USOO9066861 B2

(12) United States Patent (10) Patent No.: US 9.066,861 B2 Sulur et al. (45) Date of Patent: *Jun. 30, 2015

(54) DERMACEUTICAL CREAM MADE USING (58) Field of Classification Search SODIUMFUSDATE AND CPC ...... A61 K9/06; A61 K9/0014: A61K 31/56 USPC ...... 514/182, 170 (76) Inventors: Vanangamudi Subramaniam Sulur, See application file for complete search history. Chennai (IN); Madhavan Srinivasan, Chennai (IN); Neelakandan Narayanan (56) References Cited Chulliel, Chennai (IN); Haridas Sankar, Chennai (IN); Kausik Ghosh, U.S. PATENT DOCUMENTS Chennai (IN) 6,635,702 B1 * 10/2003 Schmucker-Castner et al...... 524,291 (*) Notice: Subject to any disclaimer, the term of this 2011/0257144 A1 10/2011 Vanangamudi et al. patent is extended or adjusted under 35 U.S.C. 154(b) by 439 days. FOREIGN PATENT DOCUMENTS This patent is Subject to a terminal dis WO WO, 2007/087806 8, 2007 claimer. OTHER PUBLICATIONS (21) Appl. No.: 13/144,932 Fucibet Lipid cream monograph, 2007.* Fucicort monograph, Sep. 2007.* (22) PCT Filed: Jan. 20, 2010 English translation of Fucicort monograph, Sep. 2007.* Remington Pharmaceutical Science, 17th ed., 1985, pp. 1278-1279.* (86). PCT No.: References Which Form a Part of the ISR Report are not Repeated S371 (c)(1), Here. (2), (4) Date: Jul.18, 2011 * cited by examiner (87) PCT Pub. No.: WO2010/084457 Primary Examiner — San-Ming Hui PCT Pub. Date: Jul. 29, 2010 (57) ABSTRACT (65) Prior Publication Data The invention discloses a dermaceutical cream containing US 2011 FO281830 A1 Nov. 17, 2011 steroids and an antibacterial agent in the form of Fusidic acid, which Fusidic acid is formed in situ from Sodium Fusidate as (30) Foreign Application Priority Data the starting raw material, wherein Sodium Fusidate is con verted into Fusidic acid under oxygen-free environment. The Jan. 21, 2009 (IN) ...... 134/MUMA2009 cream of the present invention has greater shelf-life stability and the finer particle size of the API than the conventional (51) Int. Cl. creams containing Fusidic acid. The cream of the present A6 IK3I/56 (2006.01) invention contains Fusidic acid as the API that has been A6 IK9/06 (2006.01) formed in situ from Sodium Fusidate, and steroids in a cream A6 IK9/00 (2006.01) base comprising an acid, a co-solvent, an emulsifier and a (52) U.S. Cl. waxy material along with water, preferably purified water. CPC ...... A61 K9/06 (2013.01); A61 K9/0014 (2013.01); A61 K3I/56 (2013.01) 16 Claims, No Drawings US 9,066,861 B2 1. 2 DERMACEUTICAL CREAM MADE USING Several aspects of Fusidic acid as an API are known: SODIUMFUSDATE AND STEROIDS It is thermolabile It is available in cream formulations FIELD OF INVENTION It can be obtained from Sodium Fusidate by dissolving the latter in an aqueous phase and adding acid to the solu The present invention relates to primary & secondary bac tion, whereby Fusidic acid precipitates. However, the terial skin infections and inflammations and in particular it Fusidic acid precipitate is difficult to process into a relates to the single dose treatment using a steroids cream that cream form first due to its coarse and uneven particle also contains an antibacterial agent in the form of a Fusidic size and second retrieving Fusidic acid from wet cake acid wherein the Fusidic acid has been made using Sodium 10 involves drying and further handling which deteriorates Fusidate as the starting Active Pharmaceutical Ingredient the Fusidic acid due to exposure to oxygen (API). The stability of the API in a Fusidic acid cream is unreliable due to the thermolabile nature of Fusidic acid BACKGROUND OF THE INVENTION Stabilization of medicaments containing Fusidic acid 15 against oxidation involves observing a number of stringent Use of steroids to alleviate inflammation, irritation and precautionary procedures during manufacture and storage. itching caused by skin ailments is well known. It is also well These include: known that use of Steroids compromises patient’s immune replacing Oxygen in pharmaceutical containers with inert system and exposes them to bacterial infections. Single dose gases Such as Nitrogen, Carbon dioxide, Helium and the therapies containing steroids and antibacterials are well like known. avoiding contact of the medicament with heavy metal ions Numerous single dose treatments, both topical and sys which catalyze oxidation, temic, are currently employed for the treatment of above skin storing the API at reduced temperatures throughout its inflammations. Topical and systemic inflammatory treatment shelf life before processing compositions typically employ a combination of corticoster 25 In practice this means stricter controls during the manufac oids in a base component. The active ingredients typically ture as well as storage of such API (storing it typically at 2°C. comprise such as steroids like Betametha to 8°C. in air-tight containers throughout their shelf life). sone Valerate, , Furoate, There is therefore a need to provide a Fusidic acid cream in Acetate, Acetate, which Fusidic acid will be of greater stability at the time of the Propionate. Beclomethasone Dipropionate, 30 manufacture of the cream, and which will sustain its stability Dipropionate and the like. at an acceptable level throughout its shelf life. Numerous treatments, both topical and systemic, are avail There's a need to provide dermaceutical cream containing able for the primary and secondary skin infection caused by steroids, and an antibacterial in the form of Fusidic acid, and sensitive Gram +Ve organisms such as Staphylococcus in which Fusidic acid will be of greater stability at the time of aureus, Streptococcus spp etc. Topical and systemic bacterial 35 the manufacture of the cream, and which will sustain its infection treatment compositions typically employ at least stability at an acceptable level throughout its shelf life. one active pharmaceutical ingredient (API) in combination with a base component. In the cream form, the APIs typically OBJECTS AND ADVANTAGES OF THE comprise an antibiotic/antibacterial such as Fusidic acid and INVENTION the like. 40 In the currently available Fusidic acid creams, Fusidic acid It is therefore one object of the present invention to provide in fine powder form is used as source API. The small particle a cream which contains Fusidic acid as the active API but size enhances its dermal contact by providing a large specific which has greater stability of the API throughout its shelflife. Surface area and penetration, and provides a Smooth feel on It is a further objective of the present invention to provide application to skin. However, a serious shortcoming of the 45 a dermaceutical cream containing at least one , and an fine size of Fusidic acid particles is that it presents an enor antibacterial agent in the form of Fusidic acid, in which mous Surface area for contact and reaction with molecular Fusidic acid will be of greater stability at the time of the Oxygen during manufacture, handling, and processing of the manufacture of the cream, and which will sustain its stability cream. This has serious implications to its chemical stability at an acceptable level throughout its shelf life. and results in rapid reduction in potency of the API (Fusidic 50 acid) in the final cream formulation. Degradation due to oxi BRIEF SUMMARY OF THE INVENTION dation is a major cause of instability of currently available Fusidic acid creams. Table 1 show that the degradation in the The invention discloses a dermaceutical cream containing API samples (Fusidic acid) exposed to oxygen ranged steroids such as Betamethasone Valerate, Fluticasone Propi between 7.7% and 11% for conditions ranging from room 55 onate, MometaSone Furoate, Dexamethasone Acetate, temperature to 45° C. when analysed at three months of Hydrocortisone Acetate, , Beclom exposure period at the above conditions. ethasone Dipropionate, Betamethasone Dipropionate and the It is known that greater the exposure time of Fusidic acid as like, and an antibacterial agent in the form of Fusidic acid, the raw API to Oxygen, greater the limitations on stabilising which Fusidic acid is formed in situ from Sodium Fusidate as Fusidic acid in a formulation. However, there is no published 60 the starting raw material, wherein Sodium Fusidate is con data on the stability of Fusidic acid over a period of time. verted into Fusidic acid under oxygen-free environment. The As an alternative to Fusidic acid, Sodium Fusidate is cream of the present invention has greater shelf-life stability known to have been used to make dermaceutical medica and the finer particle size of the API than the conventional ments for topical application. However, these are in the form creams containing Fusidic acid. The cream of the present of ointment rather than cream. Drawbacks of ointments over 65 invention contains Fusidic acid as the API that has been creams are well known and its generally preferable to use formed in situ from Sodium Fusidate, and steroids such as creams rather than ointments for topical application. Betamethasone Valerate, Fluticasone Propionate, Mometa US 9,066,861 B2 3 4 Sone Furoate, Dexamethasone Acetate, Hydrocortisone Stability Analysis of Sodium Fusidate Acetate, Clobetasol Propionate. Beclomethasone Dipropi onate, Betamethasone Dipropionate and the like in a cream base comprising an acid, a co-solvent, an emulsifier and a TABLE 2 waxy material along with water, preferably purified water. Results Of3 Months Old Sodium Fusidate (API) Analysis By Stability Indicating HPLC Method And Titration Method DETAILED DESCRIPTION OF THE INVENTION Name of the Sample: Sodium Fusidate BP Pack: Open & Closed Petri dish 10 Sodium Fusidate Percentage We discussed earlier the known aspects of the topical *In- Assay (% % preparations that have Fusidic acid and Sodium Fusidate as the APIs. It is evident from the current state of knowledge tial Titra- Titra that: S. No Conditions (%) tion HPLC tion HPLC Remarks Creams containing Fusidic acid that are made using RT (O) 98.7 97.71 96.25 O.99 2.45 API 15 RT (C) 98.85 97.67 –0.15 1.03 analysed Sodium Fusidate as starting API are not available. 