CN113413358A - Preparation method of contraceptive implant drug core - Google Patents
Preparation method of contraceptive implant drug core Download PDFInfo
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- CN113413358A CN113413358A CN202110656508.7A CN202110656508A CN113413358A CN 113413358 A CN113413358 A CN 113413358A CN 202110656508 A CN202110656508 A CN 202110656508A CN 113413358 A CN113413358 A CN 113413358A
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- core
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- groove
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- 239000003814 drug Substances 0.000 title claims abstract description 115
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 229940079593 drug Drugs 0.000 title claims abstract description 46
- 239000003433 contraceptive agent Substances 0.000 title claims abstract description 40
- 230000002254 contraceptive effect Effects 0.000 title claims abstract description 40
- 239000007943 implant Substances 0.000 title claims abstract description 37
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims abstract description 36
- 238000002156 mixing Methods 0.000 claims abstract description 32
- 229920002379 silicone rubber Polymers 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000004073 vulcanization Methods 0.000 claims abstract description 24
- 229920001971 elastomer Polymers 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 229910052697 platinum Inorganic materials 0.000 claims abstract description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000004907 flux Effects 0.000 claims abstract description 14
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims abstract description 13
- 239000006229 carbon black Substances 0.000 claims abstract description 13
- 229960004400 levonorgestrel Drugs 0.000 claims abstract description 13
- 230000008569 process Effects 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 238000009966 trimming Methods 0.000 claims abstract description 7
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000005303 weighing Methods 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000000047 product Substances 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 13
- WGTYBPLFGIVFAS-UHFFFAOYSA-M tetramethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C WGTYBPLFGIVFAS-UHFFFAOYSA-M 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 7
- 239000004945 silicone rubber Substances 0.000 claims description 7
- BITPLIXHRASDQB-UHFFFAOYSA-N ethenyl-[ethenyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound C=C[Si](C)(C)O[Si](C)(C)C=C BITPLIXHRASDQB-UHFFFAOYSA-N 0.000 claims description 6
- HMMGMWAXVFQUOA-UHFFFAOYSA-N octamethylcyclotetrasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 HMMGMWAXVFQUOA-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 230000007935 neutral effect Effects 0.000 claims description 5
- 229920002545 silicone oil Polymers 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- KAKZBPTYRLMSJV-UHFFFAOYSA-N vinyl-ethylene Natural products C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003921 oil Substances 0.000 abstract description 4
- 229910052710 silicon Inorganic materials 0.000 abstract description 4
- 239000010703 silicon Substances 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 description 10
- 239000000463 material Substances 0.000 description 5
- 229920001296 polysiloxane Polymers 0.000 description 4
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 241001330002 Bambuseae Species 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003756 cervix mucus Anatomy 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 238000007730 finishing process Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000016087 ovulation Effects 0.000 description 1
- 210000004681 ovum Anatomy 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- 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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61P15/18—Feminine contraceptives
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
- B29C33/44—Moulds or cores; Details thereof or accessories therefor with means for, or specially constructed to facilitate, the removal of articles, e.g. of undercut articles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/06—Preparatory processes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
- C08G77/20—Polysiloxanes containing silicon bound to unsaturated aliphatic groups
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Inorganic Chemistry (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Urology & Nephrology (AREA)
- Mechanical Engineering (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application relates to the technical field of contraceptive implant production, and particularly discloses a preparation method of a drug core of a contraceptive implant. The preparation method comprises the following steps: weighing a component A and a component B, wherein the weight ratio of the component A to the component B is 1: 1; mixing the component A and the component B to obtain mixed rubber; filling the rubber compound into a mold, and performing vulcanization treatment to obtain a crude drug core; cooling the crude drug core, and trimming to obtain the final product; the component A comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of platinum complex; the component B comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of hydrogen-containing silicon oil. The preparation method is simple in process, high in accuracy and high in flux core yield, and the prepared flux core is good in quality.
Description
Technical Field
The application relates to the technical field of contraceptive implant production, in particular to a preparation method of a drug core of a contraceptive implant.
