MXPA99000152A - Acu base pharmaceutical composition - Google Patents

Abstract

The present invention relates: An aqueous pharmaceutical composition which is capable of being sprayed into the nasal cavity of an individual and which comprises: a pharmaceutically effective amount of solid particles of medicament which is effective in the treatment of bodily conditions due to being present on the mucosal surfaces of the nasal cavity, and a suspending agent in an amount effective to keep said particles uniformly dispersed in the composition and impart the following thixotropic properties to the composition: the viscosity of the position in unstirred form it is relatively high, with the composition being in gel form, as the composition is subjected to (stirred) cutting in preparation for spraying, the viscosity of the composition becomes relatively low and such that the composition in the form of a spray flows easily inside the nasal passages to be deposited on the surfaces of the mucosa of the nasal cavity, and in deposited form on the surfaces of the mucosa, the viscosity of the composition is relatively high and such that it resists being cleaned from the surfaces of the mucosa by the inherent mucociliary forces that are present in the nasal cavity, a method for using the composition and a method for the preparation of the composition, preferably including the use of an anti-inflammatory steroid, for example, triamcinolone acetonide, and an odorless form of the composition.

Description

PHARMACEUTICAL COMPOSITION OF AQUEOUS BASE FIELD OF THE INVENTION This invention relates to an aqueous based pharmaceutical composition. More particularly, this invention relates to an aqueous composition containing a medicament that is effective in the treatment of abnormal body conditions due to being present on the surfaces of the mucosa that line the nasal cavities. The field of the present invention is initially described in connection with the treatment of particular forms of rhinitis, that is, an abnormal body condition that involves inflammation of the mucous membrane of the nose. It should be understood that the invention has a wider application, as will be described below. An estimated forty million Americans suffer from perennial and temporary allergic rhinitis. Many more millions of individuals suffer from this condition worldwide. Symptoms of perennial and seasonal allergic rhinitis include nasal itching, congestion, watery nose, sneezing and watery eyes. Temporary allergic rhinitis is commonly known as "hay fever." It is caused by allergens that are present in the air at specific times of the year. The pollen trees in the spring of the year are examples of such allergens. Perennial allergic rhinitis is caused by allergens that are present in the environment throughout the year. Examples of such allergens are mites, mold, mildew and pet dander. It is known to treat such forms of rhinitis with medications such as, for example, anti-inflammatory steroidal agents. Triamcinolone acetonide is an example of a widely used anti-inflammatory steroidal agent. Such an agent is generally used by spraying it into the nasal passages of the human patient where it is deposited on the surfaces of the mucosa that line the nasal cavities. In this position, the drug exerts its pharmacological action as it is in contact with body tissues and interacts with steroid receptors. For maximum effectiveness, a pharmaceutical composition containing the aforementioned type of medicament must have a combination of desired properties. For example, the nature of the pharmaceutical composition containing the medicament must be such that the medicament is rapidly taken to all portions of the nasal cavities (the target tissues) where it performs its pharmacological function. In addition, the medication must remain in contact with the target tissues for relatively long periods. The longer the medication remains in contact with the target tissues, the greater the opportunity for the medication to perform its function. In order to remain in contact with the white tissues, the drug must be able to resist those forces in the nasal passages that work to remove particles from the nose. Such forces, referred to as "mucosal cleansers", are recognized as extremely effective in removing particles in the nose in a rapid manner, for example, within 10-30 minutes from the moment the particles enter the nose. nose. Other desired characteristics of the pharmaceutical composition are that it does not contain ingredients that cause discomfort to the user, that it has satisfactory stability and self-healing properties, and that it does not include components that -10 are considered detrimental to the environment, for example ^^ ozone predators. The present invention relates to a pharmaceutical composition having a combination of properties that make it particularly effective and suitable for alleviating abnormal body conditions that can be treated by depositing the composition on the mucosal surface that aligns the nasal passages.

REPORTED DEVELOPMENTS The following patents disclose pharmaceutical compositions containing various types of medicaments, including medicaments that function to treat an abnormal body condition by virtue of which the medicament is present on the mucosal surfaces of the nasal cavities, patents of E.U.A. Nos. 3,780,176; 3,809,294; 3,897,779; 4,405,598; 4,250,163; 4,294,829; 4,304,765; 4,407,792; 4,432,964; 4,443,440; 4,478,818; and 5,439,670. In contrast to the compositions described in the aforementioned patents, the pharmaceutical composition of the present invention is aqueous based.

