Development and Evaluation of Hydrodynamically Balanced System of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum
Development and Evaluation of Hydrodynamically Balanced System of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum
Development And Evaluation Of Hydrodynamically Balanced System Of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum
ABSTRACT
The main purpose of the study was development and evaluation of hydrodynamically balanced capsule of Tramadol HCl by using chitosan and locust bean gum as a natural polymer that prolongs the gastric residence time. Chitosan with different grade (low molecular weight, medium and high molecular weight) and locust bean gum were used as a drug release retarding agents. The hydrodynamically balanced capsule of tramadol HCl were prepared by ordered mixing technique. The concentration of both the polymers was optimized in order to achieve the sustained release of drug (TH) for 10 hours. Then the prepared capsules were evaluated for buoyancy test and in vitro drug release were performed. And other characterization analysis was also considered like FTIR study, DSC/DTG/TGA study and interaction study were also performed on the basis of characterization analysis. From these studies it was confirmed that there is no interaction observed between drug and excipient. The drug release studies shows that the retarding drug release pattern is dependent on the concentration and molecular weight of polymer as the concentration /molecular weight increases the retarding drug release pattern was also improved. And the synergistic action of retarding drug release was observed by the addition of another polymer i.e locust bean gum. Release pattern was fitted with the different kinetic model like Zero order, First order, Higuchi model and Korsmeyer peppas and it was concluded from the models that the drug release pattern obeys zero order model which signifies high therapeutic efficacy and minimum side effects.
Keywords: Tramadol HCl, Chitosan, Locust bean gum, Hydrodynamically Balanced System, Buoyancy, Gastric Residence Time.
Author details-Pravjot Kaur1* Surabhi Ghildiyal2 and Dr. Shashank Soni3
Corresponding Author Address-1Department of Pharmacy, Sardar Bhagwan Singh Post-graduate Institute of Biomedical Sciences and Research, Dehradun, Uttarakhand, India; E-mail: [email protected]
1Department of Pharmacy, Sardar Bhagwan Singh Post-graduate Institute of Biomedical Sciences and Research, Dehradun, Uttarakhand, India; E-mail: [email protected]
2Amity Institute of Pharmacy, Amity University Uttar Pradesh, Lucknow, India; E-mail: [email protected]
INTRODUCTION
Oral route has been declared the most suitable and broadly acknowledged path of drug delivery system. Therefore oral controlled release dosage forms owes a remarkable benefit and this route is being considered as the remarkable point in the field of pharmaceutical sciences to achieve the set of goals of therapeutic advantages such as: reduced dosing frequency, better patient comforts and compliance, variation in the plasma drug level is less, Lesser total dose, reduced gastro intestinal tract side effects, improved safety and efficacy ratio.
Several difficulties has been arises in developing oral controlled release system for enhancing absorption and better bioavailability.
Difficulties include:
· Facing inability to target the drug dosage form in the area of desire in stomach.
· Drug absorption is a complicated process and owing many variables
· Rapid transit time of GIT can hinder the drug release behaviour in the absorption zone and minimises the safety and efficacy of the drug dose etc.
A novel drug delivery system was accomplish to overcome all such processed variables and one of the attempts is gastro retentive system. Gastro retentive drug delivery system is design in such way that by improve the gastric residence time of drug it resides in the gastric region for the numerous hours, by improving the gastric retention time it improves the absorption and bioavailability, decreases the drug waste and improve the solubility of drug which are less soluble in gastric pH environment (Sharma et al., 2014).
Gastro retentive drug delivery system also helps to provide a remarkable better availability of new product with new valuable therapeutic possibilities and substantial benefit for patients. Access of floating drug delivery system is most beneficial and commonly used because this system is most advantageous leads to gastric retention effervescent which liberates Co2 when comes to the contact with GI fluids and makes effort to float the dosage form. System having less density (<1.004 gm/cm³) than gastric fluid and hence it support the buoyant behaviour in the fluid and shows controlled release behaviour of drug dosage form. GI tract helps to maintain the efficient drug concentration for the extent of time in a systemic circulation. (Singh et al., 2011)(Aslam et al.,2014)
After the swallowing of the drug delivery dosage form it should be reside in the stomach and delivery of the drug in the controlled design to its absorption site for continuous release of drug.
