JP2784347B2 - Tobacco substitute - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates generally to tobacco substitutes for administering a dose of nicotine. More particularly, the present invention is directed to a nicotine-containing dosage form having a holder that can be used as part of an effective tobacco cessation program or in situations where smoking is undesirable or unacceptable.

[0002]

BACKGROUND OF THE INVENTION Nicotine is found in the peripheral and central nervous system (CN).
It is a naturally occurring drug found in tobacco which has both stimulating and sedative effects in S). Thus, nicotine is included in the broad category of CNS acting drugs. Nicotine exists as a basic, colorless to pale yellow, very hygroscopic oil-like volatile liquid with an unpleasant and irritating odor and a spicy and persistent taste. Nicotine exists in various salt forms because it forms salts with almost any acid. Nicotine is considered very toxic, and its toxic effects appear rapidly after a sharp overdose. When nicotine is obtained from tobacco by chewing, sniffing or smoking, the amount of nicotine absorbed in the body generally does not reach toxic levels.

[0003] Nicotine can be introduced into the body by many different routes. One of the most prevalent modes of nicotine use is cigarette smoking. When a cigarette in a cigarette is ignited, nicotine vapors are released during the burning process. Nicotine in cigarette smoke floating on the fine particles of "tar" is quickly absorbed through the lungs. Absorption of nicotine into the body via cigarette smoke is almost as fast as intravenous administration, and the nicotine reaches the brain within 8 seconds after inhaling tobacco smoke.

Unfortunately, when nicotine is introduced into the body in this way, many other compounds also enter the body.
The process of burning tobacco is complex, with about 4,000 compounds being generated during burning. Of these generated compounds, those that have highly undesirable effects are compounds such as carbon monoxide, carbon dioxide, nitric oxide, ammonia, and many other substances. In addition, many substances are “tar”
As it remains in the lungs. These various substances from burning tobacco include many that are believed to have significant long-term health effects. Because of this, in recent years,
Smoking is increasingly disliked, and because of indirect inhalation, there are restrictions on where individuals may smoke.

[0005] Because of these and other undesirable side effects, many attempts have been made to provide an acceptable replacement for cigarettes. Most of these substitutes contain nicotine, which is widely considered to be an addictive component in tobacco. Other factors such as social support, environmental factors (eg, advertising), and learning behaviors can also contribute to tobacco dependence.

[0006] Most heavy smokers appear to attempt to regulate nicotine concentrations within a relatively narrow range. For example, given a heavy smoker a cigarette containing a relatively high content of nicotine,
By reducing the number of cigarettes smoked and changing their inhalation patterns, the concentration of nicotine in plasma tends to be only slightly higher than their normal. Also, when heavy smokers are given cigarettes with very low nicotine content, they try to change their inhalation pattern or increase the number of cigarettes smoked to avoid lowering plasma nicotine levels.
This suggests that cigarette substitutes that mimic cigarettes, with the expectation of adjusting plasma nicotine concentrations to a certain range, may be most useful for smokers. Similarly, users of chewing tobacco or other forms of tobacco need substitutes that can mimic the plasma levels associated with using certain tobacco forms.

[0007] Withdrawal symptoms appear after the use of tobacco has ceased, which varies in strength and specific signs and symptoms from person to person. Although largely variable, the most common signs and symptoms are cigarette craving, irritability, anxiety, restlessness and difficulty concentrating. Drowsiness, headache, increased appetite, insomnia, and gastrointestinal complaints are also common. Supplementation with nicotine during this cessation period has been shown to increase the likelihood that in some cases the desire to quit smoking will be fulfilled.

[0008] Currently available substitutes include nicotine gum, sublingual lozenges, tablets, nasal sprays, vapor inhalants,
And patches. These substitutes rely on the fact that nicotine is easily absorbed from mucous membranes and skin. Because nicotine is a strong base, its absorption from the small intestine is limited unless its pH rises, where nicotine is rapidly and extensively metabolized during its first passage through the liver.

While these available substitutes eliminate the health risks associated with smoking cigarettes, they do not adequately satisfy the needs of smokers.

[0010] When smokers use nicotine gum, they are often encouraged to chew a piece of gum, with or without the urge to smoke. The instructions generally recommend chewing the gum very slowly until a slightly crisp stimulus is perceived in the mouth. When you feel this stimulating stimulus, it is recommended that you stop chewing the gum and wait until the stimulating stimulus is almost gone (usually within about 1 minute). Next, this chewing action is repeated periodically for about 30 minutes. This chewing method is designed to obtain a constant and slow oral absorption of nicotine from the gum. By obtaining a slow and constant absorption, nicotine levels in the bloodstream can be maintained at a constant level. Although there is some evidence that low and constant levels of nicotine reduce some of the nicotine withdrawal symptoms, smoker cravings for tobacco may subside at relatively low and constant levels of nicotine. No. This is why nicotine levels resulting from smoking are dramatically different from nicotine levels in the bloodstream achieved with nicotine gum in terms of nicotine concentrations in the bloodstream over time.

[0011] When nicotine is inhaled by smoking, nicotine is rapidly absorbed from the lungs and becomes smaller after the initial peak of nicotine in the bloodstream comes. The peak blood levels provided by cigarettes are higher and sharper than the uniform levels obtained from gum or transdermal systems. The initial peak nicotine blood concentration from smoking is generally 30-40 ng / ml.
Furthermore, this peak is achieved within about 10 minutes. Studies have shown that a soaring effect may be required to more completely reduce the desire in the early stages of cigarette cessation. Russell, MAH, In Nicotine Rep
lacement: A Critical Evaluation, Pomerleau, OF and
Pomerleau, CS, Alan R. Liss, Inc., New York,
See 1988, pp. 63-94. Russell shows that raising a nicotine blood level of at least 10 ng / ml within 10 minutes requires a post-synaptic effect at the nicotine receptor in the CNS and autonomic ganglia. These post-synaptic effects may be responsible for the drug-like "high" feeling such as dizziness or dizziness experienced by cigarette smokers. Thus, if nicotine can be delivered in a manner that mimics or mimics the way nicotine is delivered by smoking cigarettes, the desire of smokers for cigarettes can be reduced. The slow and constant absorption provided by the intermittent chewing of nicotine gum cannot achieve this result.

