CN117357473A - Propranolol preparation suitable for accurate administration and preparation method thereof - Google Patents
Propranolol preparation suitable for accurate administration and preparation method thereof Download PDFInfo
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- CN117357473A CN117357473A CN202311214475.6A CN202311214475A CN117357473A CN 117357473 A CN117357473 A CN 117357473A CN 202311214475 A CN202311214475 A CN 202311214475A CN 117357473 A CN117357473 A CN 117357473A
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- Prior art keywords
- bottle
- liquid medicine
- propranolol
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- liquid
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- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 229960003712 propranolol Drugs 0.000 title claims abstract description 67
- 238000002360 preparation method Methods 0.000 title claims abstract description 49
- 239000007788 liquid Substances 0.000 claims abstract description 94
- 239000003814 drug Substances 0.000 claims abstract description 71
- 238000004806 packaging method and process Methods 0.000 claims abstract description 15
- 238000012377 drug delivery Methods 0.000 claims abstract description 5
- 230000000149 penetrating effect Effects 0.000 claims abstract description 4
- 238000007789 sealing Methods 0.000 claims abstract description 4
- 238000007599 discharging Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 21
- MEAPRSDUXBHXGD-UHFFFAOYSA-N 3-chloro-n-(4-propan-2-ylphenyl)propanamide Chemical compound CC(C)C1=CC=C(NC(=O)CCCl)C=C1 MEAPRSDUXBHXGD-UHFFFAOYSA-N 0.000 claims description 19
- 235000003599 food sweetener Nutrition 0.000 claims description 19
- 229960004604 propranolol hydrochloride Drugs 0.000 claims description 19
- 239000003765 sweetening agent Substances 0.000 claims description 19
- 241001411320 Eriogonum inflatum Species 0.000 claims description 18
- -1 polyethylene Polymers 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 14
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 14
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 14
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 239000002562 thickening agent Substances 0.000 claims description 12
- 239000004698 Polyethylene Substances 0.000 claims description 10
- 229920000573 polyethylene Polymers 0.000 claims description 10
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 9
- 229940085605 saccharin sodium Drugs 0.000 claims description 9
- 239000004743 Polypropylene Substances 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 8
- 229920001155 polypropylene Polymers 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 229920000098 polyolefin Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012530 fluid Substances 0.000 claims description 4
- 239000012669 liquid formulation Substances 0.000 claims description 4
- 239000004033 plastic Substances 0.000 claims description 4
- 229920003023 plastic Polymers 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 229940081974 saccharin Drugs 0.000 claims description 4
- 235000019204 saccharin Nutrition 0.000 claims description 4
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 4
- 239000000892 thaumatin Substances 0.000 claims description 4
- 235000010436 thaumatin Nutrition 0.000 claims description 4
- 235000016623 Fragaria vesca Nutrition 0.000 claims description 3
- 240000009088 Fragaria x ananassa Species 0.000 claims description 3
- 235000011363 Fragaria x ananassa Nutrition 0.000 claims description 3
- 244000290333 Vanilla fragrans Species 0.000 claims description 3
- 235000009499 Vanilla fragrans Nutrition 0.000 claims description 3
- 235000012036 Vanilla tahitensis Nutrition 0.000 claims description 3
- 239000011521 glass Substances 0.000 claims description 3
- NUFKRGBSZPCGQB-FLBSXDLDSA-N (3s)-3-amino-4-oxo-4-[[(2r)-1-oxo-1-[(2,2,4,4-tetramethylthietan-3-yl)amino]propan-2-yl]amino]butanoic acid;pentahydrate Chemical compound O.O.O.O.O.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C.OC(=O)C[C@H](N)C(=O)N[C@H](C)C(=O)NC1C(C)(C)SC1(C)C NUFKRGBSZPCGQB-FLBSXDLDSA-N 0.000 claims description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- 239000004377 Alitame Substances 0.000 claims description 2
- 244000144730 Amygdalus persica Species 0.000 claims description 2
- 235000005979 Citrus limon Nutrition 0.000 claims description 2
- 244000131522 Citrus pyriformis Species 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 108050004114 Monellin Proteins 0.000 claims description 2
- 235000006040 Prunus persica var persica Nutrition 0.000 claims description 2
- QFVOYBUQQBFCRH-UHFFFAOYSA-N Steviol Natural products C1CC2(C3)CC(=C)C3(O)CCC2C2(C)C1C(C)(C(O)=O)CCC2 QFVOYBUQQBFCRH-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 239000004376 Sucralose Substances 0.000 claims description 2
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
- 229960004998 acesulfame potassium Drugs 0.000 claims description 2
- 239000000619 acesulfame-K Substances 0.000 claims description 2
- 235000019409 alitame Nutrition 0.000 claims description 2
- 108010009985 alitame Proteins 0.000 claims description 2
- MQRKKLAGBPVXCD-UHFFFAOYSA-L calcium;1,1-dioxo-1,2-benzothiazol-2-id-3-one;hydrate Chemical compound O.[Ca+2].C1=CC=C2C([O-])=NS(=O)(=O)C2=C1.C1=CC=C2C([O-])=NS(=O)(=O)C2=C1 MQRKKLAGBPVXCD-UHFFFAOYSA-L 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 229940043243 saccharin calcium Drugs 0.000 claims description 2
- 150000003839 salts Chemical group 0.000 claims description 2
- QFVOYBUQQBFCRH-VQSWZGCSSA-N steviol Chemical compound C([C@@]1(O)C(=C)C[C@@]2(C1)CC1)C[C@H]2[C@@]2(C)[C@H]1[C@](C)(C(O)=O)CCC2 QFVOYBUQQBFCRH-VQSWZGCSSA-N 0.000 claims description 2
- 229940032084 steviol Drugs 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims 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 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 abstract description 6
- 208000019505 Deglutition disease Diseases 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229940073935 propranolol oral solution Drugs 0.000 description 5
- 208000000884 Airway Obstruction Diseases 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000004891 communication Methods 0.000 description 3
- 238000010276 construction Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 201000011066 hemangioma Diseases 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 208000007888 Sinus Tachycardia Diseases 0.000 description 1
