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

Description of the invention

The invention relates to a tablet that disintegrates rapidly in the mouth cavity.

As pharmaceutical dosage forms intended for administration by the oral route, there are mentioned: tablet, capsule, granule, powder, etc. However, some problems may arise when taking these forms by the patient. And so, in the case of a tablet or capsule, if the patient is an elderly person or a child, sometimes taking a pharmaceutical preparation of this type may arouse aversion in the patient, because swallowing such a dosage form may prove difficult for him, or the preparation may also get stuck in their throat or in the esophagus. In addition, when it comes to granules or powder, in some cases they may be reluctant to take it, either because it will be difficult for them to swallow and the medication remains in the vestibule of the mouth, or because these forms are choking. . Since in such situations the ability to take a pharmaceutical preparation is reduced, it is desirable to have pharmaceutical dosage forms that are easy for the patient to take. As a result, disintegrating preparations in the oral vestibule are investigated and developed.

For example, a formulation called "Zydis®" was developed from RP Schere Corp. However, due to the fact that this preparation is produced by lyophilization, special equipment, such as a lyophilizer, is needed to obtain it. In addition, this formulation cannot be taken directly from the FTP cavity (the so-called "squeeze pack") by squeezing it out of the sheet due to the low mechanical strength of the tablet. Then, it may be so difficult for the elderly to remove the formulation from the packaging that such a form of the drug is not acceptable to them.

A wide variety of rapidly disintegrating tablets in the buccal cavity has been reported to be manufactured by tabletting rather than lyophilization. Thus, for example, JP 6-218028-A (EP 590963 corresponds to it) discloses a tablet that disintegrates rapidly in the mouth cavity, produced by compressing a moistened powder mixture of drug, excipient, binder etc. using water, etc., followed by drying of the molding material. However, this method requires a special tablet press to spray a fluidizing agent onto the surface of the tablet prior to compression to avoid compression problems. JP 5-271054-A (EP 553777 corresponds to it) discloses a tablet that disintegrates rapidly in the mouth cavity, prepared by a process comprising first compressing a mixture containing drug, sugar and water added in an amount sufficient to moisten said sugar, while low compression pressure, and then drying the formed tablet. WO93 / 15724 (EP 627218 corresponds to it) also discloses a rapidly disintegrating tablet prepared by pressing with moistening and drying. However, these methods have some problems such as, for example, sticking in wet pressing.

In addition, WO95 / 20380 (corresponding to US 5,576,014) discloses a tablet that disintegrates rapidly in the vestibule of the cavity. The tablet is prepared by granulating the low mouldable sugar by using high mouldable sugar and the granules thus obtained are compressed in a conventional tablet press. It is believed that there will be no major problems in implementing this production method, however, it requires the use of at least two types of sugar if there is a need to limit the type of sugar introduced due to the interaction of the drug and the sugar (e.g., drug decomposition). ). Therefore, new tablets that disintegrate rapidly in the mouth cavity and a method of producing such tablets, even nowadays, for example in the case of the preparation of said tablets, and their preparation using a single type of sugar are desired.

Further, regarding a tablet that disintegrates rapidly in the mouth cavity, the following patent application and publication disclose a proposal for the following preparation methods.

Thus, for example, JP 9-48726-A discloses a method in which a mixture of drug, sugar and / or hydrophilic polymer is used to form tablets, the mixture being compressed under low pressing pressure, whereby that the molding is carried out with moistening and drying. However, since this method aims to increase the mechanical strength of the tablet surface, especially due to the moisture of the water-soluble polymer, it is possible to cause adhesion phenomena between the tablets.

PL 207 953 B1

In Abstract of the 13^th Japan Pharmacological Pharmacy, p. 113, published on March 5, 1998, proposed a method whereby a mixture of amorphous sucrose (obtained by lyophilizing a solution of sucrose, drug and mannitol is compressed into tablets using a rotary tablet press, and the tablets thus obtained are kept under controlled conditions (temperature 25 ° C, relative humidity 34%). However, the sugar used herein is an amorphous sugar made by freeze-drying, and the use of any sugars other than sucrose is not described in this publication.

The object of the present invention is to provide a tablet that disintegrates rapidly in the mouth cavity. Tablets of this type are produced using a conventional granulator and tablet press, the strength of these tablets being increased, and increased stability of the formulation being provided.

