MXPA00009104A

MXPA00009104A - Tablets quickly disintegrating in the oral cavity and process for producing the same

Info

Publication number: MXPA00009104A
Application number: MXPA/A/2000/009104A
Authority: MX
Inventors: Janaki Ram Nyshadham; Takao Mizumoto; Yoshinori Masuda; Atsushi Kajiyama; Masahiro Yanagisawa
Original assignee: Shaklee Corporation; Yamanouchi Pharmaceutical Co Ltd
Priority date: 1998-03-16
Filing date: 2000-09-15
Publication date: 2002-07-25

Abstract

Tablets quickly disintegrating in the oralcavity which contain drugs, saccharides (A) and amorphous saccharides (B) and are produced by molding and then drying under moistening. More particularly, tablets obtained by dissolving the drugs, the saccharides (A) and the saccharides (B) which are in a crystalline state and can be converted into amorphous ones in a pharmaceutically acceptable solvent, then eliminating the solvent from the resultant solution followed by drying, molding the obtained mixture containing the amorphous saccharides (B), and then drying the same under moistening. In the production process of these tablets, the amorphous saccharides are irreversibly converted into crystalline ones after the step of drying under moistening. Thus, these tablets are stable to moisture during storage and can maintain a constant tablet stability. In these tablets, moreover, the above-mentioned saccharides and the amorphous saccharides can be produced from saccharides of a single type, which enables preparation design with a consideration of the stability of drugs. Furthermore, these tablets makes it possible to provide a production process with the use of conventional granulators and tabletting machines.

Description

TABLETS THAT ARE RAPIDLY DISINTEGRATED IN THE MOUTH CAVITY AND PROCESS TO PRODUCE THEMSELVES TECHNICAL FIELD The present invention relates to a rapid production tablet in the oral cavity and the production process thereof.

BACKGROUND OF THE INVENTION As regards the pharmaceutical dosage forms for oral use, a tablet, a capsule, a granule, a powder and the like are mentioned. However, these dosage forms will have some consequences if a patient takes them. For example, regarding a tablet or a capsule, if the patient is an elderly person or a child, there are some cases in which they dislike taking the pharmaceutical preparation, because it is difficult for them to swallow it, or the preparation is it gets stuck in your throat or esophagus. In addition, regarding a granule or a powder, in some cases they dislike taking the preparation for the reason that it is difficult for them to swallow it with their rest in the oral cavity, or for the reason that they will suffocate when they take the dose. Since in these cases a compliance is caused to fail to take the pharmaceutical preparation, it is desired to easily take the pharmaceutical dosage forms, and as a result a disintegration preparation in the oral cavity has been studied and developed. For example, "Zydis®" has been developed up to the product by RP Schere Corp. However, since this preparation is produced by means of the lyophilization method, a special manufacturing equipment-1 such as a food processing machine is needed. lyophilization. Additionally, this preparation can not be taken from the PTP receptacle, "Pressure Through the Package", for the reason that the strength of the tablet is small. In addition, it is very difficult for the elderly to take the preparation of the package that does not satisfy the elderly. Many rapid disintegration tablets have been reported in the oral cavity, which are manufactured by means of not the lyophilization method, but by means of the tabletting method. For example, JP 6-218028-A (Corresponding to EP 590,963) discloses a fast-disintegrating tablet in the oral cavity, which is manufactured by compressing the moistened powder that is mixed with a drug, an excipient, a binding agent and the like, using water or the like, and then by drying the compression molding. However, it is necessary to have a special tabletting machine that sprayed a fluidizer on the surface of a tablet, before compression, to avoid consequences in compression molding. JP 5 ~ -271054-A (corresponding to EP 553,777) describes a rapid disintegration tablet in the oral cavity, which is manufactured by compressing the mixture comprising a drug, a sugar and water, which is added to both as to moisten the sugar at low compression pressure, and by drying the tablet. The '093/15724 (corresponding to EP 627,218) also describes a rapid disintegration tablet, which is manufactured by compression with humidification and drying. However, there are some consequences in these methods, for example, adhesion when compressing with moisture. In addition, WO95 / 20380 (corresponding to US 5,576,014) describes a rapid disintegration tablet in the buccal cavity, in which the invention has been made by one of the present inventors. This tablet is manufactured by means of a sugar of little moldability being granulated by means of a sugar of high moldability, and then these granules are compressed by means of an ordinary tabletting machine. It is thought that there are few problems in practice by means of this production method, however, it is necessary to use at least two kinds of sugars, if there is a case that there is a restriction for a class of sugar added, for the opposite action between a drug and sugar (for example, the degradation of the drug). Thus, a new rapid disintegration tablet is desired in the buccal cavity and the manufacturing process thereof although in the present, for example, this tablet is manufactured, and to obtain it by using a class of sugars. Furthermore, with respect to a rapid disintegration tablet in the oral cavity, a patent application or an article describes the next proposed production process. For example, JP 9-48726-A describes the method in which a composition of the mixture consisting of a drug, a sugar and / or a hydrophilic polymer, is taken in a molding, and the mixture is compressed at low Compression pressure, and molding is low humidification and drying. However, this method is to improve the surface strength of the tablet, in particular by moistening the water-soluble polymer, it is possible to introduce the adhesion between the tablets. A method is proposed in which a mixture consisting of an amorphous sucrose, which is obtained by the lyophilization method using a solution of sucrose, a drug and mannitol, is molded into a tablet by means of a rotary tabletting machine , and the tablet obtained is kept under the controlled circumstance (at 25 ° C, 34 percent RH) (summary of the 13th Japan Pharmacological Pharmacy, page 113, published on March 5, 1998). However, a sugar is an amorphous sugar that is manufactured in greater detail by the lyophilization method, but sugars other than sucrose are not described in the article.

