MXPA03007402A - Pharmaceutical composition and container thereof comprising a steroid for intranasal administration. - Google Patents

Abstract

The present invention relates to novel aqueous pharmaceutical compositions and container thereof for intranasal administration in half and multiple doses, which contains a safe and effective amount of a glucocorticoid that pertains to a group including beclomethasone, triamicinolone, fluticasone and mometasone, as well as pharmaceutically acceptable salts and mixtures thereof. An aqueous intranasal carrier is further described, the same being pharmaceutically acceptable, sterile and free of benzalkonium chloride as a preservative. Moreover, a novel container is described, the same maintaining the composition sterile during the service life thereof, even in multiple doses usage. It is further described a method useful for treating symptoms associated with seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis that include intranasal administration by atomization of the said pharmaceutical compositions in effective and safe amounts.

Description

TITLE: PHARMACEUTICAL COMPOSITIONS AND ITS CONTAINER, WHICH CONTAIN A STEROID FOR ADMINISTRATION BY INTRANASAL ATOMIZATION INVENTORS: RODOLFO VILLALON ROJAS Address: Return Fátima 2, Fraccionamiento Burgos de Cuernavaca Temixco, Morelos 62584 MEXICO Y ROBERTO CARMONA DIAZ CORTES Address: Up to Chalma No. 914-113, Colonia Lomas de Tetela Cuernavaca, Morelos 62518 MEXICO APPLICANT: RED AND RED OF MEXICO S.A. DE C.V. Address: Return Fátima 2, Fraccionamiento Burgos de Cuernavaca Temixco, Morelos 62584 MEXICO REPRESENTATIVE: RODOLFO VILLALON ROJAS Address: Return Fátima 2, Fraccionamiento Burgos de Cuernavaca Temixco, Morelos 62584 MEXICO PHARMACEUTICAL COMPOSITIONS AND ITS CONTAINER. THAT CONTAIN A STEROID FOR ADMINISTRATION BY INTRANASAL ATOMIZATION DESCRIPTION TECHNICAL FIELD The present invention relates to novel pharmaceutical compositions and their packaging, comprising a safe and effective amount of a steroid, as well as to a method for treating seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis, by administration by the intranasal route of said compositions.

BACKGROUND OF THE INVENTION In the treatment of allergies in general, various therapeutic agents are used, among which steroid agents, and very particularly within these glucocorticoids are widely used for these purposes. They are used as much by the oral-systemic, parenteral-systemic as by local or topical routes. Particularly for certain allergic indications of the respiratory tract such as asthma and different allergic rhinitis, glucocorticoids have been used as topical agents. Glucocorticoids very useful in the present invention include those selected from the group consisting of beclomethasone, triamcinolone, fluticasone and mometasone, all of which are frequently used in the treatment of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyps. These agents are administered in aerosol pharmaceutical compositions, and in sprayed aqueous carrier compositions, both for topical intranasal use. Regarding nasal allergic diseases and their topical treatment using the intranasal route of administration, it is important to mention that many of the liquid atomizing pumps currently available on the market for pharmaceutical use, introduce external air to compensate the outflow of material when atomizing. It is the entry of external air into the atomizer container, the generator of two specific conditions pharmaceutically speaking: the first is that the composition contained within the container is contaminated, since the air that enters the container is not sterile; and the second, that it is necessary to counteract this contamination, since this could generate microbiological developments, which would not only compromise the stability of the pharmaceutical composition itself, but could also be a source of infection to the user from the first series of sprays . Experts in the area of pharmaceutical manufacture of intranasally administered liquids have recognized and addressed this fact, developing formulations that, because they contain preservative agents, manage the entrance of compensatory air that contaminates the formulation, thus avoiding microbiological development. Benzalkonium chloride is one of the most commonly used preservative agents in aqueous pharmaceutical compositions for the intranasal route, thanks to its bactericidal properties against gram positive and gram negative at low concentrations, its solubility and complementarity to be incorporated into this type of compositions. Examples of possible use or very preferred use of benzalkonium chloride, as the preservative agent of very diverse aqueous pharmaceutical compositions for the intranasal route, are US Pat. Nos. 3,975,536; 4,053,628; 4,629,835; 4,782,047; 4,983,595; 5,419,898; 5,443,833; 5,475,023; 5,837,699; 5,854,269; 5,897,858; 5,942,251; 5,976,573; 6,291,445; 6,316,483 and 6,375,984. Other references of the possible use or very preferred use of benzalkonium chloride, as preservative agent of aqueous pharmaceutical compositions for the intranasal route used in the United States of America, are the prescribing information of the glucocorticoids beclomethasone, triamcinolone, fluticasone and mometasone of Physician's Desk Reference 2001. Editorial Thompson USA, pages: 719, 1357, 1388 and 2914.

