CN103622905A - Corrective naringin oral solution and preparation method thereof - Google Patents
Corrective naringin oral solution and preparation method thereof Download PDFInfo
- Publication number
- CN103622905A CN103622905A CN201310705789.6A CN201310705789A CN103622905A CN 103622905 A CN103622905 A CN 103622905A CN 201310705789 A CN201310705789 A CN 201310705789A CN 103622905 A CN103622905 A CN 103622905A
- Authority
- CN
- China
- Prior art keywords
- naringin
- essence
- preparation
- acid
- oral liquid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000001606 7-[(2S,3R,4S,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-3-[(2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoxan-2-yl]oxy-5-hydroxy-2-(4-hydroxyphenyl)chroman-4-one Substances 0.000 title claims abstract description 82
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 240000008790 Musa x paradisiaca Species 0.000 description 2
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 2
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- 241000700157 Rattus norvegicus Species 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
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- 229940124584 antitussives Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
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- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
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- 239000008297 liquid dosage form Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
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- 238000011160 research Methods 0.000 description 2
- 238000005464 sample preparation method Methods 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000013595 supernatant sample Substances 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 240000000560 Citrus x paradisi Species 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 208000013116 chronic cough Diseases 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002207 flavanone derivatives Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000010135 fructus aurantii immaturus Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001835 salubrious effect Effects 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a corrective naringin oral solution and a preparation method thereof. The oral solution comprises the following components in parts by weight: 1 part of naringin, 12-31 parts of cyclodextrin or hydroxypropyl-beta-cyclodextrin, 1-40 parts of flavoring agent, and a proper amount of auxiliaries. By optimizing the inclusion solubilization and flavoring technology, the long-time placement stability of a naringin liquid preparation can be remarkably improved, the bioavailability of the naringin liquid preparation can be improved, the naringin has an excellent taste, the compliance of patient administration can be strengthened, and the additional value of medicines can be improved.
Description
Technical field
The present invention relates to belong to pharmaceutical technology field, be specifically related to a kind of taste masking naringin oral administration solution and preparation method thereof.
Background technology
Naringin is flavanone, is mainly present in the peel and sarcocarp of rutaceae grapefruit, Fructus Citri tangerinae, orange, and naringin is also the main effective ingredient of Chinese herbal medicine Exocarpium Citri Grandis, Rhizoma Drynariae, Fructus Aurantii Immaturus, Fructus Aurantii.Naringin can be used for the treatment of acute and chronic cough disease, and acute and chronic bronchitis is had to good relieving cough and expelling phlegm and antiinflammation.Naringin antitussive mechanism is periphery antitussive, cannot enter blood brain barrier, active to nervus centralis inanimate object, safety is splendid, being applicable to each age group crowd uses, children particularly, can avoid the hidden danger such as impact that the maincenter side effect of medicine causes childhood development and teenager medication addiction.
The advantage of oral liquid is that medicine is dispersed in medium with molecule or graininess, and dispersion is large, absorbs soon, can bring into play rapidly drug effect and be conducive to improve the bioavailability of medicine.And liquid preparation is easy to divided dose, taking convenience, is particularly suitable for infant and gerontal patient.Although naringin has good pharmacotoxicological effect and safety, in the preparation of naringin liquid preparation, many difficulties have been there are.First, naringin water solublity is poor, and dissolubility temperature influence is large, after dissolving, occurs placing wild effect by common simple solubilising technology, and room temperature is placed and within 3-10 days, occurred that a large amount of cotton-shaped crystal separates out; And make suspensoid because its dissolution properties is unstable, and in suspendible medicine put procedure, constantly occur that dissolving-recrystallization, crystal formation change the phenomenon such as grow up, limited the exploitation of naringin liquid preparation, become one of bottleneck of preparing naringin liquid preparation.And, naringin taste is extremely bitter, it is the source of Fructus Citri grandis class fruit bitterness, in the oral liquid of making by its effective dose, naringin concentration is much higher than the concentration that occurring in nature exists, bitterness more very, general traditional taste masking technique or syrup all cannot solve its bitterness, and mouthfeel is poor, and this has limited the application of naringin in infant crowd.At present, there is no the liquid dosage form of this medicine both at home and abroad.
