OA11993A - Suspension of tixocortol pivalate, mouthwash based on it and packaging containing it. - Google Patents

Abstract

The invention concerns a micronized aqueous suspension of toxicortol pivalate, in a solution containing a surfactant and a viscosity agent. The invention also concerns a mouth-wash based on said suspension. The invention is useful for treating inflammations in the laryngeal, bucco-pharyngeal and rhino-pharyngeal zones.

Description

11993

SUSPENSION OF TIXOCORTOL PIVALATE, COLLUTORY BASE

OF IT AND PACKAGING IA CONTAINING

The subject of the present invention is a suspension of detixocortol pivalate, in the form of a mouthwash and an excipient containing this suspension, the packaging further comprising a metering pump.

Several compositions based on detixocortol (or (11β) -11,17-dihydroxy-21-mercapto-pregn-4-ene-3,20-dione) are already known, in particular in the form of pivalate, for the local treatment of inflammatory conditions, including otorhinolaryngological affections. These compositions can be nebulized to be dispensed at the throat.

There is known a pressurized package equipped with a dosing valve and comprising a suspension of pivalate detixocortol in isopropyl myristate, the propellant being dichlorodifluorocarbon (F12, CFC) .The volume of the mouthwash emitted is on average 180μ1. The ban on the use of CFCs led to the suppression of the metering valve associated with the propellant. The packaging was replaced by a conditioning with a dosing pump, the composition remaining identical. In use, the patient compresses air into the pump chamber, which delivers about 50μ · 1 of suspension.

This solution is not satisfactory for several reasons. First, the suspension does not allow to deliver a sufficient volume of mouthwash (50μ1 against 180μ1 previously). Then, this suspension is relatively viscous, which does not provide a good coverage of the area to be treated. Moreover, this type of product does not make it possible to obtain 11993 'droplets of controlled size which will not pass into the bruises but will be delivered at the buccal-pharyngeal cavity.

It is not possible to adjust the volume to 180 μΐ with isopropyl myristate, the taste being unacceptable. It is therefore an object of the invention to provide a suspension which is stable in storage and which is easily removable in the form of a mouthwash having a suitable volume and size of droplets.

WO-A-9720578 discloses a tixocortol depivalate suspension in an aqueous vehicle free of preservative for the treatment of ocular and ophthalmic diseases.

WO-A-9531964 discloses a defluticasone propionate composition having a particle size of less than 12 μm, suspended in an aqueous solution comprising a surfactant and a buffering agent, for administration to the bronchi.

WO-A-9511669 discloses a composition of loteprednol etabonate suspended in an aqueous solution comprising a polymer and a nonionic surfactant and an isotonicity agent (glycerol).

None of the above documents teaches the present invention in any way whatsoever.

Thus, the invention provides an aqueous suspension of tixocortol depivalate, comprising: (a) suspended tixocortol pivalate having a particle size such that the average size of D 50 is 0.5 to 20 μm; (b) a surfactant; (c) a viscosity agent; and (d) water balance and conventional adjuvants. The invention also provides a lasuspension-based mouthwash defined above, and having a volume of between 100 and 300 microns. The invention also provides a package comprising a container containing the suspension defined above, provided with a metering pump.

Finally, the invention provides a process for the preparation of the suspension defined above, comprising the following steps: (1) preparation of the aqueous solution with water balance, the surfactant, the deviscosity agent, optionally the second principal; (2) suspending pivalate detixocortol in said solution. The invention is now described in more detail in the description which follows.

Tixocortol pivalate

The active ingredient is in micronized form, and it has a particle size such that its average size D50 (1) 50, size under which are 50% volume of the particles) is between 0.5 and 20pm, preferably between 1 and 10pm. For example, the size of the particles may be such that the value of D90 (D90, the size at which 90% by volume of the particles is located) is less than 10 μm.

The active ingredient is prepared by conventional methods. The crystals are reduced to the size desired by conventional methods, for example micronization.

The active ingredient in micronized form is also commercially available, for example at PPG (Avrillé, France).

The suspension according to the invention will comprise, by weight relative to the final volume of the suspension (in% w / v, that is to say in grams per 100 ml of suspension) by 1 19 9 $ 4 example of 0.05 at 10% w / v, in particular from 0.1 to 5% w / v, advantageously from 0.1 to 0.5% w / v, of pivalate detixocortol.

