CN116687835A - Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof - Google Patents
Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof Download PDFInfo
- Publication number
- CN116687835A CN116687835A CN202310748307.9A CN202310748307A CN116687835A CN 116687835 A CN116687835 A CN 116687835A CN 202310748307 A CN202310748307 A CN 202310748307A CN 116687835 A CN116687835 A CN 116687835A
- Authority
- CN
- China
- Prior art keywords
- gel
- long
- injected
- acting slow
- joint
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000013268 sustained release Methods 0.000 title claims description 4
- 239000012730 sustained-release form Substances 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000011159 matrix material Substances 0.000 claims abstract description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003381 stabilizer Substances 0.000 claims abstract description 27
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims abstract description 25
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims abstract description 24
- 239000007853 buffer solution Substances 0.000 claims abstract description 11
- 239000006172 buffering agent Substances 0.000 claims abstract description 11
- 230000001954 sterilising effect Effects 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000004090 dissolution Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims abstract description 7
- 230000001502 supplementing effect Effects 0.000 claims abstract description 7
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract 5
- BWHLPLXXIDYSNW-UHFFFAOYSA-N ketorolac tromethamine Chemical compound OCC(N)(CO)CO.OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 BWHLPLXXIDYSNW-UHFFFAOYSA-N 0.000 claims description 17
- 229960004384 ketorolac tromethamine Drugs 0.000 claims description 15
- 229920002385 Sodium hyaluronate Polymers 0.000 claims description 14
- 229940010747 sodium hyaluronate Drugs 0.000 claims description 14
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(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- Chemical compound [Na+].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 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 14
- 239000000872 buffer Substances 0.000 claims description 13
- 229920001661 Chitosan Polymers 0.000 claims description 10
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 10
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical group OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 10
- 239000000600 sorbitol Substances 0.000 claims description 10
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 230000003204 osmotic effect Effects 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229940043138 pentosan polysulfate Drugs 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 4
- 229920000669 heparin Polymers 0.000 claims description 4
- 229960002897 heparin Drugs 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229960003194 meglumine Drugs 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000002243 precursor Substances 0.000 claims description 3
- 101001123332 Homo sapiens Proteoglycan 4 Proteins 0.000 claims description 2
- 208000002193 Pain Diseases 0.000 abstract description 11
- 230000036407 pain Effects 0.000 abstract description 11
- 210000000988 bone and bone Anatomy 0.000 abstract description 9
- 208000012659 Joint disease Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 6
- 238000005461 lubrication Methods 0.000 abstract description 5
- 208000018934 joint symptom Diseases 0.000 abstract description 3
- 230000003139 buffering effect Effects 0.000 abstract 1
- 229960004752 ketorolac Drugs 0.000 description 13
- OZWKMVRBQXNZKK-UHFFFAOYSA-N ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 13
- 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 description 7
- 229920002101 Chitin Polymers 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 229920002674 hyaluronan Polymers 0.000 description 7
- 229960003160 hyaluronic acid Drugs 0.000 description 7
- 201000008482 osteoarthritis Diseases 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 230000000202 analgesic effect Effects 0.000 description 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 4
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010008 shearing Methods 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 3
- 206010003246 arthritis Diseases 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 210000001503 joint Anatomy 0.000 description 3
- 210000000629 knee joint Anatomy 0.000 description 3
- 150000005846 sugar alcohols Polymers 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 2
- 206010060820 Joint injury Diseases 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 210000000544 articulatio talocruralis Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 210000004394 hip joint Anatomy 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000008055 phosphate buffer solution Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 210000000323 shoulder joint Anatomy 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000001179 synovial fluid Anatomy 0.000 description 2
- DPZHKLJPVMYFCU-UHFFFAOYSA-N 2-(5-bromopyridin-2-yl)acetonitrile Chemical compound BrC1=CC=C(CC#N)N=C1 DPZHKLJPVMYFCU-UHFFFAOYSA-N 0.000 description 1
- 206010004663 Biliary colic Diseases 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000003947 Knee Osteoarthritis Diseases 0.000 description 1
