Patent Application
20070269492
Figure Legend
The core of the captioned coated gum and the captioned non-coated gum have essentially the same composition—except for their respective different content of nicotine.
The two curves were generated from data on blood samples obtained from 18 individuals, whereof 8 men and 10 women between 18 and 50 years of age (average 28 years). The values plotted are baseline subtracted mean values.
The term “core” is herein intended to mean an entity or a nucleus onto which one or more coating layers is/are applied.
The term “fast reduction of the urge to smoke or use tobacco” is herein intended to mean an initial priming of the subject so as to achieve a reduction of the urge to smoke or use tobacco.
The term “sustained” is herein intended to mean prolonged over time.
The term “complete reduction” or “complete” is herein intended to mean complete or substantially complete reduction.
The term “controlled release” is intended to mean a release of a substance from a gum or tablet by the aid of active chewing or sucking of the gum or tablet in the oral cavity of the subject, whereby the active chewing or sucking is controlling the amount of substance released.
The term “slow release” is intended to mean that the nicotine is released from the gum or tablet upon, e g chewing, over a period of time e g several minutes to an hour.
The term “unit formula” is intended to mean one chewing gum or tablet product.
The term “transient” is intended to mean a non-permanent change, upon which the relevant state, e g biological or physiological state, after a certain period of time will return to its value or behaviour prior to said change.
The terms “buccal” and “buccally” are herein intended to pertain to all of or any part of the tissue of the oral cavity.
The term “intraoral delivery” is herein intended to mean delivery into the systemic blood circulation by means of absorption of the active principle by any tissue of the oral cavity.
Presently existing nicotine chewing gums, and other oral dosage forms, provide a slow release and a slow uptake of nicotine compared to smoking. This does not always reliably create the actual sense of satisfaction when smoking, where an initial fast uptake of nicotine is achieved giving the smoker or tobacco user, i e the subject, a sense of satisfaction. Accordingly, as revealed above, the present invention relates to a coated chewing gum or tablet product for improving the absorption of nicotine in a subject, and wherein the absorption is quicker than by using current means and methods known in the art of nicotine chewing gums. Such a rapid transmucosal uptake of the nicotine in the oral cavity is expected to give more of a cigarette like sense of satisfaction and a more rapid reduction of the urge to smoke and use tobacco.
The present coated chewing gum or tablet product comprises at least one core, nicotine in any form and/or a nicotine mimicking agent, at least one coating layer and at least one other additive, wherein at least one of said coating layer is buffered.
The at least one core may be buffered in different embodiments. The core may be buffered with the same or different ways of buffering as the at least one coating layer.
Said buffering of the at least one coating layer and optionally the at least one core generates a coated chewing gum or tablet product giving improved absorption kinetics of nicotine compared to in the art known chewing gum or tablet products. Most importantly, the buffering is achieved at least partly through use of trometamol.
The chewing gum or tablet product may be a medicated chewing gum or tablet. Medicated chewing gums are herein intended to mean solid or semi-solid, single-dose preparations with a base consisting mainly of gum that are intended to be chewed but not swallowed, where the chewing gums act as a drug delivery system. They contain one or more active substances, which are released by chewing. In the present invention the active substance is nicotine and/or a nicotine mimicking agent intended for systemic delivery.
Absorption of nicotine from the oral cavity to the systemic circulation is dependent on the pH of the saliva, pH of the blood plasma and the pKa of nicotine, which is about 7.8. Assuming a pH of the saliva of 6.8, only about 10% of the nicotine will be in the free base form. Thus, in order to promote absorption of nicotine in a free base form, which is the form predominantly absorbed through the mucosa, the pH of the saliva must preferably be increased to at least pH 7 and to at most pH 10, more preferably to at least pH 8 and at most pH 9.5. At a pH of 8.8 about 90% of the nicotine will then be in the free base form.
Thus, according to the invention, the coated chewing gum or tablet product is buffered. This may be achieved by including physiologically acceptable buffering substances or agents, or by other means, whereby said substances, agents or other means at least partly comprise trometamol. Other means include any component in the product, which does not normally act as a buffering agent, such as a self-buffering additive or a gum base.
According to the invention, at least one coating layer is buffered. In specific embodiments, also the at least one core is buffered.
In specific embodiments, the at least one coating layer is buffered in such a way that upon administration of the gum or tablet the pH of the saliva is increased 0.3-4 pH units, preferably 0.5-2 pH units. The buffering is designed so as to achieve a transient buffering of the saliva of a subject during melting, disintegration or dissolution of the coating layer or layers. As the change is transient, the pH will return to its normal value after a certain period of time.