45° C. (O) 97.07 92.6S 1.63 6.05 After 3 Creams containing Fusidic acid that are made using 45° C. (C) 97.16 92.96 1.54 5.74 Months Sodium Fusidate along with steroids such as Betametha sone Valerate, Fluticasone Propionate, Mometasone In both studies the * Initial denotes the results of the Furoate, Dexamethasone Acetate, Hydrocortisone samples tested at the time of receipt of the API from the Acetate, Clobetasol Propionate. Beclomethasone Supplier. Dipropionate, Betamethasone Dipropionate and the like It can be observed from Tables 1 and 2 that: as starting APIs are not available. In the case of Fusidic Acid, there is about 7.7% loss in 3 There is no published data on the stability of Sodium Fusi 25 Months at room temperature (open condition) and about date as the API. 11% loss in 3 Months at 45° C. (open condition). Sodium Fusidate is not considered to be inherently more In the case of Sodium Fusidate, there is about 2.5% loss in stable as an API than Fusidic acid. 3 Months at room temperature (open condition) and In the face of this, it has been surprisingly discovered that about 6% loss in 3 Months at 45° C. (open condition). Sodium Fusidate as an API is significantly more stable than 30 The data thus shows that Sodium Fusidate as an API is Fusidic acid and that Fusidic acid deteriorates more rapidly more stable than Fusidic acid. than Sodium Fusidate. The applicant explored the possibility of making a cream (rather than an ointment) using Sodium Fusidate (rather than There is no published data on the stability of Sodium Fusi Fusidic acid) and steroids such as Betamethasone Valerate, date as the API. The applicant carried out experiments on 35 Fluticasone Propionate, Mometasone Furoate, Dexametha Sodium Fusidate to evaluate its stability. It can be seen from sone Acetate, Hydrocortisone Acetate, Clobetasol Propi Table 2 that the degradation of Sodium Fusidate over a tem onate, Beclomethasone Dipropionate, Betamethasone Dipro perature range of room temperature to 45° C. ranged between pionate and the like. Although Sodium Fusidate has been used 2.45% and 6%. in dermaceutical applications, it has not been possible to Tables 1 and 2 also show the comparison between the 40 make creams that use Sodium Fusidate. This is because of the stability of the Fusidic acid and Sodium Fusidate as raw APIs. inherent alkalinity of Sodium Fusidate (pH 7.5 to 9), which The study was carried out using an in-house HPLC method means it cannot be used in a cream form therefore all products developed by the applicant, which the applicant believes is a manufactured using Sodium Fusidate as starting material are true stability-indicating method as opposed to the titration ointments. A dermaceutical cream that uses Sodium Fusidate method suggested in British Pharmacopoeia (BP). This is 45 and steroids would exploit the benefit of the fact that Sodium because the BP method does not differentiate between the Fusidate is more stable than Fusidic acid and it would also intact API and the degraded form. provide a cream formulation which is far Superior in its appli cation qualities than an ointment. It would thus fill an existing Stability Analysis of Fusidic Acid need for a cream that has better stability than currently avail 50 able creams containing Fusidic acid and steroids. The applicant therefore Surprisingly discovered that in order to achieve greater stability of the API in a dermaceutical TABLE 1. cream, Sodium Fusidate rather than Fusidic acid may be used Results Of3 Months Old Fusidic Acid (API) Analysis By Stability as the starting API during the cream's manufacture. Using Indicating HPLC Method And Titration Method 55 Sodium Fusidate as starting material eliminates the drawback Name of Sample: FUSIDIC ACID BP: associated with the manufacture and storage of existing Pack: Open (O) & Closed (C) Petri dish Fusidic acid creams. Fusicic Acid Percentage The applicant has also discovered that the Fusidic acid and *In- Assay (% Drop (% Steroids cream prepared using Sodium Fusidate as the start 60 ing APIs showed good chemical stability, and efficacy, tial Tiltra- Titra The application discloses a cream containing Steroids such S. No Conditions (%) tion HPLC tion HPLC Remarks as Betamethasone Valerate, Fluticasone Propionate, 1 RT (O) 100.6 99.21 92.93 1.39 7.67 API Mometasone Furoate, Dexamethasone Acetate, Hydrocorti 2 RT (C) 99.02 94.37 1.58 6.23 analysed 3 45° C. (O) 98.52 89.52 2.08 11.08 After 3 sone Acetate, Clobetasol Propionate. Beclomethasone Dipro 4 45° C. (C) 99.10 92.12 1.50 8.48 Months 65 pionate, Betamethasone Dipropionate and the like and Fusidic acid (the API) that has been prepared using Sodium Fusidate as the starting API, in which Fusidic acid forms US 9,066,861 B2 5 6 in-situ under totally oxygen free environment by slow addi above co-solvents varying from about 5% (w/w) to 40% tion of an acid, into a molecular dispersion form (due to the (w/w) under inert gas purging and under vacuum and con presence of a co-solvent) at the intermediate stage, and which verted to Fusidic acid in-situ by adding an acid such as HCl, Fusidic acid regenerates as an extremely fine dispersion when HSO, HNO, Lactic acid and the like from about 0.005% added to a final cream base, thereby resulting in a finely and (w/w) to about 0.5% (w/w) under stirring and obtained homogeneously dispersed Fusidic acid in the final cream. All Fusidic acid in more stabilized and solution form, which these operations are performed in an environment free of makes our final product in a cream base which easily pen atmospheric oxygen. The cream of the present invention con etrates the skin and highly efficacious, and also highly derma tains Fusidic acid as the API that has been formed in situ from compatible by having a pH of about 3.0 to about 6.0. Sodium Fusidate, steroids such as Betamethasone Valerate, 10 The stability of the product is confirmed by the stability Fluticasone Propionate, Mometasone Furoate, Dexametha studies performed for 3/6 months as per ICH guidelines. sone Acetate, Hydrocortisone Acetate, Clobetasol Propi Experimental Data onate, Beclomethasone Dipropionate, Betamethasone Dipro pionate and the like in a cream base comprising an acid, a APIs-stability experiments were carried out (see tables co-solvent, an emulsifier and a waxy material along with 15 3-20) using several products that are representative of the water, preferably purified water. present invention. Tests were carried out to observe (or mea The APIs which may be employed in the present invention Sure as appropriate) the physical appearance of the product, as starting APIs are either acid-based actives or their salts well the pH value and assay of the APIs over a period of time. Each known in the art of treating bacterial primary & secondary gram of product of the present invention used for the tests infections and inflammations. Examples of Suitable acid contained Sodium Fusidate in the amount required to produce based actives or their salts which may be used include, but are 2% (w/w) Fusidic acid in the finished product and appropriate not limited to Sodium Fusidate and steroids such as amount of steroids as mentioned below Betamethasone Valerate, Fluticasone Propionate, Mometa i. Betamethasone Valerate—0.12% (w/w) Sone Furoate, Dexamethasone Acetate, Hydrocortisone ii. Fluticasone Propionate 0.05% (w/w) Acetate, Clobetasol Propionate. Beclomethasone Dipropi 25 iii. Mometasone Furoate—0.1% (w/w) onate, Betamethasone Dipropionate and the like. These acid-based active compounds or their salts require a iv. Dexamethasone Acetate—0.1% (w/w) base component to be used in the pharmaceutical composi V. Hydrocortisone Acetate—1.0% (w/w) tion that uses the compounds, since the compounds cannot, vi. Clobetasol Propionate 0.05% (w/w) by themselves, be deposited directly on to human skin due to 30 vii. Beclomethasone Dipropionate 0.025% (w/w) their harshness. viii. Betamethasone Dipropionate—0.05% (w/w) The cream base of the present invention optionally further comprises an ingredient selected from a group comprising a wherein all percentages are with respect to the final formula preservative, a buffering agent, an anti oxidant, a chelating tion. agent, and a humectant, or any combination thereof. 35 The product used for the Stability Studies tests contained The present invention provides a novel cream that has been approximately 10% extra APIs (overages). It was packaged in produced using Sodium Fusidate as the starting raw material, an aluminium collapsible tube and each gram of the product and which cream contains Fusidic acid of high therapeutic contained 20.8 mg of Sodium Fusidate (in conformance with efficacy and of chemical stability that is generally Superior to BP), which is equivalent to 20 mg of Fusidic acid (BP con the commercially available creams containing Fusidic acid. 40 formant). The Fusidic acid and steroids cream of the present inven i) Product: Sodium Fusidate+Betamethasone Valerate Cream tion has been manufactured in a totally oxygen free environ PACK: Aluminum Collapsible Tube ment under purging with inert gas and applying vacuum. Under these conditions, the Sodium Fusidate is converted in situ into Fusidic acid. The cream of the present invention is 45 Composition: Each gm contains: used in the treatment of bacterial skin infections and inflam mations. i) Sodium Fusidate BP Equivalent to Fusidic Acid BP 2.0% The pH of the product of the present invention is from ii) Betamethasone Valerate IP O.12% about 3 to 6. On the other hand, Sodium Fusidate ointments that are commercially available are greasy and cosmetically 50 non elegant. TABLE 3 It is essential that the active drug penetrates the skin for the Description Test, Batch No. SBV-01 optimum bio-dermal efficacy. The particle size of the active Measured parameter: Physical appearance drug plays an important role here. It is necessary that the Best value of measured parameter: Homogeneous White to off active drug is available in a finely dispersed form for the 55 White Viscous cream product to be being efficacious. Also this is to be achieved in Method of measurement. Observation by naked eye the safe pH compatible environment of skin (4.0 to 6.0). To Conditions Initial 1 Month 2.Month 3 Month achieve all these, it is essential to choose proper vehicles or 40° C. Homogenous Homogenous Homogenous Homogenous co-solvents for the dissolution or dispersion of the drug. 75% RH White to off White to off White to off White to off The product of the present invention is efficacious due to 60 White viscous White White White the pronounced anti-inflammatory, antibacterial activity of Ce:8 viscous viscous viscous the steroids and regenerated Fusidic acid which is available in Ce3 Ce:8 Ce:8 30° C. Homogenous Homogenous Homogenous reduced particle size than the conventional products, and in a 65% RH White to off White to off White to off finely dispersed form. White White White The inventor has screened different co-solvents such as 65 viscous viscous viscous Propylene Glycol, Hexylene Glycol, PolyEthyleneGlycol Ce3 Ce:8 Ce:8 400 & the like and dissolved the Sodium Fusidate in one of US 9,066,861 B2 7 8 TABLE 3-continued TABLE 5 Description Test, Batch No. SBV-01 Assay (%) Test, Batch No. SBV-01 Measured parameter: Physical appearance s Best value of measured parameter: Homogeneous White to off Measured parameter: Assay (%); Limits of measured parameter: 90-110 White Viscous cream 5 Method of measurement: HPLC Method Method of measurement: Observation by naked eye 1st 2nd 3rd Conditions Initial 1 s Month 2'Montha 3 ref Month Conditions Assay (%) Initial Month Month Month00 25o C. Homogenous Homogenous Homogenous 60% RH White to off White to off White to off 10 40 C. 75% i) Fusidic aci 108.57 108.46 108.16 108.11 White White White RH ii) Betamethasone 109.56 109.51 109.32 109.11 WISCOS WISCOS WISCOS Valerate Temperature — Ce3Homogenous —Ce3 C8 30° C. 65%o i) FusidicFusicic aci O8.53 108.41 108.36 cycling White to off RH ii) Betamethasone O948 10942 109.20 White 15 Valerate WISCOS 25° C. 60% i) Fusidic aci O8.54 108.42 108.40 Ce3 Freezthaw Homogenous — RH ii) Betamethasone O9.54 10942 10921 White to off Valerate White Temperature i) Fusidic aci O7.53 WISCOS 20 cycling ii) Betamethasone O9.51 Ce3 Valerate Freezthaw i) Fusicic aci O8.01 ii) Betamethasone O8.25 TABLE 4 Valerate pH Test, Batch No. SBV-01 25 Measured parameter: pH; Limits of measured parameter: 3-6 - MethodVIOOCSISISIE of measurement: DigitalBEIDI pH MeterMOS ii) Product: sodium Fusidate--Fluticasone Propionate Cream Conditions Initial 1 Month 2.Month 3 Month PACK: Aluminum Collapsible Tube

