Download development and evaluation of hollow microsphere based floating

DEVELOPMENT AND EVALUATION OF HOLLOW
MICROSPHERE BASED FLOATING TABLETS FOR THE
DELIVERY OF AN ANTI-HYPERTENSIVE DRUG
M. Pharm. Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore– 560041
By
Mr. PAVAN WALVEKAR B. Pharm.
Under the Guidance of
Prof. S. P. THAKKER
M. PHARM
Department of Pharmaceutics
S.E.T’s COLLEGE OF PHARMACY
S. R. Nagar, Dharwad–580002
2013
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR
DISSERTATION
1.
NAME OF THE CANDIDATE
AND ADDRESS
Mr. PAVAN WALVEKAR
DEPT. OF PHARMACEUTICS
SET’s COLLEGE OF PHARMACY,
S.R.NAGAR,
DHARWAD-580002
2.
NAME OF THE INSTITUTION
SET’s COLLEGE OF PHARMACY,
S. R. NAGAR,
DHARWAD-580002
3.
COURSE
OF
STUDY
AND MASTER OF PHARMACY IN PHARMACEUTICS
SUBJECT
4.
DATE OF ADMISSION TO
JANUARY 2013
COURSE
5.
TITLE OF THE TOPIC
DEVELOPMENT AND EVALUATION OF HOLLOW
MICROSPHERE BASED FLOATING TABLETS FOR THE
DELIVERY OF AN ANTI-HYPERTENSIVE DRUG.
1
6.
BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
Site specific delivery of bioactive molecules have recently been of great
interest in the field of pharmaceutical research, to achieve desired concentration of drugs at
the site of action; to avoid exposure of rest of the drug to the other parts of the body; to
reduce the frequency of administration; to reduce toxic effects and increase patient
compliance1.
Most convenient route of administration is by oral route. The oral controlled delivery
is advantageous for reduction in drug’s blood level fluctuations, dosing frequency and
adverse side effects as well as improved overall health care costs, patient convenience and
compliance. Although, attempts have been made to develop oral controlled release delivery
systems, yet certain limitations like unsatisfactory and variable drug absorption,
uncontrolled gastric transit time etc., have established the urgent need of the more intelligent
drug delivery systems, which can either prolong the transit time, or provide effective
concentration locally. The two approaches of gastro retentive and colon based controlled
delivery have been widely utilized to overcome these barriers. However, due to some
associated complications such as low pH in the stomach, presence of digestive enzymes,
typical residence time at different parts of the alimentary canal etc., makes difficulties for
effective treatment using these drugs. There are various approaches using Novel Drug
Delivery Systems (NDDS) to avoid these problems. One of the methods is floating drug
delivery system. These systems works on the principle that are based on swelling, inflation,
adhesion, low density system and ion exchange resin system mechanisms to increase the
gastro retention of dosage forms2.
Gastro retentive systems can remain in the gastric region for several hours and hence
can significantly prolong the gastric residence time of drugs. Prolonged gastric retention
improves bioavailability, reduces drug waste and improves solubility for drugs that are less
soluble in a high pH environment. It also has applications for local drug delivery to the
stomach and proximal small intestines. Gastro retention helps to provide better availability
of new products with new therapeutic possibilities and substantial benefits for patients3.
2
In the present protocol, we propose the use of hollow microspheres for developing
floating tablets to deliver an antihypertensive drug “amlodipine”. Amlodipine belongs to the
category of calcium channel blockers of anti-hypertensive drugs. It is a dihydropyridine
calcium antagonist that inhibits the movement of calcium ions into vascular smooth muscle
cells and cardiac muscle cells. However, due to the slow absorption of amlodipine, we
propose gastroretentive dosage form for once in a day administration4.
3
6.2 REVIEW OF LITERATURE:
In this work development of hollow microspheres as floating controlled-release
systems for cardiovascular drugs were prepared and release characteristics were studied.
Hollow microspheres of cellulose acetate polymer loaded with four cardiovascular drugs
(nifedipine, nicardapine hydrochloride, verapamil hydrochloride, and dipyridamole) were
