International Journal of Innovative Pharmaceutical … · RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220 Department of Pharmaceutics ISSN (online) 2347-2154

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




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].




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.




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




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.




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




* 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.




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




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


5. Drug+ Eudragit L30 D55 White


6. Drug+ Triethyl citrate White


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




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




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.




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Documents

International Journal of Innovative Pharmaceutical … · RESEARCH ARTICLE K.Veera Kumari et.al / IJIPSR / 2 (9), 2014, 2209-2220 Department of Pharmaceutics ISSN (online) 2347-2154