KR101494180B1 - Fast disintegrating tablet suitable for environmentally sensitive drug and process for manufacturing the same - Google Patents

Abstract

The present invention relates to oral preparations which rapidly disintegrate in the oral cavity, and relates to a rapid disintegration and high-hardness quick-disintegration preparation and its preparation. More particularly, the present invention relates to a quick-boil comprising low-wet granules and dry granules comprising spray-dried mannitol and a white sugar binder, and a method of making the same, wherein the quick- Especially, it is suitable for environmentally sensitive drugs such as light, temperature and moisture, and can be manufactured by a general tableting machine and a general tablet manufacturing process without any problem even if it includes drugs, excipients and additives that can cause a dyspepsia.

Description

FIELD OF THE INVENTION The present invention relates to a process for preparing a compound of formula (I), a compound of formula (I), a compound of formula (I)

The present invention relates to oral preparations which rapidly disintegrate in the oral cavity, and relates to a rapid disintegration and high-hardness quick-disintegration preparation and its preparation. More particularly, the present invention relates to a quick-boil comprising low-wet granules and dry granules comprising spray-dried mannitol and a white sugar binder, and a method of making the same, wherein the quick- In particular, it is suitable for environmentally sensitive drugs such as light, temperature and moisture, and is suitable for drugs having a small amount in tablets. Also, it can be used for general tablets and general tablets without any problem even if they include drugs, excipients, ≪ / RTI >

In order to supply the drug into the body, tablets or tablets have been used conveniently and usefully for a long period of time. However, surprisingly many people are known to have fear of swallowing tablets, as well as elderly people with hand trembling and swallowing difficulties, who are unable to swallow tablets and are fed in the form of syrups or refined tablets, , A form of preparation that is still uncomfortable for people who are unable to get water during travel, people with limited water intake (eg, kidney disease patients), and those who are lying down constantly to get up and take drugs.

The Fast Disintegrating Tablet was developed to improve this. It is a form of tablets that can be taken with saliva in the absence of water when the tablets are disintegrated within a few seconds to several tens of seconds by the saliva when the tablets are placed in the oral cavity. Rapidly Melting Tablets, Orodispersible Tablets, Fast Dissolving Tablets, Rapidly Collapsing Tablets, Oral Disintegrating Tablets, Rapidly Melting Tablets, (Rapidly Eroding Tablet) and so on. In addition to the above mentioned items, some of them are also useful for some people with mental illnesses. Some of them hide pill in the bottom of the tongue while pretending to eat tablets in front of the nurse, etc. In some cases, it is discarded, and for the more reliable administration of these, chewing is a form of formulation that can be usefully used.

The ideal chewing gum requires good physical properties such as quick and smooth disintegration in the oral cavity, as well as smooth production, transportation, packaging, and storage. Such physical properties include high hardness and low wear. Unfortunately, it is common for disintegration to result in poor physical properties of the tablet and disruption if the physical properties are good. Most of the commercially available buckets are either to find a point where they balance or compromise properly, or they should focus on one side, but make up for the lack of buckets, fill in the notes, or supplement them in other ways Most of them are released.

Examples of the manufacturing techniques of the chewing gum include freeze-drying, a method of preparing cotton candy by a similar method, a method of containing a proper amount of foaming agent in the tablet, a method using a large amount of disintegrant, A method of using the appropriate combination of high-performance forming saccharides, a method of improving the physical properties by treating the tablets obtained after the low-pressure tableting by humidification or warming, a method of improving the tablet machine, and a method of spraying a lubricant in the mold, And a method of producing a mixture without a complication is known.

However, many of the above-described techniques for manufacturing the rapid debris require specialized equipment, expensive facilities, or special upgrades because general pharmaceutical facilities can not be utilized as they are. This may lead to an increase in manufacturing cost and may be subject to various applications. In addition, even when a specific temperature and humidity condition is required after tableting or tableting, refining may be exposed to unnecessary facility investment and harsh conditions, and the application may be restricted.

Rhamosetron is a compound of formula (I) wherein the chemical name is (-) - (R) -5 - [(1-methyl-1H-indol-3- yl) carbonyl] -4,5,6,7-tetrahydro-1H -Benzimidazole ((-) - (R) -5 - [(1-methyl-1H-indol-3-yl) carbonyl] -4,5,6,7-tetrahydro- A series of tetrahydrobenzimidazole derivatives including tron and its pharmaceutically acceptable salts have excellent serotonin (5-HT) 3 receptor activity, so that based on such action, an anticancer drug such as cisplatin and radiation (European Patent No. 381422) have been proposed to prevent vomiting and migraine, multiple headache, trigeminal neuralgia, anxiety symptoms, gastrointestinal motility disorder, peptic ulcer, irritable bowel syndrome, and the like. The original source of lomosetron is Japan, and for the purpose of inhibiting digestive system symptoms such as nausea and vomiting induced by anti-malignant tumor drug, 0.1 mg of lomosetron hydrochloride is administered to adult Or 0.3 mg once a day intravenously. The country is being sold in South Korea's Oh Stella ^® OD ZE or a bond of 0.1 ㎎, and Jea ^® Injection 0.3mg trade name. For another purpose, as a hydrochloride of ramosetron for the treatment of diarrhea-related irritable bowel syndrome in men, it is usually marketed to be orally administered 2.5 or 5 μg per day to adult. In Korea, it is marketed in Astellas Korea at 2.5 and 5 μg of iribo ^® . If I ^® OD ZE-defined market for the purpose of antiemetic has been prepared without taking into bungjeong to enable water. In patients with nausea and vomiting, nausea and vomiting can also occur by taking water, so it is of great help to have the patient take the buckwheat instead of regular tablets at the time of conversion to oral administration after the injection for the patient do. In addition, a method of incorporating a stabilizer in various ways has been proposed since drugs have light-sensitive properties. Among them, iron oxide has a property of sticking to a punch when it is tableted, There are a lot of difficulties, and there are many restrictions on its use. Further, it may be difficult to tablet the tablets so that the content uniformity of 0.1 mg is ensured.

