Title:  Use of inhaled retinoids in the prevention of cancer

United States Patent:  6,251,941

Assignee:  Sloan-Kettering Institute for Cancer Research (New York, NY)

Filed:  December 29, 1998

PCT NO:  PCT/US97/05409

102(e) Date:  December 29, 1998

PCT PUB. Date:  October 30, 1997

Administration of retinoids by inhalation is used to overcome the chronic toxicity problems presented by systemic administration and to make retinoid therapy available as an option for the prevention of epithelial cancers of the respiratory tract, especially those that are associated with tobacco use. Retinoids are administered by inhalation to the respiratory tract of the individual as an air-borne composition with a metered dose aerosol-producing inhaler, in which the retinoid is dissolved in a combination of a pharmaceutically acceptable chlorofluorocarbon propellant and an alkylamine solubilizing agent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the prevention of epithelial cancer of the respiratory tract in an at-risk individual by administering by inhalation to the respiratory tract of the individual an aerosol comprising a therapeutically effective amount of at least one retinoid. The method provides delivery of the pharmaceutically active retinoid directly to the affected areas, thus increasing bioavailability and decreasing systemic toxicity. It will be recognized by persons skilled in the art that "prevention" of cancer is difficult to prove in the absolute sense because one cannot predict with certitude what will transpire in the future. Thus, as used in the specification and claims of this application, the terms "prevention" or "preventing" refer to a reduction of the risk of contracting epithelial cancer, or to a delay in the onset of epithelial cancer.

Inhalation of pharmaceutically-active compositions is not a new concept, and various compounds used in asthma therapy and the like have been administered in this manner. Commonly, however, such aerosols are formed from the active compounds solubilized in water. However, most retinoids of clinical interest, including all of the "natural retinoids" such as all-trans retinoic acid, 13-cis retinoic acid and 9-cis retinoic acid, are highly lipophilic and thus very insoluble in water. For this reason, conventional water-based formulations cannot be used for aerosol administration of these compounds. To make it possible to perform inhalation therapy using retinoids, it was therefore necessary to define a solvent system which (1) solubilized sufficient amounts of the retinoids to provide a pharmaceutically-useful dosage, i.e. from about 0.1 to 5.0 mg/ml; (2) provided a retinoid solution of sufficient stability to permit distribution of a product; and (3) was substantially non-toxic in the amounts administered and thus suitable for administration to living patients.

Working towards this goal, we first looked at organic solvents. In the course of this investigation, we found that retinoids were only slightly soluble in ethanol or ethyl acetate. Methylene chloride or chloroform provided adequate solubilization, but the potential toxicity of these materials argued against their use as carriers in an aerosol for use in inhalation therapy.

Next, because of a report that the solubility of retinol (vitamin A) in water could be increased by addition of modified beta cyclodextrin (MOLECUSOL.RTM.), we next tried to prepare aqueous solutions of all-trans retinoic acid using MOLECUSOL.RTM. to enhance the solubility. Solutions containing 45% MOLECUSOL.RTM. did in fact enhance the solubility of the all-trans retinoic acid to a useful level, but the resulting solution had a thick, syrupy consistency which was unsuited for use in the generation of an aerosol. Similarly, efforts to solubilize all-trans retinoic acid in aqueous solution using phosphatidylcholine and phosphatidylethanolamine produced a viscous colloid which was unsuited for aerosol administration.

We next tried to use salts of the retinoids to obtain a water-soluble product for aerosol generation. When all-trans retinoic acid is treated with ammonium hydroxide, a water-soluble ammonium salt is obtained. The pH of solutions of this salt is too high (pH>10). however, for direct administration as an aerosol. Neutralization of the solution after dissolution of the retinoid led to the formation of a precipitate, both in the presence and absence of added beta cyclodextrin. Thus, the approach also failed to produce an acceptable solution for use in generating an aerosol.

Because of the solubility of all-trans retinoic acid in halogenated hydrocarbon solvents, we next considered the solubility of retinoids in various chlorofluorocarbon propellants which have been used to deliver aerosolized solutions of other pharmaceutically-active compounds. All-trans retinoic acid was found to be only slightly soluble (about 0.1 mg/ml) in 1,1,2-trichlorofluoroethane and only slightly more soluble (2 mg/ml) in 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123). Thus, as an initial matter, it did not appear that these solvents would be useful for producing useful solutions of retinoids for inhalation use.

