Download formulation and evaluation of floating microspheres of diclofenac

FORMULATION AND EVALUATION OF FLOATING
MICROSPHERES OF DICLOFENAC SODIUM FOR THE
MANAGEMENT OF PAIN AND INFLAMATION IN ARTHRITIS
M.Pharm dissertation protocol submitted to
Rajiv Gandhi University of Health Sciences
Karnataka, Bangalore – 560041
By
Mr. ASHISHKUMAR DALSUKHBHAI PAIJA B.Pharm
Under the guidance of
Mr. P. R. SATHESH BABU M.Pharm
Department of Industrial Pharmacy
Acharya & B.M.Reddy College of Pharmacy
Hesaraghatta main road, Chikkabanavara (Post)
Soldevanahalli, Bangalore – 560 090.
2008 – 2010
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1
Name and address of
candidate
Mr. ASHISHKUMAR DALSUKHBHAI PAIJA
“MATRU- ASHISH”
Ashok Park-2
Navlakhi Road
Morbi- 363 641, Gujarat.
2
Name of institution
ACHARYA & B.M. REDDY COLLEGE OF PHARMACY
Hesaraghatta main road
Chikkabanavara(post)
Soldevanahalli
Bangalore- 560 090.
3
Course of study and
subject
Master of Pharmacy
(Industrial Pharmacy)
4
Date of admission
June – 2008
5
Title of the project
FORMULATION AND EVALUATION OF FLOATING
MICROSPHERES OF DICLOFENAC SODIUM FOR THE
MANAGEMENT OF PAIN AND INFLAMATION IN
ARTHRITIS
2
6
BRIEF RESUME OF INTENDED WORK
6.1 NEED FOR THE STUDY:
Arthritis is a condition involving damage to the joints of the body. It can affect people at any
stage of the life but it is the leading cause of disability in people older than 55 years. Arthritis is
not just one disease but it is a complex disorder that comprises more than 100 distinct conditions.
An arthritic person requires lifelong treatment to get relief from pain and inflammation of arthritis.
Treatment of arthritis is done by NSAIDs or DMARDs (Disease Modifying Anti Rheumatoid
Drugs) or narcotic analgesics. Most common forms of arthritis are: osteoarthritis and rheumatoid
arthritis.
In osteoarthritis (OA) bone ends rub together so destruction of bone’s cartilage that causes
permanent joint destruction. OA affects nearly 21 million people in US, accounting for 25% of
visit to primary care physicians and half of all NSAIDs prescription. In US hospitalization for OA
soared from about 322,000 in 1993 to 735,000 in 2006.
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the
joints. RA affects 2.1 million people in US or about 1% of adult population in US. RA is 2-3 times
more common in women than in men.
Diclofenac sodium belongs to a class of drugs called NSAIDs. It is used to reduce pain,
inflammation, swelling and stiffness caused by several types of arthritis. Mechanism of diclofenac
is it prevents prostaglandin synthesis which is responsible mainly for pain and inflammation in
arthritis. Diclofenac sodium is suitable for floating drug delivery system. Its half life is 3-5 hrs. Its
oral bioavailability in conventional dosage form is 50-60%. Dose of diclofenac sodium for
treatment of arthritis is 50 mg (t.i.d.), 75 mg (b.i.d.) and maximum daily dose is 150 mg.
Distribution of diclofenac in body occurs mainly in synovial fluid of joints. Diclofenac is an active
ingredient for the following brand name drugs used for the treatment of arthritis - cataflam
3
(Canada), diclofenac (Canada), voltaren (Canada), voltaflam (India) and voveran (India).
Conventional oral dosage forms such as tablets, capsules provide systemic circulation
without offering any control over the drug delivery and also cause great fluctuation in the plasma
drug levels. Multiple unit dosage form (e.g. - microspheres) have the advantage that they pass
uniformly through the GIT to avoid the vagaries of gastric emptying and provide adjustable
release, thereby reducing the inter subject variability in absorption and risk of local irritation.
