WO2009014490A1

WO2009014490A1 - Combination of (3-amino-2-fluoropropyl)phosphinic acid and omeprazole for treating tlesr, gerd, and nerd

Info

Publication number: WO2009014490A1
Application number: PCT/SE2008/050889
Authority: WO
Inventors: Göran HASSELGREN; Anders Lehmann; Hans Rydholm; Michael Wrangstadh
Original assignee: Astrazeneca Ab
Priority date: 2007-07-25
Filing date: 2008-07-24
Publication date: 2009-01-29

Abstract

The present invention is directed toa combination comprising (3-amino-2- fluoropropyl)phosphinic acid, (2R)-(3-amino-2-fluoropropyl)phosphinic acid, or (2S)-(3- amino-2-fluoropropyl)phosphinic acid, or a pharmaceutically acceptable salt thereof, and omeprazole or esomeprazole, or a pharmaceutically acceptable alkaline salt or hydrate thereof, as well as to the use of said combination for the treatment of GERD.

Description

Combination of (3-amino-2-fluoropropyl)phosphinic acid and omeprazole for treating TLESR, GERD, and NERD

Field of the invention

The present invention is directed to a novel combination comprising (i) (3-amino-2- fluoropropyl)phosphinic acid or an enantiomer thereof, or a pharmaceutically acceptable salt thereof; and (ii) omeprazole or esomeprazole, or a pharmaceutically acceptable alkaline salt thereof.

Background of the invention

The lower esophageal sphincter (LES) is prone to relaxing intermittently. As a consequence, fluid from the stomach can pass into the esophagus since the mechanical barrier is temporarily lost at such times, an event hereinafter referred to as "reflux".

Gastro-esophageal reflux disease (GERD) is the most prevalent upper gastrointestinal tract disease. The major mechanism behind reflux has been considered to depend on a hypotonic lower esophageal sphincter. However, more detailed studies (e.g. Holloway & Dent (1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535) have shown that most reflux episodes occur during transient lower esophageal sphincter relaxations (TLESR), i.e. relaxations not triggered by swallows. It has also been shown that gastric acid secretion usually is normal in patients with GERD.

Gastroesophageal reflux disease (GERD) is one of the most common upper GI disorders with a prevalence between 10-20% in the Western World. GERD patients are subdivided into two main categories: Erosive reflux disease (ERD) and non-erosive reflux disease

(NERD). While the latter frequently is viewed as a milder form, the severity and incidence of symptoms are identical in the two groups. The distribution of patients into the two groups differs between studies but in general, NERD comprise at least half of the GERD population. {Martinez SD, Malagon IB, Garewal HS, Cui H, Fass R. Alimentary Pharmacology & Therapeutics 2003; 17: 537-45). A new definition of gastro-esophageal reflux disease (GERD), has been disclosed by Vakil N et al. in Am J Gastroenterol 2006; 101: 1900-1920; "The Montreal Definition and Classification of Gastroesophageal Reflux Disease: A Global Evidence Based Consensus).

GERD is a condition which develops when reflux of gastric content causes troublesome symptoms or complications (Montreal definition of GERD). Even if acid suppressive therapy, such as PPIs, has proven to be effective in the treatment of GERD, there are still unmet medical needs to be filled since at least 40 % of GERD patients still experience GERD symptoms despite PPI treatment, especially in those patients who experience symptoms without esophagitis.

The combination therapy of idiopathic chronic hiccup with cisapride, omeprazole and baclofen has been described by Petroianu G. et al. Clinical Therapeutics (1997), 19, pp. 1031-1038. The combination therapy of idiopathic chronic hiccup with cisapride, omeprazole and gabapentin has been disclosed by Petroianu G. et al. Journal of Clinical Gastroenterology (2000), 20, pp. 321-324.

Certain pharmaceutical combinations are disclosed in e.g. WO2004/000855 and WO 2004/ 105795.

Outline of the invention

An object of the present invention was to find a novel therapy for Gastroesophageal Reflux Disease (GERD).