1.1 ANATOMY OF STOMACH
Figure 1.1- Anatomy of stomach (Sabale et al., 2010)
1.2 CONCEPT OF HYDRODYNAMICALLY BALANCED SYSTEM
Gastric emptying process of the dosage form is tremendously a variable process and the ability of the dosage form to extend and maintain the gastric emptying time is a remarkable consideration, and to abide in the stomach for the extensive interval than conventional dosage form. Various difficulties arise to design the controlled systems with an aim of better absorption and improving bioavailability. Among this one of the major issues are to reside the drug dosage form in an aim area of gastrointestinal tract. Drug absorption is very complicated phenomenons and it subject to variable process because it is associated to the contact time with small intestinal mucosa. Therefore the transit time of small intestine is very important parameter for the drug absorption. (Sabale et al.,2010)(Jain et al.,2011)
Hydrodynamically balanced systems are design in such a way that by extending the gastric residence time of drug it can abide in the gastric area for several hours and significantly prolonging the gastric retention timeof drug and this enhanced the bioavailability, decrease the drug waste and modify the solubility of drug. With the action of extending the gastric retention time of delivery system is valuable for achieving therapeutic benefit for the drug substances.
By implementing various principles like flotation, expansion, sedimentation, mucoadhesion, or by modifying shape system the controlled retention time of drug dosage forms can be achieved. (Garg et al.,2008)
1.2 MECHANISM OF HYDRODYNAMICALLY BALANCEDS SYSTEM
Figure1.2-Working principle of hydrodynamically balanced capsule
(Nasa et al.(2010)
According to this principle, hydrodynamically balanced capsule is composed of drug and gel molding hydrocolloid polymer or a matrix forming polymer. After the swallowing of this drug dosage form it comes in the contact with gastric fluid and swells, it maintains the integrity of shape and its bulk density reduces less than 1 gm/ml.
Then the air trapped between the swollen cast and convey buoyancy to this dosage form. When this drug dosage form comes in the contact with aqueous medium the hydrocolloid polymer forms a gelatinous barrier and controls the diffusion rate of solvent in and drug out from the dosage form. When the drug dosage form which is consist of drug and mixture of hydrocolloid polymer, the capsule shell dissolves and the polymer swells lead to form a gelatinous barrier and shows buoyant behaviour in the gastric fluid for extend period of time.(Patil*et al.,2005)
1.6PROPERTIES OF POLYMER THAT ARE USED IN GASTRORETENTIVE DELIEVERY SYSTEM
1.6.1 Controlled drug release
When by the process of simple drug dissolution, by membrane control, by diffusion, by osmotic systems, by erosions, retardation mediated by ionic interaction the sustained release cannot be supplied. By the use of anionic polymeric excipient controlled release for the cationic drugs can be achieved. The relation between the chitosan and therapeutic agents can be more prominent by using polyanionic drug and depend on ionic cross linking in addition form a stable complex so that the drug can be released in more prolonged duration of time.
1.6.2 Mucoadhesive property
This property is mostly based upon its cationic character and sometimes the hydrophobic interactions. Various anionic polymer excipients like hyaluronic acid, carbine, polycarbophyl their mucoadhesive properties are weak. In order to achieve high mucoadhesive properties the polymer need to display high cohesive properties like adhesive bond or else abort within mucoadhesive polymer rather than in mucus gel case and polymer.
1.6.3 In situ gelling properties
In situ gelling property offers by the hydrogels containing polymer when their pH dependent hydaratability properties are demonstrated properly and these in situ gelling property was enhanced by the thiolation process.
1.6.4 Transfection enhancing properties
For small molecules where controlled drug release for ionic drugs can be developed and large polyanionic polymer molecules like DNA-based drugs and siRNA form stable complexes. Alike nanoparticles exhibit a positive zeta potential when there is a high ratio of cationic polymer. Due of these small particles and net positive charge endocytosis can be achieved when the size is below 100nm. Few of the polymer found to have low transfection enhancing properties the polysaccharides developed the different strategies to enhance its properties. This property can also be enhancing by self branching substitution technique.
