Link:  Pharm/Biotech Resources

Title:  Two-stage transmucosal medicine delivery system for symptom relief

United States Patent:  6,893,654

Issued:  May 17, 2005

Inventors:  Pinney; John M. (Bethesda, MD); Henningfield; Jack E. (Baltimore, MD); Shiffman; Saul (Pittsburgh, PA); Gitchell; Joseph (Bethesda, MD); Cone; Edward J. (Severna Park, MD)

Assignee:  JSR, LLC (Bethesda, MD)

Appl. No.:  098307

Filed:  March 18, 2002

A two-stage medicine delivery system provides an initial dose of medicine and a second dose of medicine. The initial and second doses are capable of achieving a rapid pharmacological effect and a prolonged pharmacological effect, respectively. The two-stage medicine delivery system preferably delivers a craving reduction substance, in which case, the rapid and prolonged pharmacological effects include a rapid and prolonged craving reduction. Preferably, the delivery system is a nicotine delivery system which is provided in chewing gum form or lozenge form and which provides the nicotine in a transmucosally absorbable form. The two-stage medicine delivery system preferably releases a buffering agent which increases a pH level in a user's mouth to facilitate absorption of the medicine when the delivery system is placed in the user's mouth. A method of making the medicine delivery system also is provided. The system and apparatus can be adapted to reduce cravings for alcohol, food, drugs (e.g., cocaine, opiates and the like) and tobacco products, especially tobacco products containing nicotine.

SUMMARY OF THE INVENTION

A primary object of the present invention is to overcome the foregoing disadvantages associated with conventional medicine delivery systems, by providing a convenient, reliable, practical, and relatively painless medicine delivery system.

Another object of the present invention is to provide a two-stage medicine delivery system capable of providing initial and second doses of a craving reduction medicine, the combination of which rapidly reduces such cravings and provides protection from such cravings over a prolonged period of time beyond the initial dose.

Yet another object of the present invention is to provide a two-stage nicotine delivering gum capable of providing an initial dose of nicotine which is absorbed into the bloodstream within 5 minutes after chewing begins to achieve a pharmacologically effective concentration in the bloodstream, and also capable of providing a second dose of nicotine which keeps the concentration of nicotine in the bloodstream at or near the pharmacologically effective concentration for at least 20 minutes after chewing begins.

Still another object of the present invention is to provide a two-stage medicine delivering system which is convenient to use and which does not require trained medical personnel to administer the doses or require extensive user experience to provide a rapid pharmacological effect and/or mitigation of undesirable symptoms.

Another object of the present invention is to provide a medicine delivery system which provides a desired concentration of the medicine in the bloodstream within 5 minutes and preferably within 1-2 minutes of administration.

Yet another object of the present invention is to provide a medicine delivery system which keeps the concentration of the medicine in the bloodstream at or near the level of pharmacological effect (LPE), without significant overdosages.

To achieve these and other objects, the present invention provides a two-stage medicine delivery system. The two-stage medicine delivery system comprises means for providing an initial dose of medicine and means for providing a second dose of medicine. The initial dose of medicine is capable of achieving a rapid pharmacological effect. The second dose, by contrast, is capable of achieving a prolonged pharmacological effect.

The two-stage medicine delivery system preferably delivers a craving counteracting substance, and the rapid and prolonged pharmacological effects include a rapid and prolonged reduction of a craving.

Preferably, the delivery system is a nicotine delivery system which is provided in chewing gum form or lozenge form and which provides the nicotine in a transmucosally absorbable form.

The two-stage medicine delivery system preferably includes means for releasing a buffering agent which increases a pH level in a user's mouth to facilitate absorption of the medicine when the delivery system is placed in the user's mouth.

The present invention also provides a method of making a medicine delivery system which reduces a craving when orally retained. According to the method, a base material is provided. The base material is adapted to be retained in a user's mouth. A loading compound is mixed into the base material so that the loading compound remains releasable and rapidly transmucosally absorbable to counteract a craving within 5 minutes after the base material is orally retained. In addition, a maintenance compound is mixed into the base material so that the maintenance compound remains releasable and transmucosally absorbable over a prolonged period of time to counteract the craving for at least 20 minutes after oral retention of the base material begins.

Preferably, a buffer is also mixed into the base material so that the buffer remains releasable to elevate a pH level and facilitate transmucosal absorption of the loading and maintenance compounds within the user's mouth when the base material is orally retained. The buffer preferably is a bicarbonate type of buffer adapted to elevate the pH level to 7.5 to 9.5, preferably about 9.0, within 5 minutes after the base material is orally retained. Preferably, the base material is a gum base or a lozenge.

