WO2015165947A1

WO2015165947A1 - Composition against sleep apnea

Info

Publication number: WO2015165947A1
Application number: PCT/EP2015/059309
Authority: WO
Inventors: Haruhiko Inufusa; Markus Graf MATUSCHKA VON GREIFFENCLAU
Original assignee: Tima Foundation
Priority date: 2014-04-29
Filing date: 2015-04-29
Publication date: 2015-11-05

Abstract

The present invention relates to a composition comprising Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin and one, two or three agents selected from the group consisting of glutathione, L-cystine and L-cysteine for use in a method for the treatment and/or prevention of sleep apnea, in particular obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea. Furthermore, the invention relates to a method of treatment and/or prevention of sleep apnea in a subject comprising administering to said subject the composition according to the present invention.

Description

Composition against sleep apnea

Sleep apnea is a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing during sleep. Each pause in breathing, called an apnea, can last from at least ten seconds to minutes, and may occur 5 to 30 times or more an hour. Similarly, each abnormally low breathing event is called a hypopnea.

There are three forms of sleep apnea: central (CSA), obstructive (OS A), and complex or mixed sleep apnea (i.e. a combination of central and obstructive) constituting 0.4%, 84% and 15% of cases respectively. In CSA, breathing is interrupted by a lack of respiratory effort; in OSA, breathing is interrupted by a physical block to airflow despite respiratory effort, and snoring is common.

The treatment often starts with a behavioral therapy. Many patients are told to avoid alcohol, sleeping pills, and other sedatives, which can relax throat muscles, contributing to the collapse of the airway at night.

Moreover, also a treatment with medicaments, like acetazolamide are possible, which lower blood pH and thus, encourage respiration. Low doses of oxygen are also used as a treatment for hypoxia but are discouraged due to side effects.

Furthermore, oral appliances called a mandibular advancement splint are used in the treatment of sleep apnea. Such appliances are custom-made mouthpiece that shifts the lower jaw forward and opens the bite slightly, which opens up the airway. However, such Oral Appliance therapy (OAT) is usually successful in patients with mild to moderate obstructive sleep apnea.

In the treatment of moderate to severe sleep apnea, the most common treatment is the use of a continuous positive airway pressure (CPAP) or automatic positive airway pressure (APAP) device which keeps the patient's airway open during sleep by means of a flow of pressurized air into the throat. The patient typically wears a plastic facial mask, which is connected by a flexible tube to a small bedside CPAP machine. The CPAP machine generates the required air pressure to keep the patient's airways open during sleep. Advanced models may warm or humidify the air and monitor the patient's breathing to ensure proper treatment.

Although CPAP therapy is extremely effective in reducing apneas and less expensive than other treatments, some patients find it extremely uncomfortable. Many patients refuse to continue the therapy or fail to use their CPAP machines on a nightly basis, especially in the long term.

The CPAP therapy is the most widespread type of therapy of the sleep apnea syndrome. However, the CPAP therapy is not for all patients a practicable permanent therapy. Besides, there are several surgical alternatives which may be used in specific cases. However, few studies have been published on this topic. The risk associated with any surgery depends on the surgeon's experience with this. Moreover, there are always risks associated with such surgery such as impaired wound healing, infection, vascular and especially nerve injury (particularly mandibular is compromised) and bleeding. The cosmetic consequences of such surgery must be considered also. Also just obese patients, patients with heart disease or diabetes are at increased surgical risk, which affects many patients with sleep apnea.

Thus, there is a need for new compositions that are effective against sleep apnea.

This object is solved by the subject matter defined in the claims.

The following figures illustrate the present invention. Figure 1 shows the form Epworth Sleepiness Scale used to determine how sleepy patients are when awake presented on the internet site of British Lung Foundation http://www.blf.org.uk/Page/Epworth-Sleepiness-Scale.

Figure 2 shows a graphical representation of the snoring number per minute calculated from the Polysomnography (PSG) test at day 0 and 14 of patients to which the composition according to the invention was administered over 2 weeks in a dosage of 13.7 mg/kg body weight once a day and at day 0, 14 and 28 of patients to which the composition according to the invention was administered over 4 weeks in a dosage of 13.7 mg/kg body weight once a day.

Figure 3 shows a graphical representation of the ESS (Epworth Sleepiness Scale) score at day 0 and 14 of patients to which the composition according to the invention was administered over 2 weeks in a dosage of 13.7 mg/kg body weight once a day and at day 0, 14 and 28 of patients to which the composition according to the invention was administered over 4 weeks in a dosage of 13.7 mg/kg body weight once a day.

The term "composition" as used herein, refers to any kind of composition which could be applied to a subject in any form without causing toxic symptoms in the subject to which physiologically compatible amounts of the respective composition are applied.

The term "dosage form" as used herein, refers to an amount of medication to be taken at one time, optionally in regular intervals.