1.6.5 Permeation enhancing properties
This mechanism of permeation improving properties is totally depend on the positive charge of the polymer which shows a interact with the cell membrane leads in resulting a structural rearrangement in tight junction paired with properties.
Based on degree of acetylation and molecular mass the announced the permeation enhancing property. Polymers having high degree of acetylation and of high molecular mass demonstrate the high epithelial permeability. This result in increase the permeation enhancing effect along with rising molecular mass also observed.
By the process of thiolation technique this permeation enhancing property can also be increased by a number of folds.
1.6.6 Efflux pump inhibitory properties
If the molecular mass is in the range of 150kDa at least for chitosan derivative polymer to the most marked inhibition. (Bernkop-Schnurch et al.,2012)
3.1 AIM
Development And Evaluation Of Hydrodynamically Balanced System Of Tramadol Hydrochloride By Using Chitosan And Locust Bean Gum.
3.2 OBJECTIVE
The objective of past work was to designed and developed a hydrodynamically balanced system of Tramadol HCl as single unit gastro retentive capsules. Various weight grade of density polymers along with or without gas producing ingredient (CaC03) can be encorporating for this system. The system develop is to expected to remain in the upper part of stomach which helps in improving the gastro retention in the upper part of stomach which have a limited absorption frame.
3.2.1 Selection of drug
TH is a synthetic codeine analog and weak µ-opoid receptor against having an anormous potential impending in analgesia. A specific absorption window limited only to the upper part of small intestine coupled with high frequency of drug administration (4-6 hrs) and small dose of 50-100mg and small biological half life. It comes under the category of BCS class Ì therapeutic agent which has characteristics of highly soluble and highly permeable. By employing gastro retentive technology, after the swallowing improves the gastric residence time, reduces the drug loss and drug bioavailability and decrease the side effects of drug is insomnia, constipation, hallucination etc.(Singh et al., 2010).
3.2.2 Selection of polymer
Chitosan is a polysaccharide which are isolated from the cells of crustaceans like shrimp, crab and other sea crustaceans which include Pandalus borealisand cell wall of fungi and chemically it is 2-amino 2-deoxy-b-d-glucopyronose which has a molecular formula(C6H11O4N)N .It is also called a soluble chitin and it is practically insoluble in water, acid and alcohol.
Molecular weight ranges from 3800-20000 Daltons. It has a pka value of ~ 6.5 which lead to the protonation in acidic to neutral solution with having charge density depend on pH and deacetylation value which makes the property of soluble in nature.
Basically chitosan is cationic polymer which binds to the negative charge surface of mucosal membrane and lead to the mucoadhesion to the mucosal membrane and this all property makes the chitosan as a ideal polymer for gastro retentive. It enhances the transport of hydrophilic drug across the epithelial surface. It has also property of hydrogel development when it arrives in the open contact with aqua it forms a hydrogel structure which helps in retarding the drug from the matrices.
Locust bean gum used as sustained release carriers and release modifier for delivery of TH. It is a neutral plant galactomannans extracted from the seeds (kernels) of the carob tree Ceratonia siliqua L fabaceae. Nowadays it is focussing polymer and a lot of researchers are focussing for exploring the potential in topical drug delivery, colonic drug delivery , oral sustained drug delivery, ocular drug delivery, buccal drug delivery,
4.1 MATERIALS
Table 4.1 Materials used for formulation
S.No
Materials
Suppliers
1.
Tramadol HCl
Yarrow Chem
2.
Chitosan
Aldrich
3.
Locust bean gum
Yarrow Chem
4.
Calcium chloride
CDH026035
5.
Syringe
4.1.1. EQUIPMENT REQUIRED
Table 4.2 Equipment required for formulation
S.No.
Equipments/ Instruments
Suppliers
Model
1.
Digital Weighing Balance
SHIMADZU
FLB 300
2.
Mechnanical Stirrer
REMI ELECTROTECHNIK LIMITED
KFU25353
3.
