UNIVERSITY OF MONASTIR

FACULTY OF SCIENCES OF MONASTIR

Preparation and Characterization of Biopolymers as Carriers of Some Chronic Drugs

and Study of their Controlled Release
Presented by:

AMER RASHID HAMEED

Under Supervisor : Professor Mr. Hatem Majdoub

and Co-supervisor Mr. Fawzi Habeeb Jabrail

 1

Introduction
 Polysaccharides are vital biomacromolecules and important for all living
organisms, which are consists of homo-monosaccharides or hetero
monosaccharides beside uronic acids and all are connected with glycosidic
linkages. Polysaccharides are present in various portions of animals, plants,
bacteria, fungi and others. Recently, bioactive polysaccharides have shown
therapeutical effects against different chronic diseases because of their
biocompatibility, non-toxicity and biodegradability. In addition, polysaccharides
have shown a wide range of pharmacological properties antitumor,
antimicrobial, antioxidative, anti obesity , antidiabetic and others.
Polysaccharides are depends on their sources, structure, solubility and chemical
composition. ate .
 Polysaccharides according to their chemical composition are characterized as
Homopolysaccharides of a single type of monosaccharide and Heteropolysaccharides Homopolysaccharides
of a different type of monosaccharides.

Moreover, polysaccharides are classified according to their origins as those taken from

animals like (heparin, sulfate and others), plants like ( inulin, pectin and others), bacteria

like (peptidoglycans, exopolysaccharides and others). Polysaccharides

In general, polysaccharides are considered natural biopolymers most are well developed

and fabricate as matrix called hydrogels, in particular, CHITOSAN, PECTIN,

HEMICELLULOSE and SODIUM ALGIN

Heteropolysaccharides
The Fig tree (FICUS CARICA L.) was considered one of the first domesticated

trees, has a significant uses as food and in traditional medicine .Figs are a good

source of phenolic compounds and fiber . The fig fruit production leave behind

bio-waste, in particular, fig leaves. Fig leaves can be considered as sources of

chemical compounds, such as phenolics, organic acids, Fig organic acids, leaves

can be considered as sources of chemical compounds, such as phenolics, organic

acids, coumarins, flavonoids and volatile constituents

 Pomegranate (Punica granatum L. Punicaceae) have been widely
used in medicine as materials of excellent effects on anti-bacterial,
anti-viral, anti-cancer, anti-tumor, anti-oxidant, anti-inflammation
and many other effects to human beings . In general, 40% of
pomegranate is juice and the remaining corresponds to pomegranate
is considered by-product waste contained pomegranate peel and
seeds.
 Pomegranate peel contain number of bioactive compounds like polyphenols,
fiber, minerals, vitamins, etc. Pomegranate peels have shown treat effects for several
chronic metabolic diseases such as cardiovascular disease, obesity, and diabetes .
Pomegranate peels are represent 40 % of the pomegranate fruit and these waste are
considered an agri-waste and the bioactive compounds are concentrated in the
pomegranate peels rather than in the seeds, leaves, and even aril .

The pectin is a polysaccharide of heterogeneous structure consists of at least 17 different

monosaccharaides . Pectin is a plant polysaccharide present in the cell walls.

Pectin is biopolymer has multiple applications and a large use in foods especially as texturizer or

stabilizer in acid food products because its stability in acidic condition even at higher temperature .

Pectin can be used as an additive in pharmaceutical applications, where pectin can be used as a drug

delivery system for controlled drug release

 Chitosan is a cationic linear heteropolysaccharide and widely used for
medicine, food, nano drug delivery systems and other fields . Chitosan have very
great properties like biocompatibility abundant sources, non-toxicity,
biodegradability, and good mucoadhesion .

As chitosan has poor mechanical strength and limited chain flexibility, different methods such as grafting, cross-
linking and blending have been developed to increase its applications .Chitosan was copolymerized with other plants
origins polysaccharides which add a new function groups that modify its physicochemical properties.
 Polysaccharide extracted from Fig leaves and Pomegranate peels in current study were blended using
Copolymerization Method with another very known polysaccharide with cationic nature called Chitosan
for Hydrogel Formation.

