CN116098882A - Composition containing lidocaine prilocaine and preparation method thereof - Google Patents
Composition containing lidocaine prilocaine and preparation method thereof Download PDFInfo
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- CN116098882A CN116098882A CN202310356067.8A CN202310356067A CN116098882A CN 116098882 A CN116098882 A CN 116098882A CN 202310356067 A CN202310356067 A CN 202310356067A CN 116098882 A CN116098882 A CN 116098882A
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- CN
- China
- Prior art keywords
- prilocaine
- lidocaine
- composition
- oil phase
- sorbitan
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- 239000000203 mixture Substances 0.000 title claims abstract description 35
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 28
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 28
- 229960001807 prilocaine Drugs 0.000 title claims abstract description 27
- MVFGUOIZUNYYSO-UHFFFAOYSA-N prilocaine Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C MVFGUOIZUNYYSO-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 15
- 239000006071 cream Substances 0.000 claims abstract description 23
- 239000003921 oil Substances 0.000 claims abstract description 15
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000000126 substance Substances 0.000 claims abstract description 9
- WZSPWMATVLBWRS-UHFFFAOYSA-N 2-(diethylamino)-n-(2,6-dimethylphenyl)acetamide;n-(2-methylphenyl)-2-(propylamino)propanamide Chemical compound CCCNC(C)C(=O)NC1=CC=CC=C1C.CCN(CC)CC(=O)NC1=C(C)C=CC=C1C WZSPWMATVLBWRS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 8
- -1 polyoxyethylene Polymers 0.000 claims abstract description 6
- 238000007789 sealing Methods 0.000 claims abstract description 6
- 239000011159 matrix material Substances 0.000 claims abstract description 5
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 claims abstract description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 3
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 claims abstract description 3
- LWZFANDGMFTDAV-BURFUSLBSA-N [(2r)-2-[(2r,3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O LWZFANDGMFTDAV-BURFUSLBSA-N 0.000 claims abstract description 3
- 239000004359 castor oil Substances 0.000 claims abstract description 3
- 235000019438 castor oil Nutrition 0.000 claims abstract description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims abstract description 3
- 229920001993 poloxamer 188 Polymers 0.000 claims abstract description 3
- 229940044519 poloxamer 188 Drugs 0.000 claims abstract description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 3
- 229920000136 polysorbate Polymers 0.000 claims abstract description 3
- 229950008882 polysorbate Drugs 0.000 claims abstract description 3
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims abstract description 3
- 229940100515 sorbitan Drugs 0.000 claims abstract description 3
- 229950006451 sorbitan laurate Drugs 0.000 claims abstract description 3
- 235000011067 sorbitan monolaureate Nutrition 0.000 claims abstract description 3
- 229950004959 sorbitan oleate Drugs 0.000 claims abstract description 3
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 claims abstract 2
- 229950011392 sorbitan stearate Drugs 0.000 claims abstract 2
- 239000012071 phase Substances 0.000 claims description 16
- 235000019198 oils Nutrition 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 230000005496 eutectics Effects 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 230000001804 emulsifying effect Effects 0.000 claims description 4
- 235000019271 petrolatum Nutrition 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 3
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000004166 Lanolin Substances 0.000 claims description 2
- 239000004264 Petrolatum Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 235000013871 bee wax Nutrition 0.000 claims description 2
- 239000012166 beeswax Substances 0.000 claims description 2
- 229940092738 beeswax Drugs 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 229940082500 cetostearyl alcohol Drugs 0.000 claims description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 2
- 238000004945 emulsification Methods 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- 229940039717 lanolin Drugs 0.000 claims description 2
- 235000019388 lanolin Nutrition 0.000 claims description 2
- 229940057995 liquid paraffin Drugs 0.000 claims description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 229940056211 paraffin Drugs 0.000 claims description 2
- 239000012188 paraffin wax Substances 0.000 claims description 2
- 229940066842 petrolatum Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229940083037 simethicone Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960004274 stearic acid Drugs 0.000 claims description 2