- 208000003734 Supraventricular Tachycardia Diseases 0.000 description 1
- 241000368272 Symeria Species 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000001746 atrial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 208000001969 capillary hemangioma Diseases 0.000 description 1
- 238000000315 cryotherapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000013532 laser treatment Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000008155 medical solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- ZMRUPTIKESYGQW-UHFFFAOYSA-N propranolol hydrochloride Chemical compound [H+].[Cl-].C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 ZMRUPTIKESYGQW-UHFFFAOYSA-N 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000003229 sclerosing agent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 206010055031 vascular neoplasm Diseases 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000013585 weight reducing agent Substances 0.000 description 1
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/1412—Containers with closing means, e.g. caps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Hematology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a propranolol preparation suitable for accurate administration and a preparation method thereof, wherein the preparation comprises a liquid medicine containing propranolol with the mass concentration of 1-2%; the liquid medicine is packaged by adopting a packaging assembly capable of realizing accurate drug delivery, and the packaging assembly comprises a bottle for containing the liquid medicine, a drop plug matched with a bottle opening and a pressure screwing cover; the drip plug comprises a bottle plug main body part and a drip tube penetrating through the bottle plug main body part, wherein the bottle plug main body part is used for being tightly connected with a bottle opening and sealing the bottle opening, the inside and the outside of the drip tube are communicated with each other for discharging liquid, and after the pressure screw cap is opened and the bottle opening is vertically and downwards inverted, the liquid medicine in the bottle can be automatically dripped out along the drip tube one by one; preferably, the volume of each drop of the liquid medicine automatically dropped by the dropper is 0.045-0.055 mL, and the average dropping speed is not more than 2.5 drops/s. The propranolol preparation can realize accurate administration, has small single administration volume, and can effectively avoid the situations of dysphagia of children patients or choking and spitting of medicines of children patients.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a propranolol preparation suitable for accurate administration and a preparation method thereof.
Background
Propranolol, chemical name 1-isopropylamino-3- (1-naphthoxy) -2-propanol hydrochloride, molecular formula C 16 H 21 NO 2 . Propranolol can be used for treating arrhythmia caused by various reasons, such as atrial and ventricular premature beat (good effect), sinus and supraventricular tachycardia, atrial fibrillation and the like, and is the earliest beta receptor blocker applied to clinic.
Infant Hemangiomas (IH) are the most common pediatric vascular tumor, with a incidence of about 2% -4%, symptoms usually not apparent at birth, become apparent within 3-6 weeks after birth, and grow rapidly for the next 4-5 months. While IH has a unique feature of self-recovery after one year of birth, up to 10% of IH cases can lead to complications such as ulcers, bleeding, etc.; if IH causes dangerous symptoms such as infection, airway obstruction, vision disturbance and the like, interventional therapy needs to be considered; the current common treatment methods include surgical excision, radiation treatment, cryotherapy, laser treatment, sclerosant injection and the like, and comprehensive therapy is generally adopted.
In 2008 c.laue-labreze et al reported that beta-blockers (e.g. propranolol) can be effectively used to control and even treat the growth of capillary hemangiomas in infants. In 2014 Pierre Faber company has proposed the hydrochloric acid propranolol oral solution specially used for treating infant hemangioma, and has appeared corresponding domestic hydrochloric acid propranolol oral solution in 2021 (Hemeijia (hydrochloric acid propranolol oral solution [ 120mL:450mg (calculated by propranolol) ] developed by Hubei Wuhan Koch Foenical) is marketed) in batches, however, in order to meet the requirement of medication, the present commercial hydrochloric acid propranolol oral solution is administered once with a volume exceeding 2mL, the situation that dysphagia of the infant or cough of the infant is choked easily occurs in a single administration volume, thereby affecting the drug effect.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the propranolol preparation suitable for accurate administration and the preparation method thereof, and the propranolol preparation can realize accurate administration, has small single administration volume and can effectively avoid the situations of dysphagia of children patients or choking and spitting of the children patients.
The aim of the invention is achieved by the following technical scheme:
in a first aspect, the present invention provides a propranolol formulation suitable for precise administration, the formulation comprising a liquid formulation comprising propranolol at a mass concentration of 1% to 2%; the liquid medicine is packaged by adopting a packaging assembly capable of realizing accurate drug delivery, and the packaging assembly comprises a bottle for containing the liquid medicine, a drop plug matched with a bottle opening and a pressure screwing cover; the drip plug comprises a bottle plug main body part and a drip tube penetrating through the bottle plug main body part, wherein the bottle plug main body part is used for being tightly connected with a bottle opening and sealing the bottle opening, the inside and outside of the drip tube are communicated with each other for discharging liquid, and after the pressure screw cap is opened and the bottle opening is vertically and downwards inverted, the liquid medicine in the bottle can be automatically dripped out drop by drop along the drip tube.
