TW201831185A - Pharmaceutical formulation containing tadalafil - Google Patents

Abstract

Disclosed herein are pharmaceutical compositions comprising Tadalafil, or a salt, or derivatives thereof and pharmaceutical excipients, processes for the preparation thereof, and pharmaceutical compositions containing them. The pharmaceutical compositions have improved physicochemical properties that provide faster onset of action for the treatment of erectile dysfunction.

Description

Pharmaceutical formulation containing tadalafil

This application claims US Provisional Application No. 62/428,309, filed on November 30, 2016, US Provisional Application No. 62/438,539, filed on December 23, 2016, and US Provisional Application, filed on May 5, 2017 The disclosure of the application is hereby incorporated by reference in its entirety in its entirety in its entirety in its entirety in its entirety in its entirety.

Disclosed herein are pharmaceutical compositions comprising the active compound Tadalafil, a salt thereof, or a derivative thereof, having controlled particle size, increased apparent solubility, and increased dissolution rate, such pharmaceutical compositions It is useful in the treatment of erectile dysfunction, benign prostatic hyperplasia (combined with Finasteride or Dutasteride), pulmonary hypertension, and Duchenne muscle dystrophy. The drug composition gives an earlier _tmax and a faster onset of treatment for erectile dysfunction. Also disclosed are methods of making the pharmaceutical formulations described herein.

A selective inhibitor of tadalafil cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). Tadalafil has an empirical formula of C ₂₂ H ₁₉ N ₃ O ₄ representing a molecular weight of 389.41. Structural system:

It is a crystalline solid which is hardly soluble in water and very slightly soluble in ethanol.

CIALIS (Tadalafil) is available as an almond shaped tablet for oral administration. Each tablet contains 2.5, 5, 10, or 20 mg of tadalafil and the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, iron oxide, lactose Hydrate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate, talc, titanium dioxide, and triacetin.

The maximum plasma concentration ( _Cmax ) of tadalafil observed was achieved between 30 minutes and 6 hours (median time of 2 hours) after a single oral dose administration. The absolute bioavailability of tadalafil after oral administration was not determined. The rate and extent of absorption of tadalafil is not affected by food; therefore, CIALIS can be taken with or without food.

In the dose range of 2.5 to 20 mg, tadalafil exposure (AUC) increases proportionally with the dose in healthy subjects. Steady-state plasma concentrations were obtained within one day of dosing for 5 days and exposure was approximately 1.6-fold greater than after single administration. Tadalafil is mainly eliminated by hepatic metabolism by cytochrome P450 3A4 (CYP3A4). The concomitant use of potent CYP3A4 inhibitors such as ritonavir or ketoconazole resulted in a significant increase in the Talaflu AUC value.

The mean apparent volume of distribution after oral administration was approximately 63 L, indicating that tadalafil was distributed into the tissue. At therapeutic concentrations, 94% of tadalafil in plasma binds to proteins. A given dose of less than 0.0005% occurs in the semen of a healthy subject.

Tadalafil is mainly metabolized to catechol metabolites by CYP3A4. The catechol metabolite undergoes substantial methylation and glucuronidation to form guaiacol and guaiacol glucoside conjugates, respectively. The main circulating metabolite is guaiacol glucuronide. The guaiacol concentration is less than 10% of the glucuronide concentration. In vitro data indicate that metabolites are not expected to be pharmacologically active at the observed metabolite concentrations.

In healthy subjects, the average oral clearance for tadalafil was 2.5 L/hr and the mean final half-life was 17.5 hours. Tadalafil is mainly used as a metabolite mainly in feces (about 61% of the dose) and to a lesser extent in urine (about 36% of the dose).

The main medical concerns surrounding tadalafil are associated with slow absorption and variable onset with _tmax values in the range of 0.5-6 hours.

A variety of strategies have been used to try to overcome such problems, see, for example, WO 2014125343, WO2006049986, WO2012085927, WO2006091974, WO2007027612, WO2008134557, WO2012095151, WO2014092661, WO2014125352, WO2011135426, WO2016012539, WO2013109221, WO2013109223, WO2016001143, WO2014168455, WO2014202797, WO2016021975 , WO2010115886 and WO2014209022.

Disclosed herein are pharmaceutical compositions comprising: an active compound selected from the group consisting of tadalafil, a salt thereof or a derivative thereof; and at least one primary pharmaceutical excipient selected from the group consisting of: monoglycerides , polyethylene diglycerides and triglycerides and polyethylene glycol glycerides composed of mono- and di-esters of polyethylene glycol (eg Gelucire 44/14), polyethylene glycol (eg PEG2000, PEG6000), hydroxypropyl Cellulose (eg Klucell EF, Klucell LF), poloxamer (copolymer of ethylene oxide and propylene oxide blocks) (eg, Poloxamer 407, Poloxamer 335, Poloxamer 188, Poloxamer 338), copolymerization Vetidone (copolymer of vinylpyrrolidone and vinyl acetate) (eg Kollidon VA64), poly(2-ethyl-2- Oxazoline) (eg PEOX50, PEOX200, PEOX500), povidone (polyvinylpyrrolidone, eg Plasdone K-12, PVP 40, PVP K90, PVP 10), polyvinyl caprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer (eg Soluplus), polyoxyl 15 hydroxystearate (eg Solutol HS15), ethylene oxide / propylene oxide tetrafunctional block copolymer (eg Tetronic 1107), amino methacrylate copolymers (eg Eudragit E PO), hydroxypropyl methylcellulose acetate succinate (eg HPMCAS) and d-alpha tocopherol polyethylene glycol 1000 succinate (TPGS) The pharmaceutical formulation is characterized in that it has at least one of the following characteristics: a) is instantaneously redispersible in a physiologically relevant medium; b) is in a solid form and is stable in a colloidal solution and/or dispersion. ; c) having an apparent solubility in water of at least 0.7 mg/mL; and d) having at least when dispersed in a fasted analogy to intestinal fluid (FaSSIF) or a fed state analogy intestinal fluid (FeSSIF) biologically relevant medium PAMPA permeability of 4x10 ^-6 cm/s, which does not decrease over a period of at least 6 months.