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010050661 Platelet aggregation inhibition Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 102100028965 Proteoglycan 4 Human genes 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 206010053692 Wound complication Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 101150031809 cox1/2 gene Proteins 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 108010009030 lubricin Proteins 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229960000482 pethidine Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical group 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 208000004371 toothache Diseases 0.000 description 1
- 208000009935 visceral pain Diseases 0.000 description 1
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
- A61K9/06—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a long-acting slow-release gel capable of being injected into a joint cavity and a preparation method thereof; the gel comprises the following components in percentage by mass: 0.05 to 2.0 percent of non-steroidal anti-inflammatory drugs, 1.0 to 3.0 percent of gel matrix, 0.1 to 5.0 percent of stabilizing agent, 0.05 to 1.0 percent of buffering agent, 0.5 to 1.5 percent of auxiliary materials and the balance of water; the pH of the gel is 7.0+/-0.5; the method comprises the following steps: s1, dissolving a buffering agent in water to obtain a buffering solution; s2, dissolving the nonsteroidal anti-inflammatory drug and the stabilizer in a buffer solution to obtain a dissolution solution; s3, adding auxiliary materials and gel matrix into the dissolution liquid, stirring until the auxiliary materials and the gel matrix are completely dissolved to form a gel state, and supplementing water; s4, filtering or sterilizing by damp heat to obtain the long-acting slow release gel. Application: the gel is used for treating bone joint diseases or improving joint symptoms. The gel provided by the invention can be used for rapidly relieving pain and improving the lubrication and protection degree of the bone joint for a long time, and provides an overall treatment effect.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a long-acting slow-release gel capable of being injected into a joint cavity and a preparation method thereof.
Background
Ketorolac is a non-steroidal drug with potent analgesic activity. In order to improve the water solubility of ketorolac and meet the requirements of injection and oral administration, the ketorolac can rapidly act in body fluid and gastrointestinal tract, and the ketorolac tromethamine salt is generally prepared, and the structure of the ketorolac tromethamine salt is shown as a formula (I):
injections (30 mg/time) and oral formulations (10 mg/time) of ketorolac tromethamine can be used to relieve moderate to severe postoperative pain, swelling and pain, and pain caused by other inflammation. In addition, it can also relieve acute renal colic, biliary colic, toothache, wound pain, cancer visceral pain, and various pains which can be relieved by morphine or pethidine. The main pharmacological actions of ketorolac are to achieve analgesic, anti-inflammatory, antipyretic and platelet aggregation inhibition by inhibiting prostaglandin synthesis.
Currently, ketorolac formulations marketed in china are tablets, capsules, injections and eye drops. In order to overcome the defect of frequent administration of ketorolac oral preparations, various preparation technologies are adopted to prepare the ketorolac into oral slow-release microcapsules, osmotic pump tablets, gastric floating tablets, pulse drug release systems and the like, so as to realize the long-acting analgesic effect of the ketorolac. The ketorolac tromethamine oral preparation has the problems of gastrointestinal side effects shared by non-steroidal medicines, weak pertinence in the aspect of treating local pain and the like, so that a novel ketorolac local preparation with various administration routes such as skin, eyes, nasal cavities, oral mucosa and the like is developed, and the pain of subcutaneous soft tissues, joints, oral cavities and the like can be treated. The novel ketorolac formulation is developed around long-acting and locally targeted analgesic purposes, thereby meeting different clinical analgesic requirements.
Hyaluronic Acid (HA) is an anionic non-sulfate glycosaminoglycan, comprising N-acetyl-D-glucosamine (GlcNAc) and gluconic acid (GlcA) linked by 1, 4-glycosidic bonds to form a repeating unit, and the repeating units are linked by β -1, 3-glycosidic bonds to form a linear backbone. Hyaluronic acid is widely present in mammalian tissues, including connective, epithelial and nervous tissues, and its main biological functions include modulation of tissue fluid viscoelasticity, such as joint synovial fluid and ocular vitreous fluid. Hyaluronic acid has received extensive attention and research in the medical field due to its good hydrophilicity, biocompatibility and non-immunogenicity, for example, by treating arthritis as a supplementary synovial fluid to improve pain and function, as a filler for ophthalmic surgery, and in wound dressings, and as a drug delivery material for targeted administration or drug solubilization. In addition, hyaluronic Acid (HA) HAs also been widely used in the food and cosmetic fields. At present, a plurality of HA products are marketed for treating osteoarthritis at home.
