CN101171008A - Proton pump inhibitors in the treatment of sleep disturbance due to asymptomatic gastroesophageal reflux - Google Patents

Abstract

This invention relates to the use of proton pump inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, emeprazole, tenaprazole, lemeprazole, and omeprazole derivatives in the treatment of sleep disorders caused by asymptomatic gastroesophageal reflux.

Description

Proton pump inhibitors in the treatment of sleep disturbance due to asymptomatic gastroesophageal reflux

field of invention

The present invention relates to a new method of treating sleep disturbances caused by silent gastroesophageal reflux. In particular, the present invention relates to the use in said therapy of certain substituted benzimidazole compounds having pharmacological activity as H ⁺ , K ⁺ -ATPase inhibitors.

Background and Detailed Description of the Invention

It has been demonstrated that recurrent symptomatic reflux episodes negatively impact sleep quality. Patients with both upright and supine reflux (day and night) had more extensive esophageal mucosal damage than patients with upright (day) reflux. Decreased salivation, decreased swallowing frequency, and delayed esophageal emptying time during sleep all contribute to more extensive damage to the esophageal mucosa. Sleep is affected in approximately 50-60% of patients with gastroesophageal reflux disease (GERD). These patients may also be impaired during the day due to their symptoms/sleep disturbances.

It is well known that acid infusion induces arousal even in non-GERD subjects (Orr et al., Gastroenterology, 86, 814-819, 1984). Patients may therefore seek medical attention with sleep disturbances but no symptoms of GERD. Approximately 10-15% of the US population suffers from chronic sleep disturbances, and it is estimated that 50% of these individuals may already be suffering from acid reflux that disrupts their sleep. Sleep problems may mistakenly lead to prescriptions for sleeping pills. Since hypnotics suppress wakefulness, hypnotics may actually increase acid exposure time, since acid clearance has been shown to be gradual and greatly prolonged during deeper sleep levels (Orr, 1984). This may ultimately increase the risk of developing esophagitis (Johnson, DeMeester, American Journal of Digestive Diseases, 23(6), 498-509, 1978), esophageal ulcers, Barrett's esophagus, and similar symptoms.

The target patient population also includes those with split sleep due to frequent awakenings. Sleep causes partial amnesia, which means that even if the patient cannot remember that reflux ever occurred, episodes of reflux may still be the cause of disrupted/split sleep.

A similar mechanism can be found in patients with reflux laryngitis or acid asthma, of whom less than 50% actually experience heart pain.

The side effects of sleeping pills are well established (ie, addiction, reduced quality of life and productivity), and thus other therapeutic approaches to eradicate sleep disorders are needed.

The present invention relates to sleep disturbances due to asymptomatic gastroesophageal reflux, which should be clearly distinguished from nocturnal GERD/heart pain-related sleep disturbances, as these patients were excluded.

The use of proton pump inhibitors in the treatment of sleep disturbances caused by nocturnal heartache or nausea has been described previously. These patients with GERD present either with endoscopic signs of mucosal rupture in the esophageal mucosa, or with typical symptoms of GERD such as heartache or nausea. However, a person skilled in the art would not associate a sleep disturbance alone without any symptoms/findings described above with GERD. The present invention concerns these patients and the newly established link between asymptomatic reflux of gastric contents in the esophagus leading to sleep disturbance as the only symptom. These patients are not considered GERD patients according to the current definition of GERD. Therefore, they instead have "asymptomatic gastroesophageal reflux", a separate entity and disease.

The present invention thus relates to the treatment of patients suffering from sleep disorders caused by asymptomatic gastroesophageal reflux by administering a therapeutically effective amount of a specific substituted benzimidazole compound, a proton pump inhibitor (PPI).

In other words, the present invention relates to the treatment of sleep disturbances caused by asymptomatic gastroesophageal reflux, ie the patient does not develop symptoms of heart pain or other typical or traditional symptoms of reflux, such as nausea. Patients may wake up, or have altered sleep levels (arousals), in response to the reflux condition.

We unexpectedly found that the reflux of acid material into the esophagus can cause arousal/awakening even when the reflux episode is not related to heartache, reflux, or a sour taste. This can lead to sleep disorders that reduce sleep quality, which in turn leads to reduced quality of life and productivity.

Thus, the present invention provides unique features of: i) improved sleep ii) reduced risk of esophagitis iii) prevention of Barrett's esophagus/adenocarcinoma and iv) eventual reduction of sleeping pills in such patients.

The present invention first discloses the relationship between endogenous acid secretion and sleep disturbance and/or arousal, and establishes the temporal link between arousal and patient's EEG, EOG, EMG and/or EKG.

active ingredient

A first aspect of the invention is the use of a proton pump inhibitor in the treatment of sleep disturbances caused by asymptomatic gastroesophageal reflux. The proton pump inhibitor can be omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole, paliprazole, tenatoprazole, ilaprazole, and Any one of minprazole or its mixture.