In embodiments, the pharmaceutical composition has instant redispersibility, increased apparent solubility, and permeability, which provides a faster start to treating erectile dysfunction than currently available formulations. effect.

In an embodiment, the composite formulation exhibits X-ray amorphous features in solid form.

It has been found that only selected combinations of the primary and secondary pharmaceutical excipients disclosed in the present disclosure produce a pharmaceutical composition having improved physicochemical properties and enhanced biological properties.

The expression tadalafil is commonly used for tadalafil, or a salt thereof or a derivative thereof.

In an embodiment, the primary pharmaceutical excipient is selected from the group consisting of polyethylene glycol glycerides composed of mono- and di-glycerides of mono-, di- and triglycerides and polyethylene glycols ( For example, Gelucire 44/14), polyethylene glycol (eg PEG2000, PEG6000), hydroxypropyl cellulose (eg Klucell EF, Klucell LF), poloxamer (copolymer of ethylene oxide and propylene oxide block) (eg, Poloxamer 407, Poloxamer 335, Poloxamer 188, Poloxamer 338), copovidone (copolymer of vinylpyrrolidone and vinyl acetate) (eg Kollidon VA64), poly(2-ethyl-2-) Oxazoline) (eg PEOX50, PEOX200, PEOX500), povidone (polyvinylpyrrolidone, eg Plasdone K-12, PVP 40, PVP K90, PVP 10), polyvinyl caprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer (eg Soluplus), polyoxyl 15 hydroxystearate (eg Solutol HS15), ethylene oxide / propylene oxide tetrafunctional block copolymer (eg Tetronic 1107), amino methacrylate copolymers (eg Eudragit E PO), hydroxypropyl methylcellulose acetate succinate (eg HPMCAS) and d-alpha tocopherol polyethylene glycol 1000 succinate (TPGS) .

In an embodiment, the primary pharmaceutical excipient is selected from the group consisting of hydroxypropyl cellulose, poloxamer (copolymer of ethylene oxide and propylene oxide blocks), copolyvidone (vinyl pyrrolidone and Copolymer of vinyl acetate), povidone (polyvinylpyrrolidone), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, ethylene oxide/propylene oxide A tetrafunctional block copolymer, and d-alpha tocopherol polyethylene glycol 1000 succinate.

In an embodiment, the primary pharmaceutical excipient is copovidone (a copolymer of vinylpyrrolidone and vinyl acetate).

In an embodiment, the composition of the copolyvidone (copolymer of vinylpyrrolidone (VP) and vinyl acetate (VA)) is VP: VA = 60:40.

In an embodiment, the pharmaceutical composition further comprises at least one minor pharmaceutical excipient selected from the group consisting of sodium lauryl sulfate (SDS), sodium dioctyl sulfosuccinate (DSS), chlorination Cetylpyridinium (CPC), D-mannitol, sodium deoxycholate (SDC), poloxamer 407, and meglumine.

In an embodiment, the secondary pharmaceutical excipient is sodium dioctyl sulfosuccinate or sodium lauryl sulfate.

In an embodiment, the secondary pharmaceutical excipient is dioctyl sodium sulfosuccinate and wherein the composition is characterized by the Raman spectroscopy as shown in FIG.

In an embodiment, the secondary pharmaceutical excipient is sodium lauryl sulfate and wherein the composition is characterized by the Raman spectroscopy as shown in FIG.

In an embodiment, the pharmaceutical composition has a controlled particle size in the range between 10 nm and 500 nm.

In an embodiment, the particle size is between 10 nm and 200 nm.

In an embodiment, the pharmaceutical composition has an apparent solubility in water of at least 0.7 mg/mL.

In embodiments, the pharmaceutical composition may further comprise one or more additional active compounds.

In an embodiment, the additional active compound is selected from the group consisting of agents useful for treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy.

In an embodiment, the pharmaceutical composition provides a faster onset of treatment for erectile dysfunction compared to Cialis®.

In an embodiment, the pharmaceutical composition has at least two of the characteristics described in a)-d).

In an embodiment, the pharmaceutical composition has at least three of the characteristics described in a)-d).

In an embodiment, the pharmaceutical composition has an increased dissolution rate compared to Cialis®.

Further disclosed herein is a pharmaceutical composition comprising: an active compound selected from the group consisting of tadalafil, a salt thereof or a derivative thereof; and a copolyvidone (copolymerization of vinylpyrrolidone and vinyl acetate) At least one primary pharmaceutical excipient; and at least one secondary pharmaceutical excipient selected from the group consisting of sodium dioctyl sulfosuccinate and sodium lauryl sulfate.

In an embodiment, the composition of the copolyvidone (copolymer of vinylpyrrolidone (VP)-vinyl acetate (VA)) is VP: VA = 60:40.

In an embodiment, the pharmaceutical composition comprises a major pharmaceutical excipient which is a copolyvidone (a copolymer of vinylpyrrolidone and vinyl acetate) and is sodium dioctyl sulfosuccinate or sodium lauryl sulfate. The secondary pharmaceutical excipient, the total amount of which is in the range of from about 1.0% by weight to about 95.0% by weight, based on the total weight of the pharmaceutical composition.

In an embodiment, the pharmaceutical composition comprises a major pharmaceutical excipient which is a copolyvidone (a copolymer of vinylpyrrolidone and vinyl acetate) and is sodium dioctyl sulfosuccinate or sodium lauryl sulfate. The secondary pharmaceutical excipient, the total amount of which is in the range of from about 50.0% by weight to about 95.0% by weight, based on the total weight of the pharmaceutical composition.

