WO2025023900A1

WO2025023900A1 - The pharmaceutical combination comprising dapoxetine, phosphodiesterase type-5 inhibitor and panax ginseng

Info

Publication number: WO2025023900A1
Application number: PCT/TR2023/050734
Authority: WO
Inventors: Arzu PALANTOKEN; Vildan TOMBAYOGLU; Abdullah TASKIN; Suat Hakan OZTEKIN
Original assignee: Montero Gida Sanayi Ve Ticaret AS
Current assignee: Montero Gida Sanayi Ve Ticaret AS
Priority date: 2023-07-26
Filing date: 2023-07-26
Publication date: 2025-01-30
Anticipated expiration: 2026-01-26

Abstract

The present invention relates to a pharmaceutical combination comprising dapoxetine, a PDE5 inhibitor and furthermore panax ginseng.

Description

THE PHARMACEUTICAL COMBINATION COMPRISING DAPOXETINE, PHOSPHODIESTERASE TYPE-5 INHIBITOR AND PANAX GINSENG

Field of the Invention

Background of the Invention

Selective serotonin reuptake inhibitors (SSRI) are used in the long-term prophylaxis of many types of depression, including the endogenous type, recurrent depression, and in the treatment of obsessive-compulsive disorders, panic attack, social phobias, and the bulimia nervosa disease. Dapoxetine was first disclosed in the European patent publication EP0288188B1 is a selective serotonin reuptake inhibitor. Dapoxetine is used for the treatment of depression and premature ejaculation. The IUPAC name of dapoxetine is (S)-N, N-Dimethyl-3-(naphthalen-1- yloxy)-1-phenylpropan-1-amine and has a chemical structure shown with Formula I.

Formula I: Dapoxetine

Following oral administration, dapoxetine is rapidly absorbed and rapidly enters the circulation by almost completely binding to plasma proteins. Therefore, it achieves the peak plasma concentration (C_max) in 1 hour following oral administration. Orally-administered tablets of dapoxetine are commercially available under the name Priligy®, comprising 30 mg or 60 mg dapoxetine per tablet, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, hypromellose, titanium dioxide (E171), triacetin, black iron oxide (E172) and yellow iron oxide (E172).

On the other hand, phosphodiesterase type 5 inhibitors (PDE5 inhibitor) are used in the treatment of erectile dysfunction (ED). PDE5 inhibitors block the phosphodiesterase enzyme in a selective and efficient manner, thus increasing the level of cyclic guanosine monophosphate in the corpus cavernosum smooth muscle cells. Most frequently used PDE5 inhibitors are avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil.

Tadalafil is a PDE-5 inhibitor used in the treatment of ED and pulmonary arterial hypertension (PAH). It has a longer half life as compared to other PDE-5 inhibitors (mean, 17,5 hours). Orally-administered tablets of Tadalafil are commercially available under the name Cialis®, in the strength of 2.5 mg, 5 mg, 10 mg and 20 mg, as well as excipients including lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide (E171), triacetin, yellow iron oxide (E172), talc. The IIIPAC name of tadalafil is (6R-trans)-6-(1 ,3-benzodioxol- 5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1',2':1 ,6] pyrido[3,4-b] indole-1 , 4-dione, with the chemical structure illustrated below with Formula II. Tadalafil is a water-insoluble molecule. As a result, the problem of fluidity and content uniformity is seen.

Formula II: Tadalafil

Formulations comprising a combination of selective serotonin reuptake inhibitors with PDE5 inhibitors are known in the prior art. The patent publication W003000343, for example, discloses the use of a formulation comprising a combination of phosphodiesterase inhibitors and dapoxetine.

