Vol 7 | Issue 1 | 2017 | 29-33.

e-ISSN 2249 – 7706

International Journal of print-ISSN 2249– 7714

Advanced Pharmaceutics
www.ijapjournal.com Research Article

FORMULATION AND INVITRO ASSESSMENT OF COLON

TARGETING TRAMADOL MICROBEADS
E.Mounika1*, S.M. Shaheedha1, G.Neelima1, Chandrakala Podili2, K.Divya1,
K. Bhaskar Reddy1
1
Sri Venkateswara College of Pharmacy, RVS Nagar, Chittoor-517127, Andhra Pradesh, India.
2
Vasavi Institute of Pharmaceutical Sciences, Vasavi Nagar, Peddapalli, Madhavaram-1, Kadapa,
Andhra Pradesh 516247, India.

Access this article online

Home page: Quick Response code Corresponding Author
http://ijapjournal.com/ E.Mounika
Sri Venkateswara College of Pharmacy, RVS Nagar,
DOI: Chittoor-517127, Andhra Pradesh, India.
http://dx.doi.org/10.21276/ijap.2017.7.1.4
Email:-emounikaanjaiah@gmail.com
Received:25.06.16 Revised:12.07.16 Accepted:15.07.16

ABSTRACT
Colon targeting drug delivery system plays a vital role in treatment of Rheumatoid Arthritis by releasing
the drug at early morning hours by delaying the release of drug from dosage form by applying novel approaches in
it. This approach happens due to the chronological behavior of Rheumatoid arthritis confirms increased Joints and
knee pains in early morning hours, which need of novel dosage form which delivers the drug at pre-determined time
points in the early morning hours. Colon Targeting Tramadol microbeads were formulated with the help of different
polymers, cross linking agent and coating polymer solution. From the Invitro drug release studies data’s it was
found that T2 obeys desired release characteristics and it was an ideal formulation for colon targeting. Maximum
amount of drug was released cumulatively from T2 formulation was found to be more in Colonic pH after lag time
of about 4 hours. From these studies it was confirms that the delayed time of Tramadol release from microbeads
leads to good sustainability and target ability of drug in colon at early morning hours.

Keywords:Tramadol, Rheumatoid arthritis, Colon targeting.

INTRODUCTION
Colon specific drug delivery has gained
increased importance not just for the delivery of
drugs for the treatment of local diseases associated
with the colon but also as potential site for the
systemic delivery of therapeutic peptide and proteins
[1]. To achieve successful colon targeted drug
delivery, a drug needs to be protected from
degradation, release and/or absorption in the upper
portion of the GI tract and then ensure abrupt or
controlled release in the proximal colon [2]. Drug
modifications through covalent linkages with carrier
or prodrug approach and formulation based
approaches can be used for colonic delivery [3].
The overall goal for optimum therapy is to
match the needs of the patient while improving the
efficiency and safety of the administered drugs [4].
Various drug delivery approaches have always
played a challenging and crucial role in ensuring and
predicting the delivery of promising and successful
drugs to the target site of delivery in the human body.
Oral drug delivery is the preferred route of delivery,
accounting for more than US$15 billion in annual
global sales. Although oral delivery has become a
widely accepted route of administration of
therapeutic drugs, the gastrointestinal (GI) tract
presents several formidable barriers to drug delivery.