Similarly, the at least one core may be buffered. This may allow said change in the pH to be ensured during chewing of the core or sucking of the gum or tablet product, where the chewing or sucking allows the suitable buffer agent or substance or other means to produce a transient change in the pH of the saliva, e g an increase in the pH.
By employing the change in pH, for example an increase in said pH of the saliva, the transmucosal uptake of nicotine in the oral cavity is changed, e g increased compared to the nicotine uptake when the saliva is not buffered according to the invention. Also, since the transmucosal uptake of nicotine in the oral cavity according to the invention is faster than for nicotine which has not been buffered according to the invention, less nicotine will be swallowed to reach the gastrointestinal (G.I.) tract. The nicotine that reaches the G.I. tract will be subjected to first pass metabolism which reduces the total amount of intact nicotine absorbed. This means that the bio-availability of nicotine that is not co-administered with a buffer according to the invention will generally be lower than when administered together with a buffer as described in this invention.
Further embodiments of the invention include combinations wherein the at least one coating layer is buffered by the use of trometamol, optionally together with a buffer selected from the group consisting of a carbonate including monocarbonate, bicarbonate and sesquicarbonate; glycinate; phosphate; glycerophosphate; citrate of an alkali metal, such as potassium or sodium; ammonium citrate; and mixtures thereof.
Further embodiments may encompass combinations of trometamol with trisodium or tripotassium citrate, and mixtures thereof.
Still further embodiments may encompass use of trometamol together with different phosphate systems, such as trisodium phosphate, disodium hydrogen phosphate; and tripotassium phosphate, dipotassium hydrogen phosphate, and calcium hydroxide, sodium glycinate; and mixtures thereof.
Alkali metal carbonates, glycinates and phosphates are preferred additional buffering agents.
In order to increase the buffering capacity still further without correspondingly increasing the pH, one may in specific embodiments use a second or auxiliary buffering agent to the first trometamol buffering agent, such as e g sodium or potassium bicarbonate buffers. The second or auxiliary buffering agent may be selected from the group consisting of alkali metal bicarbonates that are preferred for this purpose. Thus, further embodiments of the invention may comprise trometamol and a mixture of an alkali metal carbonate or phosphate and alkali metal bicarbonate.
The amount of the buffering agent or agents in the chewing gum or tablet composition is preferably sufficient in the specific embodiments to raise the pH of the saliva to above 7, as specified above, to transiently maintain the pH of the saliva in the oral cavity above 7, e g pH 7-11.
The amount of buffer required to achieve said increase in pH of the different administered nicotine forms is readily calculated by the skilled man in the art. The extent and duration of the increase in pH is dependent on type and amount of the buffering agent(s) used as well as where, i e in the at least one coating layer and optionally in the at least one core, the buffer is distributed in the product and is further described within the paragraphs below.
The nicotine may be administered in different forms, e g in different complexes or salt.
Examples of particular embodiments of the invention include coated gums, tablets or other dosage forms. According to one embodiment of the invention, the chewing gum or tablet is a coated chewing gum or tablet comprising at least one coating layer. The process of coating a chewing gum, a tablet or other oral dosage forms is well known in the art. The present invention provides a coating, to facilitate the uptake of administered nicotine in any form to the subject. Known intentions of coating a chewing gum or tablet product may be to add crispiness, enhance taste, or to protect the gum or tablet, e g during storage, or to tone down bad or irritating tastes of the gum or tablet product.
Particular embodiments according to the invention may use hard coating, film coating, press/compression coating or melt coating.
For the film and hard coating, the coating procedure may be manual or the coating may be sprayed onto the gum or tablet core/pellet in rotating pans of different shapes or fluidised beds in combination with evaporation of the solvent, e g water or organic solvent.
Hard coating is a multistep process and may be divided into the following steps:
Hard coated cores have a smoother profile with less visible edges remaining from the original core. Sub-coating, by dusting with powder on a sugar alcohol solution or application of dry powder in the sugar alcohol solution, may be used. The core may be hard coated by a panning technique, e g using a hard coating pan, or by other more sophisticated techniques capable of some degree of automation.
The sugar in a hard coating may be selected from the group consisting of sucrose, sugar alcohols, polyalcohols, polyols and mixtures of two or more of the foregoing.