HYDROGELS, are hydrophilic polymers of three dimensional structure. have the ability to

absorb large amount of water during swelling process and release the absorbed water by

shrinking process . Hydrogels have many applications such as medicine, pharmaceutical,

food and agriculture fields.

Polar hydrophilic groups like, -OH, -NH₂, - CONH3 , -COOH, -SO3H, etc. in the
hydrogels help the polymer to have the following characteristic properties;
biocompatibility, biodegradability, viscoelasticity, super absorbency, softness, etc.,
which plays a big role in the hydrogel to be used as biomedical materials used in chemical

tissue engineering, drug delivery.

multi cross- cross-linking physical

linked of hydrogels

The cross-linking of hydrogels is very necessary point for studying the

strength between the hydrogel chains for formation of gel network structures.

Therefore, cross-linking of hydrogels are divided into four types includes enzymatic

chemical, physical, enzymatic and multi cross-linked hydrogels

 ORAL DRUG DELIVERY is the best way for medication
administration, due to:
 its lower cost,
 higher patient convenience in comparison with injection or
implantation.

Using oral tablets are either release drug by conventional formulations which reach drug
toxic level, or they can release the drug under controlled manner and keeping the drug
concentration level in the therapeutic window, below the toxic level . Hydrogels can release
loaded drug by diffusion or dissolution mechanisms from microspheres or nanoparticles
after swelling under external stimuli. Polysaccharides are most common natural polymers
candidate as drug delivery systems.
 Polymeric drug delivery system is a formation or it is a device that enables the
introduction of drug or therapeutic substance into the body. The drug delivery system
improves its efficacy and safety by controlling the rate, time, and the target of release
of drugs in the body .

Drug Delivery System (DDS) is technological system works on store drug molecules into proper forms such as tablets or

solutions and then used for administration. The DDS speed the reach of loaded drug to the specific targeted site inside the

body, thereby minimizing off-target drug accumulation in the body and maximizing therapeutic efficacy .
 The profile of the drug release is generally gives as a plot of drug concentration in plasma versus time. Where shows the minimum drug

level which is ineffective, and the maximum drug level with toxic concentration which is undesirable side effects occur. Keeping the drug

concentration between above minimum drug concentration and below toxic level is represent the therapeutic effectiveness . The controlled

DDS is shown a constant level of a drug in blood and body tissue for an extended period. Whereas in conventional DDS, the drug

concentration is fluctuates above and below the toxic level and minimum ineffective level respectively.
 2

Aims of Present Work

 Aims of Present Work
1 Hot-water polysaccharides extraction from Fig Leaves and Pomegranate Peels, purification, and characterization.

2 Preparation of (chitosan-co-polysaccharide) microspheres with covalent and ionic crosslinked by using spray-drying technique and their
characterization.

3 Both prepared systems (chitosan-co-polysaccharide) microspheres were maximum loaded under optimized experimental conditions using model chronic drugs such as,
Carbamazepine, Captopril, Valsartan and Metformin. The loaded microspheres have been characterized.

4 Both loaded systems with different model chronic drugs have been allowed to release and the cumulative drug release from microspheres has been
measured spectrophotometrically.

5 The microspheres after drug release have been characterized.

Carbamazepine Captopril

Valsartan Metformin
 3

Materials and Methods

 Materials and Methods
Different extraction techniques are improved, the green
methods are supercritical fluid extraction, ultra-sonication, hot
water extraction and microwave-assisted, where used for
isolation of bioactive polysaccharides .

To formation the hydrogel The polysaccharide extracted from

fig leaves or pomegranate peels has blended copolymerized with

the most abounded sustainable polysaccharide which is chitosan by

using cross-linked glutaraldehyde and sodium hexa meta

phosphate, respectively
 The loading of drug [Carbamazepine, Captopril, Valsartan; and Metformin] on hydrogel microspheres of both cross-

linking [GLU and SHMP]. Where 100 mg of each hydrogel microspheres were immersed in 50 ml of phosphate buffered

solution (pH=7). Different concentrations of one of aforesaid drugs were prepared up to 100 mg in the 50 ml loading

solution.
 The calibration curve of each drug was used for calculation of the maximum drug loading on the hydrogel microspheres.

