United States Patent:  6,110,486

Assignee:  Flemington Pharmaceuticals Co. (Flemington, NJ)

Filed:  November 25, 1998

A buccal aerosol spray or capsule using a polar solvent has now been developed which provides biologically active compounds for rapid absorption through the oral mucosa, resulting in fast onset of effect. The buccal aerosol spray of the invention comprises: polar solvent 5-50%, active compound 1-40%, flavoring agent 0.05-5%. The soft bite gelatin capsule of the invention comprises as comprising as fill composition: polar solvent 75-99%, emulsifier 0-20%, active compound 0.03-35%, and flavoring agent 0.05-60%.

SUMMARY OF THE INVENTION

A buccal spray or soft bite gelatin capsule using a polar solvent has now been developed which provides biologically active com-pounds for rapid absorption through the oral mucosa, resulting in fast onset of effect.

The oral mucosal delivery using a spray was overlooked in the past, (1) because it was thought that the time available for absorption was very short because of the natural cleaning of the mouth by swallowing the saliva, and (2) it was thought that in the time available one could not have absorption of the total dose. As a result, most, if not all formulations under development for transmucosal transfer target the nose which is thought to have a longer residence time or use sustained release mechanisms such as patches, suckers, buccal tablets, etc. Using the formulation in the present application, the time available is longer than previously expected, in that it has been found that up to 30 minutes was available for the absorption phase, before clearance of the mouth reduced the concentration of the drug in the mouth thus slowing the absorption process.

Further, it has been found that while it is true that the total dose cannot be delivered to the blood through the oral mucosa in the time available, one does not have to deliver the entire dose through the mucosal membranes to achieve the fast onset. The fraction need to achieve therapeutic blood levels is only a small part of the total dose. This is in part due to by-passing the first pass effect of the liver and in part due to the delivery of the absorption of the drug from a solution directly into the blood, instead from the stomach-intestines using a tablet, which must first undergo dissolution before absorption can take place (FIG. 1).

The buccal spray compositions of the present invention, for transmucosal administration of a pharmacologically active compound soluble in a pharmacologically acceptable polar solvent comprising in weight % of total composition: polar solvent 75-99.8%, active compound 1-20%, suitably additionally comprising, by weight of total composition a flavoring agent 0.05-5%. Preferably the composition comprises: polar solvent 75-99%, active compound 1-20%, flavoring agent 0.1-2.5%; most suitably polar solvent 75-98%, active compound 1-12.5%, flavoring agent 0.1-2.5%.

The soft bite gelatin capsules of the present invention for transmucosal administration of a pharmacologically active compound, at least partially soluble in a pharmacologically acceptable polar solvent, having charged thereto a composition comprising in weight % of total composition: polar solvent 40-99.8%, emulsifier 0-20%, active compound 0.03-35%, provided that said composition contains less than 10% of water, suitably additionally comprising, by weight of the composition: flavoring agent 0.05-60%. Preferably, the soft bite gelatin capsule still comprises: polar solvent 50-99.8%, emulsifier 0-15%, active compound 0.03-26%, flavoring agent 0.5-55%; most suitably: polar solvent 70-99.5%, emulsifier 0-10%, active compound 0.15-24.0%, flavoring agent 0.1-50%. It is particularly desirable to formulate the gelatin portion of the capsule with a softening agent such as glycerine, sodium lauryl sulfate or the like to improve chewability and shelf life.

It is an object of the invention to coat the mucosal membranes either with extremely fine droplets of spray without the use of a propellant other than slightly compressed atmospheric air containing the active compounds, or a solution or paste thereof from bite capsules.

The spray compositions of the invention are intended to be administered from a pump spray by means of low level compression of atmospheric air.

It is also an object of the invention to administer to a mammalian need of same preferably man, a predetermined amount of a biologically active compound by this method or from a soft gelatin bite capsule.

A further object is a pump spray container containing a composition of the spray formulation, and a metered valve suitable for releasing from said container a predetermined amount of said composition.

The solvent is a low molecular weight, pharmacologically acceptable alcohol, water, glycerine or polyethylene glycol or mixtures thereof.

A further object is a soft gelatin bite capsule containing a composition as set forth above. The formulation may be in the form of a viscous solution or paste containing the active compounds. Although solutions are preferred, paste fills may also be used where the active compound is not soluble or only partially soluble in the solvent of choice. Where water is used to form part of the solvent or paste composition, it should not exceed 10% thereof. (All percentages herein are by weight unless otherwise indicated.)

The polar solvent is chosen such that it is compatible with the gelatin shell and the active compound. The solvent preferably dissolves the active compound. However, other components wherein the active compound is not soluble or only slightly soluble may be used and will form a paste fill.

Soft gelatin capsules are well known in the art. See, for example, U.S. Pat. No. 4,935,243, Borkan et al., which is incorporated herein by reference for its teaching of such capsules. The capsules of the present invention are intended to be bitten into to release the high viscosity solution or paste therein, which will then coat the buccal mucosa with the active compounds. Typical capsules, which are swallowed whole or bitten and then swallowed, deliver the active compounds the stomach, which results in significant lag time before maximum blood levels can be achieved or subject the compound to a large first pass effect. Because of the enhanced absorption of the compounds through the oral mucosa and no chance of a first pass effect, use of the bite capsules of the invention will eliminate much of the lag time, resulting in hastened onset of biological effect. The shell of a soft gelatin capsule of the invention may comprise, for example: gelatine 50-75%, glycerine 20-30%, colorants 0.5-1.5%, water 5-10%, and sorbitol 2-10%.

Claim 1 of 9 Claims

1. A method of administering an effective amount of a pharmacologically active compound to a mammal in needed of same, by spraying the oral mucosa of said mammal with a buccal spray composition, formulated for dispensation from a pump spray means for transmucosal administration of said pharmacologically active compound dissolved in a pharmacologically acceptable polar solvent, comprising in weight % of total composition: polar solvent 75-99.8%, active compound 0.68-40% wherein the active compound is selected from the group consisting of non-steroidal anti-inflammatories, anti-histamines, steroid hormones, benzo-diazepams, and anti-depressants.

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