CN1931293A - Oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid and its prepn process - Google Patents

Oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid and its prepn process Download PDF

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Publication number
CN1931293A
CN1931293A CN 200610104622 CN200610104622A CN1931293A CN 1931293 A CN1931293 A CN 1931293A CN 200610104622 CN200610104622 CN 200610104622 CN 200610104622 A CN200610104622 A CN 200610104622A CN 1931293 A CN1931293 A CN 1931293A
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oil
surfactant
oral liquid
rhizoma acori
acori graminei
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CN100448430C (en
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欧阳五庆
吴旭锦
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Northwest A&F University
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Northwest A&F University
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Abstract

The oil-in-water nanometer grassleaved sweetflag oil emulsion oral liquid consists of surfactant, oil, grassleaved sweetflag oil and distilled water. Its preparation process includes the following steps: weighing surfactant with or without co-surfactant; calculating HLB value and selecting oil phase for reaching emulsifying HLB value near that of the surfactant phase; changing the ratio between the surfactant phase and the oil phase regularly; adding grassleaved sweetflag oil into surfactant through stirring; adding distilled water slowly at 20-25 deg.c to form clear and flowing O/W type nanometer emulsion liquid. The nanometer grassleaved sweetflag oil emulsion preparing process results in raised medicine stability, raised bioavailability, delayed in vivo metabolism time, reduced supplementary material amount, lowered production process and wide medicine market foreground.

Description

A kind of oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid and preparation method thereof
Technical field
The invention belongs to field of medicaments, relate to a kind of pharmaceutical product and preparation method thereof, specifically oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid of a kind of transparent and stable and preparation method thereof.
Background technology
Epilepsy is common nervous system chronic disease, and China's prevalence is 3~7%, and sickness rate is 5~7%.Epilepsy has outbreak repeatedly, stitches the clinical characters that continuous difficulty heals, and patient and families of patients are all caused heavy psychosoma convulsion and mental burden.During outbreak, often can concurrent other injuries, even threat to life, to the individual, there is significant damage in society.Present clinical most western medicine of using 20% become intractable epilepsy but still have an appointment, and the Western medicine toxic and side effects is bigger, so be necessary development of new antiepileptic from the Chinese medicine of China.Rhizoma Acori Graminei oil is one of main active of Chinese medicine Rhizoma Acori Graminei, has pharmacologically active widely, Rhizoma Acori Graminei volatile oil has the unify effect of digestive system of central nervous system, autonomic nervous system, hormonal system, cardiovascular system of regulating, its pharmacological action comprises out convulsion, have one's ideas straightened out and eliminate the phlegm, the mind calming and mentality promoting, hypnosis, vital energy regualting and blood circulation-promoting, loose wind damp eliminating, removing dampness to restore normal function of the stomach, cough-relieving, spasmolytic, relieving asthma etc., but topmostly shows as the calm anti-frightened effect of maincenter.The anticonvulsant action that Rhizoma Acori Graminei oil is good more and more causes extensive concern in recent years.Rhizoma Acori Graminei oil is a fat-soluble medicine, yellow to the brown thick liquid, have similar Camphora abnormal smells from the patient, be soluble in ethanol, methanol, ethyl acetate etc., water insoluble, unstable volatile, thereby be difficult for being processed into injection and tablet, and loss is bigger in the course of processing, the clinical treatment that is used for difficult and complicated illness such as epilepsy grand mal, syncope due to accumulation of phlegm, calentura coma, forgetful, apoplectic aphasia, tinnitus, pulmonary encephalopathy, alzheimer disease, upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis and other diseases.
Summary of the invention
With not enough, the purpose of this invention is to provide evenly accurate, the stay-in-grade Rhizoma Acori Graminei oil nanometer emulsion oral liquid of a kind of content at above-mentioned prior art problems.