BRIEF DESCRIPTION OF THE INVENTION According to the present invention, there is provided an aqueous pharmaceutical composition which is capable of being sprayed into the nasal cavity of an individual and which comprises: (A) a pharmaceutically effective amount of solid particles of medicament that is effective in the treatment of a body condition by virtue of being present on the 5 surfaces of the mucosa of the nasal cavity; and (B) an agent - of suspension in an amount effective to maintain said particles uniformly dispersed in the composition and to impart to the composition the following thixotropic properties: (i) the viscosity of the position in uncut form is relatively high, with the composition being gel-like shape; (ii) according to the composition is subjected to (stirred) cutting in preparation for spraying, the viscosity of the composition becomes relatively low and such that the composition in the form of a spray flows rapidly within the nasal passages to be deposited on the surfaces of the mucosa of the nasal cavity; and (iii) in deposited form on the surfaces of the mucosa, the viscosity of the composition is relatively high and such that it resists being cleaned from mucosal surfaces by the inherent mucosal forces that are present in the nasal cavity. In a preferred form, the medicament consists of an anti-inflammatory steroid, more preferably triamcinolone acetonide. Also in a preferred form, the composition of the present invention is odorless and includes a compound of J-O quaternary ammonium, preferably benzalalkonium chloride and a chelating agent, preferably disodium ethylenediamine tetraacetate (EDTA). Another aspect of the present invention consists of a method for applying solid particles of a medicament to the surfaces of the mucosa of the nasal cavities consisting of spraying a dose of an aqueous pharmaceutical composition containing said medicament within each of the nasal cavities, said doses containing a pharmaceutically effective amount of said medicament, said composition includes Also a suspension agent in an amount that is effective to keep said particles uniformly dispersed in the composition and to impart to the composition thixotropic properties so that the pharmaceutically effective amounts of the medicament are deposited at least on each one of the surfaces of the mucosa of the anterior regions of the nose, the frontal sinuses and the maxillary sinuses and on each of the surfaces of the mucosa that overlie the turbinates that cover the shells and in such a way that the portions of said amounts are retained on each of the surfaces of the mucosa for at least one hour. In a preferred form, the composition is applied to the nasal cavities by spray using a precompression pump. Yet another aspect of the present invention comprises a method for preparing an aqueous pharmaceutical composition consisting of a medicament in the form of solid particles, a dispersing agent for wetting said particles, and a suspending agent for keeping said particles substantially uniformly dispersed in the composition and to impart to the composition thixotropic properties consisting of: (A) forming an aqueous solution of the dispersing agent and combining the solution with the solid particles to form a suspension of the particles; (B) adding the suspending agent to the aqueous acidic solution to form a thixotropic suspension; and (C) combine each of the suspensions by introducing one of the suspensions within the lower part of the other suspension. In a preferred way, the suspension of solid particles of the drug is introduced into the lower part of the thixotropic suspension. The present invention allows numerous and important advantages in the treatment of a condition that involves the application of a medicament to the surface of the mucosa that lines the nasal cavities. As will be understood from the reading of the example section of the application, the present invention provides a means to rapidly carry a medicament to the many portions of the nasal cavities where it can perform its pharmacological function. In accordance with the present invention, the medicament remains in contact with the target tissues for relatively long periods, for example, at least 1 hour and for up to 2 or more hours. In addition, the composition of the present invention is capable of being formulated in such a way that ingredients that cause discomfort to the user are absent, the composition has satisfactory stability and shelf-life properties, for example, from one to two years, and it does not include constituents that are considered to be detrimental to the environment.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a cross-sectional view of a precompression pump which is shown in its rest position and which can be used in the application of the composition of the present invention to the nasal cavities. Figure 2 is a cross-sectional view of the pump of Figure 1 shown in its actuated position.

DETAILED DESCRIPTION OF THE INVENTION The water-based composition of the present invention consists of a medicament in the form of solid particles and other pharmaceutically acceptable ingredients, that is, materials that are compatible with the medicament, that are not toxic to the body under the conditions of use and that they avoid or minimize tissue irritation. As will be appreciated from the description that follows, there is no need to use in the water-based composition of the present invention a propellant which is a necessary ingredient of aerosol products. Water is present in the composition in a larger amount. Typically, it comprises at least 85% by weight of the composition and more typically at least 90% by weight of the composition. The medication to be used in the practice of The present invention is one that is capable of treating an abnormal body condition by virtue of being present on the surfaces of the mucosa of the nasal cavities. Examples of such a medicament are steroidal and non-steroidal anti-inflammatory agents, beta agonists and bronchodilators. Such a medication provides relief of nasal symptoms caused by inflammation of the upper respiratory tract and allergic rhinitis. It is believed that the drug that will be used most widely in the practice of the present invention will be an anti-inflammatory steroid such as, for example, clometasone, dexamethasone, fluticasone, prednisolone and triamcinolone acetonide. Such steroidal compounds are relatively potent drugs which, when applied locally, are highly effective with reduced systemic exposure. Triamsinolone acetonide is a preferred medicament for use in the practice of the present invention. A drug such as triamcinolone acetonide is substantially insoluble in water and hydrophobic. For use in the present invention, such a medicament is present in the composition in the form of solid particles which are dispersed in the aqueous phase of the composition. The sizes of the particles are such that the medicament is capable of being uniformly dispersed in the composition. For this purpose, the particle size must be no larger than 50 microns. Preferably the particles have an average size of 1 to 20 microns. The medicament is present in the composition in a pharmaceutically effective concentration. Such concentration will vary depending on the particular drug or mixture of drugs used, the condition to be treated and the nature of the individual being treated. For guide objects it is recommended that the medicament consist of 0.001 to 2% by weight of the composition, preferably 0.01 to 0.2% by weight of the composition. The composition of the present invention also contains a pharmaceutically acceptable excipient which is effective in forming a thixotropic suspension of the solid medicament particles comprising the composition. The excipient is present in an amount that keeps the medicament particles suspended in the composition during non-use and during the spraying of the composition within the nasal cavity, and also when the composition is deposited on the mucosal surfaces of the cavities. Nasal The thixotropic nature of the composition at rest (not subject to agitation) can be described as a gel in which the medicament particles are dispersed and suspended substantially uniformly. The viscosity of the composition at rest is relatively high, for example 400 to 1000 cp. As the composition is subjected to agitation forces, for example, after being subjected to forces involving it to be agitated before spraying, the viscosity of the composition decreases (e.g., from 50 to almost 200 cp) and flows easily to through the spray device and out of it in the form of a fine spray that infiltrates and deposits on the surfaces of the mucosa of at least the following parts of the nose: the anterior regions of the nose (frontal nasal cavities); the frontal sinus; maxillary sinuses; and the turbinates that overlie the shells of the nasal cavities. Thus, the thixotropic composition is such that it consists of a free-flowing liquid, and in a sprayed form, a fine dew that finds its way to and is deposited on the desired mucosa. In deposited form and relatively without tension, the composition increases in viscosity and assumes its gel-like shape which includes particles of the medicament suspended therein and which resists being cleansed from the nasal passage by the inherent mucosal forces that are present in the nasal cavities. Tests have shown that the amounts of the deposited composition remain on the surfaces of the mucosa for relatively long periods, for example, at least 1 hour or up to 2 or more hours. For convenience, the viscosity of the composition at rest is referred to as "viscosity at rest" and the viscosity of a composition that is agitated is referred to as "viscosity under agitation". As mentioned above, the resting viscosity of the composition must be sufficiently high to sustain and maintain the medicament particles dispersed substantially uniformly in the composition and to retain the composition over the extended mucosal surfaces on which it is deposited for an extended period. in the nasal cavities, that is, the composition resists being fired by the mucosal forces that are present in the nasal cavities. The stirring viscosity of the composition is sufficiently low to allow the composition to flow freely through the pump orifice and to decompose into a fine spray.

