Wet tablets and method for manufacturing wet tablets
Trehalose-based binders in wet tablets address adhesion and damage issues, enabling rapid disintegration and strength in oral cavity, improving manufacturing efficiency and product integrity.
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Patents
- Current Assignee / Owner
- ALFRESA PHARMA CORP
- Filing Date
- 2022-02-28
- Publication Date
- 2026-06-29
Smart Images
Figure 0007881325000001 
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Abstract
Description
Technical Field
[0001] The present invention relates to wet tablets and a method for manufacturing wet tablets.
Background Art
[0002] In recent years, drugs that can be easily ingested with a small amount of water or without water have been developed for people with low swallowing ability, such as the elderly and children, and people with restricted water intake. When these drugs are tablets, they are required to disintegrate quickly in the oral cavity and have a strength that is not easily damaged during the manufacturing process, shipping, and sales.
[0003] As tablets that can improve the disintegration in the oral cavity, for example, wet tablets as described in Patent Documents 1 and 2 are known. A wet tablet is a tablet obtained by molding a wet powder using a special tableting device under relatively low pressure. Because of its relatively high porosity, it has the characteristic of being easily disintegrated in the oral cavity.
[0004] In such wet tablets, polymers such as polyvinyl alcohol are generally used as binders. However, when manufacturing wet tablets using a polymer such as polyvinyl alcohol as a binder, there are manufacturing problems such as the need to use a film because the wet powder adheres to the pestle during molding, or the need for cleaning during manufacturing because the wet powder adheres to the turntable or in the mortar. Furthermore, wet tablets using such conventional binders have a problem that they are easily damaged before ingestion, such as during manufacturing and transportation, even though their disintegration in the oral cavity is good.
Prior Art Documents
Patent Documents
[0005]
Patent Document 1
Patent Document 2
Summary of the Invention
[0006] The present invention has been made in view of the problems of the prior art described above, and aims to provide a wet-formed tablet and a method for producing the same that can reduce adhesion to molding equipment and the like, can disintegrate quickly in the oral cavity, and has appropriate strength. [Means for solving the problem]
[0007] The present invention comprises an active ingredient, a binder, an excipient, and a solvent, wherein the binder includes trehalose, and the trehalose content is 1% by mass or more and 30% by mass or less of the solid component.
[0008] In the present invention, the content of trehalose in the binder may be 80% by mass or more and 100% by mass or less.
[0009] In the present invention, the excipient may be mannitol.
[0010] In the present invention, the hardness may be 20N or more, and the disintegration time may be 60 seconds or less.
[0011] In this invention, the wear rate may be less than 1%.
[0012] The present invention relates to a method for manufacturing wet tablets and includes a mixing step of mixing a powder component containing an active ingredient, a binder containing trehalose, and an excipient to obtain a powder mixture; a kneading step of kneading the powder mixture and a liquid component to obtain a wet powder; and a molding step of molding the wet powder under pressure.
[0013] In the present invention relating to a method for manufacturing wet tablets, the molding process may be carried out under pressure of 100 N to 400 N. [Effects of the Invention]
[0014] According to the present invention, it is possible to provide a wet-formed tablet and a method for producing the same that can reduce adhesion to molding equipment and the like, can disintegrate quickly in the oral cavity, and has appropriate strength. [Modes for carrying out the invention]
[0015] The following describes embodiments of the wet-processed tablets and the method for producing wet-processed tablets (hereinafter also simply referred to as the manufacturing method) according to the present invention.
[0016] [Wet-processed tablets] The following describes the wet-processed tablets of this embodiment. The wet-processed tablet of this embodiment is a wet-processed tablet comprising an active ingredient, a binder, an excipient, and a solvent, wherein the binder contains trehalose, and the trehalose content is 1% by mass or more and 30% by mass or less of the solid component.