The term "sleep apnea" as used herein refers to a sleep disorder characterized by abnormal pauses in breathing or instances of abnormally low breathing during sleep. Each pause in breathing, called an apnea, can last from at least ten seconds to minutes, and may occur 5 to 30 times or more an hour. There are three forms of sleep apnea: central (CSA), obstructive (OSA), and complex or mixed sleep apnea, i.e. a combination of central and obstructive, constituting 0.4%, 84% and 15% of cases respectively. In CSA, breathing is interrupted by a lack of respiratory effort; in OSA, breathing is interrupted by a physical block to airflow despite respiratory effort, and snoring is common. Common effects of sleep apnea include daytime fatigue, a slower reaction time, and vision problems, as well as difficulty in paying attention, working effectively and processing information when in a waking state, memory and learning is also affected, cardiovascular disease, stroke, high blood pressure, arrhythmias, diabetes, and sleep deprived driving accidents. Due to the disruption in daytime cognitive state, behavioral effects are also present. This includes moodiness, belligerence, as well as a decrease in attentiveness and drive. Another symptom of sleep apnea is sleep paralysis. In severe cases, the fear of sleep due to sleep paralysis can lead to Insomnia. There is also increasing evidence that sleep apnea may also lead to liver function impairment, particularly fatty liver diseases,

The term "obstructive sleep apnea" or "OSA" as used herein refers to a sleep disorder characterized in that the muscle tone of the body relaxes during sleep, and at the level of the throat the human airway is composed of collapsible walls of soft tissue which obstruct breathing during sleep. The risk of OSA rises with increasing body weight, active smoking and age. In addition, patients with diabetes or "borderline" diabetes have up to three times the risk of having OSA. Common symptoms include loud snoring, restless sleep, and sleepiness during the daytime. Diagnostic tests include home oximetry or polysomnography in a sleep clinic.

The term "central sleep apnea" or "CSA" as used herein refers to a sleep disorder characterized in that the basic neurological controls for breathing rate malfunction and fail to give the signal to inhale, causing the individual to miss one or more cycles of breathing. If the pause in breathing is long enough, the percentage of oxygen in the circulation will decrease to a lower than normal level (hypoxemia) and the concentration of carbon dioxide will increase to a higher than normal level (hypercapnia).

The term "mixed or complex sleep apnea" as used herein refers to a sleep disorder representing a combination of obstructive and central sleep apnea.

The present invention relates to a composition comprising Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin and one, two or three agents selected from the group consisting of glutathione, L-cystine and L-cysteine for use in a method for the treatment and/or prevention of sleep apnea, in particular obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea. In a preferred embodiment the present invention relates to a composition consisting of Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin and one, two or three agents selected from the group consisting of glutathione, L-cystine and L- cysteine for use in a method for the treatment and/or prevention of sleep apnea, in particular obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea.

A standard dose of the composition according to the present invention comprises about 1.0 g Vitamin C, 1.0 g L-glutamine, 500 mg L-cystine or L-cysteine, 40 mg riboflavin, 100 mg succinic acid or one of its salts (e.g. succinate), 100 mg fumaric acid or one of its salts (e.g. fumarate), 100 mg coenzyme Q10 and 20 mg niacin (Vitamin B3). Preferably the relation of the components of the composition is oriented towards the above given relation. The overall dosage may be adapted to the body mass weight of the consumer.

In a preferred embodiment the standard dose of the composition of the present invention comprises 100 mg coenzyme Q10, 40 mg riboflavin, 500 mg L-cystine or L-cysteine, 20 mg niacin, 940 mg Vitamin C, 100 mg succinic acid, 100 mg fumaric acid and 950 mg L- glutamine.

In another preferred embodiment the standard dose of the composition of the present invention comprises 10 mg coenzyme Q10, 4 mg riboflavin, 50 mg L-cystine or L-cysteine, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid and 85 mg L- glutamine. More preferably, the standard dose additionally comprises 20 mg cellulose, 20 mg maltose, 28.3 mg milk sugar and 6.2 mg stearic acid calcium.

In another preferred embodiment the standard dose of the composition of the present invention consists of 10 mg coenzyme Q10, 4 mg riboflavin, 50 mg L-cystine or L-cysteine, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid, 85 mg L-glutamine, 20 mg cellulose, 20 mg maltose, 28.3 mg milk sugar and 6.2 mg stearic acid calcium.

In another preferred embodiment the standard dose of the composition of the pharmaceutical combination of the present invention comprises 10 mg coenzyme Q10, 4 mg riboflavin, 100 mg glutathione, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid and 85 mg L-glutamine. More preferably, the standard dose additionally comprises 20 mg cellulose, 20 mg maltose, 28.3 mg milk sugar and 6.2 mg stearic acid calcium. In another preferred embodiment the standard dose of the composition of the pharmaceutical combination of the present invention consists of 10 mg coenzyme Q10, 4 mg riboflavin, 100 mg glutathione, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid, 85 mg L-glutamine, 20 mg cellulose, 20 mg maltose, 28.3 mg milk sugar and 6.2 mg stearic acid calcium.

Preferably, the relation of the single ingredients of the composition to the total amount of the composition is in a range of about 3 to 5% coenzyme Q10, 1 to 2% riboflavin, 15 to 20% L- cystine or L-cysteine, 0.5 to 1.0% niacin, 28 to 43% Vitamin C, 3 to 5% succinic acid, 3 to 5% fumaric acid and 27 to 42% L-glutamine, each in mass%. More preferably the relation of the single ingredients of the composition to the total amount of the composition is in a range of about 3.77% coenzyme Q10, 1.51% riboflavin, 18.87% L-cystine or L-cysteine, 0.75% niacin, 35.47% Vitamin C, 3.77% succinic acid, 3.77% fumaric acid and 32.08% L- glutamine, each in mass%.

