WO2017009824A1

WO2017009824A1 - Formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and-foot syndrome

Info

Publication number: WO2017009824A1
Application number: PCT/IL2016/050741
Authority: WO
Inventors: Meir Shinitzky
Original assignee: Neotech-Kordan Group Ltd.
Priority date: 2015-07-16
Filing date: 2016-07-11
Publication date: 2017-01-19

Abstract

The present invention discloses formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and- foot syndrome. Formulations include: a skin agent having a solubilized solution of uracil and/or thymine; and a mixture containing at least one type of material selected from the group consisting of: a water-dispersible lipid and a lipophilic substance, wherein the solution is homogeneously dispersed in the mixture in an effective final concentration of the uracil and/or the thymine. Alternatively, the solution is selected from the group consisting of: a glycerol- based solution and a propylene glycol-based solution. Alternatively, the skin agent is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion. Alternatively, the uracil includes uracil derivatives, and wherein the thymine includes thymine derivatives.

Description

FORMULATION METHODS AND OINTMENT FORMULATIONS THEREIN CONTAINING URACIL, THYMINE, AND/OR THEIR DERIVATIVES FOR TREATMENT AND PREVENTION OF HAND-AND-FOOT SYNDROME

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates to formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and- foot syndrome, caused by 5-fluorouracil (also known generically as fluorouracil, under the trade name Adrucil, and abbreviated as 5-FU) and capecitabine (also known under the trade name Xeloda) chemotherapy. It is well known that stable formulations of uracil or thymine in fluid products have never been produced due to their extremely-poor solubility.

5-fluorouracil is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug, classified as an "antimetabolite." The 5-FU analogue capecitabine is an orally-administered chemotherapeutic agent used in the treatment of numerous cancers. Capecitabine is a prodrug which is enzymatically converted to 5-fluorouracil in the body.

5-fluorouracil and its analogue capecitabine are registered as cancer chemotherapy drugs which operate by blocking cell division. One of the common side effects of such chemotherapy drugs is hand-and-foot syndrome. Hand-and-foot syndrome (also known as chemotherapy-induced acral erythema, palmar-plantar erythrodysesthesia, palmoplantar erythrodysesthesia, hand-foot syndrome, and HFS) involves the cracking, reddening, swelling, numbness, and desquamation (skin sloughing or peeling) on the palms of the hands and soles of the feet (occasionally on the knees and elbows as well) that can occur after chemotherapy in patients with cancer, and in rare instances in patients with sickle-cell disease.

Hand-and-foot syndrome, characterized broadly by dry skin, often develops painful cracks and ulcers in the skin. Ointments for topical application, containing biomolecules such as uracil, thymine (5-methyluracil), uridine, or uridine monophosphate, can, in principle, compete with such destructive skin agents (i.e., 5-FU and capecitabine) when topically applied in the affected area, allowing for competition with the local chemotherapeutic agent - and thus, recovery through the natural healing processes.

In the prior art, a 0.1% uracil ointment was developed by Cahaba Pharmaceuticals and tested for FDA approval in 2010 on patients with hand-and-foot syndrome. Uracil and its natural derivatives are by definition non-toxic (i.e., GRAS). Furthermore, the activity of uracil- based ointments is expected to correspond predictably to concentration.

It would be desirable to have formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and- foot syndrome. Such methods and formulations would, inter alia, overcome the various limitations mentioned above.

SUMMARY

It is the purpose of the present invention to provide formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of hand-and-foot syndrome (hereinafter referred to as HFS).

It is noted that the term "exemplary" is used herein to refer to examples of embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case. Similarly, the terms "alternative" and "alternatively" are used herein to refer to an example out of an assortment of contemplated embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case. Therefore, it is understood from the above that "exemplary" and "alternative" may be applied herein to multiple embodiments and/or implementations. Various combinations of such alternative and/or exemplary embodiments are also contemplated herein. Embodiments of the present invention provide formulation methods for the preparation of about 4-5% uracil ointment formulation. Alternate formulation methods for lower concentrations of about 1% and about 2% are also disclosed. Similar formulation methods of about 4-5% thymine or a mixture of about 4-5% of uracil and thymine combined, as well as alternative formulations methods for lower concentrations in the range of about 1-2% are also disclosed.

Embodiments of the present invention provide for the first time formulation methods for obtaining a relatively-high solubility of uracil and/or thymine in glycerol and/or propylene glycol at high temperature.

