CN101444511B - Low dose entecavir formulation and use - Google Patents
Low dose entecavir formulation and use Download PDFInfo
- Publication number
- CN101444511B CN101444511B CN 200810170016 CN200810170016A CN101444511B CN 101444511 B CN101444511 B CN 101444511B CN 200810170016 CN200810170016 CN 200810170016 CN 200810170016 A CN200810170016 A CN 200810170016A CN 101444511 B CN101444511 B CN 101444511B
- Authority
- CN
- China
- Prior art keywords
- entecavir
- pharmaceutical composition
- carrier matrix
- low dose
- hepatitis
- 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 - Lifetime
Links
- 229960000980 entecavir Drugs 0.000 title claims abstract description 68
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- 239000000203 mixture Substances 0.000 title abstract description 36
- 238000009472 formulation Methods 0.000 title abstract 2
- 208000002672 hepatitis B Diseases 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 239000011159 matrix material Substances 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Compositions containing a low dose of entecavir are administered on a daily basis to treat hepatitis B virus infection and/or co-infections. Formulations for the oral administration of a low dose of entecavir are provided. Other pharmaceutically active substances can be included in the entecavir composition or can be separately administered for the treatment of hepatitis B virus infection or for the treatment of co-infected patients.
Description
The application is that the application number submitted on August 29th, 2000 is dividing an application of 00126403.6 the patent application that is entitled as " low dose Etikavi Prepn and application thereof ".
Technology neck city
The present invention relates to entecavir for the preparation of the purposes of medicine, be suitable for oral Tablet and Capsula agent in particular for preparation.
Entecavir (Entecavir), [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-(methylol)-2-methylene cyclopenta]-the 6H-purine-6-one,
Be the antiviral agent that is used for the treatment of hepatitis B virus infection, carrying out at present clinical evaluation.
Background technology
The people such as Zahler disclose the application of entecavir and treatment hepatitis B thereof in United States Patent (USP) 5206244. and effective antiviral dosage of the oral or parenteral introduction of this patent disclosure is about 1.0-50mg/kg body weight, and this required dosage can reasonable time interval administration every day several.
The people such as Bisacchi disclose the method for improved synthetic entecavir in WO98/09964.
Summary of the invention
The present invention relates to contain the pharmaceutical composition of low dose entecavir and the application that this class low dose group compound is used for safe and effective treatment hepatitis B virus infection.
The invention still further relates to the entecavir of low dosage and the method for the active compound combined treatment hepatitis B virus infection of other drug. other materials that are fit to this purpose comprise other antiviral agent and/or immunomodulator. entecavir and one or more other drug active substances can be combined in the same dosage form or can be separately independently dosage form plan simultaneously or sequentially administration according to prescription.
The invention still further relates to the pharmaceutical composition of the oral administration that contains the low-dose drugs active substance. said composition is to obtain by the surface that the granule that makes pharmaceutically active substance adheres to carrier matrix. making the method for pharmaceutically active substance calmness on carrier matrix is to be reduced to minimum for the gathering that makes active substance/carrier matrix granule.
The present invention relates to contain the pharmaceutical composition of the about 25mg low dosage of 0.001mg-antiviral agent entecavir of having an appointment, said composition is administered once and is used for the treatment of the hepatitis B virus infection of adult patient every day. and preferred pharmaceutical composition contains the entecavir of the about 10mg of 0.01mg-that has an appointment, most preferred pharmaceutical composition contains the about 5mg entecavir of the 0.01-that has an appointment. and this class preferably is administered once with most preferred pharmaceutical composition and is used for the treatment of the hepatitis B virus infection of adult patient every day.
The term adult patient be defined as the age be about more than 16 years old or 16 years old and body weight be equal to or higher than 50 kilograms patient. the pharmaceutical composition that contains the low entecavir of limiting the quantity of of above-mentioned scope is suitable for child patient or body weight are lower than patient's administration of 50 kilograms.
The above-mentioned low dose entecavir pharmaceutical composition that is used for administration every day also can be not too regularly to some patient's administration. for example, to treating the controlled patient of hepatitis B virus infection who makes them and can implement and keep therapeutic scheme so that it avoids further infection by taking the low dose entecavir pharmaceutical composition every day. this therapeutic scheme of keeping comprises that every day, deficiency was once taken the low dose entecavir compositions. for example, being administered once or being administered once weekly in per three or four days, just it is enough.