In the prior art, there are also several patents which disclose combination with dapoxetine and tadalafil mostly in oral pharmaceutical dosage forms. However, while this combination is increasing the patients’ quality of life, combining more than one molecule in one dosage form may also cause undesired side effects which is nausea, vomiting, emesis, syncope, muscle, back and headache, fatigue, diarrhea, dizziness and hypotension. Panax ginseng also known as Asian ginseng, Chinese ginseng, or Korean ginseng is a species of plant whose root is the original source of ginseng. It is a perennial plant that grows in the mountains of East Asia. It is among the most extended living plants. Studies show that Panax ginseng improves learning ability, has an antidepressant effect, improves neurological functions, reduces DNA, protein and lipid damage, balances blood pressure and increases blood circulation. It is also reported that it is effective on the protection and healing of the liver, has a positive effect on men with erectile dysfunction, can inhibit cell growth in various cancer cells, and reduces the viability of various cancer cells by preventing the vascularization of cancer.

Therefore, there is a need in the prior art for a new combination of dapoxetine and tadalafil that will provide the elimination of the mentioned side effects and problems of fluidity and content uniformity with panax ginseng extract. In this present invention, panax ginseng is used to overcome the disadvantages and side effects of the combinations of dapoxetine and tadalafil meanwhile increasing the therapeutic effect and patient compliance in the desired manner.

Detailed Description of the Invention

The main object of the present invention is to provide a combination comprising dapoxetine and a PDE5 inhibitor with panax ginseng.

According to the main embodiment of the present invention, the new combinations help to recover the side effects when dapoxetine and a PDE5 inhibitor is used together, whilst increasing the therapeutic effect.

Another object of the present invention is to provide a pharmaceutical formulation that allows to obtain safe and efficient plasma levels of each pharmacological agents.

Another object of the present invention is to provide high stability of the combination and a long shelf life by the help of a suitable selection of excipients.

The present invention relates to an easily-administrable combination of dapoxetine and PDE5 inhibitor and panax ginseng, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

The term "dapoxetine" as used throughout the specification refers to not only dapoxetine, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

The term "PDE5 inhibitor" as used throughout the specification refers to not only PDE5 inhibitor, but also its other pharmaceutically acceptable salt, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs or pharmaceutically acceptable prodrugs thereof.

The term "panax ginseng" as used throughout the specification refers to not only panax ginseng, but also its other pharmaceutically active ingredients such as ginsenosides and saponins, pharmaceutically acceptable major ginsenosides of which Rg1 , Rc, Rd, Re, Rb1 , Rb2, and RbO, pharmaceutically acceptable several other active constituents, including polysaccharides, phenolic compounds, and alkaloids, also refers to all powder, granule and liquid extracts and their saponins or ginsenoids obtained from different species and geographies, thereof.

The new combination of dapoxetine and tadalafil with panax ginseng extract is developed to eliminate the mentioned side effects: hypertension, hypotension, orthostatic hypotension nausea, vomiting, emesis, syncope, muscle, back and headache, fatigue, diarrhea, dizziness and problems of fluidity and content uniformity. In this present invention, panax ginseng is used to overcome the disadvantages and side effects of the combinations of dapoxetine and tadalafil meanwhile increasing the therapeutic effect and patient compliance in the desired manner. According to this invention, an easy-to-produce, high content uniformity, stable formulation and production process has been developed.

The term “combination” means that when drugs are administered together, a combined action is obtained which is higher than the individual actions of the respective drugs when they are used separately. On the other hand, using a lower dose of each drug to be combined according to the present invention will reduce the total dosage. These are advantageous in terms of patients to be treated.

The term “immediate release phase” refers to any pharmaceutical formulations that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the therapeutic effects. According to an embodiment of the present invention, the pharmaceutical combination comprises dapoxetine and a PDE5 inhibitor, furthermore panax ginseng.

According to this embodiment, panax ginseng reduces the side effect of dapoxetine and tadalafil. Therefore, an improved sexual dysfunction problem has been achieved with the synergistic effect.

According to an embodiment of the present invention, the ratio of dapoxetine to PDE5 inhibitor is in the range of between 60: 1 to 1 :20 by weight or between 24: 1 to 1 : 1 .

