CN114569700A - Ganirelix acetate injection and preparation method thereof - Google Patents
Ganirelix acetate injection and preparation method thereof Download PDFInfo
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- CN114569700A CN114569700A CN202011376364.1A CN202011376364A CN114569700A CN 114569700 A CN114569700 A CN 114569700A CN 202011376364 A CN202011376364 A CN 202011376364A CN 114569700 A CN114569700 A CN 114569700A
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- injection
- water
- ganirelix acetate
- adjusting
- weighing
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- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 title claims abstract description 57
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 239000000243 solution Substances 0.000 claims abstract description 43
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 41
- 239000008215 water for injection Substances 0.000 claims abstract description 40
- 238000005303 weighing Methods 0.000 claims abstract description 38
- 239000002994 raw material Substances 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 29
- 108700032141 ganirelix Proteins 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229960000406 ganirelix acetate Drugs 0.000 claims abstract description 24
- 238000004090 dissolution Methods 0.000 claims abstract description 14
- 230000003204 osmotic effect Effects 0.000 claims abstract description 8
- 239000000872 buffer Substances 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 25
- 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 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 18
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical group N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 12
- 239000005695 Ammonium acetate Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 229940043376 ammonium acetate Drugs 0.000 claims description 12
- 235000019257 ammonium acetate Nutrition 0.000 claims description 12
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 11
- 239000001632 sodium acetate Substances 0.000 claims description 11
- 235000017281 sodium acetate Nutrition 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 9
- 239000011780 sodium chloride Substances 0.000 claims description 9
- 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 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000006172 buffering agent Substances 0.000 claims description 4
- 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 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims 1
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 239000008181 tonicity modifier Substances 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 18
- 238000012986 modification Methods 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 8
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 7
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 7
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 6
- 239000013065 commercial product Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 102000009151 Luteinizing Hormone Human genes 0.000 description 3
- 108010073521 Luteinizing Hormone Proteins 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002474 gonadorelin antagonist Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229940040129 luteinizing hormone Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940124041 Luteinizing hormone releasing hormone (LHRH) antagonist Drugs 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960003794 ganirelix Drugs 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 208000007984 Female Infertility Diseases 0.000 description 1
- 108700012941 GNRH1 Proteins 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 206010021928 Infertility female Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
Abstract
The invention belongs to the field of pharmaceutical preparations, and discloses a preparation method of ganirelix acetate injection, which comprises the following steps: weighing 0.6-8 wt% of osmotic pressure regulator, dissolving in 40-70 wt% of water for injection, adding 0.02-0.05 wt% of buffer, and dissolving to obtain an auxiliary material solution; weighing 25% by weight of water for injection, adjusting the pH value of the water for injection to 4.0-5.5 by using a pH regulator, and then adding 0.03-0.08% by weight of ganirelix acetate for dissolution to obtain a raw material medicine solution; and mixing the raw material solution and the auxiliary material solution, and adjusting the pH value to 4.0-5.5. The preparation process is simple and easy to operate, the liquid preparation steps and time are reduced, and the stability of the ganirelix acetate injection is effectively ensured.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and relates to a ganirelix acetate injection and a preparation process thereof.
Background
Ganirelix (Ganirelix) is a synthetic decapeptide which replaces the amino acids at the l, 2, 3, 6, 8, 10 th sites of natural gonadotropin releasing hormone (GnRH), is a GnRH antagonist, has high antagonistic activity against naturally occurring gonadotropin releasing hormone (GnRH), and can control the action of gonadotropin releasing hormone and control the production and secretion of gonadotropin and sex hormone. Ganirelix acetate, also known as luteinizing hormone releasing hormone (LH), is used for treating female infertility and preventing premature Luteinizing Hormone (LH) surge in women who receive sexual ovarian stimulation controlled by assisted reproductive technology.
Chinese patent CN 02823490.1 discloses an injection containing LHRH antagonist, which increases the solubility of the LHRH antagonist by adding organic acid and surfactant, but has poor preparation stability and obviously increased impurities after being placed at 25 ℃ for 6 months.
Chinese patent CN 201880009464.5 discloses a composition for long-acting release of gonadotropin releasing hormone (GnRH) antagonist and a preparation method thereof, wherein the composition is prepared into dosage forms such as hydrogel, microspheres, implants and the like by adding thermoplastic polymer and organic solvent, so that long-term release is realized, but the preparation process is complex and the technical requirement is higher.
