EP4611761A1

EP4611761A1 - A pharmaceutical formulation for improving obstructive sleep apnea

Info

Publication number: EP4611761A1
Application number: EP23942642.2A
Authority: EP
Inventors: Seyed Mohammad MOUSAVI MIRZAEI; Zhara KIANI; Mojgan TAVAKOLI
Original assignee: Melikoglu Ahmet
Current assignee: Melikoglu Ahmet
Priority date: 2023-09-04
Filing date: 2023-09-04
Publication date: 2025-09-10
Also published as: WO2025052157A1; EP4611761A4

Abstract

A pharmaceutical formulation for improving obstructive sleep apnea. the pharmaceutical formulation comprising a pharmaceutical water solution, the pharmaceutical water solution comprising furosemide with a final concentration of 6.4 mg/ml (with respect to the final volume of the pharmaceutical water solution), diclofenac sodium with a final concentration of 4.5 mg/ml (with respect to the final volume of the pharmaceutical water solution); propylene glycol with a final concentration of 37.8 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium hydroxide with a final concentration of 0.85 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium chloride with a final concentration of 4.8 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium metabisulfite with a final concentration of 0.18 mg/ml (with respect to the final volume of the pharmaceutical water solution); and a preservative including benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution).

Description

A PHARMACEUTICAL FORMULATION FOR IMPROVING OBSTRUCTIVE SLEEP APNEA

TECHNICAL FIELD

[0001] The present disclosure is generally related to an exemplary pharmaceutical formulation for improving obstructive sleep apnea and snoring and an exemplary method for preparation thereof, and in particular to an exemplary pharmaceutical formulation comprising furosemide and diclofenac sodium.

BACKGROUND

[0002] Obstructive sleep apnea (OSA) is a prevalent disease marked by recurrent closure of the pharyngeal airway while the patient is asleep. When awake, affected people typically breathe very properly, but they struggle to keep their airways open while they are sleeping. Most frequently, the collapse happens behind the uvula, soft palate, tongue, or a combination of these. Airway opening typically coincides with arousal from sleep, though this is not always the case. These pauses in breathing are typically accompanied by the onset of hypoxia and hypercapnia, which may be quite serious. Thus, the person alternates between apnea and hyperpnea, along with the associated intermittent hypoxia and hypercapnia, and between sleep and alertness throughout the course of the night. People who have sleep apnea frequently complain of daytime tiredness, loud snoring, and being observed gasping, choking, or having an apneic fit. Additionally, they could have depression, sexual dysfunction, and morning headaches. Patients with these complaints are then directed to a sleep laboratory for an overnight study, during which sleep, breathing effort, oxygen saturation, an EKG, and an electromyogram (EMG) of the leg are all monitored. Apnea and hypopneas are used to measure aberrant respiratory episodes. A hypopnea is comparable to an apnea but does not result in full cessation of breathing for 10 seconds or longer. In general, a hypopnea is only recorded if it is accompanied by a 3% to 4% decrease in arterial oxygen saturation or an awakening from sleep. The apnea hypopnea index (AHI) measures how many apneas and hypopneas occur throughout each hour of sleep. Conventionally, an AHI of 5 or more is regarded as abnormal. For an OSA syndrome diagnosis, there must be both an AHI more than 5 and daytime symptoms. AHI values of 5 to 15 are regarded as mild, 15 to 30 as moderate, and 30 or above as severe OSA.

[0003] According to gender and ethnicity, the most complete data to date indicate that OSA (AHI > 15) affects between 2% and 14% of adults. African Americans may have a higher prevalence. In the absence of symptoms, 24% of men and 9% of women have an AHI above 5. However, since the publication of this study in 1993, rates of obesity, one of the main causes of OSA (more on this later), have significantly increased. More recent estimates state that 6% to 7% of individuals have moderate to severe OSA (AHI > 15), and 20% of adults have mild OSA (AHI 5-15). Thus, it is a condition that is common.

