CN101437496A

CN101437496A - Chewing gum compositions providing rapid release of nicotine

Info

Publication number: CN101437496A
Application number: CNA2007800162254A
Authority: CN
Inventors: A·埃克塞尔松; A·克里斯坦森; H·翰松
Original assignee: Niconovum AB
Current assignee: Niconovum AB
Priority date: 2006-03-16
Filing date: 2007-03-16
Publication date: 2009-05-20
Also published as: CN101437497A

Abstract

Compositions comprising nicotine, which compositions provide a rapid release of nicotine. Nicotine is present in the form of a nicotine-cellulose combination. The compositions are designed for administration to the oral cavity where the nicotine is rapidly released from the composition and available for absorption through the oral mucosa. The compositions are lozenges and have excellent storage stability.

Description

The stable lozenge composition of nicotine rapid release is provided

Invention field

The present invention relates to contain the compositions of nicotine, said composition provides the rapid release of nicotine.Nicotine exists with the form of nicotine-cellulose combination.Compositions is designed to oral cavity medicine, nicotine rapid release from compositions in the oral cavity, and absorb by oral mucosa effectively.Said composition is a lozenge, and extraordinary storage stability is arranged.

Background of invention

Cigarette smoking not only has serious health risk to smoker itself, and is like this equally to the passive smoking crowd around it.So smoking cessation has been expert's suggestion for many years.Yet the smoker is to nicotine addiction, and this makes most of smoker be difficult to smoking cessation.The nicotine medication of having used other is to make great efforts the helping smoker to abandon their unhealthy custom.Present several use nicotine product oral or percutaneous dosing is available to the smoker who wants to give up smoking, as chewing gum, inhaler, patch or mouthspray.

Because Nicotiana tabacum L. itself also contains several other toxic compounds except nicotine, the nicotine replacement product also is correlated with concerning the individual who consumes Nicotiana tabacum L. by the mode beyond the smoking.Mainly in the Scandinavian Peninsula, particularly in Sweden, Nicotiana tabacum L. is consumed by chewing tobacco or Folium Nicotianae preparatum.Use the nicotine replacement product will save the chewing tobacco or the Folium Nicotianae preparatum of consumer and make the smoker avoid the carcinogenic risk that Nicotiana tabacum L. causes.

No matter as above-mentioned those the availability of several nicotine replacement product, many individuals to nicotine addiction find that still it is difficult abandoning consuming Nicotiana tabacum L..Explanation to this is possible be the combination of multiple factor, and wherein 2 are the concentration that reaches about nicotine in the blood flow and the more important thing is that nicotine arrives the speed of blood flow and therefore offers the effect that user is thirsted for.

The speed that nicotine arrives blood flow can limit by the external speed of nicotine replacement product release of nicotine.Therefore, have to have the nicotine rapid release, such as the needs of the pharmaceutical composition of the nicotine that discharges in a kind of external fast and/or body to comprising.In addition, the rapid release of nicotine make in the compositions must nicotine total content minimize, this in consumer to being favourable aspect total picked-up of this potential toxic compounds with making economic aspect.

The lozenge composition that contains nicotine has been described in front, but according to known to the inventor, can not provide a kind of and firmly not pack the lozenge composition that the rapid release that enough storage stabilities are arranged under the situation contains nicotine.Stability problem is main relevant with the volatility of nicotine (it is a liquid form as free alkali).

The invention summary

The present invention is devoted to the problems referred to above by the compositions that a kind of energy rapid release nicotine is provided, thereby the rapid release of nicotine blood plasma concentration is provided on using in vivo.The form of compositions is the tablet (form of lozenge just) that the buccal absorbs, and its shelf-life is 24 months or longer.Compositions useful as drug compositions and/or tobacco substitute compositions.

Thereby, the present invention relates to the use of a kind of nicotine-cellulose combination and one or more be used to prepare lozenge composition to reach the pharmaceutically acceptable excipient that begins fast that compositions is applied to the nicotine effect after the subject oral cavity.

The inventor finds that the resolving time should be 15 minutes or faster in the body in order to realize the quick initial release of nicotine.Resolving time is used by lozenge that institute decides the time time-consuming and decomposition fully in the body.

In addition, the invention provides a kind of lozenge composition, it has suitable storage stability and needn't be sealed by Barex and prevents any disappearance of nicotine from compositions.Shown in this paper embodiment, obtain the storage stability at room temperature at least two years.

In current context, term " nicotine-cellulose combination " meaning is the solid material that expression is made up of cellulose, it adsorbs (absorption and/or absorb) clear and definite nicotine (or as free alkali or as pharmaceutically acceptable salt, complex or solvate) of amount, for instance in space in cellulose or the hole and/or on.Term used herein " nicotine-cellulose adduct " and " nicotine-cellulose carrier complex " are equivalent in meaning with term " nicotine-cellulose combination ".Cellulose used herein is a kind of example of carrier.

Compositions of the present invention has the quick initial release of nicotine, thereby, said composition---when decomposing when test outside the acceptor---is release of nicotine in on-test back two minutes, and its release rate correspondingly is the 10%w/w of total content in the per minute compositions or more.

For as to the acceptable product of consumer, beginning fast of nicotine effect is very important.Therefore, for lozenge composition of the present invention, in 3 minutes after beginning to occur in compositions and being applied to subject oral cavity, such as in 2.5 minutes or in 2 minutes.

Therefore, in yet another aspect, the present invention relates to the compositions that contains nicotine or pharmaceutically acceptable salt, solvate, complex, adduct or derivatives thereof and one or more pharmaceutically acceptable excipient of solid or semisolid dosage form form, lozenge composition in particular, wherein---when accepting external decomposition test as herein described---release of nicotine in on-test back two minutes, its release rate correspondingly are the 7.5%w/w of total content in the per minute compositions or more.

Shown in this paper embodiment, it has been observed by the present inventors that the especially suitable quick appearance that realizes that nicotine in the blood plasma is gone up in rapid release and use in vivo subsequently of compositions of lozenge form.Therefore, in special embodiment, the present invention relates to

I) a kind of lozenge that contains nicotine or pharmaceutically acceptable salt, solvate, complex, adduct or derivatives thereof and one or more pharmaceutically acceptable excipient, wherein---when accepting external decomposition test as herein described---release of nicotine in on-test back two minutes, its release rate correspondingly are the 7.5%w/w of total content in the per minute compositions or more; With

In addition, the invention provides this method for compositions of preparation, comprise nicotine or pharmaceutically acceptable salt or derivatives thereof and one or more pharmaceutically acceptable mixed with excipients, and make it become suitable solid dosage form.