The technical scheme that realizes the foregoing invention purpose is an oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, comprises that mass percent is:
Surfactant 21%~45%
Oil 4.03%~10.00%
Rhizoma Acori Graminei oil 0.1%~15.0%
Distilled water 45%~70%
In the selection of surfactant, the present invention selects the nonionic surfactant of avirulence and good biocompatibility for use.Nonionic surfactant is more stable in solution, is not subject to the influence of strong electrolyte, inorganic salts, also is not subject to the influence of soda acid, and good with the compatibility of other surfactants, and haemolysis is less.In theory, the preparation of O/W type nanometer emulsion needs the HLB value of surfactant between 8~18, consider preparation technology's simplicity, be the stability of the easy formation of nano-emulsion and the nano-emulsion for preparing, the present invention selects the liquid nonionic surfactant of HLB between 10~15 for use, and is perhaps composite with the non-ionic surface active agent of a kind of HLB<10.Available surfactant has: any in castor oil polyoxyethylene ether (as EL-40), castor oil hydrogenated polyoxyethylene ether (as RH-40), tween 80 and the Arlacel-80 or several mixture.
The present invention is according to when the HLB of the required surfactant of emulsifying oil phase is close with surfactant, the principle that formed emulsion is stable, the oils and fats of selecting for use have any or several mixture of liquid paraffin, vitamin E oil, Semen Tritici aestivi germ oil, almond oil, ethyl acetate and olive oil.Be in a liquid state, do not have bad abnormal smells from the patient under these oily room temperature.
Another object of the present invention provides the preparation method of oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, and step is as follows:
(1) preparation of surfactant phase takes by weighing surfactant by formula proportion, use separately or with help surface activity composite in proportion, calculate the HLB value of this system, stir.The HLB value of common emulsifying agent can be found in some chemical industry handbooks, as " the chemical products handbook of chemical industry publishing house.Because hydrophile-lipophile balance (HLB) value of surfactant has additive properties, the available quality averaging method is obtained the HLB value of surfactant.For example, after two kinds of surfactant A, B mixed, the hydrophile-lipophile balance HLBAB value of its mixed surfactant was
HLBAB=(WAHLBA+WBHLBB)/(WA+WB)
WA in the formula, WB---the quality of blend surfactants A, B;
HLBA, the HLB value of HLBB---surfactant A, B.
(2) preparation of oil phase is according to the HLB value of surfactant phase, selects any or several oil, transfers its ratio, makes the required HLB value of its emulsifying close with surfactant HLB mutually.
(3) in 9: 1~1: 9 the rule change surfactant phase and the ratio of oil phase, to the Rhizoma Acori Graminei oil that wherein adds formula proportion, stirring makes it whole dissolvings, fully stir at 20 ℃~25 ℃ slow adding distil waters, until forming clear, viscosity is little and has mobile yellow or colourless O/W type nanoemulsions.
The present invention detects through transmission electron microscope, and droplet diameter distribution is between 10~100nm, and outward appearance is yellow or colourless transparent liquid, has good stability:
1, ageing stability
Ageing stability is meant when nanometer emulsion oral liquid is preserved under room temperature nature change condition, and outward appearance prolongs and the degree that changes in time.This Rhizoma Acori Graminei oil nanometer emulsion oral liquid is transparent lastingly, does not find muddy or precipitation, illustrates that then ageing stability is good.This is an important indicator estimating nanometer emulsion oral liquid.
2, heat storage stability
This Rhizoma Acori Graminei oil nanometer emulsion oral liquid is placed test tube, and sealing places 37 ℃ of constant water bath box to store 14 days, this liquid heat storage back appearance transparent.
3, anti-freeze-stable
With this Rhizoma Acori Graminei oil nanometer emulsion oral liquid in refrigerator-4 ℃ preserve a week after.Return to room temperature.If nanometer emulsion oral liquid becomes solids at-4 ℃, return to room temperature, return to transparent, and place one week the back continue transparently, think that then freezing-resistance is good.
4, accelerated stability
This Rhizoma Acori Graminei oil nanometer emulsion oral liquid is placed test tube, and sealing under the rotating speed of 15000r/min centrifugal 20 minutes, does not have layering, still clear.
Oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid of the present invention have analgesia, analgesic, dispel the wind, anti-inflammation, atherosclerosis, anticoagulant, blood pressure lowering and strengthen many-sided effect such as cellular immune function and antioxidation.Be used for the treatment of difficult and complicated illness such as epilepsy grand mal, syncope due to accumulation of phlegm, calentura coma, forgetful, apoplectic aphasia, tinnitus, pulmonary encephalopathy, alzheimer disease, upper respiratory tract infection, bronchitis, bronchial asthma, acute and chronic cholecystitis, cholelithiasis and other diseases.Usage: oral, according to the different syndromes various dose.For the lighter oral 0.13g of epileptic's degree every day, the oral 0.15g of moderate trouble patient, the oral 0.4g of severe patient.
Oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid of the present invention compared with prior art, has the following advantages:
1) thermodynamic stability height.Operation is fairly simple during preparation, not phase-splitting, do not precipitate, and bin stability improves;
2) light transmission is good, and any inhomogeneities or sedimentary existence easily are found, and sensible quality improves;
3) antiseptic property improves, because decentralized photo liquid is smaller, can prevent the intrusion of antibacterial, increases the dissolubility of some active ingredients simultaneously;
4) have good solubilization, can effectively improve the dissolubility of insoluble drug;
5) can improve the dissolubility of Rhizoma Acori Graminei oil, delay the regression time of Rhizoma Acori Graminei oil, thereby improved the bioavailability of Rhizoma Acori Graminei oil;
6) method technology is simple, is fit to large-scale production.
The specific embodiment
Below further set forth the beneficial effect of medicine of the present invention by pharmacodynamics test and contrast test.
The pharmacodynamics test of test example 1 Rhizoma Acori Graminei oil nanometer emulsion oral liquid
Epileptic's 40 examples are made a definite diagnosis in choosing clinically, change traditional Chinese medical science mind medical treatment, and the course of disease is the shortest 8 months, and is the longest 35 years, wherein male's 28 examples account for 70%, one women, 12 examples, account for 30%, minimum 4 years old of age, maximum 54 years old, simple property grand mal accounts for 76%, 40 routine patient and treated by spasmolytic medicine after a while, but symptom can not be controlled, take the Rhizoma Acori Graminei nanometer emulsion oral liquid after 3 months, produce effects 24 examples account for 60% in 40 examples, effective 10 examples account for 25%, and invalid 6 examples account for 15%.
The contrast test of test example 2 Rhizoma Acori Graminei oil nanometer emulsion oral liquid epilepsy drug effects and other preparations
Epileptic's 60 examples are made a definite diagnosis in choosing clinically, the course of disease is the shortest 6 months, the longest 22 years, patient's 16 examples that degree is lighter, moderate trouble patient 20 examples, severe patient's 24 examples, respectively be divided into 2 groups, select for use the Rhizoma Acori Graminei oil injection (to provide respectively by my school Chinese veterinarian's laboratory, Rhizoma Acori Graminei content is 0.01g/ml, the lighter patient 0.2ml intramuscular injection of degree every day, moderate trouble patient 0.2ml~0.3ml intramuscular injection, severe patient 0.3ml~0.8ml intramuscular injection) and the Rhizoma Acori Graminei oil nanometer emulsion oral liquid (Rhizoma Acori Graminei content is 15mg/g, the lighter oral 0.13g of patient of degree every day, the oral 0.15g of moderate trouble patient, the oral 0.4g of severe patient) treat, the results are shown in Table 1.
The drug effect of table 1 Rhizoma Acori Graminei oil nanometer emulsion oral liquid and the comparative test result of other preparations
The patient that degree is light Moderate trouble patient Severe patient
The result Rhizoma Acori Graminei oil nanometer emulsion oral liquid treatment group Rhizoma Acori Graminei oil injection for treating group Rhizoma Acori Graminei oil nanometer emulsion oral liquid treatment group Rhizoma Acori Graminei oil injection for treating group Rhizoma Acori Graminei oil nanometer emulsion oral liquid treatment group Rhizoma Acori Graminei oil injection for treating group
Effective 2 examples of produce effects 6 examples Effective 3 examples of produce effects 5 examples Effective 3 examples of produce effects 7 examples Effective 3 examples of produce effects 7 examples Effective 1 example of produce effects 11 examples Effective 3 examples of produce effects 9 examples
The result of table 1 clearly shows Rhizoma Acori Graminei oil nanometer emulsion oral liquid effective than Rhizoma Acori Graminei oil injection, and consumption is few, and is easy to use.