Second active ingredient

The suspension advantageously comprises a second active principle, in particular an antiseptic. This antiseptic may be chlorhexidine (especially-in saline form). Preferably the antiseptic is chlorhexidine gluconate.

Preferably, the second active ingredient is solubled in the aqueous solution.

Chlorhexidine digluconate is available as an aqueous solution, for example dosed at 20% w / v.

The suspension according to the invention will comprise, by weight relative to the final volume of the suspension (in% w / v) for example from 0.05 to 10% w / v, in particular from 0.1 to 5% w / v, advantageously from 0.1 to 0.5% w / v of chlorhexidine digluconate (expressed in dry form). Other active ingredients may also be present.

Surfactant, wetting agent

The surfactant is a wetting agent that can be selected from pharmaceutically acceptable surfactants. By way of example, there may be mentioned trioleate, mono-oleate, sorbitan monolaurate, or their polyoxyethylenated derivatives (polysorbate 20, 40, 60, 80); natural or synthetic lecithin; polyoxyethylenated oleyl, stearyl, polyoxyethylene-polyoxypropylene block copolymers; diethylene glycol dioleate; tetrahydrofurfuryl oleate, ethyl oleate, deglyceryl mono-oleate, glyceryl monolaurate; PEG400 to PEG4000; and derivatives of quaternary ammonium. These surfactants are commercially available, for example under the names Pluronic, Poloxamer, Tween. The wetting agent surfactants that are preferred in the invention are the quaternary ammonium derivatives, in particular the lauryl fatty ether derivatives; Cyclic rings comprising the quaternized nitrogen atom in the ring or not. By way of example, mention may be made of picolinium, benzalkonium and cetylpyridinium, the latter being preferred. The counterion may be any conventional counter ion, for example chloride. Mixtures are also suitable.

The suspension according to the invention will comprise, by weight relative to the final volume of the suspension (in% w / v) for example from 0.005 to 2.5% w / v, especially from 0.01 to 0.5% w / w. v, preferably from 0.01 to 0.05% w / v of surfactant.

Viscosity agent The purpose of the viscosity agent is to adjust the viscosity of the solution and ultimately the suspension. This viscosity agent (or thickening agent) can be selected from water-soluble polyvinylpyrrolidone PVP polymers, polyvinylalcohol-derived cellulose derivatives (such as PVA, hydroxypropylmethylcellulose HPMC, hydroxymethylcellulose HMC, hydroxyethylcellulose HEC, HPC, carboxymethylcellulose CMC, hydroxypropylcellulose (cyclo) dextrin, etc.). The latter class and the polyols and their derivatives include, for example, glycerol, sorbitol and emaltitol. This last class is preferred, and more particularly glycerol. This one besides the sweetening properties and will prefer appropriate appropriate softeners.

We prefer a solution (emollient).

Mixtures are that is relatively low viscosity. The viscosity of the suspension, measured according to the capillary tube method (Ph.Eur., Advantageously between 1.2 and preferably between 1.4 and 1.8 mPa.s (the viscosity of the purified water is 1.03 mPa). .s).

The slightly viscous suspension provides better coverage of the area to be treated, and better airway adhesion 2-2-9) is 2 mPa.s, 6 119 9 3 higher. In addition, this viscosity makes it possible to slow sedimentation of the particles of active principle.

The suspension according to the invention will comprise, by weight relative to the final volume of the suspension (in% w / v) for example from 1 to 50% w / v, in particular from 5 to 30% w / v, advantageously from 10 to 20% w / v. % m / v viscosity agent. Additives sweetening agents, preservatives, etc. the agentsque their

Conventional adjuvants may be added to the composition. Among these adjuvants, there are the aromas, the buffers,

These adjuvants, thus quantities, are conventional and known to those skilled in the art.

As a sweetening agent, aspartame, sodium saccharin, potassium acesulfame, sodium cyclamate, or ammonium glycyrrhizinate may be used. Acesulfame potassium will be preferred. The content of sweetening agent is, for example, from 0.025 to 0.5% w / v, in particular from 0.025 to 0.05% w / v, advantageously from 0.05 to 0.25% w / v of sweetening agent. The flavoring agent (flavor) may be present in solution or in suspension. Mixtures are appropriate.

Suspension

This suspension has good properties with respect to: - the sedimentation rate (stability) - evolution of the size and shape of the particles of tixocortol pivalate under the effect of temperature cycles. - ability to resuspend.