Korean Patent Registration No. 0642976 discloses a process for producing a chewing gum through a process in which a saccharide having a relatively low melting point, a drug, a diluent and the like is granulated and then the saccharide having a low melting point is heated to a temperature higher than the melting point and cooled, have. However, this step includes a heating step in which the tablets are placed in an oven at 120 to 160 캜 for a few minutes, and therefore, there is a restriction that they can not be applied to drugs that are unstable in temperature.

Korean Patent Registration No. 0655627 discloses a rapid disintegration process involving a saccharide and an amorphous saccharide followed by humidification and drying after tableting. According to the embodiment of the patent, the tablets are allowed to stand for 20 minutes in a thermo-hygrostat under the conditions of 35 ° C and 85% RH, and then dried in an oven at 50 ° C for several tens minutes or at 25 ° C in a thermo-hygrostat After the tablets are left for 12 to 24 hours, they are dried at 25 to 40 ° C for several hours. If the drug is poor in stability against water, there is a restriction on the use thereof and a disadvantage have.

U.S. Pat. No. 5,646,464 discloses a buckwheat containing lactose and mannitol, and agar (0.1 to 1.2 w / w% relative to the saccharides) and a process for preparing the same. In this patent, an aqueous solution in which the drug and excipients are dispersed and dissolved is prepared and put into a mold (mainly a molded PTP packaging film), and is made into a jelly form and then dried to obtain an inner bath. The obtained inner bath has high hardness and fast Disintegration time can be obtained, but the manufacturing process is complicated, the shape of the tablet may not be uniform, and the edge portion is broken well.

Therefore, in general, it is possible to produce tablets by tableting or molding without improving the tableting machine or molding machine used in the pharmaceutical process, or without using additional devices, and there is no cumbersome post-treatment process in severe conditions after tableting or molding, There is a continuing need for the development of tablets having a rapid disintegration property and a method for producing the tablets.

Furthermore, the necessity of development of a chewing gum which can be manufactured by a general tableting machine and a general tablet manufacturing process without any problem even if it includes drugs, excipients and additives which can contain environmentally sensitive drugs such as light, temperature and moisture, It is a matter of urgency.

It is an object of the present invention to provide a process for producing a molded article which can be produced by using a tablet machine or a molding machine generally used in a pharmaceutical process and has a high hardness as well as a high disintegration property without a troublesome post- The present invention also relates to a method for manufacturing a chewing gum which can be manufactured by a general tableting machine and a general tablet manufacturing process without any problem even if it includes drugs, excipients, additives and the like which contain environmentally sensitive drugs such as light, temperature and moisture, .

In order to solve the above technical problems, the present invention is characterized in that it comprises 50 to 99% by weight of low-wet granules containing spray-dried mannitol and white sugar binder and 1 to 50% by weight of dried granules containing spray-dried mannitol and white sugar binder As shown in FIG.

According to another aspect of the present invention, there is provided a method for preparing a dry granule, comprising: preparing dry granules each comprising low wet granulation, spray dried mannitol, and white sugar binder; There is provided a process for the manufacture of a chewing gum comprising the steps of forming a mixture after tableting comprising said low wet granulation and dry granulation; compressing the mixture after tableting to obtain tablets; and drying said tablets .

The rapid decay according to the present invention can be produced by using a tablet machine or a molding machine generally used in a pharmaceutical process, and it has a high hardness and a fast disintegration property without a cumbersome post-treatment process under severe conditions after molding or molding Since the chewing gum can be obtained, the production cost is low, no additional facility investment is required, packaging, transportation and storage are easy, and convenience for patients to take drugs can be increased. Also, it can be manufactured by a general tableting machine and a general tablet manufacturing process without any problem even if it contains drugs sensitive to temperature and moisture, drugs, excipients, and additives that can cause the tablet disorder. Particularly, even when a low content (for example, 0.1 mg) of the active ingredient is contained, the content uniformity is ensured and the preparation can be effectively carried out without a penile disorder.

First, some terms or expressions used throughout this specification may be defined as follows, unless otherwise stated explicitly.

As used herein, the term " loss on drying " refers to the amount of water, solvent, volatile matter, etc. contained in the sample dried and fired at a heating condition expressed as a percentage of the weight before drying. The exemplary measurement method is as follows. The weight of the sample (hereinafter referred to as " weight after drying ") was measured at 105 ° C for several to several tens of minutes using a Sartorius MA100 LOD meter until no further change in the value was observed. . After subtracting the weight after drying from the weight before drying, dividing the weight by the weight before drying and multiplying by 100, the weight loss (%) is obtained. For example, when 2.0000 g of sample is measured, the solvent or moisture is dried and blown, and when 1.9500 g is left, the drying loss is 2.50%. In order to ensure the accuracy, after one measurement, the temperature of the sample inlet is cooled to 35 ° C or less, the next measurement is started, and the average value obtained by three measurements is set as the drying loss.

The term " dry granules " referred to in the present specification refers to granules obtained by drying in a wet granulation method and then dried, and the granules are in a state in which the drying loss is no longer changed even after further drying. For example, the wet mass of agglomerated wet agglomerates is dried in a convection oven at 50 DEG C for 4 hours using the binder solution in the production step of the wet granules, and the dry weight loss of the dry granules after an additional 2 hours in the same manner Means granules of the same state. More specifically, for example, 500 g of the wet agglomerated agglomerated agglomerated agglomerate solution is passed through a 30-mesh sieve, and the agglomerated agglomerate is uniformly spread on a stainless steel plate to a thickness of about 0.1 to 2 cm, dried for 2 hours, dried again for 2 hours, dried for a total of 4 hours, and re-dried. The resulting granules were dried (dried) The dried granules may be referred to as " dry granules " if they exhibit the same numerical loss on drying, even with the results of weight loss measurements and, in the same manner, for granules further dried for 2 hours. In this case, the term "drying loss at the same value" means that the value of the drying loss is within ± 0.3%, preferably within ± 0.2% in consideration of the measurement error. The dry weight loss of such dry granules is usually within 3% or within 2%, but it may also be within 1% or within 0.5% depending on the material constituting the granules.