prepared by a novel solvent diffusion-evaporation method.
The microspheres showed
smooth surfaces, with free-flowing and good-packing properties. Scanning electron
microscopy confirmed their hollow structures, with sizes in the range 489–350 μm. The
microspheres tended to float over the gastric media for more than 12 h. The release of the
drugs loaded microspheres were controlled for more than 8 h. The release kinetics followed
different transport mechanisms depending on the nature of the drug molecules5.
Chitosan hollow microspheres were prepared by employing uniform sulfonated
polystyrene particles as templates. The chitosan was adsorbed onto the surface of the
sulfonated polystyrene templates through the electrostatic interaction between the sulfonic
acid groups on the templates and the amino groups on the chitosan. Subsequently, the
adsorbed chitosan was crosslinked by adding glutaraldehyde. After the removal of the
sulfonated polystyrene core, chitosan hollow microspheres were obtained. It was observed
that the longer the sulfonation time used, the smaller the size of the hollow particles and the
thicker the chitosan wall obtained. Fourier transform infrared spectrometry was used to
characterize the component of the microspheres. The morphologies of the PS templates and
the chitosan microspheres were observed by transmission electron microscopy and scanning
electron microscopy. The controlled release behavior of the chitosan hollow microspheres
was also primarily investigated6.
In a design based on hollow microspheres responsive to various stimuli comprised a
promising approach for the development of multifunctional and efficient systems for various
nanomedicine-related applications. Authors prepared poly(methacrylic acid-co-N,N'methylenebis(acrylamide)-co-poly(ethyleneglycol)
methyl
ether
methacrylate-co-N,N'-
bis(acryloyl)cystamine) (PMAAS-S) hollow microspheres following a two-stage distillation
precipitation polymerization procedure. Magnetic and silver nanocrystals were chemically
grown on the surface of the hollow polymer microspheres, which resulted in a composite
system with interesting properties. The performance of the composite hollow microspheres
as magnetic hyperthermia mediators and their surface enhanced Raman spectroscopy
4
activity. Assessment of Daunorubicin-loaded PMAAS-S hollow microspheres performance as
effective drug carriers were carried out through drug release experiments upon application of
different pH and reducing conditions. pH and redox responsiveness as well as basic
mechanisms of release profiles. Furthermore, in vitro cytotoxicity of empty and drug-loaded
PMAAS-S hollow microspheres against MCF-7 cancer cells were investigated in order to
evaluate their performance as drug carriers7.
Microspheres of copolymeric N-vinylpyrrolidone and 2-ethoxyethyl methacrylate
for the controlled release of nifedipine were formulated. Microspheres were prepared by
varying the amount of NVP with respect to EOEMA. Nifedipine, a water-insoluble
antihypertensive drug, was loaded into these microspheres by the oil in water emulsion
technique followed by solvent evaporation. Release data were analyzed using an empirical
relation in order to elucidate the kinetics of the nifedipine release. This analysis indicated
that a Fickian transport mode operates in this system8.
In this study polymer blends used to prepare nifedipine loaded hollow microspheres
for a floating-type oral drug delivery system were prepared and evaluated. Hollow
microspheres containing nifedipine were prepared by a solvent diffusion-evaporation
method using various ratios of PVP and EC co-dissolved with drug in ethanol/ether (5:1,
v/v) The hollow microspheres were found to float in release medium for more than 24 h,
and floating capacities were not be influenced by mixing PVP. In vitro release profiles of
hollow microspheres prepared using EC along showed an initial burst release to some
extent, and the cumulative release percentage were less than 55% after 24 h9.
Polystyrene/polycarbonate composite hollow microspheres by microencapsulation
method were successfully prepared and characterized. Fourier-transform infrared
