DESIGN AND EVALUATION OF MODIFIED PULSINCAP …ijpi.org/wp-content/uploads/may2013/1.pdf · DESIGN...

INTERNATIONAL JOURNAL OF RESEARCH ARTICLE PHARMACEUTICAL INNOVATIONS ISSN 2249-1031

1 | P a g e Volume 3, Issue 3, May ₋ June 2013 http://www.ijpi.org

DESIGN AND EVALUATION OF MODIFIED PULSINCAP OF TRAMADOL

HCL ACCORDING TO CIRCADIAN RHYTHM

Priyanka Modi*, Ghanshyam Patel, Dr. Ragin Shah,

Arihant School of pharmacy and bio- research institute, Gandhinagar, Gujarat

ABSTARCT

The objective was to design and evaluate modified pulsincap of Tramadol HCl according to

circadian rhythm using formaldehyde vapour for cross-linking to make capsule body water

insoluble and hydro gel plug to achieve a predetermined lag time for chronotherapy of

rheumatoid arthritis. The capsule body was made water insoluble by exposing the body to

formaldehyde vapour. A physical mixture of drug and excipients was filled in the treated

capsule body and hydro gel plug was fitted to the mouth of the treated body and the untreated

cap was fitted to the treated body which was coated with Eudragit S-100 to prevent variable

gastric emptying. Developed formulation was evaluated for in-vitro drug release in pH 1.2 (2

hrs), phosphate buffer pH 6.8 (3 hrs) and phosphate buffer pH 7.4. 32 full factorial design was

used for optimization. Formulation F1 and F5 both showed predetermined lag time of 6 hrs

but in formulation F1 less amount of SSG and HPMC K4M was used so it was selected as

optimized formulation showing the immediate release of the drug after the lag time of about 6

hrs.

Key words: modified pulsincap, chronotherapy, rheumatoid arthritis

INTRODUCTION

A major objective of chronotherapy in the

treatment of several diseases is to deliver

the drug in higher concentrations during

the time of greatest need according to the

circadian onset of the disease or syndrome.

To follow this principle one must have to

design the dosage forms so that it can be

given at the convenient time for example

bed time for the diseases with the drug

release in the morning.

Pulsincap is the one of the approaches for

pulsatile drug delivery. Pulsincap system

comprises of a water-insoluble capsule

body, soluble cap and hydro gel plug.

When this capsule came in contact with

the dissolution fluid, it dissolves and after

a lag time, the plug pushed itself outside

the capsule and rapidly releases the drug.

The length of the plug and its point of

insertion into the capsule controlled the lag

time. Pulsincap was studied in human

volunteers and was reported to be well

tolerated. [1-3]

Almost 20% people of the

total population of the world suffering

from arthritis. Rheumatoid arthritis is a

generic term that describes many different

*Corresponding Author

Priyanka Modi



and usually painful conditions. It is based

on the circadian rhythm of the body

because peak pain occurs in early morning

and decreases as the time passes. These

will be possible by formulating pulsatile

delivery of drug, which release the drug

rapidly in early morning followed by

predetermined lag time and thus prevent

unusual exposure of drug to the patient. [4-

6]

Tramadol hydrochloride is a synthetic

analgesic with half life of 5-6 hrs and has a

modest affinity for the µ receptor. Its

additional effect on the descending

inhibitory pathways relies on inhibition of

serotonin and norepinephrine re-uptake.

Thus it gives dual mode of analgesic

action. It doesn’t only provide analgesia

over a wide range of pathologies but it has

significant advantages like no respiratory

depression or cardiac side effects. It is the

BCS class-I drug having good absorption

throughout the GIT. The most common

side effects of Tramadol HCl are nausea

and vomiting which can be prevented by

pulsatile delivery. Hence it best suits for

this approach. [7]

The capsule bodies of size ‘1’ were treated

with formaldehyde vapor to make capsule

body water insoluble. The amino group in

the gelatin molecular chain could react

with an aldehyde group of formaldehyde

by a schiff’s base condensation reaction to

produce a water insoluble body. The

concentrations of formaldehyde solution

and exposure time to capsule bodies were

optimized by solubility study of treated

capsule bodies. [8-10]

The physical mixture

of drug and excipients was filled in

formaldehyde treated capsule body and

fitted with hydro gel plug which was

compressed having diameter of 6 mm.

Then untreated cap was fitted on the body

and the entire capsule device was coated

with Eudragit S-100. After the cap opening

in the dissolution media, the hydrogel plug

came into contact with dissolution media

and it hydrated and started to swell and

after ejection of plug from the body, the

drug was released immediately.

