CN110693816B - Loratadine nasal cavity in-situ gel and preparation method thereof - Google Patents
Loratadine nasal cavity in-situ gel and preparation method thereof Download PDFInfo
- Publication number
- CN110693816B CN110693816B CN201910980892.9A CN201910980892A CN110693816B CN 110693816 B CN110693816 B CN 110693816B CN 201910980892 A CN201910980892 A CN 201910980892A CN 110693816 B CN110693816 B CN 110693816B
- Authority
- CN
- China
- Prior art keywords
- gel
- loratadine
- nasal cavity
- gellan gum
- nasal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960003088 loratadine Drugs 0.000 title claims abstract description 61
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 238000011065 in-situ storage Methods 0.000 title claims abstract description 41
- 210000003928 nasal cavity Anatomy 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 238000001879 gelation Methods 0.000 title description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 229920002148 Gellan gum Polymers 0.000 claims abstract description 32
- 239000000216 gellan gum Substances 0.000 claims abstract description 31
- 235000010492 gellan gum Nutrition 0.000 claims abstract description 31
- 239000000661 sodium alginate Substances 0.000 claims abstract description 29
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 29
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 19
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 19
- 239000008367 deionised water Substances 0.000 claims abstract description 17
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 17
- 229920000136 polysorbate Polymers 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims description 12
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 abstract description 118
- 239000003814 drug Substances 0.000 abstract description 32
- 238000000338 in vitro Methods 0.000 abstract description 8
- 239000000853 adhesive Substances 0.000 abstract description 6
- 230000001070 adhesive effect Effects 0.000 abstract description 6
- 238000011160 research Methods 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 description 26
- 239000011159 matrix material Substances 0.000 description 19
- 229940079593 drug Drugs 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 230000008859 change Effects 0.000 description 16
- 239000003292 glue Substances 0.000 description 13
- 150000002500 ions Chemical class 0.000 description 13
- 238000011156 evaluation Methods 0.000 description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000008901 benefit Effects 0.000 description 7
- 210000002850 nasal mucosa Anatomy 0.000 description 7
- 150000001768 cations Chemical class 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000001103 potassium chloride Substances 0.000 description 4
- 235000011164 potassium chloride Nutrition 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000012086 standard solution Substances 0.000 description 3
- 230000000007 visual effect Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000003266 anti-allergic effect Effects 0.000 description 2
- 239000000739 antihistaminic agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004081 cilia Anatomy 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000007910 systemic administration Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- 238000012384 transportation and delivery Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- AEMOLEFTQBMNLQ-AZLKCVHYSA-N (2r,3s,4s,5s,6r)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid Chemical compound O[C@@H]1O[C@@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H]1O AEMOLEFTQBMNLQ-AZLKCVHYSA-N 0.000 description 1
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 description 1
- 241000512259 Ascophyllum nodosum Species 0.000 description 1
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000199919 Phaeophyceae Species 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 241000736110 Sphingomonas paucimobilis Species 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010052568 Urticaria chronic Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical class C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000035587 bioadhesion Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910001424 calcium ion Inorganic materials 0.000 description 1
- -1 calcium ions Chemical class 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000024376 chronic urticaria Diseases 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 230000009969 flowable effect Effects 0.000 description 1
- 229940009493 gel-one Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229910052739 hydrogen Chemical group 0.000 description 1
- 239000001257 hydrogen Chemical group 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229940100652 nasal gel Drugs 0.000 description 1
- 229940100656 nasal solution Drugs 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000001331 nose Anatomy 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000011022 opal Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 235000021018 plums Nutrition 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229910001427 strontium ion Inorganic materials 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000004506 ultrasonic cleaning Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
Images
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a loratadine nasal cavity in-situ gel and a preparation method thereof, belonging to the technical field of nasal cavity gels. The loratadine nasal cavity in-situ gel comprises the following components: 7.6mg/mL of loratadine, 3mg/mL of gellan gum, 2mg/mL of sodium alginate, 2mg/mL of HPMC, 801 mg/mL of Tween, 1mL/mL of ethanol and the balance of deionized water. The invention takes gellan gum and sodium alginate as gel matrixes, researches and comprehensively evaluates the aspects of the viscosity, the gelling time, the gel strength, the medicine content, the adhesive force, the stability, the in-vitro medicine release and the like of the gel, and determines an optimal loratadine nasal cavity in-situ gel prescription.
Description
Technical Field
The invention belongs to the technical field of nasal cavity gel, and particularly relates to loratadine nasal cavity in-situ gel and a preparation method thereof.
Background
In recent years, nasal administration has shown superiority as a convenient and reliable systemic administration method, especially for drugs which are not effective for oral administration and must be injected. The nasal epithelium has high permeability, and only two layers of cells are separated between the nasal cavity and the dense vascular network of the lamina propria. Nasal administration has many advantages over other routes of systemic administration, including: the composition has the advantages of quick absorption, avoidance of intestinal tract and liver effects, quick response, avoidance of gastrointestinal membrane stimulation, noninvasive drug delivery, convenience for patients to take drugs by themselves, improvement of patient compliance and the like. These have received extensive attention and research to nasal administration.
