CN102319418A - Buserelin preparation and preparation method thereof - Google Patents
Buserelin preparation and preparation method thereof Download PDFInfo
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- CN102319418A CN102319418A CN201110248693A CN201110248693A CN102319418A CN 102319418 A CN102319418 A CN 102319418A CN 201110248693 A CN201110248693 A CN 201110248693A CN 201110248693 A CN201110248693 A CN 201110248693A CN 102319418 A CN102319418 A CN 102319418A
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- Prior art keywords
- buffer
- buserelin
- pharmaceutical composition
- preparation
- agent
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- 108010037003 Buserelin Proteins 0.000 title claims abstract description 34
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 title claims abstract description 34
- 229960002719 buserelin Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000000243 solution Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 8
- 229940095064 tartrate Drugs 0.000 claims abstract description 7
- 239000008351 acetate buffer Substances 0.000 claims abstract description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims abstract description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 25
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 22
- 239000000872 buffer Substances 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 239000011780 sodium chloride Substances 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 10
- 238000000108 ultra-filtration Methods 0.000 claims description 9
- 230000002421 anti-septic effect Effects 0.000 claims description 8
- 238000011049 filling Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 239000011261 inert gas Substances 0.000 claims description 7
- 238000012856 packing Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 5
- 239000006174 pH buffer Substances 0.000 claims description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 5
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 4
- 239000007979 citrate buffer Substances 0.000 claims description 4
- 229930182817 methionine Natural products 0.000 claims description 4
- 239000007981 phosphate-citrate buffer Substances 0.000 claims description 4
- FYKDNWHPKQOZOT-UHFFFAOYSA-M sodium;dihydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].OP(O)([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O FYKDNWHPKQOZOT-UHFFFAOYSA-M 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 239000000890 drug combination Substances 0.000 claims 2
- 239000007853 buffer solution Substances 0.000 abstract description 11
- 239000006172 buffering agent Substances 0.000 abstract 2
- 230000003139 buffering effect Effects 0.000 abstract 1
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 abstract 1
- 239000008055 phosphate buffer solution Substances 0.000 abstract 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 21
- 239000007788 liquid Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Substances [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 235000019445 benzyl alcohol Nutrition 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 108700012941 GNRH1 Proteins 0.000 description 4
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 4
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 4
- 229940100630 metacresol Drugs 0.000 description 4
- 230000001568 sexual effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 201000009273 Endometriosis Diseases 0.000 description 3
- 206010062767 Hypophysitis Diseases 0.000 description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 201000001514 prostate carcinoma Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 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 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 210000002149 gonad Anatomy 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 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 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102000009151 Luteinizing Hormone Human genes 0.000 description 1
- 108010073521 Luteinizing Hormone Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 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 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000000745 gonadal hormone Substances 0.000 description 1
- 210000003016 hypothalamus Anatomy 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a buserelin preparation and a preparation method thereof. The preparation comprises buserelin and a buffering agent, wherein the pH of the preparation is 4.0-6.5, the buffering agent is one or the mixture of any two or more than two citrate buffering solution, acetate buffer solution, tartrate buffer solution, phosphate buffer solution or sodium hydrogen phosphate-citric acid buffer solution. The preparation disclosed by the invention has remarkably-improved stability.
Description
Technical field
The present invention relates to a kind of composition and method of making the same that contains polypeptide drug, relate in particular to pharmaceutical composition that contains buserelin and preparation method thereof.
Background technology
Buserelin belongs to luteinizing hormone-releasing hormone (LHRH) analog.LHRH is by the excretory decapeptide hormone of hypothalamus, can promote that hypophysis is synthetic and discharge lutropin (LH) and FSH (FSH), excites adolescence to grow and regulate reproduction, fertility and gonadal hormone to produce.When exogenous LHRH or its analog during with physiologic pulse frequency (per 90 minutes once) short-term, low dose of administration, system plays a driving role to the hypophysis gonad, is used for the therapeutic hypofunction, does not ovulate, adolescence delays; And during, heavy dose of administration long-term with non-physiologic pulse frequency; Can suppress hypophysis secretion LH and FSH; Cause gonad secreting hormone ability drop; Sexual organ's atrophy is used to treat some hormone-dependent diseases, like carcinoma of prostate, hysteromyoma, breast carcinoma, endometriosis and adolescence sexual precosity.
