JP6481453B2 - Oral solid preparation - Google Patents

Description

  The present invention relates to an oral solid preparation, and more particularly to an oral solid preparation with improved temporal stability.

  Statins are drugs that lower the cholesterol level in blood by inhibiting the action of HMG-CoA reductase. For example, pitavastatin is an agent for hyperlipidemia that has an action of inhibiting HMG-CoA reductase. It is known (Non-Patent Document 1). In addition, there are many commercial products for other drugs belonging to statins (for example, rosuvastatin and atorvastatin). These products are provided as oral solid preparations, for example.

  However, since such statins lack stability over time, conventional oral solid preparations containing such statins generate related substances during the storage period when stored for a long period of time, and the quality of the oral solid preparation itself Is known to deteriorate.

  For this reason, development of an oral solid preparation of statins that can be stored for a long time and has excellent production efficiency is desired.

“Rivalo (registered trademark) lock” package insert

  An object of the present invention is to provide an oral solid preparation containing statins having improved stability over time, which can be stored for a long period of time. is there.

  The present invention is an oral solid preparation containing statins and aminoalkyl methacrylate copolymer E.

  In one embodiment, the oral solid dosage form of the invention has a direct tablet dosage form.

  In one embodiment, the aminoalkyl methacrylate copolymer E is contained in a proportion of 80 to 400 parts by weight with respect to 100 parts by weight of the statin.

  In one embodiment, the statin is at least one drug selected from the group consisting of rosuvastatin, pitavastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin and mevastatin, and salts thereof.

  In one embodiment, the statin is rosuvastatin.

  According to the present invention, since the generation of related substances is suppressed, the quality of the oral solid preparation itself can be maintained over a long period of time. Moreover, such an oral solid preparation can be manufactured through a relatively simple process. This makes it possible to achieve both long-term storage and mass production.

  Hereinafter, the present invention will be described in detail.

  The oral solid preparation of the present invention contains statins and aminoalkyl methacrylate copolymer E.

  As used herein, the term “oral solid formulation” encompasses a solid formulation that is administered through the oral cavity without water or with a small amount of water. Examples of oral solid preparations include tablets that are solid preparations molded into a certain shape by a method such as compression molding, and orally disintegrating tablets that are tablets prepared so as to disintegrate in the oral cavity. Can be mentioned.

  When the oral solid preparation of the present invention is an orally disintegrating tablet, the shape of the orally disintegrating tablet is not particularly limited, and examples thereof include a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an oval shape, and a cap shape. A let shape is mentioned. The size is preferably small, the diameter is, for example, about 5 mm to 12 mm, and the thickness is, for example, about 2 mm to 5 mm. The mass is, for example, about 50 mg to 500 mg. Although hardness is not specifically limited, For example, it is about 40N-100N. The time required for the disintegration is not particularly limited, and for example, when taken without water, a time set to disintegrate in the oral cavity in about 10 to 60 seconds is preferable.

  It is preferable that the oral solid preparation of the present invention also has a directly compressed tablet dosage form compressed by a direct compression method as described later.

  Examples of statins in the present invention include statins such as rosuvastatin, pitavastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, pravastatin, lovastatin, mevastatin, and salts thereof, and combinations thereof. A salt of a statin is a pharmaceutically acceptable salt. The pharmaceutically acceptable salt of statin is not particularly limited, and examples thereof include sodium salt, potassium salt, calcium salt, and lower alkylamine salt. In the present invention, rosuvastatin is preferably used. In the oral solid preparation of the present invention, the content of the statin is not necessarily limited, but is preferably 0.1 wt% to 10 wt%, more preferably 0.5 wt% to 5 wt%, based on the weight of the oral solid preparation. % By weight.

  The aminoalkyl methacrylate copolymer E constituting the present invention is a cationic copolymer based on, for example, dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. Furthermore, the aminoalkyl methacrylate copolymer E is, for example, the following formula (I):

And a copolymer having a weight average molecular weight of preferably about 150,000.

