Stabilized oral pharmaceutical composition

Abstract

An orally deliverable pharmaceutical composition is provided comprising an aminosulfonyl-comprising drug, for example a selective cyclooxygenase-2 inhibitory drug such as celecoxib, and a solvent liquid comprising a polyethylene glycol and one or more free radical-scavenging antioxidants. At least a substantial part of the drug is in dissolved form in the solvent liquid. The composition has rapid-onset properties and is useful in treatment of cyclooxygenase-2 mediated conditions and disorders.

Description

[0001] This application claims priority of U.S. provisional patent application Ser. No. 60 / 284,589 filed on Apr. 17, 2001, and of U.S. provisional patent application Ser. No. 60 / 357,959 filed on Feb. 19, 2002.FIELD OF THE INVENTION [0002] The present invention relates to orally deliverable pharmaceutical compositions that comprise a drug of low water solubility, more particularly to such compositions where the drug is in dissolved form. BACKGROUND OF THE INVENTION [0003] Several compounds having a molecular structure that comprises an aminosulfonyl functional group (herein referred to as aminosulfonyl-comprising compounds) have been reported as having therapeutically and / or prophylactically useful selective cyclooxygenase-2 (COX-2) inhibitory effects, and have been disclosed as having utility in treatment or prevention of specific COX-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported...

AI Technical Summary

Benefits of technology

[0024] Compositions of the invention have been found to resolve the problem of drug instability in a surprisingly effective manner. Thus, for the first time, a poorly water-soluble drug that comprises an aminosulfonyl functional group, and / or is capable of reacting with a polyethylene glycol or polyethylene glycol degradation product to form an addition compound, is presented in a stable, concentrated solution formulation having a polyethylene glycol as a solvent. Preferably such formulations are presented in a dose form that is convenient for oral administration. Formulations of the invention are particularly advantageous because they are chemically stable, permit a high concentration of the drug, are suitable for encapsulation, and, following oral administration thereof, can permit rapid absorption of the drug into the bloodstream thereby providing rapid onset of therapeutic action.

[0025] It can be theorized that a poorly water-soluble drug can provide more rapid onset of therapeutic effect when orally administered in solution, particularly a self-emulsifiable solution, than in particulate form because the process of dissolution in the gastrointestinal tract is not required. An even greater advantage by comparison with a solid formulation such as a tablet can be postulated because neither disintegration nor dissolution is required in the case of the solution composition.

[0027] A further advantage of liquid dosage forms such as imbibable solutions and solution / suspensions for many subjects is that these dosage forms are easy to swallow. A yet further advantage of imbibable liquid dosage forms is that metering of doses is continuously variable, providing infinite dose flexibility. The benefits of ease of swallowing and dose flexibility are particularly advantageous for infants, children and the elderly.

[0028] When encapsulated, a solution or solution / suspension can provide the subject with the beneficial rapid absorption characteristics associated with liquid formulations in addition to the convenience of a discrete, easy to swallow capsule form.

[0029] The highly concentrated solutions permitted by the present invention are beneficial for several reasons. First, concentrated solutions are less costly to package and easier to transport and handle than dilute solutions. Second, concentrated solutions provide flexibility in administration as they can be administered with any desired degree of dilution. And third, concentrated drug solutions, especially when encapsulated, do not require consumption of large volumes of fluid, which can be uncomfortable for many patient populations.

Problems solved by technology

In addition, some, for example celecoxib, have relatively high dose requirements.

These properties present practical problems in formulating concentrated solutions of such drugs for rapid-onset, oral administration.

With respect to high dose, low solubility drugs, the size of the capsule or volume of solution required to provide a therapeutic dose becomes a limiting factor.

Such a volume can be inconvenient or unacceptable for consumption in imbibable form; this volume also presents particular problems where an encapsulated dosage form is desired because capsules that contain more than about 1.0 ml to about 1.5 ml of liquid are generally considered to be too large for comfortable swallowing.

Further, liquids that can easily migrate through a capsule wall, e.g., water in an amount greater than about 5% by weight of the solution, and low molecular weight water-soluble, volatile organic compounds such as alcohols, ketones, acids, amines and esters, are generally unsuitable for encapsulation.

However, we have now discovered that polyethylene glycol, when used as a solvent for an aminosulfonyl-comprising drug such as celecoxib, can result in drug instability.

This problem presents practical difficulties in forming a chemically stable solution of an aminosulfonyl-comprising drug using polyethylene glycol (which, as described above, can be otherwise advantageous) as a solvent.

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