At present, domestic still do not have the listing of buserelin preparation, so we provide a kind of stable pharmaceutical composition of buserelin.
Summary of the invention
The present invention provides a kind of composition of liquid medicine of stable buserelin, and said composition not only can be stable 2-8 ℃ of long term store, can also farthest make things convenient for patient's self-administration 25 ℃ of long term store 24 months.
The present invention provides a kind of stable pharmaceutical composition that contains buserelin, and it comprises buserelin, buffer agent, isoosmotic adjusting agent, antiseptic and acceptable accessories.Said composition is used to treat some hormone-dependent diseases, like carcinoma of prostate, hysteromyoma, breast carcinoma, endometriosis and adolescence sexual precosity.
The present invention relates to a kind of stable pharmaceutical composition and method for preparing that contains buserelin.This pharmaceutical composition mainly exists with liquid form, through parenterai administration, mainly contains the form of injection, nasal spray.
A kind of stable pharmaceutical composition that contains buserelin, it comprises buserelin, pH buffer agent, isoosmotic adjusting agent, antiseptic and acceptable accessories.Said composition is used to treat some hormone-dependent diseases, like carcinoma of prostate, hysteromyoma, breast carcinoma, endometriosis and adolescence sexual precosity.
In the aforementioned pharmaceutical compositions, the concentration of the contained buserelin of the present invention is 0.1-10mg/ml.
In the aforementioned pharmaceutical compositions, buffer agent of the present invention is in order to be that to keep the pH of solution be constant value.The applicant is surprised to find that; PH value is constant extremely important as far as the buserelin stability of formulation, even the initial pH of buserelin preparation of different formulations is identical or approaching, but as time passes; Have under the situation of stablizing the pH existence, can make preparation obtain unexpected stablizing effect.For this reason, the applicant further finds, the fulfilling medicinal demand that pH can be superior between 4-6.5, and preferred pH is between 5.0-6.5.PH is lower than at 4 o'clock, and the human tolerance is poor during administration; PH is higher than at 6.5 o'clock, and medicine stability is poor.PH is between 5.0-6.5, and medicine stability improves, and the human tolerance is good during administration.
Buffer agent comprises following substances: citrate buffer, and acetate buffer, tartrate buffer, phosphate buffer, sodium hydrogen phosphate-citrate buffer can be wherein any one or its arbitrarily two or more combinations.Phosphate buffer preferably phosphoric acid sodium dihydrogen-sodium hydrate buffer solution, sodium dihydrogen phosphate-sodium phosphate buffer.The concentration of buffer can be at about 2mM in about 500mM scope, and it has tangible buffer capacity; Preferred 2mM not only has stronger buffer capacity to 100mM, can also save the consumption of buffer agent.PH is between 4-6.5 in control, between the preferred 5.0-6.5.Wherein mM is a concentration unit, 1mM=0.001mol/L.
Isoosmotic adjusting agent in the aforementioned pharmaceutical compositions can be a polyol, like sugar or sugar alcohol, and glucose for example, trehalose, chitosan or sucrose, mannitol, sorbitol or inositol, preferred mannitol.The concentration of polyol can be in the 1-20% scope, preferred 3-10%.Be used to control within the osmotic pressure accordance with physiology value range.
In the aforementioned pharmaceutical compositions, isoosmotic adjusting agent of the present invention also comprises sodium chloride, citrate; Acetate; One or more mixture of tartrate.Preferred sodium chloride.The concentration of salt can be 0.1-10%, preferred 0.1-0.9%.Also can be used to control within the osmotic pressure accordance with physiology value range.
In the aforementioned pharmaceutical compositions; Antiseptic of the present invention comprises benzyl alcohol, chlorobutanol, phenol, metacresol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate; The concentration of antiseptic is 0.1%-5%, preferred benzyl alcohol or metacresol.
In the aforementioned pharmaceutical compositions, pharmacy acceptable auxiliary of the present invention is methionine, glycine, and concentration is 0.001%-0.1%, can avoid buserelin oxidized.