[0017] (Active ingredients) The active ingredients can be selected appropriately depending on the purpose, and examples include medicinal ingredients and food ingredients. Examples of the aforementioned active ingredients include drugs such as antitumor drugs, antibiotics, anti-inflammatory drugs, analgesics, osteoporosis drugs, antihyperlipidemic drugs, antibacterial drugs, sedatives, tranquilizers, antiepileptic drugs, antidepressants, drugs for treating digestive system diseases, drugs for treating allergic diseases, drugs for treating hypertension, drugs for treating arteriosclerosis, drugs for treating diabetes, hormone drugs, and fat-soluble vitamin drugs; vitamins; minerals such as calcium, zinc, and iron; and quasi-drugs other than drugs, such as foods for specified health uses and foods with nutritional function claims, including amino acids such as aspartic acid and arginine.
[0018] The active ingredient is not particularly limited, but for example, it may have solubility such that 1 mL or more and less than 100 mL of water is required to dissolve 1 mg of the active ingredient. In this embodiment, if the active ingredient is solid, the solubility refers to the degree to which it dissolves within 30 minutes after being powdered, placed in a solvent (water), and shaken vigorously for 30 seconds every 5 minutes at 20°C ± 5°C. Examples of the active ingredient having such solubility include drugs corresponding to "easily soluble" (1 mL or more and less than 10 mL), "slightly soluble" (10 mL or more and less than 30 mL), and "slightly insoluble" (30 mL or more and less than 100 mL) among the solubilities described in the "Eighteenth Revised Japanese Pharmacopoeia". The active ingredient having such solubility can be easily adjusted to have appropriate disintegrability and appropriate strength in the oral cavity, and is suitable for the wet granule tablets of the present embodiment.
[0019] More specifically, examples of the active ingredient corresponding to "easily soluble" include diprophylline, sennoside calcium, ethosuximide, copper chlorophyllin, diphenhydramine hydrochloride, etc.; examples of the active ingredient corresponding to "slightly soluble" include donepezil hydrochloride, aminophylline hydrate, tizanidine hydrochloride, etc.; examples of the active ingredient corresponding to "slightly insoluble" include dextromethorphan hydrobromide hydrate, diclofenac sodium, acetaminophen, azulene sulfonic acid sodium, enalapril maleate, etc. The active ingredient is at least one selected from these groups. The content of the active ingredient is not particularly limited and can be appropriately selected within a range that produces the desired effect.
[0020] (Binder) The wet granule tablets of the present embodiment contain trehalose as a binder. By using trehalose as a binder, the property (adhesiveness) that is likely to adhere to devices such as a pestle during molding can be reduced. Also, by using trehalose as a binder, the wet granule tablets are easily disintegrated in the oral cavity, and at the same time, they are less likely to be damaged before administration and have a strength that is easy to handle.
[0021] As binders used in general wet granulation tablets, polymers such as polyvinyl alcohol and polyethylene glycol are used. However, for these polymer binders, the acceptable daily intake (ADI) has been set, and the usage amount cannot be freely set. Since trehalose can be used without being restricted by ADI, it is safe and the blending amount can be freely determined.
[0022] The content of trehalose is 1% by mass or more and 30% by mass or less in the solid content, and preferably 5% by mass or more and 20% by mass or less. When the content of trehalose is within the above range, the adhesiveness can be reduced, and at the same time, the wet granulation tablet can easily disintegrate in the oral cavity and has an appropriate strength that is difficult to be damaged before taking.
[0023] In addition, in this embodiment, the solid content means components other than the liquid component.
[0024] The wet granulation tablet of this embodiment may contain a binder other than trehalose. The content of trehalose in the binder may be, for example, 80% by mass or more and 100% by mass or less, and preferably 90% by mass or more and 100% by mass or less. Alternatively, only trehalose may be used as the binder. In this case, the content of trehalose in the binder is 100% by mass. When the content of trehalose in the binder is within the above range, it leads to a reduction in the amount of additives, and it becomes easy to obtain a highly safe wet granulation tablet.
[0025] (Excipient) The wet-processed tablets of this embodiment may contain excipients. The excipients are not particularly limited as long as they are generally usable as excipients for tablets, especially wet-processed tablets. Examples include mannitol (hereinafter also referred to as "D-mannitol"), lactose (anhydrous or hydrated), xylitol, sorbitol, corn starch, sucrose, erythritol, talc, purified gelatin, hydroxypropyl starch, calcium silicate, and the like. These can be used individually or in combination of two or more.