Background
The subcutaneous implantation contraception method is a novel contraception method and has been popularized and used all over the world. The contraceptive method is that a certain amount of progestogen is put in a silicone capsule tube, and then the tube is buried under the skin to slowly release a small amount of progestogen, thereby playing the contraceptive role. The subcutaneous implantation contraceptive prevents sperms from entering the uterine cavity by changing the viscosity of cervical mucus; inhibiting the growth of endometrium, which is not beneficial to nidation of fertilized ovum; inhibiting ovarian ovulation and the like to achieve the contraceptive purpose.
The production process of the contraceptive implant comprises the following steps: producing a medicine core; producing a silicone tube; using a medical adhesive to seal one end of the silicone tube; filling the medicine core into a silica gel tube; the other end of the silicone tube is blocked by medical adhesive. Because the contraceptive implant has smaller size specification and higher quality requirement, a large amount of unqualified medicine cores can appear in the actual production of the medicine cores, and the production yield of the medicine cores in the industry is only 75-85 percent at present.
Therefore, the research of the preparation method of the medicine core, which can effectively improve the preparation yield of the medicine core, has very important significance.
Disclosure of Invention
In order to improve the preparation yield of the drug core of the contraceptive implant, the application provides a preparation method of the drug core of the contraceptive implant.
The application provides a preparation method of a contraceptive implant agent core, which adopts the following technical scheme:
a method for preparing a contraceptive implant drug core comprises the following steps:
s1, weighing a component A and a component B, and respectively premixing, wherein the weight ratio of the component A to the component B is 1: 1;
s2, mixing the component A and the component B to obtain a rubber compound;
s3, filling the rubber compound into a mold, carrying out vulcanization treatment, and opening the mold to obtain a rough flux core after the vulcanization treatment;
s4, cooling the crude drug core, and trimming to obtain the finished drug core;
in the S1, the component A comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of platinum complex by weight;
the component B comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of hydrogen-containing silicone oil by weight.
By adopting the technical scheme, the preparation method has clear flow, the component A and the component B are prepared by respectively mixing, and then the component A and the component B are mixed and mixed, so that the adding precision of the medicine core raw materials is improved, meanwhile, the medicine core raw materials are subjected to twice mixing processes, and the dispersibility of each raw material is further improved, so that the raw materials in the medicine core are uniformly distributed, the quality of the medicine core is improved, and the medicine core is fully mixed, so that when the medicine core is filled in a mold for vulcanization, the condition that a certain raw material is gathered at a certain position of the medicine core due to uneven dispersion of part of the raw materials is reduced, the medicine core is fully vulcanized, the demolding is facilitated, and the yield of the medicine core is improved.
Preferably, in S1, the LS-4100 silicone rubber is prepared by the steps of: adding a tetramethylammonium hydroxide aqueous solution into a reaction bottle, adding octamethylcyclotetrasiloxane, reacting under a vacuum condition, introducing nitrogen in the whole reaction process, adding tetramethyldivinyldisiloxane after the reaction is finished, continuing to react under the vacuum condition, introducing nitrogen in the whole reaction process, and vacuumizing after the reaction is finished to obtain the catalyst.
By adopting the technical scheme, the LS-4100 silicon rubber with better performance can be stably prepared, and the purity is higher.
Preferably, in S1, the preparation method of the platinum complex comprises: mixing chloroplatinic acid and tetramethyl divinyl dioxysilane, heating to react under the protection of nitrogen, washing with water after the reaction is finished, filtering, continuously washing the filtrate with water until the pH value is neutral, standing, and filtering again to obtain the product.
By adopting the technical scheme, the prepared platinum complex has better catalytic performance and higher purity.
Preferably, in the S3, the pressure of the vulcanization treatment is 10-14MPa, the temperature is 95-105 ℃, and the vulcanization time is 36-39 min.
By adopting the technical scheme, the rubber compound can be fully vulcanized within the parameter range, so that the demolding of the medicine core is facilitated, and the yield and the quality of the medicine core are improved.
Preferably, in the S4, the length of the finished product core is 43mm, the diameter is 2.1 + -0.01 mm, and the weight is 145-157 mg.
By adopting the technical scheme, the produced finished product medicine core has standard size and enough medicine content, and the contraception implant produced by using the medicine core can effectively realize contraception for 48 months after being implanted, and the annual contraception failure rate is less than 1%.
Preferably, in the step S2, the mixing process is repeated 3-10 times, and the total mixing time is controlled to be 3-5 min.