The present invention also provides a two-stage nicotine delivering product for use in counteracting cravings for nicotine-containing tobacco products. The product comprises a base, a nicotine loading compound, and a nicotine maintenance compound. The nicotine loading compound is mixed with the base so that oral actuation of the base causes the nicotine loading compound to be released into a user's mouth for transmucosal absorption within the first 5 minutes after oral actuation begins. The nicotine maintenance compound, by contrast, is mixed with the base so that oral actuation of the base causes the nicotine maintenance compound to be released into the user's mouth for prolonged transmucosal absorption which lasts at least 20 minutes beyond the first five minutes.

As indicated above, the present invention is well-suited for applications where the medicine is delivered orally, and more specifically, where the oral delivery of the medicine is performed via buccal transmucosal absorption. The present invention is quite useful as a craving reducer and can be adapted to reduce cravings for alcohol, food, drugs (e.g., cocaine, opiates and the like) and tobacco products, especially tobacco products containing nicotine.

As a nicotine delivery system, the present invention provides an initial dose of nicotine and a second dose of nicotine, the combination of which effectively counteracts a user's craving for cigarettes and other tobacco products. The present invention therefore can be used effectively to help smokers quit or reduce smoking.

DETAILED DESCRIPTION OF THE INVENTION

In order to avoid delays in medicine delivery and overdosages, the present invention provides a two-stage medicine delivery system. The two-stage medicine delivery system comprises means for providing an initial dose of medicine and means for providing a second dose of medicine. The initial and second doses are capable of achieving a rapid pharmacological effect and a prolonged pharmacological effect, respectively.

Preferably, the two-stage medicine delivery system delivers a craving counteracting substance, and the rapid and prolonged pharmacological effects provided by the system include a rapid and prolonged reduction in craving, respectively.

A preferred embodiment of the medicine delivery system is nicotine gum which delivers nicotine when chewed and which can be used to counteract cravings for nicotine-containing tobacco products. Although the nicotine gum form of the invention is preferred, it is understood that similar delivery systems may be provided in lozenge or other forms. Moreover, while the invention is preferably practiced in a manner relieving smoking withdrawal cravings, it has utility with other cravings, such as those related to eating disorders, stress, and the like, through suitable substitutions with the appropriate medicines.

The nicotine gum according to the preferred embodiment delivers the nicotine in a transmucosally absorbable form. The gum comprises a gum base, a nicotine loading compound, and a nicotine maintenance compound. The gum base can be implemented using one or a combination of several commercially available gum bases, some of which are commercially available from Fuisz Technologies. Preferably, the nicotine loading compound and/or the nicotine maintenance compound are substantially evenly distributed throughout the gum base so that distortion of the gum base's shape during chewing or oral manipulation does not significantly affect the amount and/or rate of nicotine release. In this regard, the gum base preferably does not include layers of different nicotine concentrations arranged to release different amounts of nicotine based on which layer of the gum is exposed.

The nicotine loading compound is mixed with the gum base so that chewing of the gum base causes the nicotine loading compound to be released into a chewer's mouth for transmucosal absorption within the first 5 minutes, and preferably within less than 3 minutes, after chewing begins. Preferably, the initial dose provided by the nicotine loading compound is between 0.2 and 0.7 milligram of nicotine. This initial dose is absorbed into the bloodstream within 5 minutes, and preferably within less than 3 minutes, after having been placed in the user's mouth. As a result, a loaded nicotine concentration in the bloodstream of 2 to 7 nanograms of nicotine per milliliter of blood (which is sufficient to provide craving relief) is achieved within about 5 minutes. Such a short delay in craving relief is acceptable to most former smokers and will not cause them to succumb to their cravings.

The nicotine maintenance compound, by contrast, is mixed with the gum base so that occasional chewing of the gum base causes the nicotine maintenance compound to be released into the chewer's mouth for prolonged transmucosal absorption which lasts at least 20 minutes beyond the first five minutes of use. The second dose provided by the nicotine maintenance compound is adapted to achieve a prolonged concentration of nicotine in the user's blood which is at least as high as a loaded nicotine concentration achieved in the user's blood by the initial dose.