The sugar used in the hard coating may according to specific embodiments also be an artificial sweetener, being (1) low or substantially free of calories and (2) less caries promoting than regular sugar, or a combination with sugar and/or sugar alcohol. Examples of artificial sweeteners and of such combinations are given below under Other additives.
Film coating involves the deposition, usually by a spray method, of a thin film of polymer surrounding the core. The solution may be sprayed to a rotated, mixed bed. The drying conditions permit the removal of the solvent so as to leave a thin deposition of coating material around each core.
The composition of the coating solutions and suspensions may differ during different parts of the process.
Press coating involves the compaction of granular material around an already manufactured core. Using press/compression coating, a further core is pressed on the outside of the initial core/cores.
If nicotine hydrogen tartrate (NHT) is used as the nicotine form then NHT and the buffers are suitably separated from each other in the coating by being kept in separate layers, especially when hard coating is used. A moisture barrier between the NHT-containing layer and the coating comprising the buffer(s) may be applied to prevent interaction between the acid salt NHT and the buffer(s) during the coating process. Suitable moisture barriers are e g apolar lipids and waxes such as carnauba wax, ethyl cellulose or a combination of ethyl cellulose and hydroxypropyl methylcellulose (HPMC) and/or plasticizer from an organic solvent or solvent mixture, aqueous ethyl cellulose dispersion such as Aquacoat EDC (FMC Corp., Philadelphia, Pa.) or Surelease (Colorcon, West Point, Pa.) preferably in combination with plasticizer, Sepifilm LP 007 or LP 010 (Seppic, Paris, France)—based mainly on HPMC and stearic acid—, Opadry AMB or High Performance Opadry II (Colorcon)—based mainly on polyvinyl alcohol—, and polymethacrylates as Eudragit L30 D-55 or EPO (Röhm, Germany). Depending on the type of barrier film selected the moisture barrier preferably accounts for a weight of around 0.3% to around 5% of the total weight of the coating.
One or more additives may be added to the coating or the core/s. Additives are further described in the paragraph Other additives.
The amount of gum base in a coated chewing gum according to the invention is about 15-80% by weight of the total gum core, and preferably at least about 40%, such as in the range of 40-80%. The amount of gum base employed for the most desirable slow release of nicotine is usually in the higher ranges when nicotine is employed as free base or when an absorbed form is used.
The gum base may be of any conventional nature known in the art. For example it may comprise a gum base of natural or synthetic origin readily available from a commercial source. Natural gum bases include e g chicle, jelutong-, lechi de caspi-, soh-, siak-, katiau-, sorwa-, balata-, pendare-, malaya-, and peach gums, natural cautchouc and natural resins such as dammar and mastix. Synthetic gum bases are a mixture of:
Other examples of gum bases are gums including agar, alginate, arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya gum, pectin, tragacanth gum, locust beam gum, gellan gum and xanthan gum.
Examples of gelling agents comprise gum arabic, starch, gelatine, agar, and pectin.
When the nicotine in any form and the buffering agent or agents are incorporated in the chewing gum mass in accordance with the present invention, it is possible to employ a wide variety of chewing gum compositions and amounts of the chewing gum base. Different chewing gum products may be composed depending on the consumer's preference and the purpose of use, in respect of the nicotine level, nicotine distribution and other additives.
The above components may be of qualities suitable for the manufacturing of gums using the mixing, rolling and scoring technology and using the direct compression technology, respectively.
As for the core of a tablet, see Example 6.
According to the invention, the coated chewing gum or tablet product comprises nicotine in any form and/or a nicotine mimicking agent. In specific embodiments, the nicotine is part of the at least one coating layer or, if multiple layers are used. at least one of the at least one coating layers.
In still further embodiments, the nicotine is a part of the chewing gum or tablet core or, if multiple cores are used, at least one of the chewing gum or tablet cores.
In still even further embodiments, the nicotine is part of the at least one coating layer or at least one of the at least one coating layers and the chewing gum or tablet core or at least one of the chewing gum or tablet cores to give a fast transmucosal uptake of the nicotine in the oral cavity of a subject so as to obtain a rapid kick or reduction of the urge to smoke and/or use tobacco. Thereby may also be achieved a systemic maintenance level of nicotine.
With nicotine it is intended to include nicotine, 3-(1-methyl-2-pyrrolidinyl)-pyridine, with its base form, including synthetic nicotine as well as nicotine extracts from tobacco plants, or parts thereof, such as the genus Nicotiana alone or in combination, or pharmaceutically acceptable salts.
