CN101628002A - Micronized composition containing Levonorgestrel - Google Patents
Micronized composition containing Levonorgestrel Download PDFInfo
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- CN101628002A CN101628002A CN200910157979A CN200910157979A CN101628002A CN 101628002 A CN101628002 A CN 101628002A CN 200910157979 A CN200910157979 A CN 200910157979A CN 200910157979 A CN200910157979 A CN 200910157979A CN 101628002 A CN101628002 A CN 101628002A
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- China
- Prior art keywords
- levonorgestrel
- pharmaceutical composition
- composition according
- cellulose
- particle
- 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.)
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- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 title claims abstract description 60
- 229960004400 levonorgestrel Drugs 0.000 title claims abstract description 60
- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 239000002245 particle Substances 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 5
- 229920002472 Starch Polymers 0.000 claims description 23
- 239000008107 starch Substances 0.000 claims description 23
- 235000019698 starch Nutrition 0.000 claims description 23
- 239000002702 enteric coating Substances 0.000 claims description 13
- 238000009505 enteric coating Methods 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 239000004925 Acrylic resin Substances 0.000 claims description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 239000004375 Dextrin Substances 0.000 claims description 9
- 229920001353 Dextrin Polymers 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 9
- 229930006000 Sucrose Natural products 0.000 claims description 9
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 9
- 235000019425 dextrin Nutrition 0.000 claims description 9
- 239000010410 layer Substances 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- 239000005720 sucrose Substances 0.000 claims description 9
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 8
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 239000008101 lactose Substances 0.000 claims description 8
- 238000000576 coating method Methods 0.000 claims description 7
- 229920000178 Acrylic resin Polymers 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 6
- 229920003081 Povidone K 30 Polymers 0.000 claims description 5
- -1 acetate phthalic acid ester Chemical class 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 229920000609 methyl cellulose Polymers 0.000 claims description 5
- 239000001923 methylcellulose Substances 0.000 claims description 5
- 235000010981 methylcellulose Nutrition 0.000 claims description 5
- 229920002689 polyvinyl acetate Polymers 0.000 claims description 5
- 239000011118 polyvinyl acetate Substances 0.000 claims description 5
- 239000002002 slurry Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 229920002301 cellulose acetate Polymers 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Chemical class 0.000 claims description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Chemical class 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical class CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 239000004354 Hydroxyethyl cellulose Chemical class 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Chemical class 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 2
- 239000008112 carboxymethyl-cellulose Chemical class 0.000 claims description 2
- 238000004132 cross linking Methods 0.000 claims description 2
- 229920001249 ethyl cellulose Chemical class 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 23
- 238000004090 dissolution Methods 0.000 abstract description 5
- 239000011247 coating layer Substances 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 20
- 239000000243 solution Substances 0.000 description 14
- 239000008187 granular material Substances 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 206010013786 Dry skin Diseases 0.000 description 5
- 239000003433 contraceptive agent Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000002254 contraceptive effect Effects 0.000 description 3
- 230000001568 sexual effect Effects 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229940124558 contraceptive agent Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 230000008673 vomiting Effects 0.000 description 2
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 230000032696 parturition Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000246 remedial effect Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a micronized composition containing Levonorgestrel, and aiming at the problem of low dissolution rate of the Levonorgestrel enteric coated preparation in the prior art, the invention provides the micronized composition containing Levonorgestrel. In the invention, 70 to 100 percent of Levonorgestrel is micronized to particles, and the grain diameter of each particle is less than or equal to 20 nanometers; the particles are combined with 60 to 97.9 percent of excipient to be prepared into a medicine core; and the medicine core is coated by a coating layer. The composition greatly improves the releasing degree and the peak time of the Levonorgestrel and Tmax.
Description
Technical field
The present invention relates to a kind of micronized pharmaceutical composition that is used to practise contraception, be specifically related to the micronized levonorgestrel compositions that contains.
Background technology
Levonorgestrel can be used to contraception as progestogen, especially can be used for emergency contraception.Emergency contraception is meant the conceived remedial measure of taking behind the sexual life of not taking any contraceptives or the contraceptive failure that prevents: or do not adopting behind the sexual life of contraceptives and taking emergency contraception in 72 hours; Or in 5 days placement of intrauterine devices.The purpose of taking emergency contraception is to stop fertilization or germ cell implantation in the shortest time.Influencing the play a role key factor of time of medicine is the dissolution rate of medicine, so in order to realize the purpose of emergency contraception better, should improve the dissolution rate of emergency contraception.