An aspect of the present invention is directed to a combination comprising (3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and omeprazole or a pharmaceutically acceptable alkaline salt thereof. A further aspect of the invention is directed to a combination comprising (2i?)-(3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and omeprazole or a pharmaceutically acceptable alkaline salt thereof.

A further aspect of the invention is directed to a combination comprising (2S)-(3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and omeprazole or a pharmaceutically acceptable alkaline salt thereof.

An aspect of the present invention is directed to a combination comprising (3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole or a pharmaceutically acceptable alkaline salt thereof. Examples of such a combination within the scope of the invention is a combination of (3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole magnesium.

An aspect of the invention is directed to a combination comprising (2i?)-(3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole or a pharmaceutically acceptable alkaline salt thereof. Examples of such a combination within the scope of the invention is a combination of (2i?)-(3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole magnesium.

Yet a further aspect of the invention is directed to a combination comprising (25)-(3- amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole or a pharmaceutically acceptable alkaline salt thereof. Examples of such a combination within the scope of the invention is a combination of (25)-(3-amino-2- fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole magnesium. An aspect of the invention is directed to a combination as described and claimed herein, for use in therapy.

An aspect of the invention is the use of a combination as described and claimed herein, for the inhibition of Transient Lower Esophageal Sphincter Relaxations (TLESR).

An aspect of the invention is the use of a combination as described and claimed herein, for the manufacture of a medicament for the treatment of gastro-esophageal reflux disease (GERD).

An aspect of the invention is a combination as described and claimed herein, for the treatment of gastro-esophageal reflux disease (GERD).

An aspect of the invention is a method for the treatment of gastro-esophageal reflux disease, whereby a combination as described and claimed herein is administered to a subject in need of such treatment.

Yet an aspect of the invention is a combination as described and claimed herein, for the treatment of GERD in a subject with an incomplete response to PPI treatment.

An aspect of the invention is a combination as described and claimed herein, for the treatment of GERD in a subject who is a non-responder to PPI treatment.

An aspect of the invention is a combination as described and claimed herein, for the treatment of GERD in a subject who is a non-responder to treatment with an acid inhibiting agent such as an H2 blocking agent.

A further aspect of the invention is the use of a combination as described and claimed herein, for the manufacture of a medicament for the treatment of regurgitation, treatment or prevention of lung disease, management of failure to thrive, treatment or prevention of esophagitis, treatment of asthma such as reflux-related asthma or non reflux-related asthma, treatment of laryngitis such as chronic laryngitis.

Still a further aspect of the invention is the use of a combination as described and claimed herein, for the manufacture of a medicament for the treatment of Barrett's esophageus.

Yet an aspect of the present invention is the use of a combination as described and claimed herein, for the manufacture of a medicament for the prevention of reflux.

Yet an embodiment of the present invention is a combination as described and claimed herein, for the prevention of reflux.

Still an aspect of the present invention is a a combination as described and claimed herein, for use in the treatment of any one of the medical conditions mentioned throughout the specification.

An aspect of the invention is a combination as described and claimed herein, for the treatment of regurgitation, treatment or prevention of lung disease, management of failure to thrive, treatment or prevention of esophagitis, treatment of asthma such as reflux-related asthma or non reflux-related asthma, treatment of laryngitis such as chronic laryngitis.

An aspect of the invention is a method for the treatment of regurgitation, treatment or prevention of lung disease, management of failure to thrive, treatment or prevention of esophagitis, treatment of asthma such as reflux-related asthma or non reflux-related asthma, treatment or prevention of laryngitis such as chronic laryngitis, whereby a combination as described and claimed herein is administered to a subject in need of such treatment. An further aspect of the invention is a method for the treatment of Barrett's esophagus, whereby a combination as described and claimed herein is administered to a subject in need of such treatment.

Yet an aspect of the present invention is the use of a combination as described and claimed herein, for the manufacture of a medicament for the treatment of non-erosive reflux disease (NERD).

A further aspect of the invention is a combination as described and claimed herein, for the treatment of non-erosive reflux disease (NERD).

