MICROPARTICULATE DRUG DELIVERY SYSTEM OF

ORCIPRENALINE SULPHATE

M.PHARM DISSERTATION PROTOCOL

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES,
KARNATAKA, BANGALORE.
BY

MANTHRI KALYAN KUMAR

UNDER THE GUIDANCE OF

Dr.S.S.BUSHETTI
M.Pharm, Ph.D

DEPARTMENT OF INDUSTRIAL PHARMACY

H.K.E.SOCIETY’s COLLEGE OF PHARMACY
SEDAM ROAD,
GULBARGA – 585105
2010-2011

0
 RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCE, KARNATAKA

BANGALORE

ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. Name of the candidate

(In block letters) MANTHRI KALYAN KUMAR.

Permanent address MANTHRI KALYAN KUMAR,

S/O MANTHRI CHANDRA MOULI,
HOUSE NO: 86-247-2
PARAMESHWAR NAGAR,
B –CAMP (P.O), KURNOOL,
STATE: ANDHRAPRADESH,
PIN CODE: 518 002.

2. Name of the institution H.K.E.S’s COLLEGE OF PHARMACY,

SEDAM ROAD, GULBARGA – 585105

3. Course of study and subjects M.PHARM

(INDUSTRIAL PHARMACY)

4. Date of admission to the course 23-06-2010

PREPARATION AND EVALUATION OF

5. Title of the topic MICROPARTICULATE DRUG DELIVERY
SYSTEM OF ORCIPRENALINE SULPHATE

6. Briefs resume of the intended

work

6.1 Need for the study:

1
 The philosophy behind the development of controlled drug delivery system is
to make a therapeutic agent do it’s best when administered into the body( it
means it should show high therapeutic efficacy with minimal toxicity) 1.
Microparticulate drug delivery system is one among the various controlled
release drug delivery systems, by which we can achieve the maximum
therapeutic efficacy with minimal toxicity. Microparticles are small, discrete
particles containing an active core material which are coated by synthetic or
natural polymers of varying thickness2.

Microparticles are prepared for,

 Sustained release
 Controlling and sustaining the action of the active substance.
 Minimizing gastric irritation.
 Environmental protection in the GIT.
 Seperating or dispensing incompatible substances.
 Masking unpleasant taste and odour etc.

The drugs of the categories (Antibiotics, bronchodilators, sulfadrugs, diuretics,

anti-inflammatory, antibacterials, antiepileptics, analgesics, anti hypertensives,
anti cancerogens etc.) can be encapsulated to achieve the above said goals.
Bronchial asthma3 is characterized by hyper responsiveness of tracheo bronchial
smooth muscle to a variety of stimuli, resulting in narrowing of air tubes, often
accompanied by increased secretion , mucosal edema, and mucus plugging.

Orciprenaline sulphate4 a β2-adreno agonist bronchodilator used in the

management of reversible airways obstruction. Orciprenaline sulphate a water
soluble drug dissolves readily, absorbed rapidly and eliminated at a faster rate
due to its shorter biological half life ( 6 hrs ) 5. This fails in maintaining the
plasma drug concentration for an extended period of time, so this needs frequent
dosing to achieve an extended plasma drug concentration. Orciprenaline sulphate
is a weakly basic drug when exposed to acidic pH may result in the poorly
soluble free base ( i.e. precipitate of orciprenaline ). The precipitated drug is no
longer capable of releasing from the formulation and resulting into the decreased
bioavailability6, this possible instability of the drug will be minimized by
preparing microparticles using some polymers with solubilizing effect in the
intestinal fluid which may operate in the micro environment immediately
surrounding the drug particles and hence the bioavailability can be improved.

Because of the high water solubility, short biological half life (6hrs) and
therapeutic use in chronic diseases, Orciprenaline sulphate is considered as an
ideal candidate for the design of oral controlled release drug delivery system. In
the proposed research work an attempt will be made to prepare polymeric
microparticles of Orciprenaline sulphate which will release the drug for an
extended period of time to achieve steady state plasma concentration of the drug, 2
3
6.2 Review of Literature:

The literature survey was carried out of by referring various scientific journals
and with the facility of internet and helinet, literature review shows that no work
has been published on formulation and evaluation of microparticles of
Orciprenlaine sulphate. Some of the published reports of similar work for various
medicinal agents are:

 Arul B et al7 prepared microspheres of chitosan containing Isoniazid by

using glutaraldehyde cross-linking method using various concentrations
of chitosan polymer. The results revealed that the increase in
concentration of chitosan causes the decrease in the rate of drug release.

