WO2019021079A1

WO2019021079A1 - Pharmaceutical composition with a range related between tramadol chlorhydrate and etoricoxib for its administration for the treatment of pain

Info

Publication number: WO2019021079A1
Application number: PCT/IB2018/054725
Authority: WO
Inventors: Oliver Daniel WALLS FLORES; Reyna Astrid SALTO RIVERA; Ramón RODRÍGUEZ HERNÁNDEZ; Alejandra ROSETE REYES
Original assignee: Laboratorios Liomont, S.A. De C.V.
Priority date: 2017-07-26
Filing date: 2018-06-27
Publication date: 2019-01-31
Also published as: MX2017009660A

Abstract

The present invention consists in a process and pharmaceutical composition of a combination of tramadol hydrochloride and etoricoxib for the treatment of pain, which obtainment process is given from granules or particulate material of tramadol hydrochloride and granules or particulate material of etoricoxib which can be contained in a powder mixture, or compressed in a bilayer tablet with or without coating or in a capsule as granules and/or tablets with or without of etoricoxib 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof.

Description

PHARMACEUTICAL COMPOSITION WITH A RANGE RELATED BETWEEN TRAMADOL CHLORHYDRATE AND ETORICOXIB FOR ITS ADMINISTRATION FOR THE TREATMENT OF PAIN . FIELD OF THE INVENTION

The present invention consists of an orally administered pharmaceutical composition of a medicament containing tramadol hydrochloride and etoricoxib for the treatment of pain in a ratio of etoricoxib between 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof.

BACKGROUND OF THE INVENTION

Etoricoxib is prescribed for the acute and chronic treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis, ankylosing spondylitis and acute gouty arthritis.for the relief of acute and chronic pain, from primary dysmenorrhea, of acute post-surgical pain of moderate to severe associated with dental surgery and acute post-surgical pain of moderate to severe associated with gynaecological abdominal surgerydue to its selective inhibitory activity of cyclooxygenase-2 (COX-2).

While tramadol hydrochloride with its dual activity as an agonist on central opioid receptors D, and its inhibition to reuptake of norepinephrine and serotonin in the central nervous system by preventing the transmission of pain through the spinal cord, is prescribed for the treatment of moderate, moderate severe pain and neuropathic pain , in the adjuvant treatment of osteoarthritis and in the treatment of restless legs syndrome and post-operative tremors.

Due to the difference in the activitiesof tramadol and etoricoxibto inhibit pain, it was possible to verify with preclinical studies the existence of a synergy when they are used for the treatment of somatic pain. This synergy can fluctuate in a relationship in which etoricoxib is between 0.15 and 0.85 of the total dose of etoricoxib and tramadol hydrochloride with a decrease in the dose to be administered if they were prescribed individually. For example, in the clinical study it was found that administering 8 mg/kg of etoricoxib + 2 mg/kg of tramadol hydrochloride to rats has an effect of 75%, which to have the equivalent effect in an individual administration a dose of 32 mg/kg of tramadol hydrochloridewould have to be administered , whereas for etoricoxib, despite having been administered 1 50 mg/kg , 75% effect was not achieved. I n this case, the combination of total administration of 10 mg/kg of etoricoxib in combination with tramadol hydrochloride gives us a ratio of 0.8 of etoricoxib and 0.2 of tramadol hydrochloride.

On the other hand , from the search of the published patents of etoricoxib in the official gazette of medicaments of Mexico, it was found that the patent MX 208595 protects its use as an active ingredient until July 8, 2017 and that the patent MX 230696 protects the form V of etoricoxib until May 22, 2021 . From the international search, the international application WO 2014/033526 was found to protect the manufacture of tablets by dry route to retain the polymorphic form of etoricoxib, the international application WO 2004/09381 1 was found to protect the combination of use of a sodium channel blocker with selective inhibitors of cyclooxygenase-2 and the international application WO 2004/09381 3 was found to protect the combination of use of a modulator of calcium blockers with selective inhibitors of cyclooxygenase-2.

Whereas from the patent search for tramadol hydrochloride, in the Mexican Official Gazette of medicaments the patent MX266401 B was found to protect the use of the combination of ketorolac with tramadol hydrochloride for the treatment of pain via oral administration , the patent MX230075B was found to protect the use of the combination of tramadol hydrochloride and the selection of an anticonvulsive agent, the patent MX27581 1 B was found to protect the use of the combination of tramadol hydrochloride with lysine clonixinate for having an analgesic pharmaceutical composition and the patent MX306974B was found to protect the combination of tramadol with lysine clonixinate. From the review of the Mexican patent data base I MPI-SIGA the patent MX31 1821 B was found to protect the use of tramadol hydrochloride co-cristals and etoricoxib.

From the patent reviews, no combination was found to protect selective inhibitors of cyclooxygenase-2, as is the case in particular of etoricoxib with tramadol hydrochloride for the treatment of pain at an administration rate from 15% to 85% of etoricoxib with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof.

Based on what has been described, it is accurate that this combination etoricoxib with tramadol hydrochloride for oral administration is a pharmaceutical product that has a high degree of technological innovation compared to the background described , so it qualifies as a beneficial product for the both Mexican and international society to treat pain-related allopathies.