29 | P a g e
Vol 7 | Issue 1 | 2017 | 29-33.
In the recent past, considerable interest has grown in
targeting the delivery of drugs to the colon [5].
Medical rationales for the development of
orally administered colonic drug dosage forms
include, The opportunity to reduce adverse effects in
the treatment of colonic inflammation and colonic
motility disorders by topical application of drugs
active at the mucosal level. Oral delivery of drugs to
the colon is valuable in the treatment of diseases of
colon like ulcerative colitis, chron’s disease,
carcinomas and infections. The elucidation of the
mode of action of some nonsteroidal anti-
inflammatory drugs (NSAID) such as sulfide
(metabolized in the colon to the active moiety,
sulfide) that were found to interfere with the
proliferation of colon polyps (first stage in colon
carcinoma) possibly in local manner. In some cases
the colon is capable of absorbing drugs efficiently.
Drug absorption enhancement works better in the
colon than in the small intestine.Protein drugs can be
absorbed better from the large bowel owing to
hypothetic reduced proteolytic activity in this organ.
The unique metabolic activity of colon, which makes
it an alternative organ for drug delivery system
designer [6].
Tramadol is a narcotic-like pain reliever.
Tramadol is used to treat moderate to severe pain.The
extended-release form of tramadol is for around-the-
clock treatment of pain. This form of tramadol is not
for use on an as-needed basis for pain.
As stated, there are several benefits of using
Tramadol for arthritis but one that stands out is that it
works well for every type of the disease. Many
people think there are just a few types of arthritis but
in reality, there are more than 100. Keep in mind that
based on a number of factors there could be people
who do not get relief by taking Tramadol but for the
most part, this is the exception and not the rule.
Osteoarthritis - Cartilage is a natural shock
absorber for joints but with osteoarthritis, elasticity
diminishes. As a result, pain develops and in more
severe cases, ligaments and tendons become stretched
beyond the normal range.
Rheumatoid Arthritis - This is one of the
more prevalent types of arthritis and one for which
Tramadol is commonly prescribed. With this form of
the disease, the synovial membrane is attacked. The
result is extreme swelling and pain but even worse,
deformity of one or more joints can occur if not
properly treated.
Juvenile Rheumatoid Arthritis - This is
similar to adult Rheumatoid Arthritis except it affects
children 16 years or younger. There are three stages
to include Pauciarticular, which is the most common
and mildest, Polyarticular that is more severe and
affects a greater number of joints, and Systemic in
which a child would have pain in multiple joints but
30 | P a g e
this form of Juvenile Rheumatoid Arthritis can also
be serious enough that it spreads to the body's organs
The main objective of this research is to
formulate and evaluate the Tramadol loaded colon
targeting microbeads for treating arthritis in early
morning hours.
MATERIALS AND METHODS
The materials used in the projects like
Tramadol are received as gift sample from Micro
Labs Hozur , Sodium alginate and Eudragit L 100
from SAR scientifics, Chennai. And other solvents
used are in analytical standards.
Formulation of Microbeads
Ionotropic gelation technique was used for
the preparation of Microbeads.
1. The polymer solution , sodium alginate solution
was prepared by dispersing the sodium alginate in de-
ionized water under continuous stirring for 30
minutes.
2. The required amount of the drug was weighed
and thoroughly mixed with the above solution
3. The resulted homogeneous dispersion was
extruded in to the 5% calcium chloride solution
through hypodermic syringe with flat tip needle
(20G)
4. The above solution was stirred for 15 minutes at
100rpm using magnetic stirrer.
5. The formed micro beads were allowed to cure
for 30 minutes in the calcium chloride solution to
complete the gelation reaction.
6. The microbeads were then filtered and dried in
hot air oven at 60˚C for 3 hr. After that it was coated
with Eudragit polymer solution. The dried beads are
filled in hard gelatin capsule. The Formulation are
shown in Table 1[8, 9, 10].
Evaluation of Microbeads [8,9,10]
Surface morphology/Scanning Electron
Microscopy (SEM):
The external morphology of the
microparticles was studied by scanning electron
microscopy. The sample of the SEM analysis was
prepared by sprinkling the microparticles onto one
side of the double adhesive stub. The stubs were then
coated with gold using polaran SC 500 sputter coater,