A further aspect of the invention is a method for the treatment and/or prevention of NERD, wherein a combination as described herein is administered to a subject in need of such treatment and/or prevention.

Yet a further aspect of the present invention is a method for the treament of GERD, or a method for the treatment of a medical condition selected from any one of regurgitation, treatment or prevention of lung disease, management of failure to thrive, treatment or prevention of esophagitis, treatment of asthma such as reflux-related asthma or non-reflux related asthma, treatment of laryngitis such as chronic laryngitis, or Barrett's esophageus, whereby a combination as described herein is administered to a patient or subject in need of such treatment.

(3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid, or (2S)-(3-amino-2-fluoropropyl)phosphinic acid, which each may be comprised in a combination according to the present invention, are of amphoteric nature and may be presented in the form of internal salts. These compounds can also form acid addition salts and salts with bases. Such salts are pharmaceutically acceptable acid addition salts, as well as pharmaceutically acceptable salts formed with bases. Examples of acids useful for the formation of such salts include, for example, mineral acids such as hydrochloric, hydrobromic, sulfuric, or phosphoric acid or organic acids such as sulfonic acids and carboxylic acids. Examples of bases useful for the formation of salts are, for example, alkali metal salts, e.g. sodium or potassium salts, or alkaline earth metal salts, e.g. calcium or magnesium salts, as well as ammonium salts, such as those with ammonia or organic amines.

(3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fiuoropropyl)phosphinic acid, or (2S)-(3-amino-2-fluoropropyl)phosphinic acid, may also be present in the form of solvates, e.g. hydrates, or in different crystal forms when used in a combination as described herein.

Compounds useful in accordance with the present invention can be prepared as described in WOO 1/42252.

Omeprazole magnesium and omeprazole sodium are known as products under inter alia the registered trademarks Losec , Losec MUPS, Losec i.v. and Prilosec .

The wording "omeprazole" as used herein comprises omeprazole in neutral form as well as an alkaline salt of omeprazole, such as a magnesium salt or sodium salt thereof, or a hydrate thereof. Omeprazole was initially disclosed in EP 0005129.

The wording "esomeprazole" as used herein comprises esomeprazole in neutral form as well as an alkaline salt of esomeprazole, such as a magnesium salt or sodium salt thereof, or a hydrate thereof, such as esomeprazole magnesium trihydrate. Esomeprazole magnesium and esomeprazole sodium are marketed under the registered trademark

® Nexium . Esomeprazole and pharmaceutically acceptable alkaline salts thereof were initially disclosed in WO94/27988. The wording "TLESR", transient lower esophageal sphincter relaxations, is herein defined in accordance with Mittal, R.K., Holloway, R.H., Penagini, R., Blackshaw, L.A. , Dent, J., 1995; Transient lower esophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.

The wording "reflux" is defined as fluid from the stomach being able to pass into the esophagus, since the mechanical barrier is temporarily lost at such times.

The wording "GERD", gastro-esophageal reflux disease, is herein defined in accordance with the Montreal Definition and Classification (Vakil N et al. Am J Gastroenterol 2006; 101:1900-1920).

The term "treatment" also includes "prevention" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

The wording "compound" as used in the specification and patent claims is herein defined as (3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid, (25)-(3-Amino-2-fluoropropyl)phosphinic acid, or a pharmaceutically and pharmacologically acceptable salt of any one of said compounds. Also within the scope of the wording "compound" is any one of said compounds in a crystalline form, or a salt thereof.

The wording PPI as used herein encompasses omeprazole or esomeprazole, or an alkaline salt thereof. Also within this scope is omeprazole or esomeprazole in a crystalline form, or an alkaline salt thereof.