The present invention also relates to be used for the treatment of the purposes of nicotine addiction and/or nicotine withdrawal symptom according to inventive compositions.

In order to understand following detailed Description Of The Invention better, foregoing has been summarized feature of the present invention and technical advantage quite widely.Invention additional features and advantage will be in following descriptions, and it forms the theme of invention claim.It will be understood by those skilled in the art that disclosed notion and particular embodiment can be easily with being to improve or design the basis that other is used for realizing the structure of the identical purpose of the present invention.One of ordinary skill in the art would recognize that this structure that is equal to does not deviate from invention spirit and category that claims are illustrated.About the novelty of its tissue and operational approach aspect, it believes it is feature of the present invention, with further target and advantage will be better understood by following description when together considering with accompanying drawing together.Yet we should be expressly understood that every figure is provided just to illustrating with purpose of description, are not to plan to be defined as restriction of the present invention.

Detailed Description Of The Invention

Be consistent with long-standing Patent Law convention, speech " " is used in this description with " one " when echoing mutually with the speech that contains, when comprising in the claim, and expression " one or more ".The invention some embodiments can by or mainly constitute by one or more elements, method step and/or inventive method.About any other method described herein or compositions, expect that any method described herein or compositions can be implemented.

As mentioned above, the present invention relates to contain the compositions of nicotine, its release of nicotine is very soon particularly to realize rising very fast in the plasma concentration by oral mucosa by administration.Especially, the present invention relates to be fit to nicotine is transported to the compositions such as the lozenge of the form of oral mucosa.

Aspect first, the present invention relates to the lozenge composition that contains nicotine or pharmaceutically acceptable salt, solvate, complex, adduct or derivatives thereof and one or more pharmaceutically acceptable excipient of a kind of solid or semisolid dosage form form, wherein---when accepting external decomposition test as herein described---release of nicotine in on-test back two minutes, its release rate correspondingly are the 7.5%w/w of total content in the per minute compositions or more.Prove that as this paper embodiment this rapid release is not by chewing gum such as Nicorette

The sale of form compositions obtained.For this reason, the lozenge composition that it has been observed by the present inventors that tablet form compares Nicorette

Chewing gum compositions has superiority especially, and, in order to obtain release as quickly as possible, use containing nicotine compound and also can having superiority of specific form.

More particularly, the 10%w/w that above-mentioned rate of release in on-test back two minutes is a total content in the per minute compositions or more is such as 11%w/w or more, 12%w/w or more, 13%w/w or more, 14%w/w or more, 15%w/w or more.

In a special embodiment, further comprise microcrystalline Cellulose (" mcc ") according to inventive compositions.Some special embodiment also can be utilized the carrier of other form, except mcc or comprise mcc, be such as but not limited to fibrous material or comprise that cellulosic carbohydrate (comprises hemicellulose, have different crystallinity and structure cellulose (such as, the various structures that comprise solid fiber, with increment or comprise fiber or the analog of various structures such as network structure and/or other structure), comprise the naturally occurring cellulose that contains bristle algae (Cladophora sp.Algae) cellulose or the like), dextran, agarose, agar, colloid, alginate, xanthan gum, chitosan, starch (comprises potato starch, or its mixture shoti starch) or the like.

Nicotine can exist with any suitable form, for example the free alkali form of nicotine or suitable salt or the form of its complex.In addition, nicotine can exist with the form of carrier complex or carrier adduct, and wherein nicotine exists with carrier compound.In a special embodiment, carrier compound is that described nicotine is contained in a kind of microparticle material and space of containing internal voids in material at least in part.When not wanting to be bound by theory, we believe that when this patent is used nicotine can interact by mode and the carrier (for example, mcc or other carrier that is fit to comprise other cellulose carrier) that absorption enters and/or is adsorbed onto on the carrier.This interaction is reversible completely or almost completely.

A kind of particularly suitable material with internal voids is a cellulose, as microcrystalline Cellulose.The special example of the microcrystalline Cellulose that is fit to is to be selected from AVICEL

Grade PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302, VIVACEL

Grade 101,102,12,20 and EMOCEL

The microcrystalline Cellulose of the group that class 5 0M and 90M or the like and composition thereof form.

Microcrystalline Cellulose can be synthetic or semisynthetic cellulose, perhaps from native cellulose.

The carrier that is fit to can be those disclosed in WO 2004/064811, and it is incorporated herein by reference.

More specifically, perhaps the high relatively surface area of our expection is important concerning the carrier that is fit to use.Therefore, the general 0.7m at least of the specific surface area that is fit to carrier ²/ g, for example 1m ²/ g.Under some operating position, the specific surface area scope can be from about 0.7m ²/ g arrives at least about 100m ²/ g, and/or can be any number in this scope, and/or can be any mixing of the different sizes in this scope.For instance, in certain embodiments, surface area can be about 0.7m ²/ g, about 1m ²/ g, about 1.5m ²/ g, about 2.0m ²/ g, about 3.0m ²/ g, about 5m ²/ g, about 7m ²/ g, about 10m ²/ g, about 15m ²/ g, about 20m ²/ g, about 25m ²/ g, about 35m ²/ g, about 45m ²/ g, about 50m ²/ g, about 75m ²/ g, about 100m ²/ g and greater than about 100m ²/ g, or its combination.This carrier with this suitable surface area can comprise, but be not limited to, mcc, fibrous material or comprise that cellulosic carbohydrate (comprises hemicellulose, have different crystallinity and structure cellulose (such as, the various structures that comprise solid fiber, with increment or comprise fiber or the analog of various structures such as network structure and/or other structure), comprise the naturally occurring cellulose of bristle algae (Cladophora sp.Algae) cellulose or the like), dextran, agarose, agar, colloid, alginate, xanthan gum, chitosan, starch (comprises potato starch, and/or its mixture shoti starch) or the like.

Usually, the mean size scope of carrier compound is to about 250 μ m from about 15.

It has been observed by the present inventors that for fear of the mouthfeel of coarse after application or gravel, the cellulose that uses a kind of small particle diameter is favourable.Therefore, the mean diameter of about 20 μ m is fit to, and an example of this material is Avicel PH-105.

