CN110420188A - A method of improving Entecavir tablet uniformity of dosage units - Google Patents
A method of improving Entecavir tablet uniformity of dosage units Download PDFInfo
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- CN110420188A CN110420188A CN201910723375.3A CN201910723375A CN110420188A CN 110420188 A CN110420188 A CN 110420188A CN 201910723375 A CN201910723375 A CN 201910723375A CN 110420188 A CN110420188 A CN 110420188A
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- entecavir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
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Abstract
The invention discloses a kind of methods for improving Entecavir tablet uniformity of dosage units, its prescription includes: Entecavir, sodium alginate, filler, glidant, disintegrating agent and pharmaceutically acceptable auxiliary material, Entecavir is mixed with the aqueous solution of sodium alginate, with the granulation of other auxiliary materials, tabletting.It by the selection of material and the optimization of preparation process, obtains Entecavir tablet of the invention and dissolves out, uniformity of dosage units is high, and in addition the present invention uses general preparation process, does not need complicated preparation equipment, is easy to industrialized production.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a method of Entecavir tablet uniformity of dosage units is improved,
Background technique
Entecavir (Entecavir) is a kind of nucleoside analog by Bristol-Myers Squibb Co.'s independent research, 2005
Obtain the listing approval of FDA year, dosage form has tablet and oral solution, chemical name: 2- amino -9- [(1S, 3R, 4S) -4- hydroxyl -
3- methylol -2- methylenecyclopentyl] -1,9- dihydro -6H- purine-6-one monohydrate；Molecular formula: C12H15N5O3H2O；Point
Son amount: 295.3；Chemical structural formula:
Entecavir is a kind of guanosine analog of effective as selective inhibition hepatitis B replication, to second
Hepatovirus polymerase is inhibited, and Canadian treating hepatitis B guide ratings Entecavir is that have strongest anti-virus ability
With the antiviral drugs of minimum drug resistance incidence, the Chronic Hepatitis B one which kind of viral load levels no matter be in can be used as
The selection of line treatment.
Entecavir is readily soluble in DMF, slightly molten in faintly acid or weakly alkaline solution, in methyl alcohol slightly soluble, in water, ethyl alcohol
Middle soluble,very slightly, it is almost insoluble in acetonitrile.Therefore, main direction of studying is concentrated on how improving entecavir by Many researchers
The dissolution of Wei preparation, thus improve in the bioavilability of Entecavir, such as patent CN1813753A, CN 101181224B,
CN102100677A etc., proposes using solid dispersions or is made the form of dispersible tablet, and purpose is to improve in preparation
The dissolution of Entecavir.
The drug content for the Entecavir tablet that original is ground be 0.5mg/200mg, i.e., 0.25%, drug content is low, in preparation mistake
It is more difficult in journey to be uniformly mixed, have a great impact to the uniformity of dosage units of tablet.Therefore, how by process optimization, improve piece
The uniformity of dosage units of agent complies with even better than pharmacopoeial requirements, improves drug safety and validity, while meeting industrialization
The needs of production also should be the emphasis for needing to pay close attention in preparation process research process.
Improve the method for the tablet content uniformity at present mainly by pelletizing after equal increments mixing, however equal increments
Method is cumbersome, will cause certain loss again in the process.
Summary of the invention
The object of the present invention is to provide a kind of methods for improving Entecavir tablet uniformity of dosage units, including prescription and system
Standby technique, using specific ratio of adjuvant and preparation process, this method simple process is suitable for industrialized production, meets drug
Standard requirements, and can be in the case where guaranteeing has good dissolution, hence it is evident that improve the uniformity of dosage units of tablet.
In order to achieve the above objectives, the present invention specifically uses following method:
A method of Entecavir tablet uniformity of dosage units, including prescription and technique being improved, wherein prescription includes: entecavir
Wei, sodium alginate, filler, glidant, disintegrating agent and pharmaceutically acceptable auxiliary material；Preparation process is by Entecavir
After mixing with the aqueous solution of sodium alginate, with other auxiliary material mixing granulations, tabletting.
The Entecavir tablet, the dosage of sodium alginate are 1%~10%, preferably 2%.
The Entecavir tablet, filler therein can be the mixing of one or both of microcrystalline cellulose, lactose
Object.
The Entecavir tablet, glidant therein can be superfine silica gel powder, magnesium stearate, talcum powder, dodecyl sulphur
One of sour sodium.
