JP2012070675A - Powder gum for tableting and tableting chewing gum - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide powder gum for tableting which can make tablet continuously without adhering to a pestle during tableting, and a tableting chewing gum which achieves a favorable texture and an excellent release property of a functional ingredient such as a biologically active substance contained therein.SOLUTION: A gum particle keeps the surface coated with a water insoluble excipient covered with powdery chitin or powdery chitosan or with chitin or chitosan. A tableting chewing gum is obtained by tableting the same.

Description

  The present invention relates to a tableting chewing gum excellent in sustained release of functional components represented by physiologically active substances and having a good texture, and to gum particles useful for the production of tableting chewing gum.

  The goal of drug administration is to effectively guide the drug to the site where the drug is desired to act, and to remain at that site to effectively exert the drug action. In that sense, drugs that are desired to act in the oral cavity, such as stomatitis, periodontal disease, and halitosis countermeasures, need to be designed to remain in the oral cavity for the time necessary for the drug to exert its action. As a form of a drug released over a long period of time in the oral cavity, a gum dosage form is preferable as a dosage form of a drug desired to act in the oral cavity.

  On the other hand, as a form to reach the drug action site, there is a method of reaching the site where the drug action is expected by placing the drug from the administration site into the systemic circulation, and as a typical drug dosage form, the drug is parenterally There are a method of administration and a dosage form which is orally administered into the intestinal tract. The parenteral administration method is an intravenous drug administration method that is directly injected into the bloodstream from outside the body. In either of these methods, the goal of drug administration is to move the drug from the site of administration to the site of action by systemic circulation.

  A problem affecting the absorption of orally administered drugs is the drug dosage form. Orally administered drugs are usually administered in tablet or capsule form. The reasons for choosing these dosage forms are mainly convenience, economy, stability and patient acceptance. Thus, these tablets or capsules must be disintegrated or dissolved prior to absorption. There are a variety of approaches that allow to alter or delay the disintegration of a solid formulation, and further, dissolution rate is a factor that determines drug availability.

Parenteral administration ensures delivery of the drug through the systemic circulation by placing the drug in the bloodstream.
However, parenteral administration is effective as a means of eliminating many problems associated with oral administration, but typical problems with parenteral administration require the assistance of medical personnel, and most It is not practical as a dosage form of drugs such as drugs and analgesics. When parenteral administration is required, there are also unpleasant problems such as patient comfort and concerns, including infections, as well as related equipment and expense contributions.

  As a method for improving the delivery of physiologically active substances to living bodies, chewing gum products containing physiologically active substances have been provided, and since the next year, the 16th revised Japanese Pharmacopoeia General Rules for Preparations have added gum agents as new formulations. It can be said that it reflects the request. It has been found that chewing gums containing these bioactive substances release the bioactive substances from the chewing gum by placing the chewing gum in the mouth under certain circumstances. If chewing gum continues to be chewed, pressure is generated in the oral cavity, and bioactive substances are released through the oral mucosa contained in the oral cavity, which is absorbed through the oral mucosa and forced to move directly to the systemic system through the circulatory system. ing. This greatly enhances the bioavailability of bioactive substances in the system in addition to drug absorption into the whole body system.

  A tableting gum is a preparation for achieving the object. In general, what is called a tableting gum is manufactured as follows. That is, a gum raw material mainly composed of sugar, gum base (elastic body, rubber, wax, emulsifier, oil, etc.) and fragrance is heated and kneaded, gummed, powdered, and then this powdered gum is punched. It is manufactured by filling a mold (mortar) and punching it into tablets. Examples of the method of powdering the gum include, for example, (1) a method in which the gum is pulverized at low temperature and powdered, and (2) the resulting gum is heated (70 ° C. or higher) and dried, then mechanically pulverized and powder (3) A method in which a binder solution such as gum arabic is added to a gum raw material and kneaded to make a gum, which is heated (70 ° C. or higher) and dried, and then mechanically pulverized into a powder (4) A method of cooling the produced gum to 0 ° C. or lower, mechanically pulverizing it, and the like are known (Patent Documents 1 to 3).

  In addition, as a method for providing a granular gum, Patent Document 4 discloses that a gum base is dissolved at a high temperature (up to 85 ° C.), mixed with other powder raw materials by a mixer equipped with a spiral blade, and then granulated. A method for producing a granular gum is reported.

