CN1660118A - Medication combination of containing finasteride and cyclodextrin or ramification - Google Patents
Medication combination of containing finasteride and cyclodextrin or ramification Download PDFInfo
- Publication number
- CN1660118A CN1660118A CN 200410075801 CN200410075801A CN1660118A CN 1660118 A CN1660118 A CN 1660118A CN 200410075801 CN200410075801 CN 200410075801 CN 200410075801 A CN200410075801 A CN 200410075801A CN 1660118 A CN1660118 A CN 1660118A
- Authority
- CN
- China
- Prior art keywords
- cyclodextrin
- finasteride
- beta
- hydroxypropyl
- schardinger dextrin
- 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.)
- Granted
Links
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 43
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 35
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 title claims description 123
- 229960004039 finasteride Drugs 0.000 title claims description 123
- 239000003814 drug Substances 0.000 title abstract description 17
- 229940079593 drug Drugs 0.000 title description 11
- 239000003826 tablet Substances 0.000 claims abstract description 19
- 239000000865 liniment Substances 0.000 claims abstract description 8
- 229940040145 liniment Drugs 0.000 claims abstract description 8
- 239000002674 ointment Substances 0.000 claims abstract description 8
- 239000002775 capsule Substances 0.000 claims abstract description 7
- -1 hydroxypropyl Chemical group 0.000 claims description 32
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 21
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims description 18
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 18
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 15
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 15
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 14
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 13
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 12
- 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 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 239000011734 sodium Substances 0.000 claims description 12
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000007919 dispersible tablet Substances 0.000 claims description 11
- 210000000214 mouth Anatomy 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 10
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 10
- 201000004384 Alopecia Diseases 0.000 claims description 9
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims description 9
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 8
- 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 8
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 8
- JVFGXECLSQXABC-UHFFFAOYSA-N ac1l3obq Chemical compound O1C(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC(C(O)C2O)C(COCC(O)C)OC2OC(C(C2O)O)C(COCC(C)O)OC2OC2C(O)C(O)C1OC2COCC(C)O JVFGXECLSQXABC-UHFFFAOYSA-N 0.000 claims description 8
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 8
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 8
- 239000000499 gel Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 7
- 235000011187 glycerol Nutrition 0.000 claims description 7
- 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 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- 241001597008 Nomeidae Species 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 206010068168 androgenetic alopecia Diseases 0.000 claims description 5
- 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 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 108010011485 Aspartame Proteins 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- 239000000605 aspartame Substances 0.000 claims description 4
- 235000010357 aspartame Nutrition 0.000 claims description 4
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 4
- 229960003438 aspartame Drugs 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 235000013877 carbamide Nutrition 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 235000019219 chocolate Nutrition 0.000 claims description 4
- 238000004132 cross linking Methods 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 150000001261 hydroxy acids Chemical class 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 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 3
- 229940109275 cyclamate Drugs 0.000 claims description 3
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims description 3
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 3
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 230000000699 topical effect Effects 0.000 claims description 3
- 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 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 2
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
- 235000013772 propylene glycol Nutrition 0.000 claims description 2
- 239000002131 composite material Substances 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
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- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 8
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 8
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 7
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- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 6
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- 230000035617 depilation Effects 0.000 description 3
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- 229960003604 testosterone Drugs 0.000 description 3
- NVKAWKQGWWIWPM-ABEVXSGRSA-N 17-β-hydroxy-5-α-Androstan-3-one Chemical compound C1C(=O)CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@H]21 NVKAWKQGWWIWPM-ABEVXSGRSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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Landscapes
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
A composite medicine in the form of form of dispersing tablet, oral disintegrating tablet, capsule, liniment, ointment, etc contains phenandrostamine and additional cyclodextrin or its derivative for higher biologic utilization rate.
Description
Technical field
The invention belongs to new pharmaceutical preparation technology of preparing.
Background technology
Finasteride is the competitive inhibitor of II type 5, can form stable multienzyme complex with 5, and the transformation of this complex is very slow, but androgen is not had affinity interaction.5 is a kind of desmoenzyme, androgen testosterone (T) can be converted into 5 α-two hydrogen testosterones (DHT).Male's sexual development is by testosterone (T) and 5 α-two hydrogen testosterones (DHT) mediation, and DHT control prostate is grown and male pattern baldness, and prostatic development increases the activity that depends on DHT.
The animal of accumulation and the data of clinical research show that finasteride can effectively improve the related symptoms of benign prostatic hyperplasia (BPH), reduce the risk of treatment failure, increase urine flow velocity degree and reduce prostate volume.Finasteride is a line medicine for the treatment of BPH at present.Some American-European countries ratify finasteride tablet again and are used for male baldness, have further expanded the clinical application and the market potential of finasteride.