Gastro-retentive floating microspheres are low density system that has a sufficient buoyancy
to float over the gastric contents and remain in stomach for prolonged period. As the system floats
over the gastric contents, the drug is released slowly at desired rate which results in increased
gastric retention with reduced fluctuation in plasma drug concentration, increased bioavailability,
increased half life of drug, decreasing the wastage of drug as well as improved patient compliance
by reducing repetitive dose.
Floating microspheres having some advantages over the conventional dosage form that are as
follows.
(1) Avoidance of gastric irritation (main side effect of all NASIDs), because of sustained release
effect, floatability and uniform release of drug through multiparticulate system.
(2) Bioavailability enhances despite first pass effect because fluctuations in plasma drug
concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug
release.
(3) Better therapeutic effect of drug can be achieved because of short half life of drug.
(4) Improves patient compliance by decreasing dosing frequency.
(5) Gastric retention time is increased because of buoyancy.
(6) Floating microspheres are especially effective for insoluble or sparingly soluble drugs.1
4
6.2 REVIEW OF LITERATURE:Shimpi et al (2) Studied the application of hydrophobic lipid, Gelucire 43/01 for the design of
multi-unit floating system of highly soluble drug, diltiazem HCl. Diltiazem HCl-Gelucire 43/01
granules were prepared by the melt granulation technique. The granules were evaluated for in vitro
and in vivo floating ability, surface topography, and in vitro drug release. It could be concluded
that gelucire 43/01 can be considered as an effective carrier for design of multi-unit FDDS of
highly water soluble drugs such as Diltiazem HCl.2
Kale et al (3) Were prepared floating microspheres of piroxicam by using an enteric polymer
with emulsification solvent evaporation method. The microspheres remained buoyant continuously
for 8-12 hrs in vitro. They were studied DSC, X-ray and SEM for microspheres. The
micromeretics properties of microspheres were found to be much improved compared with
original drug crystals. The in vitro release behavior of floating microspheres was characterized as
an enteric property. Polymer being soluble above pH 7.0. At intestinal pH drug release was faster
and continuous as compared to the amount released at gastric pH. 3
Streubel et al (4) developed floating micro particles consisting of polypropylene foam powder,
model drug [chlorpheniramine maleate (CPM), diltiazem HCl, theophylline or verapamil HCl] and
polymer [Eudragit RS or polymethyl methacrylate (PMMA)]. Microparticles were prepared by
solvent evaporation technique. Good floating behavior was observed as more than 83% of micro
particles were floating for at least 8hrs. at similar drug loading the release rates increased in the
following order PMMA< EC< eudragit S. this could be attributed to the permeability of the drug in
these polymers and the drug distribution system within the system.4
5
Nurhan et al (5) studies biodegradable microspheres containing salbutamol sulphate were
prepared using water-in-oil-in-water (w/o/w) emulsion technique. Polymers were used: PLGA
50/50 and PLGA 75/25. The in-vitro release of PLGA microspheres was studied in buffer solution
of pH 7.4 at 37°C. It was found that the biodegradable microspheres of salbutamol sulphate were
prepared with PLGA 75/25 by w/o/w emulsion technique obtained extended release obtained for 8
hrs. PVA concentration was effective on the particle size of microspheres prepared with PLGA
75/25 (p < 0.05).5
Anand et al (6) study was involved preparation of floating microspheres with cimetidine as
model drug. The microspheres were prepared by the solvent evaporation method using polymers
HPMC and ethyl cellulose. The shape and surface morphology of prepared microspheres were
characterized by optical and scanning electron microscopy, respectively. The prepared
microspheres exhibited prolonged drug release (8 hrs) and remained buoyant for > 10 hrs. The
mean particle size increased and the drug release rate decreased at higher polymer concentration.