At present, the nasal mucosa is confirmed to be an effective delivery way of chemical drugs, including biological drug products, and is rapid and efficient. It is useful for topical nasal treatments such as antihistamines and corticosteroids, and for systemic delivery of analgesics, sedatives, hormones, vaccines and cardiovascular drugs.
Nasal administration is simple and convenient and may include delivery of solutions, suspensions, powders, in situ gels and ointments.
The main drawback associated with nasal administration is rapid mucociliary clearance (MCC), which limits the time to absorb the drug from the nasal gel dosage form. Therefore, frequent administration is required to achieve a therapeutic dose. The use of gel or adhesive formulations can reduce MCC, prolong drug residence time at mucosal sites, and thus increase absorption. Compared with other dosage forms, the gel has the following advantages: the gel can reduce the liquid medicine from dripping to the back of the throat after passing through the nose, thereby reducing the problems of bad taste and the loss of nasal cavity pharmaceutical preparations to the maximum extent; the gel can reduce the front leakage of the medicine outside the nasal cavity and also reduce the medicine loss; the gel also allows the drug to adhere to the nasal mucosa, thereby providing a better opportunity for absorption of the drug.
The formulations that have been tried are hydrogel, viscous gel with high absorption rate and long-lasting drug effect, and the like. However, viscous gels have the disadvantage of being difficult to administer, and in situ gels can overcome this disadvantage. In situ gels are a new form of administration for nasal administration in recent years. Compared with nasal solution, the nasal in-situ gel is a solution with low viscosity before entering the nasal cavity, and after the nasal in-situ gel is contacted with nasal mucosa, the conformation of the polymer is changed to generate gel, so that the nasal in-situ gel can prolong the contact time of the medicine and an absorption site in the nasal cavity, slowly and continuously release the medicine, and has particularly obvious advantages for the medicine which needs to be used for a long time. In addition, the in-situ gel has the advantages of good solubility, convenient preparation, convenient administration, no foreign body sensation, accurate administration and the like, and has higher safety and patient compliance. Factors known to date to cause phase change may be pH change, temperature change or the presence of cations, uv irradiation and polymers.
Gellan gum is an anionic, extracellular deacetylated bacterial polysaccharide discovered in 1978. It is secreted by Sphingomonas paucimobilis and has 1-l-rhamnose, 1-d-glucose and 2-d-glucose tetrasaccharide repeatsUnits. The mechanism of gelation involves the formation of double helical bands, the segments of which form a three-dimensional network by complexing with cations and hydrogen bonding with water. The gelling mechanism of gellan gum solutions depends on the nature of the cation, with divalent cations promoting gelling more than monovalent cations. Gellan gum is currently approved by the united states and european union for use as a stabilizer and suspending agent in food products, and is therefore safe as a pharmaceutical material[1]. In addition, gellan gum is suitable for biomedical technologies, such as drug carriers and protein immobilization media, and is a promising in situ gelling polymer for humans.
Sodium alginate is a byproduct after extracting iodine and mannitol from brown algae such as kelp or gulfweed, and its molecule is formed by connecting-D-mannuronic acid (beta-D-mannuronic, M) and alpha-L-guluronic acid (alpha-L-guluronic, G) by 1 → 4 bond. Sodium alginate is a non-toxic food and has been introduced into the united states pharmacopeia as early as 1938. When meeting divalent or trivalent cations such as calcium ions, strontium ions and the like, a cross-linked network structure can be formed, and gel is formed.
The loratadine is a derivative of azatadine, is a long-acting tricyclic antihistamine, has good curative effect on allergic dermatitis such as allergic rhinitis, chronic urticaria, eczema, contact dermatitis and the like, and has the most remarkable antiallergic effect. The interest of more and more researchers has been raised in recent years for research in the application of anti-allergy therapy. However, loratadine is almost insoluble in water, so that the effective utilization rate is low, and adverse reactions of gastrointestinal tracts and damage to liver functions are easily caused by an oral administration mode, thereby limiting the clinical effect of loratadine. The loratadine is prepared into nasal cavity in-situ gel, so that the first-pass effect can be avoided, the bioavailability is improved, meanwhile, gastrointestinal adverse reaction and liver function damage are avoided, and the onset time is shortened.
Therefore, the method has important social significance for the research of the loratadine nasal cavity in-situ gel.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides a loratadine nasal cavity in-situ gel and a preparation method thereof.
The invention provides a loratadine nasal cavity in-situ gel, which comprises the following components: 7.6mg/mL of loratadine, 3mg/mL of gellan gum, 2mg/mL of sodium alginate, 2mg/mL of HPMC, 801 mg/mL of tween, 1mL/mL of ethanol and the balance of deionized water.
The invention provides another loratadine nasal cavity in-situ gel with different proportions, which comprises the following components: 7.6mg/mL of loratadine, 4mg/mL of gellan gum, 1mg/mL of sodium alginate, 1mg/mL of HPMC, 801 mg/mL of Tween, 1mL/mL of ethanol and the balance of deionized water.
