CN102641254A - Preparation method of aspirin enteric-coated sustained-release preparation - Google Patents
Preparation method of aspirin enteric-coated sustained-release preparation Download PDFInfo
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- CN102641254A CN102641254A CN201210137206XA CN201210137206A CN102641254A CN 102641254 A CN102641254 A CN 102641254A CN 201210137206X A CN201210137206X A CN 201210137206XA CN 201210137206 A CN201210137206 A CN 201210137206A CN 102641254 A CN102641254 A CN 102641254A
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Abstract
The invention relates to a preparation method of an enteric-coated sustained-release preparation, in particular to a preparation method of an aspirin enteric-coated sustained-release preparation. According to the preparation method, a prepared aspirin sustained-release tablet is used as a core tablet, and an enteric coating is packaged on the outer layer of the core tablet. In order to prevent aspirin in the core tablet from interacting with an enteric-coated material, an isolating layer can be packaged between the core tablet and the enteric coating. After the aspirin is prepared into the enteric-coated sustained-release preparation provided by the invention, the aspirin is not released or a little aspirin is released in a stomach, the release time in intestines is greatly extended, the phenomena of violent disintegration and dissolution do not occur in the intestines, the aspirin is released more slowly, the bioavailability is greatly increased, the degradation reaction of the aspirin in water is avoided, the frequency of administration is lower, and the compliance of a patient is improved.
Description
Technical field
The present invention relates to a kind of method for preparing of enteric-coated sustained-release preparation, particularly a kind of method for preparing of aspirin enteric-coated slow releasing preparation.
Background technology
Aspirin (Aspirin) has another name called aspirin, and (Acetylsalicylic acid ASA), is synthetic at first in 1853 by Charles Gerhardt, the NSAID that Beyer Co., Ltd in 1899 at first goes on the market.Its pharmacological action is extensive, has the effect of antiinflammatory, rheumatism, analgesia, analgesic, anticoagulant.The dosage form of listing is more, capsule, slow releasing capsule, enteric coated capsule, tablet, oral cavity disintegration tablet, sublingual tablet, slow releasing tablet, enteric coated tablet, granule, gel, ointment, injection is arranged, to chew colloid, powder, solution, drop, suppository etc. multiple.
The pharmaceutical salts of aspirin has Aspirin-d1-lysine, Aspirin-arginin etc.The former claims Aspisol (Lysine aspirin) again, is the double salt of aspirin and lysine; The latter claims Aspirin-arginine (Arginine aspirin) again, for aspirin and arginic double salt, is NSAID.Can resolve into aspirin and lysine or arginine in vivo, have analgesic, analgesia, antiinflammatory, anti-platelet aggregation effect.Its mechanism of action is identical with aspirin; Compare with the latter, have be prone to dissolve, characteristics little to GI irritation property (the Ministry of Public Health rational use of drug Committee of Experts compiles. Chinese doctor pharmacist clinical application guide (the 1st edition). Chongqing: the .2009:1334 of Chongqing publishing house).
Low dose of aspirin (every day, dosage was in 300mg) is through suppressing hematoblastic epoxidase; Reduce prostaglandin and have an anticoagulant effect, can angiocardiopathy preventing (see that Chinese Pharmacopoeia Commission compiles. Pharmacopoeia of People's Republic of China clinical application notice version (chemical medicine is rolled up with biological product) in 2005 Beijing: People's Health Publisher: 698).The clinical aspirin that confirmed comprises that to the prevention thrombotic disease diseases such as cerebral thrombosis, coronary heart disease, myocardial infarction, the past or recidivity myocardial infarction, Ischemic Stroke, transient ischemic attack, unstable angina pectoris and postoperative thrombosis and thrombosis obturation have important function.
Be used for that the routine dose of antipyretic-antalgic is less to cause untoward reaction, but long-term a large amount of medication (especially when blood drug level greater than 200g/mL time) is prone to untoward reaction.Blood drug level is higher, and untoward reaction more obviously.Modal untoward reaction is a gastrointestinal reaction; Show as nauseating, vomiting, epigastric discomfort or pain, and many can the disappearance after the drug withdrawal (the Ministry of Public Health rational use of drug Committee of Experts compiles. Chinese doctor pharmacist clinical application guide (the 1st edition). and Chongqing: the .2009:638 of Chongqing publishing house).Do not have any untoward reaction like the user, can take for a long time or all the life.
