CA2406552A1 - Release of lipophilic active agents from chewing gum - Google Patents

Abstract

Methods and compacted powder formulations for delivering a powdered medicament or agent to an individual are provided. The compacted powder formulation includes a medicament or agent. The compacted powder formulation also includes a sufficient amount of a masking agent to allow the consumer to allow at least a portion of the product to dissolve in his or her mouth due to the flavor masking abilities of the compacted powdered oral dosage form. It is believed that by placing the compacted powder formulation into the mouth of the user, the medicament or agent is released, enhancing the absorption of the drug into the systemic system as well as the bioavailability of the drug within the system.

Description

"FLAVORED PRODUCT CONTAINING MEDICAMENT
OR OTHER ACTIVE AGENT"
S
This patent application is a continuation-in-part ofU.S. Serial No.
09/421,905, filed on October 20, 1999, entitled "Powder Pharmaceutical Formulations."
BACKGROUND OF THE INVENTION
The present invention generally relates to the delivery of medicaments and other agents. More specifically, the present invention relates to the delivery of medicaments and agents using products that provide a pleasant taste.
It is of course known to provide agents to individuals for various purposes.
These agents can be used to treat diseases and as such are typically referred to as drugs or medicaments. Likewise, drugs or medicaments can be used for prophylactic purposes.
Still, it is known to provide agents to an individual for a variety of non-medical purposes including enhancing performance or maintaining or initiating alertness. There are a great variety of such agents. These agents run the gamut from stimulants such as caffeine to drugs such as analgesics, tranquilizers, cardiovascular products, insulin, etc. Some such agents are taken on an as needed basis while other agents must be taken at regular intervals by the individual.
Typically, drugs (medicaments) are administered parenterally or enterally. Of course, parenteral administration is the administration of a drug intravenously directly into the blood stream. Enteral refers to the administration of a drug into the gastrointestinal tract. In either case, the goal of the drug administration is to move the drug from the site of administration towards the systemic circulation.
Except when provided intravenously, a drug must traverse several semipermeable cell membranes before reaching general circulation. These membranes act as a biological barrier that inhibits the passage of drug molecules. There are believed to be four processes by which drugs move across a biological barrier: passive diffusion;
facilitated diffusion; active transport; and pinocytosis.

Passive diffusion is the transport across the cell membrane wherein the driving force for the movement is the concentration gradient of the solute. In orally administered drugs, this absorption occurs in the small intestines. Facilitated diffusion is believed to be based on a carrier component that combines reversibly with the substrate molecule at the cell membrane exterior. The carrier substrate complex diffuses rapidly across the membrane with release of the substrate at the interior surface. Active transport requires an energy expenditure by the cell and appears to be limited to agents with structural similarities to normal body constituents. These agents are usually absorbed from specific sites in the small intestines. Pinocytosis refers to the engulfing of particulars or fluid by a cell. It is believed to play a minor role in drug transport. Merck Manual, 16th Edition, pp. 2598-2599.
In determining the efficacy of a drug and the effectiveness of the use of a drug to treat a disease, drug absorption is a critical concern. Drug absorption refers to the process of drug movement from the site of administration toward the systemic circulation.
Oral administration of drugs is by far the most common method. When administered orally, drug absorption usually occurs due to the transport of cells across the membranes of the epithelial cells within the gastrointestinal tract.
Absorption after oral administration is confounded by numerous factors. These factors include differences down the alimentary cannel in: the luminal pH; surface area per luminal volume;
perfusion of tissue, bile, and mucus flow; and the epithelial membranes. See Merck Manual at page 2599.
A further issue effecting the absorption of orally administered drugs is the form of the drug. Most orally administered drugs are in the form of tablets or capsules. This is primarily for convenience, economy, stability, and patient acceptance.
Accordingly, these capsules or tablets must be disintegrated or dissolved before absorption can occur.
There are a variety of factors capable of varying or retarding disintegration of solid dosage forms. Further, there are a variety of factors that effect the dissolution rate and therefore determine the availability of the drug for absorption. See Merck Manual at page 2600.