40° C. 75% RH 4.25 4.24 4.23 4.24 30 30° C. 65% RH 4.23 4.24 4.23 Composition: Each gm contains: 25° C. 60% RH 4.24 4.23 4.24 Temperature cycling 4.23 i) Sodium Fusidate BP Equivalent to Fusidic Acid BP 2.0% Freezthaw 4.22 ii) FluticasOne Propionate BP O.05%

TABLE 6 Description Test, Batch No. SFC-01 Measured parameter: Physical appearance Best value of measured parameter: Homogeneous White to off White Viscous Ce3 Method of measurement. Observation by naked eye 1st 2nd 3rd 6th Conditions Initial Month Month Month Month 40° C. 75% RH Homogenous Homogenous Homogenous Homogenous Homogenous White to off White to White to White to White to White O O O O viscous White White White White Ce:8 viscous viscous viscous viscous Ce:8 Ce3 C8 Ce3 30° C. 65% RH Homogenous Homogenous Homogenous Homogenous White to White to White to White to O O O O White White White White viscous viscous viscous viscous Ce:8 Ce3 C8 Ce3 25° C. 60% RH Homogenous Homogenous Homogenous Homogenous White to White to White to White to O O O O White White White White viscous viscous viscous viscous Ce:8 Ce3 C8 Ce3 Temperature Homogenous — cycling White to O White viscous US 9,066,861 B2 9 10 TABLE 6-continued Description Test, Batch No. SFC-01 Measured parameter: Physical appearance Best value of measured parameter: Homogeneous White to off White Viscous Ce3 Method of measurement: Observation by naked eye 1st 2nd 3rd 6th Conditions Initial Month Month Month Month Freezthaw Homogenous — White to Off White viscous Ce:8

TABLE 7 TABLE 9 pH Test, Batch No. SFC-01 Description Test, Batch No. SFM-01 Measured parameter: pH; Limits of measured parameter: 3-6; Method of 20 Measured parameter: Physical appearance measurement: Digital pH Meter Best value of measured parameter: Homogeneous White to off White Viscous cream: Conditions Initial 1 Month 2 Month 3Month 6 Month Method of measurement. Observation by naked eye 40° C. 75% RH 3.51 3.SO 3.48 3.49 3.48 1st 2nd 3rd 6th 30° C. 65% RH 3.SO 3.49 3.48 3.47 25 Conditions Initial Month Month Month Month 25° C. 60% RH 3.51 3.49 3.SO 3.49 Temperature 3.49 40° C. Homo- Homo- Homo- Homo- Homo cycling 75% RH genous genous genous genous genous Freezthaw 3.48 White White White White White to off to off to off to off to off

TABLE 8 Assay (%) Test, Batch No. SFC-01 Measured parameter: Assay (%) Limits of measured parameter: 90-110 Method of measurement: HPLC Method 1st 2nd 3rd 6th Conditions Assay (%) Initial Month Month Month Month 40° C. 75% i) Fusidic acid 108.68 108.56 108.36 108.21 108.18 RH ii) Fluticasone 108.56 108.51 108.32 108.11 108.08 Propionate 30° C. 65% i) Fusidic acid 108.53 108.31 108.26 108.22 RH ii) Fluticasone 108.48 108.42 108.2O 108.11 Propionate 25° C. 60% i) Fusidic acid 108.64 108.52 108.48 108.38 RH ii) Fluticasone 108.54 108.42 108.21 108.10 Propionate Temperature i) Fusidic acid 108.10 cycling ii) Fluticasone 108.51 Propionate Freezthaw i) Fusidic acid 108.21 ii) Fluticasone 108.15 Propionate iii) Product: Sodium Fusidate--Mometasone Furoatecream TABLE 9-continued PACK: Aluminum Collapsible Tube 55 Description Test, Batch No. SFM-01 Measured parameter: Physical appearance Best value of measured parameter: Homogeneous White to off White Viscous cream: 60 Method of measurement: Observation by naked eye