Chitin, known by the chemical name poly-1, 4-beta-N-acetyl-D-glucosamine, is widely found in the exoskeletons of crustaceans and fungal cell walls. Chitosan (Chitosan) is the most important derivative of chitin, which is deacetylated by chitin and has the chemical name poly-1, 4-beta-D-glucosamine; since there are a large number of exposed amino and hydroxyl groups, chitosan readily forms strong hydrogen bonds within or between molecules, which makes it difficult to dissolve in water or conventional organic solvents, N-acylation is a common modification strategy to enhance its water solubility. Medical chitosan (for intra-articular injection) is the only polymer polysaccharide available for osteoarthritis treatment (Libao, national institute of mechanical injection 20173130026) which is currently used in the market except sodium hyaluronate. In addition, polymers such as heparin precursors (heparin), pentosan Polysulfate (PPS), human lubricin (lubrin) or polyvinyl alcohol are also gradually entering clinical trials for the treatment of arthritis, but these are also very promising therapeutic drugs or materials, although no products are yet marketed.
The polyalcohol such as mannitol, sorbitol and the like has high-density hydroxyl in the molecular structure, is easy to dissolve in water and has low toxicity, and is often used as a food additive. Therefore, the polyalcohol is used as a heat sterilization stabilizer of carboxymethyl chitin preparation, the molecular structure of carboxymethyl chitin can be stabilized through the hydrogen bond action formed between the polyalcohol and the carboxymethyl chitin preparation, and the integrity of molecular chains is protected to ensure that the carboxymethyl chitin is resistant to high-temperature degradation. Clinical treatment proves that ketorolac can effectively relieve pain caused by acute gouty arthritis, and some researches prove that the knee joint injection cavity ketorolac is effective in treating knee osteoarthritis. The long-acting gel product of ketorolac can play a role in rapidly relieving pain while continuously maintaining long-term lubrication, is a better choice for treating osteoarthritis, but the product is not seen to be marketed at present.
Disclosure of Invention
The invention aims to solve the problems in the background technology and provides a long-acting slow-release gel capable of being injected into a joint cavity and a preparation method thereof.
The invention is realized by the following technical scheme:
the long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.05 to 2.0 weight percent of non-steroidal anti-inflammatory drug, 1.0 to 3.0 weight percent of gel matrix, 0.1 to 5.0 weight percent of stabilizer, 0.05 to 1.0 weight percent of buffer and the balance of water; the pH value of the long-acting slow-release gel is 7.0+/-0.5, and the osmotic pressure is 280-380 mOsm/kg.
Specifically, the long-acting slow-release gel developed by the invention is suitable for injection of joint cavities, can be used for treating bone joint diseases, can improve the lubrication and protection degree of bone joints for a long time while rapidly relieving pain, and provides an overall treatment effect.
Further, a long-acting sustained-release gel capable of being injected into joint cavities is characterized in that the nonsteroidal anti-inflammatory drug is ketorolac tromethamine.
Furthermore, the long-acting slow-release gel capable of being injected into the joint cavity is characterized in that the gel matrix is extracted naturally or biologically fermented or chemically synthesized, and the gel matrix can be any one or a combination of two or more of crosslinked sodium hyaluronate, non-crosslinked sodium hyaluronate, medical chitosan, heparin precursor (Heparosan), pentosan Polysulfate (PPS), human lubrin (lubricin) or polyvinyl alcohol.
Furthermore, the long-acting slow-release gel capable of being injected into the joint cavity is characterized in that the molecular weight of the sodium hyaluronate is 100-10000 kD, and the molecular weight of the medical table Ding Tangfen is 100-1000 kD.
Furthermore, the long-acting slow-release gel capable of being injected into the joint cavity is characterized in that the stabilizer is sorbitol, mannitol or meglumine. The stabilizer is a polyol stabilizer.
Further, the long-acting slow release gel capable of being injected into joint cavities is characterized in that the buffering agent is selected from one or a mixture of more of phosphate, borate or citrate.