Further disclosed herein is a method for preparing the pharmaceutical composition, the method comprising the steps of: dissolving tadalafil, a salt thereof, or a derivative thereof in a pharmaceutically acceptable solvent, and at least one selected from the group consisting of The main pharmaceutical excipients: polyethylene glycol glycerides consisting of mono- and di-glycerides of mono-, di- and triglycerides and polyethylene glycols (eg Gelucire 44/14) , polyethylene glycol (eg PEG2000, PEG6000), hydroxypropyl cellulose (eg Klucell EF, Klucell LF), poloxamer (copolymer of ethylene oxide and propylene oxide blocks) (eg Poloxamer 407, Poloxamer 335, Poloxamer 188, Poloxamer 338), copovidone (copolymer of vinylpyrrolidone and vinyl acetate) (eg Kollidon VA64), poly(2-ethyl-2- Oxazoline) (eg PEOX50, PEOX200, PEOX500), povidone (polyvinylpyrrolidone, eg Plasdone K-12, PVP 40, PVP K90, PVP 10), polyvinyl caprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer (eg Soluplus), polyoxyl 15 hydroxystearate (eg Solutol HS15), ethylene oxide / propylene oxide tetrafunctional block copolymer (eg Tetronic 1107), amino methacrylate copolymers (eg Eudragit E PO), hydroxypropyl methylcellulose acetate succinate (eg HPMCAS) and d-alpha tocopherol polyethylene glycol 1000 succinate (TPGS) And mixed with an aqueous solution optionally containing at least one secondary pharmaceutical excipient in a pharmaceutically acceptable solvent mixture selected from the group consisting of sodium lauryl sulfate (SDS), Dioctyl sodium sulfosuccinate (DSS), cetylpyridinium chloride (CPC), D-mannitol, sodium deoxycholate (SDC), poloxamer 407 and meglumine.

In an embodiment, the primary pharmaceutical excipient is copovidone (a copolymer of vinylpyrrolidone and vinyl acetate).

In an embodiment, the secondary pharmaceutical excipient is sodium lauryl sulfate (SDS) or sodium dioctyl sulfosuccinate (DSS).

In embodiments, the pharmaceutically acceptable solution of tadalafil, a salt or derivative thereof, and at least one primary pharmaceutical excipient is prepared using a pharmaceutically acceptable solvent selected from the group consisting of methanol, Ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, dimethyl hydrazine, tetrahydrofuran, methyl ethyl ketone or a combination thereof.

In an embodiment, the pharmaceutically acceptable solvent mixture is selected from the group consisting of a pharmaceutically acceptable solvent and a solvent mixture of water: methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile , dimethyl hydrazine, tetrahydrofuran, methyl ethyl ketone or a combination thereof.

In an embodiment, the pharmaceutically acceptable solvent is tetrahydrofuran.

In an embodiment, the pharmaceutically acceptable solution and the aqueous solution are miscible with each other.

In an embodiment, the pharmaceutically acceptable solvent is water miscible.

In an embodiment, the aqueous solution comprises from 0.1% to 99.9% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50% to 90% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50% to 80% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50% to 70% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 50% to 60% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 45% to 55% by weight of the final solution.

In an embodiment, the aqueous solution comprises 50% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 5% to 45% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 5% to 35% by weight of the final solution.

In an embodiment, the aqueous solution comprises from 5% to 25% by weight of the final solution.

In an embodiment, the pharmaceutically acceptable solvent comprises from 0.1% to 99.9% by weight of the pharmaceutically acceptable solvent mixture.

In embodiments, the pharmaceutically acceptable solvent comprises from 50% to 90% by weight of the pharmaceutically acceptable solvent mixture.

In embodiments, the pharmaceutically acceptable solvent comprises from 50% to 80% by weight of the pharmaceutically acceptable solvent mixture.

In an embodiment, the pharmaceutically acceptable solvent comprises from 50% to 70% by weight of the pharmaceutically acceptable solvent mixture.

In embodiments, the pharmaceutically acceptable solvent comprises from 50% to 60% by weight of the pharmaceutically acceptable solvent mixture.

In embodiments, the pharmaceutically acceptable solvent comprises from 45% to 55% by weight of the pharmaceutically acceptable solvent mixture.

In an embodiment, the pharmaceutically acceptable solvent comprises 50% by weight of the pharmaceutically acceptable solvent mixture.

In an embodiment, the pharmaceutically acceptable solvent comprises from 5% to 45% by weight of the pharmaceutically acceptable solvent mixture.

In an embodiment, the pharmaceutically acceptable solvent comprises from 5% to 35% by weight of the pharmaceutically acceptable solvent mixture.

In an embodiment, the pharmaceutically acceptable solvent comprises from 5% to 25% by weight of the pharmaceutically acceptable solvent mixture.

In embodiments, the pharmaceutical composition may comprise additional pharmaceutically acceptable excipients.

In embodiments, the pharmaceutical composition is suitable for oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, aural, local, buccal, nasal, or external (topical) giving.

In an embodiment, the pharmaceutical composition is suitable for oral administration.

In an embodiment, the pharmaceutical composition is used to manufacture an agent for treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy.

In an embodiment, the pharmaceutical composition is for treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy.

A method of treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy is disclosed herein, the method comprising administering a therapeutically effective amount of a pharmaceutical composition as described herein.

In an embodiment, a method for reducing a therapeutically effective dose of tadalafil (compared to commercially available Cialis) comprises orally administering a pharmaceutical composition as described herein.

Further disclosed herein is a stable pharmaceutical composition comprising a. 10% to 40% by weight of tadalafil, a salt thereof, or a derivative thereof; b. 35% to 70% by weight Copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate); and c. 5% to 50% by weight of sodium dioctyl sulfosuccinate or sodium lauryl sulfate wherein the pharmaceutical formulation has A controlled particle size in the range between 10 nm and 500 nm; and wherein the drug composition cannot be prepared by a grinding method, a high pressure homogenization method, or an encapsulation method.

In an embodiment, the particle size is between 10 nm and 200 nm.

In the embodiment, as compared with Cialis®, the pharmaceutical composition exhibited significantly improved exposure earlier t _max, and higher C _max, which will allow a reduced dose and provide faster onset of action.

In an embodiment, the pharmaceutical composition has a faster onset of action than Cialis®.

In an embodiment, the pharmaceutical composition is instantly redispersible in a physiologically relevant medium.

In an embodiment, the pharmaceutical composition is in solid form and is stable in a colloidal solution and/or dispersion.

In an embodiment, the pharmaceutical composition has an apparent solubility in water of at least 0.7 mg/mL.

