Patent Application
20210401989
The present invention relates to semi-solid formulations in the form of an unguent, gel, cream, or ointment, containing Pirfenidone as an active ingredient, which offer advantages in the treatment and prevention of fibrotic lesions over other cutaneously administered pharmaceutical forms known in the prior art.
The present invention relates to semi-solid pharmaceutical compositions and their use in the treatment for repairing fibrotic lesional tissues and for preventing fibrotic lesions, compositions comprising 5-methyl-1-phenyl-2(1H)-pyridone as an active anti-fibrotic ingredient.
Pirfenidone is a non-peptide synthetic molecule with a molecular weight of 185.23 daltons. Its chemical elements are expressed as C12H11NO, and its structure is known. The synthesis of pirfenidone has been worked out. Pirfenidone is manufactured and clinically evaluated as a broad-spectrum anti-fibrotic drug. Pirfenidone has anti-fibrotic properties through decreased TNF-α expression, decreased PDGF expression, and decreased collagen expression. 5-Methyl--phenyl-2(1H)-pyridone has the following structural formula:
U.S. Pat. Nos. 3,974,281; 4,042,699; and 4,052,509 further disclose the use of the compound 5-methyl-1-phenyl-2-(1H)-pyridone (“pirfenidone”) for reducing serum uric acid and glucose levels, for treating inflammatory upper respiratory tract conditions, and for treating inflammatory skin conditions in humans and other mammals.
The use of pirfenidone in the repair and prevention of fibrotic lesions is disclosed in Patents EP-A-0383591 and EP-A-0702551.
Accordingly, it is a main object of the present invention to provide semi-solid compositions for repairing and preventing fibrotic lesional tissue.
Herein, the term “anti-fibro”, “anti-fibrotic” or “anti-fibrosis” refers to the repairs and/or prevention of pathological collagen polymerization, collagen disease, wrinkles, etc., and repair as well as normalization of existing pathological fibrotic tissues.
It is a further object of the invention to provide such semi-solid compositions comprising 5-methyl-1-phenyl-2-(1H)-pyridone (“pirfenidone”) as an active anti-fibrotic ingredient.
Other objects of the present invention as well as particular features and advantages thereof will be explained in, or will be apparent from the following description.
The present invention describes semi-solid pharmaceutical compositions containing Pirfenidone, which offer advantages over other cutaneously administered pharmaceutical forms known in the prior art, due to its permeability and absorption characteristics, which are useful in the treatment for restoring tissues that have suffered loss or degradation of extracellular matrix resulting in the formation of wrinkles or skin thinning. That is, to show that the use of the semi-solid composition containing Pirfenidone is effective in restoring skin imperfections caused by the loss of collagen and other extracellular matrix proteins such as fibronectin and elastin.
Another object of the present invention is to provide semi-solid compositions in the form of a cream, ointment and unguent for cutaneous administration comprising Pirfenidone as an active ingredient; an absorption base; a solubilizer; a preservative; an emollient agent, and purified water.
5-Methyl-1-phenyl-2(1H)-pyridone, pirfenidone, is the main constituent of the semi-solid composition of the present invention that induces “the filling” of the skin that has undergone the degradation of extracellular matrix proteins such as collagens, fibronectin, and elastin.
Different resources and treatments have been used to the date and none of them have shown to be actually effective. Pirfenidone has shown its efficacy as an anti-fibrotic agent in different pathologies and organs, as demonstrated in previous works, where we have seen an effect on the fibroblasts and the collagen produced by them in both experimental models and clinical tests.
Recently obtained additional information allows us to conclude that Pirfenidone induces the expression of transcription factors involved in the ignition of genes stimulating collagen and non-collagen protein degradation. However, depending on the micro-environment in which Pirfenidone is immersed, in the absence of excess extracellular matrix (such as cases of diabetic foot ulcers and varicose ulcers wherein there is extensive tissue loss and absence of extracellular matrix producing and synthesizing cells, formation of facial wrinkles, and thinning and loss of skin elasticity), it will induce precisely the opposite effect to that previously reported with regard to its ability to induce collagenases (enzymes that degrade collagens) for remodeling scars.
An unguent is defined as a soft-consistency preparation containing the drug(s) and additives incorporated into an appropriate base that provides it with body and consistency. It adheres and applies to the skin and mucous membranes. The base can be liposoluble or water soluble, it is generally anhydrous or has at the most 20 percent water. When contained a washable or water-removable base, it is also referred to as a hydrophilic unguent, also known as an ointment.
The definition of ointment was introduced in the USP in 1955. The definition is broad and includes petrolatum bases, that is, water-in-oil (W/O) or oil-in-water (O/W) emulsion bases and the so-called water-soluble bases.
They are selected or designed for optimal drug dispersion and also to impart emollient properties or other medicinal feature, since they are designed for specific uses and to facilitate their application.
A base must not be irritating, it must be easy to remove, it must not stain, it must be stable, it must not depend on pH and it must be widely compatible with a variety of drugs.