In some embodiments of the invention, the mass concentration of propranolol in the liquid medicine is 1.5% -2%, such as: 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%.
In some embodiments of the invention, the volume of each drop of liquid medicine automatically dropped by the dropper is 0.045-0.055 mL, preferably 0.050mL; the average drop velocity is not more than 2.5 drops/s, preferably not more than 2 drops/s; preferably, the average dropping speed is not less than 1 drop/2 s.
In some embodiments of the invention, the size of the liquid outlet of the dropper is greater than or equal to the size of the liquid inlet of the dropper. Wherein, the liquid inlet hole is an opening for enabling the liquid medicine to enter the dropper from the bottle after the bottle mouth is vertically inverted downwards; the liquid outlet is an opening for the liquid medicine to drop out from the dropper after the bottle mouth is vertically inverted downwards.
In some embodiments of the invention, the size of the liquid inlet hole of the dropper is 0.03-0.6 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the liquid inlet of the dropper is a round hole; more preferably, the diameter of the circular hole is 0.2 to 0.8mm, preferably 0.25 to 0.6mm.
In some embodiments of the invention, the size of the liquid outlet of the dropper is 0.1-30 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the liquid outlet of the dropper is circular; more preferably, the diameter of the circular outlet is 0.5-6 mm, preferably 2-5 mm.
In some embodiments of the invention, the dropper is a circular long tube, the smallest end of the circular long tube is provided with a liquid inlet, and the diameter of the smallest end of the circular long tube is larger than or equal to the diameter of the liquid inlet; the maximum end of the circular long tube is provided with a liquid outlet, and the diameter of the maximum end of the circular long tube is larger than or equal to the diameter of the liquid outlet.
In some embodiments of the invention, the dropper has a material thickness of 0.01 to 2mm; preferably 0.1 to 1mm.
Wherein the diameter of the smallest or largest end of the circular elongated tube refers to the inner diameter of the thickness of the material that does not include the circular elongated tube.
In some embodiments of the invention, the length of the outer end of the dropper beyond the main body portion of the bottle stopper is 0.5-3 mm.
In some embodiments of the invention, the length of the inner end of the dropper beyond the main body portion of the bottle stopper is 0-0.5 mm; preferably, the inner end of the drip tube is flush with the stopper body portion.
In some embodiments of the invention, the drip plug further comprises a vent tube, wherein the vent tube is communicated with the inside and the outside of the bottle for balancing the atmospheric pressure inside and outside the bottle.
In some embodiments of the invention, the size of the air inlet of the vent pipe is greater than or equal to the size of the air outlet. Wherein the air inlet is an opening for air to enter the vent pipe from outside the bottle; the air outlet hole is an opening for air to enter the bottle from the vent pipe.
In some embodiments of the invention, the vent hole of the vent pipe has a size of 1-1.5 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the air outlet hole of the vent pipe is a square hole, and the length of the square hole is preferably 1.68+/-0.05 mm and the width of the square hole is preferably 0.73+/-0.05 mm.
In some embodiments of the invention, the vent pipe is an umbrella-shaped circular long pipe, the minimum end of the umbrella-shaped circular long pipe is provided with an air outlet, and the maximum end of the umbrella-shaped circular long pipe is provided with an air inlet; preferably, the air inlet of the vent pipe is umbrella-shaped circular ring; more preferably, the area of the umbrella-shaped annular air inlet is equal to the area of the largest end of the umbrella-shaped annular long tube.
In some embodiments of the invention, the vent tube has a material thickness of 0.01-2 mm; preferably 0.1 to 1mm.
Wherein, the area of the largest end of the umbrella-shaped annular long tube refers to the area of the inner hole which does not comprise the thickness of the umbrella-shaped annular long tube.
In some embodiments of the invention, the length of the inner end of the vent tube beyond the body portion of the stopper is (1/4-3/4) (body length-neck length).
In some embodiments of the invention, the length of the outer end of the vent tube beyond the body portion of the stopper is 0 to 0.5mm.
In some embodiments of the invention, the vent tube is not in communication with the drip tube.
In some embodiments of the invention, the diameter ratio of the bottle body to the bottle neck is 1:1-3:1, and the height ratio is 2:1-4:1.
In some embodiments of the invention, the bottle stopper main body part comprises a part I which is jointed with the bottle mouth and a part II which is jointed with the inner diameter of the bottle neck; wherein the diameter of the part I is larger than the outer diameter D of the bottle mouth, and the diameter of the part II is equal to the inner diameter D of the bottle neck; preferably, the diameter of the portion i=d+ (1-4) mm, more preferably d=8-18 mm, preferably d=10-15 mm; further preferably, d=d- (0.2 to 3) mm.
In some embodiments of the present invention, the bottle stopper main body further comprises a portion iii having a diameter smaller than the inner diameter of the bottle neck, the portion iii being connected to the portion ii and being remote from the portion i, i.e., the bottle stopper main body comprises a three-stage structure of portion iii, portion ii, and portion i connected in sequence; preferably, the diameter of the smallest end of portion iii = d- (0.2-3) mm; more preferably, the diameter of the largest end of portion iii = d.