to neutralize the electrons and to obtain a clear
morphology of the microparticles. The SEM was
performed on microparticles after and before
dispersing it in 0.1N HCl [2].
Drug entrapment efficiency or incorporation
efficiency:
To determine the drug entrapment efficiency
or incorporation efficiency, the microparticles were
crushed in glass mortar and powered, then suspended
Vol 7 | Issue 1 | 2017 | 29-33.
in 10 ml of methanol, after 24 h the solution was
filtered and filtrate was analyzed for drug content
spectrophotometrically at 271nm for Tramadol. The
drug incorporation efficiency was calculated by the
following formula [3].
Incorporation efficiency = b/a X 100
b = calculated amount of drug present in the
formulation,
a = theoretical amount of drug present in the
formulation
Drug content
Four portions each containing 200 mg were
randomly picked from the prepared samples and were
crushed with help of mortar and pestle. Then it was
stirred continuously for 3h with simulated gastric
fluid (pH 1.2). After 3 h, the samples were filtered,
suitably diluted and estimated spectrophotometrically
at 271nm for Tramadol. The estimation was done in 3
replicates to determine the uniformity of drug in
microparticles [4,5].
Production yield
The production yield of the microparticles
can be determined by calculating accurately the initial
weight of the raw materials and the last weight of the
microparticles obtained [6,7].
Production yield (Y) =
Practical mass of Microparticles
---------------------------------------------- x 100
Theoretical Mass (Polymer+drug)
Invitro drug release of Tramadol Microbeads
The second pulse release of Tramadol was
investigated using the USP rotating basket type
dissolution apparatus at 50 rpm and maintain the bath
with 37+1ºC. The simulation of gastrointestinal
transit conditions was achieved by altering the pH of
the dissolution medium at various time intervals. The
pH of the dissolution medium was kept at 1.2 for 2 h
with 0.1 N HCl. Then, 1.7 g of KH2PO4 and 2.225 g
of Na2HPO4.2H2O were added, adjusting the pH to
4.5 by adding 1.0 M NaOH. A release rate study was
continued for another 2 h. After 4 h, the pH of the
dissolution medium was adjusted to 7.0 and
maintained for 24 h. The final volume in all cases
was 500 ml. The samples were withdrawn from the
dissolution medium at various time intervals using a
pipette fitted with a micro filter, and the filtrate was
31 | P a g e
subjected to UV analysis at 271nm. All dissolution
studies were performed in triplicate [8-14].
RESULTS AND DISCUSSION
Particle size
The particle size was determined with the
help of Particle Size Analyzer (Malvern Particle Size
Analyzer). Spherical shaped Microbeads were
observed. Among the five formulations of
Microbeads T2 possess small particle size 1.487 µm
and also uniform particle size distribution because of
optimum concentration of polymer and cross linking
agent which .The particle size ranges of formulations
were shown in Figure 1 and Table 2.
On increasing the concentration the Sodium
alginate, the amount of drug entrapped with the
polymers coat also increased, as it was observed
maximum 75.92 ± 1.24 % in T2 .This shows that the
best polymer for entrapping Tramadol in coating
microbeads was sodium alginate , Eudragit polymers
and optimum concentration of polymer is about 2%
with 5% of cross linking agent calcium chloride. The
results are shown in Table 2.
The percentage yield of Microbeads was
more than 70 % for the best formulation say T2
which shows highest percentage yield of 75.54 ±
3.66% due to increased concentration of the polymer
and cross linking agent. The results of production
yield for all the batches were shown in Table 2.
The drug content in the micro beads was
found to be in the range of 56.24± 1.26 to 78.26±
1.26 % based on the polymer and cross linking agent
ratio. Increase in concentration of the polymer and
cross linking agent there will be increase in drug
content of the formulation. The formulation T2
shows maximum drug content and the values are
given in Table 2.
The Invitro drug release studies shows that
all the formulation shows a good initial lag time of
around 4 hr in Phosphate buffer pH 1.2,4.5, that
shows that the release pattern of drug is delayed and
maximum amount of drug is released in colonic pH
7.0 at early morning hours in a cumulative
sustainable manner. This lag time may due to the
presence of Eudragit polymer coating in the
microbeads. T2 shows sustained release around
94.54±2.42 in 16thhr in a cumulative pattern. shows
maximum drug release due to increase concentration
of cross linking agent. The values are as shown in
Figure 2.
Vol 7 | Issue 1 | 2017 | 29-33.