Through adopting above-mentioned technical scheme, make the mixing of first group of component of medicine core and second group of component more abundant, simultaneously, through controlling the mixing total time, can effectively reduce because the time overlength leads to the contaminated condition of material to take place, reduce bacterial growing.
Preferably, in S3, the mold includes an upper mold and a lower mold that are fastened to each other, an upper mold plate is disposed at the bottom of the upper mold, a lower mold plate is disposed at the top of the lower mold, a plurality of first core grooves are disposed on the upper mold plate and the lower mold plate, a plurality of first guide posts are further disposed on the top surface of the lower mold, first guide grooves for inserting the first guide posts are disposed on the bottom surface of the upper mold, and handles are disposed at two ends of the upper mold and the lower mold.
By adopting the technical scheme, when the rubber compound is filled into the die, the rubber compound is filled into the first medicine core groove, the upper die and the lower die are aligned, the upper die and the lower die are accurately matched through the insertion and connection cooperation of the first guide post and the first guide groove, the upper die and the lower die are subjected to vulcanization treatment after the die is matched, and the crude medicine core is taken out and trimmed after the vulcanization treatment is finished, so that the finished product medicine core is obtained.
Preferably, the upper template and the lower template are arranged oppositely, the first medicine core grooves of the upper template and the first medicine core grooves of the lower template are arranged in a one-to-one correspondence manner, and the first medicine core grooves are semi-cylindrical grooves.
Through adopting above-mentioned technical scheme, the cooperation is used between the corresponding first medicine core groove and is formed and be cylindric medicine core, is convenient for take out the medicine core after the vulcanization.
Preferably, in S3, the mold includes a mold body and a medicine pushing device, the top surface of the mold body is provided with a first groove, the bottom surface of the mold body is provided with a second groove at a position corresponding to the first groove, the mold body is further provided with a plurality of second medicine core grooves, the second medicine core grooves communicate the first groove with the second groove, the first groove is internally provided with a first abutting block in a clamping manner, and the second groove is internally provided with a second abutting block in a clamping manner.
By adopting the technical scheme, when the rubber compound is filled into a mold, the first supporting block is opened, the rubber compound is injected into the second medicine core groove, the first supporting block is clamped into the first groove again, the mold body is put into a vulcanizing machine for vulcanization, after the vulcanization is finished, the first supporting block and the second supporting block are taken out, the medicine core is pushed out from the second medicine core groove, the occurrence of the condition that a splicing line appears on the surface of the medicine core is reduced, the roundness of the medicine core is improved, the quality of the medicine core is improved, the follow-up trimming step of the medicine core is reduced, the loss of the medicine core caused by trimming is reduced, and the yield of the medicine core is improved.
Preferably, the medicine pushing device comprises a base and ejector pins arranged on the top surface of the base, the ejector pins and the second medicine core grooves are arranged in a one-to-one correspondence mode, a plurality of second guide posts are fixedly arranged on the top surface of the base, and a plurality of second guide grooves for inserting the second guide posts are formed in the die body.
Through adopting above-mentioned technical scheme, after the vulcanization handles, open first piece and the second of supporting to the piece, in inserting the second guide post that will push away the medicine device into the second guide way, make thimble and second medicine core groove align, slowly promote and push away the medicine device, make the thimble take out the medicine core, make taking out of medicine core more convenient.
In summary, the present application has the following beneficial effects:
1. according to the preparation method, the component A and the component B are prepared by respectively mixing, and then the component A and the component B are mixed and milled, so that the raw materials of the medicine core are subjected to two mixing processes, the raw materials in the medicine core are distributed more uniformly, the quality of the medicine core is improved, meanwhile, the influence on the demoulding of the medicine core caused by the aggregation of the raw materials is reduced, the medicine core is convenient to demould, and the yield of the medicine core is improved;
2. the LS-4100 silicone rubber prepared in the application has good performance, is beneficial to promoting the vulcanization of the medicine core, has good vulcanization effect of the medicine core, is convenient for demoulding and improves the yield of the medicine core;
3. the platinum complex prepared in the application has good catalytic performance and high purity;
4. the mold helps to reduce the generation of the splicing line on the surface of the flux core, improves the quality of the flux core, and reduces the subsequent step of trimming the flux core, thereby reducing the loss of the flux core caused by trimming and improving the yield of the flux core.