Summary of the invention
The object of the invention is for naringin liquid preparation in prior art place unstable, absorb poor with and extremely bitter mouthfeel, provide a kind of and obviously improve the long-term shelf-stability of naringin liquid preparation, improve bioavailability, improve the formulation and technology of the naringin oral liquid of mouthfeel, invention provides a kind of, is applicable to the preparation method of each age group crowd, particularly infant and gerontal patient's naringin oral liquid.The adjuvant that the present invention uses and technique are convenient can be obtained, and is applicable to suitability for industrialized production.
The present invention is achieved through the following technical solutions:
Oral liquid of the present invention consists of by weight following component:
1 part of naringin, cyclodextrin or hydroxypropyl beta cyclodextrin 12-31 part, correctives 1-40 part, right amount of auxiliary materials.
Described correctives comprises sweeting agent and essence; Wherein, described sweeting agent is one or more in steviosin, sorbitol, mannitol, maltose alcohol, glycyrrhizin, mogroside, stem tea element, sucralose, sucrose; Described essence is a kind of or several in orange flavor, grape essence, strawberry essence, flavoring pineapple essence, peach flavor, apple essence, Mint Essence, cacao essence, Fructus Citri Limoniae essence.
Dosage of sucrose is between 10-40 part, and steviosin, sorbitol, mannitol, maltose alcohol, glycyrrhizin, mogroside, stem tea element consumption are between 1-15 part, and sucralose consumption is between 0.001-1 part, and essence consumption is between 0.125-1 part.
Described correctives most preferably is sucrose and orange flavor combination, and wherein sucrose is 18.75 parts by weight, and orange flavor is 0.5 part.Described adjuvant can comprise one or more in surfactant, cosolvent, antiseptic, pH adjusting agent, coloring agent, antioxidant, wherein, described surfactant or cosolvent comprise that fatty acid Pyrusussuriensis is smooth, one or more the combination in Polysorbate, poloxamer, polyoxyethylene ether, Oleum Ricini, castor oil hydrogenated, polyvinylpyrrolidone, propylene glycol, glycerol, meglumine; Described antiseptic comprises that a kind of meeting in parabens, benzoic acid and salt thereof, sorbic acid and salt thereof is several; Described pH adjusting agent is water solublity regulator, comprises one or more in phosphoric acid, acetic acid, sodium acetate, citric acid, disodium citrate, citric acid trisodium, sodium citrate, potassium citrate, sodium carbonate, sodium bicarbonate; Described antioxidant comprises one or more in sulfurous acid, sulphite, bisulfites, gallic acid and salt cysteine, ascorbic acid and salt thereof.
The preparation method of described oral liquid, comprise the following steps: it is appropriate to get purified water, by recipe quantity, add naringin, the jolting in constant temperature air bath of cyclodextrin or hydroxypropyl beta cyclodextrin is complete to dissolving enclose, add again correctives and right amount of auxiliary materials, finally regulate pH to 4 scope, add simple syrup to full dose.
Compared with prior art, the present invention has following beneficial effect:
Naringin oral liquid of the present invention dissolves naringin completely solubilizing agent and naringin interaction in solution, and the increase of solubilizing agent can make solubilizing effect have certain increase, and excessive solubilizing agent meeting reaches capacity the raising of bioavailability; In prescription, surfactant, cosolvent etc. are used in combination, and can make solubilizing effect more stable.Utilize naringin liquid preparation prepared by the present invention to deposit 6 months and to separate out without solid in 4 ℃, refrigerator.The present invention can solve that naringin liquid preparation deposits under long-term storage or low temperature environment that the crystal of generation is separated out and crystal formation change etc. hinders the unstable factor of naringin liquid preparation exploitation.
