JP2010138125A - Quickly soluble nicotine-containing film preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a nicotine-containing film which is quickly dissolved or disintegrated by the water in the oral cavity to quickly raise the nicotine concentration in blood and can inhibit the condition of craving for smoking at the initial stage of smoking cessation. <P>SOLUTION: The quickly soluble nicotine-containing film preparation 10 contains at least two nicotine layers 2, a first non-nicotine layer 1 arranged in between the nicotine layers 2, and a second non-nicotine layer 3 arranged as an outermost layer, and the nicotine layers 2 contain nicotine and an edible water soluble polymer, and the first non-nicotine layer 1 and the second non-nicotine layer 3 contain a corrective and an edible water soluble polymer and do not contain nicotine. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a nicotine-containing film preparation for use as an auxiliary means for smoking cessation or smoke saving. More specifically, the present invention relates to a nicotine-containing film preparation, which can be taken without water, and rapidly dissolves or disintegrates due to moisture in the oral cavity after taking. The present invention relates to a fast-dissolving nicotine-containing film preparation that can rapidly increase the concentration, and improves “feeling of pharyngeal irritation”, which is a burning throat irritation peculiar to nicotine, and improves “sore throat”.

  A nicotine-containing preparation by intraoral administration is used as an auxiliary means for smoking cessation or smoke saving. For example, the following preparations have been proposed. Patent Document 1 includes a chewing gum core prepared by uniformly mixing nicotine, sweeteners, fragrances, fragrances, stabilizing additives, and the like with nicotine, sweeteners, fragrances, fragrances, stabilizing additives, and the like. A chewing gum coated with a coating composition comprising is disclosed. This chewing gum maintains nicotine release by chewing for 10 to 60 minutes or longer, and corresponds to a sustained-release preparation.

  Patent Document 2 discloses that a nicotine base is released from a semipermeable wall surrounding a compartment containing a nicotine salt and an alkali salt that reacts with the nicotine salt in the presence of water to form a nicotine base. An osmotic device is disclosed for administering nicotine base over time. The osmotic device is one that releases nicotine into the oral cavity for a period of time greater than about 0.5 hours, most preferably about 1 to 4 hours.

  Further, Patent Document 3 discloses a slowly disintegrating or slowly eroding lozenge containing a specific soluble filler, a specific insoluble film forming agent, a specific swelling polymer and a pharmaceutically active substance. The lozenges can contain nicotine or a salt thereof as an active substance, but release the active substance slowly, usually within 15 to 90 minutes or longer.

  Furthermore, Patent Document 4 discloses a lozenge agent having a single layer structure containing a glassy matrix containing a non-hygroscopic sugar alcohol and nicotine active. As is apparent from the in vitro dissolution profile of FIG. 1 of the patent document, this lozenge corresponds to a sustained-release preparation because nicotine is completely released in about 20 minutes.

  The nicotine sustained-release preparation as described above is generally aimed at stabilizing the nicotine concentration in the blood at a predetermined reference level. Thus, although it is possible to alleviate some withdrawal symptoms of nicotine by stabilizing nicotine in the blood to a low level, it has been reported that it is inappropriate for the relief of smoking desire symptoms ( Non-patent document 1). That is, smoking causes a rapid increase in blood concentration in the initial stage, but the nicotine sustained-release preparation as described above does not cause a rapid increase in blood concentration in the initial stage. Therefore, the nicotine sustained-release preparation as described above has been difficult to suppress smoking desire symptoms even though it can suppress withdrawal symptoms during smoking cessation.

  A fast-dissolving nicotine-containing preparation has been proposed for the purpose of suppressing such smoking cravings. For example, Patent Document 5 discloses nicotine, a specific absorbent excipient, a specific first non-nutritive sweetener, and a sweetness that develops later than the first non-nutritive sweetener. A nicotine lozenge comprising a second non-nutritive sweetener that lasts longer or longer is disclosed. This nicotine lozenge is a tablet with a single-layer structure produced by a compressor, but dissolves 60% or more after 3 minutes in the mouth, 80% or more after 5 minutes and about 10 minutes after 10 minutes. Since it is 100% soluble, it is a preparation that does not yet have a sustained release range. Furthermore, since the usage standards of the second non-nutritive sweetener used in this nicotine lozenge differ from country to country, there are many problems to be overcome for practical use.

  Patent Document 6 discloses a nicotine-containing preparation comprising a matrix containing nicotine and one or more water-soluble polymers, wherein a space or a cavity is provided in the polymer matrix. It is described that this preparation rapidly releases nicotine in the oral cavity, and the residence time or disintegration time in the oral cavity is preferably in the range of 1 second to 5 minutes. Only preparation examples of the pharmaceutical preparation are described, and the residence time or disintegration time of the preparation in the oral cavity is not demonstrated at all.

  Furthermore, Patent Document 7 proposes a rapidly dissolving mouth consumable film, and Example 21E contains nicotine as a pharmaceutical substance and a corrigent such as acesulfame potassium salt, aspartame, menthol and the like. A nicotine-containing film formulation comprising a single layer structure is disclosed. However, no data regarding the solubility of this nicotine-containing film formulation is shown.

  Furthermore, Patent Document 8 discloses that the solubility in water is 0.5 to 3 minutes on both sides of the nicotine layer composed of nicotine having a solubility in water of 3 to 10 minutes and an edible water-soluble polymer substance. A film preparation having a three-layer structure in which a water-soluble and non-water-absorbing polysaccharide and / or edible polymer substance and a coating layer made of a softening agent are laminated is disclosed. In Examples, a preparation in which a corrigent comprising 1-menthol, sodium saccharin and citric acid is added to a nicotine layer is disclosed, but the coating layer does not contain a corrigent. Moreover, this film formulation is 10-30 minutes in the intraoral dissolution time of a unit formulation.

  Furthermore, Patent Document 9 includes an oral release component for delivering immediate release of nicotine into the oral cavity and a gastrointestinal (GI) tract release component for sustained delivery of nicotine to the stomach or intestine. Oral release controlling agents are disclosed. Example 1 is a production of a nicotine-containing preparation in which a GI tract (sustained) release core, an oral release layer, a physical barrier layer, and a buffer barrier layer are formed in order from the inside toward the outside without a taste-masking agent. An example is described and the nicotine release of the formulation is shown in FIG. 1 of the patent document.

  Patent Document 10 discloses a dosage unit including an active ingredient, a water-soluble hydrophilic colloid, and a mucosal surface protective film. Example 5 includes nicotine as an active ingredient, and a taste regulator. A film preparation having a single layer structure is described in which peppermint and aspartame are mixed with citric acid as a buffer and HPMC as an edible water-soluble polymer. This film formulation is also shown to have a disintegration time of 34.3 seconds and a dissolution time of 64.3 seconds.

Special table 2005-500206 gazette JP-T 6-502622 Japanese Patent No. 3707798 Japanese translation of PCT publication No. 2004-525928 JP 2005-320342 A JP 2005-255694 A Japanese translation of PCT publication No. 2002-525306 JP 2003-95947 A JP-T-2005-511588 Special Table 2002-535269 Russell, M.A.H.in Nicotine Replacement: a Critical Evaluation; Pomerleau, O.F. and Pomerleau, C.S., Eds .; Alan R. Liss, Inc .: New York, 1988; pp 63-94

  To suppress smoking cravings in the early stages of smoking cessation, it is considered appropriate to set the peak of nicotine blood concentration within 10 minutes after taking a nicotine-containing preparation. It is necessary to finish taking nicotine.

However, the above-mentioned Patent Documents 5 to 7 do not specifically disclose the data supporting the fast solubility, and Patent Document 8 is required to further improve the dissolution time although it dissolves relatively quickly. Furthermore, in Patent Document 9, as is clear from the amount of nicotine released in FIG. 1 of the Patent Document, it still does not leave the sustained release range. Therefore, with these preparations, it is difficult to suppress cravings even if the withdrawal symptoms during smoking cessation can be suppressed.
On the other hand, according to Patent Document 10, although it is possible to finish taking nicotine within approximately 1 minute, since this film preparation feels a strong irritation to the pharynx that is unique to nicotine, I need to improve my throat.

  Therefore, the problem of the present invention is to dissolve or disintegrate rapidly by moisture in the oral cavity, to rapidly increase the blood concentration of nicotine, to suppress the smoking craving symptoms in the initial stage of smoking cessation, and to be burned peculiar to nicotine. It is an object of the present invention to provide a fast-dissolving nicotine-containing film preparation that improves the feeling of throat irritation, which is a stimulus to the pharynx, and improves the “sore throat”.

  As a result of intensive studies in view of the above problems, the present inventors have included a specific component in each of a layer containing nicotine and a layer not containing nicotine, and laminating them in a specific order, thereby enabling oral cavity administration. A nicotine-containing film preparation that dissolves or disintegrates quickly with moisture and can quickly increase the blood concentration of nicotine, and also reduces the intense irritation of the throat that is unique to nicotine, and is excellent in the throat. It was found that it can be obtained.

That is, the present invention
At least two nicotine layers containing nicotine and an edible water soluble polymer;
A first non-nicotine layer containing a corrigent and an edible water-soluble polymer and not containing nicotine, disposed between the nicotine layers;
A fast-dissolving nicotine-containing film preparation comprising a second non-nicotine layer containing a taste-masking agent and an edible water-soluble polymer and not containing nicotine, disposed in the outermost layer.

  In the present invention, two or more nicotine layers are provided, but an even number is preferable. Thereby, since a 1st non-nicotine layer is located in the center of a formulation, irritation | stimulation peculiar to nicotine when it melt | dissolves or disintegrates in an oral cavity can be more reliably relieve | moderated.

Further, if the first and second non-nicotine layers contain a corrigent, the nicotine layer may not contain a corrigent, but as the corrigent used in the present invention, a sour agent, a high It is preferably at least one selected from the group consisting of sweetness sweeteners and refreshing agents. As the sour agent, at least one selected from the group consisting of ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof is preferable, and as the high sweetness sweetener, aspartame, stevia, sucralose, glycyrrhizic acid, At least one selected from the group consisting of thaumatin, acesulfame potassium, saccharin and salts thereof is preferred, and the refreshing agent is selected from the group consisting of fennel oil, camphor, mint oil, mint water, mint, peppermint and menthol. At least one is preferred. As a result, strong irritation to the pharynx, which is unique to nicotine, is alleviated, and it is possible to more reliably improve the throat.
The edible water-soluble polymer used in the present invention includes hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, polyvinylpyrrolidone and sodium alginate. At least one selected from the group consisting of Thereby, it becomes possible to dissolve or disintegrate more rapidly by moisture such as saliva in the oral cavity.

In the present invention, preferred combinations of the corrigents to be added to each layer are as follows. By adopting these combinations, it is possible to sufficiently relieve the strong irritation to the pharynx peculiar to nicotine, and to improve the sore throat more reliably.
(1) The nicotine layer, the first non-nicotine layer and the second non-nicotine layer contain a sour agent, a high sweetness sweetener and a refreshing agent.
(2) The nicotine layer contains a sour agent, and the first and second non-nicotine layers contain a high sweetness sweetener and a refreshing agent.
(3) The nicotine layer contains a high-sweetness sweetener, and the first and second non-nicotine layers contain a sour agent and a refreshing agent.
(4) The nicotine layer contains a refreshing agent, and the first and second taste masking film layers contain a sour agent and a high sweetness sweetener.

  Further, the content of nicotine in the unit preparation is preferably 0.1 to 5 mg, the content of the corrigent in the unit preparation is preferably 0.015 to 15 mg per 1 mg of nicotine, and the content of the sour agent in the unit preparation is 0.005 to 5 mg per 1 mg of nicotine is preferable, the content of high-sweetness sweetener in the unit preparation is preferably 0.005 to 5 mg per 1 mg of nicotine, and the content of the refreshing agent in the unit preparation is 0. 5 mg per 1 mg of nicotine. 005-5 mg is preferred.

  The fast-dissolving nicotine-containing film preparation of the present invention can be dissolved or disintegrated within 1 minute in the oral cavity, and can be dissolved in water within 3 minutes. Therefore, it is also useful as a preparation for suppressing smoking desire.

The fast-dissolving nicotine-containing film preparation of the present invention has intraoral dissolution type mucosal absorbability and digestive tract absorbability. That is, it has the property of rapidly dissolving or disintegrating by moisture in the oral cavity and absorbing the released nicotine through the oral mucosa or digestive tract, so that the nicotine blood concentration can be rapidly increased. Therefore, it is possible not only to suppress withdrawal symptoms during smoking cessation, but also to suppress smoking desire symptoms at an early stage during smoking cessation.
In addition, the fast-dissolving nicotine-containing film preparation of the present invention has good handling properties because it can be taken with only moisture in the oral cavity, and the strong irritation to the pharynx that is unique to nicotine during swallowing is alleviated. It is excellent for throat soaking.

First, terms used in this specification will be described.
As used herein, the term “orally-dissolving mucosal absorbability” means that the preparation dissolves or disintegrates in the oral cavity and nicotine released from the preparation is absorbed through the oral mucosa. Here, the oral mucosa is not particularly limited as long as it is a mucosa covered with mucus in the oral cavity. For example, the maxillary mucosa, sublingual mucosa, cheek mucosa, gingival mucosa, palatal mucosa, lip mucosa Line mucosa is illustrated.
The term “gastrointestinal absorbability” refers to swallowing after absorption or dissolution of the preparation in the oral cavity and absorption through the digestive tract.
The term “fast dissolution” refers to rapid dissolution or disintegration in the oral cavity even when the preparation is taken without water.
The term “unit preparation” means a minimum unit of a preparation to be taken. For example, in the case of preparations individually packaged, the preparation is a single preparation, and a cutting line defining the shape is provided. In the case of a sheet-form preparation in which a plurality of preparations are arranged in a matrix, it is one preparation separated along the cutting line.

  Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. In the description of the drawings, the same elements are denoted by the same reference numerals, and redundant description is omitted. For the convenience of illustration, the dimensional ratios in the drawings do not necessarily match those described.

FIG. 1 is a diagram showing an embodiment of the fast-dissolving nicotine-containing film preparation (hereinafter simply referred to as “film preparation”) of the present invention.
FIG. 1A is a plan view of the film preparation 10, and FIG. 1B is a cross-sectional view taken along the line I-I of the film preparation 10.
The film preparation 10 shown in FIG. 1 includes two nicotine layers 2, one first non-nicotine layer 1 provided between the nicotine layers, and two second non-nicotine layers disposed in the outermost layer. 3 and has a five-layer structure.
The nicotine layer contains nicotine and an edible water-soluble polymer, and the first and second non-nicotine layers contain a corrigent and an edible water-soluble polymer and do not contain nicotine. .

  As nicotine contained in the nicotine layer, those usually used in the art can be used without particular limitation, but commercially available products may be used. Specific examples include nicotine oil, nicotine ditartrate, nicotine citrate, nicotine salicylate, nicotine complex of nicotine and cyclodextrin or polymer resin (for example, nicotine polacrilex), etc. Is done. These can be used alone or in combination. Among these, at least one selected from the group consisting of nicotine oil, nicotine / tartrate, nicotine / citrate and nicotine / salicylate is preferable, and nicotine oil is particularly preferable.

  Nicotine can be used in either the free base form or the ionized form. In the case of the free base form, the effective nicotine amount can be regarded as 100% by mass. Nicotine oil is a pharmaceutical grade that conforms to the standards defined by the United States Pharmacopoeia (USP28) and contains 99% by mass or more of nicotine free base, and does not need to be converted as in the following nicotine ionized form. It can be used as an active ingredient amount.

The nicotine ionized form is a pharmaceutically acceptable salt or metal salt. “Pharmaceutically acceptable salts for acid addition” are ionic compounds formed with inorganic salts such as sulfuric acid, nitric acid, and phosphoric acid, and organic salts such as citric acid, tartaric acid, and salicylic acid. Is an ionic compound formed by metal ions such as zinc ions in addition to alkali metal ions such as sodium ions and potassium ions, alkaline earth metal ions such as calcium ions and magnesium ions.
In the case of an ionized form, the amount used must be corrected using a conversion factor calculated from the molecular weight. For example, when nicotine / tartrate is used, the conversion coefficient is nicotine molecular weight / nicotine / tartrate molecular weight = 162.23 / 498.44 = 0.325 ... ≈0.325. Therefore, 1 mg of nicotine ditartrate corresponds to 0.325 mg of nicotine.

  The nicotine content in the unit preparation is preferably 0.1 to 5 mg, more preferably 0.3 to 4 mg, and particularly preferably 0.4 to 2 mg. Thereby, the withdrawal symptom at the time of smoking cessation and the smoking desire symptom at the early stage of smoking cessation can be suppressed.

  Examples of the edible water-soluble polymer used in the present invention include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC, aka hypromellose), hydroxyethylcellulose (HEC), carboxymethylcellulose sodium (CMC-Na, aka). : Carmellose sodium), carboxymethylcellulose calcium (CMC-Ca, also known as carmellose calcium), carboxymethylcellulose potassium (CMC-K, also known as carmellose potassium), carboxymethylcellulose (CMC, also known as carmellose), polyvinylpyrrolidone (PVP), sodium alginate and the like are exemplified. These can be used alone or in combination. Among these, HPC and HPMC are particularly preferable from the viewpoint of solubility or disintegration property of the film preparation in the oral cavity. The viscosity of HPC and HPMC is not particularly limited. For example, in the case of HPC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 2.0 to 10 mPa · s, particularly 3.0 to 10 mPa · s. Some are preferable, and in the case of HPMC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 3.0 to 10 mPa · s, particularly 3.0 to 6 mPa · s. Such kinematic viscosity is a value based on the test method described in the 15th revision Japanese Pharmacopoeia.

The content of the edible water-soluble polymer in the nicotine layer is preferably 50 to 98% by mass, more preferably 60 to 95% by mass, and particularly preferably 70 to 90% by mass.
The content of the edible water-soluble polymer in the first non-nicotine layer is preferably 40 to 95% by mass, more preferably 50 to 90% by mass, in particular, relative to the total mass of the first non-nicotine layer. Preferably it is 60-85 mass%.
The content of the edible water-soluble polymer in the second non-nicotine layer is preferably 40 to 95% by mass, more preferably 50 to 90% by mass, in particular, relative to the total mass of the second non-nicotine layer. Preferably it is 60-85 mass%.
The content of the edible water-soluble polymer in the unit preparation is preferably 50 to 95% by mass, more preferably 60 to 90% by mass, and particularly preferably 70 to 85% by mass.

Examples of the corrigent used in the present invention include sour agents, high sweetness sweeteners, and refreshing agents. These can be used alone or in combination.
Examples of sour agents include ascorbic acid, tartaric acid, citric acid, malic acid, or salts thereof. These can be used alone or in combination. Of these, tartaric acid and citric acid are particularly preferred from the viewpoint of alleviating irritation to the pharynx and improving throat burning. Examples of the salt form include alkali metal salts and alkaline earth metal salts. In addition, tartaric acid, citric acid and malic acid may be in the form of an acid anhydride.
A high-intensity sweetener is a synthetic or natural sugar substitute that has a sweetness compared to sucrose, which is 50 times or more that of sucrose, but is xylitol, sorbitol, mannitol, The sweetness of sugar alcohols such as tall is lower than that of sucrose, and a large amount of addition is required to obtain the expected sweetness. Since the film preparation of the present invention has a small preparation mass, it is possible to use a sugar alcohol as an excipient or a disintegrant for obtaining fast solubility, but use a sugar alcohol for the purpose of obtaining sweetness. It is difficult. Therefore, sugar alcohol is not included in the high-sweetness sweetener according to the present invention.
Examples of the high sweetness sweetener include aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and salts thereof. These can be used alone or in combination. Of these, saccharin sodium and sucralose are particularly preferable from the viewpoint of alleviating irritation to the pharynx and improving throat burning. Examples of the salt form include alkali metal salts.
Examples of the refreshing agent include fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint, menthol and the like. These can be used alone or in combination. Among these, menthol is particularly preferable from the viewpoint of alleviating irritation to the pharynx and improving throat burning. The menthol may be a single optically active substance or a mixture thereof (for example, racemate), but a single optically active substance, particularly l-menthol is preferred.

  In the present invention, it is possible to improve the sore throat by adding a flavoring agent only to the first and second non-nicotine layers (see Taste Sensory Tests 2 and 3), but more sore throat. From the viewpoint of improving the taste, it is preferable to add a taste-masking agent to all layers (see taste sensory tests 4, 5 and 6), and especially by adding a sour agent as a taste-masking agent to the nicotine layer, It can be remarkably improved (see taste sensory tests 7 and 8).

In the present invention, preferred combinations of the corrigents to be added to each layer are as follows. By adopting these combinations, it is possible to sufficiently relieve strong irritation to the pharynx peculiar to nicotine, and to improve the sore throat more reliably.
(1) The nicotine layer, the first non-nicotine layer and the second non-nicotine layer contain a sour agent, a high sweetness sweetener and a refreshing agent.
(2) The nicotine layer contains a sour agent, and the first and second non-nicotine layers contain a high sweetness sweetener and a refreshing agent.
(3) The nicotine layer contains a high-sweetness sweetener, and the first and second non-nicotine layers contain a sour agent and a refreshing agent.
(4) The nicotine layer contains a refreshing agent, and the first and second taste masking film layers contain a sour agent and a high sweetness sweetener.

The content of the corrigent in the nicotine layer is preferably 1 to 30% by mass, more preferably 3 to 25% by mass, and particularly preferably 5 to 20% by mass with respect to the total mass of the nicotine layer.
The content of the corrigent in the first non-nicotine layer is preferably 1 to 40% by mass, more preferably 5 to 35% by mass, and particularly preferably 10 to 10% by mass with respect to the total mass of the first non-nicotine layer. 30% by mass.
The content of the corrigent in the second non-nicotine layer is preferably 1 to 40% by mass, more preferably 5 to 35% by mass, and particularly preferably 10 to 10% by mass with respect to the total mass of the second non-nicotine layer. 30% by mass.
The content of nicotine in the nicotine layer is preferably 1 to 20% by mass, more preferably 3 to 18% by mass, and particularly preferably 5 to 15% by mass with respect to the total mass of the nicotine layer.

  The content of the corrigent in the unit preparation is preferably 0.015 to 15 mg per 1 mg of nicotine. 0.15 to 7.5 mg per 1 mg of nicotine is preferable in order to sufficiently improve the throat without giving restrictions on the blending amount of other ingredients and formulation design, and without feeling unpleasant taste derived from the corrigent. . Moreover, in order to acquire the preferable throat derived from a flavoring agent at the time of taking, 0.3-4.5 mg per 1 mg of nicotine is preferable, and 0.6-3 mg per 1 mg of nicotine is especially preferable.

  The content of the sour agent in the unit preparation is preferably 0.005 to 5 mg per 1 mg of nicotine. 0.05 to 2.5 mg per 1 mg of nicotine is preferable in order to sufficiently improve the throat without giving restrictions on the blending amount of other ingredients and formulation design and without feeling unpleasant taste derived from the sour agent. . In addition, 0.1 to 1.5 mg per 1 mg of nicotine is preferable, and 0.2 to 1 mg per 1 mg of nicotine is particularly preferable in order to obtain a preferable sore throat derived from a sour agent.

  The content of the high sweetness sweetener in the unit preparation is preferably 0.005 to 5 mg per 1 mg of nicotine. 0.05 to 2.5 mg per 1 mg of nicotine is sufficient to improve the throat without giving an unpleasant taste derived from a high-sweetness sweetener without limiting the blending amount and formulation design of other ingredients. preferable. In addition, 0.1 to 1.5 mg per 1 mg of nicotine is preferable for obtaining a preferable throat derived from a high-sweetness sweetener when taken, and 0.2 to 2 mg per 1 mg of nicotine for obtaining a particularly preferable throat. 1 mg.

  The content of the refreshing agent in the unit preparation is preferably 0.005 to 5 mg per 1 mg of nicotine. 0.05 mg to 2.5 mg per 1 mg of nicotine is preferable for sufficiently improving the throat without giving an unpleasant taste derived from a refreshing agent without limiting the blending amount of the other components and the formulation design. In addition, 0.1 to 1.5 mg per 1 mg of nicotine is preferable for obtaining a preferable throat derived from a refreshing agent at the time of taking, and 0.2 to 1 mg per 1 mg of nicotine for obtaining a particularly preferable throat. .

If necessary, the nicotine layer, the first and second non-nicotine layers according to the present invention include an edible poorly water-soluble polymer, a disintegrant, an excipient, a colorant, a plasticizer, an antioxidant, an essential oil, a fragrance, and the like. These various additives can be contained.
The edible poorly water-soluble polymer is not particularly limited as long as it is sparingly soluble in water and edible, but for example, ethyl cellulose (EC), hydroxypropyl methylcellulose phthalate (HPMCP, also known as: Hypromellose phthalate ester), methylcellulose (MC), polyvinyl alcohol (PVA), carboxyvinyl polymer and the like are exemplified. These can be used alone or in combination. Among these, HPMCP is preferable from the viewpoint of improving the feeling during use.

  The disintegrant is not particularly limited as long as it is commonly used in the technical field and is edible. For example, sugars, carmellose and salts thereof, cellulose, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate , Dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate (eg, polysorbate), polyethylene glycol (eg, macrogol), anhydrous citric acid An acid etc. are illustrated. These can be used alone or in combination. . Among these, saccharides and macrogol are preferably used from the viewpoint of improving disintegration of the preparation and imparting plasticity. The sugar as used herein refers to a synthetic or natural sugar substitute whose sweetness is less than 50 times that of sucrose, such as mannitol, maltose, reduced maltose starch syrup, maltitol, erythritol, xylitol, sucrose, Examples include fructose, sorbitol, sucrose, lactose and the like. These can be used alone or in combination. Among these, mannitol, maltose, maltitol, and reduced maltose starch syrup are preferably used from the viewpoint of improving the disintegration property of the preparation.

The excipient is not particularly limited as long as it is commonly used in the art and is edible. For example, candy powder, starch, fructose, caramel, agar, xylitol, citric acid, glycerin, paraffin, Examples include cellulose, titanium oxide, tartaric acid, sorbitol, lactose, sucrose, glucose, pullulan, propylene glycol, polyoxyethylene hydrogenated castor oil, polyethylene glycol (eg, macrogol), maltitol, maltose, mannitol, malic acid, etc. . These can be used alone or in combination. Among these, titanium oxide, mannitol, and macrogol are preferably used from the viewpoint of improving the appearance of the product and workability during production.
The colorant is not particularly limited as long as it is commonly used in the technical field and is edible. However, yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar Examples thereof include a dye, an aluminum lake dye, and copper chlorophyllin sodium. These can be used alone or in combination. Of these, titanium oxide and aluminum lake dye are preferably used from the viewpoint of improving the appearance of the product and the product image.

  The plasticizer is not particularly limited as long as it is commonly used in the art and is edible. For example, glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate 80 (polyoxyethylene sorbitan monooleate (20EO), polyethylene glycol [especially Macrogol 400 (polymerization degree n of oxyethylene units is 7 to 9, hereinafter the same), Macrogol 600 (n is 11 to 13), Macrogol 1500 (n = 5-6 and n is an equal mixture of 28-36), Macrogol 4000 (n is 59-84), Macrogol 6000 (n is 165-210)], etc. These can be used alone or in combination. From the viewpoint of imparting flexibility to the adhesion improvement and product of the film layers to each other by pressure when, glycerine, propylene glycol, macrogol 400 is preferably used.

  Antioxidants are not particularly limited as long as they are commonly used in the art and are edible. For example, ascorbic acid, sodium bisulfite, sodium sulfite, sodium edetate, erythorbic acid, citric acid, Examples include tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, tocopherol, butylhydroxyanisole and the like. These can be used alone or in combination. Among these, ascorbic acid, sodium bisulfite, sodium edetate, tocopherol acetate, dibutylhydroxytoluene, and butylhydroxyanisole are preferably used from the viewpoint of improving the stability of the drug.

  Examples of the essential oil include anise oil, eucalyptus oil, orange oil, sage oil, thyme oil, lemon oil and the like excluding the above-mentioned refreshing agent, and can be appropriately added as necessary. These can be used alone or in combination.

  As a fragrance, for example, vanilla flavor, orange flavor, orange peel flavor, strawberry flavor, raspberry flavor, chocolate flavor, grapefruit flavor, cranberry flavor, ume flavor, coconut flavor, herbal flavor, coffee flavor, tea flavor, cinnamon flavor, Honey lemon flavor etc. are illustrated. These can be used alone or in combination. Among these, orange flavor and grapefruit flavor are preferable from the viewpoint of improving the refreshing feeling and the refreshing feeling when dissolving the preparation.

  In the present invention, the content of various additives can be appropriately set within a range that does not impair the object of the present invention. For example, the content of the disintegrant and the excipient in the unit preparation is 0 to 0 in total. It is preferably 49% by mass, and the content of the poorly water-soluble polymer in the unit preparation is preferably 0 to 5% by mass. Furthermore, the content of the plasticizer in the unit preparation is preferably 0 to 10% by mass, and the content of the antioxidant in the unit preparation is preferably 0 to 10% by mass.

The film preparation of the present invention can adopt a multilayer structure having a five-layer structure or more, but the thickness is preferably adjusted to 10 to 1000 μm, more preferably 20 to 500 μm, and particularly preferably 30 to 300 μm. . Thereby, it dissolves or disintegrates rapidly in the oral cavity, the gastrointestinal absorption and oral mucosal absorption are promoted by the physicochemical properties of nicotine, and the action of nicotine is rapidly expressed. The size of the film preparation is not particularly limited as long as it is easy to take, but for example, it is preferably about 1 to ⁴ cm ² . Further, the shape is not particularly limited as long as it is easy to take, but for example, a circle, an ellipse, a square, or the like can be appropriately selected.

  The film preparation of the present invention can be rapidly dissolved or disintegrated by moisture in the oral cavity as compared with conventionally known nicotine-containing film preparations, and has excellent solubility in water. For example, the dissolution or disintegration time in the oral cavity is preferably within 1 minute, particularly within 30 seconds, and the dissolution time in water is preferably within 3 minutes, particularly within 1 minute. By having such fast solubility, it is possible to quickly increase the blood concentration of nicotine, and more reliably improve unpleasant throat derived from nicotine (see Comparative Example 6). .

  In the present specification, “dissolution / disintegration time in the oral cavity” means that measured by the following oral dissolution test, and “dissolution time in water” means that measured by the following water solubility test. Say.

Intraoral dissolution test Collect a test piece cut into a circular φ12 mm size, put it in the oral cavity of a healthy adult without water, and measure the time until the test piece is completely dissolved only in the oral saliva To do. In the test, the time required for taking 6 panelists is measured, and the average value is taken as the oral dissolution time.

Water solubility test A test piece cut into a circular φ12 mm size is collected, put into a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method. Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (p. 587), the test is performed at 50 revolutions per minute using a sinker. Complete dissolution was confirmed visually, and the elapsed time was taken as dissolution time. The test is performed 5 times, and the average value is taken as the water dissolution time.

In addition, factors affecting the solubility and / or disintegration property of the film preparation of the present invention in water include the thickness of the preparation and the addition of excipients, disintegrants, and the like. In order to obtain a film preparation that can be dissolved within a predetermined time in the oral cavity and / or dissolved in water for a predetermined time without adding an excipient or a disintegrant, the thickness of the whole preparation is 10 to 100 μm. It is preferable to do. In this case, the thickness of the nicotine layer is preferably 1 to 30 μm, particularly preferably 5 to 20 μm, and each thickness of the first and second non-nicotine layers is preferably 1 to 30 μm, particularly preferably 5 to 20 μm.
Moreover, when adding an excipient | filler, a disintegrating agent, etc. and improving the solubility and disintegration of a formulation, the thickness of the whole formulation can be 30-1000 micrometers. In this case, the thickness of the nicotine layer is preferably 5 to 200 μm, particularly preferably 10 to 100 μm, and each thickness of the first and second non-nicotine layers is preferably 5 to 200 μm, particularly preferably 10 to 100 μm.

  In the present embodiment, the case where the film preparation has a five-layer structure has been described for convenience of explanation, but the film preparation of the present invention is not limited to this, and may have a laminated structure exceeding five layers. In that case, for example, the number of nicotine layers may be an odd number of 3 or more, but it is preferable to have an even number of nicotine layers from the viewpoint of mitigating irritation of the pharynx and improving the throat. Specifically, a nine-layer structure in which a nicotine layer and a second non-nicotine layer are sequentially laminated on both sides of the above-mentioned five-layer structure, and a nicotine layer and a second layer on both sides of the nine-layer structure. For example, a preparation having a 13-layer structure in which two non-nicotine layers are sequentially laminated. In the preparation having such a laminated structure, since the first non-nicotine layer is arranged at the center of the laminated structure, the first non-nicotine layer is finally dissolved when the film preparation dissolves or disintegrates in the oral cavity. It is possible to make it. As a result, the stimulation of the pharynx peculiar to nicotine can be more reliably alleviated and the throat can be further improved. In addition, the composition of a plurality of nicotine layers and the first and second non-nicotine layers may be the same or different.

  In addition, the film preparation of the present invention has the effect of improving the unpleasant throat derived from nicotine due to the presence of the first and second non-nicotine layers, but it has an effect on the ease of fast dissolution and throat irritation. For example, another functional layer may be provided adjacent to the inside and / or outside of the second non-nicotine layer. As such a layer, for example, a support layer for mainly improving the handleability with hydroxypropylmethylcellulose as a main component, a moisture-proof layer for mainly moisture-proofing with ethylcellulose as a main component, and the like are exemplified. The thickness of each layer can be appropriately set within a range that does not impair the object of the present invention. In addition, when the same kind of layers are stacked adjacent to each other, they are in close contact with each other and perform the same function, and therefore, in the present invention, they are handled as substantially one layer.

  In addition, the film preparation of the present invention can be in the form of a sheet in which a plurality of preparations are arranged in a matrix and provided with cutting lines that define the shape of the preparation. A resin film may be provided. Such a preparation can be taken by a patient while separating one preparation along a cutting line from the resin film. Examples of such resin films include polyethylene terephthalate, polyethylene naphthalate, copolymer polyester, polyimide, polypropylene, cellulose triacetate, vinyl acetate resin, ethylene-vinyl acetate copolymer, polyethylene, polyvinyl chloride, polycarbonate, polypropylene, triacetate, and fluorine resin. (ETFE, PFA, FEP) and the like can be appropriately selected from films made of a resin. Among these, polyethylene terephthalate (PET) is particularly preferable.

Next, the manufacturing method of the nicotine containing film formulation of this invention is demonstrated.
The film preparation of the present invention can be produced by employing a known method. For example, it is described in JP-A No. 2004-196784, JP-A No. 2004-043450, JP-A No. 11-116469, and the like. The method is exemplified.

In the present invention, a production method including the following steps (1) to (7) is preferably employed.
(1) A step of forming a second non-nicotine layer having a predetermined thickness by directly applying a coating liquid containing a corrigent and an edible water-soluble polymer and not containing nicotine on a resin film;
(2) On the second non-nicotine layer formed in step (1), a coating liquid containing nicotine and an edible water-soluble polymer is applied to form a nicotine layer having a predetermined thickness, and an intermediate product Obtaining A,
(3) An intermediate product B containing a corrigent and an edible water-soluble polymer and containing a nicotine-free coating solution directly on the resin film to form a first non-nicotine layer having a predetermined thickness. Obtaining a step,
(4) The nicotine layer of the intermediate product A obtained in the step (2) and the first non-nicotine layer of the intermediate product B obtained in the step (3) are superposed so as to face each other, and the resin film A step of pressurizing both from the back surface to bring the nicotine layer and the first non-nicotine layer into close contact with each other to obtain an intermediate product C;
(5) A step of peeling off only the resin film on the first non-nicotine layer side of the intermediate product C obtained in step (4) to obtain an intermediate product D;
(6) Superimposing the first non-nicotine layer of the intermediate product D obtained in step (5) and the nicotine layer of the intermediate product A so as to face each other, and pressurizing both from the back surface of the resin film To obtain an intermediate product E by bringing the first non-nicotine layer and the nicotine layer into close contact with each other,
(7) A step of peeling off at least one resin film of the intermediate product E obtained in the step (7).

In the above-described steps (1) to (3), the coating liquid can be formed on the resin film and dried. In this case, for example, the coating described in JP-A No. 2004-196784 is possible. Construction equipment can be used. Moreover, as a resin film, the thing similar to the above can be used. As a solvent used for the preparation of the coating liquid, for example, water, alcohol, ketone, ether, ester, hydrocarbon, halogenated hydrocarbon, amide, or a mixture thereof can be used without particular limitation. Alcohol (especially ethanol), ester (especially ethyl acetate) or a combination of these solvents (for example, ethanol-water mixture, ethanol-ethyl acetate mixture) is preferred.
Further, in the steps (4) and (5), for example, a crimping device described in JP-A No. 2004-196784 and JP-A No. 2005-080838 can be used. In this case, the pressure is adjusted to 0.05 to 1.5 MPa, the temperature of the layer to be pressure-bonded is adjusted to 30 to 70 ° C., and then pressure-bonded. It is preferable to cool to a lower temperature.

  EXAMPLES Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated more concretely, this invention is not restrict | limited to the following Example.

The content of the corrigent per nicotine-containing film preparation of Examples 1 to 5, Example 9 and Comparative Examples 2 to 5 was 0.623 mg for anhydrous citric acid, 0.623 mg for sodium saccharin, and 0 for l-menthol. .Unified at 208 mg.
The content of the corrigent per nicotine-containing film preparation of Examples 6 to 8 was unified at 0.083 mg for anhydrous citric acid, 0.083 mg for sodium saccharin, and 0.083 mg for l-menthol.
The thicknesses of the nicotine-containing film preparations of Examples 1 to 9 and Comparative Examples 1 to 5 were unified at 75 μm.

[Example 1]
5 layer type film preparation containing anhydrous citric acid, saccharin sodium and l-menthol in all layers 2 g of nicotine oil, 1.2 g of anhydrous citric acid, 1.2 g of saccharin sodium, and 0.6 g of D-mannitol were dissolved in 18 g of water. Next, a solution prepared by dissolving 0.4 g of l-menthol in 42 g of ethanol was added to this solution. Then, 7.3 g of hydroxypropyl methylcellulose and 7.3 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 1.2 g of D-mannitol were dissolved. Next, after adding a solution in which 0.4 g of l-menthol was dissolved in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 14 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.4 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.2 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.

Using each preparation solution, a fast-dissolving nicotine-containing film preparation was prepared according to the following procedure.
1) Manufacturing process of edible intermediate product 1 Polyethylene terephthalate film (PET film) subjected to silicone release treatment is set on the unwinding shaft of the coating machine, and the second non-nicotine layer preparation liquid is supplied to the dam part, and the PET film After the second non-nicotine layer preparation solution was applied to the surface (surface not subjected to the silicone release treatment), it was dried with warm air to form an edible second non-nicotine layer having a thickness of 15 μm. Next, the PET film on which the second non-nicotine layer is formed is set again on the unwinding shaft, and after the nicotine layer preparation liquid is applied onto the second non-nicotine layer, the PET film is dried with warm air and can be 30 μm thick. An edible intermediate product 1 was formed.
2) Manufacturing process of edible first non-nicotine layer PET film with both sides of silicone peeled is set on the unwinding shaft of the coating machine, and the first non-nicotine layer preparation liquid is supplied to the dam part. After the first non-nicotine layer preparation solution was applied to the surface of the film, it was dried with warm air to form an edible first non-nicotine layer having a thickness of 15 μm.
3) Crimping step The nicotine layer of the intermediate product 1 and the surface of the first non-nicotine layer are bonded so as to face each other, and both are crimped at a crimping temperature of 70 ° C. An intermediate product 2 having a three-layer structure having a nicotine layer, a nicotine layer, and a first non-nicotine layer was obtained.

4) Resin film peeling step Only the PET film on the first non-nicotine layer side of the intermediate product 2 was peeled off to obtain an intermediate product 3.
5) Crimping step The first non-nicotine layer of the intermediate product 3 and the nicotine layer of the intermediate product 1 are bonded so that they face each other, and both are crimped at a crimping temperature of 70 ° C. An intermediate product 4 having a five-layer structure having a non-nicotine layer, a nicotine layer, a first non-nicotine layer, a nicotine layer, and a second non-nicotine layer was obtained.
6) Resin film separation process Only one PET film of the intermediate product 4 was peeled off to obtain an intermediate product 5.
7) Punching process The intermediate product 5 was punched using a circular φ12 mm cutter so as not to reach the back surface of the PET film to obtain a nicotine-containing film preparation having a thickness of 75 μm.

[Example 2]
5-layer film preparation containing no flavourant in the nicotine layer and each containing the anhydrous citric acid, sodium saccharin and 1-menthol in the first and second non-nicotine layers, 2 g of nicotine oil and 0.6 g of D-mannitol in water And 42 g of ethanol was added to this solution. Next, 8.7 g of hydroxypropylmethylcellulose and 8.7 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
2 g of anhydrous citric acid, 2 g of sodium saccharin, and 1.2 g of D-mannitol were dissolved in 18 g of water. Next, after adding a solution prepared by dissolving 0.67 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 12.13 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
2 g of anhydrous citric acid, 2 g of sodium saccharin, and 3 g of D-mannitol were dissolved in 30 g of water. Next, a solution prepared by dissolving 0.67 g of l-menthol in 30 g of ethanol was added to this solution. Then, 12.33 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 3]
Five-layer film preparation containing citric anhydride in the nicotine layer and 1-menthol and sodium saccharin in the first and second non-nicotine layers 18 g of water, 2 g of nicotine oil, 3 g of anhydrous citric acid, 0.6 g of D-mannitol And 42 g of ethanol was added to this solution. Then, 7.2 g of hydroxypropyl methylcellulose and 7.2 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
2 g of saccharin sodium and 1.2 g of D-mannitol were dissolved in 18 g of water. Next, after adding a solution prepared by dissolving 0.67 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 14.13 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
2 g of saccharin sodium and 3 g of D-mannitol were dissolved in 30 g of water. Next, a solution prepared by dissolving 0.67 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.33 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 4]
5-layer film preparation containing l-menthol in the nicotine layer and anhydrous citric acid and saccharin sodium in the first and second non-nicotine layers 2 g of nicotine oil and 0.6 g of D-mannitol were dissolved in 18 g of water. Next, a solution prepared by dissolving 1 g of l-menthol in 42 g of ethanol was added to this solution. Then, 8.2 g of hydroxypropylmethylcellulose and 8.2 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
2 g of anhydrous citric acid, 2 g of sodium saccharin, and 1.2 g of D-mannitol were dissolved in 18 g of water. Next, 42 g of ethanol was added to this solution, and then 2 g of titanium oxide was added. Then, 12.8 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 2 g of anhydrous citric acid, 2 g of sodium saccharin and 3 g of D-mannitol were dissolved, and 30 g of ethanol was added to this solution. Then, 13 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 5]
5-layer film preparation containing saccharin sodium in the nicotine layer and anhydrous citric acid and l-menthol in the first and second non-nicotine layers 2 g of nicotine oil, 3 g of saccharin sodium and 0.6 g of D-mannitol are dissolved in 18 g of water. And 42 g of ethanol was added to this solution. Then, 7.2 g of hydroxypropyl methylcellulose and 7.2 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
2 g of anhydrous citric acid and 1.2 g of D-mannitol were dissolved in 18 g of water. Next, after adding a solution prepared by dissolving 0.67 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 14.13 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
2 g of anhydrous citric acid and 3 g of D-mannitol were dissolved in 30 g of water. Next, a solution prepared by dissolving 0.67 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.33 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 6]
5-layer film preparation containing citrate anhydrous in the nicotine layer and 1-menthol and sodium saccharin in the first and second non-nicotine layers 2 g of nicotine oil, 0.4 g of anhydrous citric acid, D-mannitol 0 in 18 g of water .6 g was dissolved, and 42 g of ethanol was added to this solution. Then, 8.5 g of hydroxypropyl methylcellulose and 8.5 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 0.27 g of saccharin sodium and 1.2 g of D-mannitol were dissolved. Next, after adding a solution prepared by dissolving 0.27 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 16.27 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 0.27 g of saccharin sodium and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.27 g of l-menthol in 30 g of ethanol was added to this solution. Then, 16.47 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 7]
A 5-layer film preparation containing l-menthol in the nicotine layer and anhydrous citric acid and sodium saccharin in the first and second non-nicotine layers. 2 g of nicotine oil and 0.6 g of D-mannitol were dissolved in 18 g of water. A solution in which 0.4 g of l-menthol was dissolved in 42 g of ethanol was added to the solution. Then, 8.5 g of hydroxypropyl methylcellulose and 8.5 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 0.27 g of anhydrous citric acid, 0.27 g of saccharin sodium, and 1.2 g of D-mannitol were dissolved. Next, 42 g of ethanol was added to this solution, and then 2 g of titanium oxide was added. Then, 16.27 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 0.27 g of anhydrous citric acid, 0.27 g of saccharin sodium, and 3 g of D-mannitol were dissolved, and 30 g of ethanol was added to this solution. Then, 16.47 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 8]
5-layer film preparation containing saccharin sodium in the nicotine layer and anhydrous citric acid and l-menthol in the first and second non-nicotine layers 2 g of nicotine oil, 0.4 g of saccharin sodium, 0.6 g of D-mannitol in 18 g of water And 42 g of ethanol was added to this solution. Then, 8.5 g of hydroxypropyl methylcellulose and 8.5 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 0.27 g of anhydrous citric acid and 1.2 g of D-mannitol were dissolved. Next, after adding a solution prepared by dissolving 0.27 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 16.27 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 0.27 g of anhydrous citric acid and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.27 g of l-menthol in 30 g of ethanol was added to this solution. Then, 16.47 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

[Example 9]
Five-layer film preparation containing citric anhydride in the nicotine layer and 1-menthol and sodium saccharin in the first and second non-nicotine layers 18 g of water, 2 g of nicotine oil, 3 g of anhydrous citric acid, 0.6 g of D-mannitol And 42 g of ethanol was added to this solution. Then, 7.2 g of hydroxypropyl methylcellulose and 7.2 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
2.0 g of saccharin sodium and 1.2 g of D-mannitol were dissolved in 18 g of water. Next, after adding a solution prepared by dissolving 0.67 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 14.13 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
In 30 g of water, 2.0 g of saccharin sodium and 3 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.67 g of l-menthol in 30 g of ethanol was added to this solution. Then, 14.33 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

  Tables 1 and 2 show the compositions per unit preparation (one nicotine-containing film preparation) in the Examples group.

[Comparative Example 1]
Single-layer film preparation containing no anhydrous citric acid, sodium saccharin and 1-menthol. 0.8 g of nicotine oil and 0.6 g of D-mannitol were dissolved in 18 g of water. Next, 42 g of ethanol was added to this solution, and then 1 g of titanium oxide was added. Then, 8.8 g of hydroxypropylmethylcellulose and 8.8 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.

Using this prepared solution, a nicotine-containing film preparation was prepared by the following procedure.
1) Production process of intermediate product Set the polyethylene terephthalate film (PET film) that has been subjected to silicone release treatment on the unwinding shaft of the coating machine, supply the nicotine layer preparation solution to the dam part, and surface the PET film (with silicone release treatment) The nicotine layer preparation solution was applied to the non-coated surface. Next, it was dried with warm air to form an edible nicotine layer having a thickness of 15 μm.
2) Crimping step The nicotine layers were bonded together so as to face each other, and both were crimped at a crimping temperature of 70 ° C. to obtain an intermediate product 11.
3) Resin film peeling process The intermediate product 12 was obtained by peeling only one PET film of the intermediate product 11.
4) Crimping step The intermediate product 12 was bonded so that the nicotine layer of the intermediate product 12 and the nicotine layer obtained in the above step 1) face each other, and both were crimped at a crimping temperature of 70 ° C. to obtain an intermediate product 13.
5) Resin film peeling step Only one PET film of the intermediate product 13 was peeled off to obtain an intermediate product 14.
6) Crimping step The intermediate product 12 and the intermediate product 14 were bonded so that the nicotine layer and the nicotine layer of the intermediate product 14 face each other, and both were crimped at a crimping temperature of 70 ° C. to obtain an intermediate product 15.
<Resin film peeling process>
Only one PET film of the intermediate product 15 was peeled off to obtain an intermediate product 16.
7) Punching process The intermediate product 16 was punched using a circular φ12 mm cutter so as not to reach the back surface of the PET film to obtain a nicotine-containing film preparation having a thickness of 75 μm.

[Comparative Example 2]
Single-layer film preparation containing anhydrous citric acid, saccharin sodium and l-menthol In 18 g of water, 0.8 g of nicotine oil, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 0.6 g of D-mannitol were dissolved. Next, after adding a solution in which 0.4 g of l-menthol was dissolved in 42 g of ethanol, 1 g of titanium oxide was added to this solution. Then, 7.4 g of hydroxypropyl methylcellulose and 7.4 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
Using this preparation solution, a nicotine-containing film preparation was obtained in the same manner as in Comparative Example 1.

[Comparative Example 3]
Three-layer film preparation containing anhydrous citric acid, saccharin sodium and l-menthol in all layers Dissolve 2.4 g of nicotine oil, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 0.6 g of D-mannitol in 18 g of water. . Next, a solution prepared by dissolving 0.4 g of l-menthol in 42 g of ethanol was added to this solution. Then, 7.1 g of hydroxypropyl methylcellulose and 7.1 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 1.2 g of anhydrous citric acid, 1.2 g of sodium saccharin, and 1.2 g of D-mannitol were dissolved. Next, after adding a solution in which 0.4 g of l-menthol was dissolved in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 14 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.

Using each preparation solution, a nicotine-containing film preparation was prepared by the following procedure.
1) Manufacturing process of edible intermediate product 21 Silicone peeled polyethylene terephthalate film (PET film) is set on the unwinding shaft of the coating machine, the second non-nicotine layer preparation liquid is supplied to the dam part, and PET The second non-nicotine layer preparation solution was applied to the surface of the film (the surface not subjected to silicone release treatment), and then dried with warm air to form an edible second non-nicotine layer having a thickness of 25 μm. The PET film on which the second non-nicotine layer is formed is set again on the unwinding shaft, and after the nicotine layer preparation liquid is applied on the second non-nicotine layer, it is dried with warm air and can be 37.5 μm thick. An edible intermediate product 21 was formed.
2) Crimping process The nicotine layer of the intermediate product 21 and the second non-nicotine layer obtained in the above process 1) are bonded so that they face each other, and both are crimped at a crimping temperature of 70 ° C., and between the two PET films. The intermediate product 22 having a three-layer structure having the second non-nicotine layer, the nicotine layer, and the second non-nicotine layer was obtained.
<Resin film peeling process>
Only one PET film of the intermediate product 22 was peeled off to obtain an intermediate product 23.
3) Punching process The intermediate product 23 was punched using a circular φ12 mm cutter so as not to reach the back surface of the PET film to obtain a nicotine-containing film preparation having a thickness of 75 μm.

[Comparative Example 4]
A three-layer film preparation containing no flavourant in the nicotine layer and containing anhydrous citric acid, sodium saccharin and l-menthol in the second non-nicotine layer. Dissolve 2.4 g of nicotine oil and 0.6 g of D-mannitol in 18 g of water. And 42 g of ethanol was added to this solution. Then, 8.5 g of hydroxypropyl methylcellulose and 8.5 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
In 18 g of water, 1.8 g of anhydrous citric acid, 1.8 g of saccharin sodium, and 1.2 g of D-mannitol were dissolved. Next, after adding a solution prepared by dissolving 0.6 g of l-menthol in 42 g of ethanol, 2 g of titanium oxide was added to this solution. Then, 12.6 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Comparative Example 3.

[Comparative Example 5]
Five-layer film formulation containing no cigarette in the second non-nicotine layer, and each containing the anhydrous citrate, sodium saccharin and 1-menthol in the nicotine layer and the second non-nicotine layer. 2 g of acid, 2 g of sodium saccharin, and 0.6 g of D-mannitol were dissolved. Next, a solution prepared by dissolving 0.67 g of l-menthol in 42 g of ethanol was added to this solution. Then, 6.37 g of hydroxypropylmethylcellulose and 6.37 g of hydroxypropylcellulose were added to this solution to obtain a nicotine layer preparation solution.
1.2 g of D-mannitol was dissolved in 18 g of water. Next, 42 g of ethanol was added to this solution, and then 2 g of titanium oxide was added. Then, 16.8 g of hydroxypropylmethylcellulose was added to this solution to obtain a second non-nicotine layer preparation solution.
2 g of anhydrous citric acid, 2 g of sodium saccharin, and 3 g of D-mannitol were dissolved in 30 g of water. Next, a solution prepared by dissolving 0.67 g of l-menthol in 30 g of ethanol was added to this solution. Then, 12.33 g of hydroxypropylmethylcellulose was added to this solution to obtain a first non-nicotine layer preparation solution.
Using each preparation solution, a nicotine-containing film preparation was obtained by the same operation as in Example 1.

  Table 3 shows the composition per unit preparation (one nicotine-containing film preparation) in the comparative example group.

Taste sensory test regarding throat soaking Six panelists took the preparations obtained in each of the examples and comparative examples, and the throat after taking was evaluated according to the following criteria. The evaluation was performed in three stages, with the formulation having the least irritation in the throat as “1 point” and the formulation having the most irritation in the throat as “3 points”, and the evaluation was made based on the average value of the scores of 6 people.

Taste sensory test 1
It carried out using Example 1, Comparative Example 2 and Comparative Example 3. The evaluation results are shown in Table 4.

As shown in Table 4, the score of throat after taking is 3 points in Comparative Example 2 which is a one-layer preparation, and 1.8 points in Comparative Example 3 which is a three-layer preparation. In Example 1, which is a five-layer preparation, the evaluation became better with an increase of 1.2 points and the number of layers, and the tendency of the drug-derived throat to be alleviated was shown.
Therefore, it was confirmed that the five-layer preparation is more effective in reducing the throat irritation derived from the drug than the one-layer preparation or the three-layer preparation.

Taste sensory test 2
This was carried out using Example 2, Comparative Example 1 and Comparative Example 4. The evaluation results are shown in Table 5.

As shown in Table 5, the score of throat after taking is 2.7 points in Comparative Example 1 which is a one-layer preparation, and 1.8 points in Comparative Example 4 which is a three-layer preparation. On the other hand, in Example 2, which is a five-layer preparation, the evaluation was good at 1.5 points, indicating a tendency that the irritation to the throat derived from the drug was alleviated.
Therefore, it is considered that the irritation to the throat derived from the drug can be alleviated more than the one-layer preparation or the three-layer preparation by using a five-layer preparation without adding a corrigent to the nicotine layer.

Taste sensory test 3
It carried out using Example 2, Comparative Example 3 and Comparative Example 5. The evaluation results are shown in Table 6.

  As shown in Table 6, the score of throat after taking is 2 points in Comparative Example 3 which is a three-layer preparation, and 2.5 in Comparative Example 5 which is a 5-layer preparation similar to Example 2. In contrast to the point, in Example 2, it was 1.5 points. From this result, it was confirmed that even in the same five-layer preparation, the degree of relaxation of the drug-derived throat changes by changing the layer to which the corrigent is added. From the comparison between Example 2 and Comparative Example 5, it is considered that the addition of a corrigent to the outermost layer that also functions as a support layer is important.

Taste sensory test 4
It was carried out using Example 1, Example 2 and Example 3. Table 7 shows the evaluation results.

As shown in Table 7, the score of the throat after taking is 1.7 points in Example 1 where the nicotine layer contains three kinds of corrigents, and only anhydrous citric acid is included. In Example 3, the score is 2 points, and in Example 2, which does not contain a corrigent, the score is 2.3. Therefore, by adding the corrigent to the nicotine layer, the evaluation is improved, and the drug-derived throat is obtained. A tendency to alleviate the irritation was shown.
In addition, the comparison between Example 2 and Example 3 showed that anhydrous citric acid is effective as a corrigent added to the nicotine layer in relieving drug-derived throat irritation.

Taste sensory test 5
It implemented using Example 1, Example 2, and Example 4. The evaluation results are shown in Table 8.

As shown in Table 8, the scoring score after taking is 1.7 points in Example 1 in which three kinds of corrigents are contained in the nicotine layer, and only l-menthol is contained. In Example 4, it is 2.2 points, and in Example 2, which does not contain a corrigent, it is 2.2 points. Therefore, by adding a corrigent to the nicotine layer, the evaluation becomes good, and the drug-derived A tendency to alleviate throat irritation was shown.
Moreover, in order to relieve the irritation | stimulation to the throat derived from a drug, it is thought that combining multiple types of the corrigent added to a nicotine layer is effective.

Taste sensory test 6
It was carried out using Example 1, Example 2 and Example 5. Table 9 shows the evaluation results.

As shown in Table 9, the score of throat after taking is 1.8 points in Example 1 where the nicotine layer contains three kinds of corrigents, and only the sodium saccharin is included. No. 5 is 2.0 points, and in Example 2 that does not contain a corrigent, it is 2.2 points. Therefore, by adding a corrigent to the nicotine layer, the evaluation becomes good, and to the drug-derived throat A tendency to alleviate the irritation was shown.
In addition, the comparison between Example 2 and Example 5 showed that saccharin sodium is effective as a corrigent added to the nicotine layer in alleviating the irritation of the drug-derived throat.

Taste sensory test 7
It was carried out using Example 3, Example 4 and Example 5. Table 10 shows the evaluation results.

As shown in Table 10, the scoring score after taking was 1.8 in Example 3 where only the anhydrous citric acid was contained in the drug layer, and Example 5 containing only saccharin sodium. In Example 4, which contains only l-menthol, the score is 2.2, so that anhydrous citric acid is most effective for alleviating drug-induced throat irritation. confirmed.
In addition, from the comparison of Examples 3, 4 and 5, it is better to add l-menthol to the second non-nicotine layer functioning as a support layer or the first non-nicotine layer than to add to the nicotine layer. It is considered effective in alleviating drug-induced throat irritation.

Taste sensory test 8
It was carried out using Example 6, Example 7 and Example 8. The evaluation results are shown in Table 11.

From Table 11, the scoring score after taking is 1.8 points in Example 6 in which only the anhydrous citric acid is contained in the drug layer, and 2 points in Example 8 in which only sodium saccharin is contained. In Example 7, which contained only 1-menthol, the score was 2.2, indicating that anhydrous citric acid is the most effective for alleviating drug-derived throat irritation. .
Also, from the comparison of Examples 6, 7 and 8, it is more stimulating to the drug-derived throat that l-menthol is added to the second non-nicotine layer or the first non-nicotine layer than to the nicotine layer. It is considered effective in mitigating

Taste sensory test 9
It was carried out using Example 3, Example 6 and Example 9. The evaluation results are shown in Table 12.

As shown in Table 12, the score of the throat after taking is 1.7 points in Example 3 using HPC-SL having a low viscosity, whereas HPC having a higher viscosity than HPC-SL. The score of Example 9 using -L was 1.8 points, and there was no significant difference between the two. Further, due to the difference in the viscosity of the HPC used, there was no significant difference in the dissolution time of the preparation.
Since the score of Example 6 in which the amount of the corrigent is less than that of Example 3 and Example 9 is 2.5 points, reducing the amount of the corrigent increases the irritation to the throat derived from the drug. Was confirmed. It was also shown that the effect on drug-derived throat irritation was minor even when the grade was changed.

  The preparations obtained in each Example and Comparative Example were subjected to the following solubility test in water and oral dissolution test. The results are shown in Table 13.

Water solubility test A test piece cut into a circular φ12 mm size was collected and placed in a test solution (purified water 900 mL), and the 15th revised Japanese Pharmacopoeia [B] General Test Method Formulation Test Method 6.10 Dissolution Test Method According to the paddle method (P587), a test was performed at 50 rpm using a sinker. Complete dissolution was confirmed visually, and the elapsed time was taken as dissolution time. The test was performed 5 times, and the average value was taken as the water dissolution time.

Intraoral dissolution test Collect a test piece cut into a circular φ12 mm size, put it in the oral cavity of a healthy adult without water, and measure the time until the test piece is completely dissolved only in the oral saliva did. In the test, the time required for taking 6 panelists was measured, and the value was taken as the oral dissolution time.

It is a figure which shows one Embodiment of the fast dissolving nicotine containing film formulation of this invention.

Explanation of symbols

1: First non-nicotine layer 2: Nicotine layer 3: Second non-nicotine layer 10: Fast-dissolving nicotine-containing film preparation

Claims (9)

At least two nicotine layers containing nicotine and an edible water soluble polymer;
A first non-nicotine layer containing a corrigent and an edible water-soluble polymer and not containing nicotine, disposed between the nicotine layers;
A fast-dissolving nicotine-containing film preparation comprising a flavoring agent and an edible water-soluble polymer and a second non-nicotine layer that does not contain nicotine, disposed in the outermost layer.   The fast-dissolving nicotine-containing film preparation according to claim 1, wherein an even number of the nicotine layers are provided.   The fast-dissolving nicotine-containing film preparation according to claim 1 or 2, wherein the nicotine layer contains a corrigent.   The fast-dissolving nicotine-containing film preparation according to any one of claims 1 to 3, wherein the taste masking agent is at least one selected from the group consisting of a sour agent, a high sweetness sweetener, and a refreshing agent.   The fast-dissolving nicotine-containing film preparation according to claim 4, wherein the sour agent is at least one selected from the group consisting of ascorbic acid, tartaric acid, citric acid, malic acid and salts thereof.   The fast-dissolving nicotine-containing film preparation according to claim 4, wherein the high-sweetness sweetener is at least one selected from the group consisting of aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, saccharin, and salts thereof.   The fast-dissolving nicotine-containing film preparation according to claim 4, wherein the refreshing agent is at least one selected from the group consisting of fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint, and menthol.   The edible water-soluble polymer is at least one selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose / sodium, carboxymethylcellulose / calcium, carboxymethylcellulose / potassium, carboxymethylcellulose, polyvinylpyrrolidone and sodium alginate. The fast-dissolving nicotine-containing film preparation according to any one of claims 1 to 7, which is a seed.   The fast-dissolving nicotine-containing film preparation according to claim 1 or 2, wherein the nicotine layer does not contain a corrigent.

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