The nicotine, also called nicotine agent, should ultimately be in a saliva soluble form to facilitate the release of the nicotine agent into the saliva in the oral cavity and, further, the subsequent uptake of the nicotine from the saliva in the oral cavity into the systemic circulation of the subject.
Nicotine may be used in the form of nicotine resinate complex, NRC. The solubility of NRC is increased in the presence of a buffer.
In preferred embodiments, the nicotine in any form is selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine derivative, such as a nicotine cation exchanger, a nicotine inclusion complex (for example nicotine in complex with betacyclodextrin) or nicotine in any non-covalent binding; nicotine bound to zeolites; nicotine bound to cellulose or starch microspheres; and mixtures of nay of the foregoing.
Numerous nicotine salts are known, and may be used, e g the salts presented in below Table 1, such as preferably the monotartrate, hydrogen tartrate (also called bi-tartrate), citrate, malate, and/or hydrochloride.
The inclusion complex may be a cyclodextrin, such as β-cyclodextrin.
Suitable cation exchangers are given in Table 2 and are further disclosed in U.S. Pat. No. 3,845,217. Preferred are nicotine cation exchangers of polyacrylates, such as the Amberlite collection from Rohm & Haas.
The product according to the invention may also comprise a nicotine mimicking agent. Such an agent may be any suitable agent with a nicotine-like acrid burning taste providing a tingling sensation in the mouth and in the throat. Examples of nicotine mimicking agents are capsaicin, piperine and zingerone.
One or more additives may be added to the coating or the core/s. Additives are further described in the below paragraph Other additives.
The nicotine in any form according to the invention is formulated to provide the subject with a dose to achieve an effect. The effect may be to provide a sense of smoking satisfaction without smoking. Another effect of the administered nicotine in any form may be a reduction of the urge to smoke or use tobacco.
The effect may also be a combination of reduction of the urge to smoke and smoking satisfaction without smoking. The amount of the nicotine should be sufficient to provide such an effect in a subject. This amount may, of course, vary from person to person.
According to the invention, embodiments of the chewable gum or tablet product comprise embodiments wherein nicotine in any form is present in an amount of 0.05-10 mg calculated as the free base form of nicotine per piece coated chewing gum or tablet product. This may in different embodiments include 0.05, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg calculated as the free base form of nicotine per piece coated chewing gum or tablet product.
Still preferred embodiments may contain embodiments where the nicotine in any form is present in an amount of 0.5-6 mg calculated as the free base form of nicotine per piece coated chewing gum or tablet product.
Even more preferred embodiments contain the nicotine in any form in an amount of 0.5-4 mg calculated as the free base form of nicotine per piece coated chewing gum or tablet product.
According to certain embodiments of the invention, the nicotine in any form is part of the at least one coating layer or at least one of the at least one coating layer.
The nicotine in any form may be in an amount of 0-8 mg calculated as free base form in at least one of the at least one coating layer. Still further embodiments comprise nicotine in an amount of 0.1-6 mg in at least one of the at least one coating layers, or even more preferably, in an amount of 0.1-5 mg in at least one of the at least one coating layer.
The nicotine in any form may be distributed in the core and/or different coating layers in different embodiments. Different distributions of the nicotine throughout the coated chewing gum or tablet will imply administration of the nicotine to the subject in different ways. This may, then, provide several possibilities to adjust the composition of the coated chewing gum or tablet according to different needs of different subjects depending on the urge to smoke or use tobacco of the subject.
Currently available nicotine-containing formulations for intraoral uptake, such as chewing gums and tablets, provide a slow release and a slow uptake of nicotine compared to smoking. The speed of said release and uptake may be expressed with AUC10min, i e the area under the nicotine blood plasma concentration versus time after administration curve at 10 minutes after administration. The larger the AUC10min the more rapid the release and uptake of nicotine.
The release of the nicotine in the coated pharmaceutical formulation according to the invention proceeds in at least one step as follows.
I) The dissolution of the one or more buffering agents in the coating, and optionally in the core(s), provides for optimized adjustment of the pH of the liquid in the oral cavity.
II) If the nicotine is, as in preferred embodiments, in a defined amount, such as the amounts described above according to different embodiments, in at least one of the at least one coating layers defined above the release of the nicotine takes place when the coating of the coated chewing gum or tablet is allowed to melt, disintegrate or dissolve to expose the chewable gum or tablet core in said product. The nicotine and its various forms is released from the coating into the saliva in the oral cavity during the time period when the coating is allowed to melt, disintegrate or dissolve such as with the use of a chewable or suckable gum or tablet. The nicotine in any form may then further be absorbed by the subject.