The invention provides the method for preparing of preparation buserelin preparation, adopt ultrafiltration to remove thermal source, can effectively reduce the loss rate of buserelin in production process, the inflated with nitrogen protection avoids buserelin oxidized, and the present invention provides method for preparing, may further comprise the steps:
(1) gets the buffer material of recipe quantity, to be used to prepare the solution that pH is 4-6.5;
(2) with isoosmotic adjusting agent, antiseptic dissolving;
(3) solution with step (2) carries out ultrafiltration except that thermal source;
(4) with the buserelin dissolving, buffer agent and step (3) ultrafiltrate carries out standardize solution;
(5) aseptic filtration, packing, and filling with inert gas protection.
Preferred scheme may further comprise the steps:
(1) get the buffer agent of recipe quantity, preparation pH is the buffer solution of 4-6.5;
(2) with isoosmotic adjusting agent, antiseptic dissolving, it is carried out ultrafiltration remove thermal source;
(3) buffer solution is added mixing in step (2) ultrafiltrate, be made into auxiliary material liquid;
(4) with water for injection buserelin is dissolved, add auxiliary material liquid and carry out standardize solution;
(5) aseptic filtration, packing, and filling with inert gas protection.
Preparation among the present invention can also contain adjuvants such as antioxidant.
Embodiment
The following example is used to explain the present invention, rather than is used to limit it.
Embodiment 1
| Buserelin | 1.0g |
| Benzyl alcohol | 10.0g |
| Sodium chloride | 4.50g |
| Sodium dihydrogen phosphate | 3.5g |
| Sodium hydroxide | 0.1g |
| Add the injection water extremely | 1000ml |
Preparation technology:
Take by weighing supplementary material by recipe quantity, subsequent use.With the sodium chloride and the benzyl alcohol dissolving of recipe quantity, carry out ultrafiltration with the ultrafilter appearance and remove thermal source.Get the buffer agent of recipe quantity, preparation pH is the buffer solution of 4-6.5; Buffer solution is added mixing in the ultrafiltrate, be made into auxiliary material liquid.With water for injection buserelin is dissolved, add auxiliary material liquid and carry out standardize solution.Aseptic filtration, packing, and filling with inert gas protection.
Embodiment 2
| Buserelin | 1.0g |
| Metacresol | 3.0g |
| Sodium chloride | 4.50g |
| Tartaric acid | 3.250g |
| 10% sodium hydroxide is transferred pH | 5.0-6.5 |
| Add the injection water extremely | 1000ml |
Preparation technology:
Take by weighing supplementary material by recipe quantity, subsequent use.With the sodium chloride and the metacresol of recipe quantity, dissolving is carried out ultrafiltration with the ultrafilter appearance and is removed thermal source.Get the buffer agent of recipe quantity, preparation pH is the buffer solution of 5-6.5; Buffer solution is added mixing in the ultrafiltrate, be made into auxiliary material liquid.With water for injection buserelin is dissolved, add auxiliary material liquid and carry out standardize solution.Aseptic filtration, packing, and filling with inert gas protection.
Embodiment 3
| Buserelin | 1.0g |
| Benzyl alcohol | 10.0g |
| Sodium chloride | 4.50g |
| Glacial acetic acid | 0.72g |
| 10% sodium hydroxide is transferred pH | 5.0-6.5 |
| Methionine | 1.0g |
| Add the injection water extremely | 1000ml |
Preparation technology:
Take by weighing sodium chloride, benzyl alcohol dissolving, mixing, and ultrafiltration by recipe quantity.Get the buffer agent of recipe quantity, preparation pH is the buffer solution of 5-6.5; Buffer solution is added mixing in the ultrafiltrate, be made into auxiliary material liquid.With water for injection glacial acetic acid, methionine, buserelin are dissolved respectively, add auxiliary material liquid and carry out standardize solution.Aseptic filtration, packing, and filling with inert gas protection.
Embodiment 4
| Buserelin | 1.0g |
| Benzyl alcohol | 10.0g |
| Sodium chloride | 4.50g |
| Add the injection water extremely | 1000ml |
Preparation technology:
Take by weighing sodium chloride, benzyl alcohol dissolving, mixing, and ultrafiltration by recipe quantity.With buserelin dissolving and add in the good adjuvant ultrafiltrate of ultrafiltration and standardize solution.Aseptic filtration, packing, and filling with inert gas protection.
Embodiment 5
40 ℃ of accelerated test results of table 1
25 ℃ of long-term results of table 2
The stability test data show, embodiment 1, embodiment 2, embodiment 3 40 ℃ quickened 6 months and 25 ℃ long-term related substance increases in 24 months not remarkable, pH changes little.And embodiment 4 (not containing the pH buffer agent) increases significantly in 40 ℃ of acceleration 6 months and 25 ℃ long-term 24 months related substances, and pH changes greatly, and medicine has obvious degradation.