BPH (benign prostatic hyperplasia) is the commonly encountered diseases of elderly men, and result of study shows that male's great majority more than 50 years old have benign prostatic hyperplasia in various degree.94 years to Beijing more than 40 years old male resident's a sampling survey show have the BPH symptom to reach 37.6%.Among 20 the Urology Surgery inpatients of big city hospital in the 1990-1991 whole nation, patient BPH accounts for 13.6%.Along with China's constant development of economy, the improving constantly of people's living standard, the continuous prolongation in population life-span, these factors all will impel the sickness rate of BPH constantly to raise.
And commonly used, that curative effect the is best clinically now medicine that is used for treatment of benign prostate hyperplasia has two classes: selectivity α
1Receptor antagonist and 5 inhibitor.α such as alfzosin
1Though the receptor antagonist short term efficacy is rapid, but only be suitable for the improvement of acute symptom, can improve patient's peak urinary flow rate rate rapidly, it is the optimum selection of medication before the corrective surgery, be unsuitable for patient's long-term prescription, and that 5 inhibitor finasteride is the prostatic hyperplasia patient is most widely used general, the medicine of long-term treatment best results.In addition, finasteride to the hair loss patient life-time service after, can effectively suppress the level of dihydrotestosterone in the hair follicle, reach the purpose of treatment male pattern baldness.The effect substrate of finasteride is the testosterone in the human plasma, and its blood plasma level has significantly rule round the clock, and the blood plasma level in general early morning will be apparently higher than afternoon and night.Thereby the blood drug level of finasteride then may be brought into play its curative effect to the full extent if adapt with it, effectively reduces the level of dihydrotestosterone in the blood plasma the most, reaches the purpose of treatment benign prostatic hyperplasia and alopecia.Finasteride is a water-insoluble drug, but the problem of solution dissolution and uniformity of dosage units becomes the key that the finasteride exploitation is prepared into various clinical application forms; Studies show that of pharmacokinetics, the single agent of finasteride (5mg) is oral, and bioavailability is 63% (34～108%), and absorption is comparatively slow, and absorption in 6-8 hour finishes, but it absorbs the influence of unable to take food thing.Therefore develop a kind of absorption more rapid and completely the finasteride preparation be very necessary, this is low for improving existing finasteride preparation bioavailability, the gastrointestinal absorption individual variation is big and absorb shortcoming slowly, has crucial meaning and value.
Summary of the invention
Finasteride is a kind of water-insoluble medicine, this is for its very unfavorable of absorption, all there is the shortcoming that absorption is slow, individual variation is big, bioavailability is not high in existing finasteride preparation, the present invention gropes by a large amount of experiments, find after finasteride is by derivant (CDD) enclose of cyclodextrin (CD) or cyclodextrin, its bioavailability significantly improves, and AUC improves about 40%; Peak time significantly shortens, and infiltration rate is obviously accelerated; About the plasma concentration of medicine on average doubles, and the individual variation that absorbs is significantly dwindled.In addition, we have also confirmed obviously to increase through the speed of the finasteride Transdermal absorption behind the cyclodextrin or derivatives thereof enclose by test, and the slurry drug level in two hours on average improves about 3 times.And the individual variation that absorbs is significantly dwindled.Finasteride by derivant (CDD) enclose of cyclodextrin (CD) or cyclodextrin after, the speed of Transdermal absorption significantly increases, this is to the local finasteride that uses of male pattern baldness patient, effectively improve the hair follicle at alopecia position and the drug level in the surrounding tissue thereof, its curative effect of more efficiently performance provides good guarantee.
