CN202777133U - Aspirin enteric controlled-release preparation - Google Patents
Aspirin enteric controlled-release preparation Download PDFInfo
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- CN202777133U CN202777133U CN 201220199167 CN201220199167U CN202777133U CN 202777133 U CN202777133 U CN 202777133U CN 201220199167 CN201220199167 CN 201220199167 CN 201220199167 U CN201220199167 U CN 201220199167U CN 202777133 U CN202777133 U CN 202777133U
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Abstract
The utility model relates to an enteric controlled-release preparation, and in particular relates to an aspirin enteric controlled-release preparation. According to the preparation, a prepared aspirin controlled-release tablet is used as a tablet core; and a coat layer of an enteric coating covers an outer layer of the tablet core. In order to prevent mutual function of the aspirin and the enteric material in the tablet core, a corrosion-type isolating layer is covered between the tablet core and the enteric coating. After the aspirin is prepared to be the enteric controlled-release preparation, the interior of the stomach nearly does not release or is released a few, so that the release time in the intestines is greatly prolonged, a furious cracking and dissolution phenomenon is avoided in the intestines, the aspirin is stably released, the bioavailability is greatly improved, the degradation reaction of the aspirin which encounters the water is avoided, the dosage time is reduced, and the complaisance of a patient is improved.
Description
Technical field
The present invention relates to a kind of enteric-coated sustained-release preparation, particularly a kind of aspirin enteric-coated slow releasing preparation.
Background technology
Aspirin (Aspirin) has another name called aspirin (Acetylsalicylic acid, ASA), is synthetic at first in 1853 by Charles Gerhardt, the NSAID (non-steroidal anti-inflammatory drug) 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, has capsule, slow releasing capsule, enteric coated capsule, tablet, oral cavity disintegration tablet, sublingual tablet, slow releasing tablet, enteric coated tablet, granule, gel, ointment, injection, elata chewing gum agent, powder, solution, drop, suppository etc. multiple.
The pharmaceutical salts of aspirin has Aspirin-d1-lysine, Aspirin-arginin etc.The former claims again Aspisol (Lysine aspirin), is the double salt of aspirin and lysine; The latter claims again Aspirin-arginine (Arginine aspirin), for aspirin and arginic double salt, is NSAID (non-steroidal anti-inflammatory drug).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 Yi Rong, characteristics little to GI irritation (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 by 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 drugs is rolled up with biological product) in 2005 Beijing: People's Health Publisher: 698).The clinical aspirin that confirmed comprises that to the antithrombotic disease diseases such as cerebral thrombosis, coronary heart disease, myocardial infarction, the past or recurrent cardiac 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 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)., can take for a long time or all the life without any untoward reaction such as the user.
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 at gastric, in preferably disintegrate of enteral and dissolving.This enteric coated preparation is usually by realizing (such as US 4716042) for tablet at its outer parcel enteric coating, but the also enteric coated enteric coated micropill (such as 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, by granulate (such as US 4857337 and CN 200810020313.8), coating, spray drying or form the mode such as solid dispersion and make the aspirin granule wrap the delayed release that enteric coating reaches aspirin.Now existing Aspirin Enteric-coated Tablets listing is such as the Baysprin of Beyer Co., Ltd's production
(external trade name:
Specification is 100mg), GSK company produces
(specification is 100mg).
Can also adopt slow controlled-release technology to reduce the gastrointestinal untoward reaction.Although greatly reduced the untoward reaction at gastric, this technology can not avoid aspirin to have part to discharge at gastric, and still larger to the infringement of stomach, life-time service also brings out gastrorrhagia (such as US 4601895).Therefore, also have aspirin made transdermal absorption formulation (such as US 5716636 and US 5861170) and suppository, the latter have marketing drugs (trade name:
).