- 229940012831 stearyl alcohol Drugs 0.000 claims description 2
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 239000003871 white petrolatum Substances 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 239000003589 local anesthetic agent Substances 0.000 abstract description 9
- 230000003444 anaesthetic effect Effects 0.000 abstract description 3
- 230000003796 beauty Effects 0.000 abstract description 2
- 230000001815 facial effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 13
- 238000000338 in vitro Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 229960005015 local anesthetics Drugs 0.000 description 5
- 229940035674 anesthetics Drugs 0.000 description 4
- 230000001427 coherent effect Effects 0.000 description 4
- 239000003193 general anesthetic agent Substances 0.000 description 4
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 2
- 230000003385 bacteriostatic effect Effects 0.000 description 2
- BLFLLBZGZJTVJG-UHFFFAOYSA-N benzocaine Chemical compound CCOC(=O)C1=CC=C(N)C=C1 BLFLLBZGZJTVJG-UHFFFAOYSA-N 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000011505 plaster Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 229960002372 tetracaine Drugs 0.000 description 2
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 2
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- VTUSIVBDOCDNHS-UHFFFAOYSA-N Etidocaine Chemical compound CCCN(CC)C(CC)C(=O)NC1=C(C)C=CC=C1C VTUSIVBDOCDNHS-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- 208000012266 Needlestick injury Diseases 0.000 description 1
- GKXVJHDEWHKBFH-UHFFFAOYSA-N [2-(aminomethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1CN GKXVJHDEWHKBFH-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960005274 benzocaine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960003976 etidocaine Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 229940052264 other local anesthetics in atc Drugs 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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 relates to the technical field of chemical pharmaceutical preparations, and discloses a composition containing lidocaine and prilocaine, which comprises 10-50g of lidocaine, 10-50g of prilocaine, 10-90g of emulsifying agent, 50-150g of film forming agent, 50-150g of oil phase matrix, 300-500g of film propping agent and 1000g of water; the emulsifier comprises one or a combination of several of sodium dodecyl sulfate, poloxamer 188, sorbitan laurate, sorbitan palmitat, sorbitan stearate, sorbitan oleate, polysorbate, polyoxyethylene hydrogenated castor oil and polyethylene glycol and the like, and on the basis of the existing products, the composition can form a sealing film within 30 minutes after being applied to human skin by optimizing a prescription and a preparation method, so that the application of the existing products to occlusive dressings is avoided, the composition is particularly suitable for children patients and facial beauty patients, and the local anesthetic effect of the lidocaine prilocaine cream composition is not obviously different from that of the existing products.
Description
Technical Field
The invention relates to the technical field of chemical pharmaceutical preparations, in particular to a composition containing lidocaine prilocaine and a preparation method thereof.
Background
Local anesthetics are drugs that temporarily and reversibly block the generation and conduction of nerve fiber impulses within a defined range of the body without losing consciousness of the patient.
Common local anesthetics are divided into amides and lipid common amide anesthetics including lidocaine, prilocaine, etidocaine and bupivacaine. Procaine, benzocaine and tetracaine are common ester anesthetics. Amide anesthetics are generally preferred over ester anesthetics due to allergic reactions of the esters. Most local anesthetics consist of lidocaine, prilocaine, tetracaine, or a combination thereof.
The advantage of local anesthetics is that some procedures can be anesthetized with little or no general exposure. However, local anesthetics are often limited to the use of occlusive dressings to enhance their epidermal penetration. Compound lidocaine cream (trade name EMLA, astra Pharmaceuticals, westborough, MA, USA, main ingredients are lidocaine and prilocaine) is generally considered to be the gold standard compared to other local anesthetics, the most common local anesthetic. It is still limited to the use of occlusive dressings.
Aiming at the defects, the invention creatively adjusts the formula composition to enable the lidocaine prilocaine cream to form an occlusion system by self film formation when being applied to the skin, thereby avoiding the use of occlusion dressing and greatly improving the medication sequence of patients.
