WO2021036058A1 - 一种特立帕肽缓释凝胶注射液及其制备方法 - Google Patents
一种特立帕肽缓释凝胶注射液及其制备方法 Download PDFInfo
- Publication number
- WO2021036058A1 WO2021036058A1 PCT/CN2019/121291 CN2019121291W WO2021036058A1 WO 2021036058 A1 WO2021036058 A1 WO 2021036058A1 CN 2019121291 W CN2019121291 W CN 2019121291W WO 2021036058 A1 WO2021036058 A1 WO 2021036058A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- teriparatide
- poloxamer
- sustained
- temperature
- injection
- Prior art date
Links
- 108010049264 Teriparatide Proteins 0.000 title claims abstract description 79
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 title claims abstract description 79
- 229960005460 teriparatide Drugs 0.000 title claims abstract description 79
- 238000002347 injection Methods 0.000 title claims abstract description 71
- 239000007924 injection Substances 0.000 title claims abstract description 71
- 239000000243 solution Substances 0.000 title claims abstract description 58
- 238000013268 sustained release Methods 0.000 title claims abstract description 58
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 60
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 55
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000000463 material Substances 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 23
- 235000011187 glycerol Nutrition 0.000 claims abstract description 16
- 229920001661 Chitosan Polymers 0.000 claims abstract description 14
- 239000000227 bioadhesive Substances 0.000 claims abstract description 10
- 239000006174 pH buffer Substances 0.000 claims abstract description 10
- 229920001983 poloxamer Polymers 0.000 claims abstract description 9
- 229960000502 poloxamer Drugs 0.000 claims abstract description 9
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 6
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 6
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 4
- 239000001913 cellulose Substances 0.000 claims abstract description 4
- 229920002678 cellulose Polymers 0.000 claims abstract description 4
- 239000004584 polyacrylic acid Substances 0.000 claims abstract description 4
- 239000004615 ingredient Substances 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 87
- 238000003756 stirring Methods 0.000 claims description 79
- 239000008215 water for injection Substances 0.000 claims description 44
- 229960000583 acetic acid Drugs 0.000 claims description 34
- 238000001914 filtration Methods 0.000 claims description 29
- 229920001992 poloxamer 407 Polymers 0.000 claims description 26
- 229940044476 poloxamer 407 Drugs 0.000 claims description 26
- 229920001993 poloxamer 188 Polymers 0.000 claims description 20
- 229940044519 poloxamer 188 Drugs 0.000 claims description 20
- 229940079593 drug Drugs 0.000 claims description 18
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 16
- 239000001632 sodium acetate Substances 0.000 claims description 16
- 235000017281 sodium acetate Nutrition 0.000 claims description 16
- 239000012362 glacial acetic acid Substances 0.000 claims description 15
- 230000001954 sterilising effect Effects 0.000 claims description 15
- 238000004659 sterilization and disinfection Methods 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000872 buffer Substances 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003002 pH adjusting agent Substances 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims 1
- 235000019799 monosodium phosphate Nutrition 0.000 claims 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 239000000022 bacteriostatic agent Substances 0.000 abstract description 2
- 230000002045 lasting effect Effects 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 49
- 239000011521 glass Substances 0.000 description 11
- 208000001132 Osteoporosis Diseases 0.000 description 10
- 210000000988 bone and bone Anatomy 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 238000001879 gelation Methods 0.000 description 5
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108090000445 Parathyroid hormone Proteins 0.000 description 3
- 102000003982 Parathyroid hormone Human genes 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 229960001319 parathyroid hormone Drugs 0.000 description 3
- 239000000199 parathyroid hormone Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000007704 transition Effects 0.000 description 3
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-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
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000002861 polymer material Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007974 sodium acetate buffer Substances 0.000 description 2
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 2
- OOSZCNKVJAVHJI-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]piperazine Chemical compound C1=CC(F)=CC=C1CN1CCNCC1 OOSZCNKVJAVHJI-UHFFFAOYSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010017076 Fracture Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 206010039984 Senile osteoporosis Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000008717 functional decline Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229920005615 natural polymer Polymers 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- BRFMYUCUGXFMIO-UHFFFAOYSA-N phosphono dihydrogen phosphate phosphoric acid Chemical compound OP(O)(O)=O.OP(O)(=O)OP(O)(O)=O BRFMYUCUGXFMIO-UHFFFAOYSA-N 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
- 229940083608 sodium hydroxide Drugs 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 210000000689 upper leg Anatomy 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
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-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
- A61K47/06—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
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
-
- 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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
Definitions
- the invention relates to a preparation process of teriparatide sustained-release gel injection, which belongs to the field of pharmaceutical preparations.
