Producing method of cream containing fusidic acid

FIELD: biotechnologies.

SUBSTANCE: invention represents a producing method of cream containing fusidic acid, which involves a stage of application of sodium fusidate as an initial active ingredient and conversion of the above sodium fusidate in situ to fusidic acid in an oxygen-free medium by immediate addition of the acid to a cream base containing a preservative, an acid, a cosolvent, an emulsifier, a wax-like product and water.

EFFECT: obtaining cream having high stability at storage and smaller particles of an active ingredient.

9 cl, 11 tbl

 

The technical field

This invention relates to primary and secondary bacterial skin infections, and, in particular, it relates to a method of manufacturing cream, useful in the treatment of these infections, this cream contains the specified fuseboy acid, which was formed in situ using fusidate of sodium as the source of pharmaceutically active ingredient (AI).

Background of invention

Currently, there are many types of treatment, both local and systemic, primary and secondary skin infections caused by gram-positive organisms such as Staphylococcus aureus, Staphylococcus spp, etc., In compositions for topical and systemic treatment of bacterial infections is usually used at least one active pharmaceutical ingredient (AI) in combination with the component framework. When using the cream, the AI usually include antibiotic/antibacterial, such as positiva acid, etc.,

In the present creams containing fuseboy acid, positiva acid in the form of a fine powder is used as AI. The small particle size increases its contact with skin and penetration due to the formation of large specific surface area and provides a sensation when applied to the skin. However, serious nedostatki is, arising due to the small particle size of fuseboy acid, is the fact that it formed a huge surface area for contact and reaction with molecular oxygen during manufacturing and processing of this cream. This has serious implications for its chemical stability and can lead to a rapid decrease in the efficiency of AI (fuseboy acid) in the final cream.

Degradation due to oxidation is the main cause of instability currently available creams. Table 1 shows that the degradation in the samples AI (fuseboy acid) when exposed to oxygen ranged from 7.7% to 11% in conditions varying from room temperature to 45°C, in the analysis three months, during which they were exposed to these conditions.

You know, the longer the time during which positiva acid as the source of AI is exposed to oxygen, the more there will be restrictions on the stabilization of fuseboy acid in the recipe. However, no published data on the stability of fuseboy acid within a certain period of time.

Alternatively, fuseboy acid known use of fusidate sodium in the manufacture of a dermatological medicines for local use. However, they submit, is received in the form of ointments, instead of creams. Disadvantages ointments compared to the creams are well known, and for local use, in General, preferable to use lotions, not creams.

Well there are several aspects of the use of fuseboy acid as AI:

it is thermolabile;

- it is available in the formulation of the cream;

is it possible to get out of fusidate sodium by dissolving the latter in the aqueous phase and add to this acid solution, while positiva acid precipitates. However, besieged fuseboy acid is difficult to enter into the cream, firstly, due to the large and uneven size of its particles, and, secondly, removing fuseboy acid from a crude sediment layer assumes its drying and further processing, which cause deterioration in the quality of fuseboy acid due to exposure to oxygen;

- stability of the AI in the cream containing fuseboy acid, is unreliable due to the lability fuseboy acid.

Stabilization of medicines containing fuseboy acid against oxidation includes compliance with the many precautions during its production and storage. They include the following:

- substitution of oxygen in the pharmaceutical containers inert gases such as nitrogen, carbon dioxide, helium, etc.;

the exception of contact is edicament with ions of heavy metals, which are oxidation catalysts;

- keeping the AI at a lower temperature throughout its period of storage before processing.

In practice, this means strict control during manufacture and storage of such AI (usually stored at temperatures between 2° to 8°C in airtight containers during the entire storage period).

Therefore, there is a need to develop a method of manufacture of a cream containing fuseboy acid, which positiva acid would have greater stability compared to the stability of fuseboy acid in traditional creams in particular during the manufacture of the cream, and which would retain its stability at an acceptable level throughout the storage period.

Objectives and advantages of the invention

Thus, one object of this invention to provide a method of manufacturing a cream that contains fuseboy acid as active pharmaceutical component, but which has greater stability of the AI compared to fuseboy acid, manufactured using other methods, throughout the period of storage.