Disclosure of Invention
The invention aims to provide a composition containing lidocaine prilocaine and a preparation method thereof, and solves the problems in the background technology.
In order to achieve the above purpose, the present invention provides the following technical solutions: a composition containing lidocaine and prilocaine comprises lidocaine 10-50g, prilocaine 10-50g, emulsifier 10-90g, film forming agent 50-150g, oil phase matrix 50-150g, film propping agent 300-500g, and water 1000g.
Preferably, the emulsifier includes, but is not limited to, one or more of sodium dodecyl sulfate, poloxamer 188, sorbitan laurate, sorbitan palmitat, sorbitan stearates, sorbitan oleate, polysorbate, polyoxyethylene hydrogenated castor oil, polyethylene glycol, and the like.
Preferably, the film forming agent includes, but is not limited to, one or a combination of several of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and the like.
Preferably, the oil phase base includes, but is not limited to, yellow petrolatum, white petrolatum, paraffin, liquid paraffin, stearic acid, stearyl alcohol, simethicone, vegetable oil, lanolin, beeswax, cetostearyl alcohol, and the like.
Preferably, the film proppants include, but are not limited to, one or a combination of several of water insoluble inorganic salts such as anhydrous dibasic calcium phosphate, calcium carbonate, and the like.
A method for preparing a composition containing lidocaine prilocaine, comprising the steps of:
s1: preparing a eutectic substance: weighing lidocaine and prilocaine according to the prescription amount, placing the lidocaine and prilocaine in an oil phase pot, stirring, heating to 50-70 ℃, and maintaining for more than 15 minutes to obtain clear liquid;
s2: preparing an oil phase: weighing emulsifier and oil phase matrix according to the prescription, placing into the oil phase pot, stirring, heating to 70-80deg.C, and maintaining for more than 15 min;
s3: preparing an aqueous phase: weighing water according to the prescription amount, adding the prescription amount of film propping agent while stirring, heating to 70-80 ℃, adding the prescription amount of film forming agent to make the film forming agent homogeneous, and maintaining the temperature at 70-80 ℃ for more than 15 minutes;
s4: emulsification: transferring the water phase into a vacuum emulsifying machine, starting stirring for 50-90rpm and homogenizing for 2000-3000rpm, transferring the oil phase prepared in the step S2 into the vacuum emulsifying machine, and stirring and homogenizing for 3-10 minutes to prepare a uniform cream intermediate;
s5: and (3) filling: transferring the cream in the step S4 into a hopper of a filling tail sealing machine, filling into an ointment tube, and sealing the tail to obtain the lidocaine prilocaine cream composition.
The following indices can be monitored during the preparation process to control the quality of the eutectic and cream intermediates:
1) Eutectic behavior: should be clear oily liquid;
2) Eutectic content composition: taking a proper amount of eutectic substances, measuring according to a high performance liquid chromatography (the rule 0512 of the fourth edition of Chinese pharmacopoeia 2020), and calculating the theoretical contents of lidocaine and prilocaine relative to the marked amount according to an external standard method by using peak areas, wherein the theoretical contents are in a range of 48.0-52.0%;
3) Cream intermediate behavior: a viscous cream of white to off-white color;
4) Cream intermediate basicity: taking 1.0g of the product, adding 10ml of water, stirring uniformly, and measuring according to a pH measuring method (China pharmacopoeia 2020 edition four general rules 0631), wherein the pH value is 7.0-10.0;
5) Cream intermediate layering phenomenon: taking 10g of the product, placing the product into a centrifuge tube with a plug, and centrifuging at 2500 rpm for 30 minutes to observe whether layering phenomenon exists or not, wherein no layering phenomenon exists;
6) Penetration of cream intermediate: taking a proper amount of the product, and measuring according to a cone penetration measuring method (four general rules 0983 of Chinese pharmacopoeia 2020 edition), wherein the cone penetration is not less than 200;
7) Cream intermediate particle size: checking according to particle size and particle size distribution measurement method (the first method of the fourth edition of Chinese pharmacopoeia 2020 edition, rule 0982), and detecting particles larger than 180 μm;
8) Cream intermediate mixing uniformity: 10 parts of the cream are taken, the theoretical content relative to the marked amount is calculated according to the peak area by an external standard method and the relative standard deviation of the content of 10 parts of samples is not more than 5.0 percent according to the measurement of high performance liquid chromatography (four-part rule 0512 in the year of Chinese pharmacopoeia 2020).