Suitable values for the viscosity at rest and for the viscosity under agitation of the composition can be determined for a particular composition, also taking into account the particular means used to apply the composition to the nasal cavities. By way of example, a quiescent viscosity of almost 400 to 800 cp is recommended for a composition containing an anti-inflammatory steroid, for example triamcinolone acetonide. A recommended stirring viscosity for such a composition is 50 to 200 cp. The -10 viscosity is measured using a Brookfield viscometer ^ Synchro-Letric Model LVT. The viscosity is measured at 20 ° C. The resting viscosity is measured after mixing at 30 rpm for 30 seconds. The stirring viscosity is measured by mixing at 30 rpm for 30 seconds after mixing on a Burrell wrist action agitator at full speed for 5 minutes. Any pharmaceutically acceptable material that is capable of maintaining the solid particles of the drug dispersed substantially uniformly in the composition and To impart the desired thixotropic properties to the composition can be used. Such a material is referred to as a "suspending agent". Examples of suspending agents include carboxymethylcellulose, veegum gum, tragacanth, bentonite, methylcellulose, and polyethylene glycols. A suspending agent Preferred is a mixture of microcrystalline cellulose and carboxymethylcellulose, the latter preferably being present in a major amount, more preferably in an amount of 85 to 95% by weight, with the last constituent consisting of 5 to 15% by weight of the mixture. The amount of suspending agent comprising the composition will vary depending on the particular medicament and the amount used, the particular suspending agent used, the nature and amounts of the other ingredients comprising the composition, and the particular viscosity values that are desired. Generally speaking, it is believed that the most widely used compositions will consist of 1 to 5% by weight of the suspending agent. The pharmaceutical composition of the present invention preferably includes other ingredients that impart desired properties to the composition. A composition containing a medicament that is hydrophobic preferably includes a pharmaceutically acceptable dispersing agent that functions to moisten the medicament particles to facilitate dispersion thereof in the aqueous phase of the composition. The amount of dispersing agent must be sufficient to moisten the hydrophobic drug particles within a short period, for example, from 5 to 60 minutes, as the aqueous dispersion of particles is mixed with conventional mixing equipment. It is preferred to use an amount of dispersing agent that will not cause foaming of the dispersion during mixing thereof. It is recommended that the dispersing agent be from 0.001 to 0.01% by weight of the composition. Any dispersing agent that is effective to moisten the particles and that is pharmaceutically acceptable can be used. Examples of dispersing agents that can be used are fatty alcohols, esters and ethers, including, for example, those sold under the trade names Pluronic, Tergitol, Span and Tween. It is preferred to use a hydrophilic, nonionic surfactant. Excellent results have been achieved using monooleate-10 polyoxyethylene sorbitan which is available under the trade mark Polysorbate 80. It is known that several drugs of the type that can be used in the composition of the present invention tend to degrade in the presence of water as a result of be. oxidized This can be avoided or eliminated by using an antioxidant. Examples of pharmaceutically acceptable antioxidants that can be used in the composition include ascorbic acid, sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxyquinoline, and N-acetyl cisterine.