On the basis of this experimental result, we have further carried out a large amount of experiments, finasteride and multiple cyclodextrin or derivatives thereof have been carried out the enclose test, and exploitation becomes a kind of preparation that can clinical use, and they comprise dispersible tablet, oral cavity disintegration tablet, conventional tablet, capsule and liniment that can local topical, ointment, gel etc.And in experiment, find, below the effect of cyclodextrin or derivatives thereof of these kinds better, for example, alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, glucosyl group alpha-cyclodextrin, malt-base alpha-cyclodextrin, dimethyl-, methyl beta-schardinger dextrin-, hydroxypropyl, ethoxy beta-schardinger dextrin-, carboxymethyl beta-schardinger dextrin-, glucosyl group beta-schardinger dextrin-, malt-base beta-schardinger dextrin-, methyl gamma-cyclodextrin or hydroxypropyl gamma-cyclodextrin etc.At dispersible tablet that can be oral, oral cavity disintegration tablet, in conventional tablet and the capsule, we have also selected in the following adjuvant one or more, to reach better effect, they comprise starch, hydroxypropyl cellulose, microcrystalline Cellulose, PVPk30, crospolyvinylpyrrolidone, micropowder silica gel, magnesium stearate, lactose, carboxymethyl starch sodium, pregelatinized Starch, Rikemal B 200, Pulvis Talci, mannitol, sodium carboxymethyl cellulose (CMC-Na), cross-linking sodium carboxymethyl cellulose, sodium alginate, crosslinked carboxymethyl fecula sodium, glucose, hydroxypropyl starch, hydroxy acid cellulose, guar gum etc.At liniment that can local topical, ointment, in the gel, we have selected adjuvants such as propylene glycol, glycerol, carboxymethyl cellulose, carbamide, carbopol 940, Tween 80, triethanolamine, add one or more uses that can reach better therapeutic and make things convenient for the patient wherein, in order to guarantee stability of formulation, can also add an amount of antiseptic.In the preparation of oral cavity disintegration tablet, add in a spot of Herba Menthae essence, aspartame, Fructus Citri Limoniae essence, Fructus Citri tangerinae essence, chocolate essence or the cyclamate one or more, can on sizable degree, improve mouthfeel.
The specific embodiment
Embodiment 1 and 2 is the pharmacokinetics experiments about the rabbit gastrointestinal absorption of finasteride cyclodextrin or derivatives thereof clathrate and Transdermal absorption.
Embodiment 1
The pharmacokinetics of the clathrate rabbit gastric infusion of finasteride and finasteride cyclodextrin or derivatives thereof relatively
Experiment purpose
Seek and verify a kind of finasteride through the gastrointestinal tract pharmaceutical composition that absorbs of rule rapidly, so as to develop a kind of bioavailability higher, reduce the finasteride preparation that absorbs individual variation.
Laboratory animal
Healthy rabbits, body weight 2.0-3.0Kg, male and female are regardless of.
Experimental technique
1. the preparation of finasteride suspension:
The finasteride crude drug is crossed 100 mesh sieves, be suspended in 8% carboxymethylcellulose sodium solution.
2. the preparation of finasteride cyclodextrin or derivatives thereof clathrate:
The finasteride crude drug is crossed 100 mesh sieves, be to be dissolved at 1: 3 in the aqueous solution (50-60 ℃) of heat with glucosyl group α-CD, β-CD, methyl β-CD, hydroxypropyl beta-CD, γ-CD or methyl γ-CD according to weight ratio respectively, keep being cooled to room temperature and getting final product more than 30 minutes.β-CD if the cooling after again crystallization separate out, can add an amount of sodium carboxymethyl cellulose suspendible or thin up and make its dissolving.
3. animal grouping and administration:
Selected rabbit is divided into finasteride group and finasteride cyclodextrin or derivatives thereof clathrate group at random by body weight.Every group 8.All rabbit all need in experiment fasting in preceding 12 hours, and two groups all irritating stomach gives finasteride 0.5mg/kg on an empty stomach.The finasteride group is irritated the carboxymethyl cellulose suspension that stomach gives finasteride, and finasteride cyclodextrin or derivatives thereof clathrate group gives glucosyl group α-CD, β-CD, methyl β-CD, hydroxypropyl beta-CD or the methyl γ-CD inclusion complex in solution of finasteride respectively.
4. instrument
Agilent 1100 liquid chromatograph-mass spectrometers; Agilent ChemStation; PM 180R high speed centrifuge; The whirlpool shaking mixer.
5. chromatograph and mass spectrum condition
Chromatographic column: Alltima C18 (5 μ m, 250mm); Mobile phase: methanol-100 μ molL
-1Sodium acetate aqueous solution; Column temperature: 25 ℃; Ion polarity: cation; Ionizing mode: pneumatic auxiliary electro-spray ionization (ESI); Ion detection mode: selectivity ion detection (SIM); Detected object: finasteride ([M+Na]
+, m/z 395), interior mark ([[M+Na]
+, m/z 409]); Transmission range voltage: 100V; Dry gas flow velocity: 10L/min; Aerochamber pressure: 45psi; 300 ℃ of dry gas temperature.
6. get the blood time
According to the result of trial test, the blood time of getting to the finasteride group determined is before the gastric infusion and behind the gastric infusion 0.5,1.0,2.0,2.5,3.0,3.5,4.0,8.0,12.0 and 24.0h gets blood 3ml from auricular vein, and the test tube of heparin is arranged in placing, and gets blood plasma after centrifugal ,-20 ℃ of preservations are to be measured.The blood time of getting of finasteride cyclodextrin or derivatives thereof clathrate group be before the gastric infusion and gastric infusion after 0.5,1.0,1.5,2.0,2.5,3.0,4.0,8.0,12.0 and 24.0h, be equipped with plasma sample with legal system and preserve to be measured.