DESCRIPTION OF THE INVENTION An object of the present invention is to provide a rapid disintegration tablet in the oral cavity, and the production thereof in which the tablets are manufactured with the normal pelletizing and tabletting machine, with the resistance of the tablet being elevated to make a more stable formulation. The present inventors examined the physiological characterization of sugar in a result, to find that a class of sugars can be changed to an amorphous state, when the sugar solution is spray dried, or the sugar solution in the granulation is used as a binder agent. The present inventors also investigated to find that when an amorphous sugar was treated under humidification and drying, the strength of the tablet was increased by changing the amorphous sugar to a crystal state, and that the disintegration preparation was obtained in the cavity. buccal with the desired tablet strength, and have completed the present invention. That is, the present invention relates to a rapid disintegration tablet in the buccal cavity, comprising: a drug, a sugar (A), and an amorphous sugar (B), wherein, after the formation of the tablet, it humidifies and dries. In more detail, the present invention relates to a fast-disintegrating tablet in the oral cavity, comprising: a mixture, comprising: a drug, a sugar (A), and an amorphous α-sugar (B), which is obtains by dissolving a crystalline sugar capable of becoming amorphous in a medically permissible solvent, and then removing the solvent from the solution, and drying, where after the formation of the tablet, it is humidified and then dried. In addition, the present invention relates to a fast-disintegrating tablet in the oral cavity, comprising: a mixture, comprising: a drug, a sugar (A), and an amorphous sugar (B), which is obtained by dissolving a crystalline sugar capable of becoming amorphous in a medically permitted solvent, and then the solution is sprayed and dried, and after the formation of the tablets , these are humidified - and then dried. In particular, the present invention relates to a rapid disintegration tablet in the buccal cavity, comprising: a crystalline sugar capable of becoming amorphous, which dissolves in a medically permissible solvent; the solution is sprayed on a drug and / or a sugar (A) to cover and / or granulate; and after forming a tablet, it is humidified and dried. For the drug to be used in the present invention there are no particular limitations, so long as it is a substance that is used as a pharmaceutical active ingredient. Examples of pharmaceutical active ingredients include: sedative hypnotics, sleep inducers, antianxiety drugs, antiepileptics, antidepressants, drugs against Parkinson's disease, psychoneural drugs, drugs that act on the central nervous system, local anesthetics, muscle-skeletal relaxants, drugs for the autonomic nervous system, analgesics against fever, anti-inflammatory drugs, anticonvulsants, anti-vertigo drugs, cardiac drugs, drugs for arrhythmia, drugs to reduce blood pressure, vasoconstrictors-, vasodilators, drugs for the circulatory organs, drugs for hyperlipidemia , respiratory stimulants, antitussives, expectorants, antitussive expectorants, bronchodilators, estegnotics, peptic ulcer drugs, digestive drugs of the stomach, antacids, laxatives, choleretics, drugs for the digestive tract, adrenal hormone drugs, drugs of h ormonas, urinary tract drugs, vitamins, hemostatic drugs, kidney drugs, drugs for the treatment of gout, drugs for diabetes, antihistamines, antibiotics, antibacterial agents, drugs for antimalign tumors, pharmacists for chemotherapy, cold medicines of multiple purposes, tonic medicines, drugs for osteoporosis, and the like. There are no particular limitations on the amount of these drugs to be mixed, as long as this is the usual amount of effective treatment. This should be about 50 percent by weight / weight or less of the entire tablet, and preferably 20 percent by weight / weight or less. In case the present invention is applied to a drug having an unpleasant taste, it is preferred that the drug be preferably treated in a taste masking method (e.g., O92 / 09275). In case the present invention is made for a drug that is desired to be sustained, it is preferred that the drug be preferably treated in a sustained release method (e.g., CA2038400-0), to obtain a particle that controls a release of the drug in a manner known per se. In addition, the preparation of the present invention can also be applied to a drug that needs to be absorbed through a membrane of the buccal cavity, since the preparation of the present invention is taken by a patient with disintegration and dissolution in the oral cavity. There are no particular limitations on the sugar (A) to be used in the present invention, as long as it is one that is normally allowed medicinally. The sugar (A) is preferably a sugar or sugar-alcohol that dissolves in the mouth. Examples include lactose, glucose, trehalose, mannitol, erythritol, and the like. The sugar (A) can be a type or two or more types combined. In addition, since the sugar (A) functions as an excipient that dissolves inside the oral cavity, the amount of sugar (A) to be added to the fast disintegrating tablet of the present invention is not particularly limited, always and when this is an effective amount in order to achieve this function in the fast disintegrating tablet. The amount of sugar (A) that is to be added also depends on the size of the tablet. The amount of sugar (A) can be adjusted as a proportion with the other excipients. The "amorphous sugar (B)" of the present invention means a sugar that is usually permitted medicinally, and that is amorphous or that is capable of becoming amorphous. For example, an amorphous sugar (B) can be obtained by dissolving a crystalline sugar capable of becoming amorphous, in a medicinally permitted solvent such as water and alcohol and the like, and then obtained by removing the solvent from this solution, and dried. There are no particular limitations for the solvent removal method, as long as this is a method normally implemented in the pharmaceutical manufacturing process. For example, these methods include the spray drying method, the freeze drying method, or different granulation methods such as the fluidized bed granulation method, the vertical granulation method, the hop granulation method. From a production point of view, the spray drying method or the different granulation methods are preferred. Among the different granulation methods, a method is preferred wherein: a crystalline sugar capable of becoming amorphous in a medically permissible solvent such as water, alcohol, and the like, is used as a binding agent; it becomes amorphous when sprayed by means of a twin fluid nozzle and covers and / or granulates the drug and / or sugar. Here, a crystalline sugar capable of becoming amorphous can be dissolved in a medicinally permissible solvent. This solution can be sprayed against the drug and / or the sugar (A), and these can be covered and granulated with an amorphous sugar (B). Examples of amorphous sugars (B) include glucose, lactose, maltose, sorbitol, trehalose, lacitol, fructose, and the like. This amorphous sugar (B) can be of one type, or it can be a combination of two or more types. In the present invention, "amorphous sugar" means a sugar that is materially amorphous, or that is capable of becoming amorphous. In the process of becoming