The present invention fills a prescription by naringin being carried out to the taste masking of enclose processing, recycling particular combination, the original disagreeable taste of naringin oral liquid is covered, and mixed good to eat mouthfeel, and this is that simple taste masking technique institute is inaccessiable.The effect that the present invention's inclusion technique used makes liquid preparation reach solubilising simultaneously, improve stability of solution and cover bitterness, has simplified formulation and technology, not only practicality but also easy.
The exploitation of naringin liquid preparation of the present invention improves the compliance of patient's medication greatly, has increased the patient of use crowd, particularly infant, old people and the dysphagia of this medicine.
At home and abroad there is no the liquid dosage form of this medicine.Naringin liquid preparation of the present invention solves the technique bottleneck of this this dosage form of medicine, adopts conventional liq preparation technology preparation to obtain, and preparation method is easy, and the adjuvant of use is easy to get, and economy is applicable to suitability for industrialized production.
Accompanying drawing explanation
Curve chart (n=8) when Fig. 1 is the oral Wistar of giving rat naringin raw material medicine and liquid preparation medicine.
The specific embodiment
By following instance, the present invention is done further and illustrated, comprise but be not restricted to following instance.
Embodiment 1: naringin oral administration solution
Prescription:
Preparation method:
Recipe quantity naringin and propylene glycol are mixed, separately recipe quantity hydroxypropyl beta cyclodextrin is dissolved in 1000ml purified water, this hydroxypropyl beta cyclodextrin solution is joined in the suspension of said medicine and propylene glycol, 60-80 ℃ of heated and stirred is to clarification.Get ethanol, add recipe quantity methyl hydroxybenzoate and propyl ester, make to dissolve, add into the liquidly, add recipe quantity sucrose and essence, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, and microporous filter membrane fine straining, is sub-packed in oral liquid bottle, seal.
Embodiment 2: naringin oral administration solution
Prescription:
Preparation method:
Recipe quantity naringin and propylene glycol are mixed, separately recipe quantity hydroxypropyl beta cyclodextrin is dissolved in 1000ml purified water, this hydroxypropyl beta cyclodextrin solution is joined in the suspension of said medicine and propylene glycol, the meglumine that adds recipe quantity under 60-80 ℃ of heated and stirred, the sodium benzoate that adds recipe quantity after all dissolving, recipe quantity vitamin C, recipe quantity sucralose and essence, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, microporous filter membrane fine straining, be sub-packed in oral liquid bottle, sealing.
Embodiment 3: naringin oral administration solution
Prescription:
Preparation method:
Recipe quantity naringin, mogroside, glycyrrhizin and Tween 80 are ground evenly, add recipe quantity glycerol extremely to dissolve 60-80 ℃ of heated and stirred, add recipe quantity hydroxypropyl beta cyclodextrin and appropriate purified water to mix after dissolving, add recipe quantity sodium benzoate, vitamin C, liquid strawberry essence stirring and dissolving, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, pure water adds to 1000ml, microporous filter membrane fine straining, be sub-packed in oral liquid bottle, sealing.
Embodiment 4: naringin oral administration solution
Prescription:
Preparation method:
Get purified water 1000ml, the hydroxypropyl beta cyclodextrin, poloxamer and the naringin that add recipe quantity, room temperature jolting is dissolved to clarification, adds recipe quantity sodium benzoate and vitamin C, stirring and dissolving, the mogroside and the liquid essence that add recipe quantity, after stirring and dissolving is complete, microporous filter membrane fine straining, is sub-packed in oral liquid bottle, sealing.
Embodiment 5: naringin oral administration solution
Prescription:
Preparation method:
Get purified water 1000ml, the hydroxypropyl beta cyclodextrin and the naringin that add recipe quantity, room temperature jolting is dissolved to clarification, adds recipe quantity sodium benzoate, stirring and dissolving, the sucrose and the liquid essence that add recipe quantity, after stirring and dissolving is complete, microporous filter membrane fine straining, is sub-packed in oral liquid bottle, sealing.