The invention provides a composition containing lidocaine prilocaine and a preparation method thereof. The composition containing lidocaine prilocaine and the preparation method thereof have the following beneficial effects:
on the basis of the existing product, the prescription and the preparation method are optimized, so that a sealing film can be formed within 30 minutes when the product is applied to the skin of a human body, the use of the existing product on the occlusive dressing is avoided, and the occlusive dressing is particularly suitable for children patients and facial beauty patients;
on the basis of the existing product, the content of related substances o-toluidine is controlled by optimizing the prescription and the preparation method, so that the content of the o-toluidine is reduced to below 0.01% from 2% in the prior art, the quality of lidocaine prilocaine emulsifiable paste is greatly improved, and the occurrence of side reactions in clinical use is reduced;
the invention avoids the use of preservative, thereby avoiding adverse reaction of partial patients to the preservative, and simultaneously verifies that the bacteriostatic efficacy of the product is not lower than that of the existing product, and meets the requirements of the four-part rule 1121 bacteriostatic efficacy inspection method of Chinese pharmacopoeia 2020 edition;
the lidocaine prilocaine emulsion plaster composition has no obvious difference with the existing products in local anesthetic effect;
the in vitro transdermal test result of the lidocaine prilocaine emulsion plaster composition shows that compared with the existing product (EMLA), the in vitro permeation rate is not obviously different; the intradermal retention rate is higher than that of the prior products, can enter the skin more and exert the local anesthetic effect more quickly.
Drawings
FIG. 1 is a table of prescription composition according to embodiment 1 of the present invention;
FIG. 2 is a table of prescription composition according to embodiment 2 of the present invention;
FIG. 3 is a table of prescription composition according to embodiment 3 of the present invention;
FIG. 4 is an intermediate monitoring table of example 4 of the present invention;
FIG. 5 shows the detection result of o-xylylenediamine as a related substance in example 6 of the present invention;
FIG. 6 shows the results of liquid phase analysis of the sample after sampling in example 7 of the present invention.
Detailed Description
Example 1 prescription composition is as in FIG. 1
The preparation method provided by the invention is used for preparing the cream composition, and a coherent semisolid is formed after application.
Example 2 prescription composition is as in FIG. 2
The preparation method provided by the invention is used for preparing the cream composition, and a coherent semisolid is formed after application.
Example 3 prescription composition is as in FIG. 3
The preparation method provided by the invention is used for preparing the cream composition, and a coherent semisolid is formed after application.
Example 4: the intermediate body is monitored and the intermediate body is used for monitoring,
examples 1-3 were monitored according to the intermediate monitoring index provided by the present invention, and the results are shown in fig. 4:
the results showed that all met the criteria for intermediate control with no significant differences between batches.
Example 5: contrast of the local anesthesia effect is carried out,
the composition of comparative example 3 and the existing product (EMLA) were subjected to syringe needle punching in a double blind, crossover study on 18 adult subjects. A layer of approximately 1 millimeter of the formulation is applied to an area of skin of an adult subject that is subject to needle sticks. Example 3 solidified into a soft coherent film and was peeled off after 30 minutes; the existing product does not form a film, and is cleaned by towel and water after 30 minutes of application. Pain scores were recorded for each subject using a visual analog pain scale. About 30 minutes after administration, the average pain scores of the test group showed no significant difference from the control group.
Example 6: the related substance o-phenylmethylamine is detected,
the lidocaine prilocaine cream prepared by the embodiment of the invention is used for long-term stability test investigation. The commercial package was simulated for 24 months under long-term test conditions (25.+ -. 2 ℃ C., relative humidity 40.+ -. 5% RH). The detection result of the related substance o-phenylmethylamine is shown in fig. 5:
example 7: in vitro transdermal test comparison is carried out,
in vitro transdermal test study comparison was performed on lidocaine prilocaine cream prepared using inventive example 3 with the existing product (EMLA).