Composition: Each gm contains: 1st 2nd 3rd 6th Conditions Initial Month Month Month Month i) Sodium Fusidate BP Equivalent 2.0% to Fusicic Acid BP White White White White White ii) Mometasone Furoate USP O.1% 65 viscous viscous viscous viscous viscous US 9,066,861 B2 11 12 TABLE 9-continued TABLE 9-continued Description Test, Batch No. SFM-01 Description Test, Batch No. SFM-O1 Measured parameter: Physical appearance Measured parameter: Physical appearance Best value of measured parameter: Homogeneous Best value of measured parameter: Homogeneous 5 White to off White Viscous cream: White to off White Viscous cream: Method of measurement: Observation by naked eye Method of measurement: Observation by naked eye 1st 2nd 3rd 6th 1st 2nd 3rd 6th Conditions Initial Month Month Month Month Conditions Initial Month Month Month Month 10 Freezthaw Homo genous 30° C. Homo- Homo- Homo- Homo- White 65% RH genous genous genous genous to off White White White White White WISCOS o off to off to off to off 15 C8 White White White White viscous viscous viscous viscous Ce3 Ce3 Ce3 Ce:8 25o C. Homo- Homo- Homo- Homo- TABLE 10 60% RH genous genous genous genous White White White White 20 pH Test, Batch No. SFM-01 Measured parameter: pH: o off to off to off to off Limits of measured parameter: 3-6 White White White White Method of measurement: Digital pH Meter viscous viscous viscous viscous Ce3 Ce3 Ce3 Ce:8 1st 2nd 3rd 6th Temperature Homo- 25 Conditions Initial Month Month Month Month cycling genous 40° C. 75% RH 3.54 3.53 3.52 3.53 3.52 White 30° C. 65% RH 3.52 3.53 3.54 3.53 o off 25° C. 60% RH 3.53 3.54 3.53 3.52 White Temp erature 3.52 cycling WISCOS 30 Freezthaw 3.53 Ce3

TABLE 11 Assay (%) Test, Batch No. SFM-01 Measured parameter: Assay (%) Limits of measured parameter: 90-110; Method of measurement: HPLC Method 1st 2nd 3rd 6th Conditions Assay (%) Initial Month Month Month Month 40° C. 75% i) Fusidic acid 108.27 108.26 108.14 108.08 107.89 RH ii) Mometasone 108.56 108.51 108.32 108.11 107.88 Furoate 30° C. 65% i) Fusidic acid 108.23 108.21 108.16 107.92 RH ii) Mometasone 108.48 108.42 108.2O 107.75 Furoate 25° C. 60% i) Fusidic acid 108.24 108.22 108.2O 107.95 RH ii) Mometasone 108.54 108.42 108.21 107.82 Furoate Temperature i) Fusidic acid 107.63 cycling ii) Mometasone 108.51 Furoate Freezthaw i) Fusidic acid 108.11 ii) Mometasone 108.15 Furoate

55 iv) Product: Sodium Fusidate--Dexamethasone Acetate Cream PACK: Aluminum Collapsible Tube

60 Composition: Each gm contains: i) Sodium Fusidate BP Equivalent 2.0% to Fusicic Acid BP ii) Dexamethasone Acetate IP O.1% 65 US 9,066,861 B2 13 14 TABLE 12 TABLE 14-continued Description Test, Batch No. SFD-01 Assay (%) Test, Batch No. SFD-01 Measured parameter: Physical appearance Measured parameter: Assay (%); Best value of measured parameter: Homogeneous Limits of measured parameter: 90-110 White to off White Wiscous cream Method of measurement: HPLC Method Method of measurement: Observation by naked eye 1st 2nd 3rd 1st 2nd 3rd Conditions Initial Month Month Month Conditions Assay (%) Initial Month Month Month 30° C. i) Fusidic acid 108.63 108.52 108.32 40° C. 75% RH Homo- Homo- Homo- Homo 10 genous genous genous genous 65% RH ii) Dexamethasone 108.14 108.12 108.09 White White White White Acetate to off o off o off o off 25o C. i) Fusidic acid 108.60 108.54 108.46 White White White White 60% RH ii) Dexamethasone 108.14 108.11 108.10 viscous viscous viscous viscous Acetate C8 C8 Ce:8 Ce3 15 Temperature i) Fusidic acid 108.52 30° C. 65% RH Homo- Homo- Homo cycling ii) Dexamethasone 107.68 genous genous genous Acetate White White White Freezthaw i) Fusidic acid 108.41 o off o off o off ii) Dexamethasone 107.84 White White White Acetate viscous viscous viscous C8 Ce:8 Ce3 25° C. 60% RH Homo- Homo- Homo genous genous genous v) Product: Sodium Fusidate+Hydrocortisone Acetate Cream White White White PACK: Aluminum Collapsible Tube o off o off o off White White White 25 Composition: Each gm contains: viscous viscous viscous C8 Ce:8 Ce3 i) Sodium Fusidate BP Equivalent to 2.0% Temperature Homo Fusicic Acid BP cycling genous ii) Hydrocortisone Acetate IP 1.0% White o off 30 TABLE 1.5 White viscous Description Test, Batch No. HAS-01 C8 Measured parameter: Physical appearance Freezthaw Homo Best value of measured parameter: Homogeneous genous White to off White Viscous cream: White 35 Method of measurement. Observation by naked eye o off White Conditions Initial 1st Month 2nd Month 3rd Month viscous 40° C. Homo- Homo- Homo- Homo C8 75% RH genous genous genous genous White White White White 40 to off o off o off o off White White White White TABLE 13 viscous viscous viscous viscous Ce3 Ce3 Ce3 C8 pH Test, Batch No. SFD-01 30° C. 65% RH Homo- Homo- Homo Measured parameter: pH genous genous genous Limits of measured parameter: 3-6 45 White White White Method of measurement: Digital pH Meter o off o off o off White White White Conditions Initial 1st Month 2nd Month 3rd Month viscous viscous viscous Ce3 Ce3 C8 40° C. 75% RH 4.22 4.21 4.20 4.2O 25° C. 60% RH Homo- Homo- Homo 30° C. 65% RH 4.22 4.21 4.2O 50 genous genous genous 25° C. 60% RH 4.21 4.21 4.2O White White White Temperature 4.21 o off o off o off cycling White White White Freezthaw 4.2O viscous viscous viscous Ce3 Ce3 C8 55 Temp cycling Homo genous TABLE 1.4 White o off Assay (%) Test, Batch No. SFD-01 White Measured parameter: Assay (%); viscous Ce3 Limits of measured parameter: 90-110 60 Method of measurement: HPLC Method Freezthaw Homo genous 1st 2nd 3rd White Conditions Assay (%) Initial Month Month Month o off White 40° C. i) Fusidic acid 108.62 108.58 108.44 108.30 viscous 75% RH ii) Dexamethasone 108.15 108.14 108.12 108.05 65 Ce3 Acetate US 9,066,861 B2 15 16 TABLE 16 TABLE 1.8 Description Test, Batch No. SPC-01 pH Test, Batch No. HAS-01 Measured parameter: Physical appearance Measured parameter: pH Best value of measured parameter: Homogeneous 5 White to off White Wiscous cream Limits of measured parameter: 3-6 Method of measurement: Observation by naked eye Method of measurement: Digital pH Meter 1st 2nd 3rd 6th Conditions Initial Month Month Month Month 1st 2nd 3rd 40° C. 75% RH Homo- Homo- Homo- Homo- Homo Conditions Initial Month Month Month 10 genous genous genous genous genous White White White White White 40° C. 75% RH 4.31 4.30 4.29 4.28 to off o off o off o off o off White White White White White 30° C. 65% RH 4.31 4.30 4.29 viscous viscous viscous viscous viscous 25° C. 60% RH 4.30 4.29 4.28 15 Ce3 Ce:8 Ce3 Ce3 Ce8 30° C. 65% RH Homo- Homo- Homo- Homo Temperature 4.29 genous genous genous genous cycling White White White White o off o off o off o off Freezthaw 4.28 White White White White viscous viscous viscous viscous 2O Ce:8 Ce3 Ce3 Ce8 25° C. 60% RH Homo- Homo- Homo- Homo genous genous genous genous TABLE 17 White White White White o off o off o off o off Assay (%) Test, Batch No. HAS-01 White White White White Measured parameter: Assay (%) 25 viscous viscous viscous viscous Limits of measured parameter: 90-110 Ce:8 Ce3 Ce3 Ce8 Method of measurement: HPLC Method Temp cycling Homo genous 1st 2nd 3rd White Conditions Assay (%) Initial Month Month Month o off White 40° C. i) Fusidic acid 108.52 1 08:48 108.34 108.2O 30 viscous 75% RH ii) Hydrocortisone 107.15 107.14 107.12 107.05 Ce:8 Acetate Freezthaw Homo 30° C. i) Fusidic acid 10851 108.42 108.32 genous 65% RH ii) Hydrocortisone 107.14 107.12 107.09 White Acetate o off 25o C. i) Fusidic acid - 108.50 108.44 108.36 35 White 60% RH ii) Hydrocortisone 107.14 107.11 107.10 viscous Acetate Temperature i) Fusidic acid 108.40 Ce:8 cycling ii) Hydrocortisone 107.11 Acetate Freezthaw i) Fusidic acid 108.31 40 ii) Hydrocortisone 107.14 TABLE 19 Acetate pH Test, Batch No. SPC-01 Measured parameter: pH Vi) Product: Sodium Fusidate--Clobetasol Propionate Cream Limits of measured parameter: 3-6 45 Method of measurement: Digital pH Meter PACK: Aluminum Collapsible Tube 1st 2nd 3rd 6th Conditions Initial Month Month Month Month Composition: Each gm contains: 40° C. 75% RH 4.22 4.21 4.20 4.2O 4.19 30° C. 65% RH 4.21 4.20 4.19 4.18 i) Sodium Fusidate BP Equivalent 2.0% 50 25° C. 60% RH 4.22 4.21 4.2O 4.20 to Fusicic Acid BP Temp cycling 4.2O ii) Clobetasol Propionate USP O.05% Freezthaw 4.19