The Entecavir tablet, disintegrating agent therein can be fine for pregelatinized starch, crospovidone, low substituted hydroxy-propyl
Tie up one of element or a variety of.
The preparation process of the Entecavir tablet, comprising the following steps:
I is configured to sodium alginate 3% aqueous solution, and Entecavir is added, and being sufficiently stirred is uniformly mixed it；
II by above-mentioned mixed solution and filler, glidant and disintegrating agent mixing granulation, and tabletting to obtain the final product.
The preparation process of the Entecavir tablet, in tableting step, key process parameter is as follows:
Tabletting principal pressure: 4~8KN；
Piece is thick: standard film thickness ± 0.02mm
Average hardness: 7.5 ± 2kg
By adopting the above technical scheme, Entecavir is blended in sodium alginate soln by the present invention, improves Entecavir
Mixture homogeneity, while sodium alginate can guarantee gained entecavir tablets as excellent disintegrating agent and adhesive
Dissolution.Compared with prior art, using the resulting entecavir tablets of technical solution of the present invention, preparation process is simple, does not need
Other organic solvents are added, the safety of production can be improved while reducing process costs, while also can guarantee Entecavir
Dissolution and improve Entecavir tablet uniformity of dosage units.
Specific embodiment
It is right combined with specific embodiments below in order to make those skilled in the art more fully understand technical solution of the present invention
The present invention is described in further detail.It should be noted that following embodiment is for explaining only the invention, without limiting this
Invention.
Reagent that following embodiment is related to, supplementary material, operating procedure unless otherwise specified can be in laboratory and correlations
It is obtained in Laboratory Manual.
Embodiment 1
Sodium alginate: being made into distilled water 3% solution by preparation process, and Entecavir is added, after stirring,
Obtain mixed solution；By above-mentioned mixed solution and lactose, microcrystalline cellulose, crospovidone mixing granulation, 20 mesh sieves, 60 DEG C
After drying, superfine silica gel powder is added, is sufficiently mixed uniformly, tabletting is made 2500,4~8KN of tablet forming technique parameter tabletting principal pressure；
Piece thickness standard film thickness ± 0.02mm；7.5 ± 2kg of average hardness.
Embodiment 2
Sodium alginate: being made into distilled water 3% solution by preparation process, and Entecavir is added, after stirring,
Obtain mixed solution；By above-mentioned mixed solution and lactose, pregelatinized starch mixing granulation, 20 mesh sieves are added after 60 DEG C of drying
Superfine silica gel powder is sufficiently mixed uniformly, and tabletting is made 2500,4~8KN of tablet forming technique parameter tabletting principal pressure；Piece thickness standard film
Thickness ± 0.02mm；7.5 ± 2kg of average hardness.
Embodiment 3
Sodium alginate: being made into distilled water 2.5% solution by preparation process, and Entecavir is added, stirs
Afterwards, mixed solution is obtained；By above-mentioned mixed solution and microcrystalline cellulose, low-substituted hydroxypropyl cellulose mixing granulation, 20 meshes are whole
Magnesium stearate is added after 60 DEG C of drying in grain, is sufficiently mixed uniformly, tabletting is made 2500, tablet forming technique parameter tabletting principal pressure
4~8KN；Piece thickness standard film thickness ± 0.02mm；7.5 ± 2kg of average hardness.
Embodiment 4
Sodium alginate: being made into distilled water 3% solution by preparation process, and Entecavir is added, after stirring,
Obtain mixed solution；By above-mentioned mixed solution and microcrystalline cellulose, crospovidone, pregelatinized starch mixing granulation, 20 meshes are whole
Talcum powder is added after 60 DEG C of drying in grain, is sufficiently mixed uniformly, tabletting is made 2500, tablet forming technique parameter tabletting principal pressure 4
~8KN；Piece thickness standard film thickness ± 0.02mm；7.5 ± 2kg of average hardness.
Embodiment 5
Sodium alginate: being made into distilled water 3% solution by preparation process, and Entecavir is added, after stirring,
Obtain mixed solution；Above-mentioned mixed solution is mixed with microcrystalline cellulose, lactose, crospovidone, low-substituted hydroxypropyl cellulose
Granulation, 20 mesh sieves are added superfine silica gel powder after 60 DEG C of drying, are sufficiently mixed uniformly, tabletting is made 2500, tablet forming technique
4~8KN of parameter tabletting principal pressure；Piece thickness standard film thickness ± 0.02mm；7.5 ± 2kg of average hardness.