[0012] In order to imitate the inhalation of nicotine by smoking a cigarette, the user should chew nicotine gum more aggressively. However, this is generally not recommended as chewing nicotine gum too quickly can result in excessive release of nicotine and side effects similar to those of excessive smoking, such as nausea, hiccups and irritation of the throat. If you chew nicotine gum aggressively,
Large amounts of nicotine are swallowed because more nicotine is released than can be easily absorbed at the oral site. If too much nicotine is swallowed, the resulting nausea will be almost vomiting. Thus, nicotine gum cannot safely obtain a nicotine plasma concentration curve similar to that obtained by smoking cigarettes.

[0013] In addition, the use of nicotine gum does not meet the psychological demands of smokers who want something ritually in their mouth and out of their mouth. Nicotine gum is
It can be difficult to tolerate long-term treatment. The usefulness of nicotine gum formulations is limited by their poor taste, cannot be used effectively by denture wearers, and can cause mouth ulcers and heartburn. In addition, nicotine gum must be used to properly control nicotine levels in the blood, so that nicotine gum can be used to control nicotine within relatively narrow plasma concentrations as desired by heavy smokers. It can be difficult to adjust the level. Tablet-type smoking substitutes have similar disadvantages.

Transdermal patches containing nicotine have also been developed. These patches are designed to be applied to human skin. Then, the nicotine in the patch is absorbed from the skin. Due to the simplicity of this nicotine patch, patient compliance is usually high. Transdermal patches are being developed so that they can be replaced periodically. For example, patches are available that need to be changed once a day or perhaps once a week. The nicotine patch can deliver nicotine in such a way as to maintain a steady state nicotine concentration in the plasma. This eliminates the fluctuations that occur when using gums or tablets that must be taken on a regular basis.

As with nicotine gum, its delivery of nicotine into the body is at a relatively constant rate. Thus, these patches cannot closely mimic the plasma nicotine concentration curve obtained by smoking cigarettes. In addition, incorrect use of these patches can result in severe poisoning. For example, if an individual applies a patch and then smokes a few cigarettes, the plasma nicotine concentration will be much higher than the individual's previous ones. This is a nicotine overdose.

When using nicotine patches, other considerations must be taken into account. The lethal dose of nicotine in the average adult is about 60 mg. One cigarette is about 1
Send in mg of nicotine. Thus, a patch that is effective for 12 or 24 hours can contain 30-60 mg of nicotine. This represents a potentially lethal dose if the delivery of nicotine from the patch is significantly increased, thus raising safety concerns. this is,
This may occur if the patient is lying on a heating pad or bed. In addition, poisoning can occur, for example, if the patch is accidentally altered or swallowed by children. Furthermore, nicotine patches are
It does not provide oral stimulation to meet the psychological aspects of cigarette craving.

Thus, the current cigarette substitute is:
Although enough nicotine can be delivered to help alleviate some physical nicotine withdrawal symptoms,
It cannot provide a sharp rise in nicotine blood levels obtained by smoking cigarettes. Nor can they respond to the psychological demands of those trying to quit smoking. During the last few years, many ritualistic acts of smoking have been developed. One such ceremonial act involves periodically putting something in and out of a person's mouth, accompanied by oral irritation of adding cigarettes to the mouth.

In addition, patients are usually underdosed because physicians do not measure baseline nicotine or cotinine levels and do not teach patients the proper use of gums, tablets and / or patches. This may indicate a somewhat lower level of success with patches and gums. Some studies have shown that only about 20% of people who have used nicotine patches under instructions have managed to quit smoking. Other studies with nicotine gum have shown similar results. Nicotine nasal sprays also cause problems such as pain or irritability to the nasal mucosa. And while adequate plasma levels of nicotine can be achieved, oral satisfaction and sensory ritual behaviors remain unfulfilled.

[0019]

It is an object of the present invention to provide a nicotine-containing dosage form that can be utilized as part of a prolonged smoking cessation program.

Another object of the present invention is to provide a nicotine-containing dosage form suitable for use as a smoking substitute whenever smoking is not allowed or desired.

It is a further object of the present invention to provide a nicotine-containing dosage form that can maintain nicotine plasma levels within a range that reduces smoking withdrawal symptoms.

It is a still further object of the present invention to provide a nicotine-containing dosage form that can provide nicotine plasma concentrations similar to those achieved by smoking cigarettes.

Yet another object of the present invention is to provide a nicotine-containing dosage form that addresses some of the psychological needs of individuals who desire to quit smoking.

It is a still further object of the present invention to provide a nicotine-containing dosage form that is suitable for use by people wearing dentures or other dental appliances.

Another object of the present invention is to provide a nicotine-containing dosage form which is easy to use and facilitates patient compliance.

Yet another object of the present invention is to eliminate the desire for cigarettes by allowing a patient to self-administer an amount of nicotine that overcomes the individual needs of the patient.

Yet another object of the present invention is to provide a
It is to provide a nicotine-containing dosage form that can be used with a patch to allow the individual to control the dose at which they are treated when eakthrough craving occurs.

A still further object of the present invention is to obviate the need for nicotine by allowing the patient to self-administer.

It is a still further object of the present invention to provide a nicotine-containing dosage form that allows to suppress the occasional urge in patients experiencing relapse without increasing baseline nicotine plasma concentration levels. It is.

A nicotine-containing dosage form is provided to achieve the above objects and in accordance with the invention as specifically set forth and outlined herein. The dosage form is shaped to have the nicotine-containing composition attached to the holder member. Nicotine is released from the dosage form and is absorbed from the oral mucosal surface as the nicotine-containing composition releases nicotine in the user's mouth. The holder member is
Facilitates the user of the dosage form in and out of the mouth. The user can selectively put and take the dosage form as desired, and selectively control the release of nicotine to meet the user's individual needs. In addition, the user can enter and exit the dosage form in a manner that meets the user's psychological demands or desires for ritual oral stimulation similar to smoking a cigarette.

