CN1768741A - Instant release type orally administered medicinal composition - Google Patents
Instant release type orally administered medicinal composition Download PDFInfo
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- CN1768741A CN1768741A CN 200510119233 CN200510119233A CN1768741A CN 1768741 A CN1768741 A CN 1768741A CN 200510119233 CN200510119233 CN 200510119233 CN 200510119233 A CN200510119233 A CN 200510119233A CN 1768741 A CN1768741 A CN 1768741A
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Abstract
The invention relates to the instant release type oral medicinal composition containing the calcium salts or hydrates of benzyl succinate derivatives represented by formula (I) as the active constituent and can be used as medicament for treating diabetes.
Description
The application be that May 21, application number in 1999 are 99816765.7 the applying date, denomination of invention divides an application for the Chinese patent application of " immediate release medicinal compositions for oral use ".
Technical field
The present invention relates to can be used as the immediate release medicinal compositions for oral use of Remedies for diabetes.
Background technology
The following formula of known effective ingredient as pharmaceutical composition of the present invention
The calcium salt of the benzyl succinic acid derivative (chemical name: (2S)-2-benzyl-3-(suitable-six hydrogen-2-isoindolinyl carbonyl) propanoic acid) of expression or its hydrate are a kind of chemical compound that has significant hypoglycemic activity, can be used as Remedies for diabetes (the open communiques of Japan's special permission 1992 No. 356459).
Sulfonylureas (SU medicine) such as the glibenclamide that often uses in treating diabetes, gliclazide will show its effect now, need the long time, and act on lasting a few hours, therefore, a problem of having been pointed out is that its danger that can cause the hypoglycemia symptom on the contrary is very big.For example, when one after each meal is enough to fully to suppress the SU medicine of amount of hyperglycemia, can't avoid between two meal, causing hypoglycemic problem.Yet chemical compound of the present invention is because persistent period of its action effect is short, and therefore, it is expected to become a kind ofly only corrects hyperglycemia state after meal and can not cause the hyperglycemia medicine for treatment of the hypoglycemia symptom between two meal.
To only correct hyperglycemia state after meal and can not cause two meal between the hypoglycemia symptom, except effective ingredient must excrete from blood early, can be absorbed rapidly after also will taking.For this reason, in the treatment of after the meal hyperglycemia, need the instant release type preparation of the stripping property excellence of the disintegrative of developing drugs compositions and effective ingredient.Generally require the instant release type preparation after taking, to discharge about medicine (drug dissolution) (exploitation of pharmaceuticals more than 75% in common 20 minutes, the 11st volume, 65-77 page or leaf, the distribution of wide river bookstore), chemical compound of the present invention is insoluble in water, and is troubling aspect stripping property.Therefore, for head it off, wish very much to develop excellent instant release type preparation early.
Summary of the invention
The present invention relates to contain following formula as effective ingredient
The calcium salt of the benzyl succinic acid derivative of expression or the immediate release medicinal compositions for oral use of its hydrate.
The invention still further relates to contain silicon dioxide at least is feature, contain the calcium salt of the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient or the immediate release medicinal compositions for oral use of its hydrate.
The invention still further relates to contain the part alphalysed starch at least is feature, contain the calcium salt of the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient or the immediate release medicinal compositions for oral use of its hydrate.
Description of drawings
The dihydrate that Fig. 1 illustrates with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) is the embodiment 1,2 of effective ingredient and the stripping property of the various tablets described in the reference example 1, vertical coordinate is the dissolution rate (%) of effective ingredient, abscissa be after on-test elapsed time (minute).
The dihydrate that Fig. 2 illustrates with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) is the embodiment 3-6 of effective ingredient and the stripping property of the various tablets described in the reference example 2-9, vertical coordinate is the dissolution rate (%) of effective ingredient, abscissa be after on-test elapsed time (minute).