 Muthushamy K et al8 preparation and evaluation of albumin- chitosan

microsphere containing Theophylline by heat stabilization method in the
presence of Span 80. Microspheres with seven drug to carrier ratios were
thermally prepared and cross linked. Drug to carrier ratio 1:1:2 showed
maximum yield and highest entrapment. The particle size range increased
approximately from 542 to 1078 µm with a peak between 779 to 948 µm
and maximum encapsulation efficiency was found to be 78.2±2.1 w/w.
In-vitro release studies were carried out in different p H for a period of 8
hour and compared with the pure drug.

 Das MK, Rama Rao K9 formulated Zidovudine ethyl cellulose

microspheres by water-in-oil-in-oil double emulsion solvent diffusion
method where Spherical free flowing microspheres having an entrapment
efficiency of 32-54 % were obtained and evaluated for the effect of
polymer drug ratio, surfactant concentration for secondary emulsification
process, volume of processing medium and stirring speed of secondary
emulsification process with respect to entrapment efficiency and in-vitro
drug release behaviors.

 Das MK et al10 prepared Furosemide loaded alginate microspheres by

ionic cross-linking technique using CaCl2, Al(SO4)3 and BaCl2 and
evaluated for the effects of sodium alginate concentration, cross- linking
agents, entrapment efficiency, particle size, surface characteristics and in-
vitro release behaviors. And there by concluded that Furosemide release
from the alginate microspheres follow anomalous transport mechanism
after an initial lag period where the drug release mechanism was found to
be Fickian diffusion controlled.

 Parasuram RR et al11 prepared delayed release Aceclofenac microspheres

and evaluated the effects of various other modern enteric polymers such
hydroxyl propyl methyl cellulose Phthalate (HPMCP ), Eudragit L 100,
Eudragit S- 100 on the release of Aceclofenac from the cellulose acetate
phthalate microspheres with an objective of attaining delayed release
rates of the drugs.

4
 Thakkar HP et al12 studied the effects of cross-linking agents on
characteristics of Celecoxib microspheres by emulsification cross-linking
method prepared by using two different cross-linking agents by simple
heat treatment and evaluated for in-vitro drug release studies which
indicated that the microspheres cross linked using glutaraldehyde
showed slow released rates than those prepared by using formaldehyde
and concluded that the heat cross linked microspheres showed a faster
release rate of the drug.

 Gupta Kumar B et al13 prepared microcapsules of Leflunomide with

Eudragit RL 100 and Eudragit RS 100 by solvent evaporation technique.
The study was carried out to achieve a slower release rate of
Leflunomide from the microcapsules. At optimal conditions of process
variables such as stirring speed, temperature of the medium, drug
polymer ratio etc., maximum encapsulation efficiency was obtained.

 Mazumder B et al14 prepared cellulose based microspheres of

Chlorpheniramine maleate by oil in oil emulsification method using
ethyl cellulose and Cellulose acetate as polymer with an objective to
achieve good entrapment efficiency of about 79-93 % and 80-89 % for
ethyl cellulose and cellulose acetate microspheres respectively.

 Rajender K et al15 prepared Terbutaline sulphate encapsulated ethyl

cellulose microspheres by water –oil-water double emulsion solvent
diffusion method using ethyl cellulose. The results revealed that for
obtaining controlled release with high entrapment efficacy, the
microspheres should be prepared using relatively low level of drug and
higher level of polymer.

 Vidyavathi M et al16 prepared microspheres of Niacin by water-in-oil-in-

oil double emulsion solvent diffusion method where spherical, free
flowing microspheres having an entrapment efficiency of 72 % were
obtained and practical yield was observed to be 85 % and particle size
range was 405 to 560 µm. The in-vitro release profiles from optimized
formulations with various kinetic models, the best fit with the highest
correlation coefficient was observed in Higuchi model, indicating
diffusion controlled principle.