In order to reduce the gastrointestinal side effect of aspirin, generally adopt the enteric technology to delay the release of aspirin, make the Genprin can not disintegrate, in enteral disintegrate preferably and dissolving at gastric.This enteric coated preparation is usually through realizing (like US 4716042) for tablet at its outer parcel enteric coating; But the also enteric coated enteric coated micropill (like US5846566,200310119379.X and CN 03144249.8) that is prepared on the piller; In addition; Also can adopt an enteric material, other adjuvants and after aspirin mixes, through granulating (like US 4857337 and CN 200810020313.8), coating, spray drying or form mode such as solid dispersion and make the aspirin granule wrap the delay that enteric coating reaches aspirin to discharge.Existing at present Aspirin Enteric-coated Tablets listing; Like Bai Asi
(external trade name:
specification is 100mg) that Beyer Co., Ltd produces,
(specification is 100mg) that GSK company produces.
Can also adopt slow controlled-release technology to reduce the gastrointestinal untoward reaction.Though greatly reduced the untoward reaction at gastric, this technology can not avoid aspirin to have part to discharge at gastric, and still bigger to the infringement of stomach, life-time service also brings out gastrorrhagia (like US 4601895).Therefore; Also have aspirin is processed transdermal absorption formulation (like US 5716636 and US 5861170) and suppository, the existing medicine listing of the latter (trade name:
).
Though enteric coated preparation can be avoided the release of aspirin at gastric; But because label or ball core or granular core are not that enteric or slow-release material are prepared from; The aspirin burst size is bigger after the film rupture of enteral enteric coating; Cause inevitably to duodenum, etc. intestinal equivalent damage (Neal M.Davies.Sustained Release and Enteric Coated NSAIDs Are They Really GI Safe [J] .J Pharm Pharmaceut Sci1999,2 (1): 5-14).
This patent provides a kind of structure of enteric-coated sustained-release preparation; Promptly be prepared into the slow release label earlier; Its outer coatings enteric coating can reduce the untoward reaction of aspirin to greatest extent, and clinical trial shows; Compare with Bai Asi
(trade name of Aspirin Enteric-coated Tablets) that Beyer Co., Ltd produces; The method that this patent provides can slowly discharge aspirin, and mean residence time is longer in the body, and bioavailability is higher.
Because aspirin is unstable, facile hydrolysis becomes salicylic acid and acetic acid, and the latter can make preparation that the bigger smell of vinegar is arranged.And the former is bigger than aspirin to the gastrointestinal zest, and toxicity also increases.Therefore, free salicylic acid is no more than 0.1% in Chinese Pharmacopoeia version regulation in 2010 the aspirin raw material, and ordinary tablet is no more than 0.3%, and enteric coatel tablets are no more than 1.5%.Common enteric material has the acrylic resin (copolymer that comprises methacrylic acid and acrylic acid methyl ester., ethyl ester or butyl ester; Commodity are called
), cellulose acetate-phthalate (CAP; Commodity are called
), polyvinyl acetate phthalic acid ester (PVAP; Commodity are called
), phthalic acid hypromellose ester (HPMCP; Commodity are called Mantrocel), succinic acid acetic acid hypromellose ester (HPMCAS, commodity are called
) etc.If it is directly enteric coated on label; Because aspirin directly contacts with enteric material, the former is quickened by hydrolysis, cause salicylic acid to exceed standard; Therefore, need to add certain adjuvant (as in US 4900559 patents, adding acidogen) or between two-layer, add sealing coat.This patent provides the back a kind of method.The advantage of this method is to add hydrolysis inhibitor such as acidogen, only needs bag stomach dissolution type contagion gown between label and enteric coating.