In addition to the above, 1. - Bernstein I. L, 2000. J Allergy Clin Immunol Vol 105, number 1 Part 1, page 40; reference to benzalkonium chloride as an excipient present in compositions for intranasal use in the United States of America of pharmaceutical products containing as active a: phenylephrine HCl, phenylephrine HCI + naphazoline HCI + pyrilamine maleate, oxymetazoline, azelastine, ipratropium bromide, sodium cromoglycate, triamcinolone acetonide, flunisolide, beclomethasone dipropionate, fluticasone propionate and mometasone furoate. In the same way that benzalkonium chloride is widely used as a preservative in intranasal pharmaceutical compositions, the adverse effects generated by this preservative on the nasal tissues where it is administered are also well documented in the specialized medical literature. In this type of compositions, the main adverse effect reported against benzalkonium chloride is that it impairs ciliary motility of the nasal mucosa. Ciliary motility is a natural defense mechanism, which consists in the coordinated sweeping of the cilia of the mucosa to mobilize the mucus constantly generated by it. The following references report studies on the deterioration of ciliary motility of the nasal mucosa and other adverse effects, generated by the administration of intranasal compositions containing benzalkonium chloride. Some of these references even suggest, considering the use of free intranasal compositions of this agent as a measure to follow: 1. - Bernstein I. L, J Allergy Clin Immunol 2000. Vol 105, number 1 Part 1, pages 39 - 44. 2. - Alberty J, Stoll W. Allergy 1998. 53: pages 986 - 989. 3. - Graf P et al. Arch Otolaryngol Head Surg 1999; 125: 1128-1132. 4 - Graf P. Clinical Therapeutics 2000 Vol. 22 No. 7: 893- 895 5.- Graf P and Hallen H. Laryngoscope1996. 106: 605-609. 6, - Naclerio R M, et al. Otolaryngol Head Neck Surg. 2003 Feb; 128 (2): 220-227. The following and very recent reference reports the adverse effects of benzalkonium chloride on the nasal mucosa in rabbits, which include morphological degenerative changes of the same: 7. - Sebahattin C et al. Eur Arch Otorhinolaryngol 2002. 259: 362-364. The nasal mucus is a natural defense, responsible for capturing foreign particles, dust and microorganisms from the air during its passage through the nasal route; ciliary motility, on the other hand, mobilizes this mucus by coordinated sweeping, taking it to the nasopharynx to be subsequently swallowed. Due to the above, any agent that deteriorates the natural ciliary motility of the nasal mucosa, deteriorates with it an important physiological and defense mechanism of the same. Therefore, said agent becomes an element with adverse or undesirable effects at this level. In conclusion, benzalkonium chloride has adverse effects on the nasal mucosa. Now, the need for an aqueous pharmaceutical composition for intranasal use to incorporate preservative agents in it, as in this case benzalkonium chloride, has been directly related to the atomizing pump used in its packaging, since in its operation, it is this pump that enters the polluting air. It is in this sense, that recently the manufacturers of atomizers for pharmaceutical products for intranasal use Pfeiffer and Valois, offer options of atomizing pumps for aqueous systems of intranasal administration without preservatives. Examples of these pumps are the "system free of preservatives" of Pfeiffer, and the atomizing pump VP7D and its actuator CB19, both last of Valois. For all the above, it is an object of the present invention to provide pharmaceutical compositions that allow the effective use of the spheroidal agents included therein, for intranasal use for the treatment of the associated symptoms of seasonal allergic rhinitis., perennial allergic rhinitis and nasal polyposis. A further object of the present is to improve the physiological interference profile of the spheroidal compositions administered by intranasal spray, by incorporating into its packaging, spray pumps designed to administer conservative-free aqueous compositions such as benzalkonium chloride, so as not to deteriorate the Ciliary motility of the nasal mucosa in its treatment. Here, by beclomethasone and by 17, 21 beclomethasone dipropionate, is meant 9-chloro-11B, 17,21-dihydroxy-16-B-methylpregna-1,4-diene-3,20-dione 17,21-dipropionate. Likewise in the present, all percentages and ratios are by weight unless otherwise specified. All the medical and pharmaceutical terms are attached according to the Official Mexican Standard and the Mexican Pharmacopoeia, in force at the time of their request before the authority, which by regulatory agreement may be subject to update. In the present by "atomization" is meant the fragmented and pressurized expulsion of the aqueous and internal contents of the container, using mechanical pumping.