In vitro studies demonstrated diffusion-controlled drug release from the microspheres.6
Asha et al (7) prepared floating microspheres of metformin hydrochloride. Floating
microspheres were prepared by non-aqueous emulsification solvent evaporation technique using
Ethyl cellulose as the rate controlling polymer. Results showed that the mixing ratio of
components in the organic phase affected the size, size distribution (250-1000 μm), drug content
(61 – 134% of theoretical load), yield (58 – 87%) and drug release of microspheres (47 – 87% after
8 hrs), floating time (> 8 hrs) and the best results were obtained at the ratio of drug: polymer:
solvent (250:750:12 and 250:146.45:9 [mg: mg: ml]), when both the batches were mixed in equal
proportions. The developed floating microspheres of metformin hydrochloride may be used in
6
clinic for prolonged drug release in stomach for at least 8 hrs, thereby improving the
bioavailability and patient compliance.7
Sunil k. jain et al (8) prepared floating microsphere consisting calcium silicate as porous
carrier, orlistat (an anti-obesity agent) and eudragit S as polymer by solvent evaporation method
and evaluated gastro retentive and controlled release properties. The effect of various formulation
and process variables on the particle morphology, micromeretics properties in vitro floating
behaviour, percentage drug entrapment, and in vitro drug release was studied. Microspheres were
found to be in regular shape and highly porous. Release pattern of orlistat in simulated gastric fluid
from all floating microspheres, followed higuchi matrix model and peppas-korsmeyer model.
Calcium silicate based floating microspheres of orlistat was residence in stomach over 6 hrs.8
Yasunori et al (9) studied Hollow microspheres (microballoons) floatable in JP XIII No.1
solution as a dosage form characterized by excellent buoyant properties in the stomach.
Microballoons were prepared by the emulsion solvent diffusion method utilizing enteric acrylic
polymers co-dissolved with drug in a mixture of dichloromethane and ethanol. The release
properties of five different drugs exhibiting distinct water solubilities (Aspirin, Salicylic acid,
Ethoxybenzamide, Indomethacin and Riboflavin) entrapped within microballoons were
investigated. Buoyancy of the microballoons decreased with increasing drug release rate. In
addition, by incorporating a polymer such as Hydroxy Propyl Methyl Cellulose within the shell of
microballoons, the release rate of Riboflavin from the microballoons could be controlled while
maintaining high buoyancy. 9
El-kamel et al (10) prepared floating microparticles of ketoprofen, by emulsion solvent
7
diffusion technique. Four different ratio of eudragit S 100 with eudragit RL were used. The
formulation containing 1:1 ratio of the two above mentioned polymers exhibited high percentage
of floating particles in all examined media as evidenced by the percentage of particles floated at
different time intervals. This can be attributed to the low bulk density, high packing velocity.10
Kawashima et al (11) studied multiple-unit hollow microspheres of tranilast by emulsion
solvent diffusion technique was prepared. Drug and acrylic polymer were dissolved in an ethanoldichloromethane mixture, and poured into an aqueous solution of PVA with stirring to form
emulsion droplets. The rate of drug release in microballoons was controlled by changing the
polymer-to-drug ratio. Microballoons were floatable in vitro for 12 hrs when immersed in aqueous
media. Radio graphical studies proved that microballoons orally administered to humans were
dispersed in the upper part of stomach and retained there for 3 hrs against peristaltic movements.11
8
6.3 OBJECTIVE OF THE STUDY:
The objectives of present study are as follows:
I.
II.
To carry out preformulation studies for the possible drug/polymer interactions by FTIR.
To develop analytical methods for the estimation of drug in formulations.
III.
To develop and formulate controlled release floating microspheres for diclofenac sodium.
IV.
To evaluate the formulated floating microspheres based on physico-chemical
characterization and in vitro release studies.
V.
To carry out short term stability studies on the most satisfactory formulation as per ICH
guidelines at 30 + 20C (65 + 5 % RH) and 40 + 20C (75 + 5 % RH).
9
7
MATERIALS AND METHODS:
7.1 SOURCE OF DATA:
Review of literature is collected from:
a. Journals such as
i. Indian journal of pharmaceutical science
ii. European journal of pharmaceutical science
iii. Journal of controlled release
iv. International journal of pharmaceutics
v. Drug development and industrial pharmacy
vi. Indian drugs
b. World Wide Web.
c. I I Sc library, Bangalore.
d. J-Gate@Helinet.
e. RGUHS library.
10
7.2 METHOD OF COLLECTION OF DATA:
I.
