JP2008201706A - Small-sized sustained release tablet - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a sustained release tablet containing ambroxol hydrochloride, administering once a day and having a small size to facilitate the swallowing even by a patient having undeveloped or lowered swallowing capability. <P>SOLUTION: The easily takable small-sized sustained release tablet is easily produced by compression molding a composition containing ambroxol hydrochloride, a water-insoluble polymer and an additive. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to a once-daily sustained-release tablet containing ambroxol hydrochloride, which is easy to take even in patients with undeveloped or reduced swallowing ability.

Ambroxol hydrochloride is an expectorant that lubricates the airway surface by promoting the secretion of pulmonary surfactants, promoting airway fluid secretion, and promoting ciliary movement, thereby promoting sputum exudation. It is particularly useful for children with undeveloped vaginal discharge or for elderly people with reduced vaginal discharge, and is an important drug for preventing respiratory infection due to bacterial infection of the respiratory tract due to vaginal retention or physical stenosis. For this reason, various dosage forms have been developed and are widely used from children to the elderly as tablets, capsules, syrups, dry syrups and internal liquids. In addition, a sustained-release preparation for once-daily use that is expected to improve compliance and QOL is also available on the market. Since expectorants are drugs used by a wide range of age groups, ease of swallowing is considered an important factor in designing new sustained-release preparations.

Currently, capsules are the only sustained-release preparations of ambroxol hydrochloride on the market in Japan. Capsules are generally harder to swallow than tablets (Monthly Pharmaceutical Affairs Vol.42, No.3, 2000), and are not suitable for a wide range of age groups. On the other hand, the size of the tablet greatly affects the ease of swallowing, so special consideration must be given to the size of the tablet, but the upper limit of the tablet diameter that is easy to take is reported to be about 9 mm. (Takeda Institute Bulletin 43 (3/4) 111-115 (1984)). Although many of the commercially available tablets of ambroxol hydrochloride are about 7 mm in diameter and are not necessarily difficult to swallow, in children with undeveloped swallowing ability and the elderly with poor swallowing ability Taking tablets is an effort, and taking three times a day is not good for medication compliance, and the burden is high. Therefore, it is very useful to provide a small sustained-release tablet that is easy to take and can be expected to have good sustainability once a day. As technical information on sustained-release preparations of ambroxol hydrochloride, there is a description of sustained-release capsules in JP-A-5-320044, which is a technique of capsules using film coating fine granules, and Are completely different. In addition, although Chinese Patent Application Publication No. 1795844 discloses a method for producing sustained-release tablets, there is no technical description or suggestion regarding a small sustained-release tablet that is easy to take, which is the subject of the present invention. Absent.

To obtain a small sustained-release tablet, it is necessary to design a drug product with a high content of the active ingredient. For this purpose, it is necessary to achieve sustained release efficiently with few sustained release agents and additives. However, when the sustained-release agent and additives are reduced, the mechanical strength of the tablet decreases and the sustained release ability is exhibited in vitro. It can happen. Therefore, it is necessary to pay close attention to the selection of sustained release agents and additives. In addition, the method for producing sustained-release preparations is often complicated and costly. In order to provide sustained-release tablets inexpensively and stably, it is necessary to establish a manufacturing method that does not include special manufacturing processes. For this purpose, it is necessary to use commercially inexpensive additives and to make the manufacturing process simple. Japanese Patent No. 2680602 discloses a technique for sustained release of a drug by insoluble cellulose having a particle size of about 1 μm. However, it is difficult to handle such a fine powder, and further, such a particle size is insoluble. Since cellulose is not commercially available, it is not suitable for commercial practice.

Monthly Pharmaceutical Affairs Vol. 42, No.3, 2000 Takeda Laboratory Report 43 (3/4) 111-115 (1984) JP-A-5-320044 Chinese Patent Application Publication No. 1795844 Japanese Patent No. 2680602

The subject of the present invention is a small tablet that is easy to take for a patient with low swallowing ability, and that has a good sustained release effect when taken once a day. Is produced by a simple method.

A small tablet that is easy to take means that the major axis is generally smaller than the acceptable tablet diameter, that is, the major axis of the tablet is 9 mm or less, and preferably a tablet of ambroxol hydrochloride currently available on the market. This indicates that the major axis is smaller than the major axis of 7 mm. In addition, it may be coated with a water-soluble film to make it easier to take. In addition, the simple method is a manufacturing method that does not require special manufacturing equipment or complicated operations. The powder is mixed and then directly compressed to obtain tablets, or after wet granules are made, It is a method of obtaining tablets by compression molding after mixing with agents. Furthermore, when an organic solvent is used in the wet granulation process, there is a concern about the burden on the environment, and equipment and cost are required for recovery. Therefore, a method that does not use an organic solvent is preferable.

As a result of intensive studies to solve the above problems, the present inventors have conducted a simple manufacturing process of compression molding a composition comprising ambroxol hydrochloride and a smaller amount of a water-insoluble polymer and additives than the main drug, The present inventors have found that a small-sized tablet that can be easily taken and that has a good sustained-release ability can be obtained.

That is, the present invention is as follows.
(1) A small sustained-release tablet formed by compression molding a composition containing ambroxol hydrochloride, a water-insoluble polymer and an additive.
(2) The small sustained-release tablet according to (1), wherein the water-insoluble polymer is ethyl cellulose.
(3) The small sustained-release tablet according to (1) or (2), wherein the average particle diameter of ethyl cellulose is 5 μm at the lower limit and 15 μm at the upper limit.
(4) The small sustained-release tablet according to any one of (1) to (3), wherein the ratio of the water-insoluble polymer to ambroxol hydrochloride is 30% lower limit and 80% upper limit.
(5) The small sustained-release tablet according to any one of (1) to (4), wherein the preparation has a major axis of 9 mm or less.
(6) The small sustained-release tablet according to any one of (1) to (5), which is a coated tablet.
(7) The small sustained-release tablet according to any one of (1) to (6), which is a water-soluble film-coated tablet.
In this specification, the average particle diameter means the median diameter on a volume basis when measured by a laser diffraction particle size distribution measuring method.

The ambroxol small sustained-release tablet of the present invention is a small sustained-release preparation that is easy to take even for elderly people and infants with low swallowing ability by a simple manufacturing method. Therefore, it is easy to take even in patients with low swallowing ability, such as elderly people and children, or general adults, and improvement in medication compliance can be expected for many patients.

The ambroxol hydrochloride in the present invention means crystalline ambroxol hydrochloride usually obtained commercially. The water-insoluble polymer used in the present invention has a property that it does not dissolve in water or hardly dissolves in water. Specific examples include cellulose ethers such as ethyl cellulose and ethyl methyl cellulose, and (meth) acrylic acid polymers such as aminoalkyl methacrylate copolymer RS. Particularly, ethyl cellulose is preferable, and more preferably, the amount of ethyl cellulose added is small. In addition, fine powder type ethylcellulose with an average particle size of 5 to 15 μm can be mentioned because of its good sustained release ability. In addition, since it is difficult to obtain small-sized tablets if the amount of water-insoluble polymer used is too large, it should be 80% or less of ambroxol hydrochloride. In addition, if the amount of water-insoluble polymer used is too small, in vitro sustained release is possible, but the strength of the tablet is insufficient in vivo and the risk of loss of sustained release increases. Should contain at least 30% of ambroxol hydrochloride. The major axis of the tablet should be 9 mm or less in consideration of ease of administration. Preferably, patients currently taking ordinary tablets do not feel difficult to drink when switching to sustained-release tablets. It should be 7 mm or less, which is smaller than the commercially available ambroxol hydrochloride tablets. Also, tablets can be coated with water-soluble film, swellable film, gel-forming film, etc. to make it easier to take. In this case, the diameter of the tablet is increased by about 0.01 to 0.2 mm depending on the coating substrate used for the film. As shown in Examples 1 and 2, an uncoated tablet with a diameter of 6 mm containing 45 mg of ambroxol hydrochloride was used. Even if it is coated with a film, a small tablet of 7mm or less can be obtained.

The type of additive used in the present invention is not particularly limited as long as it can be used as a pharmaceutical additive. For example, sugars such as lactose usually used as excipients for tablets, celluloses such as crystalline cellulose, inorganic salts such as calcium phosphate, starches such as corn starch, hydroxypropylcellulose, hydroxypropylcellulose used as binders Water-soluble celluloses such as methylcellulose, water-soluble polymers such as polyvinyl alcohol and polyvinylpyrrolidone, metal stearates such as calcium stearate used as lubricants or fluidizing agents, silicic acids such as light anhydrous silicic acid, and Its salts are listed. Examples of the coating base include cellulose ethers such as hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose. In addition, the film composition can contain titanium oxide, pigments, etc. as a light-shielding agent, and can contain excipients such as talc usually prescribed for films and plasticizers such as propylene glycol and polyethylene glycol.
In the present invention, the sustained-release agent is a pharmaceutical additive added to control the dissolution of an active ingredient from a pharmaceutical preparation in vivo. Cellulose ethers such as ethyl cellulose and ethyl methyl cellulose, aminoalkyl methacrylate copolymer RS It shows water-insoluble polymers such as (meth) acrylic acid polymers.

Examples of the tablet of the present invention include uncoated tablets, coated tablets, and dry-coated tablets. Of these, uncoated tablets can be manufactured using conventional manufacturing methods. That is, the drug is mixed with the water-insoluble polymer and, if necessary, excipients, lubricants, fluidizing agents, etc., and then mixed by direct compression, or the mixture is prepared by dry or wet granulation. Can be manufactured by tableting after adding a lubricant. There are no restrictions on wet granulation methods, including fluidized bed granulation, high-speed agitation granulation, extrusion granulation, and kneading granulation. The production method of the present invention does not require the use of an organic solvent. Coated tablets can be obtained by coating uncoated tablets with a water-soluble film. It is also possible to make a dry tablet by forming a layer with the uncoated tablet as the core.

The tablet thus obtained is a small sustained-release tablet in which a water-insoluble polymer is uniformly dispersed in the tablet, and gradually releases ambroxol hydrochloride without disintegration in the dissolution test solution. In addition, there is little variation in dissolution behavior from tablet to tablet, and it has excellent properties such that it is not easily affected by stirring strength or surfactant. Based on the above, the tablet of the present invention is small, easy to swallow, and has excellent sustained release, so that it is a tablet that is pharmacologically effective when taken once a day and is not easily affected by meals. Is a very good tablet.

Examples of the present invention are shown below, but the present invention is not limited to these examples. The particle size of ethyl cellulose used in the examples was measured with a laser diffraction scattering particle size distribution analyzer (HELOS & RODOS, Nippon Laser).

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.

Example 1
Ambroxol hydrochloride 225g, Ethylcellulose (Etocel Standard 7FP / Dow Chemical) 175g, Lactose 150g (Pharmatose 150M / DMV), Light anhydrous silicic acid 5g (Aerosil 200 / Aerosil), Calcium stearate 7g (Stear) (Calcium Phosphate / Nitto Kasei Kogyo Co., Ltd.) is taken in a container and each component is mixed uniformly, then granulated while adding water with a Shinagawa universal stirring mixer, and the resulting granulated product is shelf-type at 60 ° C for 12 hours. Dried. Next, the dried granulated product is sized with 20 mesh, and calcium stearate is mixed with the obtained granule, and then tableted with a rotary tableting machine. The diameter is 6 mm and contains 45 mg of ambroxol hydrochloride. 113 mg tablets were obtained.

Example 2
Ambroxol hydrochloride 11.25 kg, Ethylcellulose (Ethoseru Standard 7FP / Dow Chemical) 4.5 kg, lactose 11.75 kg (Pharmatose 150M / DMV), light anhydrous silicic acid 250 g (Aerosil 200 / Nippon Aerosil), calcium stearate 375g (Calcium stearate / Nitto Kasei Kogyo) was charged into a Shinagawa universal stirring mixer, and after mixing each component uniformly, granulated while adding water, and the resulting granulated product was placed on a shelf for 12 hours at 60 ° C. Formula dry. Next, the dried granulated product is sized with 20 mesh, and calcium stearate is mixed with the obtained granule, and then tableted with a rotary tableting machine. The diameter is 6 mm and contains 45 mg of ambroxol hydrochloride. 113 mg tablets were obtained.

Example 3
Dissolve and disperse 2.4 kg of hydroxypropylmethylcellulose (TC-5R / Shin-Etsu Chemical) and 0.48 kg of titanium oxide (AH-R / Freund Industries) in 37.6 kg of water in the coating equipment (High Coater 80 / Freund Industries) Then, the tablets of Example 2 were sprayed onto 24 kg to obtain white film-coated tablets.

Comparative Example 1
225 g of ambroxol hydrochloride, 325 g of lactose (Pharmatose 150M / DMV), 5 g of light anhydrous silicic acid (Aerosil 200 / Nippon Aerosil), 7 g of calcium stearate (Calcium stearate / Nitto Kasei Kogyo) were mixed in a container. After that, granulation was performed while adding water with a Shinagawa universal stirring mixer, and the resulting granulated product was shelf-dried at 60 ° C for 12 hours. Next, the dried granulated product is sized with 20 mesh, and calcium stearate is mixed with the obtained granule, and then tableted with a rotary tableting machine. The diameter is 6 mm and contains 45 mg of ambroxol hydrochloride. 113 mg tablets were obtained.

Comparative Example 2
Ambroxol hydrochloride 225g, average cellulose 305μm ethylcellulose (Etocel Standard 10 / Dow Chemical) 90g, lactose 235g (Pharmatose 150M / DMV), light anhydrous silicic acid 5g (Aerosil 200 / Nippon Aerosil), calcium stearate 7g (Stear (Calcium Phosphate / Nitto Kasei Kogyo Co., Ltd.) is taken in a container and each component is mixed uniformly, then granulated while adding water with a Shinagawa universal stirring mixer, and the resulting granulated product is shelf-type at 60 ° C for 12 hours. Dried. Next, the dried granulated product is sized with 20 mesh, and calcium stearate is mixed with the obtained granule, and then tableted with a rotary tableting machine. The diameter is 6 mm and contains 45 mg of ambroxol hydrochloride. 113 mg tablets were obtained.

Comparative Example 3
Ambroxol hydrochloride 225g, Ethylcellulose (Ethoseru Standard 100FP / Dow Chemical) 90g with an average particle size of 33μm, Lactose 235g (Pharmatose 150M / DMV), Light anhydrous silicic acid 5g (Aerosil 200 / Nippon Aerosil), Calcium stearate 7g (Stear) (Calcium Phosphate / Nitto Kasei Kogyo Co., Ltd.) is taken in a container and each component is mixed uniformly, then granulated while adding water with a Shinagawa universal stirring mixer, and the resulting granulated product is shelf-type at 60 ° C for 12 hours. Dried. Next, the dried granulated product is sized with 20 mesh, and calcium stearate is mixed with the obtained granule, and then tableted with a rotary tableting machine. The diameter is 6 mm and contains 45 mg of ambroxol hydrochloride. 113 mg tablets were obtained.

Test example 1
For tablets of Examples 1 to 3 and Comparative Example, according to the 14th revised Japanese Pharmacopoeia (hereinafter referred to as JP) dissolution test method 2 method, various conditions (paddle rotation speed) using 900 mL of JP 2 disintegration test method 2nd liquid , And whether or not a surfactant was added). The test results are shown in Tables 1 and 2.

table 1

Table 2

As shown in Test Example 1, the tablets prepared in Example 1 or Example 2 gradually released ambroxol hydrochloride without disintegration during the test, whereas the tablet of Comparative Example 1 was tested during the test. Collapsed and did not show sustained release effect. This indicates that the addition of ethylcellulose is essential in the present invention. The results regarding the tablets of Example 1 and Example 2 indicate that the dissolution rate can be controlled by changing the ethylcellulose content in the tablet. The results for the tablet of Example 3 show that there is no change in dissolution even when film coating is applied to the sustained release tablet. Comparative Example 2 is a tablet using ethyl cellulose having a large particle size, but the dissolution is faster than that of Example 2 having the same composition, indicating that the particle size of ethyl cellulose affects the dissolution property, and the particle size is small. This is advantageous for sustained release. Since the tablet of Example 2 is not affected by the paddle rotation speed and the surfactant, it can be seen that it is a sustained-release preparation that is resistant to mechanical stress and resistant to meals. On the other hand, Comparative Example 3 is a preparation using ethyl cellulose having a relatively small particle size, and shows a dissolution property equivalent to that of Example 2 when the mechanical stress during the test is small. When it is larger, the dissolution is significantly faster than that of the preparation of Example 2. This indicates that the particle size of ethyl cellulose has a great effect on the strength of the preparation when mechanical stress is large.

Test example 2
In order to investigate the bioavailability and sustained release effect of the tablet of Example 2, a commercially available ambroxol hydrochloride sustained release preparation (capsule) was used as a control, and healthy adult male subjects were subjected to a pharmacokinetic test by the crossover method. (N = 6). Figure 1 shows the test results under the feeding conditions. The sustained-release preparation of the present invention and the commercially available sustained-release capsules showed almost the same changes in plasma drug concentration, confirming that moderately-released drugs were exhibited in vivo.

Changes in plasma drug concentration

Claims (7)

Compact sustained-release tablet formed by compression molding a composition containing ambroxol hydrochloride, a water-insoluble polymer and an additive The small sustained-release tablet according to claim 1, wherein the water-insoluble polymer is ethyl cellulose. The small sustained-release tablet according to any one of claims 1 and 2, wherein an average particle diameter of ethyl cellulose is 5 µm in a lower limit and 15 µm in an upper limit. The small sustained-release tablet according to any one of claims 1 to 3, wherein the ratio of the water-insoluble polymer to ambroxol hydrochloride is a lower limit of 30% and an upper limit of 80%. The small sustained-release tablet according to any one of claims 1 to 4, wherein the major axis of the preparation is 9 mm or less. The small sustained-release tablet according to any one of claims 1 to 5, wherein the tablet is a coated tablet. The small sustained-release tablet according to any one of claims 1 to 6, wherein the tablet is a water-soluble film-coated tablet.

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