As used herein, the term "low wet granulation" refers to granules having a dry weight loss in the range of 1.05 times or more to 5 times or less of that of the "dry granules" when the loss on drying of the granules obtained by the wet granulation method is measured, Refers to granules having a dry weight loss of not less than 1.1 times and not more than 3 times, and most preferably a granule having a dry weight loss of not less than 1.2 times and not more than 2.5 times.

The low-wet granules are used in amounts normally used for tableting tablets, and have no problem in producing tablets by a general tablet production process.

General tablet production process "refers to a process that utilizes general tableting machines or molding machines used in pharmaceuticals and adopts the normal temperature and humidity conditions inside the tatami room.

A "general tablet machine or a molding machine" may be a single or multi-row tablet machine, and it is possible to use a special film to prevent the part from sticking to the punch when tablet is tableted, or to make special modifications such as spraying the lubricant into the mold Or a molding machine that is not used.

The term " normal temperature and humidity inside the tatami room " means that the condition of the air inside the space where the tablet machine or the molding machine is located is within the range of the temperature and humidity normally controlled. For example, .

A " lubricant conventionally used " is a lubricant mainly used for tablets tableting, and there is no particular restriction on its kind.

The term " amount of the lubricant conventionally used " refers to a condition in which an excessive amount of a lubricant is not used. The amount of the lubricant used in the production of general tablets is within 3% (relative to the weight of the tablet) Or less, more preferably 1.5% or less.

"There is no problem in producing tablets" means that some or all of the tablets may stick to punches or molds, some or all of the tablets may break during tableting or molding, Refers to the absence of a tabletting disorder such as partial or complete breakage during transfer to the container and also indicates that there is no problem with the flowability of the tablet for tableting so that there is no weight deviation between the tablets produced.

Hereinafter, the present invention will be described more specifically.

Low-wetting granules and method for manufacturing the same

The low wet granulation comprised in the chewing gum of the present invention is characterized by comprising spray dried mannitol and a white sugar binder.

In accordance with one embodiment of the present invention, in addition to the spray dried mannitol and saccharide binder, the low wetting granules of the present invention may also contain other additives such as the active ingredient, and / or the granule, the stability of the active ingredient, , Binding, performance improvement, improvement of the manufacturing process, and the like.

Mannitol is well soluble in water (1 part per 5.5 parts of water at 20 ° C), is chemically stable, non-hygroscopic, does not undergo amino group and Maillard reactions, and tastes good when disintegrated in the mouth .

Spray-dried mannitol is advantageous in that it is porous, dissolves rapidly in water, has good flowability, and is compressible in addition to the above-mentioned properties of mannitol. Examples of such spray dried mannitol include, but are not limited to, Mannogem ( ^TM) EZ (SPI Pharma) and Pearlitol ( ^R ) SD (Roquette). Spray-dried mannitol has many applications in the field of pharmaceuticals due to the above-mentioned characteristics, and is mainly used as a diluting agent in the direct tableting method without preparing granules. In the present invention, by utilizing spray-dried mannitol in the production of wet granules, unlike such conventional methods, it is possible to make the mannitol (mannitol powder) in powder form contain more microvoids than wet-granulate, So that they exhibit faster disintegration when they are made into tablets and have better hardness and scratch resistance.

In the present invention, the low-wet granule is preferably 20 to 98% by weight, more preferably 30 to 95% by weight, still more preferably 50 to 90% by weight, based on 100% by weight of the low- %. When the content of the spray-dried mannitol is less than 20% by weight or more than 98% by weight based on 100% by weight of the low-wet granule, the hardness may be low or the disintegration time may be delayed.

The white sugar binder may be dissolved in water, a non-aqueous solvent or a mixed solvent thereof, and more preferably, it may be dissolved in water or a mixed solvent of water and ethanol. The concentration of white sugar in the solvent may be 1 to 60% (weight / weight) (w / w), preferably 5 to 50%.

The low-wetting granules preferably contain 1 to 50 parts by weight, more preferably 2 to 30 parts by weight, more preferably 3 to 15 parts by weight of the white sugar binder in terms of the amount of dried white sugar per 100 parts by weight of the spray-dried mannitol By weight. If the content of the dried white sugar binder is less than 1 part by weight with respect to 100 parts by weight of the spray-dried mannitol, there may be a problem that the hardness of the tablet is lowered, and if it exceeds 50 parts by weight, the disintegration time may be delayed.

The low wet granulation may or may not comprise the active ingredient. When the low wet granulation contains the active ingredient, it may be mixed in a solid state such as spray-dried mannitol before the binding liquid is added for the production of the wet granules. The properties of the active ingredient may include powder state, crystal state, Granular state, fine powder state, or nanoparticle state. Alternatively, they may be dissolved or dispersed together in the production of the white sugar binding liquid.

The low wetting granules of the present invention may further comprise additional components for the granulation. Additional ingredients for granulation include dry binders, colorants, flavoring agents, sweeteners, stabilizers, antioxidants, etc., which may be added in solid form with spray dried mannitol.

Preferably, the dry binder in the granules is at most 50 parts by weight (e.g., 0.1 to 50 parts by weight), more preferably at most 30 parts by weight, more preferably at most 30 parts by weight, Preferably not more than 15 parts by weight, based on the total weight of the composition.

