Tadalafil sublingual composition

Abstract

A sublingual liquid formulation comprises tadalafil at 0.1 to 30wt%, 1 to 40wt% of an acidulant selected from the group consisting of malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, citric acid, and palmitic acid, and a pharmaceutically acceptable salt thereof; and 5 to 95wt% water. The formulation may be provided in the form of propellant free spray.

Description

Priority This application claims priority from the provisional application numbered 202311089150 filed with Indian Patent Office, New Delhi on 27 December, 2023 entitled “Tadalafil Sublingual Composition”, incorporated herein by reference. Field of the Invention The present invention relates to a pharmaceutical composition for sublingual administration and absorption. More particularly, the invention relates to a sublingual pharmaceutical composition, comprising a therapeutically effective amount of Tadalafil and optionally at least one more pharmaceutical active ingredient, and at least one pharmaceutically acceptable excipient. The present invention also discloses a process for preparation of the sublingual pharmaceutical composition. The present invention is further directed to methods of treating male sexual dysfunction or pulmonary arterial hypertension by administering sublingual formulations containing Tadalafil. Background of the Invention The drug tadalafil is used to treat pulmonary arterial hypertension, benign prostatic hyperplasia, and erectile dysfunction. It is administered orally, with effects beginning within 30 minutes and lasting up to 36 hours. A film-coated tablet form of tadalafil is marketed for the treatment of erectile dysfunction. However, this composition's or formulation's stated bioavailability and stability are quite low. Sublingual means “under the tongue.” Sublingual route refers to the delivery of a chemical or drug through the mouth in a way that allows the substance to be quickly absorbed through the blood vessels under the tongue. A sublingual formulation is preferred because it avoids hepatic first pass metabolic processes, which boost patient compliance, bioavailability, and speed up the beginning of action. Dysphagia, or trouble in swallowing, affects people of all ages and is particularly prevalent in elderly patients. The sublingual region of the mouth cavity is more permeable than the buccal region in terms of permeability. In the fields of cardiovascular medications, analgesics, steroids, enzymes, and barbiturates, sublingual drug delivery is already used. While there are various Tadalafil formulations currently available, there is still a need in the art for a quick-onset sublingual spray or drops formulation containing Tadalafil. Object of the Invention The principal object of the present invention is to provide a pharmaceutical composition for sublingual administration and absorption. Another object of the present invention is to provide a sublingual composition, comprising a therapeutically effective amount of at least one pharmaceutical active ingredient and at least one pharmaceutically acceptable excipient. Another object of the present invention is to provide a sublingual composition, comprising a therapeutically effective amount of Tadalafil and at least one pharmaceutically acceptable excipient. Another object of the present invention is to provide a propellant free sublingual spray composition comprising Tadalafil. Another object of the present invention is to provide a process for the preparation of propellant free sublingual spray composition comprising Tadalafil. Another object of the present invention is to provide methods of treating male sexual dysfunction or pulmonary arterial hypertension by administering propellant free sublingual composition containing Tadalafil. One of the key objectives is to provide a pharmaceutical composition that is well absorbed, giving optimal bioavailability to the person. Summary of the Invention In an aspect of the present invention, the present invention discloses a sublingual formulation comprising at least one pharmaceutical active ingredient and at least one pharmaceutically acceptable excipient. In another aspect of the present invention, the present invention discloses a sublingual formulation comprising Tadalafil and at least one pharmaceutically acceptable excipient. In another aspect of the present invention, the present invention discloses a sublingual formulation, comprising: (a) from about 0.1% w / w to about 30% w / w Tadalafil; (b) from about 1% w / w to about 40% w / w of an acidulent selected from the group consisting of malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, citric acid, palmitic acid and a pharmaceutically acceptable salt thereof; and (c) from about 5% w / w to about 95% w / w water. In an embodiment of the present invention, the sublingual formulation is provided in the form of propellant free spray. In an embodiment of the present invention, the Tadalafil is a pharmaceutically acceptable salt selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate. In an embodiment of the present invention, the composition further comprising a pharmaceutically acceptable solubilizer and / or surfactant and / or stabilizer; and / or permeation enhancer; and / or antioxidant; and / or preservative; and / or flavoring agent; and / or colouring agents; and / or sweetener; and / or pH regulators. In another aspect of the present invention, the present invention discloses a process for the preparation of propellant free sublingual spray or drops formulation. In another aspect, the present invention is directed to methods for treating male sexual dysfunction comprising administering the formulations of the present invention to a patient. In a further aspect, the present invention is directed to methods for treating pulmonary arterial hypertension comprising administering the formulations of the present invention to a patient. Detailed Description of the Invention The applicants unexpectedly discovered sublingual Tadalafd formulations that have improved bioavailability, a more rapid onset of action, and an improved storage stability. The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice. It is further to be understood that all terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting in any manner or scope. Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain. In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art. Unless otherwise specified, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions may be included to better appreciate the teaching of the present invention. As used in the description herein, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As used herein, the term “combination” refers to materials added together with or without substantial mixing towards achieving homogeneity. As used herein, the term “composition” and the term “formulation” has been used interchangeably. As used herein, "Tadalafil" refers to the base or a pharmaceutically acceptable salt, ester, derivative, or prodrug thereof. As used herein, "propellant free" refers to a formulation that is not administered using compressed gas. As used herein, "male sexual dysfunction" refers to erectile dysfunction or impotence. Erectile dysfunction and impotence are characterized by the inability to develop or maintain an erection of the penis during sexual activities. As used herein, "pulmonary arterial hypertension" refers to the condition of having abnormally high blood pressure in the lungs. As used herein, all numerical values relating to amounts, weights, and the like, that are defined as "about" each particular value is plus or minus 10%. For example, the phrase "about 10% w / w" is to be understood as "9% w / w to 11% w / w." Therefore, amounts within 10% of the claimed value are encompassed by the scope of the claims. As used herein "% w / w" and "percent w / w" refer to the percent weight of the total formulation. As used herein the term "effective amount" refers to the amount necessary to treat a patient in need thereof. As used herein the term "patient" refers, but is not limited to, a person that is being treated for male sexual dysfunction or pulmonary arterial hypertension. As used herein the term "pharmaceutically acceptable" refers to ingredients that are not biologically or otherwise undesirable in a sublingual dosage form. In an aspect of the present invention, the present invention discloses a sublingual formulation, comprising: (a) from about 0.1% w / w to about 30% w / w Tadalafil; (b) from about 1% w / w to about 40% w / w of an acidulent selected from the group consisting of malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, citric acid, palmitic acid and a pharmaceutically acceptable salt thereof; and (c) from about 5% w / w to about 95% w / w water. In an embodiment of the present invention, the sublingual formulation is provided in the form of propellant free spray. In an embodiment of the present invention, the Tadalafil pharmaceutically acceptable salt selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate. In an embodiment of the present invention, the composition further comprising a pharmaceutically acceptable solubilizer and / or surfactant and / or stabilizer; and / or permeation enhancer; and / or antioxidant; and / or preservative; and / or flavoring agent; and / or colouring agents; and / or sweetener; and / or pH regulators. As used herein, a "solubilizer or a surfactant or a stabilizer" refers to a compound that has at least one of these properties. The solubilizer or the surfactant or the stabilizer can be a mixture of solubilizers and / or surfactants and / or stabilizers. Other appropriate solubilizers and / or surfactants and / or stabilizers known by those of skill in the art could also be added to formulations of the present invention. In an embodiment of the present invention, the solubilizer and / or surfactant and / or stabilizer is selected from the group consisting of polysorbate, sorbitan, polyvinylpyrrolidine, sodium lauryl sulfate, poloxamer, cremophor, lactic acid and cyclodextrin. In an embodiment of the present invention, the permeation enhancer is selected from the group consisting of oleic acid, citric acid, cetyl pyridinium chloride, glyceryl oleate, menthol, L-lysine, polysorbate-20, polysorbate-80, sodium lauryl sulfate, sodium desoxycholate and a combination thereof. In an embodiment of the present invention, the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methionine, ascorbic acid, sodium ascorbate, sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, and a combination thereof. The antioxidant could also be a mixture of antioxidants. Other appropriate antioxidants known by those of skill in art could also be added to formulations of the present invention. In a preferred embodiment, the formulations contain from about 0.001% w / w to about 1% w / w of the antioxidant. In a more preferred embodiment, the formulations contain from about 0.005% w / w to about 0.05%> w / w of the antioxidant. The permeation enhancer can also be a mixture of permeation enhancers. Other appropriate permeation enhancers known by those of skill in the art could also be added to formulations of the present invention. In an embodiment of the present invention, the preservative is selected from the group consisting of methyl paraben, propyl paraben, sodium benzoate, benzoic acid, sorbic acid, and a combination thereof. Other appropriate preservatives known by those of skill in art could also be added to formulations of the present invention. In an embodiment of the present invention, the flavoring agent is selected from the group consisting of peppermint oil, blackberry, strawberry, raspberry, grape, lemon, lemon mint, cinnamon, menthol, and a combination thereof. Other appropriate flavoring agents known by those of skill in art could also be added to formulations of the present invention. In an embodiment of the present invention, the sweetener is selected from the group consisting of