Taste masked pharmaceutical liquid formulations

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

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Details

C514S230200, C424S489000, C424S497000, C424S494000

Reexamination Certificate

active

06482823

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to oral pharmaceutical liquid formulations which effectively mask the unpleasant taste of pharmaceuticals or nutritional supplements with bitter or otherwise undesirable taste characteristics. More specifically, the invention relates to liquid suspensions of reverse enteric polymer coated dosage forms that mask the unpleasant taste of the active agent. The liquid suspensions may be swallowed without producing a bitter taste in the mouth, but the coated agent is immediately bioavailable upon exposure to the pH levels found in the stomach.
BACKGROUND OF THE INVENTION
Medicaments can be administered to the patient in many forms with oral administration being the most popular. Medicaments can be given to the patient orally as liquid solutions, emulsions, or suspensions, or in solid form such as capsules or tablets. Infants, children, older persons, and many other persons are unable to swallow whole tablets and capsules. Therefore, in cases where the dosage to be administered cannot be made into a very small tablet or capsule, it is desirable to provide the medicine in liquid or chewable form.
Many active ingredients, such as antibiotics, possess a strong, unpleasant taste. When a medicament is formulated as a tablet or capsule intended to be swallowed whole, the taste of the active ingredient is usually not an issue since the capsule keeps the active ingredient from contacting the mouth and the tablet can be coated to prevent contact of the active with the mouth for the short time the tablet is present in the mouth. In contrast, masking of the unpleasant taste characteristics of the active agent is an extremely important factor in the formulation of liquid and chewable pharmaceuticals. The palatability of the liquid or chewable dosage form is a critical factor in ensuring patient compliance.
In some cases, the unpleasant taste of the active medicament in a liquid or chewable formulation can be overpowered by adding flavoring ingredients and sweeteners to improve taste and palatability. However, where the active medicament possesses a particularly strong or bitter taste, such as is the case with many antibiotics, the mere addition of such flavoring ingredients and sweeteners is insufficient to improve taste and palatability. Accordingly, various taste masked coating compositions have been employed in the formulation of liquid suspension and chewable tablet dosage forms.
U.S. Pat. No. 5,599,556 discloses liquid formulations where the active ingredient is coated with a single outer polymeric coating derived from prolamine cereal grain proteins and a plasticizing agent. The coatings are designed to rapidly degrade once the composition leaves the mouth.
U.S. Pat. No. 5,489,436 discloses chewable tablets made from a coated medicament where the coating is a “reverse enteric coating” designed to be soluble at the lower pH of the stomach but relatively water insoluble at the higher pH's of the mouth. The coatings are comprised of a polymer blend of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester.
While the above mentioned reverse enteric coating method of taste masking oral formulations are disclosed in connection with chewable tablets, there is no disclosure of their use in a liquid formulation, where the taste masking coating will need to survive in an aqueous environment for an extended period. There is thus a need for a taste masking formulation suitable for an aqueous liquid suspension which is stable and retains its taste masking properties in the aqueous environment over an extended period, yet which exhibits immediate bioavailability after swallowing and ingestion.
SUMMARY OF THE INVENTION
The present invention provides a liquid composition for oral administration comprising a pharmaceutically active medicament coated with a taste masking effective amount of a polymer blend of (a) dimethylaminoethyl methacrylate and neutral methacrylic acid ester (MM/MAE) and (b) a cellulose ester, in an aqueous vehicle, wherein the polymer weight ratio of the cellulose ester to the MM/MAE is about 40:60 to about 90:10, preferably about 60:40. The liquid composition utilizes a “reverse enteric coating” which is soluble in the acid pH's of the stomach, generally about 1.0 to 4.0, but relatively insoluble at the non-acidic pH's of the mouth. The coatings provide for rapid release and absorption of the drug, which is generally desirable in the case of liquid dosage forms.
In preferred embodiments the active medicament useful in the taste masked liquid formulations of the present invention are antibiotic drugs, particularly levofloxacin, ofloxacin and related quinolone antibiotics, as well as other known antibiotics which have an unpleasant taste and are formulated for oral liquid administration like cephalosporins, macrolide antibiotics, penicillins and the like. Other active medicaments which may be beneficially employed in the liquid compositions of the invention include analgesic drugs, such as tramadol or codeine, anti-inflammatory drugs such as ibuprofen, naproxen and other NSAID's. Other active agents which for which the liquid compositions of the invention may be employed include gastrointestinal drugs, antihistamines, decongestants, anti-depressants, anti-psychotics, antivirals, oncolytics, vaccines, antiepileptics (e.g. topiramate), anti-asthma compounds, antispasmodics, and the like.
In accordance with the invention, the particles of active medicament are generally spray coated with the polymer coating either directly or after granulation, and then the coated particles are admixed with other pharmaceutically acceptable additives such as sweeteners, flavorings and the like in an aqueous liquid vehicle for oral administration.
The invention also relates to a method of taste masking medicaments for oral liquid administration by utilizing the coating compositions of the invention.
DETAILED DESCRIPTION
The invention relates in particular to taste masked liquid preparations for oral administration comprising a pharmaceutically active medicament having an unpleasant taste which is coated with a reverse enteric coating. Reverse enteric coatings are those which are not water soluble at non-acidic pH's as are present in the mouth, but are soluble in the acid pH levels of the stomach. The coatings provide a protective layer which masks the unpleasant taste characteristics of the active ingredient in the mouth because of its low solubility therein but are readily soluble in the stomach and therefore provide immediate release of the active medicament in the stomach. The reverse enteric coatings encapsulate the active ingredient and thereby effectively and stably mask the taste of the active medicament.
In accordance with the invention, there is provided an orally consumable liquid composition comprising a pharmaceutically active agent in particle form contained in a liquid suspension having a pH greater than about 6.0, each particle comprising a core of pharmaceutically active agent, optionally associated with inactive pharmaceutical adjuvants; the core being coated with a taste masking effective amount of a polymer blend of (a) dimethylaminoethyl methacrylate and neutral methacrylic acid ester (MM/MAE) and (b) a cellulose ester, in an aqueous vehicle, wherein the polymer weight ratio of the cellulose ester to the MM/MAE is about 60:40 to about 70:30, preferably about 60:40. In a preferred embodiment, the formulation is prepared as a dry powder which is reconstituted with water to form the liquid compositions of the invention.
The details of the polymer blend used for the coatings and the coating techniques are described in U.S. Pat. No. 5,489,436, hereby incorporated by reference into the present application. In general, the cellulose acetate component, the solubility of which is pH independent, and the MM/MAE component, the solubility of which is pH dependent, are mixed in a ratio which provides the desired diffusion characteristics. The diffusion and solubility of the coating depends on the

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