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RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2209
FORMULATION AND EVALUATION OF MODIFIED
REALEASE CAPSULES OF BUDESONIDE
1K.Veera Kumari*,
2Dr. Appa Rao,
3Dr.Shaik.Harun Rasheed
1,2
Department of Pharmaceutics, Victoria College of Pharmacy, Nallapadu, Guntur, A.P, INDIA.
3Department of Pharmaceutics, DCRM College of Pharmacy, Inkollu, Prakasam, A.P, INDIA.
Corresponding Author:
K.Veera Kumari
Department of Pharmaceutics
Victoria College of Pharmacy
Nallapadu, Guntur, A.P, INDIA
Email: [email protected]
Mobile: +91-9440431070
International Journal of Innovative
Pharmaceutical Sciences and Research www.ijipsr.com
Abstract
Controlled release formulation of Budesonide modified release capsules was formulated by
suspension layering by matrix layer formulation method using aqua coat ECD, acetyl tri butyl citrate,
eudragit L30D55 and triethyl citrate. Infrared spectra of the drug along with the polymers reveal that
there is no interaction between drug and polymers. Preformulation studies were done initially and
found to be within the limits. The study was carried out by solution/suspension matrix layering, first
drug and polymer solutions were mixed, coating was done on the sugar spheres and further enteric
coating was done on the polymer matrix coated pellets. Different trails were conducted with various
percentages of polymers and other excipients in the first (drug loading) and second stage (during
enteric coating) and the formulation was finally optimized based on the Cumulative % drug release.
The evaluation test results are found to be within pharmacopieal specifications. The in-vitro
dissolution tests were performed for all trails. Dissolution profile of formulation F9 matched with the
innovator’s product and was found to be satisfactory. Stability studies both accelerated and long term
stability studies were conducted for two months. During this study, the formulation F9 was found to
be stable and no differences in the assay, moisture content and release characteristics were noticed.
Keyword: Budesonide, Controlled release formulation, modified release capsules, enteric coating,
Aqua coat ECD, Eudragit L30D55
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2210
INTRODUCTION
Pharmaceutical Oral solid dosage forms have been used widely for decades mainly due to
their convenience of administration and their suitability for delivery of drugs for systemic
effects
The salient aspect of conventional methods of drug delivery including tablets,
capsules, and liquids is the fluctuation in concentration between dosages [1]. Some drug
fluctuations cause no problems, but some drugs that cause toxic reaction when
administered above a narrow therapeutic concentration range, such a variation can cause
considerable side effects. Thus ideal goal of any drug delivery system is to provide a
therapeutic amount of drug to the proper site in the body and then maintain the desired
drug concentration. i.e., the drug delivery system should deliver the drug at a rate dictated
by the needs of the body over a specified period of treatment.
The overall action of a drug molecule is dependent on its inherent therapeutic
activity and the efficiency with which it is delivered to the site of action. An increasing
appreciation of the latter has led to the evolution and development of novel drug delivery
systems (NDDS), aimed at performance enhancement of potential drug molecules. Novel
drug delivery systems (NDDS) are the key area of pharmaceutical research and
development. The reason is relatively low development cost and time required for
introducing a NDDS ($20- 50 million and 3- 4 years, respectively) as compared to new
chemical entity (approximately $500 million and 10- 12 years, respectively) [2]. The focus
in NDDS includes design of NDDS for new drugs on one hand and on the other NDDS for
established drugs to enhance commercial viability. Oral route remains one of the most
natural routes of drug administration and has seen remarkable accomplishments in the last
couple of decades towards optimization of oral delivery of drug molecules. Oral ingestion
is one of the oldest and most extensively used routes of drug administration, providing a
convenient method of effectively achieving both local and systemic effects [3].
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2211
Modified release drug delivery system:
The oral route of drug delivery is typically considered the preferred and most patient
convenient means of drug administration. Consequently, much effort is directed during
drug discovery to identify orally active candidates that will provide reproducible and
effective plasma concentrations in vivo. The reality is that many compounds are either
incompletely or ineffectively absorbed after oral administration (i.e. bioavailability is an
issue), or that the required dosing frequency is too short to enable once or twice daily
administration (ie. Pharmacokinetic half-life is an issue) [5].
Modified release formulation technologies offer an effective means to optimize
the bioavailability and resulting blood concentration – time profiles of drugs that otherwise
suffer from limitations.
Modified release refers to controlled, delayed and extended release systems for oral
administration as well as oral delivery system s designed specifically to modify the release
of poorly water soluble drugs [4].
Sustained release systems include any drug delivery system that achieves slow
release of drug over an extended period of time. If the system can provide some control,
whether this is of a temporal or spatial nature, or both of drug release in the body, or in
other words, the system is successful maintaining constant drug levels in the target cells or
tissues, it is considered a controlled release system [6].
Potential advantages of controlled drug therapy
All controlled release products share the common goal of improving drug therapy
over that achieved with their non-controlled counter parts. This improvement in drug
therapy is represented by several potential advantages, which include:
Avoid patient compliance problems.