The contrast test of the test example antasthmatic drug effect of 3 Rhizoma Acori Graminei oil nanometer emulsion oral liquids and other preparations
Choosing suffers from patient's 40 examples of asthma clinically, be divided into 2 treatment groups, first group is Rhizoma Acori Graminei oil nanometer emulsion oral liquid (Rhizoma Acori Graminei content is 15mg/g) treatment group, totally 20 examples, woman's 8 examples, male 12 examples, 56~82 years old age, 64.3 years old mean age, 2 treatments of oral for each person every day 0.1g Rhizoma Acori Graminei oil nanometer emulsion oral liquid.Second group is Rhizoma Acori Graminei oil injection (provided by my school Chinese veterinarian's laboratory, Rhizoma Acori Graminei content is 0.01g/ml) treatment group, totally 20 examples, woman's 6 examples, male 14 examples, 48~73 years old age, 59.4 years old mean age, 2 treatments of intramuscular injection 0.2ml Rhizoma Acori Graminei oil injection for each person every day.More than 2 groups of patients all cooperate the conventional antibiotic that use.In first group of 20 example, use produce effects 10 examples after 2 days as a result, effective 8 examples, invalid 2 examples, obvious effective rate 50%, total effective rate 90% uses produce effects 14 examples after 7 days, effective 5 examples, invalid 1 example, obvious effective rate 70%, total effective rate 95%.In second group of 20 example, use produce effects 7 examples after 2 days, effective 10 examples, invalid 3 examples, obvious effective rate 35%, total effective rate 85% uses produce effects 12 examples after 7 days, effective 6 examples, invalid 4 examples, obvious effective rate 60%, total effective rate 90%.That can obviously find out the Rhizoma Acori Graminei oil nanometer emulsion oral liquid is better than the Rhizoma Acori Graminei oil injection to the asthma effect, and consumption is few.
Below the embodiment that provides by the inventor further set forth the preparation method of Rhizoma Acori Graminei oil nanometer emulsion oral liquid of the present invention.
Embodiment 1
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing tween 80 1.8g, Arlacel-80 0.6g, liquid paraffin 0.6g, put into beaker, under 25 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, the 0.1g Rhizoma Acori Graminei oil is directly added, stir fully, to wherein slowly adding distilled water, manually stir on adding distil water limit, limit then, the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is stable yellow transparent oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its gross weight is 10.0g.
Embodiment 2
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing polyoxyethylene hydrogenated Oleum Ricini 3.6g, Semen Tritici aestivi germ oil 0.4g, vitamin E oil 0.05g, put into beaker, under 20 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, the 0.5g Rhizoma Acori Graminei oil is directly added, stirring is until whole dissolvings, and to wherein slowly adding distilled water, manually stir on adding distil water limit, limit then, the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is stable water white transparency oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its gross weight is 10.0g.
Embodiment 3
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing polyoxyethylene hydrogenated Oleum Ricini 4.5g, olive oil 0.5g, put into beaker, under 25 ℃ of room temperature conditions, manually stir, the 1.0g Rhizoma Acori Graminei oil is directly added, stir until whole dissolvings with its abundant mix homogeneously, then to wherein slowly adding distilled water, manually stir on adding distil water limit, limit, and the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is stable water white transparency oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its gross weight is 10.0g.
Embodiment 4
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing polyoxyethylene hydrogenated Oleum Ricini 4.0g, almond oil 1.0g, put into beaker, under 24 ℃ of room temperature conditions, manually stir, the 1.5g Rhizoma Acori Graminei oil is directly added, stir until whole dissolvings with its abundant mix homogeneously, then to wherein slowly adding distilled water, manually stir on adding distil water limit, limit, and the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, when system unexpected when thinning, what produced this moment promptly is stable water white transparency oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its gross weight is 10.0g.
Embodiment 5
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing tween 80 1.40g, Arlacel-80 0.70g, liquid paraffin 0.90g, put into beaker, under 20 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, the 0.01g Rhizoma Acori Graminei oil is directly added, stir fully, to wherein slowly adding distilled water, manually stir on adding distil water limit, limit then, the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is stable yellow transparent oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its gross weight is 10.0g.