According to the prior art, the preparation process of the ganirelix acetate injection is complex and has poor stability in the process of placing at normal temperature, and related substances grow more; meanwhile, no buffer system exists in the commercial product, and the pH value of the preparation is easy to fluctuate.
Disclosure of Invention
In order to solve the technical problems, according to the prior art, the preparation process of the ganirelix acetate injection is complex, the stability is poor in the process of placing at normal temperature, and related substances grow more; meanwhile, no buffer system exists in the commercial product, and the pH value of the preparation is easy to fluctuate. The invention provides a stable ganirelix acetate injection with simple preparation process, which solves the problems.
The invention provides a preparation method of ganirelix acetate injection, which comprises the following steps: weighing 0.6-8 wt% of osmotic pressure regulator, dissolving in 40-70 wt% of water for injection, adding 0.02-0.05 wt% of buffer, and dissolving to obtain an auxiliary material solution; weighing 25% by weight of water for injection, adjusting the pH value of the water for injection to 4.0-5.5 by using a pH regulator, and then adding 0.03-0.08% by weight of ganirelix acetate for dissolution to obtain a raw material medicine solution; and mixing the raw material solution and the auxiliary material solution, and adjusting the pH value to 4.0-5.5.
Preferably, in the technical scheme of the invention, the preparation method comprises the following steps: weighing 0.9-5 wt% of osmotic pressure regulator, dissolving in 50-60 wt% of water for injection, adding 0.03-0.04 wt% of buffering agent, and dissolving to obtain an auxiliary material solution; weighing 25% by weight of water for injection, adjusting the pH value of the water for injection to 4.5-5.0 by using a pH regulator, and then adding 0.05-0.06% by weight of ganirelix acetate for dissolution to obtain a raw material medicine solution; and mixing the raw material medicine solution and the auxiliary material solution, and adjusting the pH value to 4.5-5.0 to obtain the traditional Chinese medicine.
In the technical scheme of the invention, the pH regulator is selected from phosphoric acid, hydrochloric acid and acetic acid, and preferably acetic acid.
In the technical scheme of the invention, the osmotic pressure regulator is selected from sodium chloride, mannitol and glucose, and preferably mannitol.
In the technical scheme of the invention, the buffering agent is selected from ammonium acetate, sodium dihydrogen phosphate and disodium hydrogen phosphate, and preferably sodium acetate.
In the technical scheme of the invention, the operation steps of the preparation method are completed in a clean and sterile medicine preparation operation room.
The invention also claims the ganirelix acetate injection prepared by the preparation method.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a preparation method of ganirelix acetate injection, which comprises the steps of dissolving ganirelix acetate in an aqueous solution with a certain pH value, adding an auxiliary material solution, uniformly mixing, adjusting the pH value to a target value, and then weighing. The preparation process is simple and easy to operate, the liquid preparation steps and time are reduced, and the stability of the ganirelix acetate injection is effectively ensured.
2. The invention adopts a new preparation process to prepare the ganirelix acetate injection, can avoid the defects of complex preparation and poor stability in the prior art, and improves the product quality and curative effect.
3. The invention adopts a new preparation process to obviously improve the stability of the ganirelix acetate injection preparation. The raw material medicines are dissolved under an acidic condition, and a buffer salt system is added into the prescription, so that the solubility of the raw material medicines is better, the stability of the pH value is ensured, the obtained preparation is more stable during stability investigation, and the increase and the content reduction of impurities are better than those of the original preparation.
Detailed Description
For a further understanding of the present invention, reference will now be made in detail to the following examples. The following examples will help understanding of the present invention, but the following examples are only for illustrating the implementation of the present invention more specifically and are not intended to limit the technical scheme of the present invention.
The embodiment of the invention discloses a prescription of ganirelix acetate injection and a preparation process thereof. Those skilled in the art can modify the process recipe implementation appropriately based on the contents provided herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the formulations and processes described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention. The method comprises the following steps:
step 1: weighing 400-700 g of injection water according to the formula amount, adding 6-80 g of osmotic pressure regulator, stirring until the mixture is completely dissolved, adding 0.2-0.5 g of buffering agent, and continuously stirring until the mixture is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 4.0-5.5 by using a pH regulator, and adding 0.3-0.8 g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw material medicine solution and the auxiliary material solution, adjusting the pH value to 4.0-5.5, and then weighing.