- Osteoporosis is a bone metabolic disease in which the balance of bone resorption and bone formation is broken after the body's function declines, resulting in increased bone fragility. Osteoporosis is divided into postmenopausal female osteoporosis and senile osteoporosis. my country is the most populous country in the world, and we have also entered the elderly society. Therefore, the development of drugs for the prevention and treatment of osteoporosis has broad market demand and social significance.
- Parathyroid hormone can regulate the metabolism of calcium and phosphorus in bone, increase the concentration of calcium in serum, reduce the clearance of calcium from the kidneys, and promote the absorption and release of calcium by bones, thereby promoting the formation of new bones.
- Teriparatide is a chemically synthesized parathyroid hormone that can promote the formation of new bone, increase bone mineral density, and improve the bone density and microstructure of patients with osteoporosis, thereby reducing the risk of fractures. It is suitable for Various types of osteoporosis.
- teriparatide injection developed by Eli Lilly
- the prescription is: glacial acetic acid, sodium acetate (anhydrous), mannitol, m-cresol, hydrochloric acid, sodium hydroxide and water for injection.
- M-cresol is a bacteriostatic agent and is easily oxidized. Therefore, currently teriparatide injection is prone to produce unknown impurities during the preparation process, resulting in poor stability of the injection.
- the specification is 20 ⁇ g: 80 ⁇ l, 2.4mL/bottle.
- the recommended dose is 20 ⁇ g subcutaneously injected daily, and the injection site is selected in the thigh or abdomen.
- the longest total treatment time is 24 months. The patient can only receive 24 months of treatment once in his lifetime.
- Futaio is a pre-installed pen-type syringe, and each pen can only be used by one patient. Each injection requires a new sterile injection needle. After each injection, Futaio should be stored in the refrigerator
- the sustained-release gel injection can be sustained for several days, which can significantly reduce the number of medications and improve patient compliance. Sex, improve the treatment effect.
- Temperature-sensitive sustained-release gel whose gelation mechanism is an in-situ gel formed by changes in ambient temperature.
- the sustained-release gel contains temperature-sensitive polymer materials that are formed due to changes in internal and external temperature after administration Non-chemically cross-linked gel. It is in a liquid state outside the body with low viscosity and can be administered by injection. After entering the joint cavity, the liquid will quickly form a uniform semi-solid gel due to the increase in temperature, which prolongs the residence time of the drug in the joint cavity and facilitates the full absorption of the drug , Improve the bioavailability of teriparatide.
- Poloxamer polymers are one of the most researched and used gel materials.
- the purpose of the present invention is to solve the shortcomings of the dosage form in the prior art, and provide a teriparatide sustained-release gel injection and a preparation method thereof, which are convenient to use, and at the same time, a drug reservoir is formed in the muscle or joint cavity.
- the action time is long, and the frequency of medication is obviously reduced.
- one aspect of the present invention provides a teriparatide sustained-release gel injection, which is made of the following components: teriparatide, pH buffer components, bioadhesive materials, temperature-sensitive gel Glue materials, pH regulators and solvents;
- the temperature-sensitive gel material is selected from a combination of temperature-sensitive poloxamer and glycerin, and the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof ;
- the solvent is water.
- the bioadhesive material refers to a natural or synthetic polymer material that has the ability to adhere to the surface of the lumen mucus or epithelial cells.
- the teriparatide sustained-release gel injection is made from the following ingredients per 100ml:
- the pH buffer component is selected from buffer pairs with a pH value of 3.5-5.5 after adding a buffer pair and a pH adjuster, preferably a buffer pair of glacial acetic acid and sodium acetate, and a phosphate diphosphate.
- a buffer pair and a pH adjuster preferably a buffer pair of glacial acetic acid and sodium acetate, and a phosphate diphosphate.
- the temperature-sensitive poloxamer is selected from poloxamer 407, poloxamer 188, a mixture of poloxamer 407 and poloxamer 188, preferably poloxamer
- the mixture of 407 and poloxamer 188 or each 100ml teriparatide sustained-release gel injection contains more than 15g of poloxamer 407; more preferably, the mass ratio of poloxamer 407 and poloxamer 188 is 1-6 :1 or more than 16g poloxamer 407 per 100ml teriparatide sustained-release gel injection.
