WO2006122462A1 - Preparation orale comprenant du chlorhydrate de dyclonine - Google Patents
Preparation orale comprenant du chlorhydrate de dyclonine Download PDFInfo
- Publication number
- WO2006122462A1 WO2006122462A1 PCT/CN2006/000048 CN2006000048W WO2006122462A1 WO 2006122462 A1 WO2006122462 A1 WO 2006122462A1 CN 2006000048 W CN2006000048 W CN 2006000048W WO 2006122462 A1 WO2006122462 A1 WO 2006122462A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- preparation
- hydrochloride
- polyvinyl alcohol
- add
- dyclonine hydrochloride
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 38
- 229960003462 dyclonine hydrochloride Drugs 0.000 title claims abstract description 27
- KNZADIMHVBBPOA-UHFFFAOYSA-N dyclonine hydrochloride Chemical compound [Cl-].C1=CC(OCCCC)=CC=C1C(=O)CC[NH+]1CCCCC1 KNZADIMHVBBPOA-UHFFFAOYSA-N 0.000 title claims abstract description 27
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 32
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 22
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 22
- 235000011187 glycerol Nutrition 0.000 claims abstract description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 239000013530 defoamer Substances 0.000 claims description 10
- 239000002518 antifoaming agent Substances 0.000 claims description 7
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 5
- 238000009472 formulation Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003349 gelling agent Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 238000005461 lubrication Methods 0.000 abstract description 7
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 206010002091 Anaesthesia Diseases 0.000 abstract description 4
- 230000037005 anaesthesia Effects 0.000 abstract description 4
- 238000001949 anaesthesia Methods 0.000 abstract 1
- 239000006260 foam Substances 0.000 abstract 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000243 solution Substances 0.000 description 14
- 239000000499 gel Substances 0.000 description 12
- 238000001839 endoscopy Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000000796 flavoring agent Substances 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 7
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 235000013305 food Nutrition 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 206010047700 Vomiting Diseases 0.000 description 5
- 230000003444 anaesthetic effect Effects 0.000 description 5
- 235000019634 flavors Nutrition 0.000 description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 description 5
- 239000003589 local anesthetic agent Substances 0.000 description 5
- 230000008673 vomiting Effects 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000003292 glue Substances 0.000 description 3
- 230000036407 pain Effects 0.000 description 3
- 238000004513 sizing Methods 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- -1 Hydroxyphenylethyl ester Chemical class 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000544066 Stevia Species 0.000 description 2
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 2
- 229910052788 barium Inorganic materials 0.000 description 2
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 210000000795 conjunctiva Anatomy 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 210000001156 gastric mucosa Anatomy 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 230000037431 insertion Effects 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 229940041616 menthol Drugs 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 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 description 2
- 229940013618 stevioside Drugs 0.000 description 2
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 2
- 235000019202 steviosides Nutrition 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 230000003457 anti-vomiting effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229960000385 dyclonine Drugs 0.000 description 1
- BZEWSEKUUPWQDQ-UHFFFAOYSA-N dyclonine Chemical compound C1=CC(OCCCC)=CC=C1C(=O)CCN1CCCCC1 BZEWSEKUUPWQDQ-UHFFFAOYSA-N 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229940050521 gelatin agent Drugs 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000017 mucous membrane irritation Toxicity 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 229940041672 oral gel Drugs 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 229940052264 other local anesthetics in atc Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 230000002335 preservative effect Effects 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
- 210000001747 pupil Anatomy 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- A61K9/08—Solutions
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
Definitions
- the present invention relates to an oral preparation of dyclonine hydrochloride for an upper gastrointestinal endoscopy having anesthesia and lubrication.
- lidocaine hydrochloride glue is often used for gastrointestinal endoscopy.
- the patient is more painful, and the visual field is not clear, the doctor is inconvenient to operate, prolongs the operation time, and increases the patient's pain.
- lidocaine hydrochloride paddle for upper gastrointestinal endoscopy
- lidocaine hydrochloride acts as a surface anesthetic, which relieves the patient's pain, but the lidocaine hydrochloride gel does not have a lubricating effect and cannot be easily inserted into the mirror. Can not eliminate the bubble in the cavity, can not prevent vomiting, clear vision, and is not convenient for clinical use.