More particularly, in one embodiment of the invention, nicotine exists as nicotine-cellulose combination, wherein said nicotine to small part is adsorbed onto on the microcrystalline Cellulose and/or partially absorbs in the carrier at least and/or partially absorb at least on the carrier (for example mcc), or on its mixture.This interaction is complete or almost completely reversible.

Therefore, in some special embodiment, nicotine is adsorbed onto on the microcrystalline Cellulose, absorption is advanced in the mcc and/or be adsorbed onto mcc, and/or in its combination.

In embodiments of the invention, carrier (for example, but be not limited to mcc and/or other naturally occurring cellulose) is partially porous at least.Porous can be because, such as but not limited to, the structure of carrier, for example, may structure foraminous bifurcated, fibrous or netted.The scope of pore size includes but not limited to about 0.01cm ³The pore volume of/g is including but not necessarily limited to from about 0.003cm ³/ g or still less arrive about 0.025cm ³/ g is to pact or greater than 0.60cm ³The scope of the pore volume of/g.

Usually, the concentration that nicotine-cellulose combination exists in the compositions of the present invention arrives about 98%w/w at least about 2%w/w such as scope at about 2%w/w, from about 2% to about 96%w/w, from about 2% to about 95%w/w, from about 3% to about 90%w/w, from about 4% to about 85%w/w, from about 5% to about 80%w/w, from about 5% to about 75%w/w, from about 5% to about 70%w/w, from about 7.5% to about 65%w/w.

In certain embodiments, nicotine absorption, as absorbing and/or absorbing quantity on the carrier, can reach composition total weight 50% or more.The scope that is adsorbed onto the nicotine quantity on the carrier of the present invention is included in all quantity in this scope from being less than about 1% about 50% to greater than compositions of composition total weight.When the applicant does not want to allow the present invention be bound by theory, we believe when preparing this application, adsorbable to and/or absorption advance the maximum quantity of the nicotine of carrier, thereby influence quantity, as nicotine account for total composition weight percentage ratio (as, largest percentage) stand under load volume property influence includes but not limited to the structure of carrier, the porous of carrier and the surface area of carrier.

In special embodiment, the concentration of nicotine carrier complex or nicotine carrier adduct for example is rendered as in the compositions of the present invention, from about 2%w/w (total composition) to about 20%w/w, from about 4%w/w to about 19%w/w, from about 5%w/w to about 18%w/w, from about 6%w/w to about 17%w/w, from about 7%w/w to about 16%w/w or from about 8%w/w to about 15%w/w.Especially, a kind of situation be nicotine need dosage relatively little as up to those situations of 10mg scope.

In selectable embodiment, carrier compound can enough nicotine form a species complex, and for example, carrier compound is the situation of ion-exchange chemical compound of comprising ion exchange resin.

The concentration of nicotine and quantity

As mentioned above, nicotine can exist with any suitable form.Normally, nicotine is selected from the group of being made up of nicotine alkali, nicotine hydrochloride, nicotine dihydrochloride, nicotine list tartrate, nicotine biatrate, nicotine sulfate, nicotine zinc chloride such as nicotine zinc chloride monohydrate and nicotine Salicylate.One preferred aspect, nicotine is a free alkali form, it can easily be adsorbed onto on the cellulose to form microcrystalline Cellulose-nicotine carrier complex or carrier adduct.

The concentration of nicotine generally is rendered as from about 0.1%w/w to about 90%w/w in the compositions, for example, from about 0.1%w/w to about 80%w/w, from about 0.1%w/w to about 70%w/w, from about 0.1%w/w to about 60%w/w, from about 0.1%w/w to about 50%w/w, from about 0.1%w/w to about 40%w/w, from about 0.1%w/w to about 30%w/w, from about 0.1%w/w to about 20%w/w, from about 0.1%w/w to about 10%w/w, usually from about 0.1%w/w to about 5%w/w.

Usually, nicotine compound (calculating with free alkali) exists with the concentration at least about 0.1%, for example in the scope of about 0.1%w/w to 50%, for example from about 0.5%w/w to about 45%w/w, from about 1.0%w/w to about 40%w/w, from about 1.5%w/w to about 35%w/w, from about 2%w/w to about 30%w/w, from about 2.5%w/w to about 25%w/w, from about 2.5%w/w to about 20%w/w, from about 3%w/w to about 15%w/w.

Particularly in the compositions that contains the relatively small amount nicotine (for example chewing gum), the concentration of nicotine compound (calculating with free alkali) is usually in the scope of about 0.1%w/w to 15%, for example from about 0.1%w/w to about 14%w/w, from about 0.1%w/w to about 13%w/w, from about 0.1%w/w to about 12%w/w,, to about 10%w/w, calculate to about 11%w/w from about 0.1%w/w from about 0.1%w/w with the nicotine free alkali.

As mentioned above, nicotine exists with the form of nicotine-cellulose combination.Normally, this combination exists with concentration of about 5% to about 100%, for example from about 10 to 100%, and from about 5% to about 50%, or alternatively from 45% to about 100%.The load of nicotine in nicotine-cellulose combination and the dosage of nicotine are depended in the selection that is fit to concentration.If it is high relatively to load, the situation that Zu He concentration can be lower relatively than load is low so, and vice versa.At a special use such as Avicel

Or in the embodiment of similar cellulose quality, the combination concentration normally from about 80%w/w to about 98%w/w, for example from about 85%w/w to about 98%w/w, from about 90%w/w to about 98%w/w, from about 92%w/w to about 98%w/w, from about 93%w/w to about 97%w/w or from about 94%w/w to about 96%w/w.

The concentration of nicotine in the combination (or pharmaceutically acceptable salt, complex or its solvate) is at most 70%w/w, for example maximum 60%w/w, 50%w/w, 45%w/w at most at most.The content of nicotine can not too high and feasible combination (it is a powder type) " diaphoresis ", to such an extent as to nicotine desorption, evaporation or other mode disappear from combination.Therefore, the load of nicotine depends on the special cellulose of use in the combination.If the surface area of cellulosic material is high relatively, so a large amount of nicotine can be included in the there with stable status during suitable at one, yet that the cellulose that normally has a small surface area has been indicated with the ability of the steady statue load nicotine that is fit to is lower.

