Field of the Invention

The present invention relates generally to allergy and sinus medications that provide relief to sufferers with blocked sinuses, itchy, watery eyes, headache and other allergic symptoms.

Background of the Invention

Cold and allergy sufferers must endure days and even weeks of congested sinuses, itchy, watery eyes, headache and swollen ear and throat passageways. Diphenhydramine hydrochloride (2-diphenylmethoxy-N _! N-dimethylethanamine hydrochloride) has been widely used over the years as an antihistamine which provides relief of these symptoms by blocking the action of histamines, the allergic response in the body. The problem that arises however, is that many who take diphenhydramine for relief of the allergic symptoms report that the antihistamine also causes a drowsiness and lethargic effect. Obviously, this side effect of the drug is not desirable during daytime or waking hours.

It is an object of the present invention then, to provide an effective allergy and cold medication that does not also cause the user to become drowsy or lethargic. An antihistamine such as diphenhydramine is combined with a stimulant such as theophylline or caffeine which counteracts the drugs' inherent lethargic effects. Whereas both compounds when administered do not peak at the same time with respect to causal effect, the stimulant is formulated as a delayed, sustained release composition so that its effect will coincide with the onset of lethargy that accompanies the systemic relief afforded by the antihistamine.

United States Patent No. 4,466,960 to Silverman et. al. discloses a pharmaceutical composition designed for the relief of pre-menstrual syndrome (PMS) . An antihistamine such as diphenhydramine is combined with an analgesic such as acetaminophen, caffeine and an ammonium salt diuretic such as pyrilamine maleate. The antihistamine assertedly relieves cramping and backache while the acetaminophen relives headache and other assorted pains. Caffeine, a central nervous stimulant, is incorporated to relieve fatigue and lethargy that accompanies PMS and admittedly counteracts the sedative effect of the antihistamine. The diuretic helps relieve bloating and water retention that also accompany PMS.

United States Patent No. 5,011,688 to Calam et. al. discloses and claims a liquid composition for the relief of premenstrual and menstrual discomfort comprising an effective amount of an analgesic such as aspirin or acetaminophen, an antihistamine such as pyrilamine maleate and a diuretic such as caffeine or ammonium chloride. The advantage of the composition is the taste masking of the bitter actives using alcohol, citrus, vanilla or mint.

Caffeine and diphenhydramine have also been combined as an anti-travel sickness drug known as kaffinautin sold in Scandanavia. It is well documented that the composition is widely abused since it often produces a stimulating euphoria which unfortunately can result in transitory psychotic symptoms.

There is nothing in the prior art however, that suggests the combination of caffeine and an antihistamine to produce a non-sedating cold and allergy medication. Moreover, whereas antihistamine/caffeine formulations have been suggested, there is no disclosure or teaching of the combination as a cold/allergy medication wherein the stimulant effects of the caffeine and the drowsiness effects of the antihistamine temporarily coincide to

negate each other. There is certainly no suggestion that the pharmacological effects of each peak at different time and means to consider the two.

Summary of the Invention

A non-sedating, non-drowsy sinus and allergy medication allows for the relief from cold, hay fever and other sinus congestion symptoms without the inherent side effects of lethargy and drowsiness that can affect ones functions when taking this drug. An antihistamine such as diphenhydramine hydrochloride is combined with a sustained release, encapsulated caffeine composition that is released and absorbed by the body at the same time as the antihistamine. This results in simultaneous drug interaction whereby the central nervous system depression caused by the antihistamine is offset by the central nervous system stimulation caused by the caffeine. Hence, relief is afforded with minimal side effects.

Detailed Description of the Invention

The mere combination of caffeine together with an antihistamine such as diphenhydramine hydrochloride without more will not prevent the onset of lethargy and drowsiness brought on by the actives' side effects. The reason for this is since the two are absorbed at different rates into the bloodstream and/or are metabolized at different rates, the times for each of the compounds peak activities are different and there is no central nervous system stimulation at the time of antihistaminic action. There is a need therefore to regulate the activity of the two so that both are acting at their peak pharmacological activities simultaneously.