Preferably, the relation of the single ingredients of the composition according to the present invention to the total amount of the composition is in a range of about 2.5 to 5% coenzyme Q10, 1 to 2% riboflavin, 25 to 35% glutathione, 0.5 to 1.0% niacin, 26 to 43% Vitamin C, 2.5 to 5% succinic acid, 2.5 to 5% fumaric acid and 25 to 42% L-glutamine, each in mass%. More preferably the relation of the single ingredients of the composition to the total amount of the composition is in a range of about 3.17% coenzyme Q10, 1.27% riboflavin, 31.75% glutathione, 0.63% niacin, 29.84% Vitamin C, 3.17% succinic acid, 3.17% fumaric acid and 26.98% L-glutamine, each in mass%.

In a preferred embodiment coenzyme Q10 of the composition according to the present invention is provided as CoQ10P40 (Nisshin Pharma, Tokyo, Japan) containing 40% coenzyme Q10.

It is possible to add further substances such as fruit juice extracts, curcuma, tannin, a powder of Panax notoginseng, and Vinca rosea in suitable amounts. Oolong tea, aloe vera and spiral water algae might also be added. Preferably, the composition according to the present invention comprises a niacin fraction in a quantity ranging from and including 0.04 to 2 mg/kg body weight, 0.1 to 1.5 mg/kg body weight, 0.2 to 0.75 mg/kg body weight, 0.04 to 0.53 mg/kg body weight, 0.04 to 0.38 mg/kg body weight, 0.04 to 0.23 mg/kg body weight, 0.08 to 0.19 mg/kg body weight, 0.1 to 0.2 mg/kg body weight, 0.11 to 0.19 mg/kg body weight or 0.11 to 0.51 mg/kg body weight, preferably 0.19 mg/kg body weight or 0.15 mg/kg body weight, more preferably 0.11 mg/kg body weight or 0.08 mg/kg body weight.

Preferably, the composition according to the present invention comprises a L-cystine or L- cysteine fraction in a quantity ranging from and including 1 to 15 mg/kg body weight, 2.5 to 10 mg/kg body weight, 5 to 8 mg/kg body weight, 0.94 to 13.21 mg/kg body weight, 0.94 to 9.43 mg/kg body weight, 0.94 to 5.66 mg/kg body weight, 1.89 to 4.72 mg/kg body weight, 2.83 to 3.77 mg/kg body weight, 1.89 to 3.77 mg/kg body weight or 2.83 to 4.72 mg/kg, preferably 4.72 mg/kg body weight or 3.77 mg/kg body weight, more preferably 2.83 mg/kg body weight or 1.89 mg/kg body weight.

Preferably, the composition according to the present invention comprises a glutathione fraction in a quantity ranging from and including 1 to 30 mg/kg body weight, 2.5 to 20 mg/kg body weight, 5 to 16 mg/kg body weight, 1.89 to 26.41 mg/kg body weight, 1.89 to 18.87 mg/kg body weight, 1.89 to 11.32 mg/kg body weight, 3.77 to 9.434 mg/kg body weight, 5.66 to 9.43 mg/kg body weight, 3.77 to 7.55 mg/kg body weight or 5.66 to 7.55 mg/kg body weight, preferably 9.43 mg/kg body weight or 7.55 mg/kg body weight, more preferably 5.66 mg/kg body weight or 3.77 mg/kg body weight.

Preferably, the composition according to the present invention comprises a L-glutamine fraction in a quantity ranging from and including 1 to 25 mg/kg body weight, 5 to 15 mg/kg body weight, 7 to 12 mg/kg body weight, 1.6 to 22.45 mg/kg body weight, 1.6 to 16.04 mg/kg body weight, 1.6 to 9.62 mg/kg body weight, 3.21 to 8.02 mg/kg body weight, 3.2 to 6.4 mg/kg body weight, 4.81 to 8.02 mg/kg body weight, 4.8 to 6.5 mg/kg body weight or 4.81 to 6.42 mg/kg body weight, preferably 8.02 mg/kg body weight or 6.42 mg/kg body weight, more preferably 4.81 mg/kg body weight or 3.21 mg/kg body weight.

Preferably, the composition according to the present invention comprises a riboflavin fraction in a quantity ranging from and including 0.05 to 2 mg/kg body weight, 0.1 to 1.5 mg/kg body weight, 0.2 to 0.75 mg/kg body weight, 0.08 to 1.06 mg/kg body weight, 0.08 to 0.75 mg/kg body weight, 0.08 to 0.45 mg/kg body weight, 0.15 to 0.38 mg/kg body weight, 0.23 to 0.38 mg/kg body weight, 0.2 to 0.3 mg/kg body weight, 0.23 to 0.3 mg/kg body weight or 0.15 to 0.3 mg/kg body weight, preferably 0.38 mg/kg body weight or 0.30 mg/kg body weight, more preferably 0.23 mg/kg body weight or 0.15 mg/kg body weight.