The loading drug can be calculated as maximum loading percentage (L max%) and efficiency of loading ELmax(%) using

Equations :

L max% = ……….…..(1)

EL% = ................................(2)

The release characteristics of GLU and SHMP cross-linked for both hydrogels were studied by immersing 100 mg of loaded microspheres

in 20 ml buffered solutions [pH=1.3, pH=7.4, pH=9.4] at 37°C. The release pH media are selected according to the stimulate pH of gastric

fluid, plasma blood fluid, and intestinal fluid in the human body respectively
The release of drug was calculated as a (Controlled, Burst, Cumulative) release percentage %, using the following Equations:

Controlled Release (CR max)% = constant ….……(3)

Burst Release (BR max)% = variable ………...……(4)

Cumulative Release (CR cum) % = …………….…...(5)

 4
Results and Discussion
Results and Discussion
The extracted polysaccharide from Fig
leaves and Pomegranate Peels have been
characterized using three analysis
techniques includes Fourier transform
infrared (FTIR) spectroscopy, proton
nuclear magnetic resonance (1H NMR)
spectroscopy and gas chromatography
Proton Nuclear Magnetic
Fourier Transform Infrared
Resonance (1H NMR)
Gas Chromatography Mass
mass spectrometry (GC-MS). (FTIR) spectroscopy Spectrometry (GC-MS).
spectroscopy

Three Analysis Techniques

Figure 1: FTIR spectrum polysaccharide extracted from Figure 2: FTIR spectrum of polysaccharide extracted
fig leaves from pomegranate peels
 Figure 3

1
H NMR spectrum of :
extracted polysaccharide
from fig leaves

.Table 1: 1H NMR chemical shifts of the main protons of extracted polysaccharide from pomegranate peels
Sample Chemical shift σ/ppm Description of protons

1.12;1.06 methyl group of rhamnose )3H, m(

1.97;1.86 acetyl group of D-galactouronic acid )3H, w(
Extracted polysaccharide methoxy group of D-galactouronic )3H, m(
3.76
acid ;esterification unit
5.11;4.03;3.92;3.8;3.69 galactouronic acid units
 .Table 2: GC/MS spectrometry of extracted polysaccharide from fig leaves

Carbohydrate Galacid Protein Πw Polysaccharide composition

Sample D
)%( )%( )%( )kDa( )%(

Extracted Ara Rha Glc Gal Man Xyl

74.3 48.6 ____ 3309 11.1
polysaccharide 9.1 7.2 8.4 53.6 17.4 4.3
.Ara= arabinose; Rha= rhamnose; Glc= glucose; Gal= galactose; Man= mannose; Xyl= xylose

Figure 4:
GC/MS spectrum of
extracted polysaccharide
from pure pomegranate
 5
Characterization of The Prepared
Hydrogel Microspheres
The hydrogel microspheres prepared by blend copolymerization process of extracted polysaccharide from fig leaves with chitosan and cross-linked

either covalently use glutaraldehyde (CH-co-FLP)/GLU, or ionic cross-linker use sodium hexa metaphosphate (CH-co-FLP)/SHMP. The

following characteristics analyses were performed on the hydrogel microspheres

Table 3: FTIR characteristic frequencies of the most important functional groups of the hydrogels (CH-co-FLP)
FTIR characteristic groups

)C=O-(
Sample υ(O-H)str str )C-H( υ(C=O)str str )N-H( P-O-P str )C-H-( str )CO-NH-( υ(C-H)str
.Symm