For most of cellulose quality, the concentration of nicotine is at most about 45%w/w in nicotine-cellulose combination, for example, maximum about 40%w/w, about at most 35%w/w, about at most 30%w/w, maximum about 25%w/w, about at most 20%w/w, about at most 15%w/w, maximum about 12.5%w/w, maximum about 10%w/w, about at most 9.5%w/w, about at most 9%w/w, maximum about 8.5%w/w or about at most 8%w/w, concentration is calculated with nicotine alkali.

The normally about 0.5mg of quantity of nicotine compound in the compositions of the present invention (calculating with free alkali) is to about 10mg, and for example about 1mg arrives about 8mg, from about 1.5mg to about 7.5mg, from about 2mg to about 5mg, from about 2.5mg to about 5mg, from about 3 to about 10mg, from about 3 to about 7.5mg, or from about 3mg to about 5mg, for example, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 5mg or about 6mg calculate with the nicotine free alkali.Especially, the dosage of 2mg, 3mg, 4mg and 6mg has commercial interest.The weight range of tablet is to about 700mg, for example 600-650mg from about 50mg.

Buffer agent

Also can contain one or more buffer agents according to inventive compositions.Known to general, slight alkaline reaction (between 7 and 8) can be strengthened the absorption of nicotine in the oral cavity.Therefore, it is favourable buffer substance being joined in the compositions so that slight alkaline reaction is provided.Especially, the compositions of release of nicotine in the oral cavity, just the compositions as chewing gum, lozenge and snuff composition can contain buffer substance easily.

The buffer agent that is fit to typically is selected from the group of being made up of acetate, glycinate, phosphate, glycerophosphate, citrate such as alkali-metal citrate, carbonate, bicarbonate and borate and composition thereof.

If exist, then one or more buffer agents with about 0.5%w/w to about 5%w/w, for example, from about 0.75%w/w to about 4%w/w, from about 0.75%w/w to about 3%w/w, or the existence of the concentration from about 1%w/w to about 2%w/w.

Sweeting agent

In order to increase the thoughts and feelings character of compositions of the present invention, can add one or more sweeting agents, for example sugar alcohol comprises xylitol, sorbitol and/or hydroxyl isomaltulose, or artificial sweetener for example aspartame, acesulfame potassium or glucide.

The concentration of one or more sweeting agents is if exist, generally at least about 0.05%, for example from about 0.075%w/w to about 5%w/w, or from about 5% to about 35%w/w, for example from about 10%w/w to about 35%w/w, from about 15%w/w to about 35%w/w or from about 20%w/w to about 30%w/w.

Antioxidant

As everyone knows, nicotine is through oxidated, and therefore, for example ascorbyl palmitate and/or sodium ascorbate are favourable to add one or more antioxidants in compositions of the present invention.

One or more antioxidants can with from about 0.05%w/w to about 0.3%w/w, for example, from about 0.1%w/w to about 0.25%w/w or the concentration from about 0.15%w/w to about 0.2%w/w exist.

Flavoring agent

In order to improve the organoleptic properties of the present composition, compositions can comprise one or more flavoring agents, for example menthol flavor, Eucalyptus, mint flavored and/or L-menthol, usually concentration (flavoring agent total concentration) is to about 12%w/w from about 0.5%w/w, from about 1%w/w to about 10%w/w, from about 1.5%w/w to about 9%w/w or from about 2%w/w to about 8%w/w.

Acceptable excipient on the other medicines

As mentioned above, compositions of the present invention can further contain pharmaceutically acceptable excipient, and for example implant, binding agent, lubricant, buffer agent, stabilizing agent, pH adjust agent, antiseptic, coloring agent, flavoring agent, odor mask, sweeting agent or the like.

Excipient is selected from the vehicle group of usually using on the pharmaceutical industries of preparation tablet, just as the excipient of filler, disintegrating agent, binding agent, lubricant or the like.For this reason, the excipient that preferably can directly compress.Can be from Rowe, people's such as R.C. Handbook ofPharmaceutical Excipients, the 4th edition, Pharmaceutical Press finds guidance among the London2003, and it is attached to herein by reference.

The filler that is fit to comprises cellulose and comprises the cellulose derivative of microcrystalline Cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose or the like, and lactose comprises the starch of potato starch, corn starch or the like.

The lubricant that is fit to comprises stearate, comprises magnesium stearate, Talcum, silica gel, silica sol or the like.

As mentioned above, the buffer agent that is fit to for example can comprise, comprises the bicarbonate of alkali metal hydrogen carbonate, or comprises the carbonate of alkaline earth metal carbonate.For example in order to protect nicotine in combination object height pH, before the use buffer agent, buffer agent can be coated in compositions of the present invention.High pH has negative interaction to the stability of nicotine.In this paper embodiment 3, with before other composition mixes, buffer agent is used

Coating.

If exist, as the sugar alcohol of sorbitol and/or hydroxyl isomaltulose can with from about 5%w/w to about 35%w/w, for example from about 10%w/w to about 35%w/w, from about 15%w/w to about 35%w/w or the concentration from about 20%w/w to about 30%w/w be used.

As mentioned above, lozenge composition of the present invention can further contain one or more antitack agents, lubricant and/or fluidizer.

In a special embodiment, one or more antitack agent, lubricant and/or fluidizer be selected from by Talcum, stearate and comprise the salt of magnesium stearate and Silicon stone, and composition thereof the group formed.

In a special embodiment, Talcum exists with the concentration from about 0.5%w/w to about 10%w/w, for example from about 1%w/w to about 8%w/w, from about 1.25%w/w to about 6%w/w or from about 1.5%w/w to about 4%w/w, and/or magnesium stearate exists to the concentration of about 5%w/w with about 0.1%w/w, for example, from about 0.2%w/w to about 4%w/w, from about 0.3%w/w to about 3.5%w/w or from about 0.5%w/w to about 3%w/w, and/or Silicon stone exists to the concentration of about 4%w/w with about 0.1%w/w, for example from about 0.2%w/w to about 3%w/w, from about 0.3%w/w to about 2%w/w or from about 0.4%w/w to about 1.5%w/w.

All above-mentioned details that relate to lozenge composition have been applied to others of the present invention with having done necessary correction.For this reason, lozenge composition can comprise similar front and mentions one or more pharmaceutically acceptable excipient in chewing gum compositions (except that gum base) and additive the picture for example buffer agent and the antioxidant of bicarbonate.If exist, the concentration of one or more antioxidants in the lozenge composition be from about 0.025%w/w to about 0.15%w/w,, for example from about 0.075%w/w to about 0.1%w/w.