  However, the powdered gum produced by any of these methods contains many problems and defects in quality and production, and various new proposals have been proposed by many companies for improvement. Has been made. For example, it contains a powder gum raw material, a binder solution, a method for tableting a powder gum comprising a water-absorbing saccharide and main components (Patent Document 5), a water-absorbing component and a poorly water-soluble component, and these are formed together with the powder gum. Chewing gum (Patent Document 6), tableting chewing gum containing lactic acid bacteria (Patent Document 7), powdered gum for tableting containing 80% by weight of reduced palatinose (Patent Document 8), sugar sweetener such as dextrin on the surface of the powdered gum Powder gum for tableting (Patent Documents 9 and 10) coated with, a technique for coating the surface of the gum with a saccharide, etc., a technique for polysaccharide tableting (Patent Documents 11 and 12), and the like have been reported.

U.S. Pat. No. 4,161,544 US Pat. No. 4,588,592 International Publication No. 2003/084338 Korean Registered Patent No. 10-0121337 Japanese Patent Application Laid-Open No. 07-066751 JP 2001-302513 A JP 2007-014237 A JP 2005-333966 A JP 2006-006310 A JP 2006-166791 A JP 2007-222161 A JP 2007-326876 A

  However, in reality, the properties and quality of the tableting chewing gum obtained by the above technique are far from the original expectations. The cause is that when trying to tablet a sticky gum, the protruding gum sticks to the punch of the tableting machine, making it difficult to continue tableting, or the gum is stuck to the punch of the tableting machine. If the formulation is designed to reduce the mixing ratio of the gum base so that it does not stick, the stickiness as a lump gum will not be exhibited, and the gum lump will be dislodged in the mouth. The reality is that a harmonious gum was not obtained.

  As a result, conventionally known powdered gums for tableting have an overwhelmingly large amount of carbohydrates compared to the weight of the gum base itself in pulverizing the gum base to a size suitable for tableting in any case. Ingredients are added to the gum base, and the gum base also floats in the sugar (usually the weight of the gum base in the powdered gum is between 20 and 30 percent, and the weight percentage of the gum base as viewed from the whole tableting gum Can only be produced in a state that can be said to be further reduced. Therefore, when the finished gum is chewed in the mouth, the entire gum collapses, and after a while the original stickiness of the gum appears. In order to improve it, there have been proposals to add a binder and the like at the time of tableting, but the resulting tableting gum has a stickiness far from that of the gum itself. The reality is that this is not the case.

  Accordingly, an object of the present invention is to provide a tableting powder gum that can be tableted continuously without adhering to the punch during tableting, and a sustained release of functional ingredients such as physiologically active substances that have a good texture and are contained therein. An object of the present invention is to provide a tableting chewing gum that ensures the properties.

Therefore, as a result of various studies to solve tableting properties, texture and sustained release of functional ingredients, the present inventor has mixed gum base with powdered chitin or powdered chitosan and crushed gum particles. Gum particles whose surface is coated with powdered chitin or powdered chitosan are obtained, and if this is tableted together with other ingredients, the gum particles can be tableted continuously without adhering to the wrinkles and the texture is good It has been found that a tableting chewing gum can be obtained.
In addition, powdered chitin or powdered chitosan is not used directly, but if mixed and ground with a gum base using a water-insoluble excipient whose surface is previously coated with chitin or chitosan, a tableting chewing gum having a better texture and It was found that gum particles were obtained.

That is, the present invention provides gum particles whose surface is coated with powdered chitin or powdered chitosan.
The present invention also provides gum particles whose surface is coated with a water-insoluble excipient whose surface is coated with chitin or chitosan.
Furthermore, the present invention provides a tableting chewing gum obtained by mixing any one of the above-mentioned gum particles and a component containing a functional component and tableting.

  If the gum particles of the present invention are used, tableting is possible without sticking during tableting, so a large amount of the functional component is contained, the food texture is good, and the functional ingredient is sustained-released. An excellent tableting chewing gum is obtained.

  The gum particles of the present invention are gum particles whose surfaces are coated with powdered chitin or powdered chitosan (also referred to as coated gum particles 1). The chitin or chitosan used can be obtained from shells of crustaceans such as crabs. In the present invention, powdered chitin or powdered chitosan is used. The particle size of the powdered chitin or powdered chitosan is preferably 200 μm or less, and more preferably 100 μm or less, from the viewpoint of tabletability and taste. The average particle diameter is preferably 10 to 200 μm, more preferably 10 to 100 μm.

  The content of the gum base in the coated gum particles 1 is preferably 10 to 60% by mass, more preferably 10 to 55% by mass, and particularly preferably 20 to 55% by mass from the viewpoint of the balance between tabletability and taste.