Wave number υ/cm-1

2874 1717
CH-co-(
3426 1555 1381 ____ 1253 959 ____
GLU/)FLP
2943 1678

1273,1161
CH-co-(
3495 2886 1655 1531 1373 ____ ____ ____
SHMP/)FLP
1088,899
 Table 4: FTIR main functional groups of hydrogels with their absorption frequencies
FTIR characteristic functional groups
υ(C=O)str υ (N-H)str υ(-C=N-)str υ(C=O)str
Sample υ(O-H)str υ (C=O)str bend )N-H( P-O-P
Amide-I Amide-II .symm
Wave number υ/cm-1
/)CH-co-PE(
3426 1717 1678 1555 1640 1381 1111 _____
GLU

/)CH-co-PE(
3460 1724 1647 1574 1622 1388 1157 1157,1069
SHMP

:Figure 5

1
H NMR spectrum
of (CH-co-FLP)/SHMP
hydrogel

.
 Table 5: 1H NMR chemical shifts with description of protons of (CH-co-PE)/GLU hydrogel
Sample Chemical shift σ/ppm Description of protons

1.0-1.7 glutaraldehyde groups )CH2(

1.04-1.1 rhamnose groups )CH3(

96 .1.84-1 Acetyl groups of pectin
D-glucopyranose of chitosan and methoxy
3.72-3.8
GLU/)CH-co-PE( group of pectin
3.5-4.0 Glucopyranose ring protons of chitosan
3.0-3.8 Cross-linking bonds between glucosamine
groups with glutaraldehyde

.Table 6: Thermal analysis (TGA, DTA and DSC) of the hydrogels

)%( TGA weight loss DTA DSC (W/g)
IDT FDT Tmax Tcr Decomposition rate /Tg

Sample o
C o
C o
C o
C o
C.min/mg o
C Hf (J/g)∆

6.6 94.2 77.4 84.0 0.08 0.92 0.07 481.3+ 3575- 567-

CH-co-FLP/GLU o
C 145.0 o
C 1000.0 o
C 337.5 o
C 390.0 o
C 104.0 o
C 393.8 o
C 690.0 o
C 81.8 C 104.0
o o
C 335.0 o
C 395.0

5.5 98.5 69.3 78.6 0.11 1.22 0.09 273.6+ 2421.7- 390.5-

CH-co-FLP/SHMP o
C 82.0 o
C 1000.0 o
C 235.0 o
C 340.0 o
C 79.0 o
C 335.0 o
C 610 o
C 72.2 o
C 81.0 o
C 335.0 o
C 590.0
 Figure 6

TGA and DSC of the

(CH-co-PE)/GLU hydrog

:Figure 7

TGA and DSC of the

(CH-co-PE)/SHMP hydrogel
Counts
CX2

400

200

0
20 30 40 50 60 70
Position [°2Theta] (Copper (Cu))

Figure 8: XRD pattern of a) (CH-co-FLP)/GLU, and b) (CH-co-FLP)/SHMP hydrogels

Counts
LX2

1000

500

0
20 30 40 50 60 70
Position [°2Theta] (Copper (Cu))

Figure 9: XRD pattern of a) (CH-co-PE)/GLU, and b) (CH-co-FLP)/SHMP hydrogel

A B

Figure 10: SEM images of (A) (CH-co-FLP)/GLU, and

(B) (CH-co-FLP)/SHMP hydrogel
 B
A

,Figure 11: SEM image of (A) (CH-co-PE)/GLU

SHMP/)CH-co-PE( )B(
 :Table 7
BET measurements of
(CH-co-FLP)/GLU
microspheres and their
.specific surface area

:Table 8
BET data of the (CH-
co-PE)/SHMP
hydrogel
 4
3.5 :Figure 12
Degree of swelling (g/g)

3
2.5 Effect of type of cross-linker on
2
1.5 SHMP degree of swelling of (CH-co-FLP)
1 GLU
hydrogel, swelling media = 20ml, buffer
0.5
0
0 5 10 15 20 25 30 35 40
solution (pH7), microspheres = 100mg, T=
Time (h) .37°C

:Figure 13

Degree of swelling of (CH-co-

PE)/GLU and (CH-co-PE)/SHMP
microspheres in pH 7 swelling
media ,and at room temperature
 Characterizations of the loaded
CH/FLP and CH/PE hydrogels
microspheres with selected model
drugs
 .Table 9: Maximum loading and efficiency of the process on hydrogel microspheres