In an embodiment, tadalafil exhibits an X-ray amorphous character in the pharmaceutical composition.

In embodiments, when dispersed in a water, FaSSIF or FeSSIF bio-related medium, the pharmaceutical composition has a PAMPA permeability of at least 4 x 10 ^-6 cm/s, the permeability not being for at least 6 months reduce.

In an embodiment, the pharmaceutical composition comprising copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate) and sodium dioctyl sulfosuccinate is represented by the Raman spectrum shown in FIG. Characterize.

In an embodiment, the pharmaceutical composition comprising copovidone (copolymer of vinylpyrrolidone and vinyl acetate) and sodium lauryl sulfate is characterized by Raman spectroscopy as shown in FIG.

In some embodiments, the pharmaceutical composition may additionally include one or more pharmaceutical excipients, auxiliary materials, carriers, active agents, or a combination thereof.

In some embodiments, the active compound can include active compounds useful for treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy.

In some embodiments, the complex structure of the pharmaceutical composition is different from core-shell abrasive particles, precipitated encapsulated particles, and micelles.

The pharmaceutical composition can be formulated: (a) for administration selected from the group consisting of oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, and ocular. , ear, topical, buccal, nasal, and external; (b) a dosage form selected from the group consisting of liquid dispersions, gels, aerosols, ointments, creams, lyophilized Formulations, sachets, tablets, capsules; (c) a dosage form selected from the group consisting of rapid release formulations, controlled release formulations, fast melt formulations, delayed release Formulations, extended release formulations, pulsatile release formulations, and mixed immediate release and controlled release formulations; or (d) any combination of (a), (b), and (c).

The pharmaceutical composition can be formulated for oral administration as a solid or liquid by addition of different types of pharmaceutical excipients; topical (powder, ointment or drops); or external administration.

In embodiments, the pharmaceutical dosage form is a solid dosage form, although any pharmaceutically acceptable dosage form can be utilized.

Solid dosage forms for oral administration include, but are not limited to, capsules, tablets, pills, powders (capsules), and granules. In such a solid dosage form, the pharmaceutical formulation is mixed with at least one of the following: one or more inert excipients (or carriers): (a) a filler or extender, eg, lactose, sucrose, Glucose, mannitol, sorbitol, dextrose, glucose binder, dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylose Alcohol, starch, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide; (b) sweeteners, flavoring agents and aromatics, such as saccharin, sodium saccharin, potassium sulfamate, Ali Sweet (alitame), aspartame, glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclohexyl sulfonate, trichloro Sucralose, tagatose, thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid, menthol, propionic acid, tartaric acid; (c) binder Such as cellulose derivatives, acrylic acid derivatives, alginates, gelatin, polyvinylpyrrolidone, Powder derivatives, dextrose, glucose binder, dextrin, maltose, maltodextrin; (d) disintegrating agents, such as crospovidone, effervescent composition, croscarmellose sodium And other cellulose derivatives, sodium starch glycolate and other starch derivatives, alginic acid, certain drug citrates and sodium carbonate; (e) solution blockers, such as acrylates, cellulose derivatives, paraffin; f) absorption enhancers such as quaternary ammonium compounds; (g) wetting agents such as polysorbates, cetyl alcohol and glyceryl monostearate; (h) lubricants such as talc, stearic acid and derivatives thereof , solid polyethylene glycol, sodium lauryl sulfate, glutamic acid ester, medium chain triglyceride or a mixture thereof. For capsules, tablets, sachets and pills, the dosage forms may also contain buffering agents.

In an embodiment, the dosage form of the invention is a liquid dispersible granule, a sachet, a liquid dispersible tablet, an orally dispersible tablet, an orally dissolvable tablet, a chewable tablet, and an immediate release (IR) tablet. .

In an embodiment, the liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets comprise the pharmaceutical formulation of the present invention. a pharmaceutically acceptable excipient together with a group selected from a filler or a bulking agent, such as lactose, sucrose, glucose, mannitol, sorbitol, dextrose, glucose binder, dextrin, erythritol , fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starch, microcrystalline cellulose, dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesium oxide.

In an embodiment, the liquid dispersible granules, capsules, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewing tablets, and immediate release (IR) tablets The medicament comprises a pharmaceutical formulation of the invention together with a pharmaceutically acceptable excipient selected from the group consisting of a sweetener, a flavoring agent and a fragrance, such as saccharin, sodium saccharin, potassium sulfamate, alitame, ar Spartame, glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclohexyl sulfonate, sucralose, tagatose, thaumatin, citric acid, adipic acid , fumaric acid, leucine, malic acid, menthol, propionic acid, tartaric acid.

Further disclosed herein are liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets, which comprise a.25%- 95% of a stable pharmaceutical formulation of the invention; b. 5%-75% filler or extender; c. 0.5%-25% binder; d. 0.1%-5% sweetener, Flavoring and perfuming agents; wherein the liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets are dispersed within 10 minutes In liquid or biologically relevant media or stomach acid.

In an embodiment, the dispersion time is between 0.1 min and 10 min.

In an embodiment, the dispersion time is between 0.1 min and 5 min.

In an embodiment, the dispersion time is between 0.1 min and 3 min.

In an embodiment, the dispersion time is between 0.1 min and 1 min.

In an embodiment, the dosage form of the pharmaceutical formulation of the invention has a Hausner-ratio of less than 1.25.

In an embodiment, the dosage form of the dosage form of the pharmaceutical formulation of the invention has a Hausner ratio between 1.00 and 1.11.

In embodiments, the granules of the pharmaceutical formulations have a particle size (D(90)) of less than 2000 microns.

In embodiments, from 60% to 80% of the granules of the pharmaceutical formulation are in a size range below 800 microns.

In embodiments, the liquid system is water, saliva, other physiologically or biologically acceptable fluids or liquids.

In an embodiment, the dosage form of the invention is a liquid dispersible granule, a sachet, a liquid dispersible tablet, an orally dispersible tablet, an orally dissolvable tablet, a chewable tablet, and an immediate release tablet.