In some embodiments of the invention, the ethanol is 98% ethanol by mass concentration.
The invention also provides a preparation method of the loratadine nasal cavity in-situ gel, which comprises the following steps: placing the gellan gum into a reaction vessel according to the formula, heating and stirring until the gellan gum is completely dissolved, taking out and cooling, adding the sodium alginate, the HPMC, the Tween 80 and the deionized water, and stirring until the sodium alginate, the HPMC, the Tween 80 and the deionized water are completely dissolved.
In some of these embodiments, the temperature of the warming agitation is 87 ℃.
Compared with the prior art, the invention has the beneficial effects that: compared with the traditional liquid spraying agent, the loratadine in-situ gel prepared by the method improves the clearance of the cilia of the nasal cavity to the medicinal preparation, and improves the bioadhesion and the detention time of the loratadine in the nasal cavity. Meanwhile, the preparation can be prevented from leaking out of the nasal cavity or dripping to the back of the throat, so that any adverse taste problem and the loss of the nasal cavity medicament formula are reduced to the maximum extent; compared with the traditional viscous gel, the gel solves the problems of difficult administration, inconvenient use and the like, is easier to prolong the retention time of the medicine on the nasal mucosa, reduces the toxicity of the medicine on the nasal mucosa cilia, and is favorable for improving the bioavailability.
Drawings
FIG. 1 is a graph of the standard curve for loratadine;
FIG. 2 is a graph of the cumulative in vitro release of loratadine.
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary and are not intended to limit the scope of the invention, which is defined in the appended claims, as may be amended by those skilled in the art upon reading the present invention.
The invention provides a loratadine nasal cavity in-situ gel, which comprises the following components: 7.6mg/mL of loratadine, 3mg/mL of gellan gum, 2mg/mL of sodium alginate, 2mg/mL of HPMC, 801 mg/mL of tween, 1mL/mL of ethanol and the balance of deionized water.
The invention provides another loratadine nasal cavity in-situ gel with different proportions, which comprises the following components: 7.6mg/mL of loratadine, 4mg/mL of gellan gum, 1mg/mL of sodium alginate, 1mg/mL of HPMC, 801 mg/mL of Tween, 1mL/mL of ethanol and the balance of deionized water.
In one embodiment, the ethanol is 98% ethanol by mass concentration.
The invention also provides a preparation method of the loratadine nasal cavity in-situ gel, which comprises the following steps: placing the gellan gum into a reaction vessel according to the formula, heating and stirring until the gellan gum is completely dissolved, taking out and cooling, adding the sodium alginate, the HPMC, the Tween 80 and the deionized water, and stirring until the sodium alginate, the HPMC, the Tween 80 and the deionized water are completely dissolved.
In one embodiment, the temperature of the warming agitation is 87 ℃.
The present invention will be described in detail with reference to examples.
Example 1
The apparatus used in the present invention is as follows:
CL-1A type magnetic stirrers (Hi-Tech instruments, Hi-Tech, Ouchi, Inc.); DF-II digital display heat collection type magnetic stirrer (Jie Rui electric appliance, Inc., Jintan city); model 85-2 constant temperature magnetic stirrer (shanghai sele instrument factory); electronic balance model FA2004B (shanghai yuepin scientific instruments (suzhou) manufacturing ltd); PS-30AL type ultrasonic cleaner (Shenzhen Shenhuatai ultrasonic cleaning equipment, Inc.); NDJ-1B type rotational viscometer (Shanghai Changji geological instruments Co., Ltd.); DHG-9035A type forced air drying cabinet (shanghai aozhe instrument manufacturing ltd); model s53 ultraviolet-visible spectrophotometer (Shanghai prism technology, Inc.); model RYJ-12B transdermal drug diffusion tester; smartphone (Hua Shi Rong V10 low profile).
The materials used in the present invention are as follows:
gellan gum (OPAL Biotech, lot 18042510); hypromellose (Shandong optical science and technology development Co., Ltd., batch No. 20151003); sodium alginate (Hubei Ge shop, auxiliary materials for Fu Zi Limited company, batch No. 150901); loratadine (shanghai alatin biochemical science and technology ltd., lot No. 1527108); sodium chloride (national pharmaceutical group chemical agents limited, lot number 20160428); potassium chloride (shanghai Lingfeng Chemicals Co., Ltd., lot number 20150507); anhydrous calcium chloride (Wuxi Spanish chemical Co., Ltd., lot number 20150603); tween 80 (sikawa jinshan pharmaceuticals ltd., lot No. 150901); pre-wetted RC dialysis bags. Wherein sodium chloride, potassium chloride and anhydrous calcium chloride are analytical pure reagents.
First, the gel formulation is shown in table 1 below:
TABLE 1 composition of different nasal gels of loratadine
Wherein, the prescription of J0-J4 only takes gellan gum as an ion sensitive matrix, the prescription of H1-H2 only takes sodium alginate as an ion sensitive matrix, and the prescription of M1-M4 takes a mixed matrix of gellan gum and sodium alginate. HPMC is used as thickener, and Tween 80 is used as solubilizer.