Carbamazepine Captopril Valsartan Metformin

Sample
%Lmax %ELmax %Lmax %ELmax %Lmax %ELmax %Lmax %ELmax
GLU/)CH-co-FLP( 18.0 30.0 28.0 46.7 37.0 61.7 28.0 70.0

SHMP/)CH-co-FLP( 19.0 47.5 31.0 51.7 33.0 55.0 30.0 50.0

.Table 10: Maximum loading and efficiency percentages with different drug models

Carbamazepine Captopril Valsartan Metformin

Sample
%Lmax %ELmax %Lmax %ELmax %Lmax %ELmax %Lmax %ELmax

GLU/)CH-co-PE( 28.0 70.0 31.0 77.5 29.0 72.5 37.0 92.5

SHMP/)CH-co-PE( 31.0 51.7 35.0 58.4 32.0 80.0 37.0 92.5

Table 11: FTIR functional groups of pure drugs and after loading different hydrogels(CH-co-FLP)
Table 12: FTIR functional groups of pure drugs and after loading different hydrogels(CH-co-PE)
 :Figure 14

SEM image of (CH-co-FLP)/GLU

hydrogel loaded with Carbamazepine
.drug

:Figure 15

SEM image of
(CH-co-FLP)/SHMP hydrogel
loaded with Carbamazepine
 :Figure 16

SEM image of (CH-co-FLP)/GLU

hydrogel loaded with Captopril drug

:Figure 17

SEM image of (CH-co-FLP)/SHMP

hydrogel loaded with Captopril
drug
 :Figure 18

SEM image of (CH-co-FLP)/GLU

hydrogel loaded with Valsartan drug

:Figure 19

SEM image of (CH-co-

FLP)/SHMP hydrogel
loaded with Valsartan
drug
 :Figure 20

SEM image of (CH-co-

FLP)/GLU hydrogel
loaded with Metformin
drug

:Figure 21

SEM image of (CH-co-

FLP)/SHMP hydrogel
loaded with Metformin
drug
 :Figure 22

SEM image of (CH-co-

PE)/GLU hydrogel loaded
with Carbamazepine drug

:Figure 23

SEM image of
(CH-co-PE)/SHMP hydrogel
loaded with Carbamazepine
drug
 :Figure 24

SEM image of (CH-co-

PE)/GLU hydrogel
loaded with Captopril
drug

:Figure 25

SEM image of (CH-co-

PE)/SHMP hydrogel
loaded with Captopril
drug
 :Figure 26

SEM image of (CH-

co-PE)/GLU hydrogel
loaded with Valsartan
drug

:Figure 27

SEM image of
(CH-co-PE)/SHMP
hydrogel loaded
with Valsartan
drug
 :Figure 28

SEM image of
(CH-co-PE)/GLU
hydrogel loaded
with Metformin
drug

:Figure 29

SEM image of
(CH-co-PE)/SHMP
hydrogel loaded
with Metformin
drug
Release Studies of Drug From
Loaded Microspheres
 :Figure 30

Effect of release solution pH on Rcum % of Carbamazepine with time(h), from GLU and SHMP cross-linked (CH-
co-FLP) hydrogels. Release media=100 mg microspheres in 20 ml buffered solution [pH=1.3,pH=7.4,pH=9.4],at
.T=37°C
 :Figure 31

Effect of release solution pH on

Rcum % of Captopril with time (h),
from GLU and SHMP cross-linked
(CH-co-FLP) hydrogels. Release
media=100 mg microspheres in 20
ml buffered solution [pH=1.3,
.pH=7.4, pH=9.4], at T=37°C

:Figure 32

Effect of release solution pH on

Rcum % of Valsartan with time (h),
from GLU and SHMP cross-linked
(CH-co-FLP) hydrogels. Release
media=100 mg microspheres in 20 ml
buffered solution [pH=1.3, pH=7.4,
.pH=9.4], at T=37°C
 :Figure 33