The method of the enteric-coated sustained-release preparation that this patent provides is different from the report of some documents; Like Yue Hongkun, Han Nana has proposed the method for preparing of aspirin enteric-coated slow releasing preparation, adopts solid dispersion technology that aspirin is processed the enteric slow release solid dispersion earlier; Add diluent, binding agent, lubricant etc. again and be pressed into sheet (Yue Hongkun; Han Nana. the research of aspirin enteric-coated slow releasing preparation [J]. Shijiazhuang College's journal, 2009,11 (6): 18-22).This method can reach the effect of enteric slow release; More (optimal proportion of principal agent, enteric material Youteqi L-100 and enteric material Youteqi RD100 is 1:1:1.5 in the document but the problem that exists is to use enteric material; If every of principal agent is 100mg; Then enteric material is 250mg), the feasible tablet of making is big (not adding under other adjuvant situation, at least also is 350mg); In addition, after the solid dispersion long term store, hardness occurs and become big, separate out crystal, drug dissolution descend also be an alarming problem (the Lu Bin chief editor. novel pharmaceutical formulation and new technique (second edition). Beijing: People's Health Publisher: 24).
Patent CN 201010195587.8 has proposed a kind of method for preparing of aspirin enteric-coated slow releasing capsule.This method is aspirin to be mixed with lipidic matrix such as cocoa butter, monopalmitin, Compritol 888 ATO and adjustment release agent such as poloxamer, polyoxyethylene monostearate by a certain percentage extrude; Bag contagion gown and enteric coating are in incapsulating at last.Owing to do not make the intervention of water, make the aspirin hydrolyzes reaction be able to suppress.
Summary of the invention
The invention provides a kind of enteric-coated sustained-release preparation that is used to suppress hematoblastic adhesion and accumulative NSAID, avoided the degradation reaction after aspirin is met water; Administration number of times is less, and patient's compliance improves; Can fierce disintegrate and stripping phenomenon not take place at enteral, the release of aspirin is milder.
The method for preparing of aspirin enteric-coated slow releasing preparation of the present invention, be with the aspirin sustained release tablet of preparing as label, be in internal layer, outside enteric coating layer is wrapped in, be in the skin of label.
Aspirin enteric-coated slow releasing preparation can adopt the following steps preparation:
(1) preparation label: with processing the slow release label behind aspirin and the direct mixed pressuring plate of acceptable accessories;
(2) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent processed enteric liquid, enteric coated on label;
The said acceptable accessories of step (1) is one or more in hypromellose, hyprolose, polyvidone, copolyvidone, starch, pregelatinized Starch, microcrystalline Cellulose, tartaric acid, citric acid, fumaric acid, lactose, dextrin or the sodium lauryl sulphate;
The said pharmaceutically acceptable enteric material of step (2) is one or more in acrylic resin, cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, phthalic acid hypromellose ester or the succinic acid acetic acid hypromellose ester;
The said plasticizer of step (2) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The said solvent of step (2) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
Produce hydrolysis for preventing that adjuvant directly contacts with aspirin in the enteric coating, between label and enteric coating layer, wrap up sealing coat.Aspirin enteric-coated slow releasing preparation of the present invention can also be prepared as follows:
The aspirin sustained release tablet of preparing as label, outside enteric coating layer is wrapped in, is in the skin of label, between label and enteric coating layer, increases sealing coat; Preparation process is following:
(1) preparation label: with processing the slow release label behind aspirin and the direct mixed pressuring plate of acceptable accessories;
(2) bag sealing coat: acceptable accessories is constituted stomach dissolution type sealing coat or erosion type sealing coat through coating;
(3) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent processed enteric liquid, enteric coated on label.
The said acceptable accessories of step (1) is one or more in hyprolose, hypromellose, starch, pregelatinized Starch, microcrystalline Cellulose, tartaric acid, citric acid, fumaric acid, lactose, dextrin, the sodium lauryl sulphate.
In the said used acceptable accessories hyprolose of step (2), hyprolose, methylcellulose, sodium alginate, guar gum, chitosan, polyvidone, stearic acid, babassu sodium, the stearyl alcohol one or more;
The said plasticizer of step (2) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The said solvent of step (2) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
In the said used acceptable accessories acrylic resin of step (3), cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, phthalic acid hypromellose ester or the succinic acid acetic acid hypromellose ester one or more;
The said plasticizer of step (3) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (3) is stearic acid and/or Pulvis Talci;
The said solvent of step (3) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
Aspirin refers to aspirin or its pharmaceutically acceptable salt among the present invention.The latter refers to Aspirin-arginin (Lysine acetylsalicylate) or Aspirin-d1-lysine (Arginine Aspirin).Wherein Aspirin-arginin has another name called aspisol.