[0004] Neurocognitive and cardiovascular effects of OSA are the two broad groups for its clinical effects. While the majority of evidence points to intermittent hypoxia as the cause of the negative cardiovascular outcomes, the neurocognitive issues are thought to be caused by the sleep disruption brought on by sleep apnea. But neither of the conclusions has been adequately supported. Negative neurocognitive effects include daytime tiredness, less concentration, a rise in industrial and vehicular accidents, and an overall decline in quality of life. While not always normalized, the majority of these issues can be significantly improved with apnea therapy. Hypertension, diabetes, cardiac arrhythmias, strokes, myocardial infarction, and the onset of congestive heart failure are just a few of the possible cardiovascular effects of OSA. Cross sectional, longitudinal, and therapeutic case series investigations are among the evidence that links sleep apnea to these unfavourable outcomes. However, no randomized, controlled trials have been conducted to evaluate the impact of OSA therapy on hard endpoint cardiovascular events. Because of this, it is now premature to declare the relationship between OSA and heart/vascular disease to be conclusive. Nasal masks are frequently used to deliver continuous positive airway pressure (CPAP), the primary treatment for OSA at the moment, but nasal pillows and masks are also frequently employed. The pharyngeal airway is thought to simply be pneumatically split open by CPAP, enabling regular breathing as you sleep. The main drawback of CPAP in treating apnea is compliance, which is almost completely unaffected by it. Numerous people are merely unable to utilize CPAP frequently enough for it to be a successful therapy for them. Other strategies must be taken into account when CPAP is not tolerated, and they often include oral appliances and upper airway surgery. Thus, there is a need to develop a formulation that contain effective therapeutic agents, with high efficacy to use in patients who suffer from obstructive sleep apnea which may not have the trouble of CPAP for them.

SUMMARY

This summary is intended to provide an overview of the subject matter of the present disclosure, and is not intended to identify essential elements or key elements of the subject matter, nor is it intended to be used to determine the scope of the claimed implementations. Its sole purpose is to present some concepts of one or more exemplary aspects in a simplified form as a prelude to the more detailed description that is presented later. The proper scope of the present disclosure may be ascertained from the claims set forth below in view of the detailed description below and the drawings.

[0005] One or more exemplary embodiments describe an exemplary pharmaceutical formulation for improving obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may comprise an exemplary pharmaceutical water solution. In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise furosemide, diclofenac sodium, propylene glycol, sodium hydroxide, sodium chloride, sodium metabisulfite, and an exemplary preservative. In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise furosemide with a final concentration between 0.9 mg/ml and 9.6 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); diclofenac sodium with a final concentration between 0.5 mg/ml and 6.7 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); propylene glycol with a final concentration between 4.5 mg/ml and 56.25 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium hydroxide with a final concentration between 0.1 mg/ml and 1.2 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium chloride with a final concentration between 0.6 mg/ml and 7.2 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium metabisulfite with a final concentration between 0.02 mg/ml and 0.27 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); and an exemplary preservative including benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution). In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise furosemide with a final concentration of 6.4 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); diclofenac sodium with a final concentration of 4.5 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); propylene glycol with a final concentration of 37.8 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium hydroxide with a final concentration of 0.85 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium chloride with a final concentration of 4.8 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium metabisulfite with a final concentration of 0.18 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); and benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution).

[0006] In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary nasal spray. In an exemplary embodiment, an exemplary nasal spray is applied between two puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary nasal drop. In an exemplary embodiment, an exemplary nasal drop is applied between two drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary oral spray. In an exemplary embodiment, an exemplary oral spray is applied between two puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary oral drop. In an exemplary embodiment, an exemplary oral drop is applied between two drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.

[0007] This Summary may introduce a number of concepts in a simplified format; the concepts are further disclosed within the “Detailed Description” section. This Summary is not intended to configure essential/key features of the claimed subject matter, nor is intended to limit the scope of the claimed subject matter. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] The novel features which are believed to be characteristic of the present disclosure, as to its structure, organization, use and method of operation, together with further objectives and advantages thereof, will be better understood from the following drawings in which an exemplary embodiment will now be illustrated by way of example. It is expressly understood, however, that the drawings are for the purpose of illustration and description only and are not intended as a definition of the limits of one or more exemplary embodiments. One or more exemplary embodiments will now be described by way of example in association with the accompanying drawings in which:

[0009] FIG. 1A illustrates an exemplary method for preparing an exemplary pharmaceutical formulation, consistent with one or more exemplary embodiments of the present disclosure; FIG. IB illustrates an exemplary method for preparing an exemplary solution of furosemide, consistent with one or more exemplary embodiments of the present disclosure; and FIG. 1C illustrates an exemplary method for preparing an exemplary solution of diclofenac sodium, consistent with one or more exemplary embodiments of the present disclosure.