The specific embodiment
The present inventor is for calcium salt or its hydrate that obtains containing the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient, the immediate release medicinal compositions for oral use that can be used as excellent disintegrative of having of Remedies for diabetes and stripping property, carried out deep research, found that, in pharmaceutical composition, add silicon dioxide or part alphalysed starch at least, can improve the disintegrative of pharmaceutical composition, and stripping property is able to tremendous improvement, has finished the present invention thus.
To contain when adding carboxymethyl starch sodium, the low disintegrating agents commonly used such as hydroxypropyl cellulose that replace in the medicinal composition for oral administration as the calcium salt of the benzyl succinic acid derivative of the above-mentioned formula (I) of effective ingredient expression or its hydrate, promptly use and it is generally acknowledged the good dry method of disintegrative (directly powders compression method) manufacturing tablet, still can not get the good preparation of stripping property fully.Gained preparation not only stripping is slow, and dissolution rate is low singularly.But add general silicon dioxide as lubricant, then amazing is that obtained tablet demonstrates extremely excellent dissolution efficiency, for example, in the dissolution test that uses Japanese Pharmacopoeia the 1st liquid, begin from testing just, just observe quick stripping, maximum dissolution rate is also high.
And, when promptly using the wet method (wet type granule compression method) that generally is considered to be wanting in to make tablet in disintegrative, adding the tablet of silicon dioxide compares with the tablet that adds carboxymethyl starch sodium, the low disintegrating agents commonly used such as hydroxypropyl cellulose that replace, demonstrate amazing significant dissolution efficiency, for example, in the dissolution test that uses Japanese Pharmacopoeia the 1st liquid, begin from testing just, just observe quick stripping, maximum dissolution rate is also high.In addition, when making tablet with wet method, even the tablet that adds carboxymethyl starch sodium, the low disintegrating agents commonly used such as hydroxypropyl cellulose that replace is after the process long duration, its dissolution rate is still low, significant difference appears in stripping property, can't be satisfactory, and the same when adding tablet that the part alphalysed starch makes as disintegrating agent, with wet method with interpolation silicon dioxide, demonstrate good stripping property.In addition, though the interpolation Carmellose demonstrates and the same high dissolution efficiency of pharmaceutical composition of the present invention as the preparation of disintegrating agent, but it is because incompatible with the calcium salt of the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient, pharmaceutical composition becomes faint yellow, and effective ingredient decomposes, therefore, its poor stability, undesirable.
Promptly, the present invention relates to contain silicon dioxide or part alphalysed starch at least is feature, contain the calcium salt of the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient or the immediate release medicinal compositions for oral use of its hydrate, it has remarkable disintegrative and active component stripping property, and compatible with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) expression, the long preservation excellence.
In the present invention, calcium salt and its hydrate that contains the benzyl succinic acid derivative of representing as the above-mentioned formula (I) of effective ingredient can be made (for example, Japan speciallys permit open communique 1992 No. 356459) with the method for document record or the method same with it etc.
The silicon dioxide that uses among the present invention is not particularly limited, and for example, can be light anhydrous silicic acid, hydrated SiO 2 etc.Incorporation to silicon dioxide is not particularly limited, but it is promptly enough to account for the 0.5-5% of total formulation weight amount.
The part alphalysed starch that can use in the present invention can be the starch of various αization degree, for example, can be the part alphalysed starch that commercially available commodity are called PCS (registered trade mark).Incorporation to the part alphalysed starch is not particularly limited, but it is promptly enough to account for the 5-20% of total formulation weight amount.
Medicinal composition for oral administration of the present invention can adopt various dosage forms, and representational dosage form for example has granule, microgranule, powder, tablet, capsule.
For example, granule, microgranule and powder can be by the well-established law manufacturings.Tablet can with granule or microgranule manufacturing, also can be made with dry method (directly powders compression method) direct pelletize by well-established law by well-established law.Capsule can be by well-established law, granule, microgranule or mixed-powder is directly charged in the capsule made.