By "pulsation" is meant the manual action executed when the actuator is pressed against the pump, and thereby generating the atomization. By "active components" is meant those agents with a defined therapeutic action. By "additives" is meant those agents without a defined therapeutic action. By symptomatic treatment of seasonal allergic rhinitis and perennial allergic rhinitis, as well as of nasal polyposis, in the present is understood, but without limitation, to that therapy aimed at the control of nasal hypersecretion or rhinorrhea, irritation and nasal blockage , as well as excessive sneezing during the course of the same. The useful life of the composition and atomizer packaging is understood to be the period comprised in the manufacture, packaging, storage, distribution, sale and reasonable use by the user. The present compositions contain in their spray bottles for sale to the user, a number of unit doses that never exceed 30 days of treatment.

DETAILED DESCRIPTION OF THE INVENTION I.- ESSENTIAL GLUCOCORTICOIDS The glucocorticoid agents of the group consisting of beclomethasone, triamcinolone, fluticasone and mometasone, their pharmaceutically acceptable salts and their mixtures are essential and very useful active components in the present invention. When used in the compositions of the present invention, the glucocorticoid component is preferably present at a concentration of 0.001 to 0.2%, preferably 0.01 to 0.1%, and is administered intranasally in sprays preferably but not limited to approximately 50 and 100 microliters for each pulse or unit dose.