These and other objects and features of the present invention are:
It will become more fully apparent from the following description and the appended claims. Otherwise, it can be learned from the embodiments of the present invention described below.

[0032]

SUMMARY OF THE INVENTION In order to obtain the above-listed and other advantages of the present invention and the objects enumerated above and other objects, a more particular description of the invention briefly described above is provided. Will be given by reference to its specific embodiments shown in the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS These drawings are only intended to illustrate exemplary embodiments of the present invention, and are not to be construed as limiting the scope thereof, but by using the accompanying drawings in which: The invention will be more particularly described and explained in detail.

FIG. 1 compares serum nicotine concentrations and shows that plasma levels change within an individual after application of cigarettes, nasal sprays, gums and products of the present invention.

FIG. 2 is a comparative graph showing the absorption rate of the buffer treatment vs. the absorption rate of the non-buffer treatment.

FIG. 3 shows a non-degradable dosage form.

FIG. 4 shows a degradable dosage form with a cachet of varying nicotine concentrations.

FIGS. 5 to 9 show non-degradable dosage forms to which variable amounts and concentrations of nicotine can be administered.

FIGS. 10-15 show a series of degradable dosage forms for administering nicotine at varying concentrations, some of which are formed from compacted powders.

The present invention provides a smoking substitute, a smoking cessation aid, or, as described below, for use in treating diseases such as colitis, Tourette's syndrome, Parkinson's disease, and Alzheimer's disease. The present invention relates to a composition for facilitating transmucosal delivery of nicotine to a patient and a method for producing the same. Briefly, the present invention relates to a selectively removable nicotine-containing dosage form that allows for the transdermal delivery of nicotine from the mucosal tissues of the mouth, pharynx, and esophagus. The nicotine-containing dosage form of the present invention provides nicotine to a patient in a manner that responds to the physical need for nicotine exhibited by smokers by achieving a blood nicotine concentration similar to that achieved by smoking a cigarette. Can be pumped into the blood. In addition, the nicotine-containing dosage forms of the present invention can optionally provide the patient with the opportunity for physical activity and oral irritation associated with cycling the dosage form into and out of the patient's mouth. It responds to some of the psychological needs of nicotine expressed by smokers.

The present invention overcomes some of the limitations associated with nicotine-containing transdermal delivery systems, or nicotine-containing gums, tablets, nasal sprays, or lozenge delivery systems. One of the major advantages of the present invention is that the amount of nicotine released from the dosage form over time can be measured, for example, by changing the rate of consumption of the dosage form, exhaling the dosage form, The ability to be selectively altered by patient-controlled actions such as entry and / or by devising adaptations that affect the level of absorbable nicotine released from particular portions of the dosage form.

The nicotine-containing dosage form of the present invention is achieved by smoking a cigarette by maintaining a lower blood nicotine concentration for a period of time after achieving a relatively rapid initial increase in blood nicotine concentration. It is possible to imitate a pattern. Thus, the nicotine-containing dosage forms of the present invention can provide a more satisfactory smoking substitute than currently available nicotine delivery systems. This ability is demonstrated in FIG. 1, which shows the effect of administration of several popular dosage forms. It has been shown that serum nicotine first peaks after smoking a cigarette and then declines gradually. Nasal sprays most closely resemble the curve of a cigarette on this graph, but nasal sprays do not provide the psychological benefits of oral dosage forms. Of the oral dosage forms tested, the invention (shown as OT-NC) has the greatest potential to mimic the physiological and psychological effects of cigarettes. By adjusting the speed and intensity of licking the dosage form, serum levels can be altered to satisfy the individual needs of the individual. Thus, the peaks for the present invention on the graph can be changed to mimic the curve of a cigarette. Information about transdermal patches is not included on this chart, but it takes several hours to reach therapeutic blood nicotine levels and results in a quasi-steady state nicotine concentration.

FIG. 1 also shows that administration of conventional nicotine gum slowly and gradually increases serum nicotine and levels out over time. Gum dosage forms cannot mimic the effects of smoking, since administration of the gum does not result in an initial peak. Similarly, patches slowly increase serum nicotine slowly and remain horizontal and constant over time. Like gums, patches also do not provide the initial peak of serum nicotine, and therefore cannot mimic the action of cigarettes.

One of the advantages of the present invention is the ability to respond to the psychological desire of a cigarette smoker to ritually handle objects held in and out of the mouth. The nicotine-containing dosage form of the present invention comprises a holder member, such as a stick, and a nicotine-containing composition attached to the stick. The holder member facilitates the selective entry and exit of the dosage form into and out of the patient's mouth, so that the desired physical and psychological effects can be achieved. Unlike nicotine-containing gums, tablets, or lozenges, the dosage forms of the present invention can be used to assess the physical effects of absorbed nicotine, to temporarily stop absorption of nicotine, or at any time. Can be easily removed to check the size and condition of the In addition, the holder member prevents inadvertent swallowing of the dosage form and facilitates placing the dosage form in the mouth in a comfortable and adjustable manner. Thus, local mucosal hypersensitivity from continuing contact with the nicotine-containing gum, lozenge, or tablet can be avoided by using this holder member to displace the dosage form to the desired location in the oral cavity. .

The present invention can be used as a smoking substitute by persons in situations where smoking is not allowed or desired. In this situation, the nicotine-containing dosage form of the present invention
By providing both physical and psychological stimulation of the smoking experience, it provides a satisfactory substitute for cigarette smoking. The present invention can also be used by those who want to quit smoking but who are experiencing difficulties due to the emerging physical dependence on nicotine and the psychological dependence on smoking rituals. Such people have to go through a period of rest during which smoking habits are gradually overcome. In this situation, the nicotine-containing dosage form of the present invention satisfies both physical and psychological needs and, confidently, that the person is within a rest period sufficient to release the person from smoking habits. A means is provided to enable the desire for cigarettes to be resisted.

