Patent Application
20070269386
As used herein, the term “oral formulation” or similar intends to mean all formulations being suitable to be placed in the oral cavity for delivering nicotine essentially to 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 an active principle by any tissue of the oral cavity.
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 nicotine from an oral formulation in the oral cavity of the subject, whereby active sucking or other manipulation of the oral formulation is controlling the amount of nicotine released.
The term “slow release” is intended to mean that nicotine is released from the oral formulation upon sucking or other manipulation over a period of time for example, several minutes to an hour.
The term “unit formula” is intended to mean one oral formulation unit.
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 behavior 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.
Most dosage forms intended for oral delivery of nicotine benefit from using trometamol as the only or main buffering agent. These formulations include e g mouth sprays, chewing gums, tablets, melt tablets, lozenges, hard boiled candies, chewy candies, gummies, capsules, oral films, and liquid as well as powder formulations for intraoral and pulmonary inhalation.
Particular formulations are mouth sprays. These are discreet dosage forms being useful for obtaining a rapid uptake of nicotine through the mucosa of the oral cavity. Mouth sprays may in particular be sprayed under the tongue. Below Example 3 discloses the manufacturing of a mouth spray according to the invention.
The amount of gum base in a chewing gum according to the invention is about 15-80% by weight of the total gum core, and preferably about 40-80%. The amount of gum base employed for slow release of nicotine is usually in the higher ranges when nicotine is employed per se 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 consumers' preference and the purpose of use, in respect of the nicotine level, nicotine distribution and other additives.
Further below follow Examples on useful chewing gums, tablets, melt tablets, mouth sprays, soft capsules, hard boiled candies, oral films, gummies and chewy candies according to the present invention. On the basis of said Examples also other useful embodiments are envisageable.
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 be increased. 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 oral formulation is buffered by use of substances, agents or other means, which at least partly comprise trometamol.
The buffering is designed so as to achieve a transient buffering of the saliva of a subject during melting, disintegration or dissolution of the oral formulation. As the change is transient, the pH will return to its normal value after a certain period of time.
By employing said change, here 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 not being 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 will generally be lower than when administered together with a buffer.
Further embodiments of the invention includes oral dosage forms being buffered with trometamol in combination with other buffers, preferably selected from the group consisting of a carbonate including mono carbonate, bicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of an alkali metal, such as potassium or sodium, or ammonium, and mixtures thereof.
Further embodiments may include combinations of trometamol with trisodium or tripotassium citrate, and mixtures thereof. Useful ratios between trometamol and such agents are provided in the below Examples.
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 buffering agent, such as e g sodium or potassium bicarbonate buffers. Thereby should be strived to maintain a pleasant taste. 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. Useful mixture ratios are provided in the below Examples.
The amount of the buffering agent or agents in the oral formulation 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 7-10.
The nicotine may be administered in different forms, e g in different complexes or salts. The amount of buffer required to achieve an 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 is further described within the paragraphs below.
According to the invention, the present oral formulation comprises nicotine in any form (for example free base, salt or complex).
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 should be in a saliva soluble form to facilitate the release of the nicotine 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. When the nicotine prevails in the form of nicotine resinate complex, NRC, its solubility is modified in the presence of a buffer.
In preferred embodiments, the nicotine in any form is selected from the group consisting of the free base form of nicotine, a nicotine salt, 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 micro spheres, and mixtures thereof.
Numerous nicotine salts are known, and may be used, e g the salts presented in Table 1, preferably monotartrate, hydrogen tartrate (also called bitartrate or bitartrate dihydrate), ditrate, malate, and/or hydrochloride.
The inclusion complex may be a cyclodextrin, such as β-cyclodextrin.
Suitable cation exchangers are given in below 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.
One or more additives may be added to the present oral formulation. Additives are further described in the below paragraph Other additives to the oral formulation.
Amount and Distribution of the Nicotine in the Oral Formulation
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 said urge and providing a sense of 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 oral formulation comprise embodiments wherein nicotine in any form is present in an amount of 0.05-8 mg calculated as the free base form of nicotine per unit dose of the oral formulation. This may in different embodiments include 0.1, 0.5, 1, 2, 3, 4, 5, 6 or 8 mg calculated as the free base form of nicotine per unit dose.
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 unit does of the oral formulation.
Even more preferred embodiments contain the nicotine in any form in an amount of 0.5-5 mg calculated as the free base form of nicotine per unit dose of the oral formulation.