Parental administration allows for the direct placement of the drug into the blood stream. This usually insures complete delivery of the dose to the general circulation.
However, administration by a route that requires drug transfer through one or more biologic membranes to reach the blood stream precludes a guarantee that all of the drug S will eventually be absorbed. Even with parental administration, because capillaries tend to be highly porous, the perfusion (blood flow/gram of tissue) is a major factor in the rate of absorption. Thus, the injection site can markedly influence a drug's absorption rate;
e.g., the absorption rate of diazepam injected IM into a site with poor blood flow can be much slower than following an oral dose. See Merck Manual at page 2601.
Not only is drug absorption an issue in drug delivery, but, also the bioavailability of the drug is also critical. Bioavailability is defined as type rate at which and the extent to which the active moiety (drug or metabolite) enters the general circulation, thereby gaining access to the site of action. Bioavailability depends upon a number of factors, including how a drug product is designed and manufactured, its physicochemical properties, and factors that relate to the physiology and pathology of the patient. See Merck Manual at page 2602.
When a drug rapidly dissolves from a drug product and readily passes across membranes, absorption from most site administration tends to be complete. This is not always the case for drugs given orally. Before reaching the vena cava, the drug must move down the alimentary cannel and pass through the gut wall and liver, which are common sites of drug metabolism. Thus, the drug may be metabolized before it can be measured in the general circulation. This causes a decrease in drug input that is called the first pass effect. A large number of drugs show low bioabilities owing to an extensive first pass metabolism. The two other most frequent causes of low bioavailability are insuff cient time in the GI tract and the presence of competing reactions. See Merck Manual at page 2602.
Bioavailability considerations are most often encountered for orally administered drugs. Differences in bioavailability can have profound clinical significance.
Although parental administration does provide a method for eliminating a number of the variables that are present with oral administration, parental administration is not a preferable route. Typically, parental ~dmiratration requires the use of medical personnel and is just not warranted nor practical for the administration of most agents and drugs, e.g., analgesics. Even when required parenteral administration is not preferred due to patient concerns including comfort, infection, etc., as well as the equipment and costs involved. However, despite best efforts certain therapies require parenterally injected drugs. For example, research for decades has focused on an attempt to deliver insulin to an individual through a non-parental means. Despite such efforts today insulin is still only administered intravenously.
A limited number of medicaments have been administered in the form of a powder. For example, headache powders have been used to provide an enteral method for the delivery of aspirin and other analgesics. Examples of such headache powders are marketed under the brand names BG and Dr. Goodys. These powders are very bitter and typically are not the desired method to enterally ingest an analgesic.
It is of course known to place medicaments or active agents in a tablet form.
Typically the tablets, such as aspirin, are swallowed immediately after being placed in 1 S the mouth. In this regard, these products typically have a bitter taste and are not designed to dissolve in the consumer's mouth or be chewed.
There is therefore a need for an improved method of delivering drugs and agents to an individual.
SUMMARY OF THE INVENTION
The present invention provides improved methods for delivering a medicament or agent to an individual. Improved formulations including medicaments and agents are also provided by the present invention. To this end, compacted powders are provided including medicaments or agents. The medicament or agent, in a powder form, is mixed with at least a masking agent, the resultant powder is then compressed or compacted into a defined shape. It has been found that the masking agent and medicament in a compacted powder form provides a product that covers up the bitter and bad flavors produced by the medicament or agent while allowing the product to be delivered through the buccal cavity.
The present invention allows a variety of medicaments and agents to be delivered directly into the systemic system of the individual through the oral mucosa contained in the buccal cavity. Such a method can greatly enhance the absorption of the drug into the systemic system as well as the bioavailability of the drug within the system.
Absorption of the drug is further enhanced by allowing the consumer to hold the compacted powder in the mouth and chew same for 1 or 2 minutes or longer if comfortable.
To this end, in an embodiment, the present invention provides a compacted powder including medicament that is designed to dissolve in the mouth of the user or that can be chewed. The compacted powder medicament includes a sufficient amount of a masking agent to improve the organoleptic properties of the powdered formula.
Preferably, the powder includes a release agent.
In an embodiment, the medicament is chosen from the group consisting of analgesics; muscle relaxants; antihistamines; decongestants; antacids; anti-inflammatories; antibiotics; antivirals; stimulants; psychotherapeutic agents;
and cardiovascular agents.
In an embodiment, the masking agent is chosen from the group consisting of zinc gluconate; ethyl maltol; glycine; acesulfame-K; aspartame; sucrolose;
saccharin;
fructose; xylitol; spray dried licorice root; glycyrrhizin; sodium gluconate;
glucono delta lactone; vanillin; normal and high-potency sweeteners; and a variety of appropriate flavors.
In an embodiment, the formulation creates a saliva content of medicament of at least 5 ppm to about 66% medicament by weight in the saliva, depending on the medicament.
In an embodiment, the release agent is chosen from the group consisting of calcium and magnesium stearate.
In another embodiment of the present invention, the present invention provides a method for delivering a medicament to an individual comprising the steps of providing a compressible formulation that includes a medicament in powder form and a sufficient amount of a masking agent to provide acceptable organoleptic properties, the compressible formulation being compressed into a defined structure; and allowing at least a portion of the defined structure to dissolve in a mouth of an individual to cause the medicament to be released from the formulation into a buccal cavity of the individual.

In an embodiment, the compressible formulation includes a compressible mono or di-saccharide, e.g., dextrose or sucrose, or a combination, or compressible sugar alcohols, e.g., sorbitol, mannitol, and iso-maltitol. The quantity of which is chosen so that it masks the taste of the medicaments.
In a further embodiment, the present invention provides a method of enhancing an individual's performance, the method comprising the steps of providing a compressible powder formulation including a performance enhancing amount of caffeine in powder form and a masking agent; compressing the powder into a solid structure; and allowing at least a portion of the solid structure to dissolve in the mouth of the individual not more than ten minutes before the performance.
In an embodiment, the performance to be enhanced is athletic.
In an embodiment, the performance to be enhanced is cognitive.
In an embodiment, the performance to be enhanced is alertness.
In an embodiment, the powder formulation is placed in the buccal cavity not more 1 S than S minutes before the performance.
Yet further, the present invention provides a method of increasing the stimulatory effect of a stimulant that has been previously ingested by an individual comprising the steps of: providing a compacted formulation that contains a stimulant and a masking agent; and placing the compacted formulation into the buccal cavity causing the stimulant to be released by the compacted formulation into an oral mucosa located in a buccal cavity of the individual.
In another embodiment, the present invention provides a compressible powder formulation comprising a powder medicament and a sufficient amount of a masking agent to provide a powder formulation having acceptable organoleptic properties.
In a further embodiment of the present invention, a method of delivering a medicament is provided. The method comprising the steps of providing a compressible powder formulation including a medicament in powder form and a sufficient amount of a masking agent to mask any offensive tastes that are associated with the medicament;
compacting the compressible formulation into a defined structure; placing the defined structure in a buccal cavity of an individual; and allowing at least a portion of the defined structure to dissolve in the buccal cavity.