II. - PHARMACEUTICALLY ACCEPTABLE AQUEOUS NASAL CARRIER Another essential component of this invention is an aqueous and pharmaceutically acceptable intranasal carrier, free of benzalkonium chloride as a preservative. This aqueous carrier will consist of purified and pharmaceutically sterile water, the ratio of which will never be less than 40%, and preferably but without limitations greater than 70%, as well as other useful additives specific to this component, and of the active component (s). essential and optional as the case may be. The fact of being an aqueous intranasal carrier free of benzalkonium chloride, makes it have less physiological interference at the level of the nasal mucosa where it acts, since it does not impair the natural mechanism of ciliary motility of said mucosa, as explained in background. In this context, although it is true that avoiding the incorporation of conservative agents such as benzalkonium chloride in intranasal compositions, it is a highly desirable theoretical model and even recommended by the literature, to implement it in a multidose intranasal pharmaceutical atomizer, It generates a technical challenge that requires innovations. This is where the multidose watery nasal carrier takes its novel and distinctive characteristic: it is pharmaceutically sterile throughout its useful life without incorporating any preservative agent. It is therefore important to note that the compositions of the present invention are free of benzalkonium chloride, as well as of other preservatives including, but not limited to: thimerosal, chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate as well as alcoholic agents such as benzyl alcohol and phenylethyl alcohol. Likewise, the present compositions are free of other preservatives such as chlorhexine gluconate, parabens and potassium sorbate. Without preservatives, the sterility condition for the entire life span of the aqueous nasal carrier and of the present compositions is achieved by incorporating in this carrier, water, essential active components, additives and, where appropriate, optional active components, all sterile, by handling Its complete production and primary packaging under 100A air conditions, as well as for its novel, sterile and own packaging for it. As essential active components of the present invention comprise a glucocorticoid agent from the group consisting of beclomethasone, triamcinolone, fluticasone and mometasone, their pharmaceutically acceptable salts their mixtures, at a concentration of 0.001 to 0.2%. The person skilled in the art will recognize that the aqueous and pharmaceutically acceptable intranasal carrier of the present invention may also contain one or more very useful additives, including but not limited to: (a) Tonicity regulating agents To the compositions of the present invention Tonicity regulating agents can additionally be incorporated. Examples of such agents include but are not limited to: sodium chloride, potassium chloride, dextrose, sorbitol and mannitol, their pharmaceutically acceptable salts and mixtures thereof. When they are used in the compositions of the present invention, they can be incorporated although without limitation in concentrations of 0.05 to 6%. (b) pH regulating agents. Also to the present compositions, acidifying and alkalinizing solutions can additionally be incorporated as pH regulating agents. Examples of such solutions include but are not limited to solutions of hydrochloric acid, sulfuric acid, sodium hydroxide and potassium hydroxide. When used in the compositions of the present invention these solutions can be used in initial concentrations and for addition of 0.01 to 1.0 Molar, most preferably 0.1 to 0.3 Molar. (c) Wetting agents Including but not limited to glycerol, polyethylene glycol and propylene glycol, their pharmaceutically acceptable salts and mixtures thereof, in concentrations of 0.05 to 6.5%. (d) Surfactants including but not limited to sorbitol and polysorbates, their pharmaceutically acceptable salts and mixtures thereof, in concentrations of 0.05 to 5.5%, most preferably but not limited to 1.0 to 2.0%. (e) Antioxidant agents including but not limited to sodium sulfite, ascorbic acid and its sodium and potassium salts, sodium citrate, as well as sodium nitrate and potassium nitrate, their pharmaceutically acceptable salts and mixtures thereof, which are used although without limitation in concentrations of 0.05 to 3.0%. (f) Thickening agents. They include but are not limited to microcrystalline cellulose, methylcellulose, carboxymethylcellulose and hydroxypropyl methylcellulose, their pharmaceutically acceptable salts and mixtures thereof, and may be used without limitation in concentrations of between 0.005 to 3.0%. (g) Chelating Agents Including but not limited to edeterate or disodium EDTA, their pharmaceutically acceptable salts and mixtures thereof, in concentrations which may be without limitations from 0.001 to 2.0%. (h) Water-soluble polymeric agents. Very useful in the present compositions are the water-soluble cyclic oligosaccharides which include but are not limited to: the different cyclodextrins such as HP CD or 2-hydroxypropyl-cyclodextrin, their pharmaceutically acceptable salts and mixtures thereof, in concentrations which can be although without limitations from 0.01 to 6.0%. The above additives of the aqueous intranasal carrier, since they are not essential components - in assets may be present individually or as their mixtures in very diverse proportions; his presence or individual absence is not essential. The present aqueous and pharmaceutically acceptable intranasal carrier can also contain other optional active components, such as the non-steroidal antiallergic agents comprising the primers of mast cells and others; sympathomimetic amines; other glucocorticoids, as well as non-steroidal anti-inflammatory agents or NSAIDs. Detail of all of them is described later in the part of optional active components. For the expert in the manufacture of pharmaceutically sterile aqueous and viscous products, the manufacturing and packaging processes are routine, and very similar to those described later in the examples section. The final pH of the compositions of the present invention will be in the range of 4.5 to 7.2, and may be adjusted by the addition of pH regulating agents. The present compositions, already contained in their multi-dose, metered dose container, provide intranasally effective and safe amounts of a glucocorticoid selected from the group consisting of beclomethasone, triamcinone, fluticasone and mometasone, their pharmaceutically acceptable salts and mixtures thereof, in amounts of the order of micrograms per unit dose, and if appropriate to another or other optional active components, administered by pulsations of the atomizing pump, which very preferably but without limitations atomize approximately 50 or 100 microliters of the composition for each pulsation. Depending on the conditions of each user, their age and the degree of severity of their case, the number of unit doses can vary without limitations, from 1 to 2 in each nostril or nostril, repeated one to four times a day . After the filling of the container and for the rest of the useful life of the composition, the sterility, as a novel and distinctive point of the present invention, depends totally and exclusively on the hermeticity of its container, as well as on the functionality of the atomizing pump and its accessories, which are part of the multi-dose and multiple dose atomizing container detailed below.