DETAILED DESCRIPTION

[00010] In the following detailed description, numerous specific details are set forth by way of examples to provide a thorough understanding of the relevant teachings related to exemplary embodiments. However, it should be apparent that the present teachings may be practiced without such details. In other instances, well known methods, procedures, components, and/or circuitry have been described at a relatively high-level, without detail, in order to avoid unnecessarily obscuring aspects of the present teachings. [00011] The following detailed description is presented to enable a person skilled in the art to make and use the methods and devices disclosed in one or more exemplary embodiments. For purposes of explanation, specific nomenclature is set forth to provide a thorough understanding of one or more exemplary embodiments. However, it will be apparent to one skilled in the art that these specific details are not required to practice the disclosed exemplary embodiments. Descriptions of specific exemplary embodiments are provided only as representative examples. Various modifications to exemplary implementations will be plain to one skilled in the art, and the general principles defined herein may be applied to other implementations and applications without departing from the scope of one or more exemplary embodiments. The present disclosure is not intended to be limited to the implementations shown, but is to be accorded the widest possible scope consistent with the principles and features disclosed herein.

[00012] Obstructive sleep apnea (OSA) is a prevalent disease marked by recurrent closure of the pharyngeal airway while the patient is asleep. When awake, affected people typically breathe very properly, but they struggle to keep their airways open while they are sleeping. People who have sleep apnea frequently complain of daytime tiredness, loud snoring, and being observed gasping, choking, or having an apneic fit. Additionally, they could have depression, sexual dysfunction, anxiety, sleep disorders, Alzheimer, Parkinson, cardiovascular disease, and morning headaches. Disclosed here is an exemplary pharmaceutical formulation that may be reduced and may improve the symptoms of obstructive sleep apnea. One of the pathologies of obstructive sleep apnea is edema and inflammation in the epithelial cells of the upper respiratory tract. Therefore, anti-edema and anti-inflammatory compounds may have therapeutic effects in these cases. Furosemide may help this improvement by acting directly on the blood vessels. A loop diuretic with a long history of usage is furosemide. The Food and Drug Administration (FDA) has approved furosemide to treat illnesses such the nephrotic syndrome that have volume overload and edema as a result of liver failure, kidney failure, or congestive heart failure aggravation. By blocking the sodium-chloride cotransport system, furosemide prevents the tubular reabsorption of sodium and chloride in the proximal and distal tubules as well as the thick ascending loop of Henle, leading to an increased excretion of water along with sodium, chloride, magnesium, and calcium. Diclofenac sodium is a non-steroid anti-inflammatory medication with a novel chemical structure that has potent anti-inflammatory, analgesic, and antipyretic effects. In vitro and in vivo prostaglandin production is inhibited, and this inhibitory effect at least partially accounts for the preparation's mode of action. Diclofenac sodium exhibits a wide therapeutic range. Additionally, compared to other very effective non-steroid anti-inflammatory drugs, its gastrointestinal tolerance is superior. In the human body, diclofenac sodium is bio-transformed into two additional metabolites, both of which have biological activity. However, the activity of these two metabolites is comparable to that of phenylbutazone and significantly weaker than that of unmodified diclofenac sodium.

[00013] In an exemplary embodiment, an exemplary pharmaceutical formulation may comprise an exemplary pharmaceutical water solution. In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise an exemplary anti-inflammatory agent, an exemplary loop-diuretic agent, propylene glycol, sodium hydroxide, sodium metabisulfite, and an exemplary preservative. In an exemplary embodiment, “antiinflammatory agent” may refer to drugs that are used to relieve pain, and reduce inflammation. In an exemplary embodiment, an exemplary anti-inflammatory agent may be selected from the group consisting of an exemplary non-steroidal anti-inflammatory drug and an exemplary steroidal anti-inflammatory drug (corticosteroids). In an exemplary embodiment, an exemplary non-steroidal anti-inflammatory drug may be selected from the group consisting of diclofenac sodium, naproxen, meloxicam, indomethacin, mefenamic acid, celecoxib, aspirin, and baclofen. In an exemplary embodiment, an exemplary steroidal anti-inflammatory drug (corticosteroids) may be selected from the group consisting of triamcinolone, methylprednisolone, budesonide, dexamethasone, prednisolone, hydrocortisone, beclomethasone, and mometasone. In an exemplary embodiment, an exemplary loop diuretic may be furosemide. In an exemplary embodiment, an exemplary preservative may be selected from the group consisting of benzalkonium chloride, methyl paraben, benzyl alcohol, and chlorobutanol.

