WO1999041233A1

WO1999041233A1 - A watersoluble nimesulide adduct also for injectable use

Info

Publication number: WO1999041233A1
Application number: PCT/IB1999/000086
Authority: WO
Inventors: Vincenzo De Tommaso
Original assignee: Micio Pharma Chemical Aktiengesellschaft
Priority date: 1998-02-17
Filing date: 1999-01-20
Publication date: 1999-08-19
Also published as: AU1885999A

Abstract

The present invention relates to a nimesulide adduct with an amino sugar, in particular N-methylglucamine, and to pharmaceutical compositions containing the same. The pharmaceutical composition may contain cyclodextrins and/or surfactants, such as Cremophor EL or Tween 80. Said adduct has a very good water solubility and can be used also in pharmaceutical formulation for injectable use.

Description

1

A WATERSOLUBLE NIMESULIDE ADDUCT ALSO FOR INJECTABLE USE

The present invention relates to a new nimesulide adduct with an amino sugar and to pharmaceutical formulations containing the same.

Nimesulide, the chemical name of which is N- (4-nitro-2- phenoxyphenyl)-methanesulfonamide, is a well-known, non-steroidal, anti-inflammatory and anti pyretic drug useful in all the affections involving pain or an inflammatory state. However, it is known that nimesulide has very poor water solubility, and this makes its use difficult in aqueous formulations for oral or injectable use. Furthermore this poor water solubility negatively affects the drug bioavailability.

WO 91 / 17774 and WO 94/02177 disclose inclusion compounds of nimesulide with cyclodextrins. By using said inclusion compounds, the nimesulide solubility increases to 0.61 mg/ml, which is about 20 times the solubility of pure crystalline nimesulide.

WO 95/34533 discloses the nimesulide salt with L-lysine. By using this salt, the nimesulide solubility is 5.42 mg/ml. Said solubility increases to 30.16 mg/ml in the presence of a γ-cyclodextrin at a concentration of 200 mM.

The present invention provides a nimesulide adduct with an amino sugar which already per se has a very good water solubility even without cyclodextrins. The nimesulide water solubility, obtained by using the adduct of the present invention, is more than 160 mg nimesulide/ml. This excellent solubility makes the nimesulide granular formulation in single dose sachets easy and rapid to dissolve in water at the time of use, without leaving any deposit as in the case of the analogous formulations on the market. This property enables the patient always to take the correct dose of nimesulide. It is possible furthermore to dissolve the usual dose of the drug

(lOOmg) in a few millilitres of water thus allowing obtaining clear injectable formulations, which remain stable, at a temperature from 25° to 40°C, for long periods. 2

Another remarkable advantage of the adducts according to the present invention is an improved bioavailability which allows a lower dosage in comparison with the formulations presently on the market.

The present invention refers to an adduct between nimesulide and an amino sugar, wherein the term "adduct, » means the addition product between nimesulide and the amino sugar. In particular the adduct may be a salt or a complex.

The molar ratio between nimesulide and amino sugar may vary from 1 : 1 to 1 : 10, preferably from 1 : 1 to 1 :6. The amino sugar may be, for example, glucamine, glucosamine, condrosamine and the derivatives thereof, such as the N-alkyl derivatives, wherein the alkyl group has 1 to 4 carbon atoms. The N-methyl derivatives are particularly preferred. Both the enantiomeric forms and their racemic mixture are comprised in the scope of the present invention. N- methyl- glucamine is the most preferred.

The nimesulide adduct with N-methylglucamine obtained according the method reported in the following Example 1 has a ratio nimesulide: N- methylglucamine of 1 :4.5.

Fig. l shows the LR. spectrum of nimesulide. Fig- shows the LR. spectrum of N-methylglucamine.

Fig.3 shows the LR. spectrum of the physical mixture of nimesulide and N-methylglucamine.

