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FORMULATION OF OIL-BASED EAR ANTI-INFECTIVE DROPS

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Abstract

ABSTRACT Ear anti-infective products, there are readily available across the country (as listed in Table 1.2). However, none of them is oil-based. All of them are produced with propylene glycol as solvent, which is not only expensive but also known to have ototoxic effects (Maria et.al., 2004; Garcia & Asenjo, 2001; Marais & Rutka, 1998; Wright & Meyerhoff, 1984). Whereas coconut oil, for example, costs only RM 6.48 per 100ml, olive oil RM 7.87 per 100ml the price of propylene glycol is almost triple (RM 18 per 100ml). With this new formulation it will be possible to make a new product available locally at a lower price since it is based on locally produced materials such as coconut oil. Therefore this study tried to develop three new anti-infective ear drops using two active ingredients in a single preparation, namely triamcinolone acetonide and clotrimazole in oil base (coconut oil, refined palm olein and olive oil). It was found that oleic acid was a suitable solvent for clotrimazole, while diethylenglycolmonoethylether was a suitable solvent for triamcinolone acetonide. Analysis of active ingredients using high performance liquid chromatography showed the compatibility of these two drugs in the formulation studied. Formula C was the most acceptable formulation because the result of the assay of its active ingredients met the USP specifications. This formula was found to show the specified high standards of quality, since the active and non-active ingredients were both chemically and physically compatible.
FORMULATION OF OIL-BASED
EAR ANTI-INFECTIVE DROPS
BY
ANDI SRI SURIATI AMAL
Dosen Prodi Farmasi, Fakultas Ilmu Kesehatan
Universitas Darussalam Gontor
SEMINAR NASIONAL HASIL RISET DAN STANDARDISASI INDUSTRI IV
BANDA ACEH, 5 6 NOVEMBER 2014
Content
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Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh
2
Introduction
Fact About Otic Anti-infective
Available Products List
Characteristics of Ideal Ear Drops
Objective
Method
Result: - Advantages & Limitation
- Practical Problems,
Quality and GMP
Conclusion
Suggestions for Further Study
Introduction
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Otitis externa, infection or inflammation
of the external ear canal, is one of the most
common diseases of the ear.
Otic preparations are commonly used to
treat diseases of the external ear and
occasionally of the middle ear.
The majority of the existing otic products
on the market are formulated as solution
dosage forms containing either a
combination of antibacterial and anti-
inflammatory agents or antifungal and
anti-inflammatory agents.
About otic preparation
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Mostly use propylene glycol or
anhydrous glycerin as main solvent.
propylene glycol as solvent, which is
not only expensive but
also known to have OTOTOXIC
effects
None of this preparation is oil-based
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NO
PRODUCT INGREDIENTS MANUFACTURER
1
.
Betnesol
-
Betamethasone sod. Phosphate
0.1 %, Neomycin
sulphate
0.5 %
UCB Pharma (BNF)
2
.
Otosporin
Polymyxin B. sulphate
10000 U/G, Neomycin
sulphate
3400 U/G, Hydrocortisone 1.0 % w/w
GSK (BNF)
3
.
Vistamethasone
-
Betamethasone sod. Phosphate
0.1 %, neomycin
sulphate
0.5%.
Martindale (BNF)
4
.
Otomize®
Dexamethazone
0.1 %, neomycin sulphate 3250
units/mL, glacial acetic acid
2 %.
GSIC Consumer Healthcare
(BNF)
5
.
Sofradex
Dexamethazone
0.05%, framycetin sulphate 0.5%,
gramicidin
0.005%
Sanovi
-Aventis (BNF)
6
.
Locorten
-Vioform®
Flumetasone pivalate
0.2%, clioguinol 1 %
Amdipharm
(BNF)
7
.
Gentisone®
Hydrocortisone acetate
1 %, gentamycin 0.5 %
Amdipharm
(BNF)
8
.
Predsol
-
Prednisolone sod. Phosphate
0.5 %, neomycin
sulphate
0.5 %
UCB
Pharma (BNF)
Table: Ear anti-infective drops available in the
market
Characteristics of Ideal Vehicle for Ear Drops
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softens cerumen
emollient properties
inert
non-irritant
viscous vehicle
prolonged contact of the active ingredients
with the surface of the ear canal
Objective
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To develop and formulate a new product
containing clotrimazole and triamcinolone
acetonide in one single oil-based
preparation that can be used for treating
antifungal and anti-inflammatory ear
infection.
Method
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Stability study
Analytical method
development
Drug-excipients compatibility
Solubility characteristics
of the drugs
Physicochemical characteristics
of the drug
Result
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DIFFERENT FORMULATIONS OF ANTI-INFECTIVE DROPS FOR THE
EAR
Formula
Clotrima
zole
%
Triamcin
olone
%
Slv for
Clot.
%
Slv for
Triam.