- the object of the present invention is to provide a practical, convenient and reliable oral preparation of dyclonine hydrochloride for clinical gastrointestinal endoscopy, which has an anesthetic effect on the mucosal surface, and has lubrication and eliminates bubble in the cavity to prevent The effect of vomiting, so that the field of vision is clear and easy to check.
- the weight percentage of the main component in the preparation of the present invention is: dyclonine hydrochloride 0.2% to 3%, polyvinyl alcohol 1% ⁇ 12%; glycerin 1% ⁇ : 12%, defoaming
- the agent is 1% ⁇ 12%, and the balance is a pharmaceutical excipient.
- the preferred weight percentage of the main component in the preparation is: dyclonine hydrochloride 0. 5% ⁇ 1. 5%, polyvinyl alcohol 3% ⁇ 8%; glycerin 2% ⁇ 6%, defoaming agent 2% ⁇ 6 %, the balance is a pharmaceutical excipient.
- the formulations of the invention are gels, solutions or syrups.
- the viscosity of the preparation is between 30 ⁇ 300mpa's, pH 2. 0 ⁇ 8. 0, preferably the viscosity is between 50 ⁇ 150mpa * s, pH 2. 3 ⁇ 5.
- the main drug of the present invention is the hydrochloride salt of the local anesthetic dyclonine.
- This product can block the transmission of various nerve impulses or stimuli, inhibit the sense of touch, pressure and pain, and has analgesic, antipruritic and bactericidal effects on the skin.
- This product has strong penetrating power and can be absorbed through the skin and mucous membranes. The effect is rapid and long-lasting. The strength and maintenance time are similar to procaine.
- the toxicity is small, and the dripping into the conjunctiva does not cause the pupil to shrink or expand.
- This product has no cross-allergy with other local anesthetics Should.
- the excipients in the preparation of the present invention mainly include: polyvinyl alcohol, glycerin, antifoaming agent, preservative, flavoring agent, pH adjusting agent, water, and the like.
- the polyvinyl alcohol in the preparation is a thickener, and the content thereof is usually between 1% and 12%, which can increase the viscosity of the preparation, and make the viscosity of the preparation within a suitable range, thereby prolonging the residence time of the drug on the mucosal surface and prolonging. Local anesthetic time.
- the dosage of glycerin in the preparation is usually between 1% and 12%, which can enhance the lubrication and anti-vomiting effect of the preparation, facilitate the insertion of the mirror, and prevent the polyvinyl alcohol boiled liquid from conjunctiva and agglomeration after cooling, which is convenient for preparation of the preparation. .
- the antifoaming agent in the preparation usually adopts PPE medical defoaming agent, which is a polyoxyethylene polyoxypropylene ether.
- PPE medical defoaming agent which is a polyoxyethylene polyoxypropylene ether.
- Other antifoaming agents for medical or food addition such as GPE, BAPE, MPE, etc., can also be used.
- GPE polyoxyethylene polyoxypropylene ether
- BAPE BAPE
- MPE MPE
- the preparation has a foaming effect, which can eliminate the bubble in the cavity and make the field of vision clear.
- the dyclonine hydrochloride gel preparation is a syrup preparation consisting of dyclonine hydrochloride and polyvinyl alcohol, glycerin, antifoaming agent, etc., which has both mucosal surface anesthetic effect and suitable viscosity, and can prolong the drug on the mucosal surface.
- the residence time prolong the time of local anesthesia, and has the functions of lubrication, sputum and vomiting, which can be easily inserted into the mirror to make the vision clear. Therefore, this product can be widely used in a variety of endoscopic examinations, especially for anesthesia, lubrication and vomiting during upper gastrointestinal endoscopy, while eliminating bubbles in the lumen to make the field clear.
- the preservatives, flavoring agents, pH adjusting agents and the like in the pharmaceutical excipients of the present invention may be selected from pharmacopoeia, textbooks and related articles contained in the literature, and adjusted according to the conventional usage.