Fig.4 shows the LR. spectrum of the nimesulide-N-methylglucamine adduct according to the invention. Another object of the present invention are also pharmaceutical formulations containing the nimesulide adduct with an amino sugar. Said formulations may optionally contain pharmaceutically acceptable excipients and /or carriers, such as, for example, talc, gum arabic, lactose, mannitol, gelatine, magnesium stearate, starch, aqueous or non-aqueous vehicles, polyvinylpyrrolidone, semisynthetic gliceiydes of fatty acids, sorbitol, glycerol, vaseline, hydroxyethylcellulose, propylene glycol, hydroxypropylethylcellulose, microcrystalline cellulose, citric acid, sodium citrate, colloidal silica, calcium phosphate, flavouring agents, sweeteners, binders, and disgregating agents. 3

The pharmaceutical formulation of the adduct according to the present invention are advantageously formulated in dosage units; each dosage unit containing from 5 to 300 mg, preferably from 20 to 150 mg nimesulide. The pharmaceutical formulations according to the present invention may further contain a cyclodextrin wherein the cyclodextrin may be an -, β-, γ-cyclodextrin, a derivative or a mixture thereof.

The pharmaceutical formulations of the adduct according the present invention may also contain a surfactant, preferably an anionic surfactant.

A suitable anionic surfactant may be, for example, the condensation product of ethylene oxide with a fatty acid such as a polyoxyethylene laurate, stearate or oleate as sold under the trademark Mirj; or the condensation product of ethylene oxide with a vegetal oil, for example castor oil or a derivative thereof, as sold under the trademarks Cremophor, Micelliphor, Texophor, Emulphor (or Mugolfen); or the condensation product of ethylene oxide with a long chain aliphatic alcohol, for example polyoxyethylene cetylether, laurylether, stearylether or oleylether, such as the products sold under the trademark Brij; or a condensation product of the ethylene oxide with a partial ester obtained from a fatty acid and a hexitol anhydride, such as polyoxyethylene sorbitan monolaurate, monopalmitate, monostearate or monooleate, as sold under the trademark Tween; or a polyoxyethylene-polyoxypropylene copolymer, as sold under the trademark Pluronic. Particularly suitable products are Tween 20, 40, 60, 80; Mirj 52 or

53; Brij 35; Pluronic F68; Emulphor (or Mugolfen) EL 620 or 719; Texophor D40 or D80; Cremophor EL, RH40 or RH60 or Micelliphor. Particularly preferred are Cremophor EL and Tween 80.

The adduct according to the present invention may be incorporated into conventional pharmaceutical composition in either solid or liquid form. Suitable forms for oral administration may be, for example, tablets, capsules, granules, oral drops, and syrup; for parenteral administration, injectable solutions; for rectal administration, suppositories; for topic administration, creams, ointments, pastes, eye drops, sprays. 4

Formulations absorbable through a mucous tissue, such as powders to be sprayed into the nose, are comprised in the scope of the present invention. Formulations for transdermic administration, such as transdermic patches, are also comprised in the scope of the present invention.

A further object of the present invention is a solid mixture of nimesulide with an amino sugar. By adding water, said mixture forms the adduct according to the present invention.

The adduct according to the present invention is obtained by a process comprising the following steps:

1. suspending nimesulide in water under vigorous stirring,

2. adding the amino sugar while stirring until the nimesulide is completely dissolved,

The solution obtained is clear. The solution is brought to the volume desired by adding water. The solution pH must be preferably be 10.2 ± 0.5. Then the solution is filtered through a special membrane with a porosity of 0.22 μm.

The obtained solution can be dried by methods well known to the persons skilled in the art such as evaporation by heating under vacuum, spray-drying, or freeze-drying.

A yellowish powder with a humidity of 1% ± 0.5 is thus obtained.