[00014] In an exemplary embodiment, an exemplary pharmaceutical formulation may comprise an exemplary pharmaceutical water solution. In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise furosemide, diclofenac sodium, propylene glycol, sodium hydroxide, sodium chloride, sodium metabisulfite, and an exemplary preservative. In an exemplary embodiment, an exemplary pharmaceutical water solution may comprise furosemide with a final concentration between 0.09 mg/ml and 9.6 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution), diclofenac sodium with a final concentration between 0.5 mg/ml and 6.7 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution), propylene glycol with a final concentration between 4.5 mg/ml and 56.25 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution), sodium hydroxide with a final concentration between 0.1 mg/ml and 1.2 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution); sodium chloride with a final concentration between 0.6 mg/ml and 7.2 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution), sodium metabisulfite with a final concentration between 0.02 mg/ml and 0.27 mg/ml (with respect to the final volume of the exemplary pharmaceutical water solution), and an exemplary preservative including benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution).

[00015] In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary nasal spray. In an exemplary embodiment, an exemplary nasal spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary nasal drop. In an exemplary embodiment, an exemplary nasal drop is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary oral spray. In an exemplary embodiment, an exemplary oral spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea. In an exemplary embodiment, an exemplary pharmaceutical formulation may be formulated as an exemplary oral drop. In an exemplary embodiment, an exemplary oral drop is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.

[00016] One or more exemplary embodiments describe an exemplary method for preparing an exemplary pharmaceutical formulation for improving obstructive sleep apnea. Referring to the figures, FIG. 1 illustrates flowchart of exemplary method 100 for preparing an exemplary pharmaceutical formulation for improving obstructive sleep apnea, consistent with one or more exemplary embodiments of the present disclosure. In an exemplary embodiment, exemplary method 100 may comprise: forming an exemplary solution of furosemide (step 102); forming an exemplary solution of diclofenac sodium (step 104); forming an exemplary solution of an exemplary pharmaceutical formulation (step 106); mixing the exemplary solution of the exemplary pharmaceutical formulation at a predetermined temperature for a predetermined time duration (step 108); adding an exemplary preservative to the exemplary solution of the exemplary pharmaceutical formulation (step 110); and adjusting an exemplary pH value of the exemplary solution of the exemplary pharmaceutical formulation between 6 and 8.5 (step 112).

[00017] In an exemplary embodiment, details of step 102 for preparing an exemplary solution of furosemide are described in context of elements presented in FIG. IB. FIG. IB illustrates an exemplary method of step 102 for preparing an exemplary solution of furosemide, consistent with one or more exemplary embodiments of the present disclosure. In an exemplary embodiment, an exemplary method 114 of step 102 may comprise: forming an exemplary first solution comprising sodium chloride and sodium hydroxide (step 116); mixing the exemplary first solution at a predetermined temperature for a predetermined time duration (step 118); forming an exemplary second solution comprising furosemide and the exemplary first solution (step 120); mixing the exemplary second solution at a predetermined temperature for a predetermined time duration (step 122); and adjusting an exemplary pH value of the exemplary second solution at a range between 8.5 to 9.1 (step 124).

[00018] In further detail with respect to step 116, step 116 may include forming an exemplary first solution comprising sodium chloride and sodium hydroxide. In an exemplary forming an exemplary first solution may include dissolving sodium chloride and sodium hydroxide in water in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, dissolving sodium chloride and sodium hydroxide in water in an exemplary laboratory container may include adding an exemplary powder of sodium chloride (e.g., using spatula) with a final concentration of about 75 mg/ml (with respect to the final volume of the exemplary solution of furosemide), an exemplary powder of sodium hydroxide (e.g., using spatula) with a final concentration of about 1.35 mg/ml (with respect to the final volume of the exemplary solution of furosemide), and water (e.g., using a sampler, graduated cylinder/tube, etc.) to an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer. In an exemplary embodiment, an exemplary powder of sodium chloride may be weighed by an exemplary laboratory scale. In an exemplary embodiment, an exemplary powder of sodium hydroxide may be weighed by an exemplary laboratory scale.

[00019] In further detail with respect to step 118, step 118 may include mixing the exemplary first solution at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary first solution may include stirring the exemplary first solution using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00020] In further detail with respect to step 120, step 120 may include forming an exemplary second solution comprising furosemide and the exemplary first solution. In an exemplary forming an exemplary second solution may include dissolving furosemide in the exemplary first solution in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, dissolving furosemide in the exemplary first solution may include adding an exemplary powder of furosemide (e.g., using spatula) with a final concentration of about 10 mg/ml (with respect to the final volume of the exemplary solution of furosemide) to the exemplary first solution in an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer. In an exemplary embodiment, an exemplary powder of furosemide may be weighed by an exemplary laboratory scale.