Drawings
FIG. 1 is a schematic view of the structure of a mold in examples 1 to 9 of the present application;
FIG. 2 is a schematic view of the mold of examples 1 to 9 of the present application, viewed from a different angle than that of FIG. 1;
fig. 3 is a schematic structural diagram of a mold body in embodiment 10 of the present application;
fig. 4 is a schematic structural diagram of a drug pushing device in embodiment 10 of the present application.
Reference numerals: 1. an upper die; 2. a lower die; 3. mounting a template; 4. a lower template; 5. a first core groove; 6. a first guide post; 7. a first guide groove; 8. a handle; 9. a mold body; 10. a medicine pushing device; 11. a first groove; 12. a second groove; 13. a second core groove; 14. a first resisting block; 15. a second resisting block; 16. a base; 17. a thimble; 18. a second guide post; 19. a second guide groove; 20. and (4) a bump.
Detailed Description
The present application will be described in further detail with reference to the following drawings and examples.
The raw materials used in the examples of the present application are commercially available, except for the following specific descriptions:
levonorgestrel is collected from the pharmaceutical company Limited of Shizu bamboo, Qinhuang island;
white carbon black is collected from EVONUK (winning group), brand: r106;
the hydrogen-containing silicone oil is obtained from the organosilicon company Limited of Jinnlong City, and the trade name is as follows: a high 202;
chloroplatinic acid was collected from chemical reagents of national drug group, ltd;
the tetramethyl divinyl disiloxane is obtained from Zhejiang Quzhou Jiangqi organosilicon Co., Ltd;
octamethylcyclotetrasiloxane is purchased from dow (zhang) investments limited;
tetramethylammonium hydroxide was obtained from chemical reagents of national drug group, ltd;
the open mill is made of the model XSK-l60A of Wuxi Ming big rubber and plastic machinery company Limited.
Preparation example
Preparation A1
A platinum complex prepared by the steps of: mixing 7g of chloroplatinic acid and 432mL of tetramethyldivinyldioxysilane, reacting at 225r/min and 117.5 ℃ for 1h, introducing nitrogen gas in the whole reaction process, wherein the nitrogen flow is 0.50L/min, washing with 75 ℃ water after the reaction is finished, repeatedly washing for 13 times, filtering, continuously washing the filtrate with water until the pH value is neutral, standing for 11h, filtering again, and discarding filter residues to obtain the product.
Preparation A2
A platinum complex prepared by the steps of: mixing 7g of chloroplatinic acid and 432mL of tetramethyldivinyldioxysilane, reacting at the temperature of 115 ℃ for 0.8h at 210r/min, introducing nitrogen in the whole reaction process, wherein the nitrogen flow is 0.25L/min, washing with 70 ℃ water after the reaction is finished, repeatedly washing for 10 times, filtering, continuously washing the filtrate with water until the pH value is neutral, standing for 10h, filtering again, and discarding filter residues to obtain the compound chloroplatinic acid.
Preparation A3
A platinum complex prepared by the steps of: mixing 7g of chloroplatinic acid and 432mL of tetramethyldivinyldioxysilane, reacting at 240r/min and 120 ℃ for 1.2h, introducing nitrogen in the whole reaction process, wherein the nitrogen flow is 0.75L/min, washing with water at 80 ℃ after the reaction is finished, repeatedly washing for 16 times, filtering, continuously washing the filtrate with water until the pH value is neutral, standing, and filtering again to obtain the product.
Preparation B1
An LS-4100 silicon rubber is prepared by the following steps: adding 1.00mL of 25% tetramethyl ammonium hydroxide aqueous solution into a reaction bottle, and treating for 30min under the conditions of vacuum pumping pressure of-50 kPa and internal temperature of 70 ℃, wherein the nitrogen flow is controlled to be 1.5L/min in the treatment process; 2375mL of octamethylcyclotetrasiloxane is added into a reaction bottle, and the mixture reacts for 1h under the conditions that the vacuumizing pressure is-75 kPa, the rotating speed is 135r/min and the internal temperature is 50 ℃, nitrogen is introduced into the whole reaction process, and the nitrogen flow is 0.50L/min; adding 15.0mL of tetramethyl divinyl disiloxane into a reaction bottle, reacting for 1h at the rotating speed of 135r/min and the internal temperature of 70 ℃, and introducing nitrogen gas in the whole reaction process, wherein the nitrogen gas flow is 0.50L/min; maintaining the rotation speed and the nitrogen flow unchanged, heating to 107.5 ℃, and continuing to react for 3 hours; keeping the rotating speed unchanged, increasing the nitrogen flow to 6L/min, heating to 155 ℃, vacuumizing to-47.5 kPa, and continuing to react for 1 h; maintaining the rotation speed and the vacuumizing pressure unchanged, heating to 185 ℃, and continuously vacuumizing for 3 hours to obtain the product.