Embodiment 6: naringin syrup
Prescription:
Preparation method:
Get purified water 400ml, add jolting under the hydroxypropyl beta cyclodextrin of recipe quantity and naringin room temperature to dissolve, add the poloxamer of recipe quantity to make to dissolve, add the sodium benzoate of recipe quantity to make to dissolve, add vitamin C and the liquid essence of recipe quantity, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, add purified water to 450ml, filter, add simple syrup to full dose.Be sub-packed in oral liquid bottle, sealing.
Embodiment 7: naringin syrup
Prescription:
Preparation method:
Recipe quantity naringin and propylene glycol are mixed, 60-80 ℃ of heated and stirred dissolved, add hydroxypropyl beta cyclodextrin and the meglumine of 400ml purified water, recipe quantity stir and dissolve, the essence, the potassium sorbate that add recipe quantity, it is dissolved, and with potassium dihydrogen phosphate and dipotassium hydrogen phosphate solution, regulating pH value is 3-5, adds purified water to 450ml, microporous filter membrane fine straining, adds simple syrup to full dose.Be sub-packed in oral liquid bottle, sealing.
Embodiment 8: naringin syrup
Prescription:
Preparation method:
Get purified water 300ml, add the glycerol of recipe quantity to mix, add naringin and the PVP K30 of recipe quantity, 60-80 ℃ of stirring and dissolving, adds the Fructus Citri Limoniae essence of recipe quantity, stirring and dissolving.Get the ethanol of recipe quantity, add methyl hydroxybenzoate and propyl ester, stirring and dissolving, joins in medicinal liquid, with sodium hydrogen phosphate and potassium dihydrogen phosphate, regulating pH value is 3-5, adds purified water to 450ml, filters, then adds simple syrup to 1000ml, in fill and syrup bottle, sealing.
Embodiment 9: naringin syrup
Prescription:
Preparation method:
Getting recipe quantity naringin, Tween 80 and poloxamer is ground, add 25 ℃ of air bath joltings of recipe quantity hydroxypropyl beta cyclodextrin and 400ml purified water to be dissolved to clarification, add recipe quantity steviosin, liquid flavoring banana essence, sodium benzoate stirring and dissolving, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, and pure water adds to 450ml, filters, add again simple syrup to 1000ml, in fill and syrup bottle, sealing.
Embodiment 10: naringin syrup
Prescription:
Preparation method:
Get recipe quantity naringin, Tween 80 is ground, add recipe quantity hydroxypropyl beta cyclodextrin, meglumine and 25 ℃ of air bath joltings of 400ml purified water to be dissolved to clarification, add recipe quantity sucrose, liquid flavoring banana essence, sodium benzoate stirring and dissolving, with citric acid soln and liquor sodii citratis, regulating pH value is 3-5, and pure water adds to 450ml, filters, add again simple syrup to 1000ml, in fill and syrup bottle, sealing.
Embodiment 11: the research of naringin liquid preparation Pharmacokinetics in Rat
1 instrument and reagent
Instrument: 1200SL RRLC-6410QQQ liquid phase-GC-MS (U.S. Agilent company); Centrifuge5415R table-type high-speed refrigerated centrifuge (German Eppendorf company); Vortex-Genie2 vortex agitator (U.S. Scientific Industries company); BP211D electronic analytical balance (German Sartorius company); Series Precision pipettor (French Gilson company, German Eppendorf company); Electric-heated thermostatic water bath (HWS24 type, Shanghai Yi Heng Science and Technology Ltd.).
Reference substance: naringin reference substance (lot number: 110722-200309,110722-200610, is purchased from Nat'l Pharmaceutical & Biological Products Control Institute, for assay); (article No.: N5893-1G, is purchased from Sigma company to naringenin reference substance, content >=95%, lot number: 035K1316); Isoquercitrin reference substance (article No.: 17793-50mg is purchased from Sigma company, >=90%(HPLC), lot number: 1316197).