7. the processing of plasma sample
The accurate plasma sample 1ml that adds in centrifuge tube, inner mark solution (1 μ g/ml) 40 μ l, the vortex mixing adds 0.1mol/L NaOH solution 0.1ml, and the vortex mixing adds ethyl acetate 5ml, vortex 3min, the centrifugal 5min of 4000r/min.Divide and get organic 4ml of making an appointment in another centrifuge tube, in 50 ℃ of water-baths, dry up with nitrogen current.Residue dissolves with 100 μ l mobile phases, and the centrifugal 5min of 16000r/min draws supernatant and is transferred in the automatic sampler sample cell sample introduction analysis.
Experimental result
Gained medicine-time data through 3P87 pharmacokinetics routine processes, are calculated peak serum concentration (C
Max), peak time (t
Max), area (AUC under the drug-time curve
0-∞) and plasma half-life (t
1/2) wait pharmacokinetic parameter.Our experimental result is found, obviously accelerate in the intravital infiltration rate of rabbit through the finasteride behind the cyclodextrin or derivatives thereof enclose, peak time significantly shortens, and the raising that peak serum concentration has reaches more than one times, AUC improves about 40%, and the individual variation that absorbs is significantly dwindled.The derivant of concrete every kind of cyclodextrin or cyclodextrin sees Table 1 to the data result of finasteride inhalation effects.
The clathrate of table 1. finasteride and finasteride cyclodextrin or derivatives thereof at the intravital pharmacokinetics of rabbit relatively
| Group | ????C max | ????t max | ????AUC 0-∞ | ????t 1/2 |
| Finasteride group glucosyl group α-CD inclusion group β-cdinclusion group methyl β-cdinclusion group hydroxypropyl β-cdinclusion group γ-CD inclusion group methyl γ-CD inclusion group | ??301.5±175.3 ??589.6±89.8 **??601.3±78.9 **??580.4±66.5 **??619.7±65.8 **??602.6±69.2 **??579.5±70.1 ** | 2.84±0.89 1.97±0.67 *2.05±0.59 *2.16±0.62 *1.82±0.90 *1.99±0.65 *2.01±0.83 * | 2039.7±945.6 2836.7±312.3 *2846.5±296.8 *2840.2±302.5 *2967.4±208.4 *2851.3±269.7 *2821.9±278.2 * | ?5.36±1.25 ?4.63±1.02 ?4.54±1.43 ?4.76±1.25 ?4.40±1.05 ?4.59±1.30 ?4.81±1.59 |
*Compare P＜0.05. with the finasteride group
*Compare P＜0.01. with the finasteride group
Embodiment 2
The pharmacokinetics of the clathrate rabbit Transdermal absorption of finasteride and finasteride cyclodextrin or derivatives thereof relatively
Experiment purpose
Seek and verify the pharmaceutical composition that a kind of finasteride can Transdermal absorption, become a kind of pharmaceutical preparation that can the external curing male pattern baldness so that finasteride is developed in the future.
Laboratory animal
Healthy male adult rabbit, age 6-10 month, body weight 2.0-3.0Kg.
Experimental technique
1. the preparation of finasteride suspension:
The finasteride crude drug is crossed 100 mesh sieves, be suspended in 8% carboxymethylcellulose sodium solution.The concentration of finasteride is 0.5mg/ml.
2. the preparation of finasteride cyclodextrin or derivatives thereof clathrate:
The finasteride crude drug is crossed 100 mesh sieves, be dissolved in the aqueous solution (50-60 ℃) of heat at 1: 3 according to weight ratio with malt-base α-CD, β-CD, carboxymethyl β-CD, glucosyl group β-CD, γ-CD or hydroxypropyl γ-CD respectively, keep being cooled to room temperature more than 30 minutes.Form 8% suspension after adding an amount of sodium carboxymethyl cellulose swelling.The concentration of finasteride is 0.5mg/ml.
3. animal grouping, back depilation and administration:
Selected rabbit is divided into finasteride group and finasteride cyclodextrin or derivatives thereof clathrate group at random by body weight.Every group 8, a few days ago the rabbit hair of every tame rabbit back is cut 3 * 3cm what test
2After, with the sodium sulfite depilation, smear the above-mentioned pharmaceutical composition 2ml that contains finasteride at the position of every rabbit depilation two days later, the application area of every rabbit should equate.The finasteride group is smeared the carboxymethyl cellulose suspension of finasteride, and finasteride cyclodextrin or derivatives thereof clathrate group is smeared malt-base α-CD, β-CD, carboxymethyl β-CD, glucosyl group β-CD, γ-CD or the hydroxypropyl γ-CD clathrate sodium carboxymethyl cellulose suspension of finasteride respectively.