Preparation B2
An LS-4100 silicon rubber is prepared by the following steps: adding 1.00mL of 25% tetramethyl ammonium hydroxide aqueous solution into a reaction bottle, and treating for 25min under the conditions of vacuum pumping pressure of-45 kPa and internal temperature of 68 ℃, wherein the nitrogen flow is controlled to be 1L/min in the treatment process; 2375mL of octamethylcyclotetrasiloxane is added into a reaction bottle, reaction is carried out for 0.8h under the conditions that the vacuumizing pressure is-65 kPa, the rotating speed is 120r/min and the internal temperature is 48 ℃, nitrogen is introduced in the whole reaction process, and the nitrogen flow is 0.25L/min; adding 15.0mL of tetramethyl divinyl disiloxane into a reaction bottle, reacting for 0.8h at the rotation speed of 120r/min and the internal temperature of 68 ℃, introducing nitrogen in the whole reaction process, wherein the nitrogen flow is 0.25L/min; keeping the rotating speed and the nitrogen flow unchanged, heating to 105 ℃, and continuing to react for 2.8 hours; maintaining the rotating speed unchanged, increasing the nitrogen flow to 5L/min, heating to 150 ℃, vacuumizing to-40 kPa, and continuing to react for 0.8 h; maintaining the rotation speed and the vacuumizing pressure unchanged, heating to 180 ℃, and continuously vacuumizing for 2 hours to obtain the product.
Preparation B3
An LS-4100 silicon rubber is prepared by the following steps: adding 1.00mL of 25% tetramethyl ammonium hydroxide aqueous solution into a reaction bottle, and treating for 35min under the conditions of vacuum pumping pressure of-55 kPa and internal temperature of 72 ℃, wherein the nitrogen flow is controlled to be 2L/min in the treatment process; 2375mL of octamethylcyclotetrasiloxane is added into a reaction bottle, and the mixture reacts for 1.2h under the conditions that the vacuumizing pressure is-85 kPa, the rotating speed is 150r/min and the internal temperature is 52 ℃, nitrogen is introduced in the whole reaction process, and the nitrogen flow is 0.75L/min; adding 15.0mL of tetramethyl divinyl disiloxane into a reaction bottle, reacting for 1.2h under the conditions that the rotating speed is 150r/min and the internal temperature is 72 ℃, introducing nitrogen in the whole reaction process, wherein the nitrogen flow is 0.75L/min; keeping the rotating speed and the nitrogen flow unchanged, heating to 110 ℃, and continuing to react for 3.2 h; maintaining the rotating speed unchanged, increasing the nitrogen flow to 7L/min, heating to 160 ℃, vacuumizing to-55 kPa, and continuing to react for 1 h; maintaining the rotation speed and the vacuumizing pressure unchanged, heating to 190 ℃, and continuously vacuumizing for 4 hours to obtain the product.
Examples
Example 1
A method for preparing a contraceptive implant drug core comprises the following steps:
s1, weighing 75.0g of the component A and 75.0g of the component B;
s2, opening the open mill, adjusting the distance between the two rollers to be less than 0.25mm, adding the component A and the component B between the two rollers, shoveling the rubber material back to the center of the rollers when the rubber material covers the whole rollers (namely the rubber material covers the positions 3cm away from the two ends of the rollers), mixing repeatedly for 5 times (after the component A and the component B are added, the rubber material covers the whole rollers from the center of the rollers, and the mixing is recorded as mixing for 1 time), and controlling the mixing time for 5 times to be 3 min;
s3, filling the rubber compound into a mold, putting the mold into a flat vulcanizing machine, vulcanizing for 36min under the conditions of 10MPa and 95 ℃, and opening the mold to obtain a rough flux core;
s4, cooling the crude drug core, cutting off the redundant parts at two ends, cutting into 43mm, and if there is burr or waste edge on the surface of the crude drug core, scraping to be smooth, to obtain the final product.