Preferably, the composition according to the present invention comprises a succinic acid fraction in a quantity ranging from and including 0.1 to 10 mg/kg body weight, 0.5 to 5 mg/kg body weight, 0.75 to 2 mg/kg body weight, 0.19 to 2.64 mg/kg body weight, 0.19 to 1.89 mg/kg body weight, 0.19 to 1.13 mg/kg body weight, 0.38 to 0.94 mg/kg body weight, 0.57 to 0.94 mg/kg body weight, 0.5 to 0.8 mg/kg body weight or 0.57 to 0.76 mg/kg body weight, preferably 0.94 mg/kg body weight or 0.75 mg/kg body weight, more preferably 0.57 mg/kg body weight or 0.38 mg/kg body weight.

Preferably, the composition according to the present invention comprises a fumaric acid fraction in a quantity ranging from and including 0.1 to 10 mg/kg body weight, 0.5 to 5 mg/kg body weight, 0.75 to 2 mg/kg body weight, 0.19 to 2.64 mg/kg body weight, 0.19 to 1.89 mg/kg body weight, 0.19 to 1.13 mg/kg body weight, 0.38 to 0.94 mg/kg body weight, 0.57 to 0.94 mg/kg body weight, 0.5 to 0.8 mg/kg body weight or 0.57 to 0.76 mg/kg body weight, preferably 0.94 mg/kg body weight or 0.75 mg/kg body weight, more preferably 0.57 mg/kg body weight or 0.38 mg/kg body weight.

Preferably, the composition according to the present invention comprises a coenzyme Q10 fraction in a quantity ranging from and including 0.1 to 10 mg/kg body weight, 0.5 to 5 mg/kg body weight, 0.75 to 2 mg/kg body weight, 0.19 to 2.64 mg/kg body weight, 0.19 to 1.89 mg/kg body weight, 0.19 to 1.13 mg/kg body weight, 0.38 to 0.94 mg/kg body weight, 0.57 to 0.94 mg/kg body weight, 0.5 to 0.8 mg/kg body weight or 0.57 to 0.76 mg/kg body weight, preferably 0.94 mg/kg body weight or 0.75 mg/kg body weight, more preferably 0.57 mg/kg body weight or 0.38 mg/kg body weight.

Preferably, the composition according to the present invention comprises a Vitamin C fraction in a quantity ranging from and including 1 to 25 mg/kg body weight, 5 to 17 mg/kg body weight, 7 to 12 mg/kg body weight, 1.78 to 24.83 mg/kg body weight, 1.78 to 17.73 mg/kg body weight, 1.78 to 10.64 mg/kg body weight, 3.55 to 8.87 mg/kg body weight, 3.5 to 7.1 mg/kg body weight, 5.32 to 7.1 mg/kg body weight or 5.32 to 8.87 mg/kg body weight, preferably 8.87 mg/kg body weight or 7.1 mg/kg body weight, more preferably 5.32 mg/kg body weight or 3.55 mg/kg body weight.

In a preferred embodiment the composition according to the present invention may be administered in a concentration of 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70 mg/kg body weight, preferably in a concentration ranging from 5 to 70 mg/kg body weight or from 20 to 70 mg/kg body weight or 20 to 50 mg/kg body weight, more preferably in a concentration ranging from 10 to 25 mg/kg body weight, 10 to 20 mg/kg body weight or 15 to 20 mg/kg body weight. In a preferred embodiment the relation of the amounts of the single components of the composition of the present invention comprises 10 mg coenzyme Q10, 4 mg riboflavin, 100 mg glutathione and/or 50 mg L-cystine or L-cysteine, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid and 85 mg L-glutamine, i.e. in total 265 mg and 315 mg, respectively. In another preferred embodiment the relation of the amounts of the single components of the composition of the present invention consists of 10 mg coenzyme Q10, 4 mg riboflavin, 100 mg glutathione and/or 50 mg L-cystine or L-cysteine, 2 mg niacin, 94 mg Vitamin C, 10 mg succinic acid, 10 mg fumaric acid and 85 mg L- glutamine.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a Vitamin C fraction of about 35.47 mass% i.e. a quantity of Vitamin C in the range from 0.78 to 1.18 g, preferably 1.0 g, more preferably 940 mg within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a Vitamin C fraction in the range from about 140 mg to 2g, 140 mg to 1.4 g, 140 to 851 mg, 284 to 709 mg, 287 to 567 mg or 425 to 709 mg, preferably 283 mg or 425 mg, more preferably 567 mg or 709 mg within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a L- glutamine fraction of about 32.08 mass%, i.e. a quantity of said L-glutamine fraction in the range from 0.78 to 1.18 g, preferably 1.0 g, more preferably 950 mg within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a L-glutamine fraction in the range from about 120 mg to 2 g, 120 mg to 1.8 g, 128 mg to 1.28 g, about 128 mg to 770 mg, 257 mg to 641 mg, 256 mg to 513 mg or 385 mg to 513 mg or 385 mg to 641 mg, preferably 257 mg or 385 mg, more preferably 513 mg or 641 mg within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a L- cystine or L-cysteine fraction of about 18.88 mass%, i.e. a quantity of said L-cystine or L- cysteine fraction in the range from 460 to 540 mg, preferably 500 mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a L-cystine or L-cysteine fraction in the range from 75 mg to 1.1 g, 76 mg to 754 mg, about 76 mg to 453 mg, 151 mg to 377 mg, 151 mg to 302 mg, 226 mg to 377 mg, 226 mg to 302 mg or 302 mg to 377 mg, preferably 151 mg or 226 mg, more preferably 302 mg or 377 mg within a dose for a person with a body weight of about 80 kg.