The preparation method comprises the following steps: weighing gellan gum with corresponding mass in a beaker, heating and stirring for 20 minutes on a digital display heat collection type magnetic stirrer by using water bath at 87 ℃ until complete dissolution, taking out and cooling, adding sodium alginate, HPMC, Tween 80 and deionized water, and stirring on the magnetic stirrer at normal temperature until complete dissolution and uniform mixing.
The above gel was subjected to property evaluation:
1. and (3) viscosity testing: an appropriate amount of the gel was put into a 50mL centrifuge tube, stirred with a glass rod, defoamed by ultrasound, and the viscosity was measured using an NDJ-1B rotational viscometer. And adjusting the level of the viscometer, selecting a No. 2 rotor to insert gel to the marking depth, starting to rotate, selecting the rotating speed of 60r/min, paying attention to the fact that the rotor does not collide with the wall of the centrifugal tube, a sample cannot contain bubbles, and recording the viscosity value after the number on a display is stable. The experimental temperature was room temperature (8 ℃).
The prescription of the invention is ion sensitive, so the simulated artificial nasal fluid (SNF) mainly simulates ionic components in the nasal fluid. The preparation method comprises the following steps: 4.385g NaCl, 1.49g KCl, 0.29g CaCl were weighed2Then, the resulting mixture was dissolved in 500mL of deionized water to prepare 500mL of SNF. The concentration of each component in the solution is as follows: NaCl 8.77mg/mL, KCl 2.98mg/mL, CaCl2 0.59mg/mL。
2. Testing gelling time: and (3) putting the SNF into a water bath kettle at 37 ℃ to preheat for 30min, and simulating the human nasal cavity environment. And (3) putting the corresponding volume of the gel solution into a 15mL centrifuge tube, adding SNF with the specified volume by using a pipette gun, timing by using a stopwatch, taking out the gel solution at certain time intervals, and observing the gel forming condition. The discrimination standard of complete gelling is as follows: inversion can hang from the tube wall and does not slide off within 15 s.
In the experiment, when the gel is formed in a small-volume centrifugal tube according to each formula, certain quality difference can be seen through visual observation of the formed gel, and the following standards are made for visual observation and evaluation of the formed gel:
TABLE 2 visual inspection of gel quality standards
3. Gel Strength test
Taking 50g of glue solution, adding SNF according to the SNF ratio (the best SNF ratio) of 2.3.3 to gelatinize the glue solution of each formula, taking out 50mL of gelatinized glue blocks, placing the gelatinized glue blocks into a 100mL measuring cylinder (the height of the gel is 50cm), and ultrasonically defoaming to form flat and foamless complete large blocks.
Self-made plums: a small-size magnetic stirring rotor and a miniature magnetic stirring rotor are placed in a 5mL disposable plastic centrifuge tube to be used as falling weights with proper density and volume in a gel strength test, so that the falling time of the weights is easy to measure. The centrifugal tube is in a conical head straight tail shape, and two symmetrical bulges are arranged on the edge of the cover due to the design of the folding tube cover.
And (3) freely dropping the weight from the upper part of the rubber block (the bottom of the weight is loose at the position where the bottom of the weight is attached to the upper plane of the rubber block), and recording the time of dropping the weight by 30cm and 35cm and the maximum dropping height as the judgment basis of the gel strength. Because the falling speed of part of samples is high, errors generated by visual observation and timing according to a stopwatch are large, so that the intelligent mobile phone video is adopted in the experimental process (the video is recorded at 30 frames/second), and then the video is slowly played on a computer to determine the accurate falling time. The experimental temperature was room temperature (20 ℃).
4. Adhesion test
Placing the smooth glass plate at an angle of 45 degrees with the horizontal plane, dripping 2 drops of each gelled prescription 2.4.1 places on the glass plate to enable the glass plate to slide down naturally, and recording the time required for the glue drops to slide for 1cm distance. The experimental temperature was room temperature (20 ℃).
Example 2
Preparation of loratadine nasal in-situ gel: 0.7624g of loratadine raw material medicine is weighed and transferred to a 10mL volumetric flask, 98% ethanol is added until the volume is determined by the scale mark, and ultrasonic dissolution is carried out for standby. A blank gel was prepared according to the recipe of Table 1 and the method described in Table 2.3.2, 10g of the gel was taken out and placed in a 15mL centrifuge tube, 1mL of loratadine-ethanol solution was added to the gel taken out, and the gel was stirred with a glass rod to be used as a sample to be measured.
1. And (3) determining the content of loratadine: it is known that loratadine has ultraviolet absorption at 247nm and no absorption of other substances in the preparation at this wavelength by using 50% ethanol aqueous solution as a solvent, and therefore, the content of loratadine can be determined by ultraviolet-visible spectrophotometry.
And (3) drawing a standard curve of the loratadine solution: weighing 125.3mg of loratadine, transferring the loratadine to a 500mL volumetric flask, and fixing the volume to a scale by using a 50% ethanol water solution to be used as a standard concentrated solution for later use.