Low dose entecavir pharmaceutical composition of the present invention can be mixed with the form through any suitable administration. and for example preferred composition for oral administration can be tablet; capsule; granule or powder type; it perhaps can be elixir; solution or form of suspension. according to method well known in the art; the low dose entecavir pharmaceutical composition also can be mixed with non-gastrointestinal; the form of rectum or via intranasal application administration. this class preparation can comprise pharmaceutically acceptable excipient, and described excipient comprises extender commonly used in this based composition; lubricant; disintegrating agent; binding agent etc. the present invention also comprises slow releasing preparation.
Unexpectedly find now, take once low dose entecavir pharmaceutical composition of the present invention every day and can effectively treat hepatitis B virus infection, and can not be created in the harmful side effect that the high dose scheme administration described in the United States Patent (USP) 5206244 brings.
The invention still further relates to the method for uniting one or more other drug active substance treatment hepatitis B virus infections with above-mentioned low dose entecavir compositions. the other drug active substance that is suitable for this purpose comprises one or more antiviral agent, didanosine for example, lamivudine, abacavir, adefovir, adefovir dipivoxil, famciclovir, (2R, 4R)-4-(2,6-diaminourea-9H-purine-9-yl)-2-methylol-1,3-dioxolanes (DPAD), hepatitis B immune is regulated albumen (EHT899 of Enzo Biochem), emtricitabine, 1-(2-deoxidation-2-fluoro-beta-D-arabinofuranosyl base) thymus pyrimidine (FMAU), GLQ-223 (compd A, α-trichosanthin), epvudine (L-dT), epcitabine (L-dC), ribavirin, tenofovir (PMPA), 2 ', 3 '-dideoxy-2 ', 3 '-two dehydrogenations-β-L (-)-5-fluorine cytidine [L (-) Fd4C], and other fluoro L-and D-nucleoside. the pharmaceutically active substance that is suitable for this purpose also comprises one or more immunomodulators, alpha-interferon for example, beta-interferon, the pegylated interferon, alpha-Thymosin and Hepatitis B virus vaccine, for example HBV/MF59, Hepagene and Theradigm-HBV.
When the other drug active substance is suitable for oral administration, if they can be combined with low dose entecavir tablet or the capsule that forms single dose. one or more other drug active substances can not with the entecavir compatibility be combined in the same dosage form, for example, if administering mode is different or if administration frequency is different, then one or more other pharmaceutically active substance can be individually dosed, the dosage of one or more other active substances be its separately treatment usual amounts or decide the minimizing consumption by the doctor for the treatment of. independently dosage form can be planned simultaneously or sequentially administration according to prescription.
The present invention also comprises the method with above-mentioned low dose entecavir combination treatment accompanying infection patient. the accompanying infection patient is except infecting hepatitis B virus, also suffer from other the infecteds viral or the non-viral disease. especially, this class Therapeutic Method can be used for the hepatitis B patient of accompanying infection hepatitis C or HIV. and this accompanying infection patient preferably uses above-mentioned low dose entecavir compositions and the active compound combined treatment of one or more above-mentioned other drugs. and for example the patient of concurrent hepatitis B and hepatitis C also should use the low dose entecavir compositions to treat except using ribavirin and interferon treat.
On the other hand, the present invention is the preparation method of the pharmaceutical composition that content is less than or equal to about 10mg entecavir, especially Tablet and Capsula. and this based composition is not by making the even good preparation of content with active substance and mixed with excipients simply. and traditional method of granulating also is unsuitable for the biologically active prod of low dosage like this.
The Tablet and Capsula preparation that contains the about 10mg entecavir of the 0.001mg-that has an appointment can be prepared by the following method, with the efficient of guaranteeing product and good uniformity. at first the entecavir calmness is prepared compositions to the surface of carrier matrix. this step is finished by following operation: the solution that forms entecavir and adhesive material, then when keeping motion, the carrier matrix granule uses this solution in the mode of spraying or liquid stream. and controlled condition is so that the gathering of granule drops to minimum. subsequently, from the carrier surface desolventizing, the remaining entecavir that adheres to the carrier matrix surface. this has prevented that entecavir from separating with substrate and make the loss of entecavir drop to minimum in operation subsequently.