Magnetic Stirrer
PERFIT
KFU25353
4.
U.S.P. Dissolution test apparatus
ELECTROLAB
1301014
5.
UV-Visible Double Beam Spectrophotometer
SHIMADZU
2101
6.
Digital pH meter
SYSTRONICS MK
886131
7.
Hardness Tester
Monsanto
EHO1P
9.
FourierTransformInfra Red (FTIR)
SHIMADZU, MUMBAI,INDIA
10.
Scanning electron microscopy(SEM)
435 VF
LEO, India
11.
Digital Melting point apparatus
1013 A
PERFIT Instruments, Mumbai, India
12.
Hot Air Oven
NSW- 143
NARANG SCIENTIFIC WORK Pvt, ltd, India
METHODS
5.1. FORMULATION TABLE-
Formulation code
TH
(mg)
LMWCH (mg)
MMWCH (mg)
HMWCH (mg)
LBG
(mg)
LF1
200
60
---
---
---
LF2
200
70
---
---
---
LF3
200
80
---
---
---
LF4
200
60
---
---
LF5
200
70
---
---
35
LF6
200
80
---
---
40
MF1
200
---
60
---
---
MF2
200
---
70
---
---
MF3
200
---
80
---
---
MF4
200
---
60
---
30
MF5
200
---
70
---
35
MF6
200
---
80
---
40
HF1
200
---
---
60
---
HF2
200
---
---
70
---
HF3
200
---
---
80
---
HF4
200
---
---
60
30
HF5
200
---
---
70
35
HF6
200
---
---
80
40
All the compositions of drug and excipients were chosen on the basis of initial trial studies for buoyancy studies and drug retarding pattern
TH- Tramadol hydrochloride LMWCH- Low Molecular Weight Chitosan MMWCH- Medium Molecular Weight Chitosan HMWCH- High Molecular Weight Chitosan LBG-Locust Bean Gum
Drug retarding polymer of chitosan (high, medium, low) depends on degree of acetylation and viscosity. In LMWCH the degree of deacetylation is low and this degree of acetylation is high in HMWCH and this acetyl group is responsible for binding with drug and form a drug-polymer complex and it also depend upon the charge present on the drug. As the pka value of TH is approx 9.3 which is highly basic in nature and posses the negative charge as well as the pka value of chitosan is 6.5 and it posses positive charge and hence they easily bind with each other and form a complex and this resulted complex retards the drug discharge pattern in gastric surface.
With chitosan another natural based polymer LBG is also encorporated with drug formulation to analyze the drug discharge pattern. Hence it was observed that by the addition of LBG with chitosan it promotes the retardation pattern of drug release.
In this the mechanism involves, that by encorporating the polymers with drug it forms a gelatinous barrier over the drug when arrives in the open contact with the gastric fluid and lead to the decrease in the density of dosage form and it exhibits buoyant behaviour to dosage form and the aqueous medium penetrates in the polymeric strand then the dosage form maintains the diffusion rate by solvent in and drug out technique. So in this case as the concentration of polymer increases the binding efficiency will also improves and hence it retards the drug release pattern.
5.1.3 Preparation of HBS-TH capsules
Hydrodynamically balanced system capsulesl was prepared by ordered mixing technique by placing the drug between the layers of polymers in a borocil glass vial (10mg) and shaken vigorously by hand for 5 min followed by encapsulation colourless hard gelatincapsule shell(size#00). The procedure have advantage that it does not cause the size reduction neither drug nor polymers during mixing that it would believe to effect the release profile of formulation (Soni et al., 2013)
RESULTS AND DISCUSSION
6.1PREFORMULATION STUDIES
6.1.1Physical characteristics
The obtained Tramadol HCl sample was found white or almost white and was in accordance with Merck Index.
6.1.2 Melting point determination
To determine the melting point of the powdered drug was first filled in capillary tube with one end open and one end closed and then the capillary was placed in Digital melting point apparatus and the temperature at which the powdered API first start melting was noted as the melting point. It was found to be 179°C against the range of 179°C-181°C.