According to an embodiment of the present invention, the ratio of dapoxetine to panax ginseng is in the range of between 60: 1 to 1 :60 by weight or between 25: 1 to 1 :25.

According to an embodiment of the present invention, the ratio of PDE5 inhibitor to panax ginseng is in the range of between 300: 1 to 1 :300 by weight or between 75: 1 to 1 :75.

It has been found surprisingly that the combination with these ratios have a synergistic effect over active agents’ activity and providing the composition with long-term stability.

According to an embodiment of the present invention, a PDE5 inhibitor is selected from the group comprising tadalafil, sildenafil, avanafil, lodenafil, mirodenafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil.

According to an embodiment of the present invention, the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.

According to one embodiment, the dose of tadalafil or a pharmaceutically acceptable salt thereof is selected from 2.5 mg, 5 mg, 10 mg or 20 mg.

According to one embodiment, the dose of panax ginseng is selected from 10 to 750 mg and more preferably 100 mg or 300 mg.

According to one embodiment, the dose of dapoxetine or a pharmaceutically acceptable salt thereof is selected from 30 mg, or 60 mg.

According to an embodiment of the present invention, the combination comprises at least one pharmaceutically acceptable excipient is selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants, glidants, surfactants, taste masking, sweeteners, flavoring agents, coating agents, coloring agents or mixtures thereof.

Suitable fillers are selected from the group comprising microcrystalline cellulose, lactose, mannitol, spray-dried mannitol, lactose monohydrate, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, starch, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), sugars, glucose syrup, natural gums, collagen, proteins such as gelatin, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, chitosan, copovidone, starch, corn starch and pregelatinized starch, starch mucilage, acacia mucilage, dextrates, dextrin, dextrose, ethylcellulose, glyceryl behenate, guar gum, hydrogenated vegetable oil type I, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hypromellose, liquid glucose, magnesium aluminum silicate, maltodextrin, maltose, methylcellulose, pectin, poloxamer, polycarbophil, polydextrose, polyethylene oxide, polymethacrylates, aluminia hydroxide, stearic acid, sucrose, bentonite, laponit, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.

Suitable disintegrants are selected from the group comprising cross-linked polyvinil pyrrolidone (crospovidone), povidone, cross-linked carboxymethyl cellulose (croscarmellose sodium), low- substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, magnesium aluminium silica, sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.

According to one embodiment, the total amount of disintegrants in the composition is 1.0% to 40.0% by weight, preferably 1.0% to 10.0% by weight and thus desired level of dissolution rate is provided.

Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.

Suitable lubricants are selected from the group comprising magnesium stearate, colloidal silicon dioxide, calcium stearate, zinc stearate, talc, waxes, boric acid, hydrogenated vegetable oil, sodium chlorate, magnesium lauryl sulfate, sodium oleate, sodium acetate, sodium benzoate, polyethylene glycol, stearic acid, fatty acid, fumaric acid, glyseryl palmito sulphate, sodium stearyl fumarate or mixtures thereof.

Suitable glidants are selected from the group comprising talc, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.

Suitable surfactants are selected from the group comprising sodium lauryl sulfate, cetylpyridinium chloride, docusate sodium, lauric acid, polyoxyethylene sorbitan fatty acid esters (polysorbate), phospholipids, cetrimide, polyoxyethylene stearates, polyethylene glycol, polyoxyethylene hydrogenated castor oil, ascorbyl palmitate, glyceryl monooleate or mixtures thereof.

According to one embodiment, the total amount of surfactants in the composition is 0.1% to 5.0% by weight, preferably 0.5% to 2.5% by weight.

The most frequently encountered problem in oral dapoxetine formulations is the bitter taste. The tablets can be coated with coating agents, and mixtures of sweeteners or flavours have been used for masking the bitter taste.