In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a glutathione fraction in the range from 151 mg to 2.1 g, 151 mg to 1.5 g, 151 mg to 906 mg, 302 mg to 755 mg, 453 mg to 755 mg, 453 mg to 604 mg or 302 mg to 604 mg, preferably 302 mg or 453 mg, more preferably 604 mg or 755 mg within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a riboflavin fraction of about 1.51 mass% i.e. a quantity of said riboflavin in the range from 32 to 48 mg, preferably 40mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a riboflavin fraction in the range from 5 mg to 85 mg, 6 mg to 60 mg, about 6 mg to 36 mg, 12 mg to 30 mg, 12 mg to 24 mg, 18 mg to 30 mg or 18 mg to 24 mg, preferably 12.1 mg or 18.1 mg, more preferably 24.1 mg or 30.2 mg within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a succinic acid fraction or one of its salts (e.g. succinate) of about 3.77 mass%, i.e. a quantity of said succinic acid in the range from 90 to 110 mg, preferably 100 mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a succinic acid fraction in the range from 15 mg to 220 mg, 15 mg to 151 mg, about 15 mg to 91 mg, 30 mg to 75 mg, 30 mg to 60 mg, 45 mg to 60 mg or 45 mg to 75 mg, preferably 30.2 mg or 45.3 mg, more preferably 60.4 mg or 75.5 mg or within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a fumaric acid fraction or one of its salts (e.g. fumarate) of about 3.77 mass%, i.e. a quantity of said fumaric acid in the range from 90 to 110 mg, preferably 100 mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a fumaric acid fraction in the range from 15 mg to 220 mg, 15 mg to 151 mg, about 15 mg to 91 mg, 30 mg to 75 mg, 30 mg to 60 mg, 45 mg to 60 mg or 45 mg to 75 mg, preferably 30.2 mg or 45.3 mg, more preferably 60.4 mg or 75.5 mg or within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a coenzyme Q10 fraction of about 3.77 mass%, i.e. a quantity of said coenzyme fraction in the range from 30 to 300 mg, preferably 250 mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a coenzyme Q10 fraction in the range from 15 mg to 220 mg, 15 mg to 151 mg, about 15 mg to 91 mg, 30 mg to 75 mg, 30 mg to 60 mg, 45 mg to 60 mg or 45 mg to 75 mg, preferably 30.2 mg or 45.3 mg, more preferably 60.4 mg or 75.5 mg or within a dose for a person with a body weight of about 80 kg.

Preferably, the composition is constituted in a manner wherein a dosage of same includes a niacin fraction of about 0.75 mass%, i.e. a quantity of said niacin fraction in the range from 5 to 45 mg, 1 to 40 mg, preferably 20 mg, within a dose of 2.75 g for a person with a body weight of about 80 kg. In another preferred embodiment the composition of the present invention is constituted in a manner wherein a dosage of same includes a niacin fraction in the range from about 3 mg to 45 mg, 3 mg to 30 mg, 3 mg to 18 mg, 6 mg to 15 mg, 6 mg to 12 mg, 9 mg to 12 mg or 9 mg to 15 mg, preferably 6 mg or 9 mg, more preferably 12 mg or 15 mg within a dose for a person with a body weight of about 80 kg. More preferably, each ingredient of the composition is in the range from about 1 mg to about 100 gram, preferably from about 3 mg to 50 gram, more preferably from about 3 mg to about 2.5 g.

In a preferred embodiment the composition according to the invention is provided in liquid form. The composition according to the invention in liquid form may additionally comprise a buffer system for solubility reasons. Preferably, the buffer system is bicarbonate, phosphate or any other buffering system. In another preferred embodiment the composition according to the invention is provided in liquid form with added bicarbonate, preferably the standard dose of the composition according to the invention comprises a sodium bicarbonate fraction ranging from and including 0.2 to 10 mg/kg body weight, 0.5 to 5 mg/kg body weight, 0.2 to 0.95 mg/kg body weight, 0.5 to 0.63 mg/kg body weight or 1 to 4 mg/kg body weight, preferably 0.95 mg/kg body weight, more preferably 0.48 mg/kg body weight. In another preferred embodiment the liquid composition according to the invention is constituted in a manner wherein a dosage of same includes a sodium bicarbonate fraction of about 2.96 mass%, i.e. a quantity of said sodium bicarbonate fraction in the range from 1 to 100 mg, preferably 84 mg, within a dose of 2.834 g for a person with a body weight of about 80 kg.

In another preferred embodiment the liquid composition according to the invention is constituted in a manner wherein a dosage of same includes a sodium bicarbonate fraction in the range from 12 to 76 mg, preferably 38 to 50.7 mg, more preferably 38 mg for a person with a body weight of about 80 kg.