amorphous, the present invention also includes states wherein a portion is not amorphous. The amount of amorphous sugar (B) to be added is 2-20 weight percent / weight relative to the previous sugar (A), or 2-20 weight percent / weight of the whole tablet. As for the convenience for using an amorphous sugar in the present invention, it is easy to increase the strength of the tablet by the humidification and drying steps. Since an amorphous sugar has a low critical moisture, the tablet can be treated at the low humidity level such that it can be absorbed by an amorphous • sugar. In addition, the moisture that is absorbed in a humidification process dissolves a part of the surface of the sugar particles around, later, in a drying process, the resistance of the tablet can be increased due to the fact that they are put together again the sugar particles. On the other hand, contrary to the present invention, it is easy to predict that the production process had some difficulties, for example, in the case that the sugar consists of sugars in a crystalline state, since sufficient moisture adsorption will not occur in the crystalline state. a low humidification condition, the resistance of the tablet will not increase, in the case of a high humidification condition, the adhesion between the tablets will occur, and it can be easily predicted that this has difficulty in the actual manufacture. As for the other advantage to using the amorphous sugar in the present invention, since a sugar in the amorphous state is changed to a crystalline state in a process of humidification and drying irreversibly, a dry tablet has a critical humidity point high. As a result, the tablet can maintain a tablet resistance against moisture in the stored condition. In addition, a class of sugar consisting of the crystalline state and the amorphous state can make a fast disintegrating tablet in the oral cavity, to avoid a restriction to select a sugar that does not pass the changes against a drug. In the present invention, "forming" means forming into a tablet or the like, with a pressure equal to or greater than the pressure that is required to maintain the desired shape. In the training process, normal tablet machines can be used. Examples include a single tablet machine or a rotary tablet machine. In the present invention, "humidification", when implemented in combination with the next drying step, is to increase the strength of the tablet, the humidification conditions being determined by the apparent relative humidity of the mixture of a drug, a sugar (A), an amorphous sugar (B), and means increasing the humidity to more than, or equal to the critical relative humidity of this mixture. For example, the humidity is 30-100 percent RH, and preferably it is 50-90 percent RH. At this time, the temperature is 15-50 ° C, and preferably 20- 0 ° C. The point of the humidification process of the present invention is to convert the sugar in the amorphous state to a crystalline state, to raise the resistance of the tablet, and to make the tablet more stable. In the present invention, the "drying" is implemented in order to remove the water absorbed by the humidification of the amorphous sugar. There are no particular limitations for drying conditions, as long as these are the usual conditions for removing the water content. For example, these should be 10-100 ° C, and preferably 20-60 ° C. The rapid disintegrating tablet in the oral cavity can contain different medicinally permissible excipients, such as disintegrating agents, stabilizing agents, binding agents, diluting agents, lubricating agents, and the like: The production method of the invention is described below. Rapid disintegration tablet in the oral cavity. For the production method of the present invention, a drug, a sugar (A), and an amorphous sugar (B) are mixed, "and after forming the mixture in a tablet, it is humidified and dried. , in the production method of the present invention, the mixture of the following is formed: a drug, a sugar (A), and an amorphous sugar (B) obtainable by dissolving a crystalline sugar capable of becoming amorphous , in a medically permissible solvent, and removing the solvent from the solution and drying, and the tablet is humidified and dried In addition, in the production method of the present invention, a mixture of the following is formed in a tablet: drug, a sugar (A), and an amorphous sugar (B) that can be obtained by dissolving a crystalline sugar capable of becoming amorphous, in a medically permissible solvent, and by spraying and drying the solution, and the tablet is humidified and dries up, in particular, in the pro method duction of the present invention, after dissolving a crystalline sugar capable of becoming amorphous, in a medically permissible solvent, and by the use of a binding agent, the solution is sprayed with a twin fluid nozzle or the like, against a drug and / or sugar (A), and then forming a coated product and / or a granulated product, by means of coating and / or granulating with an amorphous sugar (B), and after forming a tablet, it is humidified and dried. Here, the definitions and preferred modalities of the "drug", the "sugar (A)", and the "amorphous sugar (B)", as well as the processing steps for the production of the fast-disintegrating tablet in the oral cavity, which include "training", "humidification", and "drying". In addition, as a method for removing the solvent in the present invention, there are no particular limitations, as long as this is a method implemented in the normal manufacturing process. For this method, examples include the spray drying method, the freeze drying method, or different granulation methods such as the fluidized bed granulation method, the vertical granulation method, the hop granulation method, or Similar. From a production point of view, the spray drying method or the different granulation methods are preferred. Among these, in the different granulation methods, a method is preferred wherein: a crystalline sugar capable of becoming amorphous is used, and which is dissolved in a medically permissible solvent such as water, alcohol, as a binding agent, and it becomes amorphous when sprayed and coated or granulated with a twin fluid nozzle or the like, against the drug and / or the sugar. Here, the sugar The crystalline which is capable of becoming amorphous can be dissolved in a medically permissible solvent, and the solution can be sprayed, and the drug and / or sugar (A) can be covered and granulated with the amorphous sugar (B). In the production method of the present invention, different medicinally permissible excipients such as disintegrating agents, stabilizing agents, binding agents, diluents, lubricants, or the like can be added at any of the production steps.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the stability of the resistance of the tablet in the present invention. In the figure, the horizontal axis represents time, and the vertical axis represents the resistance of the tablet. '25 BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further explained by means of citing examples. The present invention is not limited to these modalities. In addition, with respect to the tablet of the present invention, the resistance of the tablet and the disintegration time in the buccal cavity have been evaluated. Because it is considered that it has little influence on the evaluation categories, the drug is not always included.