In step S1, the component A is prepared by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and platinum complex according to the weight ratio of 98:93:3:0.5, the LS-4100 silicon rubber is prepared by preparation example B1, and the platinum complex is prepared by preparation example A1;
the component B is prepared by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and hydrogen-containing silicon oil according to the weight ratio of 98:93:3:0.5, wherein the LS-4100 silicon rubber is prepared by preparation example B1;
in step S3, referring to fig. 1 and 2, the mold includes a rectangular upper mold 1 and a rectangular lower mold 2, the upper mold 1 and the lower mold 2 are fastened to each other, a rectangular upper mold plate 3 is fixedly disposed at the center of the bottom of the upper mold 1, a rectangular lower mold plate 4 is fixedly disposed at the center of the top of the lower mold 2, a plurality of first core slots 5 for filling rubber compound are disposed on the bottom surface of the upper mold plate 3 and the top surface of the lower mold plate 4, the first core slots 5 are semi-cylindrical slots, the length of the first core slots 5 is 43mm, the diameter is 2.1 ± 0.01mm, the first core slots 5 are uniformly spaced along the length direction of the upper mold plate 3 or along the length direction of the lower mold plate 4, the upper mold plate 3 and the lower mold plate 4 are disposed opposite to each other, the first core slots 5 on the upper mold plate 3 and the first core slots 5 on the lower mold plate 4 are in one-to-one correspondence, when the upper mold 1 and the lower mold 2 are fastened, the two corresponding first medicine core grooves 5 are communicated to form a cylindrical medicine core shaping area, a plurality of first guide posts 6 are fixedly arranged on the top surface of the lower die 2, the bottom surface of the upper die 1 is provided with first guide grooves 7 for the first guide posts 6 to insert, and the upper die 1 and the lower die 2 are accurately buckled through the matching between the first guide posts 6 and the first guide grooves 7, so that the two corresponding first medicine core grooves 5 are prevented from being deviated, the roundness of the prepared rough medicine core is improved, the production of splicing lines on the surface of the rough medicine core is reduced, the subsequent finishing process is reduced, the medicine core loss caused by finishing is reduced, the quality and the yield of the medicine core are improved, and in order to separate the upper die plate 3 and the lower die plate 4, T-shaped handles 8 are fixedly arranged at the two ends of the upper die plate 3 and the lower die plate 4;
in step S4, if the length of the finished product core is 43mm, the diameter is 2.1 + -0.01 mm, and the weight is 145-157mg, the finished product core is qualified, otherwise, the finished product core is unqualified.
Example 2
A preparation method of a contraceptive implant drug core is different from that of example 1 in that in step S1, a component A is formed by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and a platinum complex compound according to a weight ratio of 100:95:4:1, the LS-4100 silicon rubber is prepared by preparation example B1, and the platinum complex compound is prepared by preparation example A1;
the component B is prepared by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and hydrogen-containing silicon oil according to the weight ratio of 100:95:4:1, and the LS-4100 silicon rubber is prepared by preparation example B1.
Example 3
A preparation method of a contraceptive implant drug core is different from that of example 1 in that in step S1, a component A is formed by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and a platinum complex compound according to a weight ratio of 102:97:5:1.5, the LS-4100 silicon rubber is prepared by preparation example B1, and the platinum complex compound is prepared by preparation example A1;
the component B is prepared by mixing levonorgestrel, LS-4100 silicon rubber, white carbon black and hydrogen-containing silicon oil according to the weight ratio of 102:97:5:1.5, and the LS-4100 silicon rubber is prepared by preparation example B1.
Example 4
A method for preparing a core of a contraceptive implant, which differs from example 1 in that in step S1, of the component a, LS-4100 silicone rubber was prepared from preparation B2; the platinum complex was prepared from preparation A2;
in the B component, LS-4100 silicone rubber was obtained from preparation B2.
Example 5
A method for preparing a core of a contraceptive implant, which differs from example 1 in that in step S1, of the component a, LS-4100 silicone rubber was prepared from preparation B3; the platinum complex was prepared from preparation A3;
in the B component, LS-4100 silicone rubber was obtained from preparation B3.