spectroscopy, scanning electron microscopy, differential scanning calorimetry and
thermogravimetric analysis were used for the characterization of the obtained hollow
microspheres. SEM images showed that there were a big cavity and some small cavities
inside the composite hollow microspheres, and the hollow microspheres prepared at 420C
presented better morphology and smaller size distribution compared with that prepared at
higher temperature of solvent evaporation10.
5
A new simple method was developed by the authors for the formation of hollow
polyethersulfone microspheres was reported in this paper. Coaxial electrospraying
equipment and nonsolvent precipitating bath were used to produce hollow microspheres in
one step. The properties of the core solution affected the formation of hollow
polyethersulfone microspheres. The supporting layer formed by the micro-phase that was
caused by the phase separation of the core or shell solution exhibited as the key factor for
the formation of hollow polyethersulfone microspheres. This method provided a new simple
way to form hollow polymer microspheres and can be extended to other polymers to prepare
hollow microspheres in one step11.
Hollow microsphere exhibit to be a potential approach for gastric retention. The
recent developments of floating drug delivery system including approaches to design singleunit and multiple-unit floating systems, mechanism of floating microspheres, methods of
preparation of hollow microsphere, list of polymers used in hollow microspheres,
characterization of hollow microspheres and their classification and formulation aspects
were covered in a review12.
Opened hollow microspheres of organoclays were prepared via spray drying the
suspension of modified Na+- montmorillonite with alkylsulfonate. The microstructure and
thermal properties of these opened hollow spheres were characterized by means of wideangle X-ray diffraction, field emission scanning electron microscopy and thermogravimetric
analysis. On the basis of the morphological investigation authors observed that the
organoclays containing alkylsulfonate with different molecular length, the formation of the
opened hollow microspheres were found to be related to the intercalation structure of the
organoclays. The larger the interlayer distance of the organoclays was, the more the opened
hollow microspheres were formed. Moreover, intercalating Co2+ ion within MMT galleries
of the opened hollow microspheres via ion exchange could be applied to in situ synthesize
clay/carbon nanotubes (clay/CNTs) composite by chemical vapor deposition after
reduction13.
Nearly monodispersed silica-poly (methacrylic acid) (SiO2-PMAA) core-shell
microspheres were synthesized by distillation-precipitation polymerization from 3(trimethoxysilyl) propylmethacrylate-silica (SiO2-MPS) particle templates. SiO2-PMAASiO2 trilayer hybrid microspheres were subsequently prepared by coating of an outer layer
of SiO2 on the SiO2-PMAAcore-shell microspheres in a sol-gel process. pH-Responsive
PMAA hollow microspheres with flexible (deformable) shells were obtained after selective
6
removal of the inorganic SiO2 core from the SiO2-PMAA core-shell microspheres by HF
etching14.
Hollow hydroxyapatite microspheres as a device for controlled delivery of proteins
were successfully prepared. Hollow hydroxyapatite (HA) microspheres (106–150 µm) with a
hollow core diameter equal to 0.6 the external diameter and a mesoporous shell wall were
prepared by allow temperature glass conversion route and evaluated as a device for
controlled delivery of a model protein, bovine serum albumin15.
6.3 OBJECTIVE OF STUDY:
Objectives of proposed research are,
 Preparation of blank hollow microspheres by solvent-evaporation technique/spray
drying technique.
 Preparation of hollow microspheres of amlodipine in different loadings.
 Preparation of solid unit dosage forms of amlodipine containing hollow
microspheres as well as blank microspheres.
 Evaluation parameters:
a. Spectral analysis: Various spectral analysis such as SEM, FTIR, DSC and
7
XRD of blank as well as drug loaded microspheres.
b. In-vitro tests:

Particle size and buoyancy tests for microspheres prepared.

Determination of drug content and drug loading efficiency.

In-vitro drug release.
c. Formulation of solid unit dosage forms containing blank hollow
microspheres.
d. Formulation of solid unit dosage forms containing drug loaded hollow
microspheres.
e. Evaluation of solid unit dosage forms for various tests.
f. In-vitro release kinetics studies will be undertaken.
MATERIALS AND METHODS :
A. MATERIALS:
Drug: Amlodipine
Polymers: Chitosan, Eudragit, Cellulose acetate pthalate
B. METHOD:


Preformulation studies

Solubility

Melting point

pH

UV Analysis
Preparation of solid unit dosage forms.

These systems are prepared by suitable punching machine.
7.
8

Evaluation:

Interaction studies of drug polymer by using FTIR.

Surface topography by SEM.

Particle size distribution of prepared microparticles by microscopic
technique and drug nature by DSC/XRD.

Drug entrapment efficiency.

In vitro release kinetic study.
7.1 SOURCE OF DATA :

Text books

www.sciencedirect.com

www.informahealth care.com

www.ijps online.com
7.2 Method of collection of data:
The data will be collected from various standard journals, prepared formulations,
in vitro evaluation and various standard reference books, & other sources like research
literature data bases such as Science Direct etc.
7.3 DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVENTION TO BE
CONDUCTED ON PATIENTS OR OTHER HUMANS OR ANIMALS? IF SO
PLEASE MENTION BRIEFLY.
---------No -----------
9
7.4 HAS ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR
INSTITUTION IN CASE OF 7.3?
------------- Not applicable ----------
10
8.
REFERENCES:
1. Soppimath KS, Kulkarni AR, Rudzinski WE, Aminabhavi TM. Microspheres
as floating drug delivery systems to increase gastric retention of drugs. Drug
Metabolism Reviews 2001;33:149-160.
2. Chien YW. Novel Drug Delivery Systems. 2nd ed. New York (NY): informa
health care; 139,164.
3. Jain NK. Introduction to Novel Drug Delivery Systems. 1st Ed. Delhi: Vallabh
Prakashan; 2010; 35,36,40.
4. Brunton
LL,
Lazo
JS,
Parker
KL.
Goodman
&
Gilman’s
The
Pharmacological Basis of Therapeutics. 11th Ed. New York (NY): Mc Graw
Hill; 2005; 857.
5. Soppimath KS, Kulkarni AR, Aminabhavi TM. Development of Hollow
Microspheres as Floating Controlled-Release Systems for Cardiovascular
Drugs: Preparation and Release Characteristics. 2001; 27: 507-515.
6. Haiming Li, Wang M, Song Li, Xuewu Ge. Uniform chitosan hollow
microspheres prepared with the sulfonated polystyrene particles templates.
Colloid Polym Sci 2008;286:819-825.
7. Chatzipavlidis A, Bilalis P, Tziveleka LA, Boukos N, Charitidis CA, Kordas
G. Nanostructuring the Surface of Dual Responsive Hollow Polymer
Microspheres
for
Versatile
Utilization
in
Nanomedicine-Related
Applications. Langmuir 2013; 29:9562−9572.
8. Kumar SV, Shelke NB, Prasannakumar S, Sherigara BS, Aminabhavi TM.
Microspheres
of
copolymeric
N-vinylpyrrolidone
and
2-ethoxyethyl
methacrylate for the controlled release of nifedipine. J Polym Res
2011;18:359–366.
9. Zhao L, Wei Yu, Yu Yu, Zheng W. Polymer Blends Used to Prepare
Nifedipine Loaded Hollow Microspheres for a Floating-type Oral Drug
Delivery System:In Vitro Evaluation. Arch Pharm Res 2010;33:443-450.
10. Jie Li, Wang S, Liu H, Wang S, You L. Preparation and characterization of
polystyrene/polycarbonate
composite
hollow
microspheres
by
microencapsulation method. J Mater Sci 2011;46:3604-3610.
11. Zhang Q, Wang L, Wei Z, Wang X, Long S, Yang J. A new simple method to
11
prepare hollow PES microspheres. Colloid Polym Sci 2012;290:1257–1263.
12. Gholap SB, Banarjee SK, Gaikwad DD, Jadhav SL, Thorat RM. Hollow
microsphere: A Review. International Journal of Pharmaceutical Sciences
Review and Research 2010;1:74-79.
13. Du X, Jiang Z, Meng X, Wang Z, Yu H, Li M,Tang T. Syntheses of Opened
Hollow Clay Microspheres through a Spray-Drying Approach and Their
Derivative Clay/Carbon Nanotubes Composites. J. Phys. Chem. C
2008;112:6638-6642.
14. Li G, Liu G, Kang ET, Neoh KG, Yang X. pH-Responsive Hollow Polymeric
Microspheres and Concentric Hollow Silica Microspheres from SilicaPolymer Core-Shell Microspheres. Langmuir 2008;24:9050-9055.
15. Fu H, Rahaman MN, Day DE, Brown RF. Hollow hydroxyapatite
microspheres as a device for controlled delivery of proteins. J Mater Sci:
Mater Med 2011;22:579-591.
12
9.
SIGNATURE OF CANDIDATE
10.
REMARK OF THE GUIDE
The above information and literature has been extensively investigated, verified and
was found to be correct. The present study will be carried out under my supervision and this
project is proposed for financial support from AICTE, under RPS scheme.
11.
11.1 NAME AND DESIGNATION
OF THE GUIDE
Prof. S. P. THAKKER., M. Pharm,
PROFESSOR AND HEAD
DEPT.OF PHARMACEUTICS,
S E T’s COLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
11.2 SIGNATURE
11.3 NAME AND DESIGNATION
OF CO-GUIDE
11.4 SIGNATURE
11.5 HEAD OF THE
DEPARTMENT
Dr. A. R. Kulkarni., M. Pharm, Ph.D
PROFESSOR AND HEAD
DEPT.OF PHARMACOLOGY
S E T’s COLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
Prof. S. P. THAKKER., M. Pharm.
PROFESSOR AND HEAD,
DEPT.OF PHARMACEUTICS,
S E T’s COLLEGE OF PHARMACY,
S. R. NAGAR, DHARWAD-580002.
11.6 SIGNATURE
12.
12.1 REMARK OF THE
PRINCIPAL
The above mentioned information is correct and I
recommend the same for approval.
12.2 SIGNATURE
Dr. V. H. Kulkarni., M. Pharm., Ph.D.
PROFESSOR AND PRINCIPAL,
S E T’s COLLEGE OF PHARMACY
S. R. NAGAR,
DHARWAD-580002.
13