  The average particle size of the coated gum particles 1 is preferably 50 to 2000 μm, and more preferably 100 to 800 μm, from the viewpoints of particle mobility, tabletability, and component content uniformity.

  The coated gum particles 1 can be produced by mixing powdered chitin or powdered chitosan and a gum base and pulverizing the mixture. The pulverization treatment is not particularly limited as long as the gum base can be pulverized and the particle diameter can be reduced to 1000 μm or less, and examples thereof include a hammer mill, an oscillator, a cutter pulverizer, and the like, among which a cutter pulverizer is preferable.

According to the mixed pulverization of powdered chitin or powdered chitosan and gum base according to the present invention, it is not necessary to cool to 20 ° C. or lower as in the conventional method, and gum particles can be obtained stably at room temperature.
In other words, in the present invention, a softer gum base is cut at room temperature under the coexistence of chitin or chitosan fine particles and gum base lump, which is far finer and harder than the gum base particles that are finally pulverized. By crushing and crushing the gum base with a crusher such as an automatic crusher, hammer mill, or oscillator, the gum base particles that have been shredded and pulverized at the same time as the gum base are shredded and crushed into water By covering with a uniform layer of fine particles such as chitin or chitosan which is insoluble, non-hygroscopic and has no binding property itself, the crushed particles of the gum base once formed become stable particles, while maintaining their shape. It became possible to obtain a powdery gum without reassociating each other. Therefore, there is no need to grind the gum base at a low temperature which has been conventionally required. This produces a merit that it is much easier to handle in terms of operability in the manufacturing process. Under room temperature opening, the non-hygroscopic chitin and gum base fine particles covered with the chitosan layer independently maintain the shape at the time of manufacture, but once formed by pressurization during tableting. The gum base breaks down, breaks through the chitin and chitosan layers, and the gum base is pushed out from the inside to the surface. At the same time, the gum bases pushed out from the surrounding powdery gum particles are bonded together to form a lump of chewing gum as a whole. In this way, powdered gum particles that originally have no binding property develop binding properties between the gum particles by means of tableting, and form a single gum mass.
Moreover, in the conventional powder gum, the ratio of the gum base was not able to be tableted unless it was about 20 to 30% by mass. However, according to the present invention, even the gum particles containing 10 to 60% by mass gum base were punched. Lockable. Therefore, since the gum base content in the tableting chewing gum to be obtained can be increased, the texture is remarkably improved.

  Another gum particle of the present invention is a gum particle (also referred to as coated gum particle 2) coated with a water-insoluble excipient whose surface is coated with chitin or chitosan. Examples of the water-insoluble excipient used include cellulose (crystalline cellulose, powdered cellulose), talc, silicon dioxide, aluminum oxide and the like, and cellulose is particularly preferable. The average particle size of the water-insoluble excipient is preferably from 5 to 800 μm, more preferably from 50 to 200 μm, from the viewpoint of tabletability and taste. The chitin or chitosan used is the same as described above.

  The content ratio of chitin or chitosan covering the surface of the water-insoluble excipient is preferably 1: 5 to 30: 1 by mass ratio to the water-insoluble excipient from the viewpoint of texture, and more preferably 10: 3 to 10: 1. preferable.

  The content of the gum base in the coated particles 2 is preferably 10 to 60% by mass, more preferably 10 to 55% by mass, and even more preferably 20 to 55% by mass, from the viewpoint of balance between tabletability and taste. preferable.

  The average particle size of the coated gum particles 2 is preferably 5 to 2000 μm, and more preferably 100 to 800 μm, from the viewpoints of particle mobility, tableting property, and component content uniformity.

The coated particles 2 of the present invention use a water-soluble excipient coated with a thin layer of chitin or a thin layer of chitosan, so that the rough feeling and taste of chitin or chitosan are improved. That is, by first coating the surface of the water-insoluble excipient with a chitin solution or chitosan solution, the chitin and chitosan are not fine particles, but the central portion is a water-insoluble excipient and the surrounding area is a thin film. By making the chitin and chitosan layers coexist with the gum base and crushing with a pulverizer, the gum base is coated with chitin and chitosan coated on the surface of the water-insoluble excipient, resulting in recombination of the gums. A tableted gum obtained by tableting the powdered gum with a tableting machine has an unpleasant taste such as chitin and chitosan gummy, even if it is chewed in the mouth. In addition to removal, it was possible to eliminate the rough feeling remaining on the tongue.
On the other hand, such as chitin and chitosan can not be eliminated with water-soluble excipients such as citric acid, malic acid, and lactic acid, and also with carrageenan and polyphenol.