Preferably, the nicotine maintenance compound is selected so that the prolonged concentration of nicotine is at least 10 nanograms per milliliter of blood and so that this prolonged nicotine concentration is maintained for at least 20 minutes and preferably 35 minutes after use begins.

The preferred nicotine delivering gum of the present invention achieves concentrations of nicotine in the bloodstream which, over time, substantially obey the concentration curve CC^p illustrated in FIG. 5. Notably, the concentration curve CC^p rises within 5 minutes after chewing begins and continues to rise to a level at or near the level of pharmacologic effect (LPE). Thereafter, the concentration curve CC^p remains at or near the level of pharmacologic effect for at least 20 minutes, and preferably 35 minutes. The concentration curve CC^p of the present invention advantageously does not exceed the LPE to such an extent that the user is exposed to an overdosage of nicotine.

In order to facilitate rapid craving relief, the nicotine gum of the preferred embodiment includes a releasable buffering agent which increases the pH level in the user's mouth prior to or along with release of the nicotine so that when nicotine is released into the saliva, it will be rapidly absorbed. The increased pH level thus enables rapid transmucosal absorption of the nicotine loading compound, as well as transmucosal absorption of the nicotine maintenance compound. Preferably, the buffering agent is adapted to elevate the pH level in the user's mouth to between about 7.5 and 9.5, preferably about 9.0, within 5 minutes of having been placed in the user's mouth.

Preferably, the nicotine loading compound is 0.2 to 0.7 milligram of nicotine salt, such as nicotine tartrate, which is mixed into the gum base. A preferred nicotine loading compound is 0.7 milligram of nicotine hydrogen tartrate.

The nicotine maintenance compound preferably consists of 1 to 4 milligrams of nicotine that may be held in an ion exchange resin gum, such as nicotine polacrilex. Alternatively, the nicotine maintenance compound can be provided using 1 to 4 milligrams of encapsulated nicotine salt. An exemplary nicotine maintenance compound is 1.5 milligrams of nicotine polacrilex, which in conjunction with the aforementioned preferred nicotine loading compound, achieves a total nicotine content of 2.2 milligrams of nicotine.

Preferably, the amount of buffering agent is 30 to 70 milligrams. A bicarbonate buffer may be used as the buffering agent. The type and amount of bicarbonate buffer preferably is selected to raise the pH level in the user's mouth to between about 7.5 and 9.5, preferably about 9.0, within 1 to 5 minutes after chewing begins and to maintain that pH level for about 15-30 minutes (i.e., the approximate range of time during which the gum will remain in the mouth). Preferably, the bicarbonate buffer is a sodium-free bicarbonate buffer. Alternatively, the buffer may be a carbonate buffer, which preferably is sodium-free. Calcium carbonate, for example, would be an appropriate sodium-free carbonate. Other examples of buffers which can be used include potasium citrate and dipotasium phosphate.

A buffer combination for the first dosage of sodium bicarbonate and sodium carbonate advantageously provides favorable mouth-feel and taste, and in this regard, may be preferred over other buffers. This buffer combination preferably is achieved using 20 milligrams of sodium bicarbonate and 10 milligrams of encapsulated sodium carbonate.

When the foregoing ingredients are combined, the resulting gum achieves a loaded nicotine concentration in the bloodstream of 2 to 7 nanograms per milliliter of blood within 5 minutes after use begins (stage 1) and eventually achieves a maintenance concentration of nicotine in the bloodstream of at least 5 nanograms of nicotine per milliliter of blood for an additional 20 to 35 minutes (stage 2). Notably, the gum sustains release of the nicotine in addition to providing a rapid initial release and absorption of the nicotine. This represents a significant advance over conventional gums, which generally provide a sustainable release without providing rapid release and absorption.

The rapid absorption of nicotine provided by the present invention provides additional advantages. Some research indicates that, even if the same total amount of nicotine is delivered, the psychoactive effects of nicotine on craving relief are enhanced when the rate of absorption increases. Thus, the present invention's ability to provide a prompt and rapid rise in the concentration of nicotine in the blood makes the present invention a significantly more effective craving reducer.

Advantageously, the present invention provides the rapid rise in absorption without replicating the explosive bolus associated with nasal nicotine sprays. Such sprays typically deliver 1 milligram of nicotine to the bloodstream, but pose a more significant risk of abuse and addiction. The present invention more effectively avoids such risks by employing transmucosal absorption, as opposed to the more rapid nasal absorption.