[00021] In further detail with respect to step 122, step 122 may include mixing the exemplary second solution at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary second solution may include stirring the exemplary second solution using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00022] In further detail with respect to step 124, step 124 may include adjusting an exemplary pH value of the exemplary second solution at a range between 8.5 and 9.1. In an exemplary embodiment, adjusting an exemplary pH value of the exemplary second solution may include adding hydrochloric acid or sodium hydroxide to the exemplary second solution in an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00023] In an exemplary embodiment, details of step 104 for preparing an exemplary solution of diclofenac sodium are described in context of elements presented in FIG. 1C. FIG. 1C illustrates an exemplary method 126 of step 104 for preparing an exemplary solution of diclofenac sodium, consistent with one or more exemplary embodiments of the present disclosure. In an exemplary embodiment, an exemplary method of step 104 may comprise: forming an exemplary third solution comprising sodium metabisulfite and sodium hydroxide (step 128); mixing the exemplary third solution at a predetermined temperature for a predetermined time duration (step 130) forming an exemplary liquid mixture comprising diclofenac sodium and propylene glycol (step 132); mixing the exemplary liquid mixture at a predetermined temperature for a predetermined time duration (step 134); forming an exemplary fourth solution comprising the exemplary third solution and the exemplary liquid mixture (step 136); mixing the exemplary fourth solution at a predetermined temperature for a predetermined time duration (step 138); and adjusting an exemplary pH value of the exemplary fourth solution at a range between 7 and 8.5 (step 140).

[00024] In further detail with respect to step 128, step 128 may include forming an exemplary third solution comprising sodium metabisulfite and sodium hydroxide. In an exemplary embodiment, forming an exemplary third solution may include adding sodium meta bisulfide, sodium hydroxide, and hot water to an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, adding sodium meta bisulfide, sodium hydroxide, and hot water to an exemplary laboratory container may include adding an exemplary powder of sodium meta bisulfide (e.g., using a spatula) with a final concentration of about Img/ml (with respect to the final volume of the exemplary solution of diclofenac sodium), an exemplary powder of sodium hydroxide (e.g., using a spatula) with a final concentration of about 0.383 mg/ml (with respect to the final volume of the exemplary solution of diclofenac sodium) and an exemplary hot water (e.g., using a sampler, graduated cylinder/tube, etc.) with a temperature between 60 and 100 °C to an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer. In an exemplary embodiment, an exemplary powder of sodium meta bisulfide may be weighed by an exemplary laboratory scale. In an exemplary embodiment, an exemplary powder of sodium hydroxide may be weighed by an exemplary laboratory scale.

[00025] In further detail with respect to step 130, step 130 may include mixing the exemplary third solution at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary third solution may include stirring the exemplary second solution using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00026] In further detail with respect to step 132, step 132 may include forming an exemplary liquid mixture comprising diclofenac sodium and propylene glycol. In an exemplary embodiment, forming an exemplary liquid mixture may include adding diclofenac sodium and propylene glycol to an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, adding diclofenac sodium and propylene glycol to an exemplary laboratory container may include adding an exemplary powder of diclofenac sodium (e.g., using spatula) with a final concentration of about 25 mg/ml (with respect to the final volume of the exemplary liquid mixture) and propylene glycol in a form of liquid (e.g., using a sampler, graduated cylinder/tube, etc.) with a final concentration of about 210 mg/ml (with respect to the final volume of the exemplary liquid mixture) to an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00027] In further detail with respect to step 134, step 134 may include mixing the exemplary liquid mixture at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary liquid mixture may include stirring the exemplary liquid mixture using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00028] In further detail with respect to step 136, step 136 may include forming an exemplary fourth solution comprising the exemplary third solution and the exemplary liquid mixture. In an exemplary embodiment, forming an exemplary fourth solution may include adding the exemplary third solution and the exemplary liquid mixture to an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, adding the exemplary third solution and the exemplary liquid mixture to an exemplary laboratory container may include adding the exemplary third solution (e.g., using a sampler, graduated cylinder/tube, etc.) and the exemplary liquid mixture (e.g., using a sampler, graduated cylinder/tube, etc.) with a volumetric ratio (the exemplary third solution: the exemplary liquid mixture) of 1:1 to an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00029] In further detail with respect to step 138, step 138 may include mixing the exemplary fourth solution at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary fourth solution may include stirring the exemplary fourth solution using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00030] In further detail with respect to step 140, step 140 may include adjusting an exemplary pH value of the exemplary fourth solution at a range between 6 and 8.5. In an exemplary adjusting an exemplary pH value of the exemplary fourth solution may include adding hydrochloric acid or sodium hydroxide to the exemplary fourth solution in an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00031] In further detail with respect to step 106, step 106 may include forming an exemplary solution of an exemplary pharmaceutical formulation. In an exemplary embodiment, forming an exemplary solution of an exemplary pharmaceutical formulation may include adding the exemplary solution of furosemide and the exemplary solution of diclofenac sodium to an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, adding the exemplary solution of furosemide and the exemplary solution of diclofenac sodium to an exemplary laboratory container may include adding the exemplary solution of furosemide (e.g., using a sampler, graduated cylinder/tube, etc.), the exemplary solution of diclofenac sodium (e.g., using a sampler, graduated cylinder/tube, etc.), and water with a volumetric ratio of 3:1:1 (exemplary solution of furosemide: exemplary solution of diclofenac sodium: water) to an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00032] In further detail with respect to step 108, step 108 may include mixing the exemplary solution of the exemplary pharmaceutical formulation at a predetermined temperature for a predetermined time duration. In an exemplary embodiment, mixing the exemplary solution of the exemplary pharmaceutical formulation may include stirring the exemplary solution of the exemplary pharmaceutical formulation using stirrer, e.g., a magnetic stirrer with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes in an exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc.