In some embodiments of the invention, the height of the bottle stopper body portion is 4 to 18mm, preferably 5 to 16mm; preferably, the height of the part I is 0.8-2.4 mm, and/or the height of the part II is 3-16 mm, and/or the height of the part III is 2-10 mm.
In some embodiments of the invention, the thickness of the material of the part III, the part II and the part I is independently 0.01-3 mm; preferably 0.1 to 2mm.
The diameters of the part III, the part II and the part I refer to the diameters after the thickness of the materials.
In some embodiments of the invention, the outer diameter d=13 mm of the bottle mouth of the bottle, the inner diameter d=12 mm of the neck of the bottle; the diameter of the part I is 14.6mm, the height is 1.6mm, the diameter of the part II is 12mm, the height is 5.8mm, the diameter of the largest end of the part III is 12mm, the diameter of the smallest end is 10.8mm, and the height is 6.2mm.
In some embodiments of the invention, the stopper body portion is a stopper having a hollow interior and protruding toward the interior of the bottle; namely, when the main body part of the bottle stopper only comprises a part II and a part I, the structure of the part II close to the bottle opening and the structure of the part I are annular, and a plugging layer is arranged only at the innermost side of the part II extending to the bottle; when the main body part of the bottle plug only comprises a part III, a part II and a part I, the structure of the part III close to the bottle opening, the structure of the part II and the structure of the part I are all annular, and a plugging layer is arranged on the innermost side of the bottle extending to the part III.
In some embodiments of the invention, the inner end of the drip tube extends through and is flush with the stopper layer.
In some embodiments of the invention, the outermost end of the vent tube is connected to the stopper layer and communicates with the hollow structure of the body portion of the stopper so that internal and external communication is achieved through the vent tube to balance the atmospheric pressure inside and outside the bottle when the drip stopper is inserted into the bottle.
In some embodiments of the present invention, the drip plug is made of polyolefin, preferably polyethylene, polypropylene or a mixture of polyethylene and polypropylene.
In some embodiments of the invention, the bottle is made of plastic or glass.
In some embodiments of the present invention, the material of the press-and-screw cap is plastic, preferably polyolefin; preferably, the polyolefin is polyethylene, polypropylene or a mixture of polyethylene and polypropylene.
In some embodiments of the invention, the medical fluid further comprises a thickener; preferably, the thickener is hydroxyethyl cellulose, preferably more than one type of hydroxyethyl cellulose selected from the group consisting of 250L, 250 HHHX, 250HX, 250G and 250M, more preferably more than one type of hydroxyethyl cellulose selected from the group consisting of 250HHX, 250HX and 250M; more preferably, the dosage of the hydroxyethyl cellulose in the liquid medicine is between 0.1 and 6mg/mL, and more preferably between 0.1 and 5 mg/mL.
In some embodiments of the invention, the liquid medicine further comprises a sweetener; preferably, the sweetener is a non-sugar sweetener; more preferably, the non-sugar sweetener is selected from more than one of saccharin, saccharin salts, sucralose, acesulfame potassium, stevioside, steviol, mannitol, erythritol, lactitol, maltitol, alitame, thaumatin, monellin, and thaumatin.
In some embodiments of the invention, the amount of sweetener in the liquid formulation is between 2 and 9 mg/mL.
In some embodiments of the invention, the non-sugar sweetener is a salt of saccharin; preferably, the saccharin salt comprises saccharin sodium, saccharin calcium; more preferably, the sweetener included in the medical fluid is sodium saccharin; further preferably, the amount of saccharin sodium in the medical solution is between 2 and 8mg/mL, preferably between 2 and 6mg/mL, such as 2mg/mL, 3mg/mL, 4mg/mL, 5mg/mL or 6mg/mL.
In some embodiments of the invention, the medicinal solution further comprises a fragrance; preferably, the essence is selected from more than one of strawberry essence, vanilla essence, peach essence and lemon essence.
In some embodiments of the invention, the amount of essence in the liquid medicine is between 0.01 and 0.1 mg/mL.
In some embodiments of the present invention, each bottle of propranolol formulation has 1 dosage unit of 10 drops of the drug solution from the dropper, and the weight of each dose of drug solution must not be 1 dose exceeding the average weight of 1 dosage unit of the bottle of propranolol formulation by + -10% or 1 dose exceeding the indicated amount by + -15%.
In a second aspect, the present invention provides a method for preparing a propranolol preparation according to the first aspect, wherein the method comprises packaging a liquid medicine containing propranolol with a mass concentration of 1% -2% by using a packaging assembly capable of achieving accurate administration. The preparation method of the liquid medicine comprises the following steps:
(1) Dissolving propranolol hydrochloride in water to prepare a liquid medicine containing propranolol with the mass concentration of 1-2%;
optionally, (2) adjusting the pH value of the liquid medicine to 2.5-4.0; preferably, citric acid is used for regulating the pH value of the liquid medicine to 2.5-4.0.
Preferably, the thickener is added into water first, and propranolol hydrochloride is added after the thickener is dissolved.
More preferably, the preparation method of the liquid medicine further comprises the steps of adding the sweetener and then adding propranolol hydrochloride after the thickener is dissolved.
Further preferably, the preparation method of the liquid medicine further comprises adding essence after the propranolol hydrochloride is dissolved.