III. - THE MEASURED AND MULTIPLE DOSE ATOMIZING CONTAINER An essential element of the present invention is the multiple dose metered dose container for the intranasal route, which consists of four parts that are: 111.1. - The sterile container. This sterile container is the base of the atomizer, which can be very preferably but without limitations, a sterile glass bottle type I (one) amber color. Very preferably, but without limitations, this bottle has a 20 mm diameter mouth or opening. 111.2. - The sterile atomizing pump. It must be capable not only of administering intranasally by multiple atomizations and of measured doses the compositions of the present invention, but also of maintaining them since they are free of benzalkonium chloride as a preservative agent, sterile throughout their useful life. The expert in pharmaceutical fluids administered by the intranasal route recognize that examples of this type of pump are the "non-conservative system" of Pfeiffer, which can be used in the present invention. Most preferably, but without limitation, the compositions herein use the VP7D pump supplied by Valois, which is a spray pump designed especially for intranasal administration in measured and multiple doses of preservative-free fluids. This pump can be used in the present invention very preferably but without limitations in the models that atomize approximately 50 or 100 microliters for each pulsation, engargolada to the container. 111.3. - The sterile actuator The actuator must also be sterile and compatible with the atomizing pump and its characteristics. The present invention uses, very preferably but without limitation, the model CB19 also supplied by Valois, which is an additive compatible with the VP7D pump.

III.4. - The actuator plug. Very preferably, but without limitation, the standard model for the CB19 actuator, supplied in the same way by Valois, is used. This element can be but without limitations also sterile. These 4 parts, and very particularly the numbers III.1, III.2 and III.3, together form the multiple and metered dose atomizer container, which is an essential element of the present invention.

IV.- OPTIONAL ACTIVE COMPONENTS The person skilled in the art will recognize that one or several optional active components can be incorporated into the present compositions. These can be incorporated either unitarily or as mixtures of these in very different combinations, since many variations of these are possible without departing from the spirit and scope thereof, and their presence or absence is not essential. IV.1. - Non-steroidal anti-inflammatory agents, or NSAID agents. These NSAIDs include, but are not limited to: ibuprofen, naproxen, diclofenac, piroxicam, and ketorolac their pharmaceutically acceptable salts and mixtures thereof. They are used in concentrations of 0.05 to 6%, preferably from 0.1 to 2.0%. iv.2. - Sympathomimetic agents. These include but are not limited to sympathomimetic amines: pseudoephedrine and epinephrine, their pharmaceutically acceptable salts and mixtures thereof. These can be used although without limitation in concentrations of 0.1 to 2.5%. IV.3. - Other non-steroidal anti-allergic agents. Very useful in the present compositions are other non-steroidal antiallergens, including but not limited to those that stabilize the membrane of mast cells, such as sodium cromoglycate, and others such as ketotifen, its pharmaceutically acceptable salts and mixtures thereof. These can be used in concentrations of 0.1 to 5%. IV.4. - Other non-essential glucocorticoid agents.

Very useful in the general treatment of allergies and in the present compositions are other non-essential glucocorticoid agents, including but not limited to hydrocortisone, betamethasone, dexamethasone and prednisone, their pharmaceutically acceptable salts and mixtures thereof. These can be used in concentrations of 0.01 to 7%.

V. TREATMENT The administration of the present invention can be indicated in the symptomatic treatment of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis. These symptoms include but are not limited to rhinorrhea, excessive sneezing as well as irritation and nasal blockage. This treatment, its dosage, duration and general measures, will be a function of the chronicity of the same, the general condition of the patient and their age, and therefore remain at the discretion of the attending physician. Typically, administration by intranasal spray may be from 1 to 2 doses in each nostril, from one to four times a day, which in total may be from 1 to 8 total sprays per day. The appropriate total daily doses of the essential active component may be, but are not limited to, in the range of 100 to 1200 micrograms. Each atomization can be without limitations of approximately 25, 50 100 microliters, each providing approximately 25, 50, 100, 200 and 250 micrograms, very preferred and approximately 50 micrograms.

Each sales package may contain, but is not limited to, 50, 100, 150, 200 or 300 useful measured doses.

EXAMPLES The following examples further describe and demonstrate the embodiments within the scope of the present invention. The examples are given solely for purposes of illustration and should not be considered as limitations of the present invention, since many variations thereof are possible without departing from the spirit and scope thereof.

