CN101433546B - Capecitabine sustained and controlled release oral formulation and preparation method thereof - Google Patents
Capecitabine sustained and controlled release oral formulation and preparation method thereof Download PDFInfo
- Publication number
- CN101433546B CN101433546B CN2007100481374A CN200710048137A CN101433546B CN 101433546 B CN101433546 B CN 101433546B CN 2007100481374 A CN2007100481374 A CN 2007100481374A CN 200710048137 A CN200710048137 A CN 200710048137A CN 101433546 B CN101433546 B CN 101433546B
- Authority
- CN
- China
- Prior art keywords
- capecitabine
- release
- preparation
- coating
- magnesium stearate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a capecitabine oral sustained-release preparation and a preparation method thereof. The oral sustained-release preparation comprises the following components by weight percentage: 1) 50 to 90 percent of capecitabine, or pharmaceutically acceptable salt thereof, or ester derivative thereof, and 2) 10 to 50 percent of pharmaceutically acceptable accessories which comprise 4 to 44 percent of pharmaceutically acceptable sustained-release accessory. The preparation adopts the marketed pharmaceutical accessories, has high content of pharmaceutically active components (the weight percentage is more than 50 percent), and can release for 12 to 24 hours in a sustained mode.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of capecitabine oral sustained-release preparation and preparation method thereof.
Background technology
Cancer is to threaten one of the most serious disease of human life.In recent years, along with people's rhythm of life is accelerated, increasing environmental pollution, the sickness rate of cancer presents continuous trend of rising.In present stage, treatment for cancer adds chemotherapy based on operation.
Capecitabine (Capecitabine) is the novel prodrug of the 5-fluorouracil (5-FU) of Roche Holding Ag's exploitation, and its chemistry is by name: 5-deoxidation-5-fluoro-N-[(amoxy) carbonyl]-cytidine.Itself does not have activity capecitabine, finally changes 5-FU into and plays a role by three step enzyme reactions in vivo: (1) Carboxylesterase in liver changes 5 into '-deoxidation-5-fluorine cytidine (5 '-DFCR); (2) in liver and tumor tissues active higher cytosine deoxidation aminase be converted into doxifluridine (5 '-DFUR); (3) the gland pyrimi piperidine deoxidating nucleus glycosides phosphorylase (dThdPase) in tumor tissues is converted into activated 5-FU.
The existing preparation of capecitabine is often to release Film coated tablets, and two kinds of specifications of 150mg and 500mg are arranged, and adopts the form of taking half an hour after meal.Said preparation (medicine) being taken before meal usefulness absorbs rapidly fully, capecitabine and metabolite (5 '-DFC, 5 '-DFUR and 5-FU) peak time about 0.5 hour (5 '-DFC, 5 '-DFUR and 5-FU slightly delay successively), the elimination half-life is about 1 hour.One after each meal, food can not only postpone capecitabine and metabolite thereof (5 '-DFC, 5 '-DFUR and 5-FU) peak time (Tmax) is about 1.5 hours, can also reduce the highest blood drug level and bioavailability 60% and 35% of capecitabine respectively, the highest blood drug level and the bioavailability that reduce 5-FU are 43% and 21%.
From initial drug design, capecitabine wishes that also by oral route reaches the effect that the simulation vein continues infusion (continuousinfusion) 5-FU except the enzyme activating reaction by each step reaches certain cancer target.The effect that generally believes the venoclysis (continuousinfusion) that continues of 5-FU clinically is better than intravenous drip (bolous infusion).Present stage, vein continues infusion 5-FU and generally takes 24 hours continuous intravenous injections, and about 3 time-of-weeks to be a treatment cycle.Purpose is to keep the long stable state valid density of 5-FU.But after the existing preparation of capecitabine was taken in accordance with regulations, blood medicine peak time was about 2 hours, and eliminating the half-life is about 1 hour, can't reach and keep the purpose that vein continues to inject equally effective Css.
Document (S.A.Agnihotri, T.M.Aminabhavi.Novel interpenetrating networkchitosan-poly (ethylene oxide-g-acrylamide) hydrogel microspheres for thecontrolled release of capecitabine.International Journal of Pharmaceutics, 2006,324,103-115) adopting half mutual crosslinking net hydrogel microsphere of chitosan-poly-(oxirane-g-acrylamide) is slow-release material, as cross-linking agent, can make capecitabine reach 10 hours effect of external slow release with glutaraldehyde.But this material safety does not obtain estimating as yet, and the microsphere Chinese medicine content of its preparation is lower, and the dry weight ratio that medicine accounts for microsphere is 25～50% (envelop rates 78.2～87.2%).According to this ratio, need take the amount (calculating) of the preparation about 4g～8g every day according to routine dose, the preparation dose is big, may reduce compliance of patients, particularly may have unnecessary trouble to itself with regard to the patient that dysphagia is arranged.