The compound (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid may exist in different crystal forms such as Form A and Form B. Preparation of (2R)-(3-Amino-2-fluoropropyl)phosphinic acid. Form A

320 g (1.11 moles) (2R)-3-[(tert-butoxycarbonyl)amino]-2-fluoro-propyl phosphinic acid ammonium salt dissolved in methanol (960 ml, 23.72 moles ) was treated with sulphuric acid (105.43 ml, 1.90 moles) at 55°C. After complete reaction, the reaction mixture was cooled to 30⁰C and pH was adjusted to approximately 5 by addition of ammonium acetate dissolved in methanol (180 g, 2.34 moles, 420 ml methanol). During the pH-adjustment ammonium sulphate remaining ammonium acetate and other salts precipitated. The neutralised reaction mixture was clear filtrated. Isopropanol (3.84 L, 50.23 moles) was added at 50⁰C and (2R)-(3-Amino-2-fluoropropyl)phosphinic acid, Form A, crystallised. The slurry was cooled to 0⁰C. The crystals were isolated and dried under vacuum.

¹H-NMR (400 MHz, D₂O): δl.93 (1 H, m), 2.13 (1 H, m), 3.31 (2 H, m), 5.14 (1 H, dm, J=50 Hz), 7.07 (1 H, d, J=528 Hz).

The crystals were analysed by X-ray powder diffraction (XRPD). The diffractogram of form A shows the following d-values given in Angstrom and relative intensities:

The relative intensities are presented by the following definitions.

Definitions used % Relative Intensity vs (very strong): 100-70

S (strong): 70-40 m (medium): 40-10 w (weak): 10-5 vw (very weak): <5

The relative intensities were derived from diffractograms measured with variable slits.

Preparation of (2R)-(3-Amino-2-fluoropropyl)phosphinic acid. Form B

40 g of (2R)-(3-Amino-2-fluoropropyl)phosphinic acid form A, was added to 15OmL methanol and 65 mL water. The slurry was heated to 40⁰C until all was dissolved. 320 mL of acetone was added to the solution over 10 hrs. The slurry was stirred at 40⁰C for 33 hours. Then obtained crystals were filtered and dried in vacuum at 40⁰C overnight. 36.67 g of (2R)-(3-Amino-2-fluoropropyl)phosphinic acid, form B, was obtained after drying.

¹H-NMR (400 MHz, D₂O): δl.95 (1 H, m), 2.15 (1 H, m), 3.33 (2 H, m), 5.16 (1 H, dm, J=50 Hz), 7.08 (1 H, d, J=528 Hz).

The crystals were analysed by X-ray powder diffraction (XRPD). The diffractogram of form B shows the following d-values given in Angstrom and relative intensities:

The relative intensities are presented by the following definitions:

Definitions used % Relative Intensity vs (very strong): 31-100 s (strong): 8.1-31 m (medium): 3.1-8.1 w (weak): 0.7-3.1 vw (very weak): 0-0.7

The relative intensities are derived from diffractograms measured with variable slits.

The wording "incomplete response to treatment with an acid inhibiting agent" as used herein, is defined as a subject or patient already on therapy with an acid inhibiting agent such as a PPI or an H2 blocking agent, but still experiencing GERD symptoms.

The wording "non-responder to treatment with a an acid inhibiting agent" as used herein, is defined as a subject or patient already on therapy with an acid inhibiting agent such as a PPI or an H2 blocking agent, but not experiencing improvement of GERD symptoms.

A further aspect of the present invention, is therapy in a patient already on therapy with an acid inhibiting agent such as a PPI.

In one aspect of the invention a patient may be on therapy with a PPI or on therapy with an H2 blocking agent, but still experiencing GERD symptoms.

A further aspect of the invention is symptom control in a patient or subject with persistent GERD symptoms despite PPI treatment.

An aspect of the invention is a "combination" in the form of a "fix combination" or as a "kit of parts combination". A "fix combination" is herein defined as a combination wherein (3-Amino-2- fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid, or (2<S)-(3- Amino-2-fluoropropyl)phosphinic acid, or a salt of any one of said compounds, and omeprazole or esomeprazole, or an alkaline salt thereof, are present in one dosage unit.