In a still further embodiment, the present invention provides a product including a medicament. The product includes a compressible powder medicament having an offensive taste; a sufficient amount of a compressible masking agent to provide acceptable organoleptic properties; and a release agent.
Accordingly, an advantage of the present invention is to provide new methods and compositions for delivering medicaments or agents to an individual.
Still further, an advantage of the present invention is to provide a method of delivering medicaments to an individual that provides for increase absorption and bioavailability as compared to medicaments that are designed to be absorbed in the GI
tract.
Further, an advantage of the present invention is to provide a method of administering a medicament or agent to an individual at a level that is lower than is typically administered orally while still achieving the same effect.
Furthermore, an advantage of the present invention is to provide a method for administering drugs or agents to an individual that heretofore were administered parentally.
Additionally, an advantage of the present invention is to provide a method for administering drugs that is more palatable than current methods.
Another advantage of the present invention is to provide a method for enhancing the performance of an individual through the administration of an agent.
Moreover, an advantage of the present invention is to provide improved methods for drug delivery.
Still, an advantage of the present invention is to provide a method for creating a triggering effect that creates a synergistic effect with an agent that is present in the systemic circulation of the individual.
Additional features and advantages of the present invention will be described in and apparent from the detailed description of the presently preferred embodiments.

DETAILED DESCRIPTION OF THE
PRESENTLY PREFERRED EMBODIMENTS
The present invention provides improved methods for delivering medicaments and other agents to an individual as well as improved formulations including such medicaments and agents. Pursuant to the present invention, a medicament or agent is contained in a compacted powder formulation that includes a masking agent. As used herein, the term "masking agent" includes compounds and agents that alter or disguise the taste of a product that is ingested or placed in the mouth. As such, the term masking agent includes sweeteners and flavors.
It has been found that by adding a masking agent to a powder formulation, that a much more palatable formulation, including a powder medicament, can be provided.
In this regard, even though the medicament in its powder form may be bitter or have an offensive taste, the powder matrix of the present invention, including the masking agent, will afford a product having acceptable organoleptic properties. It has been surprisingly found that by solubilizing a powdered matrix of medicament and masking agent, this increases the ability of the masking agent to cover up any bitter and/or bad flavors produced by the medicament or agent. By selecting specific masking agents based on the bad or off taste produced by the medicament, one can provide a palatable powder formulation.
For example, if one is attempting to cover an astringent flavor such as aspirin, one would use masking agents found to be effective against astringency such as fructose and high-intensity sweeteners, e.g., sucrolose, saccharin, aspartame, and acesulfame-K. In the case of a moderately bitter active ingredient, such as caffeine, one would use ingredients such as glycine, ethyl maltol, zinc gluconate, licorice root powder, high-intensity sweeteners, etc. In the case of a very bad tasking active ingredient such as acetaminophen, combinations of these masking agents or larger quantities may have to be used in order to combat the undesirable bitterness, e.g., peppermint and a high-intensity sweetener.
The masking agents, in an embodiment, are selected from the group consisting of sucrolose; zinc gluconate; ethyl maltol; glycine; acesulfame-K; aspartame;
saccharin;
_g_ fructose; xylitol; maltitol; isomalt; spray dried licorice root; glycyrrhizin;
sodium gluconate; glucono delta-lactone; ethyl vanillin; and vanillin.
In a prefer ed embodiment, it has been found that using at least approximately 1.5 grams to about 3 grams of bulk sweetener (e.g., dextrose, sucrose, sorbitol, and S isomaltitol) with a high-intensity sweetener provides an excellent masking agent in typically envisioned products. This quantity of bulk sweetener masking agent is able to mask the bitterness of many medicaments and active agents.
By insuring that the powder formulation includes compressible components, a solid dosage form of the product can be created. In this regard, the powder formulation can be compacted into a pill-like, mint-like, tablet-like, or similar structure. Preferably the compacted powder has a matte finish, although if desired, the product can be coated.
In use, the compacted powder formulation is placed in the mouth of the user.
Due to the present invention, as the compacted powder formulation begins to dissolve, it has acceptable organoleptic properties allowing the consumer to maintain the product in his mouth for a sufficient time to allow as much of the product as possible to dissolve. As the product dissolves, the powder medicament or agent is released into the saliva. The medicament or agent in the saliva then passes through the oral mucosa in the buccal cavity. The oral mucosa has a thin epithelium and a rich vascularity. Thus, the oral mucosa favors drug absorption.
In contrast to a typically orally ingested drug, wherein the solution is in contact too briefly for absorption to be appreciable through the oral mucous, if the product is allowed to dissolve in the mouth, an increase in the absorption of the drug is achieved as well as an increase in the bioavailability of the drug as compared to typical oral administration. It has been found that the drug or agent is absorbed much quicker when it is allowed to dissolve in the mouth of the consumer than if it was swallowed as in a typical oral administration.
It is believed that less powder medicament or agent can be placed in the formulation than is typically orally administered to an individual to achieve an effect and the same bioequivalence can be achieved.
For example, caffeine is commonly used as a stimulant to alleviate the effects of sleep deprivation. It is almost completely metabolized in the liver and therefore classified as. a low clearance, flow independent drug. This means its rate of inactivation is unaffected by delivery to the liver and can only be modified by a change in the hepatic enzyme activity.
The pharmacokinetics of caffeine have been well documented and there is no significant difference between oral and intravenous administration. However, data set forth in detail below, suggests that the absorption rate constant (Ka) is significantly increased when caffeine is administered through chewing gum. This means that the caffeine is moving into the systemic circulation at a significantly faster rate. A similar change in the onset of dynamic response has also been noted, e.g., alertness and performance.
It is believed that for at least certain agents that placing the agent in a compacted powder formulation that is placed in the mouth can have a triggering effect on the agent that may be in the systemic circulation. For example, it has been found that with respect to caffeine that is ingested orally, that after the ingestion of a certain amount of caffeine, and the elapse of a certain period of time, that further ingestion of caffeine has a negligible effect on the individual. However, it is believed that if caffeine is placed in a powdered formulation with caffeine there has been observed a triggering effect that appears to create a synergistic effect with the caffeine that is in the systemic circulation.
It is believed that this triggering effect will also be present with other agents, e.g., analgesics.
It is envisioned, that a variety of different medicaments and other active agents can be used in the compacted powder formulation. By the terms "active agent"
the present invention refers to a compound that has a desired therapeutic or physiological effect once ingested and/or metabolized. The therapeutic effect may be one which decreases the growth of a xenobiotic or other gut flora or fauna, alters the activity of an enzyme, provides the physical relief from a malady (e.g., diminishes pain, acid reflux, or other discomfort), has an effect on the brain chemistry of molecules that determine mood and behavior. Of course these are just examples of what is intended by therapeutic effect. Those of skill in the art will readily recognize that a particular agent has or is associated with a given therapeutic effect.

