FORMULATION OF OIL-BASED EAR ANTI-INFECTIVE DROPS

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 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       

Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh 11/5/2014 - 11/6/2014

Introduction 3

 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 antiinflammatory agents or antifungal and anti-inflammatory agents.


About otic preparation 4

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 Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh 11/5/2014 - 11/6/2014

Table: Ear anti-infective drops available in the market 5

NO PRODUCT 1. Betnesol-N®

INGREDIENTS Betamethasone sod. Phosphate 0.1 %, Neomycin sulphate 0.5 %

MANUFACTURER 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-N®

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-N®

Prednisolone sod. Phosphate 0.5 %, neomycin sulphate 0.5 %

UCB Pharma (BNF)


Characteristics of Ideal Vehicle for Ear Drops 6

 softens cerumen  emollient properties  inert

 non-irritant  viscous vehicle  prolonged contact of the active ingredients

with the surface of the ear canal Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh 11/5/2014 - 11/6/2014

Objective 7

 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 8

Stability study Analytical method development Drug-excipients compatibility Solubility characteristics of the drugs Physicochemical characteristics of the drug


Result 9



DIFFERENT FORMULATIONS OF ANTI-INFECTIVE DROPS FOR THE EAR Formula Clotrima Triamcin

Slv for

Slv for

Coconut

Refined

Olive oil

zole

olone

Clot.

Triam.

oil

palm

%

%

%

%

%

%

olein %

1

0.1

10

10

Up to

-

-

Up to

-

A

100% B

1

0.1

10

10

-

100% C

1

0.1

10

10

-

-

Up to 100%


Chemical Structure 10

Triamcinolone acetonide (C24H31FO6)

Triamcinolone acetonide was halogenated corticosteriod to be widely used topically and was found to be therapeutically effective for psoriasis

Clotrimazole (C22H17ClN2)

Clotrimazole, is known to be active against a broad spectrum of pathogenic fungi, but is also effective for treating systemic blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis and paracoccidioidomycosis.


Advantages of This New Product 11

 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) Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh 11/5/2014 - 11/6/2014

Advantages of This New Product 12

 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 13

 Most antimicrobials, anti-fungal and anti-

inflammatory are water soluble.  More difficult to make this preparation of oil-based

ear anti-infective drops

Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh

11/5/2014 - 11/6/2014

Result 14

 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. Andi Sri Suriati Amal - Seminar Nasional Hasil Riset dan Standardisasi Industri IV - Banda Aceh 11/5/2014 - 11/6/2014

Result 15

 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 16

Formula/Test

A

B

C

USP 23 (1993)

pH

5.97

6.01

5.96

5.0 – 7.2 (pH of the normal skin of the external auditory canal)

Density

0.9091

0.9111

0.9097

± 1.0000

Viscosity (cps)

6.8045

10.0674

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 17  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 Sample

18

Active Ingredient

Expected value (µg)

Value obtained (µg)

Inaccuracy (%)

Recovery (%)

Coefficient of variation (%)

Triamcinolone

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

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

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

A Clotrimazole

Triamcinolone B Clotrimazole

Triamcinolone C Clotrimazole

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 19


Conclusion 20

 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.


11/5/2014 - 11/6/2014

Suggestion for Further Study 21

 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.


11/5/2014 - 11/6/2014

Acknowledgement 22

 The author research programs are supported by

FELDA grants 4111169 “Penyelidikan Felda”.


11/5/2014 - 11/6/2014

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FORMULATION OF OIL-BASED EAR ANTI-INFECTIVE DROPS

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