Another component of most allergy/sinus medications that heightens or adds to the lethargic, drowsy effects is the use of alcohol as a solvent for the actives and

additives. Alcohol may comprise up to from about 25% to about 30% w/v of the composition and at the higher levels may certainly depress central nervous system function. The caffeine then must be formulated in such a way that it's release is not only delayed and timed so as to provide stimulation upon onset of the antihistaminic effect but also in a sustained and delayed manner so as to offset and combat the more long term effects of the alcohol.

Caffeine, (1,3,7-trimethyll xanthine) is an odorless, bitter tasting compound that is a well known central nervous system stimulant that has been useful as both a cardiac and respiratory stimulant as well as a diuretic. The t _max for any given active compound is the time that the compound takes from administration or absorption to the time when its concentration in the blood plasma is at a maximum; i.e., the time at which the effect of the drug in the system is at its greatest. Whereas the t _max for caffeine is 42 minutes, the tmax for diphenhydramine hydrochloride is 102 minutes. In order to reduce the lethargic effects of the diphenhydramine, these t _max values must be equalized. Whereas the t _maχ of diphenhydramine will not easily be lowered, it was surprisingly found that the t _max value for caffeine can be increased so that the desired pharmacological effect would be obtained.

Delayed and sustained release of the caffeine was obtained through the encapsulation of the drug using natural and artificial gums such as xanthan and guar gum, water soluble polymers, acrylic resin, acrylic acid polymers such as Carbopol AP (B.F. Goodrich Co.) polysaccharides, polyesters, waxes such as carnauba wax and mixtures thereof. More specifically, these compounds include cellulose polymers such as hydroxypropyl cellulose (HPC), methyl cellulose (MC) hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxy

cellulose, ethyl cellulose, celulose acetate, sodium carboxymethyl cellulose, sodium cross carmellose, and the like. Other suitable coating agents include polyvinyl pyrrolidone, polyethylene oxides, polyethylene glycols and mixtures thereof. Preferably, formulations of the present invention will comprise diphenhydramine hydrochloride in amounts of from about 25 mg. to about 75 mg. per dose, more preferably from about 40 mg. to about 60 mg. per dose and most preferably, about 50 mg./dose. Caffeine is employed in the formulations in amounts of from about 100 mg. to about 300 mg./dose, preferably, from about 150 mg. to about 250 mg./dose and most preferably about 200 mg. per dose.

The preferred formulation of the present invention that insures that both the caffeine and the diphenhydramine hydrochloride possess the same or similar t _max values comprises a sustained release core containing the caffeine and an immediate release coating thereon containing the diphenhydramine. The core is comprised of caffeine in an amount of from approximately 100 mg./tablet to about 300 mg./tablet combined with a food grade polymer such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, cellulose acetate, cellulose ethers, microcrystalline cellulose and mixtures thereof. Standard tabletting materials known in the art such as magnesium stearate, silicon dioxide and the like are added so that a defined core is made.

Diphenhydramine hydrochloride is then mixed in an aqueous solution of a film-forming agent such as Opadry®, a polyvinyl chloride polymer. Also useful as film-forming agents are polyvinyl pyrrolidone, polyvinyl acetate, polyethylene glycol, polypropylene, polyethylene, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof. The antihistamine and film forming agent are combined on a 1:1 weight ratio but

SUBSTITUTESHEET(RULE25)

ratios outside this range are certainly possible, this is merely the preferred ratio. Fifty mgs.. of antihistamine may be mixed with 50 mg. film forming agent in water and this may be applied as a coating to the caffeine core by any one of the many coating procedures known in the art including spray drying, pan coating, condensation and the like. The coating is dried about the core removing the water and solidifying the drug/film-former coating thereon.