- the amount of glycerol added is such that the final concentration in the gel injection is 50mg/ml-100mg/ml.
- the bioadhesive material is selected from chitosan, hyaluronic acid, cellulose derivatives, polyacrylic acid or a combination thereof, preferably chitosan.
- the pH adjusting agent is selected from phosphoric acid, acetic acid, citric acid, hydrochloric acid and sodium hydroxide, preferably acetic acid.
- the pH buffer range of the pH buffer solution is 3.5-5.0.
- the pH of the teriparatide sustained-release gel injection is 3.8-4.5.
- Another aspect of the present invention provides a preparation method of teriparatide sustained-release gel injection, which comprises the following steps:
- the sterile liquid medicine is divided into vials, prefilled syringes or cartridge bottles, preferably into prefilled syringes.
- the concentration of acetic acid and glacial acetic acid are different, the concentration of acetic acid is 36%, and the concentration of glacial acetic acid is 98%.
- Teriparatide ordinary injection has no sustained-release effect, and patients need to inject daily, which brings great pain and inconvenience to patients; while the sustained-release gel injection of teriparatide of the present invention has a long sustained release For several days, the frequency of medication can be significantly reduced, patient compliance can be improved, and the treatment effect can be improved.
- the prescription process of the present invention avoids the use of antibacterial agents and achieves the same effect.
- the embodiment of the invention discloses a preparation method of teriparatide sustained-release gel injection.
- Those skilled in the art can learn from the content of this article and appropriately improve the realization of the process prescription.
- all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
- the method of the present invention has been described through the preferred embodiments. It is obvious that relevant personnel can modify or appropriately change and combine the prescription or process described herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention.
- Invent technology can modify or appropriately change and combine the prescription or process described herein without departing from the content, spirit and scope of the present invention to realize and apply the present invention.
- Example 11 Determination of phase transition temperature and reversibility of teriparatide sustained-release gel injection
- Test sample Teriparatide sustained-release gel injection or teriparatide injection prepared according to the prescription and preparation method described in Examples 1-10 and Comparative Example 1.
- Phase transition temperature determination method Take 1mL teriparatide sustained-release gel injection, place it in a 10mL test tube, place it in a constant temperature water bath and gradually increase the temperature. The temperature rises to 0.1°C in each step, and it is stable for 1min after reaching the specified temperature. Make judgments based on the flow-no-flow principle and record the temperature. After the phase change occurs, take it out and put it in the refrigerator. After 10 minutes, observe whether it returns to liquid and judge whether the phase change is reversible.
- the average temperature of the human body is 36°C ⁇ 37°C, so as long as the sample is liquid at normal temperature, the temperature at body temperature can turn into a semi-solid gel, that is, as long as the sample is at the gelation temperature of 20°C ⁇ 37°C It meets the requirements, and is better for samples at 25°C-33°C.
- Example 12 Investigation of the in vitro release of teriparatide sustained-release gel injection
- teriparatide sustained-release gel injection was investigated using a constant temperature shaker method: Take 2g of teriparatide sustained-release gel injection or teriparatide injection into a vial ( ⁇ 13mm), Place in a constant temperature shaker at 37°C for 10 minutes, and then add 2 mL of acetic acid-sodium acetate buffer solution (pH 4.0) at 37°C constant temperature shaking (50 rpm) for 4h, 8h, 12h, 24h, 48h, 72h, 120h, 168h, Take a sample of 0.5mL at 240h and add 0.5mL of acetic acid-sodium acetate buffer solution (pH4.0). Each time 0.5mL of the sample taken out is processed, and 20 ⁇ L is injected into the high performance liquid chromatograph to obtain the concentration of the sample solution and calculate its accumulation For the release degree Q, the result of drawing the curve is shown in the following formula:
- C n is the drug concentration measured at the n-th time sampling point (mg/mL)
- C i is the drug concentration measured at the i-th time sampling point (mg/mL)
- M is 2g teriparatide The total amount of drug in sustained-release gel injection.
- Examples 1-10 Teriparatide sustained-release gel injection have obvious sustained-release effect, avoid peak and valley phenomenon of drug concentration, have a long drug action time, reduce the number of administrations, and greatly improve patient compliance.