For the purposes of this application, the term "proton pump inhibitor" (PPI) means any substituted benzimidazole compound having pharmacological activity as an H ⁺ , K ⁺ -ATPase inhibitor, including, but not limited to, the neutral form or salt forms of omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, paliprazole, tenatoprazole, ilaprazole, and leminoprazole, Its single enantiomers or isomers, or other derivatives like basic salts of its enantiomers.

Examples of suitable salt forms of PPI are basic salts such as Mg ²⁺ , Ca ²⁺ , Na ⁺ , K ⁺ or Li ⁺ salts.

Further, a given chemical formula or name shall include all stereo and optical isomers and their racemates as well as mixtures of individual isomers in varying proportions if such isomers and enantiomers exist, and pharmaceutically acceptable salts thereof and solvates such as hydrates thereof. The compounds listed above may also be used in their tautomeric forms. Derivatives of the above-listed compounds, such as prodrugs, which possess the biological function of the listed compounds, are also included in the present invention. Examples of suitable prodrugs are

It is therefore one aspect of the present invention to administer a therapeutically effective amount of a proton pump inhibitor to a patient suffering from sleep disturbance caused by asymptomatic gastro-oesophageal reflux.

In a further aspect the present invention relates to the use of a PPI in the treatment of a patient suffering from sleep disturbance caused by asymptomatic gastro-oesophageal reflux.

The present invention further relates to a method of treatment of sleep disorders caused by asymptomatic gastroesophageal reflux, which consists in administering an effective amount of a PPI to a patient in need of such treatment.

The present invention further relates to the use of PPI in the preparation of a medicament for the treatment of sleep disorders caused by asymptomatic gastroesophageal reflux.

The invention further relates to pharmaceutical preparations for the treatment of sleep disturbances caused by asymptomatic gastroesophageal reflux, which contain at least one PPI as active compound.

In one embodiment of the invention, the pharmaceutical formulation is intended to give an immediate release profile.

In another embodiment of the invention, the pharmaceutical formulation is intended to give a modified release profile.

The present invention further relates to a ready-to-use medicament containing PPI as active compound, comprising reference to the fact that the ready-to-use medicament can be used for the treatment of sleep disturbances caused by asymptomatic gastroesophageal reflux .

Dosage form or form, process for preparing pharmaceutical formulation and active ingredient and/or pharmaceutical formulation The method of administration, including dose level and frequency.

immediate release formulation

According to one embodiment of the present invention, there is provided an immediate release pharmaceutical formulation for the treatment of sleep disturbance caused by asymptomatic gastroesophageal reflux, comprising: (a) an active ingredient (selected from any of the above listed compound), or a pharmaceutically acceptable salt of any of these compounds; and (b) a pharmaceutically acceptable diluent or carrier, the formulation is hereinafter referred to as "immediate release formulation of the invention".

The term "immediate release" pharmaceutical formulations will be well understood by those skilled in the art to include formulations in which the onset and/or rate of drug release and/or absorption is not significantly or intentionally delayed by medical treatment. In this case, immediate release may be provided by means of a suitable pharmaceutically acceptable diluent or carrier that does not prolong the onset and/or rate of drug release/absorption to appreciable degree. Accordingly, those skilled in the art will understand the term to exclude formulations adapted to provide "modified" or "controlled" release, including "sustained," "extended," "extended" or "delayed" release, of a drug.

In this context, the term "release" is understood to include the supply (or introduction) of drug from the formulation to the gastrointestinal tract, to body tissues and/or into the systemic circulation.

In one embodiment of the invention, the immediate release formulation may comprise an aqueous solution/suspension of omeprazole or any other PPI, such as lansoprazole, in a pharmaceutically acceptable carrier comprising a Group IA metal of bicarbonate. For the purposes described, the compositions include solutions and/or suspensions of omeprazole or other substituted benzimidazoles. Suitable amounts of active ingredient and pharmaceutically acceptable diluent or carrier are described in US 6,489,346, which is incorporated by reference.

According to the present invention, there is provided a pharmaceutical composition for the treatment of sleep disorders caused by asymptomatic gastroesophageal reflux, which comprises omeprazole or any other PPI such as lansoprazole pharmaceutically acceptable Aqueous solutions/suspensions in a carrier comprising a Group IA metal bicarbonate, preferably sodium bicarbonate.

In one embodiment of the invention, the immediate release formulation is Zegerid. Immediate release formulations substantially identical to Zegerid, but substituting another PPI for omeprazole as the active ingredient, are also included in the present invention.

Mediation

According to the present invention, there is provided a modified release pharmaceutical formulation for the treatment of sleep disorders caused by asymptomatic gastroesophageal reflux, which comprises an active ingredient, or a pharmaceutically acceptable salt of the active ingredient, the formulation Hereafter referred to as "modified release formulation of the invention".