Depicted value (drug bank.ca)
Observed value(°C)
181°C
179°C-181°C
6.1.3 Solubility profile of drug in 0.1N HCl
Solubility of (TH) in 0.1N HCl was found to be 0.73mg/ml.
Table 6.1 Observation table of solubility of TH in 0.1N HCl
Solvent
Solubility (mg/ml)
0.1N HCl
0.73 mg/ml
6.1.4 Partition coefficient of drug
The partition coefficient of drug was found to be 8.5. Thus, the drug is classified to be hydrophilic in nature.
6.2. Analytical study Studies of Drug
6.2.1 Determination of λmax of drug in 0.1N HCl
In 0.1N HCl, the λmax of the drug was found to be 215nm.
Figure 6.1 Spectrum of drug in 0.1N HCl
Table 6.2 Calibration curve data of Tramadol Hydrochloride in 0.1N HCl
Concentration
(µg/ml)
Absorbance
(units)(1)
Absorbance
(units)(2)
Absorbance
(units)(3)
Average
Absorbance
±S.D
0
0
0
0
0
0
0.2
0.230
0.230
0.231
0.230
0.00058
0.4
0.346
0.348
0.348
0.347
0.00115
0.6
0.472
0.474
0.471
0.472
0.00153
0.8
0.636
0.636
0.636
0.634
0.00132
1.0
0.794
0.796
0.796
0.795
0.001
1.2
0.988
0.988
0.983
0.986
0.00280
Figure 6.2 Calibration curve data of Tramadol Hydrochloride in 0.1N HCl
6.2.3THERMAL CHARACTERIZATION USING DSC/DTG/TGA
Differential Scanning Calorimetry (DSC) was performed by EXSTAR TG/DTA 6300. DSC was employed to find out the characteristic peak (exothermic and endothermic) and exact melting point of the drug, excipient and drug excipient samples used in the present investigation. The DSC analysis was carried out over melting point at a rate of 5°C, in presence of inert nitrogen (N2) using duplicate samples of 5mg in crimped aluminium pans (Reetika Ganjoo et.al.2016).
6.2.3 Thermal Analysis Study:
Figure 6.3 Thermal Analysis of pure drug Tramadol hydrochloride(TH)
Thermal Analysis of pure drug Tramadol hydrochloride(TH)
Figure 6.3 shows DTG thermogram of TH represents that the drug is stable at 264°C and maximum loss of mass occurs from 200°C to 315°C which is represented by biphasic thermogram and maximum loss of mass occurs is 8.4%. The DSC thermogram represents the small endothermic peak at 182°C is melting point of TH another broad endothermic peak at 271°C and broad endothermic peak at 556°C represents the degradation of TH under the experimental condition.
Figure6.4 Thermal Analysis of chitosan
Thermal Analysis of chitosan
Figure 6.4 shows the thermal behaviour of chitosan . DTG thermogram shows that chitosan is stable upto temperature of 295°C which is characterized by exothermic peak. It also shows the small exothermic peak at 77°C. This shows the vapourization of water molecule from the void spaces and from the surface of chitosan degradation and maximum loss of water molecule represented by thermogram and it shows the biphasic curve maximum loss of mass takes place from temperature 200°C-300°C and this period about 61.6% loss of mass takes place. The DSC thernogram of chitosan represents 1 broad exothermic peak 304°C (enthalpy-6.31Joule/mg) which results in the slow degradation of chiotosan.
Figure 6.5 Thermal Analysis locust bean gum
Thermal Analysis of locust bean gum
Figure6.5 shows the DTG thermogram of locust bean gum suggests the polymer is stable at 291°C and maximum loss of mass takes place between temperature 200°C-312°C and 199°C-557°C showing the %loss of mass 48.7%and 33.3% respectively. The DSC thermogram explains the glass transition temperature at 302°C by broad exothermic peak at 607°C represents the rapid degradation of polymer under experimental conditions.