In this study an attempt had been made to

develop modified capsule which will give

pulsatile release of Tramadol HCl for

arthritic pain.

MATERIAL AND METHODS

Materials

Tramadol HCl was obtained from Apex

pharma, Hyderabad. Sodium starch

glycolate, HPMC K4M, Na-alginate,

Eudragit S-100, Acetone were from S.D

Fine chemicals, Mumbai. Formaldehyde,

Sodium chloride, Potassium permanganate

was from Dow chemical’s Rajkot. All

other ingredients used were either

pharmaceutical or analytical grade.

Methods

Formaldehyde treatment and its

optimization

Formalin treatment has been employed to

modify the solubility of gelatin capsules.[8-

11] Hard gelatine capsule of size ‘1’ and 50

in number taken. Their bodies were

separated from the caps. 25 ml of 5%, 7%,

10% (v/v) formaldehyde was taken into

separate desiccators and a pinch of

potassium permanganate was added to it

respectively, to generate formalin vapours.

The wire mesh containing the empty

bodies of capsule was then exposed to



formaldehyde vapours. The caps were not

exposed leaving them water-soluble. The

desiccators were tightly closed. The

reaction time was optimized by removing

capsule bodies at different time intervals

and dried at 50°C for 30 min to ensure

completion of reaction between gelatin and

formaldehyde vapors. The bodies were

then dried at room temperature to facilitate

removal of residual formaldehyde. These

capsule bodies were capped with untreated

caps and stored in a polythene bag.

Tests for Formaldehyde Treated Empty

Capsules

Various physical and chemical tests were

carried out simultaneously for

formaldehyde treated and untreated

capsules.

a) Physical tests

Identification attributes: The size ‘1’

capsule were one with a red cap and

white colored body. They were

lockable type, odourless, softy and

sticky when treated with wet fingers.

After formaldehyde treatment, there

were no significant changes in the

capsules. They were non-tacky when

touched with wet fingers.

Visual defect: In about 50 capsule

bodies treated with formaldehyde,

about five were found to be shrunk or

distorted.

Dimensions: Variations in dimensions

between formaldehyde, treated and

untreated capsules were studied. The

length and diameter of the capsules

were measured before and after

formaldehyde treatment, using dial

caliper.

b) Chemical test

Qualitative test for free

formaldehyde

Standard formaldehyde solution used is

formaldehyde solution (0.002 w/v) and

sample solution is formaldehyde treated

bodies (about 25 in number) were cut into

small pieces and taken into a beaker

containing distilled water. This was stirred

for 1 hrs with a magnetic stirrer, to

solubilise the free formaldehyde. The

solution was then filtered into a 50 ml

volumetric flask, washed with distilled

water and volume was made up to 50 ml

with the washings. 1ml of sample solution,

9 ml of water was added. One ml of

resulting solution was taken into a test tube

and mixed with 4 ml of water and 5 ml of

acetone reagent. The test tube was warmed

in a water bath at 40oC and allowed to

stand for 40 min. The solution was not

more intensely colored than a reference

solution prepared at the same time and in

the same manner using 1ml of standard

solution in place of the sample solution.

The comparison should be made by

examining tubes down their vertical axis.

Drug-excipient compatibility study

FTIR absorption spectra of pure drug,

physical mixture and pulsincap

formulation were recorded in the range of

400 to 4000 cm-1

by KBr disc method

using FTIR spectrophotometer.

Selection of core physical mixture and

hydrogel plug

In the present study for the preparation of

modified pulsincap the composition of

physical mixture and the type of hydrogel

plug. Here the effect of osmogen (NaCl)

and superdisintegrant (SSG) in core



physical mixture was checked on the

immediate drug release after the lag time.

Hydrogel plug of two polymers HPMC

K4M and Na-alginate were selected. Both

are swellable hydrophilic polymers and

control the lag time. Eudragit S-100 was

selected for enteric coating of entire

capsule device. 5% w/v solution of

Eudragit S-100 in acetone was selected for

enteric coating which was suitable for

uniform dip coating.

Preliminary trial formulations of modified pulsincap

Table 1: Composition of preliminary formulation

Ingredients (mg) P1 P2 P3 P4 P5 P6

Tramadol HCl 50 50 50 50 50 50

MCC 150 100 100 150 100 100

NaCl - 50 40 - 50 40

SSG - - 10 - - 10

HPMC K4M plug 50 50 50 - - -

Na-alginate plug - - - 50 50 50

Total weight* (mg) 352.5

±6.2

349.4

±7.6

350.7

±6.9

355.5

±8.1

351.0

±7.2

357.9

±6.5

*Values are mean± S.D, n=10

Wt. of empty capsule =78 mg,

Avg. wt gain by 5% Eudragit S-100 coating solution= 7.53%

Evaluation of modified pulsincap

Lag time [12]

Lag time is the total time period after

which the plug is ejected out of the capsule

body and the drug releases immediately.