Summary of the invention

In the invention disclosed a method of manufacturing a dermatological cream containing fusi the OIC acid, which is formed in situ from fusidate sodium, used as starting material, while fusidate sodium becomes fuseboy acid environment containing oxygen, created using inert gas, preferably nitrogen. The cream is manufactured according to the method proposed in this invention has high storage stability, and particle AI are smaller than traditional creams containing fuseboy acid. The cream is manufactured according to the method proposed in this invention, contains fuseboy acid as AI, which is formed in situ from fusidate sodium cream base containing preservative, an acid, a co-solvent, an emulsifier and a waxy product with water, preferably purified water. The cream is manufactured according to the method proposed in this invention may, additionally, contain an ingredient selected from the group comprising: a buffering agent, antioxidant, chelating additive and hygroscopic means or any combination of them.

Detailed description of the invention

Earlier we discussed the known aspects of the compositions for topical application which contain fuseboy acid and fusidate sodium as the active ingredients. It is now known that:

- creams containing fuseboy acid, to the which are manufactured using fusidate of sodium as the source of AI, are not available.

- There are no published data on the stability of fusidate sodium as AI.

- It is believed that fusidate sodium has no more stability as an AI than positiva acid.

With this in mind, it has been unexpectedly discovered that fusidate sodium as the AI is much more stable than positiva acid, and that positiva acid breaks down much faster than fusidate sodium.

There are no published data on the stability of fusidate sodium as AI. The applicant conducted a series of experiments with fusidate sodium in order to assess its stability. From Table 2 one can see that the degradation of fusidate sodium in the temperature range from room temperature up to 45°C ranged from 2.45 per cent to 6 per cent.

In Tables 1 and 2 also shows a comparison between the stability of fuseboy acid and fusidate sodium used as the source of AI. The study was conducted using the method of liquid chromatography high pressure developed by the applicant, which, according to the applicant, is an accurate method of determining stability compared with the titration method proposed in the British Pharmacopoeia (BP). This occurs in consequence of the fact that BP method does not distinguish between intact AI and its degraded form.

Studies of stability in the spine of fuseboy acid:

Table 1
The results of stability studies fuseboy acid AI after three months of storage by liquid chromatography high pressure and titration method
No.conditionsinitial (%)sample fuseboy acid (%)reduction (%)comments
titrationliquid chromatography high pressuretitrationliquid chromatography high pressure
1room temperature (open)99,2192,931,39to 7.67AI was analyzed after 3 months
2room temperature (closed)100,6 99,0294,371,586,23
345°C (open)98,5289,522,0811,08
445°C (closed)99,1092,121,508,48

Name of sample: acid BP

Container: open and closed Petri dish.

Stability studies of fusidate sodium

Table 2
The results of stability studies of fusidate sodium (AI) after three months storage by liquid chromatography high pressure and titration method
No.conditionsinitial (%)samples of fusidate sodium (%)reduction (%)comments
titrationfluid is STN chromatography high pressure titrationliquid chromatography high pressure
AI was analyzed after 3 months
1room temperature (open)97,7196,250,992,45
2room temperature (closed)98,798,8597,67-0,151,03
345°C (open)97,0792,651,636,05
445°C (closed)97,1692,961,545,74

Sample name: fusidate sodium BP

Container: open and closed Petri dish.

In both studiesHome oboznachaet the results related to the samples analysed during the receipt of AI from the provider.

From Tables 1 and 2 we can draw the following conclusions.

- In case for fuseboy acid has a loss of about 7.7% for the 3 months of storage at room temperature (open container) and about 11% for 3 months at 45°C (open container).

- In the case of fusidate sodium has lost about 2.5% for the 3 months of storage at room temperature (open container) and about 6% for 3 months at 45°C (open container).

Thus, these data show that fusidate sodium used as the active ingredient, is more stable than positiva acid.

Applicants investigated the possibility of making the cream rather than the ointment) using fusidate sodium (and not fuseboy acid). Although fusidate sodium is used in dermatological practice, it was impossible to produce creams that use fusidate sodium. This is due to the inherent fusidate sodium alkalinity (pH from 7.5 to 9), which means that it cannot be used in cream form, so all the products are manufactured using fusidate of sodium as the source of the product are ointments. Dermatological cream, which uses the I fusidate sodium, has the advantage consisting in the fact that fusidate sodium has a greater stability than positiva acid, and it allows you to create a recipe of cream, which is much higher than the ointment on quality when applying. Thus, it will fill an existing need in the cream, which would have had better stability than currently available creams containing fuseboy acid.

Thus, the applicant has unexpectedly found that, in order to achieve greater stability of the AI in dermatological cream, as the source of AI at the time of manufacture of the cream is preferable to use fusidate sodium, and not fuseboy acid. The use of fusidate of sodium as the source of the product eliminates the disadvantages associated with the manufacture and storage of existing creams containing fuseboy acid.