In special embodiment, the present invention relates to:

A kind of lozenge that contains nicotine comprises

I) carrier;

Ii) nicotine, or pharmaceutically acceptable salt, solvate, complex or derivatives thereof, wherein the use phosphate buffer pH7.4 that describes in Ph.Eur or USP (oar formula) begins in the back two minutes as the in vitro tests of disintegrant 50 or 100rpm, and the colloid that contains nicotine discharges the total composition nicotine of 7.5%w/w at least.

A kind of lozenge that contains nicotine comprises

I) carrier;

Ii) nicotine, or pharmaceutically acceptable salt, solvate, complex or derivatives thereof, wherein picked-up is fast in the human body of the content measurement by nicotine in the human serum.

A kind of lozenge that contains nicotine comprises

I) nicotine-cellulose combination (concentration range: 0.5 to 50%w/w)

Ii) buffer agent (concentration range: 0-10%w/w such as 2-6%w/w)

Iii) one or more artificial sweeteners (concentration range: 0-2%w/w as 0.1 to 1%w/w),

Iv) one or more flavoring agents (concentration range: 0-10%w/w such as 2-8%w/w) and

V) one or more pharmaceutically acceptable excipient (, all) (concentration range: 10-99.5%w/w such as 20-95%w/w, 30-90%w/w, 40-85%w/w or 50-80%w/w) if any the filler that increases sweet function, as sugar alcohol as filler.

Nicotine the method to the individual of transporting comprised the lozenge that contains nicotine as herein described is transported step to the individual.

The method that manufacturing contains the lozenge of nicotine comprises the steps:

I) preparation contains carrier and nicotine, or the compositions that contains nicotine of pharmaceutically acceptable salt, solvate, complex or derivatives thereof, and wherein picked-up is fast in the human body of the content measurement by nicotine in the human serum,

To contain ii) that the compositions of nicotine is optional to be compressed into lozenge with one or more pharmaceutically acceptable excipient.

The lozenge composition that contains nicotine-cellulose combination compares Nicorette

The bioavailability that improvement is arranged, this improvement show uses AUC _{The 0-infinity}(compositions of test)/AUC _{The 0-infinity}(Nicorette

) relative bioavailability that calculates of x100% is 120% at least, for example be at least about 130%, be about 140% or be that about 150%-condition is said composition and Nicorette at least at least

The nicotine that contains equal number with free alkali calculating.

All the above-mentioned details and the details that relate to the lozenge aspect are applied in the above-mentioned special embodiment substantially with having done necessary correction.

Others

The present invention also relates to the method for a kind of preparation according to inventive compositions.The visible this paper embodiment of detailed content, and one skilled in the art will know that how to find guidance method for example looks for from excipient how to select to be fit to and the Arzneibucs that how to prepare this compositions.

Further, the present invention relates to according to inventive compositions as tobacco substitute or be used for relaxing the purposes that nicotine is given up symptom.

In another aspect of the present invention, compositions of the present invention is as drug use.

The present invention in the embodiment of figure below and indefiniteness by more detailed description.

Method

External decomposition test

Must reach specific (special) requirements according to inventive compositions about the nicotine release in vitro.The testing in vitro that is fit to depends on specific group compound in question.Normally, those skilled in the art can find about how selecting particular composition to decompose the guidance of test accordingly in official's monograph such as European Pharmacopoeia.Be description below about the suitable decomposition test of lozenge composition.

The method and apparatus that uses is according to Ph.Eur. (oar formula method).

Following examples are used for proving the preferred embodiment of the invention.It will be understood by those skilled in the art that the disclosed technology of embodiment represented the technology of the operational excellence in the present invention that the inventor finds, thereby also can be considered to formulate preferred practice model.Yet, according to present disclosure, it will be understood by those skilled in the art that and in disclosed particular embodiment, carried out many changes, and still obtained same or similar result not deviating under spirit of the present invention and the category.

Embodiment

Embodiment 1

The preparation of nicotine-cellulose combination

As described in WO 2004/056363, nicotine is adsorbed onto on the microcrystalline Cellulose (MCC).Therefore, in the present embodiment, the nicotine of 2.40ml is dissolved in the ethanol of 25ml (99.5%).47.6g PH-102 type MCC is loaded into high-speed mixer, and nicotine adds at leisure.Behind the wet piece vacuum drying of gained, obtain the finegrained white powder of nicotine-cellulose combination.

Embodiment 10

Lozenge composition K, L, M and N

As described in the embodiment 1 and nicotine-crystallite carrier complex of making in the Turbula blender, mixed 10 minutes with the described residual components of following table (except magnesium stearate).Magnesium stearate is added to 0.5%w/w then, continues to mix 3 minutes again.Be 250g in batches, the tablet weight of wanting is 625mg.

Composition	Compositions K	Compositions L	Compositions M	Compositions N
Composition	Compositions K	Compositions L	Compositions M	Compositions N	Nicotine-MCC carrier complex (MCC (PH-105) that adds 5% nicotine)	20.36g	28.50g	20.37g	28.51g
Maltulose alcohol (DC100)	206.20g	198.06g	193.69g	185.55g		20.36g	28.50g	20.37g	28.51g
Maltulose alcohol (DC100)	206.20g	198.06g	193.69g	185.55g	Carbopol(974)	---	---	12.50g	12.50g
Mentha arvensis L. syn.M.haplocalyxBrig, dry local flavor (501432TP055)	7.50g	7.50g	7.50g	7.50g	Carbopol(974)	---	---	12.50g	12.50g
	7.50g	7.50g	7.50g	7.50g	Eucalyptus, dry local flavor (501034TP0551)	7.50g	7.50g	7.50g	7.50g
Na ₂CO ₃	6.00g	6.00g	6.00g	6.00g	Eucalyptus, dry local flavor (501034TP0551)	7.50g	7.50g	7.50g	7.50g
Na ₂CO ₃	6.00g	6.00g	6.00g	6.00g	Aspartame (particulate)	1.20g	1.20g	1.20g	1.20g
Magnesium stearate	1.24g	1.24g	1.24g	1.24g	Aspartame (particulate)	1.20g	1.20g	1.20g	1.20g

Tablet is by the mixture of powders that obtains preparation in the one-shot lathe (Diaf TM20) of equipment 12mm diameter punch.The unfaithful intention setting is as the indicator of the compaction force of using, because pelleter is not equipped strength sensor.For not containing the lozenge K and the L of carbomer, use unfaithful intention that 6.1 (compositions K) and 6.15 (compositions L) are set.For containing the lozenge M and the N of carbomer, use unfaithful intention to be provided with 7.0.