AXLE 1 Under air conditions class 100A for the manufacture and primary packaging, and having active components, additives, containers, atomizing pumps and actuators previously sterile, the pharmaceutical composition of the present invention is prepared, using conventional techniques similar to those described below. The multi-dose and multi-dose atomizing container elements are sterilized using conventional techniques and machinery well known to those skilled in the pharmaceutical manufacture of using sterile bottles, containers and accessories. VP7D atomizing pumps and CB19 actuators can be provided sterile directly by the supplier. The active component and the additives are sterilized separately. With all these elements the following composition is prepared: Component% by weight beclomethasone dipropionate 0.840 monohydrate hydroxypropyl methylcellulose 2910 0.100 HPPCD 5.500 polysorbate 80 0.010 sodium chloride 0.700 potassium chloride 0.100 disodium EDTA 0.025 sodium citrate 0.005 purified water c.b. 100 ml In a container of adequate size, the glucocorticoid and the micronized additives are homogenized with the purified water. The suspension formed is packaged in amber-colored Type I glass bottle with a 20 mm diameter mouth. Subsequently, the containers are engargolados with the pump VP7D atomizadora. Finally, the CB19 actuator and its cap are inserted into the upper piston of the atomizing pump. The product is ready for cartoning and routine conditioning in its own area for this purpose. The filling of the containers is done using conventional techniques and machinery well known by those experts in. the pharmaceutical manufacturing that fills sterile liquid products. The engargolado of the containers is realized using the conventional techniques and machinery well known by those experts in the pharmaceutical manufacture that engargola sterile liquid products. The atomizing pump can be used but without limitation, in two of its various options for intranasal administration of approximately 50 or 100 microliters. The first spray pump option provides approximately 50 microliters of composition, which provide 50 micrograms of beclomethasone dipropionate. The second spray pump option provides approximately 100 microliters of composition, which provide 100 micrograms of beclomethasone dipropionate. The final pH of the composition may be from 5.8 to 6.8, preferably from 6.1 to 6.6. It can be corrected with acidifying or alkalizing solutions. The administration of approximately 50 or 100 microliters of the composition is used depending on the choice of the spray pump chosen, for topical intranasal application that provides 50 or 100 micrograms of beclomethasone dipropionate, to provide symptomatic treatment of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis.

EXAMPLE 2 Under the same conditions of example 1 of manufacture, primary packing active components, additives, containers, atomizing pumps, actuators and plugs, the following composition is prepared: Component% by weight beclomethasone dipropionate 0.84 monohydrate disodium phosphate betamethasone 0.50 dextrose 5.00 avice! RC 591 1.10 polysorbate 80 0.045 purified water c.b.p. 100 ml The homogenization, packaging in the container, engargolado and placement of the actuator and plug are made as in example 1. The product is ready for cartoning and final packaging. The first spray pump option provides approximately 50 microliters of composition, which provide 50 micrograms of beclomethasone dipropionate. The second spray pump option provides approximately 100 microliters of composition, which provide 100 micrograms of beclomethasone dipropionate. The final pH of the composition may be from 5.8 to 6.8, preferably from 6.1 to 6.6. It can be corrected with acidifying or alkalizing solutions. The administration of approximately 50 or 100 microliters of the composition is used depending on the choice of the spray pump chosen, for topical intranasal application that provides approximately 50 or 100 micrograms of beclomethasone dipropionate, to provide symptomatic treatment of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis.

EXAMPLE 3 Under the same conditions of example 1 of manufacture, primary packaging components, containers, atomizing pumps, actuators and plugs, the following composition is prepared: Component% by weight acetonide triamcinolone 0.110 ketorolac 0.250 dextrose 5000 aviceI RC 591 1,100 polysorbate 80 0.045 sodium citrate 0.005 purified water cbp 100 ml The homogenization, packed in the container, engargolado and placement of the actuator and plug are made as in the example 1. The product is ready for cartoning and final conditioning. The first spray pump option provides approximately 50 microliters of composition, which provide 55 micrograms of triamcinolone acetonide. The second spray pump option provides approximately 100 microliters of composition, which provide 110 micrograms of triamcinolone acetonide. The final pH of the composition can be from 4.5 to 6.0, preferably from 4.5 to 5.5. It can be corrected with acidifying or alkalizing solutions. The administration of approximately 50 or 100 microliters of the composition is used according to the option of the chosen atomizing pump, for the topical intranasal application which provides 55 or 110 micrograms of triamcinium acetonide, to provide treat- ment. Symptomatic of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis.