  The coated particles 2 of the present invention can be produced by mixing a water-insoluble excipient coated with chitin or chitosan and a gum base, and pulverizing the mixture. Here, in order to coat the surface of the water-insoluble excipient with chitin or chitosan, both of these may be mixed, but once chitin or chitosan is dissolved in an acidic solution, it is neutralized or weakly alkaline. Thus, it can be produced by depositing and attaching chitin molecules and chitosan molecules on the surface of the water-insoluble excipient, followed by drying. Furthermore, coating with chitin or chitosan and powdering of cellulose fibers (production of powdered cellulose) may be performed simultaneously. That is, chitin or chitosan is dissolved in an acidic aqueous solution, cellulose fibers (for example, absorbent cotton) are added to the aqueous solution, the cellulose fibers are hydrolyzed, and then dried.

Chitin and chitosan can be dissolved in a weak acid such as hydrochloric acid, sulfuric acid, nitric acid, citric acid, lactic acid, malic acid, or the like to make a low-concentration aqueous solution having a pH of about 4 to 0.1%.
When cotton such as absorbent cotton is added to the solution and heated to 50-60 ° C. while stirring so that it is uniformly covered with chitin and chitosan aqueous solution, the cellulose forming the absorbent cotton begins to hydrolyze, and the fibrous filaments Gradually cut. When the mixture is homogenized, it is gradually neutralized with a basic aqueous solution such as 0.1 to 5% sodium hydroxide, and finally the pH is adjusted to 8.2 to 8.5. Chitosan gradually becomes insoluble and is coated in a form covering the surface of fibrous cellulose with chitin and chitosan film. And it is alkaline and alkali oxidative decomposition proceeds, and the fiber filaments of cotton are further cut, resulting in fine powder coated with a film of chitin and chitosan.

In this way, a fine powdery cellulose coated with chitin and chitosan film is obtained, but in order to eliminate the rough feeling during chewing, it is preferable to use a wet grinding machine, for example, a media mill, such as a wet shaker. In addition to mills, wet planetary vibration mills, wet ball mills, wet roll mills, wet coball mills, wet bead mills, wet paint shakers, etc., high pressure homogenizers can be used. As the high-pressure homogenizer, a type in which the slurry is guided to a fine orifice at a high pressure of about 500 kg / cm ² or more and collides with each other at a high flow rate is effective. The optimum grinding concentration using these mills varies depending on the model, but a solid content concentration of 3 to 15 w / v% for a medium mill and 5 to 20 w / v% for a high-pressure homogenizer is generally suitable.

The obtained fine powder of cellulose covered with chitin and chitosan film can be dried by heating or drying to obtain a dry fine powder. In order to obtain a dry fine powder effectively, freeze-drying or spray-drying is possible. However, the method of drying into a film is excellent. The method of drying in a film form is a method of casting and drying on a substrate such as glass, stainless steel, aluminum, nickel / chromium plated steel plate or the like. The substrate may be preheated, or may be heated with infrared rays, hot air, high frequency, etc. after casting. The drying temperature is preferably 200 ° C. or less, and the casting thickness is preferably 10 mm or less as the thickness of the slurry. The slurry concentration is not particularly limited as long as it can be developed in the form of a film, but is practically suitable for obtaining a work that can be easily developed with a solid content concentration of about 5% to 20% and a good dried product. Yes. Industrially, a dryer such as a steel belt dryer, a drum dryer, or a disk dryer can be employed. Products dried in this film form include film, foil, flakes, scales, filaments, and powders. It becomes a shape.
The product moisture content of the composition thus obtained is preferably 2% or less of the total weight.

  The mixed pulverization of the water-insoluble excipient coated with the thin layer film of chitin or chitosan and the gum base obtained in the same manner as in the case of the coated particles 1 can be performed.

  The gum base used in the present invention is conventionally used, and is appropriately selected from, for example, resins, elastic bodies, waxes, minerals, emulsifiers, and the like.

  Examples of the resin include natural resins such as chill and gelton, and synthetic resins such as ester gum and vinyl acetate resin, which may be used alone or in combination.