If in the manufacturing process the equipment is sanitized and the raw materials are apyrogenic, a product suitable for parenteral use is obtained. EXAMPLE 1

PREPARATION OF THE NIMESULIDE-N-METHYLGLUCAMINE ADDUCT

640 ml distilled water are placed into a small dissolver. 26.7 g nimesulide are suspended under vigorous stirring and 79.095 g N- methylglucamine are slowly added. The suspension is kept under vigorous stirring until the nimesulide is completely dissolved. The solution is brought to the final volume of 800 ml by adding distilled water. The pH which must be 10.2 ± 0.5, is checked. Possible adjustments must be carried out by adding nimesulide or N- methylglucamine. 5

The thus obtained solution is filtered through a membrane having a porosity of 0.22 μm. The yellow-orange coloured solution is then freeze- dried using the following parameters:

-freezing for 5 hours at -40°C -heating to +45°C with a gradient of 0. 15°C/min at a vacuum of 0.2 mm Hg.

-final heating to +45°C for 8- 10 h at a vacuum of less than 0.2 mm Hg. The residual humidity is 1 ± 0.5 %.

EXAMPLE 2

VIAL/AMPOULE FORMULATION: 100 mg/3ml

Nimesulide-N-methylglucamine adduct 385 mg

Water for injections q.s. to 3 ml

EXAMPLE 3 VIAL/AMPOULE FORMULATION: 100 mg/5ml

Nimesulide-N-methylglucamine adduct 385 mg

Absolute ethyl alcohol 350 mg

Cremophor El 1800 mg

Water for injections q.s. to 5 ml

The pH of the final solution was adjusted to 8,5-9 by adding glacial acetic acid or N- methylglucamine.

EXAMPLE 4 FORMULATIONS IN UNIT DOSAGE SACHETS: 100 mg/sachet

Nimesulide-N-methylglucamine adduct 385 mg

Sucrose 2.8 g

Orange flavour 85 mg

Maltodextrins 23 mg The above reported amounts of nimesulide-N-methylglucamine adduct, sucrose (containing maltodextrins) and orange flavour are placed into a suitable powder mixer. All these raw materials have been previously sieved. 6

Mixing is continued for about 30 min or at any rate until the mixture is homogeneous.

The so obtained granulate is divided into sachets of a coupled material of aluminium-paper-polyether having an average weight of 3.293 g-

EXAMPLE 5

FORMULATION IN TABLETS: 100 mg /tablet

Nimesulide-N-methylglucamine adduct 385 mg

Avicel 100 mg Magnesium stearate 15 mg

Talcum 10 mg

Sodium carboxymethylcellulose 40 mg

The above reported amounts of nimesulide-N-methylglucamine adduct, Avicel, magnesium stearate, talcum and sodium carboxymethylcellulose are placed into a suitable powder mixer. All these raw materials must have been previously sieved.

Mixing is continued for about 30 min or at any rate until the mixture is homogeneous. The thus obtained granulate is compressed into tablets having an average weight of 550 mg.

Claims

I . An adduct of nimesulide with an amino sugar.

2. An adduct according to claim 1 wherein the amino sugar is selected from the group consisting of glucamine, glucosamine, condrosamine and a N-(C╬╣-4) alkyl-derivative thereof.

3. An adduct according to claim 2 wherein the amino sugar is N-methylglucamine.

4. An adduct according to claims 1 to 3 wherein the molar ratio of nimesulide to amino sugar may vary from 1 : 1 to 1 : 10.

5. An adduct according to claim 3 wherein the molar ratio of nimesulide to N-methylglucamine is 1 :4.5.

6. A pharmaceutical formulation containing the adduct according to claims 1 to 5 and optionally one or more pharmaceutically acceptable excipients and /or carriers.

7. A pharmaceutical formulation according to claim 6 further comprising a cyclodextrin.

8. A pharmaceutical formulation according to claim 7 wherein the cyclodextrin is an ╬▒-, ╬▓- or ╬│-cyclodextrin or a derivative or a mixture thereof.

9. A pharmaceutical formulation according to any one of the claims 6 to 8 further containing a surfactant.

10. A pharmaceutical formulation according to claim 9 wherein the surfactant is Cremophor EL or Tween 80.

I I . A pharmaceutical formulation in solid form containing a mixture of nimesulide and of an amino sugar.

12. An adduct according to claims 1 to 5 for therapeutic use.

13. Use of an adduct according to claims 1 to 5 for manufacturing a medicament for the treatment of inflammatory affections.