# Patent

## Title
Gel containing pirfenidone

## Abstract

The invention relates to a gel composition containing pirfenidone, which is advantageous over other cutaneously administered pharmaceutical forms known in the prior art and which can be used in treatment for the restoration of tissues with fibrotic lesions and for the prevention of fibrotic lesions.

## Background
RELATED APPLICATIONS
This application is a continuation of and claims priority under 35 U.S.C. § 120 to U.S. patent application U.S. Ser. No. 16/450,150, filed Jun. 24, 2019, which is a divisional application of and claims priority under 35 U.S.C. § 120 to U.S. patent application Ser. No. 15/435,494, filed on Feb. 17, 2017, which is a divisional application of and claims priority under 35 U.S.C. § 120 to U.S. patent application Ser. No. 13/893,626, filed on May 14, 2013, which is a divisional application of and claims priority under 35 U.S.C. § 120 to U.S. patent application Ser. No. 12/673,304, filed on Apr. 28, 2010, which is a national stage filing under 35 U.S.C. § 371 of International Application PCT/MX2008/000107, filed on Aug. 14, 2008, which claims priority to Mexican Patent Application Serial No. MX/a/2007/009796, filed on Aug. 14, 2007, each of which is incorporated herein by reference.


FIELD OF INVENTION
The present invention is related to a gel formula that contains Pirfenidone, which offers advantages over other pharmaceutical forms of known cutaneous administration in the state of the technique.
BACKGROUND OF THE INVENTION
The 5-methyl-1-phenyl-2(1H)-pyridone, formula;




It is a drug that has been applied in the restoration of tissues with lesions with fibrosis and the prevention of fibrotic lesions. This compound, Pirfenidone, it is by itself a known compound and its pharmacological effects has been described, for example, in Japanese applications numbers 87677/1974 and 1284338/1976, as an anti-inflammatory agent that includes antipyretic and analgesics. The U.S. Pat. No. 3,839,346, published Oct. 1, 1974; the number 3, 974, 281, published Aug. 10, 1976; the U.S. Pat. No. 4,042,699 published Aug. 16, 1977, and the U.S. Pat. No. 4,052,509 published Oct. 4, 1977, which described the methods for the obtained Pirfenidone, as well as its use as an anti-inflammatory agent. In the Mexican patent 182, 266 the antifibrotic activity of the 5-methyl-1-phenyl-2(1H)-pyridone is described.
Different resources and treatments have been used to the date and none of them have shown to be really effective. Pirfenidone has shown its efficacy as an anti-fibrotic agent in different pathologies and organs, and has been demonstrated in previous works, where we have observed an effect on the fibroblasts and the production of collagen and extracellular matrix, as well as in experimental models and in clinical tests also.
Many substances could form gels when a gelificant agent is added. This is use in many diverse products in the manufacturing industry, from food to paint, passing through adhesives.
Gels are also important in the chemistry part related with the processes SOL GEL and in the synthesis of solid materials with nanopores.
Gels are classified in: aqueous (hydrogels) or organic (organogels), depending if the aqueous component is water or an organic solvent; organic or inorganic in nature, colloidal or thick grain, according to the size of the particles; and rigid gels, elastic or tixothrophic, according to its mechanic properties.
The hydrocolloids are substances that are produced from vegetable and animal proteins or multiple sugars. They have the capacity to swell themselves and to bind to water. The hydrocolloids are used to thicken, solidify and stabilize food.


OBJECT OF THE INVENTION
The object of the present invention is to provide a gel composition for its cutaneous administration that contains Pirfenidone, a viscous agent; a solubilizer; a non ionic solubilizer; a conserving agent; a neutralizer agent and purified water.
Also, it is the object of the present invention to provide a process of manufacture of a gel that contains pirfenidone for its cutaneous application.
Another objective of the present invention is to provide a gel medicine to be used as an anti-fibrotic and anti-inflammatory agent.
SPECIFICATION OF THE INVENTION
Composition of the Gel
The composition of the gel contains from 2 to 12% of Pirfenidone is elaborated utilizing from 0.4 to 1.2% of a viscous agent, from 10 to 30% of a solubilizer, from 5 to 15% of a non ionic solubilizer, from 0.2 to 1% of a conserving agent, from 0.4 to 1.2% a neutralizer agent and the rest of purify water. The viscous agent is selected from a carbomer 940 (MR); Ultrex 10 (MR), cellulose derivatives; gums; polioxameres; ethylic alcohol and propylenglycol; the conserving agent is selected from a group that consist of Diazolidinyl urea, iodopropinil-butilcarbamate; methylparabene and a mix of these compounds; the neutralizer agent is selected from a group of primary, secondary and tertiary aliphatic amines of the mono-, bi- and triethanolamine type, and of the hydroxide alkaline metals, such as sodium hydroxide.
An example of the composition of the gel is shown in the table 1:















Component
Quantity (g)
%




















Pirfenidone
8
8



Viscous agent
0.5
0.5



Solubilizer
20
20



Non ionic solubilizer
11.5
11.5



Conserving agent
0.5
0.5



Neutralizer
0.5
0.5



Purified water up to
100
59










The gel containing Pirfenidone is manufactured as follows:

    
    
        a) Mix 50% of the total water to be used with the viscous agent, allowing the complete humectation of the viscous agent;
        b) Mix separately and with constant agitation the Pirfenidone with the solubilizer agent;
        c) Dissolve separately the non ionic solubilizer agent in the 25% water to be used at 40° C., once dissolved, the 15% of the total water is added;
        d) Add the solution from part c) to the mix from part b), agitate until the mix is homogenate.
        e) Dilute the neutralizer agent 10% of the total water to use, agitate until the mix is homogenate; and
        f) Add with constant agitation and homogenate in each addition to the mix from part a) the solution from part d); the conservative and the solution from part e).