Further embodiments of the present invention provide formulation methods for the preparation of analogous ointments of thymine.

Therefore, according to the present invention, there is provided for the first time a formulation for treating hand-and-foot syndrome, the formulation including: (a) a skin agent having a solubilized solution of uracil and/or thymine; and (b) a mixture containing at least one type of material selected from the group consisting of: a water-dispersible lipid and a lipophilic substance, wherein the solution is homogeneously dispersed in the mixture in an effective final concentration of the uracil and/or the thymine.

Alternatively, the solution is selected from the group consisting of: a glycerol-based solution and a propylene glycol-based solution.

Alternatively, the effective final concentration is a total concentration of either the uracil alone, the thymine alone, or the uracil and the thymine combined, wherein the total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%), greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%. Alternatively, the skin agent is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

Alternatively, the uracil includes uracil derivatives, and wherein the thymine includes thymine derivatives.

According to the present invention, there is provided for the first time a method for preparing formulations for treating hand-and-foot syndrome, the method including the steps of: (a) combining uracil and/or thymine with a solubilizing agent; (b) heating the uracil and/or the thymine in the solubilizing agent above about 100°C until a clear solution is produced; (c) adding a lipophilic solution while the clear solution is hot to form a clear lipophilic solution; (d) adding a mixture containing at least one type of water-dispersible lipid to the clear lipophilic solution while hot, wherein the mixture is initially heated above about 50°C until a clear lipid solution is produced; and (e) mixing the mixture and the clear lipophilic solution to form a homogeneous product while allowing to cool.

Alternatively, the solubilizing agent is selected from the group consisting of: glycerol and propylene glycol.

Alternatively, the effective final concentration is a total concentration of either the uracil alone, the thymine alone, or the uracil and the thymine combined, wherein the total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%.

Alternatively, the homogeneous product is suitable for a skin agent selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

Alternatively, the uracil includes uracil derivatives, and wherein the thymine includes thymine derivatives. According to the present invention, there is provided for the first time a method for preparing formulations for treating hand-and-foot syndrome, the method including the steps of: (a) combining uracil and/or thymine with a solubilizing agent; (b) heating the uracil and/or the thymine in the solubilizing agent above about 100°C until a clear solution is produced; (c) allowing the clear solution to cool to a temperature above an opaqueness point of the clear solution; (d) adding a lipophilic mixture; and (e) mixing the lipophilic mixture and the clear solution to form a homogeneous product while allowing to cool.

Alternatively, the lipophilic mixture is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

According to the present invention, there is provided for the first time a kit for treating hand-and-foot syndrome, the kit including: (a) a skin agent having a solubilized solution of an effective final concentration of uracil and/or thymine homogeneously dispersed in a mixture containing at least one type of water-dispersible lipid; and (b) a label indicating administration by applying the skin agent to an affected skin region in a continuing regimen at a frequency of up to twice per day. Alternatively, the solution is selected from the group consisting of: a glycerol-based solution and a propylene glycol-based solution.

Alternatively, the skin agent is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

These and further embodiments will be apparent from the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is herein described, by way of example only, with reference to the accompanying drawing, wherein:

Figure 1 is a depiction of the chemical structures of thymine, uracil, and 5-fluorouracil, according to the prior art.

DESCRIPTION OF THE ILLUSTRATIVE EMBODFMENTS

The present invention relates to formulation methods and ointment formulations therein containing uracil, thymine, and/or their derivatives for treatment and prevention of HFS. The principles and operation for providing such methods and formulations, according to the present invention, may be better understood with reference to the accompanying description, and drawing, as well as the exemplary formulation methods, formulations, and application.

Referring to the drawing, Figure 1 is a depiction of the chemical structures of thymine, uracil, and 5-fluorouracil, according to the prior art. It can be readily observed that the structures share a common backbone structure, differing only in their ring substituents at the 5-position.

Uracil is sparingly soluble in water. The highest concentrations of solubilized uracil obtained are a solution of about 5% uracil in hot glycerol and a solution of about 3.5% in a hot 12%) urea- water mixture. In both solutions, uracil precipitates out of solution once the solution reaches room temperature. Therefore, either of these solutions should be added to the formulation mixtures described below while hot. The highest final concentration of uracil cream made with glycerol solution was about 4% uracil, while the optimal stability is at about 2% uracil.