The active agent may be any agent that is traditionally used as a medicament and lends itself to being administered through the oral cavity. Such active agents may be vitamins, cancer chemotherapeutics; antimycotics; oral contraceptives, nicotine, nicotine replacement agents, minerals, analgesics, antacids, muscle relaxants, antihistamines, decongestants, anesthetics, antitussives, diuretics, anti-inflammatories, antibiotics, antivirals, psychotherapeutic agents, anti-diabetic agents, and cardiovascular agents, bioengineered pharmaceuticals, nutraceuticals, and nutritional supplements.
Vitamins and co-enzymes that may be delivered using this invention include but are not limited to water or fat soluble vitamins such as thiamin, riboflavin, nicotinic acid, pyridoxine, pantothenic acid, biotin, flavin, choline, inositol, and paraminobenzoic acid, carnitine, vitamin C, vitamin D, and its analogs, vitamin A and the carotenoids, retinoic acid, vitamin E, and vitamin K.
Examples of cancer chemotherapeutics agents include, but are not limited to, cisplatin (CDDP), procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, bisulfan, nitrosurea, dactinomycin:
danunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, taxol, transplatinum, S-fluorouracil, vincristin, vinblastin, and methotrexate or any analog or derivative variant thereof.
Antimicrobial agents that may be used include, but are not limited to, naficillin, oxacillin, vancomycin, clindamycin, erythromycin, trimethoprim-sulphamethoxazole, rifampin, ciprofloxacin, broad spectrum penicillin, amoxicillin, gentamicin, ceftriazoxone, cefotaxime, chloramphenicol, clavunate, sulbactam, probenecid, doxycycline, spectinomycin, cefixime, penicillin G, minocycline, P-lactamase inhibitors;
meziocillin, piperacillin, aztreonam, norfloxacin, trimethoprim, ceftazidime, dapsone.
Antifungal agents that may be delivered include but are not limited to ketoconazole, fluconazole, nystatin, itraconazole, clomitrazole, and amphotericin B.
Antiviral agents that may be used include but are not limited to acyclovir, trifluridine, idoxorudine, foscamet, ganciclovir, zidovudine, dideoxycytosine, dideoxyinosine, stavudine, famciclovir, didanosine, zalcitabine, rifimantadine, and cytokines.
Antacids include cimetidine, ranitidine, nizatidine, famotidine, omeprazole, bismuth antacids, metronidazole antacids, t: ~racy.;,ine antacids, clarthromycin antacids, hydroxides of aluminum, magnesium, sodium bicarbonates, calcium bicarbonate, and other carbonates, silicates, and phosphates.
Antihistamines are represented by, but are not limited to, cimetidine, ranitidine, diphenydramine, prylamine, promethazine, chlorpheniramine, chlorcyclizine, S terfenadrine, carbinoxamine maleate, clemastine fumarate, diphenhydramine hydrochloride, dimenhydrinate, prilamine maleate, tripelennamine hydrochloride, tripelennamine citrate, chlorpheniramine maleate, brompheniramine maleate, hydroxyzine pamoate, hydroxyzine hydrochloride, cyclizine lactate, cyclizine hydrochloride, meclizine hydrochloride, acrivastine, cetirizine hydrochloride, astemizole, levocabastine hydrochloride, and loratadine.
Decongestants and antitussives include agenis such as dextromethorphan hydrobromide, levopropoxyphene napsylate, noscapine, caretapentane, caramiphen, chlophedianol, pseudoephedrine hydrochloride, pseudoephedrine sulfate, phenylephidrine, diphenhydramine, glaucine, pholcodine, and benzonate.
Anesthetics include etomidate, ketamine, propofol, and benodiazapines (e.g., chlordiazepoxide, diazepame, clorezepate, halazepam, flurazepam, quazepam, estazolam, triazolam, alprozolm, midazolam, temazepam, oxazepam, lorazepam), benzocaine, dyclonine, bupivacaine, etidocaine, lidocaine, mepivacaine, promoxine, prilocaine, procaine, proparcaine, ropivacaine, tetracaine. Other useful agents may include amobartital, aprobarbital, butabarbital, butalbital mephobarbital, methohexital, pentobarbital, phenobarbital, secobarbital, thiopental, paral, chloralhydrate, ethchlorvynol, clutethimide, methoprylon, ethinamate, and meprobarnate.
Analgesics include opioids and other medicaments such as morphine, mepidine, dentanyl, sufentranil, alfentanil, aspirin, acetaminophen, ibuprofen, indomethacine, naproxen, atrin, isocome, midrin, axotal, firinal, phrenilin, ergot, and ergot derivatives (wigraine, cafergot, ergostat, ergomar, dihydroergotamine), imitrex, and ketoprofen.
Diuretics include but are not limited to acetazolamide, dichlorphenamide, methazolamide, furosemide, bumetanide, ethacrynic acid torseimde, azosemide, muzolimine, piretanide, tripamide, bendroflumethiazide, benthiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, indapamide, metolazone, quinethazone, amiloride, triamterene, sprion olactone, canrenone, and potassium canrenoate.
Anti-inflammatories include but are not limited to salicylic acid derivatives (e.g., aspirin), indole and indene acetic acids (indomethacin, sulindac, and etodalac) heteroaryl S acetic acids (tolmetin diclofenac and ketorolac) aryl propionic acid derivatives (ibuprofen, naproxen, ketoprofen, fenopren, oxaprozine), anthranilic acids (mefanamic acid, meclofenamic acid) enolic acids (piroxicam, tenoxicam, phenylbutazone, and oxyphenthatrazone).
Psychotherapeutic agents include thorazine, serentil, mellaril, millazinetindal, permitil, prolixin, trilafon, stelazine, suprazine, taractan, navan, clozarill haldol, halperon, loxitane, moban, orap, risperdal, alprazolam, chordiaepoxide, clonezepam, clorezepate, diazepam, halazepam, lorazepam, oxazepam, prazepam, buspirone, elvavil, anafranil, adapin, sinequan, tofranil, surmontil, asendin, norpramin, pertofrane, ludiomil, pamelor, vivactil, prozac, luvox, paxil, zoloft, effexor, wellbutrin, serzone, desyrel, nardil, parnate, 1 S eldepryl.
Cardiovascular agents include, but are not limited to, nitroglycerin, isosorbide dinitrate, sodium nitroprisside, captopril, enalaprill, enalaprilat, quinapril, lisinopril, ramipril, losartan, amrinone, linnone, vesnerinone, hydralazine, nicorandil, prozasin, doxazosin, bunazosin, tamulosin, yohimbine, propanolol, metoprolol, nadolol, atenolol, timolol, esmolol, pindolol, acebutolol, labetalol, phentolamine, carvedilol, bucindolol, verapamil, nifedipine, amlodipine, and dobutamine, or a sexual dysfunction agent like sildenafil citrate (Viagra).
It is envisioned that depending on the active agent or medicament, the resultant product can be used to treat inter alias coughs, colds, motion sickness;
allergies; fevers;
pain; inflammation; sore throats; cold sores; migraines; sinus problems;
diarrhea;
diabetes, gastritis; depression; anxiety, hypertension; angina, and other maladies and symptoms. Also these gums may be useful in ameliorating cravings in substance abuse withdrawal or for appetite suppression. Specific active agents or medicaments include by way of example and limitation: caffeine, aspirin, acetaminophen; ibuprofen;
ketoprofen; cimetidine, ranitidine, famotidine, dramamine, omeprazole, dyclonine hydrochloride, chlorpheniramine maleate, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, benzocaine, sodium naproxen, and nicotine.
Nutraceuticals and nutritional supplements may also be added to the product as active agents. Among these are herbs and botanicals that include, but are not limited to, capsicum, chamomile, cat's claw, echinacea, garlic, ginger, ginko, various ginseng, green tea, golden seal, kava kava, nettle, passion flower, saw palmetto, St. John's wont, and valerian. Also included are mineral supplements such as calcium, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorous, selenium, and zinc. Other nutraceuticals that also can be added to chewing gum as active agents are benzoin, fiucto-oligosaccharides, glucosamine, grapeseed extract, guarana, inulin, phosphotidylserine, phytosterols, phytochemicals, isoflavones, lecithin, lycopene, oligofiuctose, polyphenol, and psyllium as well as weight loss agents such as chromium picolinate and phenylpropanolamine.
Preferably, the agents or medicaments are contained in the powder formulation 1 S at levels of approximately 50 micrograms to 1000 milligrams. The specific levels will depend on the active ingredient. For example, if chromium picolinate is the active ngredient in an embodiment, it would be present at a level of approximately 20 to about 50 micrograms per dosage; aspirin would be preset at a level of approximately SO to about 650 milligrams per dosage; caffeine would be preset at a level of approximately 20 to about 600 milligrams per dosage; and acetaminophen would be preset at a level of approximately 87 to about 1000 milligrams per dosage.
The level of medicament or agent in the compacted powdered formulation is selected so as to create, when the compacted powder formulation is placed in the mouth, a sufficiently high concentration of the medicament or agent in the saliva.
For example, when the agent is a stimulant such as caffeine, the level of the stimulant in the compacted powder formulation should be such that it creates a saliva content of stimulant of approximately 1% to about 66% after the formulation is placed in the mouth. At this level, a sufficient amount of stimulant will be delivered to the user to create the effects set forth in the application. If a medicament is used such as a medicinal (e.g., analgesics), sufficient medicinal should be present in the compacted powder formulation to create a salvia content of approximately 1 % to about 66%. For botanicals (e.g., chamomile, kava, kola, nut, ginseng, and Echinacea), the agent should be present in a sufficient amount to create a saliva content of approximately 1 % to about 66%. For a metabolizer, for example, chromium picolineate and hydroxi-chitic acid, the agents should be present in an amount to create a saliva content of approximately 1 % to S about 66%. If the agent is a vitamin or mineral (e.g., phosphatidy serine, vitamin C, and zinc), the agent should be present in the amount to create a saliva content of the vitamin or mineral of approximately 2%to about 30%.
Pursuant to the present invention, depending on the agent or medicament, the dosing regiment will change. For example, if the medicament is an analgesic, the compacted powdered formulation would be taken on an as needed basis. Of course, similar to the oral administration of an analgesic, there would be restrictions.on the doses taken, for example, not more often than one powdered formulation every four hours and not more often than four to five times a day.
If the agent is a stimulant, such as caffeine, to be used to enhance performance than the compacted powdered formulation would be ingested, in a preferred embodiment ten minutes or less before the performance.
Sufficient masking agent will be used to improve and provide acceptable organoleptic properties to the compacted powder product. As used herein to provide "acceptable organoleptic properties" means that the compacted powder formulation will have a sufficiently pleasant, or at least non-offensive taste, to allow the consumer to allow at least a majority of the compacted powder formulation to dissolve in his mouth.
The amount of masking agent will thereby vary depending on medicament or agent. Of course, more than one masking agent can be used, e.g., zinc gluconate and a sweetener or flavor.
Generally, it is believed that the masking agent will comprise approximately 50%
to about 99+% by weight of the powder formulation. For example, if the agent is caffeine, approximately 10 to about 50 milligrams of masking agent should be present per milligram of caffeine; for aspirin, approximately 4 to about 32 milligrams of masking agent should be present per milligram of aspirin; and for acetaminophen, approximately 4 to about 32 milligrams of masking agent should be present per milligram of acetaminophen. Of course, more than one masking agent can be used.