Figure 6.6 Thermal Analysis of tramadol hydrochloride, chitosan and locust bean gum mixture
Thermal Analysis of tramadol hydrochloride, chitosan and locust bean gum mixture
Figure 6.6 represents the thermogram of physical mixture under experimental condition. DTG thermogram at 259°C represents that the physical mixture is stable at 259°C. The maximum loss of mass occurs from 200°C-300°C and 400°C-500°C showing the % loss of mass 34.02% and 28.84% respectively. DSC thermogram explains that there is two endothermic peaks shows the melting point at 182°C and 268°C, the first endothermic shows the melting point of TH and this endothermic peak is also presence.
Figure1 second endothermic peak represents the glass transition temperature at 268°C. The broad exothermic peak at 517°C, 557°C and at 884°C represents the slow degradation of physical mixture in experimental condition. From the thermogram interpretation we can reveal that there is no any possible drug excipient interaction takes place.
6.2.4 FTIR STUDY:
Figure 6.7 FTIR of Tramadol HCl
Figure 6.7 FTIR of Tramadol HCl (jagadeesh et al,2017)
Table6.3- FTIR interpretation of Tramadol HCl
Functional group
Type of Vibration
Wavelength (cm-1)
Reported value
(cm-1)
Peak Characterization (cm-1)
N-H
Stretching
3305
3300
3000-3700
C-H
Stretching
2933
2961
2960-2850
C=C
Stretching
1465
1461
1450-1600
C-N
Stretching
1048
936
1000-1410
C-O
Stretching
940
1044
900-1410
C-C
Stretching
855
836
800-1200
FTIR of chitosan-
Figure 6.8 FTIR of chitosan
Table 6.4- FTIR interpretation of chitosan
Functional group
Type of Vibration
Wavelength (cm-1)
Peak Characterization (cm-1) (Ganjoo et al.2016).
C-H
Stretching
2920
2500-3200
O-H
Stretching
3290
Near about 3000
CH2
Stretching
1384
1000-1500
C-O-C
Stretching
1151
1000-1500
N-H(1)
Stretching
3500-3300
Near about 3000
Figure 6.9 FTIR of locust bean gum
Table6.5- FTIR interpretation of locust bean gum-
Functional group
Type of Vibration
Wavelength (cm-1)
Peak Characterization (cm-1)
O-H
Stretching
3339
3200-3500
C-H
Bending/wagging
2888
2800-2950
C-OH
Stretching
1022
1000-1100
C=O
Stretching
1722
1680-1750
C-O-C
Stretching
1413
1000-1500
FTIR of Physical mixtures (trmadol HCl, locust bean gum and chitosan mixture)-
Figure 6. 10 FTIR of Physical mixtures (tramadol HCl, locust bean gum and chitosan mixture)
Table 6.6- FTIR interpretation of Physical mixtures (trmadol HCl, locust bean gum and chitosan mixture)-
Functional group
Type of Vibration
Wavelength (cm-1)
Peak Characterization (cm-1)
N-H
Stretching
3301
3000-3700
O-H
Stretching
3447
3200-3500
CH2
Stretching
2625
2500-3200
C-H
Stretching
2933
2500-3200
C=C
Stretching
1465
1450-1100
C-N
Stretching
1179
1000-1410
C=O
Stretching
1722
1700-1750
C-O-C
Stretching
1413
1000-1500
C-OH
Stretching
1011
1000-1100
C-O
Stretching
1290
1000-13200