[Example 1] 602 grams of mannitol and 602 grams of lactose were mixed. This was passed through a screen (14 mesh). 433 grams of glucose solution (15 weight percent / volume) was used as a binder for this mixture, and the mixture was granulated in a fluidized bed granulator. Up to 157 grams of the solution was used to cover the previous mixture, at a spray pressure of 2.5 kilograms / square centimeter. Then it was granulated with a spray pressure of 1.5 kilograms / square centimeter. After drying the granule, 10 grams of mint flavor, 12 grams of stearic acid, 10 grams of magnesium stearate were combined. The rotary tablet machine was used to make tablets that were 540 milligrams per tablet (hardness of the tablet, 1.4 kp (n = 5)). This tablet was then hydrolyzed and heated for 20 minutes in a thermo-hygrostat at 35 ° C, 85 percent RH. Then, it was dried for 15 minutes at 50 ° C (30 percent humidity), and the tablet of the present invention was obtained. The tablet obtained had a hardness of 9.1 kp, and a disintegration time in the oral cavity of 17 seconds.

[Example 2] 175 grams of a lactose solution (10 weight percent / volume) was a binding agent for 350 grams of lactose (Domo milk Corp.). This was granulated in a fluidized bed granulator (Ohka ara Seisakusho). Up to 70 grams of the previous solution was used to cover the lactose with a spray pressure of 2.5 kilograms / square centimeter. Then, it was granulated with a spray pressure of 1 kilogram / square centimeter. After drying the granule 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 10 mm, 10 mmR), tablet hardness of 2.3 kp (n = 5)) of 300 milligrams per tablet were produced using a rotary tablet machine. The tablet was then stored under humidified, heated conditions of 25 ° C / 70% RH for 19 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 25 ° C (50 percent humidity). The tablet of the present invention was obtained. The tablet obtained had a hardness of 4.1 kp (n = 5) and a disintegration time in the oral cavity of 20 seconds.

