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TABLE 3: VISCOSITY OF NASAL FORMULATION AT
DIFFERENT TEMPERATURES
Formulation
F1
F2
Viscosity at
250 in cP
Viscosity at
350 in cP
Gelling point
by graph (0)
25
51
839
1089
34
34
F3
88
1474
32
F4
107
1847
31
F5
129
2247
29
Viscosity by Brookfield viscometer cap 2000+ spindle No. 1 at 5 rpm of nasal
formulation at different temperature 250 for solutions and 350 forgels
Various solubilizers were tried during preformulation
study. Propylene glycol and Transcutol were selected
as solubilizers for further study. Poloxamer 407
gives gelation temperature in nasal temperature range
28 0 to 35 0 in 18% w/v concentration. Addition of
bioadhesive polymer from 0.2% to 0.7% further
lowered the gelation temperature from 34 0 to 29 0.
Gelation temperatures obtained using two different
methods (visual inspection and rheological method)
did not vary more than ±10. The gelation temperature
lowering effect of bioadhesive polymer might have
caused in part by the increased viscosity after
dissolution of mucosadhesive polymer. The pH values
of all formulations were found in the range of 5.3 to
5.6. Formulation should posses’ mild acidic pH for
activation of lysozyme (A natural antibacterial enzyme
important for controlling nasal microbial count
which becomes inactive at alkaline pH). The pKa of
ondansetron hydrochloride is 7.4; so drug present in
solubilised form in pH range 5 to 6.5 (ondansetron
hydrochloride precipitate above 6.8). It was observed
that the concentration of bioadhesive polymer increased
from 0.2% to 0.7% showed retardation of ondansetron
hydrochloride release, probable mechanism for such
retardation of release may be reduction in number
and dimensions of the channels in gel structure by
increased viscosity of the formulation. From the study
it can be concluded that the nasal in situ gels can be
formulated of ondansetron hydrochloride using PF127
and bioadhesive polymer.
ACKNOWLEDGMENTS
We would like to thank Dr. Reddy’s Lab. and Signet
Chemicals for supplying drug and polymer samples
respectively.
REFERENCES
1.
2.
3.
4.
5.
6.
Cho E, Gwak H, Chun I. Formulation and evaluation of ondansetron
nasal delivery systems. Int J Pharm 2008;349:101-7.
Schmolka IR. Artificial skin: Preparation and properties of Pluronic
F-127 gels for treatment of burns. J Biomed Mater Res 1972;6:571-82.
Miller SC, Donovan MD. Effect of poloxamer 407 gels on the miotic
activity of pilocarpine nitrate in rabbits. Int J Pharm 1982;5:142-52.
Shinde JV, Mali KR, Dias RJ, Havaldar VD, Mahajan NS.
In situ Mucoadhesive nasal gels of metaclopramide hydrochloride:
preformulation & formulation studies. J Pham Res 2008;1:88-96.
Yong CS, Choi JS, Quan QZ, Rhee JD, Kim CK. Effect of sodium
chloride on gelation temperature, gel strength and bioadhesive
force of poloxamer gels containing diclofenac sodium. Int J Pharm
2001;226:195-205.
Zaki NM, Awad GA, Mortada ND, AbdelHady SS. Enhanced
bioavailability of metaclopromide HCl by intranasal administration of
a mucoadhesive in situ gel with modulated rheological and mucociliary
transport properties. Eur J Pharm Sci 2007;32:296-307.