EXAMPLE 4 Under the same conditions of Example 1 of manufacture, primary packaging components, containers, atomizer pumps, actuators and plugs, the following composition is prepared: Component% by weight acetonide of triamcinolone 0. 10 hydroxypropyl methylcellulose 2910 0.100 HP CD 1,000 polysorbate 80 0.010 sodium chloride 0.700 potassium chloride 0.100 sodium citrate 0.005 purified water cbp 100 ml The homogenization, packaging in the container, engargolado and placement of the actuator and plug are made as in example 1. The product is ready for cartoning and final packaging. The first spray pump option provides approximately 50 microliters of composition, which provide 55 micrograms of triamcinolone acetonide. The second spray pump option provides approximately 100 microliters of composition, which provide 1.0 micrograms of beclomethasone dipropionate. The final pH of the composition may be from 4.50 to 6.0, preferably from 4. 5 to 5.5 It can be corrected with acidifying or alkalizing solutions. The administration of approximately 50 or 100 microliters of the composition is used depending on the choice of the spray pump chosen, for topical intranasal application that provides approximately 55 or 110 micrograms of triamcinolone acetonide, to provide symptomatic treatment of seasonal allergic rhinitis, perennial allergic rhinitis and nasal polyposis.

Therapeutic results for the same indications can be obtained using equivalent or similar amounts of other glucocorticoids such as fluticasone and mometasone, their pharmaceutically acceptable salts and mixtures thereof. Having described the invention as above, property is claimed as contained in the following:

Claims (16)

1. - A pharmaceutical composition and its package, characterized in that it comprises (a) a safe and effective amount of a glucocorticoid selected from the group consisting of beclomethasone, triamcinolone, fluticasone and mometasone. (b) an aqueous and pharmaceutically acceptable intranasal carrier, wherein the composition is free of benzalkonium chloride as a preservative, (c) a self-atomizing container suitable for intranasal use, which provides multiple doses and measurements of the present compositions.

2. - A pharmaceutical composition according to claim 1 further characterized in that it is pharmaceutically sterile throughout its useful life.

3. - A pharmaceutical composition according to claim 2 further characterized in that the glucocorticoid essential active component is beclomethasone dipropionate.

4. - A pharmaceutical composition according to claims 1 to 3, further characterized in that the glucocorticoid essential active component is present in a concentration from 0.01 to 0.2% based on the total weight of the formulation.

5. - A pharmaceutical composition according to claims 1 to 4 characterized in that it contains one or more optional active components.

6. - A container suitable for supplying an aqueous pharmaceutical composition, for intranasal use, of multiple, atomized, metered doses, free of benzalkonium chloride, and characterized in that it is also capable of maintaining the sterile free preservative composition throughout its useful life, which consists of container, atomizing pump and actuator with stopper, according to any of claims 1 to 5.

7. - A container according to claim 5, further characterized in that the container is a glass bottle type I amber color.

8. - A container according to claim 5, further characterized in that the container has 20 millimeters in mouth diameter.

9. - A container according to claim 5, further characterized in that the atomizing pump is proper and suitable to deliver intranasally liquids without preservatives.

10. - A container according to claim 5, further characterized in that the actuator and its cap are proper and suitable to supply intranasally liquids without preservatives, in coordination with the atomizing pump.

11. The use of the compliance composition according to claim 2, for the manufacture of a medicament for treating the symptoms associated with seasonal allergic rhinitis, using an effective and safe amount thereof.

12. - The use of the compliance composition according to claim 2, for the manufacture of a medicament for treating the symptoms associated with perennial allergic rhinitis, using an effective and safe amount thereof.

13. - The use of the compliance composition according to claim 2 for the manufacture of a medicament for treating the symptoms associated with nasal polyposis, using an effective and safe amount thereof.

14. - The use of the compliance composition according to claim 5, for the manufacture of a medicament for treating the symptoms associated with seasonal allergic rhinitis, using an effective and safe amount thereof.

15. The use of the compliance composition according to claim 5, for the manufacture of a medicament for treating the symptoms associated with perennial allergic rhinitis, using an effective and safe amount thereof.

16. - The use of the compliance composition according to claim 5, for the manufacture of a medicament for treating the symptoms associated with nasal polyposis, using an effective and safe amount thereof.