The present invention has mainly adopted two kinds of technology to reach the enteric slow release effect, and has reduced aspirin to greatest extent in the gastrointestinal untoward reaction, reduces the undulatory property of blood drug level simultaneously, makes blood drug level more steady, plays long lasting characteristics in vivo.This present invention has adopted slow release method and enteric technology simultaneously.The former has avoided the rapid release of aspirin, is aspirin after the enteric coating dissolving, still reposefully in vivo dissolving with absorb.The latter has avoided the release of aspirin at gastric, makes untoward reaction such as gastric is hemorrhage, nauseating, vomiting, epigastric discomfort drop to minimum.
This technology is different from the various preparation techniques of having reported at present.Reported a kind of method for preparing of enteric-coated sustained-release tablet like people such as Yue Hongkun, adopted solid dispersion to prepare the granule of aspirin, be mixed with out tablet with unclassified stores.Gold celebrating equality people discloses a kind of method for preparing (patent CN 201010195587.8) of enteric-soluble controlled-release capsule; This patent is earlier aspirin to be mixed with biodegradation framework material and release regulator; Successively wrap contagion gown and enteric coating again, in incapsulating at last.
The advantage of method provided by the invention has: 1. directly mix with slow-release material and other adjuvants through aspirin, avoided the degradation reaction after aspirin is met water; 2. compare with the tablet of common release behavior, administration number of times is greatly less, and patient's compliance greatly improves; 3. compare with the tablet of enteric release behavior, the generation of side effect also greatly reduces, and can't phenomenons such as fierce disintegrate and stripping take place at enteral, makes the release of aspirin milder; 4. compare with the metformin hydrochloride with framework material preparation, the metformin hydrochloride of osmotic pumps preparation does not receive the not influence of coordination section of gastrointestinal tract, or influence is very little, discharges medicine and has the zero-order release characteristic; 5. compare with the Bai Asi that has gone on the market
(Beyer Co., Ltd's production); The preparation that this patent provides reaches peak concentration and peak time prolongs to some extent; Blood drug level is milder, and bioavailability has slightly high.6. dosage can correspondingly reduce.Because the method bioavailability that provides of this patent is higher, therefore,, can reduce dosage for reaching in the identical body area (AUC) under the blood drug level and time graph.
Description of drawings
The aspirin enteric-coated slow releasing preparation that Fig. 1 is made up of label and enteric coating layer;
The aspirin enteric-coated slow releasing preparation that Fig. 2 is made up of label, sealing coat and enteric coating layer;
Fig. 3 is the stripping curve comparison diagram of Bai Asi
and embodiment 1-8;
Fig. 4 is the stripping curve comparison diagram of Bai Asi
and embodiment 9-16.
Fig. 5 is the blood drug level comparison diagram of own product and Baysprin.
The specific embodiment
Below in conjunction with embodiment the present invention is further described.
Prescription
⑴ label
⑵ enteric coating layer
Technology
⑴ film-making core is got aspirin and is added hypromellose K15M, microcrystalline Cellulose PH102, lactose and sodium lauryl sulphate, mix homogeneously.Place in the rotary tablet machine (C&C800, Bo Jiawei Science and Technology Ltd. is created in Beijing, down together), adopting diameter is the circular stamping of dimple form of 6mm, and adjustment sheet weighs and pressure, and control hardness is 50-80N, prepares 1000 altogether.
⑵ enteric-coating layer is got Eudragit RS 30D and Eudragit RL 30D aqueous dispersion (both are the product of German Romo Co.,Ltd), adds triethyl citrate Pulvis Talci, 95% ethanol (v/v) and water, stirs.Above-mentioned tablet is placed coating machine (BGB-5B type; The Pharmaceutical Equipment Factory, Wenzhou City, down together) in, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base; Control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-12%.Wrapped behind the clothing about 2 hours of 60 ℃ of following heat preservation and drynesses.
Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 25mg.
Prescription
⑴ label
⑵ contagion gown layer
Hypromellose 17g
PEG400 3g
60% alcoholic solution (v/v) 280g
⑶ enteric coating layer
Technology
⑴ film-making core is got aspirin and is added hypromellose K4M, microcrystalline Cellulose PH102, pregelatinized Starch and sodium lauryl sulphate, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of dimple form of 6.5mm, the heavy and pressure of adjustment sheet, and control hardness is 60-100N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose, PEG400 is dissolved in 60% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 5-8%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds cellulose acetate-phthalate, propylene glycol and stearic acid, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-12%.Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 50mg.