In some embodiments of the present invention, the method of preparing the medical fluid includes the steps of:
(S1) adding a thickening agent into water, stirring and dissolving, and then adding a sweetener;
(S2) taking propranolol hydrochloride, adding the propranolol hydrochloride into the solution obtained in the step (S1), and stirring for dissolution;
(S3) adding essence and adjusting the pH value of the liquid medicine to 2.5-4.0 by using citric acid.
The beneficial effects of the invention are as follows:
the invention provides a propranolol preparation suitable for accurate administration, which comprises a liquid medicine containing low-concentration propranolol with the mass concentration of 1-2%, wherein the liquid medicine is packaged by a packaging component capable of realizing accurate administration, the accurate administration can be realized, the administration volume of applicable people can be controlled within 10 drops, namely, the single administration volume is not more than 0.5mL, the physiological characteristics of infants and young children are met, choking cough caused by the overlarge administration volume is avoided, the administration effectiveness is further ensured, and the compliance of administration is improved.
The viscosity of the propranolol liquid medicine can be regulated and controlled by adding the thickening agent, so that the average dropping speed of the liquid medicine is controlled within a proper range, the choking situation caused by the excessively high dropping speed is avoided, and the medicine preparation meets the medicine prescription in pharmacopoeia; meanwhile, the influence on the use experience of the patient due to the too slow dropping speed can be avoided. In addition, proper amount of sweetener can be added into the propranolol liquid medicine to cover the bitter taste of propranolol hydrochloride, so that the taste of the propranolol liquid medicine is improved, and the medicine taking compliance of patients is improved.
The packaging assembly provided by the invention has a simple structure, the packaging of the liquid medicine is realized through the drip plug and the pressure rotary cover, and the special structural design and the size design of the drip plug enable the liquid medicine in the bottle to automatically drip out along the dropper drop by drop when the bottle mouth is opened to vertically and downwards invert the pressure rotary cover, so that the medicine metering and the medicine feeding are not needed through an additional medicine feeder, and the medicine feeding is more convenient and more accurate.
The propranolol liquid medicine disclosed by the invention is simple in preparation process, simple in structure of a packaging assembly, favorable for realizing industrial production, and good in development prospect in the aspect of preparing a propranolol preparation which can be applied to accurate administration, especially a propranolol preparation which is applied to infant administration.
Drawings
Fig. 1 shows a physical view of a typical construction of a packaging assembly of the present invention.
Fig. 2 shows a block diagram of a typical construction of the drip plug of the present invention, including front, top and bottom views of the drip plug when placed upside down.
Fig. 3 shows a block diagram of an exemplary construction of a drop plug of the present invention, including a front view of the drop plug when placed horizontally.
Fig. 4 shows a physical view (inverted) of a typical structure of the drip plug of the present invention.
Fig. 5 shows a physical view (horizontally placed) of a typical structure of a drop plug of the present invention.
Fig. 6 shows a trend of the concentration of propranolol hydrochloride versus the solubility of saccharin sodium.
Detailed Description
The technique of the present invention is further illustrated by the following examples. These examples are illustrative and exemplary of the invention and are not intended to limit the scope of the invention in any way.
Example 1
A package assembly for achieving accurate administration, an actual view of which is shown in fig. 1; a typical structure of the drop plug is shown in figures 2-3, and a physical diagram is shown in figures 4-5, wherein the dimension units in figures 2-3 are all mm.
The package assembly comprises a bottle for containing liquid medicine, a drop plug matched with the bottle mouth and a pressing and screwing cover, and is shown in figure 1. The drop plug comprises a bottle plug main body part, a dropper penetrating through the bottle plug main body part and a breather pipe, as shown in figures 2-5; the bottle stopper main body part is used for being tightly connected with the bottle opening and sealing the bottle opening, the inside and outside of the dropper is communicated with the liquid outlet, the inside and outside of the air pipe is communicated with the inside and outside of the air pipe to balance the atmospheric pressure inside and outside the bottle, and after the pressure screw cap is opened and the bottle opening is vertically inverted downwards, the liquid medicine in the bottle can automatically drip out drop by drop along the dropper.
The diameter ratio of the bottle body to the bottle neck of the bottle is 2:1, and the height ratio is 3:1.
The bottle stopper main body part comprises a part I which is jointed with the bottle mouth, a part II which is jointed with the inner diameter of the bottle neck, and a part III which is smaller than the inner diameter of the bottle neck; the part III is connected with the part II and is far away from the part I, namely the main body part of the bottle stopper comprises a part III, a part II and a part I which are sequentially connected from inside to outside (one side close to the pressure rotating cover is the outside).
The outer diameter D=13 mm of the bottle mouth of the bottle, the inner diameter d=12 mm of the bottle neck, and the height of the bottle neck is 12mm; the diameter of the part I is 14.6mm, the height is 1.6mm, the diameter of the part II is 12mm, the height is 5.8mm, the diameter of the largest end of the part III is 12mm, the diameter of the smallest end is 10.8mm, and the height is 6.2mm.
The bottle stopper main body part is a plug with a hollow structure and protrudes towards the inside of the bottle; namely, the structure of the part III close to the bottle mouth, the structure of the part II and the structure of the part I are all annular, and a plugging layer is arranged only on the innermost side of the part III extending to the bottle.
