Title:  Aqueous compositions containing corticosteroids for nasal and pulmonary delivery

United States Patent:  6,241,969

Assignee:   Elan Corporation plc (Dublin, IL)

Filed:  June 26, 1998

The present invention provides compositions containing corticosteroid compounds as active agents for the treatment of ailments and diseases of the respiratory tract, particularly the lungs, by way of nasal and pulmonary administration. The corticosteroid compounds are present in a dissolved state in the compositions. The compositions can be formulated in a concentrated, essentially non-aqueous form for storage or in a diluted, aqueous-based form for ready delivery. In a preferred embodiment, the corticosteroid composition contains an ethoxylated derivative of vitamin E and/or a polyethylene glycol fatty acid ester as the high-HLB surfactant present in the formulation. The compositions are ideally suited for inhaled delivery with a nebulizer or for nasal delivery.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions containing corticosteroid compounds as active agents for the treatment of ailments and diseases of the respiratory tract, particularly the lungs, by way of nasal and pulmonary administration. The compositions can be formulated such that they contain the corticosteroid active agent(s) in a dissolved state. The formulations can be stored either in a concentrated form to be diluted at the time of use or a ready-for-use, diluted state. The present invention also sets forth methods for using the compositions for nasal or inhaled delivery.

The corticosteroid compositions of the present invention are preferably formulated with ethoxylated derivatives of vitamin E as the high-HLB surfactant component. An example of a preferred high-HLB surfactant from this class of surfactants is tocopheryl polyethylene glycol 1000 succinate ("TPGS"). TPGS is commercially available from Eastman Chemical Company as "Vitamin E TPGS", and has been used as a water-soluble Vitamin E supplement for oral ingestion. It is a waxy solid at room temperature and has melting point around 40^oC. It has been found that the use of TPGS in corticosteroid compositions is particularly advantageous due to the ability of TPGS to solubilize corticosteroids and to form a stable micellar solution upon dilution in an aqueous phase, and also due to the neutral taste of TPGS when used in a corticosteroid composition that is administered either nasally or by inhalation. Consequently, an embodiment of the present invention that is particularly well suited for ease of manufacturing is one in which the corticosteroid compound is initially dissolved in TPGS to form a "concentrate" that is diluted with an aqueous phase to form the final corticosteroid composition. This composition is a micellar solution because the concentration of TPGS is far above the critical micellar concentration (CMC) of TPGS, which is about 0.02 wt. percent in water at 37^oC. This embodiment is easy to manufacture, has a low level of excipients, and has a neutral taste for inhalation delivery.

Compositions designed for inhaled administration have a level of the high-HLB surfactant in the final, diluted corticosteroid composition from about 0.1 to about 20, preferably from about 0.25 to about 15, and more preferably from about 0.5 to about 5, percent by weight. Compositions designed for nasal administration have a level of the high-HLB surfactant in the final, diluted corticosteroid composition from about 1 to about 20, preferably from about 2.5 to about 15 and more preferably from about 5 to about 10, percent by weight.

The corticosteroids that are useful in the present invention generally include any steroid produced by the adrenocortex, including glucocorticoids and mineralocorticoids, and synthetic analogs and derivatives of naturally occurring corticosteroids having anti-inflammatory activity. Examples of corticosteroids that can be used in the compositions of the invention include aldosterone, beclomethasone, betamethasone, budesonide, cloprednol, cortisone, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluorometholone, flurandrenolone, fluticasone, halcinonide, hydrocortisone, icomethasone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, tixocortol, triamcinolone, and their respective pharmaceutically acceptable derivatives, such as beclomethasone diproprionate, dexamethasone 21-isonicotinate, fluticasone propionate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide. Particularly preferred are compounds such as beclomethasone diproprionate, budesonide, flunisolide, fluticasone propionate, mometasone and triamcinolone acetonide.

The corticosteroid compound is present in the final, diluted corticosteroid composition designed for inhalation in an amount from about 5 .mu./ml to about 5 mg/ml, preferably from about 10 .mu.g/ml to about 1 mg/ml, and more preferably from about 20 .mu.g/ml to about 500 .mu.g/ml. For example, the preferred drug concentration is between about 20 and 100 .mu.g/ml for beclomethasone dipropionate, between about 30 and 150 .mu.g/ml for triamcinolone acetonide, and between about 50 and 200 .mu.g/ml for budesonide, depending on the volume to be administered. By following the preferred methods of the present invention, relatively high solubilities of the corticosteroid can be achieved in an aqueous-based composition. The solubility of the corticosteroid can be greater than about 50, preferably greater than about 75, and more preferably greater than about 100, in some cases greater than about 150 or about 200, .mu.g/ml.

Similarly, the corticosteroid compound is present in the final, diluted corticosteroid composition designed for nasal administration in an amount from about 50 .mu.g/ml to about 10 mg/ml, preferably from about 100 .mu.g/ml to about 2 mg/ml, and more preferably from about 300 .mu.g/ml to about 1 mg/ml. For example, the preferred drug concentration is between about 200 and 900 .mu.g/ml for beclomethasone dipropionate, between about 250 .mu.g/ml and 1 mg/ml for triamcinolone acetonide, and between about 400 .mu.g/ml and 1.6 mg/ml for budesonide, depending on the volume to be administered.