Prescription
⑴ label
⑵ enteric coating layer
Technology
⑴ film-making core is got aspirin and is added hydroxyl methylcellulose Klucel HF (production of Aqualon company), tartaric acid, dextrin, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of dimple form of 6.5mm, the heavy and pressure of adjustment sheet, and control hardness is 60-100N, prepares 1000 altogether.
⑵ enteric-coating layer is got acetone, adds phthalic acid hypromellose ester, triacetyl glycerine and glycerol, stirs, and adds entry and Pulvis Talci again, mix homogeneously.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-12%.
Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 75mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got aspirin, adds hypromellose K100M, citric acid, dextrin and sodium lauryl sulphate, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of dimple form of 6.5mm, the heavy and pressure of adjustment sheet, and control hardness is 60-100N, prepares 1000 altogether.
⑵ bag sealing coat is got polyvidone, acetylation triethyl citrate and Macrogol 600, is dissolved in 40% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 4-8%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds succinic acid acetic acid hypromellose ester, Polyethylene Glycol 3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-12%.
Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 100mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got aspirin, adds hypromellose K4M, hypromellose K100M, 30 POVIDONE K 30 BP/USP 90 and fumaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 7 * 15mm, the heavy and pressure of adjustment sheet, and control hardness is 100-150N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, triethyl citrate and propylene glycol, is dissolved in 40% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 5-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, propylene glycol, Polyethylene Glycol 3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-12%.
Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 300mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got aspirin, adds hypromellose K15M, starch, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 8 * 15mm, the heavy and pressure of adjustment sheet, and control hardness is 100-150N, prepares 1000 altogether.
⑵ bag sealing coat is got sodium alginate, Macrogol 4000, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 5-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triacetyl glycerine and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the aspirin enteric-coated slow releasing tablet that specification is 500mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspisol, adds hypromellose K15M, starch, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of 6.0mm, the heavy and pressure of adjustment sheet, and control hardness is 70-120N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, polyethylene glycol 6000, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin II number, acrylic resin III number, triacetyl glycerine and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspisol enteric-coated sustained-release tablet that specification is 45mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspisol, adds hypromellose K15M, starch, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of 6.5mm, the heavy and pressure of adjustment sheet, and control hardness is 70-120N, prepares 1000 altogether.
⑵ bag sealing coat is got methylcellulose, polyvidone, PEG400, Polyethylene Glycol 3350 and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, glycerol, triethyl citrate and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspisol enteric-coated sustained-release tablet that specification is 90mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspisol, adds hypromellose K4M, hypromellose K100M, citric acid, 30 POVIDONE K 30 BP/USP 90 and fumaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 6.5 * 12mm, the heavy and pressure of adjustment sheet, and control hardness is 70-120N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, triethyl citrate and propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 5-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triethyl citrate and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspisol enteric-coated sustained-release tablet that specification is 180mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspisol, adds hypromellose K100M, dextrin, starch and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 8.0 * 15mm, the heavy and pressure of adjustment sheet, and control hardness is 100-180N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, Macrogol 4000, propylene glycol, triethyl citrate and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triethyl citrate and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspisol enteric-coated sustained-release tablet that specification is 540mg.
Embodiment 11
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspisol, adds hypromellose K4M, hypromellose K100M, citric acid, 30 POVIDONE K 30 BP/USP 90 and fumaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 9 * 18mm, the heavy and pressure of adjustment sheet, and control hardness is 150-200N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, polyethylene glycol 6000, Macrogol 600, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, acetylation triethyl citrate, Polyethylene Glycol 3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspisol enteric-coated sustained-release tablet that specification is 900mg.
Prescription
⑴ label
⑵ enteric coating layer
Technology
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, dextrin, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the circular stamping of 5.0mm, the heavy and pressure of adjustment sheet, and control hardness is 60-120N, prepares 1000 altogether.
⑵ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triacetyl glycerine, propylene glycol and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 6-10%.
Above-mentioned method for preparing can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 50mg.
Embodiment 13
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspirin-arginine, adds hypromellose K4M, hypromellose K100M, citric acid, 30 POVIDONE K 30 BP/USP 90 and fumaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 6.0 * 12mm, the heavy and pressure of adjustment sheet, and control hardness is 80-120N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, Macrogol 4000, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triacetyl glycerine and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 100mg.