The dropper is a circular long tube, and the central axis of the circular long tube is overlapped with the central axis of the bottle plug main body part. The smallest end of the circular long tube is provided with a liquid inlet, and the diameter of the smallest end of the circular long tube is equal to the diameter of the liquid inlet; the maximum end of the circular long tube is provided with a liquid outlet, and the diameter of the maximum end of the circular long tube is equal to the diameter of the liquid outlet. The liquid inlet of the dropper is a round hole with the diameter of 0.28mm; the liquid outlet of the dropper is circular, and the diameter of the circular liquid outlet is 4mm. The length of the outer end of the dropper, which exceeds the main body part of the bottle stopper, is 1.5mm; the inner end of the dropper is flush with the main body part of the bottle plug, namely the inner end of the dropper penetrates through the plugging layer of the part III and is flush with the plugging layer.
The vent pipe is an umbrella-shaped annular long straight pipe, the innermost end of the umbrella-shaped annular long straight pipe is provided with an air outlet, and the outermost end of the umbrella-shaped annular long straight pipe is provided with an air inlet. The outermost end of the umbrella-shaped annular long straight tube is connected with the part III of the plugging layer and is communicated with the hollow structure of the main body part of the bottle stopper, so that when the drip stopper is inserted into the bottle, the internal and external communication of the bottle can be realized through the vent pipe to balance the internal and external atmospheric pressure of the bottle. The air inlet is umbrella-shaped circular ring, and the area of the umbrella-shaped circular ring air inlet is equal to the opening area of the outermost end of the umbrella-shaped circular ring long straight bobbin; the diameter of the umbrella-shaped annular air inlet corresponding to the small circular arc is 5mm, the diameter of the large circular arc corresponding to the large circular arc is 10mm, and the angles of the circular arcs are 60 degrees. The air outlet holes are square holes, and the length of each square hole is 1.68mm and the width of each square hole is 0.73mm. The length of the inner end of the vent pipe exceeding the main body part of the bottle stopper is 10.5mm.
The vent pipe is not communicated with the dropper.
The drip plug is made of polyethylene.
The bottle is made of glass.
The pressing and screwing cover is made of polyethylene.
Example 2
A propranolol formulation suitable for precise administration, wherein the formulation of a propranolol drug solution is as follows:
the preparation method of the propranolol liquid medicine comprises the following steps:
(S1) adding hydroxyethyl cellulose into purified water, stirring and dissolving, and then adding saccharin sodium;
(S2) taking propranolol hydrochloride, adding the propranolol hydrochloride into the solution obtained in the step (S1), and stirring for dissolution;
(S3) adding strawberry essence and vanilla essence, and regulating the pH value of the liquid medicine to 2.5-4.0 by using citric acid.
And filling the obtained propranolol liquid medicine into a bottle in the embodiment 1, inserting a drop plug, covering a pressure screw cap, and obtaining a propranolol preparation finished product.
The finished product of the propranolol preparation prepared by the method is opened, the bottle mouth is vertically inverted downwards, the volume of each drop of propranolol liquid automatically dropped by the dropper is about 0.05mL, the average dropping speed is not more than 2 drops/s, and the average dropping speed is not less than 1 drop/2 s.
Example 3
Taking the propranolol preparation finished product prepared in the embodiment 2 of the invention, opening a press-screwing cap, vertically inverting a bottle mouth downwards to naturally drop out a plurality of drops, discarding, naturally dropping out 10 drops (1 dose unit), precisely weighing the total weight of the 10 drops of liquid medicine, repeating the operation for 9 times, and calculating the average weight of 10 doses, thereby obtaining the dose uniformity of the propranolol preparation finished product, and the result is shown in Table 1.
TABLE 1 determination of dose uniformity of Propranolol formulation finished product
Taking a propranolol preparation finished product prepared in the embodiment 2 of the invention, opening a press-screwing cap, vertically inverting the bottle mouth downwards to naturally drip out a plurality of drops, and discarding the drops; then naturally dropping 10 drops (single maximum dose) and simultaneously counting by a stopwatch; continuously operating for three times, and calculating the average dropping speed; two additional bottles of propranolol preparation finished products were taken, the average dropping speed of each bottle of propranolol preparation finished products was calculated by the same method, and the results are shown in Table 2.
TABLE 2 average drop velocity measurement results for Propranolol formulation finished products
Example 4
The amounts of hydroxyethylcellulose of the model 250HHX, 0mg/mL, 0.4mg/mL, 1mg/mL and 3.5mg/mL of propranolol liquid medicine were prepared respectively by the amounts and the preparation methods according to the prescription of the example 2, and the viscosities of the propranolol liquid medicines and the average dropping speeds of the propranolol preparations were measured, and the results are shown in the following Table 3.
TABLE 3 viscosity of propranolol liquid medicine and average dropping speed of propranolol preparation prepared by different dosage of hydroxyethyl cellulose
Example 5
The viscosities of the propranolol solutions and the average dropping speeds of the propranolol preparations were measured using 250L, 250HX, 250G, and 250M hydroxyethylcellulose instead of 250HHX hydroxyethylcellulose in example 2, respectively, and the results are shown in Table 4 below.