Development of Room Temperature Stable Formulation
of Formoterol Fumarate/Beclomethasone HFA pMDI
D. PUROHIT*, A. TREHAN AND V. ARORA
Research & Development Centre (R&D I), Ranbaxy Laboratories Limited, Plot No. 20, Sector 18, Udyog Vihar
Industrial Area, Gurgaon-122 015, India
Purohit et al.: Room Temperature Stable Formoterol Fumarate/Beclomethasone HFA pMDI
The primary aim of present investigation was to develop and formulate room temperature stable formulation of
formoterol fumarate and beclomethasone dipropionate with extra fine part size of hydrofluoroalkane pressurized
metered dose inhalers. Particle size distribution of hydrofluoroalkane pressurized metered dose inhalers was evaluated
using Twin Stage Glass Impinger and Anderson Cascade Impactor. A tetrafluoroethane and/or heptafluoropropane
were evaluated for preparation of hydrofluoroalkane pressurized metered dose inhalers. The fine particle fractions
delivered from hydrofluoroalkane propellant suspension pressurized metered dose inhalers can be predicted on the
November - December 2009
Indian Journal of Pharmaceutical Sciences
713
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basis of formulation parameters and is dependent of metering chamber of valve and orifice size of actuators. The
results presented in investigation showed the importance of formulation excipients with formulation of pressurized
metered dose inhalers viz, canister, valve and actuators used in formulations.
Key words: Impinger, aerosols, deposition of emitted dose, delivered dose uniformity
dipropionate to be able to deliver the desired doses
to the patient. Beclometasone dipropionate/formoterol
fumarate in above formulation is characterized by
an extra-fine particle size distribution which results
in a more potent effect than individual formulation
of beclomethasone available in market. The above
combination is indicated for regular treatment of
asthma where use of a combination product (inhaled
corticosteroid and long-acting beta 2 -agonist) is
appropriate.
pMDIs were prepared by single step manufacturing
process as given here: Introduction of active/
excipients into pressure vessel, Addition of required
quantity of propellant to provide sufficient number
of doses, Filling of drug/propellant mixture into precrimped aluminum canister (supplied by Presspart,
UK).
RESULTS AND DISCUSSION
Delivered dose uniformity results obtained with a
DF316/50 valve fitted with a 0.3 mm outlet orifice
Delivered Dose Uniformity (DDU)
To develop room temperature stable formulation of
formoterol fumarate/beclomethasone dipropionate
hydrofluoroalkane (HFA) pressurized metered dose
inhalers (pMDI) for lung delivery. The HFA pMDI
were prepared from ozone friendly propellants
viz, tetrafluoroethane and/or heptafluoropropane.
A HFA based formulation of formoterol fumarate/
beclomethasone dipropionate was developed to deliver
6 +100/200 µg per actuation over 120 doses. The
present formulation comprises polyvinylpyrrolidone
and/or polyethylene glycol in an amount sufficient
to enhance the physical stability of suspension and
provide extra fine particle size of formoterol fumarate/
beclomethasone dipropionate. Formoterol fumarate and
beclomethasone dipropionate have different modes
of action. Beclomethasone dipropionate, a synthetic
glucocorticoid given by inhalation at recommended
doses has an antiinflammatory action, which plays
an important role in the efficacy of beclomethasone
dipropionate in controlling symptoms and improving
lung function in asthma. Inhaled beclomethasone
dipropionate probably acts topically at the site of
deposition in the bronchial tree after inhalation.
Formoterol is a selective β2 adrenergic agonist that
produces relaxation of bronchial smooth muscle
in patients with reversible airways obstruction. In
addition to its bronchodilator action, formoterol also
inhibits mast cell mediator release, plasma exudation
and may reduce sensory nerve activation. Thus these
two classes of drug address complementary aspects of
the pathophysiology of asthma and COPD that neither
drug class is able to achieve alone.
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MATERIALS AND METHODS
7
Beclomethasone
Excipients selected for evaluation were polyethylene
glycol (at levels of 0.05 to 2.5% w/w, supplied by
Clariant, India) and polyvinylpyrrolidone (at levels
of 0.002 to 0.5% w/ w, supplied by Signet, India).
The amount of micronised formoterol fumarate
and beclomethasone dipropionate were mixed in
a pressure vessel in a way to get the appropriate
dose of formoterol fumarate and beclomethasone
*Address for correspondence
E-mail: [email protected]
714
10
Dose number
Formoterol
Fig. 1: Delivered dose uniformity of the formulation using 0.3 mm
actuator
Delivered dose uniformity of the formulation containing (──)
formoterol and (──) beclomethasone at initial conditions using a
0.3 mm actuator fitted on a DF316/50 valve.