[Example 3] 378 grams of mannitol (Towa Chemical Industry Corp.) was passed through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohka a? A Seisakusho), with 133 grams of an aqueous solution of crystalline hydrated glucose (Nippon Shokuhin Kako Corp.) > (15 percent by weight / volume) as a binding agent. Up to 50 grams of the previous solution was used to cover the mannitol with a spray pressure of 2.5 kilograms / square centimeter. After, this was granulated with a spray pressure of 1.5 kilograms / square centimeter. At this time, the disappearance of the absorption peak derived from the glucose crystals (ie, the glucose is amorphous) was confirmed, using a differential scanning calorimeter (DSC for short). 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8 mm, 9.6 mmR), tablet hardness 2.0 kp (n = 5)) of 150 milligrams per tablet, were produced using a rotary tablet machine with a compression pressure of approximately 0.18 tons / punzo'nazo . The tablet was then stored under humidified, heated conditions of 25 ° C / 70% RH for 24 hours, using a thermo-hygrostat (Tabiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The tablet obtained had a hardness of 5.4 kp (n = 5) and a disintegration time in the oral cavity of 20 seconds. In addition, by measuring the tablet obtained with a differential scanning calorimeter, it was confirmed that an absorption peak derived from the glucose crystals was present, and that the glucose was said to be crystallized.