The corticosteroid composition can also contain various excipients that improve the storage stability of the composition, but which do not significantly affect the overall efficacy of the composition in its freshly prepared state. Such excipients include buffers, osmotic (tonicity-adjusting) agents, low toxicity antifoaming agents, and preservatives.

Buffers are used in the present compositions to adjust the pH to a range of between about 4 and about 8, preferably between about 4.5 to about 7, and more preferably between about 5 and about 6.8. The buffer species may be any pharmaceutically approved buffer providing the aforementioned pH ranges, such as citrate, phosphate, malate, etc.

The osmotic agent can be used in the compositions to enhance the overall comfort to the patient upon delivery of the corticosteroid composition. It is preferred to adjust the osmolality of the composition to about 280-300 mOsm/kg. Such agents include any low molecular weight water-soluble species pharmaceutically approved for pulmonary and nasal delivery such as sodium chloride and glucose.

Preservatives can be used to inhibit microbial growth in the compositions. The amount of preservative is generally that which is necessary to prevent microbial growth in the composition for a storage period of at least six months. Examples of pharmaceutically acceptable preservatives include the parabens, benzalkonium chloride, thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, and potassium sorbate.

Corticosteroid compositions that contain the high-HLB surfactant can be prepared as follows. TPGS will be used as the representative high-HLB surfactant for illustrative purposes. First, the TPGS may be heated to a temperature of at least about 40^oC., preferably at least about 45^oC., and generally about 45-60^oC. The appropriate quantity of the corticosteroid compound is then dissolved in the molten TPGS at the same temperature, thus forming the concentrated corticosteroid composition. To achieve the final, diluted corticosteroid composition, the molten concentrated corticosteroid composition is slowly added under continuous stirring to an aqueous phase. The aqueous phase is preferably water containing the additives necessary to adjust the pH and tonicity, and preservatives if the formulation is intended for multiple use. It is preferred that the aqueous phase be heated prior to the addition of the molten corticosteroid concentrate to aid in dispersion. Generally, the aqueous phase should be heated to about 55-85^oC., more preferably from about 60-70^oC.

It is preferred that the diluted corticosteroid composition be formulated by first dissolving the drug in the molten TPGS and then dispersing this concentrate in the aqueous phase. If the drug is added to a prediluted mixture of TPGS and aqueous phase, it may not be possible to achieve the final desired concentration of the drug in a dissolved state. To ensure that the drug is solubilized and stable in the diluted composition, it is preferred that the level of the drug in the concentrated composition be from about 1 to about 30 mg/ml, preferably from about 2 to about 20 mg/ml, and more 5 preferably from about 2 to about 10 mg/ml prior to dilution. The level of water in the concentrated corticosteroid composition should be below 5% by weight, preferably below 2% by weight, and more preferably below 1% by weight, and in general, it is advantageous not to add any water to the concentrated corticosteroid composition.

The aqueous phase, which is composed of water and optionally buffering, tonicity, and/or preservation additives, is present in the diluted corticosteroid compositions containing TPGS in an amount of at least about 70, preferably at least about 80, more preferably at least 90, and even more preferably at least about 95, percent by weight. The various other additives, such as buffers, tonicity adjusting agents, and preservatives, are preferably blended into the compositions as part of the aqueous phase, and the use of the term "aqueous phase" is intended to include such components, if used.

It has been found that the inclusion of any one of a group of cosolvents in these TPGS corticosteroid compositions can aid in the processing of the compositions and in the solubilizing of the drug. Preferred cosolvents include mono- and polyvalent alcohols, such as propylene glycol, ethanol, glycerol, glycofurol (available as Tetraglycol from Sigma), ethoxydiglycol (available as Transcutol from Gattefosse), and polyethylene glycol (PEG) having an average molecular weight between about 200 and 4000, preferably between 200 and 1000, more preferably PEG 400, and combinations thereof. The cosolvents can be present individually in the final, diluted corticosteroid compositions in concentrations from about 0.1 to about 20, preferably from about 0.25 to about 15, more preferably from about 0.5 to about 5, and even more preferably from about 0.5 to about 2.5, percent by weight. The total level of cosolvents combined in the final, diluted corticosteroid compositions is from about 0.1 to about 20, preferably from about 0.25 to about 15, more preferably from about 0.5 to about 10, and even more preferably from about 0.5 to about 5, percent by weight.

When preparing the corticosteroid compositions, the cosolvents can be added to the molten TPGS, to the TPGS/drug concentrate, or to the aqueous phase in which the TPGS/drug concentrate will be dispersed. Any way, stable diluted corticosteroid compositions can be produced with the drug in a dissolved state. If the cosolvents are blended with the molten TPGS prior to the addition of the drug, the temperature of this concentrate can then be reduced during the dissolution process. In general, the temperature of the TPGS/cosolvent mixture can be maintained below about 50^oC., preferably below about 45^oC., in order to dissolve the drug. In some cases, such as when a volatile cosolvent like ethanol is used, no heating is necessary to achieve dissolution. In addition, when the concentrated composition contains a cosolvent, it is not necessary to heat the aqueous phase used as the dilution medium to form the diluted corticosteroid composition.