It should be noted that the order of preparation of the adjuvant solution and the raw material solution may be reversed.
The pH regulator is selected from phosphoric acid, hydrochloric acid, acetic acid, etc.; the osmotic pressure regulator is selected from sodium chloride, mannitol, glucose, etc.; the buffer is selected from ammonium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc.
For a further understanding of the present invention, reference will now be made in detail to the following examples.
Example 1: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.3g
Sodium chloride: 9.0g
Phosphoric acid: adjusting pH to 4.0
Disodium hydrogen phosphate: 0.2g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 700g of water for injection, adding 9g of sodium chloride, stirring until the sodium chloride is completely dissolved, adding 0.2g of disodium hydrogen phosphate, and continuously stirring until the disodium hydrogen phosphate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 4.0 by using phosphoric acid, and adding 0.3g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 4.0 by using phosphoric acid, and then weighing to 1000 g.
Example 2: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.4g
Sodium chloride: 6.0g
Acetic acid: adjusting pH to 4.5
Sodium acetate: 0.2g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 650g of water for injection, adding 6g of sodium chloride, stirring until the sodium chloride is completely dissolved, adding 0.2g of sodium acetate, and continuously stirring until the sodium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 4.5 by using acetic acid, and adding 0.4g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 4.5 by using acetic acid, and then weighing to 1000 g.
Example 3: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.5g
Mannitol: 50g
Acetic acid: adjusting pH to 5.0
Sodium acetate: 0.4g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 600g of water for injection, adding 50g of mannitol, stirring until the mannitol is completely dissolved, adding 0.4g of sodium acetate, and continuously stirring until the sodium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 5.0 by using acetic acid, and adding 0.5g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 5.0 by using acetic acid, and then weighing to 1000 g.
Example 4: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.6g
Mannitol: 80g of
Acetic acid: adjusting pH to 5.5
Ammonium acetate: 0.5g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 700g of water for injection, adding 80g of mannitol, stirring until the mannitol is completely dissolved, adding 0.5g of ammonium acetate, and continuously stirring until the ammonium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 5.5 by using acetic acid, and adding 0.6g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 5.5 by using acetic acid, and then weighing to 1000 g.
Example 5: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.5g
Glucose: 50g
Hydrochloric acid: adjusting pH to 4.7
Sodium acetate: 0.5g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 400g of water for injection, adding 50g of glucose, stirring until the glucose is completely dissolved, adding 0.5g of sodium acetate, and continuously stirring until the sodium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 4.7 by using hydrochloric acid, and adding 0.5g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 4.7 by using hydrochloric acid, and then weighing to 1000 g.
Example 6: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.5g
Mannitol: 60g of
Phosphoric acid: adjusting pH to 5.1
Disodium hydrogen phosphate: 0.5g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 500g of water for injection, adding 60g of mannitol, stirring until the mannitol is completely dissolved, adding 0.5g of disodium hydrogen phosphate, and continuously stirring until the disodium hydrogen phosphate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 5.1 by using phosphoric acid, and adding 0.5g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 5.1 by using phosphoric acid, and then weighing to 1000 g.
Example 7: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.5g
Mannitol: 50g
Acetic acid: adjusting pH to 4.3
Ammonium acetate: 0.3g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 550g of water for injection, adding 50g of mannitol, stirring until the mannitol is completely dissolved, adding 0.3g of ammonium acetate, and continuously stirring until the ammonium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 4.3 by using acetic acid, and adding 0.5g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 4.3 by using acetic acid, and then weighing to 1000 g.
Example 8: the preparation of the ganirelix acetate injection is prepared according to the following proportion:
ganirelix acetate: 0.5g
Mannitol: 50g
Acetic acid: adjusting pH to 5.3
Ammonium acetate: 0.4g
Adding water for injection to: 1000g
The method specifically comprises the following steps:
step 1: weighing 450g of water for injection, adding 50g of mannitol, stirring until the mannitol is completely dissolved, adding 0.4g of ammonium acetate, and continuously stirring until the ammonium acetate is dissolved to obtain an auxiliary material solution;
step 2: weighing 250g of water for injection, adjusting the pH value to 5.3 by using acetic acid, and adding 0.5g of ganirelix acetate for dissolution to obtain a raw material medicine solution;
and step 3: mixing the raw materials and the auxiliary materials, adjusting the pH value to 5.3 by using acetic acid, and then weighing to 1000 g.