The character of gained tablet is as shown in the table:

Character	Lozenge composition K	Lozenge composition L	Lozenge composition M	Lozenge composition N
Character	Lozenge composition K	Lozenge composition L	Lozenge composition M	Lozenge composition N	Highly, mm (10)	6.50	6.60	5.90	5.90
Weight, mg (20)	620	621	634	625	Highly, mm (10)	6.50	6.60	5.90	5.90
Weight, mg (20)	620	621	634	625	Resolving time, min (6)	(4.90 external) 4.3 (in the body)	(4.90 external) 5.7 (in the body)	(12.5 in the body)	(13.8 in the body)
Crushing strength, kp (10)	6.70	7.30	>20	>20	Resolving time, min (6)	(4.90 external) 4.3 (in the body)	(4.90 external) 5.7 (in the body)	(12.5 in the body)	(13.8 in the body)
Crushing strength, kp (10)	6.70	7.30	>20	>20	Actual nicotine concentration, mg (10)	2.26	3.27	2.34	3.22
The nicotine concentration of wishing, mg	2.5	3.5	2.5	3.5	Actual nicotine concentration, mg (10)	2.26	3.27	2.34	3.22

According to last table, carbopol has increased the crushing strength and the disintegration time of tablet.

Nicotine concentration is measured by HPLC.

Embodiment 3

The stability that contains the lozenge composition of nicotine in 2.5mg nicotine-cellulose combination

This medicine is white, circular (diameter 12mm), protruding tablet, and the per unit that gross weight is about 625mg contains the 2.5mg nicotine.

Lozenge contains the nicotine of nicotine-fiber combinations form.In this embodiment, used the nicotine biatrate.The nicotine biatrate is loaded into cellulosic method has used the nicotine biatrate to substitute the nicotine free alkali as described in Example 1.

The complete combination thing of table 1 2.5mg nicotine lozenge

Composition	Quantity (mg/ unit)	Function	Standard
Composition	Quantity (mg/ unit)	Function	Standard
Active substance
Active substance				Nicotine biatrate dihydrate	8.32 ¹	Crude drug	The world 1, Siegfried
				Nicotine biatrate dihydrate	8.32 ¹	Crude drug	The world 1, Siegfried
				Excipient
Hydroxyl isomaltulose	484	Filler, sweeting agent	Ph.Eur.	Excipient
Hydroxyl isomaltulose	484	Filler, sweeting agent	Ph.Eur.	Cellulose, crystallite, PH-105	44.18	The nicotine carrier	Ph.Eur.
Peppermint flavor	18.75	Spice	The world, Firmenich	Cellulose, crystallite, PH-105	44.18	The nicotine carrier	Ph.Eur.
Peppermint flavor	18.75	Spice	The world, Firmenich	Eucalyptus spice	18.75	Spice	The world, Firmenich
Sodium carbonate (Na ₂CO ₃)	30.0	Buffer agent	Ph.Eur.	Eucalyptus spice	18.75	Spice	The world, Firmenich
Sodium carbonate (Na ₂CO ₃)	30.0	Buffer agent	Ph.Eur.	Carbomer, Carbopol 974	12.5	Sweller	Ph.Eur.
Magnesium stearate	3.125	Lubricant	Ph.Eur.	Carbomer, Carbopol 974	12.5	Sweller	Ph.Eur.
Magnesium stearate	3.125	Lubricant	Ph.Eur.	Aspartame	3.00	Sweeting agent	Ph.Eur.
Methacrylic acid-methylmethacrylate copolymer (1:1), Eudragit L100	2.10	The sodium carbonate coating	Ph.Eur.	Aspartame	3.00	Sweeting agent	Ph.Eur.
	2.10	The sodium carbonate coating	Ph.Eur.	Ethanol, anhydrous	(32.3+11.9) ²	Solvent	Ph.Eur.
Pure water	11.9 ²	Solvent	Ph.Eur.	Ethanol, anhydrous	(32.3+11.9) ²	Solvent	Ph.Eur.
Pure water	11.9 ²	Solvent	Ph.Eur.
Gross weight	625

¹10% is extra, to remedy the loss in manufacture process.

8.32mg the corresponding 2.75mg nicotine of nicotine biatrate dihydrate, just the nicotine than 2.5mg exceeds the quata 10%.

²In manufacture process, evaporate.

32.3 milligram ethanol is used for dissolving jointly the nicotine salt of water and 11.9 milligrams and is used to dissolve acrylic resin L100.

Lozenge is packed in the double-layer polyethylene plastic bag.Last introduction is

-aluminum bag is used

The LL-OPET/ polyethylene; Polyester 12 μ m/ aluminum 9 μ m/Polyethylene 60 μ m make,

Each contain 20 lozenge and

-aluminum bubble-cap is with PVC/PVDC-paper tinsel 250 μ m/40g/m ²-20 μ m standard aluminium foils (containing protection enamelled coating and heat seal lacquer) make, and each contains 10 lozenge.

Lozenge composition is subjected to accelerated stability research.Result below having obtained:

Zonnic 2.5mg nicotine lozenge is stored in the stability data of aluminum bag under 40 ℃/75%RH, 200 units/batch No.90905-0603-26.

N.d.=does not survey

In addition, compositions is tested in the consumer tests that comprise 10 experimenters.Lozenge composition of the present invention and commercial product " Commit " compare.Contain the nicotine of 2.5mg 2.5/5 show compositions of the present invention, and the disintegration time of having an appointment 5 minutes.Contain the nicotine of 3.5mg 3.5/15 show compositions of the present invention, and the disintegration time of having an appointment 15 minutes.Below note about " time and effect ":

	2，5/5	Commit	3，5/15
	2，5/5	Commit	3，5/15	Oversize	3	6	6
Good	7	2	2	Oversize	3	6	6
Good	7	2	2	Too fast	0	2	0

The result shows that 15 minutes disintegration time causes product oversize " time and effect ", and the product of 5 minutes disintegration time is acceptable.

Reference

Patent of mentioning in all description and publication are conspicuous for one of ordinary skill in the art of the present invention.All patents and publication are attached to herein by all in detail also being expressed independently with quoting of combined by reference same degree as each publication.