The term "modified release" pharmaceutical formulation will be well understood by those skilled in the art to include any modified release formulation in which the onset and/or rate of drug release is altered by medical treatment, and thus includes United States Pharmacopoeia (USP XXII) The definitions provided on pages xliii and xliv of the Preamble/Preamble, the relevant disclosures in these documents are hereby incorporated by reference.

In this case, modified release may be provided by means of a suitable pharmaceutically acceptable carrier and/or other means which, as the case may be, cause a change in the onset and/or rate of release of the active ingredient. Accordingly, those skilled in the art will understand that the term includes modified release formulations (wherein the drug is released at a sufficiently delayed rate) suitable (such as described herein) to provide "sustained", "prolonged" or "extended" release of the drug to produce a therapeutic response for a desired period of time, optionally including obtaining an initial amount of drug supply within a predetermined time after administration to produce an initial desired therapeutic response); including modified release formulations that provide "delayed" release of the drug ( wherein drug release is delayed until a defined region of the gastrointestinal tract is reached, after which drug release may be pulsed or further modified as described above); and include so-called "repeat-action" formulations (where a drug is administered immediately after administration Or released at intervals, while others are released at a later time).

We prefer that the modified release formulations provided by the present invention be substantially similar to those used in commercially available PPIs (other than Zegerid). Proper ions of commercially available PPIs are the following patented products: Nexium, Priolosec, Losec, Losec MUPS, Protonix, Prevacid, Aciphex, Omeprazole Eon, Omeprazole Impax Labs, Omeprazole Kremers Urban Dev, Omeprazole Lek Pharms, Omeprazole Mylan, Omeprazole Torpharm.

For the avoidance of controversy, our term "treatment" includes treatment of symptoms as well as prevention.

One aspect of the invention is the administration of a pharmaceutically active amount of the active ingredient at bedtime.

One aspect of the invention is the twice daily administration of a pharmaceutically active amount of the active ingredient.

One aspect of the invention is the administration of a pharmaceutically active amount of the active ingredient drug in a pulsatile manner.

Advantages of the present invention include, but are not limited to, limiting the use of hypnotics for sleep disorders, limiting the amount of fluid excreted by the stomach, and reducing interpatient variability (intervariability) between patients compared to other therapeutic doses that have this effect. Drugs are more effective in suppressing acid secretion.

Example

The following examples are only used as examples and should not be considered as limiting the present invention.

Example 1

Eligible subjects will undergo medical history and physical examination. All subjects will undergo standard drug screening tests. Subjects will complete the Pittsburgh Sleep Quality Index, Functional Outcomes of Sleep Questionnaire, Beck Depression Inventory, and the SF-36 to assess quality of life. All subjects will complete up to two weeks of daily sleep. At the end of this "running" period, a disturbed night or morning with vague sleep will be evaluated. Following eligibility, all subjects will undergo a complete polysomnography (PSG) to include monitoring of esophageal pH. All subjects will complete the questionnaire before going to bed and after waking up in the morning. They were used to assess activity and mental status on the day prior to the sleep study, as well as morning mental status and subjective reports of waking and heartache symptoms experienced during the sleep study.

The subjects are then randomized into two groups, one group will receive the active compound and one group will receive a placebo.

PSG Research:

PSG studies consist of monitoring EEG, EOG, EMG and EKG. Breathing is measured by the nose-mouth sensor. The following parameters were determined using standard internationally accepted criteria:

Total Sleep Time (TST)

Sleep Onset Latency (SOL)

Sleep efficiency (time asleep/time to bed)

Waking After Sleep Onset (WASO)

Arousal Response (Arousal Response is defined by current AASM Operating Guidelines guidelines)

Percentage of REM sleep

Percentage of Periods 3 and 4

Esophageal pH Study:

A standard pH probe with dual sensors was placed more than 5 cm above the proximal edge of the lower esophageal sphincter (LES) measured with a manometer. The second pH sensor is approximately 5 cm proximal to the distal sensor. This will be done at approximately 4:00 pm prior to each PSG study. Determine the following pH parameters:

Number of reflux events on distal and proximal pH sensors

Arousal response associated with reflux conditions (arousal response is defined as occurring within 5 minutes after pH falls below 4.0)

Average Clearance Time/Case

% acid contact time

Cases exceeding the duration of 5 minutes

data analysis

Data analysis consisted of comparing two randomized groups, one with drug and one with placebo. Compare the results of the tests discussed above, namely the Pittsburgh Sleep Quality Index, Sleep Inventory Function Results, Becker Depression Survey, SF-36 for Quality of Life, Polysomnography (PSG), Life in Patients with Reflux and Dyspepsia Quality (QOLRAD) and esophageal pH.

