FR2662360A1 - INCLUSION COMPOUNDS OF NIMESULIDE WITH CYCLODEXTRIN, PROCESSES FOR THE PREPARATION THEREOF AND PHARMACEUTICAL COMPOSITIONS WITH ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY CONTAINING SAME - Google Patents

Abstract

The invention relates to inclusion compounds of nimesulide with cyclodextrin alfa, beta and gamma, substituted or in hydrated form, in a nimesulide / cyclodextrin molecular ratio of between 1: 0.5 and 1:15. To prepare these compounds, it is possible: - to react an aqueous solution of cyclodextrin with an organic solution of nimesulide and to isolate the inclusion compound by filtration, - to react the nimesulide and the cyclodextrin in an ammoniacal solution and to isolate the inclusion compound by desiccation of the solution, - or to react the nimesulide and the cyclodextrin in an ammoniacal solution and to isolate the inclusion compound by lyophilization.

Description

The present invention relates to nimesulide inclusion compounds with

  cyclodextrin which increase significantly

  bioavailability and maximum plasma concentration of nimesulide.

  It also relates to processes for the preparation of these compounds.

  Nimesulide (international common name for nitro-4

  phenoxy-2-menthanesulfonamide), which is a drug with

  inflammatory drug used in the treatment of inflammatory forms

  and extra-articular, has a solubility in water and a

  bioavailability that are very low.

  By forming a complex with nimesulide by inclusion in cyclodextrin M (alpha), B (beta), e (gamma), substituted or in its hydrated form, a compound is obtained which has analgesic and anti-inflammatory activity and which has good solubility in water, while

  that nimesulide is absorbed in a faster way.

  Cyclodextrins are cyclic oligosaccharides in which the glucopyranosyl units are chain units

  glycosidic The cyclodextrin molecules have an outer surface

  hydrophilic, while their inner central cavity is apolar, which allows other molecules that are less polar than water to enter the lipophilic cavity of the cyclodextrin

inclusion complex.

  The cyclodextrins used in the present invention are substituted or unsubstituted alpha, beta and gamma cyclodextrins or a hydrated form thereof.

  preferably beta-cyclodextrin.

  The invention relates to inclusion compounds of nimesulide with cyclodextrin alfa, beta and gamma, substituted or in hydrated form, in a molecular ratio nimesulide / cyclodextrin included

between 1: 0.5 and 1:15.

  The methods of preparation of the inclusion compounds of the nimer-

  sulide with a cyclodextrin in a molecular ratio of between 1: 0.5 and 1:15 (preferably 1: 1) are described below:

  1) The aqueous solution of the cyclodextrin and the aqueous solution are stirred

  nimesulide in a suitable organic solvent and separated by

  filtration the complex that is formed.

  2) The nimesulide and the cyclodextrin are placed in aqueous ammonia solution at room temperature and the resulting compound is recovered.

by lyophilization.

  3) Nimesulide and cyclodextrin are mixed in water.

  This mixture is stirred for 7 days and the mixture is recovered by evaporation.

complex that is formed.

  The invention relates to processes for the preparation of the inclusion compounds considered, which processes respectively consist in: reacting an aqueous cyclodextrin solution with an organic nimesulide solution and isolating the inclusion compound by filtration; react the nimesulide and the cyclodextrin in an ammoniacal solution and to isolate the inclusion compound by desiccation of the solution, to react the nimesulide and the cyclodextrin in a

  ammonia solution and isolate the inclusion compound by lyophilization.

  Pharmaceutical Compositions With the active ingredient (nimesulide complexed by inclusion in the cyclodextrin), it is possible to obtain pharmaceutical compositions whether in solid or liquid form and these compositions can be administered.

  oral, rectal, parenteral or topical application.

  The subject of the invention is therefore also pharmaceutical compositions

  ticks with analgesic and anti-inflammatory activity that contain

  active ingredient the inclusion compounds described above.

  It more particularly relates to pharmaceutical compositions

  which contain the active substance at the rate of 20 to 150 mg

dosing unit.

