FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
Provisional Specification
(See section 10 and rule 13)
I A process to manufacture a novel cream
Apex Laboratories Private Limited
SIDCO Garment Complex, III Floor, Guindy, Chennai-600 032, Tamil Nadu
State, India
An Indian company registered under the Companies Act, 1956

The following specification describes the invention:
358MUM2009
1 8 FEB 2009

A process to manufacture a novel cream
Background of the invention:
This invention is a continuation of the Indian patent application no.2645/MUM/2008 submitted on 19th December, 2008. All information submitted in the provisional specification that accompanied said patent application is incorporated herein by reference.
Summary of the invention:
The invention provides a novel process of making Sodium Fusidate cream in which the fusidic acid is formed in-situ in a cream base. A process of selection of right quality API is also disclosed. The composition of the Sodium fusidate cream produced by the process as disclosed herein has been disclosed in the application no. 2645/MUM/2008.
Detailed description of the invention:
According to the preferred embodiment of the present invention, there is a process of making a composition for the topical treatment of bacterial skin infections on human skin, the composition, which was originally disclosed in the application no. 2645/MUM/2008, comprising
a) 40 to 50 percent Purified Water;
b) 1 to 2.5 percent Sodium Fusidate;
2

c) 1 to 15 percent Emulsifying wax, preferably 12.5 percent Cetostearyl Alcohol;
d) 5 to 20 percent White soft paraffin; preferably 12.5 percent White Soft Paraffin
e) 1 to 5 percent Non ionic Surfactant/emulsifier; preferably 2 percent Polysorbate 80
f) 5 to 40 percent Propylene Glycol; preferably 25 percent Propylene Glycol
g) 0.05 to 0.5 percent Preservative; preferably 0.2 percent Benzoic Acid
h) 0.01 to 0.1 percent Antioxidant; preferably 0.01 Butylated Hydroxy Toluene i) 0.01 to 1 percent Chelating Agent; preferably 0.01 percent Disodium Edetate j) 0.005 to 0.5 percent Acid; preferably 2.5 percent 1 Molar HNo3 Solution
The novel Sodium Fusidate cream formulation of the present invention is made by modifying the standard procedure of manufacturing pharmaceutical creams. All ingredients are mixed thoroughly at ambient or elevated temperature. Sodium Fusidate is dissolved in propylene glycol under oxygen free 100% pure nitrogen flushing and added to the bulk emulsion formed. The ingredients are thoroughly mixed so that the product is homogeneous.
Processing equipments suitable for preparing the cream are known in the art and include mixers, homogenizers, stirrers and the like.
The cream of the present invention has a pH range from 3.0 to 6 and viscosity
from 20,000 to 100,000 CPS. pH was measured at 25 deg C using Cyber scan 510
pH meter. Viscosity was measured at 25 deg C using a Brookfield viscometer
with Spindle 4 at 6 RPM.
3

One of the novel aspects of the process of the present invention is the selection of the API of required quality. It is a well known fact that the API in the form of fusidic acid currently available for use in preparation of fusidic acid cream is unstable when exposed to oxygen or atmosphere during the in general. Pharmaceutical products made from fusidic acid suffer from this drawback in that any exposure of fusidic acid to oxygen environment during the transport and manufacturing process will lead to degradation of the API. There is a need to minimize the degradation of the API used for manufacture of creams containing fusidic acid. The British Pharmacopia recommends that both fusidic acid and sodium fusidate are to be stored at a temperature between 2 to 8 °C. Although some degradation is expected of both substances when exposed to oxygen environment, it has been observed that sodium fusidate is much more stable than fusidic acid under the same conditions (see Tables 1 and 2).
The inventors have found that sodium fusidate, rather than fusidic acid, is used as the starting raw material the API in the finished product is of a superior quality than the API is the fusidic acid creams that are currently available.
The inventor has also found that the current methods of testing the quality of the
starting raw ingredient of the API, namely the titration method, provides
inaccurate or misleading results. For example the API degradation observed by
the titration method suggests that the API is stabler than it actually is (as indicated
4

by the % degradation figure), in the case of both fusidic acid assays as well as the Sodium Fusidate assays.
The HPLC method designed by the inventors to test the stability of the API allows superior control over quality of API selected and in turn the quality of the end product.
In our present invention Sodium Fusidate API is analyzed by stability indicating, in-house developed HPLC method vis-a-vis titration method as per British Pharmacopoeia. The titration method is not stability indicating where as our in-house developed HPLC method is stability indicating .The Sodium Fusidate is used only if it complies with British Pharmacopoeia assay requirements of not less than 97.5% -101.0%.
Tables 1 and 2 show the comparison between the stability of the fusidic acid and sodium fusidate. A study was carried out to show the stability indicating nature of in-house developed HPLC method vis-a-vis the Titration method of British Pharmacopoeia for testing Fusidic Acid API / Sodium Fusidate API.
5

A. Fusidic Acid:
Name of the Sample: FUSIDIC ACID BP Manufactured by : Ercros, Spain
Lot Number : FS 228 Manufactured date : 08.07.2008
Date of Receipt : 07.08.2008 Expiry date : 06.01.2011
Pack : Open & Closed Petri dish

S.No Conditions ♦Initial (%) Fusidic Acid Assay (%) Percentage Drop (%) Remarks

Titration HPLC Titration HPLC API
analysed After 3 Months
1 RT (Open) 100.6 99.21 92.93 1.39 7.67