Prescription
⑴ label
⑵ enteric coating layer
Technology
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, hyprolose, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 6.5 * 10mm, the heavy and pressure of adjustment sheet, and control hardness is 100-150N, prepares 1000 altogether.
⑵ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triacetyl glycerine, Polyethylene Glycol 3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 200mg.
Embodiment 15
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, starch, 30 POVIDONE K 30 BP/USP 30 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 7 * 14mm, the heavy and pressure of adjustment sheet, and control hardness is 150-200N, prepares 1000 altogether.
⑵ bag sealing coat is got hyprolose, PEG400, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed tablet machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 5-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triethyl citrate and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 6-10%.
Above-mentioned method for preparing can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 600mg.
Embodiment 16
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technology
⑴ film-making core is got aspirin, adds hypromellose K4M, hypromellose K100M, 30 POVIDONE K 30 BP/USP 90 and tartaric acid, mix homogeneously.Place rotary tablet machine, adopting diameter is the oval stamping of 8.5 * 16mm, the heavy and pressure of adjustment sheet, and control hardness is 200-250N, prepares 1000 altogether.
⑵ bag sealing coat is got hypromellose E15, propylene glycol and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is uniformly dispersed.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is at 6-10%.
⑶ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triethyl citrate, propylene glycol and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed the coating machine, regulate coating machine rotating speed, hydrojet speed, EAT, air intake air pressure, atomizing pressure, sheet spray base, control tablet temperature is 35-43 ℃, and the weightening finish of control coating is about 8-10%.
Above-mentioned method for preparing can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 1000mg.
Stripping curve is measured:
A: burst size in the acid
Drug release determination method: see two appendix XD of Chinese Pharmacopoeia version in 2010, the second method method 1
Device: see two dissolution method first methods of Chinese Pharmacopoeia version in 2010
The hydrochloric acid solution of dissolution medium: 0.1mol/L
Rotating speed: per minute 50 changes
Time: 2 hours
Sampling amount: 5ml
Assay method: HPLC
B: burst size in the buffer
Drug release determination method: see two appendix X of Chinese Pharmacopoeia version in 2010 D, the second method method 1
Device: see two dissolution method first methods of Chinese Pharmacopoeia version in 2010
Dissolution medium: pH value is 6.8 phosphate solutions
Rotating speed: per minute 50 changes
Time: 1,2,4,6 hours
Sampling amount: 5ml
Assay method: HPLC
C: chromatographic condition:
Filler: octadecylsilane chemically bonded silica
Mobile phase: acetonitrile-oxolane-glacial acetic acid-water (20:5:5:70)
Detect wavelength: 276nm
Sample size: 10 μ l
The stripping curve of embodiment 1-16 is seen accompanying drawing 3 and 4
Clinical trial
Supply test preparation: aspirin enteric-coated slow releasing tablet (specification: the 50mg/ sheet is also referred to as own product)
Reference preparation: Bai Asi
(Beyer Co., Ltd produces, specification: the 100mg/ sheet)
Experimenter's example number: 20 healthy volunteers;
Sex: be the male, the age: 18-40 year;
Body weight: SBW ± 10%
Subject enrollment requires: must the heart, detections such as liver, kidney are normal person; Experiment the last fortnight and experimental session are not taken other drug; No tobacco and wine hobby; The medicine-less allergy history; The mental status is good, no familial psychiatric history; Diseases such as no gastritis, stomach concealed bleeding or gastric ulcer.
Experimental program: adopt dual crossing EXPERIMENTAL DESIGN scheme, promptly 20 men's health experimenters are divided into two groups of A, B immediately by body weight district group, take the Baysprin (100mg/ sheet) that Beyer Co., Ltd produces for one group; Another group is taken own product (50mg/ sheet); Dosage is 300mg; Two kinds of preparation 2 weeks of interval; The experimenter uses the 200ml warm water delivery service in 7:00 (medicine) being taken before meal usefulness in morning; Blood 3.0ml was got in ulnar vein in 1.0,2.0,3.0,4.0,5.0,6.0,7.0,8.0,10.0,12.0,24.0,48.0 hours in the back in taking medicine; Put in the heparinization test tube; Centrifugal under 3000rpm, shift blood plasma, place-80 ℃ of refrigerators to preserve immediately until analysis.Before the analysis, blood plasma melts the back and extracts in ice-water bath.