4. instrument
Agilent 1100 liquid chromatograph-mass spectrometers; Agilent ChemStation; PM 180R high speed centrifuge; The whirlpool shaking mixer.
5. chromatograph and mass spectrum condition
Identical with last experiment.
6. get the blood time
After every rabbit is smeared administration 20,50 and 120min get blood 3ml from auricular vein, the test tube of heparin is arranged in placing, get blood plasma after centrifugal ,-20 ℃ of preservations are to be measured.
7. the processing of plasma sample
Identical with last experiment.
The pharmacokinetics of the clathrate rabbit Transdermal absorption of table 2. finasteride and finasteride cyclodextrin or derivatives thereof relatively
| Group | ??20min | ????50min | ????120min |
| Finasteride group malt-base α-CD enclose group β-CDBao He group carboxymethyl β-CDBao He group | ??12.9±10.5 ??55.6±13.2 **??40.4±10.8 **??59.2±15.6 ** | ????26.5±21.3 ????96.3±18.9 **????85.6±15.6 **????101.2±17.2 ** | ????30.2±28.6 ????121.7±20.3 **????108.5±21.5 **????133.4±28.0 ** |
| Glucosyl group β-CDBao He group γ-CD enclose group hydroxypropyl γ-CD enclose group | ??62.3±9.7 **??49.8±12.8 **??64.7±17.6 ** | ????121.5±14.0 **????86.7±18.3 **????117.1±16.5 ** | ??152.9±20.7 **??115.4±17.2 **??158.0±21.9 ** |
*Compare P＜0.01. with the finasteride group
Experimental result
Our experimental result finds that the speed of the finasteride Transdermal absorption behind the process cyclodextrin or derivatives thereof enclose obviously increases, and the slurry drug level in two hours on average improves about 3 times.And the individual variation that absorbs is significantly dwindled.The derivant of concrete every kind of cyclodextrin or cyclodextrin sees Table 2 to the data result of finasteride inhalation effects.
Following examples are the concrete preparation prescriptions that contain finasteride and cyclodextrin or derivatives thereof.Recipe quantity is 1000 consumptions.
Embodiment 3
The finasteride oral cavity disintegration tablet
Finasteride 5g
Methyl beta-schardinger dextrin-15g
Glucose 50g
Crosslinked carboxymethyl fecula sodium 20g
Herba Menthae essence 1g
Distilled water is an amount of
Magnesium stearate 0.5g
Preparation technology:
Principal agent is crossed 120 mesh sieves and dimethyl-fully grinds mixing, glucose, crosslinked carboxymethyl fecula sodium, Herba Menthae essence are crossed 100 mesh sieves, take by weighing mix homogeneously by recipe quantity, it is an amount of to add distilled water, granulates oven dry, granulate, add the recipe quantity magnesium stearate, mixing, tabletting are promptly.
Embodiment 4
The finasteride oral cavity disintegration tablet
Finasteride 2g
Beta-schardinger dextrin-6g
Mannitol 60g
Cross-linking sodium carboxymethyl cellulose 10g
Aspartame 0.5g
Distilled water is an amount of
Pulvis Talci 0.5g
Preparation technology:
Principal agent crosses 120 mesh sieves and beta-schardinger dextrin-is dissolved in 60～80 ℃ of hot water, keep more than the 60min, and cooling, beta-schardinger dextrin-is separated out after-filtration, and oven dry is sieved; Crospolyvinylpyrrolidone, aspartame are crossed 100 mesh sieves, take by weighing by recipe quantity, and mix homogeneously, the adding distilled water is an amount of, granulates, oven dry, granulate adds the recipe quantity Pulvis Talci, and mixing, tabletting are promptly.
Embodiment 5
The finasteride oral cavity disintegration tablet
Finasteride 10g
Hydroxypropyl 35g
Mannitol 90g
Carboxymethyl starch sodium 15g
Fructus Citri Limoniae essence 1g
Distilled water is an amount of
Magnesium stearate 1g
Preparation technology:
With embodiment 3, the Fructus Citri Limoniae essence in the present embodiment also can replace with chocolate essence.
Embodiment 6
The finasteride oral cavity disintegration tablet
Finasteride 3g
Gamma-cyclodextrin 10g
Mannitol 70g
Fructus Citri tangerinae essence 1g
Distilled water is an amount of
Preparation technology:
With embodiment 3.