Surprisingly, however, we found that the solubility of retinoids in chlorofluorocarbon solvents could be significantly increased by the addition of alkylamines, particularly secondary, tertiary and quaternary alkylamines having alkyl groups containing from 2 to 8 carbon atoms such as trioctylamine, spermine, triethylamine or tetramethylammonium bromide, and that the resulting solutions were stable for periods of 5 days or longer, and can be solubilized by shaking. Thus, one aspect of the present invention is a solution comprising a retinoid, a chlorofluorocarbon solvent, for example HCFC-123, HCFC-134A or HCFC-227, and an alkylamine which is effective to solubilize the retinoid in the chlorofluorocarbon solvent. The solution preferably contains from 0.1 to 10 mg of the retinoid and 0.1 to 5 mg of the alkylamine, more preferably to 2 mg of the retinoid and 0.1 to 0.5 mg of the alkylamine, per ml of solution.

Retinoids useful in the present invention include the "natural retinoids" as well as pharmaceutically acceptable salts and esters thereof. Retinoids of particular interest in the present invention are all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, and salts and esters thereof.

The alkylamine is suitably a charged or uncharged secondary, tertiary or quaternary amine, having alkyl groups of 2 to 8 carbon atoms. Specific examples of suitable alkylamines include trioctylamine, triethylamine, spermine and tetrabutylammonium bromide.

This solution is packaged in an inhaler effective to provide a metered dosage of from 50 to 500 .mu.g, preferably about 100 .mu.g, of retinoid per inhalation as shown generally in FIG. 2. Such an inhaler is a combination of a container 1 and a dispenser assembly 2. The dispenser assembly 2 is an open tubular construction which has an actuator portion 3 for receiving the container 1, an oral tube 4 through which the retinoid is dispensed, and an actuator seat 5 which interacts with a metering valve 6 of the container 1. When the container 1 is pressed downwards within the actuator portion 3, the actuator seat 5 opens the metering valve 6, releasing a dose of retinoid 7 from the container 1, through an orifice 8 in the actuator seat 5 and out through the oral tube 4. A suitable inhaler is a Nasacort.RTM. metered dose container. Additional propellant material, for example butane, may be included within the inhaler.

The inhaler is used to administer retinoids directly to the lungs of a patient at risk of epithelial cancer of the respiratory tract. Patients in this category can be identified by behavioral characteristics. For example, individuals who are heavy smokers can be categorized as being at high-risk. Alternatively, a more quantitative approach may be used. Thus, the capacity to metabolize a small test dose of all-trans retinoic acid can be used as an indicator of risk, as described in U.S. patent application Ser. No. 07/885,130 filed May 18, 1992, which is incorporated herein by reference.

The inhaler provides dosages of from 50 to 500 .mu.g of retinoid per inhalation and is suitably used 1 to 5 times per treatment, with the treatment being repeated 1 to 3 times per day.

A further format which can be used in accordance with the invention to administer an air-borne composition comprising a retinoid to an individual involves the use of a dry powder carrier. Suitable carriers include those which are known to be useful in dry powder inhaler compositions especially the mono-saccharides such as fructose mannitol, arabinose, xylitol and dextrose (glucose) and their monohydrates, disaccharides such as lactose maltose or sucrose and polysaccharides such as starches, dextrins or dextrans. Retinoids can be formulated into a dry powder with these carrier materials by coating the retinoid onto the surface of the carrier in a micronizer as described generally in U.S. Pat. No. 5,376,386 which is incorporated herein by reference. Dry powders containing retinoids are dispensed using known dry powder inhalers in amounts effective to provide dosages comparable to the solubilized formulations discussed above.

Claim 1 of 22 Claims

What is claimed is:

1. A solution comprising

a retinoid,

a chlorofluorocarbon solvent, and

an alkylamine which is effective to solubilize the retinoid in the chlorofluorocarbon solvent.

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