Improve the levonorgestrel dissolution rate at present following way arranged:
CN200410044067.1 discloses the oral cavity disintegration tablet of levonorgestrel, adopts and add disintegrating agent in prescription, to reach the effect of rapid disintegrate;
CN200810016477.3 discloses the Levonorgestrel drop pills that can improve dissolution rate.
The Peroral solid dosage form for contraception that contains levonorgestrel at home and abroad is extensive use of, and is graceful as giving birth of China, the PlanB of the U.S. etc., in the package insert of these medicines, mention exist after taking medicine feel sick, phenomenon such as vomiting, influence patient's compliance.In order to overcome above-mentioned defective, application number is that the solution of the U.S. Patent Publication of US6156742 is: contraceptive is enteric coated, make the insoluble under one's belt or slightly soluble of medicine, just dissolving discharges after arriving small intestinal.CN02148956.4 also discloses the enteric dosage form of levonorgestrel.Above scheme is by postponing the release time of medicine, just begins the dissolving absorption after making medicine enter small intestinal, influenced the infiltration rate of medicine, more early takes the good more characteristics of effect for emergency contraception, will clearly influence its action effect.
Summary of the invention
For the delay of the enteric dosage form that solves the levonorgestrel that exists in the prior art discharges, prolonged the drug absorption time, thereby influence the problem of emergency contraception effect, the invention provides a kind of incidence rate that can reduce vomiting, levonorgestrel is discharged rapidly in vivo, onset reaches the micronized compositions that contains levonorgestrel of emergency contraception purpose better.
The technical scheme that realizes the object of the invention is:
A kind of pharmaceutical composition comprises:
Medicated core: account for gross weight 70-98%, comprise that weight ratio is that levonorgestrel and the weight ratio of 0.1-10% is the excipient of 90-99.9%,
Coatings is an enteric coating, accounts for the 2-30% of gross weight,
Levonorgestrel micronization wherein, the particle diameter of the levonorgestrel particle of 70-100% be smaller or equal to 20 microns,
Excipient comprises: filler, disintegrating agent, binding agent and lubricant.
Coatings comprises: contagion gown accounts for the 0-10% of gross weight; Enteric coating accounts for the 2-20% of gross weight.
Filler is one or more in lactose, sucrose, mannitol, dextrin, starch or the microcrystalline Cellulose.In preferably sucrose, dextrin or the starch one or more.
Disintegrating agent is one or more in hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or the dried starch.Preferred carboxymethyl starch sodium.
Binding agent is the water of 30 POVIDONE K 30 BP/USP 30 or in alcoholic solution, hypromellose solution or the starch slurry one or both, the alcoholic solution of preferred starch slurry or 30 POVIDONE K 30 BP/USP 30.
Wherein, coatings is acrylic resin I-IV, polyacrylic resin class, Opadry
One or more of series, Lac, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, carboxymethyl cellulose salt class, cellulose acetate class, benzene front three cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalic acid ester, succinic acid hydroxypropylmethylcellulose acetate methylcellulose or crosslinked alginate apoplexy due to endogenous wind.Preferred acrylic resins I-IV, polyacrylic resin class, polyvinyl acetate phthalic acid ester or Opadry
Series.
The preferred 0.1-2% of the weight ratio of levonorgestrel.
Said composition is prepared to tablet or capsule, and the amount that contains levonorgestrel in the per unit dosage (every/every) is 0.1mg, 0.15mg, 0.75mg, 1.5mg or 2.0mg.
The particle of the preferred 50-90% of particle diameter of levonorgestrel is smaller or equal to 10 microns, and wherein 70% particle is more suitable smaller or equal to 10 microns.
Beneficial effect of the present invention is as follows:
1, compositions of the present invention is by turning to particle diameter smaller or equal to 20 microns with levonorgestrel 70-100% particle micropowder, even micropowder turns to 10 microns particle, make the rapid in vivo dissolved absorption of medicine, blood drug level can reach peak concentration very soon, rapid-action, these characteristics make levonorgestrel to bring into play drug effect in the short as far as possible time, can be used for emergency contraception better.Below interior medicine dynamics experimental results show that the micronized levonorgestrel of the present invention accelerated about 1 hour than the time that not micronized levonorgestrel enteric coatel tablets reach the blood peak concentration of drug, this has very important significance for emergency contraception.
2, the present invention outer enteric coated with the levonorgestrel compositions also makes levonorgestrel not dissolve fully or almost completely at gastric, just begins dissolving when arriving small intestinal.And compositions of the present invention is stripping fast in small intestinal, has improved the release of levonorgestrel greatly, following release evidence, and the micronized levonorgestrel ratio not release of the enteric coatel tablets of micronized levonorgestrel is obviously accelerated.
