume upto 100 ml.

ii. From this solution 5 ml was diluted upto 50 ml with distilled water

to get final concentration of 50 µg/ml.

C. Preparation of 80%, 100% and 120% solution:

i. 2 ml of solution A and 1.6 ml of solution B was taken and volume

made upto 10 ml so as to obtain the concentration of 18 µg / ml.

CSDDS

ii. Solution A (2 ml) and solution B (1.6 ml) was taken and volume

made upto 10ml so as to obtain the concentration of 20 µg / ml.

iii. 2ml of solution A and 2.4ml of solution B was taken and volume

made upto 10ml so as to obtain the concentration of 22 µg / ml.

iv. The absorbance of the above solutions was recorded at 276nm and

the percent recovery was calculated.

4.4 DRUG AND EXCIPIENTS COMPATIBILITY STUDIES:

The diclofenac sodium was triturated with excipients like talc, sodium

starch glycolate, lactose and microcrystalline cellulose (in 1:1 ratio). They

were subjected to storage at elevated temperature of 400C for one month

and evaluated by DSC and FTIR for any dug excipient interaction.

4.5 PREPARATION AND EVALUATION OF DICLOFENAC SODIUM

CORE TABLET

Initially 3 different formulations of diclofenac sodium tablet (F1, F2, and

F3) were prepared by wet granulation technique with polyvinyl pyrrolidon

solution (3% w/v) in IPA as a binder (Table 4.2). Formulation F2 and F3

contained different concentrations of superdisintegrant (2.5 & 5%) and

F1 is without superdisintegrant. In order to study effect of

superdisintegrant on site specificity and release pattern, core tablets (F1)

were prepared without superdisintegrant. Tablets were compressed on 8

mm standard concave punch on single rotary tablet compression

machine (Rimek, Mumbai). Tablets were tested for weight variation,

CSDDS

thickness ,friability (Roche friability tester), and breaking force

(Monsanto hardness tester) and disintegration test, as per methods

reported in USP100. Assay of tablet was done for which tablet blend of 20

tablets each containing 50 mg of diclofenac Na was prepared. The

quantity equivalent to 50 mg of diclofenac Na was weighed accurately,

and diluted to get the concentration of 50 µg / ml. The standard stock

solution (50 μg/ ml) was further diluted with distilled water to make

solution of concentration of 10 μg/ ml. The UV absorbance’s was

recorded at λmax and concentration of Diclofenac Na was determined

from regression equation. Six replicate analysis were carried out. For

drug content uniformity 10 tablets were individually weighed and then

each tablet was crushed and dissolved in 150 ml methanol and diluted

with water. The samples were assayed spectrophotometrically (Jasco V-

530) at 276 nm. For in vivo human study placebo tablet with radio-

opaque agent barium sulphate was prepared with all above ingredients,

containing 5%w/w of superdisintegrant, except drug using wet

granulation method and subjected to disintegration test, uniformity of

weight and breaking force.

CSDDS

Table 4.2: Composition of different diclofenac sodium tablets

4.6

PREPARATION AND EVALUATION OF CSDDS BASED ON PH

APPROACH

4.6.1 HPMC barrier film Coating of tablets

The test tablets were bulked with placebo tablets and coated in Insta

coat R&D coater (Mumbai) in 12” diameter pan containing baffles. Drying

(inlet) air at 550C was introduced approximately perpendicular to tablet

bed. HPMC 15cps solution was sprayed from gun of 08 mm nozzle

diameter, under 0.2 bars atomizing pressure and rate of feed was 1

g/min. Coating was continued till desired level of 1 to 2 % w/w weight

gain was achieved.