Reagent: methanol (chromatographically pure, B & J company), ethyl acetate (chromatographically pure, B & J company); Ammonium formate, methyl tertiary butyl ether(MTBE) (chromatographically pure, Sigma company); Millipore ultra-pure water; β-glucuronidase (Type H-1， Sigma company, article No.: G0751); Sodium chloride injection (world, Guizhou Pharmaceutical Co., Ltd, lot number: 0808172A); PEG400 (1Guanghua Chemical Plant Co., Ltd., Guangdong, lot number: 20060311); Formic acid (sigma company, article No.: 09676-100mL).
Test sample: the development of modern Chinese medicine quality research development centre, naringin ，You Zhongshan University Guangzhou, pale yellow powder, lot number 20080203; Naringin liquid preparation.
Animal: Wistar rat (SPF level) ，You Zhongshan University Experimental Animal Center provides.
Medication design and the blood specimen collection of 2 pharmacokinetics experiments
Adopt single-dose, 32 of Wistar rats, body weight is 250 native 20g, is divided at random 4 groups, experiment fasting the previous day 12h, freely drinks water, and gavages respectively the naringin liquid preparation (being equivalent to crude drug 42mg/kg) of naringin raw material suspension and different proportionings, in predetermined time point (0,0.5,1,1.5,2,3,4,5,6,8,12,24h) rat eye socket is got blood 0.5ml, puts 1.5ml in the plastic centrifuge tube of heparin processing, the centrifugal 10min of 3000rpm; Get supernatant blood plasma, put refrigerator-80 ℃ preservation.
The mensuration of 3 naringin blood drug level
3.1 solution preparation
Naringin storing solution preparation: get 105 ℃ of naringin reference substances that are dried to constant weight, accurately weighed 12.22mg, puts in 50mL measuring bottle, uses dissolve with methanol standardize solution, and product storing solution (107.30 μ g/mL), saves backup in 4 ℃ of refrigerators in contrast.
Naringin reference substance solution preparation: accurate absorption naringin standard reserving solution is appropriate, put in 10mL measuring bottle, with methanol-water (50:50, V/V) solution stepwise dilution becomes series concentration reference substance solution, concentration is followed successively by 26.82,53.65,107.30,536.50,1073.00,5365.00,10730.00ng/mL, standby.
Naringenin storing solution preparation: get 105 ℃ of naringenin reference substances that are dried to constant weight, accurately weighed 10.18mg, puts in 50mL measuring bottle, uses dissolve with methanol standardize solution, and product storing solution (100.98 μ g/mL), saves backup in 4 ℃ of refrigerators in contrast.
Naringenin reference substance solution preparation: accurate absorption naringenin standard reserving solution is appropriate, put in 10mL measuring bottle, with methanol stepwise dilution, become series concentration reference substance solution, concentration is followed successively by 25.24,50.49,101.0,504.9,1010.00,5049.00,10100.00ng/mL, as naringenin reference substance solution, standby.
Interior mark isoquercitrin reference substance solution preparation: get phosphorus pentoxide drying under reduced pressure to the isoquercitrin reference substance of constant weight, accurately weighed 9.75mg, puts in 50mL measuring bottle, with dissolve with methanol and be diluted to scale, shakes up, as stock solution; With methanol-water (50:50, V/V) solution, storing solution is diluted to 1950.00ng/mL, in 4 ℃ of refrigerators, saves backup.
GRD beta-glucuronidase solution preparation: accurately weighed GRD beta-glucuronidase powder 10mg is dissolved in (pH=5.0) in 4mL0.2mM acetate buffer solution, be mixed with the GRD beta-glucuronidase solution that is equivalent to 10Unit/ μ L, subpackage saves backup in-20 ℃ of refrigerators.