In the present invention, nicotine can be used in the form of a free base or a salt. Nicotine base is easily absorbed from mucous membranes but is very volatile. Nicotine salts, on the other hand, are not readily absorbed from the mucous membrane but are much more stable. Nicotine is also available as an ionic complex in the form of a polyacrylate cation exchange resin. Pharmaceutically acceptable nicotine salts include, but are not limited to, nicotine hydrochloride, nicotine dihydrochloride, nicotine sulfate, nicotine monotartrate, nicotine bitartrate, nicotine citrate, nicotine zinc chloride monohydrate and nicotine salicylate Not done. In an alkaline environment, ie, a pH above about 7, and in the presence of an aqueous medium such as saliva in the oral cavity, nicotine salts react to form nicotine base. Since saliva usually has a somewhat neutral pH, the addition of an alkaline salt into the dosage form of the present invention facilitates the reaction to produce a nicotine base that is easily absorbed as the pH is buffered. You. Preferred alkaline salts include sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium oxalate,
Includes sodium succinate, sodium citrate, trimetamine, and sodium salicylate. Buffer treatment can also affect stability. The results of the buffer treatment are shown graphically in FIG.

In addition to nicotine in a releasable form that is easily transmucosally absorbed, the nicotine-containing composition according to the present invention may also be used in flavors, sweeteners, flavor enhancers, lubricants, binders and fillers. Other components can be included. It should be noted that with regard to flavorings, it is desirable to deter nicotine use by young people. Therefore, it may be desirable to add a flavoring to the nicotine-containing composition in a manner that does not attract young people. It would even be desirable to provide a flavoring-free nicotine-containing composition that fits the mouth of a smoker who is accustomed to the taste of nicotine, but is unattractive to those less experienced.

The nicotine-containing dosage form of the present invention comprises any nicotine-containing composition capable of delivering nicotine that can be readily absorbed into the oral mucosal tissue, and a holder member attached in combination therewith. The form of nicotine incorporated in the nicotine-containing composition may be pure nicotine or any compound thereof. The method of manufacture may be any suitable method known in the art, including soluble or non-soluble matrix buccals intended to dissolve in the mouth to lick or do nothing. Includes, but is not limited to, adding a form of nicotine to the dosage form. Similarly, the method of attaching the holder member may be any suitable method known in the art, including placing the holder member in a non-solidified nicotine-containing composition and then compressing, injection molding or other. This includes, but is not limited to, solidifying by means and attaching to the previously prepared nicotine-containing composition by gluing, such as is done in confectionery glues, or by other means.

One method according to the present invention involves mixing the desired components to form a powdered, compressible matrix material and compressing it under high pressure into an integral solid mass. This method is called "powder compaction". The mass is attached to the holder member during compression to form a nicotine-containing dosage form. Alternatively, the mass may be attached to the holder member by another method such as bonding such as performed by a glue for confectionery.

More specifically, the components of the present invention are prepared by mixing each component, including the compressible carbohydrate filler and the binder, in dry form with the other components. At this time, the geometric dilution (geom
etric dilution).

Other ingredients typically used in powder compression methods include ingredients such as flavorings, sweeteners, flavor enhancers, release agents, and buffers. Even if these components happen to be insoluble or chemically incompatible, it is preferred to provide them in powder form so as to facilitate mixing.

Once thoroughly mixed, the mixture is compressed with relatively high force to obtain a cohesive dosage form. At present about 10
A compression force of 0 Newtons to about 150 Newtons is preferred, but any force sufficient to compress these components into a coherent mass may be used. As a result, the compacts are held together by physical rather than chemical means.

The degree of compressive force can be adjusted to vary the rate of dissolution, ie, the rate at which the composition dissolves in the oral cavity. In particular, the greater the compression force used, the slower the dissolution rate will be. The dissolution rate can also be affected chemically by other components. For example, the dissolution rate can be reduced by adding a hydrophobic substance such as calcium stearate, and the dissolution rate can be increased by adding a hydrophilic substance.

When using the present invention, it is not necessary to heat the mixture into a molten mass as is conventional in the manufacture of drug-containing sugars. As a result, the method avoids using high temperatures that would volatilize the nicotine, and also avoids undesirable chemical reactions that may occur between the various components in a heated or liquid environment. Nevertheless, good mixing and a homogeneous product are obtained.

The confectionery mass can be mounted on a holder such as a stick or other similar type of holder. The holder can be glued to the confection by a confectionery glue or other food glue. Further, the holder may be compressed into the present dosage form by the above-mentioned compression force.

One method of making an embodiment of the present invention utilizes a front-sided mold block having cavities formed in any desired shape to combine the components described above so that a suitably shaped dosage form can be formed. This is a method of sufficiently compressing.
The mold block is separated in half so that the confection can be removed once it has been sufficiently compressed. A ram is used to compress the cavity. After compressing the confection, stick the stick firmly in place.

This stick can take various shapes. For example, the cross-section of the stick may be oval or triangular.

Another method utilized to make embodiments of the present invention involves a non-soluble matrix having nicotine incorporated therein.

Nicotine can be incorporated into a variety of possible insoluble containment matrices. For example, incorporating nicotine into a sponge-like matrix, encapsulating nicotine in a microcapsule, retaining nicotine in a microsponge, including nicotine in a permeable membrane or screen-like barrier, or Nicotine may be retained in other non-soluble, containment vehicles capable of releasing nicotine for transmucosal administration.

The scope of the present invention includes embodiments having a permeable membrane or screen-like barrier that holds the nicotine-containing vehicle.

The barrier may be like a screen with relatively large pores or a membrane with relatively small pores. The barrier preferably has pores large enough to allow nicotine to pass therethrough. It is important that nicotine is retained in the barrier under conditions outside the patient's mouth and that nicotine can penetrate the barrier in the patient's mouth.

For example, in one preferred embodiment within the scope of the present invention, the viscosity of the drug medium is sufficiently high outside the mouth so that the surface tension in the pores of the barrier prevents nicotine from penetrating the barrier. To do it. However, once the dosage form is placed in the patient's mouth, the viscosity of the drug medium is reduced, allowing nicotine to penetrate the barrier. In one embodiment, the viscosity of the drug medium is lower in the mouth due to contact between saliva and the drug medium. In other embodiments, the temperature of the drug medium is lower in the mouth due to the higher temperature in the mouth.