%
Coconut
oil
%
Refined
palm
olein %
Olive oil
%
A 1 0.1 10 10 Up to
100%
- -
B 1 0.1 10 10 - Up to
100%
-
C 1 0.1 10 10 - - Up to
100%
Chemical Structure
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Triamcinolone acetonide (C24H31FO6)
Clotrimazole (C22H17ClN2)
Triamcinolone acetonide was
halogenated corticosteriod to
be widely used topically and
was found to be therapeutically
effective for psoriasis
Clotrimazole, is known to be active
against a broad spectrum of
pathogenic fungi, but is also
effective for treating systemic blas-
tomycosis, candidiasis, cocci-
dioidomycosis, histoplasmosis and
paracoccidioidomycosis.
Advantages of This New Product
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Meet all the criteria of an ideal
ear drops preparation.
Lower cost
For example: coconut oil, costs only
RM 6.48 per 100ml, olive oil RM
7.87 per 100ml the price of
propylene glycol is almost triple
(RM 18 per 100ml)
Advantages of This New Product
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All the solvents were more natural in terms of its
availability in local markets such as coconut oil &
palm oil.
Harmless to the skin when compared with
propylene glycol, which is known for its ototoxicity
effect.
Limitation
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Aceh
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Most antimicrobials, anti-fungal and anti-
inflammatory are water soluble.
More difficult to make this preparation of oil-based
ear anti-infective drops
Result
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Practical Problems
The major challenge in developing these new otic
preparations containing two or more active
components were:
1. To choose a solvent in which the two ingredients
can dissolve since the two drugs chosen have
different solubility profiles.
2. To find the solvent that can mix up with the oil as
a main solvent.
Result
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Quality and GMP (USP 23 (1997))
1. Evaluation of formulation like
density, viscosity, pH and clarity had
been checked.
2. This formula showed the specified
high standards of quality, with its
active and non-active ingredients
being chemically and physically
compatible.
Physicochemical properties of product
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Formula/Test
A
C
USP
23 (1993
)
pH
5.97
5.96
5.0
7.2
(pH of the normal skin of the
external auditory canal)
Density
0.9091
0.9097
±
1.0000
Viscosity (cps)
6.8045
10.5416
10
-30
Formula A using coconut oil as main solvent
Formula B using refined palm olein as main solvent
Formula C using olive oil as main solvent
Result
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CHROMATOGRAM OF TRIAMCINOLONEACETONIDE,
CLOTRIMAZOLE AND PROGESTERONE
(Analysis of active ingredients using high performance liquid chromatography
(HPLC))
Accuracy, Recovery and coefficient of variation of analysis of
clotrimazole and triamcinolone in the new anti-infective drops
preparation (n=6) using HPLC method
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Sample
Active Ingredient
Expected value
(µg)
Value obtained
(µg)
Inaccuracy (%)
Recovery (%)
Coefficient of
variation (%)
A
Triamcinolone
Clotrimazole
4
10
15
40
100
150
4.2732
9.7800
15.0500
40.2732
79.0800
123.7920
7.57
2.23
1.09
7.57
20.92
17.52
106.23
97.77
99.95
106.83
79.08
82.39
8.1
0.8
2.5
8.1
1.9
1.3
B
Triamcinolone
Clotrimazole
4
10
15
40
100
150
4.9272
10.0145
15.3603
32.2403
87.5412
123.9250
23.18
0.62
2.40
0.19
12.46
4.30
123.75
100.15
102.40
80.60
87.54
95.70
1.0
0.9
0.6
4.6
2.5
1.2
C
Triamcinolone
Clotrimazole
4
10
15
40
100
150
4.9272
10.0145
15.3603
40.9272
94.0145
150.3603
23.18
0.62
2.40
2.32
6.06
0.24
123.18
100.16
102.40
102.32
94.02
100.24
1.03
0.97
0.64
1.03
5.03
0.06
USP 23 (1993), recovery test for topical solution should contain not less than 90.0% and not more than 115.0 % of the labeled amount of
triamcinolone acetonide and for clotrimazole should not less than 90.0% and not more than 115.0%.
Result
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Conclusion
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Riset dan Standardisasi Industri IV - Banda Aceh
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Three new anti-infective combination ear drops consisting of
two active ingredients, i.e. triamcinolone acetonide and
clotrimazole in oil base (coconut oil, refined palm olein and
olive oil) have been developed.
Analysis of active ingredients using high performance liquid
chromatography (HPLC) showed the compatibility of these
two drugs in the formulation study.
Formula C was found to be the most acceptable formulation
because it complied with the USP specifications for its active
ingredient assay. This formula showed the specified high
standards of quality, with its active and non-active ingredients
being chemically and physically compatible.
Suggestion for Further Study
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Andi Sri Suriati Amal - Seminar Nasional Hasil
Riset dan Standardisasi Industri IV - Banda Aceh
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The formulation containing anti-fungal and anti-
inflammatory in the oil base can now be made to
replace the propyleneglycol-based ear anti-infective
drops that have been known to have ototoxicity
effect.
However, additional studies are needed to determine
if these concepts are applicable under in vitro and/or
in vivo conditions.
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Riset dan Standardisasi Industri IV - Banda Aceh
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The author research programs are supported by
FELDA grants 4111169 Penyelidikan Felda.
Acknowledgement
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