The present inventors have studied the physiological characteristics of sugar and found that a number of sugars can be rendered amorphous when a sugar solution is subjected to spray drying or when a sugar solution is used as a binder in a granulating operation. The inventors further found that when the amorphous sugar is subjected to wetting and drying, the strength of the tablet is increased by converting the amorphous form of the sugar into a crystalline state, and that a disintegrating in the vestibule of the mouth is obtained with the desired strength. The subject of the invention is:

1. A tablet that disintegrates rapidly in the mouth cavity containing a mixture of a drug, sugar (A) and amorphous sugar (B), one type or a combination of two, selected from the group consisting of erythritol and lactitol, obtained by dissolving crystalline sugar capable of becoming amorphous in a medically acceptable solvent such as water or alcohol and then removing the solvent from the solution thus formed and drying the residue and, after forming the tablet, subjecting it to moistening and drying, the humidity being in the range of 30 to 100% relative humidity, the temperature being 15 to 50 ° C, and the hardness of the tablet is 3, 1 kg or more, the tablet containing the drug and amorphous sugar (B) in an amount of 2 to 20 wt.%. % based on sugar (A), or 2 to 20 wt. whole tablet;

- the humidification conditions are met at a humidity not lower than the apparent critical relative humidity of the mixture consisting of the drug, sugar (A) and amorphous sugar (B),

- the tablet contains amorphous sugar (B) obtained by lyophilization and / or granulation carried out by various methods.

2. A tablet that disintegrates rapidly in the mouth cavity, containing a mixture of drug, sugar (A) and amorphous sugar (B), one or a combination of two types selected from the group consisting of erythritol and lactitol, obtained by dissolving crystalline sugar capable of becoming amorphous , in a medically acceptable solvent such as water or alcohol, and then spray-drying the solution thus formed, and after forming the tablet, it is moistened and dried, the humidity is in the range of 30 to 100% relative humidity, the temperature is 15 to 50 ° C, and the tablet hardness is 3.1 kg or more, the tablet containing the drug and sugar amorphous (B) in an amount of 2 to 20 wt.% based on sugar (A), or 2 to 20 wt. whole tablet;

- the humidification conditions are met at a humidity not lower than the apparent critical relative humidity of the mixture consisting of the drug, sugar (A) and amorphous sugar (B),

- the tablet contains amorphous sugar (B) obtained by lyophilization and / or granulation carried out by various methods.

3. Fast disintegrating tablet in the mouth of the mouth containing a solution of one type of amorphous sugar (B) or a combination of two types selected from the group consisting of erythritol and lactitol, obtained by dissolving an amorphous crystalline sugar in a medically acceptable solvent such as water or alcohol which is sprayed onto the drug and / or sugar (A) giving a coated and / or granulated product, and after forming the tablet, subjecting it to moistening and drying, the humidity being in the range of 30 to 100% relative humidity, the temperature being 15 to 50 ° C, and the tablet hardness being 3.1 kg or more. wherein the tablet comprises the drug, amorphous sugar (B) in an amount of 2 to 20 wt.%. % based on sugar (A) or 2 to 20 wt. whole tablet

- the humidification conditions are met at a humidity not lower than the apparent critical relative humidity of the mixture consisting of the drug, sugar (A) and amorphous sugar (B).

- the tablet contains amorphous sugar (B) obtained by lyophilization and / or granulation.

PL 207 953 B1

As for the medicament to be used according to the invention, there are no particular limitations as long as it is a substance to be used as a pharmaceutically active ingredient. Examples of pharmaceutically active ingredients include the following medicaments: sedative hypnotics, sleep inducers, anti-anxiety drugs, antiepileptic drugs, antidepressants, antiparkinsonian drugs, antipsychonics, drugs affecting the central nervous system, local anesthetics, drugs relaxant skeletal muscles, drugs that affect the autonomic nervous system, antipyretics painkillers, anti-inflammatory drugs, anticonvulsants, anti-vertigo drugs, heart drugs, anti-arrhythmic drugs, diuretics, blood pressure lowering drugs, vasoconstrictor drugs, vasodilators, drugs to treat cardiovascular organs, anti-hyperlipoproteinemic drugs, respiratory stimulants, antitussive drugs, expectorants, expectorants, antitussive drugs, bronchodilators, astringents, drugs for peptic ulcer, drugs that improve gastric digestion, antacids, laxatives, drugs that stimulate bile secretion, drugs to treat gastrointestinal diseases, drugs based on adrenal hormones, hormonal drugs, drugs to treat the urinary tract, vitamins, antihaemorrhagics, liver drugs, drugs to treat gout, drugs for diabetes, antihistamines, antibiotics, antibacterials, anti-cancer drugs, chemotherapy drugs, multi-purpose cold medications, tonic medications, osteoporosis medications, etc. Also, there is no particular limitation on the amount of these drugs used in the preparation of said mixtures, as long as it is therapeutically effective. It should be about 50% by weight of the total tablet or less, preferably 20% by weight or less.