TABLE 20

Assay (%) Test, Batch No. SPC-01 Measured parameter: Assay (%); Limits of measured parameter: 90-110 Method of measurement: HPLC Method

1st 2nd 3rd 6th Conditions Assay (%) Initial Month Month Month Month

40° C. 75% i) Fusidic acid 108.38 108.33 108.24 108.10 108.01 RH ii) Clobetasol 107.41 107.34 107.22 107.15 107.10 Propionate US 9,066,861 B2 17 18 TABLE 20-continued Assay (%) Test, Batch No. SPC-01 Measured parameter: Assay (%); Limits of measured parameter: 90-110 Method of measurement: HPLC Method

1st 2nd 3rd 6th Conditions Assay (%) Initial Month Month Month Month 30° C. 65% i) Fusidic acid 108.31 108.32 108.22 108.11 RH ii) Clobetasol 107.38 107.32 107.29 107.22 Propionate 25° C. 60% i) Fusidic acid 108.30 108.24 108.15 108.08 RH ii) Clobetasol 10740 107.34 107.30 107.24 Propionate Temperature i) Fusidic acid 108.28 cycling ii) Clobetasol 107.21 Propionate Freezthaw i) Fusidic acid 108.22 ii) Clobetasol 107.11 Propionate

2O vii) Product: Sodium Fusidate+Beclomethasone Dipropi- TABLE 22 onate Cream PACK: Aluminum Collapsible Tube pH Test, Batch No. SFB-01 25 Measured parameter: pH Limits of measured parameter: 3-6 C ompositionition: Eachacingn containstains: Method of measurement: Digital pH Meter

i) Sodium Fusidate BP 2.0% 30 Conditions Initial 1st Month 2nd Month 3rd Month (Equivalent to Fusidic Acid BP) ii) Beclomethasone dipropionate IP O.025% 40° C. 75% RH 4.33 4.32 4.32 4.31 30° C. 65% RH 4.31 4.30 4.31 35 25° C. 60% RH 4.32 4.33 4.32 TABLE 21 Temperature 4.31 Description Test, Batch No. SFB-01 cycling Measured parameter: Physical appearance Freezthaw 4.32 Best value of measured parameter: Homogeneous White to off White Viscous cream; Method of measurement: Observation by naked eye 40

Conditions Initial 1st Month 2nd Month 3rd Month TABLE 23 40° C. Homogenous Homogenous Homogenous Homogenous Assay (%) Test, Batch No. SFB-01 75% RH White to White to White to White to Measured parameter: Assay (%); Limits of measured parameter: 90-110 off White off White off White off White 45 Method of measurement: HPLC Method viscous viscous viscous viscous C8 Ce3 Ce3 C8 1st 3rd 30° C. Homogenous Homogenous Homogenous Conditions Assay (%) Initial Month Month Month 65% RH White to White to White to 40° C. 75% i) Fusidic aci 108.28 108.25 108.20 108.12 off White off White off White 50 RH ii) 108.12 O8.04 107.98 107.88 viscous viscous viscous Becomethasone Ce3 Ce3 C8 iropionate 25o C. Homogenous Homogenous Homogenous 30° C. 65% i) Fusidic aci O8.25 108.22 108.18 60% RH White to White to White to RH ii) O8.11 107.96 107.68 off White off White off White Beclomethasone viscous viscous viscous 55 g 0. proponate Ce3 Ce3 C8 25° C. 60% i) Fusidic aci O8.22 108.18 108.15 Temp cycling — Homogenous — RH ii) O8.OS 108.OO 107.90 Becomethasone White to iropionate o White Temperature i) Fusidic aci O8.23 WISCOS 60 cycling ii) O7.68 Ce3 Becomethasone Freezthaw Homogenous — iropionate White to Freezthaw i) Fusicic aci O8.11 off White ii) O7.58 viscous Becomethasone Ce3 65 iropionate US 9,066,861 B2 19 20 viii) Product: Sodium Fusidate+Betamethasone Dipropi TABLE 26 onate Cream Assay (%) Test, Batch No. STD-01 PACK: Aluminum Collapsible Tube Measured parameter: Assay (%) Limits of measured parameter: 90-110 Method of measurement: HPLC Method

Composition: Each gm contains: 1st 2nd 3rd Conditions Assay (%) Initial Month Month Month i) Sodium Fusidate BP Equivalent to Fusidic Acid BP 2.0% 40° C. 75% i) Fusidic acid 108.82 108.78 108.70 108.52 10 RH ii) Betamethasone 107.52 107.44 107.38 107.28 ii) Betamethasone dipropionate USP 0.05% dipropionate 30° C. 65% i) Fusidic acid 108.75 108.62 108.48 RH ii) Betamethasone 107.48 107.36 107.22 dipropionate TABLE 24 25° C. 60% i) Fusidic acid 108.62 108.58 108.45 RH ii) Betamethasone 107.28 107.21 107.19 15 dipropionate Description Test, Batch No. STD-01 Temperature i) Fusidic acid 108.63 Measured parameter: Physical appearance cycling ii) Betamethasone 107.28 dipropionate Best value of measured parameter: Homogeneous White to Freezthaw i) Fusidic acid 108.41 off White Viscous cream ii) Betamethasone 107.38 Method of measurement: Observation by naked eye dipropionate

