The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor and l-arginine

Abstract

The present invention relates to a pharmaceutical combination comprising a PDE5 inhibitor and l-arginine.

Description

[0001] THE PHARMACEUTICAL COMBINATION COMPRISING PHOSPHODIESTERASE TYPE- 5 INHIBITOR AND L-ARGININE

[0002] Field of the Invention

[0003] The present invention relates to a pharmaceutical combination comprising a PDE5 inhibitor and l-arginine.

[0004] Background of the Invention

[0005] 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.

[0006] 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 IUPAC 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 I. Tadalafil is a water-insoluble molecule. As a result, the problem of fluidity and content uniformity is seen.

[0007] Formula I: Tadalafil L-argi nine is an amino acid that serves as a building block for making proteins in the body. It’s been shown to lower blood pressure by boosting levels of nitric oxide, a substance that relaxes blood vessels (a process called vasodilation). Nitric oxide acts to widen blood vessels in the bloodstream, which may help certain circulatory conditions. Because of nitric oxide’s impact on blood flow, it plays a critical role in achieving and maintaining an erection.

[0008] The studies have determined that nitric oxide (NO) is an important mediator of penile erection. Relaxation of cavernous smooth muscle is a parasympathetic and non-adrenergic, non- cholinergic mediated process that requires nitric oxide (NO). NO is synthesized from L-arginine by NO synthase (NOS). Some studies have shown that in the treatment of erectile dysfunction, oral L-arginine is an effective treatment for ED, especially for patients affected by mild to moderate ED.

[0009] The studies show that combining L-arginine and prescription erectile dysfunction medication may help the drugs be more effective in the body. One study found that men given tadalafil and L-arginine had better outcomes and were more satisfied with the results than those given either treatment on its own.

[0010] The use of high doses of tadalafil in the formulation causes side effects such as headache, back pain, muscle aches, pain in arms and legs, facial flushing, nasal congestion, and indigestion seen common. Also, dizziness, stomach ache, feeling sick, being sick (vomiting), reflux, blurred vision, eye pain, difficulty in breathing, presence of blood in urine, prolonged erection, pounding heartbeat sensation, a fast heart rate, high blood pressure, low blood pressure, nose bleeds, ringing in the ears, swelling of the hands, feet or ankles and feeling tired could be seen. Therefore, while increasing the quality of life of patients by reducing the dose of tadalafil, there is a need for a new combination of tadalafil and l-arginine that can be easily produced, have a high content uniformity and fluidity, a stable formulation and a production process that has been developed. In this present invention, the combination of tadalafil and l-arginine is used to overcome the disadvantages and side effects meanwhile increasing the therapeutic effect and patient compliance in the desired manner.

[0011] Detailed Description of the Invention

[0012] The main object of the present invention is to provide a combination comprising a PDE5 inhibitor and l-arginine. According to the main embodiment of the present invention, the new combinations reduce the side effects when a PDE5 inhibitor and l-arginine is used together, whilst increasing the therapeutic effect.

[0013] 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.

[0014] Another object of the present invention is to provide high stability of the combination and a long shelf life by the help of selection of active agents in a certain ratio.

[0015] The present invention relates to an easily-administrable combination of PDE5 inhibitor and I- arginine, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

[0016] 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.

[0017] The term "l-arginine" as used throughout the specification refers to not only l-arginine, 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.

[0018] The new combination of tadalafil and l-arginine is developed to eliminate the mentioned side effects: headache, back pain, muscle aches, pain in arms and legs, facial flushing, nasal congestion, indigestion, dizziness, stomach ache, feeling sick, being sick (vomiting), reflux, blurred vision, eye pain, difficulty in breathing, presence of blood in urine, prolonged erection, pounding heartbeat sensation, a fast heart rate, high blood pressure, low blood pressure, nose bleeds, ringing in the ears, swelling of the hands, feet or ankles, feeling tired and problems of fluidity and content uniformity. In this present invention, l-arginine is used to overcome the disadvantages and side effects of 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.

[0019] 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.

[0020] According to an embodiment of the present invention, the pharmaceutical combination comprises PDE5 inhibitor and l-arginine.

[0021] According to this embodiment, l-arginine reduces the side effect of tadalafil. Therefore, an improved sexual dysfunction problem has been achieved with the synergistic effect.

[0022] According to an embodiment of the present invention, the ratio of PDE5 inhibitor to l-arginine is in the range of between 20:1 to 1 :500 by weight or between 20:1 to 1 :20.

[0023] 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.

[0024] 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.

[0025] According to an embodiment of the present invention, the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.

[0026] According to one embodiment, the amount of tadalafil or a pharmaceutically acceptable salt thereof is 0.1% to 15% by weight and more preferably 0.2% to 3% in the composition.

