United States Patent:  5,968,913

Assignee:  Inspire Pharmaceuticals, Inc. (Durham, NC)

Filed:  December 23, 1997

Novel pharmaceutical compositions of uridine 5'-triphosphate (UTP) for use in promoting increased mucociliary clearance of retained mucous secretions of the human airways, middle/inner ears or sinuses are disclosed. Novel Formulation I comprises UTP and aqueous solution having a therapeutic concentration between 5 and 45 mg/mL, a controlled tonicity within the range of 250 to 100 mOsM, a pH between 7.0 and 7.5, and is sterile. The pH-adjusted composition is capable of long-term storage in the refrigerated state with a shelf life of up to 30 months. Formulation I may be delivered therapeutically either in a nebulized form or in a liquid form. Novel Formulation II comprises UTP in an aqueous solution or suspension having a therapeutic concentration approaching the limit of UTP's solubility at ambient temperature. This high concentration allows delivery of a therapeutic amount of UTP in very small volumes (50 to 100 .mu.L) suitable for administration via portable hand-held devices such as metered dose inhalers. Formulation II has extended shelf life without the need for refrigeration after being dispensed to the patient.

SUMMARY OF THE INVENTION

Novel pharmaceutical compositions of UTP are disclosed. The compositions comprise a UTP raw material, e.g., uridine 5'-triphosphate trisodium salt dihydrate, in a sterile aqueous solution or suspension. Formulation I is sterilized, of controlled tonicity, pH-adjusted and capable of extended shelf life when kept properly refrigerated. It is compatible for use in a variety of commercially available nebulizers, such as jet or ultrasonic nebulizers.

Formulation II is highly concentrated and suitable for administration via a small, portable hand-held devices that are capable of efficiently generating fine respirable aqueous based aerosols from small pre-measured volumes or of metering a small volume from a liquid reservoir. Additionally, Formulation II is also well suited for topical delivery of small volumes via metered pump based systems which would deliver a therapeutically effective amount of UTP via the nose or ear.

These novel formulations of UTP are well suited to be therapeutically administered in order to promote mucociliary clearance in patients suffering from retained mucous secretions in the lungs, sinuses or middle/inner ears; increase expectoration and sputum production to induce sputum for the purposes of diagnostic analysis, clear the lungs of various airborne toxins, clear the lungs prior to radiological imaging and clear the lungs prior to vaccination or gene therapy.

The formulations of the present invention also encompasses the pharmaceutically acceptable salts of UTP, e.g., an alkali metal salt such a sodium or potassium; an alkaline earth salt; or an ammonium or tetraalkyl ammonium salt i.e., NX₄⁺ wherein X is C_1-4.

Because UTP is heat labile, Formulations I and II of the present invention are sterilized by filtration rather than by heat.

A second aspect of the present invention is that the tonicity of Formulation I can be controlled, e.g., for an isotonic formulation; thus UTPNa₃ is dissolved in the appropriate amount of saline or other aqueous solution to control tonicity within the osmolarity range of 250 to 1000 mOsM; the preferred osmolarity level is between 250 to 450 mOsM; the most preferred osmolarity is approximately 300 mOsM, i.e., an isotonic solution.

A third aspect of the present invention is that Formulation I is pH-adjusted to be in the range of 6.0 to 8.5; the preferred pH level is between 7.0 and 7.5.

A fourth aspect of the present invention is that Formulation I may be formulated in multiple concentrations of UTP between 0.1 and 100 mg/mL; the preferred therapeutic UTP concentration is between 5 and 45 mg/mL.

A fifth aspect of the present invention is that Formulation I with a pH value of 7.0 to 7.5 will remain in stable form for up to 30 months when stored at a temperature between 0^o to 10^oC. The preferred storage temperature is approximately 5^oC.

In a sixth aspect of the present invention, Formulation II is highly concentrated, either approaching the limit of solubility of UTP over a temperature range of -20^o to +40^oC., or as a microfine particulate suspension.

In a seventh aspect of the present invention, a very small volume of Formulation II can be administered while maintaining therapeutic efficacy. The volume range of this highly concentrated UTP Formulation Is from 10 to 1000 .mu.L, preferably 25 to 500 .mu.L and most preferable 50 to 100 .mu.L.

In an eighth aspect of the present invention, since Formulation II is delivered to the target site and is rapidly diluted by airways surface liquid, there is no need to maintain the osmolality of this Formulation It a physiologically isotonic value or to maintain a physiological pH.

In a ninth aspect of the present invention, Formulation II does not need refrigeration once it has been dispensed to the patient.

In a tenth aspect of the present invention, Formulation II does not require inclusion of a preservative.

Claim 1 of 6 Claims

1. A sterile pharmaceutical composition comprising uridine 5'-triphosphate (UTP) in a sterile suspension with a concentration of UTP between 45 and 1000 mg/mL, a pH between 6.5 and 12; such that the composition is capable of delivering a therapeutic amount of UTP in a volume range of 10 to 100 .mu.L.

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