The present invention also provides the desired first and second doses regardless of whether the gum is chewed at regular intervals or is manipulated using the "park and chew" (or "chew and park") method.

The present invention also provides a method of making a medicine delivery system, and more specifically, a medicine delivery system which reduces a craving when orally retained. According to the method, a base material is provided. The base material is adapted to be retained in a user's mouth. A loading compound is mixed into the base material so that the loading compound remains releasable and rapidly transmucosally absorbable to counteract a craving within 5 minutes after the base material is orally retained. In addition, a maintenance compound is mixed into the base material so that the maintenance compound remains releasable and transmucosally absorbable over a prolonged period of time to counteract the craving for at least 20 minutes after the base material is placed in the mouth.

A buffer preferably is mixed into the base material so that the buffer remains releasable to elevate a pH level and facilitate transmucosal absorption of the loading and maintenance compounds within the user's mouth when the base material is orally retained. The buffer preferably is a bicarbonate buffer adapted to elevate the pH level to about 7.5 to 9.5 (preferably, about 9.0) within 5 minutes after the base material is orally retained. Preferably, the base material is a gum base, and the loading and maintenance compounds are therapeutic substances which counteract a user's cravings.

According to a preferred application of the method, the therapeutic substance is nicotine and the exemplary nicotine loading and maintenance compounds described above are used as the loading and maintenance compounds of the method. In addition, the exemplary buffering agent described above can be used as the buffering agent described in connection with the method.

The present invention, as indicated above, is well-suited for applications where the medicine is delivered orally, and more specifically, where the oral delivery of the medicine is performed via transmucosal absorption. The present invention is quite useful as a craving reducer and can be adapted to reduce cravings for alcohol, food, drugs (e.g., cocaine, opiates, and the like), and tobacco products, especially tobacco products containing nicotine.

The present invention also may include flavorants which are added to the base and which provide flavor, such as mint flavor, upon oral actuation. Spearmint oil or other types of mint flavor, sorbitol, xylitol, and the like are examples of the types of flavorants which can be added to the present invention. Other flavorants will become readily apparent to those of ordinary skill in the art upon reading the instant disclosure.

As an oral nicotine delivery system, the present invention provides an initial dose of nicotine and a second dose of nicotine, the combination of which effectively counteracts a user's craving for cigarettes and other tobacco products. The present invention therefore can be used effectively to help former smokers avoid smoking.

While the preferred ranges of nicotine concentrations and amounts of nicotine have been described above, it is understood that the invention is not limited to such concentrations and amounts. To the contrary, the concentrations and amounts can be adjusted depending on the target population. Some target populations require more nicotine than others. For example, smokers in Mexico generally tend to require less nicotine than many other population groups to achieve the same amount of craving relief. Heavy smokers versus light smokers also will have different nicotine requirements in general. Other factors which may affect the nicotine concentrations and amounts for different target populations include environmental, geographic, and biological differences between the target populations. Thus, it is well within the scope and spirit of the present invention to adjust the concentrations and amounts of nicotine accordingly.

In addition, the medicine need not be released in separate loading and maintenance dosages but rather can be releasable from the gum in a single initial form or manner which remains in the mouth or is reabsorbed and re-released by the base material during oral manipulation. In such an arrangement, the maintenance dosage is provided to the bloodstream by appropriately releasing a maintenance dose of buffer over the prolonged period of time, thereby facilitating the desired rate of transmucosal absorption over the maintenance period.

While this invention has been described as having a preferred embodiment, it is understood that the invention is not limited to the illustrated and described features. To the contrary, the invention is capable of further modifications, usages, and/or adaptations following the general principals of the invention and therefore includes such departures from the present disclosure as come within known or customary practice in the art to which the invention pertains, and as may be applied to the central features set forth above, and which fall within the scope of the appended claims.

Claim 1 of 32 Claims

1. A two-stage nicotine delivering product for use in counteracting cravings for nicotine-containing tobacco products, comprising:

a base;

a nicotine loading compound mixed with the base so that oral actuation of the base causes the nicotine loading compound to be released into a user's mouth for transmucosal absorption within the first 5 minutes after oral actuation begins; and

a nicotine maintenance compound mixed with the base so that oral actuation of the base causes the nicotine maintenance compound to be released into the user's mouth for prolonged transmucosal absorption which lasts at least 20 minutes beyond said first five minutes, said nicotine maintenance compound is 1 to 4 milligrams of encapsulated nicotine salt,

wherein the product is in lozenge form.

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