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WO2025023902A1 - The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor, l-arginine and panax ginseng - Google Patents

The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor, l-arginine and panax ginseng Download PDF

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Publication number
WO2025023902A1
WO2025023902A1 PCT/TR2023/050736 TR2023050736W WO2025023902A1 WO 2025023902 A1 WO2025023902 A1 WO 2025023902A1 TR 2023050736 W TR2023050736 W TR 2023050736W WO 2025023902 A1 WO2025023902 A1 WO 2025023902A1
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weight
pharmaceutical combination
tablets
combination according
arginine
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French (fr)
Inventor
Arzu PALANTOKEN
Vildan TOMBAYOGLU
Abdullah TASKIN
Suat Hakan OZTEKIN
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Montero Gida Sanayi Ve Ticaret AS
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Montero Gida Sanayi Ve Ticaret AS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the present invention relates to a pharmaceutical combination comprising a PDE5 inhibitor, l-arginine and panax ginseng.
  • Phosphodiesterase type 5 inhibitors 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.
  • 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.
  • L-arginine 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.
  • nitric oxide 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.
  • 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.
  • WO2011087755A2 numbered patent application relates to a method to safely and effectively treat Distress Dysfunction conditions, symptoms and/or disorders in a subject in need comprising: administering at least one Receptor Switcher to the subject and at least one compound to the subject selected from the group consisting of an Endorphin Enhancer, an Exogenous Opioid, a Synergistic Enhancer, and any combination thereof.
  • an Endorphin Enhancer an Exogenous Opioid
  • a Synergistic Enhancer a combination thereof.
  • tadalafil among the molecules that can be selected as "Endorphin Enhancer” ginseng and arginine among the molecules that can be selected as "Synergistic Enhancer” are counted, but a combination of all of them is not specified.
  • 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.
  • the combination of tadalafil, l-arginine and panax ginseng is used to overcome the disadvantages and side effects meanwhile increasing the therapeutic effect and patient compliance in the desired manner.
  • the main object of the present invention is to provide a combination comprising a PDE5 inhibitor, l-arginine and panax ginseng.
  • the new combinations reduce the side effects when a PDE5 inhibitor, l-arginine and panax ginseng 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 selection of active agents in a certain ratio.
  • the present invention relates to an easily-administrable combination of PDE5 inhibitor, I- arginine and panax ginseng, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
  • PDE5 inhibitor 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.
  • l-arginine 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.
  • panax ginseng 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.
  • tadalafil, l-arginine and panax ginseng extract 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.
  • l-arginine and panax ginseng is used to overcome the disadvantages and side effects of tadalafil meanwhile increasing the therapeutic effect and patient compliance in the desired manner.
  • 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.
  • using a lower dose of each drug to be combined according to the present invention will reduce the total dosage.
  • 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.
  • the pharmaceutical combination comprises PDE5 inhibitor, l-arginine and panax ginseng.
  • l-arginine and panax ginseng reduce the side effect of tadalafil. Therefore, an improved sexual dysfunction problem has been achieved with the synergistic effect.
  • the ratio of PDE5 inhibitor to l-arginine is in the range of between 20:1 to 1:500 by weight.
  • the ratio of l-arginine to panax ginseng is in the range of between 1:100 to 250:1 by weight.
  • the ratio of PDE5 inhibitor to panax ginseng is in the range of between 4:1 to 1 :300 by weight.
  • a PDE5 inhibitor is selected from the group comprising tadalafil, sildenafil, avanafil, lodenafil, mirodenafil, vardenafil, udenafil, zaprinast, benzamidenafil, dasantafil or mixtures thereof.
  • the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil.
  • the amount of tadalafil or a pharmaceutically acceptable salt thereof is 0.2% to 3% by weight in the composition.
  • the dose of tadalafil or a pharmaceutically acceptable salt thereof is selected from 2.5 mg, 5 mg, 10 mg or 20 mg.
  • the amount of l-arginine is 30% to 80% by weight in the composition.
  • the dose of l-arginine is selected from 500 mg, 1000 mg or 1250 mg.
  • the amount of panax ginseng is 3% to 7% by weight in the composition.
  • the dose of panax ginseng is selected from 10 to 750 mg and more preferably 50 mg or 100 mg.
  • 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, alumini
  • 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.
  • cross-linked polyvinil pyrrolidone crospovidone
  • povidone cross-linked carboxymethyl cellulose
  • croscarmellose sodium cross-linked carboxymethyl cellulose
  • low-substituted hydroxypropyl cellulose pregelatinized starch
  • the total amount of disintegrants in the composition is 0.5% to 15.0% by weight, preferably 2.0% to 8.0% by weight and more preferably 3.0% to 6.0% 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PVA polyvinyl alcohol
  • PEG polyethylene glycol
  • talc polyvinyl alcohol-polyethylene glycol copolymers
  • Karelease® ethylcellulose dispersions
  • PVP-VA polyvinylprolidone
  • PVP-VA polyvinylprolidone-vinyl acetate copolymer
  • the pharmaceutical combination is administered orally.
  • 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.
  • 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.
  • 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.
  • each type of particle comprises at least one active agent.
  • the pharmaceutical combination is in the form of film-coated tablets, tablets.
  • 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.
  • 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.
  • 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 tadalafil, l-arginine and panax ginseng in stable dosage form with desired content uniformity, compressibility and dissolution profile.
  • 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 a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsule formulation (Panax ginseng extract in dry powder form)
  • Example 2 The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
  • Example 3 The combination comprising a PDE5 inhibitor, l-arginine 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) Blendig 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 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
  • Example 4 The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (
  • Example 6 The combination comprising a PDE5 inhibitor, l-arginine 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 l-arginine, panax ginseng extract 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 mixing with cubic mixer until homogeneous d) adding magnesium stearate then mixing e) filling into capsule or compressing the total mixture into tablets f) then coating with coating agents the tablets
  • Example 7 The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at capsule formulation (Panax ginseng extract in dry powder form)