The nicotine in any form may be distributed in the oral formulations in different embodiments. Different distributions of the nicotine throughout the oral formulations will imply administration of the nicotine to the subject in different ways. This may, then, provide several possibilities to adjust the composition of the oral formulation according to different needs of different subjects depending on the urge to smoke or use tobacco of the subject. In the below Examples are disclosed different such embodiments.
Other additives may be added optionally to the oral formulation. Optional additives comprise at least one or more additives selected from the group consisting of solvents, such as ethanol and water; co-solvents, such as propylene glycol; stabilisers, such as preservatives, e g antioxidants; softeners, such as sorbitol and glycerine; thickening agents, such as colloidal silicon dioxide; binding agents, such as xanthan gum; filling agents, such as mannitol, isomalt, cocoa powder and Crospovidone; solubilizers, such as Polysorbat 80 and Atmos 300; rubbers, lipid barriers, such as sucrose fatty acid esters and hydrogenated vegetable oils; film forming agents, such as porcine gelatine, Pullulan, carrageenan, pectin, locust bean gum and xanthan gum; emulsifiers, such as pectin, soy lecithin, glycerol monostearate, castor oil and poloxamer; glidants, such as colloidal silicon dioxide; lubricants, such as magnesium stearate; coating agents, such as castor oil and sorbitol; melting vehicles, such as vegetable oils; sweeteners, flavors, aromatics, cooling agents, enhancers, colouring agents, vitamins, minerals, fluorine, breath fresheners, tooth whitening agents and mixtures thereof. According to the invention, at least one of such additives is optionally added to the product.
Enhancers may be added essentially to increase the transmucosal uptake of nicotine from the oral cavity.
Sweeteners are added essentially to improve the taste. Sweeteners comprise one or more synthetic or natural sugars, i e any form of carbohydrates suitable for use as sweetener, as well as so called artificial sweeteners such as saccarin, sodium saccarin, aspartame, e g NutraSweet®, acesulfame or Acesulfame K, potassium acesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone, alitame, miraculin, monellin, stevside and neotame.
Suitable sweeteners may be selected from the group consisting of sugar alcohols, such as sorbitol, 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, e g starch hydrolysates, containing a mixture of dextrose, maltose and a range of complex sugars, invert sugar syrup, e g 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 flavor and aroma additives may comprise one or more synthetic or natural taste-masking, flavoring or aromatizing agents. Flavor 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 flavor of the fruit, e g strawberry, raspberry and black currant; artificial and natural flavors 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).
The invention may be used to deliver nicotine to the subject (person) in a variety of ways. According to one embodiment of the invention, a method for delivering nicotine in any form to a subject comprises the steps of:
a) administering to a subject an oral formulation containing nicotine in any form according to the invention into the oral cavity of the subject, and
b) if needed allowing the nicotine in any form in the oral formulation to be released in the saliva in the oral cavity and absorbed into the blood plasma of the subject.
The method for delivering nicotine in any form may further comprise the steps of:
c) administering the nicotine in any form in a sustained way over a period of time to the subject. Such a time period may be at least 5, 10, 20, 30 or 40 minutes.
Another feature of the invention is the ability to use the invention to reduce the urge to smoke. 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 an oral nicotine-containing formulation,
b) administering to a subject an oral formulation containing nicotine in any form into the oral cavity of the subject, and
c) if needed allowing the nicotine in any form in the oral formulation coating to be released in the saliva in the oral cavity and absorbed by the subject.
In another embodiment, the method according to the invention further comprises the steps of administering the nicotine in any form in a sustained way over a period of time to the subject. The period of time may be at least 5, 10, 20, 30 or 40 minutes.
Further embodiments of the method for delivering nicotine to a subject may comprise the steps of combining administration of the oral formulation with at least one other method for obtaining reduction of the urge to smoke or use of tobacco.
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 invention may also be used to reduce the urge to smoke or use tobacco. Still, to continue the feeling or sense of satisfaction of the subject, and to avoid that the craving returns, a sustained craving relief may be obtained after the initial craving relief. A sustained craving relief is obtained by using the oral formulation in such a way as 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 by using the oral formulation over a period of time, such as 5, 10, 20, 30 or 40 minutes or longer, e g a slow release of the nicotine caused by a controlled release, e g by individual use.
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 behavioral. This cessation of smoking or the urge to use tobacco 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 oral formulation 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 an oral formulation according to the invention. Different types of smokers include e g peak seekers or smokers that crave for a plasma level of nicotine constantly being above the level for withdrawal symptoms.
One strategy may be to lower the frequency of the administered oral formulation. Other embodiments include varying the dose of the nicotine in said oral formulations as well as the combination of these two. Also, the strategy may include an oral formulation with substantially no nicotine in any form. Such an oral formulation 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 particularly for obtaining craving relief. Such a system comprises an oral formulation 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 an oral formulation according to the invention and at least one other method or means for obtaining reduction of the urge to smoke or use tobacco. Other methods and means 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 oral formulation according to the invention may include 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 an oral formulation 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.
The use may give a quick reduction of the urge to smoke or use tobacco.
Other embodiments will imply a use giving a slow reduction of the urge to smoke or use tobacco.
The oral formulation according to the invention may be used in therapy and treatment. 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.
Nicotine may also be used for an oral formulation according to the invention for the treatment of said diseases.
Further, nicotine may be used in the production of a nicotine-containing oral formulation according to the invention for the treatment of said diseases.
The oral formulations according to the present invention are basically produced according to methods known in the art. Exemplary, but not limiting, production methods are provided below under Examples. In the below Examples is described the mixing, rolling and scoring as well as the compression of chewing gums. The below Examples also provide information on manufacturing of other embodiments of the present invention.
Conveniently, the compositions of additives according to the invention, e g the buffer system, are made simultaneously, according to known procedures in the art for formulating e g the buffers. Depending on the physical properties of the buffer system incorporated, it may be convenient to add the buffer system/s either with the liquid part or with the solid part of the composition. In the case of buffering systems available as fine powders, it may, of course, be most convenient to add those powders with the solid, powdered part of other additives.
The final product may then be analysed and further wrapped.
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 bioanalysis for the determination of nicotine or its metabolites in the plasma of a subject.
The below examples on embodiments of the present invention are illustrative and non-limiting. 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. If not stated otherwise procedures and equipment known in the art are used in the below manufacturing.
The above ingredients are blended. The blend is then compressed into tablets by means of direct compression according to methods known in the art.
The manufacturing as such takes place at room temperature. A part of the fatty component, i e the vegetable oil, is melted. The solid components, i e the nicotine salt, the cocoa powder, the buffering agent, the mannitol, the titatnium oxide, the sweeteners and the flavoring agents are added and mixed. A reduction of particle size of the solid components is performed by milling the mixture in a roll-refiner. If the solid components have already got the required particle size, e g by milling before the mixing with the fatty component, roll refining is dispensed with. After possible treatment in the roll-refiner the mixture is mixed with the rest of the melted vegetable oil or remelted (if solidified) and mixed with the rest of the melted vegetable oil. A mixing of the melt is performed in a suitable mixer. The liquid component, i e the soy lecithin, is added.
Tablets are subsequently made using suitable techniques, such as molding, extrusion or congealing, including pastillation, when necessary after suitable preconditioning. Also other suitable manufacturing methods known in the art may be used.
1. Ethanol is charged into a vessel.
2. The flavoring agents and poloxamer are added. The components are dissolved during mixing.
3. Purified water is gently added while stirring.
4. Tetracemindinatrium, trometamol, sweeteners are added and mixing is continued.
5. Nicotine is added to the solution while gently stirring.
6. pH of the solution is measured. When needed, the pH is adjusted to 9.0 by adding hydrochloric acid 1M.
7. Purified water is added q.s. to batch quantity. The solution is mixed until a clear solution is obtained.
Seamless soft gel capsules are soft gelatin capsules that are distinguished by their spherical shape and thin, seamless gelatin shell. The thin shell makes the capsules suitable for use in orally dissolving products compared to conventionally produced soft gelatin capsules that are intended to be chewed or swallowed.
Seamless soft gel capsules are manufactured by formation of droplets consisting of two or more concentric layers. The droplets are formed by feeding different liquids through concentric nozzles. The outermost nozzle feeds a hydrophilic solution consisting of gelatin and additives e g plasticizers. The one or more inner nozzles feed a lipophilic liquid (e g oils, triglycerids) wherein one or more active substances may be dispersed. The lipophilic center and hydrophilic perimeter of the formed droplets ensure a good phase separation between shell and core contents. The formed capsules are then subjected to sequential processing steps such as cooling, drying, washing and selection of size and shape.
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 and the solid materials 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 the sheet into correctly sized pieces.
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.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0601089-6 | May 2006 | SE | national |