In an embodiment, the liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets comprise the pharmaceutical formulation of the present invention. a pharmaceutically acceptable excipient together with a group selected from a filler or a bulking agent, such as lactose, sucrose, glucose, mannitol, sorbitol, dextrose, glucose binder, dextrin, erythrelose Alcohol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, calcium carbonate, calcium lactate, calcium phosphate, calcium citrate, calcium sulfate, powdered cellulose , microcrystalline cellulose, deuterated microcrystalline cellulose, corn starch, pregelatinized corn starch, fumaric acid, magnesium carbonate, magnesium oxide, polymethacrilate, sodium chloride, talc, alumina, Magnesium aluminum silicate, colloidal cerium oxide.

In an embodiment, the liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets comprise the pharmaceutical formulation of the present invention. a pharmaceutically acceptable excipient together with a group selected from the group consisting of a dissolution modifier, such as sodium carboxymethylcellulose, hypromellose, hypromellose ethyl sulfosuccinate, cross-linked Ketones, cyclodextrins, agar, alginic acid, carbomer, carnauba wax, carrageenan, guar gum, hydroxypropyl cellulose, hypromellose phthalate, A Cellulose, Potassin potassium, polyethylene oxide, polyoxylglyceride, polyvinyl alcohol, sodium acetate, sodium alginate, sodium hyaluronate, xanthan gum, polycarbophil, ten Hexaol, chitosan.

In an embodiment, the liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets comprise the pharmaceutical formulation of the present invention. And a pharmaceutically acceptable excipient selected from the group consisting of a sweetener, a flavoring agent, and a fragrance, such as saccharin, sodium saccharin, potassium sulfamate, alitame, aspartame, glycine , inulin, neohesperidin dihydrochalcone, neotame, sodium cyclohexyl sulfonate, sucralose, tagatose, thaumatin, citric acid, adipic acid, fumaric acid, leucine Acid, malic acid, menthol, propionic acid, tartaric acid.

Further disclosed herein are liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets, which comprise a.25%- 95% of a stable pharmaceutical formulation of the invention; b. 0.5% to 75% of a filler or extender such as lactose, sucrose, glucose, mannitol, sorbitol, dextrose, glucose binder, dextrin , erythritol, fructose, isomalt, lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, calcium carbonate, calcium lactate, calcium phosphate, calcium citrate, calcium sulfate, Powdered cellulose, microcrystalline cellulose, deuterated microcrystalline cellulose, corn starch, pregelatinized corn starch, fumaric acid, magnesium carbonate, magnesium oxide, polymethacrylate, sodium chloride, talc, alumina , magnesium aluminum silicate, colloidal cerium oxide; c. 0.5% -25% of dissolution modifiers, such as sodium carboxymethyl cellulose, hypromellose, hypromellose acetyl succinate , crospovidone, cyclodextrin, agar, alginic acid, carbomer, carnauba wax, carrageen Gum, guar gum, hydroxypropyl cellulose, hypromellose phthalate, methyl cellulose, potassium blakelin, polyethylene oxide, polyoxyglyceride, polyvinyl alcohol, sodium acetate, Sodium alginate, sodium hyaluronate, xanthan gum, polycarbophil, cetyl alcohol, chitosan; d. 0.1%-5% sweeteners, flavorings and fragrances, such as saccharin, sodium saccharin , acesulfame potassium, alitame, aspartame, glycine, inulin, neohesperidin dihydrochalcone, neotame, sodium cyclohexyl sulfonate, sucralose, tag Sugar, thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid, menthol, propionic acid, tartaric acid; e. 0.1% - 1% lubricant; f. 0.1% - 15% Sodium docusate, sodium lauryl sulfate, ammonium lauryl ether sulfate, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, polyoxyethylene alkylphenyl ether polo Polyoxyethelene alkylphenylethersm poloxamer, polyoxyethelene fatty acid glyceride, sorbitan ester; wherein the liquid dispersible granules, capsules Liquid dispersible tablets, oral dispersible tablets, orally dissolving tablets, chewable tablets and immediate release tablets dispersed within 10min.

In an embodiment, the dispersion time is between 0.1 min and 3 min.

In an embodiment, the dispersion time is between 0.1 min and 1 min.

In embodiments, the dosage form is selected from the group consisting of liquid dispersible granules, sachets, liquid dispersible tablets, orally dispersible tablets, orally dissolvable tablets, chewable tablets, and immediate release tablets.

Advantages of the tadalafil pharmaceutical composition disclosed herein include, but are not limited to, (1) physical and chemical stability, (2) instantaneous redispersibility, and (3) stabilization of the colloidal solution or dispersion during the treatment time window. (4) increased apparent solubility and permeability compared to conventional tadalafil formulations, (5) reduced onset time for treatment of erectile dysfunction, and (6) good processability .

In an embodiment, the tadalafil pharmaceutical composition has increased pharmacokinetic properties. The tadalafil pharmaceutical composition exhibited a reduced _tmax and onset time when compared to a commercially available formulation of tadalafil.

[Example]

Specific non-limiting embodiments will be further illustrated by the following examples.

Selection of tadalafil pharmaceutical compositions with improved material properties

Several primary and secondary pharmaceutical excipients and combinations thereof were tested to determine compositions having instantaneous redispersibility, as shown in FIG.

An example of exhibiting acceptable levels of redispersibility was selected for further analysis.

The PAMPA permeability of the selected composition was measured in order to select the tadalafil drug composition with optimal in vitro properties (Figure 2). As described by M. Kansi et al. (Journal of medicinal chemistry, 41, (1998) p. 1007), based on S. Bendels et al. (Pharmaceutical Research, 23 (2006) The 2525 page was modified to perform PAMPA permeability measurements. Permeability was measured across an artificial membrane consisting of dodecane and 20% soy lecithin supported by a PVDF membrane (Millipore, USA) in a 96-well plate assay. The receiver compartment was supplemented with 1% sodium dodecyl sulfate phosphate buffered saline (pH 7.0). The assay was performed at room temperature; incubation time was 4 hours in ultrapure water or 10-20 and 30 minutes in simulated saliva, respectively. The concentration in the receiver compartment was determined by UV-VIS spectrophotometry (Thermo Scientific Genesys S10).