[Example 4] 425.25 grams of erythritol (Nikken Chemical Corp.) was passed through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohka ara Seisakusho), with 150 grams of an aqueous solution of maltose (Product name, Sanmalt-S, Hayashibara Shoji Corp.) (15 percent weight / volume) as a binding agent. Up to 60 grams of the previous solution was used to cover the erythritol with a spray pressure of 3.0 kilograms / square centimeter. Then, it was granulated with a spray pressure of 1.4 kilograms / square centimeter. 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8 mm, 9.6 mrtiR), tablet hardness 2.0 kp (n = 5)) of 150 milligrams per tablet were produced using a rotary tablet machine with a compression pressure of approximately 0.3 tons / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 24 hours, using a thermostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The tablet obtained had a hardness of 7.6 kp (n = 5) and a disintegration time in the oral cavity of 20 seconds.

[Example 5] 360 grams of mannitol (Towa Chemical Industry) was passed through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohkawara Seisakusho), with 266 grams of an aqueous solution of fructose (Hayashibara Shoji Company) (15 percent weight / volume) as a binding agent. With respect to this granule, it was confirmed by a differential scanning calorimeter that the absorption peak derived from the fructose crystals disappeared, and the fructose was amorphous. 0.5% magnesium stearate was mixed with the granule. Tablets were produced ((phi 8 mm, 9.6 mR), tablet hardness of 1.1 kp (n = 5)) of 150 milligrams per tablet, using a rotary tablet machine with a compression pressure of approximately 0.06 tons / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for ~ 2 hours at 40 ° C. The tablet of the present invention was obtained. The tablet obtained had a hardness of 5.6 kp (n = 5) and a disintegration time in the oral cavity of 15 seconds.

[Example 6] 133 grams of an aqueous lactitol solution (Towa Chemical Industry Corp., Milhen) (15 weight percent / volume) was a binding agent for 380 grams of lactose (Domo milk Corp.). This was granulated in a fluidized bed granulator (Ohkawara Seisakusho). With respect to this granule, it was confirmed by a differential scanner calorimeter that the absorption peak derived from the lactitol crystals disappeared and the lactitol was amorphous. 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8 mm, 9.6 mmR), tablet hardness of 1.0 kp (n = 5)) of 150 milligrams per tablet, were produced using a rotary tablet machine with a compression pressure of approximately 0.1 ton / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Company, PR-35C). This was then dried for 2 hours at 40 ° C. The tablet of the present invention was obtained. The tablet obtained had a hardness of 3.7 kp (n = 5) and a disintegration time in the oral cavity of 15 seconds. In addition, by measuring the tablet obtained with a differential scanning calorimeter, it was confirmed that an absorption peak derived from the lactitol crystals was present, and the lactitol had crystallized.

[Example 7] 133 grams of an aqueous solution of trehalose (Hayashibara Shoji) (15 weight percent / volume) were a binding agent for 380 grams of crystalline hydrated glucose (Nippon Shokuhin). This was granulated with a fluidized bed granulator (Ohkawara Seisakusho). 0.5% magnesium stearate was mixed with the granule. Tablets were produced ((phi 8 mm, 9.6 mmR), tablet hardness of 1.0 kp (n = 5)) of 150 milligrams per tablet, using a rotary tablet machine with a compression pressure of approximately 0.1 ton / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 12 hours, using a thermostat (Tabaiespec Company, PR-35C). This was then dried for 2 hours at 40 ° C. The tablet of the present invention was obtained. The tablet obtained had a hardness of 4.3 kp (n = 5) and a disintegration time in the oral cavity of 20 seconds.