The preparation method of the long-acting slow-release gel capable of being injected into the joint cavity is characterized by comprising the following specific steps of:
s1, dissolving the buffer in water to obtain a buffer solution;
s2, dissolving the nonsteroidal anti-inflammatory drug and the stabilizer in the buffer solution to obtain a dissolution solution;
s3, adding the gel matrix into the dissolution liquid, stirring until the gel matrix is completely dissolved to form a gel state, supplementing water, and regulating the pH value of the system to 7.0+/-0.5;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
The preparation method of the long-acting slow-release gel capable of being injected into the joint cavity is characterized by comprising the following specific steps of:
s1, dissolving the buffer in water to obtain a buffer solution;
s2, adding the gel matrix into the buffer solution, and stirring until the gel matrix is completely dissolved to obtain a gel system;
s3, adding the non-steroidal anti-inflammatory drug and a stabilizer into the gel system, supplementing water, and regulating the pH value of the system to 7.0+/-0.5;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
The application is as follows: the long-acting slow-release gel capable of being injected into the joint cavity can be used for treating bone joint diseases or improving joint symptoms. Wherein: the bone joint diseases may include knee joint, hip joint, shoulder joint, ankle joint, knuckle joint, etc., joint injury, osteoarthritis, rheumatoid arthritis, etc.
The invention has the beneficial effects that:
(1) The invention relates to ketorolac tromethamine which is prepared into long-acting slow-release gel capable of being injected into joint cavities for the first time and is used for treating osteoarthritis; the invention aims to reduce the irritation of the medicine, reduce systemic adverse reactions, increase the curative effect and the medication safety, and simultaneously has good biocompatibility and in vivo degradability. Wherein: the ketorolac tromethamine adopted in the invention is COX1/2 nonsteroidal anti-inflammatory drug, and can avoid causing gastrointestinal adverse reaction and liver and kidney toxicity through local administration of the joint cavity. Meanwhile, the long-acting slow-release gel provided by the invention can be injected through the joint cavity, and the joint cavity is a relatively closed space and is relatively safe after local administration, so that the long-acting slow-release gel has higher medicinal safety.
(2) The long-acting slow-release gel capable of being injected into the joint cavity can quickly relieve pain, improve lubrication and protection degree of bone joints for a long time and provide an overall treatment effect. Wherein: the lubrication and protection are mainly the viscoelastic supplement performance of gel, and can be used as a drug release carrier to improve the overall treatment effect of arthritis.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. The following description of at least one exemplary embodiment is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The device comprises: viscotester IQ Air; a rotor: P35/Ti-01150939; temperature: 25 ℃; shear rate: 0.1-100/s.
Example 1
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.75wt% of non-steroidal anti-inflammatory drug, 2.0wt% of gel matrix, 4.0wt% of stabilizer, 0.65wt% of buffer and the balance of water; the pH value of the long-acting slow-release gel is 6.8-7.4, the osmotic pressure is 280-350 mOsm/kg, and the shearing viscosity is more than 3Pas;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is prepared from the following components in percentage by mass: 1 with medical chitosan; the stabilizer is sorbitol; the buffering agent is phosphate.
The preparation method of the long-acting slow-release gel capable of being injected into the joint cavity comprises the following steps:
s1, dissolving phosphate in water to obtain a phosphate buffer solution;
s2, dissolving ketorolac tromethamine and sorbitol in a phosphate buffer solution, and stirring for 1-3 hours at the temperature of 5-50 ℃ to obtain a solution;
s3, adding a gel matrix (sodium hyaluronate and medical chitosan) into the dissolution liquid, stirring for 1-10 hours at the temperature of 5-50 ℃, supplementing water when the gel matrix is completely dissolved into a gel state, and regulating the pH value of the system to be 6.8-7.4;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
The long-acting slow-release gel can be injected through joint cavities for treating bone joint diseases or improving joint symptoms. Wherein: the bone joint diseases may include knee joint, hip joint, shoulder joint, ankle joint, knuckle joint, etc., joint injury, osteoarthritis, rheumatoid arthritis, etc.