The plasma analysis instrument: the HP1100LC/MSD combined system contains two high-pressure pump, online vacuum degassing machine, automatic sampler, column oven, the four-electrode spectrum detector of electro-spray ionization interface and HP ChemStation RevA 06.03 chromatographic work stations.
Analyze chromatographic condition:
Mobile phase: methanol-acetonitrile-1% ammonium acetate (46:23:31, v/v/v)
Chromatographic column: Kromasil-ODS, 5 μ m, 250mm * 4.6mm I.D.
Flow velocity: 0.7ml/min
Column oven: 25 ℃
The MS detection parameters and electron spray parameter
MSD: selectivity ion detection
Ion polarity: anion
Ionizing mode: electro-spray ionization
Detect ion: aspirin 137 [M-CH
3CO]
-
Acetaminophen 150 [M-H]
-
Transmission voltage: 70V
Dry gas flow velocity: 10L/min
Aerochamber pressure: 30psig
Dry gas temperature: 300 ℃
Capillary voltage: 4000V
The processing of plasma sample: the accurate blood plasma 0.5ml that adds in test tube, and mark acetaminophen standard solution 20 μ l (20ng/ μ l) in adding, vibrated 10 seconds, add 0.1mol/l hydrochloric acid 0.1ml again, vibrated 30 seconds; (chloroform-isopropyl alcohol 95:5 v/v), vibrated 2 minutes, under 3000rpm centrifugal 10 minutes to add the 5ml organic solvent then.The quantitative 4ml of lower floor's organic facies is transferred in another test tube, and ice-water bath nitrogen dries up.With 200 μ l mobile phase dissolved residues, descended centrifugal 10 minutes for 4 ℃ in 18000rpm, supernatant is divided into two parts (each 80 μ), to measure with LC-MSD, sample size is 20 μ l.All operations all carries out under ice-water bath.
20 health volunteer's single dose own products (6 * 50mg/ sheet/people) back aspirin blood drug level-time data table (ng/ml)
(ND: be lower than concentration limit)
20 health volunteer's single dose Baysprin (3 * 100mg/ sheet/people) back aspirin blood drug level-time data table (ng/ml)
(ND: be lower than concentration limit)
Table 20 health volunteer's single oral dose own product (T) and Baysprin (R) back aspirin be area (AUC) and absorbance (%) under average blood drug level-time
Single dose aspirin The results of analysis of variance table
| ?Souce?of?variance | Freedom | SS | MS | F | P |
| ?Total?variance | 39 | 14.327 | |||
| ? |
1 | 0.7869 | 0.7869 | 4.6687 | 0.0444 * |
| ? |
1 | 2.0022 | 2.0022 | 11.8795 | 0.0029 ** |
| ?Subject | 19 | 8.5040 | 0.4476 | 2.6555 | 0.0217 * |
| ?Variances | 18 | 3.0338 | 0.1685 |
*: significant difference (p is arranged<0.05);
*: utmost point significant difference (p is arranged<0.01)
The two one-side t examination tables (α=0.05) of single dose aspirin
| Parameter | S | T 1 | T 2 | T (1-0.05)(18) | 90% confidence interval |
| AUC | 0.411 | 3.88 | -0.44 | 1.734 | 124.8-199.6% |
Aspirin pharmacokinetic parameter table behind the single oral dose own product
Aspirin pharmacokinetic parameter table behind the single oral dose Baysprin
The pharmacokinetics conclusion:
With Bai Asi
(R sheet) is reference preparation, is 166.2% (is index with the aspirin) with the average bioavailability of the own product (T sheet) of TG-AUC method estimation.AUC
0-24Through variance analysis, the result shows that there were significant differences for degree of absorption between two preparations and individuality.Two one-side t assays show, biological inequivalence between two preparations.90% confidence interval is 124.8-199.6%, and the AUC that receives test preparation is obviously greater than reference preparation.The biological half-life of Baysprin is 3.37 hours, and the half-life of own product is 5.06 hours, and it is the result owing to slow releasing function in the preparation that the latter is higher than the former.