III) The nicotine in any form from the chewable or suckable gum or tablet is released by controlled release, e g by chewing or sucking the gum or tablet core whereby the chewing is controlling the amount of released nicotine from the gum or tablet core. The release of the nicotine is thereby sustained over a period of time. This period of time may be, in different embodiments about 5, 10, 20, 30 or 40 minutes.
The release may be varied by the incorporation of the nicotine in any form in a given quantity into the coating layers and/or the gum or tablet core.
Not only the amount of the nicotine released from the different parts of the chewing gum or tablet product is of value, but also, according to the present invention the specific transmucosal uptake from the oral cavity of the nicotine to the systemic circulation of the subject whereby the one or more buffering agents account for provision of a suitable adjustment of the pH of the liquid of the oral cavity.
According to the present invention a sense of satisfaction may be reached after a short period of time due to a rapid initial burst dose of nicotine in the coating followed by a rapid transmucosal uptake in the oral cavity due to the buffered coating. The intraoral uptake of nicotine from the present coated pharmaceutical formulation is preferably more rapid than from non-coated solid or semisolid pharmaceutical formulations for intraoral uptake with the same total nicotine content. This means that AUC10min for the present formulation is higher than AUC10min for a non-coated solid or semisolid pharmaceutical formulation for intraoral uptake with the same total nicotine content.
Other additives may be added optionally to the core and/or to coating layers.
Optional additives comprise at least one or more additive selected from the group consisting of stabilisers, such as preservatives, e g antioxidants; softeners, thickening agents, filling agents, film forming agents, emulsifiers, glidants, lubricants, sweeteners, flavours, aromatics, enhancers, colouring agents, vitamins, minerals, fluorine, breath fresheners and tooth whitening agents and mixtures thereof. According to the invention, at least one of such additives is optionally added to the product.
Enhancers are added essentially to improve, i e increase, the transmucosal uptake from the oral cavity.
Sweeteners are added essentially to improve the taste. Sweeteners comprise one or more members selected from synthetic or natural sugars (for example any form of carbohydrates suitable for use as a sweetener), as well as so called artificial sweeteners such as saccharin, sodium saccarin, aspartame (sold as NutraSweet®), acesulfame K or acesulfame, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, stevside.
Suitable sweeteners may be selected from the group consisting of sugar alcohols, such as sorbitol and xylitol, single sugars including sugars extracted from sugar cane and sugar beet (sucrose), dextrose (also called glucose), fructose (also called leavulose), and lactose (also called milk sugar); sorbitol, mannitol, glycerol, xylitol, erythritol, maltitol syrup (or hydrogenated starch hydrolyzate), isomalt, lactitol; and mixtures of sugars including glucose syrup, (for example starch hydrolysates, containing a mixture of dextrose, maltose and a range of complex sugars), invert sugar syrup (for example sucrose inverted by invertase (also called sucrase or sacchrase) containing a mixture of dextrose and fructose), high sugar content syrups (such as treacle and honey containing a mixture of particular leavulose, dextrose, maltose, lactitole, sucrose, resins, dextrin and higher sugars); and malt or malt extracts.
The flavour and aroma additives may comprise one or more synthetic or natural flavouring or aromatizing agents.
Flavour and aroma agents may be selected from essential oils including distillations, solvent extractions, or cold expressions of chopped flowers, leaves, peel or pulped whole fruit comprising mixtures of alcohols, esters, aldehydes and lactones; essences
including either diluted solutions of essential oils, or mixtures of synthetic chemicals blended to match the natural flavour of the fruit, e g strawberry, raspberry and black currant; artificial and natural flavours of brews and liquors, e g cognac, whisky, rum, gin, sherry, port, and wine; tobacco, coffee, tea, cocoa, and mint; fruit juices including expelled juice from washed, scrubbed fruits such as lemon, orange, and lime; spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla, liquorice, menthol, eucalyptus, aniseeds, nuts (e g peanuts, coconuts, hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder, flour, or vegetable material parts including tobacco plant parts, e g genus Nicotiana, in amounts not contributing significantly to the level of nicotine, and ginger.
Colouring additives may be selected from dyes being approved as a food additive.
Stabilizing additives may be selected from the group consisting of antioxidants including vitamin E, i e tocopherole, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid and edetate salts; and preservatives including citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic acid. Preferred embodiments comprise an antioxidant as the stabiliser, and even more preferably the antioxidant vitamin E and/or butylated hydroxytoluene (BHT).