After the drying, with any other composition that comprises in the carrier matrix granule of entecavir coating and the compositions, for example disintegrating agent and/or mix lubricant. then the powder that obtains is pressed into sheet or is filled in the capsule.
During spray step, make the carrier matrix granule keep motion by mechanical agitation or airflow stirring. in the mechanical agitation method, carrier matrix is put into machinery (high shear) blender to be stirred. and the solution that will contain entecavir and adhesion substance is sprayed on the carrier matrix granule under atomizing pressure (0-2 bar) with the speed of controlling. and calm to carrier for making entecavir maximum ground, in case spray round carrier guaranteeing in the position of adjusting sprayer unit. the speed that control is calm and spray pattern are so that the gathering of granule drops to minimum. contain the solution of entecavir on the calmness, with wet entecavir/carrier matrix transfer of granules in exsiccator, pan dryer or fluidized bed dryer all are suitable for. at elevated temperatures desolventizing. and when solvent was water or the water of regulating pH, suitable temperature was about 50 ℃-Yue 80 ℃.
In the airflow stirring method, carrier matrix is put into the bottom with the cylinder of fine ga(u)ge screen. regulate the air-flow that enters so that the motion of matrix granule keeps constant and mobile. the balance carrier mass makes it reach about 25 ℃-Yue 80 ℃. and the solution that will contain entecavir and adhesive material is being sprayed on the carrier matrix granule under the above-mentioned atomizing pressure with speed control. has again, spray round carrier guaranteeing in the position of adjusting sprayer unit, in case and the speed of control calmness is so that the gathering of granule drops to minimum. calm upper entecavir solution, temperature is raise with desolventizing. when solvent is water or the water of regulating pH, the temperature that is fit to is about 50 ℃-Yue 80 ℃. in the airflow stirring method, the entecavir calmness can carried out in same device with the two steps operation of desolventizing on the carrier matrix, but in the mechanical agitation method, then need two kinds of devices.
Said method also has and reduces contacting of operator and entecavir in the facility environment.
Although what top method was described is the preparation that contains the pharmaceutical composition of the about 10mg entecavir of about 0.005mg-, they also can be used for preparing the pharmaceutical composition that contains any soluble agents active substance of low dosage.
Preferred solvent in the said method is water or the water of regulating pH. can be by adding acid, and for example the pH of hydrochloric acid reduction water improves the dissolubility of entecavir in water.
Adhesive material preferably has the polymer of high-consistency. and suitable material comprises polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, guar gum and xanthan gum, and polyvidone is preferred. and the content of adhesive material is preferably about 10% (weight) of about 1%-of compositions gross weight in the whole compositions.
Carrier matrix is the pharmaceutically useful material that is easy to by spray coating and is difficult for assembling. and suitable material comprises microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose, and microcrystalline Cellulose is preferred. and the content of carrier mass is preferably about 95% (weight) of about 80%-of compositions gross weight in the whole compositions.
About 1%-about 7%. suitable disintegrating agents that the disintegrant content that comprises in the whole compositions is preferably the compositions gross weight comprise polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose, Explotab, pre-gelatinized starch and corn starch, and polyvinylpolypyrrolidone is preferred.
About 0.1%-about 5%. suitable disintegrating agents that the lubricant content that comprises in the whole compositions is preferably the compositions gross weight comprise magnesium stearate, stearic acid, stearyl fumarate and sodium lauryl sulfate, and magnesium stearate is preferred.
The tablet of gained or capsule can be the film coatings, so that take. the suitable material that is used for the film coating is the coating materials of polymerization, pigment, plasticizer, solubilizing agent etc. the coating materials that is fit to comprises hydroxypropyl methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate etc. also can comprise the Polyethylene Glycol as plasticizer in the film coated composition. also can use other plasticizer in the film coated composition, for example citric acid diethylester and triethyl citrate. suitable solubilizing agent comprises polyoxyethylene sorbitan carboxylic ester, especially polysorbate80. suitable pigment comprises titanium dioxide and various ferrum oxide.
Composition in the coated composition being dispersed in suitable solvent, in the preferred water. coated composition can adopt conventional pan coating or spray coating technology to be used for tablet or capsule.
The specific embodiment
The following example illustrates low dose entecavir compositions of the present invention.