- the oral preparation of dyclonine hydrochloride of the present invention is usually contained in the throat of 8-10ml of the product before the endoscopy examination of the upper digestive tract. After a while, it is slowly swallowed, and it is feasible to be in the upper digestive tract after about 10-15 minutes. Speculoscopy, the amount can also be adjusted according to the concentration of the main drug dyclonine hydrochloride and the actual conditions of endoscopy. 8%, the remarkable efficiency of the present invention is 74. 8%, the excellent rate of the foaming effect is 91.8%, the effective efficiency of the present invention is 74. 5%, the total effective rate was 95.5%, which was significantly better than the control group. In clinical studies, this product has not been found to have significant adverse effects.
- the oral preparation for digestive tract endoscopy according to the present invention is as follows:
- the remaining dose groups can be prepared by referring to the above examples and adjusting the process recipe according to the routine.
- the local anesthetic effect of dyclonine hydrochloride gel was determined by rabbit corneal method and frog skin method.
- the results of rabbit corneal method showed that Dakronin hydrochloride solution and gelatin had a dose-dependent effect on the corneal surface of rabbit cornea, and the gelatin agent had similar aging and dose-effect with Dakronin hydrochloride solution. relationship.
- the results of the frog skin test showed that there was a significant dose-dependent dependence of the sizing agent and the dyclonine hydrochloride solution in the dose range of 0.5- 2%.
- the sizing agent and hydrochloric acid There was no significant difference in the local anesthetic effect of the dacronnin solution.
- Oral L, and 95% confidence limit for mice with dyclonine hydrochloride was: 0. 21g/kg (0. 19 ⁇ 0. 23g/kg), equivalent to 126 times the recommended clinical dose.
- mice The intraperitoneal injection of LDTM and the 95% confidence limit for dyclonine hydrochloride mice were: 0. 047g/kg (0. 044 ⁇ 0. 050g/kg), equivalent to 28.2 times the recommended clinical dose.
- Dakronin hydrochloride gelatin rats were orally administered 1 ⁇ . And the 95% confidence limit is: 0. 37g / k g (0. 32 ⁇ 0. 42g / kg), equivalent to 222 times the recommended clinical dose.