  Guar gum (polysaccharide obtained from endosperm of seeds of Cyamopsis tetragonolobus (leguminosae)), locust bean gum (purified from the endosperm part of seeds of carob tree Ceratonia siliqua L. (Legumonasae), xanthan) Polysaccharides obtained by fermentation using Xanthomonas campestris, karaya gum (gum extracted from the resin of Starculia urens tree), guar gum, hydroxypropyltrimethylammonium chloride (O- [2- Hydroxy-3- (trimethylammonio) propyl] guar gum (mainly glycidyl trimethyl ammonium chloride added to guar gum) The resulting cationic polymer), ester gum (mainly composed of esters of abietic acid and glycerin), hydrogenated ester gum (mainly a mixture of disproportionated dehydroabietic acid and tetrahydroabietic acid) ), Maleic acid-modified ester gum (“ester gum” modified with maleic acid), and the like can be used.

  The elastic body is also called a rubber-like substance, and examples thereof include polyisobutylene (isobutylene polymer), polybutene, butyl rubber, polyisoprene, natural rubber and the like, and these may be used alone or in combination.

  Examples of the wax (hydrocarbon, wax, etc.) include Weiss wax, candeari wax, microcrystalline wax, carnauba wax and the like, and these may be used alone or in combination.

  Examples of inorganic substances include calcium carbonate, talc, and aluminum oxide. These may be used alone or in combination.

  Examples of the emulsifier include propylene glycol fatty acid ester, monoglycerin fatty acid ester, polyglycerin fatty acid ester, and sucrose fatty acid ester. These may be used alone or in combination.

  A tableting chewing gum can be produced by mixing the gum particles of the present invention with ingredients containing various functional ingredients and tableting. Here, various functional components include saccharide raw materials, non-saccharide sweeteners, fragrances, physiologically active substances, and the like.

  Among these, the physiologically active substance includes various physiologically active substances including pharmaceuticals.

  Examples of pharmaceuticals added to the tableting chewing gum include pharmaceuticals absorbed through the oral mucosa and all pharmaceuticals that exhibit an action in the oral cavity. More specifically, pharmaceuticals, analgesics, tranquilizers, and cardiovascular agents that are absorbed from the oral mucosa with small molecules such as insulin and calcitonin.

  It is a well-known fact that insulin is absorbed into the living body through the oral mucosa, and in particular, by adding DHA, which is a polyunsaturated fatty acid, it is absorbed at a pharmacological utilization rate of about 43%. .

  One of the other drugs expected to be absorbed from the oral mucosa is nitrate. Nitrate drugs are known to vary greatly in the onset and duration of effects due to differences in absorption route and dosage form. Currently, nitropen tablets and nitroglycerin tablets (sublingual tablets 0.3 mg: Nippon Kayaku, effect onset time: 1-2 minutes, duration: 8-30 minutes), nitrol tablet (sublingual tablet 5 mg: Eisai, effect onset time: 5 minutes, duration: 60-100 minutes, oral preparation 15 ~ 80 mg: Same as above, effect onset time: 15 minutes, duration: 4-6 hours), myoconal spray as an oral spray (oral mucosal absorbent 1-2 spray: Toei Eyo, effect onset time: 1 minute, duration; 30 minutes), buccal (basolator PR2.5 (oral mucosa absorbent 2.5 mg: Sanwa Chemical, effect onset time: 5 minutes, duration: 12 hours), nitrol R (oral release tablet 20 m as an oral release tablet) : Eisai, onset time: 1 hour, duration: 8 hours), etc. As these data indicate, sublingual tablets and sprays are generally less effective at once. Since the time until onset is short, the duration is shortened, so in the case of the tableting gum of the present invention, since it can be released in the oral cavity, the time until onset of effect is shortened, and per tablet Since the amount of the drug that can be contained is 100 to 200 mg, it is a means that has a sufficient function as a long-term sustained release preparation.

Even more surprisingly, it has been found that the same bioavailability can be achieved with chewing gum containing a smaller amount of bioactive substance than the typical oral administration normally used.
In fact, surprisingly, in at least certain examples relating to certain bioactive substances, administration of pharmaceuticals or bioactive substances using chewing gum via the oral cavity has an enhanced effect compared to parenteral administration. I know.

For example, caffeine is usually used as a stimulating substance for reducing sleep-blocking action. It is almost completely metabolized in the liver and is therefore classified as a pharmaceutical unrelated to low clearance flow. This means that the rate of inactivation is not affected by delivery to the liver and is only altered by changes in liver enzyme activity.
The pharmacokinetics of caffeine has not been fully elucidated and there is no significant difference between oral and intravenous administration. However, it is known that the absorption rate constant (Ka) increases significantly when caffeine is administered as chewing gum. This means that caffeine moves into the systemic circulation at a significantly faster rate. Similar changes in the onset of dynamic reactions have been observed, for example, in alertness and work.