0.5mL, 1mL, 1.5mL, 2mL, 5mL of the solution was taken out of the concentrated standard solution and transferred to a 25mL volumetric flask, 50% ethanol aqueous solution was added to the volume to the scale, 6 concentrations of standard solution of 5. mu.g/mL, 10. mu.g/mL, 15. mu.g/mL, 20. mu.g/mL, 25. mu.g/mL, 50. mu.g/mL were prepared, absorbance was measured at a wavelength of 247nm by the spectrophotometry, linear regression was performed with the absorbance A for the concentration c (. mu.g/mL), the concentration (. mu.g/mL) was plotted on the abscissa and the absorbance A was plotted on the ordinate.
2. Determination of content of loratadine gel test sample
1g of a test sample in each prescription is taken and placed in a 250mL volumetric flask, 50% ethanol water solution is used for fixing the volume to the scale, the test sample is shaken up, 5mL of the test sample is taken and placed in a 10mL volumetric flask, 50% ethanol water solution is used for fixing the volume to the scale, the absorption value of the solution at the position of 247nm is measured, and the drug content of loratadine is read on a standard curve.
3. Stability test
After 24 hours of the content measurement, the content of the drug in the test sample was measured again by the method 2.6.1.2, and the change was calculated.
4. In vitro Release test
In vitro release tests of drugs were performed in Franz diffusion cells with dialysis membrane modifications. When the artificial membrane is prepared, the dialysis membrane is soaked in phosphate buffer solution with pH of 7.2 for 12h, and then is arranged on a diffusion cell (the volume between receptors is 6.5mL, and the permeation area is 2.6 cm)2). After preheating at 37 ℃ for 20min, 2mL of the drug-loaded formulation was placed in the donor compartment, and phosphate buffer pH 7.2 was placed in the receptor compartment. The prescription samples were gelled by adding 0.5mL of SNF simulant nasal fluid. The receptor compartment temperature was maintained at 37 ± 1 ℃. At times of 10min, 20min, 30min, 60min, 120min, 180min, 360min, 720min, 1440min, 1.5mL samples were withdrawn from the receptor chamber and analyzed spectrophotometrically at 247 nm. After each sampling the sampling volume was replaced by phosphate buffer pH 7.4.
The viscosity test results are as follows.
The viscosity measurements at each point without SNF exposure are shown in table 3 below:
TABLE 3 viscosity at various places without SNF contact
The formulas J1, J2, H1 and H2 are small in initial viscosity, namely the single cold glue formula with small concentration and the single sodium alginate formula with larger concentration, and the viscosities of the other formulas are relatively large, wherein the formula M2 has too large viscosity, so that the requirements of low viscosity and high fluidity before the in-situ gel contact phase transition condition are not met, and subsequent quality investigation is not carried out.
The change in viscosity of each gel using gellan gum as the ion sensitive matrix after SNF was added one milliliter by one milliliter is shown in table 4 below:
TABLE 4 change in viscosity of SNF after mL addition of J0-J4
The viscosity of the treatment sample generally increased with the gradual addition of SNF. The change was not significant at first, even because the addition of deionized water in the SNF was reduced slightly. With the exception of J0, all of the prescription samples exhibited a maximum viscosity after the addition of 9mL of SNF, with a more pronounced sudden increase from 8mL to 9 mL. After 9mL, the SNF is added continuously, the viscosity is reduced, the added SNF is considered to be excessive, all gellan gum is formed into a cross-linked network structure, and the added SNF has no difference with distilled water and only plays a role in diluting the gel. It was initially thought that the gel achieved the optimum viscosity after the addition of 9mL of SNF. In addition, the maximum viscosity of the formula J1 is too low to be fluid and not to form a colloidal state, so that the subsequent evaluation of each index is not performed on J1.
The viscosity change of each place of the gel using sodium alginate as the ion sensitive matrix is shown in the following table 5 after adding SNF into the gel per milliliter:
TABLE 5 change in viscosity of SNF after mL-by-mL addition of H1-H2
It can be seen that the sodium alginate viscosity change has better ion correlation, and the maximum value appears at the position where 9mL of SNF is added, which is consistent with the maximum value appearance point of the J-type sample. However, the samples were always in a flowable state, could not form a gel, and did not have the ability to act as a gel matrix alone, so samples H1-H2 were not evaluated for further projects, but could be considered as a gel matrix together with gellan gum in order to achieve better gel performance.
The viscosity change of each part of the gel taking gellan gum and sodium alginate as ion sensitive matrixes after adding SNF into the gel one milliliter by one milliliter is shown in Table 6:
from the above results, it was found that since the recipe reaches the maximum value of the viscosity change when about 9mL of SNF is added, the viscosity change was recorded for the mixed recipe directly from the point of adding 8mL of SNF.
TABLE 6 change in viscosity after SNF addition of M1, M3, M4
It can be seen that the maximum viscosity of the mixed ion-sensitive matrix is significantly greater than that of the single matrix, the maximum viscosity appearing at 8
The M1 formula requires less SNF, unequal at mL, 9mL, and the mixed matrix is considered to be a more optimal formula compared to the single matrix in the viscosity test.