Summary of the invention
Therefore, the technical problem to be solved in the present invention just provides a kind of capecitabine oral sustained-release preparation, and said preparation not only can delay the controlled release capecitabine, and what use is that safety has obtained the pharmaceutic adjuvant of proving conclusively, and active constituents of medicine content is higher.
The technical problem that the present invention also will solve provides the preparation method of described capecitabine oral sustained-release preparation.
The inventor is surprised to find that through extensive and deep research, uses the pharmaceutic adjuvant that has gone on the market to make the oral sustained-release preparation of capecitabine, and lasting drug release time can reach more than 12 hours.
Therefore, the present invention solves the problems of the technologies described above the technical scheme that is adopted and is: a kind of capecitabine oral sustained-release preparation, can contain following composition by the tablet total weight amount:
1) 50～90% capecitabine or its pharmaceutically acceptable salt or ester;
2) 10～50% acceptable accessories is comprising the adjuvant of 4～44% pharmaceutically acceptable slow-releasing and controlled-releasing actions.
The active component of capecitabine oral sustained-release preparation of the present invention is capecitabine or its pharmaceutically acceptable salt or ester.Described pharmaceutically acceptable salt can be hydrochlorate, sulfate, nitrate, acetate, tartrate, citrate, mesylate or maleate.
Preferable, the adjuvant of described slow-releasing and controlled-releasing action can be selected from one or more of hydrophilic gel material, wax lipid material and insoluble material.
Better, described hydrophilic gel material can be selected from hydroxypropyl emthylcellulose, carbopol, sodium carboxymethyl cellulose and alginate; Perhaps, described wax lipid material can be selected from hexadecanol, octadecanol, Cera Flava, Glyceryl Behenate, stearic acid and Brazil wax; Perhaps, described insoluble material can be selected from ethyl cellulose, acrylic resin, polyoxyethylene and polyethylene.
Preferable, described acceptable accessories can also be selected from conventional used other adjuvants such as porogen, filler, binding agent, lubricant, plasticizer and correctives of pharmaceutics, such as methylcellulose, polyoxyethylene ketopyrrolidine, lactose, microcrystalline Cellulose, starch, pregelatinized Starch, Icing Sugar, magnesium stearate, micropowder silica gel, Polyethylene Glycol, sodium bicarbonate, sodium carbonate and low-substituted hydroxypropyl cellulose etc.
Preferable, described sustained-release preparation is tablet, capsule or granule.Capsule can use pharmaceutically available any capsule as container containing.
Better, described tablet can be matrix tablet, film controlled release tablet or osmotic pump tablet; Perhaps, the implant of described capsule can be the small pieces of piller, film controlled release piller or the film controlled release of matrix type; Perhaps, described granule can be the piller or the small pieces of matrix type or coating type.
The present invention also provides a kind of preparation method of described capecitabine oral sustained-release preparation, and it comprises and will directly be prepared into the matrix type piller after slow controlled-release material and capecitabine or its pharmaceutically acceptable salt or the mixing of its esters derivative; Perhaps, will delay controlled-release material and capecitabine or its pharmaceutically acceptable salt or its esters derivative and mix, granulate tabletting; Perhaps, the medicine layer that is surrounded by capecitabine or its pharmaceutically acceptable salt or its esters derivative on celphere is made piller or small pieces.
Preferable, gained material reuse coating material carries out coating, perhaps punches behind the coating again.
Capecitabine oral sustained-release preparation of the present invention can be used for paclitaxel and includes that the anthracycline antibiotics chemotherapy regimen fails to respond to any medical treatment late period constitutional or metastatic breast cancer, gastric cancer and knot, rectal cancer etc.
Major advantage of the present invention is:
1) adopt the existing pharmaceutic adjuvant that goes on the market, safety is secure;
2) active constituents of medicine content higher (percentage by weight＞50%) can reduce the amount that patient takes preparation, improves compliance of patients;
3) controlled release be can delay 12 to 24 hours, capecitabine and metabolite thereof kept than stable blood concentration.