Pharmacokinetics test in the body
Select 10 routine non-lactation period healthy womens, age 18-45 year, body weight 55-80kg, voluntary participation research, and sign Informed Consent Form.Use methods contraceptions such as condom, sexual repression, operation sterillization, nearly 1 month oral hormone class contraceptive not, nearly 4 months injection contraception pins.Be divided into two groups at random, every group 5 example.Give the micronized 1.5mg levonorgestrel compositions of the embodiment of the invention 1 preparation.It is as shown in the table that medicine reaches time of peak concentration after measured:
| Medicine | Tmax(h) |
| Micronized levonorgestrel compositions | 2.4±0.6 |
Among the Biomed.Chromatogr.22:519-526 (2008) in the contrast test of disclosed levonorgestrel enteric coatel tablets and ordinary tablet the peak time (Tmax) of enteric coatel tablets be 3.4h.
By contrast as can be seen, the micronized levonorgestrel compositions of the present invention's preparation is compared with the levonorgestrel enteric coatel tablets, and peak time has shortened 1 hour, and significant difference is arranged.The peak time of medicine shortens the release and the infiltration rate of explanation medicine and accelerates.Soak time shortens 1 hour and have very significant meaning for emergency contraception.
The release test
Medicine: one group is: according to application number is the levonorgestrel enteric coatel tablets of the 1.5mg of 02148956.4 disclosed embodiment 1 preparation, and another group is: according to the micronized levonorgestrel compositions of embodiments of the invention 2 disclosed 1.5mg.
Assay method: get each 6 of two groups of medicines respectively, measure according to drug release determination method (2005 editions two appendix X D second method methods 2 of Chinese Pharmacopoeia), adopt dissolution method second subtraction unit, with 0.1mol/L hydrochloric acid solution 500ml is release medium, rotating speed is that per minute 75 changes, operation in accordance with the law, through 2 hours, discard 0.1mol/L hydrochloric acid solution in above-mentioned each stripping rotor, phosphate buffer (PH6.8) 900ml that contains 0.1% (g/ml) sodium lauryl sulphate that adds 37 ℃ immediately, rotating speed is constant, respectively at 10,20,30,40,60, the 90min sampling and measuring, get its meansigma methods, the result is as follows:
| Medicine | ?10min | ??20min | ??30min | ??40min | ??60min | ??90min |
| The levonorgestrel enteric coatel tablets | ?2.3 | ??43.4 | ??65.1 | ??77.7 | ??83.3 | ??89.2 |
| Micronized levonorgestrel compositions | ?24.6 | ??65.5 | ??91.9 | ??100.4 | ??101.5 | ??99.7 |
As can be seen from the above table, micronized levonorgestrel compositions of the present invention is significantly accelerated than the rate of release of 02148956.4 disclosed levonorgestrel enteric coatel tablets.
The specific embodiment
Embodiment 1
Medicated core:
Micronized levonorgestrel 1.5g
Lactose 5g
Starch 45g
Sucrose 35g
Dextrin 5g
5% starch slurry is an amount of
Carboxymethyl starch sodium 2g
Magnesium stearate 1g
The contagion gown layer:
Opadry YS-1-7027 3g
Water 22g
Enteric coating layer:
Opadry 93063209 5g
Water 20g
The particle that micropowder is turned to 70%-90% smaller or equal to 10 microns levonorgestrel powder by equivalent progressively increase method and lactose, sucrose, starch, dextrin mix homogeneously, add an amount of 5% starch slurry and make granule, 60 ℃ of aeration-dryings, granulate, add carboxymethyl starch sodium, magnesium stearate mix homogeneously, tabletting wraps contagion gown, enteric coating on sheet, make 1000.
Embodiment 2
Medicated core:
Micronized levonorgestrel 1.5g
Lactose 60g
Microcrystalline Cellulose 30g
The alcoholic solution of 10% 30 POVIDONE K 30 BP/USP 30 is an amount of
Magnesium stearate 1g
The contagion gown layer:
Hydroxypropyl methylcellulose 3g
Polyethylene Glycol 0.5g
Titanium dioxide 0.7g
Pulvis Talci 0.6g
Enteric coating layer:
Acrylic resin 8g
Triethyl citrate 0.8g
Pulvis Talci 1.6g
The particle that micropowder is turned to 50%-70% smaller or equal to 10 microns levonorgestrel powder by equivalent progressively increase method and lactose, microcrystalline Cellulose mix homogeneously, the alcoholic solution that adds an amount of 10% 30 POVIDONE K 30 BP/USP 30 is made granule, 60 ℃ of aeration-dryings, granulate, add the magnesium stearate mix homogeneously, tabletting wraps contagion gown, enteric coating on sheet, make 1000.