Suitable sweeteners are selected from the group comprising aspartame, thaumatin, mogroside, erythritol, inulin, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, saccharin, sugars such as sucrose, glucose, lactose, fructose or sugar alcohols such as mannitol, sorbitol, xylitol, erythritol or mixtures thereof.

Suitable flavoring agents are selected from the group comprising menthol, peppermint, cinnamon, chocolate, vanillin or fruit essences such as cherry, orange, strawberry, grape, black currant, raspberry, banana, red fruits, wild berries or mixtures thereof.

Suitable taste masking is eudragit E-100. Eudragit E-100 is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1 :1. Ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl alcohol, and polyvinyl acetate and derivatives of these polymers.

Suitable coating agent are selected from the group comprising hydroxypropyl methylcellulose, lactose monohydrate, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all kinds of Opadry®, pigments, dyes, titanium dioxide, iron oxide or mixtures thereof.

According to an embodiment of the present invention, the pharmaceutical combination is administered orally.

According to an embodiment of the present invention, the pharmaceutical combination is in the form of tablet, capsule, strip, syrup, powder, pastilles, sachet, effervescent formulations, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solutions, solids, elixirs, tinctures, suspensions, colloidal dispersions, dispersions, emulsions.

According to an embodiment of the present invention, the pharmaceutical combination is in the form of tablet, capsule, powder, pastilles, sachet, effervescent formulations, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solids.

In this present invention, the pharmaceutical combination is formulated as tablet. Tablet may comprise of different type of particles, for example; mini-tablets, pellets, granules, powders or mixtures thereof.

According to an embodiment of the present invention, each type of particle comprises at least one active agent.

According to another embodiment of the present invention, the pharmaceutical combination according to any preceding claims, wherein the pharmaceutical combination is formulated as tablets comprising compressed tablets, film-coated tablets, orally disintegrating tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles. One embodiment of this present invention is directed to tablet coating, it is applied, for example by spray-coating with a water-based film coating formulation.

According to an embodiment of the present invention, the pharmaceutical combination is formulated as capsule. Capsule may comprise of different type of particles, for example minicapsules, powders, granules, mini-tablets, pellets, beads or mixtures thereof and these particles are filled into capsules. Each type of particle comprises at least one active agent.

An embodiment of this present invention, selected particles is filled into capsules. Capsules may comprise of separated compartments and each active ingredient and these particles is filled into each compartment.

An embodiment of this present invention is to combine dapoxetine, tadalafil and panax ginseng in stable dosage form with desired dissolution profiles and content uniformity.

According to an embodiment of the present invention, the formulation has an immediate release phase.

The pharmaceutical formulation of the present invention can be prepared, using standard techniques and manufacturing processes well known in the art, such as direct compression, wet or dry granulation, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion/spheronization, slugging, spray drying and solvent evaporation.

Example 1 : The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)

Example 2: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)

Process of wet granulation for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) blending a half of mannitol and half of crospovidone, tadalafil and dry powder form of panax ginseng extract to prepare a mixture b) polyvinylpyrrolidone and sodium lauryl sulfate dissolving in water c) granulating step (a) mixture with this step (b) solution d) drying the granules and sieving e) adding the other half of mannitol and microcrystalline cellulose, half of crospovidone, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and colloidal silicon dioxide then blending until homogeneous mixture. f) adding magnesium stearate then mixing g) filling into the capsule or compressing the total mixture into tablets h) then coating the tablets with coating agents

Example 3: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in liquid form)

Example 4: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in liquid form)

Process of wet granulation for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) blending 2/3 of microcrystalline cellulose, 2/3 of polyvinylpyrrolidone and half of croscarmellose sodium, tadalafil and liquid form of panax ginseng extract to prepare a mixture b) dissolving sodyum lauril sulphate in water or organic solvent such as ethanol, isopropyl alcohol, acetone, methylene chloride or mixture of waterorganic solvent(s) with various ration from 0 to 100 percent c) granulating step (a) with this mixture of step (b) d) drying the granules and sieving e) adding 1/3 of microcrystalline cellulose, 1/3 of polyvinylpyrrolidone, half of croscarmellose sodium, dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof and colloidal silicon dioxide then mixing until homogeneous f) adding magnesium stearate then mixing g) filling into the capsule or compressing the total mixture into tablets h) then coating the tablets with coating agents