To carry out preformulation study.
i. Drug-polymer interactions by FTIR.
II.
III.
Formulation of floating microspheres by using emulsion solvent diffusion method.
Evaluation of various floating properties of floating microspheres.
i. Floating properties:
1. Floating lag time
2. Total floating time
ii. Physico-chemical properties:
1. Particle size by optical microscopy
2. Percentage yield
3. Percentage drug entrapment efficiency
iii. In vitro dissolution study will be carried out in a USP type 2 dissolution
apparatus containing simulated gastric fluid (pH- 1.2, without enzyme).
IV.
To carry out short term stability study on the most satisfactory formulation as per ICH
guidelines at 30 + 20C (65 + 5 % RH) and 40 + 20C (75 + 5 % RH).
11
DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVESTIGATION TO BE
7.3
CONDUCTED ON PATIENT OR OTHER HUMANS OR ANIMALS?
“NO”
7.4
HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN
CASE OF 7.3?
“NOT APPLICABLE”
12
8
REFERENCES:1. Yeole P, Khan S, Patel V. Floating drug delivery system: need and development. Ind J Pharm
Sci 2005;67(3):265-72.
2. Shimpi S, Chauhan B, Mahadik K R, Paradkar A. Preparation and evaluation of diltiazem
hydrochloride-gelucire
43/01
floating
granules
prepared
by melt
granulation.
AAPS
Pharm.Sci.Tech 2004;5(3):1-6.
3. Kale RD, Tayade PT. A multiple unit floating drug delivery system of piroxicam using
eudragit polymer. Ind J pharm Sci 2007;69(1):120-23.
4. Streubel A, Siepmann J, Bodmeier R. Floating micro particles based on low density foam
powder. Int J Pharm 2002;241(2):279-92.
5. Nurhan E, Nevin C. Factors influencing release of salbutamol sulphate from Poly (lactide-coglycolide) microspheres prepared by water-in-oil-in-water emulsion technique. Int J Pharm
1996;137:57-66.
6. Anandkumar S, Devendra N, Saurabh W. Floating microspheres of cimetidine: formulation,
characterization and in vitro evaluation. Acta Pharm 2005;55:277–85.
7.
Asha P, Subhabrata R, Ram S. In vitro evaluation and optimization of Controlled release
floating drug delivery system of metformin hydrochloride. DARU 2006;14(2).
8.
Sunil K, Govind P, Narendra K. Evaluation of porous carrier-based floating orlistat
microspheres for gastric delivery. AAPS pharm sci tech 2006;7(4) article 90.
9. Yasunori S, Yoshiaki K, Hirofumi T, Hiromitsu Y. In vitro evaluation of floating and drug
releasing behaviors of hollow microspheres (microballoons) Prepared by the emulsion solvent
diffusion method. Eur J Pharm and Biopharm 2004;57:235–43.
10. El-kamel AH, Sokar MS, Gamal SS, Nagger VF. Preparation and evaluation of ketoprofen
floating oral drug delivery system. Int J Pharm 2001;220(1):13-21.
11. Kawashima Y, Niwa T, Takeuchi H, Hino T, Ito Y. Preparation of multiple unit hollow
13
microspheres (microballoons) with acrylic resins containing tranilast and their drug release
characteristics (in vivo). J Control Rel 1991;16:279-90.
14
9
Signature of the candidate:
10
Remarks of the guide:
11
Name and designation of:
11.1
Institutional guide:
Mr. P.R. Sathesh Babu
Asst. Professor
Dept. of Industrial Pharmacy
11.2
Signature:
11.3
Co-guide:
11.4
Signature:
11.5
Head of the department:
Dr. Roopa Karki
Professor & HOD
Dept. of Industrial Pharmacy
12
11.6
Signature:
12.1
Remarks of the principal:
12.2
Signature:
Dr. Divakar Goli
Principal
ACHARYA & B.M. REDDY COLLEGE OF PHARMACY
HESARAGHATTA MAIN ROAD
CHAIKKABANAVARA (post)
SOLDEVANAHALLI
BANGALORE-90.
15
16