A prepared composition according to procedure describe is shown in table 2.

    
    
















Component
Quantity (g)



















Pirfenidone
8



Carbomer
0.5



N-methylpirrolidone
20



Macrogolglycerol
11.5



Hidroxiestearate 40




Diazolidinilurea and
0.5



Iodopropinil-butilcarbamate




Triethanoalamine
0.5



Purified water up to
100










These compositions are shown in an example mode, but they are not limited in any level of the reach of the description of the present invention.

## Claims

1. A method for preparing a composition of pirfenidone gel comprising:
(i) 2-12% pirfenidone;
(ii) 0.4-1.2% of a viscous agent selected from the group consisting of Carbomer 940® (crosslinked polyacrylic acid polymer), cellulose derivatives, gums, and poloxamers;
(iii) 10-30% of a solubilizer selected from the group consisting of N-methylpyrrolidone, ethyl alcohol, and propylene glycol;
(iv) 5-15% of a non-ionic solubilizer;
(v) 0.2-1% of a conserving agent selected from the group consisting of diazolidinyl urea, iodopropynyl butylcarbamate, methylparaben, propylparaben, and combinations of these conserving agents;
(vi) 0.4-1.2% of a neutralizer agent selected from the group consisting of primary, secondary, and tertiary, mono-, bi-, and triethanolamine aliphatic amines, and hydroxide alkaline metals; and
(vii) water;

the method comprising the steps of:
(a) mixing approximately 50% of the total water to be used with the viscous agent and allowing complete humectation of the viscous agent;
(b) mixing pirfenidone and the solubilizer separately and with agitation;
(c) dissolving separately the non-ionic solubilizer in approximately 25% of total water at approximately 40° C. and once dissolved, adding approximately 15% of the total water;
(d) adding the solution from part (c) to the mix from part (b), and agitating until homogenous;
(e) diluting the neutralizer agent in approximately 10% of the total water to be used, and agitating until homogenous; and
(f) combining the solutions of parts (a)-(e).

2. The method of claim 1, wherein the viscous agent is Carbomer 940®.

3. The method of claim 1, wherein the viscous agent is in the amount of 0.5%.

4. The method of claim 1, wherein the viscous agent is Carbomer 940® and is in the amount of 0.5%.

5. The method of claim 1, wherein the solubilizer is N-methylpyrrolidone.

6. The method of claim 1, wherein the solubilizer is propylene glycol.

7. The method of claim 1, wherein the non-ionic solubilizer is macrogolglycerol hydroxystearate 40.

8. The method of claim 1, wherein the conserving agent is diazolidinyl urea.

9. The method of claim 1, wherein the conserving agent is iodopropynyl butylcarbamate.

10. The method of claim 1, wherein the conserving agent is methylparaben.

11. The method of claim 1, wherein the conserving agent is propylparaben.

12. The method of claim 1, wherein the neutralizer agent is triethanolamine.

13. The method of claim 1, wherein the neutralizer agent is a hydroxide alkaline metal.

14. The method of claim 1, wherein the neutralizer agent is sodium hydroxide.

15. The method of claim 1, wherein the viscous agent is Carbomer 940®, the solubilizer is N-methylpyrrolidone, the conserving agent is diazolidinyl urea, and the neutralizer agent is triethanolamine.

16. The method of claim 1, wherein the viscous agent is Carbomer 940®, the solubilizer is N-methylpyrrolidone, the conserving agent is iodopropynyl butylcarbamate, and the neutralizer agent is triethanolamine.

17. The method of claim 1, wherein the composition of pirfenidone gel comprises: 8% pirfenidone, 0.5% of the viscous agent, 20% of the solubilizer, 11.5% of the non-ionic solubilizer, 0.5% of the conserving agent, 0.5% of the neutralizer agent, and 59% of purified water.

18. The method of claim 1, wherein the viscous agent is Carbomer 940®, the solubilizer is N-methylpyrrolidone, the non-ionic solubilizer is macrogolglycerol hydroxystearate 40, the conserving agent is diazolidinyl urea and iodopropynyl butylcarbamate, and the neutralizer agent is triethanolamine.

19. The method of claim 1, wherein the composition of pirfenidone gel consists of 8% pirfenidone, 0.5% of Carbomer 940®, 20% of N-methylpyrrolidone, 11.5% of the macrogolglycerol hydroxystearate 40, 0.5% of diazolidinyl urea and iodopropynyl butylcarbamate, 0.5% of triethanolamine, and 59% of purified water.