Conditions Initial 1st Month 2nd Month 3rd Month From the above data, it is evident that product of the present 40° C. Homogenous Homogenous Homogenous Homogenous invention is quite stable at ambient conditions and also at 25 75% RH White to White to White to White to elevated temperature & humid conditions of storage. off White off White off White off White According to the preferred embodiment of the present viscous viscous viscous viscous invention, there is provided a single dose composition com C8 Ce3 Ce:8 Ce:8 prising at least one steroid and at least one antibacterial agent 30° C. Homogenous Homogenous Homogenous 30 for the topical treatment of bacterial skin infections and 65% RH White to White to White to inflammations on human skin, the composition comprising a off White Off White Off White steroid selected from a group comprising Betamethasone Val viscous viscous viscous erate, Fluticasone Propionate, Mometasone Furoate, Dexam Ce3 Ce:8 Ce:8 ethasone Acetate, Hydrocortisone Acetate, Clobetasol Propi 25o C. Homogenous Homogenous Homogenous 35 onate, Beclomethasone Dipropionate, Betamethasone 60% RH White to White to White to Dipropionate and the like, and Fusidic acid made in situ by a off White off White off White conversion of Sodium Fusidate, a cream base containing pri viscous viscous viscous mary and secondary emulsifiers, waxy materials, co-solvents, Ce3 Ce:8 Ce:8 and acids, and water. Temperature — Homogenous — 40 The proportions of various components of the preferred cycling White to embodiment are as follows: off White a. Fusidic acid from about 0.1% (w/w) to about 25% (w/w) viscous by weight, preferably from about 0.5% (w/w) to about Ce3 45 5% (w/w) by weight and more preferably about 2.00% Freezthaw Homogenous — (w/w), which has been converted in situ from Sodium White to Fusidate from about 0.1% (w/w) to about 25% (w/w) by off White weight, preferably from about 0.5% (w/w) to about 5% viscous (w/w) by weight and more preferably about 2.08% 50 Ce3 (w/w), and from about 0.001% (w/w) to about 5% (w/w) by weight, preferably from about 0.005% (w/w) to about 2.00% (w/w) by weight, and most preferably from about 0.05% (w/w) to 1.0% (w/w) by weight, of a corticoster TABLE 25 oid active compound, 55 pH Test, Batch No. STD-01 b. a cream base containing primary and secondary emulsi Measured parameter: pH fiers, waxy materials, co-solvents, acids, and water Limits of measured parameter: 3-6 wherein Method of measurement: Digital pH Meter primary and secondary emulsifiers are selected from a Conditions Initial 1st Month 2nd Month 3rd Month 60 group comprising Cetostearyl alcohol, Cetomac 40° C. 75% RH 4.31 4.30 4.31 4.30 rogol-1000, Polysorbate-80, Span-80 and the like 30° C. 65% RH 4.31 4.30 4.31 from about 1% (w/w) to 15% (w/w), preferably 15% 25° C. 60% RH 4.30 4.31 4.31 (w/w), more preferably 14.5% (w/w) Temperature 4.31 cycling waxy materials are selected from a group comprising Freezthaw 4.30 65 White Soft Paraffin, Liquid Paraffin, Hard Paraffin and the like from about 5% (w/w) to 20% (w/w), preferably 15% (w/w), more preferably 12.5% (w/w), US 9,066,861 B2 21 22 co-solvents are selected from a group comprising Pro Composition of the Typical Cream of the Preferred Embodi pylene Glycol, Hexylene Glycol, PolyEthylene Gly ment of the Present Invention and on which the Experimental col-400 and the like from about 5% (w/w) to 40% Results Presented in the Foregoing Description have been (w/w), preferably 30% (w/w), more preferably 25% Based are Now Provided. 5 (w/w), TABLE 27 acids are selected from a group comprising HCl, H2SO4. HNO3, Lactic acid and the like from about 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more i. Sodium Fusiciate + Betamethasone Valerate Cream preferably 0.25% (w/w), and 10 S. water in the amount in the range of 20% (w/w) to 75% (w/w), preferably 35% (w/w) to 50% (w/w), more No Ingredients Specification % (w.fw) preferably 40% (w/w) to 43% (w/w), preferably puri 1 Fusicic acid made from Sodium Fusiciate BP 2.OO fied water. 15 2 Betamethasone Valerate C O.12 In another embodiment of the present invention the product of the preferred embodiment is further provided with preser 3 Cetostearyl Alcohol C 12.5 Vatives, wherein said preservatives are selected from a group 4. White Soft Paraffin C 12.5 comprising Methylparaben, Propylparaben, Chlorocresol, 5 Polysorbate 80 C 2 Potassium sorbate, Benzoic acid and the like from about 20 6 Propylene Glycol C 25 0.05% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), more 7 Benzoic Acid C O.2 preferably 0.2% (w/w). 8 Butylated Hydroxy Toluene C O.O1 In a still further embodiment of the present invention, the 9 Disodium Edetate C O.1 product of the preferred embodiment is further provided with as 10 1M Nitric Acid C 4.0 a buffering agent selected from a group comprising Di 11 Disodium hydrogen Orthophosphate C O.OS Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen anhydrous Ortho Phosphate and the like from about 0.01% (w/w) to 1.00% (w/w), preferably 0.5% (w/w), more preferably 0.05% 12 Purified Water C 41.56 (w/w). 30 In yet another embodiment of the present invention, the product of the preferred embodiment is further provided with TABLE 28 an anti oxidants are selected from a group comprising Buty lated Hydroxy Anisole. Butylated Hydroxy Toluene and the ii. Sodium Fusidate + FluticasOne Propionate Crean like from about 0.001% (w/w) to 5% (w/w), preferably 0.1% S. (w/w), more preferably 0.01% (w/w). No Ingredients Specification % (w.fw) In a further embodiment of the present invention, the prod 1 Fusicic acid made from Sodium Fusiciate BP 2.OO 2 FluticasOne Propionate BP O.OS uct of the preferred embodiment is further provided with a 3 Cetostearyl Alcohol IP 12.5 chelating selected from a group comprising Disodium EDTA 40 4. White Soft Paraffin IP 12.5 and the like from about 0.01% (w/w) to 1% (w/w), preferably 5 Polysorbate 80 IP 2 6 Propylene Glycol IP 25 0.5% (w/w), more preferably 0.1% (w/w). 7 Benzoic Acid IP O.2 In still another embodiment of the present invention, the 8 Butylated Hydroxy Toluene IP O.O1 9 Disodium Edetate IP O.1 product of the preferred embodiment is further provided with 45 10 1M Nitric Acid IP 4.0 a humectant selected from a group comprising Glycerin, Sor 11 Disodium hydrogen Orthophosphate IP O.OS bitol, Propylene glycol and the like from about 5% (w/w) to anhydrous 40% (w/w) preferably 30% (w/w), more preferably 25% 12 Purified Water IP 41.6 (w/w). In another embodiment of the present invention, the prod- 50 uct of the preferred embodiment further is provided with at TABLE 29 least one component selected from a group comprising buff iii. Sodium Fusiciate + Mometasome Furoate Cream ering agents, preservatives, anti oxidants, chelating agents, humectants, or any combination thereof in respective propor S. % tions disclosed in the earlier described embodiments. No Ingredients Specification (ww) 1 Fusicic acid made from Sodium Fusiciate BP 2.OO In a further embodiment of the present invention, a novel 2 Mometasome Furoate USP O.1 dermaceutical cream is disclosed wherein sodium fusidate is 3 Cetostearyl Alcohol P 12.5 converted in-situ under totally oxygen free environment by 4. White Soft Paraffin P 12.5 5 Polysorbate 80 P 2 slow addition of an acid, into Fusidic acid of a molecular 60 6 Propylene Glycol P 25 dispersion form (due to the presence of a co-solvent) at the 7 Benzoic Acid P O.2 intermediate stage, and which Fusidic acid regenerates into 8 Butylated Hydroxy Toluene P O.O1 an extremely finely dispersed form when added to a final 9 Disodium Edetate P O.1 10 1M Nitric Acid P 4.0 cream base, thereby resulting in a finely and homogeneously 11 Disodium hydrogen Orthophosphate anhydrous IP O.OS dispersed Fusidic acid in the final cream; all operations of 65 12 Purified Water P 41.56 converting sodium fusidate into Fusidic acid carried out pref erably in an environment free of atmospheric oxygen. US 9,066,861 B2 23 24 TABLE 30 TABLE 33-continued iv. Sodium Fusiciate + Dexamethasone Acetate Cream vii. Sodium Fusidate + Becomethasone Dipropionate Cream S. % % No Ingredients Specification (wfw) 5 S. No Ingredients Specification (wiw) Fusicic acid made from Sodium Fusiciate BP 2.OO 9 Disodium Edetate IP O.1 Dexamethasone Acetate BP O.1 1 O 1M Nitric Acid IP 4.0 Cetostearyl Alcohol IP 12.5 1 1 Disodium hydrogen Orthophosphate IP O.OS White Soft Paraffin IP 12.5 anhydrous Polysorbate 80 IP 2 10 1 2 Purified Water IP 41.6 Propylene Glycol IP 25 Benzoic Acid IP O.2 Butylated Hydroxy Toluene IP O.O1 Disodium Edetate IP O.1 TABLE 34 1M Nitric Acid IP 4.0 Disodium hydrogen Orthophosphate anhydrous IP O.OS 15 viii. Sodium Fusidate + Betamethasone Dipropionate Crean Purified Water IP 41.56 S. % No Ingredients Specification (ww) 1 Fusicic acid made from Sodium Fusiciate BP 2.OO TABLE 31 2 Betamethasone Dipropionate USP O.OS 3 Cetostearyl Alcohol IP 12.5 V. Sodium Fusidate + Hydrocortisone Acetate Crean 4. White Soft Paraffin IP 12.5 5 Polysorbate 80 IP 2 S. % 6 Propylene Glycol IP 25 No Ingredients Specification (wfw) 7 Benzoic Acid IP O.2 8 Butylated Hydroxy Toluene IP O.O1 Fusicic acid made from Sodium Fusiciate BP 2.OO 25 Hydrocortisone Acetate IP 1 9 Disodium Edetate IP O.1 Cetostearyl Alcohol IP 12.5 10 1M Nitric Acid IP 4.0 White Soft Paraffin IP 12.5 11 Disodium hydrogen Orthophosphate anhydrous IP O.OS Polysorbate 80 IP 2 12 Purified Water IP 41.6 Propylene Glycol IP 25 Benzoic Acid IP O.2 30 Butylated Hydroxy Toluene IP O.O1 It is evident from the foregoing description that the present Disodium Edetate IP O.1 invention comprises the following embodiments. 