# Patent

## Title
Stabilized steroid composition and method for its preparation

## Abstract

Stabilized 17-substituted hydrocortisone containing compositions and methods of manufacture. Isomerization of the hydrocortisone component of topical steroid compositions is markedly reduced by introducing an omega-6. acid in the form of linoleic acid into the skin preparation. Preferably, the linoleic acid is added as a component of refined safflower oil. The omega-6 acid has been found to be an effective way of preventing the isomerization of hydrocortisone 17-butyrate into the undesirable isomer HC21-B.

## Background
This application claims priority of U.S. Provisional Patent Application Ser. No. 60/442,114 filed Jan. 23, 2003, which is incorporated herein by reference.


FIELD OF THE INVENTION
This invention relates generally to stabilized steroid compositions. More specifically, the invention relates to compositions and methods for stabilizing hydrocortisone compounds. Still more specifically, the invention relates to methods for stabilizing 17-substituted hydrocortisone compounds. Most specifically, the invention relates to methods and compositions for stabilizing hydrocortisone 17-butyrate.
BACKGROUND OF THE INVENTION
Hydrocortisone compounds have a very strong anti-inflammatory effect on many tissues. Consequently, these materials are often employed as topical agents for the relief of various inflammations. Hydrocortisone esters are one preferred class of steroidal anti-inflammatory agents, and hydrocortisone 17-butyrate (HC17-B) is one particularly preferred hydrocortisone material which is in widespread use as a therapeutic agent.
In this description, conventional IUPAC numbering will be followed for steroid molecules. Shown below is the molecular structure of HC17-B. As can be seen, the butyrate moiety is joined to the molecule at the 17 position.




One problem which has been encountered in connection with HC17-B formulations is that the molecule is prone to rearrange so as to form an isomer in which the butyrate group is attached to the remainder of the molecule through the 21 position. This isomer is generally referred to as HC21-B. Similar rearrangements occur in other hydrocortisone 17-esters.
This isomerization reaction is generally enhanced when materials such as HC17-B are in a solution or dispersion, as they usually are in a pharmaceutical formulation such as a topical lotion or cream. Isomerization is of particular concern to pharmaceutical formulators since the isomerization reaction raises therapeutic and regulatory issues regarding the efficacy and composition of isomerized compositions. Therefore, the pharmaceutical industry has sought methods and materials whereby steroid compositions such as HC17-B can be stabilized against isomerization or other degradation. However, any such methods or materials should be compatible with the intended therapeutic utility of the hydrocortisone composition; and in this regard, resultant compositions should be effective and nontoxic. Ideally, any such method should employ materials which have previously been demonstrated to be safe.
As will be explained hereinbelow, the present invention provides materials and methods for inhibiting the degradation of HC17-B and the like. The materials and methods of the present invention are easy to implement, low in cost, safe, and are compatible with pharmaceutical compositions and methods of the type generally employed in connection with hydrocortisone containing agents.
SUMMARY OF THE INVENTION
Disclosed and claimed herein is a method of stabilizing 17-substituted hydrocortisone compounds, as well as the stabilized 17-substituted hydrocortisone compounds themselves. The method comprises the step of adding a quantity of an omega-6 acid to a 17-substituted hydrocortisone composition.
In a particularly preferred embodiment of the method of the present invention, the omega-6 acid comprises linoleic acid. Since linoleic acid is a component of safflower oil, the linoleic acid may be added to the 17-substituted hydrocortisone composition in the form of safflower oil. Safflower oil is, itself, an effective emollient and enhances the skin treatment properties of the stabilized composition. In a particularly preferred embodiment, the safflower oil is added to the hydrocortisone composition in at least equimolar proportion to the hydrocortisone. It has been found that it is highly desirable to add the safflower oil in considerable excess to the proportion of the hydrocortisone, even as much as ten, twenty, thirty or more times as much.
Practicing the method of the present invention, the 17-substituted hydrocortisone may comprise hydrocortisone 17-butyrate.
In addition to the 17-substituted hydrocortisone and omega-6 acid, the composition of the present invention may further comprise a number of other compounds typically found in pharmacological hydrocortisone creams and lotions, such as vanous alcohols, mineral oil, white petroleum, preservative such as BHT, propylparaben and/or butylparaben, citric or other mild acids, sodium citrate, glycerin, fragrances, coloring agents, etc. Generally speaking, the majority of the composition of the present invention will constitute purified water.
DETAILED DESCRIPTION OF THE INVENTION
In accord with the present invention, it has been unexpectedly found that the presence of an omega-6 acid will inhibit the isomerization of 17-substituted hydrocortisones and other steroid materials. The present invention has particular utility in the stabilization of hydrocortisones having an ester moiety at the 17 position, and is particularly useful in stabilizing HC17-B, and will be described with particular reference to the stabilization of HC17-B.
There are a variety of omega-6 acids which function to stabilize the substituted hydrocortisones, and linoleic acid is one particularly preferred acid. Linoleic acid is generally a very safe material, and is readily available. Safflower oil contains large amounts of linoleic acid, and in particular embodiments of the present invention, safflower oil is used as a stabilizing agent for HC17-B and similar materials. Safflower oil is particularly advantageous for use in pharmaceutical compositions, since it is generally nontoxic, and has been approved for both topical and internal formulations. Additionally, safflower oil, as well as other omega-6 acid materials, has additional beneficial effects in topical formulations since they can enhance skin penetration and restore lipid content to the skin.
In general, the omega-6 acid will be present in an amount which is at least equimolar with the steroid compound which is to be stabilized. In most practical formulations, the omega-6 acid is present in a relatively large excess, since it further functions as a skin conditioning agent. For example, it may be present in a weight percentage ten, twenty, thirty or even more times the weight percentage of the steroid compound.