  In the present invention, the aminoalkyl methacrylate copolymer E can be obtained, for example, as an aqueous dispersion. Examples of the aqueous dispersion of the aminoalkyl methacrylate copolymer E include Eudragit (registered trademark) E 100, Eudragit (registered trademark) E PO, and Eudragit (registered trademark) E 12.5 manufactured by EVONIK INDUSTRIES.

  The content of the aminoalkyl methacrylate copolymer E in the oral solid preparation of the present invention is not necessarily limited, but is preferably 80 parts by weight to 400 parts by weight, more preferably 100 parts by weight to 100 parts by weight of the statin. The ratio is 250 parts by weight. When the content of the aminoalkyl methacrylate copolymer E is less than 80 parts by weight, the stability over time to the extent that the obtained oral solid preparation can be satisfied may not be obtained. When the content of the aminoalkyl methacrylate copolymer E exceeds 400 parts by weight, there is a possibility that poor tableting during production and poor elution of statins during use may occur.

  The oral solid preparation of the present invention may contain any additive in a content that does not impair the medicinal effects of the statins contained therein. Examples of such additives include excipients, disintegrants, stabilizers, fluidizers, binders, colorants, flavoring agents, lubricants, and perfumes, and combinations thereof.

  The excipient is not particularly limited, and examples thereof include celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose) and the like) and derivatives thereof, starch (corn starch (corn starch), potato starch). , Wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc. and derivatives thereof, sugar (glucose, lactose, sucrose (including purified sucrose), powdered sugar, trehalose, dextran, dextrin, etc.), sugar alcohol (D- Mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminate metasilicate, synthetic hydrotalcite), light anhydrous silicic acid, anhydrous phosphorus Calcium, precipitated calcium carbonate, calcium silicate, calcium hydrogen hydrate phosphoric acid, inorganic salts such as sodium hydrogen carbonate, and combinations thereof. Examples of preferred excipients include D-mannitol, lactose, crystalline cellulose, and starch, and combinations thereof.

  The disintegrant is not particularly limited, and for example, crospovidone, crystalline cellulose, carboxymethylcellulose (carmellose), croscarmellose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, starch, partially pregelatinized starch, sodium starch glycolate , Hydroxypropyl starch, calcium carbonate, precipitated calcium carbonate, calcium citrate, light anhydrous silicic acid, synthetic aluminum silicate, and combinations thereof. Examples of preferred disintegrants include croscarmellose sodium, sodium starch glycolate, and crospovidone, and combinations thereof.

  The stabilizer is not particularly limited. For example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate, magnesium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, sodium dihydrogen phosphate , Magnesium oxide, magnesium hydroxide, L-arginine, L-lysine, meglumine, magnesium aluminate metasilicate, and combinations thereof. An example of a preferred stabilizer is magnesium carbonate.

  The fluidizing agent is not particularly limited, and examples thereof include hydrous silicon dioxide, light anhydrous silicic acid, talc, synthetic aluminum silicate, titanium oxide, stearic acid, magnesium stearate, calcium stearate, magnesium aluminate metasilicate, and the like. The combination of these is mentioned. Examples of preferred fluidizing agents include talc, hydrous silicon dioxide, and light silicic anhydride, and combinations thereof.

  The binder is not particularly limited. Partially pregelatinized starch, as well as combinations thereof. Examples of preferred binders include hydroxypropylcellulose, hypromellose, and polyvinylpyrrolidone, and combinations thereof.

  The colorant is not particularly limited, and examples thereof include titanium oxide, iron sesquioxide, yellow iron sesquioxide, food red No. 2, food red No. 3, food yellow No. 4, and food yellow No. 5, and combinations thereof. Can be mentioned.

  The corrigent is not particularly limited, and examples thereof include aspartame, stevia, sugar alcohol, saccharin sodium, dipotassium glycyrrhizin, thaumatin, acesulfame potassium, and sucralose, and combinations thereof. Preferred flavoring agents are aspartame, thaumatin, and acesulfame potassium, and combinations thereof.