- the dextroprofen hydrochloride gel of the present invention is used for clinical trials of upper gastrointestinal endoscopy in 220 cases of upper gastrointestinal endoscopy and treatment of outpatients and inpatients, aged 19 to 79 years old, including 121 males , 99 women. Patients were divided into two groups by random double-blind method, 110 in each group. The control drug was lidocaine hydrochloride gel. The results showed that all 220 patients were enrolled in the observation. The age, sex and disease of the two groups were basically the same. The optimistic rate of the effect of the blistering effect was 91. 8 ° /.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Anesthesiology (AREA)
- Inorganic Chemistry (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
一种盐酸达克罗宁口服制剂 技术领域
本发明涉及一种用于上消化道内窥镜检查具有麻醉和润滑作用的盐酸达克 罗宁口服制剂。
背景技术
目前， 临床上进行消化道内窥镜检查时， 常使用钡餐或盐酸利多卡因胶浆。 使用钡餐进行消化道内窥镜检査时， 病人较为痛苦， 而且视野不太清晰， 医生 操作不便， 延长了操作时间， 增加了病人的痛苦。 使用局部麻醉药盐酸利多卡 因胶桨进行上消化道内窥镜检查时， 盐酸利多卡因起表面麻醉作用， 减轻了病 人的痛苦， 但盐酸利多卡因胶浆不具有润滑作用， 不能方便插镜， 不能祛除腔 道内泡沬， 不能防止呕吐， 使视野清晰， 不便于临床使用。 因此， 临床上需要 一种既具有粘膜表面麻醉作用， 又具有润滑作用， 便于插镜， 并且可祛除腔道 内泡沬， 防止呕吐， 使视野清晰的消化道内窥镜检査用药物。
发明内容
本发明的目的在于为临床进行消化道内窥镜检查时提供一种实用、 方便、 可靠的盐酸达克罗宁口服制剂， 既对粘膜表面具有麻醉效果， 又具有润滑、 祛 除腔道内泡沬， 防止呕吐的作用， 从而使视野清晰便于检查。
为实现上述目的， 本发明制剂中主要成分的重量百分含量为： 盐酸达克罗 宁 0. 2%〜3%， 聚乙烯醇 1%〜12% ； 甘油 1%〜： 12%， 消泡剂 1%〜12%， 余量为药 用辅料。
制剂中主要成分的优选重量百分含量为： 盐酸达克罗宁 0. 5%〜1. 5%， 聚乙 烯醇 3%〜8%； 甘油 2%〜6%， 消泡剂 2%〜6%， 余量为药用辅料。
本发明的制剂为凝胶剂、溶液剂或糖浆剂。
制剂的黏度在 30〜300mpa ' s 之间， pH值 2. 0〜8. 0， 优选黏度在 50〜 150mpa * s之间， pH值 2. 3〜5. 0。
本发明中的主药盐酸达克罗宁 （dyclonine hydrochloride) 为局部麻醉药 达克罗宁 （dyclonine) 的盐酸盐。 本品能阻断各种神经冲动或刺激的传导， 抑 制触觉、 压觉和痛觉， 对皮肤有止痛、 止痒及杀菌作用。 本品穿透力强， 可通 过皮肤及粘膜吸收， 作用迅速而持久， 强度与维持时间与普鲁卡因近似， 毒性 小， 滴入结膜不致引起瞳孔缩小或扩大。 本品与其他局部麻醉药无交叉过敏反
应。 本发明制剂中的辅料主要包括： 聚乙烯醇、 甘油、 消泡剂、 防腐剂、 矫味 剂、 pH值调节剂、 水等。
制剂中的聚乙烯醇为增稠剂，其含量通常在 1%〜12%之间，可增加制剂的黏 度， 使制剂的黏度在适宜的范围内， 从而延长药物在粘膜表面的停留时间， 延 长局部麻醉作用时间。
制剂中的甘油， 用量通常在 1%〜12%之间， 可增强制剂的润滑和止呕作用， 方便插镜， 并可以防止聚乙烯醇水煮液遇冷后结膜、 结块， 便于制剂成型。
制剂中的消泡剂， 通常采用 PPE医用消泡剂， 为一种聚氧乙烯聚氧丙烯醚， 也可以使用其他的医用或食品添加用消泡剂， 如 GPE、 BAPE、 MPE等， 用量通常 在 1%〜12°/。之间， 使制剂具有祛泡作用， 可祛除腔道内泡沬， 使视野清晰。
盐酸达克罗宁胶浆制剂为盐酸达克罗宁和聚乙烯醇、 甘油、 消泡剂等组成 的胶浆制剂， 既具有粘膜表面麻醉效果， 又具有适宜的黏度， 可延长药物在粘 膜表面的停留时间， 延长局部麻醉作用时间， 并具有润滑、 祛泡和止呕作用， 可方便插镜， 使视野清晰。 因而本品可广泛应用于各种腔道内窥镜检查， 尤其 用于上消化道内窥镜检査时的麻醉、 润滑和止呕， 同时祛除腔道内泡沬， 使视 野清晰。