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Abstract
一种特立帕肽缓释凝胶注射液，其由以下成分制成：特立帕肽、pH缓冲组分、生物粘附材料、温度敏感型凝胶材料、pH调节剂以及溶剂；所述温度敏感型凝胶材料选自温敏型泊洛沙姆和甘油的组合，生物粘附材料选自壳聚糖、透明质酸、纤维素类衍生物、聚丙烯酸或其组合；所述溶剂为水。所述的特立帕肽缓释凝胶注射液，其缓释长达数天，可以明显减少用药次数，提高患者顺应性，提高治疗效果，同时避免使用抑菌剂，并达到了相同的效果。
Description
本发明涉及特立帕肽缓释凝胶注射液的制备工艺，属于药物制剂领域。
骨质疏松症是由于人体身体机能下降后，骨质吸收和骨质形成平衡被打破，导致骨质脆性增加的一种骨代谢性疾病。骨质疏松症分为绝经后女性骨质疏松症和老年性骨质疏松症。我国是世界上人口最多的国家，而且我们也已经步入了老年社会，因此开发预防和治疗骨质疏松症的药物具有广泛的市场需求和社会意义。
甲状旁腺激素(PTH)能够调节骨中的钙磷代谢，增加血清中钙的浓度水平，减少钙从肾脏中清除，促进骨骼对钙的吸收和释放，从而促进新骨形成。特立帕肽是一种化学合成的甲状旁腺激素，能够促进新骨的形成，增加骨矿物质密度，改善骨质疏松症患者的骨密度和微观结构，从而降低发生骨折的风险，适用于各类型的骨质疏松症。
2002年FDA批准了美国礼来公司研制的特立帕肽注射液
成为首个被FDA批准的用于治疗骨质疏松症的药物。2011年3月，特立帕肽注射液被SFDA批准进入中国市场，用于治疗绝经后女性的骨质疏松症。
目前，美国礼来公司研制的特立帕肽注射液
其处方为：冰醋酸、醋酸钠(无水)、甘露醇、间甲酚、盐酸、氢氧化钠和注射用水。间甲酚为抑菌剂，易被氧化，因此目前特立帕肽注射液在制备过程中容易产生未知杂质，导致注射液稳定性变差。其规格为20μg：80μl，2.4mL/支，推荐剂量为每日皮下注射20μg，注射部位选择在大腿或腹部。总共治疗的最长时间为24个月。病人终身仅可接受1次为期24个月的治疗。复泰奥为预装笔式注射器，每支笔仅限一名患者使用。每次注射需使用新的无菌注射针头，每次注射后，复泰奥应放回冰箱内保存。
在上述原研制剂中，其为普通注射剂，患者需要每日皮下注射，但骨质疏松症的治疗周期较长，长时间的注射给药给患者带来了很大的痛苦和不便，导致患者的顺应性较差，因此开发一种长效且具有缓释作用的特立帕肽制剂具有重要的现实意义，该缓释凝胶注射剂缓释长达数天，可以明显减少用药次数，提高患者顺应性，提高治疗效果。
温度敏感型缓释凝胶，其胶凝化机制是通过环境温度的变化而形成的原位凝胶，该缓释凝胶含有温度敏感型高分子材料，给药后因体内外温度变化而形成非化学交联的凝胶。在体外呈液体状态，粘度小，能够注射给药，进入关节腔后，因为温度升高，药液很快形成均匀的半固体凝胶，延长药物在关节腔的停留时间，有利于药物充分吸收，提高了特立帕肽的生物利用度。
泊洛沙姆类聚合物是其中研究和运用最多的一类凝胶材料，已公开的专利：一种两亲性 多糖衍生物/泊洛沙姆温敏型原位水凝胶及其制备方法(专利号：CN 104888224B)，制备得到的原位水凝胶具有更高的稳定性和更长的药物缓释时间，为实现注射给药及提高药物生物利用度提供了可能，可应用于黏膜给药、经皮给药和注射给药系统。
发明内容
本发明的目的在于解决现有技术中剂型的不足之处，提供一种特立帕肽缓释凝胶注射液及其制备方法，其使用方便，同时肌肉或者关节腔内形成药物贮库，药物作用时间长，明显减少用药次数。
为达到上述目的，本发明一个方面提供了一种特立帕肽缓释凝胶注射液，其由以下成分制成：特立帕肽、pH缓冲组分、生物粘附材料、温度敏感型凝胶材料、pH调节剂以及溶剂；
优选地，所述温度敏感型凝胶材料选自温敏型泊洛沙姆和甘油的组合，生物粘附材料选自壳聚糖、透明质酸、纤维素类衍生物、聚丙烯酸或其组合；所述溶剂为水。
在本发明的技术方案中，所述的生物粘附材料是指具有的能够粘附到腔道粘液或上皮细胞表面的能力的天然或合成的高分子物质。
在本发明的技术方案中，所述的特立帕肽缓释凝胶注射液，每100ml由以下成分制成：
在本发明的技术方案中，所述的pH缓冲组分选自加入缓冲对及pH值调节剂后pH值在3.5-5.5之间的缓冲对，优选为冰醋酸和乙酸钠缓冲对，磷酸二氢钠和磷酸氢二钠、柠檬酸和柠檬酸钠、琥珀酸。
在本发明的技术方案中，所述的温敏型泊洛沙姆选自泊洛沙姆407，泊洛沙姆188，泊洛沙姆407和泊洛沙姆188混合物，优选为泊洛沙姆407和泊洛沙姆188的混合物或每100ml特立帕肽缓释凝胶注射液中包含15g以上泊洛沙姆407；更优选地泊洛沙姆407和泊洛沙姆188质量比为1-6:1或每100ml特立帕肽缓释凝胶注射液中包含16g以上泊洛沙姆407。