In another embodiment within the scope of the present invention, nicotine in the drug medium permeates the barrier by the action of pressure in the mouth. For example, the negative pressure created by licking this dosage form pulls the drug out of the barrier. Also, the positive pressure created by squeezing the dosage form pushes the drug out of the barrier.

[0063] One embodiment utilizes microencapsulated drug particles held within a permeable barrier. Microencapsulated drugs are nicotine particles or droplets coated with a protective coating material. Typical coating materials include fats; waxes; triglycerides; fatty acids;
Fatty alcohols; ethoxylated fatty acids and alcohols;
Poly (ethylene glycol); gums; hydrocolloids; latex; and various polymers such as polyethylene, ethyl cellulose, ethylene-vinyl acetate, ethylene-acrylic acid, polyamides and some enteric polymers. Base formulations are included.

The microencapsulated nicotine protective coating material inhibits nicotine degradation due to moisture, slows nicotine oxidation, reduces evaporation and sublimation, protects nicotine from reaction with other components, and reduces nicotine's unpleasant Mask the taste. Nicotine microencapsulation methods are known in the art.

Another embodiment utilizes a plurality of drug-containing sponge-like matrices held in a barrier. Sponge-like matrices, including microsponges, are devices that can release a drug over time after it has been entrapped. These sponge-like matrices
It is biologically inert, non-irritating, non-mutagenic, non-allergic, non-toxic and non-biodegradable. They can even improve the stability of the drug. Suitable microsponges or sponge-like matrices are known in the art.

Like a real sponge, this sponge-like matrix or microsponge contains a myriad of interconnected voids in a non-collapsible structure having a large porous surface. The size of this sponge-like matrix and the number and size of the internal pore structure can be varied depending on the size and viscosity of the drug.

Drug is released from the sponge-like matrix in response to a suitable "trigger". For example, rubbing or applying pressure to a sponge-like matrix, increasing the temperature of the matrix (same as in the patient's mouth relative to ambient temperature), or introducing a suitable solvent such as saliva will control the drug. Can be released. Pressure can also be used to release the drug from the sponge-like matrix. Squeezing or licking a dosage form containing a sponge-like matrix saturated with drug will release the drug.

In another embodiment within the scope of the present invention, a sponge-like matrix or microencapsulated nicotine particles are coated with a biocompatible binding substance or adhesive such as sodium carboxymethylcellulose, sodium alginate, and tragacanth, even if soluble. (Which may be insoluble).

In yet another embodiment of the present invention, the sponge-like matrix or microencapsulated nicotine particles may be held in a compressed powder dosage form or other degradable dosage form using the powder compression method described above. it can.

In these embodiments, a plurality of microencapsulated nicotine particles are compressed into a dosage form together with a compressible sugar and other ingredients described above. Preferably,
A handle is also attached to the dosage form.

The handle or holder can be mounted within the non-soluble matrix by incorporating the holder into the non-soluble matrix when forming the dosage form.

Also, once the non-soluble matrix has been formed, the holder may be glued, compressed, screwed on, snapped into the matrix,
Or it can be mounted in other ways. In still other embodiments, the dosage form can be assembled immediately before use by sliding the non-dissolvable connectable dosage element containing the appropriate drug onto a suitably shaped holder. In some cases, a soluble or non-soluble connectable element with a flavoring agent may be slid onto the holder.

In one embodiment, shown in FIG. 3, a permeable barrier 40 defines a chamber 42 and an opening 44 to the chamber. This chamber contains micro sponge, microencapsulated drug particles, drug medium,
Or nicotine composition 4 in the form of another similar drug-containing formulation
6 is filled. Holder 48 includes a cover 50 for opening 44. The cover 50 is shaped to securely seal the opening 44 while providing a means for attaching the holder 48 to the dosage form. In this way, a certain amount and concentration of nicotine can be placed in the dosage form before use. If needed, nicotine can be replenished or replaced during use.

It will be appreciated that mounting the nicotine-containing matrix on a holder facilitates transmucosal absorption of various therapeutic agents. Attaching the holder makes it easier to ascertain the transfer of the drug to the patient. For example,
The drug may be dyed such that a lighter color indicates the transfer of the drug to the patient. The holder is
It provides a convenient reference point that allows the nicotine containment matrix to be placed at the desired location in the patient's mouth and allows a health professional to ascertain the exact location of the matrix.

The dosage form 60 shown in FIG. 4 contains a plurality of connectable administration elements 62. Dosing element 62 includes a solid core 64 that defines a male connection 66 and a female connection 68. The dosing cap 70 is shaped substantially the same as the dosing element 62 except that its solid core does not define a male connection. These dispensing elements are preferably composed of a screen-like material such as a woven or perforated sheet material molded or assembled around a solid core. The solid core can be composed of a suitable biocompatible material, such as polystyrene. This screen-like material defines a chamber for holding the desired drug and releases the drug in substantially the same manner as described above in connection with FIGS.

The dosage form 60 is constructed by interlocking a plurality of dosage elements with their respective male and female coupling hands. A holder 72 comprising a male connecting hand 74 formed at one end thereof is preferably connected to the connectable dosing elements. Because the dosage form can be assembled before use, it can be "customized" to an individual patient or situation. In this way, different concentrations of one drug or even multiple drugs can be administered.

FIGS. 5 and 6 illustrate other possible dosage form embodiments within the scope of the present invention. Dosage form 80 contains semi-solid core 8
4 includes a cover material 82 molded around. This semi-solid core is preferably mounted on a holder 86. The cover material 82 is preferably a thick mesh or perforated sheet having the desired drug 88 embedded therein to allow the drug to leach or enter the patient's mucosa. Will. The drug may be in powder, liquid, microencapsulated, or otherwise packaged within cover material 82 for release into the oral environment.