Description of drawings:
Further specify the present invention with accompanying drawing below, but the present invention is not limited.
Fig. 1 is the release in vitro curve of the capecitabine sustained-release preparation of embodiment 1 preparation.
Fig. 2 be among the embodiment 1 preparation and marketed tablet the capecitabine of beasle dog (beagle dog) and the plasma concentration curve of 5-fluorouracil.
The specific embodiment
Further specify the present invention with embodiment below, the condition that other not concrete experiment conditions that indicate are advised according to routine or manufacturer, but the present invention is not so limited.
Embodiment 1
Film controlling type delays controlled release micro pill, and its percentage by weight proportioning is as follows:
Capecitabine 80%
Preparation technology: adopt the known method of pharmaceuticals industry, principal agent is mixed with the filler microcrystalline Cellulose, add the aqueous solution that the adhesive sodium carboxymethyl cellulose is mixed with, the preparation soft material sieves granulate, preparation pastille micropill is used Aquacoat (Surelease then
) coating solution carries out coating.
This film controlling type delays controlled release micro pill, at 37 ℃, in the distilled water of the 900ml degassing, changes under 100 rpms of release conditions of basket method, can continue to discharge 12 hours.The release profiles of said preparation is seen Fig. 1.
The slow-release tablet of hydrophilic gel matrix material, its percentage by weight proportioning is as follows:
Capecitabine 51%
Hydroxypropyl methylcellulose 34%
Magnesium stearate 1%
Preparation technology: adopt the known method of pharmaceuticals industry,, prepare soft material with dehydrated alcohol with principal agent and adhesive polyvinylpyrrolidone, filler lactose and slow-release material hydroxypropyl methylcellulose uniform mixing, sieve, granulate, oven dry, granulate adds the magnesium stearate lubricant mixing, tabletting.
The slow-release tablet of this hydrophilic gel matrix material at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 16 hours.
Embodiment 3
Two kinds of bonded slow controlled release matrix tablets of wax lipid framework material, its percentage by weight proportioning is as follows:
Capecitabine 52%
Brazil wax 20%
Stearic acid 17%
Magnesium stearate 1%
Preparation technology: adopt the known method of pharmaceuticals industry, with principal agent and slow-release material Brazil wax and stearic acid, and and filler lactose uniform mixing, water is granulated, oven dry, granulate, adding magnesium stearate lubricant mixing, tabletting.
These two kinds of bonded slow controlled release matrix tablets of wax lipid framework material at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 24 hours.
Enteric membranous type sustained-release preparation, its percentage by weight proportioning is as follows:
Capecitabine 90%
Magnesium stearate 1%
Acrylic resin II 9%
Preparation technology: adopt the known method of pharmaceuticals industry, principal agent is directly granulated with aqueous solution, mix being pressed into label again with magnesium stearate, wrap acrylic resin II again as enteric coating.
This enteric membranous type sustained-release preparation at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 12 hours.
Embodiment 5
The matrix tablet of hydrophilic gel and insoluble material preparation, in conjunction with sustained release coating, its percentage by weight proportioning is as follows:
Capecitabine 75%
Ethyl cellulose 5%
Hydroxypropyl methylcellulose 14%
Magnesium stearate 1%
Polyacrylic resin 5%
Preparation technology: adopt the known method of pharmaceuticals industry, principal agent is mixed with slow-release material hydroxypropyl methylcellulose, ethyl cellulose, ethyl cellulose is mixed with 2% solution with ethanol, prepares soft material with it, sieve, granulate, oven dry, granulate and magnesium stearate lubricant mix, tabletting.The aqueous coatings liquid coating of reuse polyacrylic resin (Eudragit NE30D).
The matrix tablet of this hydrophilic gel and insoluble material preparation in conjunction with sustained release coating, at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 24 hours.
The bonded slow controlled release matrix tablet of hydrophilic gel material and wax lipid framework material, its percentage by weight proportioning is as follows:
Lactose 8%
Hydroxypropyl methylcellulose 20%
Polyvinylpyrrolidone 5%
Magnesium stearate 1%
Preparation technology: adopt the known method of pharmaceuticals industry,, granulate with dehydrated alcohol with principal agent and slow-release material hydroxypropyl methylcellulose and stearic acid, filler lactose, adhesive polyvinylpyrrolidone uniform mixing, oven dry, granulate adds the magnesium stearate lubricant mixing, tabletting.
This hydrophilic gel material and the bonded slow controlled release matrix tablet of wax lipid framework material at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 12 hours.