EXAMPLE
Two experimental hydrocortisone 17-butyrate formulations were prepared. One (formulation R6546) contained a substantial weight percentage (3.0% w/w) of refined safflower oil. The other formulation (R6539) was similar in composition to the first formulation, but lacked any safflower oil. In both formulations, the HC17-B was present in a weight percentage of 0.1. Table 1 shows, respectively, the recipes for the two formulations, showing the various components respectively thereof as weight percentages.








TABLE 1







R6546
R6539











%,

%,


Ingredient
w/w
Ingredient
w/w













Ceteth-20
2.0
Ceteth-20
2.0


Cetostearyl alcohol
4.0
Cetostearyl alcohol
4.0


White petrolatum
2.5
White petrolatum
2.5


Light mineral oil
5.5
Light mineral oil
7.5


Safflower oil
3.0
Propylparaben
0.1


BHT
0.02
Butylparaben
0.05


Propylparaben
0.1
Hydrocortisone 17-butyrate
0.1


Butylparaben
0.05
Citric acid
0.42


Hydrocortisone 17-butyrate
0.1
Sodium citrate (dehydrate)
0.32


Citric acid
0.42
Purified water
83.01


Sodium citrate (dehydrate)
0.32


Purified water
81.99









Table 2 shows the analytic results of samples of the resultant respective compositions, showing the exact percentages of the HC17-B (as well as propylparaben and butylparaben) found in the two formulations expressed as weight percentages.












TABLE 2







HCB
Propylparaben
Butylparaben




(%, w/w)
(%, w/w)
(%, w/w)



















R6539
Sample #1
0.104
0.104
0.052



Sample #2
0.103
0.103
0.051



Average
0.104
0.104
0.052


R6546
Sample #1
0.100
0.102
0.051



Sample #2
0.101
0.102
0.050



Average
0.101
0.102
0.051









From Table 2, it can be ascertained that the formulation containing the safflower oil had an average weight percentage of 0.101 HC17-B, whereas the sample which did not contain the safflower oil had an average weight percentage of HC17-B of 0.104, a slightly greater weight percentage.

The stability of the respective formulations was tested by analyzing the two formulations over a six-month period, at various intervals. The stability study was performed at a temperature 40° Centigrade, considerably greater than normal room temperature.













TABLE 3











Other




HCB
Propylparaben
Butylparaben
HC21-B
impurities




(%, w/w)
(%, w/w)
(%, w/w)
(%)
(%)





