Alternatively, the drug can be first dissolved in the cosolvent or blend of cosolvents at 20-50^oC. and then that solution is blended with the molten TPGS to form the concentrated corticosteroid composition.

Other preferred high-HLB surfactants that can be used in place of, or in admixture with, ethoxylated derivatives of vitamin E are polyethylene glycol fatty acid esters. The fatty acid moiety preferably has from about 8 to about 18 carbon atoms. A preferred polyethylene glycol fatty acid high-HLB surfactant product is "Solutol HS-15," available from BASF Fine Chemicals. Solutol HS-15 is a mixture of polyethyleneglycol 660 12-hydroxystearate (70%) and polyethylene glycol (30%). It is a white paste at room temperature that becomes liquid at about 30^oC. and has an HLB of about 15. Aqueous solutions of this surfactant, like those of TPGS, have a neutral taste. Similar preferred manufacturing processes and behavior regarding the dissolution of drugs, dilution methods, and the addition of cosolvents apply to Solutol HS-15 as those mentioned above for TPGS.

The corticosteroid compositions can contain other high-HLB surfactants, such as ethoxylated hydrogenated castor oil (Cremophor RH40 and RH60, available from BASF), tyloxapol, sorbitan esters such as the Tween series (from ICI Surfactants) or the Montanox series (from Seppic), etc. The corticosteroid compositions preferably contain either, or both, of the ethoxylated derivatives of vitamin E or the polyethylene glycol fatty acid esters as all or part of the high-HLB surfactant component, and in general the sum of these two types of surfactants will account for at least 50%, preferably at least 75%, and more preferably at least 90% by wt. of the high-HLB surfactant component.

Optionally, low HLB surfactants, having an HLB value below about 8, can also be used in the present invention. Examples of such low HLB surfactants include phospholipids, such as phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol; and medium-chain mono- and diglycerides, i.e., mono- and di-glycerides of C₈ to C₁₂ fatty acids, and mixtures thereof. The low HLB surfactants can be used in general at levels from about 0.1 to about 3 percent by weight in the diluted composition.

Optionally, an oil can also be incorporated into the compositions. Examples of pharmaceutically acceptable oil compounds include triglycerides and propylene glycol diesters of C₈ to C₁₂ fatty acids such as the Captex series available from Abitec. Oils can be used in general in levels from about 1 to about 30 percent by weight in the concentrated compositions and from about 0.1 to about 3 percent by weight in the diluted composition.

It is necessary to add the drug to the compositions containing high-HLB and low HLB surfactants, and/or cosolvents, and/or the oil compounds, to form the concentrated corticosteroid compostion prior to dilution with the aqueous phase.

The diluted corticosteroid compositions using high-HLB surfactants such as TPGS or Solutol HS-15 to solubilize the drug are believed to be micellar compositions. This belief is based on the fact that the critical micelle concentration for both TPGS and Solutol HS-15 is about 0.02% by weight at 37^oC., which is below their concentration in the diluted corticosteroid compositions. If an oil component is present with or without a low HLB surfactant, an oil-in-water (o/w) microemulsion may be formed as the diluted corticosteroid composition.

The aforementioned diluted compositions can be administered to the body in the form of an aerosol. For administration to the respiratory tract, particularly the lungs, a nebulizer is used to produce appropriately sized droplets. Typically, the particle size of the droplet produced by a nebulizer for inhalation is in the range between about 0.5 to about 5 microns. If it is desired that the droplets reach the lower regions of the respiratory tract, i.e., the alveoli and terminal bronchi, the preferred particle size range is between about 0.5 and about 2.5 microns. If it is desired that the droplets reach the upper respiratory tract, the preferred particle size range is between 2.5 microns and 5 microns. The nebulizer operates by directing pressurized air to fluidize the droplets of the diluted corticosteroid composition, which resultant aerosol is directed through a nozzle and subsequently through a baffle system that removes larger particles.

For the treatment of bronchial constriction, the diluted corticosteroid composition is prepared as described above. The corticosteroid for such treatment is preferably either beclomethasone dipropionate, betamethasone, budesonide, dexamethasone, flunisolide, fluticasone propionate, or triamcinolone acetonide, and is formulated in the concentrations set forth above. The daily dose of the corticosteroid is generally about 0.4 to 2 mg, depending on the drug and the disease, in accordance with the Physician's Desk Reference.

Claim 1 of 29 Claims

What is claimed is:

1. An aerosolized composition for administering a therapeutic dose of a corticosteroid to respiratory tract, consisting essentially of:

(a) from 5 .mu.g/mL to about 5 mg/mL of a dissolved corticosteroid;

(b) from about 0.1 to about 20 percent by weight of a pharmaceutically acceptable, high-HLB surfactant component containing one or more surfactants having an HLB of greater than 10, wherein The high-HLB surfactant component comprises at least 50% by weight of an ethoxylated derivative of vitamin E; and

(c) at least about 70 weight percent aqueous phase.

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