  It is further surprising that it has been found that at least certain substances of the bioactive substance placed in the chewing gum can have a triggering action on substances present in the systemic circulation. For example, with regard to caffeine taken orally, while taking a certain amount of caffeine and after a certain period of time, further intake of caffeine is insignificant in the action on the body When caffeine contained in chewing gum is ingested, a triggering action that produces a synergistic effect with caffeine in the systemic circulation can be recognized. Such a triggering action is also observed in other drugs such as analgesics.

Drugs included in tableting gum include analgesics, antibiotics, antiviral drugs, antihistamines, anti-inflammatory drugs, decongestants, antacids, muscle relaxants, psychotherapeutics, insulin and cardiovascular agents. Can be mentioned. Depending on the drug, treat the resulting tableting gum, especially cough, cold, movement disorder, allergy, fever, analgesia, inflammation, sore throat, cold pain, sinus disorder, diarrhea, diabetes, mania, anxiety and other Can be used to treat diseases and symptoms.
Specific substances (drugs) include caffeine, aspirin, acetaminophen, ibuprofen, hydroxycitric acid, chromium picolinate, phosphatidylcholine, nicotine, insulin, zinc, vitamin C, carrots, berries, cauacaua, Although chamomile etc. are mentioned, these are not limited to the above.

  Since there are many substances that irritate the sensory organs such as bitterness and puffing in medicines, a sufficient amount of masking agent is required for tableting gum that releases medicines in the mouth. As this masking agent, sucralose, zinc gluconate, ethyl maltol, glycine, acers farm k, aspartame, saccharin, fructose, trehalose, xylitol, licorice, glycerhidine, dextrol, sodium gluconate, gluconolactone, ethyl vanillin, Although vanillin etc. are mentioned, it is not specifically limited to these sweeteners.

  For example, fructose and high-intensity sweeteners such as saccharin, aspartame, sucralose, and acesulfame κ may be effective as astringent masking agents in attempts to conceal astringent flavors such as aspirin. Are known. In addition, when an active ingredient such as caffeine has moderate bitterness, glycine, ethyl maltose, zinc gluconate, licorice powder, and a sweetener with a high degree of sweetness are effective. In the case of very unpleasant active ingredients such as acetaminophen, peppermint functions very effectively, but it requires the addition of a high sweetness sweetener such as aspartame.

  The tableting chewing gum of the present invention may further contain a seasoning, a pigment, a stabilizer, and an emulsifier.

  EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.

Example 1
By continuously pulverizing 2 kg of chitosan (Kyoyo Chemical Co., Ltd. Chitosan FM-80: 80 mesh pass 95% or more) and 3 kg of gum base (manufactured by Fuji Chemical Co., Ltd.) at 3000 to 4000 rpm for 1 minute. A finely divided powdery gum with a gum base content of 60% was obtained.

Example 2
By continuously crushing 3 kg of chitosan (Kyoyo Chemical Co., Ltd. Chitosan FM-80: 80 mesh pass 95% or more) and 2 kg of gum base (Fuji Chemical Co., Ltd.) at 3000 to 4000 rpm for 1 minute with a mill of Akira Kiko Co., Ltd. A finely divided powdery gum with a gum base content of 40% was obtained.

Example 3
Based on the formulation shown in Table 1, tableting gum was produced from the powdery gum containing 60% gum base produced in Example 1 and the powdered gum containing 40% gum base produced in Example 2.

(result)
Although the mixed powder consisting of each prescription was tableted with a tableting machine, prescription (1) was impossible to continue tableting from adhering to the punch of the tableting machine, but as a lubricant Tableting was possible when an appropriate amount of magnesium stearate was added. However, Formula (2) -1 and Formula (2) -2 were able to be tableted without requiring addition of a lubricant.

  From the tableting results of Formula (1), Formula (2) -1 and Formula (2) -2, it was confirmed that tableting is possible with a gum base content of 40 to 60% by mass.

Example 4
In order to confirm the tableting performance, tableting gums of Formulations 1 to 3 having a gum base content in the range of 51.6% by mass to 32.4% by mass were produced without using a lubricant.

(result)
There was no problem in tableting in any prescription.
That is, tableting was possible at a gum base content of 30 to 50% by mass without the addition of excipients.

  Since the rough feeling caused by the fine particles of chitosan remains, 2.5 kg of chitosan (chitosan FM-200 manufactured by Koyo Chemical Co., Ltd .: 95% or more 95% or more) with a fine particle diameter of chitosan to solve the problem By pulverizing 2.5 kg of gum base continuously at 3,000 to 4,000 rpm for 1 minute with a pulverizer manufactured by Akira Kiko Co., Ltd., a finely pulverized powdered gum having a gum base content of 50% by mass is obtained.

(result)
Furthermore, it removes the rough feeling, astringency, and tingling sensation derived from chitosan that remains on the tongue when chewed even if tableting is performed by adding citric acid or arginine added to speed up dissolution of chitosan or chitosan. I couldn't. However, continuous tableting was possible.

  Since the rough feeling caused by the fine particles of chitosan remains, 2.5 kg of chitosan (chitosan FM-200 manufactured by Koyo Chemical Co., Ltd .: 95% or more 95% or more) with a fine particle diameter of chitosan to solve the problem A finely pulverized powdery gum with a gum base content of 50% is obtained by continuously pulverizing 2.5 kg of gum base (Fuji Chemical Co., Ltd.) with a pulverizer manufactured by Akira Kiko for 1 minute at 3,000 to 4,000 rpm.

(result)
Furthermore, for the purpose of masking chitosan derived from chitosan and -NH ₂ group derived from chitosan for the purpose of improving the unpleasant taste of chitosan, carrageenan having -SO ₄ group and catechin having phenolic -OH group are added and mixed, When tableting was performed, the rough feeling derived from chitosan remaining on the tongue during chewing was not improved, but unpleasant tastes such as astringency and puffiness could be removed.

Example 5
(Production method of finely pulverized cellulose coated with uniform chitosan film)
10 liters of a 1% aqueous hydrochloric acid solution was prepared, 500 g of chitosan was added with stirring, and the mixture was heated to 30 ° C. for complete dissolution. 5 kg of absorbent cotton was immersed in the mixture and mixed uniformly. After uniformly mixing for 30 minutes, 1% aqueous sodium hydroxide solution was gradually added to set the final concentration to pH 8.0. After further mixing uniformly for 30 minutes, 90 ° C. warm air was blown to dry the absorbent cotton and left for a whole day and night. By doing so, fine powdery absorbent cotton (cellulose) whose surface is uniformly coated with a chitosan film can be obtained.
The powdered absorbent cotton is passed through a 100 mesh sieve to obtain finely pulverized chitosan-coated cellulose.

Example 6
A fine powdery cellulose having a gum base content of 50% is obtained by continuously grinding 2.5 kg of finely powdered cellulose coated with a uniform chitosan film and 2.5 kg of gum base for 1 minute at 3,000 to 4,000 rpm with a pulverizer manufactured by Akira Kiko Co., Ltd. A crushed tableting powder gum was obtained.

Example 7
10 liters of a 1% aqueous hydrochloric acid solution was prepared, 500 g of chitosan was added with stirring, and the mixture was heated to 30 ° C. for complete dissolution. Thereto was added 5 kg of microcrystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) with stirring, and then a 1% aqueous sodium hydroxide solution was gradually added to set the final concentration to pH 8.0. After further mixing uniformly for 30 minutes, 90 ° C. warm air was blown to dry the absorbent cotton and left for a whole day and night. By doing so, fine powdery absorbent cotton (cellulose) whose surface is uniformly coated with a chitosan film can be obtained.
The powdered absorbent cotton is passed through a 100 mesh sieve to obtain finely pulverized chitosan-coated cellulose. In the same manner as in Example 6, this was mixed with a gum base and pulverized with a pulverizer to obtain a powdered gum for tableting having a gum base content of 50%.

Example 8
When the tableting powder gum obtained in Example 6 and Example 7 was used for tableting with a tableting machine, it was confirmed that tableting was possible without any problems.
When 10 healthy people chewed these tableting gums, no one felt the rough texture on the tongue, the chitosan's original puffiness or bitterness.

Example 9
Based on the prescription (total amount: 1.5 kg) shown in the following table for the 50% tableting powdered gum obtained in Example 6, tableting gums (total 950) containing sweeteners and caffeine were obtained. . There was no inconvenience in continuous tableting.

  After 6 healthy people (age: 22-62 years old) chew this tableting gum one by one, 5 minutes later, 10 minutes later, 20 minutes later, 30 minutes later, 40 minutes later, 60 minutes later The ruminant mass of each gum was collected, the caffeine content remaining in it was measured, and the average value of 6 was obtained.

Caffeine quantification method:
1) Measurement principle Reversed phase column separation was performed by liquid chromatography (HPLC), and measurement was performed by ultraviolet absorbance.
2) HPLC conditions (1) Equipment used: High performance liquid chromatograph (JASCO LC-2000)
(2) Column: This column; Develosil ODS-HG-5 (inner diameter 4.6 mm, length 15 cm, Nomura Chemical)
Guard column; Develosil ODS-HG-5 (inner diameter 4.6 mm, length 1 cm, Nomura Chemical)
(3) Setting conditions: (i) Mobile phase flow rate: 1 mL / min, (ii) Column temperature: 40 ° C., injection volume: 10 μl
(4) Detection condition: UV detection (detection wavelength: 230 nm)
3) Preparation method of extraction solution Deionized water, acetonitrile and 85% phosphoric acid are mixed at a ratio of 49.9: 50: 0.1.
4) Preparation method of internal standard solution 5 g of catechol as an internal standard substance is dissolved in 100 mL of the extraction solution.
5) Method for adjusting mobile phase (1) Method for adjusting mobile phase (0.085% phosphoric acid aqueous solution) Distilled water and 85% phosphoric acid are mixed in a ratio of 999: 1.
6) Preparation method of sample solution (1) Put a gum mass into a stoppered Erlenmeyer flask containing 1 mL of internal standard solution and 49 mL of the extraction solution.
(2) Apply ultrasonic waves for 30 minutes with an ultrasonic cleaner.
(3) 1 mL of the supernatant and 1 mL of deionized water are mixed, filtered through a 0.45 μm PTFE membrane filter, and used for analysis.
7) Under such conditions, the retention time of the internal standard catechol in liquid chromatography is around 8.5 minutes, and the retention time of caffeine is around 10 minutes.
8) A calibration prepared from the peak area of the caffeine standard solution having a known concentration is prepared, and the amount of caffeine (mg) in the sample is obtained.
Table 14 summarizes the average values of the gum masses obtained from six subjects.

Example 10
A preliminary experiment was conducted for the purpose of confirming that caffeine in the tableting gum obtained in Example 9 was absorbed in the oral cavity.
The caffeine content in the saliva of two subjects (32 and 62 years old, both men) chewing cinnamon-flavored caffeine gum was measured.
Each subject chewed one tableting gum for 20 minutes and exhaled all saliva into the container. After chewing, each subject gargled twice with 10 mL of water and combined with the collected saliva.
The content of caffeine in the collected saliva was measured by the same method as described in Example 9. As a result, it was confirmed that most caffeine (80% to 100%) in the gum was released in the saliva of two subjects after 20 minutes.

Example 11
In order to confirm that caffeine released from the tableting gum obtained in Example 9 is absorbed from the oral mucosa, the caffeine content in the blood of two subjects (31 years and 60 years) was measured. did. Under the observation of a doctor, blood was collected with a 2 mL blood collection tube containing EDTA, separated from serum, and stored frozen at −20 ° C. until measurement of caffeine content in the serum. The caffeine content was measured according to the above-described high performance liquid chromatography method.
The results are shown in Table 15.

  From this result, it was found that caffeine released in the oral region was absorbed through the oral mucosa and acted for a long time, demonstrating the usefulness of the tableting gum in the medical field.

  According to the present invention, it is possible to provide a tableting chewing gum that has a good texture, contains a large amount of functional components such as pharmaceuticals, and has good sustained release properties.

Claims (8)

  Gum particles whose surface is coated with powdered chitin or powdered chitosan.   The gum particles according to claim 1, which is a powdered gum for tableting.   The gum particles according to claim 1 or 2, which are obtained by mixing powdered chitin or powdered chitosan and a gum base and pulverizing the mixture.   Gum particles whose surface is coated with a water-insoluble excipient whose surface is coated with powdered chitin or powdered chitosan.   The gum particles according to claim 4, which is a powder gum for tableting.   The gum particles according to claim 4 or 5, which are obtained by mixing a water-insoluble excipient whose surface is coated with chitin or chitosan and a gum base, and pulverizing the mixture.   The gum particle according to any one of claims 4 to 6, wherein the water-insoluble excipient is at least one selected from cellulose, talc, silicon dioxide and aluminum oxide.   The tableting chewing gum obtained by mixing the gum particle of any one of Claims 1-7, and the component containing a functional component, and tableting.