It is recommended that the composition consist of 0.001 to 0.01% by weight of the antioxidant. Also, for stability objects, the composition should be protected from microbial contamination and culture. Pharmaceutical examples of antimicrobial agents Acceptable which can be used in the composition include quaternary ammonium compounds, for example, benzalkonium chloride, benzethonium chloride, cetrimide, and cetylpyridinium chloride; mercurial agents, for example, phenylmercuric nitrate, phenylmercuric acetate, and trimerosal; alcoholic agents, for example, chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterial esters, for example, esters of para-hydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, and polymyxin. It is recommended that the composition consist of 0.001 to 1% by weight of the antimicrobial agent. As mentioned above, one aspect of the present invention consists of a composition that is odorless and that contains a mixture of stabilizing agents that function as an antioxidant and as an antimicrobial agent. The mixture consists of a quaternary ammonium compound that has antimicrobial properties and a material that is generally recognized as a chelating agent. The use in the composition of this combination of materials with the medicament, for example, triamsinolone acetonide, results in a highly stable composition which is resistant to oxidative degradation and the growth of bacteria and the like. In a preferred form, the mixture consists of benzalkonium chloride and ethylenediamine disodium tetraacetate. The odorless composition will generally consist of 0.004 to 0.02% by weight of the quaternary ammonium compound and 0.01 to 0.5% by weight of the chelating agent. By virtue of the use of the aforementioned mixture of compounds, it is not necessary to include in the composition a material that is considered as an antioxidant. The composition of the present invention preferably includes an iso-osmotic agent that functions to prevent irritation of the nasal mucosa by the composition. Dextrose in anhydride form is a preferred ixo-osmotic agent. Examples of other pharmaceutically acceptable iso-osmotic agents that can be used include sodium chloride, dextrose, and calcium chloride. It is recommended that the The composition consists of up to 5% by weight of the iso-osmotic agent.

^^ The pH of the composition will vary depending on the particular medication used and taking into account the biological acceptance and stability of the medication.

Typically, the ph of the composition will fall within the scale from 4.5 to 7.5. The preferred pH for a composition containing triamcinolone acetonide is 4.5 to 6, more preferably almost 5. Examples of pharmaceutically acceptable materials that can be used to adjust the pH of the composition include hydrochloric acid and sodium hydroxide. The composition of the present invention can be prepared in any suitable form. In a preferred form, an aqueous suspension of the solid particles of medicament and the dispersing agent is formed and combined with an aqueous suspension containing the suspending agent. He The latter is preferably prepared by adding the medicament to an aqueous solution of the dispersing agent and mixing thoroughly. The latter is prepared by acidifying the water (pH of about 4.7 to 5.3) before adding the suspending agent. In a particularly preferred form, an aqueous solution of the quaternary compound (antimicrobial agent) is added to the aqueous suspension of the medicament, and the other ingredients (for example, the iso-osmotic agent, the antioxidant agent or chelator) are added to the suspension Thixotropic Each of the aforementioned batches of composition are thoroughly mixed before being combined. The media Preferred to combine the batches of composition is to introduce one of the batches, preferably the batch of "medicament" into the lower part of the next batch, for example, by pumping the batch up through the other batch. The composition consisting of the combined lots is mixed deeply. The use of a preferred method of preparation provides an efficient and effective way to formulate a composition having the solid particles of medicament f dispersed substantially uniformly therein while avoiding problems that are generally associated with the Preparation of water-based pharmaceutical compositions, for example, excessive foaming and non-uniformity of the particle dispersion. The amount of medication applied to each of the nasal passages will vary depending on the particular medication used, the nature of the condition being treated and the nature of the individual being treated. For guidance purposes, it is suggested that the dose unit applied to one of the nasal cavities consists of 200 to 450 mcg of the medication, or less as described hereinafter. In continuous use of the composition, the user can determine that the daily dosage needed for effective relief can be reduced, for example, from 100 to 225 mcg of the drug per nasal cavity. The use of the preferred form of the composition of the present invention provides the advantage that the composition -10 can be effectively applied once a day. For When dosing once a day, it is recommended that the amount of medication, for example, triamcinolone acetonide, applied to one nostril be 100 to 220 mcg, more preferably 100 to 130 mcg. In the case of use By continuing the preferred form of the composition, the user can determine that the daily dosage for effective relief can be reduced, for example, from 55 to 110 mcg of drug per nasal cavity. For applications that involve children who are under 12, it is recommended that the daily dosage per nasal cavity be 100 to 225 mcg of the drug and, for the preferred form of the composition, that the daily dosage per nasal cavity be 50 to 110 mcg of medication, reducible to a daily dosage of 30 to 55 mcg per nasal cavity on the continuous use of the medicine. The preferred means for applying the pharmaceutical composition of the present invention to the nasal passages is by the use of a precompression pump. A preferred precompression pump is the VP7 model manufactured by Valois Sa of France and marketed in the United States by Valois of America, 15 Valley Drive, Greenwich, Connecticut 06831. Referring to Figure 1, the pre-printing pump 10 has a housing 12 and includes means such as screw threads 14 for connecting the pump 10 to a container of the composition. The housing 12 includes a cylindrical outer wall 16 defining a hollow tube 18, a housing socket 20 connected to an immersion tube 22 through which the liquid enters the pump 10 from the container (not shown), and a cylindrical inner wall 24 positioned between the socket 20 of the intake tube 22 and the outer wall 16. A stem 26 extends from the upper part of the housing 12 and has a lower section 28 placed inside the hollow housing tube 18 by slidingly fitting the wall outer 16 to form a liquid seal. A central tube 30 within the stem connects a stem outlet 32 to a stem outlet 34 through which the liquid is dispensed to an atomizer to generate a spray. A leaf 36 is slidably positioned within the hollow tube 18 between the stem 26 and the inner wall 24. The leaf 36 has a head section 38 which adjusts the stem socket 32 to prevent the liquid from flowing through it, a shoulder 40, and a bell-shaped lower section 42 designed to slide over and seal against the inner housing wall 24 when the wing 36 is moved A downward. A spring 44 between the lower part of the housing 12 and the lower part of the head section of the flap 38 deflects the head of the flap to adjust and seal the stem intake 32. The pump 10 operates as follows. In the rest position, as shown in Figure 1, the swing head 38 closes the stem take 32 to prevent the liquid from flowing.