 Arunachalam A, Stephen Rathinaraj B et al17 formulated Ofloxacin

microspheres using natural gelatin polymer by using coacervation/ phase
seperation method and evaluated for various parameters and in –vitro
release pattern. They concluded that the percentage drug entrapment was
in the range of 78 – 90 % and the formulation showed a sustained release
of drug over a period of 8 hours.

5
 Bipul Nath et al18 prepared and characterized Salbutamol sulphate loaded
ethyl cellulose microspheres using water–oil-oil emulsion technique with
an objective to formulate and evaluate microencapsulated controlled
release preparation of highly water soluble drug concluding that the
release of Salbutamol sulphate was influenced by altering the drug to
polymer ration and the drug release was found to be diffusion controlled.

 Rahman M Md et al19 prepared and evaluated cellulose acetate phthalate

and ethyl cellulose based microcapsules of Diclofenac sodium using
emulsification and solvent evaporation method by studying the effect of
various polymers on the loading efficiency of Diclofenac sodium and
concluded that the combination of ethyl cellulose and cellulose acetate
phthalate showed more sustaining action than the individual polymer
formulations.

 Sanat Kumar B et al20 prepared Ketorolac Tromethamine microspheres

by complex coacervation and simple coacervation methods and
evaluated by chitosan/ gelatin B complex coacervation with an objective
to design a controlled drug delivery system for the prolonged release of
Ketorolac Tromethamine by possible reduction of time intervals between
administrations.

 Sathiya Sunder R et al21 prepared Carprofen microspheres by using

emulsion solvent evaporation technique using cellulose acetate phthalate
(CAP ) as the polymer and concluded that the formulated drug was
showing good drug release rates (88.35 %), which comprises with I.P
official requirement.

 Sudhamani T et al22 prepared and evaluated ethyl cellulose microspheres

of Ibuprofen for sustained drug delivery by using solvent evaporation
method with an objective to increase percentage of loading of Ibuprofen
with respect to polymer. And concluded that the in–vitro release studies
of Ibuprofen microspheres of 1:2 ratio showed better sustained effect
over a period of 8 hours.

 Sunitha S et al23 prepared and characterized Ondansetron Hydrochloride

microspheres using various cellulose polymers by employing solvent
evaporation technique with an objective was to study the drug excipient
compatibility by using fourier transform infrared spectroscopy ( FT-IR )
and differential thermal analysis ( DTA). and concluded that the drug
release profile was extended maximum upto 12 hours with ethyl
cellulose FTIR and differential scanning colorimetry ( DSC ) results
showed Ondansetron Hydrochloride was compatible with excipients.

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 6.3 Objectives of the study:

In the proposed research work, we are planning to prepare Orciprenaline

sulphate microparticles with the following objectives.

1. Orciprenaline sulphate microparticles will be prepared using ethyl

cellulose, cellulose acetate phalate, chitosan etc. in varying concentration
by coacervation/ phase seperation method.

2. The prepared microparticles will be evaluated for various parameters like

practical yield, particle size, particle shape, surface morphology, wall
thickness, angle of repose, entrapment efficiency, in-vitro drug release
and stability studies etc.,

3. The microparticles prepared will delay the drug release and helps in
maintaining plasma drug concentration for an extended period of time.

4. With the preparation of microparticles we can minimize the eratic release

and absorption of thr drug, as a result the steady state concentration will
be maintained.

5. This extended plasma drug concentration profile minimizes the

frequency of dosing(associated with conventional dosage form) to
maintain the plasma drug concentration for an extended period of time.

6. This extended release microparticles will minimize the dose dependent

side effects associated with the immediate / rapid release of the drug.

7. The microparticles prepared will help in maintaining the drug in stable

form by avoiding exposure to acidic pH, due to the use of pH- dependent
soluble polymers (i.e. acid-resistant polymers).

8. The microparticles prepared will help in masking the bitter taste of the
drug.

With the preparation of microparticles we can deliver orciprenaline sulphate

in a more stable, efficacious and in a sustained/controlled release manner.

7. Materials and Methods

7.1 Source of Data:

 Internet.
 Helinet facility of our affiliating university RGUHS Bangalore.
 International pharmaceutical journals.
 National Pharmaceutical journals.

7
7.2 Materials:

Drug : Orciprenaline sulphate

Polymers : Ethyl Cellulose (EC), cellulose acetate phalate (CAP),

Chitosan, etc.