Examples of the dry binders include saccharides, sugar alcohols, starches, polysaccharides, cellulose derivatives, and mixtures thereof. Specific examples thereof include fructose, lactitol, lactose, maltitol, maltose, mannitol, sorbitol, sucrose, erythritol, xylitol, maltodextrin, isomalt, dextrin, dextrose, dextrates, Starch, microcrystalline cellulose, silicified microcrystalline cellulose, powdered cellulose, cellulose acetate, STARLAC® (spray dried solids containing 15% corn starch and 85% alpha-lactose monohydrate, manufactured by Roquette American, Inc.) , MICROCELAC® (spray dried solids containing 75% alpha-lactose monohydrate and 25% microcrystalline cellulose, manufactured by Meggle excipients & technology) and CELLACTOSE® (consisting of 75% alpha-lactose monohydrate and 25% cellulose powder Spray-dried compound, manufactured by Meggle excipients & technology), and the like, but is not limited thereto.

Among the additional components for granulation, the components other than the dry binder, that is, colorants, flavors, sweeteners, stabilizers, and antioxidants may be dissolved or dispersed during the preparation of the white sugar binding liquid.

The low wet granulation as described above preferably comprises the steps of forming a granulate comprising spray dried mannitol and a saccharide binder and drying the granules to a dry weight loss value of at least 1.05 times, Wet granules having a mean particle size of less than about < RTI ID = 0.0 > 50% < / RTI >

Preferably, the saccharide binder is used in the form of dissolving in water, a non-aqueous solvent or a mixed solvent thereof when preparing the mixture for granulation comprising spray-dried mannitol and white sugar binder.

The granules containing the spray-dried mannitol and the saccharide binder may further contain an active ingredient and / or an additional ingredient for granulation, and the method of introducing them into the mixture has been described above.

The production of low wet granules can be generally carried out utilizing the method of making wet granules used in the pharmaceutical field. According to one embodiment of the present invention, spray dried mannitol and saccharide binder, and optionally, active ingredients and additives, such as granules, mixers, U-shaped mixers, high speed mixers, fluid bed granulators, / RTI > may be prepared in the form of agglomerated particle agglomerates. The agglomerated agglomerated agglomerated particles may be directly dried or may be subjected to a drying step after sieving. According to one embodiment of the present invention, agglomerated particle agglomerates can be passed through a sieve of 30 mesh to be granulated.

Drying for the production of low wet granules can be carried out utilizing a method for drying of general granules. For example, the drying operation may be performed by a convection oven, a vacuum oven, a fluidized bed dryer, a dryer, natural drying at room temperature, or the like. During the drying or in the state where the drying is completed, the low-wet granules of the desired size may be obtained by once again sieving.

Dry granules and methods for their manufacture

The dried granules included in the chewing gum of the present invention also include spray-dried mannitol and white sugar binder, and the difference from the low-wet granules described above is in a dry state. In addition, This is the same as that described previously for low wet granulation.

According to a preferred embodiment of the present invention, drugs, excipients, additives and the like which are susceptible to the external environment such as temperature, light, moisture and the like can be included in the dry granules.

In one embodiment of the present invention, when the dry granules contain drugs sensitive to the external environment such as temperature and moisture or drugs, excipients and additives capable of causing disturbances in tabletting, they can be dried under mild conditions have. For example, it may be dried in a convection oven, a vacuum oven, a fluidized bed drier, a drier, or the like under mild conditions such as a temperature of 40 ° C or lower or by natural drying at room temperature.

Chewing

The rapid decay of the present invention is characterized by comprising the low wet granulation and dry granules described above.

The amount of the low wetting granules included in the chewing gum of the present invention is preferably 50 to 99% by weight, more preferably 60 to 98% by weight, still more preferably 70 to 97% by weight based on 100% by weight of the tablet . When the content of the low wet granules is less than 50% by weight with respect to 100% by weight of the tablet, there may be a problem that high hardness and fast disintegration do not exhibit rapid disintegration characteristics. When the content is less than 99% by weight, .

The amount of the dried granules contained in the chewing gum of the present invention is preferably 1 to 50% by weight, more preferably 2 to 35% by weight, still more preferably 3 to 25% by weight based on 100% by weight of the tablet. If the content of the dry granules is less than 1% by weight based on 100% by weight of the tablet, there may be a problem in the uniformity of the content when the drug is contained, and if the content is more than 50% by weight, .

When the content of the dried granules is within the above-mentioned range, there is no problem in the production of the chewing gum. In addition, when iron chelating agents such as iron oxide, which may cause dyspepsia, should be included in the inner shell, if it is contained in the dry granule, there will be no penile dysfunction or decrease significantly during the stroke.

In addition to the spray-dried mannitol and saccharide binders included in the low-wet granulation and dry granules, the instant chewing of the present invention may further comprise additional ingredients for the production of active ingredients and / or tablets. These active ingredients and / or additional ingredients for the preparation of the tablets may be introduced into the low wet granulation, or alternatively may be introduced upon formation of the post mixture for tableting. The active ingredient that is introduced in the aftermixing step may be in a powder state, a crystalline state, a granular state, a fine powder state, a nanoparticle state, a microparticle state coated with a taste shielding or sustained release control, and the like. Additional ingredients for tablet preparation may be introduced for additional purposes such as tableting efficiency, disintegration promotion, stability of the active ingredient, appearance, color, protection, maintenance, binding, performance improvement, and manufacturing process improvement. Examples of additional components for preparing tablets include, but are not limited to, disintegrants, lubricants, surfactants, dry binders, colorants, flavors, sweeteners, stabilizers, antioxidants,

The specific kind of the above-mentioned additional ingredients, how to use them, and the method of introducing such substances into the tablets of the present invention are well known in the art, and can be modified in various categories.

Specifically, the disintegrant may be at least one selected from the group consisting of sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl cellulose sodium, starch, and the like. The disintegrant may suitably be contained in an amount of 7 wt% or less, preferably 5 wt% or less, more preferably 3 wt% or less, within 100 wt% of the tablet.