[0027] 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.

[0028] According to one embodiment, the amount of l-arginine is 30% to 80% by weight in the composition. According to one embodiment, the dose of l-arginine is selected from 500 mg, 1000 mg or 1250 mg.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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 dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.

[0033] According to one embodiment, the total amount of disintegrants in the composition is 0.1% to 25.0% by weight, preferably 0.5-15% to 2.0-8.0% by weight and thus desired level of disintegration time and 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.

[0034] 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, sodium lauryl sulphate or mixtures thereof.

[0035] Suitable glidants are selected from the group comprising talc, aluminium silicate, colloidal silica, calcium silicate, magnesium silicate, magnesium oxide, starch or mixtures thereof.

[0036] 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.

[0037] The tablets can be coated with coating agents, and mixtures of sweeteners or flavours have been used for masking the bitter taste.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] According to an embodiment of the present invention, the pharmaceutical combination is administered orally.

[0043] 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.

[0044] According to an embodiment of the present invention, 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.

[0045] 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.

[0046] According to an embodiment of the present invention, each type of particle comprises at least one active agent.

[0047] According to another embodiment of the present invention, the pharmaceutical combination is in the form of film-coated tablets, tablets.

[0048] 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.

[0049] 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.

[0050] An embodiment of this present invention is to combine tadalafil and l-arginine in stable dosage form with content uniformity, compressibility and desired dissolution profiles.

[0051] According to an embodiment of the present invention, the formulation has an immediate release phase.

[0052] 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.

[0053] A combination comprising tadalafil and l-arginine, in separate or same unit dosage forms, said forms being suitable for administration separately, sequentially or together in effective amounts, optionally further comprising polyester coil packing material or humectant or both.

[0054] Example 1 : The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets or capsule formulation

[0055]

[0056] Example 2: The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets or capsule formulation Example 3: The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets or capsule formulation

[0057] 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 and tadalafil to prepare a mixture b) polyvinylpyrrolidone and sodium lauryl sulfate dissolving in water c) granulating with this mixture of step (a) and step (b) d) drying the granules and sieving e) adding the other half of mannitol, microcrystalline cellulose, half of crospovidone, I- arginine and colloidal silicon dioxide then blending until homogeneous f) adding magnesium stearate then blending g) filling into the capsule or compressing the total mixture into tablets h) then coating with coating agents the tablets

[0058] Example 4: The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets or capsule formulation

[0059] Example 5: The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets or capsule formulation

[0060] Example 6: The combination comprising a PDE5 inhibitor and l-arginine at film coated tablets formulation

[0061] Process for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) blending 1 / 3 of l-arginine and tadalafil to prepare a mixture b) adding 2 / 3 of l-arginine and blending c) adding mannitol, microcrystalline cellulose, polyvinylpyrrolidone and colloidal silicon dioxide then blending with cubic mixer until homogeneous d) adding magnesium stearate then blending e) filling into the capsule or compressing the total mixture into tablets f) then coating with coating agents the tablets

Claims

CLAIMS1. A pharmaceutical combination comprising a PDE5 inhibitor and l-arginine.

2. The pharmaceutical combination according to claim 1 , wherein the ratio of PDE5 inhibitor to l-arginine is in the range of between 20: 1 to 1 :500 by weight or between 20: 1 to 1 :20.

3. 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.

4. The pharmaceutical combination according to claim 3, wherein the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.

5. The pharmaceutical combination according to any preceding claims, further comprising 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.

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

7. The pharmaceutical combination according to any preceding claims, wherein 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.

8. 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.

9. The pharmaceutical combination according to any preceding claims, wherein the combination is in the form of film-coated tablets or tablets.

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

11. 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.

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

13. The pharmaceutical combination according to claim 11 , wherein the film-coated tablets comprising; a) 0.2% to 3.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 30.0% to 80.0% by weight of l-arginine c) 3.0% to 15.0% by weight of mannitol d) 3.0% to 15.0% by weight of microcrystalline cellulose e) 1 .0% to 10.0% by weight of polyvinylpyrrolidone f) 1 .0% to 10.0% by weight of crospovidone 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.

14. The pharmaceutical combination according to claim 10, wherein the capsule comprising; a) 0.2% to 3.0% by weight of tadalafil or a pharmaceutically acceptable salt, solvate or polymorph thereof b) 30.0% to 80.0% by weight of l-arginine c) 3.0% to 15.0% by weight of mannitol d) 3.0% to 15.0% by weight of microcrystalline cellulose e) 1 .0% to 10.0% by weight of polyvinylpyrrolidone f) 1 .0% to 10.0% by weight of crospovidone 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 of the total composition.

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