Reduction in frequency of dosing.
Employ minimum total drug.
Minimize or eliminate local side effects.
Minimize or eliminate systemic side effects.
Cure or control condition more promptly.
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2212
Reduce fluctuations in drug level.
Improve bioavailability of some drugs.
Minimize drug accumulation with chronic dosing.
Improve efficacy in treatment.
Make use of special effects e.g. sustained release aspirin for morning relief of
arthritis by dosing before bedtime.
Mups for CR Systems
Oral modified drug delivery systems can be classified into two broad groups:
1. Single Unit dosage forms.
2. Multiple unit particles.
Multiple unit particles (MUPS), such as granules, pellets, or mini tablets
The concept of MUPS was initially introduced in 1950s. The production of MUPS is a
common strategy to control the release of drug as shown by the reproducibility of the
release profiles when compared to the ones obtained with SUDFS. The concept of MUPS
is characterized by the fact that the dose is administered as a number of sub units, each one
containing the drug. Then the dose is sum of the quantity of the drug in each sub unit and
the functionality of individual sub-units. In contrast to Monolithic dosage forms multiple
unit dosage forms offer several advantages. Controlled release systems can be developed
by multi-unit dosage forms. The capsule comprised of a multiple unit pellets when
administered, freely disperse in the GIT as a sub unit, each pellet acting as a separate drug
delivery unit. Thus, maximizing drug absorption and reducing the peak plasma
fluctuations, consequently, potential side effects can be minimized without imparting drug
bioavailability [7].
Methods of preparation of multiple unit dosage forms
To understand the complete strategy of the multiple unit dosage forms, it is necessary to
have a brief idea regarding how pellets are prepared and principles involved in it.
Pelletization
This technique is referred to an agglomeration process that convert fine powder or granules
of bulk drug or excipient in to small , free flowing , spherical or semi spherical pellets
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2213
where size range typically from 0.5-1.5mm [8]. The most widely used Pelletization
processes in pharmaceutical industries are,
Extrusion
Spheronization
Spherical Agglomeration
Liquid-induced agglomeration
Spray drying and spray congealing
Melt-induced agglomeration.
Cryopelletization
MATERIALS
Aquacoat ECD (30%), Acetyl tributyl citrate, Eudragit L30 D55, Triethyl citrate, Tween 80,
Talc, and Sugar spheres .
METHOD
Standard Calibration Curve of Budesonide
A 100 mg of Budesonide was transferred to a 100 ml of standard flask and then
dissolved in to the required quantity of phosphate buffer pH 7.5 and then make up to the
volume in 100 ml of standard flask.
From this stock solution the aliquots of 5µg, 10µg, 15µg, 20µg, and 25µg/ml were
withdrawn and volume made up to 10ml. The absorbance of the concentration was
measured at 244nm using UV- spectrophotometer.
Drug – excipients compatibility study:
In this study, the active pharmaceutical ingredient and excipients were mixed
separately and stored at different conditions for a time period of 1 month. The physical
properties (colour change) were monitored regularly. The change in the colour in any
mixture was the basis for disregarding the study.
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2214
Solution/suspension layering by matrix layer formulation Drug and polymer matrix
layering on sugar spheres:
The required quantity of sugar spheres (18/20#) were weighed and transferred into
a fluidized bed processor and required quantity of acetyl tributyl citrate and talc were
dissolved in specified volume of water. Required volume of aqua coat ECD was added to
above solution under continuous stirring. Later required quantity of budesonide was
dispersed in above suspension by stirring. This suspension was sprayed on sugar spheres
by bottom spray technique. This drug-polymer layered pellets were further used for enteric
coating.
Enteric Coating by Using Eudragit L30 D55
The required quantity of drug-polymer matrix layered pellets were loaded into the
FBC and required quantity of triethyl citrate, tween 80 and eudragit L30 D55 were
dissolved in specified volume of water under continuous stirring for 20 min. Later required
quantity of talc was added to the above solution and sprayed on drug-polymer matrix
layered pellets in bottom spray FBC.
Table:1 Composition of drug and polymer matrix coated pellets for the formulation
trial (F1-F9)
Note: # the material balance would become 600gm only after enteric coating step.
Name of the excipient
Weight of the Excipients (gm/500gm batch)
% of polymer F1 F2 F3 F4 F5 F6 F7 F8 F9
Budesonide 4.25 4.25 4.25 4.25 4.25 4.25 4.25 4.25 4.25
Aqua coat ECD 30% 10 11.66 13.33 15.0 16.66 16.66 16.66 16.66 16.66
Acetyl tri butyl citrate 0.24 0.29 0.36 0.40 0.40 0.40 0.45 0.475 0.50
Talc 0.225 0.28 0.34 0.40
0.375 0.40 0.425 0.45 0.50
Sugar spheres 460.38 455.88 451.84 448.64 458.07 454.13 450.06 448.05 444.60
Purified water q.s q.s q.s q.s
q.s q.s q.s q.s q.s
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2215
* Aquacoat ECD is a 30% suspension contained ethyl cellulose (30%), sodium lauryl
sulphate (0.9-1.7%), cetyl alcohol (1.7-3.3%), (FMC Biopolymers).