With regard to sedimentation rate, sedimentation rates at room temperature are above 90% after 45 min, ie the height of the sedimentation front is 90% of the initial total height.

With regard to the evolution of the size and shape of the tixocortol pivalate particles under the effect of temperature cycles, no change was observed, after a 50 ° C cycle for 1 h, 5 ° C for 1 h, 50 ° C for 1 h, 5 ° C for 1 h, 50 ° C for 1 h, there is no difference with a control sample stored at room temperature.

With respect to the ability to resuspend, the present invention provides excellent results. After 24 hours resting at room temperature, it suffices for 2 to 4 revolutions of the test piece for which the preparation resumes homogeneous suspension. Thus, the user will not - to shake the bottle for several minutes before use, but some reversals of the bottle will suffice.

The suspension comprises the active ingredient always in micronized form, the aggregation or flocculation being minimal. Thus, the particle size of the active ingredient in suspension is generally at most five times, preferably twice, the initial size.

The suspension according to the invention has a good resistance to microbial contamination.

The suspension is prepared by any suitable method. A typical process comprises the following stages, for example carried out at ambient temperature: - preparation of an aqueous solution, with water, the antiseptic agent (chlorhexidine digluconate), the surfactant (cetylpyridinium), the adjuvants; solubilization / dispersion of the viscosity agent (glycerol); and - suspending (puishomogenization dispersion) of the tixocortol pivalate.

A two-step process may also be used, the first step comprising preparing the aqueous solution with all water-soluble or hydrodispersible ingredients and then suspending the tixocortol pivalate.

The equipment used is conventional and known to those skilled in the art. 119 9s 8

mouthwash

The mouthwash is in the form of an aerosol of droplets.

The dispensed volume of the mouthwash is generally comprised between 100 and 300μ1, preferably between 150 and 220μ1, advantageously about 180μ1.

The droplets have a mean size (D'50) such that these droplets do not penetrate into the bronchi, but rather remain at the level of the throat areas intended to receive the anti-inflammatory treatment, namely the laryngeal and thinopharyngeal zone. It should be noted that generally the temperature does not alter the particle size of the spray. From 50 is in general between 20 and 500pm, advantageously between 50 and 200pm, preferably about ΙΟΟμπι.

The suspension and the mouthwash based on it are intended in particular for the treatment of inflammations of the laryngeal, bucco pharyngeal and nasopharyngeal zone, in particular angina, laryngitis and rhinopharyngitis. A dose will generally comprise a quantity of pivalate of tixocortol of between 0.2 and 1. 2. mg, in particular about 0.6 mg. One dose will generally include an amount of chlorhexidine digluconate in the range of 0.05 to 0.6 mg, particularly about 0.18 mg.

Conditioning

The package comprises a container and a dosing pump.

The dosing pump has appropriate volumes of mouthwash. To deliver slurry pump metering is suitable for such droplets such a commercially available.

The following examples illustrate the invention without limiting it.

Example 1. 119 9 3 9

A composition having the desired composition (in the following m / v) is prepared:

Ingredient Quantity 1 Tixocortol pivalate 0.333 g 1 Chlorhexidine digluconate 0.143 g Polysorbate 80 0.050 g Glycerol 15 g Adjuvants (flavoring and sweetener) 0.7 g [Water qs 100 ml

First, an aqueous solution is prepared with water, the 20% w / v solution of chlorhexidine digluconate, polysorbate 80, the adjuvants, by mixing at room temperature.

In a second time, the glycerol is dispersed.

Finally, the tixocortol pivalate is suspended by dispersion and homogenization.

Example 2

A composition having the following composition (in m / v) is prepared:

Ingredient Quantity I Tixocortol pivalate 0.333 g | [Chlorhexidine digluconate 0.143 g Cetylpyridinium chloride 0.025 g Glycerol 15 g [Adjuvants (aroma and sweetener) 0.7 g (Water qs 100 ml

The procedure is the same as in Example 1 but replacing the polysorbate 80 with decetylpyridinium chloride.

Example 3

A container is filled with the suspensions of Examples 1 or 2, and a metering pump is crimped onto the body of the container. The delivered dose is 180μ1 decollutory, corresponding to 0.6mg and 0.257mg of pivalate of tixocortol and chlorhexidine digluconate, respectively. The droplets of the mouthwash have a size of about 100 pm.