在本发明的技术方案中，甘油的添加量为使其在凝胶注射液中的终浓度为50mg/ml-100mg/ml。
在本发明的技术方案中，所述的生物粘附材料选自壳聚糖，透明质酸、纤维素类衍生物、 聚丙烯酸或其组合，优选壳聚糖。
在本发明的技术方案中，所述的pH调节剂选自磷酸，醋酸，柠檬酸，盐酸和氢氧化钠优选醋酸。
在本发明的技术方案中，所述的pH缓冲液的pH值缓冲范围为3.5-5.0。
在本发明的技术方案中，所述特立帕肽缓释凝胶注射液的pH值为3.8-4.5。
本发明另一个方面提供了特立帕肽缓释凝胶注射液的制备方法，其包括以下步骤：
1)将特立帕肽原料药溶解于注射用水中，得到第一溶液；
2)以pH缓冲液溶解生物粘附材料，得到第二溶液；
3)将温度敏感型凝胶材料加入第二溶液中，搅拌溶解，控制搅拌温度在0-10℃，得到第三溶液；
4)将第一溶液和第三溶液混合均匀，混合温度在0-10℃，以pH调节剂调节pH值至3.5-5.5，用注射用水定容；
5)无菌条件下用0.22μm过滤器除菌过滤，控制过滤温度在0-15℃；
6)过滤除菌后的药液分装。
在本发明的技术方案中，无菌药液分装于西林瓶，预灌封注射器或卡式瓶中，优选分装于预灌封注射器。
在本发明的技术方案中，醋酸和冰醋酸浓度不同，醋酸浓度为36％，冰醋酸98％。
1、特立帕肽普通注射剂，没有缓释效果，患者需要每日注射，给患者带来了很大痛苦和不便；而本发明的特立帕肽缓释凝胶注射液，其缓释长达数天，可以明显减少用药次数，提高患者顺应性，提高治疗效果。
2、本发明的处方工艺避免使用抑菌剂，并达到了相同的效果。
本发明实施例公开了一种特立帕肽缓释凝胶注射液的制备方法。本领域技术人员可以借鉴本文内容，适当改进工艺处方实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的处方或工艺进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。通过下述实例将有助 于理解本发明，但以下实例仅用于更具体的说明本发明的实施，不用于对本发明技术方案的限定。
对比实施例1:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，接着加入10mg乙酸钠搅拌溶解，再加入4.54g甘露醇搅拌溶解；
3)将0.3g间甲酚加入2)中，搅拌溶解，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。对比实施例2:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，再加入10mg乙酸钠搅拌溶解；
3)将15g泊洛沙姆407加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。对比实施例3:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入500mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将5g甘油和14g泊洛沙姆407、0.5g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例1:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入800mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和18g泊洛沙姆407、3g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例2:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入200mg透明质酸搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将5g甘油和18g泊洛沙姆407、3g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于2mL西林瓶中(1.15ml)，置于2-8℃冰箱中贮存，即得。
实施例3:特立帕肽缓释凝胶注射液
1)将特立帕肽5mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入5000mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将10g甘油和12g泊洛沙姆407、3g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在10-15℃。
6)过滤除菌后的药液分装于卡式瓶中(3.3ml)，置于2-8℃冰箱中贮存，即得。