When making pharmaceutical composition of the present invention, also can optionally use the additive that is fit to each preparation, as excipient, binding agent, surfactant, lubricant, fluidizer, coating material, humidizer, coloring agent, spice etc.These additives are so long as normally used material on the galenic pharmacy, and can not produce harmful effect and get final product the stripping property of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) expression or its hydrate, the compatibility etc., can be any material.
Excipient for example can be cellulose or cellulose derivatives such as crystalline cellulose, starch or starch derivatives such as corn starch, wheaten starch, cyclodextrin, sugar or sugar alcohols such as lactose, D-mannitol, inorganic excipients such as Aluminium Hydroxide, winnofil, metasilicic acid magnesium aluminate, calcium hydrogen phosphate.
Binding agent for example can be hydroxypropyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, dextrin, amylopectin, hydroxypropyl starch, polyvinyl alcohol, arabic gum, agar, gelatin, Tragacanth, Polyethylene Glycol etc.
Surfactant for example can be fatty acid cane sugar ester, KIKKOL MYS-40, polyoxyethylene hydrogenated Oleum Ricini, polyoxyethylene polyoxy propylene glycol, sorbitan sesquioleate, anhydrosorbitol trioleate, anhydrosorbitol monostearate, sorbitan-monopalmityl ester, sorbitan monolaurate, polysorbate, glyceryl monostearate, sodium lauryl sulfate, lauryl Polyethylene Glycol etc.
Lubricant for example can be stearic acid, calcium stearate, magnesium stearate, Pulvis Talci etc.
Fluidizer for example can be Aluminium Hydroxide, magnesium silicate etc.
Coating material for example can be the amino alkyl ester copolymer E of hydroxypropyl methylcellulose 2910, methacrylic acid, polyvinyl acetal diethyl amino yl acetate, polyethylene glycol 6000, titanium oxide etc.
Plasticizer for example can be triethyl citrate, glyceryl triacetate, polyethylene glycol 6000 etc.
Pharmaceutical composition of the present invention is highly stable, even placed for 1 week under the harsh conditions of hot and humid degree, outward appearance does not change yet, and does not also observe the effective ingredient decomposition and does not find that dissolution rate changes.
Below by reference example, embodiment and test example content of the present invention is described in more detail, but the invention is not restricted to these contents.
Reference example 1
Active component 5.0mg
Crystalline cellulose 27.5mg
Lactose 28.7mg
Corn starch 10.0mg
The low hydroxypropyl cellulose 3.0mg that replaces
Calcium stearate 0.8mg
(total) 75.0mg
With dihydrate (active component) 75.0g of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) and crystalline cellulose 412.5g, lactose 430.5g, corn starch 150.0g, the low hydroxypropyl cellulose (trade name: L-HPC/LH-11 that replaces, Shin-Etsu Chemial Co., Ltd's product) after 45.0g and calcium stearate 12.0g mix, be shaped with disc (5R) drift of diameter 6mm exert pressure, make the tablet of above-mentioned composition with about 700kg.
Reference example 2
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Carmellose 8.0mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and Carmellose (trade name: NS-300 (registered trade mark) with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), five moral pharmaceutical industries Co., Ltd. products) after 0.8g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Reference example 3
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Carboxymethyl starch sodium 8.0mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and carboxymethyl starch sodium (trade name: Primogel (registered trade mark) with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), SongGu Chemical Industrial Co., Ltd's product) after 0.8g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Reference example 4
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
The low hydroxypropyl cellulose 8.0mg that replaces
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and the low hydroxypropyl cellulose (trade name: L-HPC/LH-11 that replaces with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Shin-Etsu Chemial Co., Ltd's product) after 0.8g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Reference example 5
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
The low hydroxypropyl cellulose 8.0mg that replaces
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and the low hydroxypropyl cellulose (trade name: L-HPC/LH-22 that replaces with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Shin-Etsu Chemial Co., Ltd's product) after 0.8g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Reference example 6
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Part alphalysed starch 8.0mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and part alphalysed starch (trade name: PCS with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Asahi Chemical Industry Co., Ltd's product) after 0.8g, hydroxypropyl cellulose 0.24g and calcium stearate 0.12g mix, be shaped with disc (9.5R) drift of diameter 7mm exert pressure, make the tablet of above-mentioned composition with 500kg.