Example 2

One hundred and four patients with documented sleep complaints, at least three nights per week, were included. Patients will be excluded if they have a history of GERD. Patients were randomly selected after a two-week sleep rescheduling exercise. Eighty-one patients completed two sleep assessments including polysomnography of distal esophageal pH 10-21 days apart. Of the 81 subjects studied, 26% had reflux (pH < 4.0 for more than 30see) on at least one night. Of the participants with reflux, 21% had an acid contact time (ACT) of more than 4%, 25% had at least one instance lasting more than five minutes, with a mean ACT of 28%. The average duration of each reflux episode was 34.4 minutes. Almost all (94%) documented episodes of reflux were associated with arousal or wakefulness. A historical comparison of symptomatic GERD patients with sleep complaints had a mean ACT of only 12% (p<0.05), see Orr et al., Am Journal of Gastroenterology 2005; 100(Suppl9): S50-51, Abs 82, here Incorporated by reference.

Example 3

Sixteen subjects were recruited into the study, eight potential reflux subjects and eight controls based on the Carlsson questionnaire. Exclude patients with a history of medication, or with a diagnosis such as restless legs syndrome, periodic limb movements, Alzheimer's disease, Huntington's disease, Parkinson's disease, sleep apnea, or known gastric- Patients with a history of esophageal disease. The mean Carlson questionnaire score in the reflux group was 13.75 (range 10-17): the control group scored 0. There were 10 men and 6 women (age 22-62 years; mean 41.4 years). Body mass index was 25.7±1.2 (mean±S.E.). Six (75%) subjects with high Carlson scores and five (62.5%) subjects with low Carlson scores were found to have reflux conditions during sleep. Eleven subjects with reflux (six men and five women: age 22-62 years; mean 41.2 years) were evaluated. A total of 53 reflux episodes occurred, which were associated with 41 arousals and 128 arousals. All reflux conditions were associated with wakefulness or wakefulness or both. Analyzes were performed on subjects with reflux (pre- and post-treatment with omeprazole). The number of awakenings (mean fS.E.) following reflux episodes decreased from 3.7±0.9 to 1.3±0.5 (P<0.05). The number of arousals following a reflux event decreased from 11.6±3.8 to 1.5±0.8 (P<0.01). The total time (pH<4) decreased from 38.7±13.7 to 5.3±1.6min (P<0.05). Six subjects with <80% sleep efficiency prior to omeprazole were further analyzed. Data were analyzed (pre- and post-treatment with omeprazole). The total time (pH<4) decreased from 59.2±13.7 to 4.0±1.6min with omeprazole (P<0.05). Sleep efficiency increased from 70.2% to 81.6% (P<0.05). The total sleep time (mean ± S.E.) increased from 294.0+15.Y to 345.6+55.6min (P<0.05), and the total wake-up time decreased from 99.1±17.9 to 46.1±15.3min (P<0.05) and the rapid eye Sleep time improved from 55.0±4.5 to 94.5±18.9min (P<0.05). Among the six sleep-impaired subjects, the number of awakenings decreased from 8.7±2.0 to 3.2±0.7 (P<0.01), while the number of awakenings decreased from 3.3 f1.2 to 1.5k 0.6 (P<0.05 ), see DiMarina et al.: Aliment Pharmacol Ther 2005:22:325-329, incorporated herein by reference.

The following terms are used throughout the specification unless otherwise stated.

Reflux Conditions - Esophageal pH decreases to below about 4.0.

Arousal - Sudden increase in frequency on EEG (except spindle) or insomnia lasting at least about 3 seconds but less than about 15 seconds.

Waking - a recorded period of insomnia lasting at least approximately 15 seconds.

Sleep efficiency—the ratio of total sleep time to time spent in bed, expressed as a percentage.

A sleep efficiency of ~80% is considered abnormal.

Total Awake Time—The cumulative amount of time spent awake during the recording period.

Apnea - cessation of nasal and oral airflow for at least about 10 seconds.

Claims (6)

CLAIMS 1. Use of PPIs in the treatment of sleep disorders caused by asymptomatic gastroesophageal reflux. 2. purposes as claimed in claim 1, wherein PPI is selected from neutral omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, tenatoprazole, Aipur Prazole, and leminoprazole, or pharmaceutically acceptable salt forms and/or single enantiomers thereof. 3. purposes as claimed in claim 1, wherein PPI is

4. A method of treating sleep disorders caused by asymptomatic gastro-oesophageal reflux, which consists in administering to a patient in need of such treatment an effective amount of a PPI. 5. The method as claimed in claim 4, wherein the PPI is selected from neutral omeprazole, lansoprazole, pantoprazole, rabeprazole, esomeprazole, tenatoprazole, alpra Prazole, and leminoprazole, or pharmaceutically acceptable salt forms and/or single enantiomers thereof. 6. The method of claim 4, wherein the PPI is