The technical advantage from the use of formulations in the form of creams or unguents over the prior art in gel formulations consists substantially of the following properties attributable to the type of formulation: Satisfactory antioxidant stability, good physiological tolerability, sufficient release of Pirfenidone, good sensitivity; the objective pursued by the application of the ointment on the skin is that the drug deeply penetrates into the skin unlike the previous formulations, the therapeutic effect of which exhibits efficacy on wounds or skin lesions.
By means of most of the ointments used, a local therapy is attempted.
Before the drug can penetrate the skin, it must be released from the ointment base.
One criterion for the suitability of an ointment base in therapy is the transfer rate of the drug.
By rubbing or massaging, the drug penetration is doubled or tripled.
CERATE: when the ointment contains wax in a ratio of at least 25%.
They are pharmaceutical forms made up of two phases, one lipophilic and the other aqueous.
They have a soft consistency and a Newtonian or pseudoplastic flow due to their high water content.
A difference between the cream and the ointment is that the ointment hardly flows and the creams easily flow, also the ointments are always monophasic.
The semi-solid composition containing from 2% to 12% Pirfenidone is made by using from 20% to 60% of a solvent-humectant, from 5% to 10% of one or a combination of emulsifiers, from 2% to 8% of a consistency and emollience agent, from 0.5% to 3% of one or various emollients, from 0.1% to 2% of a preservative, from 0.05% to 0.2% of a rheological or viscosity agent, from 0.05% to 0.2% of a neutralizer, from 0.05% to 0.2% of a preservative, and from 0.0005% to 0.003% of a stabilizer, and optionally, from 0.008 to 0.8% of an antiseptic/preservative.
Wherein the solvent-humectant is selected from the group consisting of Glycerin, Ethyl alcohol, Transcutol-P, N-Methylpyrrolidone, 2-pyrrolidone, Cremophor RH-40, Propylene Glycol; the emulsifiers are selected from the group consisting of Cetyl alcohol, Stearyl alcohol, Cetostearyl alcohol, Span 80, Span 60, Glyceryl monostearate, Polyethylene glycol stearate, Cremophor A-6, Cetostearyl alcohol, Cetyl alcohol, Glyceryl monostearate, Spermaceti, Cremophor A-25; the consistency and emollience agents are selected from the group consisting of Cetostearyl alcohol, Macrogol cetostearyl ether, Ceterareth-25, Cetyl alcohol, Spermaceti, Beeswax, Glyceryl monostearate, Solid Paraffin, Cetyl alcohol, and Stearyl alcohol; the emollient is selected from the group consisting of Dimeticon, Mineral oil, Isopropyl adipate, Isohexadecane, Capryl/caprylic triglyceride, Myristyl glucoside, Behenyl alcohol, C12-15 Alkylbenzoate, isopropyl isostearate; the preservative is selected from the group consisting of Sodium Methylparaben, Sodium propylparaben, Phenoxyethanol, Diazolinidyl urea, Iodopropynyl butylcarbamate; the viscosity agent is selected from the group consisting of Sodium propylparaben, the neutralizer may be Triethanolamine or Sodium hydroxide; the stabilizer can be selected from the family of Citric acid or synthetic Vitamin C.
For a better understanding of the invention, the process of preparing the semi-solid composition containing pirfenidone and illustrative examples of the use and application thereof are shown below.
Semi-solid composition prepared according to the following process:
A) Oily Phase
Identify Oily Phase
B) Mixture A
Identify Mixture A
C) Solution “A”
(Identify Solution “A”)
D) Solution “B”
Identify as Solution “B”
E) Aqueous Phase
Identify as Aqueous Phase
F) Phase Mixture
G) Solution “C”
H) Final Mixture
A) Oily Phase
Identify Oily Phase
B) Solution “A”
C) Phase Mixture
A) Oily Phase
Petrolatum in a reactor, stirring and heating to (75° C.-80° C.), until completely melted.
Identify Oily Phase
B) Solution “A”
C) Solution “B”
D) Aqueous Phase
E) Aqueous Phase
Example of a cream-type semi-solid composition is shown in Table 1:
Example of an ointment-type semi-solid composition is shown in Table 2:
Example of an unguent-type semi-solid composition is shown in Table 3:
Although the present invention has been described with respect to a limited number of embodiments, the specific features of one embodiment should not be attributed to other embodiments of the invention. A single embodiment is not representative of all aspects of the invention. In some embodiments, the compositions or methods may include several compounds or steps not mentioned herein. In other embodiments, the compositions or methods do not include, or are substantially free of compounds or steps not indicated herein. There are variations and modifications based on the described embodiments.
| Number | Date | Country | Kind |
|---|---|---|---|
| MX/A/2018/010528 | Aug 2018 | MX | national |
This application is a national stage filing under 35 U.S.C. § 371 of International PCT Application No. PCT/MX2019/000093, filed Aug. 23, 2019, which claims priority to Mexican Application, MX/a/2018/010528, filed Aug. 31, 2018, each of which is incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/MX2019/000093 | 8/23/2019 | WO | 00 |