The J-type formula, although not as viscous as the M-type, can form a gel mass and still has continued research value.
The gelling time test results are as follows:
about 4mL of each formulation was put into a 15mL centrifuge tube, and about 1mL of SNF was added to form a gel mass in an optimum state according to the result of 2.2. And (4) observing the glue forming condition, finely adjusting the volumes of the glue solution and the SNF until a glue block with the best quality of the prescription is formed, and recording the corresponding results of volume, time, quality and the like.
Table 7 glue ratio, time and quality of glue
Complete gelation of 4mL of the gum was a gradual process. At the moment when the SNF is added into the test tube, the gelation phenomenon appears around the added liquid, the gelation phenomenon gradually diffuses towards the direction, and finally a large complete gel block is formed, which marks the end of the measurement process.
The J0 prescription rubber block has the advantages of optimal quality, shortest gelling time and moderate SNF dosage, and is the optimal prescription in the evaluation of gelling time. Except J0, the glue prepared by the M1-M3 formula is obviously better than J1-J4 in quality and shorter in glue forming time, but the dosage of SNF is more than that of the J formula. The gel formation time was based on 300s, which was considered to be good within 90 s.
The gel strength test is as follows:
TABLE 8 gel Strength results
Note: time 1 refers to the time taken to fall 30cm, and time 2 refers to the time taken to fall 35 cm.
Due to the lack of accurately measured laboratory instruments, only a relatively qualitative analysis of the gel strength of the samples was carried out here. Thus, a number of indicators were measured for comprehensive analysis. In the J2 and J3 samples, the gravity drops rapidly, the gravity sinks in less than 1s, namely the resistance from the gel is small, and in the seven prepared prescription samples, the difference from the other 5 samples is large, and the gel strength is considered to be too small, so that the gel strength does not meet the requirement on the gel strength after the in-situ gel is formed. In the M1 and M3 prescription samples, the weights could fall at a slower rate and eventually settle after a period of more than 10 seconds. Gel strength was at moderate strength in the seven prescription samples. The samples J0, J4 and M4 started dropping at a very slow speed after the weight was put into the gel and stopped dropping before reaching the bottom of the cylinder, indicating that the gel strength is best, and the maximum dropping height of the weight in each prescription sample was also recorded by the pen. Although the M3 prescription sample finally settled, the drop time was long, and the time taken for the same distance to move before settling was even more than the three non-settled prescription samples J0, J4, and M4, so the gel strength of M3 was considered to be sufficiently good.
The gel strength is a parameter for reflecting the size of intermolecular force of the high polymer material, and the larger the gel strength value is, the larger the intermolecular force is, the better the stability of the molecular structure of the gel is, and the gel is less prone to damage. From the gel strength test data, the strength of the two prescription samples J2 and J3 is small, and the difference between the two prescription samples and other test samples is large, so that the gel strength requirements are not met; the M1 prescription sample has larger strength and is barely in line with the requirement; the M3 sample has the longest falling time, but has a large falling distance, and basically meets the requirements; the maximum falling height of the three prescription samples J0, J4 and M4 is less than 50cm, and the gel strength requirement is met.
The in vitro adhesion test results are as follows:
TABLE 9 adhesion results
The adhesive force of the nasal cavity in-situ gel is in a proper range, so that the medicine has a certain retention time in the nasal cavity, but the damage of the nasal mucosa caused by the retention time is not caused. The evaluation criteria of the loratadine nasal cavity in-situ gel in the invention are as follows: the adhesive force is proper when the retention time is between 180s and 600s, the adhesive force is too small and more than 600s when the retention time is less than 180s, and the adhesive force is too large. The adhesion of the three prescription samples of J3, M1 and M4 is 178-600 s, which meets the evaluation standard, and the adhesion of the other samples is insufficient.
Example 3 drug content testing and stability
1. Plotting a loratadine standard curve, the absorbance at 247nm of each standard solution is shown in the following table:
TABLE 10 determination of concentration of loratadine standard
A standard curve is plotted based on the absorbance corresponding to the concentration, as shown in FIG. 1, and as can be seen from FIG. 1, the linear relationship is good.
2. The content determination results of the loratadine gel test article are shown in the following table:
TABLE 11 content of loratadine gel test samples
The drug content of more than 90 percent meets the standard. Except J0, the loratadine nasal cavity in-situ gel has better drug content, and the J2, M1 and M3 have the highest effective rate.
3. The stability test results are given in the following table:
TABLE 12 loratadine 24h stability test
The stability was considered better when the content remained above 95% after 24h, thus the J0-J3 samples were less stable and the rest were more stable.
Example 4 in vitro gel Release test for Loratadine for nasal use
The 24 hour in vitro release of loratadine nasal in situ gel is shown in figure 2 with less variance at various locations. With the greatest release of J2. Cumulative release above 40% is a qualifying criterion, whereby all prescriptions meet the standard.