One aspect of the invention is a unit dosage e.g. a pharmaceutical product, wherein the active ingredients are not in admixture with each other but being present as a combination, said combination comprising any one of (3-Amino-2-fluoropropyl)phosphinic acid, (2R)- (3-Amino-2-fluoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid, or a salt of any one of said compounds, and omeprazole or esomeprazole, or an alkaline salt thereof such as a magnesium salt or a sodium salt thereof. Examples of such a fix combination is e.g. a capsule filled with each active ingredient.

A "kit of parts combination" is herein defined as a combination wherein (i) (3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid, or a salt of any one of said compounds, is provided as a formulated product in combination with (ii) a formulated product of omeprazole or esomeprazole, or an alkaline salt thereof.

Examples of such a "kit of parts combination" is without any limitation a combination of (i) (3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fluoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid, or a salt of any one of said compounds provided as a formulated product in combination with (ii) a formulated product of a magnesium or sodium salt of omeprazole, or a magnesium or sodium salt of esomeprazole.

Still a further aspect of the invention is a combination wherein each active ingredient may be administered simultaneously, separately or seqentially, in any order.

Still an aspect of the invention is add-on therapy, whereby (3-Amino-2- fluoropropyl)phosphinic acid, (2R)-(3-Amino-2-fluoropropyl)phosphinic aci, (2<S)-(3- Amino-2-fluoropropyl)phosphinic acid, or a salt of any one of said compounds, is administered to a patient already being treated with omeprazole or esomeprazole, or an alkaline salt of any one of said compounds.

Pharmaceutical formulations For clinical use, a compound useful in accordance with the present invention may be formulated into a pharmaceutical formulation for oral administration. Also parenteral or any other route of administration may be contemplated to the skilled man in the art of formulations. Thus, a compound useful in accordance with the invention is formulated with at least one pharmaceutically and pharmacologically acceptable carrier or adjuvant. The carrier may be in the form of a solid, semi-solid or liquid diluent.

In the preparation of an oral pharmaceutical formulation in accordance with the invention, the compound or combination to be formulated may be mixed with solid powdered ingredients, fillers, disintegrating agents and lubricating agents. The mixture is then processed into granules and/ or compressed into tablets.

Soft gelatine capsules may be prepared with capsule containing a mixture of the active compounds comprised in a combination in accordance with the invention and other suitable pharmaceutical agents and/or vehicles for soft gelatine capsules. Hard gelatine capsules may contain the compound(s) in combination with solid powdered ingredients.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions, containing the active compounds and the remainder of the formulation consisting of sugar or sugar alcohols, and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agent. Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use. Solutions for parenteral administration may be prepared as a solution of the compounds in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients and/or buffering ingredients and are dispensed into unit doses in the form of ampoules or vials. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable solvent extemporaneously before use.

Suitable pharmaceutical formulations of omeprazole and esomeprazole, and alkaline salts thereof, are disclosed in for example EP 247983 and WO97/ 01623.

A daily dose of (3-Amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2- fluoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid or a salt of any one of said compounds useful in accordance with the invention, may be up to 2200 mg per day, such as up to 480 mg per day. The compound may for example be administered once or twice daily. In one embodiment of the invention the compound may be administered in a dose of up to 240 mg bid (i.e. twice daily amounting to up to 480 mg per day).

In one embodiment of the invention, (3-Amino-2-fluoropropyl)phosphinic acid, (2R)-(3- Amino-2-fluoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid or a salt of any one of said compounds, may be administered in a dose of from 30 to 240 mg bid.

In yet an embodiment, the daily dose of (3-Amino-2-fluoropropyl)phosphinic acid, (2R)- (3-Amino-2-fiuoropropyl)phosphinic acid, or (25)-(3-Amino-2-fluoropropyl)phosphinic acid or a salt of any one of said compounds, may be administered in a dosage such as 30 mg bid, 60 mg bid, 120 mg bid and 240 mg bid. The wording bid means that a compound is administered twice daily, and the daily dose of a compound may be such as 60 mg, 120 mg, 240 mg and 480 mg.