Claims (10)
1. the method for preparing of an aspirin enteric-coated slow releasing preparation is characterized in that preparing earlier the aspirin sustained release tablet core, to the label enteric-coating layer, comprises the steps: again
(1) preparation label: with processing the slow release label behind aspirin and the direct mixed pressuring plate of acceptable accessories;
(2) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent processed enteric liquid, enteric coated on label.
2. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 1, it is characterized in that: the said acceptable accessories of step (1) is one or more in hypromellose, hyprolose, polyvidone, copolyvidone, starch, pregelatinized Starch, microcrystalline Cellulose, tartaric acid, citric acid, fumaric acid, lactose, dextrin or the sodium lauryl sulphate.
3. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 1, it is characterized in that: the said pharmaceutically acceptable enteric material of step (2) is one or more in acrylic resin, cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, phthalic acid hypromellose ester or the succinic acid acetic acid hypromellose ester;
The said plasticizer of step (2) is triethyl citrate, triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The said solvent of step (2) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
4. the method for preparing of an aspirin enteric-coated slow releasing preparation is characterized in that: preparation aspirin sustained release tablet core earlier, wrap sealing coat, at last enteric-coating layer more again; Preparation process is following:
(1) preparation label: with processing the slow release label behind aspirin and the direct mixed pressuring plate of acceptable accessories;
(2) bag sealing coat: acceptable accessories is constituted stomach dissolution type sealing coat or erosion type sealing coat through coating;
(3) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent processed enteric liquid, enteric coated on label.
5. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 4, it is characterized in that: the said acceptable accessories of step (1) is one or more in hyprolose, hypromellose, starch, pregelatinized Starch, microcrystalline Cellulose, tartaric acid, citric acid, fumaric acid, lactose, dextrin, polyvidone, the sodium lauryl sulphate.
6. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 4 is characterized in that: one or more in the said used acceptable accessories hyprolose of step (2), hyprolose, methylcellulose, sodium alginate, guar gum, chitosan, polyvidone, stearic acid, babassu sodium, the stearyl alcohol;
The said plasticizer of step (2) is triethyl citrate, triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The said solvent of step (2) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
7. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 4 is characterized in that: one or more in the said used acceptable accessories acrylic resin of step (3), cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, phthalic acid hypromellose ester or the succinic acid acetic acid hypromellose ester;
The said plasticizer of step (3) is triethyl citrate, triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, Polyethylene Glycol 3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The said antiplastering aid of step (3) is stearic acid and/or Pulvis Talci;
The said solvent of step (3) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
8. according to the method for preparing of the arbitrary described aspirin enteric-coated slow releasing preparation of claim 1 ~ 7, it is characterized in that: said aspirin is aspirin or its pharmaceutically acceptable salt.
9. the method for preparing of aspirin enteric-coated slow releasing preparation according to claim 8, it is characterized in that: said aspirin pharmaceutically acceptable salt is Aspirin-arginin or Aspirin-d1-lysine.
10. according to claim 1 or 4 described method for preparinies, it is characterized in that: containing under pH6.8 phosphate buffer, 37 ℃ and the 50rpm condition, according to two dissolution method the 2nd methods of Chinese Pharmacopoeia version in 2010, dissolution is as follows:
There is the aspirin of 10-40% to discharge after 1 hour;
There is the aspirin of 20-70% to discharge after 2 hours;
There is the aspirin of 40-90% to discharge after 4 hours;
There is the aspirin more than 80% to discharge after 6 hours.
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| CN1868482A (en) * | 2005-05-24 | 2006-11-29 | 张利 | Aspirin slow-release tablet and its prepn. method |
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| CN1868482A (en) * | 2005-05-24 | 2006-11-29 | 张利 | Aspirin slow-release tablet and its prepn. method |
| CN101596166A (en) * | 2008-06-04 | 2009-12-09 | 永信药品工业(昆山)有限公司 | Aspirin Intestine-soluble micro-pill |
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| CN103083275A (en) * | 2013-01-31 | 2013-05-08 | 扬子江药业集团有限公司 | Enteric coated tablet of fenofibric acid and physiologically acceptable salts and preparation method of enteric coated tablet |
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| CN109646412B (en) * | 2018-12-12 | 2021-07-02 | 中国药科大学 | Enteric-coated pharmaceutical composition and preparation method and application thereof |
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