The medicament or agent can be contained in a variety of different compacted powder formulation compositions. For example, the formulation can be low or high moisture, sugar or sugarless, andlor low calorie.
The formulation can include a water soluble bulk portion and one or more flavoring agents. The water soluble portion can include bulk sweeteners, high intensity sweeteners, flavoring agents, softeners, emulsifiers, colors, acidulants, fillers, antioxidants, and other components that provide desired attributes.
Bulk sweeteners, which also can function as the masking agent, include both sugar and sugarless components. Bulk sweeteners, if present, will typically constitute about 50% to about 98% by weight of the formulation. Bulk sugar sweeteners generally include saccharide-containing components commonly known in the confectionary art, including but not limited to, sucrose, dextrose, maltose, dextrin, dried invert sugar, fructose, levulose, glactose, corn syrup solids, and the like, alone or in combination.
Bulk sugarless sweeteners include, but are not limited to, sugar alcohols such as sorbitol, mannitol, xylitol, hydrogenated starch hydrolysates, maltitol, and the like, alone or in combination. As noted earlier, in a preferred embodiment, approximately 1.5 to about 3.0 grams of bulk sweeteners are present in the product.
High intensity artificial sweeteners can also be used, alone or in combination, with the above. Preferred sweeteners include, but are not limited to, sucralose, aspartame, salts of acesulfame, alitame, saccharin and its salts, cyclamic acid and its salts, glycerrhizinate, dihydrochalcones, thaumatin, monellin, and the like, alone or in combination. In order to provide longer lasting sweetness and flavor perception, it may be desirable to encapsulate or otherwise control the release of at least a portion of the artificial sweetener. Such techniques as wet granulation, wax granulation, spray drying, spray chilling, fluid bed coating, coacervation, and fiber extension may be used to achieve the desired release characteristics.
Combinations of sugar and/or sugarless sweeteners may be used in the formulation. Additionally, the softener may also provide additional sweetness such as with aqueous sugar or alditol solutions. As noted above, depending on the powder agent or medicament, sweeteners can comprise a part of, or the entire masking agent.