sucralose, sucrose, sorbitol, fructose, acesulfame K, aspartame, sodium saccharin, stevia, xylitol, an ammonium salt of Glycyrrhizic Acid, and a combination thereof. In an embodiment of the present invention, the composition comprising from about 0.1% w / w to about 30% w / w Tadalafil, from about 5% w / w to about 95% w / w water, and from about 1% w / w to about 40% w / w malic acid. In some embodiments of the present invention, the composition is provided in the form of sublingual sprays and sublingual drops. In a preferred embodiment, the formulations of the present invention do not discolour when stored at 40° C ± 2°C at 75% ± 5% relative humidity for six months. In another preferred embodiment, the formulations of the present invention do not become contaminated with impurities when stored at 40° C ± 2°C at 75% ± 5% relative humidity for six months. In yet another embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv (10) is from about 18 to about 32 microns during administration. In a further embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv (50) is from about 50 to about 160 microns during administration. In yet another embodiment, the formulations of the present invention are capable of producing a droplet size distribution wherein the mean Dv (90) is from about 400 to about 500 microns during administration. In yet another embodiment, the formulations of the present invention are capable of producing a spray span ((Dv 90 - Dv 10) / Dv 50) of from about 3 to about 7. In another aspect, the present invention is directed to methods for treating male sexual dysfunction comprising administering the formulations of the present invention to a patient. In a further aspect, the present invention is directed to methods for treating pulmonary arterial hypertension comprising administering the formulations of the present invention to a patient. One of the main advantages achieved by sublingual administration is circumventing the exposure of active substances to digestive enzymes of the gastrointestinal tract and avoiding the first pass effect from hepatic enzymes immediately upon absorption. This also helps in quickly attaining maximum levels of the active substance in the blood plasma. The mucosa of the mouth is well vascularised and well suited for the absorption of lipophilic, nonionized compounds. The sublingual route is particularly beneficial for active substances which are administered in low amounts and need to provide desired blood levels. The sublingual composition enables the administration of the drug active substance by avoiding to be swallowed, and also increases the absorption rate of the drug via the blood vessels under the tongue. The present invention is further exemplified in the following non limiting examples. Various modifications and alternate embodiments of the disclosed embodiments will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined. Examples The present invention is further explained in the form of following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Specifically, the doses / concentration of the ingredients provided in below examples are just illustrative as the products are developed in other strengths too. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention. Example 1 Sublingual formulation 1 was prepared as shown in Table 1 below. The components of the formulation were weighed in an amount as mentioned below. Then, water was added to malic acid to form a solution. The solution was mixed until the malic acid was dissolved. Tadalafil was then added and mixed until a clear solution was formed. Accordingly, a 20% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 1 Ingredients Amount (in wt%) Tadalafil 20 Malic acid 30 Water 50 Total 100 Example 2 Sublingual formulation 2 was prepared in a similar manner as was formulation 1 using the components as shown in Table 2 below. Accordingly, a 20% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 2 Ingredient Amount (in wt%) Tadalafil 20 Malic acid 30 Flavouring Agent (strawberry) 0.08 Sucralose 0.7 Water (quantity sufficient to produce) 100 Example 3 Sublingual formulation 3 was prepared in a similar manner as was formulation 1 using the components as shown in Table 3 below. Accordingly, a 14.6% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 3 Ingredient Amount (in wt%) Tadalafil 14.6 Malic acid 26 Flavouring Agent (raspberry) 0.08 MagnaSweet® 0.15 Water (quantity sufficient to produce) 100 Example 4 Sublingual formulation 4 was prepared in a similar manner as was formulation 1 using the components as shown in Table 4 below. Accordingly, a 10% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 4 Ingredient Amount (in wt%) Tadalafil 10 Malic acid 18 Flavouring Agent (peppermint oil) 0.12 Sucralose 0.5 MagnaSweet® 0.1 Water (quantity sufficient to produce) 100 Example 5 Sublingual formulation 5 was prepared in a similar manner as was formulation 1 using the components as shown in Table 5 below. Accordingly, a 7% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 5 Ingredient Amount (in wt%) Tadalafil 7 Malic acid 10 Flavouring Agent (lemon mint) 0.15 Sucralose 0.25 MagnaSweet® 0.05 Water (quantity sufficient to produce) 100 Example 6 Sublingual formulation 6 was prepared in a similar manner as was formulation 1 using the components as shown in Table 6 below. Accordingly, a 1% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 6 Ingredient Amount (in wt%) Tadalafil 1 Malic acid 08 Flavouring Agent (peppermint oil) 0.12 Sucralose 0.2 Water (quantity sufficient to produce) 100 Example 7 Sublingual formulation 7 was prepared in a similar manner as was formulation 1 using the components as shown in Table 7 below. Accordingly, a 0.5% w / w Tadalafil composition was prepared for use as a sublingual formulation that does not require a propellant for administration. Table 7 Ingredient Amount (in wt%) Tadalafil 0.5 Malic acid 07 Flavouring Agent (peppermint oil) 0.05 Sucralose 0.1 MagnaSweet® 0.02 Water (quantity sufficient to produce) 100