Example 5: The combination comprising dapoxetine, a PDE5 inhibitor and panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)

Example 6: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)

Process for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) blending 1/3 of powder form of panax ginseng extract and tadalafil to prepare a mixture b) adding 2/3 of panax ginseng extract and dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof then mixing c) adding microcrystalline cellulose, polyvinylpyrrolidone and colloidal silicon dioxide, sodium lauryl sulfate then blending with cubic mixer until homogeneous d) adding magnesium stearate then mixing e) compressing the total mixture into tablets f) then coating the tablets with coating agents

Example 7: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at orally disintegrating tablet formulation

Example 8: The combination comprising dapoxetine, a PDE5 inhibitor and an panax ginseng at orally disintegrating tablet formulation

Process for preparing the pharmaceutical combination for orally disintegrating tablet comprises the following steps: a) blending half of mannitol, half of crospovidone, tadalafil and panax ginseng to prepare a mixture b) polyvinylpyrrolidone, sucrose, coloring agent and sodium lauryl sulfate dissolving in water c) drying the granules and sieving d) coating dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof in fluidized bed with polymethacrylates (Eudragit) dissolved in water e) drying the granules and sieving f) mixing all dried granules g) adding the other half of mannitol, half of crospovidone, sucralose, flavouring agent then blending h) adding sodium stearyl fumarate and then mixing i) compressing the total mixture into tablets

Claims

1 . A pharmaceutical combination comprising dapoxetine and a PDE5 inhibitor, furthermore panax ginseng.

2. The pharmaceutical combination according to claim 1 , wherein the ratio of dapoxetine to PDE5 inhibitor is in the range of between 60:1 to 1 :20 by weight or between 24:1 to 1 :1.

3. The pharmaceutical combination according to claim 1 , wherein the ratio of dapoxetine to panax ginseng is in the range of between 60:1 to 1 :60 by weight or between 25:1 to 1 :25.

4. The pharmaceutical combination according to claim 1 , wherein the ratio of PDE5 inhibitor to panax ginseng is in the range of between 300:1 to 1 :300 by weight or between 75:1 to 1 :75.

5. The pharmaceutical combination according to claim 1 , wherein the PDE5 inhibitor is selected from the group comprising avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, udenafil, zaprinast, benzamidenafil or dasantafil or mixtures thereof.

6. The pharmaceutical combination according to claim 5, wherein the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.

7. The pharmaceutical combination according to any preceding claims, further comprising at least one pharmaceutically acceptable excipient which is selected from fillers, binders, disintegrants, diluents, dispersing agents, lubricants, glidants, surfactants, taste masking, sweeteners, flavoring agents, coating agents, coloring agents or mixtures thereof.

8. The pharmaceutical combination according to any preceding claims, wherein the pharmaceutical formulation is administrated orally.

9. The pharmaceutical combination according to any preceding claims, wherein the combination is in the form of tablet, capsule, powder, pastilles, sachet, effervescent formulations, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solids.

10. The pharmaceutical combination according to any preceding claims, wherein pharmaceutical combination according to any preceding claims, wherein the pharmaceutical combination is formulated as tablets comprising compressed tablets, film-coated tablets, orally disintegrating tablets, coated or uncoated tablets, multilayer tablets, mini tablets, bilayer tablet, buccal tablets, sublingual tablets, effervescent tablets, immediate release tablets, tablets, gastric disintegrating tablets, chewable tablet, dispersing tablet, lozenges or pastilles.

11. The pharmaceutical combination according to any preceding claims, wherein the combination is formulated as capsule.

12. The pharmaceutical combination according to any preceding claims, wherein the capsule comprising mini-capsule, powder, granule, mini-tablet, pellet, beads or mixtures thereof and these particles are located into capsules.