In a preferred embodiment the composition according to the invention provided in liquid form comprises Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin and one or both agents selected from the group consisting of glutathione and L-cystine. More preferably, the composition according to the invention provided in liquid form comprises Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin, one or both agents selected from the group consisting of glutathione and L-cystine, and a buffer system for solubility reasons. Preferably, the buffer system is bicarbonate, phosphate or any other buffering system. It is possible to add further substances such as fruit juice extracts, curcuma, tannin, a powder of Panax notoginseng, and Vinca rosea in suitable amounts. Oolong tea, aloe vera and spiral water algae might also be added.

The composition according to the present invention may be administered by any route of administration, for example oral, topical, nasopharyngeal, enteral, parenteral, intravenous, intramuscular, subcutaneous or rectal.

The composition according to the present invention may be provided in form of a tablet, capsule, dragee, pill, powder, suppository, or any other galenic formulation. The tablet, capsule, dragee, pill, powder, suppository, or any other galenic formulation may be contained in a dosage receptacle. Preferably, the dosage form may comprise suitable carriers, stabilizers, flavourings, buffers or other suitable reagents, such as cellulose, maltose, milk sugar, stearic acid calcium. The standard dosage of the composition of the invention may be provided in one or more tablets, capsules, dragees, pills, powders, suppositories, or any other galenic formulations, preferably in 5 tablets, capsules, dragees, pills, powders, suppositories, or any other galenic formulations. Preferably, the composition according to the present invention is provided as a solution, emulsion or suspension. In another preferred embodiment the compounds of the composition according to the present invention are solubilized or microparticulate active agents.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations.

In another embodiment, the composition of the present invention is provided as a tablet with conventional tablet bases such as lactose, sucrose, and cornstarch in pharmaceutical combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or nonaqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art. For parenteral administration, the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Suitable pharmaceutical carriers may be water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, and buffers as are known in the art.

Topical preparations may be provided by simply preparing a solution of the compound to be administered, preferably using a solvent known to promote transdermal absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without other excipients. Preferably topical administration will be accomplished using a patch either of the reservoir and porous membrane type or of a solid matrix variety.

When the composition according to the present invention is to be used as an injectable material, it can be formulated into a conventional injectable carrier. Suitable carriers include biocompatible and pharmaceutically acceptable phosphate buffered saline solutions, which are preferably isotonic.

The composition according to the present invention may be administered or taken prior, during or after occurrence of radicals or species of the reactive radical group, preferably oxygen radicals or reactive oxygen species or other harmful forms of oxygen. The composition according to the present invention may be taken or administered to any subject, preferably to mammals, more preferably to humans or pets or farmed animals. Pets may be for example dogs and cats, rodent pets, such as gerbils, hamsters, chinchillas, fancy rats, and guinea pigs; avian pets, such as canaries, parakeets, and parrots; reptile pets, such as turtles, lizards and snakes; and aquatic pets, such as tropical fish and frogs. Farmed animals may be for example cattle, goats, horses, rabbits, sheeps and pigs.

In a preferred embodiment the composition according to the present invention is combined with any medicament. The composition according to the present invention may be administrated or taken at the same time, prior or after the administration of the medicament.

Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically the therapeutically effective amount of the compound will be admixed with a pharmaceutically acceptable carrier. In a further aspect the present invention relates to a method of treating a disorder, disease or condition in a subject in need of treatment and/or prevention, which method comprises administering to said subject an effective amount of composition according to the present invention. In particular said method of treatment may be for the treatment and/or prevention of sleep apnea, in particular obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea.

The dosage and route of administration used in a method of treatment or prevention according to the present invention depends on the specific disease or disorder to be treated. The route of administration may be for example oral, topical, nasopharyngeal, parenteral, intravenous, rectal or any other route of administration.

Further scope of applicability of the present invention will become apparent from the detailed description given hereinafter, however, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

The following examples explain the present invention but are not considered to be limiting.

Example 1: treatment of patients suffering from sleeping disorders with the composition according to the present invention

Composition:

Wt (mg)

Coenzyme Q10 10

Ascorbic acid 94

L-Cystine 50

L-Glutamine 85 Fumaric acid 10

Succinic acid 10

Riboflavin 4

Niacin 2

Total 265

The composition above was administered to 35 patients suffering from marked snoring and at least two other symptoms as listed below for one month. The dose of the composition administered to the patients was 15 to 20 mg/kg body weight. The composition was administered one time per day just after wake up with 200ml water.

Details on the patients:

Number: 35

Sex: Male

Age: Average 57.2 years

Body weight: Average 78.6 kg

Complications: 21 patients suffer from Diabetes mellitus, 7 patients suffer from hypertension and 26 patients suffer from obesity.

Treatment of sleep disorder: No patient was treated by CPAP therapy or other treatment for sleep disorder during monitoring of the patient and blood sampling.

Symptoms:

1. Marked snoring.

2. Wake up mid night by breath difficulty.

3. Cannot sleep well.

4. Sleepy in the day time.

5. Depression

6. Difficulties in concentrating in the day time.

7. Breath pauses during sleep (pointed out by family members).

8. Marked snoring (pointed out by family members).

9. Go to the restroom many time at midnight

10. Headache when got up in the morning. ( that is caused by Oxygen deficit)

11. Thirsty when got up in the morning.

12. Increase all symptoms when drink alcohol before sleep The patients were asked to answer the questions in the questionnaire as given below after the one month treatment with the composition.