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Abstract

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

Description

THE PHARMACEUTICAL COMBINATION COMPRISING PHOSPHODIESTERASE TYPE- 5 INHIBITOR, L-ARGININE AND PANAX GINSENG
Field of the Invention
The present invention relates to a pharmaceutical combination comprising a PDE5 inhibitor, l-arginine and panax ginseng.
Background of the Invention
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 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.
Figure imgf000003_0001
Formula I: Tadalafil
L-arginine 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.
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.
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.
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. WO2011087755A2 numbered patent application relates to a method to safely and effectively treat Distress Dysfunction conditions, symptoms and/or disorders in a subject in need comprising: administering at least one Receptor Switcher to the subject and at least one compound to the subject selected from the group consisting of an Endorphin Enhancer, an Exogenous Opioid, a Synergistic Enhancer, and any combination thereof. In the description, tadalafil among the molecules that can be selected as "Endorphin Enhancer", ginseng and arginine among the molecules that can be selected as "Synergistic Enhancer" are counted, but a combination of all of them is not specified.
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, l-arginine and panax ginseng 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, l-arginine and panax ginseng is used to overcome the disadvantages and side effects 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 a PDE5 inhibitor, l-arginine and panax ginseng.
According to the main embodiment of the present invention, the new combinations reduce the side effects when a PDE5 inhibitor, l-arginine and panax ginseng 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 selection of active agents in a certain ratio. The present invention relates to an easily-administrable combination of PDE5 inhibitor, I- arginine and panax ginseng, eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.
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 "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.
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 tadalafil, l-arginine and panax ginseng extract 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 and panax ginseng 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.
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 PDE5 inhibitor, l-arginine and panax ginseng.
According to this embodiment, l-arginine and panax ginseng reduce the side effect of 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 PDE5 inhibitor to l-arginine is in the range of between 20:1 to 1:500 by weight.
According to an embodiment of the present invention, the ratio of l-arginine to panax ginseng is in the range of between 1:100 to 250:1 by weight.
According to an embodiment of the present invention, the ratio of PDE5 inhibitor to panax ginseng is in the range of between 4:1 to 1 :300 by weight.
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 or mixtures thereof.
According to an embodiment of the present invention, the PDE5 inhibitor is tadalafil or sildenafil, preferably tadalafil. According to one embodiment, the amount of tadalafil or a pharmaceutically acceptable salt thereof is 0.2% to 3% by weight in the composition.
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 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.
According to one embodiment, the amount of panax ginseng is 3% to 7% by weight in the composition.
According to one embodiment, the dose of panax ginseng is selected from 10 to 750 mg and more preferably 50 mg or 100 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 dodesyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof.
According to one embodiment, the total amount of disintegrants in the composition is 0.5% to 15.0% by weight, preferably 2.0% to 8.0% by weight and more preferably 3.0% to 6.0% 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.
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.
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. 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, powder, pastilles, sachet, effervescent formulations, pills, coated bead systems, granules, microspheres, dragees, films, orally administrable films, solids.
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. 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 is in the form of film-coated tablets, tablets.
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 tadalafil, l-arginine and panax ginseng in stable dosage form with desired content uniformity, compressibility and dissolution profile.
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 a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsule formulation (Panax ginseng extract in dry powder form)
Figure imgf000011_0001
Example 2: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
Figure imgf000011_0002
Example 3: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
Figure imgf000012_0001
Process of wet granulation for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) Blendig 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 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 Example 4: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
Figure imgf000013_0001
Example 5: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
Figure imgf000013_0002
Figure imgf000014_0001
Example 6: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at film coated tablets or capsules formulation (Panax ginseng extract in dry powder form)
Figure imgf000014_0002
Process for preparing the pharmaceutical combination for film-coated tablet or capsule comprises the following steps: a) Blending 1/3 of l-arginine, panax ginseng extract 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 mixing with cubic mixer until homogeneous d) adding magnesium stearate then mixing e) filling into capsule or compressing the total mixture into tablets f) then coating with coating agents the tablets Example 7: The combination comprising a PDE5 inhibitor, l-arginine and an panax ginseng at capsule formulation (Panax ginseng extract in dry powder form)
Figure imgf000015_0001

