Patent Application
20150202168
The present invention relates to a formulation comprising a combination of dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for preparing this formulation and to the use thereof in the treatment of the premature ejaculation related to the erectile dysfunction.
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, which was first disclosed in the European patent publication EP 0288188 B1 is a selective serotonin reuptake inhibitor. Dapoxetine is used for the treatment of the depression and the premature ejaculation and has the chemical structure shown in Formula I. Additionally, dapoxetine was approved in Switzerland and in Finland for use in the treatment of the premature ejaculation.
Following oral administration, dapoxetine is rapidly absorbed and rapidly enters the blood circulation by almost completely binding to the plasma proteins. Therefore, it achieves the peak plasma concentration (Cmax) 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 hydrochloride 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.
The most frequently encountered problem in the oral dapoxetine formulations is the bitter taste thereof. The tablets have typically been coated with the coating agents, and the mixtures of sweeteners or cation exchange resins have been used for masking the bitter taste.
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 (cGMP) in the corpus cavernosum smooth muscle cells. Most frequently used PDE5 inhibitors are avanafil, lodenafil, mirodenafil, sildenafil, tadalafil, vardenafil, and udenafil. Tadalafil is a PDE5 inhibitor used in the treatment of ED and pulmonary arterial hypertension (PAH). It has a longer half life as compared to other PDE5 inhibitors (mean, 17.5 hours). The chemical designation 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 in Formula II.
The formulations comprising the combination of selective serotonin reuptake inhibitors with PDE5 inhibitors are known in the prior art. The patent publication WO03000343, for example, discloses the use of the formulation comprising phosphodiesterase inhibitors and dapoxetine. On the other hand, M J. Dresser et al. stated that dapoxetine, a selective serotonin reuptake inhibitor, does not have pharmaceutical interactions with PDE5 inhibitors and may be used for the treatment of the premature ejaculation (Int J Impot Res. 2006 January-February; 18(1):104-10).
Various formulations and methods for preparing oral film formulations are already known. However, concerning oral administration, oral film formulations have become an issue with increasing importance in terms of patient compliance as compared to conventional solid dosage forms such as capsules and tablets. This issue is more important in terms of patients having difficulty in swallowing. Additionally, concerning many drugs, the swallowing of the same usually necessitates fluids to increase the gastric volume and increases the likelihood of nausea and vomiting. Probably the greatest advantage of an oral film dosage form is that the solid dosage forms rapidly dissolve or disintegrate in the oral cavity so that a solution or suspension forms therein without having to take any liquid. Additionally, the oral films having a low layer thickness and therefore a large surface area rapidly disintegrate in the mouth mucosa. Thus, it will suffice to administer the dosage form briefly before the patient will need it. In addition to these, the oral film dosage forms are more easily used and carried. They are preferred by patients since they do not require carrying any blister packs. Additionally, since tadalafil which is poorly soluble in water is similarly poorly dissolved in gastric juice, its absorption in the stomach is low. For these reasons, the oral film dosage forms are one of the advantageous ways for administering drugs such as dapoxetine and tadalafil and provide a better patient compliance along with the recommended pharmaceutical therapies.
Apart from that, the oral film dosage forms are one of the advantageous ways for administering these drugs to such patients. The oral film formulations provide for a more rapid absorption of the drug in the buccal mucosa, and this may reduce the first pass effect and thus the efficiency of the drug is enhanced. Since this dosage form stays away from the hepatic first-pass metabolism, it increases the clinic effects of some drugs by increasing the bioavailability and decreasing the side-effects thereof. Additionally, since the oral disintegration time thereof is lower as compared to the orally-disintegrating tablet formulations, they are more rapidly absorbed by the mucosa.
Developing an oral film composition is known to be difficult for several different reasons. First, the oral film formulations comprising an acid source may be problematic based on their unpleasant taste. Moreover, these compositions should be flexible and not too rigid. These compositions are quite susceptible to the moisture and the films are prone to adhere to each other. As a result of this, they may show some stability problems.