Comparative example 1
Preparation process: Entecavir air-flow crushing, Entecavir and 20g lactose is progressively increased by equivalent by D90=11.8 μm
Mode is uniformly mixed, then is uniformly mixed with the crospovidone of remaining lactose, microcrystalline cellulose, half amount, and povidone is added
Aqueous solution granulation, whole grain, and dry particl is obtained with fluidized bed drying, remaining crospovidone and magnesium stearate is added in dry particl
Mixing, tabletting form.
Comparative example 2
Prescription: Entecavir 2.5g pregelatinized starch 500g microcrystalline cellulose 500g
Preparation process: microcrystalline cellulose, pregelatinized starch are crossed into 80 meshes, Entecavir is sieved with 100 mesh sieve spare；By grace
It is mixed 4 times for Ka Wei and microcrystalline cellulose using equivalent gradually-increased, crosses 80 meshes after mixing every time, obtain mixture 1., will mix
1. object progressively increases with 1 equivalent of pregelatinized starch progress being sieved mixes, and the dispersion of 80 meshes is crossed after mixing, obtains mixture 2., will
Mixture 2., remaining microcrystalline cellulose, remaining pregelatinized starch mixing；Mixed-powder is placed in Mixers with Multi-direction Movement and is carried out
Total mix, sets mixing velocity as 1100r/min, incorporation time 30min；Pressed powder forms.
Comparative example 3
Preparation process: then 80 DEG C of heating meltings of copolyvidone are added recipe quantity Entecavir, are stirred to dissolve, then
This molten liquid is pelletized on lactose and the mixed powder of crospovidone, recipe quantity magnesium stearate is added in 20 mesh sieves, and mixing is equal
Even, tabletting forms.
1 dissolution determination of experimental example
Tablet made from above-described embodiment and comparative example is taken, measures the dissolution rate of Entecavir respectively.
Measuring method: it is measured according to dissolution method (four general rules of Chinese Pharmacopoeia version in 2015,0,931 second method).
Using the phosphate buffer 1 000ml of pH6.8 as dissolution medium, revolving speed is 50 turns per minute, is operated according to methods, through 20
It when minute, takes dissolution fluid appropriate, filters, take subsequent filtrate as test solution；Separately take Entecavir reference substance appropriate, precision claims
Calmly, it is dissolved with the phosphate buffer of pH6.8 and quantifies dilution and solution identical with test solution concentration is made, as control
Product solution.It measures according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), is bonded with octadecylsilane
Silica gel is filler, and with acetonitrile-water (8: 92) for mobile phase, 30 DEG C of column temperature, flow velocity 1.0ml/min, Detection wavelength is
254nm.Precision measures test solution and control solution in right amount (each each 50 μ l of 100 μ l, 1mg specification of 0.5mg specification), respectively
Liquid chromatograph is injected, chromatogram is recorded.Go out with calculated by peak area every the amount of dissolution by external standard method.
The dissolution determination result of 1 embodiment of table and comparative example
| Embodiment | Dissolution rate (%) |
| Embodiment 1 | 100.3 |
| Embodiment 2 | 100 |
| Embodiment 3 | 99.4 |
| Embodiment 4 | 99.8 |
| Embodiment 5 | 98.9 |
| Comparative example 1 | 79.5 |
| Comparative example 2 | 81.4 |
| Comparative example 3 | 77.6 |
As shown in Table 1, embodiment each group substantially all dissolution in 5 minutes, comparative example obtain result of extraction significantly lower than this
Invention.
Experimental example 2: Determination of Content Uniformity
Entecavir tablets made from Example and comparative example measure uniformity of dosage units.
Measuring method: it is measured according to high performance liquid chromatography (four general rules 0941 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica；With acetonitrile-water (3:
It 97) is mobile phase A；Using acetonitrile as Mobile phase B, according to the form below carries out gradient elution；30 DEG C of column temperature, flow velocity 1.0ml/min, detection
Wavelength is 254nm.It is appropriate to weigh Entecavir reference substance, adds mobile phase A to dissolve and dilutes and be made in every 1ml containing about Entecavir
200 μ g are as system suitability solution.It takes 20 μ l to inject liquid chromatograph, records chromatogram.
