Topical formulation of alkyl-, phenyl-pyridone

Details Topical formulation of alkyl-, phenyl-pyridone Topical formulation of alkyl-, phenyl-pyridone

2001-05-23

2002-12-10

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06492395

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to topical formulations, e.g. creams, ointments, gels and the like containing as active ingredient one or more alkyl, phenyl pyridones, more particularly a substituted pyridone of the formula:
n
-(R
1
)-1-R
2
-2-(1H)-pyridone
or a pharmaceutically acceptable salt or ester thereof, where R
1
is selected from methyl, ethyl, propyl, carboxyl and a carboxymethyl or carboxyethyl ester group, R
2
is selected from phenyl, methylphenyl, ethylphenyl, propylphenyl, and a carboxyphenyl or carboxyethylphenyl ester group, and n is 3, 4 or 5 (position of substitution). The preferred active ingredient is Pirfenidone (CAS 53179-13-8, 5-methyl-1-phenyl-2-(1H)-pyridone).
As described in U.S. Pat. No. 5,310,562 and EP 0 383 591, Pirfenidone has a broad spectrum of applications in the prevention and treatment of fibrotic diseases, especially for the reparation and prevention of fibrotic lesional tissues, contiguous warts, contact dermatitis, keloids, fibrosis of the lung, fibrosis of the prostate, sclerosis, the healing of burns after surgery and Alzheimer disease. Although the possibility of topical application is mentioned, there is no description of any specific formulation.
The application of active ingredients of the class mentioned, (hereafter called alkyl,phenyl pyridones) e.g. Pirfenidone for e.g. the treatment of burns and keloids may possibly be carried out using a solution or a suspension of the agent in aqueous or oily excipient such as emulsions, creams, ointments, gels, microemulsions, liquid emulsions, nanocapsule suspensions, liposome formulations, lotions and the like; however, an ointment, cream or gel formulation is preferable because of their soothing effect and easy application. Because these formulations are used in the treatment of humans they are considered to be pharmaceutical preparations, and as thus have to be proven to be physically and chemically stable before they are permitted on the market. For this reason, each formulation must undergo a stability test. Without the necessary data on stability and shelf life, the formulation cannot be approved by any health authority.
Typical parameters for stability include homogeneity of the formulation in all parts of its volume, absence of coalescence of emulsion droplets, practically constant viscosity, a semi-solid structure, complete dissolution of the active ingredient, and absence of recrystallisation of the active ingredient. Also, the formulation should be prepared using pharmaceutically acceptable excipients, preferably described in pharmacopoeias, otherwise the acceptability of the excipients must be proven separately in costly programs that comprise among others a complete toxicology investigation or other means that show safety, tolerance and efficacy for the intended medicinal treatment.
It was found that standard excipient preparations e.g. as described in the USP (United States Pharmacopoeia) are unsuitable for use in the preparation of pharmaceutically acceptable topical formulations such as ointments containing a sufficient dosage of the active ingredient. The preparations lack physical stability. It was found that 5-methyl-1-phenyl-2-(1H)-pyridone is a so called emulsion destabiliser, i.e. tends to destabilise physically emulsions and other colloidal systems.
SUMMARY OF THE INVENTION
The main object of the present invention is to provide a pharmaceutically acceptable topical formulation with an excipient which permits the dissolution or dispersion of a sufficient amount of Pirfenidone (or like pharmaceutically acceptable alkyl,phenyl pyridone or salt or ester thereof) to be useful for medical treatment, and that at the same time provides the formulation with sufficient stability and shelf life.
The invention provides a pharmaceutically acceptable topical formulation for the treatment and/or prevention of skin ailments, more particularly of fibrotic nature such as fibrotic lesional tissues, contiguous warts, contact dermatitis, and keloids, and to assist the healing of burns after surgery, comprising as active ingredient a substituted pyridone of the formula:
n
-(R
1
)-1-R
2
-(1H)-pyridone
or a pharmaceutically acceptable salt or ester thereof, where R
1
is selected from methyl, ethyl, propyl, carboxyl and a carboxymethyl or carboxyethyl ester group, R
2
is selected from phenyl, methylphenyl, ethylphenyl, propylphenyl, and a carboxyphenyl or carboxyethylphenyl ester group, and n is 3, 4 or 5, together with an excipient, characterised in that the excipient comprises one or more plasticisers, one or more antioxidants, one or more gel-forming agents and sufficient pH adjusting agent to bring the pH of the formulation to a value from 4 to 8. Preferably the pH of the formulation is from about 5 to about 7.5.
The preferred active ingredient is 5-methyl-1-phenyl-2-(1H)-pyridone (Pirfenidone), or a pharmaceutically acceptable salt or ester thereof. The concentration of said active ingredient is preferably within the range of about 0.5% (by weight) to about 9% (weight), preferably from about 3% (by weight) to about 7% (by weight) calculated to the weight of the entire composition.
As plasticiser it is preferred to use one or more alkyl glycols and polyalkylene glycols, e.g. polyethylene glycol and/or polypropylene glycol. Other possible plasticisers include benzyl benzoate, chlorobutanol, mineral oil, (CTFA mixture of mineral oils, e.g. Amerchol L-101, Protalan M-16, Protalan M-26), petrolatum (CTFA, mixture of petrolatum, e.g. Amerchol CAB, Forlan 200), and lanolin alcohols, sorbitol, triacetin, dibutyl sebacate, diethyl phthalate, glycerine, petrolactam and triethyl citrate.
As antioxidant it is preferred to use sodium metabisulfite. Other possible antioxidants include alphatocopherol, ascorbic acid, malic acid, sodium ascorbate, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, fumaric or maleic acid, and propyl gallate.
As a gel-forming agent it is preferred to use a carboxypolyalkylene, especially Carbomer (carboxypolymethylene, CAS 541823-57-9) of which different grades with various molecular weights are commercially available. Other possible gel-forming agents include cetostearyl alcohol, colloidal silicon dioxide, gelatine, guar gum, sodium or calcium carboxymethyl cellulose, hydroxyethyl or hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl or ethyl cellulose, maltodextrin, polyvinyl alcohol, propylene carbonate, povidone, propylene glycol alginate, alginic acid sodium alginate, sodium starch glycolate, starch, sucrose.
The gel-forming agents can be included with emulsifying agents or gums such as acacia gum, guar gum, tragacanth, xanthan gum and fillers or thickening agents such as bentonite and magnesium aluminium silicate.
Preferred emulsifying agents are acacia, anionic emulsifying wax, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, glyceryl monostearate, hydrous lanolin, lanolin, lanolin alcohols, lecithin, monobasic sodium phosphate, monoethanolamin, nonionic emulsifying wachs, oleic acid, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbiaten fatty acid esters, polyoxyethylene stearates, propylene glycol alginates, sodium lauryl sulfates, sorbitan esters, stearic acid, triethanolamine.
Antimicrobial agents such as benzyl benzoate may be included. Preferred antimicrobial agents are also benzalkonium chloride, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, cetrimide, chlorhexidine, chlorobutanol, chlorocresol, cresol, glycerin, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate, potassium sorbate, sodium benzoate, sodium proprionate, sorbic acid, thiomersal.
Although purified water, preferably de-ionised, is used as the main vehicle, one or more alcohols may be included, such as ethanol and/or isopropanol.
Methylparaben and/or Propylparaben may be included. For the adjustment of the pH is preferred to use alk

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