Embodiment 1
Adopt said method to prepare 10 microgram entecavir tablets
| Composition | Amount % (w/w) | Amount/sheet |
| Entecavir | 0.01 | 0.01mg |
| Microcrystalline Cellulose, NF | 93.24 | 93.24mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Polyvidone, USP | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
* remove by drying.
Embodiment 2
Adopt said method to prepare 10 milligrams of entecavir capsules.
| Composition | Amount % (w/w) | Amount/piece |
| Entecavir | 10.00 | 10.00mg |
| Microcrystalline Cellulose, NF | 82.03 | 82.03mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Polyvidone, USP | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Hydrochloric acid | 1.22 | 1.22mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
Capsule shells----
* remove by drying.
Embodiment 3
Adopt said method to prepare 50 microgram entecavir capsules.
| Composition | Amount % (w/w) | Amount/piece |
| Entecavir | 0.05 | 0.05mg |
| Dicalcium phosphate, NF | 93.20 | 93.20mg |
| Polyvinylpolypyrrolidone, NF | 4.00 | 4.00mg |
| Hydroxypropyl cellulose, NF | 2.50 | 2.50mg |
| Magnesium stearate, NF | 0.25 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
Capsule shells----
* remove by drying.
Embodiment 4
Adopt said method to prepare 1 milligram of entecavir tablet.
| Composition | Amount % (w/w) | Amount/sheet |
| Entecavir | 1.00 | 1.00mg |
| Mannitol, NF | 90.00 | 90.00mg |
| Cross-linking sodium carboxymethyl cellulose, NF | 4.00 | 4.00mg |
| Methylcellulose, NF | 2.50 | 2.50mg |
| Stearic acid, NF | 2.50 | 0.25mg |
| Pure water, USP * | In right amount | --- |
| Amount to | 100.00 | 100.00mg |
* remove by drying.
Embodiment 5
Adopt conventional pan coating or spray coating technology to carry out the film coating with the compositions of listing below to the 100mg tablet that contains the 0.01mg entecavir of embodiment 1 and the 100mg tablet that contains the 1.0mg entecavir of embodiment 4.
* remove by drying.
1Suppose heavily to calculate as 100mg take sheet.
2Suitable plasticizer is citric acid diethylester and triethyl citrate.
Embodiment 6
Human patients to chronic hbv-infection gives 28 days entecavir, with at random, safety and the antiviral activity of double blinding, placebo, dose titration test method research entecavir. under all test doses, entecavir all demonstrates effective antiviral activity. take respectively dose every day and be 0.05,0.1,0.5 and 1.0mg entecavir medicament, the average logarithm minimizing of the hepatitis B virus DNA level in the time of the 28th day in the blood is respectively 2.21,2.25,2.81 and 2.42.Entecavir is easy to the tolerance into the patient.
Claims (4)
1. an administration frequency is the oral pharmaceutical composition that is used for the treatment of the human patients hepatitis B virus infection once a day, contain the entecavir that is adhered to carrier matrix, wherein said carrier matrix is selected from microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose, and described entecavir is to be adhered on the substrate by stickum, and described pharmaceutical composition is tablet or capsule, wherein said stickum is polyvidone, and the content of described entecavir is 0.5mg.
2. an administration frequency is the oral pharmaceutical composition that is used for the treatment of the human patients hepatitis B virus infection once a day, contain the entecavir that is adhered to carrier matrix, wherein said carrier matrix is selected from microcrystalline Cellulose, calcium phosphate, dextrin, glucose, dextrates, mannitol, sorbitol and sucrose, and described entecavir is to be adhered on the substrate by stickum, and described pharmaceutical composition is tablet or capsule, wherein said stickum is polyvidone, and the content of described entecavir is 1.0mg.
3. the pharmaceutical composition of claim 1, wherein said carrier matrix is microcrystalline Cellulose.