If a low calorie formulation is desired, a low caloric bulking agent can be used.
Examples of low caloric bulking agents include: polydextrose; Raftilose, Raftilin;
Fructooligosaccharides (NutraFlora); Palatinose oligosaccharide; Guar Gum Hydrolysate (Sun Fiber); or indigestible dextrin (Fibersol). However, other low calorie bulking agents S can be used.
A variety of flavoring agents can also be used, if desired. If present, the flavor can be used in amounts of about 0.5 to about 10 weight percent of the formulation. As noted above, depending on the medicament or agent, flavor can comprise a part of, or the entire masking agent. Flavoring agents may include essential oils, synthetic flavors or mixtures thereof including, but not limited to, oils derived from plants and fruits such as citrus oils, fivit essences, peppermint oil, spearmint oii, other mint oils, clove oil, oil of wintergreen, anise and the like. Artificial flavoring agents and components may also be used. Natural and artificial flavoring agents may be combined in any sensorially acceptable fashion.
In addition to the medicament and masking agent, preferably the product includes a release agent. The release agent functions to release the product from the mold or similai apparatus during compacting or compression of the powder formulation.
A
variety of release agents can be used including calcium and magnesium stearate.
Preferably, the release agent comprises approximately 0.5% to about 3% by weight of the product.
There are a variety of methods for constructing the product of the present invention. As a first step, generally the formulations would be constructed by blending a medicament in powder form with a powder masking agent and other components as desired. The powder can then be, for example, made into a compacted product by conventional tablet forming machines.
The product then would be packaged in bottles, blister packs, strip packs, roll wraps, or tins.
By way of example, and not limitation, examples of some product including a medicament or agent are as follows:
Example No. 1 In egr diem Percen Acetaminophen 20.86%