Embodiment 7
The finasteride oral cavity disintegration tablet
Finasteride 3g
Methyl gamma-cyclodextrin 10g
Mannitol 70g
Cross-linking sodium carboxymethyl cellulose 10g
Chocolate essence 1g
Cyclamate 1g
Distilled water is an amount of
Magnesium stearate 1g
Preparation technology:
With embodiment 3.
Embodiment 8
The finasteride dispersible tablet
Finasteride 6g
Glucosyl group alpha-cyclodextrin 20g
Hydroxypropyl cellulose 115g
Micropowder silica gel 4g
Preparation technology:
Principal agent is crossed 100 mesh sieves, and glucosyl group alpha-cyclodextrin, hydroxypropyl cellulose are crossed 80 mesh sieves, takes by weighing the principal agent and the abundant mix homogeneously of glucosyl group alpha-cyclodextrin of recipe quantity, after the grinding, add the hydroxypropyl cellulose and the lubricant micropowder silica gel of recipe quantity, mixing, tabletting, promptly.
Embodiment 9
The finasteride dispersible tablet
Finasteride 3g
Alpha-cyclodextrin 10g
Crospolyvinylpyrrolidone 80g
Microcrystalline Cellulose 110g
5%PVP
K30Ethanol solution is an amount of
Magnesium stearate 3g
Preparation technology:
Principal agent is crossed 100 mesh sieves, and alpha-cyclodextrin and other adjuvants are crossed 80 mesh sieves, takes by weighing the principal agent and the abundant mix homogeneously of alpha-cyclodextrin of recipe quantity, after adding an amount of ethanol grinding, the crospolyvinylpyrrolidone and the microcrystalline Cellulose that add recipe quantity, fully mixing adds 5%PVP
K30Ethanol solution is granulated, oven dry, and the micropowder silica gel of adding recipe quantity, mixing, tabletting, promptly.
Embodiment 10
The finasteride dispersible tablet
Finasteride 8g
Ethoxy-beta cyclodextrin 25g
Hydroxypropyl cellulose 40g
Crospolyvinylpyrrolidone 40g
10% starch slurry is an amount of
Magnesium stearate 4g
Preparation technology:
With embodiment 9.
Embodiment 11
The finasteride dispersible tablet
Finasteride 5g
Gamma-cyclodextrin 15g
Carboxymethyl starch sodium 30g
Crospolyvinylpyrrolidone 15g
Microcrystalline Cellulose 140g
10% starch slurry is an amount of
Magnesium stearate 6g
Preparation technology:
With embodiment 9.
Embodiment 12
The finasteride dispersible tablet
Finasteride 3g
Hydroxypropyl gamma-cyclodextrin 10g
Pregelatinized Starch 300g
Preparation technology:
Principal agent is crossed 100 mesh sieves, and 80 mesh sieves are crossed in hydroxypropyl gamma-cyclodextrin and pregelatinized Starch, takes by weighing the principal agent of recipe quantity, and grinds behind the abundant mixing of hydroxypropyl gamma-cyclodextrin, and with the pregelatinized Starch mix homogeneously, direct compression promptly again.
Embodiment 13
The finasteride dispersible tablet
Finasteride 10g
Glucosyl group beta-schardinger dextrin-30g
Hydroxypropyl starch 160g
The 10%PVPk30 alcoholic solution is an amount of
Pulvis Talci 2g
Preparation technology:
With embodiment 9.
Embodiment 14
The finasteride dispersible tablet
Finasteride 3g
Carboxymethyl beta-schardinger dextrin-10g
Sodium alginate 30g
The 10%PVPk30 alcoholic solution is an amount of
Rikemal B 200 1g
Preparation technology:
With embodiment 9.
Embodiment 15
The finasteride capsule
Finasteride 6g
Dimethyl-40g
Hydroxy acid cellulose 200g
Guar gum 50g
10% starch slurry is an amount of
Preparation technology:
Earlier all solid adjuvant materials are crossed 100 mesh sieves, take by weighing by recipe quantity, with finasteride and dimethyl-mixing, add after an amount of distilled water fully grinds, adding hydroxy acid cellulose, guar gum and 10% starch slurry granulates in right amount, oven dry below 60 ℃, 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 17
Finasteride tablet
Finasteride 2g
Hydroxypropyl 220g
Preparation technology:
Finasteride is crossed 120 mesh sieves, and hydroxypropyl is crossed 100 mesh sieves, takes by weighing the abundant mixing of recipe quantity, adds an amount of dehydrated alcohol and fully grinds, granulate, and oven dry, tabletting gets final product.