1M Nitric Acid IP 4.0 1. A novel dermaceutical cream containing at least one Disodium hydrogen Orthophosphate anhydrous IP O.OS , and Fusidic acid which is made in situ Purified Water IP 40.65 under oxygen-free environment using Sodium Fusidate, 35 wherein said cream comprises Fusidic acid made in situ by a conversion of Sodium Fusidate, and a cream base TABLE 32 containing at least one of each of a preservative, a pri mary and secondary emulsifier, a waxy material, a co vi. Sodium Fusidate + Clobetasol Propionate Crean Solvents, an acid, and water, preferably purified water. S. % 40 2. A novel dermaceutical cream as described in item 1, No Ingredients Specification (wfw) wherein said corticosteroid is added from about 0.001% (w/w) to about 5% (w/w) by weight, preferably from Fusicic acid made from Sodium Fusiciate BP 2.OO Clobetasol Propionate USP O.OS about 0.005% (w/w) to about 2.00% (w/w) by weight, Cetostearyl Alcohol IP 12.5 and most preferably from about 0.05% (w/w) to 1.0% White Soft Paraffin IP 12.5 45 (w/w) by weight and said Fusidic acid is present in an Polysorbate 80 IP 2 Propylene Glycol IP 25 amount from about 0.1% (w/w) to about 25% (w/w), Benzoic Acid IP O.2 preferably from about 0.5% (w/w) to about 5% (w/w), Butylated Hydroxy Toluene IP O.O1 and more preferably about 2.00% (w/w), and in which Disodium Edetate IP O.1 the amount of said Sodium Fusidate used to form in situ 1M Nitric Acid IP 4.0 50 said Fusidic acid is in the range between about 0.1% Disodium hydrogen Orthophosphate anhydrous IP O.OS (w/w) to about 25% (w/w), preferably from about 0.5% Purified Water IP 41.6 (w/w) to about 5% (w/w) and more preferably about 2.08% (w/w), and said preservatives is selected from a group comprising TABLE 33 55 Methylparaben, Propylparaben, Chlorocresol, Potas sium Sorbate, Benzoic acid and the like, either singly or vii. Sodium Fusidate + Becomethasone Dipropionate Cream any combination thereof, to form a proportion from % about 0.05% (w/w) to 0.5% (w/w), preferably 0.3% S. No Ingredients Specification (wfw) (w/w), more preferably 0.2% (w/w), Fusidic acid made from Sodium Fusiciate BP 2.OO 60 said primary and secondary emulsifier is selected from a Beclomethasone Dipropionate IP O.O2S group comprising Cetostearyl alcohol, Cetomacrogol Cetostearyl Alcohol IP 12.5 1000, Polysorbate-80, Span-80 and the like, either sin White Soft Paraffin IP 12.5 gly or any combination thereof, to form a proportion Polysorbate 80 IP 2 Propylene Glycol IP 25 from about 1% (w/w) to 15% (w/w), preferably 15% Benzoic Acid IP O.2 65 (w/w), more preferably 14.5% (w/w), Butylated Hydroxy Toluene IP O.O1 said waxy material is selected from a group comprising White soft paraffin, Liquid Paraffin, Hard paraffin and US 9,066,861 B2 25 26 the like, either singly or any combination thereof, to eous environment formed of inert gas selected from a form a proportion from about 5% (w/w) to 20% (w/w), group comprising carbon dioxide, nitrogen, helium and preferably 15% (w/w), more preferably 12.5% (w/w), the like. said co-solvent is selected from a group comprising Pro 10. A method of treating primary & secondary skin infec pylene Glycol, Hexylene Glycol, PolyEthylene Glycol 5 tions and inflammations said method comprising apply 400 and the like, either singly or any combination ing of a cream containing at least one corticosteroid and thereof, to form a proportion from about 5% (w/w) to Fusidic acid which is made in situ under oxygen-free 40% (w/w), preferably 30% (w/w), more preferably environment using Sodium Fusidate, wherein said 25% (w/w), cream comprises Fusidic acid made using Sodium Fusi said acid is selected from a group comprising acids such as 10 date, a cream base containing a preservative, primary HCl, H2SO4, HNO3, Lactic acid and the like, either singly or any combination thereof, to form a proportion and secondary emulsifiers, waxy materials, co-solvents, from about 0.005% (w/w) to 0.5% (w/w), preferably acids, and water. 0.3% (w/w), more preferably 0.25% (w/w), and 11. A method of treating primary & secondary skin infec water in the amount in the range of 20% (w/w) to 75% 15 tions and inflammations said method comprising apply (w/w), preferably 35% (w/w) to 50% (w/w), more pref ing of a cream as described in item 10, wherein said erably 40% (w/w) to 43% (w/w), preferably purified cream further comprises any of a group comprising a Water. buffering agent, an antioxidant, a chelating agent, and a 3. A novel dermaceutical cream as described in item 1 humectant, or any combination thereof. which further comprises a buffering agent, wherein said 12. A method of treating primary & secondary skin infec buffering agent is selected from a group comprising Di tions and inflammations said method comprising apply Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen ing of a cream as described in item 11, wherein said Ortho Phosphate and the like, either singly or any com corticosteroid is added from about 0.001% (w/w) to bination thereof, to form a proportion from about 0.01% about 5% (w/w) by weight, preferably from about (w/w) to 1.00% (w/w), preferably 0.5% (w/w), more 25 0.005% (w/w) to about 2.00% (w/w) by weight, and preferably 0.05% (w/w). most preferably from about 0.05% (w/w) to 1.0% (w/w) 4. A novel dermaceutical cream as described in items 1 to by weight, 3 which further comprises an anti-oxidant, wherein said said Fusidic acid is present in an amount from about 0.1% anti-oxidant is selected from a group comprising Buty (w/w) to about 25% (w/w), preferably from about 0.5% lated Hydroxy Anisole. Butylated Hydroxy Toluene and 30 the like, either singly or any combination thereof, to (w/w) to about 5% (w/w), and more preferably about form a proportion from about 0.001% (w/w) to 5% 2.00% (w/w), and in which the amount of Sodium Fusi (w/w), preferably 0.1% (w/w), more preferably 0.01% date used to form in situ said Fusidic acid is in the range (w/w). between about 0.1% (w/w) to about 25% (w/w), prefer 5. A novel dermaceutical cream as described in items 1 to 35 ably from about 0.5% (w/w) to about 5% (w/w) and most 4 which further comprises a chelating agent, wherein preferably about 2.08% (w/w), said chelating agent is selected from a group comprising said primary and secondary emulsifier is selected from a Disodium EDTA and the like, either singly or any com group comprising Cetostearyl alcohol, Cetomacrogol bination thereof, to form a proportion from about 0.01% 1000, Polysorbate-80, Span-80 and the like, either sin (w/w) to 1% (w/w), preferably 0.5% (w/w), more pref 40 gly or any combination thereof, to form a proportion erably 0.1% (w/w). from about 1% (w/w) to 15% (w/w), preferably 15% 6. A novel dermaceutical cream as described in items 1 to (w/w), more preferably 14.5% (w/w), 5 which further comprises a humectant, wherein said said waxy material is selected from a group comprising humectant is selected from a group comprising Glyc white soft paraffin, liquid paraffin, Hard paraffin and the erin, Sorbitol, Propylene glycol and the like, either sin 45 like, either singly or any combination thereof, to form a gly or any combination thereof, to form a proportion proportion from about 5% (w/w) to 20% (w/w), prefer from about 5% (w/w) to 40% (w/w), preferably 30% ably 15% (w/w), more preferably 12.5% (w/w), (w/w), more preferably 25% (w/w). said co-solvent is selected from a group comprising Pro 7. A novel dermaceutical cream as described in items t to 6 pylene Glycol, Hexylene Glycol, PolyEthylene Glycol wherein sodium fusidate is converted in-situ under 50 400 and the like, either singly or any combination totally oxygen free environment by slow addition of an thereof, to form a proportion from about 5% (w/w) to acid, into Fusidic acid of a molecular dispersion form 40% (w/w), preferably 30% (w/w), more preferably (due to the presence of a co-solvent) at the intermediate 25% (w/w), stage, and which Fusidic acid regenerates into an said acid is selected from a group comprising HCl, H2SO4. extremely finely dispersed form when added to a final 55 HNO3, Lactic acid and the like, either singly or any cream base, thereby resulting in a finely and homoge combination thereof, to form a proportion from about neously dispersed Fusidic acid in the final cream; all 0.005% (w/w) to 0.5% (w/w), preferably 0.3% (w/w), operations of converting Sodium fusidate into Fusidic more preferably 0.25% (w/w), acid carried out preferably in an environment free of said preservative is selected from a group comprising atmospheric oxygen. 