TABLE 4 viscosity of propranolol liquid medicine and average dropping speed of propranolol preparation prepared from different types of hydroxyethyl cellulose
| Hydroxyethyl cellulose model (dosage) | Viscosity of liquid medicine (cp) | Average drop velocity (drop/second) |
| 250L(6mg/mL) | 2.73cp | 1.54 |
| 250HX(0.8mg/mL) | 3.41cp | 1.49 |
| 250G(2mg/mL) | 2.78cp | 1.63 |
| 250HHX(0.4mg/mL) | 2.25cp | 1.31 |
| 250M(0.5mg/mL) | 2.11cp | 1.49 |
Example 6
The inventors of the present invention found that when sodium saccharin is used as a sweetener, the solubility of sodium saccharin is affected by the concentration of propranolol hydrochloride, and therefore examined the mutual solubility of sodium saccharin and propranolol hydrochloride by the following method:
adding saccharin sodium into 25mL of propranolol hydrochloride solution with different concentrations by adopting a weight reduction method, and calculating the amount of the saccharin sodium added at the moment when the solution is just turbid; according to experiments, when the concentrations of propranolol hydrochloride are 34.2mg/mL, 27.36mg/mL, 25.08mg/mL, 22.8mg/mL, 15.96mg/mL, 13.68mg/mL, 11.40mg/mL, 5.70mg/mL, 4.30mg/mL and 2.85mg/mL, the solubility of saccharin sodium is 12.98mg/mL, 10.12mg/mL, 9.40mg/mL, 8.00mg/mL, 4.84mg/mL, 4.08mg/mL, 3.04mg/mL, 4.60mg/mL, 7.09mg/mL and 7.57mg/mL respectively; the relationship between the concentration of propranolol hydrochloride and the solubility of saccharin sodium is shown in figure 6.
Example 7
Taking a propranolol preparation finished product prepared in the embodiment 2 of the invention, and standing for 0 month, 1 month, 2 months, 3 months and 6 months at 40 ℃; meanwhile, taking the propranolol preparation finished product prepared in the embodiment 2 of the invention, and placing the propranolol preparation finished product at 25 ℃ and 30 ℃ for 0 month, 3 months and 6 months; the stability of the propranolol preparation finished product after being stored for different times under different environments is then measured, and the results of the detected impurities and the content thereof, the propranolol content, the property and pH value of the propranolol liquid medicine, the dose uniformity and the average dropping speed of the propranolol preparation finished product are shown in Table 5.
Table 5 results of stability investigation of propranolol formulations
In table 5, "ND" means "undetected", and "NA" means "undetected".
Example 8
The final product of propranolol preparation prepared in example 2 of the present invention was compared with a propranolol oral solution of resultant Symeria hydrochloride (120 mL:450mg (as propranolol) in the specification) and the results are shown in Table 6 below.
Table 6 dosing comparison results
Therefore, the finished propranolol preparation can be used for drug delivery, and more accurate drug delivery can be realized.
It should be noted that the above-described embodiments are only for explaining the present invention and do not constitute any limitation of the present invention. The invention has been described with reference to the embodiments, but it should be understood that the words which have been used are words of description and illustration, rather than words of limitation. Modifications may be made to the invention as defined in the appended claims, and the invention may be modified without departing from the scope and spirit of the invention. Although the invention is described herein with reference to particular means, materials and embodiments, the invention is not intended to be limited to the particulars disclosed herein, as the invention extends to all other means and applications which perform the same function.
Claims (10)
1. The propranolol preparation suitable for accurate administration is characterized by comprising a liquid medicine containing propranolol with the mass concentration of 1-2%; the liquid medicine is packaged by adopting a packaging assembly capable of realizing accurate drug delivery, and the packaging assembly comprises a bottle for containing the liquid medicine, a drop plug matched with a bottle opening and a pressure screwing cover; the drip plug comprises a bottle plug main body part and a drip tube penetrating through the bottle plug main body part, wherein the bottle plug main body part is used for being tightly connected with a bottle opening and sealing the bottle opening, the inside and outside of the drip tube are communicated with each other for discharging liquid, and after the pressure screw cap is opened and the bottle opening is vertically and downwards inverted, the liquid medicine in the bottle can be automatically dripped out drop by drop along the drip tube.
2. The formulation according to claim 1, wherein the volume of each drop of liquid medicine automatically dropped by the dropper is 0.045-0.055 mL, preferably 0.050mL; the average drop velocity is not more than 2.5 drops/s, preferably not more than 2 drops/s;
and/or the size of the liquid outlet of the dropper is larger than or equal to the size of the liquid inlet hole of the dropper, preferably, the size of the liquid inlet hole of the dropper is 0.03-0.6 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the liquid inlet of the dropper is a round hole; more preferably, the diameter of the circular hole is 0.2 to 0.8mm, preferably 0.25 to 0.6mm;
and/or the drop plug further comprises a vent pipe, wherein the inside and the outside of the vent pipe are communicated with each other to balance the atmospheric pressure inside and outside the bottle; preferably, the size of the air inlet of the vent pipe is larger than or equal to the size of the air outlet hole, preferably, the size of the air outlet hole of the vent pipe is 1-1.5 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the More preferably, the air outlet hole of the air pipe is a square hole, preferably, the length of the square hole1.68 plus or minus 0.05mm wide by 0.73 plus or minus 0.05mm;
and/or the diameter ratio of the bottle body to the bottle neck is 1:1-3:1, and the height ratio is 2:1-4:1.