The applicant has also found that a cream containing fuseboy acid, manufactured using fusidate of sodium as the source of AI, showed good chemical stability, efficiency and antibacterial activity.

This application discloses a method of manufacturing a cream containing fuseboy acid (AI), which was manufactured using fusidate of sodium as the source of AI and in which positiva acid is formed in situ in completely devoid of color the Yes environment created through the use of an inert gas, preferably nitrogen, by slow addition of any acid in molecular variance (due to the presence of co-solvent) at the intermediate stage, and positiva acid is recovered in the form of extremely fine dispersion when added to the final cream base, which leads to the formation of fine and homogeneous dispersion of fuseboy acid in the final cream. All these operations are performed in an environment free of atmospheric oxygen, created through the use of an inert gas, preferably nitrogen. Cream, manufactured using the method proposed in this invention, contains fuseboy acid as the AI, which was formed in situ from fusidate sodium cream base containing a buffering agent, a preservative, an acid, a co-solvent, an emulsifier and a waxy product with water, preferably purified water.

The active ingredients which can be used in this invention as the source of AI are either acid active substances or their salts, are well known in the field of treatment of primary and secondary bacterial infections. Examples of suitable acid active substances or their salts that may be used is, but not limited by,fusidate sodium.

These acidic active compounds or their salts require component basis to ensure that they can be used in pharmaceutical compositions which include these compounds, since these compounds cannot by themselves be applied directly to human skin due to their krupnodernytsi.

Base cream, manufactured using the method proposed in this invention may, additionally, contain an ingredient selected from the group comprising antioxidants, chelating additive and hygroscopic means or any combination of them.

The present invention proposes a method of manufacture of a new cream that was made with the use of fusidate of sodium as the source material, this cream contains fuseboy acid, which has a high therapeutic efficacy and chemical stability, which is usually greater than the industrial manufactured creams containing fuseboy acid.

Cream containing fuseboy acid, manufactured using the method proposed in this invention, was made in an environment completely devoid of oxygen, injecting an inert gas and vacuum, with an inert gas, preferably represents nitrogen. Under these conditions, fusidate sodium is converted in situ in fuseboy sour is. Cream, proposed in the present invention, is used in the treatment of bacterial skin infections.

Detailed description of the method of manufacture of a new cream containing fusidic sodium

The preferred embodiment of No. 1

In a preferred embodiment, the disclosed method of manufacture of a dermatological cream containing fuseboy acid, while the method includes a step of using fusidate of sodium as the source of active ingredient (AI) and turning it in situ in fuseboy acid cream base not containing oxygen environment.

Option run No. 1

In one embodiment, the present invention discloses a method of manufacturing a composition in which phase transformations of fusidate sodium in situ in fuseboy acid in the preferred embodiment includes the following steps:

A. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 35% in weight ratio to 50% in weight ratio, more preferably from 40% in weight ratio to 43% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,

b. add in the specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, either one, or any combination thereof in amounts of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,

c. stirring the mixture using a mixer at a speed of from 10 to 50 rpm and the temperature of the mixture from 70°C to 80°C,

d. adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,

e. add in the specified vessel for the oil phase of the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly secondary emulsifier defined the group, including Polysorbate-80, Span-80 and the like, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,

f. transfer the contents of the vessel for the aqueous phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,

g. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,

h. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, the impact on the contents of the vessel for the active ingredient by blowing inert the first gas, when this is specified, the inert gas is preferably nitrogen, and adding to the mixture of fusidate sodium, while fusidate sodium is added in an amount of from 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mixture,

i. regulation of the pH of the mixture formed in the vessel for the active substance in step h, to values below 2 by using an acid, selected from the group consisting of acid such as Hcl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in weight ratio,

j. transfer the contents of the vessel with the active substance obtained in step i, in the mixer described in step g with continuous stirring at a speed ranging from 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,

k. cooling maintain the second mixer, obtained in step j to a temperature from 30°C to 37°C using circulation of cooled water with temperatures ranging from 8°C to 15°C from the tower in the cooling jacket of the mixer,

1. the inclusion of the agitator and the homogenizer and removing the mixture from step to, from the mixer to the storage container.

Option run No. 2

In one embodiment of the present invention a joint solvent described above in step h option, run No. 1, also acts as a hygroscopic means. However, in another embodiment, the present invention can add additional hygroscopic agent selected from the group comprising glycerin, sorbitol, propylene glycol and the like, any one, or any combination thereof in an amount of from about 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

Option run No. 3

In another embodiment, the present invention is the method described in embodiment No. 2, includes, in addition, adding a chelating additive selected from the group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more than before occhialino 0.1% in terms of weight.