Claims (26)

11993 11 CLAIMS 1. An aqueous pivalate suspension comprising: tixocortol, (a) suspended tixocortol pivalate having a particle size such that the average size D50 is 0.5 to 20 μm; (b) a surfactant; (c) a viscosity agent; and (d) water balance and conventional adjuvants. 2. The suspension according to claim 1, wherein the tixocortol pivalate has a particle size such that its average size D50 is between 1 and 10 μm. 3. The suspension of claim 1 or 2, wherein the tixocortol pivalate has a particle size such that its average size D90 is less than 10 μm. 4. The suspension according to any one of claims 1 to 3, wherein the surfactant is derived from quaternary ammonium. 5. The suspension according to claim 4, wherein the quaternary ammonium derivative is ducetylpyridinium. 6. The suspension of any one of Claims 1 to 5, wherein the viscosity agent is glycerol. 7. The suspension according to any one of claims 1 to 6, comprising, in% by weight of the suspension: 12 11993 (a) of 0.05 to 10% w / v of tixocortolen suspension pivalate, having a particle size such as that its average size D50 is between 0.5 and 20pm; (b) from 0.005 to 2.5% w / v of a surfactant; (c) from 1 to 50% w / v of a viscosity agent; and (d) water balance and conventional adjuvants. 8. The suspension according to any one of claims 1 to 7, comprising, in% by mass volume of the suspension: (a) from 0.1 to 5% w / v of tixocortol pivalate; (b) from 0.01 to 0.5% w / v of a surfactant; (c) from 5 to 30% w / v of a viscosity agent; and (d) water balance and conventional adjuvants. 9. The suspension according to any one of claims 1 to 8, including, in mass% by volume of the suspension: (a) from 0.1 to 0.5% w / v of tixocortol pivalate; (b) from 0.01 to 0.05% w / v of a surfactant; (c) from 10 to 20% w / v of a viscosity agent; and (d) water balance and conventional adjuvants. 10. The suspension according to any one of claims 1 to 9, which has a viscosity of between 1.2 and 2 mPa.s. 11. The suspension according to any one of claims 1 to 10, which has a viscosecomprise between 1.4 and 1.8 mPa.s. The suspension of any one of claims 1 to 11, further comprising: (e) an antiseptic. 1199 3 13 13. The suspension of claim 12, wherein the antiseptic is chlorhexidine. 14. The suspension according to claim 12 or 13, comprising, in mass% by volume of the suspension: (e) from 0.05 to 10% w / v of antiseptic. The suspension of claim 12, 13 or 14 comprising, in mass% by volume of lasuspension: (e) 0.1 to 5% w / v of antiseptic. 16. The suspension according to claim 1 having the following percentage composition: 0.333 g of pivalate detixocortol, 0.143 g of chlorhexidine digluconate, 0.025 g of cetylpyridinium chloride, 15 g of glycerol, 0.7 g of adjuvants and the amount of water required. to reach a volume of 100ml 17. The suspension according to any one of claims 1 to 16, for the treatment of inflammation of the laryngeal zone, bucco pharyngée etrhinopharyngée. 18. Muffler based on a suspension according to any one of claims 1 to 17, having a volume delivered between 100 and 300μ1. 19. Mouthpiece according to claim 18, having a delivered volume of between 150 and 220μ1. 20. The mouthwash according to claim 18 or 19, wherein the droplets have a particle size such that its average size of 50 is between 20 and 500 pm. 119 9 3 14 21. The mouthwash according to claim 18, 19 or 20, the droplets of which have a particle size such that its average size of 50 is between 50 and 200 μm. 22. The mouthwash according to any one of claims 18 to 21, comprising between 0.2 and 1.2 mg tixocortol depivalate. 23. Packaging comprising a containercontenant the suspension according to any of claims 1 to 17, provided with a metering pump. 24. Process for the preparation of the suspension according to any one of claims 1 to. 17, comprising the following steps: (1) preparation of the aqueous solution with water balance, the surfactant, the deviscosity agent, optionally the second principal; (2) suspending pivalate detixocortol in said solution. 25. The method of claim 24, whereinstep (1) comprises two substeps, the first substep comprising preparing an aqueous solution with the water balance, the surfactant, and optionally the second active ingredient. the second sub-step including solubilization / dispersion of the agent. 26. A process for the preparation of a mouthwash according to any of claims 18 to 22, comprising the action of the metering pump of the package according to claim 23.