6.2.5 Buoyancy and Lag Time Studies
Table 6.7 showing Buoyancy and Lag time
FORMULATION
FLOATING TIME (Hours)
LF1
LF2
3
LF3
3.5
LF4
3
LF5
3
LF6
3.5
MF1
3
MF2
3
MF3
3.5
MF4
3
MF5
3
MF6
3.5
HF1
3
HF2
3
HF3
3.5
HF4
3
HF5
3
HF6
3.5
6.2.6 In vitro drug release-
Table 6.7 %Cumulative drug release of formulation LF1-LF6
TIME
(hours)
Cumulative % Drug Release ± S.D
LF1
LF2
LF3
LF4
LF5
LF6
0
0
0
0
0
0
0
1
26.859±0.25
21.328±0.13
20.248±0.32
15.512±0.46
19± 0.37
14.125±0.21
2
40.8± 0.41
38.7780.22
35.579±0.31
24.848±0.25
29.911±0.30
31.241±0.13
3
45.56± 0.27
41.055±0.43
28.523±0.56
42.549±0.46
34.263±0.14
25.120±0.25
4
54.164±0.22
49.1590.26
31.37± 0.21
43.389±0.14
42.216±0.26
28.021±0.31
5
72.56± 0.32
57.53± 0.42
33.901±0.36
51.634±0.23
50.704±0.32
30.122±0.31
6
76.347±0.43
63.378±0.20
48.005±0.38
58.78± 0.39
58.758±0.45
45.311±0.21
7
81.358±0.14
64.649±0.34
62.378±0.20
78.544±0.11
61.64±0.344
58.111±0.12
8
92.417±0.25
84.192±0.35
77.071±0.30
87.27±0.26
76.93±0.37
75.322±0.13
9
95.417±0.125
89.652±0.27
84.50± 0.29
91.82± 0.36
87.814±0.35
82.510±0.31
Figure 6.11 %Cumulative drug release of formulation LF1-LF6
Table 6.8 %Cumulative drug release of formulation MF1-MF6
Time(hr)
% Cumulative drug Release
MF1
MF2
MF3
MF4
MF5
MF6
0
0
0
0
0
0
0
1
12.845±0.2
12.067±0.36
11.678±0.32
11.547±0.13
11.540±0.46
10.878±0.21
2
29.652±0.1
28.481±0.36
23.177±0.22
26.990±0.21
25.647±0.25
22.922±0.36
3
35.882±0.32
32.999±0.34
32.237±0.12
33.117±0.37
30.732±0.36
31.174±0.20
4
47.38±0.14
41.637±0.30
40.059±0.28
45.994±0.45
37.060±0.34
39.496±0.32
5
58.370±0.22
57.471±0.20
52.702±0.28
56.193±0.11
53.180±0.12
48.526±0.34
6
66.693±0.45
64.892±0.36
64.702±0.12
64.311±0.24
61.631±0.30
60.767±0.11
7
72.391±0.31
74.420±0.21
76.111±0.55
68.330±0.36
73.123±0.28
75.147±0.32
8
84.638±0.12
82.626±0.26
80.118±0.30
82.011±0.11
81.257±0.20
78.669±0.38
9
93.638±0.55
91.472±0.11
90.717±0.54
92.748±0.30
89.257±0.43
88.36±0.31
Figure 6.12 %Cumulative drug release of formulation MF1-MF6
Table 6.9 %Cumulative drug release of formulation HF1-HF6
Time (Hours)
Cumulative % Drug Release ± S.D
HF1
HF2
HF3
HF4
HF5
HF6
0
0
0
0
0
0
0
1
12.845±0.13
12.067±0.46
8.678±0.30
11.547±0.41
12.54±0.47
8.878±0.21
2
19.652±0.21
20.481±0.25
23.481±0.41
18.99±0.45
25.647±0.30
21.988±0.35
3
30.882±0.31
32.999±0.36
30.237±0.43
29.944±0.66
30.732±0.23
31.174±0.20
4
47.838±0.11
39.088±0.34
37.059±0.20
370117±0.55
37.06±0.14
35.496±0.34
5
52.37±0.24
48.637±0.120
43.702±0.36
51.193±0.31
43.18±0.31
41.526±0.11
6
60.693±0.35
58.471±0.30
57.390±0.28
59.33±0.26
55.351±0.0
54.767±0.32
7
67.391±0.22
64.892±0.20
64.675±0.12
69.311±.55
74.123±0.25
75.147±0.38
8
74.08±0.34
74.42±0.26
72.118±0.54
72.066±0.43
72.257±0.54
70.669±0.49
9
91.638±0.52
86.472±0.46
82.717±0.52
89.748±0.41
84.803±0.45
80.577±0.48
Figure 6.12 %Cumulative drug release of formulation HF1-HF.