In the embodiments shown in FIGS. 7 to 9, the nicotine administration rate can be controlled by adjusting the pressure applied to the drug vehicle. Dosage form 90 shown in FIGS.
Includes a holder 92 and a screw 94 threaded through the interior of the holder 92. A semi-permeable membrane 98 that is securely tied to the holder 92 and screw cap 96 provides a containment barrier for a quantity of the drug medium 100. The membrane 98 is similar to the one described above by having pores large enough to allow the drug to pass through it in the oral environment. The drug vehicle may be a liquid drug solution or a suspension.

In use, the dosage form 90 is placed in the patient's mouth, and the screw 94 is turned to place the drug medium 100 under pressure, thereby increasing the rate at which the drug permeates the membrane 98.

The embodiment shown in FIG. 9 is similar to the embodiment shown in FIGS. 7 and 8, except that the drug is embedded in a semi-solid drug medium 102 that can be compressed. In use, the dosage form is placed into the patient's mouth, and the drug is directly released and absorbed from the patient's mucosa by turning the screw 94 and compressing the drug medium 102.

FIGS. 10 and 11 show yet another possible embodiment within the scope of the present invention. Dosage form 110 includes a plurality of tube-like members 112 located around the outer periphery of semi-solid core 114. This semi-solid core is preferably mounted on holder 116. In some cases, a layer of intumescent material 118 may be applied between the tube-like member and the semi-solid core.

These tube-like members are formed from a screen-like material 120 such as nylon or Dacron mesh molded into a semi-cylindrical shape. These tube-like members are mounted on the expandable material 118 so that the screen-like material provides a barrier for a quantity of the drug 122. Preferably, the expandable material 118 comprises methylcellulose or a similar material wrapped in a porous mesh that hydrates and expands when placed in the patient's mouth. When inflated, the high pressure on the porous tube-like member increases the rate at which the drug is released from the dosage form.

The embodiment shown in FIG. 12 is similar to the embodiment shown in FIGS. 10 and 11, except that the drug is embedded directly in the expandable material 124, such as methylcellulose. The drug is released as the material 124 expands in the patient's mouth.

In another optional embodiment not shown in these figures, the semi-solid core 114 is made of a polyethylene or similar material that is capable of expanding upon injection of air relative to the drug-containing tube-like member. Replace with a hollow tube configured. The pressure over the tube-like member (from a known volume of infused air) and the size of the pores govern the delivery rate of the drug.

FIGS. 13 and 14 show a modified dosage form of the embodiment shown in FIG. Dosage form 13 of FIGS. 13 and 14
0 includes a plurality of tube-like members 132. FIG. 14 shows a cross-sectional view of the tube-like member 132. The member 132 is
A screen-like material 134 is included that encloses an amount of the drug medium 136 therein. A hard mandrel 136 is attached to the screen-like material 134 and is shaped to slide and lock into corresponding grooves formed in the solid core 138. Handle 140 is preferably rigidly attached to the solid core to facilitate access to the dosage form.

The dosage form 130 can be assembled prior to use by sliding the rigid mandrel of the plurality of tube-like members 132 into corresponding grooves formed in the solid core. Because the dosage form can be assembled before use, it is possible to "customize" the dosage form to an individual patient or situation. In this way, different concentrations of nicotine or even multiple drugs can be administered.

FIG. 15 shows another possible dosage form embodiment that can be assembled separately before use. The dosage form 150 of FIG. 15 is assembled from a plurality of dosing elements 152. Each dosing element includes a ring 154 disposed around a semi-solid disk 156. Ring 154 may be woven nylon or Dacron or perforated nylon,
Made from a suitable porous material, such as a sheet of polypropylene or polyethylene. Ring 154 is filled with either a liquid or powdered drug. These semi-solid disks define holes 158 therein so that a plurality of dosing elements can be assembled on the holder. Because the dosage form 150 can be assembled prior to use, it is possible to “customize” the dosage form for an individual patient or situation. In this way, different concentrations of nicotine or even multiple drugs can be administered.

The above dosage forms have been set forth to illustrate various embodiments that can be made in accordance with the present invention.
It should be understood that the relative disposition of the above dosage forms is not exhaustive or exhaustive of many types of embodiments of the present invention. It is important that the relative configuration of the non-degradable dosage form is biocompatible and capable of releasing nicotine for absorption from the patient's mucosal tissue. This relative arrangement should preferably have a structure, shape, and texture that fits the patient's mouth.

Placing the nicotine dosage form on a holder also facilitates the temporary removal of the drug when needed for testing or reducing its action. Unlike administering nicotine orally or sublingually, the composition can be easily removed at any particular time to assess the effect elicited. With pills or lozenges, it is generally difficult, if not impossible, to take action out of the patient's mouth at an intermediate stage, if not impossible.

In contrast to lozenges, insoluble drug-containment matrices attached to holders can also prevent or make the dosage form more difficult to swallow. One of the major problems with current lozenges and the like is that they tend to collapse. Once the lozenges disintegrate, the control of transmucosal delivery is less than ideal and swallows the particles. Many of the dosage forms described herein dissolve but do not or cannot disintegrate.

In addition, one or both of the drug and the permeation enhancer may be uniformly dispersed throughout the soluble solid matrix composition, or may be selectively dispersed, ie, layered or coated. The absorption of the drug from selected portions of the soluble solid matrix can also be altered. It will be appreciated that the layered nicotine-containing composition can be formulated to maintain a relatively low blood nicotine concentration after providing a relatively sharp initial rise in blood nicotine concentration. This can be achieved, for example, by formulating a two-layer composite matrix comprising an inner matrix and an outer matrix. The solubility of the matrices could be different such that the outer matrix dissolves more rapidly in the oral cavity than the inner matrix.

Also, the concentration of the nicotine compound in the matrices could be different, such that the outer matrix releases more nicotine than the inner matrix. In any of these multi-layer embodiments, blood nicotine levels will rise relatively more rapidly while the patient is consuming the outer matrix than while the patient is consuming the inner matrix.