When the present invention is used to formulate a medicament having an unpleasant taste, it is preferred that the medicament be subjected to a taste masking treatment (for example as described in WO92 / 09275).

When the invention is used to formulate a medicament for which a prolonged action is desired, preferably the medicament should be treated with a sustained release drug (for example as described in CA20238400-0) to obtain a controlled release drug particle for a method known in the art.

Further, the tablet of the invention can be used to deliver a drug that requires absorption by the oral vestibule, since the tablet of the invention, when taken by a patient, disintegrates and dissolves in the vestibule of the mouth.

There are no particular restrictions on the type of sugar (A) used in the invention as long as this sugar is normally medically permitted. Preferably, the sugar (A) is a sugar or alcohol derived from a simple sugar that dissolves in the mouth. Examples of such compounds are: lactose, glucose, trehalose, mannitol, erythritol, etc. The sugar (A) may be a single type of sugar, or it may be a combination of two or more different sugars. Moreover, since sugar (A) acts as an excipient that dissolves in the mouth cavity, the amount of sugar (A) incorporated in the rapidly disintegrating tablet of the invention is not particularly limited as long as it is used in an effective amount in terms of providing just such action in a rapidly disintegrating tablet. The amount of sugar (A) introduced depends on the amount of the drug and can be adjusted accordingly. In other words, in the case where the amount of drug is small, the amount of sugar (A) to be added becomes larger, and in the case where the amount of drug is large, the amount of sugar (A) to be added becomes smaller. . The amount of sugar (A) introduced depends only on the size of the tablet. The amount of sugar (A) can be determined as the ratio between the amount of sugar (A) and other excipients.

The term "amorphous sugar (B)" as used herein means a sugar which is usually medically acceptable and which is amorphous or capable of becoming amorphous. For example, an amorphous sugar (B) can be obtained by dissolving an amorphous crystalline sugar in a medically acceptable solvent such as water and alcohol etc., and then removing the solvent from the solution thus formed, and finally drying the residue. There are no particular restrictions on the method of removing the solvent as long as it is a method normally practiced in a pharmaceutical manufacturing process. For example, methods of this type include spray drying, freeze drying, and various granulation methods such as fluidized bed granulation, vertical granulation, and drum granulation. From a production standpoint, spray drying or various granulation methods are preferred. Of these, for these different granulation methods,

This method is preferred in which a crystalline sugar capable of being amorphous and which is dissolved in a medically acceptable solvent such as water or alcohol used as a binder becomes amorphous when sprayed through a double nozzle. jet and the like, and coats and / or granules the drug and / or sugar. Thus, an amorphous crystalline sugar can be dissolved with a medically acceptable solvent. The drug or sugar (A) can be sprayed with the thus obtained solution, whereby they are coated and granulated with the amorphous sugar (B). Examples of amorphous sugars (B) include: glucose, lactose, maltose, sorbitol, trehalose, lacticol, fructose, etc. This amorphous sugar (B) may be a single type of sugar, or it may be a combination of two or more types of sugar. The term "amorphous sugar" as used herein means a sugar that is substantially amorphous or that is capable of becoming amorphous. As for the amorphous transition process, the invention also covers those states in which a portion of the material is not amorphous. The amount of amorphous sugar (B) to be added is 2 to 20 wt.% With respect to the sugar (A), or 2 to 20 wt.% Of the total tablet.

Regarding the advantages of using amorphous sugar according to the invention, it should be noted that it is easy to increase the mechanical strength of the tablet in the moistening and drying steps. Since amorphous sugar has a low critical moisture, the tablet can be processed at a low moisture level so that the amorphous sugar can absorb the moisture. In addition, the moisture absorbed during the moistening operation dissolves some of the surface around the sugar particles, and then, in the drying operation, the strength of the tablet may increase due to the sugar particles re-fusing. On the other hand, in contrast to the present invention, it is easy to envision that such a production process may imply some difficulties, for example in the case where the sugar consists of sugars in a crystalline state, since no moisturization will be obtained under low humidity conditions. at a sufficient level and the strength of the tablet will not be enhanced, and adhesion between tablets will occur under high humidity conditions. Thus, it is easy to anticipate that practical implementation will be difficult.