Although enteric coated preparation can avoid aspirin in the release of 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 larger 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, namely is prepared into first the slow release label, and its outer coatings enteric coating can reduce the untoward reaction of aspirin to greatest extent, and clinical trial shows, with the Baysprin of Beyer Co., Ltd's production
(trade name of Aspirin Enteric-coated Tablets) compared, and 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 larger smell of vinegar is arranged.And the former is larger 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 acrylic resin, and (copolymer that comprises methacrylic acid and acrylic acid methyl ester., ethyl ester or butyl ester, commodity are by name
), (CAP, commodity are by name for cellulose acetate-phthalate
), (PVAP, commodity are by name for the polyvinyl acetate phthalic acid ester
), (HPMCAS, commodity are by name for Hydroxypropyl Methyl Cellulose Phthalate (HPMCP, commodity are called Mantrocel), succinic acid acetic acid hypromellose ester
) etc.If directly enteric coated on label, because aspirin directly contacts with enteric material, the former is accelerated 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 the 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, such as Yue Hongkun, Han Nana has proposed the preparation method of aspirin enteric-coated slow releasing preparation, adopt solid dispersion technology that aspirin is made first the enteric slow release solid dispersion, add again diluent, binding agent, lubricant etc. 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, but the problem that exists is to use enteric material more (optimal proportion of principal agent, enteric material Youteqi L-100 and enteric material Youteqi RD100 is 1:1:1.5 in the document, if every of principal agent is 100mg, then enteric material is 250mg), so that the tablet of making large (not adding in other adjuvant situations, at least also is 350mg); In addition, after the solid dispersion long term store, hardness occurs and become large, crystallize out, 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 preparation method of aspirin enteric-coated slow releasing capsule.The method is aspirin to be mixed by a certain percentage with the lipidic matrix such as cocoa butter, monopalmitin, Glyceryl Behenate and the adjustment release agent such as poloxamer, polyoxyethylene monostearate extrude, bag contagion gown and enteric coating are in incapsulating at last.Owing to do not make the intervention of water, so that the aspirin hydrolyzes reaction is suppressed.
The utility model content
This utility model provides a kind of enteric-coated sustained-release preparation of the NSAID (non-steroidal anti-inflammatory drug) be used to suppressing hematoblastic adhesion and gathering, has 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 occur at enteral, the release of aspirin is milder.
Aspirin enteric-coated slow releasing preparation of the present invention is to coat enteric coating layer in aspirin sustained release tablet sandwich layer outside.Be the aspirin sustained release tablet that will prepare 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: will make the slow release label behind aspirin and the direct mixed pressuring plate of pharmaceutically acceptable adjuvant;
(2) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent made enteric liquid, enteric coated on label;
The described pharmaceutically acceptable adjuvant 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 described pharmaceutically acceptable enteric material of step (2) is one or more in acrylic resin, cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate or the succinic acid acetic acid hypromellose ester;
The described plasticizer of step (2) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, PEG3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The described antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The described 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 aspirin sustained release tablet sandwich layer 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 prepared 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 as follows:
(1) preparation label: will make the slow release label behind aspirin and the direct mixed pressuring plate of pharmaceutically acceptable adjuvant;
(2) bag sealing coat: pharmaceutically acceptable adjuvant is consisted of stomach dissolution type sealing coat or erosion type sealing coat by coating;
(3) enteric-coating layer: after pharmaceutically acceptable enteric material, plasticizer, antiplastering aid and solvent made enteric liquid, enteric coated on label.
The described pharmaceutically acceptable adjuvant 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 described used pharmaceutically acceptable adjuvant hyprolose of step (2), hyprolose, methylcellulose, sodium alginate, guar gum, chitosan, polyvidone, stearic acid, babassu sodium, the stearyl alcohol one or more;
The described plasticizer of step (2) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, PEG3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The described antiplastering aid of step (2) is stearic acid and/or Pulvis Talci;
The described solvent of step (2) is ethanol and/or acetone, or the mixed solvent of ethanol and/or acetone and water.
In the described used pharmaceutically acceptable adjuvant acrylic resin of step (3), cellulose acetate-phthalate, polyvinyl acetate phthalic acid ester, Hydroxypropyl Methyl Cellulose Phthalate or the succinic acid acetic acid hypromellose ester one or more;
The described plasticizer of step (3) is triethyl citrate, triacetyl glycerine, PEG400, Macrogol 600, Macrogol 4000, PEG3350, polyethylene glycol 6000, propylene glycol, glycerol or acetylation triethyl citrate;
The described antiplastering aid of step (3) is stearic acid and/or Pulvis Talci;
The described 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 (ArginineAspirin).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 to greatest extent aspirin in the gastrointestinal untoward reaction, reduces simultaneously the undulatory property of blood drug level, makes blood drug level more steady, plays in vivo long-acting characteristics.This present invention has adopted slow release method and enteric technology simultaneously.The former has avoided the quick 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 the 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.Report a kind of preparation method of enteric-coated sustained-release tablet such as 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 preparation method (patent CN 201010195587.8) of enteric-soluble controlled-release capsule, this patent is first aspirin to be mixed with biodegradation framework material and release regulator, successively wrap contagion gown and enteric coating again, in incapsulating at last.