OBJECT OF THE INVENTION One object of the invention consists in providing a pharmaceutical composition as a new alternative for the treatment of pain.

Another object of the invention is to have an alternative to dose in a single dose the two active substances etoricoxib-tramadol hydrochloride in a ratio of etoricoxib between 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof.

Another object of the invention is to provide a novel combination of etoricoxib-tramadol hydrochloride in a pharmaceutical form that can be administered orally in a ratio of etoricoxib between 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof. DETAILED DESCRIPTION OF THE INVENTION

For this reason, a novel pharmaceutical composition of the combination of etoricoxib with tramadol hydrochloride in an etoricoxib ratio between 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof was developed to be administered orally, which was found to have unexpected effects, as well as the concentration proposed, which exceeds the effects that exist to this day; the elaboration process is described as follows, which is not limited to the examples hereunder which are described in order to exemplify the processes:

1 ) Sieving the etoricoxib or similar salts, one or more diluents, and, one or more surfactants with a mesh; add each component to a mixer and mix the powders.

2) To the mixture of powders from step 1 , add a solvent and stir until a wet powder mixture is formed.

3) Sieving one or more diluents with a mesh, add to the wet mixture of powders and mix the powders.

4) Sieving the mixture of powders from step 3 with a mesh , add one or more pre-sieved diluents and mix the powders.

5) Add one or more lubricants, antiadherents or glidants previously sieved to the mixture of powders of step 4 and mix the powders.

6) In a tableting machine compress the mixture obtained from step 5 to the required concentration between 1 0 mg to 120 mg of etoricoxib and/or similar salts.

7) Dispersing at least one tablet coating material in a solvent in a container.

8) In a coating equipment, coating the tablets from step 6 with the dispersion from step 7

9) Dispersing at least one binding agent in a solvent in a container.

10) With a mesh sieve tramadol hydrochloride or similar salts, one or more diluents, add each component to a mixer and mix the powders.

1 1 ) With the solution of step 9, granulate the powder mixture from step 10.

12) Sieving the granulate from step 1 1 with a sieve and dry in an oven . 13) Sieving the granulate from step 12 with a sieve and mix with one or more lubricant and/or glidants and/or antiadherents.

14) In a tableting machine compress the mixture obtained from step 1 3 to the required concentration between 1 0 mg to 300 mg of tramadol hydrochloride and/or similar salts. 15) Dispersing at least one tablet coating material in a solvent in a container.

16) In a coating equipment, coat the tablets of step 14 with the dispersion of step 15.

17) Fill in capsules with the tablets obtained from step 8 and 16 to the required dose of etoricoxib or similar salts and tramadol and/or similar salts in an etoricoxib ratio from 15% to 85% with respect to the total administered of etoricoxib in combination with tramadol hydrochloride or similar salts.

Example 1

1 ) Dispersing the surfactant in a solvent in a container.

2) Sieving the etoricoxib or similar salts, one or more diluents, and, one or more disintegrating agents with a mesh; add each component to a mixer and mix the powders.

3) With the solution of step 1 , moisten the powder mixture from step 2.

6) Dispersing at least an agglutinant in a solvent in a container.

7) Sieving the tramadol hydrochloride or similar salts, one or more diluents with a sieve, add each component to a mixer and mix the powders.

8) Granulate the mixture of powders of step 7 with the dissolution of step 6.

9) Sieve the granulate of step 8 with a sieve and dry in an oven.

10) Sieve the dry granulate of step 9 with a sieve and mix with one or more lubricants, and/or glidants, and/or antiadherents. 1 1 ) In a tableting machine compress the mixture obtained from steps 5 and 10 to the required concentration between 10 mg to 120 mg of etoricoxib and/or similar salts and from 1 0 mg to 300 mg of tramadol hydrochloride and/or similar salts in a ratio from 15% to 85% with respect to the total administered of etoricoxib in combination with tramadol hydrochloride or similar salts.

Example 2

I ) Dispersing the surfactant in a solvent in a container.

2) Sieving the etoricoxib or similar salts, one or more diluents, one or more agglutinant agents, and, one or more disintegrating agents with a mesh; add each component to a mixer and mix the powders.

3) With the solution of step 1 , granulate the powder mixture from step 2.

4) Sieving the mixture of powders from step 3 with a mesh, add dry in an oven.

5) Sieve the dry granulate of step 4 with a sieve and mix with one or more lubricants, and/or glidants, and/or antiadherents.

6) Dispersing at least an agglutinant in a solvent in a container.

8) Granulate the mixture of powders of step 7 with the dissolution of step 6.

9) Sieve the granulate of step 8 with a sieve and dry in an oven.

10) Sieve the dry granulate of step 9 with a sieve and mix with one or more lubricants, and/or glidants, and/or antiadherents.

I I ) In a tableting machine compress the mixture obtained from step 5 to the required concentration between 1 0 mg to 300 mg of tramadol hydrochloride and/or similar salts.