[00033] In further detail with respect to step 110, step 110 may include adding an exemplary preservative to the exemplary solution of the exemplary pharmaceutical formulation. In an exemplary embodiment, adding an exemplary preservative to the exemplary solution of the exemplary pharmaceutical formulation may include adding an exemplary preservative comprising benzalkonium chloride to the exemplary solution of the exemplary pharmaceutical formulation in exemplary laboratory container including, but not limited to, beakers, tins, flasks, bottles, buckets, basins, bowls, vials, tubes, barrels, cannisters, etc. In an exemplary embodiment, adding an exemplary preservative comprising benzalkonium chloride in exemplary laboratory container may include adding benzalkonium chloride in a form of liquid (e.g., using a sampler, graduated cylinder/tube, etc.) to the exemplary solution of the exemplary pharmaceutical formulation with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution) in an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

[00034] In further detail with respect to step 112, step 112 may include adjusting an exemplary pH value of the exemplary solution of the exemplary pharmaceutical formulation at a range between 6 and 8.5. In an exemplary adjusting an exemplary pH value of the exemplary solution of the exemplary pharmaceutical formulation may include adding hydrochloric acid or sodium hydroxide to the exemplary solution of the exemplary pharmaceutical formulation in an exemplary laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer.

EXAMPLES

[00035] Hereinafter, one or more exemplary embodiments will be described in further detail with reference to examples. It will be obvious to a person having ordinary skill in the art that these examples may be for illustrative purposes only and are not to be interpreted to limit the scope of one or more exemplary embodiments.

Example 1: Preparation of an exemplary pharmaceutical formulation comprising pharmaceutical water solution for improving obstructive sleep apnea

[00036] In this example, a procedure for preparing an exemplary pharmaceutical formulation for improving obstructive sleep apnea was described. At first, a solution of furosemide and a solution of diclofenac sodium was prepared. For this purpose, a first solution was prepared. In order to prepare the first solution, the powder of sodium hydroxide with a final concentration of about 1.35 mg/ml (with respect to the final volume of the solution of furosemide), the powder of sodium chloride with a final concentration of about 75 mg/ml (with respect to the final volume of the solution of furosemide), and water were added to a laboratory container while stirring using a magnetic stirrer with a speed of about 60-300 rpm at a temperature between 15 °C and 30 °C for a time duration between 10 and 30 minutes. After that, a powder of furosemide with a final concentration of about 10 mg/ml (with respect to the final volume of the solution of furosemide) was added to the first solution while stirring using a magnetic stirrer with a speed of about 60-300 rpm at a temperature between 15 °C and 30 °C for a time duration between 10 and 30 minutes and finally the second solution comprising the solution of furosemide was prepared. The pH value of the solution of furosemide must be adjusted at a range between 8.5 and 9.1.