  The lubricant is not particularly limited. For example, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester, and talc. And combinations thereof. Preferred lubricants are sodium stearyl fumarate, magnesium stearate, calcium stearate, and sucrose fatty acid esters, and combinations thereof.

  The fragrance is not particularly limited, and examples thereof include mint, lemon fragrance, orange corton, pineapple flavor, and l-menthol.

  The oral solid preparation of the present invention may also have a form in which the above-mentioned content components (that is, statins and aminoalkyl methacrylate copolymer E, and additives that can be added as necessary) are coated with a coating agent. . Examples of such coating agents are not particularly limited. For example, polyethylene glycol (PEG) such as sugar, sugar alcohol, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hypromellose, triethyl citrate, triacetin, macrogol, and polysorbates. , Talc, yellow ferric oxide and titanium oxide, and combinations thereof. Furthermore, the sugar is not particularly limited, and examples thereof include glucose, fructose, lactose, sucrose, reduced maltose, trehalose, and combinations thereof. The sugar alcohol is not particularly limited, and examples thereof include mannitol, erythritol, sorbitol, xylitol, maltitol, and lactitol, and combinations thereof. The content of the coating agent in the present invention is not particularly limited and can be appropriately selected by those skilled in the art.

  When the oral solid preparation of this invention has the form coated with the said coating agent, it is preferable that the coating layer has covered the whole surface of the particle | grains which comprise the said content component. Moreover, it is preferable that the thickness of a coating layer is substantially equal over the whole surface of the oral solid formulation of this invention. The thickness of the coating layer that can constitute the present invention is not particularly limited, and an appropriate thickness can be set by those skilled in the art.

  The oral solid preparation of the present invention can be produced, for example, as follows.

  Hereinafter, a method for producing a direct compression tablet as the oral solid preparation of the present invention will be described.

  First, the statins and aminoalkyl methacrylate copolymer E and, if necessary, the above additives are mixed until substantially uniform. The mixing method is not particularly limited.

Next, the obtained mixture is tableted by a hydraulic hand press, a single-punch tableting machine, a rotary tableting machine or the like using, for example, a tabletting mortar, a tableting upper punch and a lower punch. . Tableting is preferably performed by adjusting so that the resulting tablet has an appropriate hardness. The tableting pressure can be appropriately adjusted according to the tableting method, the equipment used for tableting, the size of the tablet, and the like. Tableting pressure is preferably ^{20kg / cm 2 ~2000kg / cm 2} , more preferably ^{100kg / cm 2 ~1000kg / cm 2} .

  In this way, the oral solid preparation of the present invention can be produced as a direct compression tablet.

  The obtained oral solid preparation is sealed in a container using a means known in the art. After enclosing in a container, the oral solid preparation of the present invention is stored under appropriate storage conditions until use.

  According to the oral solid preparation of the present invention, the stability over time is excellent, and the generation of related substances due to decomposition during storage can be suppressed. For this reason, even if a part of the product obtained through mass production is stored in stock, the quality can be maintained for a long time.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited by these Examples.

Example 1
Rosuvastatin calcium 5.35 kg, lactose hydrate 100.15 kg, crystalline cellulose 30 kg, crospopidone 3 kg, aminoalkyl methacrylate copolymer E (Eudragit (registered trademark) E 100 manufactured by EVONIK INDUSTRIES) 10 kg, and magnesium stearate 1.5 kg Was mixed in a blender (Tokuju Kogyo Co., Ltd .: TCV-30) and mixed well to obtain a mixture for tableting. The obtained mixture was put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VGRGO) for tableting, and an uncoated tablet having a tablet diameter of 7 mm, a weight of 150 mg, and a hardness of 40 N or more was obtained.

  This uncoated tablet is fully aerated with 2.46 mg hypromellose, 15 mg Macrogol 6000 (manufactured by Sanyo Chemical Industries), 0.3 mg titanium oxide and 0.09 mg yellow ferric oxide per tablet. Film coating was carried out using an inclining drum coating apparatus (Pauleck Coater (PRC-75) manufactured by Paulec Co., Ltd.) to obtain rosuvastatin tablets.