Option run No. 4

In yet another embodiment, the present invention is the method described in versions of the No. 2 and 3, includes, in addition, adding a buffering agent selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0.01% in weight ratio to 1.00% in terms of weight, preferably 0.5% in terms of weight, more preferably 0.05% in terms of weight.

Option run No. 5

In yet another embodiment, the present invention is the method described in the variants of execution No. 2-4, includes, in addition, the addition of an antioxidant selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like in an amount of from about 0,001% in weight ratio to 5% in weight ratio, preferably 0.1% in terms of weight, more preferably 0.01% in terms of weight.

Option run No. 6

Discloses another method of manufacturing a composition according to a preferred variant implementation, while this method includes the following steps:

a. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 35% in weight ratio to 50% in weight ratio, more preferably from 40% in weight ratio to 3% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,

b. add in the specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, or one, or any combination thereof in amounts of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,

c. add in the specified vessel for the aqueous phase, described in step b, the chelate additives selected from the group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in weight ratio,

d. add in the specified vessel for the aqueous phase, described in step C, a buffering agent selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0.01% in weight ratio to 1.00% in terms of weight, preferably 0.5% in terms of weight, more preferably 0.05% in weight ratio,

e. mixing the mixture obtained in step d, using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70° is up to 80°C,

f. adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,

g. add in the specified vessel for the oil phase of the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,

h. transfer content from the perception to the aqueous phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,

i. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,

j. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, and the dissolution of an antioxidant selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like, or one, or any combination thereof in amounts of from 0.001% in weight ratio to 5% in terms of weight, preferably 0.1% in terms of weight, more preferably 0.01% in weight ratio, preferably butylhydroxytoluene in the specified glycol by continuous mixing,

k. the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas, preferred the nutrient is nitrogen, and adding to the mixture of fusidate sodium, while fusidate sodium is added in an amount of from 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mixture,

l. regulation of the pH of the mixture formed in the vessel for the active substance in step k, to values below 2 by using an acid, selected from the group consisting of acid such as Hcl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in weight ratio,

m. transfer the contents of the vessel with the active substance obtained in step 1 in the mixer described in step i, with continuous stirring speed of 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,

n. cooling the contents of the mixer from step m to a temperature from 30°C to 37°C With what ispolzovaniem circulation of chilled water with temperatures ranging from 8°C to 15° from the tower in the cooling jacket of the mixer,

O. the inclusion of the agitator and the homogenizer and removing the mixture from step n from the mixer into the container for storage.

Joint solvent as described in step i, it also serves as a hygroscopic means. However, in another embodiment, the present invention can add additional hygroscopic agent selected from the group comprising glycerin, sorbitol, propylene glycol and the like, any one, or any combination thereof in an amount of from about 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

The cream obtained using the method proposed in this invention is a homogeneous, white to cream color and has a viscous consistency. Product made in accordance with the method proposed in this invention has a pH of about 3 to 6. On the other hand, industrial manufactured ointments that contain fusidate sodium, are greasy and cosmetically unappealing.

It is important that the active substance has penetrated into the skin for optimal bioeffectives in the skin. Here the important role played by the particle size of the active substance. It is necessary that the active substance was available in fine form for the product was uh is effective. It also should be achieved in an environment that is safe compatible pH of the skin (pH 4.0 to 6.0). To satisfy these requirements, it is important to choose the appropriate transporting substances or co-solvents for dissolving or dispersing the drug.

Analysis of particle size was conducted for this product (product Apex), proposed in the present invention, and for the few examples of industrial manufactured products (samples a, C, D, F, G, and K). Were estimated maximum and minimum particle size and standard deviation, and coefficient of variation.

Table 3
the minimum particle size (µm)the maximum particle size (microns)the average particle size (µm)the standard deviationthe coefficient of variation
this invention (Apex)2,3316,3010,013,9820,397
Andof 7.2339,5818,09 9,2510,511
6,0732,6914,116,6920,474
D9,827,5218,48to 4.980,269
Fto 7.9319,9014,824,0330,272
G7,2929,48of 14.256,0650,398
Toof 5.7532,63Ls 16.808,1120,483

The analysis of the distribution of particle size definitely indicates the presence of fuseboy acid in the form of fine particles in the product as proposed in the present invention, the size of which is significantly less than traditional products. This can be attributed to the fact that the direct product is manufactured using fusidate n is sodium, using the reaction conversion in situ of fusidate sodium fuseboy acid in fine form. All measured parameters were better than the industrial manufacture of creams containing fuseboy acid. This is another obvious benefit of the product, unveiled here, compared to industrially produced products.