In order to fulfill all these requirements described above, a special drug formulation is needed and therefore the excipients should be selected carefully. The selected excipients, however, may give formulations with improper bioavailability as compared to equivalent conventional dosage forms. For this reason, the excipients should be selected very carefully. For instance, in the patent application WO2007/002125 is used an orally-disintegrating carrier for providing a rapid oral disintegration of the formulation comprising a PDE5 inhibitor and a SSRI. However, no oral film formulation was disclosed previously which comprises the combination of dapoxetine and tadalafil.
Therefore, the oral film composition of dapoxetine and tadalafil and a process for preparing this composition are required. Other advantages and embodiments of the present invention will be clarified in the following description.
The main object of the present invention is to provide an improved oral film composition of the combination of dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof by making use of convenient excipients, which overcomes the problems mentioned above and is useful in the treatment of the premature ejaculation and the related symptoms thereof.
Another object of the present invention is to provide a process for preparing an improved oral film composition of a combination of dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof.
In one embodiment, the amount of dapoxetine or a pharmaceutically acceptable salt thereof is 5.0 to 30% by weight and of the amount of tadalafil or a pharmaceutically acceptable salt thereof is 5.0 to 30% by weight in the oral film composition.
A further object of the present invention is to provide stable oral film dosage forms, which do not stick to each other, and have a taste which is not unpleasant, comprising a combination of dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof. According to this object, unexpected advantages are found with an oral film composition according to the invention, as compared to currently-available conventional solid dosage forms.
In the orally-disintegrating oral film compositions according to the present invention, suitable amounts of suitable excipients have to be used which do not adhere to each other during storage and therefore are stable throughout the shelf life, and prevent the bitter taste. The selection of the sweetener or the mixture of sweeteners from the group comprising thaumatin, mogroside, sucralose, erythritol, inulin, fructose and the mixtures thereof has surprisingly provided the oral film dosage forms which does not stick to each other and have a taste which is not unpleasant.
According to an embodiment, it was observed that a proper adjustment of the amount of the sweetener made the oral film composition stable throughout the shelf life and prevented the adherence of oral film dosage forms to each other. Accordingly, setting the amount of the sweetener or of the sweetener mixture from 0.01 to 20.0%, preferably from 0.1 to 15.0% and more preferably from 1.0 to 10.0% of the total weight of the composition has avoided the occurrence the aforesaid problems.
It was surprisingly observed that the use of a stability-enhancing agent beside the sweetener in the oral film formulation, comprising dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof, increased the stability of the oral film formulation and thus contributed to obtaining the oral film composition which is stable throughout the shelf life, as well as positively influenced the mechanical resistance of the formulation.
According to an embodiment, the amount of the stability-enhancing agent is from 0.001 to 20.0%, preferably from 0.05 to 15.0%, and more preferably from 0.1 to 10.0% of the total weight of the oral film composition, wherein these amounts provide for a significant increase in the stability of the oral film composition. Amounts below those indicated negatively influence the integrity of the oral film composition and make it prone to disintegration.
According to this embodiment of the present invention, keeping the ratio of the total weight of the sweeteners to the weight of the stability-enhancing agent in the oral film composition between 100:1 to 1:50, preferably between 50:1 to 1:10, and more preferably between 10:1 to 1:1 positively influences the stability of the oral film composition.
According to another embodiment, preferably mogroside is used as the sweetener. Mogroside is a natural sweetener and is used in many fields. Mogroside, which is 300-400 times sweeter than sucrose is used in diabetic foodstuffs. Studies conducted have shown that mogroside, which is composed of proteins bound by disulfide bonds, is not toxic to human body. Mogroside masks the bitter taste by providing a sweet taste without increasing the blood sugar and provides an aroma enhancing effect. In addition to these, since the melting point of the mogroside sweetener is below 190° C., the oral film dosage formulations comprising mogroside do not stick to each other as compared to the oral film dosage formulations comprising sucrose. Thus, the oral film dosage forms can be obtained which are stable throughout the shelf life. Additionally, since mogroside does not increase the blood sugar, it does not cause weight gain and may be used by diabetic patients. Thus, the patient compliance can be increased.
According to a further embodiment, preferably glutathione or tocopherol is used as the stability-enhancing agent.