According to the invention, a method for delivering nicotine in any form to a subject comprises the steps of:
a) administering to a subject a coated chewing gum or tablet product containing nicotine in any form according to the invention into the oral cavity of the subject, and
b) allowing the nicotine in any form in the coated chewing gum or tablet product to be released in the saliva in the oral cavity and absorbed into the blood plasma of the subject.
According to the invention, the transmucosal uptake of the nicotine in the oral cavity is more rapid than with presently known oral pharmaceutical formulations as expressed by AUC10min mentioned above.
The method for delivering nicotine in any form may further comprise the step of
c) administering the nicotine in any form in a sustained way over a period of time to the subject, for example at least 5, 10, 20, 30 or 40 minutes.
A method for obtaining reduction of the urge to smoke or use tobacco-containing material and/or for providing a sense of smoking satisfaction without smoking according to the invention comprises the steps of
a) replacing at least partly the tobacco containing material with a coated oral dosage form according to the present invention,
b) administering to a subject a coated oral dosage form containing nicotine in any form according to the present invention into the oral cavity of the subject, and
c) allowing the nicotine in any form in the coating of the coated oral dosage form to be released into the saliva in the oral cavity and absorbed by the subject.
Further embodiments of the method for delivering nicotine to a subject may comprise the steps of combining at least one other method for obtaining reduction of the urge to smoke or use of tobacco with the product of the invention.
Tobacco containing material may be material used for e g smoking, snuffing or chewing and may comprise a cigarette, a cigar, pipe tobacco, snuff, snus and chewing tobacco.
The coated oral dosage form may be used for obtaining a quick and/or sustained and/or complete reduction of the urge to smoke or use of tobacco and/or for providing a sense of smoking satisfaction without smoking as further discussed below.
The fast relief provides the subject with a sense of rapid smoking satisfaction without smoking. Such a satisfaction will decrease the craving more rapidly than other known solid or semisolid oral dosage forms.
The quick craving relief is obtained when a dosage of nicotine is released from at least one of the at least one coating layers of the coated oral dosage form in embodiments wherein nicotine is in the coating layers in the presence of one or more buffering agents in the coating and optionally in the core(s). This provides the subject with an initial rapid transmucosal uptake of nicotine in the oral cavity that will induce an initial peak, which results in that the subject gets a feeling or sense of satisfaction and the initial craving will disappear.
The invention may provide sustained reduction of the urge to smoke or use tobacco and give the subject an ability to feel a sense of satisfaction even after the initial craving relief. A sustained craving relief is obtained by chewing or sucking the core part of the coated oral dosage to allow a sustained uptake of the nicotine. The sustained craving relief and/or feeling or sense of satisfaction of the subject will continue as long as the subject maintains the blood plasma levels of nicotine at a level high enough to reach this sense of feeling.
The subject may achieve this sustained relief by chewing the core of the coated oral dosage form over a period of time, such as 5, 10, 20, 30 or 40 minutes or longer, thereby obtaining the slow release by chewing.
For some of the users, it may be a goal to terminate the usage of nicotine completely, due to several reasons e g health, economical, social or behavioural. This may be achieved by further decreasing the amount of nicotine in any form gradually over time. In a specific embodiment of the invention, the method described above for obtaining craving relief may further comprise the steps of decreasing the amount of nicotine in the total coated oral dosage form product described above gradually over time, so as to achieve a complete relief of tobacco craving. This method results in a weaning process gradually over time.
Different types of smokers reach the sense of reduced craving at different plasma levels of nicotine. This may, of course, affect the individual types of administration programs of a coated chewing gum or tablet according to the invention. Different types of smokers include e g peak seekers or smokers that crave a plasma level of nicotine, which is constantly above the level for withdrawal symptoms.
One strategy may be to lower the frequency of the administered coated oral dosage form. Other embodiments include varying the dose of the nicotine in said coated oral dosage forms as well as the combination of these two. Also, the strategy may include a coated oral dosage form with substantially no nicotine in any form. Such a coated oral dosage form may be administered at the end of the treatment period, when the craving is low or substantially absent.
According to the invention there is a system for delivering nicotine in any form to a subject. Such a system comprises a coated oral dosage form according to the invention and at least one other means for obtaining reduction of the urge to smoke.