Effect of release solution pH on Rcum %

of Metformin with time (h), from GLU
and SHMP cross-linked (CH-co-FLP)
hydrogels. Release media=100 mg
microspheres in 20 ml buffered
solution [pH=1.3, pH=7.4, pH=9.4], at
.T=37°C

:Figure 34

Effect of release solution pH on Rcum

% of Carbamazepine with time (h),
from GLU and SHMP cross-linked
(CH-co-PE) hydrogels. Release
media=100 mg microspheres in 20 ml
buffered solution [pH =1.3, 7.4, 9.4] ,
.at T=37°C
 :Figure 35

Effect of release solution pH on Rcum %

of Captopril with time (h), from GLU
and SHMP cross-linked (CH-co-PE)
hydrogels. Release media=100 mg
microspheres in 20 ml buffered
solution [pH =1.3, 7.4, 9.4] , at
.T=37°C

:Figure 36

Effect of release solution pH

on Rcum % of Valsartan with time (h),
from GLU and SHMP cross-linked
(CH-co-PE) hydrogels. Release
media=100 mg microspheres in 20 ml
buffered solution [pH =1.3, 7.4, 9.4] ,
at T=37°C
 :Figure 37

Effect of release solution pH on Rcum % of Metformin with time (h), from GLU and SHMP cross-linked (CH-co-PE)
.hydrogels. Release media=100 mg microspheres in 20 ml buffered solution [pH =1.3, 7.4, 9.4] , at T=37°C
Characterizations Studies of The
Hydrogels After Release
.Table 13: FTIR main functional groups of GLU and SHMP cross-linked (CH-co-FLP) hydrogel after release their loaded drugs
.Table 14: FTIR main functional groups of GLU and SHMP cross-linked (CH-co-PE) hydrogel after release their loaded drugs
EM Studies of The Hydrogels After
Release
 :Figure 38

SEM image of (CH-co-FLP)/GLU

hydrogel after release of
Carbamazepine drug

:Figure 39
SEM image of (CH-co-FLP)/SHMP
hydrogel after release of
Carbamazepine drug
 :Figure 40
SEM image of (CH-co-FLP)/GLU
hydrogel after release of Captopril
drug

:Figure 41
SEM image of
(CH-co-FLP)/SHMP
hydrogel after release of
Captopril drug
Figure 42: SEM image of (CH-co-FLP)/GLU hydrogel after release of Valsartan drug

Figure 43: SEM image of (CH-co-FLP)/SHMP hydrogel after release of Valsartan drug
 :Figure44
SEM image of (CH-co-FLP)/GLU hydrogel after release of Metformin drug

:Figure 45
SEM image of (CH-co-FLP)/SHMP hydrogel after release of Metformin drug
 :Figure 46

SEM image of (CH-co-PE)/GLU

hydrogel after release of
Carbamazepine drug

:Figure 47

SEM image of (CH-co-PE)/SHMP

hydrogel after release of
Carbamazepine drug
 :Figure 48 :Figure 49

SEM image of (CH-co-PE)/GLU hydrogel after release of Captopril drug SEM image of (CH-co-PE)/SHMP hydrogel after release of Captopril drug
 :Figure 50 :Figure 51

SEM image of (CH-co-PE)/GLU hydrogel after release of Valsartan drug SEM image of (CH-co-PE)/SHMP hydrogel after release of Valsartan
drug
Figure 52: SEM image of (CH-co-PE)/GLU hydrogel Figure 53: SEM image of (CH-co-PE)/SHMP hydrogel
after release of Metformin drug after release of Metformin drug
General Conclusion
Extraction of biomaterial polysaccharides from fig leaves and pomegranate peels was worked efficiently using a simple method called hot-water

polysaccharide extraction. The method was found safe and extracted polysaccharides were characterized after purification and the analyses

showed the extracted materials are pectin-like with traces of other hydrocarbons extracted from fig leaves and given fig leaves polysaccharide