According to another object of the present invention, the thickness of the oral films obtained influences the flexibility and the friability of the oral films. Accordingly, the thickness of the oral film is between 0.001 and 3 mm, preferably between 0.003 and 1.1 mm, and more preferably between 0.004 and 1 mm.
In addition to these active agents, the sweetener, and the stability-enhancing agent, the oral film composition according to the present invention further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising of plasticizers, fillers, acid sources, polymers, pH regulating agents, aromatic agents, and colorants.
It was unexpectedly found that the use of a plasticizer in addition to the sweetener or the mixture of sweeteners and stability-enhancing agents in the oral film formulations containing dapoxetine or a pharmaceutically acceptable salt thereof and tadalafil or a pharmaceutically acceptable salt thereof has a synergistic effect on the oral film dosage forms in that they can be stored in a storage container without sticking to each other. Suitable plasticizers are polyethylene glycol or dibutylphtalate. According to this object, the oral film composition according to the present invention comprises the plasticizer in an amount from 0.1 to 30.0% and preferably from 1 to 20.0% based on the total weight of the composition.
Suitable fillers include, but are not limited to sugars, mannitol, sorbitol, sucrose, inorganic salts, calcium salts, polysaccharides, dextrose, dicalsium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixtures, xylitol, trehalose, heavy magnesium carbonate, and the mixtures thereof. The oral film formulation according to the present invention comprises a filler in an amount from 5.0 to 50.0% and preferably from 10.0 to 40.0% based on the total weight of the composition.
Suitable acid sources include, but are not limited to citric acid, tartaric acid, ascorbic acid, fumaric acid, malic acid; amino acid hydrochlorides, sodium dihydrogen citrate, disodium hydrogen citrate, sodium acid phosphate and similar acid salts; nicotinic acid, acetylsalicylic acid, adipic acid, and the mixtures thereof. The oral film formulation according to the present invention comprises an acid source in an amount from 0.1 to 10.0% and preferably from 1 to 5.0% based on the total weight of the composition.
Suitable polymers include, but are not limited to poloxamer, polyacrylamide, polyvinyl alcohol and similar synthetic polymers, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, methyl cellulose and similar semi-synthetic polymers; polymethacrylates, polyvinyl acetate, cellulose acetate phthalate, ethylene vinyl acetate, methyl aminoethyl methacrylate, neutral methacrylic acid esters, polyactide, polyactide covinyl glycolide, low molecular weight polyethylene/polyisobutylene, polyanhydrates, diethyl aminoethyl methacrylate, and the mixtures thereof. The oral film formulation according to the present invention comprises a polymer or a mixture of polymers in an amount from 0.1 to 60.0% and preferably from 1 to 50.0% based on the total weight of the composition.
Suitable pH regulating agents include, but are not limited to aluminum potassium sulfate, anhydrous citric acid, anhydrous disodium, hydrogen phosphate, anhydrous sodium dihydrogen phosphate, citric acid, dibasic potassium sulfate, dry sodium carbonate, diluted hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate, and the mixtures thereof. The oral film formulation according to the present invention comprises a pH regulating agent in an amount from 0.1 to 10.0% based on the total weight of the composition
Suitable aromatic agents include, but are not limited to fruit aromas like those of orange, banana, strawberry, cherry, wild cherry, lemon, etc., and cardamom, anis, mint, menthol, vanillin, and ethyl vanillin, and other aromas, and the mixtures thereof. The oral film formulation according to the present invention comprises an aromatic agent in an amount from 0.1 to 6.0% based on the total weight of the composition.
Suitable colorants include, but are not limited to, food, drug, and cosmetic (FD&C) dyes (e.g. FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lake), ponceau, indigo drug & cosmetic (D&C) blue, indigotine FD&C blue, carmoisine indigotine (indigo carmine); iron oxides (e.g. iron oxide red, yellow, black), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow, etc., and the mixtures thereof.
In another aspect, the present invention shows the possibility of providing significant influences on the disintegration time of the oral film dosage form by modifying the size and the shape thereof. In general terms, the disintegration process of an oral film dosage form occurs after the entire surface of an oral film dosage form gets wet by means of capillary effect. Additionally, all shapes maximizing the contact surface with saliva may provide a significant reduction in the disintegration time.