Peppermint Flavor 0.44 Menthol Flavor 0.37 Dextrose 76.07 Sucrolose 0.19 Magnesium Stearate 1.70 Aspartame 0.37 100.00%
Example No. 2 Ingredient Percent Acetaminophen 10.1 S

Dextrose 87.39 Sucrolose 0.19 Bubble Gum Flavor0.19 Magnesium Stearate 1.70 Aspartame 0.38 100.00%

Example No. 3 Ingredient Grams Percent Pseudoephedrin 60.00 3.75%

Menthol Flavor 30.00 1.88 Eucalyptus Flavor 2.00 0.13 Aspartame 32.00 2.00 Magnesium Stearate 27.20 1.70 Dextrose 1_ 44~ 90.55 1,600.00 100.00%

It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its attendant advantages. It is therefore intended that such changes and modifications be covered by the appended claims.

Claims (36)

WE CLAIM:

1. A method for delivering a medicament to an individual comprising the steps of:
providing a compressible formulation that includes a medicament in powder form and a sufficient amount of a masking agent to provide acceptable organoleptic properties, the compressible formulation being compressed into a defined structure; and allowing at least a portion of the defined structure to dissolve in a mouth of an individual to cause the medicament to be released from the formulation into a buccal cavity of the individual.

2. The method of Claim 1 wherein the compressible formulation includes a compressible mono or di-saccharide.

3. The method of Claim 1 wherein the compressible formulation includes at least 50% by weight bulk sweeteners.

4. The method of Claim 1 wherein the medicament in powder form is chosen from the group consisting of analgesics; muscle relaxants; antibiotics;
antivirals;
stimulants; antihistamines; decongestants; anti-inflammatories; antacids;
psychotherapeutic agents; insulin; vitamins; minerals; oral contraceptives;
anesthetics;
diuretics; antibacterial agents; nutraceuticals; and cardiovascular agents.

5. The method of Claim 1 wherein the masking agent is chosen from the group consisting of zinc gluconate, ethyl maltol, glycine, acesulfame-K, aspartame;
saccharin; fructose; xylitol; isomalt; maltitol; spray dried licorice root;
glycyrrhizin;
sucralose; sodium gluconate; glucono delta-lactone; vanillin; and ethyl maltol.

6. The method of Claim 1 wherein the masking agent comprises approximately 50% to about 99% by weight of the compressible formulation.

7. The method of Claim 1 wherein the defined structure includes approximately 1.5 to about 3.0 grams of bulk sweetener.

8. The method of Claim 1 wherein the compressible formulation includes a release agent selected from the group consisting of calcium stearate and magnesium stearate.