Embodiment 18
Finasteride tablet
Finasteride 6g
Malt-base beta-schardinger dextrin-120g
Sodium carboxymethyl cellulose 10g
Lactose 100g
Starch 20g
The 10%PVPk30 alcoholic solution is an amount of
Magnesium stearate 2g
Preparation technology:
With embodiment 9.
Embodiment 19
The finasteride liniment
Finasteride 6g
Dimethyl-20g
Propylene glycol 500ml
Ethyl hydroxybenzoate 5g
Sterile distilled water adds to 1000ml
Preparation technology:
Principal agent finasteride and dimethyl-are crossed 100 mesh sieves respectively, take by weighing according to recipe quantity, mixing adds an amount of sterile distilled water, fully grinds propylene glycol and the ethyl hydroxybenzoate that the back adds recipe quantity, and sterile distilled water adds to 1000ml and gets final product.
Embodiment 20
The finasteride liniment
Finasteride 3g
Hydroxypropyl 30g
Glycerol 500ml
Methyl hydroxybenzoate 3g
Sterile distilled water adds to 1000ml
Preparation technology:
With embodiment 19.
Embodiment 21
The finasteride ointment
Finasteride 8g
Hydroxypropyl 40g
Carboxymethyl cellulose 30g
Glycerol 400g
Ethyl hydroxybenzoate 2g
Sterile distilled water adds to 1000ml
Preparation technology:
Finasteride and hydroxypropyl are crossed 100 mesh sieves respectively, take by weighing according to recipe quantity, mixing adds an amount of sterile distilled water and fully grinds; With carboxymethyl cellulose and glycerol mixing, add an amount of hot distilled water then, after placement was waited to be swelled into gel, the aqueous solution of finasteride after adding is ground again and hydroxypropyl, ethyl hydroxybenzoate added water to capacity and gets final product.
Embodiment 22
The finasteride ointment
Finasteride 3g
Hydroxypropyl gamma-cyclodextrin 20g
Carboxymethyl cellulose 50g
Propylene glycol 200g
Ethyl hydroxybenzoate 5g
Carbamide 10g
Distilled water adds to 1000ml
Preparation technology:
Finasteride and hydroxypropyl gamma-cyclodextrin are crossed 100 mesh sieves respectively, take by weighing according to recipe quantity, mixing adds an amount of sterile distilled water and fully grinds; With carboxymethyl cellulose and propylene glycol mixing, add an amount of hot distilled water then, place wait to be swelled into gel after, add the finasteride that contains after the grinding and the aqueous solution of hydroxypropyl gamma-cyclodextrin and carbamide and ethyl hydroxybenzoate again, add water to capacity and get final product.
Embodiment 23
The finasteride gel
Finasteride 5g
Malt-base-α cyclodextrin 25g
Carbopol 940 1.5g
Glycerol 60g
Tween 80 2g
Ethyl hydroxybenzoate 0.5g
The about 4g of triethanolamine
Distilled water adds to 1000ml
Preparation technology:
Finasteride and malt-base-α cyclodextrin are crossed 100 mesh sieves respectively, take by weighing according to recipe quantity, mixing adds an amount of sterile distilled water and fully grinds; The carbopol of recipe quantity is joined in the aqueous solution of the finasteride that contains after the grinding and malt-base-α cyclodextrin, form low viscous acid solution, after adding glycerol, Tween 80 and the ethyl hydroxybenzoate of recipe quantity, regulate pH value to 7.0 with triethanolamine and get final product.
Claims (7)
1. pharmaceutical composition that is used for the treatment of benign prostatic hyperplasia or male pattern baldness is characterized in that it contains the derivant of finasteride and cyclodextrin or cyclodextrin.
2. the derivant of cyclodextrin as claimed in claim 1 or cyclodextrin, they are in alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, glucosyl group alpha-cyclodextrin, malt-base alpha-cyclodextrin, dimethyl-, methyl beta-schardinger dextrin-, hydroxypropyl, ethoxy beta-schardinger dextrin-, carboxymethyl beta-schardinger dextrin-, glucosyl group beta-schardinger dextrin-, malt-base beta-schardinger dextrin-, methyl gamma-cyclodextrin or the hydroxypropyl gamma-cyclodextrin one or more.
3. pharmaceutical composition as claimed in claim 1, but the application forms that it can be prepared into has dispersible tablet, oral cavity disintegration tablet, conventional tablet, capsule and liniment that can local topical, ointment, gel.