Preparation of improved material properties by selecting copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate) and sodium dioctyl sulfosuccinate and sodium lauryl sulfate as primary and secondary pharmaceutical excipients. The drug composition of tadalafil.

High-performance composition of tadalafil

A solid tadalafil pharmaceutical composition is prepared by using different ratios of primary and secondary pharmaceutical excipients. The ratio of primary and secondary pharmaceutical excipients has no effect on the PAMPA permeability of the prepared pharmaceutical composition. Selected to include tadalafil with a weight ratio of 1:3:0.5: copovidone (copolymer of vinylpyrrolidone and vinyl acetate): tadalafil composition of dioctyl sodium sulfosuccinate Things are used for further work. Also selected is a tadalafil comprising a weight ratio of 1:4:1: copovidone (copolymer of vinylpyrrolidone and vinyl acetate): a second tadalafil pharmaceutical composition of sodium lauryl sulfate Used for further work.

Manufacture of tadalafil's pharmaceutical composition

A solution mixture of the tadalafil pharmaceutical composition is prepared by a mixing process. Solution 1 containing 1-10 mg/mL tadalafil and 3-30 mg/mL copovidone (copolymer of vinylpyrrolidone and vinyl acetate) in tetrahydrofuran and containing 0.125-1.5 mg/mL sulfo group Aqueous solution 2 of sodium dioctyl succinate was mixed at different ratios. The resulting solution mixture of the tadalafil pharmaceutical formulation is produced at atmospheric pressure and ambient temperature. The resulting solution mixture was frozen on an acetone-dry ice mixture, and then lyophilized using a freeze dryer equipped with a -110 ° C ice condenser equipped with a vacuum pump.

Also, 10-60 mg/mL of tadalafil, 40-240 mg/mL of copovidone (copolymer of vinylpyrrolidone and vinyl acetate) and 10-60 mg/mL of sodium lauryl sulfate were dissolved in tetrahydrofuran. A solution of the tadalafil pharmaceutical composition was prepared in a solution mixture of water = 2:1. The resulting solution was prepared at atmospheric pressure and ambient temperature and then fed to a spray dryer.

Different concentrations and solvent ratios were tested to determine the highest performance manufacturing conditions.

Based on these results, 5 mg/mL of tadalafil, 15 mg/mL of copovidone (copolymer of vinylpyrrolidone and vinyl acetate) and 0.625 mg/mL of sulfosuccinic acid were selected for the initial concentration. Dioctyl sodium. The highest performance ratio of these solutions was found to be at 1:4. Spray dried pharmaceutical formulations were used for in vivo dog PK studies.

Based on these results, 5 mg/mL of tadalafil, 15 mg/mL of copovidone (copolymer of vinylpyrrolidone and vinyl acetate) and 1.25 mg/mL of sodium lauryl sulfate were selected for the initial concentration. . The highest performance ratio of these solutions was found to be at 1:2.

Based on these results, 17 mg/mL of tadalafil, 62 mg/mL of copovidone (copolymer of vinylpyrrolidone and vinyl acetate) and 17 mg/mL of sodium lauryl sulfate were selected for the initial concentration. The solvent mixture was tetrahydrofuran: water = 2:1. The spray dried drug composition was used for in vivo dog PK studies.

Spray-dried (Yamato DL-410/GAS410) a solution mixture of the highest performance tadalafil pharmaceutical formulation to obtain a solid powder. Based production parameters used are as follows: T _inlet = 95 ℃, dry gas = 0.8m ³ / min, the solution feed rate = 18mL / min, atomization pressure = 1 bar, T _a = 63 ℃ -64 ℃.

Improved apparent solubility of tadalafil's drug composition

The apparent solubility of the tadalafil drug composition was measured by UV-VIS spectroscopy at room temperature. The solid tadalafil pharmaceutical compositions are dispersed in ultrapure water at a non-equivalent concentration range of 0.1-0.5 mg/mL of tadalafil. The resulting solution was filtered through a 100 nm disposable syringe filter. The tadalafil content of the filtrate was measured by UV-Vis spectrophotometry and the apparent solubility was calculated. The filtrate may contain particles of a tadalafil pharmaceutical composition that cannot be filtered using a 100 nm pore size filter.

When the 1 mg/mL tadalafil equivalent composition was separately dispersed in ultrapure water, the apparent solubility of the tadalafil pharmaceutical composition was 0.7 mg/mL.

The apparent solubility of the tadalafil drug composition is at least 0.7 mg/mL.

Improved dissolution profile of tadalafil drug composition

A dissolution test comparing the tadalafil drug composition, unformulated crystalline tadalafil and Cialis® (commercial formulation). The samples were dispersed in purified water at a concentration of 0.2 mg/mL. After 30 minutes, the analog gastric juice was added to the systems. After another 30 minutes, the pH was neutralized with sodium maleate and the FaSSIF solution was added. After filtration at different time points with a 0.1 μm pore size filter, the amount of dissolution was measured by UV-VIS spectrophotometry. For crystalline tadalafil or Cialis®, tadalafil does not dissolve more than 10%. The dissolution rate of tadalafil was over 60% for these pharmaceutical formulations within two hours (Figure 3).

Comparative in vitro PAMPA assay

The PAMPA permeability of tadalafil's pharmaceutical composition in water (H ₂ O), FaSSIF (Fa) and FeSSIF (Fe) media is more than 7.6 x 10 ^-6 cm/s and 7.2 x 10 ^-6 cm/s, respectively. and 4.3 x 10 ^-6 cm / s, while for the reference crystalline unformulated water, FaSSIF and FeSSIF media lines which ^{0.6 x 10 -6 cm / s,} 0.6 x 10 -6 cm / s and 0.8 * 10 ^{- 6} cm/s. The PAMPA permeability of Cialis® in water, FaSSIF and FeSSIF media is over 0.9 x 10 ^-6 cm/s, 0.8 x 10 ^-6 cm/s and 1.1 x 10 ^-6 cm/s, respectively.