TABLE 1: DEPOSITION OF EMITTED DOSE BY TSLI
Drug
Beclomethasone
dipropionate
Formoterol fumarate
0.3 mm Actuator
0.48 mm Actuator
40.23%
49.89%
56.81%
69.03%
Values are in terms of % of Label Claim
Indian Journal of Pharmaceutical Sciences
November - December 2009
Delivered Dose Uniformity (DDU)
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fumarate was selected by using HFA propellants closely
matching the density of the micronised actives.
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Dose number
Beclomethasone
Formoterol
Fig. 2: Delivered dose uniformity of the formulation using a
0.48 mm actuator
Delivered dose uniformity of the formulation containing (──)
formoterol and (──) beclomethasone at initial conditions using a
0.48 mm actuator fitted on a DF316/50 valve.
diameter actuator are shown in fig. 1 and those
obtained with a DF316/50 valve fitted with a 0.48
mm outlet orifice diameter actuator are shown in
fig. 2. Deposition of emitted dose by TSLI results
are summarized in Table 1. During this study,
Polyethylene glycol at levels less than 0.5% w/w was
found to ensure good product performances and valve
functioning throughout the MDI units’ life. The level of
polyvinylpyrrilodone selected also helped to decrease
the settling of particles and prevents agglomeration of
actives. This formulation was readily re-dispersible and
avoiding invariability dosing of the drug. The stable
suspension of particulate beclomethasone/ formoterol
In conclusion, the novel combination of formoterol
fumarate and beclomethasone dipropionate is a
suspension based HFA pMDI product. The combined
characteristics of room temperature stable formulation
with good deposition of both drugs in lung provides
unique characteristics to the above fixed dose
combination, highly attractive in terms of patient
usage requirements and commercial supply.
ACKNOWLEDGEMENTS
The authors would like to thank Valois, France &
Presspart, UK for supplying canisters and valves for
development trials.
REFERENCES
1.
2.
3.
4.
Purewal T. Formulation of metered dose inhalers, Metered dose inhalers
technology, Buffalo Grove: Interpharm Press; 1998, p. 1-8.
Vervaet C, Byron PR. Drug-surfactant-propellant interactions in HFAformulations. Int J Pharm 1999;186:13-30.
Hickey AJ. Inhalation Aerosols, Physical and Biological Basis for
Therapy, 2nd ed. In; Lenfant C. Editors. Lung Biology in Health and
Disease. Vol. 221. Boca Raton: In-forma Health Care; 2007.
Murnane D, Martin GP, Marriott C. Investigations into the Formulation
of Metered Dose Inhalers of Salmeterol Xinafoate and Fluticasone
Propionate Microcrystals. Pharm Res 2008;25:2283-91.
Brain-Targeted Nasal Clonazepam Microspheres
J. SHAJI*, A. PODDAR AND S. IYER
Prin. K. M. K. College of Pharmacy, Colaba, Mumbai-400 005, India
Shaji et al.: Nasal Clonazepam Microspheres
Gelatin-chitosan mucoadhesive microspheres of clonazepam were prepared using the emulsion cross linking method.
Mirospheres were evaluated using the in vitro and ex vivo drug release patterns. In vivo CNS drug distribution
studies were carried out in rats by administering the clonazepam microspheres intra-nasally and clonazepam solution
intravenously. From the drug levels in plasma and CSF, drug targeting index and drug targeting efficiency were
calculated. Results obtained indicated that intranasally administered clonazepam microspheres resulted in higher
brain levels with a drug targeting index of 2.12. Gelatin-chitosan cross linked mucoadhesive microspheres have the
potential to be developed as a brain-targeted drug delivery system for clonazepam.
Key words: Gelatin-chitosan cross linked microspheres, mucoadhesive microspheres, clonazepam, brain-targeted
drug delivery, drug targeting index
*Address for correspondence
E-mail: [email protected]
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Indian Journal of Pharmaceutical Sciences
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