As the weight of chitosan increases in formulation(LF1-LF3) the drug release pattern was retarding with increase in molecular weight whereas in addition of locust bean gum (LF4-LF6) with increasing concentration it results in synergistic action in retarding drug release pattern as compared with (LF1-LF3). The same effect was observed with medium molecular weight chitosan formulation (MF1-MF6) and with high molecular weight chitosan (HF1-HF6). But as increasing the molecular weight of chitosan (low, medium, high) in different batches, there is decresae in the drug release pattern as shown above. This retardation of drug release is due to the degree of deacetylation, as the molecular weight of chitosan increase there is more amino and hydroxyl group present in our polymer for binding with moiety and hence there will be strong cross linking complex with increase in molecular weight of chitosan, and as well as the locust bean gum posses a good gelling property so with the addition of this polymer it improves the gelatinous barrier over the drug and retards the drug release pattern.
6.2.7 DRUG RELEASE KINETICS
Table 6.10 -Table showing data for release kinetics
Formulation no.
r2
n value
Zero Order
First order
Higuchi
Korsmeyer
Peppas
LF1
0.608
0.537
0.984
0.608
1.23
LF2
0.973
0.844
0.845
0.963
1.32
LF3
0.970
0.582
0.956
0.651
1.25
LF4
0.983
0.659
0.928
0.731
1.36
LF5
0.995
0.722
0.920
0.815
1.46
MF1
0.989
0.667
0.934
0.739
1.35
MF2
0.991
0.722
0.894
0.777
1.39
MF3
0.992
0.695
0.915
0.764
1.38
MF4
0.993
0.724
0.897
0.786
1.38
MF5
0.986
0.724
0.897
0.786
1.41
MF6
0.972
0.732
0.884
0.809
1.47
HF1
0.990
0.695
0.927
0.772
1.39
HF2
0.988
0.712
0.899
0.773
1.39
HF3
0.992
0.730
0.902
0.816
1.46
HF4
0.995
0.718
0.905
0.786
1.41
HF5
0.995
0.698
0.920
0.769
1.39
HF6
0.994
0.710
0.918
0.791
1.43
In this release kinetic data were fitted to various different models like Zero order, First order, Higuchi model and Korsmeyer peppas kinetics in order to know about the release pattern. By using MS EXCEL statistical functions various release data were processed.
From the above kinetic drug release table 6.10 it was concluded that all formulation follows zero order model, it means the drug release pattern is independent on the concentration of drug, so it depicts that if the concentration of polymers rises the delayed of drug release declines and the diffusion of drug takes place from high conc. to the low concentration. Therefore if maximum formulations follows zero order model this lead the high therapeutic efficacy and minimum side effects. (Dubey et al., 2015)
From the n value it was depicted that it follows super case II transport model because this n value which was observed is greater than 1. Hence it means that the drug release is through erosion of polymeric chain stresses and state-transition in hydrophilic polymers which swell in water or biological fluids.
CONCLUSION
The present study was aimed at development of hydrodynamically balanced system of Tremadol hydrochloride by using chitosan and Locust Bean gum, use of chitosan and locust bean gum proved to form an ideal formulation as it retarded the time period of the drug for the extended period of time. This formulation can help in retardation of drug for extended period of time due to the effect of polymer and it will cause no toxicity as we employed natural polymer such as chitosan which we get from shrimp shells and locust bean gum which is plant based polymer, so when the polymer will bind with the mucin layer no side effect will happen to the layer. The Locust Bean gum will help in forming gel type structure when it will come in contingence with intestinal fluid due to its swelling properties. A proper evaluation of the dosage form was carried out along with various studies such as DSC/DTG/DTA, FTIR, In vitro drug release, buoyancy ,and release kinetics were found out.
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02468101200.230.347000000000003190.472000000000000310.636000000000009340.795000000000000040.98599999999999999
Concentration (µg/ml)
Absorbance
28
0510
0
50
100
LF1
LF2
LF3
LF4
LF5
Time (Hours)
Cumulative % Drug Release
0510
0
50
100
MF1
MF2
MF3
MF4
MF5
MF6
Time (Hours)
Cumulative % Drug Release
0510
0
50
100
HF1
HF2
HF3
HF4
HF5
HF6
Time (Hours)
Cumulative % Drug Release