3.2 testing conditions
Liquid phase chromatogram condition
Chromatographic column: Agilent RRHT ZORBAX Eclipse Plus C18(2.1 * 100mm, 1.8-Micron); Column temperature: 40 ℃; Mobile phase: methanol-0.25% formic acid solution (V/V)=52:48, flow velocity: 0.2mL/min; Sampling volume: 10 μ L.
Mass spectrum condition
Source parameters: Capillary4000V, Drying Gas9L/min, Neb Pressure30psi, Gas Temp:350 ℃, ESI electrospray ionization source, adopts anion to detect, the many reactive ion monitorings of MRM() mode, detect ion pair and be respectively:
Naringin: 579.2/271.0, Fragmentor:200V, Collision Energy:35V;
Naringenin: 271.0/151.0, Fragmentor:90V, Collision Energy:20V;
Isoquercitrin: 463.0/299.8, Fragmentor:130V; Collision Energy:25V.
3.3 plasma sample processing methods
Linearity and QC sample preparation methods: get blank plasma 50 μ L, naringin/naringenin the reference substance solution that adds respectively 10 μ L series concentration, mix, make naringin concentration and be respectively: 9.78,19.55(QC L), 97.76,195.52(QC M), 977.60,1955.20(QC H) ng/mL and naringenin concentration is respectively: 4.07,10.18(QC L), 20.36,101.80(QC M), 203.60,1018.00(QC H), the plasma sample of 2036.00ng/mL.In the blood plasma after mixing, add GRD beta-glucuronidase 10 μ L(10U/ μ L), mix 37 ℃ of water-bath 2h.After taking-up, add interior mark reference substance solution 10 μ L, after mixing, add after 2% formic acid 6 μ L acid, add again ethyl acetate 800 μ L, vortex 3min, 10, the centrifugal 10min of 000rpm, shifts supernatant to new centrifuge tube, adds ethyl acetate 400 μ L after the ultrasonic 30s of residue again, vortex 3min, the centrifugal 10min of 10,000rpm, merge supernatant and volatilize, add 100 μ L mobile phases to redissolve, vortex 3min after ultrasonic 30s, after the centrifugal 10min of 13,000rpm, getting 10 μ L supernatant sample introductions measures.
Plasma sample preparation method: get plasma sample 50 μ L, add GRD beta-glucuronidase 10 μ L(10U/ μ L), mix 37 ℃ of water-bath 2h.After taking-up, add 50% methanol aqueous solution (v/v), 20 μ L and inner mark solution 10 μ L, after mixing, add after 2% formic acid (V/V), 6 μ L acid, add again ethyl acetate 800 μ L, vortex 3min, the centrifugal 10min of 10,000rpm, shift supernatant to new centrifuge tube, after the ultrasonic 30s of residue, add again ethyl acetate 400 μ L, vortex 3min, 10, the centrifugal 10min of 000rpm, merge supernatant and volatilize, add 100 μ L mobile phases to redissolve, vortex 3min after ultrasonic 30s, after the centrifugal 10min of 13,000rpm, getting 10 μ L supernatant sample introductions measures.
Plasma sample dilution process: when plasma sample records concentration and exceeds the range of linearity, will as above operate after this diluting blood sample with blank plasma, extension rate is determined to exceed situation again.
The mensuration of 3.4 plasma samples
Unknown sample is measured by " plasma sample processing method " lower operation, and each analyzes a batch standard curve of preparation, prepares the QC sample of basic, normal, high 3 concentration simultaneously, and the QC sample of each concentration carries out two-sample analysis.According to each, analyze the concentration that the standard curve of criticizing calculates QC sample and unknown sample.The 15%(minimum point that allows at most the sample of two variable concentrations to exceed theoretical value in above-mentioned QC sample is 20%), otherwise this batch data is invalid.
AUC0-t after animal subject administration, Cmax and Tmax adopt mean ± standard deviation to be described.The value of Cmax and Tmax is directly read from data; Pharmacokinetic parameter is from DAS2.0 software statistics result.