[0026] The content of the excipient in the wet-processed tablets is not particularly limited, and may be, for example, 40% by mass or more and 98% by mass or 60% by mass or more and 90% by mass or less. By keeping the excipient content within the above range, the wet-processed tablets achieve appropriate strength, allowing them to disintegrate easily in the oral cavity and preventing them from breaking before administration.
[0027] (solvent) The solvent is not particularly limited as long as it can sufficiently disperse the aforementioned components, and can be used as appropriate, such as purified water, deionized water, or deionized water, or organic solvents such as alcohol. Considering safety, water, alcohol, or mixtures thereof are preferred. In the manufacturing method of this embodiment, the amount of solvent used is not particularly limited and can be arbitrarily selected from a range that provides an effect of appropriately dispersing each of the components. For example, the amount may be 5% to 50% by mass, or 8% to 30% by mass, relative to the solid component.
[0028] Furthermore, a mixture of water and alcohol may be used as the solvent. When using such a mixture as a solvent, the alcohol concentration in the solvent should be greater than 0% and 80% or less, or 10% or more and 70% or less.
[0029] (Other ingredients) In addition to the above-mentioned components, the wet-processed tablets of this embodiment may also contain other components, as long as they do not impair the effects of the present invention. Examples include fluidizers, surfactants, plasticizers, disintegrants, lubricants, flavoring agents, fragrances, and pH adjusters. These can be used individually or in combination of two or more.
[0030] The wet-processed tablets of this embodiment have a hardness of 20N or higher, preferably 30N or higher, and more preferably 34N or higher. At the same time, the wet-processed tablets of this embodiment have a disintegration time of 60 seconds or less, preferably 30 seconds or less, and more preferably 20 seconds or less. The hardness and disintegration time of the wet-processed tablets fall within the above range, allowing them to disintegrate quickly in the oral cavity while maintaining appropriate strength.
[0031] In this embodiment, hardness refers to the value measured by the method shown in the examples described later. Furthermore, the decay time in this embodiment refers to the time (in seconds) measured by the method shown in the embodiment described later.
[0032] The wet-processed tablets of this embodiment have a wear rate of less than 1%, preferably less than 0.5%. Because the abrasion rate of the wet-processed tablets falls within the above range, the wet-processed tablets disintegrate quickly in the oral cavity while maintaining appropriate strength. In this embodiment, the wear rate refers to the value measured by the method shown in the example described later.
[0033] [Method for manufacturing wet tablets] The method for producing wet tablets according to this embodiment will be described below. The method for producing wet tablets according to this embodiment includes a mixing step of mixing an excipient, a binder containing trehalose, and a powder component containing an active ingredient to obtain a powder mixture, The process includes a mixing step of mixing the aforementioned powder mixture with a liquid component to obtain a wet powder.
[0034] [Mixing process] The mixing process involves mixing the active ingredient with a binder containing trehalose and an excipient to obtain a powder mixture. In this process, powder components other than the active ingredient, binder, and excipient may be mixed. The mixing method is not particularly limited, and known mixing devices such as ribbon mixers and high-speed stirring granulators can be used. The mixing conditions are not particularly limited, but can be described as mixing under conditions such as temperature, mixing time, and rotation speed that yield the desired state.
[0035] [Kneading process] The mixing process involves mixing the powder mixture with the liquid component to obtain a wet powder. Examples of liquid components to be added to and kneaded into the powder mixture obtained in the aforementioned mixing step include water, solvents such as alcohol, and other liquid components. In the mixing process, the powder mixture and liquid components are mixed using known mixing methods. The mixing method is not particularly limited, and known mixing devices, such as ribbon mixers and high-speed stirring granulators, can be used.
[0036] The wet powder may be molded as tablets in the molding process as is, or it may be granulated before molding to form wet-processed granules. In this case, known granulation equipment may be used as the granulation device. For example, cylindrical granulators, extrusion granulators, speed mills, power mills, minimizers, power kneaders, speed mills, marmelizers, etc., can be used. The conditions for granulation are not particularly limited, but include stirring and granulating under conditions such as granulation temperature, time, and rotation speed that allow the desired state to be obtained.