[00037] In order to prepare the solution of diclofenac, a third solution and a liquid mixture was prepared. At first, propylene glycol in a form of liquid with a final concentration of about 210 mg/ml (with respect to the final volume of the liquid mixture) and a powder of diclofenac sodium with a final concentration of about 25 mg/ml (with respect to the final volume of the liquid mixture) was added to a laboratory container while stirring using a magnetic stirrer with a speed of about 60-300 rpm at a temperature between 15 °C and 30 °C for a time duration between 10 and 30 minutes and the liquid mixture was prepared. Then a third solution was prepared by adding a powder of sodium metabisulfite with a final concentration of about 1 mg/ml (with respect to the final volume of the solution of diclofenac sodium), a powder of sodium hydroxide with a final concentration of about 0.383 mg/ml (with respect to the final volume of the solution of diclofenac sodium), and hot water with a temperature between 80 and 90 °C to a laboratory container while stirring using a magnetic stirrer with a speed of about 60-300 rpm at a temperature between 20 °C and 25 °C for a time duration between 5 and 15 minutes. After that, the third solution and the liquid mixture with a volumetric ratio (the third solution: the liquid mixture) of 1:1 were added to a laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer at a temperature between 15 °C and 30 °C for a time duration between 10 and 30 minutes and then a fourth solution was prepared. The pH value of the fourth solution must be adjusted at a range between 6 and 8.5.

[00038] Finally, the solution of furosemide, the solution of diclofenac sodium, and water with a volumetric ratio of 3:1:1 (solution of furosemide: solution of diclofenac sodium: water) was added to a laboratory container, such as a beaker, while stirring using a stirrer, e.g., a magnetic stirrer, with a speed of about 60-300 rpm at a predetermined temperature between 15 °C and 30 °C for a predetermined time duration between 10 and 30 minutes. The preservative comprising benzalkonium chloride in a form of liquid with a final concentration of 0.002 % (w/w) (with respect to the final weight of the exemplary pharmaceutical water solution) were added to a laboratory container while stirring using a stirrer, e.g., a magnetic stirrer and the pharmaceutical water solution was prepared.

Example 2: Evaluating improvement in sings of obstructive sleep apnea with a clinical trial

[00039] For this purpose, twenty patients with obstructive sleep apnea were included in the clinical trial. These patients were examined with stop bang with an instrument called Viatom Checkme^TR O2 Pulse Oximeter. Moreover, these patients were evaluated for depression and anxiety with beck and Hamilton depression scale and sleep quality with Pitsburgh Sleep Quality Index (PSQP). Those patients whom were pregnant or with drug sensitivity, renal failure, and liver failure were excluded from the clinical trial. The nasal spray of the pharmaceutical formulation of the present disclosure were applied in the patients in the clinical trial. For this purpose, the nasal spray of the pharmaceutical formulation of the present disclosure was applied two puffs in each nasal cavity every 12 hours a day for 60 days. After 60 days, the assessment described above was performed in the patients. Table 1 below shows the results of the tests in patients at day 0 and 60 after applying the exemplary pharmaceutical formulation, consistence with exemplary embodiments of the present disclosure. As shown in Table 1, the mean O2 saturation was increased in patients after 60 days. Moreover, the mean Score of PSQI and beck and Hamilton depression scale was decreased after 60 days. It is be noted that the mean frequency of stop in breathing during sleep was reduced. Table 1: The results of the tests in patients at day 0 and 60 after applying the exemplary pharmaceutical formulation, consistence with exemplary embodiments of the present disclosure.

[00040] While the foregoing has described what are considered to be the best mode and/or other examples, it is understood that various modifications may be made therein and that the subject matter disclosed herein may be implemented in various forms and examples, and that the teachings may be applied in numerous applications, only some of which have been described herein. It is intended by the following claims to claim any and all applications, modifications and variations that fall within the true scope of the present teachings.

[00041] Unless otherwise stated, all measurements, values, ratings, positions, magnitudes, sizes, and other specifications that are set forth in this specification, including in the claims that follow, are approximate, not exact. They are intended to have a reasonable range that is consistent with the functions to which they relate and with what is customary in the art to which they pertain.

[00042] The scope of protection is limited solely by the claims that now follow. That scope is intended and should be interpreted to be as broad as is consistent with the ordinary meaning of the language that is used in the claims when interpreted in light of this specification and the prosecution history that follows and to encompass all structural and functional equivalents. Notwithstanding, none of the claims are intended to embrace subject matter that fails to satisfy the requirement of Sections 101, 102, or 103 of the Patent Act, nor should they be interpreted in such a way. Any unintended embracement of such subject matter is hereby disclaimed.

[00043] Except as stated immediately above, nothing that has been stated or illustrated is intended or should be interpreted to cause a dedication of any component, step, feature, object, benefit, advantage, or equivalent to the public, regardless of whether it is or is not recited in the claims.

[00044] It will be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective areas of inquiry and study except where specific meanings have otherwise been set forth herein. Relational terms such as first and second and the like may be used solely to distinguish one entity or action from another without necessarily requiring or implying any actual such relationship or order between such entities or actions. An element proceeded by “a” or “an” does not, without further constraints, preclude the existence of additional identical elements in the process, method, article, or apparatus that comprises the element.

