Title:  Single-dose antihistamine/decongestant formulations for treating rhinitis

United States Patent:  6,521,254

Issued:  February 18, 2003

Inventors:  Weinstein; Robert E. (Boston, MA); Weinstein; Allan M. (Potomac, MD)

Assignee:  J-Med Pharmaceuticals, Inc. (Boston, MA)

Appl. No.:  757852

Filed:  January 10, 2001

Pharmaceutical dosage forms for oral administration of an antihistamine and a decongestant are disclosed. The dosage forms provide an antihistamine in an amount and formulation to exhibit antihistaminic activity in a human for greater than 22 hours; and a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours. The formulation of the invention can be taken once per day to afford symptomatic relief of rhinitis while avoiding stimulation at night.

DETAILED DESCRIPTION OF THE INVENTION

The single dosage unit of the present invention for treating the symptoms of rhinitis contains a combination of medications that include nasal decongestants and antihistamines. The dosage unit may be in the form of a tablet, pill, capsule, caplet, or other recognized oral form of medication. The dosage unit contains a sedating or non-sedating antihistamine, and the components are formulated so as to produce the pharmacokinetic and therapeutic characteristics desired. The preparation such formulations employs techniques well-known in the art.

Preferred decongestants are pseudoephedrine and phenylpropanolamine. To achieve the desired release profile, the pseudoephedrine is usually present in an amount of 120 mg or less for embodiments that exhibit stimulatory and/or decongesting activity in a human for less than 16 hours. When decongesting activity beyond 16 hours is desired, an amount of 120 mg to 160 mg of pseudoephedrine is formulated for non-linear release, so that up to 120 mg is released within 12 hours of administration, a discontinuity of release occurs between 12 and 16 hours and the remainder is released after the discontinuity, i.e. beyond 12 hours. To achieve the desired release profile, the phenylpropanolamine is usually present in an amount of 75 mg or less for embodiments that exhibit stimulatory and/or decongesting activity in a human for less than 16 hours. When decongesting activity beyond 16 hours is desired, an amount of 75 mg to 100 mg of phenylpropanolamine is formulated for non-linear release, so that up to 75 mg is released within 12 hours of administration, a discontinuity of release occurs between 12 and 16 hours and the remainder is released after the discontinuity. Oral sustained release drug delivery systems are well known to those skilled in the art, and general methods of achieving sustained release of orally administered drugs are found in any standard pharmacy school textbook, for example Remington: The Science and Practice of Pharmacy. Chapter 94 of the 19th edition of Remington entitled "Sustained-Release Drug Delivery Systems" describes the more common types of oral sustained-release dosage forms (pages 1660-1675.) The disclosure is incorporated herein by reference. To obtain a discontinuity of release, when that is desired, one would normally formulate a portion of the decongestant in a sustained-release formulation and another portion in a delayed-release formulation. For example, one may prepare one set of granules of pseudoephedrine for immediate release, another set of granules of pseudoephedrine with hardened gelatin, methyl or ethyl cellulose, polyhydroxymethacrylate, or hydroxypropylcellulose for sustained release and, when a lower serum concentration beyond 12 hours is desired, a third set of granules of pseudoephedrine coated with an acrylic resin, such as an EUDRAGIT.TM. resin, for delayed release. The various types of pseudoephedrine granules are then mixed in appropriate proportion for the desired release profile and filled into gelatin capsules with the antihistamine.

Preferred antihistamines include loratidine, descarboethoxyloratidine, cetirizine, astemizole, norastemizole and fexofenadine. The loratidine, astemizole and norastemizole are preferably in an amount of 10 mg or more. The cetirizine and descarboethoxyloratidine are preferably in an amount of 5 mg or more. The fexofenadine is preferably in an amount of 120 mg or more.

The duration of antihistaminic activity of a particular formulation in a human may be measured most readily by the well-known wheal-and-flare test, but the use of a "Vienna Challenge Chamber" as described by Hayrack et al. [Arzneim.-Forsch. 46, 1077-1081 (1996); Klin. Wochenschr. 14, 509 (1987) and J. Int. Med. Res. 20, 422 (1992)] provides a measure that is presumably closer to the clinical situation for rhinitis. In the United States, the Food and Drug Administration (FDA) must approve a drug for the therapeutic efficacy and safety before it can be marketed, and approve the labeling for its recommended dosing. Antihistamines which have met the FDA standard of having a duration of therapeutic benefit suitable for 24 hour dosing and which are so labeled are: cetirizine 5 mg; cetirizine 10 mg; loratidine 10 mg; and fexofenadine 180 mg. The duration of decongestant activity can be measured as described by Empey et al. Br. J. Clin. Pharmacol. 9, 351-358 (1980) for nasal airway resistance. The duration of stimulatory activity of the decongestant may be evaluated by observing pulse rate elevation [also described by Empey et al. Br. J. clin. Pharmacol. 9, 351-358 (1980) and by Dickerson et al. Europ. J. clin. Pharmacol. 14, 253-259 (1978)] or by observing EEG activity as described by Rombaut et al. Med. Sci. Res. 17, 831-833 (1989). The disclosures of these references are incorporated herein by reference.

The terms "day" and "night" as used herein are intended to be synonymous with the period of wakefulness, when stimulation might be acceptable, and the period of sleeping, when stimulation would be undesired, respectively. Such times vary in accordance with the schedule of individuals.