[0037] In the mixing process, the liquid component added may be, for example, 5% to 50% by mass, or 8% to 30% by mass, relative to the powder component. When the amount of liquid component relative to the powder component is within the above range, the wet-formed tablet disintegrates quickly in the oral cavity while maintaining appropriate strength.
[0038] [Molding process] The molding process is a process in which wet powder is molded under pressure. In the molding process, the pressure applied to the wet powder can be, for example, 100N to 400N, or 100N to 300N. By molding with the above pressure, the wet tablets disintegrate rapidly in the oral cavity while maintaining appropriate strength. In the molding process of the wet tablet manufacturing method of this embodiment, the wet powder has low adhesion to the molding apparatus, etc., making molding easy.
[0039] In the molding process, the wet tablets molded under pressure may be dried as appropriate. The wet tablets of this embodiment may be used as plain tablets, or they may be further coated to become coated tablets.
[0040] The wet-processed tablets and their manufacturing method according to this embodiment are as described above, but the embodiments disclosed herein should be considered in all respects to be illustrative and not restrictive. The scope of the present invention is indicated by the claims rather than the foregoing description, and all modifications within the meaning and scope equivalent to the claims are intended to be included. [Examples]
[0041] Next, embodiments of the present invention will be described together with comparative examples. However, the present invention is not limited to the embodiments described below.
[0042] The materials, apparatus, and methods used to prepare the examples and comparative examples are as follows.
[0043] (Materials used) Excipients Mannitol 1: Pairitol 25C, manufactured by ROQUETTE. Mannitol 2: Mannit P, manufactured by Mitsubishi Corporation Foodtech Co., Ltd. Binder Trehalose: Trehalose P, manufactured by Hayashibara Co., Ltd. Polyvinyl alcohol: Gosenol EG-05, manufactured by Mitsubishi Chemical Corporation. solvent Ethanol: 99% specific alcohol, manufactured by Nippon Alcohol Co., Ltd. purified water Active ingredients Active ingredient 1: Dextromethorphan hydrobromide hydrate, manufactured by Alps Pharmaceutical Co., Ltd. Active ingredient 2: Diprophylline, manufactured by Shizuoka Caffeine Co., Ltd.
[0044] (Equipment used) Tensilon Universal Tester: RTG-1210, manufactured by A&D Co., Ltd. Grinding machine: R-8, manufactured by Nippon Rikagaku Kikai Co., Ltd. Shelf-type dryer: DAE 20 model, manufactured by Sanwa Chemical Industries Co., Ltd. Mortar 7mm: WR (9.8 x 2.8) 7mm mortar Hardness meter: KHT-20N, manufactured by Fujiwara Seisakusho Co., Ltd. Abrasion resistance tester: TFT-120, manufactured by Toyama Sangyo Co., Ltd. Disintegration tester: NT-60H, manufactured by Toyama Sangyo Co., Ltd.
[0045] [Test 1] Example 1 and Comparative Example 1 were prepared using the formulations shown in Table 1 by the following method.
[0046] (Example 1) Mannitol 1 and trehalose were placed in a pulverizer and operated for 10 seconds to grind them. A solvent mixture of alcohol and purified water was added to the pulverizer and operated for another 10 seconds. The mixture that had stuck to the inner surface of the pulverizer was removed, and this 10-second operation was repeated twice to obtain a wet powder. The mortar was filled with wet powder (123 mg: 110 mg solids), compressed and molded at 200 N using a Tensilon universal testing machine, and then dried.
[0047] (Comparative Example 1) Mannitol 2 was placed in a pulverizer and run for 10 seconds to pulverize it. A mixed solvent of alcohol and purified water, in which polyvinyl alcohol was dissolved, was added to the pulverizer and run for another 10 seconds. The mixture that had stuck to the inner surface of the pulverizer was removed, and the 10-second run process was repeated twice to obtain a wet powder. When a mortar was filled with wet powder (123 mg: 110 mg solids) and compressed and molded at 200 N using a Tensilon universal testing machine, the wet powder adhered to the punch and molding was not possible.