R6539
1-month
0.102
0.103
0.052
0
0



2-month
0.100
0.101
0.051
0
0



3-month
0.095
0.100
0.050
—
—



6-month
0.086
0.100
0.050
6.36
2.81


R6546
1-month
0.103
0.103
0.051
0
0



2-month
0.101
0.102
0.052
0
0



3-month
0.099
0.103
0.051
2.51
0.45



6-month
0.095
0.102
0.052
5.00
0.56









As can be readily ascertained by comparing the six-month results for the two compositions, the composition containing the safflower oil (R6546) did lose some HC17-B. The weight percentage went from 0.101 at the start of the study (from Table 2) to 0.095 after six months. Furthermore, the isomer HC21-B began to make its appearance at the three-month interval, and was found at the six-month endpoint of the study in a concentration of 5.00 weight percent of the HC17-B content. Furthermore, there were various other impurities found at the six-month endpoint in a percentage of 0.56 weight percent.
In contrast, the formulation which did not contain the safflower oil (R6539), although starting out containing slightly more HC17-B, it lost this component more rapidly and wound up with a considerably lower weight percentage of 0.86 at the six-month endpoint of the study. As would be expected, the formulation without the safflower oil and its constituent linoleic acid contained an even larger percentage of the isomer HC21-B, namely, 6.36%. Furthermore, other impurities were found in this formulation after six months in a much larger percentage as well, namely, 2.81 weight percent as compared to only 0.56 weight percent.
As can be seen from this data, adding the omega-6 acid in the form of the linoleic acid-containing safflower oil considerably increased the stability of the valuable hydrocortisone 17-butyrate compound. In fact, the formulation which did not contain the safflower oil lost approximately 18% of its original HC 17-B, whereas the formulation containing the safflower oil lost only approximately 6%. In other words, the improvement in stability was practically threefold. Furthermore, the level of the HC21-B isomer and the other impurities was about 60% less in the formulation containing the safflower oil than in the formulation where the safflower oil was absent.
Thus, adding an omega-6 acid in the form of the linoleic acid component of safflower oil has been shown to be an effective way of stabilizing 17-substituted hydrocortisone compounds. Of course, while the methods and compositions of the present invention have been described with reference to certain exemplifications and embodiments thereof, the invention is by no means limited to the specifically depicted examples and embodiments. For example, other 17-substituted hydrocortisone compounds could be used with equal efficacy. The omega-6 acid could be provided in other forms than as linoleic acid generally, or as safflower oil specifically. It is only necessary that the omega-6 acid be provided in a form which is pharmacologically compatible with topical hydrocortisone creams and lotions. Doubtless, one of skill in the art could, after routine experimentation, employ other pharmacologically compatible omega-6components with similar efficacy without departing from the scope of the present invention. It is the claims appended hereto, rather than the exact exemplifications and embodiments, which define the scope of the present invention.

## Claims

1. A method for stabilizing a composition including hydrocortisone 17-butyrate therein, said method comprising the step of: adding an omega-6 acid to said composition.

2. The method of claim 1, wherein said step of adding an omega-6 acid comprises adding linoleic acid to said composition.

3. The method of claim 1, wherein said step of adding an omega-6 acid to said composition comprises adding safflower oil to said composition.

4. The method of claim 1, wherein the step of adding an omega-6 acid further comprises adding said acid in an amount at least equimolar to a quantity of said hydrocortisone 17-butyrate.

5. The method of claim 4, wherein said amount of acid is substantially greater than said quantity of hydrocortisone 17-butyrate.

6. A method for inhibiting the isomerization of hydrocortisone 17-butyrate to hydrocortisone 21-butyrate, said method comprising the step of: disposing said hydrocortisone 17-butyrate in a composition which includes an omega-6 acid therein.

7. The method of claim 6, wherein the step of disposing said omega-6 acid comprises disposing linoleic acid.

8. The method of claim 6, wherein the step of disposing said omega-3 acid comprises disposing omega-3 acid as a component of safflower oil.

9. The method of claim 6, wherein the step of adding an omega-6 acid further comprises adding said acid in an amount at least equimolar to a quantity of said hydrocortisone 17-butyrate.

10. The method of claim 6, wherein said amount of acid is substantially greater than said quantity of hydrocortisone 17-butyrate.

11. A method for stabilizing a hydrocortisone compound having an ester linkage at the 17 position, said method comprising the step of: disposing said hydrocortisone compound in a composition which includes an omega-6 acid therein.

12. The method of claim 11, wherein the step of disposing said omega-6 acid comprises disposing linoleic acid.

13. The method of claim 11, wherein the step of disposing said omega-6 acid comprises adding omega-6 acid as a component of safflower oil which is present in said composition.

14. The method of claim 13, wherein the step of adding an omega-6 acid further comprises adding said acid in an amount at least equimolar to a quantity of said hydrocortisone 17-butyrate.

15. The method of claim 13, wherein said amount of acid is substantially greater than said quantity of hydrocortisone 17-butyrate.

16. In a composition which includes hydrocortisone 17-butyrate therein, the improvement comprising in composition: said composition having an omega-6 acid therein in an amount sufficient to stabilize said hydrocortisone 17-butyrate.

17. A method for stabilizing a composition including a 17-substituted hydrocortisone, said method comprising the step of: adding an omega-6acid to said composition.

18. The method of claim 17, wherein said 17-substituted hydrocortisone is a hydrocortisone ester.