As for the other advantages relating to the use of amorphous sugar according to the invention, since the amorphous sugar has changed irreversibly during the moistening and drying operation to a crystalline state, the dried tablets show a high level of critical moisture. As a result, these tablets can maintain their mechanical strength to the effect of moisture under the storage conditions. Then, by using one type of sugar that exists in a crystalline state and in an amorphous state, tablets can be made to disintegrate rapidly in the mouth cavity, avoiding the constraints of sugar selection and not altering the drug.

The term "molding" as used herein refers to forming a tablet or the like using a pressure equal to or greater than that needed to maintain the desired shape. Normal equipment can be used for the forming operation. For example, a tablet press may be used to make single tablets or a rotary tablet press.

The term "moistening" as used herein, performed in conjunction with a subsequent drying step, to increase the mechanical strength of the tablets, the moistening conditions being determined by the apparent critical relative humidity of the mixture of drug, sugar (A) and amorphous sugar (B ), means increasing the humidity to a level equal to or higher than the critical relative humidity level of this mixture. For example, the humidity is 30-100% relative humidity, preferably 50-90% relative humidity. At the same time, the temperature is 15-50 ° C and preferably 20-40 ° C. The essence of the moistening process is the conversion of amorphous sugar into crystalline sugar in order to increase the mechanical strength of the tablets and to make the tablets more stable.

According to the invention, "drying" is performed to remove the water absorbed in the moistening of the amorphous sugar. There are no particular restrictions on the drying conditions as long as they are normal water removal conditions. For example, the drying temperature may be in the range of 10 to 100 ° C, preferably in the range of 20 to 60 ° C.

The rapidly disintegrating tablet in the buccal cavity can contain a variety of medically acceptable excipients such as disintegrants, stabilizing agents, binders, diluents, lubricants, etc.

The method of producing a rapidly disintegrating tablet in the mouth cavity is described below.

PL 207 953 B1

To carry out the invention, the drug, sugar (A) and amorphous sugar (B) are mixed together and, after forming a tablet, the mixture is moistened and dried. More specifically, a mixture of the following ingredients is formed: drug, sugar (A) and amorphous sugar (B) (which can be obtained by dissolving an amorphous crystalline sugar in a medically acceptable solvent, removing the solvent from the resulting solution, and drying residues), and then the formed tablet is moistened and dried. Thereafter, a tablet is formed from a mixture of the drug, sugar (A) and amorphous sugar (B) (which can be obtained by dissolving amorphous crystalline sugar in a medically acceptable solvent, and then spraying and drying the formed sugar). solution), and then the formed tablet is moistened and dried. In particular, after dissolving the amorphous crystalline sugar in a medically acceptable solvent using a binder, the formed solution is sprayed with a double jet nozzle or the like onto the drug and / or sugar (A) and after obtaining the coated product and / or or granulated by coating and / or granulation with amorphous sugar (B), the formed tablet is moistened and dried.

The definitions and preferred embodiments as used herein, namely "drug", "sugar (A)", and "amorphous sugar (B)" as well as the steps in the process of making a rapidly disintegrating tablet in the mouth cavity, including "forming", "moistening" "And" drying "have been described in the description.

Regarding the solvent removal method, there are no particular restrictions as long as the procedure adopted is that used in the normal manufacturing process. In the case of the described method, exemplary methods include spray drying, freeze drying, or various granulation methods such as fluidized bed granulation, vertical granulation, drum granulation, etc. From a production standpoint, spray drying or various granulation methods are preferred. Of these, for these different granulation methods, the method is preferable in which a crystalline sugar capable of being amorphous and dissolved in a medically acceptable solvent such as water or alcohol used as a binder becomes amorphous. when sprayed by double jet nozzle etc. and coats and / or granules the drug and / or sugar. Thus, an amorphous crystalline sugar can be dissolved with a medically acceptable solvent. The drug or sugar (A) can be sprayed with the thus obtained solution, whereby they are coated and granulated with the amorphous sugar (B).

Various medically acceptable excipients, such as disintegrants, stabilizing agents, binders, diluents, lubricants, etc., may be included at any stage in the process.