Specifically, the lubricant is selected from the group consisting of stearic acid, glyceryl behenate, glyceryl monostearate, magnesium stearate, calcium stearate, silicon dioxide, talc, sugar ester, sodium stearyl fumarate and magnesium silicate, sodium stearate, Poly (ethylene glycol), polyoxypropylene-polyoxyethylene block copolymer, colloidal silicon dioxide, sucrose fatty acid ester, and the like. The lubricant may be contained in an amount of 3 wt% or less, preferably 2 wt% or less, more preferably 1.5 wt% or less, within 100 wt% of the tablet.

The fast buckling of the present invention preferably has at least one of the following properties, more preferably at least two, more preferably at least three, even more preferably at least four and most preferably at least five properties:

- Hardness of the tablet: 2.5 Kp or more (e.g. 2.5 to 20 Kp), preferably 3.0 Kp or more, more preferably 4.0 Kp or more

- the degree of fatigue of the tablet: not more than 1.0% (e.g., 0.001 to 1.0%), preferably not more than 0.8%, more preferably not more than 0.5%

- Disintegration time in water: within 2 minutes (for example 1 second to 2 minutes), preferably within 1 minute, more preferably within 40 seconds

- Disintegration time in oral cavity: within 40 seconds (for example, 1 second to 40 seconds), preferably within 30 seconds, more preferably within 25 seconds

- Content uniformity: Even with a trace amount of drug, it has a uniform content (preferably 95 to 105% of the indicated content) of the drug in the tablet

Process for the manufacture of chewing gum

As described above, the rapid decantation of the present invention comprises: preparing the low-wet granulation and the dry granule, respectively; Forming a post-rinsing mixture comprising the low wet granulation and the dry granules; compressing the mixture after tableting to obtain tablets; and drying the tablets .

The method for manufacturing the rapid buckling of the present invention can be carried out using a tablet machine or a molding machine generally used in the pharmaceutical field. In addition, the tablet can be performed by a low-pressure compression method, and the tablet can be dried under mild conditions.

The compression pressure used to compress and purify the mixture after tableting is generally less than about 150 MPa (e.g., 1 Pa to 150 MPa), preferably less than about 35 MPa, more preferably less than about 10 MPa to be.

In order for the tablet to disintegrate rapidly in the mouth, the tablet should rapidly absorb water into its inner core, and the ingredients must dissolve quickly. Thus, it is important that the compressed tablet maintains high-porosity. Low-pressure tableting is generally required to maintain high-porosity after compression, but when tablets are produced at low pressure, their hardness and wear resistance are inferior. However, when the low-wet granulation and dry granules according to the present invention are mixed, it is possible to produce tablets even under low-pressure conditions without such problems, and through the drying step, good physical properties such as high hardness and low scratch resistance as well as quick disintegration , ≪ / RTI >

The mild condition for drying the tablets may be a condition of room temperature which is not very damp, for example, a temperature of 20 to 30 DEG C and a humidity condition of 40% RH or less. For faster and more reliable drying, a convection oven at a low temperature of 20 to 50 DEG C can be utilized, and a method of supplying dry air, a method using a dehumidifier, a method using a dehumidifying agent, or the like may be used.

Active ingredient

In the present invention, the active ingredient may be mixed with the solid content in the production step of the low wet granule, added at the time of preparing the white sugar binder solution, or introduced at the post mixture forming step. Such active ingredients may be in solution, paste, powder, crystalline, granular, micropowder, nanoparticulate, taste-shielded or sustained-release coated microparticles. Also, one active ingredient may be used alone or in combination with two or more active ingredients.

The active ingredients to which the present invention is applicable are so varied as not to be mentioned herein. For example, representative classes of drugs that can be formulated with the instant chelation of the present invention include, but are not limited to, the following:

Anti-migraine drugs such as almotriptan, ergotamine tartrate, probastriptan, methysergide maleate, sumatriptan succinate, zolmitriptan and the like;

ADHD (Attention Deficit Hyperactivity Disorder) drugs such as methylphenidate, atomocetin and the like;

Erectile dysfunction drugs such as sildenafil, vardenafil, alprostadil, tadalafil, mirodenefil, and udenafil;

Anti-rheumatic drugs such as auranopin, azathioprine, cyclosporine, hydroxychloroquine sulfate, reupunomide, methotrexate, penicillamine, sulfasalazine and the like;

But are not limited to, acetaminophen, aspirin, dichlorophenac, etodolac, fenoprofen, ibuprofen, ketoprofen, naproxen, indol methacin, ketoalloc, sulindac, tolmetin, meclofenamate, mefenamic acid, Non-steroidal anti-inflammatory drugs such as meloxicam, piroxicam, celecoxib, rofecoxib and the like;

Opioids such as buprenorphine, codeine, fentanyl, hydrocodone, hydro morphone, laborpanol, meperidine, morphine, oxycodone, pentazocine, propoxyphene, tramadol and the like;

Anti-mycobacterium drugs such as aminosalicylate, clofazimine, cycloserine, ethionamide, rifabutin and the like;

Anti-parasitic drugs such as albendazole, ivermethine, mebendazole, plagiocantel, and the like;

Antiviral drugs such as valacyclovir, didanosine, palmyclovir, published cyclovir, indinavir, lamivudine, nelfinavir mesylate, nevirapine, ritonavir, stavudine, oseltamivir phosphate and the like;

Beta-lactam, such as amoxicillin, amoxicillin and potassium clavulanate, ampicillin, cefuroxin sodium, cefuroxime acetyl, penicillin G and Y salts, cefditoren, sepic, sodium croctin sodium, dicloxycin sodium and the like;

Markrolide antibiotics such as erythromycin esters, erythromycin ethyl succinate, erythromycin stearate, and the like;

Fluoroquinolones such as ciprofloxacin, enoxacin, and the like;

Tetracycline such as demeclocycline hydrochloride, doxycycline calcium, tetracycline, tetracycline hydrochloride and the like;