Embodiment 7
The slow controlled release granule formulation of coating type, its percentage by weight proportioning is as follows:
Capecitabine 51%
Hexadecanol 36%
Polyacrylic resin 5%
Preparation technology: adopt the known method of pharmaceuticals industry, earlier with principal agent and slow-release material hexadecanol, lecithin mixing, the adhesive polyvidone is mixed with alcoholic solution, prepare soft material with it, sieve, granulate, oven dry, granulate is prepared into sustained and controlled release granule with polyacrylic resin (EudragitE30D) coating.
The slow controlled release granule formulation of this coating type at 37 ℃, in the distilled water of the 900ml degassing, changes under 100 rpms of release conditions of basket method, can continue to discharge 16 hours.
Sustained and controlled release capsule, its percentage by weight proportioning is as follows:
Carbopol 28%
Micropowder silica gel 3%
Magnesium stearate 1%
Preparation technology: adopt the known method of pharmaceuticals industry, earlier with principal agent and slow-release material carbopol, ethyl cellulose mixing, 10% the povidone solution that adding is mixed with ethanol is as adhesive, the preparation soft material, sieve, granulate adds lubricant micropowder silica gel and magnesium stearate, is filled in the hard capsule.
This sustained and controlled release capsule at 37 ℃, in the distilled water of the 900ml degassing, changes under 100 rpms of release conditions of basket method, can continue to discharge 12 hours.
Embodiment 9
The agent of coating type slow-release tablet, its percentage by weight proportioning is as follows:
Low-substituted hydroxypropyl cellulose 6%
Hydroxypropyl emthylcellulose 7%
Acrylic resin 7%
Preparation technology: adopt the known method of pharmaceuticals industry, with principal agent and adhesive low-substituted hydroxypropyl cellulose, filler lactose mixing, granulate earlier, oven dry, granulate, adding magnesium stearate lubricant mixing, tabletting.Sealing coat is used its coating, drying with coating material hydroxypropyl emthylcellulose aqueous solution.Slow release layer coating material acrylic resin is mixed with isopropyl alcohol-acetone (both volume ratios 3: 2) solution of 12.5%, carries out coating again with it.
The agent of this coating type slow-release tablet at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 16 hours.
The osmotic pump type slow-release tablet, its percentage by weight proportioning is as follows:
Mannitol 16%
Polyvinylpyrrolidone 22%
Magnesium stearate 1.5%
Polyethylene Glycol 0.5%
Preparation technology: adopt the known method of pharmaceuticals industry,, add binding agent water system soft material, granulation, drying, granulate, adding magnesium stearate lubricant mix homogeneously, tabletting with principal agent and porogen mannitol, partially filled dose of polyvinylpyrrolidone uniform mixing.Slow-release material cellulose acetate, plasticizer Polyethylene Glycol and remaining polyvinylpyrrolidone are mixed with acetone soln, use its coating, and drying is solidified, and punches on the clothing film.
This osmotic pump type slow-release tablet at 37 ℃, in the distilled water of the 900ml degassing, under 100 rpms of release conditions of oar method, can continue to discharge 12 hours.
Experimental example 1
Laboratory animal:
6 healthy Beagle dogs, male and female half and half, body weight 12～15kg.Fasting 12h before the experiment, unified feed behind the administration 4h.
Administration and blood sampling scheme:
6 Beagle dogs are divided into two groups of A and B at random, determine medication order at random.In first week, the slow releasing tablet group: fasting is 12 hours before 3 beagle dogs, administration, give embodiment 1 made slow controlled release micro pill 500mg early morning, settle the stream sticking of needle of a 18G at its forelimb venule place, 0.25h after the administration, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 5.0h, 6.0h, 8.0h, 10.0h, 12.0h and 14.0h respectively vein get blood 3ml, place the plastic centrifuge tube that scribbles heparin, immediately 3000rmin
-1Centrifugal 10min, it is standby in-20 ℃ of preservations to get isolating blood plasma.The ordinary tablet matched group: fasting is 12 hours before 3 beagle dogs, administration, gives 1 of capecitabine ordinary tablet (500mg) early morning, settle the stream sticking of needle of a 18G at its forelimb venule place, 0.25h after the administration, 0.5h, 1.0h, 2.0h, 3.0h, 4.0h, 5.0h, 6.0h, 8.0h 10.0h, 12.0h and 14.0h vein respectively get blood 3ml, place the plastic centrifuge tube that scribbles heparin, immediately 4000rmin
-1Centrifugal 10min, it is standby in-20 ℃ of preservations to get isolating blood plasma.The first week experiment finishes, and eluting carries out the cross-over experiment in second week after one week, changes the sustained-release preparation group of last week into the ordinary tablet matched group, and the ordinary tablet matched group changes the sustained-release preparation group into, other experimental procedures same last weeks.