Although the present invention and advantage thereof are described in detail, should understand this paper and can carry out various variations, substitute and transform and do not deviate from invention spirit and category as the claims definition.In addition, do not wish that the application's category is confined to the particular embodiment of technology, machine, processing, material compositions, means, method and the step of description description.Because those skilled in the art understand easily according to content disclosed by the invention, technology, machine, processing, material compositions, means, method and step, basic execution that it exists at present or development after a while and corresponding embodiment identical function described herein or reach with corresponding embodiment identical result described herein substantially, can be utilized according to invention.

Claims

1. combination of nicotine-cellulose and one or more pharmaceutically acceptable excipient are used to prepare lozenge composition and to reach solid dosage forms are applied to the purposes that the nicotine effect begins fast after the subject oral cavity.

2. according to the purposes of claim, wherein under the temperature lucifuge that is no more than 25 ℃ was stored, the compositions shelf-life was 24 months or longer.

3. according to the purposes of claim 1 or 2, wherein the resolving time is 15 minutes or faster in the lozenge composition body.

4. according to the purposes of aforementioned each claim, compositions wherein---when accepting external decomposition test as herein described---is release of nicotine in on-test back two minutes, and its release rate correspondingly is the 7.5%w/w of total content in the per minute compositions or more.

5. according to the purposes of claim 4, the 10%w/w that wherein said release rate in on-test back two minutes is a total content in the per minute compositions or more is such as 11%w/w or more, 12%w/w or more, 13%w/w or more, 14%w/w or more, 15%w/w or more.

6. according to the purposes of aforementioned each claim, the 17%w/w that wherein said release rate in on-test back two minutes is a total content in the per minute compositions or more is such as 18%w/w or more, 19%w/w or more, 20%w/w or more, 21%w/w or more, 22%w/w or more, 23%w/w or more, 24%w/w or more, 25%w/w or more.

7. according to the purposes of aforementioned each claim, the 65%w/w at least of nicotine total content in the compositions wherein such as 70%w/w at least, discharged in 5 minutes when accepting external decomposition test as herein described.

8. according to the purposes of aforementioned each claim, the 75%w/w at least of nicotine total content in the compositions wherein such as 85%w/w at least, discharged in 10 minutes when accepting external decomposition test as herein described.

9. according to the purposes of aforementioned each claim, wherein the nicotine effect began such as maximum 2.5 minutes in 5 minutes at the most after giving experimenter's administration composition.

10. according to the purposes of aforementioned each claim, wherein the cellulose of nicotine-cellulose combination contains internal voids and/or hole.

11. according to the purposes of claim 10, wherein said space and/or hole to small part contains described nicotine.

12. according to the purposes of aforementioned each claim, wherein cellulose is the cellulose from plant, algae, antibacterial, fungus or its combination.

13. according to the purposes of aforementioned each claim, wherein cellulose surface amasss and is at least 0.7m ²/ g.

14. according to the purposes of aforementioned each claim, wherein cellulose is the crystal fibre element that comprises microcrystalline Cellulose.

15. according to the purposes of aforementioned each claim, wherein said cellulose be selected from by

Grade PH-100, PH-102, PH-103, PH-105, PH-112, PH-113, PH-200, PH-300, PH-302,

Grade 101,102,12,20 Hes

16. according to the purposes of claim 14 or 15, wherein said microcrystalline Cellulose is synthetic or semisynthetic cellulose, perhaps from native cellulose.

17. according to the purposes of aforementioned each claim, wherein cellulosic average particle size range is to about 250 μ m from about 15.

18. according to the purposes of aforementioned each claim, wherein nicotine to small part is adsorbed onto on the cellulose.

19. purposes according to aforementioned each claim, wherein the concentration of nicotine in the compositions-cellulose combination is at least about 2%w/w, as scope at about 2%w/w to about 98%w/w, from about 2% to about 96%w/w, from about 2% to about 95%w/w, from about 3% to about 90%w/w, from about 4% to about 85%w/w, from about 5% to about 80%w/w, from about 5% to about 75%w/w, from about 5% to about 70%w/w, from about 7.5% to about 65%w/w.

20. purposes according to aforementioned each claim, wherein the concentration of nicotine in the compositions-cellulose combination from about 2%w/w to about 20%w/w, for example from about 4%w/w to about 19%w/w, from about 5%w/w to about 18%w/w, from about 6%w/w to about 17%w/w, from about 7%w/w to about 16%w/w or from about 8%w/w to about 15%w/w.

21. purposes according to aforementioned each claim, wherein in the compositions concentration of nicotine at least about 0.01%w/w, arrive about 75%w/w as scope about 0.05, from about 0.1 to about 70%w/w, from about 0.3 to about 70%w/w, from about 0.4 to about 50%w/w, from about 0.1%w/w to about 50%w/w, from about 0.5%w/w to about 45%w/w, from about 1.0%w/w to about 40%w/w, from about 1.5%w/w to about 35%w/w, from about 2%w/w to about 30%w/w, from about 2.5%w/w to about 25%w/w, from about 2.5%w/w to about 20%w/w, from about 3%w/w to about 15%w/w.

22. purposes according to aforementioned each claim, wherein in the compositions concentration range of nicotine at about 0.1%w/w to about 15%, for example from about 0.1%w/w to about 14%w/w, from about 0.1%w/w to about 13%w/w, from about 0.1%w/w to about 12%w/w,, to about 10%w/w, calculate to about 11%w/w from about 0.1%w/w from about 0.1%w/w with the nicotine free alkali.

23. according to the purposes of aforementioned each claim, wherein said nicotine exists to the concentration of about 90%w/w with about 0.1%w/w.

24. according to the purposes of aforementioned each claim, wherein in the compositions nicotine content from about 0.5mg to about 10mg, for example about 1mg is to about 8mg, from about 1.5mg to about 7.5mg, from about 2mg to about 5mg, from about 2.5mg to about 5mg, from about 3 to about 10mg, from about 3 to about 7.5mg, or from about 3mg to about 5mg, for example, about 1.5mg, about 2mg, about 2.5mg, about 3mg, about 3.5mg, about 4mg, about 5mg or about 6mg calculate with the nicotine free alkali.

25. according to the purposes of aforementioned each claim, wherein compositions contains the nicotine with the calculating of nicotine free alkali of 1.25mg.