  Other features and advantages of the invention are

  from the description that follows, as a non-limiting example and

  with reference to the accompanying drawings, in which: FIG. 1 represents various thermograms corresponding to the

  nimesulide, beta-cyclodextrin, nimesulide-beta-cyclodex-

  trine and the inclusion compound of nimesulide with beta-cyclodextrin,

  the abscissae being in degrees centigrade and the exothermic heat exo-

  thermometer being plotted on the ordinate, FIG. 2 represents the infrared spectra of the mixture of

  nimesulide-beta-cyclodextrin and nimetric inclusion compound

  sulide-beta-cyclodextrin of the invention, the wavelength being plotted on the abscissa, and

  Figure 3 shows two graphs that represent the parameters

  very kinetic AUC and Cmax corresponding to nimesulide and the compound

  nimesulide-beta-cyclodextrin inclusion.

  Characterization of the inclusion compound of nimesulide with beta-cyclo

  dextrin The inclusion compound was characterized by the following elements: 1) Quantitative determination of nimesulide included in betacyclodextrin. The amount of nimesulide included in the complex with beta-cyclodextrin was characterized by HPLC (High Pressure Liquid).

  Chromatography, that is, high-pressure liquid chromatography

  l O sion) with the following experimental conditions: Mobile phase: phosphate buffer 0.002 M p H 7 acetonitrile ratio 70:30 Flow rate: 1.5 ml / min Temperature: ambient Column: R Ps ym (Hewlett-Packard) Wavelength used: 420 nm Duration: approximately 5 minutes 2) Differential thermal analysis: Figure 1 shows the thermograms for nimesulide (curve A), beta-cyclodextrin (curve B), a mixture of nimesulide

  and beta-cyclodextrin (curve C) and an inclusion compound of the nimer-

  sulide with beta-cyclodextrin (curve D).

  The inclusion compound curve (curve D) does not show the

  peak melting at 149 C, which is present on the curve of the nimer-

  sulide (curve A), which proves that the formation of the inclusion compound

occurred.

3) Infrared spectrography.

  In FIG. 2, we see the IR (infrared) spectra of the mixture

  1: 1 (mol: mol) (curve E) and the inclusion compound of the nimer-

  sulide with beta-cyclodextrin (curve F) Significant differences

  between the inclusion product and the mixture of materials are evident in the figure, which confirms what we saw in the analysis.

differential thermal.

  Bioavailability and Pharmacokinetics Plasma kinetics are achieved in the Beagle dog when oral equivalent doses of nimesulide and nimesulide-betacyclodextrin inclusion compound (1: 1 molar ratio) are

following the pattern "cross-over".

  Six male Beagle dogs weighing between 11.5 and 12.6 kg were taken, fasted for 18 hours and administered orally (in capsule form) with the following compounds: nimesulide at a dose of 10 mg / kg of the nimesulide-betacyclodextrin inclusion compound (1: 1 molar ratio) in a dose of 46.84 mg / kg corresponding to 10 mg / kg of nimesulide. The period of "interruption" between one preparation and the other has

been 15 days.

  The blood samples taken from the dogs were collected in heparinized test tubes 1, 3, 5, 7, 24 and 48 respectively.

  hours after administration of both preparations.

  Plasma levels of nimesulide were determined by high pressure liquid chromatography (HPLC) according to A Alessandri et al.

described in Clin Ter 118 1986.

  The results obtained are presented in Table 1 This table

  indicates the plasma levels of nimesulide in the dog after administration.

  oral administration of nimesulide (10 mg / kg) (1) and the inclusion compound

  nimesulide-beta-cyclodextrin (2).