Figure 1 shows the stability of the mechanical strength of the tablet according to the invention. In this figure, the horizontal axis represents time and the vertical axis represents the mechanical strength of the tablet.

The invention is explained in the following examples, where example 8 is an example illustrating the invention and the remaining examples are given for the purpose of knowledge and information.

The mechanical strength of the tablet according to the invention and the disintegration time in the mouth cavity were assessed. As the presence of a drug has only a minor impact on the assessment categories, the drug was not always included in the formulation.

Example 1

602 g of mannitol and 602 g of lactose were mixed together. The mixture thus formed was passed through a screen (14 mesh). 433 g of a glucose solution (15% w / v) was used as a binder for this mixture and the entire mixture was granulated in a fluid bed granulator. Not more than 157 g of the solution was used to coat the above mixture at a spray pressure of 2.5 kg / cm². The whole was then granulated at a spray pressure of 1.5 kg / cm². After the granules had dried, 10 g of mint flavor, 12 g of stearic acid and 10 g of magnesium stearate were included. A rotary tablet press was used to produce tablets. The weight of one tablet was 540 mg and its hardness was 1.4 kg (n = 5). Subsequently, these tablets were moistened and heated for 20 minutes in a thermo-hygrostat at 35 ° C and 85% relative humidity. Thereafter, the tablets were dried for 15 minutes at 50 ° C (30% humidity) to obtain tablets according to the invention. The tablets obtained in this way showed a hardness of 9.1 kg, and their disintegration time in the mouth vestibule was 17 seconds.

Example 2

175 g of a lactose solution (10% w / v) was used as a binder for 350 g of lactose (Domo milk Corp.). Everything was granulated in a fluid bed granulator (Ohkawara Seisakusho). To be coated

In lactose, not more than 70 g of the above-mentioned solution was used, with a spray pressure of 2.5 kg / cm². The whole thing was then granulated at a spray pressure of 1 kg / cm². After the granules had dried, 0.5% magnesium stearate was blended in. A rotary tablet press was used to produce tablets. Thus, tablets with the following characteristics were obtained: diameter 10 mm, R 10 mm; hardness 2.3 kg (n = 5); weight 300 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 19 hours using a PR-35C thermo-hygrostat (Tabiespec Corp.). Subsequently, it was dried for 2 hours at 25 ° C (50% humidity). The tablets according to the invention were obtained. The tablets obtained in this way showed a hardness of 4.1 kg (n = 5), and their disintegration time in the buccal cavity was 20 seconds.

Example 3

378 g of mannitol (Towa Chemical Industry Corp.) were passed through a 20 mesh screen, and the mannitol screened was granulated using a fluid bed granulator (Ohkawara Seisakusho) with 133 g of an aqueous solution of hydrated crystalline glucose (15% w / v) ( Nippon Shokuhin Kako Corp.) as a binder. Not more than 50 g of the above-mentioned solution was used to coat the mannitol with a spray pressure of 2.5 kg / cm.². Then, it was granulated at a spray pressure of 1.5 kg / cm². At this point, using a differential scanning calorimeter (abbreviated: DSC), the disappearance of the absorption peak derived from the glucose crystals (meaning that the glucose was already amorphous) was confirmed. 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.18 tonnes / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 2.0 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 24 hours using a PR-35C thermo-hygrostat (Tabiespec, Corp.). Thereafter, it was dried completely for 2 hours at 30 ° C (humidity 40%) to obtain the tablets of the present invention. The tablets produced in this way had a hardness of 5.4 kg (n = 5), and their disintegration time in the mouth cavity was 20 seconds. Thereafter, the obtained tablets were tested by DSC and the presence of an absorption peak derived from glucose crystals (glucose crystallized) was found.

Example 4

425.25 g of erythritol (Nikken Chemical Corp.) was passed through a 20 mesh screen. Then, the screened erythritol was granulated using a fluid bed granulator (Ohkawara Seisakusho) with 150 g of an aqueous maltose solution (15% w / v) (product name: Sanmalt-S, Hayashibara Shoji Corp.) as a binder. Not more than 60 g of the above-mentioned solution was used to coat the erythritol at a spray pressure of 3.0 kg / cm². The whole was then granulated at a spray pressure of 1.4 kg / cm². 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of approximately 0.3 tonnes / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 2.0 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 24 hours using a PR-35C thermo-hygrostat (Tabiespec, Corp.). Subsequently, it was dried for 2 hours at 30 ° C (humidity 40%). The tablets according to the invention were obtained. The tablets produced in this way showed a hardness of 7.6 kg (n = 5), and their disintegration time in the mouth cavity was 20 seconds.