Embodiment 1, embodiment 2, embodiment 3, embodiment 4 contain antiseptic accelerated test and long term test its can be effectively antibacterial, sterility test is qualified.
Claims (10)
1. pharmaceutical composition that contains buserelin comprises:
Buserelin;
Keep the stable buffer agent of pH.
2. pharmaceutical composition according to claim 1 is characterized in that: the pH scope is between 4.0-6.5.
3. pharmaceutical composition according to claim 1 is characterized in that: the pH scope is between 5.0-6.5.
4. pharmaceutical composition according to claim 1; It is characterized in that: the pH buffer agent is a citrate buffer; Acetate buffer, any one or its arbitrarily two or more the combination in tartrate buffer, phosphate buffer or the sodium hydrogen phosphate-citrate buffer.
5. pharmaceutical composition according to claim 2; It is characterized in that: the pH buffer agent is a citrate buffer; Acetate buffer, any one or its arbitrarily two or more the combination in tartrate buffer, phosphate buffer or the sodium hydrogen phosphate-citrate buffer.
6. pharmaceutical composition according to claim 3; It is characterized in that: the pH buffer agent is a citrate buffer; Acetate buffer, any one or its arbitrarily two or more the combination in tartrate buffer, phosphate buffer or the sodium hydrogen phosphate-citrate buffer.
7. according to any described pharmaceutical composition of claim 1-6, it is characterized in that: contain isoosmotic adjusting agent, isoosmotic adjusting agent comprises any one or any several kinds mixture of sodium chloride, citrate, acetate, tartrate.
8. according to any described pharmaceutical composition of claim 1-6, it is characterized in that: contain methionine or glycine.
9. one kind according to any described preparation of drug combination method of claim 1-8, may further comprise the steps:
Get the buffer material of recipe quantity, to be used to prepare the solution that pH is 4-6.5;
With isoosmotic adjusting agent, antiseptic dissolving;
The solution of step (2) is carried out ultrafiltration except that thermal source;
With the buserelin dissolving, buffer agent and step (3) ultrafiltrate carries out standardize solution;
Aseptic filtration, packing, and filling with inert gas protection.
10. preparation of drug combination method according to claim 9 is characterized in that: the pH of step (1) obtain solution is 5.0-6.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201110248693A CN102319418A (en) | 2011-08-26 | 2011-08-26 | Buserelin preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110248693A CN102319418A (en) | 2011-08-26 | 2011-08-26 | Buserelin preparation and preparation method thereof |
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| CN102319418A true CN102319418A (en) | 2012-01-18 |
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| CN201110248693A Pending CN102319418A (en) | 2011-08-26 | 2011-08-26 | Buserelin preparation and preparation method thereof |
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| CN105749245A (en) * | 2016-03-02 | 2016-07-13 | 张光泉 | Anti-cancer drug degarelix acetate injection and preparation method thereof |
| CN106924194A (en) * | 2015-12-31 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of long-acting Pharmaceutical composition and preparation method |
| CN111544569A (en) * | 2020-05-13 | 2020-08-18 | 吉林吉力生物技术研究有限公司 | Buserelin acetate freeze-dried powder injection for animal injection and preparation method and application thereof |
| CN112569340A (en) * | 2020-12-31 | 2021-03-30 | 苏州素仕生物科技有限公司 | Sterile buserelin injection and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106924194A (en) * | 2015-12-31 | 2017-07-07 | 深圳翰宇药业股份有限公司 | A kind of long-acting Pharmaceutical composition and preparation method |
| CN105749245A (en) * | 2016-03-02 | 2016-07-13 | 张光泉 | Anti-cancer drug degarelix acetate injection and preparation method thereof |
| CN111544569A (en) * | 2020-05-13 | 2020-08-18 | 吉林吉力生物技术研究有限公司 | Buserelin acetate freeze-dried powder injection for animal injection and preparation method and application thereof |
| CN112569340A (en) * | 2020-12-31 | 2021-03-30 | 苏州素仕生物科技有限公司 | Sterile buserelin injection and preparation method and application thereof |
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Application publication date: 20120118 |