2 RT (Closed)
99.02 94.37 1.58 6.23

3 45°C (Open)
98.52 89.52 2.08 11.08

4 45°C (Closed)
99.10 92.12 1.50 8.48

Table 1
RESULTS OF 3 MONTHS OLD FUSIDIC ACID ( API) ANALYSIS BY
STABILITY INDICATING HPLC METHOD AND TITRATION METHOD
B. Sodium Fusidate:
Name of the Sample : Sodium Fusidate Bp Manufactured by : Ercros, Spain
Lot Number : FST 208 Manufactured date: 25.04.2008
Date of Receipt : 07.08.2008 Expiry date : 24.10.2010
Pack : Open & Closed Petri dish

S.No Conditions ♦Initial (%) Sodium Fusidate Assay(%) Percentage (%) Remarks

Titration HPLC Titration HPL C API
analysed After 3 Months
1 RT (Open) 98.7 97.71 96.25 0.99 2.45

2 RT (Closed)
98.85 97.67 -0.15 1.03

3 45°C (Open)
97.07 92.65 1.63 6.05

4 45°C (Closed)
97.16 92.96 1.54 5.74

Table 2 : Results Of 3 Months Old Sodium Fusidate (Api) Analysis By Stability Indicating HPLC Method And Titration Method
In both studies the * Initial denotes the results of the samples tested at the time of
receipt of the API from the supplier.
6

It can be seen from the above tables that:
> In Fusidic Acid, there is about 7.67% loss in 3 Months at room temperature condition (Open) and about 11.08% loss in 3 Months at 45°C condition (Open),
> Meanwhile in Sodium Fusidate, there is about 2.45% loss in 3 Months at room temperature condition (Open) and about 6.05% loss in 3 Months at 45°C condition (Open).
> The above 3 Months data indicates how the in-house developed HPLC method is stability indicating vis-a-vis the non-stability indicating nature of Titration method (BP method) and better stability of Sodium Fusidate API over Fusidic acid API.
Details of the process of manufacturing the novel sodium fusidate cream of the application no. 2645/MUM/2008
A process of making the composition, which was originally disclosed in the patent application no. 2645/MUM/2008 and has been detailed in this description, is now disclosed. The process comprises the steps of:
1. Heating purified water in a water-phase vessel to 75 ° C +/- 5 ° C.
7

' 2. Adding a preservative, preferably Benzoic acid, preferably 0.05 to 0.5 percent, more preferably 0.2%
3. Adding a chelating agent, preferably Disodium edetate, preferably 0.01 to 1 percent, more preferably 0.01%.
4. Mixing the mixture using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 75 °C +/- 5 °C.
5. Adding an emulsifying wax, preferably Cetostearyl alcohol, preferably 1 to 15 percent, more preferably 12.5 percent and White Soft Paraffin, preferably 5 to 20 percent, more preferably 12.5 percent to an oil-phase vessel and melting them by heating to 75 ° C +/- 5 ° C.
6. Adding a non ionic Surfactant/emulsifier, preferably 1 to 5 percent,more preferably 2 percent Polysorbate 80 to the oil phase vessel and mixing the mixture thoroughly using an agitator at 10 to 50 RPM while maintaining the temperature of the mixture at 75 °C +/- 5 °C.
7. Transferring the contents of the water-phase and oil-phase vessels to a mixing vessel under vacuum conditions in the range of-1000 to -300 mm of Hg and at 75 ° C +/- 5 ° C and mixing the mixture at 10 to 50 RPM to form an emulsion.
8. Cooling the emulsion to 45 ° C preferably by circulating cold water (8 to 15 ° C) from cooling tower in the jacket of the mixing vessel.
9. In an API vessel adding propylene glycol and dissolving an antioxidant,
preferably 0.01 to 0.1 percent,more preferably 0.01 percent Butylated
Hydroxy Toluene in it by continuous mixing.
8

10. Subjecting the contents of the API vessel to nitrogen gas flushing and adding Sodium Fusidate to the mixture and dissolving it in the mixture.
11. Adjusting the pH of the mixture in the API vessel to below 2 by using an acid, preferably 0.005 to 0.5 percent; more preferably 2.5 percent of 1M Nitric acid solution.
12. Transferring the contents of the API vessel to the mixing vessel of step 8 with continuous stirring at 10 to 50 RPM and homogenizing the mixture at 1000 to 3000 RPM under Nitrogen gas flushing and under vacuum of-1000 to-300 mm of Hg.
13. Cooling the contents of the Mixing vessel of step 12 to 30 ° C to 37 ° C using circulation of cooled water from cooling tower at 8 deg C to 15 deg C into the jacket of mixing vessel.
14. Turning off the agitator and the homogenizer and removing the mixture of the Mixing vessel of step 13 to a storage container.
The composition of the final cream is given in the table below.

S.No Ingredients Specification Quantify For
350 Kg UOM %
1 Sodium Fusidate BP 7.650 Kg 2.18%
2 Cetostearyl Alcohol IP 43.750 Kg 12.5%
3 White Soft IP 43.750 Kg 12.5%
9

Paraffin
4 Polysorbate 80 IP 7.000 Kg 2%
5 Propylene Glycol IP 87.500 Kg 25%
6 Benzoic Acid IP 0.700 Kg 0.2%
7 Butyl ated
Hydroxy
Toluene IP 0.035 Kg 0.01%
8 Disodium
Edetate IP 0.035 Kg 0.01%
9 1 M Nitric Acid solution IP 8.750 Lit 2.5%
10 Purified Water IP 150.850 Kg 43.1%
Dated this 18th February 2009
(Tase, Vijay Sharatchandra)
Patent Agent for the Applicant
Registration Number IN/PA 987 To,
The Controller of Patents The Patent Office, Mumbai Branch
10