The metering chamber 46 is filled with the composition. HE The volume of the dosing chamber 46 is defined by the outer wall of the housing 16, the inner wall of the housing 24, the wing 36, and the stem 26. The dosing volume is controlled by the dimensions of these elements several defining the dosing chamber 46. The action of the user's finger pressing on the stem 26 causes the stem 26 and the leaf 36 to move downward. As seen in Figure 2, the dosing chamber 46 is closed by the lower section 42 of the leaf that adjusts the The inner wall of the housing 24. (Figure 2 shows a side spray nozzle, it being understood that this is for illustration purposes only and that other shapes may be used such as an upward spray nozzle). The additional pressure causes an increase in pressure hydraulic in the composition now isolated in the dosing chamber 46 in relation to the pressure of the composition within the inner wall of the housing 24. Since the liquid is essentially incompressible, the hydraulic pressure increased of the composition in the dosing chamber 46 creates a downward net force on the leaf 36. Once this downward force exceeds the upward force on the leaf 36, such as from the spring 44, the leaf moves further down away from the stem 26 to open the leaf. take stem 32 and allow the liquid composition to flow from the metering chamber 46 to the stem outlet 34 to generate the spray. After spraying, when the action of the user's finger releases the stem, the spring 44 returns to the wing 36 to adjust and seal the socket 32 and returns it to its resting position. This movement creates a vacuum that carries the composition into the dosing chamber 46 through the socket 20 of the intake tube 22 for the next dose. A precompression pump provides a spray higher than that of conventional pumps. During normal use, the precompression pump will carry a full dose of the composition. As previously described, the composition will not be sprayed until the hydraulic pressure of the composition reaches a pressure "threshold" within the pump sufficient to disengage the leaf 36 from the stem intake 32. Once the mismatch leaf 36 of the stem take 32, the hydraulic pressure provided by the user's finger forces the predetermined amount of composition into the stem take 32 for sprinkling. Thus, no spray is released before reaching the pressure threshold, and the full dose is released after the pressure threshold is reached. With conventional pumps, an amount less than the full dose can be released if a quantity can be released if one is applied or if it is not applied in an appropriate manner. With the precompression pump, it is extremely difficult to release less than the full dose when the pump is normally used. Another advantage of the precompression pump is that atomization of the spray is ensured. With conventional pumps, sufficient pressure may not be provided by the user to adequately atomize the spray. The precompression pump, however, does not release the composition until the pressure threshold is reached, which is designed to be sufficient for atomization. Additionally, the precompression pump depends less on the user. Because it will not spray until the pressure threshold is reached, the force and methods of depression applied by the user have less effect on the spray.

EXAMPLES The following examples are illustrative of the present invention.

EXAMPLE 1 A preferred pharmaceutical composition of the present invention is described below.

Component% by weight Amount in mg- Triamcinolone acetonide, USP micronised topical grade (TAA) 0.055 9.075 -10 Mixture of microcrystalline cellulose and carboxymethyl cellulose-sodium. NF 2.0 330.00 Surfactant NF, Polysorbate 80 0.004 0.66 Ethylenediamine disodium tetraacetate, USP 0.05 8.25 20 Benzalkonium chloride solution (BzCl), 50% by weight of BzCl, NF 0. 03 4. 95 25 Dextrose (anhydride), USP 5. 0 825. 00 Purified water, USP 92. 86 15, 322 o Hydrochloric acid • diluted, NF * * 0.1 N NaOH solution. * * Total weight 16.5 g 35 * Used for pH adjustment.