The product offered by the present invention, is effective through the apparent antibacterial activity restored fuseboy acid, which is available in the form of smaller particles than traditional products, and in fine form.

The inventor has selected different co-solvents such as propylene glycol, hexyleneglycol, polyethylene glycol-400 and so on, and dissolved fusidate sodium in one of the above joint solvents, the content of which varied from approximately 5% (in weight ratio) to 40% (in weight ratio), injecting an inert gas in the vacuum and turned it into fuseboy acid in situ by adding an acid, such as Hcl, H2SO4, HN3, lactic acid, etc. in respect of approximately 0.005% (in weight ratio) to about 0.5% (in weight ratio) with stirring and received fuseboy acid is more stable and soluble form, which helped to make our OK Nately product on cream base, which easily penetrates the skin and makes it highly efficient and highly compatible with the skin due to the fact that it has a pH from about 3.0 to about 6,0.

The stability of the product is confirmed by the stability studies that were performed within 6 months according to the ICH guidelines, and comparison studies of adverse factors, conducted for manufactured at the place of product and samples of industrially produced comparable products.

Experimental data

Experiments to determine the stability of the active ingredients was conducted (see Table 4-9) using the product proposed in this invention, and products, industrial currently produced. The tests were carried out to observe (or measure respectively the appearance of the product, the pH value and the quantitative analysis of the active ingredient within a certain period of time. Trials were also conducted to assess the stability when exposed to the product of adverse factors, such as tests in an autoclave and test for oxidative degradation. In addition, a study was carried out in vitro antimicrobial zone of suppression during the period of time. Each gram of the product proposed in this invention and used in the test contained fusi is at sodium in number, necessary for the formation of 2% (in weight ratio) of fuseboy acid in the final product.

The product used in the stability studies and trials in the autoclave and the test for oxidative degradation, contained approximately 10% excess of the AI. The product of this invention, used for research, contained the cream with fuseboy acid, produced using fusidate of sodium as the source material. He was Packed in soft aluminum tube, and each gram of the product contained 20,8 mg of fusidate sodium (according to BP), which is equivalent to 20 mg of fuseboy acid (according to BP). The details of this analysis are comparable industrial products (creams containing fuseboy acid) are presented in Tables 8 and 9, respectively.

Table 4
The described test, batch No. ASF-09
Measured parameter: appearance
The best possible values of measured parameter: Homogeneous white to cream-colored viscous cream
Method of measurement: Observation by naked eyes
conditionsthe initial valuethe first monththe second IU the yats the third monthsixth month
40°C 75% relative humidityhomogeneous viscous cream white to cream-colouredthe best possible valuesthe best possible valuesthe best possible valuesthe best possible values
30°C, 65% relative humiditythe same thingthe same thingthe same thingthe same thing
25°C 60% relative humiditythe same thingthe same thingthe same thingthe same thing
thermal Cyclingthe same thing---
freeze-thawthe same thing

Table 5
Measurement of pH, Batch No. ASF-09
Measured parameter: pH
The limits of measured parameter: 3-6
Method of measurement: Digital pH meter
conditionsthe initial valuethe first monththe second monththe third monthsixth month
40°C 75% relative humidity4,214,224,204,19
30°C, 65% relative humidity4,224,204,214,214,20
25°C 60% relative humidity4,214,214,204,19
thermal Cycling4,22---
amariana-defrosting 4,21

Table 6
Quantitative analysis(%), Batch No. ASF-09
Measured parameter: Quantitative analysis (%)
The limits of measured parameter: 90-110%
Method of measurement: the method of liquid chromatography high pressure
conditionsthe initial valuethe first monththe second monththe third monthsixth month
40°C 75% relative humidity108,56108,26108,11108,05
30°C, 65% relative humidity108,60108,53108,36108,26108,11
25°C 60% relative humidity108,59108,45108,39 108,26
thermal Cycling107,53---
freeze-thaw108,01

When considering Tables 4-6, it becomes apparent that all items: pH, appearance, and stability, the product offered by the present invention has a high quality.

Table 7 summarises the key dates for samples A-I, which was taken for analysis from a number of industrial manufactured creams containing fuseboy acid.