Example 9:
the samples of examples 1 to 8 and a commercial product (trade name: Ogal) were taken, and the stability of the preparations was compared by examining the changes of the relevant substances, pH and content in the preparations at normal temperature of 25 ℃ and at high temperature of 40 ℃. The results of the investigation are as follows:
table 1 formulation stability test results
From the results in table 1, it can be demonstrated that the modified preparation process of ganirelix acetate injection of the inventor, as in example 3, the obtained injection has better insoluble particles, maximum single impurity, total impurity and content than the commercial preparation under the conditions of long-term 25 ℃ and accelerated 40 ℃, and the product of the invention has better stability than the commercial product (ougali) and is stable and effective.
Those skilled in the art can modify the process recipe implementation appropriately based on the contents provided herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the method of the present invention has been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the formulations and processes described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (7)
1. A preparation method of ganirelix acetate injection is characterized by comprising the following steps: weighing 0.6-8 wt% of osmotic pressure regulator, dissolving in 40-70 wt% of water for injection, adding 0.02-0.05 wt% of buffer, and dissolving to obtain an auxiliary material solution; weighing 25% by weight of water for injection, adjusting the pH value of the water for injection to 4.0-5.5 by using a pH regulator, and then adding 0.03-0.08% by weight of ganirelix acetate for dissolution to obtain a raw material medicine solution; and mixing the raw material medicine solution and the auxiliary material solution, and adjusting the pH value to 4.0-5.5 to obtain the traditional Chinese medicine.
2. The method for preparing a ganirelix acetate injection according to claim 1, comprising the steps of: weighing 0.9-5 wt% of osmotic pressure regulator, dissolving in 50-60 wt% of water for injection, adding 0.03-0.04 wt% of buffering agent, and dissolving to obtain an auxiliary material solution; weighing 25% by weight of water for injection, adjusting the pH value of the water for injection to 4.5-5.0 by using a pH regulator, and then adding 0.05-0.06% by weight of ganirelix acetate for dissolution to obtain a raw material medicine solution; and mixing the raw material medicine solution and the auxiliary material solution, and adjusting the pH value to 4.5-5.0 to obtain the traditional Chinese medicine.
3. The method for preparing a ganirelix acetate injection according to claim 1 or 2, wherein the pH adjusting agent is selected from phosphoric acid, hydrochloric acid, acetic acid, preferably acetic acid.
4. The method for preparing a ganirelix acetate injection according to claim 1 or 2, wherein the tonicity modifier is selected from the group consisting of sodium chloride, mannitol, and glucose, preferably mannitol.
5. The method for preparing a ganirelix acetate injection according to claim 1 or 2, wherein the buffer is selected from the group consisting of ammonium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate, preferably sodium acetate.
6. The process for preparing a ganirelix acetate injection according to claim 1 or 2 wherein the process steps are performed in a clean and sterile pharmaceutical compounding room.
7. A ganirelix acetate injection prepared according to the method of claim 1 or 2.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030092628A1 (en) * | 1999-06-23 | 2003-05-15 | De Greef Henrik Johan Matthieu Maria | Gonadotropin releasing hormone antagonist |
| US20030100509A1 (en) * | 2001-11-27 | 2003-05-29 | Werner Sarlikiotis | Injectable solution of an LHRH antagonist |
| CN105749245A (en) * | 2016-03-02 | 2016-07-13 | 张光泉 | Anti-cancer drug degarelix acetate injection and preparation method thereof |
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2020
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030092628A1 (en) * | 1999-06-23 | 2003-05-15 | De Greef Henrik Johan Matthieu Maria | Gonadotropin releasing hormone antagonist |
| US20030100509A1 (en) * | 2001-11-27 | 2003-05-29 | Werner Sarlikiotis | Injectable solution of an LHRH antagonist |
| CN105749245A (en) * | 2016-03-02 | 2016-07-13 | 张光泉 | Anti-cancer drug degarelix acetate injection and preparation method thereof |
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