Embodiment 6
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing polyoxyethylene castor oil 4.5g, ethyl acetate 0.5g, vitamin E oil 0.03g, put into beaker, under 20 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, the 0.07g Rhizoma Acori Graminei oil is directly added, stir fully, to wherein slowly adding distilled water, manually stir on adding distil water limit, limit then, the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is stable water white transparency oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its weight is 11.1g.
Embodiment 7
With determining optimal proportion according to 9: 1~1: 9 rule drafting pseudo-ternary phase diagram by calculating HLB value selected oil and surfactant, cosurfactant.Accurately take by weighing polyoxyethylene hydrogenated Oleum Ricini 3.6g, ethyl acetate 0.4g, vitamin E oil 0.02g, put into beaker, under 24 ℃ of room temperature conditions, manually stir its abundant mix homogeneously, the 0.8g Rhizoma Acori Graminei oil is directly added, stir fully, to wherein slowly adding distilled water, manually stir on adding distil water limit, limit then, the system viscosity is less during beginning, along with the increase of the distillation water yield, it is sticky that system can become, and this moment, liquid crystal state or water-in-oil type nanoemulsion may appear in system, continue to drip and constantly stir, unexpected when thinning when system, what produced this moment promptly is stable water white transparency oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, claims that its weight is 10.42g.

Claims (9)

1, a kind of oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid, it is made up of the following weight proportion raw material: surfactant 21%~45%, oil 4.03%~10.00%, Rhizoma Acori Graminei oil 0.1%~15.0%, distilled water 45%~70%.
2, Rhizoma Acori Graminei oil nanometer emulsion oral liquid according to claim 1, it is characterized in that: described surfactant is a nonionic surfactant.
3, Rhizoma Acori Graminei oil nanometer emulsion oral liquid according to claim 2 is characterized in that: described nonionic surfactant is one or more the mixture in castor oil polyoxyethylene ether, castor oil hydrogenated polyoxyethylene ether, tween 80 and the Arlacel-80.
4, Rhizoma Acori Graminei oil nanometer emulsion oral liquid according to claim 2 is characterized in that: described oil is one or more mixture of liquid paraffin, vitamin E oil, almond oil, Semen Tritici aestivi germ oil, ethyl acetate and olive oil.
5, according to described any Rhizoma Acori Graminei oil nanometer emulsion oral liquid of claim 1~4, it is characterized in that: this Rhizoma Acori Graminei oil nanometer emulsion oral liquid particle diameter is 10nm~100nm.
6, prepare the method for the described Rhizoma Acori Graminei oil nanometer emulsion oral liquid of claim 1, it is characterized in that, comprise the following steps:
(1) preparation of surfactant phase takes by weighing surfactant by formula proportion, use separately or with help surface activity composite in proportion, calculate the HLB value of this system, stir.
(2) preparation of oil phase is selected one or more oil according to the HLB value of surfactant phase, transfers its ratio, makes the required HLB value of its emulsifying close with surfactant HLB mutually.
(3) in 9: 1~1: 9 the rule change surfactant phase and the ratio of oil phase, to the Rhizoma Acori Graminei oil that wherein adds formula proportion, fully stir, fully stir at 20 ℃~25 ℃ slow adding distil waters, until forming clear, viscosity is little and has mobile yellow or water white O/W type nanometer emulsion.
7, the application of the described Rhizoma Acori Graminei oil nanometer emulsion oral liquid of claim 1 in the medicine of the insane pain of preparation treatment.
8, the application of the described Rhizoma Acori Graminei oil nanometer emulsion oral liquid of claim 1 in the medicine of preparation treatment or prevention of asthma.
9, the application of the described Rhizoma Acori Graminei oil nanometer emulsion oral liquid of claim 1 in the medicine of preparation treatment or prevention of stroke.
CNB2006101046224A 2006-09-21 2006-09-21 Oil-in-water type nanometer grassleaved sweetflag oil emulsion oral liquid and its prepn process Expired - Fee Related CN100448430C (en)

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