Exemplary Ointment Formulation Method 1 for an ~2% Uracil Ointment Formulation in Glycerol

1. Add 2.4g. of uracil (e.g., from Sigma-Aldrich Co.) to lOOg. of glycerol, and then dissolve by stirring components and heating to about 150°C at which a clear solution is produced.

2. Add gradually a solution of 1.6g. liquid soy lecithin in lOmL of water while the clear solution is hot.

3. Allow the final mixture to cool to room temperature, and store (e.g., in disposable plastic tubes in portions of 5mL). Exemplary Ointment Formulation Method 2 for an -2.5% Uracil Ointment Formulation in Glycerol

1. Add 4g. of uracil to 136g. of glycerol, and then dissolve by stirring components and heating to about 150°C at which a clear solution is produced.

2. Add 16mL of water (or ethanol) containing a lipophilic substance to the hot solution.

3. Prepare a mixture of 85% cetyl alcohol and 15% oleyl alcohol by stirring components and heating to about 60°C at which a clear mixture is produced.

4. Add 20g. of the mixture of Step 2 to the solution of Step 1 while the solution is hot, and mix well. A creamy final mixture is obtained which solidifies at room temperature.

Exemplary Ointment Formulation Method 3 for an -2.5% Uracil Ointment Formulation in Glycerol

1. Add 4g. of uracil to 120g.of glycerol, and then dissolve by stirring components and heating to about 150°C at which a clear solution is produced.

4. Add 20g. of the mixture of Step 3 to the solution of Step 2 while the solution is hot, and mix well. The final mixture containing about 10% water is a soft, white paste having a homogeneous texture at room temperature, and is best stored in ampoules or tubes.

Exemplary Ointment Formulation Method 4 for an -2% Thymine & an -1% Uracil Mixed Ointment Formulation in Propylene Glycol

1. Add 2g. of thymine and lg. of uracil to 47g. of propylene glycol, and then dissolve by stirring components and heating to about 140°C at which a clear solution is produced. 2. Allow the mixture to gradually cool to slightly above about 60-80°C (below which the mixture will turn opaque).

3. Add 50g. of any suitable skin cream (e.g., hand, foot, face, or body cream) to the mixture of Step 2 in order to prevent crystallization, and mix on a cold surface to cool gradually until reaching room temperature. The final mixture is a soft, white cream having a homogeneous texture at room temperature (suitable for application to the skin), and is best stored in ampoules or tubes.

Exemplary Ointment Formulation Method 5 for an ~3% Thymine Ointment Formulation in Propylene Glycol

1. Add 6g. of thymine to lOOg. of propylene glycol, and then dissolve by stirring components and heating to about 140°C at which a clear solution is produced.

2. Allow the mixture to gradually cool to slightly above about 60-80°C (below which the mixture will turn opaque).

3. Add lOOg. of any suitable skin cream to the mixture of Step 2 in order to prevent crystallization, and mix on a cold surface to cool gradually until reaching room temperature. The final mixture is a soft, white cream having a homogeneous texture at room temperature (suitable for application to the skin), and is best stored in ampoules or tubes.

Exemplary Ointment Formulation Method 6 for an ~3% Thymine Ointment Formulation in Glycerol

1. Add 6g. of thymine to lOOg. of glycerol, and then dissolve by stirring components and heating to about 140°C at which a clear solution is produced. 2. Allow the mixture to gradually cool to slightly above about 100°C (below which the mixture will turn opaque).

The solubility of thymine in water or glycerol is slightly higher than comparable solutions of uracil. Therefore, the formulation procedures above for thymine ointments (as well as for the mixed thymine/uracil ointment of Method 4 above) are similar to those of uracil. Moreover, the "opaqueness point" (i.e., the temperature at which the clear hot solution turns opaque) is lower for propylene glycol than for glycerol (~60-80°C compared to ~100°C, respectively), indicating a higher solubility for propylene glycol formulations compared to glycerol formulations. It is expected that the greater solubility of thymine may result in higher stability of its ointment. Furthermore, the ultimate therapeutic healing effect of thymine may exceed that of uracil due to the close similarity between thymine (also known as 5- methyluracil) and 5-FU as can be understood from Figure 1.