Caffeine then, will comprise from about 3% to about 90% by weight of the entire formulation and preferably from approximately 20% to about 70%. The sustained release agent core material such as hydroxypropyl methyl cellulose will comprise from about 10% to about 30% by weight of the formulation and preferably about 20% thereof. The diphenhydramine hydrochloride will comprise from approximately 1% to about 40% by weight and preferably from about 3% to about 20% thereof. The water soluble film forming polymer will comprise from about 3% to about 30% and preferably from about 10% to 20% by weight of the total weight of the formulation. Bulking agents such as macrocrystalline cellulose, tableting agents such as colloidal silicon dioxide and lubricants such as magnesium stearate may be added in deminimus amounts of from about 0.1 to 2.0% by weight as is known in the art.

The non-drowsy, non-sedating sinus and allergy medications of the present invention can also be dosed in one of several possible embodiments. On the one hand, the composition can be formulated as a two layer tablet with the caffeine encapsulated or uniformly distributed in the polymer matrix as one layer and the diphenhydramine in the other immediate release layer. The release of each active can be coordinated depending on the encapsulant and the amount thereof used. The medication can also be dosed as a

spanule capsule delivery system whereby the caffeine is granulated, coated and formed into spanules which are then mixed with uncoated spanules of diphenhydramine. The two are then maintained in a gelatin type capsule.

The following examples are provided to more fully describe and set forth that which applicants deem their invention to be. They are provided for illustrative purposes only and it is recognized that many minor variations and modifications are possible which cannot possibly be fully disclosed herein. It is to be understood that such variations are still considered to fall within the spirit and scope of the present invention as recited by the claims that follows:

Example 1

The following ingredients were collected in their respective amounts.

Ingredient Amount per Tablet (mg)

Core:

Caffeine 200.0

Hydroxypropyl Methylcellulose 80.0

Microcrystalline Cellulose 116.8

Colloidal Silicon Dioxide 1.2

Magnesium Stearate 2.0

Coat:

Diphenhydramine HC1 50.0

Opadry 50.0

Total 500.0 mg

The caffeine, hydroxypropyl methylcellulose and microcrystalline cellulose were slowly mixed together as dry powders until completely blended. To this was added the tabletting agents colloidal silicon dioxide and magnesium stearate. The mixture was then tabletted into specific 500 mg. tablets.

The caffeine core was then coated with an aqueous solution of the diphenhydramine hydrochloride and the film forming agent using a spray drying chamber as is known in the art. The finished tablets are then collected and

bottled.

The release profiles of diphenhydramine hydrochloride (DPH) and caffeine were evaluated using USP XXII dissolution method 1 at a rotating speed of 100 rpm. Nine hundred milliliters of water maintained at 37°C was used as dissolution medium. The results are summarized as follows:

% Dissolved (based on labelled amount) Time (minutes) DPH Caffeine

10 55 0

20 84 4

30 93 13

40 94 24

50 95 36

60 95 47

70 57

80 67

90 75

100 82

110 88

120 93

130 97

The release rate of caffeine was calculated at ^" 1.82 mg/min. (lag time = 20 minutes) which is very close to the target (2 mg/min.) for diphenhydramine HCl, particularly if experimental errors and formulation variability are taken into consideration.

Example 2

Using the process and ingredients set forth in Example 1 the following dose formulations were prepared. Amounts shown are per tablet.

1. 25 mg. diphenhydramine HCl (DPH) and 200 mg. caffeine

2. 25 mg. DPH and 30 mg. caffeine.

3. 50 mg. DPH and 200 mg. caffeine.

4. 25 mg. DPH

5. 50 mg. DPH

6. Placebo

Seventy-eight ( 78 ) human subjects suffering from

sinus and/or allergy symptoms were given one or several of the above dosage forms and observed for the onset of lethargy and/or drowsiness and for symptomatic relief afforded. Under the conditions employed, the 20 mg. diphenhydramine dose either with or without caffeine showed no significant difference in drowsiness effect and relief from the double placebo. The fifty (50) mg. dose of DPH showed a considerable increase in lethargy or drowsiness over that of the placebo, however, when formulated with the 200 mg. caffeine encapsulated core, substantial sinus relief was afforded without lethargy or drowsiness. The reduction in drowsiness and relief afforded was found to occur at approximately 3.5 hours after drug administration.