Solid form stability

The PAMPA permeability of the solid tadalafil drug composition is used to monitor the physical stability of the drug formulation. PAMPA permeability was measured after storage under different conditions. Referring to Table 2, the compositions comprising DSS and SDS, respectively, stored at 40 ° C, 75% relative humidity for 2 months and 6 months did not show a significant decrease in measured PAMPA permeability under any of the conditions tested. .

Powder X-ray diffraction (pXRD) was used to monitor the stability of the solid tadalafil pharmaceutical formulation. pXRD was measured after storage of the pharmaceutical formulations under different conditions. Storage at 40 ° C / 75% relative humidity for 1 month did not show crystallization under any of the conditions tested (Figure 4).

Structural analysis

The morphology of the tadalafil drug was studied using a FEI Quanta 3D scanning electron microscope. Tadalafil pharmaceutical formulations contain spherical particles in the size range of less than 110 nm (Figure 7).

Structural analysis was performed by using a LabRAM HR UV-VIS-NIR spectrometer.

In an embodiment, the tadalafil drug composition is characterized by Raman spectroscopy as shown in Figures 6 and 7.

The structure of the tadalafil pharmaceutical formulation was investigated by powder X-ray diffraction (XRD) analysis (Philips PW 1050/1870 RTG powder diffractometer). These measurements show that the tadalafil XRD is amorphous in the pharmaceutical formulations (see Figure 4). The characteristic reflection of the tadalafil drug formulation on the diffraction pattern at 2θ of 43 and 44 can be attributed to the sample holder.

In vivo pharmacokinetics

In vivo PK testing in large animals

The Bigger study was conducted in the fasted state, using the drug composition of tadalafil at a dose of 20 mg/kg. These pharmaceutical compositions are administered as a reconstituted dispersion. Tadalafil fast absorption coefficient, where t _maximum value at 0.5-0.75 hours. Tadalafil Cialis® tablets from the slow absorption coefficient, wherein _{the maximum} value of t in the range of 2-4 hours. When the drug composition was administered, the maximum plasma concentration measured for Cialis® tablets was reached within 15 minutes (Figure 9). Comparison of these results with the published beagle dog pharmacokinetic data (at a dose of 10 mg/kg) indicates that for a composition comprising DSS and a composition comprising SDS, the granulated drug composition Oral bioavailability was 74% and 92%, respectively, while Cialis' oral bioavailability was 33% (Figure 10 and Table 3). Table 3 shows the pharmacokinetic parameters (N=3) after oral administration of 20 mg of Cialis® or a pharmaceutical formulation to a fasted Beagle.

Those skilled in the art can readily determine the essential characteristics from the foregoing description, and various changes and modifications can be made to adapt to various usages and conditions without departing from the spirit and scope.

The drawings, which are incorporated in and constitute a part The drawings are intended to explain specific modes to those skilled in the art.

Figure 1. Shows the redispersibility of tadalafil's pharmaceutical formulation in ultrapure water.

Figure 2. Shows PAMPA permeability and redispersibility of the selected tadalafil pharmaceutical formulation.

Figure 3. Shows the dissolution of unformulated crystalline tadalafil, Cialis®, tadalafil composition comprising DSS, and tadalafil composition comprising SDS.

Figure 4. Tadalafil-containing pharmaceutical formulation containing unformulated crystalline tadalafil, immediately after production (t0) and stored at 40 °C for 6 months (6M40), immediately after production (t0) and a dX-Da drug formulation containing DSS and a pXRD diffraction pattern of crystalline SDS after storage for 5 months at 40 °C (5M40).

Figure 5. SEM image showing a tadalafil pharmaceutical formulation containing copovidone (a copolymer of vinylpyrrolidone and vinyl acetate) and dioctyl sodium sulfosuccinate.

Figure 6. Raman spectra showing the following: A) unformified crystalline tadalafil; B) lyophilized reference tadalafil; C) copolyvidone (vinylpyrrolidone and acetic acid) a pharmaceutical formulation of a copolymer of vinyl ester) and dioctyl sodium sulfosuccinate; D) a copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate) and sulfosuccinic acid a control sample of dioctylsodium; E) copovidone (copolymer of vinylpyrrolidone and vinyl acetate); F) dioctyl sodium sulfosuccinate.

Figure 7. Raman spectra showing the following: A) unformified crystalline tadalafil; B) lyophilized tadalafil C) containing copolyvidone (vinylpyrrolidone and vinyl acetate) Copolymer) and a pharmaceutical formulation of tadalafil of sodium lauryl sulfate; D) a sample of a control containing copolyvidone (a copolymer of vinylpyrrolidone and vinyl acetate) and sodium lauryl sulfate; Copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate); F) dioctyl sodium sulfosuccinate.

Figure 8. Shows the plasma concentration of tadalafil after oral administration of 20 mg Cialis® or a drug composition comprising DSS and SDS to a fasted beagle dog. N=3.

Claims (31)