[0048] For the wet-processed tablets used in the examples, the amount of adhesion, hardness, disintegration time, and abrasion rate were measured. The evaluation was conducted using the following evaluation items and criteria.
[0049] (Adhesive) The mass of the material adhering to the pestle during compression was measured. The amount of material initially filled into the mortar was also measured, and the amount of material adhering to the mortar was expressed as a mass percentage. This measurement was taken three times, and the average value was calculated. (mass) The mass of 10 tablets was measured, and the average value was calculated. (hardness) The hardness of 10 tablets was measured using a hardness tester, and the average value was calculated. (wear rate) Twenty tablets were placed in the drum of an abrasion tester and rotated at 25 rpm for 4 minutes to measure the amount of abrasion. The abrasion rate was calculated by dividing the amount of abrasion by the total weight of the tablets before measurement. (Collapse time) The disintegration time of six tablets was measured using a disintegration test machine in accordance with the disintegration test method of the 17th edition of the Japanese Pharmacopoeia, and the average value was calculated. The results are shown in Tables 2 and 3.
[0050] [Table 1]
[0051] [Table 2]
[0052] [Table 3]
[0053] As shown in Table 2, the wet-processed tablets in the examples had low adhesion. Furthermore, as shown in Table 3, the wet-processed tablets in the examples had a hardness of 20N or higher, a wear rate of less than 1%, and a disintegration time of 60 seconds or less.
[0054] [Exam 2] Wet-processed tablets of Examples 2 and 3 were prepared using the formulations shown in Table 4. For each example, hardness, abrasion rate, and disintegration time were measured using the same method as in Test 1. The results are shown in Table 5.
[0055] [Table 4]
[0056] [Table 5]
[0057] As shown in Table 5, the wet-processed tablets in the examples had a hardness of 20N or higher, a wear rate of less than 1%, and a disintegration time of 60 seconds or less.
[0058] [Exam 3] As shown in Table 6, wet tablets for each example were prepared by varying the content of the binder, excipient, and solvent, and by changing the pressure during molding. For each example, hardness, abrasion rate, and disintegration time were measured using the same method as in Test 1. Note that the alcohol ratio in the table refers to the concentration of alcohol in the mixed solvent of purified water and alcohol. The results are shown in Table 6.
[0059] [Table 6]
[0060] As shown in Table 6, the wet-processed tablets in the examples had a hardness of 20N or higher, a wear rate of less than 1%, and a disintegration time of 60 seconds or less.
Claims
1. It contains an active ingredient, a binder, and an excipient. The aforementioned binder includes trehalose, A wet-processed tablet wherein the trehalose content is 1% by mass or more and 30% by mass or less of the solid component.
2. The wet-processed tablet according to claim 1, wherein the content of trehalose in the binder is 80% by mass or more and 100% by mass or less.
3. The wet tablet according to claim 1 or 2, wherein the excipient is mannitol.
4. The wet-processed tablet according to claim 1 or 2, wherein the active ingredient is at least one selected from the group consisting of diprophylline, sennoside calcium, ethosuximide, copper chlorophylline, diphenhydramine hydrochloride, donepezil hydrochloride, aminophylline hydrate, tizanidine hydrochloride, dextromethorphan hydrobromide hydrate, diclofenac sodium, acetaminophen, azulene sulfonate sodium, and enalapril maleate.
5. A wet-processed tablet according to any one of claims 1 to 4, wherein the hardness is 20 N or more and the disintegration time is 60 seconds or less.
6. A wet-processed tablet according to any one of claims 1 to 5, wherein the abrasion rate is less than 1%.
7. A mixing step to obtain a powder mixture by mixing an active ingredient, a binder containing trehalose, and an excipient, A mixing step of kneading the aforementioned powder mixture with a solvent to obtain a wet powder, A method for producing a wet tablet, comprising a molding step of applying pressure to the wet powder to form it.
8. The method for manufacturing a wet tablet according to claim 7, wherein the molding process is performed by applying a pressure of 100 N to 400 N.