TABLE 1

  PREPARATION DOG MEASUREMENTS LEVELS PLASMATIC Syg / g DE NIMESULIDE

  ERRORS HOURS AFTER ADMINISTRATION

STANDARD

1 3 5 7 24 48

  1 6 X i 2,125 9,740 11,532 9,321 1,32 0.155

  E.S 0.601 0.833 2.345 1.439 0.531 0.104

  2 6 X i 12,010 26,310 22,605 19,050 2,945 0,148

  E.S 2,464 1,474 1,790 2,033 1,256 8,066

  The kinetic parameters AUC (area under the curve) and Cmax (maximum plasma concentration), calculated from the plasma levels of nimesulide, are presented in Table 2 and Figure 3. Table 2 shows the mean values of Some kinetic parameters In FIG. 3, the curve G corresponds to nimesulide and the curve H to the inclusion compound nimesulide-beta-cyclodextrin. The kinetic parameters are statistically very significant, so

  It can be concluded that the inclusion compound nimesulide-beta-cyclodex-

  trine significantly increases bioavailability and concentration.

  Maximum plasma concentration (Cmax) of nimesulide.

TABLE 2

PREPARATION NUMBER OF AUC Cmax

DOGS (O 48)

lg h / ml ig / ml

| 1 6 163.20 11.53

| 2 | 6,358.97 26.31

Examples of compounds

  Some examples of compounds which illustrate the present invention

are presented below:

Example 1

  A solution of nimesulide (0.75 g in 22.5 ml of methylene chloride) was added to a solution of beta-cyclodextrin (2.76 g in 375 ml of water) (molar ratio nimesulide / cyclodextrin 1: 1). We kept

  the two solutions, mixed, with stirring for 4 hours at a temperature of

  The precipitate was collected by filtration and was

  then subjected to desiccation under vacuum.

Example 2

  A suspension of a mixture of nimesulide (47 g) and betacyclodextrin (435 g) in a molar ratio of 1: 2.5 in 10,000 was formed.

  ml of water 46 ml of a 30% ammonium hydroxide solution were added.

  After 24 hours, the solution was desiccated and

the desired complex.

Example 3

  A suspension of a mixture of nimesulide (0.93 g) and betacyclodextrin (3.39 g) in a 1: 1 molar ratio was formed in 480 ml of water and stirred for 12 days at 55 C We have

  the solution was then heated to 22 C, left

  pores and the residue was subjected to vacuum desiccation.

Example 4

  A suspension of a mixture of nimesulide (15 g) and betacyclodextrin (55.25 g), in a molar ratio of 1: 1, was formed in 3250 ml of water containing 0.38% hydroxide. 30% aqueous ammonium The mixture was stirred for 24 hours at a temperature of 22 ° C. and after this time the solution was lyophilized. The residue was filtered and vacuum dried before treatment. with ethyl acetate. Examples of pharmaceutical compositions The pharmaceutical compositions are formulated below in the form of dosage units and each of these units can contain from 5 to 300

mg of active ingredient.

  The following are examples that illustrate the composi-

  pharmaceutical products that can be obtained by means of the present invention.

  it is well established that the examples presented are not exhaustive.

Example 5

  COMPRESSES (obtained by direct compression) Nimesulide-beta-cyclodextrin (1: 1) 240 mg (corresponding to 50 mg of nimesulide) Lactose 50 mg Calcium phosphate 60 mg Magnesium stearate 5 mg 355 mg Nimesulide beta-cyclodextrin (1: 1) 480 mg (corresponding to 100 mg nimesulide) Lactose 100 mg Calcium phosphate 120 mg Magnesium stearate 10 mg 710 mg Preparation method

  The nimesulide-beta-cyclodextrin inclusion compound was mixed

  with lactose and calcium phosphate. The stearate of

  magnesium to this mixture and the final mixture was compressed to obtain

  tablets each containing 50 to 100 mg nimesulide.

Example 6

CAPSULES

  Nimesulide-beta-cyclodextrin (1: 1) 240 mg (corresponding to 50 mg nimesulide) Hydroxypropyl methylcellulose 70 mg Magnesium stearate 15 mg 325 mg Nimesulide-beta-cyclodextrin (1: 1) 480 mg (corresponding to 100 mg nimesulide) Hydroxypropyl methylcellulose 140 mg Magnesium stearate 20 mg 640 mg Preparation method

  The nimesulide-beta-cyclodex-inclusion compound was mixed

  trine with hydroxypropyl methylcellulose and magnesium stearate and the mixture was introduced into gelatin capsules, each capsule

  containing 50 and 100 mg of nimesulide.