Example 6
A preparation method of a contraceptive implant agent core is different from the embodiment 1 in that in the step S2, the mixing process is repeated for 6 times, and the total mixing time is controlled to be 4 min.
Example 7
A preparation method of a contraceptive implant agent core is different from the embodiment 1 in that in the step S2, the mixing process is repeated for 10 times, and the total mixing time is controlled to be 5 min.
Example 8
A preparation method of a contraceptive implant agent core is different from the embodiment 1 in that in the step S3, the pressure of vulcanization treatment is 12MPa, the temperature is 100 ℃, and the vulcanization time is 37.5 min.
Example 9
A preparation method of a contraceptive implant agent core is different from the embodiment 1 in that in the step S3, the pressure of vulcanization treatment is 14MPa, the temperature is 105 ℃, and the vulcanization time is 39 min.
Example 10
A method for preparing a contraceptive implant drug core, which is different from that of embodiment 1, in step S3, referring to fig. 3 and 4, the die includes a die body 9 and a drug pushing device 10 for assisting drug core demoulding, a rectangular first groove 11 is formed in a top surface of the die body 9, a rectangular second groove 12 is formed in a bottom surface of the die body 9, a plurality of second drug core grooves 13 are formed in a portion, located in the first groove 11, of the die body 9, the second drug core grooves 13 are cylindrical grooves, the length of each second drug core groove 13 is 43mm, the diameter of each second drug core groove is 2.1 ± 0.01mm, the first groove 11 and the second groove 12 are communicated through the second drug core grooves 13, a first abutting block 14 is clamped in the first groove 11, a second abutting block 15 is arranged in the second groove 12, and interference fit is formed between the first abutting block 14 and the first groove 11, and between the second abutting block 15 and the second groove 12. When the rubber compound is filled, the first abutting block 14 is opened, the rubber compound is injected into the second medicine core groove 13, after the rubber injection is finished, the first abutting block 14 is clamped into the first groove 11 again, and the mold body 9 is placed in a vulcanizing press for vulcanization.
The medicine pushing device 10 comprises a base 16 and a thimble 17 arranged on the top surface of the base 16, wherein a convex block 20 matched with the second groove 12 is integrally formed on the top surface of the base 16, and the thimble 17 is fixedly arranged on the top surface of the convex block 20. The ejector pins 17 are arranged in one-to-one correspondence with the second core grooves 13. The top surface of the base 16 is also fixedly provided with a plurality of second guide posts 18, the die body 9 is provided with a plurality of second guide grooves 19 for the second guide posts 18 to insert, when the cores are required to be demoulded after the vulcanization treatment is finished, the first abutting block 14 and the second abutting block 15 are firstly taken down, the second guide posts 18 are aligned with the second guide grooves 19, the bumps 20 are slowly clamped into the second grooves 12, and the ejector pins 17 are used for ejecting out and demoulding the rough cores in the second core grooves 13. Due to the arrangement, the roundness of the flux core is improved, the generation of splicing lines on the surface of the flux core is effectively reduced, and the phenomenon of flux core loss caused by later-stage flux core repair is reduced, so that the product yield is improved.
Yield and analysis
The yield of the finished cores of the preparation process of the cores of the contraceptive implants of examples 1-10 was calculated separately and the results are included in table 1 below.
Table 1 finished product drug core yield (%)
As can be seen from the data in Table 1, when the preparation method of the drug core of the contraceptive implant agent is used for preparing the drug core, the yield of the finished drug core is more than 92 percent and is far higher than the average yield level (75-85 percent) of the drug core in the prior industry, so that the preparation method of the drug core of the contraceptive implant agent can obviously improve the preparation yield of the drug core of the contraceptive implant agent, reduce the loss of the drug core and greatly improve the economic benefit.
The present embodiment is only for explaining the present application, and it is not limited to the present application, and those skilled in the art can make modifications of the present embodiment without inventive contribution as needed after reading the present specification, but all of them are protected by patent law within the scope of the claims of the present application.