Table:2 Composition of enteric coated pellets for the formulation trials (F1-F9)
Name of the excipient
Weight of the Excipients (gm/500gm batch)
% of polymer F1 F2 F3 F4 F5 F6 F7 F8 F9
Eudragit D30 L55 83.33 91.66 100 103.33 83.33 91.66 100 103.3 110.0
Tri ethyl citrate 1.75 2.062 2.4 2.79
1.75 2.062 2.40 2.79 3.3
Talc 5.0 6.05 6.60 7.75
5.0 6.05 7.2 7.75 8.58
Tween 80 0.15 0.178 0.21 0.232
0.15 0.178 0.21 0.232 0.264
Water q.s q.s q.s q.s q.s q.s q.s q.s q.s
Evaluation of formulation (capsules):
Average Fill Weight of Capsule:
Weigh an intact capsule. Open the capsule without losing any part of the shell and
remove the contents as completely as possible. Weigh the shell. The weight of the contents
is the difference between the weighings. Repeat the procedure with a further 19 capsules.
Determination of the average weight = (Weight of 20 capsules (g)/20)*1000=......mg
Dissolution studies:
Dissolution studies were carried out by using USP Type-2 (Paddles with sinker)
with 0.1N HC1 and pH 7.5 phosphate buffers as a dissolution medium. The samples were
withdrawn for 2hours for 0.1N Hcl as a dissolution medium and 1-8 hours for pH 7.5
phosphate buffer and samples were analyzed by using HPLC and dissolution data was
compared with the innovator product.
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2216
RESULTS AND DISCUSSION
Table:3 Calibration curve of Budesonide Figure:1 Calibration curve of Budesonide
in Phosphate Buffer in pH 7.5
Figure:2 FT-IR spectrum of Budesonide
Figure :3 FTIR Spectrum of Eudragit D30 L55
S.
No.
Concentration
in(mcg/ml)
Absorbance at
274 nm 1 5 0.080
2 10 0.162
3 15 0.242
4 20 0.321
5 25 0.391
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2217
Figure :4 FTIR Spectrum of F9
Table: 4 drug – excipients compatibility study:
S.No
Drug + Excipient Initial After 1 month
at
40˚c / 75%RH
After 1 month
at
25˚c / 60%RH
Compatible
1. Drug White powder NCC NCC Yes
2. Drug +Aquacoat ECD White
suspension NCC NCC Yes
3. Drug+ Talc White powder NCC NCC Yes
4. Drug+ Acetyl tri butyl
citrate
White
suspension NCC NCC Yes
5. Drug+ Eudragit L30 D55 White
suspension NCC NCC Yes
6. Drug+ Triethyl citrate White
suspension NCC NCC Yes
7. Drug+ Tween 80 White powder NCC NCC Yes
* NCC-No Colour Change
Compatibility studies at different temperatures and relative humidity showed that the drug
itself was stable at higher temperature and relative humidity, as well as compatible with all
the above excipients
Average fill weight:
Weight of 20 capsules /20*1000
The Average fill weight of capsule was found to be= 7173.7mg/20 = 359.7mg
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2218
Dissolution studies:
Table: 5 cumulative% drug release of budesonide MR capsules in the formulation
trails and innovator product (3mg):
Fig: 5 Dissolution Profile comparison of Fig: 6 Dissolution Profile comparison of
Formulation F1-F3 Formulation F4-F6
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2219
Fig : 7 Dissolution Profile comparison of Fig:8 Dissolution Profile comparison of
Formulation F1-F3 Optimized Formulation F9 and Innovator
CONCLUSION
The study was undertaken with an aim to formulate budesonide modified release
capsules. The drug budesonide is corticosteroid and currently used for the treatment of Crohn’s
disease.
Before going to develop the formulation, a detail product literature review was carried
out to know about the innovator’s type of dosage form available in market, weights, all other
parameters and excipients used product and the patent status of the drug.
The study was carried out by solution/suspension matrix layering , first drug and
polymer solutions were mixed, coating was done on the sugar spheres; further enteric coating
was done on the polymer matrix coated pellets. Different trails were conducted with various
percentages of polymers and other excipients in the first (drug loading) and second stage (during
enteric coating) and the formulation was finally optimized based on the Cumulative % drug
release.
The optimized pellets were evaluated for tests like average fill weight, assay and
content uniformity.
The in-vitro dissolution tests were performed for all trails. Dissolution profile of
formulation F9 matched with the innovator’s product and was found to be satisfactory.
Stability studies were also performed; both accelerated and long term stability studies
were conducted for two months. During this study, the formulation F9 was found to be stable and
no differences in the assay, moisture content and release characteristics were noticed.
RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220
Department of Pharmaceutics ISSN (online) 2347-2154
Available online: www.ijipsr.com September Issue 2220
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