Table 1. Formulation of Tramadol Microbeads

Formulation code Amount of Amount of Amount of Coating Polymer
Tramadol (mg) Sodium alginate calcium chloride Eudragit L 100 w/v
T1 20 1% 5% 10%
T2 20 2% 5% 10%
T3 20 4% 5% 10%
T4 20 6% 5% 10%
T5 20 8% 5% 10%

Table 2. Physical evaluation of Microbeads MF1-MF8

Formulation code Particle size Product yield in Drug content in % drug
(µm) % % entrapment
T1 1.894 64.28± 4.02 60.24 ± 1.24 70.16 ± 1.34
T2 1.487 75.54 ± 3.66 78.26± 1.26 75.92 ± 1.24
T3 1.946 67.84± 3.42 64.32± 1.26 68.64 ± 1.54
T4 2.048 54.52± 2.04 59.32± 2.20 65.42 ± 1.24
T5 2.542 50.12± 2.06 56.24± 1.26 60.08 ± 1.64
*standard deviation (n = 3)

Fig 1. Particle Size for the F2 Formulation (1.487 µm) Fig 2. Cumulative % drug release profile for
Tramadol Microbeads T1 – T5 in pH 1.2, 4.5 &
7.0

CONCLUSION
From the above data it was concluded that ACKNOWLEDGEMENT
the newly formulated Tramadol colon targeting None.
microbeads produce effective control of Rheumatoid
arthritis at early morning risk hours by allowing the CONFLICT OF INTEREST:
drug to release after a lag time at colonic pH, with The authors declare that they have no conflicts of
reduced dose and dosing frequency are achieved interest.
which leads to better patient compliance.

REFERENCES
1. Sarasija S, Hota A. Colon-specific drug delivery systems. Indian journal of pharmaceutical sciences, 62(1),
2000, 1-8.
2. Bussemer T, Dashevsky A, Bodmeier R. A pulsatile drug delivery system based on rupturable coated hard
gelatin capsules. J. Control. Release., 93(3), 2003, 331-339.
3. Lym-Ly and Wan-LS, Propranolol Binding in Calcium Alginate Beads. Drug Develop. Indi. Pharm, 23(10),
1997, 973 -980.
4. Gazzaniga A, Iamartino P, Maffino G, Sangalli ME. Oral delayed release system for colonic specific drug
delivery. Int J Pharm, 108, 1994, 77-83.

32 | P a g e
Vol 7 | Issue 1 | 2017 | 29-33.

5. Sindhu A, Srinath MS. Development of modified pulsincap drug delivery system of metronidazole for drug
targeting. Indian J Pharm Sci, 69(1), 2007, 24-27.
6. Lin, S.Y., Li, M.J., Lin, K.H., 2004. Hydrophilic excipients modulate the time lag of time-controlled
disintegrating press-coated tablets. AAPS Pharm Sci Tech, 5(4), 2004, 34-39.
7. Laila FAA, Sanjeev C, Multiparticulate formulation approach to colon specific drug delivery: Current
Prospective. J Pharm PharmaceutSci, 9(3), 2006, 327-333.
8. Watts P, Illum L. Colonic drug delivery. Drug DevInd Pharm, 23, 1997, 893-913.
9. Chourasia MK, Jain S K. Pharmaceutical approaches to colon targeted drug delivery systems. J Pharm Sci, 6,
2003, 33-66.
10. Laila FAA, Sanjeev C, Multiparticulate formulation approach to colon specific drug delivery: Current
Prospective. J Pharm PharmaceutSci, 9(3), 2006, 327-33.
11. Manna A, Ghosh I, Goswami N, Ghosh L.K and Gupta B.K., “Design and Evaluation of an oral controlled
Release Microparticulate Drug Delivery system of Nimesulide by Ionotropic Gelation Technique and Statistical
Optimization by Factorial Analysis. J.Sci.Ind.Res., 58(9), 1999, 717 – 722.
12. Ghimire M, McInnes FJ. In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet
formulations: A pharmacoscintigraphic study in the beagle dog. European Journal of Pharmaceutics and
Biopharmaceutics, 67, 2007, 515–523.
13. Ishibashi T, Hatano H, Kobayashi M, Mizobe M, Yoshino H. Design and evaluation of a new capsule-type
dosage form for colon-targeted delivery of drugs. Int. J. Pharm., 168 (1), 1998, 31-40.
14. Mohmad A Dashevsky A. pH dependent pulsatile drug delivery system based on hard gelatin capsules and
coated with aquueous dispersion Aquacoat ECD. European Journal of Pharmaceutics, 64, 2006, 173-179.

Cite this article:

Mounika E, Shaheedha SM, Neelima G, Chandrakala Podili, Divya K, Bhaskar Reddy K. Formulation and Invitro
Assessment of Colon Targeting Tramadol Microbeads. International Journal of Advanced Pharmaceutics. 2017;
7(1):29-33. DOI: http://dx.doi.org/10.21276/ijap.2017.7.1.4

Attribution-NonCommercial-NoDerivatives 4.0 International

33 | P a g e