Table 1 : Results of questionnaires

The evaluation of the questionnaires shows that the symptoms of OSAS were improved in 85.7% of the patients.

Example 2: Examination of the blood of patients treated with the composition according to the present invention

Blood sampling was performed from 7 patients who showed improved symptoms in example 1. The first blood sampling was performed during continuous administration of the composition. Second blood sampling was performed one week after termination of the administration of the composition. The blood samples were analyzed by d-ROMs test and BAP test.

Measurement of free radicals in the blood samples: The d-ROMs (Reactive Oxygen Metabolites) test by using Free Carpe Diem photometric analytical system (Diacron, Grosseto, Italy) was used for the measurement of free radical metabolites in the blood samples of the mice. It is a spectrophotometric method that assesses overall oxidative stress by measuring total hydroperoxide levels, given that hydroperoxides are intermediate oxidative products of lipids, peptides, and amino acids. Briefly, 0.02 ml plasma was diluted in 1 ml acetate-buffered solution. Hydroperoxide groups react with the transition metal ions liberated from the proteins in the acidic medium, and are converted to alkoxyl and peroxyl radicals according to the Fenton reaction. These newly formed radicals, the quantities of which are directly proportional to those of the peroxides, were trapped chemically with 0.02 ml chromogen (N, N-diethyl-para-phenylendiamine), leading to the formation of the radical cation of this chromogen. The purple colour resulting from this reaction over time was monitored in a spectrophotometer (Wismerll FRAS4, Tokyo, Japan) at 505 nm. The results of this method were expressed in μιηοΐ per liter.

BAP (Biological Antioxidant Power) Test

The BAP test informs about the condition of the anti-oxidative defense system of the body against free radicals. The test demonstrates how well the body is able to make free radicals harmless so as to protect itself from harm. Simultaneously, a possible lack of antioxidants is detected.

The BAP test allows a reliable determination of the anti-oxidative potential, the part of the plasma barrier which is affected directly by an oxidation due to its involved reduction and oxidation potentials under physiological conditions. TBAP (Biological Antioxidant Power) test is based on the capacity of a colored solution, containing a source of ferric (Fe³⁺) ions adequately bound to a special chromogenic substrate, to decolour when Fe³⁺ ions are reduced to ferrous ions (Fe²⁺), as it occurs by adding a reducing/antioxidant system, i.e. a blood plasma sample. Therefore, in the BAP test, a small quantity of blood plasma (10 μΐ) to be tested is dissolved in a colored solution, which has been previously obtained by mixing a source of ferric ions (i.e. ferric chloride, Fe(¾) with a special chromogenic substrate (i.e. a thiocyanate derivative). After a short incubation (5 min), at 37°C, such solution will decolor and the intensity of this chromatic change will be directly proportional to the capacity of plasma to reduce, during the incubation, ferric ions (initially responsible for the color of solution) to ferrous ions. By photometrically assessing the intensity of decoloration, the concentrations of reduced ferric ions can be adequately determined thus allowing a measurement of reducing capacity or antioxidant potential of tested blood plasma. Such "potential" is obviously not absolute but relative to the tested substrate, i.e. ferric ions. Considering that such ions are naturally occurring components of our body, BAP test provides a measure of antioxidant power of the fraction of plasma barrier to oxidation which is directly involved, due to the implicated reducing-oxidant potentials, against the attack of reactive chemical species in "physiological" or "biological" conditions.

Table 2: Results of the d-ROM test and BAP test

(d-ROMs: U. CARR, BAP: μιηοΙ/L)

The results of the d-ROM test show that the free radical metabolites were increased by 17.1% after the termination of the administration of the composition. A significant difference was observed by statistical analyses of Student's t-test with a value of P=0.0041.

The results of the BAP test show that the antioxidants were decreased by 14.1%. A significant difference was observed by statistical analyses of Student's t-test with a value of P=0.045.

The clinically most important factor is the ratio of the results of the BAP-test to the results of the d-ROM test which was decreased by 26.6%. These results reveal that the concentration of free radicals in patients suffering from OSAS was significantly decreased by the composition, and symptoms were improved. Example 3: Clinical trial with patients suffering from sleep apnea or heavy snoring

A clinical trial was conducted by Dr. Masayuki Takashima at the Utsunomiya sleep apnea center (Utsunomiya, Japan). Ten patients who diagnosed with sleep apnea or heavy snoring symptom by medical doctor was selected for the clinical trial using the composition according to the present invention. Patients were all male, their average age was 39.0 + 12.2 year, their average height was 169.8 ± 5.1 cm, their average body weight was 79.6 + 9.5 kg and their average BMI (kg/m2) was 27.6 + 2.9. The patients were divided in two groups: a 2 weeks administration group (5 patients), and a 4 weeks administration group (5 patients).