(FLP) title, and pectin also with traces of some hydrocarbons extracted from pomegranate peel and given pectin (PE) title.
The extracted polysaccharides (FLP and PE) are copolymerized with chitosan. The formed hydrogels (CH-co-FLP) and (CH-co-PE) are cross-

linked by ionically using sodium hexametaphosphate (SHMP) and covently by gluteraldehyde (GLU). The new hydrogels were characterized and

their chemical and crystalline structure were examined besides their morphological and thermal form were studied. The size particles and shape

factors of their surfaces were measured, the ionic cross-linked hydrogels have shown particles smooth surface; whereas, the covalent cross-linked

hydrogel showed particles with high degree of roughness

The prepared hydrogels are preamble for loading and release in controlled drug delivery systems. First of all, the hydrogels were

examined the maximum degree of swelling where this property is very effective character of microspheres shows their ability for loading

drugs and in the same time release the loaded materials. The (CH-co-FLP)/GLU hydrogel showed DS%= 295% and (CH-co-FLP)/SHMP

hydrogel gave DS%= 380% due to the ionic cross-linking the SHMP hydrogel showed more degree of swelling. Similarly, the (CH-co-

PE)/GLU hydrogel showed DS%= 290%, while (CH-co-PE)/SHMP gave DS%= 250%, is lower due to the anionic nature of pectin
Four drugs model are loaded into the prepared hydrogels, Captopril, Valsartan, and Metformin. (CH-co-FLP) hydrogels have shown different

maximum loading percentages (Lmax%). Valsartan showed Lmax%= 37% in (CH-co-FLP)/GLU hydrogel because of its weak acid nature.

Similarly, valsartan showed Lmax%= 33% in (CH-co-FLP)/SHMP hydrogel. On the other hand, the (CH-co-PE) hydrogel systems have shown

high maximum loading percentages. Where, Metformin drug was highest Lmax%= 37% in both hydrogel (CH-co-PE)/GLU and

(CH-co-PE)/SHMP maybe because Metformin has strong basic nature help for more interactions between Metformin ions and the functional

groups of the hydrogels.

The release behavior of the loaded hydrogels were tested at 37 in different pH media, where pH= 1.3, pH= 7.4, and pH= 9.4 are simulate the pH of
gastric fluid, plasma blood fluid, and intestinal fluid in the human body, respectively. The release character from loaded microspheres showed the
cumulative release (Rcum%) on different elements, type of cross-linker, pH of release media and composition of drug used. The release curves
showed that the carbamazepine drug loaded (CH-co-FLP)/GLU hydrogel has cumulative controlled release for 24 h in pH= 9.4. While valsartan
drug loaded (CH-co-FLP)/GLU hydrogel has controlled Rcum% for 18 h in pH= 9.4. Captopril loaded (CH-co-FLP)/SHMP hydrogel has
controlled Rcum% for 18 h in pH= 9.4. Finally, Metformin loaded (CH-co-FLP) hydrogels for both cross-linkers have bad controlled Rcum% due
to the high interactions between drug molecules and hydrogel components.
The (CH-co-PE) hydrogels system showed release curves almost different profile in comparison with (CH-co-FLP) hydrogels. Where,

carbamazepine loaded (CH-co-PE) hydrogel with both cross-linker showed controlled cumulative release Rcum% for 18 h in pH= 7.4. Captopril

loaded (CH-co-PE)/GLU hydrogel showed controlled Rcum% for 18 h in pH= 7.4. Valsartan loaded (CH-co-PE)/SHMP hydrogel showed

controlled Rcum% for 18 h in pH= 1.3 and pH= 9.4 where in both release media the drug molecules repulse with hydrogel components. Whereas,

metformin in both systems (CH-co-PE) with GLU and SHMP showed non-controlled release character similar to the (CH-co-FLP) hydrogel

systems.
Anyway, the fig leaves and pomegranate peels are excellent candidate for extraction of biomedical polysaccharide. The hydrogel microspheres,

in general showed high degree of swelling and their maximum loading percentages was moderate, and finally the microspheres are suitable to

use in controlled drug delivery systems.

THANK YOU !
For Your Attention