Example 2
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
1.5wt% of non-steroidal anti-inflammatory drug, 1.5wt% of gel matrix, 4.0wt% of stabilizer, 0.65wt% of buffer and the balance of water; the pH value of the long-acting slow-release gel is 7.0+/-0.5, the osmotic pressure is 280-380 mOsm/kg, and the shearing viscosity is more than 3Pas;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is prepared from the following components in percentage by mass: 1 with medical chitosan; the stabilizer is sorbitol; the buffering agent is borate.
Example 3
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.75wt% of non-steroidal anti-inflammatory drug, 1.0wt% of gel matrix, 1.0wt% of stabilizer, 0.85wt% of buffer and the balance of water; the pH value of the long-acting slow-release gel is 7.0+/-0.5, the osmotic pressure is 280-330 mOsm/kg, and the shearing viscosity is more than 8Pas;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is sodium hyaluronate; the stabilizer is sorbitol; the buffering agent is phosphate.
Example 4
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.375wt% of non-steroidal anti-inflammatory drug, 2.0wt% of gel matrix, 4.0wt% of stabilizer, 0.45wt% of buffer and the balance of water; the pH value of the long-acting slow-release gel is 7.0+/-0.5, the osmotic pressure is 280-360 mOsm/kg, and the shearing viscosity is more than 0.5Pas;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is medical chitosan; the stabilizer is sorbitol; the buffering agent is phosphate.
Example 5
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.05wt% of non-steroidal anti-inflammatory drug, 1.0wt% of gel matrix, 0.1wt% of stabilizer, 0.05wt% of buffer and the balance of water; the pH value of the long-acting slow release gel is 7.0+/-0.5;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is non-crosslinked sodium hyaluronate with the molecular weight of 100-10000 kD; the stabilizer is mannitol; the buffering agent is a mixture of phosphate and borate.
The preparation method of the long-acting slow-release gel capable of being injected into the joint cavity comprises the following steps:
s1, dissolving phosphate and borate in water to obtain a buffer solution;
s2, adding non-crosslinked sodium hyaluronate into the buffer solution, and stirring for 1-10 hours at the temperature of 5-50 ℃ until the non-crosslinked sodium hyaluronate is completely dissolved, so as to obtain a gel system;
s3, adding ketorolac tromethamine and mannitol into the gel system, supplementing water, and regulating the pH value of the system to 7.0+/-0.5;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
Example 6
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
2.0wt% of non-steroidal anti-inflammatory drug, 1.2wt% of gel matrix, 5.0wt% of stabilizer, 1.0wt% of buffer and the balance of water; the pH value of the long-acting slow release gel is 7.0+/-0.5;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is crosslinked sodium hyaluronate; the stabilizer is meglumine; the buffering agent is citrate.
Comparative example 1
The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.75wt% of non-steroidal anti-inflammatory drug, 1.0wt% of gel matrix, 0.85wt% of buffer and the balance of water; the pH value of the long-acting slow release gel is 7.0+/-0.5;
wherein: the non-steroidal anti-inflammatory drug is ketorolac tromethamine; the gel matrix is sodium hyaluronate; the buffering agent is phosphate; the auxiliary material is sodium chloride.
Comparative example 1 differs from example 3 in that: in comparative example 1, no sorbitol stabilizer was added, and the rest was the same as in example 3.
The addition of sorbitol stabilizer in the invention also has the function of regulating osmotic pressure.
The above-described preferred embodiments of the present invention are only for illustrating the present invention, and are not to be construed as limiting the present invention. Obvious changes and modifications of the invention, which are introduced by the technical solution of the present invention, are still within the scope of the present invention.
Claims (8)
1. The long-acting slow-release gel capable of being injected into joint cavities is characterized by comprising the following components:
0.05 to 2.0 weight percent of non-steroidal anti-inflammatory drug, 1.0 to 3.0 weight percent of gel matrix, 0.1 to 5.0 weight percent of stabilizer, 0.05 to 1.0 weight percent of buffer and the balance of water; the pH value of the long-acting slow-release gel is 7.0+/-0.5, and the osmotic pressure is 280-380 mOsm/kg.
2. The long-acting sustained-release gel for intra-articular injection of claim 1, wherein the non-steroidal anti-inflammatory drug is ketorolac tromethamine.