4. the pharmaceutical composition of claim 2, wherein said carrier matrix is microcrystalline Cellulose.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18567200P | 2000-02-29 | 2000-02-29 | |
| US60/185672 | 2000-02-29 | ||
| US60/185,672 | 2000-02-29 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 00126403 Division CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
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| Publication Number | Publication Date |
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| CN101444511A CN101444511A (en) | 2009-06-03 |
| CN101444511B true CN101444511B (en) | 2013-01-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200810170016 Expired - Lifetime CN101444511B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN 00126403 Pending CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
| CN 200510128719 Ceased CN1813753B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN2012101468842A Pending CN102772413A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CNA2008101492879A Pending CN101385732A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
Family Applications After (4)
| Application Number | Title | Priority Date | Filing Date |
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| CN 00126403 Pending CN1310999A (en) | 2000-02-29 | 2000-08-29 | Low dose Etikavi Prepn. and the use thereof |
| CN 200510128719 Ceased CN1813753B (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CN2012101468842A Pending CN102772413A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
| CNA2008101492879A Pending CN101385732A (en) | 2000-02-29 | 2000-08-29 | Low dose entecavir formulation and use |
Country Status (4)
| Country | Link |
|---|---|
| CN (5) | CN101444511B (en) |
| HK (1) | HK1040196A1 (en) |
| UY (1) | UY26595A1 (en) |
| ZA (1) | ZA200205900B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1732944B (en) * | 2005-09-02 | 2013-05-08 | 海南中和药业有限公司 | Entecavir dispersible tablet and its preparation process |
| CN1820744B (en) * | 2006-04-04 | 2011-01-26 | 中国人民解放军军事医学科学院毒物药物研究所 | Oseltamivir phosphate granula and its preparing method |
| CN101244260B (en) * | 2007-02-14 | 2011-12-28 | 成都地奥九泓制药厂 | Combined medicament for treating chronic hepatitis B |
| CN101371841A (en) * | 2007-08-23 | 2009-02-25 | 浙江医药股份有限公司新昌制药厂 | Crystallization type Entecavir formulation as well as preparation method and use thereof |
| CN102578564A (en) * | 2011-11-01 | 2012-07-18 | 江苏江山制药有限公司 | Preparation method for rapid-disintegrating directly-pressed particle mannitol preparation |
| CN102416003A (en) * | 2011-12-08 | 2012-04-18 | 南京优科生物医药有限公司 | Method for preparing entecavir tablets |
| CN102552210B (en) * | 2012-01-10 | 2013-12-11 | 四川海思科制药有限公司 | Entecavir capsule and preparation method thereof |
| KR101285008B1 (en) * | 2012-04-18 | 2013-07-10 | 제일약품주식회사 | A method for preparing oral formulation of low dose entecavir |
| MX2017009913A (en) * | 2015-02-01 | 2018-08-15 | Orsenix Holdings Bv | High surface-area lyophilized compositions comprising arsenic for oral administration in patients. |
| CN112535736B (en) * | 2020-12-14 | 2023-08-29 | 石家庄四药有限公司 | Entecavir composition and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PH30929A (en) * | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
-
2000
- 2000-08-29 CN CN 200810170016 patent/CN101444511B/en not_active Expired - Lifetime
- 2000-08-29 CN CN 00126403 patent/CN1310999A/en active Pending
- 2000-08-29 CN CN 200510128719 patent/CN1813753B/en not_active Ceased
- 2000-08-29 CN CN2012101468842A patent/CN102772413A/en active Pending
- 2000-08-29 CN CNA2008101492879A patent/CN101385732A/en active Pending
-
2001
- 2001-02-23 UY UY26595A patent/UY26595A1/en not_active IP Right Cessation
-
2002
- 2002-03-04 HK HK02101639.3A patent/HK1040196A1/en unknown
- 2002-07-23 ZA ZA200205900A patent/ZA200205900B/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4489026A (en) * | 1982-09-07 | 1984-12-18 | The Upjohn Company | Process for preparing solid unit dosage forms of ultra-low dose drugs |
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
Non-Patent Citations (1)
| Title |
|---|
| A. Graul et al.BMS-200475.《Drugs of the Future》.1999,第24卷(第11期),1173-1177. * |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200205900B (en) | 2004-03-29 |
| CN102772413A (en) | 2012-11-14 |
| CN1813753B (en) | 2010-04-07 |
| CN1813753C (en) | |
| HK1040196A1 (en) | 2002-05-31 |
| UY26595A1 (en) | 2001-09-28 |
| CN1310999A (en) | 2001-09-05 |
| CN101444511A (en) | 2009-06-03 |
| CN1813753A (en) | 2006-08-09 |
| CN101385732A (en) | 2009-03-18 |
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