(Comparative Example 1)
A rosuvastatin tablet was obtained in the same manner as in Example 1 except that 10 kg of meglumine was used instead of aminoalkyl methacrylate copolymer E.

(Comparative Example 2)
A rosuvastatin tablet was obtained in the same manner as in Example 1 except that 10 kg of synthetic hydrosartite was used in place of the aminoalkyl methacrylate copolymer E.

(Test Example 1: Measurement of increase in related substances)
With respect to the rosuvastatin tablets obtained in Example 1, Comparative Example 1 and Comparative Example 2, the rate of increase of related substances derived from rosuvastatin under the following conditions was measured.

(Condition 1-1)
About each rosuvastatin tablet obtained in Example 1, Comparative Example 1 and Comparative Example 2, a keto body and a lactone body derived from rosuvastatin contained in the tablet immediately after production, and all related substances (total related substances) The content was calculated as a ratio (%) of the peak area of each related substance to the peak area of rosuvastatin from the detection result of liquid chromatography of each tablet. The obtained results are shown in Table 1.

(Condition 1-2)
Each rosuvastatin tablet obtained in Example 1, Comparative Example 1 and Comparative Example 2 was individually wrapped with aluminum foil and completely shielded from light, and the resulting package was stored at 60 ° C. for 1 week. did. Immediately after the storage, the contents of keto and lactone derived from rosuvastatin and all related substances (total related substances) contained in the tablets were measured in the same manner as in Condition 1 above. The obtained results are shown in Table 1.

(Condition 1-3)
About each rosuvastatin tablet obtained in Example 1, Comparative Example 1 and Comparative Example 2, each was individually wrapped with aluminum foil and completely shielded from light, and the resulting package was kept at a temperature of 40 ° C. for one month. Stored. Immediately after the storage, the contents of keto and lactone derived from rosuvastatin and all related substances (total related substances) contained in the tablets were measured in the same manner as in Condition 1 above. The obtained results are shown in Table 1.

(Condition 1-4)
Each of the rosuvastatin tablets obtained in Example 1, Comparative Example 1 and Comparative Example 2 was irradiated with white light from a D65 lamp continuously for 1 week at an intensity of 2000 lx · hour without being individually packaged. Immediately after the irradiation, the contents of keto and lactone derived from rosuvastatin and all related substances (total related substances) contained in the tablets were measured in the same manner as in Condition 1 above. The obtained results are shown in Table 1.

(Condition 1-5)
Each rosuvastatin tablet obtained in Example 1, Comparative Example 1 and Comparative Example 2 was stored for 1 week at 25 ° C. and 90% RH without being individually packaged. Immediately after the storage, the contents of keto and lactone derived from rosuvastatin and all related substances (total related substances) contained in the tablets were measured in the same manner as in Condition 1 above. The obtained results are shown in Table 1.

  As shown in Table 1, the rosuvastatin tablet obtained in Comparative Example 1 and Comparative Example 2 is one of the keto, lactone and total related substances in any of the above conditions 1-1 to 1-5. The content was higher than that of Example 1 and the other comparative example. On the other hand, the rosuvastatin tablet obtained in Example 1 always shows a low value in the production of keto, lactone and all related substances under any of the above conditions 1-1 to 1-5. It was. From this, it can be seen that the rosuvastatin tablet obtained in Example 1 can stably suppress the production of various types of related substances under various storage conditions.

(Example 2)
Rosuvastatin calcium 5.35 kg, lactose hydrate 104.15 kg, crystalline cellulose 30 kg, crospovidone 3 kg, aminoalkyl methacrylate copolymer E (Eudragit (E) 100 manufactured by EVONIK INDUSTRIES) 6 kg, and magnesium stearate 1.5 kg Was mixed in a blender (Tokuju Kogyo Co., Ltd .: TCV-30) and mixed well to obtain a mixture for tableting. The obtained mixture was put into a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd .: VGRGO) for tableting, and an uncoated tablet having a tablet diameter of 7 mm, a weight of 150 mg, and a hardness of 40 N or more was obtained.