Embodiment 3
Medicated core:
Micronized levonorgestrel 0.75g
Sucrose 55g
Dextrin 20g
Carboxymethyl starch sodium 2g
2% hypromellose solution is an amount of
Magnesium stearate 1g
Enteric coating layer:
Polyvinyl acetate phthalic acid ester 10g
Pulvis Talci 1.6g
The particle that micropowder is turned to 70%-100% smaller or equal to 20 microns levonorgestrel powder by equivalent progressively increase method and sucrose, dextrin, carboxymethyl starch sodium mix homogeneously, add an amount of 2% hypromellose solution and make granule, 60 ℃ of aeration-dryings, granulate, add the magnesium stearate mix homogeneously, filling is in No. 3 capsules, and is enteric coated on capsule, makes 1000.
Embodiment 4
Medicated core:
Micronized levonorgestrel 2.0g
Lactose 45g
Starch 50g
Polyvinylpolypyrrolidone 5g
5% hypromellose solution is an amount of
Magnesium stearate 1g
Enteric coating layer:
Acrylic resin 5g
Pulvis Talci 1.6g
Water 45g
The particle that micropowder is turned to 80%-90% smaller or equal to 10 microns levonorgestrel powder by equivalent progressively increase method and lactose, starch, polyvinylpolypyrrolidone mix homogeneously, add an amount of 5% hypromellose solution and make granule, 60 ℃ of aeration-dryings, granulate, add the magnesium stearate mix homogeneously, tabletting, enteric coated on sheet, make 1000.
Embodiment 5
Medicated core:
Micronized levonorgestrel 0.1g
Sucrose 60g
Dextrin 15g
Carboxymethyl starch sodium 10g
2% hypromellose solution is an amount of
Magnesium stearate 1g
The contagion gown layer:
Opadry 3g
Methylcellulose 5g
Enteric coating layer:
Polyacrylic resin 8g
Triethyl citrate 0.5g
The particle that micropowder is turned to 90%-100% smaller or equal to 10 microns levonorgestrel powder by equivalent progressively increase method and sucrose, dextrin, carboxymethyl starch sodium mix homogeneously, add an amount of 2% hypromellose solution and make granule, 60 ℃ of aeration-dryings, granulate, add the magnesium stearate mix homogeneously, filling is wrapped contagion gown, enteric coating in No. 3 capsules on capsule, make 1000.
Claims (11)
1, a kind of pharmaceutical composition is characterized by and comprises:
Medicated core: account for gross weight 70-98%, comprise that weight ratio is that levonorgestrel and the weight ratio of 0.1-10% is the excipient of 90-99.9%,
Coatings: account for the 2-30% of gross weight,
Levonorgestrel micronization wherein, the particle diameter of the levonorgestrel particle of 70-100% be smaller or equal to 20 microns,
Excipient comprises: filler, disintegrating agent, binding agent and lubricant,
Coatings is an enteric coating, accounts for the 2-30% of gross weight.
2, pharmaceutical composition according to claim 1 is characterized by coatings and also comprises contagion gown, and contagion gown wherein accounts for the 0-10% of gross weight; Enteric coating accounts for the 2-20% of gross weight.
3, pharmaceutical composition according to claim 1 and 2, the particle diameter of levonorgestrel particle that it is characterized by 50-90% is smaller or equal to 10 microns.
4, pharmaceutical composition according to claim 1 and 2, the particle diameter of levonorgestrel particle that it is characterized by 70%-90% is smaller or equal to 10 microns.
5,, it is characterized by filler and be in lactose, sucrose, mannitol, dextrin, starch or the microcrystalline Cellulose one or more according to claim 3 or 4 described pharmaceutical compositions.
6, pharmaceutical composition according to claim 5 is characterized by disintegrating agent and is in hydroxypropyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose or the dried starch one or more.
7, pharmaceutical composition according to claim 6 is characterized by water that binding agent is a 30 POVIDONE K 30 BP/USP 30 or in alcoholic solution, hypromellose solution or the starch slurry one or both.