The back skin of a Ba Ma Xiaoxiang pig (1 month old, male) is selected as skin of an in vitro transdermal test animal, phosphate buffer solution with pH7.0 is used as a transdermal medium, sampling time points are 20, 40, 60, 90, 120, 180, 240 and 360 minutes, other experimental conditions and detection methods are consistent with in vitro release, and Franz diffusion Chi Fa is adopted: the diameter of the injection hole of the diffusion cell is 15mm, the medium temperature is 32+/-0.5 ℃, the medium volume is 12ml, 6 groups of reference preparations are prepared, the sample loading amount is 300mg of emulsifiable paste, the two preparations are administered in two sequences, the sample volume is 2ml, the fluid infusion is 2ml, and the liquid phase analysis sample is carried out after the sampling. The results are shown in FIG. 6:
the pharmaceutical composition prepared in the embodiment 3 of the invention has higher intradermal retention rate than the existing product (EMLA) and can enter the skin more; there was no significant difference in the in vitro permeation rate.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A composition comprising lidocaine prilocaine, characterized in that: comprises 10-50g of lidocaine, 10-50g of prilocaine, 10-90g of emulsifying agent, 50-150g of film forming agent, 50-150g of oil phase matrix, 300-500g of film propping agent and 1000g of water.
2. A lidocaine prilocaine-containing composition of claim 1, characterized in that: the emulsifier includes, but is not limited to, one or a combination of several of sodium dodecyl sulfate, poloxamer 188, sorbitan laurate, sorbitan palmitat, sorbitan stearate, sorbitan oleate, polysorbate, polyoxyethylene hydrogenated castor oil, polyethylene glycol, and the like.
3. A lidocaine prilocaine-containing composition of claim 1, characterized in that: the film forming agent includes, but is not limited to, one or a combination of several of polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, and the like.
4. A lidocaine prilocaine-containing composition of claim 1, characterized in that: the oil phase base includes, but is not limited to, one or more of yellow petrolatum, white petrolatum, paraffin, liquid paraffin, stearic acid, stearyl alcohol, simethicone, vegetable oil, lanolin, beeswax, cetostearyl alcohol, and the like.
5. A lidocaine prilocaine-containing composition of claim 1, characterized in that: the film proppants include, but are not limited to, one or a combination of several of water insoluble inorganic salts such as anhydrous dibasic calcium phosphate, calcium carbonate, and the like.
6. A method for preparing a composition containing lidocaine prilocaine, which is characterized in that: the method comprises the following steps:
s1: preparing a eutectic substance: weighing lidocaine and prilocaine according to the prescription amount, placing the lidocaine and prilocaine in an oil phase pot, stirring, heating to 50-70 ℃, and maintaining for more than 15 minutes to obtain clear liquid;
s2: preparing an oil phase: weighing emulsifier and oil phase matrix according to the prescription, placing into the oil phase pot, stirring, heating to 70-80deg.C, and maintaining for more than 15 min;
s3: preparing an aqueous phase: weighing water according to the prescription amount, adding the prescription amount of film propping agent while stirring, heating to 70-80 ℃, adding the prescription amount of film forming agent to make the film forming agent homogeneous, and maintaining the temperature at 70-80 ℃ for more than 15 minutes;
s4: emulsification: transferring the water phase into a vacuum emulsifying machine, starting stirring for 50-90rpm and homogenizing for 2000-3000rpm, transferring the oil phase prepared in the step S2 into the vacuum emulsifying machine, and stirring and homogenizing for 3-10 minutes to prepare a uniform cream intermediate;
s5: and (3) filling: transferring the cream in the step S4 into a hopper of a filling tail sealing machine, filling into an ointment tube, and sealing the tail to obtain the lidocaine prilocaine cream composition.
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