Claims (10)
1. A method for preparing a contraceptive implant agent core is characterized by comprising the following steps:
s1, weighing a component A and a component B, and respectively premixing, wherein the weight ratio of the component A to the component B is 1: 1;
s2, mixing the component A and the component B to obtain a rubber compound;
s3, filling the rubber compound into a mold, carrying out vulcanization treatment, and opening the mold to obtain a rough flux core after the vulcanization treatment;
s4, cooling the crude drug core, and trimming to obtain the finished drug core;
in the S1, the component A comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of platinum complex by weight;
the component B comprises 98-102 parts of levonorgestrel, 93-97 parts of LS-4100 silicon rubber, 3-5 parts of white carbon black and 0.5-1.5 parts of hydrogen-containing silicone oil by weight.
2. The method for preparing a contraceptive implant drug core according to claim 1, wherein in S1, the LS-4100 silicone rubber is prepared by the steps of: adding a tetramethylammonium hydroxide aqueous solution into a reaction bottle, adding octamethylcyclotetrasiloxane, reacting under a vacuum condition, introducing nitrogen in the whole reaction process, adding tetramethyldivinyldisiloxane after the reaction is finished, continuing to react under the vacuum condition, introducing nitrogen in the whole reaction process, and vacuumizing after the reaction is finished to obtain the catalyst.
3. The method for preparing a contraceptive implant core as claimed in claim 1, wherein the step of preparing the platinum complex in S1 is: mixing chloroplatinic acid and tetramethyl divinyl dioxysilane, heating to react under the protection of nitrogen, washing with water after the reaction is finished, filtering, continuously washing the filtrate with water until the pH value is neutral, standing, and filtering again to obtain the product.
4. The method for preparing a contraceptive implant agent core according to claim 1, wherein in the step S3, the pressure of the vulcanization treatment is 10-14MPa, the temperature is 95-105 ℃, and the vulcanization time is 36-39 min.
5. The method for preparing a core for a contraceptive implant according to claim 1, wherein in S4, the length of the finished core is 43mm, the diameter is 2.1 ± 0.01mm, and the weight is 145-157 mg.
6. The method for preparing a medicated core of a contraceptive implant according to claim 1, wherein in S2, the mixing process is repeated 3-10 times, and the total mixing time is controlled to be 3-5 min.
7. The preparation method of the contraceptive implant agent core according to claim 1, wherein in the step S3, the mold comprises an upper mold (1) and a lower mold (2) which are fastened with each other, an upper template (3) is arranged at the bottom of the upper mold (1), a lower template (4) is arranged at the top of the lower mold (2), a plurality of first core grooves (5) are formed in the upper template (3) and the lower template (4), a plurality of first guide posts (6) are further arranged on the top surface of the lower mold (2), a first guide groove (7) for the first guide post (6) to be inserted into is formed in the bottom surface of the upper mold (1), and handles (8) are arranged at two ends of the upper mold (1) and the lower mold (2).
8. The method for preparing the drug core of the contraceptive implant agent according to claim 7, wherein the upper template (3) and the lower template (4) are oppositely arranged, the first drug core groove (5) of the upper template (3) and the first drug core groove (5) of the lower template (4) are uniformly and correspondingly arranged, and the first drug core groove (5) is a semi-cylindrical groove.
9. The preparation method of the contraceptive implant agent core according to claim 1, wherein in the step S3, the mold comprises a mold body (9) and a drug pushing device (10), a first groove (11) is formed in the top surface of the mold body (9), a second groove (12) is formed in the bottom surface of the mold body (9) at a position corresponding to the first groove (11), the mold body (9) is further provided with a plurality of second drug core grooves (13), the second drug core grooves (13) communicate the first groove (11) with the second groove (12), a first abutting block (14) is arranged in the first groove (11) in a clamping manner, and a second abutting block (15) is arranged in the second groove (12) in a clamping manner.
10. The preparation method of the contraceptive implant agent core according to claim 9, wherein the drug pushing device (10) comprises a base (16) and ejector pins (17) arranged on the top surface of the base (16), the ejector pins (17) and the second agent core grooves (13) are arranged in a one-to-one correspondence manner, a plurality of second guide posts (18) are further fixedly arranged on the top surface of the base (16), and the mold body (9) is provided with a plurality of second guide grooves (19) for the second guide posts (18) to be inserted into.
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| WO2023174450A3 (en) * | 2022-03-18 | 2023-11-09 | 沈阳星华医药科技有限公司 | Silicone material, silicone tube, implant, pharmaceutical composition, and test method for amount of drug released |
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