The composition administered is composed of:

Wt (mg)

Coenzyme Q10 10

Ascorbic acid 94

L-Cystine 50

L-Glutamine 85

Fumaric acid 10

Succinic acid 10

Riboflavin 4

Niacin 2

Total 265

The present composition was administrated in the dosage 13.7mg/ kg body weight, once a day at early morning for 2 weeks to the patients oft he 2 weeks administration group and for 4 weeks to the patients of the 4 weeks administration group. All patients entered to Utsunomiya sleep apnea center overnight at day 0 and 14. Only the patients of the 4 weeks group went to Utsunomiya sleep apnea center overnight on day 28. At the center the patients were examined by Polysomnography (PSG) test from which the snoring number/min was calculated. Further it is determined how sleepy the patients are when awake by filling the form Epworth Sleepiness Scale (ESS) (see http://www.blf.org.uk/Page/Epworth-Sleepiness-Scale) as illustrated in Figure 1. Moreover, the patients were asked to answer the questions in the questionaries' of snoring. Polysomnography test (PSG)

The snoring number per minutes was calculated from PSG test at day 0 and 14 in patients of the 2 weeks administration group and at day 0, 14 and 28 in patients of the 4 weeks administration group. The results are presented in Figure 2. Eight patients (80%) showed reduced number of snoring. Seven patients showed significant reduction rate of 35-96%. Thus, the administration of the present composition results in a strong reduction of snoring in these patients.

Epworth Sleppiness Scale (ESS)

The Epworth Sleepiness Scale was determined by filling the form as presented in Fig. 1. The results are shown in Fig. 3.

At day 14, 9 patients showed significantly reduced score. ESS score reflects apnea at sleeping. This result shows strong reduction of symptoms of sleep apneas syndrome due to the administration of the composition according to the present invention.

Questionaries' of snoring

Twelve questions of sleep apnea symptoms were scaled at 4 degree.

Table 3: Results of the questionaires

1 Snoring reduced 1(1) 6(2) 1(0) 3(2)

Wake up midnight breath difficulty

2 2(1)

reduced 1(1) 5(3) 2(0)

3 Can sleep deeply 3(3) 4(2) 2(0) 1(0)

4 Sleepy at midday reduced 4(0) 3 (3) 2(2) 1(0)

5 Depression feel reduced 1(1) 1(0) 5(4) 3(0)

6 Can concentrate at day time 1(0) 3 (2) 2(2) 4(1)

Family point out reduced no breathing at

7 2(0) 2(1) 3(3)

sleep 3(1)

8 Family point out reduced heavy snoring 0(1) 6(3) 2(1) 2(0)

Go to bathroom many times at night

9 1(1) 2(0) 4(4) 3(0)

reduced

10 No headache at wake up 1(1) 0(0) 5(4) 4(0)

11 No thirst at wake up 1(0) 3 (3) 3(2) 3(0)

12 No sever snoring with alcohol drinking 0(0) 3(1) 4(2) 3(2)

Six patients recognized reduced snoring by himself and family as well. Seven patients reported that reduced sleepy in day time and also deep sleeping at night time. This means that 70% patients recognizes symptoms of sleep apnea reduced by themselves.

Claims

1. A composition comprising Vitamin C, L-glutamine, riboflavin, succinic acid, fumaric acid, coenzyme Q10, niacin and one, two or three agents selected from the group consisting of glutathione, L-cystine and L-cysteine for use in a method for the treatment and/or prevention of sleep apnea.

2. The composition according to claim 1 for use in a method for the treatment and/or prevention of obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea.

3. The composition for use according to any of the preceding claims, wherein the composition is in the form of a capsule, dragee, pill, powder, suppository, or any other galenic formulation.

4. The composition for use according to any of the preceding claims, wherein the composition comprises 3 to 5 mass% coenzyme Q10, 1 to 2 mass% riboflavin, 15 to 20 mass% L-cystine or L-cysteine, 0.5 to 1.0 mass% niacin, 28 to 43 mass% Vitamin C, 3 to 5 mass% succinic acid, 3 to 5 mass% fumaric acid and 27 to 42 mass% L-glutamine.

5. The composition for use according to any of the preceding claims, wherein the composition comprises 2.5 to 5 mass% coenzyme Q10, 1 to 2 mass% riboflavin, 25 to 35 mass% glutathione, 0.5 to 1.0 mass% niacin, 26 to 43 mass% Vitamin C, 2.5 to 5 mass% succinic acid, 2.5 to 5 mass% fumaric acid and 25 to 42 mass% L-glutamine.

6. The composition for use according to any of the preceding claims, wherein the composition comprises 35.47 mass% Vitamin C, 32.08 mass% L-glutamine, 18.87 mass% L- cystine or L-cysteine, 1.51 mass% riboflavin, 3.77 mass% succinic acid, 3.77 mass% fumaric acid, 3.77 mass% coenzyme Q10, and 0.75 mass% niacin.

7. The composition for use according to any of the preceding claims, wherein the composition comprises 29.84 mass% Vitamin C, 26.98 mass% L-glutamine, 31.75 mass% glutathione, 1.27 mass% riboflavin, 3.17 mass% succinic acid, 3.17 mass% fumaric acid, 3.17 mass% coenzyme Q10, and 0.63 mass% niacin.

8. The composition for use according to any one of the preceding claims, wherein the composition is administered in a concentration ranging from 10 to 25 mg/kg body weight.

9. A method of treatment and/or prevention of sleep apnea in a subject comprising administering to said subject the composition according to any of the preceding claims.

10. The method of treatment and/or prevention according to claim 9, wherein the sleep apnea is obstructive sleep apnea, central sleep apnea and/or mixed or complex sleep apnea.