Table 7
Sample numberdate of manufacturedate of expiration
this inventionOct 09Sep 11
a sample AndAug 09Jul 11
sampleAug 09 Jul 11
sampleJul 09Jun 11
sample DJul 09Jun 11
sample EAug 09Jul 11
sample FAug 09Jul 11
sample GAug 09Jul 11
sample NJul 09Jun 11
the sample IDec 09Nov 11

Table 8
Reference analysis (%) when tested in the autoclave
Measured parameter: Quantitative analysis (%)
The limits of measured parameter: 90-110%
Measurement method: Method of liquid chromatography high pressure
No.product name and detailsAnalysis I (%)Analysis II (%) the average value in the Analysis I and Analysis II (%)
the initial valueafter the autoclavereduced the group (%)the initial valueafter the autoclavereduction (%)
1this invention110,47104,615,86110,62104,865,76of 5.81
2A sample And101,8191,7910,02100,9391,659.28 are9,65
3Sample92,69at 83.549,1591,1383,088,058,6
4Sample110,4798,56 11,91110,299,2110,99of 11.45
5Sample D101,394,846,46102,1394,65of 7.486,97
6Sample E100,9994,516,48100,2193,516,706,59
7Sample F96,3384,1512,1895,8885,1210,7611,47
8Sample G104,7593,19to 11.56103,2593,1210,1310,84
9The image of the C H 101,2688,3512,91100,8687,9812,8812,89
10The sample I101,5887,0614,52100,6188,0112,613.56MHz

Table 9
Quantitative analysis in the test for oxidative degradation
Measured parameter: Quantitative analysis (%)
The limits of measured parameter: None
Measurement method: Method of liquid chromatography high pressure
No.product name and detailsAnalysis (%)
the initial valueafter oxidationdegradation (%)
1this invention110,47106,75 3,72
2A sample And101,8195,636,18
3Sample92,6983,159,54
4Sample110,47101,938,54
5Sample D101,393,258,05
6Sample E100,9995,475,52
7Sample F96,3390,705,63
8Sample G104,7596,468,29
9Sample N101,2694,53of 6.73
10 The sample I101,5888,9212,66

The conclusion from Table 8: Results of quantitative analysis when tested in an autoclave (121°C, heated for 15 minutes) show that samples of industrially produced cream containing fuseboy acid (№ p/p 2-10) show a more significant decrease in the percentage content of active ingredient, compared to the product offered in this invention (№ p/p 1).

Conclusions Table 9: the above results of quantitative analysis when tested in oxidative degradation (30% solution of hydrogen peroxide was affected in 12 hours) show that different samples present on the market creams containing fuseboy acid (№ p/p 2-10) show significantly greater degradation of the active ingredient (shown as a reduction of AI per cent) compared with the product proposed in the present invention (№ p/p 1).

From the above data it is obvious that the product proposed in this invention is quite stable when stored in ambient conditions and in conditions of high temperature and humidity. Research in the autoclave and studies of oxidative degradation is even more confirmed the stability of this product. This JW is aetsa its main advantage compared to currently available creams with fuseboy acid. The stability of the product, in addition, confirmed the prediction of the shelf life of this recipe by using curve degradation Arrhenius equation using the software Nova-LIMS.

Antimicrobial/antibacterial activity of this product is confirmed by studies of antimicrobial zone of suppression for a given product against Staphylococcus aureus, performed in vitro. Details of these studies are provided below in Table 10.

Table 10
No.sampledosethe diameters of the zones (mm)conclusion
1the pattern (positiva acid)10 mg21-33sensitive
20 mcg20-30sensitive
50 mcg25-32sensitive
2the positive control (Pinicillin G)10 units21-27 stable
3the negative control (DMSO 1%)no datanullnull
4sample (test substance) (ASF product of the present invention 2%)10 mg21-23sensitive
20 mcg24-26sensitive
50 mcg21-24sensitive

From the above data it is obvious that this product has an appropriate antimicrobial/antibacterial activity for the treatment of primary and secondary bacterial infections.

The final composition of the cream is given below in Table 11.

Table 11
No.ingredientsspecificationthe number to 350 kgunits%
1fused the sodium BP7,28kg2,08
2cetostearyl alcoholIP43,75kg12,5
3white soft paraffinIP43,75kg12,5
4Polysorbate-80IP7,0kg2
5propylene glycolIP87,5kg25
6benzoic acidIP0,7kg0,2
7butylhydroxytolueneIP0,035kg0,01
8Dean is trieva salt EDTA IP0,35kg0,1
9odnokolernyh solution of nitric acidIP14,0kg4
10dvuhkamernyi orthophosphoric acid sodiumIP0,175kg0,05
11purified waterIP145,46kg41,56

BP - British Pharmacopoeia, IP - Indian Pharmacopoeia

Although the above description contains much specificity, this should not be construed as limiting the scope of the invention, but only as an illustrated example of the preferred option it is running. You need to understand that based on the above disclosure, it is possible to make various modifications and variations which will not go beyond the nature and scope of this invention. Therefore, the scope of this invention should be determined not illustrated variants of execution, but when agemame points of patent claims and their legal equivalents.