本发明所涉及的药用辅料中防腐剂、 矫味剂、 PH调节剂等， 可选用药典、 教科书及文献收载的相关品种， 依常规用法用量调整。
本发明盐酸达克罗宁口服制剂， 在临床上通常于上消化道内窥镜检查前将 本品 8-10ml含于咽喉部， 片刻后慢慢吞下， 约 10- 15分钟后可行上消化道内窥 镜检查， 其用量也可以根据主药盐酸达克罗宁的浓度和需进行内窥镜检查的实 际情况进行适当调整。 临床试验结果表明， 本发明盐酸达克罗宁胶浆剂的插镜 及麻醉效果的优良率为 93. 6%， 祛泡效果的优良率为 91. 8%， 本发明的显效率为 74. 5%， 总有效率为 95. 5%， 均明显优于对照组。 临床研究中， 未发现本品有明 显的不良反应。
具体实施方式
本发明所涉及的消化道内窥镜检査用口服制剂的实施例如下：
实施例 1 盐酸达克罗宁胶浆
盐酸达克罗宁 10g
医用消泡剂 （PPE) 40ml
聚乙烯醇 60g
甘油 20ml
羟苯乙酯 0. 3g
甜菊甙 0. 75g
薄荷脑 0. 6g
柠檬酸 3. 25g
柠檬酸钠 0. 75g
食用香精 5ml
纯化水 加至 1000ml
制备工艺
取聚乙烯醇， 加入处方量 60%的水， 搅拌蒸煮； 加入羟苯乙酯和甜菊甙， 待 聚乙烯醇溶解完全后， 加入甘油， 放冷； 另取柠檬酸， 加适量热水溶解后， 加 入盐酸达克罗宁， 搅拌溶解后， 加入到上述溶液中； 另取柠檬酸钠， 加适量热 水溶解后， 加入到上述溶液中； 再加入医用消泡剂； 另取薄荷脑用食用香精溶 解后， 加入到上述溶液中， 加水至 1000ml , 搅拌均匀， 灌装， 即得。
实施例 2 盐酸达克罗宁口服溶液剂
盐酸达克罗宁 15g
消泡剂 （GPE) 20ml
聚乙烯醇 20g
甘油 35ml
0. 5g
80g
10ml
纯化水 加至 1000ml
制法：
取聚乙烯醇， 加入处方量 30%的水， 搅拌蒸煮； 加入蔗糖和山梨酸， 待聚乙 烯醇溶解完全后， 加入甘油， 放冷； 另取盐酸达克罗宁， 加适量热水溶解后， 加入到上述溶液中； 再将消泡剂和香精加入到上述溶液中， 加水至 1000ml , 搅 拌均匀， 灌装， 即得。
盐酸达克罗宁口服凝胶剂
盐酸达克罗宁 2g
消泡剂 （BAPE) 10ml
聚乙烯醇 120g
甘油 100ml
苯甲酸钠 2g
甜菊甙 lg
磷酸二氢钾 100g
食用香精 8ml
纯化水 加至 1000ml
制备工艺：
取聚乙烯醇， 加入处方量 50%的水， 搅拌蒸煮； 加入苯甲酸钠和甜菊甙， 待聚乙烯醇溶 解完全后， 加入甘油， 放冷； 另取磷酸二氢钾， 加适量热水溶解后， 加入盐酸达克罗宁， 搅 拌溶解后， 加入到上述溶液中； 再加入医用消泡剂和食用香精， 加水至 1000ml , 搅拌均勾， 灌装， 即得。
盐酸达克罗宁糖浆剂
盐酸达克罗宁 30g
消泡剂 （MPE) 100ml
聚乙烯醇 10g
甘油 10ml
蔗糖 450g
苯甲酸 2g
食用香精 6ml
稀盐酸
纯化水 加至 1000ml
制备工艺：
取聚乙烯醇， 加入处方量 55%的水， 搅拌蒸煮； 加入蔗糖和苯甲酸， 待聚乙烯醇和蔗糖 溶解完全后， 加入甘油， 放冷； 另取盐酸达克罗宁， 加适量热水溶解后， 加入到上述溶液中； 用稀盐酸适量调节 pH 值至 3. 0± 0. 2， 再将消泡剂和食用香精加入到上述溶液中， 加水至 1000ml , 搅拌均匀， 灌装， 即得。
其余剂量组可参照上述实施例， 依常规调整工艺处方制得。
动物实施例 1 本发明盐酸达克罗宁胶浆剂的主要药效学试验
采用兔角膜法和蛙皮肤法测定盐酸达克罗宁胶浆的局麻疗效。 兔角膜法实 验结果表明， 盐酸达克罗宁溶液与胶浆剂对兔角膜的表麻作用有很好的剂量依 赖关系， 且胶浆剂与盐酸达克罗宁溶液有相似的时效与量效关系。胶浆剂的 ED5„ 与盐酸达克罗宁溶液的 E „无显著性差异。蛙皮肤法实验结果表明，胶浆剂与盐 酸达克罗宁溶液在 0. 5- 2%的剂量范围内有明显的量效依赖关系， 胶浆剂与盐酸
达克罗宁溶液的局麻作用无明显差别。
动物实施例 2 本发明盐酸达克罗宁胶浆剂的动物急性毒性试验
盐酸达克罗宁胶浆小鼠口服 L ,及 95%可信限为： 0. 21g/kg (0. 19〜 0. 23g/kg)， 相当于推荐临床剂量的 126倍。
盐酸达克罗宁胶浆小鼠腹腔注射 LD™及 95%可信限为： 0. 047g/kg (0. 044〜 0. 050g/kg)， 相当于推荐临床剂量的 28. 2倍。
盐酸达克罗宁胶浆大鼠口服 1^。及 95%可信限为： 0. 37g/kg (0. 32〜 0. 42g/kg) , 相当于推荐临床剂量的 222倍。
空白胶浆小鼠口服 LD「1()〉80ml/kg
动物实施例 3 本发明盐酸达克罗宁胶浆剂的粘膜刺激性试验
选择健康 SD大鼠 40只， 雌雄各半， 分成三组， 分别为对照组、 低剂量组 和高剂量组， 对照组 8只， 低剂量组和高剂量组各 16只， 分别一次灌胃给予生 理盐水、 1%盐酸达克罗宁胶浆 5ml/kg和 1%盐酸达克罗宁胶浆 10ml/kg， 于给药 后 1、 2、 8和 24h按分组分别将动物处死， 肉眼和显微镜观察口腔、 食道和胃 粘膜的变化， 结果表明， 本品灌胃 1、 2、 8和 24h后， 无论肉眼观察和病理镜 检均未发现对胃粘膜有明显的损伤， 是安全的。