3. The formulation according to claim 2, wherein the length of the outer end of the dropper beyond the main body portion of the bottle stopper is 0.5-3 mm;
and/or the size of the liquid outlet of the dropper is 0.1-30 mm 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the liquid outlet of the dropper is circular; more preferably, the diameter of the circular liquid outlet is 0.5-6 mm, preferably 2-5 mm;
and/or the dropper is a circular long tube, the smallest end of the circular long tube is provided with a liquid inlet, and the diameter of the smallest end of the circular long tube is larger than or equal to the diameter of the liquid inlet; the largest end of the circular long tube is provided with a liquid outlet, and the diameter of the largest end of the circular long tube is larger than or equal to the diameter of the liquid outlet;
and/or the length of the inner end of the vent pipe exceeding the main body part of the bottle stopper is (1/4-3/4) (length of bottle body-length of bottle neck);
and/or the vent pipe is an umbrella-shaped annular long pipe, the minimum end of the umbrella-shaped annular long pipe is provided with an air outlet, and the maximum end of the umbrella-shaped annular long pipe is provided with an air inlet; preferably, the air inlet of the vent pipe is umbrella-shaped circular ring; more preferably, the area of the umbrella-shaped annular air inlet is equal to the area of the largest end of the umbrella-shaped annular long tube.
4. A formulation according to any one of claims 1 to 3, wherein the stopper body portion comprises a portion i which conforms to the neck of the bottle and a portion ii which conforms to the inner diameter of the neck of the bottle; wherein the diameter of the part I is larger than the outer diameter D of the bottle mouth, and the diameter of the part II is equal to the inner diameter D of the bottle neck; preferably, the diameter of portion i = d+ (1-4) mm; more preferably, d=8 to 18mm, preferably d=10 to 15mm; further preferably, d=d- (0.2 to 3) mm;
and/or the height of the main body part of the bottle stopper is 4-18 mm, preferably 5-16 mm.
5. The formulation of claim 4, wherein the height of the portion i is 0.8-2.4 mm;
and/or the height of the part II is 3-16 mm;
and/or the bottle stopper main body part further comprises a part III with a diameter smaller than the inner diameter of the bottle neck, and the part III is connected with the part II and is far away from the part I; preferably, the diameter of the smallest end of portion iii = d- (0.2-3) mm; more preferably, the height of said portion III is between 2 and 10mm.
6. The formulation according to any one of claims 1 to 5, wherein the plug is made of a polyolefin, preferably polyethylene, polypropylene or a mixture of polyethylene and polypropylene;
and/or the bottle is made of plastic or glass;
and/or the material of the pressure spiral cover is plastic, preferably polyolefin; preferably, the polyolefin is polyethylene, polypropylene or a mixture of polyethylene and polypropylene.
7. The formulation of any one of claims 1-6, further comprising a thickener in the liquid formulation; preferably, the thickener is hydroxyethyl cellulose, preferably more than one type of hydroxyethyl cellulose selected from 250L, 250HHX, 250HX, 250G and 250M; more preferably, the dosage of the hydroxyethyl cellulose in the liquid medicine is between 0.1 and 6mg/mL.
8. The formulation of any one of claims 1-7, wherein the liquid formulation further comprises a sweetener and optionally a flavoring; preferably, the method comprises the steps of,
the sweetener is a non-sugar sweetener; more preferably, the non-sugar sweetener is selected from more than one of saccharin, saccharin salts, sucralose, acesulfame potassium, stevioside, steviol, mannitol, erythritol, lactitol, maltitol, alitame, thaumatin, monellin, and thaumatin;
and/or the essence is selected from more than one of strawberry essence, vanilla essence, peach essence and lemon essence.
9. The formulation of claim 8, wherein the non-sugar sweetener is a salt of saccharin; preferably, the saccharin salt comprises saccharin sodium, saccharin calcium; more preferably, the sweetener included in the medical fluid is sodium saccharin;
and/or the dosage of the sweetener in the liquid medicine is 2-9 mg/mL;
and/or the dosage of the essence in the liquid medicine is 0.01-0.1 mg/mL.
10. The preparation method of the propranolol preparation according to any one of claims 1 to 9, which is characterized in that the preparation method comprises the steps of packaging a liquid medicine containing propranolol with a mass concentration of 1 to 2 percent by adopting a packaging assembly capable of realizing accurate administration; preferably, the preparation method of the liquid medicine comprises the following steps:
(1) Dissolving propranolol hydrochloride in water to prepare a liquid medicine containing propranolol with the mass concentration of 1-2%;
optionally, (2) adjusting the pH value of the liquid medicine to 2.5-4.0; preferably, citric acid is used for regulating the pH value of the liquid medicine to 2.5-4.0;
preferably, firstly adding a thickener into water, and then adding propranolol hydrochloride after the thickener is dissolved;
more preferably, the preparation method of the liquid medicine further comprises the steps of adding a sweetener and then propranolol hydrochloride after the thickener is dissolved;
further preferably, the preparation method of the liquid medicine further comprises adding essence after the propranolol hydrochloride is dissolved.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311214475.6A CN117357473A (en) | 2023-09-19 | 2023-09-19 | Propranolol preparation suitable for accurate administration and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311214475.6A CN117357473A (en) | 2023-09-19 | 2023-09-19 | Propranolol preparation suitable for accurate administration and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117357473A true CN117357473A (en) | 2024-01-09 |
Family
ID=89390191
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311214475.6A Pending CN117357473A (en) | 2023-09-19 | 2023-09-19 | Propranolol preparation suitable for accurate administration and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117357473A (en) |
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2023
- 2023-09-19 CN CN202311214475.6A patent/CN117357473A/en active Pending
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