Alkylating agents such as althretamine, vanillin, chlorambucil, melphalan, cyclophosphamide, proccarbazine hydrochloride, temozolomide and the like;

Antimetabolites such as methotrexate, mercaptopurine, thioguanine and the like;

Hormonal drugs and antagonists such as bicalutamide, flutamide, nilutamide, aminoglutethimide, anastrozole, exemestane, letrozole, tamoxifen citrate, toremifensitrate and the like;

Mitotic inhibitors such as etoposide phosphate and the like;

Immunosuppressive agents such as azathioprine, cyclosporin, mycophenolate mopetil, sylolimus, tacrolimus and the like;

Aminodalon hydrochloride, digoxin, dysopyramide phosphate, dofetilide, plicainide acetate, mesylate hydrochloride, morishine hydrochloride, procainamide hydrochloride, propphenone hydrochloride, quinidine sulfate, quinidine glucoside Drugs for treating arrhythmias such as Nate, Sartorol Hydrochloride, Tocanide and the like;

But are not limited to, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, salicylic acid, Examples such as minoxidil, moexipril, trandolapril, candesartan, irbesartan, losartan, telmisartan, valsartan, guanabenzoate acetate, guanadrel sulfate, guanfacine hydrochloride, Hypertensive drugs;

Beta-adrenergic receptor antagonists such as cortisol, cortisol, cortisol, cortisol, cortisol, cortisol, cortisol, Adrenaline blocking drugs;

Calcium channel blockers such as amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisol dipine, verapamil and the like;

Lipid lowering drugs such as fenofibrate, gemfibrozil, niacin, atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and the like;

Nitrates such as isosorbide dinitrate, nitroglycerin, sodium nitroprusside and the like;

But are not limited to, carbamazepine, clonazepam, ethoxysimide, felbamate, gabapentin, lamotrigine, levetiracetam, oxacarbazepine, phenobarbital, phenytoin, primidone, thiabarbine, topiramate, valproate, Anticonvulsants such as xanthate, jonisamid and the like;

Amlodipine, mirtazapine, bupropion, amoxapine, phenelzine, tranylcypromine, citalofram, fluoxetine, fluobosamine, paroxetine, sertraline, venlafaxine, mafrotilin, trazodone, Antidepressants such as tiline, clomipramine, desipramine, dessefine, imipramine, nortriptyline, prothropylline, trimipramine and the like;

Such as chlorpromazine, thioridazine, rosopin, mollidone, clozapine, olanzapine, quetiapine, risperidone, ziprasidone, fluphenazine, haloperidol, perphenazine, trifluoresin, thiothien, Antipsychotic drugs;

The present invention relates to a medicament for the treatment and / or prevention of a disease, such as alprazolam, lorazepam, oxazepam, chlordiazepoxide, clorazepate, diazepam, halazepam, midazolam, triazolam, zaleprone, zolpidem, Antipruritics, sedatives and hypnotics such as meflobamate, phenobarbital, chloral hydrate, etchlorvinol, glutetimide, pentobarbital, secobarbital and the like;

Degenerative neurodegenerative drugs such as amantadine, benztropine mesylate, carbidopa and levodopa, donepezil, bromocriptine, pergolide, pramiphexol, lopinilol and the like;

Glaucoma medications such as acetazolamide, dichlorphenamide, metazolamide and the like;

Drugs for the treatment of acid-pepsin such as aluminum carbonate, aluminum hydroxide, magnesium hydroxide, sodium bicarbonate, calcium carbonate, mangaldate and the like;

Bismuth salts, cimetidine, famotidine, nizatidine, ranitidine, misoprostol, lansoprazole, omeprazole, pantoprazole, rabeprazole, sucralfate and the like;

But are not limited to, but are not limited to, but are not limited to, butyricin, cyclin, cyclin, dimenhydrinate, diphenhydramine, , Pomegranate agents such as dolasitone, granisetron, ondansetron, dexamethasone, laajepam, ganisitron, ramosetron, aprepitant and the like;

Gastrointestinal motility drugs such as bisacodyl, diphenoxylate hydrochloride and atropine sulfate, doxate salts, rofelamide, magnesium salts, methocloframide, ursodiol, and the like;

Clotting agents and anticoagulants such as clopidogrel bisulfate, phytonadione, ticlopidine, and sodium paraparin;

Hematopoietic drugs such as iron salts;

Adrenal hormones such as cortisone, hydrocortisone, methylprednisolone, prednisone, triamcinolone, betamethasone, dexamethasone, furoproctcisone and the like;

Such as anti-diabetic drugs such as acarbose, metformin, nateglinide, repaglinide, acetohexamide, chlorpropamide, tolazamide, tolbutamide, glymefrid, glipizide, gliburide, pioglitazone, rosiglitazone, drug;

Contraceptives such as Norrettinone, Norgestrel, Levonorgestrel and the like;

Feminine hormones such as estradiol and its esters, estrogen, estropypate, medroxyprogesterone, mifepristone, norretindron acetate, progesterone, laloxifene and the like;

Thyroid and antithyroid drugs such as iodide, sodium levothioxin, sodium thiothiocyanate, riotrix, methimazole, propylthiouracil and the like;

But are not limited to, amylolide hydrochloride, bumetanide, ethacrynic acid, furosemide, torsemide, hydrochlorothiazide, chlothiazide, chlortalidone, indapamide, metolazone, polythiazide, Diuretics such as tricomethiazide, spironolactone, triamterene and the like;

Electrolytic materials such as chelated magnesium, magnesium chloride, magnesium hydroxide, magnesium oxide, potassium salts and the like;

Gout treatment drugs such as allopurinol, colchicine, probenecid, sulfinpyrazone and the like;

Asthma treatment agents such as albuterol sulfate, montelukast sodium, theophylline, zileuton and the like;

But are not limited to, acarbastine, azatadine, bromopenyramine maleate, carbinoxamine maleate, cetirizine hydrochloride, chlorpenilamine maleate, diphenhydramine hydrochloride, clemastine fumarate, ciprohepadine hydrochloride, Antihistamines such as hydroxyzine, loratadine, desloratadine and the like;

Cough and cold drugs such as dextromethorphan hydrobromide, guaiifensine, pseudoephedrine hydrochloride and the like;

And health functional food.

According to one preferred embodiment of the present invention, the chewing gum of the present invention is a drug sensitive to the environment such as light, temperature, moisture, or the like, a drug having a low content in tablets, a drug itself or added for stability or performance improvement It is particularly suitable when the excipient or additive is a drug capable of causing a ptosis. In one embodiment of the present invention, the drug may be ramosetron or a pharmaceutically acceptable salt thereof, but the present invention is not limited thereto. In this case, the drug can be contained in the chewing gum of the present invention, preferably in the form contained in the dried granules. Means that the content of the drug in the tablet is a very small amount, that is, the content of the drug relative to the weight of the tablet is 5% or less, preferably 3% or less, more preferably 1% or less and most preferably 0.5% or less.

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the present invention is not limited thereto.

[Example]

First, the characteristics analysis methods performed in the following Examples and Comparative Examples are as follows.

Hardness measurement

The hardness of the tablets was measured using a hardness tester 8M (Hardness tester 8M, Dr. Schleuniger, Switzerland) and at least 6 samples were measured and the average value was described.

Measurement of wear

Tablet Friability of the General Chapters for USP (US Pharmacopoeia) 25 general tests and analyzes.

Underwater disintegration test

The test was conducted according to the Disintegration Test Method in the General Test Methods of the Korean Pharmacopoeia (8th Edition). Water was used as the test solution. Six specimens were tested at 37 ° C and the average value was described.

Oral disintegration test

In the case of a fast-breaking marine tablet, a disintegration test of the fast-breaking marine tablet in the mouth was performed to the applicant. The volunteers were randomly selected and rinsed with water. The disinfection time was measured by placing the tablets on the applicant's tongue and immediately activating the stopwatch. Applicants were allowed to use their tongue to move the cruciform marine tablets to the mouth of the mouth, to smoothly roll the tablets, or to roll them to the left or right. The stopwatch was stopped and the time recorded as soon as the tablet had disintegrated and swallowed with the needle.

Dry weight loss

For dry weight loss of powder or granules, about 2 g of sample was taken and spread evenly on an aluminum plate. The sample was measured at 105 ° C for several to several minutes using a Sartorius MA100 LOD meter. And the test was ended.

In the case of drying loss of the tablet, about 2 g of the sample was taken and placed in an aluminum dish and measured in the same manner as in the measurement of loss on drying of the powder or granules.

In the case of the dry weight reduction of the pulverized tablets, about 2 g of the tablets were taken and ground into a pulverized state in a mortar and then measured in the same manner as in the measurement of loss of dry weight of the powder or granules.

Content uniformity

The test was conducted according to the content uniformity test method in the uniformity test method of the Korean Pharmacopoeia. One tablet of the drug to be tested was placed in 5 ml of mobile phase and shaken to completely disintegrate. The solution was centrifuged and the supernatant was filtered through a membrane filter having an pore size of 0.45 탆. About 2 ml of the first filtrate was discarded, and the next filtrate was taken and used as the sample solution. 10 μl of the test solution was tested according to the general method described in the Japanese Pharmacopoeia Liquid Chromatography and detected at a wavelength of 254 nm using an appropriate column and a flow rate. The preparation of the mobile phase was as follows: phosphoric acid diluted in 0.05 mol / l potassium dihydrogen phosphate solution was added to adjust the pH to 4.0, and 100 ml of methanol and 100 ml of tetrahydrofuran were added to 800 ml of this solution.

Example 1

(1) Preparation of low wet granules

106.8 g of spray dried mannitol (Mannogem ^TM EZ, SPI), 2.8 g of corn starch and 2.8 g of fructose were placed in a 1 L high speed mixer, and impeller 150 rpm, chopper 31.3 g of sucrose (Samyang) 50% (w: w) solution (ethanol: water = 4: 6 (w: w)) was added while rotating under the condition of 1700 rpm, mesh (sieve size: 600 mu m) sieve, and dried in an oven at 50 DEG C for about 30 minutes. The drying time was appropriately adjusted so that the final dry weight loss of the low wet granulation was about 1.5%. The final dry weight loss of the dried low wet granules was 1.78%.

(2) Production of dry granules

(Mannogem ^TM EZ, SPI), 0.7 g of corn starch, 0.7 g of fructose, 0.85 g of red iron oxide and 0.85 g of yellow iron oxide were placed in a plastic bag, 7.8 g of a 50% w / w Samyang solution (ethanol: water = 4: 6 (w: w)) was added and manually kneaded and passed through a 30 mesh (sieve size: 600 μm) , Dried in an oven at 40 DEG C for about 2 hours, and further dried for 30 minutes to obtain dried granules. The final drying loss of the dried granules was 0.90%.

(3) Manufacture of genus conglomerates

128.3 g of the prepared low-wet granule was mixed with 33.8 g of dried granules, 5.1 g of low-substituted hydroxypropyl cellulose (L-HPC) and 2.55 g of sodium stearyl fumarate (Pruv.RTM.), (EK-0, Korsch) so as to obtain a fast-thawing of 170 mg. The hardness of the tablet immediately after tableting was about 1.4 Kp. After the tableting was completed, the tablets were left at room temperature (about 25 ° C, 10 to 30% RH) for 2 days and packed. The hardness of the packed tablets was 4.1 Kp. The degree of fatigue was 0.41%, the disintegration time in water was 20.5 seconds, the disintegration time in the oral cavity was 18 seconds, the loss on dry weight loss of tablets was 0.88% Was 0.98%. The uniformity of the content of the tablets was 3.6% based on the content uniformity test method in the general test method of KIPPO, and it was found to be equivalent to the standard (it is judged to be uniform when the judgment value is within 15.0% Absolute value of determination value (%) = [100-average content%] + 2.2 * standard deviation).

Example 2

(1) Preparation of low wet granules

297g of spray-dried mannitol (Mannogem ^TM EZ, SPI) and 15.5g of lactose (Pharmatose 200M) were placed in a 3L capacity high-speed mixer and mixed with 50% sucrose (Samyang) w (w: w) solution (ethanol: water = 4: 6 (w: w)) was put into a kneader. Minute. The drying time was appropriately adjusted so that the final dry weight loss of the low wet granules was approximately 1.0%. The final dry weight loss of the dried low wet granules was 1.01%.

(2) Production of dry granules

0.25 g of ramosetron hydrochloride, 66.2 g of spray dried mannitol (Mannogem ^TM EZ, SPI) and 3.47 g of lactose were added to a plastic bag and mixed well. Then, 0.5 g of red iron oxide, 0.5 g of yellow iron oxide, 0.76 g of acesulfame potassium 12.7 g of melted or dispersed 50% (w: w) solution of Samyang (ethanol: water = 4: 6 (w: w)) was added and manually kneaded, and 30 mesh And dried for about 2 hours in an oven at 40 DEG C, followed by further drying for 30 minutes to obtain dried granules. The final dry weight loss of the dried granules was 0.51%.

(3) Manufacture of genus conglomerates

After mixing 284.9 g of the prepared low-wet granules, 72.2 g of dried granules, 11.2 g of low-substituted hydroxypropylcellulose (L-HPC) and 5.61 g of calcium stearate, a 8.5 mm diameter, (EK-0, Korsch). The hardness of the tablet immediately after tableting was about 1.4 Kp. After the tableting was completed, the tablets were left at room temperature (about 25 ° C, 10 to 30% RH) for 2 days and packed. The hardness was 4.3 Kp, the degree of grind was 0.27%, the disintegration time in water was 18 seconds, the disintegration time in the mouth was 15 seconds, the loss on dry weight loss of tablets was 0.21% Was 0.45%. The uniformity of the content of the tablets was 3.4% based on the content uniformity test in the general test method of the Korean Pharmacopoeia.

Comparative Example 1

(Mannogem ^TM EZ, SPI), 2.74 g of corn starch and 2.74 g of fructose were placed in a high-speed mixer having a capacity of 1 L and mixed while rotating under the conditions of an impeller 150 rpm and a chopper 1700 rpm, 30.7 g of Samyang 50% (w: w) solution (ethanol: water = 4: 6 (w: w)) was added and kneaded. Then, the mixture was taken out and passed through a sieve of 30 mesh And dried in an oven at 50 ° C for about 30 minutes. The drying time was appropriately adjusted so that the final dry weight loss of the low wet granulation was about 1.5%. The final dry weight loss of the dried low wet granules was 1.72%.

117 g of the low-wet granules thus prepared were mixed with 1.265 g of yellow iron oxide, 3.8 g of low-substituted hydroxypropylcellulose (L-HPC) and 1.89 g of Pruv, and then kneaded into a single- -0, Korsch). The hardness of the tablet immediately after tableting was about 1.4 Kp. When some punches were observed, the punch was observed to stick to the punches and the shape of the punches was not completely observed. After the punch was wiped, the punch was performed, but after several tens of punches, the punch was stuck again.

Claims (12)

50 to 99% by weight of a low wet granulation containing spray-dried mannitol and white sugar binder and having a dry weight loss value of at least 1.05 times the dry weight loss of the dry granules; And
1 to 50% by weight of dried granules comprising spray dried mannitol and white sugar binder;
Wherein the fast buckling of the fast buckling. 2. The buck according to claim 1, wherein at least one of the low wet granulation and the dry granulation further comprises a dry binder. The chewing gum according to claim 2, wherein the dry binder is a sugar, a sugar alcohol, a starch, a polysaccharide, a cellulose derivative, or a mixture thereof. The chewing gum according to claim 1, wherein the low wet granulation comprises spray dried mannitol in an amount of 20 to 98% by weight based on 100% by weight of the low wet granulation. The chewing gum according to claim 1, wherein the low wetting granulate comprises 1 to 50 parts by weight of the white sugar binder as an amount of dried white sugar relative to 100 parts by weight of the spray-dried mannitol. The quick-boil according to claim 2, wherein the dry binder is contained in an amount of 50 parts by weight or less based on 100 parts by weight of spray-dried mannitol. The quick-boil according to claim 1, which has at least one of the following characteristics (1) to (5):
(1) Hardness of tablets: 2.5 Kp or more
(2) Degree of fatigue of tablet: 1.0% or less
(3) Disintegration time in water: within 2 minutes
(4) Oral disintegration time: within 40 seconds.
(5) Content uniformity: 95 to 105% of the indicated content. 8. A fasting bath according to any one of claims 1 to 7, further comprising an active ingredient. 9. A buckwheat according to claim 8, characterized in that the active ingredient is contained in the dry granules. Preparing dry granules containing spray-dried mannitol and white sugar binder and low-wet granules having a dry weight loss value of not less than 1.05 times and not more than 5 times the dry weight loss of the dry granules, respectively, and dried granules comprising spray dried mannitol and white sugar binder;
Forming a post-rinse mixture comprising the low wet granulation and the dry granules;
Compressing the mixture after tableting to obtain tablets; And
And drying the tablet. 11. The process for producing a quick-boil according to claim 10, wherein the tableting mixture is compressed under a pressure of not more than 150 MPa to obtain tablets. The method of claim 10, wherein the step of drying the tablet is carried out at a temperature of 20 to 30 DEG C and a humidity of 40% RH or less, in a convection oven at 20 to 50 DEG C or by supplying dry air, Or a dehumidifying agent. ≪ RTI ID = 0.0 > 15. < / RTI >