Finally, the evaluation results of the indexes of the above prescription samples are summarized in the following table:
TABLE 13 summary of evaluation results of each index
Note: in the table, "good" indicates that a prescribed sample is excellent in some property evaluation, "ok" indicates that the sample is not optimal but still meets the quality standard, other characters indicate that the sample does not meet the quality standard, and "-" indicates that the sample is not measured.
As is apparent from the table, the samples meeting the requirements of all the evaluation items are M1 and M4, which can be used as the final prescription. At least one item of the rest of the prescriptions does not meet the standard. The J0 prescription has better performances in terms of gelling time, gelling quality and gelling strength, the viscosity before and after gelling, the stability of drug content and the like basically meet the requirements, the prescription is simple and convenient to prepare, but the J0 prescription without adding the solubilizing agents HPMC and Tween 80 has obvious defects in terms of drug content and stability. The three formulas J2, J3 and J4 have general performances, the viscosity before and after gelation is clear, the gelation time and the quality are general, any one of the three formulas has no advantages, the gel strength or in vitro adhesion strength is poor, and the stability of the medicine cannot be ensured, so the three formulas J2, J3 and J4 are not used as options of final formulas. The gel matrix content of the J1 prescription is too low, the gel matrix content of the M2 prescription is too high, and the basic requirements of the gel are greatly different from those of nasal in-situ gel. The M1 formula performs better in terms of post-gelation viscosity, and the M4 formula performs better in terms of both post-gelation viscosity and gel strength, for reasons that M4 is a slightly better formula option than M1.
The final loratadine nasal in situ gel prescription was 2:
recipe 1: 7.6mg/mL of loratadine; gellan gum 3 mg/mL; 2mg/mL of sodium alginate; HPMC 2 mg/mL; tween 801 mg/mL; the balance of deionized water.
Prescription 2: 7.6mg/mL of loratadine; gellan gum is 4 mg/mL; 1mg/mL of sodium alginate; HPMC 1 mg/mL; tween 801 mg/mL; the balance of deionized water.
The invention aims to research and design a nasal cavity in-situ gel taking the existence of ions as a phase change causing element, and relates to nasal cavity ion sensitive gel matrixes of gellan gum and sodium alginate. Preparing blank gel, adding nasal cavity ion simulation liquid to gelatinize a sample, measuring various indexes after gelatinization, and performing comprehensive evaluation. The prescription design comprises three types of single gellan gum matrix, single sodium alginate matrix and gellan gum-sodium alginate mixed matrix, and HPMC and Tween 80 are used as auxiliary materials to form the whole blank prescription.
The gelation viscosity change test is firstly passed, and the possibility of single sodium alginate as an ion sensitive in-situ gel matrix is eliminated, and the J1 prescription with the matrix dosage being too small and the M2 prescription with the matrix concentration being too large are also eliminated.
In the test of the gel forming time, the gel forming quality is found to be greatly different by naked eyes when the gel sampling is less, so the gel forming time and the gel forming quality are evaluated as a comprehensive evaluation item. The gelling time in the results varies from 0.5min to 4.5min, but gelation is a process of gradual transition from contacting ions, and in practical application, liquid gel is sprayed in a mist shape, the gelling volume is smaller, and the complete gelling time is believed to be shorter.
The terms designed in the present invention are shown in the following table:
TABLE 14 glossary
The embodiments of the present invention have been described in detail with reference to the above examples, but the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art.
Claims (5)
1. The loratadine nasal cavity in-situ gel is characterized by comprising the following components: 7.6mg/mL of loratadine, 3mg/mL of gellan gum, 2mg/mL of sodium alginate, 2mg/mL of HPMC, 801 mg/mL of tween, 1mL/mL of ethanol and the balance of deionized water.
2. The loratadine nasal cavity in-situ gel is characterized by comprising the following components: 7.6mg/mL of loratadine, 4mg/mL of gellan gum, 1mg/mL of sodium alginate, 1mg/mL of HPMC, 801 mg/mL of Tween, 1mL/mL of ethanol and the balance of deionized water.
3. The loratadine nasal in-situ gel according to claim 1 or 2, wherein the ethanol is 98% ethanol by mass.
4. The method for preparing loratadine nasal in-situ gel according to claim 1 or 2, characterized by comprising the following steps:
the method comprises the following steps: placing gellan gum into a reaction vessel according to the formula, heating and stirring until the gellan gum is completely dissolved, taking out and cooling, adding sodium alginate, HPMC, Tween 80 and deionized water, and stirring until the gellan gum is completely dissolved to obtain gel;
step two: and (3) carrying out constant volume on the loratadine raw material medicinal ethanol, carrying out ultrasonic dissolution, and then adding the loratadine raw material medicinal ethanol into the gel obtained in the step one to obtain the loratadine nasal cavity in-situ gel.