The composition is prepared using a two container method to mix the individual ingredients 40 listed above. A large batch of the composition is prepared in the manner described below. A portion of 16.5 g is extracted from the large batch to fill a spray bottle as described below as well. To a stainless steel kettle equipped with a variable speed sweeping mixer, a variable speed stirrer, and a fixed speed disperser, almost 500 kg of purified water are added. Almost 0.4125 kg of disodium ethylenediamine tetraacetate (hereinafter "EDTA") and 41.25 kg of dextrose are added to the water. After the above ingredients are mixed for 25 minutes, the disperser and agitator are stopped and the mixer is turned on. Almost 0.6 kg of dilute hydrochloric acid solution ("HCl") is added to the EDTA and the dextrose solution. The disperser is re-ignited, followed by the addition of 16.5 kg of a mixture of microcrystalline cellulose and carboxymethyl cellulose-sodium to the acidified EDTA / dextrose solution. The resulting suspension is homogenized by mixing continuously for 10 minutes. All the mixers are then stopped so that the boiler is scraped. The homogenization is resumed using the sweeping mixer and the disperser for 15 minutes. To a second stainless steel boiler equipped with a fixed speed disperser and a fixed speed mixer, almost 250 kg of purified water are added. The disperser and the mixer are ignited, followed by the addition of 0.033 kg of Polysorbate 80 (wetting agent). After 10 minutes of mixing, one liter of the solution is removed. With continuous mixing, 0.45375 kg of triamcinolone acetonide TAA are added to the boiler containing the dissolved surfactant. The container with "TAA" is rinsed with the surfactant solution removed and the rinse is added to the boiler. The TAA suspension is homogenized for 25 minutes using the disperser and the mixer. With the disperser turned off, 0.2475 kg of the benzalkonium chloride solution (BzCl) are added and dissolved in the resulting TAA dispersion. The "BzCl" container is rinsed -10 with approximately 1 kg of purified water and the rinse is ^ added to the TAA dispersion. The "TAA" dispersion is transferred to the "thixotropic" portion of the composition by pumping the TAA dispersion through the lower outlets of the two boilers. The "TAA" boiler is rinsed with 10 kg of water Purified and rinsing is added to the composition consisting of the combined TAA dispersion and the thixotropic portion. The pH of the resulting composition is then determined. The white pH of the preferred embodiments of the present invention is on the scale of 4.7-5.3. Yes it is As necessary, the pH is adjusted by adding, more preferably, either: 1) dilute HCl, NF which is further diluted with purified water (20 parts of water: one part of diluted HCl, NF); or 2) 0.1N NaOH solution (prepared by dissolving 4 g of sodium hydroxide, NF in purified water, and diluting to 1000 ml). The amount of added HCl or NaOH solution is measured, and an amount equal to this is removed from 4.5 kg of purified water. After the removed portion is removed, the remaining water is added to the composition, followed by homogenization using the disperser for 2 minutes. The composition is then transferred to a boiler 5 equipped with a fixed speed mixer. The mixer is set at 6 rpm and the composition is thoroughly mixed. The composition has a pH of 4.8 and at rest (without tension, not subjected to agitation) consists of a suspension in the form of gel. The TAA particles are uniformly dispersed throughout the composition. A 16.5 gram portion of the composition is then added to a 20 ml HDPE round bottle. Before the bottle is filled, 0.2u of filtered compressed air is blown into the bottle. The bottle is then covered with a measuring pump. The measuring pump is a Valois VP7 / 100S pump that has an immersion tube, an actuator, an overcap, and a safety clip.