4. dispersible tablet as claimed in claim 3, oral cavity disintegration tablet, conventional tablet or capsule, it is characterized in that it also contains in the following adjuvant one or more, they are starch, hydroxypropyl cellulose, microcrystalline Cellulose, PVPk30, crospolyvinylpyrrolidone, micropowder silica gel, magnesium stearate, lactose, carboxymethyl starch sodium, pregelatinized Starch, Rikemal B 200, Pulvis Talci, mannitol, sodium carboxymethyl cellulose (CMC-Na), cross-linking sodium carboxymethyl cellulose, sodium alginate, crosslinked carboxymethyl fecula sodium, glucose, hydroxypropyl starch, hydroxy acid cellulose, guar gum.
5. liniment as claimed in claim 3, ointment or gel is characterized in that it also contains in propylene glycol, glycerol, carboxymethyl cellulose, carbamide, carbopol 940, Tween 80, the triethanolamine one or more.
6. liniment as claimed in claim 3, ointment or gel is characterized in that it also contains antiseptic.
7. oral cavity disintegration tablet as claimed in claim 3 is characterized in that it also contains in Herba Menthae essence, aspartame, Fructus Citri Limoniae essence, Fructus Citri tangerinae essence, chocolate essence or the cyclamate one or more.
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|---|---|---|---|
| CNB2004100758010A CN1294913C (en) | 2004-12-23 | 2004-12-23 | Medication combination of containing finasteride and cyclodextrin or ramification |
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|---|---|---|---|
| CNB2004100758010A CN1294913C (en) | 2004-12-23 | 2004-12-23 | Medication combination of containing finasteride and cyclodextrin or ramification |
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| CN1989972B (en) * | 2005-12-27 | 2011-08-31 | 杭州咸达医药科技有限公司 | Finasteroid oral preparation and method for preparing same |
| CN103381148A (en) * | 2012-05-04 | 2013-11-06 | 北京韩美药品有限公司 | Solid preparation including finasteride and preparation method thereof |
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| CN104739790A (en) * | 2015-02-28 | 2015-07-01 | 王菊明 | Finasteride tablet for treating hyperplasia of prostate and preparation method of finasteride tablet |
| CN104784047A (en) * | 2014-01-16 | 2015-07-22 | 南京瑞尔医药有限公司 | Finasteride composition |
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| CN1379784A (en) * | 1999-11-01 | 2002-11-13 | 多坎化学有限公司 | Complexation with Group I or Group II metal salts to produce polymorphic Forms I and II of finasteride |
| WO2002020553A1 (en) * | 2000-09-07 | 2002-03-14 | Dr. Reddy's Laboratories Ltd. | NOVEL POLYMORPHIC FORM OF 17-β-(N-TER.BUTYL CARBAMOYL)-4-AZA-5-α-ANDROST-1-EN-3-ONE AND A PROCESS FOR PREPARING IT |
| CN1528316A (en) * | 2003-10-08 | 2004-09-15 | 南昌弘益科技有限公司 | Finasteride drop pill and preparing method thereof |
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2004
- 2004-12-23 CN CNB2004100758010A patent/CN1294913C/en not_active Expired - Fee Related
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| CN1989972B (en) * | 2005-12-27 | 2011-08-31 | 杭州咸达医药科技有限公司 | Finasteroid oral preparation and method for preparing same |
| CN101041076B (en) * | 2007-04-27 | 2010-08-25 | 大连理工大学 | Controlled-release ointment combination matrix and preparation method thereof |
| CN102038658A (en) * | 2009-10-20 | 2011-05-04 | 江苏联环药业股份有限公司 | Epristeride tablets with high dissolution rate and preparation method thereof |
| CN103381148A (en) * | 2012-05-04 | 2013-11-06 | 北京韩美药品有限公司 | Solid preparation including finasteride and preparation method thereof |
| CN103381148B (en) * | 2012-05-04 | 2017-04-05 | 北京韩美药品有限公司 | Solid pharmaceutical preparation comprising Finasteride and preparation method thereof |
| CN103638038A (en) * | 2013-11-13 | 2014-03-19 | 青海互丰农业科技集团有限公司 | Chinese caterpillar fungus recuperation oral liquid used for treating alopecia, and formulas thereof |
| CN104784047A (en) * | 2014-01-16 | 2015-07-22 | 南京瑞尔医药有限公司 | Finasteride composition |
| CN104739790A (en) * | 2015-02-28 | 2015-07-01 | 王菊明 | Finasteride tablet for treating hyperplasia of prostate and preparation method of finasteride tablet |
| CN104739790B (en) * | 2015-02-28 | 2017-10-31 | 薛光玉 | It is a kind of to treat Finasteride tablet of hyperplasia of prostate and preparation method thereof |
| WO2016177269A1 (en) * | 2015-05-05 | 2016-11-10 | 谢秉权 | Compound topical drug for treating and/or preventing male-pattern alopecia |
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| Publication number | Publication date |
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| CN1294913C (en) | 2007-01-17 |
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