1. The method of manufacture of a cream containing fuseboy acid, comprising the stage of use of fusidate of sodium as the source of the active ingredient and the transformation specified fusidate sodium in situ in fuseboy acid not containing oxygen environment by slowly adding the acid in a cream base containing a preservative, an acid, a joint solvent, an emulsifier, a waxy product and water.

2. A method of manufacturing a cream under item 1, in which water is purified water.

3. A method of manufacturing a cream under item 1, in which stage the use of fusidate of sodium as the source of the active ingredient and the transformation specified fusidate sodium in situ in fuseboy acid cream base not containing oxygen environment includes the following steps:
A. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 35% in weight ratio to 50% in weight ratio, more preferably from 40% in weight ratio to 43% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,
b. add in the specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, or one, or any combination thereof in amounts of from 0.05% by weight respect to the NII to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,
C. stirring the mixture using a mixer at a speed of from 10 to 50 rpm and the temperature of the mixture from 70°C to 80°C,
d. adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,
e. add in the specified vessel for the oil phase of the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80 in an amount of from 1 to 5% in novom respect, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,
f. transfer the contents of the vessel for the aqueous phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,
g. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,
h. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas is preferably nitrogen, and adding fusidate sodium in the number ot,1% in terms of weight to approximately 25% in terms of weight, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mix,
i. regulation of the pH of the mixture formed in the vessel for the active substance in step h, to values below 2 by using an acid, selected from the group consisting of acid such as Hcl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in terms of weight,
j. transfer the contents of the vessel with the active substance obtained in step i, in the mixer described in step g with continuous stirring at a speed ranging from 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,
k. cooling the contents of the mixer from step j to a temperature from 30°C to 37°C using circulation of cooled water with temperatures ranging from 8°C to 15° from the tower in the cooling jacket of the mixer,
l. the inclusion of the agitator and the homogenizer and the pressure of the mixture, obtained in step k, from the mixer to the storage container.

4. The method of manufacture of cream on p. 3, in which, in addition, in the mixer in step a, paragraph 3, add a hygroscopic agent, such hygroscopic agent selected from a group comprising glycerin, sorbitol, propylene glycol and the like, any one, or any combination thereof in an amount of from about 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in terms of weight.

5. The method of manufacture of the cream according to any one of paragraphs.3 and 4, in which, in addition, in the mixer in step and in PP.3 and 4 add chelate additive, with the specified chelating additive is chosen from a group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in terms of weight.

6. The method of manufacture of the cream according to any one of paragraphs.3 and 4, in which, in addition, in step and in PP. 3 and 4 add a buffering agent, such as a buffering agent selected from the group including dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0.01% in weight ratio to 1.00% in the weight against the AI, preferably 0.5% in terms of weight, more preferably 0.05% in terms of weight.

7. The method of manufacture of the cream according to any one of paragraphs.3 and 4, in which, in addition, at step h in PP. 3 and 4 add antioxidant, with the specified antioxidant is chosen from the group including butylhydroxyanisole, butylhydroxytoluene and the like in an amount of from about 0,001% in weight ratio to 5% in weight ratio, preferably 0.1% in terms of weight, more preferably 0.01% in terms of weight.

8. A method of manufacturing a cream under item 1, in which the specified creamy Foundation contains a preservative, an acid, a joint solvent, an emulsifier and a waxy product with water, preferably purified water, and one ingredient selected from the group comprising a buffering agent, antioxidant, chelating additive, hygroscopic agent, or any combination thereof.