应用例 1 本发明盐酸达克罗宁胶浆剂用于上消化道内窥镜检查的临床试验 上消化道内窥镜检查及治疗的门诊和住院病人 220例， 年齢 19〜79岁， 其 中男性 121例， 女性 99例。 采用随机双盲法将患者分成二组， 每组各 110例。 对照药物为盐酸利多卡因胶浆。 结果表明， 全部 220例入选患者均完成本次观 察， 两组病例的年龄、 性别及病种等基本相同。 盐酸达克罗宁胶浆组插镜及麻 醉效果的优良率为 93. 6% (103/110)， 祛泡效果的优良率为 91. 8°/。（101/110)， 优 于盐酸利多卡因胶桨组的 70. 9% (78/110)和 49. 1% (54/110)， 两组相比有显著差 异（P<0. 05 =。 盐酸达克罗宁胶浆组的显效率为 74. 5 (82/110)， 总有效率为 95. 5% (105/110)，明显优于盐酸利多卡因胶浆组的显效率 30. 9% (34/110)和总有 效率 63. 6% (70/110)， 二组相比具有显著性差异 (P<0. 05)。 二组在用药中均未 发现有明显的不良反应。
Claims
1、 一种盐酸达克罗宁口服制剂， 其特征是该制剂中主要成分的重量百分含 量为：盐酸达克罗宁 0. 2%〜3%，聚乙烯醇 1%〜12% ；甘油 1%〜12%， 消泡剂 1%〜 12%, 余量为药用辅料。
2、 根据权利要求 1所述的制剂， 其特征是该制剂中主要成分的优选重量百 分含量为： 盐酸达克罗宁 0. 5%〜1. 5%， 聚乙烯醇 3%〜8°/。； 甘油 2%〜6%， 消泡剂 2%〜6%， 余量为药用辅料。
3、 根据权利要求 1或 2所述的制剂， 其特征是所述消泡剂为 GPE、 BAPE或
MPE。
4、根据权利要求 1或 2所述的制剂， 其特征是该制剂为凝胶剂、溶液剂或糖 桨剂。
5、根据权利要求 1或 2所述的制剂，其特征是制剂的黏度在 30〜300mpa -s 之间， pH值为 2. 0〜8. 0。
6、 根据权利要求 5所述的制剂， 其特征是制剂的黏度在 50〜150mpa · s之 间， pH值为 2. 3〜5. 0。
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/914,681 US7696228B2 (en) | 2005-05-16 | 2006-01-13 | Oral preparation of dyclonine hydrochloride |
| CNA2006800144459A CN101166530A (zh) | 2005-05-16 | 2006-01-13 | 一种盐酸达克罗宁口服制剂 |
| EP06705470.0A EP1884241B1 (en) | 2005-05-16 | 2006-01-13 | A oral preparation comprising dyclonine hydrochloride |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510040093.1 | 2005-05-16 | ||
| CNA2005100400931A CN1729975A (zh) | 2005-05-16 | 2005-05-16 | 一种盐酸达克罗宁口服制剂 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006122462A1 true WO2006122462A1 (fr) | 2006-11-23 |
Family
ID=35962420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2006/000048 WO2006122462A1 (fr) | 2005-05-16 | 2006-01-13 | Preparation orale comprenant du chlorhydrate de dyclonine |
Country Status (4)
| Country | Link |
|---|---|
| US (1) | US7696228B2 (zh) |
| EP (1) | EP1884241B1 (zh) |
| CN (2) | CN1729975A (zh) |
| WO (1) | WO2006122462A1 (zh) |
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| CN103170016B (zh) * | 2013-04-19 | 2014-03-12 | 江苏迪沃生物制品有限公司 | 一种医用润滑剂 |
| CN106692036A (zh) * | 2017-01-19 | 2017-05-24 | 遂成药业股份有限公司 | 一种温敏型盐酸达克罗宁凝胶的制备方法 |
| CN110947008B (zh) * | 2019-12-20 | 2022-03-18 | 郑州弘新医疗科技有限公司 | 一种可口服盐酸奥布卡因胃镜润滑液及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US527032A (en) | 1894-10-02 | Brush-support | ||