9. A method for reducing the amount of agent necessary to achieve an effect in an individual as compared a typical agent that is swallowed comprising the steps of:
providing a product comprising a compressed powder formulation including an agent that is typically swallowed by an individual to achieve a specific effect, the powder formulation including less than the typical amount of agent that is swallowed by the individual to achieve the effect and a sufficient amount of a masking agent to provide acceptable organoleptic properties to the product; and placing the product in the buccal cavity of the individual and allowing at least a portion of the powder formulation to dissolve in the mouth of the individual and thereby causing the agent to be released into the salvia of the individual.

10. The method of Claim 9 wherein the agent is a medicament.

11. The method of Claim 10 wherein the medicament is chosen from the group consisting of analgesics; muscle relaxants; antibiotics; antivirals;
stimulants;
antihistamines; decongestants; anti-inflammatories; antacids;
psychotherapeutic agents;
insulin; vitamins; minerals; oral contraceptives; anesthetics; diuretics;
antibacterial agents; nutraceuticals; and cardiovascular agents.

12. The method of Claim 9 wherein the masking agent comprises approximately 50 to about 99 percent by weight of the powder formulation.

13. The method of Claim 9 wherein the powder formulation includes at least 50% by weight of a compressible saccharide.

14. The method of Claim 9 wherein the defined structure includes approximately 1.5 to about 3.0 grams of bulk sweetener.

15. The method of Claim 9 wherein the compressible formulation includes a release agent selected from the group consisting of calcium stearate and magnesium stearate.

16. A solid product including a medicament comprising:
a compressible powder medicament having an offensive taste;
a sufficient amount of a compressible masking agent to provide acceptable organoleptic properties; and a release agent.

17. The product of Claim 16 wherein the masking agent is chosen from the group consisting of zinc gluconate, ethyl maltol, glycine, acesulfame-K, aspartame;
saccharin; fructose; xylitol; isomalt; maltitol; spray dried licorice root;
sucralose;
glycyrrhizin; sodium gluconate; glucono delta-lactone; and vanillin.

18. The product of Claim 16 including at least 50% by weight of a bulk sweetener.

19. The product of Claim 16 wherein the product has a matte outer surface.

20. The product of Claim 16 wherein approximately 50% to about 99% by weight of the formulation is the masking agent.

21. The product of Claim 16 wherein the medicament is aspirin and the masking agent includes a high-intensity sweetener.

22. The powder formulation of Claim 16 wherein the medicament is acetaminophen and the masking agent is zinc gluconate.

23. The powder formulation of Claim 16 wherein the compressible formulation includes a release agent selected from the group consisting of calcium stearate and magnesium stearate.

24. The method of Claim 16 wherein the defined structure includes approximately 1.5 to about 3.0 grams of bulk sweetener.

25. A method of enhancing an individual's performance comprising the steps of:
providing a compressible powder formulation including a performance enhancing amount of caffeine in powder form and a masking agent;
compressing the powder into a solid structure; and allowing at least a portion of the solid structure to dissolve in the mouth of the individual not more than ten minutes before the performance.

26. The method of Claim 25 wherein the performance to be enhanced is athletic.

27. The method of Claim 25 wherein the performance to be enhanced is cognitive.

28. The method of Claim 25 wherein the performance to be enhanced is alertness.

29. The method of Claim 25 wherein at least a portion of the solid structure is allowed to dissolve five minutes or less before the performance.

30. A method of delivering a medicament comprising the steps of:
providing a compressible powder formulation including a medicament in powder form, a release agent, and a sufficient amount of a masking agent to mask any offensive tastes that are associated with the medicament, the masking agent including at least 50%
by weight of a bulk sweetener;
compacting the compressible formulation into a defined structure; and placing the defined structure in a buccal cavity of an individual and allowing at least a portion of the definitive structure to dissolve in the buccal cavity.

31. The method of Claim 30 wherein the medicament is chosen from the group consisting of analgesics; muscle relaxants; antibiotics; antivirals;
antihistamines;
decongestants; anti-inflammatories; antacids; psychotherapeutic agents; and cardiovascular agents.

32. A method of increasing the stimulatory effect of a stimulant that has been previously swallowed by an individual comprising the steps of:
providing a compacted formulation that contains a stimulant, a release agent, and a masking agent; and placing the compacted formulation into the buccal cavity causing the stimulant to be released by the compacted formulation into an oral mucosa located in a buccal cavity of the individual.

33. The method of Claim 32 wherein the stimulant is caffeine.

34. The method of Claim 32 wherein the compacted formulation includes a compressible saccharide.

35. The method of Claim 32 wherein the masking agent is chosen from the group consisting of glycine, ethyl maltol, zinc gluconate, and licorice root powder.

36. A method for formulating a product including an active agent:
providing an active agent in a powdered form;
adding to the powdered active agent a sufficient amount of masking agent to mask any bitter or unpleasant taste of the active agent;

adding to the powdered active agent a release agent; and compacting a resultant powdered formulation into a defined structure that comprises at least 50% by weight bulk sweetener.