12) Fill in capsules with the powder mixture obtained from step 5 and with the tablets obtained from step 1 1 at the required dose of 1 0 mg to 120 mg of etoricoxib and/or similar salts and at the required dose of 10 mg to 300 mg of tramadol and/or similar salts in a ratio of etoricoxib from 15% to 85% with respect to the total administered of etoricoxib in combination with tramadol hydrochloride or similar salts.

Example 3

1 ) Dispersing the surfactant in a solvent in a container.

2) Sieving the etoricoxib or similar salts, one or more diluents, one or more agglutinants, and , one or more disintegrating agents with a mesh; add each component to a mixer and mix the powders.

3) With the solution of step 1 , moisten the powder mixture from step 2.

4) Sieving the mixture of powders from step 3 with a mesh, and dry in an oven.

6) Dispersing at least an agglutinant in a solvent in a container.

8) Granulate the mixture of powders of step 7 with the dissolution of step 6.

9) Sieve the granulate of step 8 with a sieve and dry in an oven.

10) Sieve the dry granulate of step 9 with a sieve and mix with one or more lubricants, and/or glidants, and/or

1 1 ) Fill in capsules with the powder mixture obtained from steps 5 and 10 to the required dose of 10 mg to 120 mg of etoricoxib and/or similar salts and at the required dose of 1 0 mg to 300 mg of tramadol and/or similar salts in a ratio of etoricoxib from 1 5% to 85% with respect to the total administered of etoricoxib in combination with tramadol hydrochloride or similar salts.

Claims

1 . A pharmaceutical composition, comprising a combination of tramadol hydrochloride or similar pharmaceutically acceptable salts thereof and etoricoxib or similar pharmaceutically acceptable salts, characterized in that the etoricoxib is present in the composition in a ratio of 15% to 85% with respect to the total of etoricoxib or salts thereof in combination with tramadol hydrochloride or similar salts thereof.

2. The pharmaceutical composition according to claim 1 , further characterized in that the particle size of etoricoxib and or pharmaceutically acceptable salts thereof is less than or equal to 30 microns at a d90.

3. The pharmaceutical composition according to claims 1 and 2, further characterized in that the active ingredients tramadol hydrochloride or similar pharmaceutically acceptable salts thereof and etoricoxib or pharmaceutically acceptable salts thereof are in the form of granules or particulate material individually or in combination .

4. The pharmaceutical composition according to claims 1 to 3, further characterized in that the etoricoxib or pharmaceutically acceptable salts thereof is present in an amount of 10 mg to 120 mg and the tramadol hydrochloride or similar pharmaceutically acceptable salts is present in a amount of 10 mg to 300 mg .

5. The pharmaceutical composition according to claims 1 to 4, further characterized in that it is formulated as an oral composition.

6. The pharmaceutical composition according to claims 1 to 5, further characterized in that it is orally administrable individually in a simultaneous or successive manner.

7. Use of a combination of tramadol hydrochloride or similar pharmaceutically acceptable salts thereof and etoricoxib or pharmaceutically acceptable salts thereof, for manufacturing a medicament useful for the treatment of pain.

8. A process for the preparation of a pharmaceutical composition comprising a combination of tramadol hydrochloride or similar pharmaceutically acceptable salts thereof and etoricoxib or pharmaceutically acceptable salts thereof, characterized in that it comprises the steps of:

a) Sieving and adding into a mixer the active ingredient etoricoxib or pharmaceutically acceptable salts thereof, one or more diluents, one or more surfactants and mix;

b) Add a solvent to the mixture from step a) and stir until a moist mixture is obtained; c) Sieving with a mesh and add one or more diluents to the wet mixture of step b) and mix;

d) Sieving with a mesh the mixture of step c); add one or more previously sieved diluents and mix;

e) Add one or more previously sieved lubricants to the mixture of step d) and mix;

f) Compressing the mixture obtained from step e) In a tablet press to a required concentration of between 10 mg to 120 mg of etoricoxib or pharmaceutically acceptable sales thereof;

g) Dispersing at least one tablet coating material in a solvent in a container;

h) In a tablet coating machine, coating the tablets of step f) with the dispersion of step g); i) In a container dispersing at least one binder in a solvent;

j) Sieving with a mesh and adding into a mixer the tramadol hydrochloride or similar pharmaceutically acceptable salts thereof, one or more diluents and mixing ;

k) Granulate the solution of step i) with the mixture of step j);

I) Sieve with a mesh the granulate of step k) and dry in an oven ;

m) Sieve with a mesh the dry granulate of step I) and mix with one or more lubricants, glidants or antiadherents.

n) In a tablet press, compress the mixture obtained in step m) to the required concentration of between 10 mg to 300 mg of etoricoxib or pharmaceutically acceptable sales thereof;

o) In a container dispersing at least one tablet coating material in a solvent;

p) In a coating machine, coating the tablets of step n) with the dispersion of step o); q) Fill capsules with the tablets obtained in steps h) and p) to the required dose of etoricoxib and tramadol in an etoricoxib or pharmaceutically acceptable sales ratio thereof of 15% to 85% with respect to the total of the combination of tramadol hydrochloride or similar pharmaceutically acceptable salts thereof and etoricoxib or pharmaceutically acceptable salts thereof.