EXAMPLE 2 Another composition within the scope of the present invention is prepared using the method and ingredients described in example 1, but with the following changes. In the first mentioned boiler, EDTA, dextrose and water are mixed for 10 minutes measured from the time when EDTA and dextrose are added to the water. Almost 0.53 kg of diluted HCl, NF is added to the EDTA and dextrose solution contained in the boiler. The preparation of the "TAA" portion of the composition and the transfer thereof to the "Thixotropic" portion of the composition is carried out as described in example 1. During the step of the pH adjustment that takes place after the Transfer of the "TAA" portion to the "thixotropic" portion, the amount of added HCl or NaOH solution is measured, and an equal amount is removed from 4.57 kg of purified water. -10 After the removed portion is removed, the water that ^ 0 remains is added to the composition, followed by homogenization using the disperser for 2 minutes. The pH of the composition is 5. The TAA particles are dispersed evenly throughout the composition. The 15 'bottle filling method is the same as that described in example 1. The following constitutes a description of examples B of how the composition of the present invention can be used. 20 Compositions such as those described in the examples 1 and 2 can be inhaled nasally for an effective treatment of symptoms of allergic rhinitis. As described in Examples 1 and 2, each of the compositions is packaged in a metering pump spray bottle containing 16.5 g of the composition. A dose of the composition can be delivered to a human patient by spraying the composition into each of the patient's nasal cavities. To deliver the dose, the measuring precompression pump (Valois VP7 / 100S) is placed in a hole in the nose of the patient and is then triggered by the patient, resulting in a spray into the nasal cavity. After the initial coating, each actuation of the pump carries from the nasal actuator almost 100 mg of the composition containing 55 mcg of TAA. Each bottle of composition will provide the -10 minus 120 doses measured. For the exemplified compositions, ^ The recommended dosage once a day for adults and children 12 years and older initiates 220 megs of TAA, equivalent to two sprays in each nasal cavity. As the composition is used continuously, consideration should be given to reducing the d dosage to 110 megs of TAA (almost 55 megs per nasal cavity). A composition consisting of the formulation of Examples 1 and 2 was administered to two volunteer patients. After administration, patients were evaluated by positron emission tomography in order to determine 1) the amount of time that led to the maximum dosage of the TAA drug to be taken to the different regions of interest within the nasal cavity, and 2) the amount of medication TAA deposited on the regions of interest during a period of 2 hours. For evaluation purposes, the volume of the head region was segmented into 104 different regions of interest. Included in the regions of interest are the following white sites: the frontal cavities, the frontal sinus, the maxillary sinus, the superior concha, and the inferior concha. The results of the evaluation 5 indicate a rapid distribution of the drug TAA to the white regions of the nose. For one of the volunteers, the maximum amount of the TAA drug that was in contact with the shell regions was 65% of the total taken to the nose and this occurred -10 in almost 45 seconds after the dose. Almost 46% of the dose ^ total was in contact with the lower shell and almost 19% of the total dose was in contact with the upper shell. The amount of TAA medication in contact with shell tissues declined over time, until a constant value of 1? > almost 3.4-4% of the total dose administered remained in the shell tissues in the final period. The maximum amount of TAA medication that was in contact with the cavity of the frontal region was almost 41% and this occurred at almost 45 seconds after dosing. The maximum amount of medication TAA that contacted the region of the frontal cavity declined slowly as a function of time, maintaining constant levels of 12% 2 hours after the dose. Based on this information, the frontal cavity is considered a white tissue because the deposited composition is maintained as a reserve or endorsement of the medication. The slow migration of the viscous composition back to the shell tissues through mucosilar cleansing suggests that the medicament TAA is continuously bathing the target tissues, thus counting for the efficacy of the preferred once-a-day dosing. Interestingly, the drug seems to enter the 5 contact with both maxillary and frontal sinuses. The data suggest that the drug particles are carried to the sinus due to the turbulent airflow during nasal inhalation. The maximum amount deposited was approximately 3.5% and 3.9% of the dose within the sinuses -10 frontal and maxillary respectively, and this occurred within ™ 30 seconds after dosing. The data include that the TAA drug is cleared from the frontal sinus within one hour and that approximately 1% of the drug is still present at two hours from the time of sample acquisition in the maxilla sinus. For the other volunteer, the maximum amount of the medication that came in contact with the shell regions was almost 53% of the total dose taken to the nose, almost 25% associated with the upper shell and 75% associated with the shell lower. The maximum amount of the TAA drug that was in contact with the upper shell region occurred at almost 25 seconds after the dose and for the lower shell region at almost 3.5 minutes. These data suggest that the drug TAA moves within the shell region from the area of the frontal cavity. At almost two hours after administration, almost 6-8% of the administered dose remained in contact with the shell regions, with the drug slowly being cleared from the target site. The maximum amount of the TAA drug that was in contact with the frontal cavity was 55% of the total dose 5 taken to the nose and this occurred within 30 seconds after the dose. The medication appeared to leave the nasal cavity slowly with approximately 225 of the dose still resident after two hours. A small percentage of the administered dose of the drug TAA was in contact with -10 maxillary and frontal sinuses. The maximum amount was ^ deposited within 30 seconds after the dose, with values around 3.5% for the frontal sinus and 2% for the maxillary sinus. These values remained relatively constant, with approximately 0.5% to 1% of the dose remaining still in the sinus after two hours. The evaluation also included a determination of the percentage of the TAA drug remaining on the target sites two hours after it was administered to each of the patients. This percentage was determined by dividing the amount remaining in each region of interest for the total amount remaining in the 104 regions of interest. The results of this evaluation indicate that more than 85% of the dose was directly deposited on the target sites, including the frontal cavity, the frontal sinus, the sinuses jaws, the upper shell and the lower shell. For the first of the volunteers described above, the results indicate that 47.9% of the total TAA drug remained deposited in the frontal cavity two hours after the medication was administered. The percentage of the total drug deposited in the region of the lower shell two hours after the administration (almost 27.8%), when combined with the amount deposited in the upper shell region (almost 8.6%), added 36.4% of the amount remaining from the dose administered to the main white region of the nose. After a period of two hours, almost 1.2% of the dose was deposited on the frontal sinuses while almost 3% of the dose was deposited in the region of the maxillary sinus. Adding the percentages of the drug administered remaining on the target sites two hours after the medication was administered indicates that almost 88.5% of the administered dose was directly deposited on the target tissues during a period of two hours of series of samples. For the second of the volunteers described above, the results indicate that almost 52.2% of the administered dose remained deposited in the frontal cavity two hours after administration. Almost 23.5% of the doses remained deposited in the lower shell and almost 6.9% of the dose remained deposited on the upper shell. The total percentage of the dose remaining deposited on the shell regions was almost 30.4% of the total dose delivered. The values for frontal and maxillary sinuses were almost 1.6% and 1.4% of the dose administered respectively. Adding the percentages of the medication administered remaining on the target sites two hours after the medication was administered indicate that almost 85.6% of the administered dose was directly deposited on the target tissues after a period of two hours of serial samples. It should be appreciated that the present invention provides effective and improved means for relieving patients of abnormal disturbing body conditions.

Claims (20)

NOVELTY OF THE INVENTION CLAIMS

1. A method for applying solid particles of a medicament to the mucosal surfaces of the nasal cavities consisting of spraying a dose of an aqueous pharmaceutical composition containing said medicament within each of the nasal cavities, said dosage containing a quantity pharmaceutically effective of medicament, said composition also includes a suspending agent in an amount that is effective to maintain said dispersed particles uniformly in the composition and to impart thixotropic properties to the composition so that pharmaceutically effective amounts of the medicament are deposited on each of the surfaces of the mucosa of the anterior regions of the nose, the frontal sinuses and the maxillary sinuses and on each of the surfaces of the mucosa that overlie the turbinates that cover the shells and in such a way that the portions of said quantities are retained on each of the mentioned surfaces of the mucosa for at least one hour.