Another system according to the invention may also be a system for obtaining reduction of the urge to smoke or use of tobacco and/or for providing a sense of smoking satisfaction without smoking. Such a system comprises a coated oral dosage form according to the invention and at least one other method for obtaining reduction of the urge to smoke or use tobacco. Other methods may also be a concomitant or concurrent method selected from the group consisting of administration through mouth sprays, nasal sprays, transdermal patches, inhaling devices, lozenges, tablets and parenteral methods, subcutaneous methods, and transmucosal methods; or use of tobacco.
In a specific embodiment, the at least other method comprises administration of nicotine.
The use of the coated oral dosage form according to the invention is for obtaining a fast and/or sustained and/or complete reduction of the urge to smoke and use tobacco or for providing a sense of smoking without smoking as described above.
The dose of the nicotine is chosen to give the subject an individual sensory perception and satisfaction with an effect of the nicotine in any form. The use of the coated oral dosage form may also be a sole use according to the invention or a combination with other means or methods known in the field of drug abuse. Specifically, the present invention may be used in combination with other means as described above in the methods in the paragraphs above.
According to the invention, a use of a coated oral dosage form according to the invention is also disclosed for delivering nicotine in any form to a subject.
Coated oral dosage forms according to the invention can be maintained in several production steps depending on the total number of cores and the total number of coated layers to be included.
One method for the production of the coated oral dosage form according to the invention is disclosed below. Alternatively other production methods would be useful, e g manufacturing using compression technology.
The method comprises the steps of
a) providing at least one core, and/or providing at least one nicotine containing core,
b) providing nicotine in any form,
c) providing at least one coating layer that is buffered with at least trometamol,
d) adding the nicotine in any form to the at least one core and/or to the at least one coating, and
e) coating the at least one core with the at least one coating layer that is buffered.
The method may in specific embodiments further comprise
f) buffering the at least one core, and/or
g) providing at least one coating layer not being buffered, and optionally
h) adding the nicotine in any form to at least one of said at least one coating layer not being buffered, and optionally
i) providing the nicotine in the coating and the buffer in the coating in separate layers, preferably separated by a moisture barrier.
In one embodiment, the nicotine is selected from the group consisting of a nicotine salt, the free base form of nicotine, a nicotine derivative, such as a nicotine cation exchanger, a nicotine inclusion complex or nicotine in any non-covalent binding; nicotine bound to zeolites; nicotine bound to cellulose or starch microspheres; and mixtures thereof.
The at least one coating layer may in some embodiments be buffered by the use of a buffer selected from the group consisting of trometamol or trometamol in combination with a buffer selected from a carbonate buffer, such as the carbonate, bicarbonate, sesquicarbonate of an alkali metal, e g potassium, sodium; or ammonium; sodium glycinate, alkali metal phosphate, sodium or potassium glycerophosphate, trisodium or tripotassium citrate, and mixtures thereof wherein the at least one coating layer is buffered in such a way that upon administration of the gum the pH of the saliva is increased by 0.3-4 pH units. The buffering may be transient.
In still further embodiments, the at least one coating layer is buffered in such a way that upon administration of the gum the pH of the saliva is increased by 0.5-2 pH units.
In the case of chewing gums the core composition may be formed simply by
mixing, rolling and scoring or compression of the gum base with at least one of the forms of nicotine, e g the nicotine-ion exchanger complex, or the nicotine as a free base or a salt. Before adding any solid component, except for the gum base, it is desirable to grind and size the solid component first, to ensure good distribution. The mixing is preferably conducted at a suitably elevated temperature depending on the viscosity of the gum core used. The increase in temperature decreases the viscosity of the gum and thereby enables the nicotine and other additives to be evenly and intimately distributed within the core/pellet of the chewing gum. The gum mass with additives is cooled, rolled, scored and hardened sufficiently, and then coated according to the above paragraph The coating and Examples 1-4.
According to the method disclosed in the invention, some embodiments are
disclosed where the coating of the at least one chewing gum or tablet core with at least one layer of the at least one buffered coating comprises the steps of:
a) film coating, and/or
b) press coating, and/or
c) hard coating, and/or
d) melt coating.
The product may then be analysed and further wrapped according to methods known in the art.
The different embodiments of the invention are manufactured using technology known in the art.
The coated chewing gum or tablet product according to the invention may be used in therapy. Said therapy may be a treatment of a disease selected from the group consisting of tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
The nicotine may also be used for the production of a chewing gum or tablet product according to the invention for the treatment of a disease selected from the group consisting of Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, ulcerous colitis and post-smoking-cessation weight control.