4 experimental results
After naringin raw material medicine and liquid preparation oral administration when pharmacokinetics and medicine curve in Table 1 and Fig. 1.When naringin and hydroxypropyl beta cyclodextrin mol ratio are 1:3, preparation improves with respect to crude drug inanimate object availability, and relative bioavailability is 98.23 ± 32.96%.When naringin and hydroxypropyl beta cyclodextrin mol ratio are 1:6 and 1:10, bioavailability significantly improves, mol ratio 1:6 formula is better than mol ratio 1:10 formula, it is visible when hydroxypropyl beta cyclodextrin ratio is too high, effect is run counter to desire, therefore prescription is optimum formula because naringin and hydroxypropyl beta cyclodextrin molar ratio being controlled between 1:4-1:10.By experimental result, learn that naringin liquid preparation has improved oral absorption and the bioavailability of naringin, optimum formula liquid preparation is 1.5 times of crude drug bioavailability.
The different prescription of table 1. preparation is in SD Pharmacokinetics in Rat parameter comparison (mean ± S.D., n=8).
* there are significant difference, p<0.05. with matched group ratio
Embodiment 12: the experiment of naringin liquid preparation taste masking
Method: in different prescription ratio allotment oral liquids, by 40 volunteers, taste, each prescription is given a mark, narration mouthfeel, statistical result draws the combination of more excellent prescription.Marking detailed rules and regulations: tasteless is 0 minute; Bitterness, the negative mouthfeel such as bad smell is made negative score, and scope is-1～-10; Sweet taste, the good to eat mouthfeel such as fragrance is just made score, and scope is 1～10.Result is as follows:
The comparison of table 2 single correctives taste masking result
As shown in table 2, the contrast liquid taste that volunteer feedback does not add any correctives is extremely bitter, cannot entrance; Prescription 1 after hydroxypropyl beta cyclodextrin enclose, bitterness reduces a lot, but still has bitterness, and has a kind of new disagreeable taste, and supposition is the taste that hydroxypropyl beta cyclodextrin is brought into; Separately, with the prescription 2 of syrup seasoning, front taste is pleasantly sweet, but aftertaste bitterness is very heavy and continuity for a long time.Through this test draw independent use wherein a kind of correctives cannot cover bitterness and bad smell, mouthfeel is undesirable.
Table 3 is by the taste masking comparison on the liquid preparation basis after hydroxypropyl beta cyclodextrin enclose
As shown in table 3, by continuing taste masking on the basis after hydroxypropyl beta cyclodextrin enclose, sweet taste is more obvious, and the bitterness of a large portion is covered.It is sweet that all prescriptions are front taste, and aftertaste still has some bitterness, but bitterness can accept, and sweet taste accounts for leading, and because individual mouthfeel differs, someone has a preference for the syrup that sweet taste is heavy, and someone has a preference for the salubrious low concentration sucrose taste of selecting.But the strange taste that front taste also has HP-β-CD to bring into except sweet taste cannot be covered, and this taste makes mouthfeel poor.
Table 4 is by the taste masking comparison on the liquid preparation basis after hydroxypropyl beta cyclodextrin enclose
As shown in table 4, mogroside has good sweet taste and naturally pure and fresh, although aspartame and acesulfame potassium are sweet, has introduced other strange taste simultaneously, and just like the taste of metal, plastics, mouthfeel is bad, in final prescription, casts out.
Table 5 covers by essence the abnormal flavour that hydroxypropyl beta cyclodextrin is introduced
As shown in table 5, volunteer feedback is good without essence by essence taste masking mouthfeel, and essence can be covered the abnormal flavour of hydroxypropyl beta cyclodextrin, wherein best with Fructus Citri sinensis taste, add after essence, oral liquid bitterness is very light and only in aftertaste, occur, mate the most with the taste of Fructus Citri junoris, naturally pure, taste is as fruit juice.