26. according to each purposes of claim 1-24, wherein compositions contains the nicotine that calculates with the nicotine free alkali of 2.5mg.

27. according to each purposes of claim 1-24, wherein compositions contains the nicotine that calculates with the nicotine free alkali of 5mg.

28. according to the purposes of aforementioned each claim, wherein said nicotine is selected from the group of being made up of nicotine alkali, nicotine hydrochloride, nicotine dihydrochloride, nicotine list tartrate, nicotine biatrate, nicotine sulfate, nicotine zinc chloride such as nicotine zinc chloride monohydrate and nicotine Salicylate.

29. according to the purposes of aforementioned each claim, wherein nicotine is the form of its free alkali in nicotine-cellulose combination.

30. according to the purposes of aforementioned each claim, wherein compositions further contains one or more buffer agents.

31. according to the purposes of claim 30, wherein one or more buffer agents are selected from the group of being made up of acetate, glycinate, phosphate, glycerophosphate, citrate such as alkali-metal citrate, carbonate, bicarbonate and borate and composition thereof.

32. purposes according to claim 30 or 31, wherein one or more buffer agents arrive about 10%w/w with about 0.1%w/w, for example from about 0.5%w/w to about 5%w/w, for example from about 0.75%w/w to about 4%w/w, to about 3%w/w, or the concentration from about 1%w/w to about 2%w/w exists from about 0.75%w/w.

33. according to the purposes of claim 31 or 32, wherein one or more buffer agents are applied with film coating.

34. purposes according to aforementioned each claim, wherein compositions further contains one or more sweeting agents, for example sugar alcohol comprises xylitol, sorbitol, maltose alcohol and/or hydroxyl isomaltulose, or artificial sweetener for example aspartame, acesulfame potassium or glucide.

35. purposes according to claim 34, wherein the concentration of one or more sweeting agents is at least about 0.05%, for example from about 0.075%w/w to about 5%w/w, or from about 5% to about 35%w/w, for example from about 10%w/w to about 35%w/w, from about 15%w/w to about 35%w/w or from about 20%w/w to about 30%w/w.

36. purposes according to aforementioned each claim, wherein compositions further contains one or more antioxidants, for example ascorbyl palmitate, sodium ascorbate, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, betacarotene, tocopherol, propyl gallate.

37. according to the purposes of claim 36, wherein one or more antioxidants with from about 0.05%w/w to about 0.3%w/w, for example, from about 0.1%w/w to about 0.25%w/w or the concentration from about 0.15%w/w to about 0.2%w/w exist.

38. according to the purposes of claim 36 or 37, wherein in the compositions one or more antioxidant concentrations be from about 0.025%w/w to about 0.15%w/w, for example from about 0.075%w/w to about 0.1%w/w.

39. according to the purposes of aforementioned each claim, wherein compositions contains one or more flavoring agents, such as menthol flavor, Eucalyptus, mint flavouring and/or L-menthol.

40. according to the purposes of claim 39, wherein in the chewing gum compositions flavoring agent total concentration be from about 0.5%w/w to about 12%w/w, from about 1%w/w to about 10%w/w, from about 1.5%w/w to about 9%w/w or from about 2%w/w to about 8%w/w.

41. purposes according to aforementioned each claim, acceptable salt on nicotine-cellulose combined traditional Chinese medicine thing wherein, solvate, or the nicotine concentration of complex is at most 70%w/w, for example maximum 60%w/w, maximum 50%w/w, maximum 45%w/w, about at most 40%w/w, about at most 35%w/w, maximum about 30%w/w, maximum about 25%w/w, about at most 20%w/w, about at most 15%w/w, maximum about 12.5%w/w, maximum about 10%w/w, about at most 9.5%w/w, about at most 9%w/w, maximum about 8.5%w/w or about at most 8%w/w, concentration is calculated with nicotine alkali.

42. purposes according to aforementioned each claim, wherein nicotine concentration is to about 20%w/w from about 3%w/w in nicotine-cellulose combination, for example from about 4%w/w to about 19%w/w, from about 5%w/w to about 18%w/w, from about 6%w/w to about 17%w/w, from about 7%w/w to about 16%w/w or from about 8%w/w to about 15%w/w.

43. purposes according to aforementioned each claim, wherein compositions contains pharmaceutically acceptable excipient, and for example filler, binding agent, lubricant, fluidizer, antitack agent, buffer agent, stabilizing agent, pH adjust agent, antiseptic, coloring agent, flavoring agent, odor mask, sweeting agent or the like.

44. according to the purposes of claim 43, wherein one or more antitack agents, lubricant and/or fluidizer be selected from by Talcum, stearate and comprise its salt of magnesium stearate and Silicon stone, and composition thereof the group formed.

45. according to the purposes of claim 43 or 44, wherein the Talcum concentration that contains of compositions from about 0.5%w/w to about 10%w/w, for example from about 1%w/w to about 8%w/w, from about 1.25%w/w to about 6%w/w or from about 1.5%w/w to about 4%w/w.

46. according to each purposes of claim 43-45, wherein the magnesium stearate concentration that contains of compositions from about 0.1%w/w to about 5%w/w, for example, from about 0.2%w/w to about 4%w/w, from about 0.3%w/w to about 3.5%w/w or from about 0.5%w/w to about 3%w/w.

47. according to each purposes of claim 43-46, wherein the silica concentration that contains of compositions from about 0.1%w/w to about 4%w/w, for example from about 0.2%w/w to about 3%w/w, from about 0.3%w/w to about 2%w/w or from about 0.4%w/w to about 1.5%w/w.

48. according to the purposes of aforementioned each claim, wherein compositions is used AUC behind the administration experimenter _{The 0-infinity}(compositions of test)/AUC _{The 0-infinity}

The relative bioavailability that x 100% calculates is 120% at least, for example be at least about 130%, at least be about 140% or be at least about 150%-condition be said composition and

The nicotine that contains equal number with free alkali form calculating.

49. according to the purposes of aforementioned each claim, in order to treat and/or prevent nicotine addiction.

50. contain the compositions of nicotine just like each definition of claim 1-49-cellulose combination and one or more pharmaceutically acceptable excipient.

51. the method for compositions of each definition of preparation claim 1-50 comprises nicotine-cellulose combination is made tablet with one or more pharmaceutically acceptable mixed with excipients and with the mixture that obtains by compression.