A stable pharmaceutical composition comprising: an active compound selected from the group consisting of tadalafil, a salt thereof or a derivative thereof; and at least one main pharmaceutical excipient selected from the group consisting of monoglycerides , polyethylene diglycerides and triglycerides and polyethylene glycol glycerides composed of mono- and di-esters of polyethylene glycol, polyethylene glycol, hydroxypropyl cellulose, poloxamer (ethylene oxide) Copolymer with propylene oxide block), copovidone, poly(2-ethyl-2- Oxazoline), povidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol 15 hydroxystearate, ethylene oxide/propylene oxide a functional block copolymer, an amino methacrylate copolymer, hydroxypropyl methylcellulose acetate succinate and d-alpha tocopherol polyethylene glycol 1000 succinate; the pharmaceutical composition is characterized in that it has At least one of the following characteristics: a) instantaneously redispersible in a physiologically relevant medium; b) in solid form and stable in a colloidal solution and/or dispersion; c) having at least 0.7 mg/mL An apparent solubility in water; and d) having a PAMPA permeability of at least 4 x 10 ^-6 cm/s when dispersed in a water, FaSSIF or FeSSIF biologically relevant medium, the permeability being for at least 6 months Not lowering.  The pharmaceutical composition according to claim 1, wherein the main pharmaceutical excipient is selected from the group consisting of hydroxypropylcellulose, poloxamer (copolymer of ethylene oxide and propylene oxide blocks), Copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate), povidone (polyvinylpyrrolidone), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymerization , an ethylene oxide/propylene oxide tetrafunctional block copolymer, and d-alpha tocopherol polyethylene glycol 1000 succinate.    The pharmaceutical composition according to claim 2, wherein the main pharmaceutical excipient is copovidone (copolymer of vinylpyrrolidone and vinyl acetate).    The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one secondary pharmaceutical excipient selected from the group consisting of sodium lauryl sulfate and sulfonate. Sodium dioctyl succinate, cetylpyridinium chloride, D-mannitol, sodium deoxycholate, poloxamer 407 and meglumine.    The pharmaceutical composition according to claim 4, wherein the secondary pharmaceutical excipient is selected from the group consisting of sodium dioctyl sulfosuccinate and sodium lauryl sulfate.    The pharmaceutical composition according to claim 5, wherein the secondary pharmaceutical excipient is dioctyl sodium sulfosuccinate and wherein the composition is pulled by the method as shown in FIG. Mann spectrum is characterized.    The pharmaceutical composition according to claim 5, wherein the secondary pharmaceutical excipient is sodium lauryl sulfate and wherein the composition is characterized by the Raman spectrum as shown in FIG. .    The pharmaceutical composition of claim 1, wherein the pharmaceutical formulation has a controlled particle size in a range between 10 nm and 500 nm.    The pharmaceutical composition according to claim 8, wherein the particle size is between 10 nm and 200 nm.   The pharmaceutical composition of claim 1, wherein the pharmaceutical composition exhibits an earlier _tmax and a time of onset when compared to a commercially available drug containing tadalafil.  The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has at least two of the characteristics described in a) to d).    The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has at least three of the characteristics described in a) to d).    The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition exhibits an X-ray amorphous characteristic in a solid form.    The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has an increased dissolution rate compared to Cialis®.    A pharmaceutical composition according to claim 1, comprising: at least one main pharmaceutical excipient which is a copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate); and sulfosuccinic acid At least one secondary pharmaceutical excipient of dioctyl sodium or sodium lauryl sulfate in a total amount ranging from about 1.0% by weight to about 95.0% by weight, based on the total weight of the pharmaceutical composition.    The pharmaceutical composition according to claim 15, comprising: at least one main pharmaceutical excipient which is a copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate); and sulfosuccinic acid At least one secondary pharmaceutical excipient of octyl sodium or sodium lauryl sulfate in a total amount ranging from about 50.0% by weight to about 95.0% by weight, based on the total weight of the pharmaceutical composition.    A stable pharmaceutical composition comprising: an active compound selected from the group consisting of tadalafil, a salt thereof or a derivative thereof; and at least one major copolyketone (copolymer of vinylpyrrolidone and vinyl acetate) a pharmaceutical excipient; and at least one secondary pharmaceutical excipient which is dioctyl sulfosuccinate or sodium lauryl sulfate; wherein the pharmaceutical composition is obtained by a mixing process.    A method for the preparation of a pharmaceutical composition according to claim 17, which comprises the steps of: containing tadalafil, a salt thereof, or a derivative thereof in a pharmaceutically acceptable solvent, and a pharmaceutically acceptable solution of at least one major pharmaceutical excipient which is a copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate) and contains sodium dioctyl sulfosuccinate or sodium lauryl sulfate An aqueous solution of at least one secondary pharmaceutical excipient is mixed.    A method for the preparation of a pharmaceutical composition according to claim 17, which comprises the steps of dissolving tadalafil in a pharmaceutically acceptable solvent and a pharmaceutically acceptable solvent mixture of water, a salt thereof, or a derivative thereof, and at least one main pharmaceutical excipient which is a copolyvidone (copolymer of vinylpyrrolidone and vinyl acetate), and is sodium dioctyl sulfosuccinate or lauryl sulfate At least one secondary pharmaceutical excipient for sodium.    The method of any one of claims 18 or 19, wherein the pharmaceutically acceptable solvent is selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, acetone, acetonitrile, and dimethylene. Anthraquinone, tetrahydrofuran, methyl ethyl ketone or a combination thereof.    The method of claim 20, wherein the pharmaceutically acceptable solvent is tetrahydrofuran.    The method of any one of claims 18 or 19, wherein the pharmaceutically acceptable solvent comprises from 0.1% to 99.9% by weight of the final solution mixture.    The method of claim 22, wherein the aqueous solution comprises from 40% to 99.99% by weight of the final solution mixture.    The method of claim 23, wherein the aqueous solution comprises from 60% to 99.99% by weight of the final solution mixture.    A pharmaceutical dosage form comprising a pharmaceutical composition according to any one of claims 1 or 15 together with a pharmaceutically acceptable excipient.    A pharmaceutical dosage form comprising the pharmaceutical composition according to claim 25, wherein the pharmaceutical dosage form is suitable for oral administration.    A pharmaceutical composition according to any one of claims 1 to 15 for use in the manufacture of a medicament for treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy .    The pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment of erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy.    A method of treating erectile dysfunction, benign prostatic hyperplasia, pulmonary hypertension, and Duchenne muscle dystrophy, the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 or 15. .   A method for reducing _tmax and onset time when compared to current oral formulations, the method comprising orally administering a pharmaceutical composition according to any one of claims 1 or 15 or as The pharmaceutical dosage form described in claim 25 of the patent application.  A stable pharmaceutical composition comprising: a) 10% to 40% by weight of tadalafil, a salt thereof, or a derivative thereof; b) 35% to 70% by weight of copovidone (vinyl a copolymer of pyrrolidone and vinyl acetate); and c) 5% to 50% by weight of sodium dioctyl sulfosuccinate or sodium lauryl sulfate wherein the pharmaceutical formulation has between 10 nm and 500 nm Controlled particle size within the range; and wherein the drug composition is not obtainable by milling, high pressure homogenization, and encapsulation.