A daily dose of omeprazole or esomeprazole, or an alkaline salt such as a magnesium or sodium salt thereof, useful in a combination according to the invention, may be in the range of from 5 to 200 mg per day, such as 10, 20, 40 or 80 mg per day. Examples of suitable dosages of said PPI's are commercially available doses of omeprazole or esomeprazole, or an alkaline salt thereof such as a magnesium or sodium salt thereof.

In one aspect of the invention, (2i?)-(3-Amino-2-fiuoropropyl)phosphinic acid or a salt thereof, is administered in a dosage of 65 mg b.i.d. (i.e. twice daily) as add-on therapy to omeprazole or esomeprazole, or an alkaline salt of any one of said compounds, such as a magnesium or sodium salt of omeprazole or esomeprazole..

In one aspect of the invention, each active compound may be administered as a single dose or as at least one repeated dose, simultaneously, separately or sequentially in any order of administration.

Claims

1. A combination comprising (3-amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and omeprazole or a pharmaceutically acceptable alkaline salt thereof.

2. A combination comprising (2i?)-(3-amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and omeprazole or a pharmaceutically acceptable alkaline salt thereof.

3. A combination comprising (25)-(3-amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and omeprazole or a pharmaceutically acceptable alkaline salt thereof.

4. A combination comprising (3-amino-2-fiuoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and esomeprazole or a pharmaceutically acceptable alkaline salt thereof.

5. A combination comprising (2i?)-(3-amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and esomeprazole or a pharmaceutically acceptable alkaline salt thereof.

6. A combination comprising (2S)-(3-amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof; and esomeprazole or a pharmaceutically acceptable alkaline salt thereof.

7. A combination according to any one of claims 1-6, for use in a subject with an incomplete response to therapy with an acid inhibiting agent.

8. A combination according to claim 7, wherein said acid inhibiting agent is a PPI.

9. A combination according to claim 7, wherein said acid inhibiting agent is an H2 blocking agent.

10. A combination according to any one of the preceding claims, wherein the daily dose of any one of (3-amino-2-fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2- fluoropropyl)phosphinic acid, or (25)-(3-amino-2-fluoropropyl)phosphinic acid, or a pharmaceutically acceptable salt of any one of said compounds, is up to 2200 mg per day.

11. A combination according to claim 10, wherein the daily dose of (3-amino-2- fluoropropyl)phosphinic acid, (2i?)-(3-Amino-2-fiuoropropyl)phosphinic acid, or (25)-(3-amino-2-fluoropropyl)phosphinic acid, or a pharmaceutically acceptable salt of any one of said compounds, is from 30 to 240 mg bid.

12. A combination according to any one of the preceding claims, wherein the daily dose of omeprazole or esomeprazole, or an alkaline salt thereof, is in the range of from 10 to 200 mg per day.

13. A combination according to any one of the preceding claims, wherein the alkaline salt of omeprazole or esomeprazole is a magnesium salt or a hydrate thereof.

14. A combination according to any one of the preceding claims, wherein each active ingredient is administered simultaneously, separately or sequentially.

15. A combination according to any one of the preceding claims, said combination being a fix combination.

16. A combination according to claim 15, said combination being a kit of parts combination.

17. A combination according to any one of the preceding claims, comprising (2R)-(3- Amino-2-fluoropropyl)phosphinic acid or a pharmaceutically acceptable salt thereof, and esomeprazole magnesium.

18. A combination according to any one of the preceding claims, for the inhibition of TLESR.

19. A combination according to any one of the preceding claims, for the treatment of gastroesophageal reflux disease (GERD).

20. A combination according to any one of the preceding claims, wherein the reflux disease to be treated is non-erosive reflux disease (NERD).

21. A method for the inhibition of TLESR, whereby a combination according to any one of claims 1-17 is administered to a subject in need of said inhibition.

22. A method for the treatment of GERD, whereby a combination according to any one of claims 1-17 is administered to a subject in need of said treatment.

23. A method according to claim 20, wherein the GERD indication to be treated is non- erosive reflux disease (NERD).