Cross linking agents : Glutaraldehyde etc,.

Equipments:

 UV-visible spectrophotometer (Shimadzu 1800)

 Digital balance (shimadzu)
 Scanning electron microscopy (SEM)
 USP XXIII dissolution test apparatus
 Stability chamber
 Digital Controlled Speed Stirrer (Remi motors RQ 121/D)

Preparation of microparticles of Orciprenaline sulphate:

The microparticles of Orciprenaline sulphate will be prepared using above

listed materials by coacervation/ phase seperation technique21.

The phase separation method is specially designed for preparing the

reservoir type of system, i.e. to encapsulate water soluble drugs. The process is
based on the principle of decreasing the solubility of the polymer in the organic
phase to affect the formation of the polymer rich phase called the coacervates.
The coacervation can be brought about by addition of the third component to the
system which results in the formation of two phases, one rich in the polymer,
while the other one, i.e. supernatant, depleted of the polymer.

In this technique, the polymer is first dissolved in a suitable solvent and then
drug is dispersed by making it’s aqueous solution. Phase seperation is then
accomplished by changing the solution conditions by using various methods like
salt addition, non –solvent addition, addition of the incompatible polymer or
change in pH. The choice of method selected is largely dependent upon the
polymer and set of conditions.

Evaluation of Orciprenaline sulphate microparticles :

The prepared microparticles will be evaluated25 for

 Practical yield
 Particle size
 Particle shape
 Surface morphology
 Wall thickness
 Angle of repose
 Entrapment efficiency
 In –vitro drug releases
 Stability studies
8
 7.3 Does the study require any investigation or intervention to be conducted on
patients or other humans or animals? If so please describe briefly

…………………. Not under the plan of the work…………………..

Has ethical clearance have been obtained from your institution in case of 7.4

7.4 …………………Not applicable………………………….

8 List of References

1. Jayakrishnan A, Latha MS. Biodegradable polymeric microspheres as drug

carriers In: Jain N K, editor. Controlled and novel drug delivery. New Delhi:
CBS ;2008. P.236.
2. Ramesh Chaudhari P, Harshad Parmar G, Hiren Patel J, Dushyant Shah A.
Microparticulate system: a revolution in drug delivery. Int J Pharm Informa; J
Pharm and Cosmetology 2010;1(1).p. 2.
3. Tripathi KD. Drugs for cough and bronchial asthma. In: Tripathi M, editor. 6 th
edition. Essesntials of medical pharmacology. Jaypee ; 2009.P.216.
4. British Pharmacopoeia ; Medicines and health care products regulatory agency
(MHRA) London ; 2008 ; vol-2 ;2008.p.1605.
5. http://www.drugbank.ca/drugs/DB00816 as seen on 9-12-2010.
6. Sweetman SC , editor : Martindale : The complete drug reference , 33rd edition,
Pharmaceutical press : London (U.K) ;2007. P.1012.
7. Arul B, Kothai R, Sangameswaran B, Jayakar B. Formulation and evaluation of
chitosan microspheres containing Isoniazid. Indian J Pharm Sci 2003;65(6):
640-42.
8. Muthushamy K, Shibi KP, Ravi TK. Preparation and evaluation of Albumin –
Chitosan microspheres containing Theophylline. Indian J Pharm Sci 2004;66(2):
245-48.
9. Das MK, Rama Rao K. Microencapsulation of Zidovudine by double emulsion
solvent diffusion technique using ethyl cellulose. Indian J Pharm Sci 2007;69(2):
244-50.
10. Das MK, Senapati P. Furosemide loaded alginate microspheres prepared by ionic
cross-linking technique: morphology and release characteristics. Ind J Pharm Sci
2008;70(1): 77-84.
11. Parasuram RR, Moidutty L, Chetan HB. Preparation and evaluation of delayed
release Aceclofenac microspheres. Asian J Pharmaceutics 2008;2(4): 252-54.
12. Thakkar HP, Murthy RR. Effect of cross-linking agent on the characteristics of
Celecoxib loaded chitosan microspheres. Asian J Pharm 2008;2(4): 246-51.
13. Gupta kumar B, Rabindranath Pal, Mansa C, Rabindra D . Design, evaluation
and optimization of microcapsules of Leflunomide with Eudragit RL 100 and
Eudragit RS100 by solvent evaporation technique. Asian J Pharm 2009;3(4);
309-13.