  This uncoated tablet uses 3.6 mg of hypromellose, 0.32 mg of titanium oxide and 0.08 mg of yellow ferric oxide per tablet. Film coating with (PRC-75) gave rosuvastatin tablets.

(Comparative Example 3)
A rosuvastatin tablet was obtained in the same manner as in Example 1 except that 6 kg of sodium carbonate was used instead of the aminoalkyl methacrylate copolymer E.

(Comparative Example 4)
A rosuvastatin tablet was obtained in the same manner as in Example 1 except that 6 kg of magnesium carbonate was used in place of the aminoalkyl methacrylate copolymer E.

(Comparative Example 5)
A rosuvastatin tablet was obtained in the same manner as in Example 1 except that 6 kg of tricalcium phosphate was used in place of the aminoalkyl methacrylate copolymer E.

(Test Example 2: Measurement of increase in related substances)
About the rosuvastatin tablet obtained in Example 2 and Comparative Examples 3-6, the increase rate of the related substance derived from rosuvastatin in each of the following conditions was measured.

(Condition 2-1)
About each rosuvastatin tablet obtained in Example 2 and Comparative Examples 3-6, keto body and lactone body derived from rosuvastatin contained in the tablet immediately after production, and contents of all related substances (total related substances) Was measured in the same manner as in Condition 1 of Test Example 1 and calculated as a percentage (%) relative to the tablet weight. The obtained results are shown in Table 2.

(Condition 2-2)
Each rosuvastatin tablet obtained in Example 2 and Comparative Examples 3 to 6 was individually wrapped with aluminum foil and completely shielded from light, and the resulting package was stored at 60 ° C. for 1 week. Immediately after storage, the keto bodies and lactone bodies derived from rosuvastatin contained in the tablets, and the contents of all related substances (total related substances) were measured in the same manner as in Condition 1 of Test Example 1, It was calculated as a percentage (%) relative to the tablet weight. The obtained results are shown in Table 2.

(Condition 2-3)
About each rosuvastatin tablet obtained in Example 2 and Comparative Examples 3-6, each was individually wrapped with an aluminum foil and completely shielded from light, and the resulting package was stored at 40 ° C. for 1 month. . Immediately after storage, the keto bodies and lactone bodies derived from rosuvastatin contained in the tablets, and the contents of all related substances (total related substances) were measured in the same manner as in Condition 1 of Test Example 1, It was calculated as a percentage (%) relative to the tablet weight. The obtained results are shown in Table 2.

  As shown in Table 2, the rosuvastatin tablet obtained in Comparative Examples 3 to 5 contains any one of keto, lactone and total related substances in any of the above conditions 2-1 to 2-3. However, compared with Example 2 and the other comparative example, the high value was shown. On the other hand, the rosuvastatin tablet obtained in Example 2 always shows a low value in the production of keto, lactone and all related substances under any of the above conditions 2-1 to 2-3. It was. From this, it can be seen that the rosuvastatin tablet obtained in Example 2 can stably suppress the production of various types of related substances under various storage conditions.

  According to the present invention, it is possible to obtain a solid preparation that is excellent in stability over time and suppresses the generation of related substances even for long-term storage. For this reason, even if mass production is carried out at one time, it is possible to store the statins contained as medicinal ingredients for a desired period of time while maintaining sufficient medicinal effects. Therefore, it is useful as a preparation that can be stably supplied to a patient.

Claims (4)

An oral solid preparation comprising a direct compression tablet containing statins and aminoalkyl methacrylate copolymer E and a coating layer covering the direct compression tablet . The oral solid preparation according to claim 1, wherein the aminoalkyl methacrylate copolymer E is contained in an amount of 80 to 400 parts by weight with respect to 100 parts by weight of the statin. The statins, rosuvastatin, pitavastatin, atorvastatin, cerivastatin, fluvastatin, simvastatin, at least one agent pravastatin, lovastatin and mevastatin, and is selected from the group consisting of salts, according to claim 1 or 2 Oral solid formulation. The oral solid preparation according to claim 1 or 2 , wherein the statin is rosuvastatin.