The utlity model has following advantage:
1. directly mix with slow-release material and other adjuvants by 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 the phenomenons such as fierce disintegrate and stripping occur 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 is not subjected to the not impact of coordination section of gastrointestinal tract, or impact is very little, discharges medicine and has the zero-order release feature; 5. with the Baysprin that has gone on the market
(Beyer Co., Ltd's production) is compared, and the preparation that this patent provides reaches peak concentration and peak time prolongs to some extent, and 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, for reaching in the identical body area (AUC) under the blood drug level and time graph, can reduce dosage.
Description of drawings
The aspirin enteric-coated slow releasing preparation that Fig. 1 is comprised of label and enteric coating layer;
The aspirin enteric-coated slow releasing preparation that Fig. 2 is comprised of label, sealing coat and enteric coating layer;
Fig. 3 is Baysprin
Stripping curve comparison diagram with embodiment 1-8;
Fig. 4 is Baysprin
Stripping curve comparison diagram with embodiment 9-16;
Fig. 5 is the blood drug level comparison diagram of own product and Baysprin;
Among the figure: 1, aspirin sustained release tablet core; 2, sealing coat; 3, enteric coating layer.
The specific embodiment
The invention will be further described below in conjunction with embodiment.
Aspirin enteric-coated slow releasing preparation described in the utility model, its characteristics are: aspirin sustained release tablet sandwich layer 1 outside coats enteric coating layer 3; Between aspirin sustained release tablet sandwich layer 1 and enteric coating layer 3, increase sealing coat 2.
Prescription
⑴ label
⑵ enteric coating layer
Technique
⑴ film-making core is got aspirin and is added hypromellose K15M, microcrystalline Cellulose PH102, lactose and sodium lauryl sulphate, mix homogeneously.Place rotary tablet machine (C﹠amp; C800, Beijing wound Bo Jiawei Science and Technology Ltd., lower with) in, adopting diameter is the circular stamping of dimple form of 6mm, the heavy and pressure of adjustment sheet, control hardness is 50-80N, prepares altogether 1000.
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 seed-coating machine (BGB-5B type, the Pharmaceutical Equipment Factory, Wenzhou City, lower same) in, seed-coating machine rotating speed, hydrojet speed, inlet temperature, air intake air pressure, atomizing pressure, sheet spray base regulated, 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 lower heat preservation and drynesses.
Above-mentioned preparation method 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
Technique
⑴ film-making core is got aspirin and is added HPMC 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 altogether 1000.
⑵ bag sealing coat is got hypromellose, PEG400 is dissolved in 60% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the aspirin enteric-coated slow releasing tablet that specification is 50mg.
Prescription
⑴ label
⑵ enteric coating layer
Technique
⑴ film-making core is got aspirin and is added hydroxyl methylcellulose Klucel HF(Aqualon company and produce), 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 altogether 1000.
⑵ enteric-coating layer is got acetone, adds Hydroxypropyl Methyl Cellulose Phthalate, triacetyl glycerine and glycerol, stirs, and adds entry and Pulvis Talci, mix homogeneously again.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the aspirin enteric-coated slow releasing tablet that specification is 75mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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, PEG3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the aspirin enteric-coated slow releasing tablet that specification is 100mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
⑴ film-making core is got aspirin, adds HPMC 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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, PEG3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the aspirin enteric-coated slow releasing tablet that specification is 300mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
⑴ film-making core is got aspirin, adds hypromellose K15M, starch, PVP K30 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the aspirin enteric-coated slow releasing tablet that specification is 500mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
⑴ film-making core is got Aspisol, adds hypromellose K15M, starch, PVP K30 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the Aspisol enteric-coated sustained-release tablet that specification is 45mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
⑴ film-making core is got Aspisol, adds hypromellose K15M, starch, PVP K30 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 altogether 1000.
⑵ bag sealing coat is got methylcellulose, polyvidone, PEG400, PEG3350 and Pulvis Talci, is dissolved in 40% alcoholic solution, stirs it is dissolved fully.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the Aspisol enteric-coated sustained-release tablet that specification is 90mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
⑴ film-making core is got Aspisol, adds HPMC 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the Aspisol enteric-coated sustained-release tablet that specification is 180mg.
Prescription
⑴ label
⑵ contagion gown layer
⑶ enteric coating layer
Technique
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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method 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
Technique
⑴ film-making core is got Aspisol, adds HPMC 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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, PEG3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the Aspisol enteric-coated sustained-release tablet that specification is 900mg.