The exemplary ointment formulations described above are well-adapted for treatment of FIFS for cancer patients undergoing chemotherapy with 5-FU, Xeloda, and/or other derivatives of natural nucleic-acid components. Similar procedures have been employed to produce ointment formulations of uracil and/or thymine at a final concentration of up to about 5%. It is understood that the exemplary ointment formulations described above can be employed using either uracil, thymine, or any combination of the two. Exemplary Ointment Formulation Application

Topical application of the ointment formulations described above on cracked skin, caused by 5-FU or capecitabine treatments, is expected to finally result in scarring after a much longer time (i.e., several weeks to even months) than the usual healing time (i.e., days up to a week), as in ordinary wound healing. It is suggested to apply such ointment formulations once or twice a day by massaging the ointment into the skin with wet hands. Such ointments formulations can be also used as preventative ointments for HFS.

While the present invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications, and other applications of the present invention may be made.

Claims

WHAT IS CLAIMED IS:

A formulation for treating hand-and-foot syndrome, the formulation a skin agent having a solubilized solution of uracil and/or thymine; and a mixture containing at least one type of material selected from the group consisting of: a water-dispersible lipid and a lipophilic substance, wherein said solution is homogeneously dispersed in said mixture in an effective final concentration of said uracil and/or said thymine.

2. The formulation of claim 1, wherein said solution is selected from the group consisting of: a glycerol-based solution and a propylene glycol-based solution.

3. The formulation of claim 1, wherein said effective final concentration is a total concentration of either said uracil alone, said thymine alone, or said uracil and said thymine combined, wherein said total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%.

4. The formulation of claim 1, wherein said skin agent is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

5. The formulation of claim 1, wherein said uracil includes uracil derivatives, and wherein said thymine includes thymine derivatives.

6. A method for preparing formulations for treating hand-and-foot syndrome, the method comprising the steps of:

(a) combining uracil and/or thymine with a solubilizing agent;

(b) heating said uracil and/or said thymine in said solubilizing agent above about 100°C until a clear solution is produced;

(c) adding a lipophilic solution while said clear solution is hot to form a clear lipophilic solution;

(d) adding a mixture containing at least one type of water-dispersible lipid to said clear lipophilic solution while hot, wherein said mixture is initially heated above about 50°C until a clear lipid solution is produced; and

(e) mixing said mixture and said clear lipophilic solution to form a homogeneous product while allowing to cool.

7. The method of claim 6, wherein said solubilizing agent is selected from the group consisting of: glycerol and propylene glycol.

8. The method of claim 6, wherein said effective final concentration is a total concentration of either said uracil alone, said thymine alone, or said uracil and said thymine combined, wherein said total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%.

9. The method of claim 6, wherein said homogeneous product is suitable for a skin agent selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

10. The method of claim 6, wherein said uracil includes uracil derivatives, and wherein said thymine includes thymine derivatives.

11. A method for preparing formulations for treating hand-and-foot syndrome, the method comprising the steps of:

(a) combining uracil and/or thymine with a solubilizing agent;

(c) allowing said clear solution to cool to a temperature above an opaqueness point of said clear solution;

(d) adding a lipophilic mixture; and

(e) mixing said lipophilic mixture and said clear solution to form a homogeneous product while allowing to cool.

12. The method of claim 11, wherein said solubilizing agent is selected from the group consisting of: glycerol and propylene glycol.

13. The method of claim 11, wherein said effective final concentration is a total concentration of either said uracil alone, said thymine alone, or said uracil and said thymine combined, wherein said total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%.

14. The method of claim 11, wherein said lipophilic mixture is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

15. The method of claim 11, wherein said uracil includes uracil derivatives, and wherein said thymine includes thymine derivatives.

16. A kit for treating hand-and-foot syndrome, the kit comprising:

(a) a skin agent having a solubilized solution of an effective final concentration of uracil and/or thymine homogeneously dispersed in a mixture containing at least one type of water-dispersible lipid; and

(b) a label indicating administration by applying said skin agent to an affected skin region in a continuing regimen at a frequency of up to twice per day.

17. The kit of claim 16, wherein said solution is selected from the group consisting of: a glycerol-based solution and a propylene glycol-based solution.

18. The kit of claim 16, wherein said effective final concentration is a total concentration of either said uracil alone, said thymine alone, or said uracil and said thymine combined, wherein said total concentration is selected from the group consisting of: greater than about 0.2%, greater than about 0.5%, greater than about 1%, greater than about 1.5%, greater than about 2%, greater than about 3%, greater than about 4%, and about 5%.

19. The kit of claim 16, wherein said skin agent is selected from the group consisting of: a hand cream, a foot cream, a face cream, a body cream, an ointment, and a skin lotion.

20. The kit of claim 16, wherein said uracil includes uracil derivatives, and wherein said thymine includes thymine derivatives.