8, pharmaceutical composition according to claim 7 is characterized by coatings by acrylic resin I-IV, polyacrylic resin class, Opadry
One or more preparations of series, Lac, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, carboxymethyl cellulose salt class, cellulose acetate class, benzene front three cellulose acetate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalic acid ester, succinic acid hydroxypropylmethylcellulose acetate methylcellulose or crosslinked alginate apoplexy due to endogenous wind.
9, pharmaceutical composition according to claim 8 is characterized by enteric coating layer by acrylic resin I-IV, polyacrylic resin class, polyvinyl acetate phthalic acid ester or Opadry
One or more preparations in the series.
10, pharmaceutical composition according to claim 9, the weight ratio that it is characterized by levonorgestrel in the label is 0.1-2%.
11, pharmaceutical composition according to claim 10 is characterized by said composition and is prepared to tablet or capsule, and the amount that contains levonorgestrel in the per unit dosage is 0.1mg, 0.15mg, 0.75mg, 1.5mg or 2.0mg.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101579792A CN101628002B (en) | 2009-07-21 | 2009-07-21 | Micronized composition containing Levonorgestrel |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101579792A CN101628002B (en) | 2009-07-21 | 2009-07-21 | Micronized composition containing Levonorgestrel |
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| CN101628002A true CN101628002A (en) | 2010-01-20 |
| CN101628002B CN101628002B (en) | 2011-09-21 |
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| CN2009101579792A Active CN101628002B (en) | 2009-07-21 | 2009-07-21 | Micronized composition containing Levonorgestrel |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772377A (en) * | 2011-05-11 | 2012-11-14 | 北京以岭生物工程技术有限公司 | Preparation method for ultra-micro co-grinding levonorgestrel tablets |
| EP2730284A1 (en) * | 2012-11-12 | 2014-05-14 | Naari AG | Levonorgestrel-only-composition for optimized oral contraception with defined levonorgestrel content, dosage regimen and pharmaceutical preparation |
| CN103877058A (en) * | 2014-03-26 | 2014-06-25 | 邵娜 | Levonorgestrel tablet and preparation process thereof |
| CN105796573A (en) * | 2014-12-30 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Preparation method of levonorgestrel and ethinylestradiol tablets |
| CN110917154A (en) * | 2019-12-12 | 2020-03-27 | 上海信谊天平药业有限公司 | Preparation method of levonorgestrel tablets |
| US11679114B2 (en) | 2021-07-26 | 2023-06-20 | Navad Life Sciences Pte | Progestogen-only oral contraception |
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2009
- 2009-07-21 CN CN2009101579792A patent/CN101628002B/en active Active
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102772377A (en) * | 2011-05-11 | 2012-11-14 | 北京以岭生物工程技术有限公司 | Preparation method for ultra-micro co-grinding levonorgestrel tablets |
| CN102772377B (en) * | 2011-05-11 | 2015-09-30 | 北京以岭生物工程技术有限公司 | A kind of ultra micro pulverizes the preparation method of levonorgestrel altogether |
| EP2730284A1 (en) * | 2012-11-12 | 2014-05-14 | Naari AG | Levonorgestrel-only-composition for optimized oral contraception with defined levonorgestrel content, dosage regimen and pharmaceutical preparation |
| WO2014072245A1 (en) * | 2012-11-12 | 2014-05-15 | Naari Ag | Levonorgestrel-only-composition for optimized oral contraception with defined levonorgestrel content, dosage regimen and pharmaceutical preparation |
| EA029329B1 (en) * | 2012-11-12 | 2018-03-30 | Наари Пте. Лтд. | Levonorgestrel composition for optimized oral contraception with defined levonorgestrel content, dosage regimen and pharmaceutical preparation |
| CN103877058A (en) * | 2014-03-26 | 2014-06-25 | 邵娜 | Levonorgestrel tablet and preparation process thereof |
| CN105796573A (en) * | 2014-12-30 | 2016-07-27 | 浙江仙琚制药股份有限公司 | Preparation method of levonorgestrel and ethinylestradiol tablets |
| CN105796573B (en) * | 2014-12-30 | 2018-08-21 | 浙江仙琚制药股份有限公司 | A kind of preparation method of ethinyl estradiol levonorgestrel piece |
| CN110917154A (en) * | 2019-12-12 | 2020-03-27 | 上海信谊天平药业有限公司 | Preparation method of levonorgestrel tablets |
| US11679114B2 (en) | 2021-07-26 | 2023-06-20 | Navad Life Sciences Pte | Progestogen-only oral contraception |
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|---|---|
| CN101628002B (en) | 2011-09-21 |
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