4.6.2 Eudragit FS30 D dispersion preparation for coating

Ingredient (mg/tablet)Formulation

F1 F2 F3

Diclofenac Sodium I.P. 50 50 50

Sodium Starch Glycolate - 5 10

Microcrystalline Cellulose 10 10 10

Talc 5 5 5

Magnesium Stearate 4 4 4

Lactose Monohydrate 131 126 121

CSDDS

The coating dispersion (Table 4.3) was prepared by incorporating

Eudragit FS 30 D (30%) dispersion supplied by Colorcon, a wetting agent

polysorbate 80 and a glidant glyceryl monostearate added to water. This

mixture was heated to 600C with stirring for 10 min at 50 rpm to get

homogeneous dispersion. The film forming temperature of dispersion is

140C and has low glass transition so no plasticizer was needed54.

Table 4.3: Composition of Eudragit FS30 D aqueous dispersion for

coating

Ingredients Quantity

Eudragit FS 30 D USP 63 %

Glyceryl Monostearate 0.93 %

Tween 80 1.17 %

Water qs100%

4.6.3 Eudragit FS 30 D aqueous dispersion coating on sealed coated

tablets.

Aqueous dispersion of coating was passed through sieve of 0.25 mm

aperture diameter before coating. The HPMC seal coated tablets were

used. Rate of spray and bed temperature during the coating process were

2 g/min and 30- 350C respectively. Tablet bed was preheated to 40o prior

to coating. Tablets prepared without superdisintegrant were also coated

in same manner. 5, 10, 15, and 20 % w/w total weight gain were coated

on tablet (F3A, F3B, F3C and F3D respectively for core with

CSDDS

superdisintegrant and F1A, F1B and F3C respectively for core without

superdisintegrant).

4.6.4 In vitro drug release study

The in vitro dissolution studies of Eudragit FS coated tablet were

conceded in dissolution apparatus II USP XXIII (Veego) at a 100 rpm

rotation speed in 900 ml medium at temperature 370 C. Tablets (n=6)

were transferred to dissolution medium. The samples were collected at

chosen time intervals, filtered through Whatman filter paper no. 41 and

analyzed by UV spectrophotometer (V-530 Jasco) at 276 nm. For

simulating pH conditions of gastro intestinal tract the continuous

dissolution test method was used. In first phase tablets were tested in

700 ml at pH 1.2 (0.1N HCl) for 2 hrs. After 2 hrs, 200 ml of 0.2M

tribasic sodium phosphate buffer was added to all the dissolution vessels

and pH was adjusted to 6.5, 6.8 and 7.2 by using 2M NaOH or 2M HCl

for 1, 2 h and till the end respectively. In order to study influence of

superdisintegrant on release rate, dissolution study was performed on

core tablet without superdisintegrant (F1) and similarly coated with

Eudragit FS 30 D (F3) at coating level of 5, 10 & 15% w/w weight gain.

4.6.5 In vivo studies in humans

to In order to monitor tablet performance all the way through

gastrointestinal system X-ray imaging was done. In vivo studies were

approved by B. J. Medical College,Pune Ethics Committee of vide project

No. NDO 308015-15 and performed on healthy male volunteers, with age

CSDDS

of range 22–40 and body weight of 50–80 kg. Informed consent was

obtained from all volunteers and an expert radiologist and physician

supervised the studies. Placebo tablets containing superdisintegrant

(table 4.4) with coating level of 10% w/w, 15% w/w and without

superdisintegrant coated with 10% w/w was administered to two

volunteers each after overnight fast. Abdominal radiograph were taken at

set time intervals and digital X-ray imaging (Wipro GE 300 MA) was done

to visualize location of tablet to observe their disintegration status in GI

tract. Volunteers were served with food after 2 hrs and lunch after4 hrs

after oral administration of the tablet. Each volunteer received total

radiation dose less than 0.7rem which is safe as per the European

guideline of X ray exposure101

A volunteer was administered with barium sulphate suspension and

Sr.no. Ingredients Quantity per

tablet (mg)

Use

1 Barium sulphate 9 Radio opaqueagent

2 Sodium starchglycolate

5 Superdisintegrant

3 Microcrystallinecellulose

0.5 disintegrant

4 Talc 2 Lubricant

5 Magnesiumstearate

2.5 Flow promoter

6 LactoseAnhydrous

81 Diluent

CSDDS

subjected to X- ray imaging in order to indicate different colonic regions.

Table no. 4.4 Formulation details of barium sulphate containing

placebo tablet

4.6.6 Scanning Electron Microscopy (SEM)

To study morphology of coated polymeric films SEM of coated tablet with

10, 15 and 20 % w/w coating level was carried out. At first samples of

coated tablets were cut vertically in half and coated with chromium in

coating chamber for 70 seconds. Then the sample was scanned with

scanning electron microscope (JEOL JSM-6360).

4.6.7. COMPARISON OF EUDRAGIT FS30D AND EUDRAGIT S100 ASCOATING POLYMER FOR CSDDS4.6.7.1 Preparation of non aqueous Eudragit S100 coating

solution99

Preparation of S100 dispersion A: The solution of Eudragit S100

was prepared by dissolving 9.75g of Eudragit S100 dry polymer in

the mixture of 62ml of isopropyl alcohol (IPA) and 3.75ml of water

at room temperature (Table 4.5).

Preparation of Eudragit S100 organic coating solution: In the

72.19ml of IPA 1.88g of talc and 0.94ml of plasticizer were added with

constant stirring, after a homogenous mixture was obtained, dispersion

A was added with a continuous stirring. The final coating solution was

stirred for a 10 min.

CSDDS

4.6.7.2 Coating of Diclofenac sodium tablets with Eudragit S100 non

aqueous coating solution:

For Eudragit S100 coating the rate of spray and the bed temperature

during the coating process were 2 gm/min and 30- 350C respectively.

The various coating parameters controlled during coating process are

given in Table

4.6.The tablets

bed was preheated

to the 40oC

temperature for 15 min before coating. The tablets were coated to a 5,

10, 15, and 20 % w/ w total weight gain, coded as S5, S10, S15 and S20

respectively.

Sr.no.

Ingredients Quantity (%)

A.S100 Dispersion

1 Eudragit S100 12.9

2 IPA 82.1

3 Water 4.9

B.Eudragit S100 coating solution

CSDDS

Table 4.5:

Formulation details of Eudragit S100 coating solution.

Table 4.6: Process parameters for Eudragit S100 non aqueouscoating.

4 Coating Dispersion A 48.27

5 Dibutyl phthalate 0.64

6 Talc 1.29

7 IPA 49.78

Parameters Specification

Batch size 50 gm

2 gm/min

1 mm

0.5 bar

50-60o C

30-40 RPM

10 min

Spray rate

Nozzle diameter

Atomizing air

pressure

Air inlet

temperature

Pan speed

Preheating of core

tablets

CSDDS

4.6.7.3 Drug release studies with EudragitS100 coating:

The in vitro dissolution study was carried out by changing pH method

mentioned in section 4.6.4.

4.6.7.4 Comparison of EudragitS100 and Eudragit FS30D:

In order to evaluate the appropriateness of Eudragit FS 30 D in

comparison with Eudragit S100 for colon targeting, the in vitro

dissolution profile of the tablets with the 10% and 15% weight gain

(coating) were studied in phosphate buffers (0.2M) at pH 6.8 and 7.2

after 2 hr incubation in pH 1.2 till more than 90% of drug release occur.

Dissolution study was performed as described earlier (section

4.6.4).Formulation F3B (10% coating level) and F3C (15% coating level)

coded as A1 TO A4 and S10(10% coating level) and S15 (15% coating

level) as A5 to A8 for this experiment.

Table 4.7: Dissolution test method in phosphate buffer at different

pH

Systemcode

Polymers Coating level(w/w)

pH of 0.2 Mphosphate buffer

A1 Eudragit FS 30 D 10 % 6.8

A2 Eudragit FS 30 D 10 % 7.2

A3 Eudragit FS 30 D 15 % 6.8

A4 Eudragit FS 30 D 15 % 7.2

A5 Eudragit S100 10 % 6.8

A6 Eudragit S100 10 % 7.2

CSDDS

4.6.7.5 In vivo studies in human

X-ray imaging of optimized Eudragit S100 coated tablet was done as per

the protocol mentioned in section 4.6.5.

4.6.8 Intersubject variability:

Due to intersubject variation in GI transit times, the drug release

occurred prematurely in the small intestine in some individuals, while in

others the formulations passed the ascending colon intact. Additionally

performance of time dependent formulation can be affected significantly

by the pathophysiological conditions associated with GI tract.

Accelerated transit through different segments of the colon has been

reported in patients with irritable bowel syndrome, carcinoid

syndrome102, 103, 2.

In perspective of a forthcoming evaluation of the colon targeted drug

delivery based on pH approach, objective of this study is to examine the

of potential of pH dependent approach in presence of inter subject

variability in gastric transit time of formulation in humans. For this

purpose, placebo tablets coated with an optimized coating level of

10%w/w of Eudragit FS30D for colon targeting were prepared

administered to six subjects, abdominal radiographs of these volunteers

taken at different time intervals.

A7 Eudragit S100 15 % 6.8

A8 Eudragit S100 15 % 7.2

CSDDS

4.7 PREPARATION AND EVALUATION OF CSDDS BASED ON

BACTERIAL APPROACH

The objective of the present study was to develop and evaluate colonic

drug delivery systems for diclofenac sodium which release the drug

specifically and instantly at target site using amylose as a carrier. Full

factorial design was used for optimization of coating level for colon

targeting. Amylose and HPMC concentration were selected as

independent variables and lag time prior to drug release and T90 are

dependable responses. Compression coated tablets of diclofenac sodium

were evaluated for in vitro and in vivo characterstics. The results of this

study presented factorial design for optimization of coating formulations

to accomplish colonic delivery. Superdisintegrant SSG played a

significant role in colon targeting. It was concluded that coating

consisted of amylose 285 mg and HPMC 150mg has potential for colon

targeting delivery of diclofenac sodium irrespective of change in pH in

patient with IBD.

4.7.1.1 Preparation and evaluation of diclofenac sodium core tablet

The core tablet of diclofenac sodium was prepared by means of wet

granulation with and without sodium starch Glycolate (SSG) as a

superdisintegrant (F1and F2). Tablets were compressed on 8 mm

standard concave punch on single rotary tablet compression machine

CSDDS

(Rimek, Mumbai) and were subjected to various evaluation tests. For in

vivo study placebo tablets containing radio-opaque agent barium

sulphate were prepared with and without SSG and evaluated for

disintegration test, weight variation and breaking force (shown in

Table4.8).

Table 4.8: formulation of core tablets

4.7.1.2 Preparation of compression coated tablets:

Coating material was prepared by wet granulating amylose and HPMC

K100 LV using PVP K30 as binder. A two factor three level factorial

design was constructed for optimizing the composition of amylose and

HPMC K100LV in coating. About 47% of the coating material was placed

in the 12.5 mm die cavity. The 8 mm core tablet Diclofenac sodium was

then positioned in the center of the die cavity and remaining 63% of

coating material was added followed by compression around the core

Sr.no. Ingredients Qty/tablet (mg)

1 Diclofenac sodium IP 50

2 Sodium Starch Glycolate 10

3 Microcrystalline cellulose 4

4 Talc 5

5 Magnesium stearate 10

6 Lactose monohydrate 121

CSDDS

tablets at 4000-5000 kg applied force with 12.5mm round concave

punches. Placebo tablets were also coated similarly and evaluated.

4.7.2 Optimization of compression coat:

A three level two factor (32) design was constructed to optimize coat

composition to evaluate the effect of content of polymers on targeting

efficiency of drug delivery system in colon. The amounts of amylose (X1)

and HPMC K100LV (X2) are independent variables; levels of independent

factors were chosen by of initial experimentation. Rest of the formulation

factors and process variables were kept constant throughout the study.

The translation of the coded levels to the experimental units used in the

study is summarized in Table 4.9 and 4.10. All formulations were

subjected to evaluation as mentioned above.30. The cores prepared earlier

F1, F2 were coated with optimized coating composition of amylose and

HPMC.

Table 4.9: Experimental design: independent variable and responses

Independent variables Levels used dependent variables

1 0 -1

X1 = Amylose(mg) 325 300 275 Y1 = % release in lag time

X2 = HPMC K100 LV(mg) 125 150 175 Y2 = T90 % drug release

CSDDS

Table 4.10: Experimental formulations Composition

4.7.3 Drug

release studies:

In vitro drug release studies of compression coated tablets were carried

out in dissolution type II apparatus (TDT 08L Electrolab) at 50 rpm

rotation speed and 370C. The tablets (n=3) were transferred to

Code

Variable factors

X1 = Amylose(mg) X2 = HPMC K100

LV(mg)

R1 325 125

R2 325 150

R3 325 175

R4 300 125

R5 300 150

R6 300 175

R7 275 125

R8 275 150

R9 275 175

CSDDS

dissolution medium and samples were withdrawn at chosen time

intervals followed by filteration through Whatmann filter paper and

analyzed by UV spectrophotometer (V-530 Jasco) at 276 nm. The

continuous dissolution method was used to simulate GI tract conditions.

At first tablets were added in 700 ml of pH 1.2 (0.1 N HCl) for 2 h (stage

I). At the end of 2 hr 233.3 ml of solution of tribasic sodium phosphate

(Tris HCl) (0.2 M) was added to all the dissolution vessels and the pH 6.8

was adjusted to by 2 M NaOH or 2 M HCl and dissolution was carried for

further 3h (stage II). The effect of enzyme on the drug release was studied

on all formulations by adding 770 mg of α-amylase into buffer, at the

beginning of 5th h (stage III )27.

4.7.3.1. Effect of coating composition

In order to study influence of HPMC on site specificity of drug release,

core tablet coated with plain HPMC K100LV (formulation B2) was

subjected to dissolution studies as mentioned above then compared with

tablet coated with HPMC and amylose (B1).

4.7.3.2. Effect of superdisintegrant

The core tablets with (F1) and without (F2) superdisintegrant coated with

optimized coating formula of amylose and HPMC K100 LV (285:150 ratio)

and then subjected to dissolution studies as above.

4.7.3.3. Effect of media pH

The influence of pH on release of drug from compression coated tablet of

amylose and HPMC K 100LV (285:150 ratio) in different colonic pH (5.0

CSDDS

and 6.8) was studied using modified dissolution medium at the

commencement of stage III i.e. acetate buffer and Tris-HCl buffer

separately.

4.7.4 Invivo studies:

Subjects were fasted overnight and administered barium sulphate

containing core tablet and coated with amylose and HPMC K100LV

polymer, two volunteers received core tablets with superdisintegrant and

two volunteers received core tablet without superdisintegrant with 200

ml of water. Abdominal X ray radiographs (CR30X AGFA, MSXML 4.0)

were taken at set time intervals to determine whether it reaches and

remains in the caecum for 4.30h. Studies were conducted with approved

protocol from Medical Ethical Committee of Nagpur, (Ref. no.

55721052009) in accordance with internationally accepted principles.

CSDDS

4.8 PREPARATION AND EVALUATION OF CSDDS BASED ONTIME

DEPENDENT APPROACH

Time dependent delivery system releases drug load after a

preprogrammed delay in time. The system consists in a drug-loaded core

coated with Eudragit RSPO,a swellable hydrophilic polymer providing lag

phase prior the onset of release. The hydrophilic polymer undergoes a

glassy-rubbery transition in aqueous fluids and, it becomes more

permeable, dissolves and/or erodes in the rubbery state. This

mechanisms is responsible for lag time in colonic drug delivery by time

dependent. The rationale of this study was to set up a new time triggered

colonic drug delivery system based on Eudragit RSPO coating and use of

a superdisintegrant in tablet core which will release drug specifically and

instantly in the colon. The influence of formulation variables such as

coating thickness on drug release was studied and the passage of

optimized formulation through GIT was investigated by in vivo X ray

studies in human volunteers. In vivo studies showed that tablet with

coating level of 5% w/w has lag time of 4.30h which corresponds to

ileocaecal region and it release the drug instantly after lag time, so drug

is available in disperse or dissolved form. In vivo studies shows similar

result as that of in vitro with lag time of 4-5h before disintegration of

tablet.

4.8.1 Preparation and evaluation of diclofenac sodium core tablets:

CSDDS

The core tablet of diclofenac sodium was prepared by wet granulation

technique with a superdisintegrant SSG. Tablets were compressed on 8

mm standard concave punch on single rotary tablet compression

machine (Rimek, Mumbai). Tablets were tested for various official and

unofficial evaluation tests.

4.8.1 Coating of tablets with HPMC:

Tablets were coated with HPMC 15cps with different coating level of 10%,

15% and 20% coating level. The bed temperature and spray rate during

the coating process were 30- 350C and respectively2 gm/min. Tablet bed

was preheated to 40o prior to coating.

4.8.2 Preparation of Eudragit Coating Solution and coating of tablets

with Eudragit RSPO:

As indicated in Table no 4.11 required quantity of RSPO was dissolved in

sufficient quantity of organic solvent IPA and acetone mixture (1:1)

proportion. Then dispersion of talcum, magnesium stearate, glycerin and

PEG 400 in IPA and acetone mixture was prepared and added to the

polymeric solution. Di ethyl phthalate plasticizer was added to the

resultant polymeric dispersion under stirring and passed through 80 no

mesh.

4.8.2 Coating of Diclofenac sodium tablets with Eudragit RSPO

The coating dispersion was passed through 80 no mesh before use. The

various coating parameters controlled during coating process are given in

Table 4.12. The tablets bed was preheated to the 40oC temperature for

CSDDS

15 min before coating. The tablets were coated to a 3, 5, and 7% coating

level

Table 4.11:

Composition of Eudargit RSPO coating solution

Table 4.12: Coating parameters for tablet Eudargit RSPO coating

Sr.No. Items Qty

1 Eudragit RSPO 5gm

2 Talc 5gm

3 Glycerin I.P 2ml

4 Diethyl Phthalate .010ml

5 PEG 4000 0.15ml

6 Magnesium Stearate 2.0gm

7 IPA / Acetone A.R (q.s) 100ml

Coating parameter Specification

CSDDS

4.8.3 Drug release studies:

In vitro drug release study was done by changing pH method simulating

the GI tract as mentioned in section 4.6.4.

4.8.4 In vivo studies:

The in vivo studies were approved by the MedicalEthics Committee ,

central for clinical ethics, Nagpur vide project No. 55721052009 and

performed by protocol mentioned in section 4.5.8.

4.9 Stability Studies 104

In any rationale design and evaluation of dosage forms for drugs, the

stability of the active component must be major criteria in determining

their acceptance or rejection. The stability studies of the optimized

formulations, at 400C/ 75% RH was done for a period of three months.

The sample tablets were wrapped in the laminated aluminum foils and

Spray rate 0.8 ml/min

Atomizing air pressure 2lb/inch2

Tablet bed temperature 30-350 C

Pan speed 25 rpm

Preheating of pan 15 minutes (10

rpm- 400C)

CSDDS

were placed in the accelerated stability chamber (Remi Instrument Ltd.,

Mumbai). Sampling was done at a predetermined time intervals of 0, 1, 2

and 3 months. The tablets were evaluated for drug release studies and %

assay.