Measuring method precision weighs this product 1, sets in 50ml measuring bottle, adds 0.01mol/L hydrochloric acid appropriate, ultrasound makes Entecavir
Dissolution, lets cool to room temperature, adds 0.01mol/L hydrochloric acid to be settled to scale, shake up, and filters, takes subsequent filtrate as test solution；Separately
Take Entecavir reference substance appropriate, it is accurately weighed, add 0.01mol/L dissolving with hydrochloric acid and quantify dilution and is made in every 1ml containing about grace
For the solution of card Wei 0.1mg, as reference substance solution.Precision measures each 20 μ l of test solution and control solution, infuses respectively
Enter liquid chromatograph, record chromatogram, by external standard method with calculated by peak area to get.
2 embodiment of table and comparative example Determination of Content Uniformity result
As can be seen from Table 2, embodiment and comparative example is all satisfied the requirement of A+2.2S≤15.0, but is compared by RSD,
The RSD of embodiment each group is significantly less than comparative example each group, shows that embodiment each group uniformity of dosage units is more preferable compared with comparative example.
Claims (8)
1. a kind of method for improving Entecavir tablet uniformity of dosage units, including prescription and technique, wherein prescription includes: entecavir
Wei, sodium alginate, filler, glidant, disintegrating agent and pharmaceutically acceptable auxiliary material；Preparation process is by Entecavir
After mixing with the aqueous solution of sodium alginate, with other auxiliary material mixing granulations, tabletting.
2. Entecavir tablet as described in claim 1, which is characterized in that the dosage of sodium alginate is 1% ~ 10%.
3. Entecavir tablet as described in claim 1, which is characterized in that the dosage of sodium alginate is 2%.
4. Entecavir tablet as described in claim 1, which is characterized in that filler therein can be microcrystalline cellulose, cream
The mixture of one or both of sugar.
5. Entecavir tablet as described in claim 1, which is characterized in that glidant therein can be superfine silica gel powder, tristearin
One of sour magnesium, talcum powder are a variety of.
6. Entecavir tablet as described in claim 1, which is characterized in that disintegrating agent therein can be pregelatinized starch, friendship
Join one of povidone, low-substituted hydroxypropyl cellulose or a variety of.
7. the preparation process of Entecavir tablet as described in claim 1, comprising the following steps:
I is configured to sodium alginate 3% aqueous solution, and Entecavir is added, and being sufficiently stirred is uniformly mixed it；
II by above-mentioned mixed solution and filler, glidant and disintegrating agent mixing granulation, and tabletting to obtain the final product.
8. the preparation process of Entecavir tablet as claimed in claim 6, which is characterized in that in tableting step, critical process ginseng
Number is as follows:
Tabletting principal pressure: 4 ~ 8KN；
Piece is thick: standard film thickness ± 0.02mm
Average hardness: 7.5 ± 2kg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112402384A (en) * | 2020-11-27 | 2021-02-26 | 苏州中化药品工业有限公司 | Preparation method of rivaroxaban tablet, rivaroxaban tablet and rivaroxaban oral medicine |
| CN113730367A (en) * | 2021-09-28 | 2021-12-03 | 海南海灵化学制药有限公司 | Preparation process of entecavir tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732944A (en) * | 2005-09-02 | 2006-02-15 | 北京阜康仁生物制药科技有限公司 | Entecavir dispersible tablet and its preparation process |
| 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 |
-
2019
- 2019-08-06 CN CN201910723375.3A patent/CN110420188A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1732944A (en) * | 2005-09-02 | 2006-02-15 | 北京阜康仁生物制药科技有限公司 | Entecavir dispersible tablet and its preparation process |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 乔延江: "《中华医学百科全书中药制剂学》", 30 June 2017 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112402384A (en) * | 2020-11-27 | 2021-02-26 | 苏州中化药品工业有限公司 | Preparation method of rivaroxaban tablet, rivaroxaban tablet and rivaroxaban oral medicine |
| CN113730367A (en) * | 2021-09-28 | 2021-12-03 | 海南海灵化学制药有限公司 | Preparation process of entecavir tablets |
| CN113730367B (en) * | 2021-09-28 | 2022-12-02 | 海南海灵化学制药有限公司 | Preparation process of entecavir tablets |
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