Also disclosed is the use of a coated chewing gum or tablet product for the production of a nicotine containing chewing gum or tablet product according to the invention for the treatment of a disease selected from the group consisting of tobacco or nicotine dependence, Alzheimer's disease, Crohn's disease, Parkinson's disease, Tourette's syndrome, and ulcerous colitis.
The analysis of nicotine uptake and effect according to the invention may be done according to standard procedures known in the art, e g using a bioanalysis for the determination of nicotine or its metabolites in the plasma of a subject.
The below examples are illustrative and non-limiting. Examples 1-4 describe four different coatings and coating compositions that may be used according to the invention, i e hard coating in Example 1, film coating in Example 2, press coating in Example 3 and melt coating in Example 4, all onto a chewing gum or tablet core. The coating is buffered in each case and contains nicotine as well. The coatings in Examples 1-4 may be combined with different cores. Examples of cores are given in Example 5 and further described below.
The skilled person may on the basis of the following examples envisage also other embodiments of the present invention.
Batch sizes for the manufacture of the below formulations may be modified
according to the actual need and to the actual production facilities.
Objective—The objective of this example is to provide a hard nicotine-containing and buffered coating. The nicotine is in the amount of 0, 5, 1, 2, 3 or 4 mg, respectively.
Material Hard Coating*
Objective
The objective of this example is to provide a nicotine-containing and buffered film coating. The nicotine is in the amount of 0, 5, 1, 2, 3 or 4 mg, respectively.
Material Film Coating
a= HPMC = hydroxypropyl methylcellulose
b= PEG = polyethylene glycol
Objective
The objective of this example is to provide a nicotine-containing and buffered press coating. The nicotine is in the amount of 0, 5, 1, 2, 3 or 4 mg, respectively.
Material Press Coating
Objective
The objective of this example is to provide a nicotine-containing and buffered melt coating, The nicotine is in the amount of 0, 5, 1, 2, 3 or 4 mg, respectively.
Material Melt Coating
Objective
The objective of this example is to provide a core suitable for a chewing gum product according to the invention. The nicotine is incorporated as the free base (NFB), nicotine β-cyclodextrin complex (NCC), nicotine hydrogen tartrate (NHT) or as a nicotine resin complex (NRC). The amount of nicotine in each formula unit, i e per core, is 0, 0, 5, 1, 2, 3 or 4 mg.
Principle
The gum core is formed by a mixing, rolling and scoring process or by a compression process.
Composition of the Cores
I) Mixing, Rolling and Scoring
Mixing, rolling and scoring is done by a conventional procedure. Double sigma blade mixers are used for mixing the gum base with the other components of the formulation. The gum base is softened in the mixer. By heat (from the heating jacket) and mixing, the gum base becomes plastic. So, the softened base is mixed with the liquid components, e g flavours, liquid, sorbitol and glycerol, when used and the solid materials, e g nicotine in any form, buffer, bulk sweetener, colour as a powder mixture. The warm mass is discharged from the mixer in form of loaves stacked on trays on a truck and stored in a conditioned area until the next step starts. This is to cool the gum.
After this, the rolling and scoring takes place. The gum is extruded into a thick sheet, which is rolled by multiple sets of calender rolls to the correct thickness. The scoring rolls, usually two sets, cut into the correct size.
The sheets are then transferred to a conditioned area on trays, where the sheets are cooled to make them brittle enough to be broken. The conditioned gum sheets are then passed through a breaker, which is a rotating drum that parts the sheets into separate pieces of gum along the scores.
At a sorting stage deformed gums are sorted away. The accepted gums are passed through a metal detector.
II) Compressing
Chewing gums produced by compression (usually being a dry method), i e tabletted gums, are made out of a special gum base. High velocity mixers can be used for granulation to give correctly sized particles of the mixture. This mixture is then compressed in a tablet machine.
At a sorting stage deformed gums are sorted away. The accepted gums are passed through a metal detector.
This example describes without limiting the invention the manufacture of different tablet cores according to the invention.
The above ingredients are dry-blended and thereafter compressed into tablet cores. The cores are then coated using any of the methods according to Examples 1-4.
Nicotine hydrogen tartrate and dextrose powders are dry-blended and then granulated with a solution of PVP in water in a fluid bed granulator. The granulated material is then sieved, dry-blended with PEG and compressed into tablets. The cores are then coated using any of the methods according to Examples 1-4.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0601090-4 | May 2006 | SE | national |