Claims

1. A sublingual liquid formulation comprising:(a) 0.1% w / w to 30% w / w Tadalafil;(b) 1% w / w to 40% w / w of an acidulent selected from the group consisting of malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, citric acid, palmitic acid and a pharmaceutically acceptable salt thereof; and(c) 5% w / w to 95% w / w water.

2. The sublingual formulation according to claim 1, wherein said formulation is suitable for administration as spray.

3. The sublingual formulation according to any of the preceding claims, wherein said formulation is provided in the form of propellant free spray.

4. The sublingual formulation according to any of the preceding claims, wherein Tadalafil is a pharmaceutically acceptable salt selected from the group consisting of citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate, carbonate, mesylate and lactate.

5. The sublingual formulation according to any of the preceding claims further comprises a pharmaceutically acceptable solubilizer and / or surfactant and / or stabilizer; and / or permeation enhancer; and / or antioxidant; and / or preservative; and / or flavoring agent; and / or colouring agents; and / or sweetener; and / or pH regulators.

6. The sublingual formulation according to claim 5, wherein(a) the solubilizer and / or surfactant and / or stabilizer is selected from the group consisting of polysorbate, sorbitan, poly vinylpyrrolidine, sodium lauryl sulfate, poloxamer, cremophor, lactic acid, cyclodextrin and a combination thereof;(b) the permeation enhancer is selected from the group consisting of oleic acid, citric acid, cetylpyridinium chloride, glyceryl oleate, menthol, L- lysine, polysorbate-20, polysorbate-80, sodium lauryl sulfate, sodium desoxy cholate, and a combination thereof;(c) the antioxidant is selected from the group consisting of butylated hydroxy anisole (BHA), butylated hydroxy toluene (BHT), methionine, ascorbic acid, sodium ascorbate,sodium thiosulfate, sodium bisulfite, sodium metabisulfite, ascorbyl palmitate, thioglycerol, and a combination thereof;(d) the preservative is selected from the group consisting of methyl paraben, propyl paraben, sodium benzoate, benzoic acid, sorbic acid, and a combination thereof;(e) the flavoring agent is selected from the group consisting of peppermint oil, blackberry, strawberry, raspberry, grape, lemon, lemon mint, cinnamon, menthol, and a combination thereof;(f) the sweetener is selected from the group consisting of sucralose, sucrose, sorbitol, fructose, acesulfame K, aspartame, sodium saccharin, stevia, xylitol, an ammonium salt of Glycyrrhizic Acid, and a combination thereof.

7. A sublingual liquid formulation comprising:(a) 0.1 % w / w to 20% w / w Tadalafil;(b) 5% w / w to 35% w / w of malic acid; and(c) 20% w / w to 90% w / w water.

8. The formulation according to claim 7 further comprising 0.05 % w / w to 2% w / w of a sweetener and 0.05% w / w to 0.2% w / w of a flavoring agent.

9. A sublingual liquid formulation comprising:(a) 0.5% w / w to 20% w / w Tadalafil;(b) 5% w / w to 35% w / w malic acid;(c) 0.1 % w / w to 2% w / w sweetener;(d) 0.1% w / w to 0.2% w / w of a flavoring agent(e) 25% w / w to 90% w / w water.

10. The sublingual formulation according to any of the preceding claims, wherein said formulation when stored at 40° C ± 2°C at 75% ± 5% relative humidity for six months neither discolour nor become contaminated with impurities.

11. A process for the preparation of a sublingual formulation comprising 0.1%w / w to 30%w / w Tadalafil, 1% w / w to 40% w / w of an acidulent selected from the group consisting of malic acid, maleic acid, adipic acid, fumaric acid, tartaric acid, citric acid, palmitic acid and a pharmaceutically acceptable salt thereof; and 5% w / w to 95% w / w water; whereinsaid process comprising adding water with the acidulent to form a solution followed by adding and mixing Tadalafil in it until a clear solution is formed for use as a sublingual formulation.

12. A method of treating sexual dysfunction in men comprising administering the formulation of any of the preceding claim numbers 1 to 10 to a patient in need thereof.

13. A method of treating pulmonary arterial hypertension in a human comprising administering the formulation of any of the preceding claim numbers 1, 7 or 9 to a patient in need thereof.