实施例4:特立帕肽缓释凝胶注射液
1)将特立帕肽75mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于30ml注射用水中，加入500mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将5g甘油和29.17g泊洛沙姆407、5.83g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0， 用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例5:特立帕肽缓释凝胶注射液
1)将特立帕肽15mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入500mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和20g泊洛沙姆407、5g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至3.5，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例6:特立帕肽缓释凝胶注射液
1)将特立帕肽15mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入1000mg透明质酸搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将5g甘油和20g泊洛沙姆407、5g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至5.5，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例7:特立帕肽缓释凝胶注射液
1)将特立帕肽10mg溶解于10ml注射用水中；
2)将2.5g二水合磷酸二氢钠溶解于50ml注射用水中，加入800mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和18g泊洛沙姆407、3g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至5.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例8:特立帕肽缓释凝胶注射液
1)将特立帕肽20mg溶解于10ml注射用水中；
2)将1.0g一水合柠檬酸溶解于50ml注射用水中，加入800mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和20g泊洛沙姆407、10g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例9:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将1.0g一水合柠檬酸溶解于50ml注射用水中，加入2000mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和10g泊洛沙姆407、10g泊洛沙姆188加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0， 用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例10:特立帕肽缓释凝胶注射液
1)将特立帕肽25mg溶解于10ml注射用水中；
2)将41mg冰醋酸溶解于50ml注射用水中，加入800mg壳聚糖搅拌溶解后，再加入10mg乙酸钠搅拌溶解；
3)将7.5g甘油和20g泊洛沙姆407加入2)中，冰浴中搅拌溶解，控制搅拌温度在0-10℃，得到辅料溶液；
4)将1)中药液加入3)中，搅拌均匀，控制搅拌温度在0-10℃，用醋酸调节pH值至4.0，用注射用水定容至100ml；
5)用0.22μm过滤器除菌过滤，控制过滤温度在0-10℃。
6)过滤除菌后的药液分装于预灌封玻璃注射器(1.05ml)，置于2-8℃冰箱中贮存，即得。
实施例11:特立帕肽缓释凝胶注射液的相变温度及可逆性测定
测试样品：按照实施例1-10和对比例1所述处方和制备方法制备的特立帕肽缓释凝胶注射液或特立帕肽注射液。
相变温度测定方法：取1mL特立帕肽缓释凝胶注射液，置于10mL试管中，将其放置于恒温水浴锅中逐渐升温，每步升温为0.1℃，达到指定温度后稳定1min，根据流动-不流动的原则进行判断，记录温度。发生相变后，取出置冰箱中，10min后观察是否恢复为液体，判断相变是否可逆。