13. The pharmaceutical combination according to claim 10, wherein the film-coated tablets comprising; a) 1.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 0.6% to 10.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof c) 10.0% to 75.0% by weight of panax ginseng extract in dry powder form d) 1.0% to 60.0% by weight of mannitol e) 5.0% to 50.0% by weight of microcrystalline cellulose f) 1.0% to 10.0% by weight of polyvinylpyrrolidone g) 1.0% to 40.0% by weight of crospovidone h) 0.1% to 5.0% by weight of magnesium stearate i) 0.1% to 5.0% by weight of colloidal silicon dioxide j) 0.1% to 5.0% by weight of sodium lauryl sulfate k) 1 ,0%-5.0% by weight of coating agents of the total composition.

14. The pharmaceutical combination according to claim 10, wherein the film-coated tablets comprising; a) 1.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 0.6% to 10.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof c) 10.0% to 75.0% by weight of panax ginseng extract in liquid form d) 8.0% to 60.0% by weight of microcrystalline cellulose e) 2.0% to 10.0% by weight of polyvinylpyrrolidone f) 2.0% to 10.0% by weight of croscarmellose sodium g) 0.1 % to 5.0% by weight of magnesium stearate h) 0.1 % to 5.0% by weight of colloidal silicon dioxide i) 0.1% to 5.0% by weight of sodium lauryl sulfate j) 1 .0 %-5.0% by weight of coating agents of the total composition.

15. The pharmaceutical combination according to claim 10, wherein the orally disintegrating tablets comprising; a) 1.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 0.6% to 10.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof c) 10.0% to 75.0% by weight of panax ginseng extract in dry powder form d) 1 .0% to 50.0% by weight of mannitol e) 0.1 % to 5.0% by weight of polyvinylpyrrolidone f) 1 .0% to 40.0% by weight of crospovidone g) 1 .0% to 20.0% by weight of sucrose h) 0.01% to 5.0% by weight of sucralose i) 2.0% to 20.0% by weight of eudragit E100 j) 0.1 % to 5.0% by weight of flavoring agent k) 0.2% to 5.0% by weight of sodium lauryl sulfate l) 0.1 % to 10.0% by weight of sodium stearyl fumarate m) 0.001 % to 5.0% by weight of coloring agents of the total composition.

16. The pharmaceutical combination according to claim 11 , wherein the capsule or tablet comprising; a) 1.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 0.6% to 10.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof c) 10.0% to 75.0% by weight of panax ginseng extract in dry powder form d) 1.0% to 60.0% by weight of mannitol e) 5.0% to 50.0% by weight of microcrystalline cellulose f) 1.0% to 10.0% by weight of polyvinylpyrrolidone g) 1.0% to 40.0% by weight of crospovidone h) 0.1 % to 5.0% by weight of magnesium stearate i) 0.1 % to 5.0% by weight of colloidal silicon dioxide j) 0.1% to 5.0% by weight of sodium lauryl sulfate k) 1 ,0%-5.0% by weight of coating agents of the total composition.

17. The pharmaceutical combination according to claim 11, wherein the capsule or tablet comprising; a) 1.0% to 35.0% by weight of dapoxetine or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 0.6% to 10.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof c) 10.0% to 75.0% by weight of panax ginseng extract in liquid form d) 8.0% to 60.0% by weight of microcrystalline cellulose e) 2.0% to 10.0% by weight of polyvinylpyrrolidone f) 2.0% to 10.0% by weight of croscarmellose sodium g) 0.1 % to 5.0% by weight of magnesium stearate h) 0.1 % to 5.0% by weight of colloidal silicon dioxide i) 0.1% to 5.0% by weight of sodium lauryl sulfate j) 1 ,0%-5.0% by weight of coating agents of the total composition.

18. The pharmaceutical combination according to any preceding claims, wherein the formulation has an immediate release.