Example 5

360 mannitol (Towa Chemical Industry) was passed through a 20 mesh screen and the mannitol screened was granulated using a fluid bed granulator (Ohkawara Sesakusho) with 266 g of fructose aqueous solution (15% w / v) (Hayashibara Shoji Company) as a binder . These granules were examined by DSC and the absorption peak from fructose crystals (fructose has already turned amorphous) was found to disappear. 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.06 tons / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 1.1 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% RH for 12 hours using a PR-35C thermo-hygrostat (Tabiespec, Corp.). Subsequently, it was dried for 2 hours at 40 ° C. The tablets according to the invention were obtained. So prepared tablets

They showed a hardness of 5.6 kg (n = 5), and their disintegration time in the oral vestibule was 15 seconds.

Example 6

133 g of a lactitol solution (15% w / v) (Towa Chemical Industry Corp., Milhen) was used as a binder for 380 g of lactose (Domo milk Corp.). Everything is granulated in a fluid bed granulator (Ohkawara Seisakusho). These granules were examined by DSC and the absorption peak from lacticol crystals disappeared (lacticol became amorphous). 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.1 ton / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 1.0 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% RH for 12 hours using a PR-35C thermo-hygrostat (Tabiespec, Corp.). Then it was dried for 2 hours at 40 ° C. The tablets according to the invention were obtained. The tablets thus produced showed a hardness of 3.7 kg (n = 5); and their disintegration time in the oral vestibule was 15 seconds. Then, the obtained tablets were tested by DSC and the presence of an absorption peak derived from lacticol crystals (lacticol crystallized) was found.

Example 7

133 g of trehalose solution (15% w / v) (Hayashibara Shoji) was used as a binder for 380 g of hydrated crystalline glucose (Nippon Shokuhin). Everything is granulated in a fluid bed granulator (Ohkawara Seisakusho). 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.1 ton / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 1.0 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 12 hours using a PR-35C thermo-hygrostat (Tabiespec, Cor.). Subsequently, it was dried for 2 hours at 40 ° C. The tablets according to the invention were obtained. The tablets produced in this way had a hardness of 4.3 kg (n = 5), and their disintegration time in the buccal cavity was 20 seconds.

Example 8

40 g of famotidine and 336.8 g of erythritol (Nikken Chemical Corp.) were passed through a 20 mesh screen. Then, the whole was granulated in a fluid bed granulator (Ohkawara Seisakusho) with 100 g of an aqueous lacticol solution (20% w / v) (Towa Chemical Industry Corp.) as a binder. 0.8% calcium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.14 tons / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8.5 mm, R 10.2 mm; hardness 1.1 kg (n = 5); weight 200 mg. The tablets were then stored under heating at 25 ° C and humidifying at 80% RH for 12 hours using a PR-35C thermo-hygrostat (Tabiespec, Corp.). Subsequently, it was dried for 2 hours at 30 ° C (humidity 40%). The tablets according to the invention were obtained. The tablets produced in this way showed a hardness of 6.2 kg (n = 5), and their disintegration time in the mouth cavity was 20 seconds.

Example 9

100 g of 4-acetylaminophenol and 227 g of lactose (Domo milk Conpany) were passed through a screen (20 mesh). Then, the whole was granulated in a fluid bed granulator (20% w / v) (Ohkawara Seisakusho) with 100 g of an aqueous trehalose solution (Hayashibara Shoji) as a binder. 0.5% calcium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of approximately 0.3 tonnes / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8.5 mm, R 10.2 mm; hardness 1.4 kg (n = 5); weight 200 mg. The tablets were then stored under heating at 25 ° C and humidifying at 80% RH for 12 hours using a PR-35C thermo-hygrostat (Tabaiespec Company). Then it was dried for 2 hours (at 30 ° C (humidity 40%). The tablets according to the invention were obtained. The tablets produced in this way had a hardness of 3.1 kg (n = 5), and their disintegration time in the buccal cavity was 25 seconds.