测试结果如下表所示：
表1特立帕肽缓释凝胶注射液相变温度及可逆性结果
人体的平均温度36℃～37℃，因而只要样品在常温下为液体，体温状态下的温度能够变成半固体凝胶即可，即只要是在20℃～37℃胶凝化温度的样品均是符合要求的，对于25℃-33℃的样品更优。
测试结果表明，本发明特立帕肽缓释凝胶注射液在胶凝化温度20℃～37℃以下为液体，给药方便，患者顺应性好，经肌肉或者关节腔注射给药后，在凝胶化温度下1～3min能够形成半固体凝胶，胶凝速度较快，从而形成药物贮库，缓慢释放出活性物质特立帕肽，发挥疗效。而当泊洛沙姆407和泊洛沙姆188质量比为1-6:1或每100ml特立帕肽缓释凝胶注射液中包含16g以上泊洛沙姆407时效果更佳。
实施例12:特立帕肽缓释凝胶注射液的体外释放度的考察
采用恒温摇床法考察特立帕肽缓释凝胶注射液的体外释放行为：，取2g特立帕肽缓释凝胶注射液或特立帕肽注射液于西林瓶中(Φ13mm)，在37℃恒温摇床中放置10min，后加入2mL的醋酸-醋酸钠缓冲溶液(pH4.0)37℃恒温震荡(50rpm)，分别于4h、8h、12h、24h、48h、72h、120h、168h、240h取样0.5mL，并补加0.5mL的醋酸-醋酸钠缓冲溶液(pH4.0)，每次取出的样品0.5mL处理，取20μL注入高效液相色谱仪，求得样品溶液浓度，计算其累积释放度Q，绘制曲线结果见如下式：
式1-1中C
n为第n个时间取样点测得药物浓度(mg/mL)，C
i为第i个时间取样点测得药物浓度(mg/mL)，M为2g特立帕肽缓释凝胶注射液的药物总量。
表2特立帕肽缓释凝胶注射液累计释放度结果
注1由于其在37℃并不会胶凝，该组实验为采用39℃恒温震荡(50rpm)完成的实验
实施例1～10特立帕肽缓释凝胶注射液具有明显的缓释作用，避免了药物浓度的峰谷现象，药物作用时间长，减少了给药次数，大大提高了患者顺应性。
Claims (10)
- 一种特立帕肽缓释凝胶注射液，其由以下成分制成：特立帕肽、pH缓冲组分、生物粘附材料、温度敏感型凝胶材料、pH调节剂以及溶剂；优选地，所述温度敏感型凝胶材料选自温敏型泊洛沙姆和甘油的组合，生物粘附材料选自壳聚糖、透明质酸、纤维素类衍生物、聚丙烯酸或其组合；所述溶剂为水。
- 根据权利要求1所述的所述的特立帕肽缓释凝胶注射液，每100ml由以下成分制成：
- 根据权利要求1-2任一项所述的特立帕肽缓释凝胶注射液，所述的pH缓冲组分选自加入缓冲对及pH值调节剂后pH值在3.5-5.5之间的缓冲对，优选为冰醋酸和乙酸钠缓冲对，磷酸二氢钠和磷酸氢二钠、柠檬酸和柠檬酸钠、琥珀酸。
- 根据权利要求1-3任一项所述的特立帕肽缓释凝胶注射液，所述的温敏型泊洛沙姆选自泊洛沙姆407，泊洛沙姆188，泊洛沙姆407和泊洛沙姆188混合物，优选为泊洛沙姆407和泊洛沙姆188的混合物或每100ml特立帕肽缓释凝胶注射液中包含15g以上泊洛沙姆407；更优选地泊洛沙姆407和泊洛沙姆188质量比为1-6:1或每100ml特立帕肽缓释凝胶注射液中包含16g以上泊洛沙姆407。
- 根据权利要求1-4任一项所述的特立帕肽缓释凝胶注射液，甘油的添加量为使其在凝胶注射液中的终浓度为50mg/ml-100mg/ml。
- 根据权利要求1-5任一项所述的特立帕肽缓释凝胶注射液，所述的pH调节剂选自磷酸，醋酸，柠檬酸，盐酸和氢氧化钠，优选醋酸。
- 根据权利要求1-6任一项所述的特立帕肽缓释凝胶注射液，所述的pH缓冲液的pH值缓冲范围为3.5-5.0。
- 根据权利要求1-7任一项所述的特立帕肽缓释凝胶注射液，所述特立帕肽缓释凝胶注射液的pH值为3.8-4.5。
- 根据权利要求1-8任一项所述的特立帕肽缓释凝胶注射液的制备方法，其包括以下步骤：1)将特立帕肽原料药溶解于注射用水中，得到第一溶液；2)以pH缓冲液溶解生物粘附材料，得到第二溶液；3)将温度敏感型凝胶材料加入第二溶液中，搅拌溶解，控制搅拌温度在0-10℃，得到第三溶液；4)将第一溶液和第三溶液混合均匀，混合温度在0-10℃，以pH调节剂调节pH值至3.5-5.5，用注射用水定容；5)无菌条件下用0.22μm过滤器除菌过滤，控制过滤温度在0-15℃；6)过滤除菌后的药液分装。
- 根据权利要求9所述的制备方法，其中无菌药液分装于西林瓶，预灌封注射器或卡式瓶中，优选分装于预灌封注射器。
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| CN115634234A (zh) * | 2022-10-24 | 2023-01-24 | 山西医科大学 | 一种含氯己定/枙子苷/透明质酸的泊洛沙姆407抑菌抗炎温敏水凝胶及制备与应用 |
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