60 Methylparaben, Propylparaben, Chlorocresol, Potas 8. A novel dermaceutical cream as described in items 1 to sium Sorbate, Benzoic acid and the like, either singly or 7 wherein said conversion of Sodium Fusidate into said any combination thereof, to form a proportion from Fusidic acid and the following formation of said Fusidic about 0.05% (w/w) to 0.5% (w/w), preferably 0.3% acid in a finely dispersed form in the final cream base (w/w), more preferably 0.2% (w/w), take place in an oxygen-free environment. 65 said buffering agentis selected from a group comprising Di 9. A novel dermaceutical cream as described in item 8 Sodium Hydrogen Ortho Phosphate, Sodium Hydrogen wherein said oxygen-free environment comprises a gas Ortho Phosphate and the like, either singly or any com US 9,066,861 B2 27 28 bination thereof, to form a proportion from about 0.01% Sorbate, benzoic acid, and combinations thereof and is (w/w) to 1.00% (w/w), preferably 0.5% (w/w), more present at a proportion from about 0.05% (w/w) to 0.5% preferably 0.05% (w/w), (w/w); said anti-oxidant is selected from a group comprising the primary and secondary emulsifier are selected from a Butylated Hydroxy Anisole. Butylated Hydroxy Tolu 5 group consisting of cetostearyl alcohol, cetomacrogol ene and the like, either singly or any combination 1000, polysorbate-80, span-80, and combinations thereof, to form a proportion from about 0.001% (w/w) thereof and are present at a proportion from about 1% to 5% (w/w), preferably 0.1% (w/w), more preferably (w/w) to 15% (w/w): 0.01% (w/w), the waxy material is selected from a group consisting of said chelating agent is selected from a group comprising 10 white Soft paraffin, liquid paraffin, hard paraffin, and Disodium EDTA and the like, either singly or any com combinations thereof and is presentata proportion from bination thereof, to form a proportion from about 0.01% about 5% (w/w) to 20% (w/w): (w/w) to 1% (w/w), preferably 0.5% (w/w), more pref the co-solvent is selected from a group consisting of pro erably 0.1% (w/w), and pylene glycol, hexylene glycol, polyethylene glycol said humectant is selected from a group comprising Glyc 15 erin, Sorbitol, Propylene glycol and the like, either sin 400, and combinations thereof and is present at a pro gly or any combination thereof, to form a proportion portion from about 5% (w/w) to 40% (w/w); from about 5% (w/w) to 40% (w/w), preferably 30% the acid is selected from a group consisting of HCl, HSO, (w/w), more preferably 25% (w/w), and HNO, lactic acid, and combinations thereof and is said water in the amount in the range of 20% (w/w) to 75% present at a proportion from about 0.005% (w/w) to (w/w), preferably 35% (w/w) to 50% (w/w), more pref 0.5% (w/w); and erably 40% (w/w) to 43% (w/w), preferably purified the water is present at a proportion from about 20% (w/w) Water. to 75% (w/w). It is evident from the foregoing description that the present 3. The dermaceutical cream of claim 1, wherein the fusidic invention has the following distinctions and advantages over 25 acid is presentata proportion from about 0.5% (w/w) to about the commercially available comparable products: 5.0% (w/w). It has been prepared using Sodium Fusidate which is more 4. The dermaceutical cream of claim 1, wherein the corti stable than Fusidic acid costeroid is present at a proportion from about 0.05% (w/w) It has a more stable and quality enriched Fusidic acid as the to about 1.0% (w/w). final API 30 5. The dermaceutical cream of claim 1, wherein the cream The Fusidic acid in the present invention degrades more further comprises a buffering agent selected from the group slowly than the conventional products consisting of disodium hydrogen orthophosphate, sodium The stability level of the Fusidic acid in the present inven hydrogen orthophosphate, and combinations thereofat a pro tion remains within the acceptable limits throughout the portion from about 0.01% (w/w) to 1.00% (w/w). shelf life of the product 35 6. The dermaceutical cream of claim 1, wherein the cream The particle size of the Fusidic acid is finer and overall further comprises an anti-oxidant selected from the group particle distribution in the cream is better, thereby pro consisting of butylated hydroxy anisole, butylated hydroxy viding better dermaceutical efficacy toluene, and combinations thereof at a proportion from about While the above description contains much specificity, 0.001% (w/w) to 5% (w/w). these should not be construed as limitation in the scope of the 40 7. The dermaceutical cream of claim 1, wherein the cream invention, but rather as an exemplification of the preferred further comprises EDTA at a proportion from about 0.01% embodiments thereof. It must be realized that modifications (w/w) to 1% (w/w). and variations are possible based on the disclosure given 8. The dermaceutical cream of claim 1, where in the cream above without departing from the spirit and scope of the further comprises a humectant selected from a group consist invention. Accordingly, the scope of the invention should be 45 ing of glycerin, Sorbitol, propylene glycol, and combinations determined not by the embodiments illustrated, but by the thereof at a proportion from about 5% (w/w) to 40% (w/w). appended claims and their legal equivalents. 9. A method of treating primary and secondary bacterial skin infections and skin inflammations, the method compris The invention claimed is: ing applying the cream of claim 1 to the skin. 1. A dermaceutical cream comprising: 50 10. A method of treating primary and secondary bacterial (a) fusidic acid which is made in situ under an oxygen-free skin infections and skin inflammations, the method compris environment using sodium fusidate, wherein the cream ing applying the cream of claim 2 to the skin. comprises fusidic acid made by dissolving sodium fusi 11. A method of treating primary and secondary bacterial date in a co-solvent under inert gas purging and under skin infections and skin inflammations, the method compris vacuum, and converting the Sodium fusidate to fusidic 55 ing applying, the cream of claim 3 to the skin. acid in situ by adding an acid under stirring; 12. A method of treating primary and secondary bacterial (b) at least one corticosteroid; and skin infections and skin inflammations, the method compris (c) a cream base comprising at least one preservative, at ing applying the cream of claim 4 to the skin. least one of each of primary and secondary emulsifier, a 13. A method of treating primary and secondary bacterial waxy material, and water. 60 skin infections and skin inflammations, the method compris 2. The dermaceutical cream of claim 1, wherein: ing applying the cream of claim 5 to the Skin. the fusidic acid is present at a proportion from about 0.1% 14. A method of treating primary and secondary bacterial (w/w) to about 25% (w/w): skin infections and skin inflammations, the method compris the corticosteroid is present at a proportion from about ing applying the cream of claim 6 to the skin. 0.001%(w/w) to about 5% (w/w); 65 15. A method of treating primary and secondary bacterial the preservative is selected from the group consisting of skin infections and skin inflammations, the method compris methylparaben, propylparaben, chlorocresol, potassium ing applying the cream of claim 7 to the skin. US 9,066,861 B2 29 30 16. A method of treating primary and secondary bacterial skin infections and skin inflammations, the method compris ing applying, the cream of claim 8 to the skin. k k k k k