# US 2021/0275531 A1 · Phosphodiesterase-5 inhibitor combinations, methods of making, and methods of use thereof

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- Number: US 2021/0275531 A1
- Document ID: US20210275531A1
- Status: Published application
- Kind: A1
- Application number: 17/190,774
- Filed: 2021-03-03
- Published: 2021-09-09
- Earliest claimed: 2020-03-04
- Applicants: VK Research Associates Inc
- Inventors: Siva Rama Krishna Nutalapati; Victor Chehebar
- Web page: https://patentgrep.com/patent/US20210275531A1

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2068: {Compounds of unknown constitution, e.g. material from plants or animals (oils, fats, waxes, shellac A61K9/2013)}
- A61K 9/209: {containing drug in at least two layers or in the core and in at least one outer layer}
- A61K 9/2095: {Tabletting processes}
- A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 31/138: Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377)
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 31/195: having an amino group
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/415: 1,2-Diazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/616: by carboxylic acids, e.g. acetylsalicylic acid
- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- A61K 31/80: Polymers containing hetero atoms not provided for in groups A61K31/755 - A61K31/795
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61K 33/10: Carbonates; Bicarbonates
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/36: Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Combination oral formulations comprising a phosphodiesterase-5 inhibitor and an additional active agent that can reduce or eliminate a side effect associated with phosphodiesterase-5 inhibitor therapy are described. Methods of treatment using the combinations and kit formulations are included.

## Claims

### Claim 1

A combination oral formulation, comprising
a phosphodiesterase-5 inhibitor; and
an additional active agent that can reduce or eliminate a side effect associated with phosphodiesterase-5 inhibitor, wherein the additional active agent is an analgesic, an antacid, an anti-migraine agent, a H2 blocker, a proton pump inhibitor, an anti-gas agent, or a combination thereof.

### Claim 2 (depends on 1)

The formulation of claim 1, wherein
the phosphodiesterase-5 inhibitor is avanafil, sildenafil, tadalafil, vardenafil, lodenafil, udenafil, mirodenafil, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the phosphodiesterase-5 inhibitor is avanafil, sildenafil citrate, tadalafil, vardenafil monohydrochloride, or a combination thereof;
the analgesic is a non-steroidal, anti-inflammatory or a pharmaceutically acceptable salt thereof, specifically the analgesic is acemetacin, acetaminophen, aminoprofen, aspirin, benoxaprofen, bucloxic acid, carisoprodol, carprofen, celecoxib, clidanac, cyclobenzaprine, diclofenac, diflurisal, fentiazac, flufenamic acid, flurbiprofen, fenoprofen, flubufen, flufenisal, isoxicam, ketoprofen, ibuprofen, indomethacin, indoprofen, ketorolac, naproxen, nabumetone, meclofenamic acid, meclofenate, mefenamic acid, metaxalone, methocarbamol, muroprofen, niflumic acid, orphenadrine, oxaprozin, oxpinac, piroprofen, piroxicam, pramoprofen, sudoxicam, sulindac, suprofen, tiaprofenic acid, tiopinac, tolmetin, tolfenamic acid, trioxaprofen, zidometacin, zomepirac, or a pharmaceutically acceptable salt thereof, and more specifically the analgesic is naproxen sodium, orphenadrine citrate, or a combination thereof;
the antacid is a pharmaceutically acceptable alkali or alkaline earth metal carbonate, a pharmaceutically acceptable alkali or alkaline earth metal hydroxide, or a combination thereof, specifically calcium carbonate, magnesium carbonate, sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, or a combination thereof;
the anti-migraine agent is a beta blocker, a calcium channel blocker, an antidepressant, an antiseizure medication, a CGRP inhibitor, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, timolol, a pharmaceutically acceptable salt thereof, or a combination thereof, the calcium channel blocker is nimodipine, verapamil, a pharmaceutically acceptable salt thereof, or a combination thereof, the antidepressant is amitriptyline, nortriptyline, a pharmaceutically acceptable salt thereof, or a combination thereof, the antiseizure medication is gabapentin, topiramate, valproic acid, a pharmaceutically acceptable salt thereof, or a combination thereof, and the CGRP inhibitor is erenumab, fremanezumab, a pharmaceutically acceptable salt thereof, or a combination thereof;
the H2 blocker is cimetidine, famotidine, nizatidine, ranitidine, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the 1-12 blocker is cimetidine hydrochloride, famotidine, nizatidine, ranitidine hydrochloride, or a combination thereof;
the proton pump inhibitor is esomeprazole, dexlansoprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the proton pump inhibitor is esomeprazole magnesium, esomeprazole sodium, esomeprazole strontium, dexlansoprazole, lansoprazole, omeprazole magnesium, omeprazole sodium, omeprazole strontium, pantoprazole sodium, rabeprazole sodium, or a combination thereof; and
the anti-gas agent is simethicone.