Can obtain by experiment, single correctives cannot reach the mouthfeel of expection, needs specific combination formula, and synergism, learns from other's strong points to offset one's weaknesses mutually, could promote mouthfeel and cover disagreeable taste.The present invention finds to pass through certain combination matching of enclose, sweeting agent and edible essence, the bitterness of naringin oral liquid can be covered, and clean taste is good to eat, and taste is as fruit juice, and attracting babies patient uses.
Claims (6)
1. a taste masking naringin oral liquid, is characterized in that described oral liquid consists of by weight following component:
1 part of naringin, cyclodextrin or hydroxypropyl beta cyclodextrin 12-31 part, correctives 1-40 part, right amount of auxiliary materials.
2. oral liquid as claimed in claim 1, is characterized in that, described correctives comprises sweeting agent and essence; Wherein, described sweeting agent is one or more in steviosin, sorbitol, mannitol, maltose alcohol, glycyrrhizin, mogroside, stem tea element, sucralose, sucrose; Described essence is one or more in orange flavor, grape essence, strawberry essence, flavoring pineapple essence, peach flavor, apple essence, Mint Essence, cacao essence, Fructus Citri Limoniae essence.
3. oral liquid as claimed in claim 2, it is characterized in that, described dosage of sucrose is between 10-40 part, steviosin, sorbitol, mannitol, maltose alcohol, glycyrrhizin, mogroside, stem tea element consumption are between 1-15 part, sucralose consumption is between 0.001-1 part, and essence consumption is between 0.125-1 part.
4. oral liquid as claimed in claim 2, is characterized in that, described sweeting agent is sucrose, and described essence is orange flavor or strawberry essence, and sucrose is 18.75 parts by weight, and orange flavor is 0.5 part, and strawberry essence is 0.5 part.
5. oral liquid as claimed in claim 1, it is characterized in that, described adjuvant comprises one or more in surfactant, cosolvent, antiseptic, pH adjusting agent, coloring agent, antioxidant, wherein, described surfactant or cosolvent comprise that fatty acid Pyrusussuriensis is smooth, one or more the combination in Polysorbate, poloxamer, polyoxyethylene ether, Oleum Ricini, castor oil hydrogenated, polyvinylpyrrolidone, propylene glycol, glycerol, meglumine; Described antiseptic comprises that a kind of meeting in parabens, benzoic acid and salt thereof, sorbic acid and salt thereof is several; Described pH adjusting agent is water solublity regulator, comprises one or more in phosphoric acid, acetic acid, sodium acetate, citric acid, disodium citrate, citric acid trisodium, sodium citrate, potassium citrate, sodium carbonate, sodium bicarbonate; Described antioxidant comprises one or more in sulfurous acid, sulphite, bisulfites, gallic acid and salt cysteine, ascorbic acid and salt thereof.
6. the preparation method of oral liquid as claimed in claim 1, it is characterized in that, comprise the following steps: it is appropriate to get purified water, by recipe quantity, add naringin, the jolting in constant temperature air bath of cyclodextrin or hydroxypropyl beta cyclodextrin is complete to dissolving enclose, add again correctives and right amount of auxiliary materials, finally regulate pH to 4, add simple syrup to full dose.
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| CN110025568A (en) * | 2019-03-06 | 2019-07-19 | 广州中天康顺生物医药有限公司 | A kind of thixotroping pharmaceutical hydrogel matrix and its shaddock ped glycosides formulation and preparation method |
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| CN115413707B (en) * | 2022-10-14 | 2024-05-24 | 广东李金柚农业科技有限公司 | Anti-browning agent for fruits and vegetables, and preparation method and application method thereof |
| CN115919756A (en) * | 2022-10-19 | 2023-04-07 | 梅州市珍宝金柚实业有限公司 | Golden pomelo raw pulp oral liquid and preparation method and application thereof |
| CN116270457A (en) * | 2023-03-22 | 2023-06-23 | 浙江贝灵生物医药有限公司 | Mixed liquid pharmaceutical adjuvant for clinical preparation of medicines and preparation method thereof |
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