[Example 8] 40 grams of famotidine, 336.8 grams of erythritol (Nikken Chemical Corp.) were passed through a screen (20 mesh). This was then granulated with a fluidized bed granulator (Ohkawara Seisakusho), with 100 grams of an aqueous lactitol solution (Towa Chemical Industry Corp.) (20 weight percent / volume) as a binding agent. Calcium stearate was mixed at 0.8 percent with the granule. Tablets ((phi 8.5 mm, 10.2 mmR), tablet hardness of 1.1 kp (n = 5)) of 200 milligrams per tablet, were produced using a rotary tablet machine with a compression pressure of approximately 0.14 tons / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 80% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The obtained tablet had a hardness of 6.2 kp (n = 5) and a disintegration time in the oral cavity of 20 seconds.

[Example 9] 100 grams of acetaminophen, 227 grams of lactose (Domo milk Company) were passed through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohkawara Seisakusho), with 100 grams of a trehalose (Hayashibara Shoji) solution (20 weight percent / volume) as a binding agent. 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8.5 mm, 10.2 mmR), tablet hardness of 1.4 kp (n = 5)) of 200 milligrams per tablet were produced, using a rotary tablet machine with a compression pressure of approximately 0.3 tons / puncture . The tablet was then stored under humidified conditions heated to 25 ° C / 80% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Company, PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The obtained tablet had a hardness of 3.1 kp (n = 5) and a disintegration time in the buccal cavity of 25 seconds.

[Example 10] An aqueous solution (25 weight percent / volume) of trehalose (Hayashibara Shoji Company) was spray dried using a spray dryer (Daiwa Kagahu DL-41). An amorphous trehalose powder was obtained. 5 parts of trehalose powder were mixed with 95 parts of mannitol (Towa Chemical Industry Corp.) in a mortar. This mixture was made into tablets of a 150 milligram tablet ((phi 8 mm, 9.6 mmR), tablet hardness of 1.1 kp (n = 5)) using an oil pressure device. The tablet was then stored under humidified conditions heated to 25 ° C / 80% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The tablet obtained had a hardness of 6.1 kp (n = 5) and a disintegration time in the oral cavity of 15 seconds.

[Example 11] 380 grams of mannitol (Towa Chemical Industry) was passed through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohkawara Seisakusho), with 133 grams of a trehalose solution (Hayashibara Shoji Company) (15 weight percent / volume) as a binder. 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8 mm, 9.6 mmR), tablet hardness of 2.8 kp (n = 5)) of 150 milligrams per tablet were produced using a rotary tablet machine with a compression pressure of approximately 0.4 tons / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the present invention was obtained. The tablet obtained had a hardness of 3.9 kp (n = 5).

[Comparative Example 1] A sugar (B), xyritol, which does not change to the amorphous state was used to replace the trehalose in Example 11. In particular, 380 grams of mannitol were passed (Towa Chemical Industry Corp.) through a screen (20 mesh). This was then granulated in a fluidized bed granulator (Ohkawara Seisakusho), with 130 grams of an aqueous solution of xyritol (Towa Chemical Industry Corp.) (15 weight percent / volume) as a binding agent. With respect to this granule, it was confirmed by means of a differential scanning calorimeter that the absorption peak derived from the crystals of xiritol remained, and the xyritol was in the crystalline state. 0.5% magnesium stearate was mixed with the granule. This was granulated with a fluidized bed granulator (Ohkawara Seisakusho). 0.5% magnesium stearate was mixed with the granule. Tablets ((phi 8 mm, 9.6 mmR), tablet hardness 3.2 kp (n = 5)) of 150 milligrams per tablet were produced using a rotary tablet machine with a compression pressure of about 0.8 tons / puncture. The tablet was then stored under humidified conditions heated to 25 ° C / 70% RH for 12 hours, using a thermo-hygrostat (Tabaiespec Corp., PR-35C). This was then dried for 2 hours at 30 ° C (40 percent humidity). The tablet of the Comparative Example was obtained. The tablet obtained had a hardness of 3.5 kp (n = 5). In case of using a sugar that did not change to the amorphous state, it was confirmed that a resistance of the tablet did not show a large increase through a process of humidification and drying.