9
14. Mazumder B, Sanjay D, Sanjib B, Sushanta S, Bibhash M. Studies on
formulation and characterization of cellulose–based microspheres of
Chlorpheniramine maleate. Arch Pharm Sci Res 2009;1(1): 66-74.
15. Rajendra K, Vishnu Patel, Harsha Patel, Bhavram Salaniya. Evaluation of
Terbutaline Sulphate encapsulated ethyl cellulose microspheres: A factorial
approach. Int J Pharm Tech Res 2009;1(4): 1271-8.
16. Vidyavathi M, Nirmala D, Asha S, Joginapalli S. Design and evaluation of
Niacin microspheres. Indian J Pharm Sci 2009;71(6): 663-669.
17. Arunachalam A, Stephen Rathinaraj B, Subramanian, Prasanta Kumar C,
Kishore reddy A, Fareedullah Md. Preparation and evaluation of Ofloxacin
microspheres using natural gelatin polymer. Int J App Biology Pharm Tech
2010; 1(1): 61-7.
18. Bipul N, Lila Kanth Nath, Bhaskar Mazumder, Pradeep Kumar, Niraj Sharma,
Bhanu Pratap Sahu. Preparation and characterization of Salbutamol Sulphate
loaded ethyl cellulose microspheres using water-in-oil-oil emulsion technique.
Iranina J Pharm Res 2010; 9(2); 97-105.
19. Rahman Md M, Saiful islam Md, Nahid Sharmin, Jhakir Ahmed C, Reza-ul Jalil.
Preparation and evaluation of cellulose acetate phthalate and ethyl cellulose
based microcapsules of Diclofenac sodium using emulsification and solvent
evaporation method. Dhaka Univ J Pharm Sci 2010; 9(1): 39-46.
20. Sanat KB, Kavitha K, Rupesh Kumar M. Evaluation of Ketorolac Tromethamine
microspheres by chitosan/ gelatin B complex coacervation. Sci Pharm 2010;78:
79-92.
21. Sathiya Sundar R, Murugesan A, Venkatesan P, Manavalan R. Formulation
development and evaluation of Carprofen microspheres. Int J Pharm Tech Res
2010; 2(3): 1674-76.
22. Sudhamani T, Noveen Kumar Reddy K, Ravi Kumar VR, Revathi R, Ganesan V.
Preparation and evaluation of ethyl cellulose microspheres of Ibuprofen for
sustained drug delivery. Int J Pharm Res Dev 2010; 2(8): 119-25.
23. Sunitha S, Amareshwar P, Santosh Kumar M . Preparation and characterization
of Ondansetron Hydrochloride microspheres using various cellulose polymers.
Int J Current Pharm Res 2010; 2(2): 44-9.
24. Vyas SP, Khar RK. Microspheres. Targeted and controlled drug delivery . New
Delhi: CBS;2010.P. 423-4.
25. Alagusundaram M, Madhu Sudana Chetty C, Umashankari K, Venkata
Badrinath A, Lavanya C, Ramakanth S. Microspheres as a novel drug delivery
system- A review. Int J Chem Tech Res 2009; 1(3): 526-34.

10
 9. Signature of candidate [MR. Manthri Kalyan Kumar].

10. Remarks of Guide The proposed research work is novel one and with
the development of microparticles we can deliver
Orciprenaline sulphate more efficiently and
effectively. So recommended for registration.

11. Name and designation of

(in block letters)

Dr. S.S.BUSHETTI
11.1 Guide M.Pharm,Ph.D
PROFESSOR
DEPT.OF INDUSTRIAL PHARMACY
H.K.E.S’s COLLEGE OF PHARMACY
SEDAM ROAD, GULBARGA – 585105

11.2 Signature

M.V. RAMPURE
M. Pharm ,(Ph.D)
11.3 Co-guide ASST. PROFESSOR
DEPT. OF PHARM.TECHNOLOGY
H.K.E.S’s COLLEGE OF PHARMACY
SEDAM ROAD, GULBARGA -585105

11.4 Signature

12 12.1 Remarks of Chairman

and Principal

12.2 Signature

11