2. A method according to claim 1, further characterized in that the medicament consists of an anti-inflammatory steroid.

3. - A method according to claim 2 further characterized in that the anti-inflammatory steroid consists of triamcinolone acetonide and said dose includes said triamcinolone acetonide in an amount effective to provide relief of symptoms of allergic rhinitis.

4. A method according to claim 3, further characterized in that the resting viscosity of the composition is 50 to 200 centipoise and the viscosity under stirring of the composition is 400 to 1000 centipoise.

5. A method according to claim 4, further characterized in that said composition is odorless and also includes a quaternary ammonium compound and a chelating agent and according to which said suspending agent consists essentially of a mixture of microcrystalline cellulose and carboxymethyl cellulose. sodium cellulose.

6. - A method according to claim 5, further characterized in that said ammonium compound consists essentially of benzalkonium chloride and said chelating agent consists essentially of EDTA.

7. A method according to claim 1, further characterized in that said composition is sprayed by a precompression pump.

8. - An aqueous pharmaceutical composition that is capable of being sprayed into the nasal cavity of an individual and that consists of: (A) a pharmaceutically effective amount of solid particles of medicament that is effective in treating an abnormal body condition by virtue of being present on the surfaces of the mucosa of the nasal cavity; and (B) a suspending agent in an amount effective to keep said particles uniformly dispersed in the composition and to impart to the composition the following 5 thixotropic properties: (i) the viscosity of the position in non-agitated form is relatively high, with the composition being in gel form having said particles suspended therein; (ii) as the composition is cut (agitation) in the preparation for sprinkling, the viscosity of -10 the composition becomes relatively low in such a way that the ^ Composition in the form of a spray easily flows into the nasal passages to deposit on the mucosal surfaces of the nasal cavity; and (iii) in deposited form on the surfaces of the mucosa, the viscosity of the The composition is relatively high and in such a way that it resists being wiped from the surfaces of the mucosa by the inherent mucosal forces that are present in the nasal cavity.

9. - A composition according to claim 8, further characterized in that the viscosity The relatively low composition is 50 to 200 centipoise and the relatively high viscosity of the composition is 400 to 1000 centipoise.

10. A composition according to claim 8, further characterized in that the medicament is an anti-inflammatory steroid.

11. A composition according to claim 9, further characterized in that the medicament is an anti-inflammatory steroid.

12. A composition according to claim 10, further characterized in that the steroid consists essentially of triamcinolone acetonide.

13. - A composition according to claim 11, further characterized in that the steroid consists essentially of triamcinolone acetonide.

14. A composition according to claim 12, further characterized in that it is odorless and includes a quaternary ammonium compound and a chelating agent.

15. A composition according to claim 14, further characterized in that the quaternary ammonium compound consists essentially of benzalkonium chloride, the chelating agent consists essentially of EDTA and the suspending agent consists of a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose.

16. - A composition according to claim 15, further characterized in that the resting viscosity of the composition is 400 to 800 centipoise and the viscosity under stirring is 50 to 200 centipoise.

17. A method for preparing an aqueous pharmaceutical composition consisting of a medicament in the form of solid particles, a dispersing agent for moistening said particles, and a suspending agent for keeping said particles substantially uniformly dispersed in the composition and for imparting to the composition properties 4 thixotropics consisting of: (A) forming an aqueous solution of the dispersing agent and combining the solution with the solid particles to form a suspension of the particles; (B) adding the suspending agent to an aqueous acidic solution to form a thixotropic suspension; and (C) combine each of the suspensions by introducing one of the suspensions within the lower part of the other suspension. 10 18.- A method in accordance with the claim "17, further characterized in that the particle suspension is introduced into the lower part of the thixotropic solution 19. A method according to claim 18, further characterized in that the particle suspension includes triamcinolone acetonide particles, a nonionic hydrophilic surfactant and a quaternary ammonium antimicrobial agent and in which the thixotropic suspension includes a chelating agent and an anti-osmotic agent 20. A method according to claim 19, further characterized in that the antimicrobial agent consists essentially of benzalkonium chloride, the chelating agent consists essentially of EDTA and the antiosmotic agent consists essentially of dextrose. SUMMARY OF THE INVENTION An aqueous pharmaceutical composition which is capable of being sprayed into the nasal cavity of an individual and which comprises: a pharmaceutically effective amount of solid particles of medicament which is effective in the treatment of bodily conditions due to being present on the surfaces of the mucosa of the nasal cavity; and a suspending agent in an amount effective to keep said particles uniformly dispersed in the composition and to impart the following thixotropic properties to the composition; the viscosity of the position in non-agitated form is relatively high, with the composition being in gel form; as the composition is subjected to shearing (agitated) in preparation for spraying, the viscosity of the composition becomes relatively low and such that the composition in the form of a spray flows easily into the nasal passages to be deposited on the surfaces of the mucous of the nasal cavity; and in deposited form on the surfaces of the mucosa, the viscosity of the composition is relatively high and such that it resists being cleansed from mucosal surfaces by the inherent mucociliary forces that are present in the nasal cavity, a method for using the composition and a method for preparing the composition, preferably including the use of an anti-inflammatory steroid, for example, triamcinolone acetonide, and an odorless form of the composition. P98 / 1551F SR / elt *.