3. The long-acting slow release gel capable of being injected into joint cavities according to claim 1, wherein the gel matrix is at least one of crosslinked sodium hyaluronate, non-crosslinked sodium hyaluronate, medical chitosan, heparin precursor, pentosan polysulfate, human lubricin or polyvinyl alcohol.
4. The long-acting slow release gel capable of being injected into joint cavities according to claim 1, wherein the molecular weight of the sodium hyaluronate is 100-10000 kD, and the molecular weight of the medical grade Ding Tangfen is 100-1000 kD.
5. The long-acting slow release gel for injecting a joint cavity as claimed in claim 1, wherein said stabilizer is sorbitol, mannitol or meglumine.
6. The long-acting slow release gel for injecting into joint cavities according to claim 1, wherein the buffering agent is selected from one or a mixture of more of phosphate, borate or citrate.
7. A method for preparing a long-acting slow-release gel capable of being injected into a joint cavity, which is characterized in that the method is used for preparing the long-acting slow-release gel capable of being injected into the joint cavity according to any one of claims 1 to 6, and comprises the following steps:
s1, dissolving the buffer in water to obtain a buffer solution;
s2, dissolving the nonsteroidal anti-inflammatory drug and the stabilizer in the buffer solution to obtain a dissolution solution;
s3, adding the gel matrix into the dissolution liquid, stirring until the gel matrix is completely dissolved to form a gel state, supplementing water, and regulating the pH value of the system to 7.0+/-0.5;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
8. A method for preparing a long-acting slow-release gel capable of being injected into a joint cavity, which is characterized in that the method is used for preparing the long-acting slow-release gel capable of being injected into the joint cavity according to any one of claims 1 to 6, and comprises the following steps:
s1, dissolving the buffer in water to obtain a buffer solution;
s2, adding the gel matrix into the buffer solution, and stirring until the gel matrix is completely dissolved to obtain a gel system;
s3, adding the non-steroidal anti-inflammatory drug and a stabilizer into the gel system, supplementing water, and regulating the pH value of the system to 7.0+/-0.5;
s4, filtering or wet-heat sterilizing to obtain the long-acting slow-release gel capable of being injected into the joint cavity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310748307.9A CN116687835A (en) | 2023-06-25 | 2023-06-25 | Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310748307.9A CN116687835A (en) | 2023-06-25 | 2023-06-25 | Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116687835A true CN116687835A (en) | 2023-09-05 |
Family
ID=87843138
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310748307.9A Pending CN116687835A (en) | 2023-06-25 | 2023-06-25 | Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116687835A (en) |
-
2023
- 2023-06-25 CN CN202310748307.9A patent/CN116687835A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11090328B2 (en) | Compositions and methods for treating joints | |
| Necas et al. | Hyaluronic acid (hyaluronan): a review | |
| US8877243B2 (en) | Cross-linked polysaccharide composition | |
| US9511088B2 (en) | Stabalized glycosaminoglycan preparations and related methods | |
| CN102231985B (en) | Composition for preventing adhesion | |
| ES2284714T3 (en) | USE OF HIALURONIC ACID DERIVATIVES FOR THE INHIBITION OF INFLAMARORTIC ARTHRITIS. | |
| US8784850B2 (en) | Highly biocompatible dual thermogelling chitosan/glucosamine salt composition | |
| KR101916193B1 (en) | Injectable composition comprising nucleic acid and chitosan for articular cavity | |
| JP5898682B2 (en) | Highly biocompatible dual heat gelled chitosan / glucosamine salt composition | |
| Fakhari | Biomedical application of hyaluronic acid nanoparticles | |
| CN116687835A (en) | Long-acting sustained-release gel capable of being injected into joint cavity and preparation method thereof | |
| US10857176B2 (en) | Composition comprising polyglucosamine-glyoxylate solutions mixed with hyaluronan | |
| CA2956658C (en) | Composition comprising polyglucosamine-glyoxylate solutions mixed with hyaluronan | |
| US20220339100A1 (en) | Thermosensitive modified chitin hydrogel local anesthetic-loaded sustained-release analgesia system, preparation method and use | |
| AU2004229592B2 (en) | Cross-linked polysaccharide composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |