JP5563835B2 - Method for producing aspirin tablets - Google Patents

Description

  The present invention relates to a method for producing aspirin tablets by compression molding without the use of a lubricant.

Aspirin is a drug that has been widely used as an antipyretic analgesic. In recent years, it has also attracted attention as an antiplatelet agent, and it suppresses thrombus and embolization to prevent angina pectoris, myocardial infarction, and ischemic cerebrovascular disorder. It is a drug that is expanding its use as a medicine.

On the other hand, aspirin is a drug that is difficult to formulate because it has properties such as being easily hydrolyzed and easily changing its formulation with additives. According to the Japanese Pharmacopoeia, it is described that aspirin is deacetylated due to moisture absorption, and acetic acid generated at this time further promotes changes, and aspirin is a drug that is easy to change, and changes when combined with aspirin. The following examples are shown as compounds that cause a) Wet within one week: sodium caffeine benzoate, sodium theobromine salicylate, sodium bicarbonate, hexamine, b) Discolor within one week: digitalis preparation, iodide, c) 1 depending on quality and storage conditions Wet within a week: ethyl aminobenzoate, aminopyrine, antipyrine, sulpyrine, d) Discoloration within one week depending on quality and storage conditions: Iron sulfate, e) Other drugs that cause changes in formulation: Phenobarbital sodium, iodine Potassium chloride, acid, hydroxide, carbonate, stearate.

In this way, aspirin is easily hydrolyzed and has the property of causing compounding changes with many drugs and formulation additives. Therefore, it is formulated by a dry method using limited tablet additives. Although the method has become common, in the case of compression tableting using a normal mortar, it is technically necessary to produce an uncoated tablet that is chemically stable and has good appearance without sticking to the mortar. It is very difficult.

In the case of an aspirin tablet, a lubricant (release agent) is particularly problematic. In the medical tablets that are commercially available, most drugs are manufactured as a lubricant by blending highly lubricated magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, etc. These lubricants cannot be blended because there are blending changes with aspirin. Therefore, it is conceivable to use substitutes such as talc instead of these, but substitutes such as talc, hydrogenated oil, and sucrose fatty acid ester cannot satisfactorily prevent adhesion to the mortar during compression molding. .

  JP-A-2009-89982 (Patent Document 1) discloses tableting without adding a lubricant by coating a granulated product of a drug that is likely to stick to a mortar during tableting with a polymer film agent. A method for producing a granulated product that can be easily tableted without hindrance is described. Polyvinyl alcohol is used as a polymer film agent, but aspirin is not used as a drug. In many embodiments, a mixed powder of a drug such as ibuprofen and light anhydrous silicic acid is granulated, and the surface of the granulated material is a solution obtained by suspending corn starch in a solution obtained by dissolving polyvinyl alcohol or the like in water. The granulated product obtained by spraying and coating is dried and sieved to obtain a tablet by compression molding without adding a lubricant. Although there is no description suggesting that this method can be applied to aspirin, this method is a wet granulation method in which an aqueous solution of a polymer film is sprayed and coated while granulating a mixed powder of a drug and light anhydrous silicic acid. On the other hand, since light anhydrous silicic acid has the property of promoting hydrolysis of aspirin, and aspirin itself has the property of being easily hydrolyzed, it is not possible to divert this method to aspirin. Can not.

JP 2009-89982 A

  Therefore, the subject of this invention is providing the manufacturing method of the aspirin tablet which can be shape | molded by compression molding without using a lubricant.

The present invention
a) spraying aspirin with a polyvinyl alcohol aqueous solution to granulate and drying; and b) adding a formed component mainly comprising starch and optionally containing other excipients to the resulting granulated product, Provided is a method for producing an aspirin tablet comprising a step of compression molding without adding a lubricant.

  Aspirin tablets can account for 60% or more of the total weight.

  According to a preferred embodiment, the amount of polyvinyl alcohol sprayed as an aqueous solution in step b) is 0.5-3% by weight of aspirin, and the step of granulating aspirin by spraying polyvinyl alcohol is a fluidized bed construction. This is done using a grain coating machine.

  Aside from the fact that the drug is aspirin, the method of the present invention differs from the prior art disclosed in Patent Document 1 in that the granulated product is not a mixture of drug and light anhydrous silicic acid. Light silica is a porous silica gel powder whose apparent specific gravity is extremely small as its name suggests.It absorbs and retains a large amount of water and is incompatible with aspirin, so it is extremely hydrolyzed. Should not be incorporated into easy aspirin. However, in the case of granulating by spraying an aqueous solution of polyvinyl alcohol on aspirin alone, hydrolysis does not occur substantially because the contact time with water is short.

  Whether it is a direct tableting method in which a mixture of drugs and excipients is compression-molded in a powder state, or a method in which the mixture is once granulated and then compression-molded, compression molding into tablets is usually smooth. The use of an agent is necessary. Without the use of a lubricant, the release of compressed tablets is poor, and part of the tablet surface is chipped off and adheres to the tableting pestle and die, preventing smooth tableting and the surface. A defective tablet with defects is generated. In addition, there is a problem that the tablet-forming mixture is stuck firmly on the surface of the turntable of the rotary tableting machine and cannot be tableted.

  In the case of aspirin, as mentioned above, there are a large number of contraindicated ingredients, and magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, etc., which are commonly used as lubricants, impair the chemical stability of aspirin. I can not use it. According to the knowledge of the present inventor, talc, which is considered not to affect the chemical stability of aspirin, is used as a lubricant, a mixture with corn starch as an excipient is compression-molded by a dry method, and 100 mg of aspirin is added. When an attempt was made to produce a tablet of 130 mg containing it, the powder that had fallen off from the tablet adhered firmly to the surface of the punch and mortar of the tableting machine, and it was not possible to obtain a tablet with no defects on the surface. Similarly, the same test was carried out using sucrose fatty acid ester and hydrogenated oil, which are considered as other lubricants, as lubricants, but no favorable results were obtained.

  Since the method of the present invention uses an aqueous solution of polyvinyl alcohol, a kind of wet granulation method is used. However, the aqueous polyvinyl alcohol solution is not used as a binding liquid for granulating a mixture of an agent such as a drug and an excipient, but rather is used to coat the surface of aspirin particles with polyvinyl alcohol. As a result of coating with polyvinyl alcohol, it was found that the surface of the aspirin particles was modified, and a granulated product having no adhesion to the pestle or mortar was obtained without using a lubricant. In addition, by adding an excipient mainly composed of starch to the granulated product at the time of compression molding, the release property of the tablet formed by compression molding of the starch having a slight lubricating action and the tableting machine This is thought to enhance the prevention of the tableting mixture from adhering to the turntable.

  In the pharmaceutical preparation technical field, water-soluble cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hypromellose and CMC, water-soluble synthetic polymers such as polyvinyl alcohol and povidone, and the like are used as binders. Of these, only polyvinyl alcohol was found to form a coating film rich in lubricity.

  As described above, when a granulated aspirin coated with polyvinyl alcohol is compressed into a tablet, the release property of the tablet is further enhanced by adding an excipient based on starch. . Examples of the starch used here include corn starch, potato starch, and modified starch. Starch is mainly used, and sugars such as lactose, glucose, mannitol, sorbitol, and powdered cellulose, sugar alcohols, and polysaccharides other than starch may be used in combination.

  Tablets produced in accordance with the present invention typically contain 60% or more of the total weight of the tablet, preferably 70% or more, most preferably 80% or more of aspirin. The remainder is occupied by polyvinyl alcohol and adjuvants such as excipients. Of these, polyvinyl alcohol is sufficient up to 0.5-3%, preferably up to 2%, based on the weight of aspirin. Excessive coating adversely affects disintegration.

  In addition to the above components, the addition of a trace amount of conventional additives is optional.

Even when the surface is modified with polyvinyl alcohol, when compression molding is performed with a lubricant such as talc, there is no adhesion of the tablet to the surface at the beginning of the work, As time passed, sticking matter gradually adhered to the surface of the heel, and it was not possible to obtain a tablet with a good surface and good release properties from the mortar over a long period of time. This is due to the direct contact between the aspirin and the lubricant due to pressure compression over time, and the lubricant denatures the aspirin due to the heat generated during pressure compression and generates a small amount of decomposition products. This is considered to be due to the phenomenon that the trace component starts to adhere to the soot due to this phenomenon, and the amount of this deposit gradually increases with the passage of time, and finally the adherent matter adheres to the well.

Although the method for producing the tablet is a wet method, it is important that the surface of aspirin is covered with polyvinyl alcohol so that the surface properties of the aspirin are concealed. It is essential to spray and apply a solution in which water is dissolved in water to make the polyvinyl alcohol adhere to the surface of the aspirin. By adopting this method, the surface of aspirin is coated with polyvinyl alcohol and modified to a smooth surface, and good results are obtained.

In this coating type spray granulation, any apparatus capable of spray coating can be used. However, an apparatus having excellent drying efficiency and good working efficiency is preferable, and from this viewpoint, a fluidized bed granulation coating apparatus is the best.

In kneading granulation methods such as kneading granulation, kneading granulation, and stirring granulation, aspirin dissolves in the polyvinyl alcohol solution during the kneading operation, and as a result, the surface of the granulated granule is polyvinyl alcohol. Since aspirin is exposed in a mixed manner, surface modification of aspirin is not achieved and the intended effect is reduced.

The invention is illustrated by the following non-limiting examples.

[Example 1]
96 g of polyvinyl alcohol was dissolved in 2304 g of water. 8kg of aspirin is taken into a fluidized bed granulator (Freund Sangyo, FLO-15), and this solution is used for coating granulation by the top spray method (amount of spray liquid: 50 mL / min, spray air pressure) : 0.25 MPa, supply air temperature: 60 ° C., exhaust temperature: 28.5-36.2 ° C.), and aspirin particles were obtained. The particles were mixed with 784 g of powdered cellulose and 960 g of anhydrous corn starch, and compressed into a tablet weight of 123 mg using a 12-piece rotary tablet press using a 7.0 mm diameter and 7.5 R pestle to produce a tablet. However, no adhesion of the tablets to the wrinkles was observed, and tablets with good appearance (tablet hardness: 60 N) were obtained. Moreover, the salicylic acid content of the tablet stored in a glass bottle, sealed and stored at 60 ° C. for 1 week is about 0.2 mg / Tab (initial value: about 0.1 mg / Tab), which is a stable tablet. I understood it.

[Example 2]
100 g of polyvinyl alcohol was dissolved in 2400 g of water. 14.3 kg of aspirin was taken and charged into a fluidized bed granulator (Freund Sangyo, FLO-15), and this solution was used for coating granulation by the top spray method (amount of spray liquid: 120 mL / min, Spraying air pressure: 0.25 MPa, supply air temperature: 60 ° C., exhaust temperature: 21.3-29.4 ° C.), aspirin particles were obtained. This particle is mixed with 1.22 kg of powdered cellulose and 1.64 kg of anhydrous corn starch, and compressed with a 12-piece rotary tableting machine to 120.7 mg using a 12 mm diameter rotary tableting machine. As a result, tablets were not observed to adhere to the wrinkles, and tablets with good appearance (tablet hardness: 65.8 N) were obtained. Moreover, the salicylic acid content of the tablet stored in a glass bottle, sealed and stored at 60 ° C. for 1 week is about 0.2 mg / Tab (initial value: about 0.1 mg / Tab), which is a stable tablet. I understood it.

[Comparative Example 1]
120 g of polyvinyl alcohol was dissolved in 2880 g of water. 12 kg of aspirin and 960 g of anhydrous corn starch are taken into a fluidized bed granulator (Freund Sangyo Co., Ltd., FLO-15), and this solution is used for coating granulation by the top spray method (amount of spray liquid: 100 mL / min, spraying air pressure: 0.25 MPa, supply air temperature: 60 ° C., exhaust temperature: 23.7-32.2 ° C.), aspirin particles were obtained. When 960 g of anhydrous corn starch and 960 g of talc are mixed with these particles, a tablet having a diameter of 7.0 mm and 7.5 R is pressed and compressed into a tablet weight of 125 mg using a 12-piece rotary tablet press. Gradually, the tablet was attached to the wrinkles, and dents were observed on the surface of the tablet, and it was impossible to obtain a tablet with a good appearance until the end. The tablet hardness was 60.6 N, and there was no problem in tablet strength.

Claims (4)

a) Step of spraying and granulating an aspirin with an aqueous solution containing 0.5 to 3% by weight of polyvinyl alcohol of aspirin as a solid content and drying, and b) The resulting granulated product mainly comprising starch. A method for producing an aspirin tablet comprising a step of adding a forming component containing any other excipient and compression molding without adding a lubricant.   The method of claim 1, wherein aspirin accounts for 60% or more of the total tablet weight. The method according to claim 1 or 2, wherein the amount of polyvinyl alcohol sprayed as an aqueous solution in step a) is 2% by weight or less of aspirin.   The method according to any one of claims 1 to 3, wherein an aqueous polyvinyl alcohol solution is sprayed onto aspirin using a fluidized bed granulation coating apparatus in step a).