5. The method for preparing loratadine nasal cavity in-situ gel according to claim 4, wherein the temperature of the temperature raising and stirring is 87 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910980892.9A CN110693816B (en) | 2019-10-15 | 2019-10-15 | Loratadine nasal cavity in-situ gel and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910980892.9A CN110693816B (en) | 2019-10-15 | 2019-10-15 | Loratadine nasal cavity in-situ gel and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110693816A CN110693816A (en) | 2020-01-17 |
| CN110693816B true CN110693816B (en) | 2022-05-20 |
Family
ID=69199696
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910980892.9A Active CN110693816B (en) | 2019-10-15 | 2019-10-15 | Loratadine nasal cavity in-situ gel and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110693816B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20230015630A1 (en) * | 2021-07-19 | 2023-01-19 | Chuckie C Weber | Cold Medicine Composition, Preparation Method and Use Thereof |
| CN117665230B (en) * | 2024-01-31 | 2024-04-16 | 南京海鲸药业股份有限公司 | Preparation method and monitoring system of ion-sensitive in-situ gel for nasal cavity |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101015559A (en) * | 2007-02-06 | 2007-08-15 | 复旦大学 | Instant gelling agent for treating allergic rhinitis |
| KR20080076667A (en) * | 2007-02-15 | 2008-08-20 | 주식회사 중외제약 | Thixotropic pharmaceutical compositions |
| CN102078285A (en) * | 2009-11-26 | 2011-06-01 | 天津金耀集团有限公司 | Nasal in-situ gel containing corticosteroids and H1 receptor antagonists |
| CN102462713A (en) * | 2010-11-09 | 2012-05-23 | 复旦大学 | Panax notoginseng total saponin nasal in situ gel with phase transition property |
| EP3675873A4 (en) * | 2017-09-01 | 2021-06-16 | Pmidg, Llc | Functionalized and crosslinked polymers |
-
2019
- 2019-10-15 CN CN201910980892.9A patent/CN110693816B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110693816A (en) | 2020-01-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Altuntaş et al. | Formulation and evaluation of thermoreversible in situ nasal gels containing mometasone furoate for allergic rhinitis | |
| Liu et al. | In situ gelling gelrite/alginate formulations as vehicles for ophthalmic drug delivery | |
| CN104546716B (en) | A kind of nose temperature-sensitivtype type hydrogel spray | |
| HOU et al. | Sustained release of indomethacin from chitosan granules | |
| Parodi et al. | Development and characterization of a buccoadhesive dosage form of oxycodone hydrochloride | |
| CN110693816B (en) | Loratadine nasal cavity in-situ gel and preparation method thereof | |
| Kubo et al. | Oral sustained delivery of ambroxol from in situ-gelling pectin formulations | |
| Mahajan et al. | In situ gels of metoclopramide hydrochloride for intranasal delivery: in vitro evaluation and in vivo pharmacokinetic study in rabbits | |
| Bhowmik et al. | Study of thermo-sensitive in-situ gels for ocular delivery | |
| EP2922581B1 (en) | Mucoadhesive compositions comprising hyaluronic acid and chitosan for topical application | |
| Viram et al. | Development and evaluation of ion-dependent in-situ nasal gelling systems of metoclopramide hydrochloride as an antimigraine model drug | |
| Rupal et al. | Preparation and evaluation of topical gel of valdecoxib | |
| Hani et al. | Development of miconazole nitrate thermosensitive bioadhesive vaignal gel for vaginal candidiasis | |
| GS et al. | Formulation and development of nasal in situ gels of triptans for anti migraine activity | |
| CN108721207A (en) | Amination poloxamer derivative responsive to temperature type instant gelling agent and preparation method thereof | |
| Saudagar et al. | Review on in-situ nasal gel drug delivery system | |
| Malviya et al. | Design and Characterization of pH Dependent Phase Transition System of Almotriptan Malate for Nasal Drug Delivery System by Employing Factorial Design | |
| Bhimani et al. | Development and evaluation of floating in situ gelling system of clarithromycin | |
| MX2010013685A (en) | In situ gelling systems as sustained delivery for front of eye. | |
| Pongjanyakul et al. | Modulating drug release and matrix erosion of alginate matrix capsules by microenvironmental interaction with calcium ion | |
| Shinde et al. | In situ mucoadhesive nasal gels of metoclopramide hydrochloride: preformulation and formulation studies | |
| CN103399129A (en) | Method for measuring in-vitro release degree and adhering time/corrosion time of bioadhesive preparation | |
| CN116539824A (en) | Method for measuring dynamic dissolution curve of medicine | |
| Shi et al. | Development of injectable in situ hydrogels based on hyaluronic acid via Diels-Alder reaction for their antitumor activities studies | |
| Kantibhai et al. | Test methods of bioadhesive system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20240305 Address after: 050000 b-1-0901, Shenghe Plaza, 88 Qilian street, high tech Zone, Shijiazhuang City, Hebei Province Patentee after: Hebei Sanhe Shichuang Biotechnology Co.,Ltd. Country or region after: China Address before: 213100 No. 21, middle Lake Road, Hutang Town, Wujin District, Changzhou, Jiangsu Patentee before: CHANGZHOU University Country or region before: China |
|
| TR01 | Transfer of patent right |