Reference example 7
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Carboxymethyl starch sodium 8.0mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and carboxymethyl starch sodium (trade name: Primogel (registered trade mark) with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), SongGu Chemical Industrial Co., Ltd's product) after 0.8g, hydroxypropyl cellulose 0.24g and calcium stearate 0.12g mix, be shaped with disc (9.5R) drift of diameter 7mm exert pressure, make the tablet of above-mentioned composition with 500kg.
Reference example 8
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
The low hydroxypropyl cellulose 8.0mg that replaces
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and the low hydroxypropyl cellulose (trade name: L-HPC/LH-11 that replaces with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Shin-Etsu Chemial Co., Ltd's product) after 0.8g, hydroxypropyl cellulose 0.24g and calcium stearate 0.12g mix, be shaped with disc (9.5R) drift of diameter 7mm exert pressure, make the tablet of above-mentioned composition with 500kg.
Reference example 9
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
The low hydroxypropyl cellulose 8.0mg that replaces
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and the low hydroxypropyl cellulose (trade name: L-HPC/LH-22 that replaces with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Shin-Etsu Chemial Co., Ltd's product) after 0.8g, hydroxypropyl cellulose 0.24g and calcium stearate 0.12g mix, be shaped with disc (9.5R) drift of diameter 7mm exert pressure, make the tablet of above-mentioned composition with 500kg.
Embodiment 1
Active component 5.0mg
Crystalline cellulose 27.5mg
Lactose 27.9mg
Corn starch 10.0mg
The low hydroxypropyl cellulose 3.0mg that replaces
Calcium stearate 0.8mg
Light anhydrous silicic acid 0.8mg
(total) 75.0mg
With dihydrate (active component) 50.0g of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) and crystalline cellulose 275.0g, lactose 279.0g, corn starch 100.0g, the low hydroxypropyl cellulose (trade name: L-HPC/LH-11 that replaces, Shin-Etsu Chemial Co., Ltd's product) 30.0g, calcium stearate 8.0g and light anhydrous silicic acid (trade name: Adsolider (registered trade mark) 101, Freund Industry Co., Ltd product) after 8.0g mixes, be shaped with disc (5R) drift of diameter 6mm exert pressure, make the tablet of above-mentioned composition with 700kg.
Embodiment 2
Active component 5.0mg
Crystalline cellulose 27.5mg
Lactose 27.3mg
Corn starch 10.0mg
The low hydroxypropyl cellulose 3.0mg that replaces
Calcium stearate 0.8mg
Light anhydrous silicic acid 1.4mg
(total) 75.0mg
With dihydrate (active component) 50.0g of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) and crystalline cellulose 275.0g, lactose 273.0g, corn starch 100.0g, the low hydroxypropyl cellulose (trade name: L-HPC/LH-11 that replaces, Shin-Etsu Chemial Co., Ltd's product) 30.0g, calcium stearate 8.0g and light anhydrous silicic acid (trade name: Adsolider (registered trade mark) 101, Freund Industry Co., Ltd product) after 14.0g mixes, be shaped with disc (5R) drift of diameter 6mm exert pressure, make the tablet of above-mentioned composition with 700kg.