### Claim 3 (depends on 1)

The formulation of claim 1, wherein each of the phosphodiesterase-5 inhibitor and the additional active agent individually are formulated for immediate release or controlled release.

### Claim 4 (depends on 3)

The formulation of claim 3, wherein the controlled release is achieved with a controlled release matrix, a functional coating, or a combination thereof; and
wherein the controlled release is extended release, delayed release, pulsed release, or a combination thereof.

### Claim 5 (depends on 1)

The formulation of claim 1, wherein the oral formulation is a solid, semisolid, or liquid formulation; specifically wherein the oral formulation is a tablet, a capsule, a pellet, a film, a sachet, a powder, a chewable gummy, a solution, a suspension, or an emulsion.

### Claim 6 (depends on 1)

The formulation of claim 1, wherein the oral formulation is a compressed tablet or a capsule.

### Claim 7 (depends on 1)

The formulation of claim 1, wherein
the oral formulation is an immediate release tablet or capsule formulation comprising a combination of sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and enteric coated esomeprazole subunits as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release Propranolol HCl subunits as the beta blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of migraine, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor, immediate release and/or extended release naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic, and enteric coated esomeprazole subunits as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, dyspepsia, gastritis (heartburn), or a combination thereof, and wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and immediate release ranitidine hydrochloride as the H2 blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and immediate release calcium carbonate, magnesium carbonate, sodium bicarbonate, aluminum hydroxide, or magnesium hydroxide as the antacid for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and enteric coated esomeprazole granules as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and an extended release Naproxen Sodium, acetaminophen, ibuprofen, or celecoxib pellets as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof; or
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release Propranolol HCl subunits as the beta blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of migraine, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles.

### Claim 8 (depends on 1)

A kit comprising the formulation of claim 1.

### Claim 9

A method of treating a condition treatable with phosphodiesterase-5 inhibitor therapy, comprising
administering a combination oral formulation comprising a phosphodiesterase-5 inhibitor and an additional active agent to a patient in need of phosphodiesterase-5 inhibitor therapy thereof;
wherein the additional active agent is an analgesic, an antacid, an anti-migraine agent, a H2 blocker, a proton pump inhibitor, an anti-gas agent, or a combination thereof; and
wherein the combination results in a reduction or elimination of a side effect associated with phosphodiesterase-5 inhibitor therapy alone.

### Claim 10 (depends on 9)

The method of claim 9, wherein the condition to be treated is erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, and
wherein the side effect is headache, migraine, back ache, myalgia, dyspepsia, gastritis (heartburn), or a combination thereof.