[00045] Unless otherwise stated, all measurements, values, ratings, positions, magnitudes, sizes, and other specifications that are set forth in this specification, are approximate, not exact. They are intended to have a reasonable range that is consistent with the functions to which they relate and with what is customary in the art to which they pertain.

[00046] It will be understood that the terms and expressions used herein have the ordinary meaning as is accorded to such terms and expressions with respect to their corresponding respective areas of inquiry and study, except where specific meanings have otherwise been set forth herein. Relational terms such as “first” and “second” and the like may be used solely to distinguish one entity or action from another without necessarily requiring or implying any actual such relationship or order between such entities or actions.

[00047] The Abstract of the Disclosure is provided to allow the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. In addition, in the foregoing Detailed Description, it may be seen that various features are grouped together in various implementations. This is for purposes of streamlining the disclosure, and is not to be interpreted as reflecting an intention that the claimed implementations require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive subject matter lies in less than all features of a single disclosed implementation. Thus, the following claims are hereby incorporated into the Detailed Description, with each claim standing on its own as a separately claimed subject matter.

[00048] While various implementations have been described, the description is intended to be exemplary, rather than limiting and it will be apparent to those of ordinary skill in the art that many more implementations and implementations are possible that are within the scope of the implementations. Although many possible combinations of features are shown in the accompanying figures and discussed in this detailed description, many other combinations of the disclosed features are possible. Any feature of any implementation may be used in combination with or substituted for any other feature or element in any other implementation unless specifically restricted. Therefore, it will be understood that any of the features shown and/or discussed in the present disclosure may be implemented together in any suitable combination. Accordingly, the implementations are not to be restricted except in light of the attached claims and their equivalents. Also, various modifications and changes may be made within the scope of the attached claims.

Claims

What is claimed is:

1. A pharmaceutical formulation for improving obstructive sleep apnea, the pharmaceutical formulation comprising: a pharmaceutical water solution, the pharmaceutical water solution comprising: furosemide with a final concentration of 6.4 mg/ml (with respect to the final volume of the pharmaceutical water solution); diclofenac sodium with a final concentration of 4.5 mg/ml (with respect to the final volume of the pharmaceutical water solution); propylene glycol with a final concentration of 37.8 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium hydroxide with a final concentration of 0.88 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium chloride with a final concentration of 4.8 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium metabisulfite with a final concentration of 0.18 mg/ml (with respect to the final volume of the pharmaceutical water solution); and a preservative including benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w (with respect to the final weight of the pharmaceutical water solution).

2. A pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is formulated in a nasal spray, wherein the nasal spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea.

3. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is formulated in a nasal drop wherein the nasal drop is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.

4. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is formulated in an oral spray wherein the oral spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea.

5. The pharmaceutical formulation of claim 1, wherein the pharmaceutical formulation is formulated in a nasal drop wherein the oral drop is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.

6. A pharmaceutical formulation for improving obstructive sleep apnea, the pharmaceutical formulation comprising: a pharmaceutical water solution, the pharmaceutical water solution comprising: furosemide with a final concentration between 0.9 mg/ml and 9.6 mg/ml (with respect to the final volume of the pharmaceutical water solution); diclofenac sodium with a final concentration between 0.5 mg/ml and 6.7 mg/ml (with respect to the final volume of the pharmaceutical water solution); propylene glycol with a final concentration between 4.5 mg/ml and 56.25 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium hydroxide with a final concentration between 0.1 mg/ml and 1.2 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium chloride with a final concentration between 0.6 mg/ml and 7.2 mg/ml (with respect to the final volume of the pharmaceutical water solution); sodium metabisulfite with a final concentration between 0.02 mg/ml and 0.27 mg/ml (with respect to the final volume of the pharmaceutical water solution); and a preservative including benzalkonium chloride with a final concentration between 0.002 % (w/w) and 0.2% (w/w) (with respect to the final weight of the pharmaceutical water solution).

7. A pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is formulated in a nasal spray, wherein the nasal spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea.

8. The pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is formulated in a nasal drop wherein the nasal spray is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.

9. The pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is formulated in an oral spray wherein the oral spray is applied between 2 puffs every 12 hours a day and 5 puffs every 6 hours a day in a patient with obstructive sleep apnea.

10. The pharmaceutical formulation of claim 6, wherein the pharmaceutical formulation is formulated in an oral drop wherein the oral drop is applied between 2 drops every 12 hours a day and 5 drops every 6 hours a day in a patient with obstructive sleep apnea.