| US4917894A (en) | 1988-06-29 | 1990-04-17 | Beecham Inc. | Rapid-onset long-duration oral anesthetic composition |
| US5055461A (en) | 1989-02-15 | 1991-10-08 | Richardson-Vicks Inc. | Anesthetic oral compositions and methods of use |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5276032A (en) * | 1989-12-28 | 1994-01-04 | King O Newton | Vision aid and anesthetic composition |
| US5814659A (en) * | 1996-04-23 | 1998-09-29 | Dtr Dermal Therapy (Barbados) Inc. | Topical analgesic composition |
-
2005
- 2005-05-16 CN CNA2005100400931A patent/CN1729975A/zh active Pending
-
2006
- 2006-01-13 CN CNA2006800144459A patent/CN101166530A/zh active Pending
- 2006-01-13 US US11/914,681 patent/US7696228B2/en active Active
- 2006-01-13 WO PCT/CN2006/000048 patent/WO2006122462A1/zh not_active Application Discontinuation
- 2006-01-13 EP EP06705470.0A patent/EP1884241B1/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US527032A (en) | 1894-10-02 | Brush-support | ||
| US4917894A (en) | 1988-06-29 | 1990-04-17 | Beecham Inc. | Rapid-onset long-duration oral anesthetic composition |
| US5055461A (en) | 1989-02-15 | 1991-10-08 | Richardson-Vicks Inc. | Anesthetic oral compositions and methods of use |
Non-Patent Citations (6)
| Title |
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| LU Z.-Y., CHIN PHARM J, vol. 32, no. 12, 31 December 1991 (1991-12-31), pages 749 - 750, XP008092600 * |
| See also references of EP1884241A4 * |
| XING S.-A. ET AL., ZHONG GUO YAO, vol. 6, no. 7, 31 December 2003 (2003-12-31), pages 421 - 422, XP008118843 * |
| YANG L. ET AL., JOURNAL OF SHENYANG PHARMACEUTICAL UNIVERSITY, vol. 17, no. 3, 31 May 2000 (2000-05-31), pages 174 - 175, AND 187, XP008092627 * |
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| YUAN Y.-F. ET AL., DI ER JUNYI DAXUE XUE BAO, vol. 10, 31 December 2000 (2000-12-31), pages 919, AND 923, XP008092751 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1884241A1 (en) | 2008-02-06 |
| US7696228B2 (en) | 2010-04-13 |
| US20080200506A1 (en) | 2008-08-21 |
| EP1884241B1 (en) | 2016-11-23 |
| EP1884241A4 (en) | 2010-07-07 |
| CN1729975A (zh) | 2006-02-08 |
| CN101166530A (zh) | 2008-04-23 |
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