Lag time was determined visually using

phosphate buffer pH 6.8 and 7.4. For lag

time determinations USP paddle apparatus

was used. Capsules were tied with the

paddle by cotton thread; temperature was

maintained at 37°C at 50 rpm. Results of

preliminary trial formulations are

depicated in Table 9.

In-vitro release profile [9, 13]

Dissolution studies were carried out by

using USP XXIII dissolution test apparatus

(Basket) method. Capsules were placed in

a basket so that the capsule should be

immersed completely in dissolution media

but not float. In order to simulate the pH

changes along the GI tract, three

dissolution media with pH 1.2, 6.8 and 7.4

were sequentially used referred to as

sequential pH change method. When

performing experiments, the pH 1.2

medium (0.1 N HCl) was first used for 2

hrs (since the average gastric emptying

time is 2 hrs) then removed and the fresh

pH 6.8 phosphate buffer was added. After

3 hrs (average small intestinal transit time

is 3 hrs) the medium was removed and

fresh pH 7.4 dissolution medium was

added for subsequent hrs. 900ml of the

dissolution medium was used at each time.



Rotation speed was 100 rpm and

temperature was maintained at 37±0.5 °C.

5 ml of dissolution media was withdrawn

at predetermined time intervals and fresh

dissolution media was replaced. The

withdrawn samples were analyzed at 270

nm, by UV absorption spectroscopy.

Results of drug release study are shown in

Figure 4.

Optimization of variables using 32 full

factorial design [9, 14, 15]

A full factorial 32 design is used for

optimization procedure. It is suitable for

investigating the quadratic response

surfaces and for constructing a second-

order polynomial model, thus enabling

optimization of the modified pulsincap.

Table 2 summarizes the independent along

with their levels. The resulted formulations

are listed in Table 3. A statistical model

incorporating interactive and polynomial

term will be used to evaluate the response.

Y = β0 + β1X1+ β2X2 + β12X1X2 + β11X12

+ β22X22

Where, Y is the dependent variables.

Table 2: Coding of variable

Coded values Actual values

X1(conc. ratio of SSG and NaCl) X2 ( wt. of hydrogel plug in mg)

-1 10:90 40

0 20:80 50

+1 30:70 60

Dependent variables is

Y = Lag time

Table 3: Compositions of factorial formulations

Ingredients

(mg) F1 F2 F3 F4 F5 F6 F7 F8 F9

Tramadol

HCl 50 50 50 50 50 50 50 50 50

MCC 100 100 100 100 100 100 100 100 100

NaCl 45 40 35 45 40 35 45 40 35

SSG 05 10 15 05 10 15 05 10 5

HPMC K4M

plug 40 40 40 50 50 50 60 60 60

Total

weight*

(mg)

345.9

± 5.2

347.0

± 4.6

344.3

± 4.1

356.6

± 6.1

354.2

± 5.7

356.2

± 5.9

365.4

± 5.5

368.1

± 6.3

365.2

± 6.9

*Values are mean ± S.D where, n=10

Avg. wt gain by 5% Eudragit S-100 coating solution= 8.23 %



Statistical analysis of the data

Statistical analysis of the factorial design

formulations was performed by multiple

regression analysis using Microsoft Excel

2007. 3D response plots were constructed

using Design expert 8.0 trial version

software

Result and Discussion

Optimization of formaldehyde

concentration & exposure time for cross-

linking

The solubility of the capsule bodies

checked and it was found that 10% v/v

formaldehyde solution and 6 hrs exposure

times was optimum in which capsule

bodies remained intact up to 12 hrs in all

the media (Table 4). So it was used in

cross-linking of capsule bodies. After

formaldehyde treatment of 100 capsule

bodies about 10 were found to be

distorted. Then they were subjected to

measurement of dimensions as shown in

Table 5.

Table 4: Solubility study of cross-linked capsule bodies

Formaldehyd

e conc.

(%v/v)

Time of

exposur

e

(hrs)

Observation in dissolution media

0.1 N HCl Phosphate buffer

6.8

Phosphate buffer

7.4

5 % 2 softened in 1 hr softened in 1 hr softened in 1 hr

4 softened in 2 hrs softened in 2 hrs softened in 2 hrs


7% 2 softened in 3 hrs softened in 3 hrs softened in 3 hrs



10% 2 softened in 9 hrs softened in 9 hrs softened in 9 hrs

4 Intact up to 10 hrs Intact up to10 hrs Intact up to10 hrs

6 Intact up to 12 hrs Intact up to12 hrs Intact up to 12 hrs

Table 5: Comparison of dimension of capsule bodies

Parameter Before treatment After treatment

Avg. capsule length (mm) 15.23 14.75

Avg. diameter of capsule body (mm) 6.5 6.1

Avg. length of capsule body (mm) 11.39 10.97

From the observations of the cross linked capsule bodies it was found that there was slight

decrease in the diameter and length after formaldehyde treatment.



Qualitative test for free formaldehyde

The formaldehyde capsules were tested for

the presence of free formaldehyde. The

sample solution was not more intensely

colored than the standard solution inferring

that less than 20 µg free formaldehyde is

present in 25 capsules.

Drug- excipient compatibility study

FTIR spectrum of Tramadol HCl, physical

mixture and pulsincap formulation are

shown in Figure 1, 2 and 3 respectively.

From the FTIR spectra of physical mixture

and pulsincap formulation, it was found

that drug and excipients are compatible

with each other.

Figure 1: FTIR spectra of Tramadol HCl

Figure 2: FTIR spectra of physical mixture of Drug and excipients



Figure 3: FTIR spectra of pulsincap formulation

Evaluation of hydrogel plug

Table 6: Evaluation of Hydrogel plug of trial formulations

Type of plug Thickness

(mm)

Friability (%) Swelling index (%)

( in 6 hrs)

pH 6.8 pH 7.4

HPMC K4M 2.40 ± 0.07 0.53 65.9 ± 1.2 64.2 ±1.5

Na-Alginate 2.42 ± 0.06 0.58 80.6 ± 2.1 81.8 ± 1.7

values are mean± S.D, n=3

The swelling index of Na-alginate was found to be more in comparison with the HPMC K4M

plug at the end of 6 hrs.

Evaluation of modified pulsincap formulations

Lag time

Table 7: Lag time of preliminary trial formulations

Batch Lag time (min.)

P1 460 ± 12

P2 447 ± 15

P3 365 ± 10

P4 416 ± 10

P5 405 ± 16

P6 320 ± 13

Values are mean ± S.D, n=3

Due to enteric coating by Eudragit S-100

pulsincap remained intact in 0.1N HCl But

starts to dissolve in phosphate buffer. It

was postulated that after the dissolution of

coating the cap starts to dissolve and fluid

enters the body because it was insoluble



but permeable. After entering the body the

osmogen and superdisintegrant creates the

pressure on swollen plug and hence plug

ejected out of the body. From the results of

lag time of preliminary trial formulations,

it was found that there is no significant

effect of osmogen (NaCl) alone on the lag

time but in combination with the

superdisintegrant (SSG) it helps in ejection

of plug after lag time and releases the drug

immediately.

In vitro drug release study

Figure 4: In-vitro drug release study of preliminary formulations

From the drug release study it was also

found that sustaining capacity of HPMC

K4M plug is more than the Na-alginate

plug. From the result of lag time it was

observed that the P1-P6 had the lag time in

the range of 5-8 hrs. P3 formulation had

the lag time of about 6 hrs having the ratio

of NaCl to SSG was 80:20 (40 mg NaCl

and 10 mg SSG) and the HPMC K4M plug

of 50 mg weight. Hence it was used for the

setting of levels and factors for the 32 full

factorial designs.

Evaluation of modified factorial formulations

Lag time

Table 8: Lag time of factorial formulations

Batch Lag time (min)

F1 365 ± 09

F2 315 ± 11

F3 275 ± 10

F4 405 ± 15

F5 363 ± 13

F6 320 ± 10

F7 425 ± 12

F8 409 ± 14

F9 393 ± 10

Values are mean ± S.D, n=3

0

20

40

60

80

100

120

0 2 4 6 8 10% c

um

ula

tive

dru

g re

leas

e

Time (hrs)

P1

P2

P3

P4

P5

P6



From the lag time determination study of the factorial formulations, it was found that as the

weight of the hydrogel plug increases the lag time also increases and as the amount of super

disintegrant increases the lag time decreases. From all the formulations F1 and F5 shows the

lag time of about 6 hrs.

In vitro drug release study of factorial formulations

Figure 5: In-vitro drug release study of factorial formulations

Pulsincap formulation of F1-F9 showed

distinct lag time as given in Figure 5. It

showed that lag time increases with

increase in weight of hydrogel plug and

decreases with increase in ratio of SSG

and NaCl. Upon contact with dissolution

media the hydro gel plug starts to swell

and due to pressure inside the capsule

body plug comes out. So both the

parameters affect the lag time and drug

release from the pulsincaps.

Formulations F1 (SSG to NaCl ratio 20:80

and HPMC K4M plug of 40 mg) and F5

(SSG to NaCl ratio 10:90 and HPMC K4M

plug of 50 mg) provides the desired lag

time of about 6 hrs.

Statistical analysis of the data

The fitted full model equation relating the

response Y (lag time) to the transformed

factor are shown in following equation.

Y= 362 – (35X1) + (44.83X2) + (13.75X1X2) +

(1X12) + (0.5X2

2)

The P value for X1, X2 and X1X2 was

found to be 0.00164, 0.00079 and 0.00394

respectively which is less than 0.05. Thus

X1, X2 and X1X2 has significant effect on

the dependent variable Y (Lag time) while

other term X12 and X2

2 were rendered

insignificant having P value greater than

0.05.

0

20

40

60

80

100

120

0 1 2 3 4 5 6 7 8 9

%cu

mu

lati

ve d

rug

rele

ase

stu

dy

Time (hrs)

F1

F2

F3

F4

F5

F6

F7

F8

F9



Table 9: Regression Statistics for Y (Lag time)

Regression Statistics for Y

Multiple R 0.9954

R Square 0.9909

Adjusted R Square 0.9757

Standard Error 7.854

Observations 9

Coefficients P- value

β0 = 362 9.31959E-06

β1 = - 35 0.00164

β2 = 44.83 0.00079

β12 = 13.75 0.03944

Β11 = 1 0.86858

Β22 = 0.5 0.9339

Table 9 shows the results of the analysis of variance (ANOVA), which was performed to

identify insignificant factors. The high values of correlation coefficient for lag time indicate a

good fit, i.e., good agreement between the dependent and independent variables. The

significance test for regression coefficients was performed by applying the student F test.

(Table 10)

Positive value of coefficient of X1 indicates that dependent variable (lag time) is directly

proportional to the X1 variable (weight of plug) and negative value of coefficient of X2

indicates that if there is increase in X2 variable (ratio SSG:NaCl), there is decrease in lag time

Table 10: Testing the model in portions

Lag time (Y)

DF SS MS F R2

Fcal = 0.0477

Regression

FM 5 20319.7 4063.93 59.66 0.9909

RM 3 20313.2 6771.06 160.58 0.9907

Fcri = 9.5520 Error

FM 3 204.33 68.11 - -

RM 5 210.83 42.17 - - DF = (2,3)

DF: degree of freedom, SS: sum of squares, MS: mean of squares, F: Fischer’s ratio, R2:

regression coefficient, FM: full model, RM: reduced model.



So, the reduced model equation is as follows:

Y= 362 – (35X1) + (44.83X2) + (13.75X1X2)

The results for testing the model in portions are shown in Table 5.19. Since the calculated

value (F = 0.0477) is less than critical value, it may be concluded that the quadratic terms β11

and β22 do not contribute significantly to the prediction of lag time and therefore can be

omitted from the full model.

Figure 6: Contour plot showing relationship between two independent variables on lag

time

Figure 7: Response surface plot showing the influence of independent variables on lag

time.



Figure 6 and 7 showed the countor plot

and response surface plot of ratio of SSG

to NaCl (X1) and plug weight (X2) versus

lag time respectively. It was also observed

that the X1 and X2 appear to favor the

preparation of modified pulsincap of

Tramadol HCl. It can say that the lag time

and drug release profile may be changed

by appropriate selection of the X1 and X2

levels. The area in contour plot (Figure

5.12) shows if we selected X1 and X2 in

this range we get the desired release

profile of Tramadol HCl modified

pulsincap.

CONCLUSION

Tramadol HCl was successfully

formulated as a modified pulsincap to

deliver drug after predetermine lag time of

6 hrs. Formulation F1 and F5 both gave

the lag time of about 6 hrs but the F1 (

Ratio SSG to NaCl 10:90 and plug weight

40 mg) was selected as optimized

formulation hence less amount of SSG and

HPMC K4M were used in that in

comparison with F5. 100 % drug was

released in 1 hr after the lag time in

optimized formulation which is necessary

in pulsatile release.

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