Example 7

Granules

  Nimesulide-beta-cyclodextrin (1: 1) 240 mg (corresponding to 50 mg nimesulide) Sorbitol 2,920 mg Lemon flavoring 22 mg Aspartame 18 mg 3,200 mg Method of preparation The nimesulidebeta-cyclodextrin inclusion compound was diluted sorbitol; aspartame and lemon aroma were successively added; the mixture thus obtained was introduced into sachets and

  each heat-sealed pouch contains nimesulide equivalent to 50 mg.

Example 8

MONODOSE BOTTLES

  Nimesulide-beta-cyclodextrin (1: 1) 240 mg (corresponding to 50 mg nimesulide) Mannitol 460 mg Lemon flavoring 22 mg Saccharin 7 mg 729 mg Deionized water 21,000 mg Preparation method The mannitol was dissolved in a buffered solution at pH 7.2; nimesulide-beta-cyclodextrin inclusion compound was added; we have

  added the lemon flavor and the solution was finally filtered.

  The filtered solution is placed in bottles each containing 50 mg

  nimesulide, and lyophilization is finally carried out.

Example 9

SUPPOSITORIES

  Nimesulide-beta-cyclodextrin (1: 1) (corresponding to 50 mg nimesulide) Fatty acid glycerides 240 mg 1,320 mg 1,560 mg Preparation method The glycerides of fatty acids that make up the dough used to suppositories; after the fusion, nimesulide-beta-cyclodextrin was added and the mixture was emptied into the molds for

  suppositories The whole was allowed to cool, and suppositions were obtained.

  which contains 50 mg of nimesulide.

Example 10

SYRUP

  Nimesulide-beta-cyclodextrin (1: 1) (corresponding to 500 mg nimesulide) 75% sorbitol solution Hydroxyethylcellulose Glycerin Benzoic acid Tartaric acid Lemon aroma Demineralized water 2,400 mg 000 mg mg 13,000 mg 220 mg mg 350 mg. 000 mg. Method of preparation Hydroxyethylcellulose was added to hot water; we have

  added to this solution tartaric acid, benzoic acid, nimesu-

  lide-beta-cyclodextrin and glycerine.

  Once all the substances, mentioned above, in solution,

  the sorbitol solution was added to 75% and finally the lemon aroma.

  ml of the solution thus obtained contains 50 mg of nimesu-

lide.

Claims (6)

  1 Inclusion compounds of nimesulide with cyclodextrin alfa, beta and gamma, substituted or in hydrated form, in a ratio   molecular weight nimesulide / cyclodextrin between 1: 0.5 and 1:15.   Compounds according to Claim 1, characterized in that the cyclodextrin is of the beta type and in that the molecular ratio   nimesulide / cyclodextrin is 1: 1.   Process for the preparation of compounds according to one of   Claims 1 and 2, characterized in that a solution is reacted   aqueous cyclodextrin with an organic solution of nimesulide and   isolates the inclusion compound by filtration.   Process for the preparation of compounds according to one of   Claims 1 and 2, characterized in that nimesulide is reacted and   cyclodextrin in an ammoniacal solution and in that the   embedding compound by desiccation of the solution.   Process for the preparation of compounds according to one of   Claims 1 and 2, characterized in that nimesulide is reacted and   cyclodextrin in an ammoniacal solution and in that the   inclusion compound by lyophilization.   6 Pharmaceutical compositions with analgesic and anti-inflammatory activity which contain as active ingredient the compounds   of inclusion of one of claims 1 and 2.   Pharmaceutical compositions according to claim 6, which   contain the active ingredient at a rate of 20 to 150 mg per dosage unit.