A preferred shape of the oral film composition according to the present invention is a disk, circle, ellipse, triangle, square, polygon, sphere, bar, etc.
A formulation according to the present invention may be produced by means of solvent casting method, semi-solid casting method, solid dispersion extrusion method, rolling method, hot melt extrusion method.
In the solvent casting method, polymer(s) in a formulation are dissolved in a suitable solvent to give a solution. The active agents and other excipients in the formulation are dissolved in a suitable solvent to give another solution. Then both solutions are mixed and entrapped air is removed under vacuum. The resulting solution is cast to form oral film. Then the film is dried and cut into a desired size.
In the semi-solid casting method, separate solutions of the water-soluble polymer and the acidic polymers, e.g. cellulose acetate phthalate, are prepared in suitable solvents. Both these solutions are mixed and then the other excipients and the active agents are added to this mixture. The resulting mixture is coated onto unprocessed cast oral film. Then the film is dried, and cut into a desired size.
In the solid dispersion extrusion method, a solid dispersion of the active agent is prepared together with other materials in the formulation and then processed in a hot melt extrusion device. The resulting product is turned into the oral films. Then the film is cooled and cut into a desired size.
In the rolling method, the solutions of the active agents and other excipients are prepared in the suitable solvents. Then these solutions are rolled onto a substrate to give oral film. Then the film is dried by means of a roller and brought into a desired shape and size.
In the hot melt extrusion method, the active agents and the polymer are mixed together. Other excipients are added to the mixture and the resulting mixture is stirred. Then, it is taken to a hot melt extrusion device and is subjected to the heat treatment. The resulting product is turned into oral film. Then the film is dried and cut into a desired size.
The most preferred processes among those described above are the solvent casting method and the hot melt extrusion method.
The present invention is described in the following examples in more details. These examples are not limiting the scope of the present invention and should be considered under the light of the foregoing detailed disclosure.
Pullulan used as the polymer is dissolved in a suitable solvent to give a solution. Dapoxetine, tadalafil, starch, dibutyl phthalate, mogroside, glutathione, aroma and citric acid are dissolved in a suitable solvent and the solution is obtained. Then both solutions are mixed and entrapped air is removed under vacuum. The resulting solution is cast to form a film. Then the film is dried and cut into a desired size.
Dapoxetine, tadalafil and pullulan are mixed together. Into this mixture starch, polyethylene glycol, mogroside, tocopherol, aroma and citric acid are added and the resulting mixture is mixed. Then, it is taken to the hot melt extrusion device and is subjected to the heat treatment. The resulting product is turned into a film. Then the film is dried and cut into a desired size.
Polyvinylpyrrolidone is dissolved in a suitable solvent to give a solution. Tadalafil, dapoxetine, polyethylene glycol, mogroside, aroma, citric acid and preferably tocopherol are dissolved in a suitable solvent and the solution is obtained. Then both solutions are mixed and entrapped air is removed under vacuum. The resulting solution is cast to form a film. Then the film is dried and cut into a desired size.
Separate solutions of pullulan and cellulose acetate phthalate (acidic polymer) are prepared in the suitable solvents. Both these solutions are mixed together. Then, into this mixture dibutyl phthalate, mogroside, aroma, citric acid, dapoxetine, tadalafil and preferably glutathione are added. The resulting mixture is coated onto unprocessed cast oral film. Then the film is dried, and cut into a desired size.
A solid dispersion of tadalafil and dapoxetine is prepared together with polyvinyl alcohol, poloxamer, dibutyl phthalate, mogroside, aroma, iron oxide, malic acid and preferably glutathione, and then this dispersion is processed in a hot melt extrusion device, the resulting product is turned into a film. Then the film is cooled and cut into a desired size.
Solutions of tadalafil, dapoxetine, starch, pullulan, polyethylene glycol, mogroside, the aroma, citric acid and preferably glutathione are prepared in suitable solvents. Then these solutions are rolled onto a substrate and a film is obtained. The film is dried by means of a roller and brought into a desired shape and size.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2012/09599 | Aug 2012 | TR | national |
| 2012/12850 | Nov 2012 | TR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/TR2013/000271 | 8/14/2013 | WO | 00 |