Example 10

An aqueous solution (25% w / v) of trehalose (Hayashibara Shoji) was spray dried using a spray dryer (Daiwa Kagaku DL-41) to obtain an amorphous trehalose powder. In a mortar, 5 parts of trehalose powder were mixed with 95 parts of mannitol

PL 207 953 B1 (Towa Chemical Corp.). From the resulting mixture, tablets were produced with the use of an oil press having the following characteristics: diameter 8 mm, R 9.6 mm; hardness 1.1 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 80% RH for 12 hours using a PR-35C thermo-hygrostat (Tabaiespec Corp.). Subsequently, it was dried for 2 hours (at 30 ° C (humidity 40%), to obtain tablets according to the invention. The tablets thus produced had a hardness of 6.1 kg (n = 5), and their disintegration time in the vestibule was oral cavity was 15 seconds.

Example 11

380 g of mannitol (Towa Chemical Industry) was passed through a screen (20 mesh). Then, sieved mannitol was granulated in a fluid bed granulator (Ohkawara Seisakusho) with 133 g of an aqueous trehalose solution (15% w / v) (Hayashibara Shoji Company) as a binder. 0.5% calcium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.4 tons / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; hardness 2.8 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 12 hours using a PR-35C thermo-hygrostat (Tabaiespec Corp.). It was then dried for 2 hours (at 30 ° C (humidity 40%). The tablets of the invention were obtained. The tablets thus produced showed a hardness of 3.9 kg (n = 5).

Comparative example 1

As sugar (B), xylitol was used instead of trehalose as in example 11; not changing its state to the amorphous state. Specifically, 380 g of mannitol (Towa Chemical Industry Corp.) was passed through a screen (20 mesh). The screened mannitol was granulated in a fluid bed granulator (Ohkawara Seisakusho) with 130 g of xylitol solution (15% w / v) (Towa Chemical Industry Corp.) as a binder. These granules were examined by DSC and the absorption peak derived from xylitol crystals remained (xyrritol was still crystalline). 0.5% magnesium stearate was mixed with the granules. Everything is granulated using a fluid bed granulator (Ohkawara Seisakusho). 0.5% magnesium stearate was mixed with the granules. A rotary tablet press was used to produce tablets. A compression pressure of about 0.8 tons / punch was used. Thus, tablets with the following characteristics were obtained: diameter 8 mm, R 9.6 mm; a hardness of 3.2 kg (n = 5); weight 150 mg. The tablets were then stored under heating at 25 ° C and humidifying at 70% relative humidity for 12 hours using a PR-35C thermo-hygrostat (Tabiespec, Cor.). Then it was dried for 2 hours at 40 ° C. The tablets according to the comparative example were obtained. The tablets thus produced showed a hardness of 3.5 kg (n = 5). It has been found that when sugar is used which does not turn its amorphous state into an amorphous state, the mechanical strength of the tablet does not increase significantly as a result of the moistening and drying operation.

Experiment 1

The tablets were tested for the stability of the mechanical strength under the storage conditions according to the invention. In the experiment described here, the tablets prepared in Example 11 were treated as the tablets of the invention, and the tablets obtained in Comparative Example 1 were used as controls, with the moisturizing and drying treated tablets (Example 1) tested or the tablets tested prior to this treatment (comparative example 2). Storage conditions: temperature 25 ° C, humidity 75%. Fig. 1 shows the results of the experiment. Fig. 1 suggests that the formulation according to the invention shows the stability of the mechanical strength with only slight variations under humid storage conditions. In contrast, it was found that the mechanical strength of the tablets of the comparative examples decreased to half the original gradient values ​​from the start of the experiment. Therefore, the present invention provides a formulation with increased stability with respect to moisture during storage.

Industrial feasibility

After the tablet according to the invention has been subjected to a humidifying and drying treatment during the manufacturing process, the amorphous sugar changes its state to a crystalline state irreversibly. This condition is permanent as regards the influence of moisture during storage. The mechanical strength of the tablet can be maintained in a stable manner. Moreover, in the case of the tablet according to the invention, it is possible to obtain the sugar and the amorphous sugar according to the invention from sugar of one and the same type. As a result, it is possible to design the tablet with stability in mind

Drug. Further, in the case of the tablets according to the invention, it is possible to provide a manufacturing method using a conventional granulator and tablet press.

In particular, the production method according to the invention consists in dissolving an amorphous sugar in a medically acceptable solvent; the solution formed is sprayed onto the drug and / or sugar (A); these products are coated and / or granulated; a freeze dryer is not needed. The process of the invention employs a granulator and tablet press, generally employed in tablet forming processes. As a result of this state of affairs, the method according to the invention is a valuable method due to its high production efficiency.