9. A method of manufacturing a cream under item 1, in which stage the use of fusidate of sodium as the source of the active ingredient and the transformation specified fusidate sodium in situ in fuseboy acid cream base not containing oxygen environment includes the following steps:
A. heating purified water in an amount of from 20% (in weight ratio) to 75% in weight ratio, preferably from 35% in weight ratio to 50% in weight ratio, valueproposition from 40% in weight ratio to 43% in weight ratio in the vessel for the aqueous phase to a temperature from 70°C to 80°C,
b. add in the specified vessel for the aqueous phase of a preservative selected from the group comprising methylparaben, propylparaben, chlorocresol, potassium sorbate, benzoic acid and the like, or one, or any combination thereof in amounts of from 0.05% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.2% in terms of weight, more preferably benzoic acid,
C. adding a specified vessel for the aqueous phase, described in step b, the chelate additives selected from the group comprising disodium salt of EDTA and the like, or one, or any combination thereof, in an amount of from about 0.01% in weight with respect to 1% in weight ratio, preferably 0.5% in terms of weight, more preferably 0.1% in terms of weight,
d. add in the specified vessel for the aqueous phase, described in step C, a buffering agent selected from the group comprising dvuhkamernyi orthophosphoric acid sodium, phosphoric acid, sodium and the like in an amount of from about 0.01% in weight ratio to 1.00% in terms of weight, preferably 0.5% in terms of weight, more preferably 0.05% in terms of weight,
e. mixing the mixture obtained in step d, using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°is,
f. adding waxy products selected from the group comprising white soft paraffin, liquid paraffin, hard paraffin and the like, or one, or any combination thereof in an amount of from 5% in weight ratio to 20% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight with respect to the vessel for the oil phase and the melting of the specified wax by heating it to a temperature of from 70°C to 80°C,
g. add in the specified vessel for the oil phase of the primary emulsifier, preferably in the form of a nonionic surfactant selected from the group comprising cetostearyl alcohol, cetomacrogol-1000, or one, or any combination thereof, preferably cetostearyl alcohol in an amount of from 1% in weight ratio to 15% in weight ratio, preferably 15% in weight ratio, more preferably 12.5% in weight ratio, and possibly a secondary emulsifier selected from the group comprising Polysorbate-80, Span-80 and the like, preferably Polysorbate-80 in an amount of from 1 to 5% in weight ratio, more preferably 2% in weight ratio, and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm while maintaining the temperature of the mixture from 70°C to 80°C,
h. transfer the contents of the vessels of the La water phase and oil phase in the mixer under vacuum in the range from -1000 to -300 mm RT.article and at a temperature from 70°C to 80°C and thoroughly stirring the mixture, preferably using a stirrer at a speed of from 10 to 50 rpm before formation of the emulsion,
i. the specified cooling the emulsion to 45°C, preferably by creating a circulation of cold water, preferably with temperatures ranging from 8 to 15°C from the tower in the cooling jacket of the mixer,
j. adding to the vessel for the active ingredient joint solvent selected from the group comprising propylene glycol, hexyleneglycol, polyethylene glycol-400 and the like, or one, or any combination thereof, in an amount of from 5% in weight ratio to 40% in weight ratio, preferably 30% in terms of weight, more preferably 25% in weight ratio, preferably propylene glycol, and the dissolution of an antioxidant selected from the group including butylhydroxyanisole, butylhydroxytoluene and the like, or one, or any combination thereof in amounts of from 0.001% in weight ratio to 5% in terms of weight, preferably 0.1% in terms of weight, more preferably 0.01% in weight ratio, preferably butylhydroxytoluene in the specified glycol by continuous mixing,
k. the impact on the contents of the vessel for the active ingredient by blowing an inert gas, with the specified inert gas preferably is is nitrogen, and adding fusidate sodium in amounts of from 0.1% in weight ratio to approximately 25% in weight ratio, preferably from about 0.5% in weight ratio to approximately 5% in terms of weight and more preferably approximately 2,08% in weight ratio, and dissolving the specified fusidate sodium in the mix,
l. regulation of the pH of the mixture formed in the vessel for the active substance in step k, to values below 2 by using an acid, selected from the group consisting of acid such as Hcl, H2SO4, HNO3, lactic acid and the like, or one, or any combination thereof, preferably nitric acid in an amount of from about 0,005% in weight ratio to 0.5% in weight ratio, preferably 0.3% in terms of weight, more preferably 0.25% in terms of weight,
m. transfer the contents of the vessel with the active substance obtained in step l, the mixer described in step i, with continuous stirring speed of 10 to 50 rpm and homogenizing the mixture at a speed ranging from 1000 to 3000 rpm by injecting an inert gas under vacuum from -1000 to -300 mm RT.art., when this is specified, the inert gas is preferably nitrogen,
n. cooling the contents of the mixer from step m to a temperature from 30°C to 37°C using circulation of cooled water from the is the temperature value from 8°C to 15° from the tower in the cooling jacket of the mixer,
O. the inclusion of the agitator and the homogenizer and removing the mixture from step n, from the mixer to the storage container.



 

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