### Claim 11 (depends on 9)

The method of claim 9, wherein
the phosphodiesterase-5 inhibitor is avanafil, sildenafil, tadalafil, vardenafil, lodenafil, udenafil, mirodenafil, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the phosphodiesterase-5 inhibitor is avanafil, sildenafil citrate, tadalafil, vardenafil monohydrochloride, or a combination thereof;
the analgesic is a non-steroidal, anti-inflammatory or a pharmaceutically acceptable salt thereof, specifically the analgesic is acemetacin, acetaminophen, aminoprofen, aspirin, benoxaprofen, bucloxic acid, carisoprodol, carprofen, celecoxib, clidanac, cyclobenzaprine, diclofenac, diflurisal, fentiazac, flufenamic acid, flurbiprofen, fenoprofen, flubufen, flufenisal, isoxicam, ketoprofen, ibuprofen, indomethacin, indoprofen, ketorolac, naproxen, nabumetone, meclofenamic acid, meclofenate, mefenamic acid, metaxalone, methocarbamol, muroprofen, niflumic acid, orphenadrine, oxaprozin, oxpinac, piroprofen, piroxicam, pramoprofen, sudoxicam, sulindac, suprofen, tiaprofenic acid, tiopinac, tolmetin, tolfenamic acid, trioxaprofen, zidometacin, zomepirac, or a pharmaceutically acceptable salt thereof, and more specifically the analgesic is naproxen sodium, orphenadrine citrate, or a combination thereof;
the antacid is a pharmaceutically acceptable alkali or alkaline earth metal carbonate, a pharmaceutically acceptable alkali or alkaline earth metal hydroxide, or a combination thereof, specifically calcium carbonate, magnesium carbonate, sodium bicarbonate, aluminum hydroxide, magnesium hydroxide, or a combination thereof;
the anti-migraine agent is a beta blocker, a calcium channel blocker, an antidepressant, an antiseizure medication, a CGRP inhibitor, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the beta blocker is acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol, timolol, a pharmaceutically acceptable salt thereof, or a combination thereof, the calcium channel blocker is nimodipine, verapamil, a pharmaceutically acceptable salt thereof, or a combination thereof, the antidepressant is amitriptyline, nortriptyline, a pharmaceutically acceptable salt thereof, or a combination thereof, the antiseizure medication is gabapentin, topiramate, valproic acid, a pharmaceutically acceptable salt thereof, or a combination thereof, and the CGRP inhibitor is erenumab, fremanezumab, a pharmaceutically acceptable salt thereof, or a combination thereof;
the H2 blocker is cimetidine, famotidine, nizatidine, ranitidine, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the 1-12 blocker is cimetidine hydrochloride, famotidine, nizatidine, ranitidine hydrochloride, or a combination thereof;
the proton pump inhibitor is esomeprazole, dexlansoprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole, a pharmaceutically acceptable salt thereof, or a combination thereof, specifically the proton pump inhibitor is esomeprazole magnesium, esomeprazole sodium, esomeprazole strontium, dexlansoprazole, lansoprazole, omeprazole magnesium, omeprazole sodium, omeprazole strontium, pantoprazole sodium, rabeprazole sodium, or a combination thereof; and
the anti-gas agent is simethicone.

### Claim 12 (depends on 9)

The method of claim 9, wherein each of the phosphodiesterase-5 inhibitor and the additional active agent individually are formulated for immediate release or controlled release.

### Claim 13 (depends on 12)

The method of claim 12, wherein the controlled release is achieved with a controlled release matrix, a functional coating, or a combination thereof; and
wherein the controlled release is extended release, delayed release, pulsed release, or a combination thereof.

### Claim 14 (depends on 9)

The method of claim 9, wherein the oral formulation is a solid, semisolid, or liquid formulation; specifically wherein the oral formulation is a tablet, a capsule, a pellet, a film, a sachet, a powder, a chewable gummy, a solution, a suspension, or an emulsion.

### Claim 15 (depends on 9)

The method of claim 9, wherein the oral formulation is a compressed tablet or a capsule.

### Claim 16 (depends on 9)

The method of claim 9, wherein
the oral formulation is an immediate release tablet or capsule formulation comprising a combination of sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and enteric coated esomeprazole subunits as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release Propranolol HCl subunits as the beta blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of migraine, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor, immediate release and/or extended release naproxen sodium, acetaminophen, ibuprofen, or celecoxib as the analgesic, and enteric coated esomeprazole subunits as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, dyspepsia, gastritis (heartburn), or a combination thereof, and wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and immediate release ranitidine hydrochloride as the H2 blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a tablet or a capsule formulation comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and immediate release calcium carbonate, magnesium carbonate, sodium bicarbonate, aluminum hydroxide, or magnesium hydroxide as the antacid for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and enteric coated esomeprazole granules as the proton pump inhibitor for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of dyspepsia, gastritis (heartburn), or a combination thereof;
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and an extended release Naproxen Sodium, acetaminophen, ibuprofen, or celecoxib pellets as the analgesic for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of headache, migraine, back pain, myalgia, or a combination thereof; or
the oral formulation is a powder for suspension comprising a combination of immediate release sildenafil citrate or tadalafil as the phosphodiesterase-5 inhibitor and extended release Propranolol HCl subunits as the beta blocker for the treatment of erectile dysfunction, benign prostatic hyperplasia, idiopathic pulmonary hypertension, premature ejaculation associated with erectile dysfunction, high altitude illness, penile rehabilitation after radical prostatectomy, angina pectoris, heart failure, stroke, peripheral neuropathy, male infertility, peripheral arterial disease, diabetic nephropathy, or a combination thereof, wherein the patient experiences a reduction or elimination of migraine, wherein the subunits are a plurality of granules, microtablets, minitablets, caplets, pellets, or particles.