[Experiment 1] Stability of the resistance of the tablet in a condition stored in the present invention was under examination. In the present experiment, the tablet obtained in Example 11 in the present invention was examined as the tablet of the present invention. On the contrary, with respect to the tablet obtained in Comparative Example 1, the tablet was under a process of humidification and drying, to obtain a tablet (Example 1), or the tablet was before in a process of humidification and drying (Comparative Example 2) ). The storage condition was at 25 ° C (75 percent humidity). Figure 1 shows the result of the Experiment. Figure 1 suggested that the preparation in the present invention had a stability to show few changes in tablet resistance, under storage in a moisture condition. On the contrary, it was found that the resistance of the tablet in the Comparative Examples decreased to half the initial resistance per gradient from the time the experiment started. Therefore, the present invention is to provide more stability against moisture under storage.

INDUSTRIAL VIABILITY After the tablet of the present invention was processed by humidification and drying during the production process, the amorphous sugar irreversibly changes to the crystalline state. This is stable with respect to storage humidity. The strength of the tablet can be maintained in a stable manner. In addition, in the tablet of the present invention, it is possible to produce the sugar and amorphous sugar of the present invention from a type of sugar. As a result, it is possible to design a tablet that takes into account the stability of the drug. In addition, in the tablet of the present invention, it is possible to provide a production method using the standard tablet machine and granulator. In particular, in the production method of the present invention, wherein: the sugar that is capable of becoming amorphous is dissolved in a medically permissible solvent; the solution is sprayed against the drug and / or the sugar (A); this is covered and / or granulated, a freeze dryer is not necessary. The present invention uses the granulator and tablet machine which is a widely accepted part-plate forming process. As a result, this is a valuable method due to its high production efficiency.

Claims

1. A fast-disintegrating tablet in the oral cavity, comprising: a mixture comprising: a drug; a sugar (A); An amorphous sugar (B); and after the formation of the tablet, it is humidified and dried.

2. The rapid disintegrating tablet in the oral cavity, according to claim 1, comprising: a mixture comprising: a drug; a sugar (A); and an amorphous sugar (B) obtainable by dissolving a crystalline sugar capable of becoming amorphous in a medically permissible solvent, and removing the solvent from the solution, and drying; and after the formation of a tablet, it is humidified and dried.

3. The fast-disintegrating tablet in the oral cavity, according to claim 1 or claim 2, comprising: a mixture comprising: a drug; a sugar (A); and an amorphous sugar (B) obtainable by dissolving a crystalline sugar capable of becoming amorphous in a medically permissible solvent, and drying by sprinkling said solution; wherein, after the formation of a tablet, this tablet is humidified and dried.

4. The rapid disintegrating tablet in the oral cavity, according to claim 1 or claim 2, comprising: a crystalline sugar capable of becoming amorphous, which dissolves in a medically permissible solvent; the solution is sprayed on a drug and / or a sugar (A) to coat and / or granulate it, and after the formation of a tablet, it is humidified and dried.

5. The fast-disintegrating tablet in the oral cavity, according to any of claims 1 to 4, wherein the drug is presented in an amount effective to cure a patient, wherein the amorphous sugar (B) is not less to 2 weight percent / weight by weight of the preparation, and wherein the sugar (A) is in an amount of 100 weight percent / total weight of the preparation consisting essentially of the drug, sugar (A) and the amorphous sugar (B).

6. The rapid disintegrating tablet in the oral cavity, according to any of Claims 1 to 5, wherein the condition for humidification is performed at not less than an apparent critical relative humidity of a mixture consisting of a drug, a sugar (A) and an amorphous sugar (B).

7. The rapid disintegrating tablet in the oral cavity, according to any of Claims 1 to 6, wherein the condition for humidity is 30 to 100 percent RH, and wherein said condition is 15 to 50 ° C .

8. The fast-disintegrating tablet in the oral cavity, according to any of claims 1 to 7, wherein the amorphous sugar (B) is obtained by mediantfe lyophilization and / or different granulation methods.