Embodiment 3
Active component 22.0mg
Lactose 56.0mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Part alphalysed starch 8.0mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.6g, corn starch 2.4g, crystalline cellulose 1.32g and part alphalysed starch (trade name: PCS with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Asahi Chemical Industry Co., Ltd's product) after 0.8g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Embodiment 4
Active component 22.0mg
Lactose 60.7mg
Corn starch 26.0mg
Crystalline cellulose 13.2mg
Light anhydrous silicic acid 1.3mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 6.07g, corn starch 2.6g, crystalline cellulose 1.32g and light anhydrous silicic acid (trade name: Adsolider (registered trade mark) 101 with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), Freund Industry Co., Ltd product) after 0.13g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Embodiment 5
Active component 22.0mg
Lactose 54.7mg
Corn starch 24.0mg
Crystalline cellulose 13.2mg
Part alphalysed starch 8.0mg
Light anhydrous silicic acid 1.3mg
Hydroxypropyl cellulose 2.4mg
Calcium stearate 1.2mg
(total) 126.8mg
Dihydrate (active component) 2.2g and lactose 5.47g with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I), corn starch 2.4g, crystalline cellulose 1.32g, part alphalysed starch (trade name: PCS, Asahi Chemical Industry Co., Ltd's product) 0.8g and light anhydrous silicic acid (trade name: Adsolider (registered trade mark) 101, Freund Industry Co., Ltd product) after 0.13g mixes, add hydroxypropyl cellulose 6 weight % aqueous solution 4g and (be converted into hydroxypropyl cellulose, be 0.24g), stirring-granulating in mortar, with sieving after the cylinder dryer drying, make the following granule of 30 orders (500 μ m).This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.95%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Embodiment 6
Active component 22.0mg
Lactose 56.9mg
Corn starch 24.4mg
Crystalline cellulose 14.0mg
Part alphalysed starch 9.0mg
Hydroxypropyl cellulose 2.5mg
Calcium stearate 1.2mg
(total) 130.0mg
Dihydrate (active component) 220g and lactose 569g, corn starch 244g, crystalline cellulose 140g and part alphalysed starch (trade name: PCS with the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I); Asahi Chemical Industry Co., Ltd's product) after 90g mixes; add hydroxypropyl cellulose 6 weight % aqueous solution 416.7g and (be converted into hydroxypropyl cellulose; be 25g); with mixed at high speed stirring granulating machine stirring-granulating; and, make the following granule of 30 orders (500 μ m) with sieving after the fluidized bed dryer drying.This granule is mixed with calcium stearate, make the amount of calcium stearate reach 0.92%, use of the exert pressure shaping of disc (9.5R) drift of diameter 7mm then, make the tablet of above-mentioned composition with 500kg.
Test example 1
Dissolution test (1)
Dissolution test the 2nd method (with the slurry paddling process) by the 13rd edition record of Japanese pharmacopeia, (quantitative approach: HPLC detects wavelength: 220nm) with 50rpm the tablet of embodiment 1～2 and reference example 1 to be carried out dissolution test as experimental liquid with Japanese Pharmacopoeia the 1st liquid 900mL.The dissolution test of these tablets the results are shown in Figure 1.Compare with the tablet of reference example 1, the tablet of embodiment 1～2 demonstrates excellent stripping property.
Test example 2
Dissolution test (2)
Dissolution test the 2nd method (with the slurry paddling process) by the 13rd edition record of Japanese pharmacopeia, with Japanese Pharmacopoeia the 1st liquid 900mL as experimental liquid with 50rpm to the tablet of embodiment 3～6 and reference example 2～9 carry out dissolution test (quantitative approach: the UV absorbance measurement, detect wavelength: 205nm).The dissolution test of these tablets the results are shown in Figure 2.Compare with the tablet of reference example 3～9, the tablet of embodiment 3～6 and reference example 2 demonstrates excellent stripping property.
Test example 3
Compatibility test
The dihydrate 1g of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) is mixed respectively with following each additive 1g, with mixture under 60 ℃, the condition of relative humidity 80%, place 2 week the back observe outward appearances.