The mensuration of plasma drug level:
Blood plasma employing acetonitrile/ethyl acetate (1/4, V/V) be extractant, liquid-liquid extraction, the HPLC method is measured its concentration.As interior mark, measure capecitabine and 5 fluorouracil with ftorafur and 5-bromouracil simultaneously.A (1% formic acid), B (methanol) and C (water) ternary gradient elution 30min, preceding 20min adopt 10%A+90%C to carry out eluting, and back 10min adopts 10%A+70%B+20%C to carry out eluting.30 ℃ of column temperatures.Measure capecitabine and ftorafur with two utmost point array pipe detectors at 310nm, 266nm measures 5-fluorouracil and 5-bromouracil.
Fig. 2 is the capecitabine of the beasle dog (beagle dog) of the conventional tablet of slow controlled release micro pill of this film controlling type and contrast and the plasma concentration curve of 5-fluorouracil.
Claims (1)
1. capecitabine oral sustained-release preparation is characterized in that it is in following any:
(1) the slow controlled release micro pill of film controlling type, its percentage by weight proportioning is as follows:
Capecitabine 80%
Microcrystalline Cellulose 10%
Sodium carboxymethyl cellulose 2%
Ethyl cellulose 8%
Preparation technology: capecitabine is mixed with the filler microcrystalline Cellulose, add the aqueous solution that the binding agent sodium carboxymethyl cellulose is mixed with, the preparation soft material sieves, granulate, and preparation pastille micropill is used Aquacoat Surelease then
Coating solution carries out coating;
(2) enteric membranous type sustained-release preparation, its percentage by weight proportioning is as follows:
Capecitabine 90%
Magnesium stearate 1%
Acrylic resin II 9%
Preparation technology: capecitabine is directly granulated with aqueous solution, mix being pressed into label again with magnesium stearate, wrap the acrylic resin II again as enteric coating;
(3) coating type slow-release tablet agent, its percentage by weight proportioning is as follows:
Capecitabine 70%
Lactose 10%
Low-substituted hydroxypropyl cellulose 6%
Magnesium stearate 2%
Hydroxypropyl emthylcellulose 7%
Acrylic resin 7%
Preparation technology:, granulate earlier oven dry, granulate, adding magnesium stearate lubricant mixing, tabletting with capecitabine and binding agent low-substituted hydroxypropyl cellulose, filler lactose mixing; Sealing coat is used its coating, drying with coating material hydroxypropyl emthylcellulose aqueous solution; Slow release layer coating material acrylic resin is mixed with isopropyl alcohol-acetone soln of 12.5%, and isopropyl alcohol and acetone volume ratio 3: 2 are carried out coating again with it;
(4) osmotic pump type slow-release tablet, its percentage by weight proportioning is as follows:
Capecitabine 60%
Mannitol 16%
Polyvinylpyrrolidone 22%
Magnesium stearate 1.5%
Cellulose acetate 4%
Polyethylene Glycol 0.5%
Preparation technology: with capecitabine and porogen mannitol, partially filled dose of polyvinylpyrrolidone uniform mixing, add binding agent water system soft material, granulate, drying, granulate, adding magnesium stearate lubricant mix homogeneously, tabletting; Slow-release material cellulose acetate, plasticizer Polyethylene Glycol and remaining polyvinylpyrrolidone are mixed with acetone soln, use its coating, and drying is solidified, and punches on the clothing film.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100481374A CN101433546B (en) | 2007-11-13 | 2007-11-13 | Capecitabine sustained and controlled release oral formulation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100481374A CN101433546B (en) | 2007-11-13 | 2007-11-13 | Capecitabine sustained and controlled release oral formulation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101433546A CN101433546A (en) | 2009-05-20 |
| CN101433546B true CN101433546B (en) | 2011-03-30 |
Family
ID=40708288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100481374A Expired - Fee Related CN101433546B (en) | 2007-11-13 | 2007-11-13 | Capecitabine sustained and controlled release oral formulation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101433546B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201115211D0 (en) * | 2011-09-02 | 2011-10-19 | Slotervaart Participaties Bv | Composition |