Further selectivity and control of nicotine release and absorption rates can be achieved with more matrix layers and / or in the manner described above, ie, altering matrix solubility, altering permeation enhancers, or It could be obtained by combining methods such as changing the concentration. It will be appreciated that more than two layers can be incorporated into the multilayer nicotine-containing composition to further vary the effect as desired. The presence of an additional layer can be indicated by a change in color or flavor.

In the disclosed formulations, the amount of nicotine in each dosage form is preferably less than 30 mg, most preferably 0.5 to 0.5 to avoid accidental overdose by swallowing.
20.0 mg. A currently preferred embodiment is one that utilizes nicotine bitartrate. The dosage forms of the present invention include a holder member to prevent swallowing of the dosage form, but are still ingested by keeping the nicotine dose low in individual dosage forms, thereby controlling the number of dosage forms used. It would be preferable to allow the patient to easily and selectively control the amount of nicotine.

As disclosed in the patents referred to above,
Nicotine-containing compositions intended to be licked are preferably buffered so as to enhance transmucosal absorption by enhancing transport or absorption from the oral mucosa, so that the percentage of unionized drug can be increased or maintained. You. Preferred formulations have a pH of 6.8-11. As described above, buffered formulations include sodium carbonate, sodium phosphate, calcium carbonate, magnesium hydroxide,
It would include trimetamine and other materials known in the art.

The stability can be increased by adding a buffer. Further, a buffer may be confined in a water-soluble material to improve stability. Nevertheless, the unit can still provide an optimal pH in the mouth as it dissolves.

The buffered nicotine-containing composition formulated by direct compression comprises a directly compressible excipient, a pharmaceutically acceptable salt of nicotine, and a base sufficient to maintain a particular pH level in the patient's mouth. Can be included. The formulation is mixed with a suitable diluent and compressed, or compressed with a particulate "core" containing a portion of the buffering base component.

Other methods include cold-pressing a mixture containing an inert filler material, an inert binder material, and a solution of nicotine or a nicotine-containing substance in alcohol,
Methods of extruding or drying to formulate nicotine-containing dosage forms are included. This form can include, for example, a coating containing a substance to enhance the solubility of the composition or a substance that acts as a local anesthetic to reduce local irritation perceived from nicotine absorption sites. Nicotine is released in different amounts or absorbed at different rates in each layer, similar to the approach described above for "layered" soluble solid matrices using a method similar to this "coating" method It will be appreciated that a multi-layered nicotine-containing composition can also be obtained that is capable of being performed.

Another embodiment of the present invention utilizes a compressed carbohydrate powder matrix having a substantially uniform mixture of a buffer coated therein. The buffer is coated with a water-soluble material so that it is released in the patient's mouth. Upon release, the buffer will slightly alter the pH of saliva in the patient's mouth, enhancing nicotine absorption. By coating the buffer before mixing with the matrix, the stability of the mixed matrix is maintained.

In addition, methods for formulating dissolvable nicotine-containing matrices for buccal dosage forms that melt in the user's mouth but are stable at high shipping and storage temperatures are known and can be incorporated.

As explained above, tobacco substitutes have several uses. Smokers who do not want to expose others to the effects of secondhand smoke can use tobacco substitutes for short periods of time, such as when traveling by plane or during working hours.

[0102] Long-term tobacco users will no longer use these products because they can be chewed and damaged from cigarettes, but they still feel the need for nicotine.

For those who want to stop smoking or using snuff, tobacco substitutes can be used to cut off the individual from nicotine cravings. By slowly reducing the amount of nicotine consumed, an individual can reduce its desire without experiencing the major side effects of stopping.

A similar group of tobacco substitute users is:
We use that substitute only to address peak demand periods. These individuals do not use the substitute on a regular basis, but instead use it only when necessary to address the occasional desire to exceed their determination.

While nicotine is often consumed in the form of cigarettes with the deleterious effects of tar and smoke, nicotine is beneficial in treating Alzheimer's disease, ulcerative colitis, Tourette's syndrome, and Parkinson's disease. Has been found to have a significant effect. Although provided as a tobacco substitute, the present invention is also directed to beneficial administration of nicotine for the treatment of these and other diseases. In these applications, by handling the product of the present invention, patients can precisely determine the amount of nicotine in order to prevent side effects such as nausea. The present dosage form not only contributes to patient comfort by preventing side effects, but also provides additional safety measures because the dosage form can be removed by the patient as well as by other care providers. Unlike other dosage forms that have a slower or slower absorption rate,
The user can remove the dosage form at the first sign of nausea and does not need to use up the entire dosage form. This opportunity is not available with slower acting dosage forms such as swallowable therapeutics or patches.

The present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The described embodiments are to be construed in all respects only as illustrative and not restrictive. The scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes that come within the meaning and range of equivalency of the claims should be included within their scope.

[Brief description of the drawings]

FIG. 1 is a graph comparing serum nicotine concentrations, showing that plasma levels change in an individual after application of cigarettes, nasal sprays, gums and the invention.

FIG. 2 is a comparative graph showing the absorption rate of buffer treatment vs. the absorption rate of unbuffered agent treatment.

FIG. 3 is an illustration of a non-degradable dosage form.

FIG. 4 is an illustration of a degradable dosage form having a cachet of varying nicotine concentrations.

FIG. 5 is an illustration of a non-degradable dosage form that can administer variable amounts and concentrations of nicotine.

FIG. 6 is an illustration of a non-degradable dosage form that can administer variable amounts and concentrations of nicotine.

FIG. 7 is an illustration of a non-degradable dosage form that can administer variable amounts and concentrations of nicotine.

FIG. 8 is an illustration of a non-degradable dosage form that can administer variable amounts and concentrations of nicotine.

FIG. 9 is an illustration of a non-degradable dosage form that can administer variable amounts and concentrations of nicotine.

FIG. 10 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

FIG. 11 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

FIG. 12 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

FIG. 13 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

FIG. 14 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

FIG. 15 is an illustration of a degradable dosage form for administering nicotine at varying concentrations.

Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 9/50 A61K 9/50 NV (72) Inventor Brian I Hague 84119, Utah, United States, West Valley City, South Howard 4478 (58) Fields surveyed (Int.Cl. ⁶ , DB name) A61K 31/465 ADR A61K 31/465 AAM A61K 9/00 A61K 9/20 A61K 9/48 A61K 9/50

Claims (24)

(57) [Claims] 1. A selectively removable nicotine delivery device for use in transmucosal delivery of nicotine to a patient, comprising: (a) a matrix soluble in the oral cavity of the patient; A pharmaceutically effective dose of nicotine dispersed in the matrix, wherein the pharmaceutically effective dose of nicotine is dissolved in the patient's mouth, pharynx, and when the matrix dissolves in the patient's mouth. Nicotine released for absorption from mucosal tissue of the esophagus; (c) a buffer that slightly alters saliva pH in the patient's mouth;
And (d) a holder member securely attached to the matrix so as to facilitate handling of the nicotine delivery device and to allow for selective access of the delivery device into and out of the patient's mouth. Holder member formed in 2. The dose of the nicotine free base equivalent is 0,2.
2. The selectively removable nicotine delivery device of claim 1, wherein the nicotine delivery device is in the range of 1-30 mg. 3. The selectively removable nicotine delivery device of claim 1, wherein the nicotine is present in the matrix in the form of a nicotine free base. 4. The selectively removable nicotine delivery device of claim 1, wherein the nicotine is present in the matrix in the form of a nicotine salt. 5. The composition of claim 1, further comprising a buffer dispersed within said matrix, said buffer being capable of increasing the pH in said oral cavity, thereby enhancing the absorption of said drug from said oral mucosa. Ionization part can be increased,
The selectively removable nicotine delivery device of claim 4. 6. The selectively removable nicotine delivery device of claim 1, wherein said matrix further comprises a multilayer composition. 7. The selectively removable nicotine delivery device of claim 6, wherein the multilayers contain different amounts of nicotine. 8. The selectively removable nicotine delivery device of claim 1, further comprising a coating layer containing an absorption enhancer. 9. The selectively removable nicotine delivery device of claim 1, further comprising an outer coating layer containing nicotine. 10. The method of claim 1, wherein the concentration of nicotine available for absorption from mucosal tissues of the mouth, pharynx, and esophagus changes over time as the matrix dissolves in the patient's mouth. 2. The selectively removable nicotine delivery device of claim 1, wherein nicotine is dispersed within the matrix. 11. The selectively removable nicotine delivery device of claim 6, wherein the concentration of nicotine in the outer layer of the matrix is higher than the concentration of nicotine in the inner layer of the matrix. 12. A method of making a selectively removable nicotine delivery device for transmucosal delivery of nicotine to a patient, comprising: (a) obtaining a pharmaceutically effective dose of nicotine. (B) dispersing the nicotine in a mixture of matrix material that can be dissolved in the mouth of a patient; (c) forming the matrix material and nicotine into an integrated solid mass; Securely attached to the integrated solid mass. 13. A selectively removable nicotine delivery device for use in transmucosal delivery of nicotine to a patient, comprising: (a) a soluble, compressible, substantially powdered carbohydrate. (B) nicotine distributed within the carbohydrate material,
It can be absorbed from the mucosal tissues of the mouth, pharynx, and esophagus, and is distributed substantially uniformly throughout the carbohydrate material at a temperature below the melting point of the nicotine and the carbohydrate material and within the patient's mouth Because it is compressed with the carbohydrate material into an integral solid mass that can be dissolved,
Nicotine released for absorption from the mucosal tissues of the mouth, pharynx, and esophagus upon dissolution of the solid mass in the patient's mouth; (c) also substantially uniform throughout the mass A microencapsulation buffer, which slightly changes and maintains the pH in the mouth so that most of the drug remains unionized to facilitate transmucosal absorption of the drug And (d) a holder rigidly attached to the monolith, the holder being shaped to allow the nicotine-containing monolith to be conveniently inserted into and out of the patient's mouth. . 14. The selectively removable nicotine delivery device of claim 13, wherein the microcapsules are water soluble so as to dissolve in the mouth of the patient. 15. The selectively removable nicotine delivery device of claim 13, wherein the buffer is encapsulated in a water-soluble material. 16. The selectively removable nicotine delivery device of claim 13, wherein the nicotine is in the form of a nicotine salt. 17. The selectively removable nicotine delivery device of claim 13, wherein the nicotine is in a free base form. 18. A selectively removable non-soluble nicotine delivery device for use in transmucosal delivery of nicotine to a patient, comprising: (a) a non-soluble drug-entrapping matrix; (b) A pharmaceutically effective dose of nicotine in a form that can be absorbed from the mucosal tissues of the mouth, pharynx, and esophagus and contained within the non-soluble drug-containing matrix, wherein the matrix comprises the mouth, pharynx, and Nicotine capable of releasing the drug into the patient's mouth for absorption from the mucosal tissue of (c) a buffer that slightly alters the pH of saliva in the patient's mouth; and (d) nicotine delivery. A holder secured to the drug-containing matrix to form a device, the holder being shaped to allow the nicotine-containing matrix to be conveniently inserted into and out of the patient's mouth. Over. 19. The selectively removable non-soluble nicotine delivery device for use in transmucosal delivery of nicotine to a patient according to claim 18, wherein the delivery device further comprises a buffer. 20. The selectively removable non-soluble nicotine delivery device for use in transmucosal delivery of nicotine to a patient according to claim 18, wherein the buffer is encapsulated in a water-soluble material. 21. The selectively removable non-soluble nicotine delivery device for transmucosal delivery of nicotine to a patient according to claim 18, wherein the nicotine is in the form of a nicotine salt. 22. The selectively removable non-soluble nicotine delivery device for use in transmucosal delivery of nicotine to a patient according to claim 18, wherein the nicotine is in a free base form. 23. The nicotine delivery device for transmucosal delivery of nicotine to a patient according to claim 18, wherein the nicotine is microencapsulated. 24. The drug delivery device for transmucosal delivery of nicotine to a patient according to claim 18, wherein the nicotine is contained in a plurality of micro sponges.