Additive
Part alphalysed starch (trade name: PCS (registered trade mark), Asahi Chemical Industry Co., Ltd's product)
Carmellose (trade name: NS-300 (registered trade mark), five moral pharmaceutical industries Co., Ltd. products)
Carmellose calcium (trade name: ECG-505 (registered trade mark), five moral pharmaceutical industries Co., Ltd. products)
Carmellose sodium (trade name: Ac-Di-Sol, Asahi Chemical Industry Co., Ltd's product)
Light anhydrous silicic acid (trade name: Adsolider (registered trade mark) 101, Freund Industry Co., Ltd product)
It the results are shown in following table 1.The dihydrate of the calcium salt of the benzyl succinic acid derivative of above-mentioned formula (I) is stable with part alphalysed starch or light anhydrous silicic acid compatibility the time, but then can variable color during with Carmellose, Carmellose calcium or carmellose sodium compatibility.
Table 1
| Additive | Outward appearance |
| The part alphalysed starch | No change |
| Carmellose | Become faint yellow |
| Carmellose calcium | Become little yellow |
| Carmellose sodium | Become little yellow |
| Light anhydrous silicic acid | No change |
Test example 4
Stability test
With the tablet of embodiment 3～4 and reference example 2 under 60 ℃, the condition of relative humidity 80%, place 1 week the back check tablet appearance, the amount of analyte and the variation of the dissolution time in Japanese Pharmacopoeia the 1st liquid.The result, the outward appearance of tablet that contains the reference example 2 of Carmellose becomes little yellow, show that analyte increases, the tablet of the tablet of the embodiment 3 of use part alphalysed starch and the embodiment 4 of use light anhydrous silicic acid does not then detect any variation, dissolution time is no change also, shows that tablet is highly stable.
Claims (4)
1. the preparation method of immediate release medicinal compositions for oral use adopts wet type granule compression method, and described preparation method comprises the following formula as effective ingredient
The calcium salt of the benzyl succinic acid derivative of expression or its hydrate and disintegrating agent combination,
It is characterized in that described pharmaceutical composition can be dissolved in dissolution test the 1st liquid of Japanese Pharmacopoeia record and discharged effective ingredient more than 75% in 20 minutes,
Described disintegrating agent is the part alphalysed starch.
2. preparation method as claimed in claim 1 is characterized in that described part alphalysed starch accounts for the 5-20% of composition total weight.
3. preparation method as claimed in claim 1 or 2 is characterized in that described pharmaceutical composition also comprises excipient, and described excipient comprises (a) crystalline cellulose, (b) lactose and (c) corn starch.
4. immediate release medicinal compositions for oral use, it is made with each described preparation method among the claim 1-3, and described pharmaceutical composition can be dissolved in dissolution test the 1st liquid of Japanese Pharmacopoeia record and discharged effective ingredient more than 75% in 20 minutes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510119233 CN1768741A (en) | 1999-05-21 | 1999-05-21 | Instant release type orally administered medicinal composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510119233 CN1768741A (en) | 1999-05-21 | 1999-05-21 | Instant release type orally administered medicinal composition |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN998167657A Division CN1352558B (en) | 1999-05-21 | 1999-05-21 | Immediate release medicinal compositions for oral use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1768741A true CN1768741A (en) | 2006-05-10 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200510119233 Pending CN1768741A (en) | 1999-05-21 | 1999-05-21 | Instant release type orally administered medicinal composition |
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| Country | Link |
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| CN (1) | CN1768741A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109414051A (en) * | 2016-06-28 | 2019-03-01 | 株式会社日本抗菌总和研究所 | Excipient and tablet |
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1999
- 1999-05-21 CN CN 200510119233 patent/CN1768741A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109414051A (en) * | 2016-06-28 | 2019-03-01 | 株式会社日本抗菌总和研究所 | Excipient and tablet |
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Application publication date: 20060510 |