| CN102302466A (en) * | 2011-09-09 | 2012-01-04 | 上海希迪制药有限公司 | Capecitabine medicinal composition capable of direct powder tableting, and application thereof |
| CN103156877B (en) * | 2011-12-13 | 2015-11-25 | 深圳海王药业有限公司 | A kind of capecitabine fast release micropill and preparation method thereof |
| CN103211798A (en) * | 2012-01-18 | 2013-07-24 | 北京天衡药物研究院 | Losartan potassium membrane controlled-release pellet capsule |
| CN102988328A (en) * | 2012-06-12 | 2013-03-27 | 上海中科高等研究院 | Method for preparing oral medicine for curing cancer, oral medicine for curing cancer and application thereof |
| WO2016203358A1 (en) * | 2015-06-13 | 2016-12-22 | Intas Pharmaceuticals Ltd. | Extended release capecitabine capsules |
| JP6866113B2 (en) * | 2016-11-01 | 2021-04-28 | 日本化薬株式会社 | Pharmaceutical preparation containing capecitabine as an active ingredient |
| CN114796147B (en) * | 2022-02-22 | 2023-05-05 | 郑州大学第一附属医院 | Capecitabine skeleton sustained-release preparation and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634584A (en) * | 2004-11-22 | 2005-07-06 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antimetabolite |
-
2007
- 2007-11-13 CN CN2007100481374A patent/CN101433546B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1634584A (en) * | 2004-11-22 | 2005-07-06 | 山东蓝金生物工程有限公司 | Anti-cancer medicine composition containing antimetabolite |
Non-Patent Citations (1)
| Title |
|---|
| 毕殿洲.第二节 片剂的辅料 第四节 缓释、控释制剂的处方和制备工艺.药剂学.人民卫生出版社,2003,(4),316-325，411，413-421. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101433546A (en) | 2009-05-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101433546B (en) | Capecitabine sustained and controlled release oral formulation and preparation method thereof | |
| KR20080059409A (en) | Pharmaceutical dosage forms having immediate release and/or controlled release properties | |
| CN101951896A (en) | Composite preparation | |
| CN104136004A (en) | Formulation of doxylamine and pyridoxine and/or metabolites or salts thereof | |
| CN103006612B (en) | Lisinopril controlled-release tablet and preparation method thereof | |
| CN101695575A (en) | Pharmaceutical composition containing statin-type lipid-lowering medicaments, phenformin-type hypoglycemic medicaments and nicotinic acid | |
| CN103919715A (en) | Controlled Release Drug Combination Containing Choline Alfoscerate Or Salt Thereof And Method For Preparing Same | |
| KR20170086063A (en) | Pharmaceutical bead formulations comprising dimethyl fumarate | |
| CN100475197C (en) | Oral sustained release pharmaceutical composition | |
| CN101380327B (en) | Anti-cancer composite sustained-release composition and preparation method thereof | |
| CN100486568C (en) | Loxoprofen sodium sustained release preparation | |
| CN102488670B (en) | Preparation method of dual slow-release potassium citrate sustained release preparation | |
| CN100556457C (en) | The pharmaceutical composition that contains nitrate esters medicine and Ivabradine | |
| CN1961887A (en) | Sustained releasing formulation of compound glucosamine, preparation process and application thereof | |
| CN101099762B (en) | Blood pressue lowering sustained-release preparation with chrysanthemum flower and pearl | |
| CN1248693C (en) | Sustained release formulation of glucosamine salt, its preparation and usage | |
| KR101925590B1 (en) | Formulation of fenofibric acid with improved bioavailability | |
| CN102058564A (en) | Zaltoprofen slow-release/controlled-release preparation and preparation method thereof | |
| CN102188388B (en) | Diclofenac sodium sustained-release pellet preparation and preparation method thereof | |
| CN104288107B (en) | Sustained-release floating micropill, pharmaceutical composition containing the pellet and preparation method thereof | |
| CN100490808C (en) | Gliquilone slow-releasing preparation | |
| CN104288106B (en) | Sustained-release floating micropill, pharmaceutical composition containing the micropill and preparation method thereof | |
| CN104856971B (en) | A kind of pulse dual-release preparation and the preparation method and application thereof | |
| CN106822014A (en) | Gliclazide gastric floating tablet and preparation method thereof | |
| CN102697761A (en) | Ibuprofen slow release solid composition and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110330 Termination date: 20161113 |