Examples of the single dosage units of the present invention include:

EXAMPLE 1

A single dosage unit consisting of 120 mg pseudoephedrine, a stimulating decongestant, prepared so as to be released over a 10-12 hour time, and 10 mg loratidine, a non-sedating antihistamine, formulated so as to be released immediately. When taken at the start of the day (a time anticipating a desire to be awake for 12 to 16 hours), this dosage unit provides immediate dosing with loratidine, which is known to exert an antihistaminic effect 1 to 3 hours after dosing, reach a maximum at 8 to 12 hours, and last in excess of 24 hours. Once released, pseudoephedrine has a 4 to 6 hour half-life, considerably shorter than that of loratidine. The comparatively short decongestant effect of pseudoephedrine is extended by a sustained release formulation. This dosage unit provides both immediate and delayed action of pseudoephedrine, so as to exert a decongestant effect during waking hours, when the stimulation of pseudoephedrine is best tolerated, but not at night. One such time-release method, well-known in the art, involves formulation of the decongestant with cellulose ether base materials, such as hydroxypropyl methylcellulose. Such time-release methods may be utilized to delay the bioavailability of all or only a portion of the ingested dose, and for varying lengths of time. The antihistamine and decongestant components of this formulation are similar to that of CLARITIN-D.RTM. 24-HOUR Extended-Release Tablets which contain 10 mg loratidine (antihistamine) and 240 mg pseudoephedrine hydrochloride (decongestant), and which are recommended to be taken every 24 hours in adults. The present invention formulation differs, however, in that it contains a lesser dose of pseudoephedrine, and that it limits the duration of action of pseudoephedrine to 12-16 hours, thus avoiding the stimulation of pseudoephedrine at night.

EXAMPLE 2

A single dosage unit consisting of 75 mg phenylpropanolamine, a stimulating decongestant, prepared so as to be released over a 10-hour time period, and 10 mg cetirizine, a non-sedating antihistamine, prepared so as to be released immediately. When taken at the start of the day, this formulation provides immediate dosing with cetirizine, which is known to exert an antihistaminic effect within one hour after dosing and to persist for 24 hours. This formulation also preferably provides immediate and delayed action of phenylpropanolamine over a period not to exceed 16 hours after administration so as to exert effect during daytime hours, when stimulation is best tolerated, but exerts no effect at night. Like pseudoephedrine, the comparatively short half-life and decongestant effect of phenylpropanolamine are prolonged in this formulation by incorporating a prolonged release of phenylpropanolamine over time so as to achieve efficacy through the waking hours, but not so long as to provide phenylpropanolamine activity during the time when stimulation is undesired.

EXAMPLE 3

A single dosage unit consisting of 75 mg pseudoephedrine, a stimulating decongestant prepared so as to be released over a 10-hour time period, and 120 mg of fexofenadine, a non-sedating antihistamine, formulated so as to be active over a 24-hour period. Fexofenadine, when given alone, exhibits antihistaminic effect within one hour, achieves a maximum effect at 12 hours, and still has a measurable effect at 24 hours. This formulation provides immediate and delayed activity of fexofenadine over a 24-hour span and of pseudoephedrine over a period not in excess of 16 hours after administration.

EXAMPLE 4

A once-per-morning dosage, in syrup form, consisting of 5 mg cetirizine (immediate release), and 30 mg of pseudoephedrine (immediate release). This dosage contains a quantity of cetirizine which provides a therapeutic antihistaminic therapeutic benefit for 24 hours. The pseudoephedrine, immediately released, results in a 4-6 hour duration of action during the early part of the day. The formulation would be particularly appropriate for children from ages 6-11, as it is in liquid form, and it has decongestant action early in the day, during school hours. This timing would accomplish decongestant action at a time when symptoms often peak, and when such action is needed. It is noted that cetirizine is associated with slightly more sedation than other non-sedating antihistamines but not as great as sedating antihistamines. In those individuals who experience sedation with cetirizine, the simulation of decongestant, during initial absorption, when blood levels of cetirizine peak, might be desirable. This dosage would not cause stimulation later in the day at more sedentary times or interfere with sleep at night. Individuals differ in their susceptibility to the stimulatory side effects of decongestants, and this dosage regimen might also be particularly suitable for an adult individual who is sensitive to decongestant side effects, but who can tolerate a short period of stimulation early in the day.

In addition to antihistamines and decongestants, additional therapeutic ingredients for the treatment of rhinitis may be formulated if desired. For example, leukotriene inhibitors and analgesics such as salicylates and acetaminophen may be considered for inclusion in such dosage units and are within the scope of this invention. These examples do not constitute an exhaustive list of potential combinations, and variations and modifications may be made by those of ordinary skill in the art. Those of skill in the art may also recognize modifications to these presently disclosed embodiments. One such modification might involve a time-release of decongestant over periods other than those exemplified, but not so as to allow stimulation at night. These variations and modifications are meant to be covered by the spirit and scope of the present claims.

Claim 1 of 23 Claims

We claim:

1. An oral dosage unit consisting essentially of:

(a) an antihistamine in an amount and formulation to exhibit antihistaminic activity in a human for greater than 22 hours; and

(b) a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours.
 

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