Prescription
⑴ label
⑵ enteric coating layer
Technique
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, dextrin, PVP K30 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method 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
Technique
⑴ film-making core is got Aspirin-arginine, adds HPMC 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method can obtain the Aspirin-arginine enteric-coated sustained-release tablet that specification is 100mg.
Prescription
⑴ label
⑵ enteric coating layer
Technique
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, hyprolose, PVP K30 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 altogether 1000.
⑵ enteric-coating layer is got 95% ethanol (v/v), adds acrylic resin I number, acrylic resin III number, triacetyl glycerine, PEG3350 and Pulvis Talci, stirs, and adds entry, mix homogeneously again.Above-mentioned tablet is placed seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method 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
Technique
⑴ film-making core is got Aspirin-arginine, adds hypromellose K15M, starch, PVP K30 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 altogether 1000.
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 seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method 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
Technique
⑴ film-making core is got aspirin, adds HPMC 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 altogether 1000.
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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 seed-coating machine, regulate seed-coating machine rotating speed, hydrojet speed, inlet temperature, 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 preparation method 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 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
The hydrochloric acid solution of dissolution medium: 0.1mol/L
Rotating speed: per minute 50 turns
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 turns
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: Baysprin
(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: standard body weight ± 10%
Subject enrollment requires: must the heart, the detections such as liver, kidney are normal person; Experiment the last fortnight and experimental session are not taken other drug; Have a liking for without tobacco and wine; The medicine-less allergy history; The mental status is good, without the familial psychiatric history; Without diseases such as gastritis, stomach concealed bleeding or gastric ulcers.
Experimental program: adopt dual crossing EXPERIMENTAL DESIGN scheme, namely 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 2 weeks of preparation interval; The experimenter uses the 200ml warm water delivery service in 7:00 (medicine) being taken before meal usefulness in morning; Got blood 3.0ml 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 after take medicine, put in the heparinization test tube, centrifugal under 3000rpm, shift blood plasma, place immediately-80 ℃ of Refrigerator stores until analyze.Before the analysis, after melting in ice-water bath, extracts blood plasma.
The plasma analysis instrument: the HP1100LC/MSD combined system contains two high-pressure pumps, online vacuum degassing machine, automatic sampler, column oven, the four-electrode spectrum detector of Electrospray Ionization Interface and HP ChemStation RevA06.03 chromatographic work station.
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 again 0.1mol/l hydrochloric acid 0.1ml, vibrated 30 seconds; Then add 5ml organic solvent (chloroform-isopropyl alcohol 95:5, v/v), vibrated 2 minutes, under 3000rpm centrifugal 10 minutes.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 in 4 ℃ of 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.
Aspirin blood drug level behind 20 health volunteer's single dose own products (6 * 50mg/ sheet/people)-time data table (ng/ml)
(ND: be lower than concentration limit)
Aspirin blood drug level behind 20 health volunteer's single dose Baysprin (3 * 100mg/ sheet/people)-time data table (ng/ml)
(ND: be lower than concentration limit)
The rear aspirin of table 20 health volunteer's single oral dose own product (T) and Baysprin (R) is 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＜0.05) is arranged; *: utmost point significant difference (p＜0.01) is arranged
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% |
Pharmacokinetics of Aspirin parameter list behind the single oral dose own product
Pharmacokinetics of Aspirin parameter list behind the single oral dose Baysprin
The pharmacokinetics conclusion:
With Baysprin
(R sheet) is reference preparation, is that 166.2%(is take aspirin as index with the average bioavailability of the own product (T sheet) of area under curve method estimation).AUC
0-24Analysis of variance, 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%, is subjected to the AUC of test preparation 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 because the result of slow releasing function in the preparation that the latter is higher than the former.
Claims (1)
1. an aspirin enteric-coated slow releasing preparation is characterized in that: aspirin sustained release tablet sandwich layer (1) outside coating enteric coating layer (3), increase erosion type sealing coat (2) between aspirin sustained release tablet sandwich layer (1) and the enteric coating layer (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201220199167 CN202777133U (en) | 2012-05-07 | 2012-05-07 | Aspirin enteric controlled-release preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201220199167 CN202777133U (en) | 2012-05-07 | 2012-05-07 | Aspirin enteric controlled-release preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN202777133U true CN202777133U (en) | 2013-03-13 |
Family
ID=47804490
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201220199167 Expired - Lifetime CN202777133U (en) | 2012-05-07 | 2012-05-07 | Aspirin enteric controlled-release preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN202777133U (en) |
-
2012
- 2012-05-07 CN CN 201220199167 patent/CN202777133U/en not_active Expired - Lifetime
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