Claims

1. A pharmaceutical combination comprising a PDE5 inhibitor, l-arginine and panax ginseng.
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.
3. The pharmaceutical combination according to claim 1 , wherein the ratio of l-arginine to panax ginseng is in the range of between 1 :100 to 250:1 by weight.
4. The pharmaceutical combination according to claim 1 , wherein the ratio of PDE5 inhibitor to panax ginseng is in the range of between 4: 1 to 1 :300 by weight.
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 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 combination is administrated orally.
9. 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.
10. 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.
11. The pharmaceutical combination according to any preceding claims, wherein the combination is in the form of film-coated tablets or tablets.
12. The pharmaceutical combination according to any preceding claims, wherein the combination is formulated as capsule.
13. 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.
14. The pharmaceutical combination according to any preceding claims, wherein the formulation has an immediate release phase.
15. 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 thereo b) 30.0% to 80.0% by weight of l-arginine c) 0.1 % to 45.0% by weight of panax ginseng in dry powder form d) 3.0% to 15.0% by weight of mannitol e) 3.0% to 15.0% by weight of microcrystalline cellulose f) 1.0% to 10.0% by weight of polyvinylpyrrolidone g) 1.0% to 10.0% 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.
16. The pharmaceutical combination according to claim 12, 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) 0.1 % to 45.0% by weight of panax ginseng in dry powder form d) 3.0% to 15.0% by weight of mannitol e) 3.0% to 15.0% by weight of microcrystalline cellulose f) 1.0% to 10.0% by weight of polyvinylpyrrolidone g) 1.0% to 10.0% 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 of the total composition.
PCT/TR2023/050736 2023-07-26 2023-07-26 The pharmaceutical combination comprising phosphodiesterase type-5 inhibitor, l-arginine and panax ginseng Pending WO2025023902A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338862B1 (en) * 2001-03-26 2002-01-15 Sarfaraz K Niazi Composition and method of use in treating sexual dysfunction using cGMP-specific phosphodiesterase type 5 inhibitors
US20220152032A1 (en) * 2020-11-13 2022-05-19 Pharma America Holding Inc. Sexual therapy formulation and method of treatment
US20220265664A1 (en) * 2020-11-13 2022-08-25 Pharma America Holding Inc. Sexual therapy formulation and method of treatment

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6338862B1 (en) * 2001-03-26 2002-01-15 Sarfaraz K Niazi Composition and method of use in treating sexual dysfunction using cGMP-specific phosphodiesterase type 5 inhibitors
US20220152032A1 (en) * 2020-11-13 2022-05-19 Pharma America Holding Inc. Sexual therapy formulation and method of treatment
US20220265664A1 (en) * 2020-11-13 2022-08-25 Pharma America Holding Inc. Sexual therapy formulation and method of treatment

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