CN109700762A - A kind of mixing Osthole foaming microemulsion and preparation process - Google Patents

A kind of mixing Osthole foaming microemulsion and preparation process Download PDF

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Publication number
CN109700762A
CN109700762A CN201910182031.6A CN201910182031A CN109700762A CN 109700762 A CN109700762 A CN 109700762A CN 201910182031 A CN201910182031 A CN 201910182031A CN 109700762 A CN109700762 A CN 109700762A
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osthole
microemulsion
deionized water
foaming
ethyl oleate
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杨荣平
张传辉
江敏渝
王云红
周文杰
赵崧钧
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Chongqing Yue Hua Yue Biotechnology Co Ltd
Southwest University
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Chongqing Yue Hua Yue Biotechnology Co Ltd
Southwest University
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    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention proposes a kind of Osthole foaming microemulsion and preparation method thereof of mixing optimization, belongs to drug and medicine manufacture technology field.Osthole foaming microemulsion includes Osthole and auxiliary material, and wherein auxiliary material includes ethyl oleate, mixed surfactant and deionized water；The mixed surfactant includes Emulsifier EL-60 40 and diethylene glycol monoethyl ether.Ethyl oleate: polyoxyl 40 hydrogenated castor oil: diethylene glycol monoethyl ether: deionized water=8.13:14.81:6.58:71.44.The invention has the benefit that the solubility of Osthole is at least improved 201 times by Osthole foaming microemulsion emulsification prescription, achieve the purpose that, to its solubilising, this provides certain guidance meaning for the later period Osthole foaming further preparations shaping of micro emulsion.

Description

A kind of mixing Osthole foaming microemulsion and preparation process
Technical field
The invention belongs to drug and medicine manufacture technology field, in particular to a kind of Osthole foaming of mixing optimization is micro- Emulsion and its preparation process.
Background technique
Vaginitis is common gynecological disease and frequently-occurring disease, is the total of a variety of vaginal mucosa diseases caused by cause pathogeny imcrobe infection Claim.Trichomonas, bacillary and monilial vaginitis[3]It is clinical most commonly seen.Osthole is a kind of coumarin kind compound, With inflammation-resisting itch-stopping, anti-bacteria and anti-virus improves immunity and antianaphylactic effect, trichomonas treating based on clinical external application There is unique curative effect in terms of vaginitis and eczema of vulva.But due to Osthole poorly water-soluble, deposit solubility in vivo it is low, The problems such as poor bioavailability, limits clinical application.
The solubilising of insoluble drug is still one of the emphasis of current Pharmaceutical study, and micro emulsion is as ideal stability Pharmaceutical carrier, partial size is small, and property is stable and permeability is strong, improves bioavilability, reduces toxic side effect.But needed in micro emulsion using Surfactant and cosurfactant, they are generally all irritant to mucous membrane, therefore find the efficient surface-active of low toxicity Agent and cosurfactant, or even low level of surfactant is found by process optimization and is asked as the emphasis of current micro emulsion research Topic.
Foaming microemulsion is a kind of micro emulsion can be sprayed foam without propellant using specific device Novel medicine feeding mode.Compared to lotion and emulsifiable paste on the market, foaming microemulsion practicability and compliance are more preferable, can effectively promote Drug is set to reach lesion, convenient drug administration and delivery period is long, the generation of foam more can be reduced the stimulation to inflammation part.Than Aerosol, foaming microemulsion do not add propellant, reduces irritation, and cost reduces, and can come for the treatment zone of vaginitis more excellent The product of matter.
Summary of the invention
For the solubilized problem of Osthole, the present invention is on the basis of early stage work study, by measuring Osthole Solubility in auxiliary material, screening solubilizing effect preferably oily phase, surfactant, cosurfactant, draws ternary phase diagrams And the optimal mixture experiment design optimization of D- is combined to obtain optimal foaming microemulsion formulation.
A kind of Osthole of mixing foams microemulsion, including Osthole and auxiliary material, wherein auxiliary material include ethyl oleate, Mixed surfactant and deionized water；The mixed surfactant includes Emulsifier EL-60 40 and diethylene glycol list second Base ether.
Further, in the auxiliary material each ingredient mass percent are as follows: ethyl oleate 1.30%~9.95%, mixture table Face activating agent 17.69%~27.92%, deionized water 65.73%~81.01%；
Further, the mass ratio of each ingredient is as follows in the auxiliary material:
Ethyl oleate: polyoxyl 40 hydrogenated castor oil: diethylene glycol monoethyl ether: deionized water=8.13:14.81: 6.58:71.44。
Further, the mass ratio of Osthole foaming each ingredient of microemulsion is as follows:
Ethyl oleate: polyoxyl 40 hydrogenated castor oil: diethylene glycol monoethyl ether: deionized water: Osthole= 8.13∶14.81∶6.58∶71.44∶1.36。
A kind of Osthole foaming microemulsion preparation method of mixing optimization, comprising the following steps:
S1, weigh by a certain percentage ethyl oleate, polyoxyl 40 hydrogenated castor oil, diethylene glycol monoethyl ether, go from Sub- water and Osthole, and sustained-release liquid is made in the mixing that is vortexed；
S2, above-mentioned sustained-release liquid is placed in 37 DEG C, is vibrated 24 hours in 150 revs/min of constant temperature oscillation case, then taken out；
S3, it is put into 10000 revs/min of centrifuge and is centrifuged 10 minutes, take supernatant.
Advantageous effects of the invention are as follows: the solubility of Osthole is at least improved 201 times by emulsification prescription, is reached To the purpose of its solubilising, this provides certain guidance meaning for later period Osthole foaming micro emulsion further preparations shaping.
Detailed description of the invention
Fig. 1 is micro emulsion pseudo-ternary phase diagram；
Fig. 2 is OD value two dimension contour map；
Fig. 3 is the current potential (A) and partial size (B) distribution map of optimizing prescriptions；
Fig. 4 is that the formation of foam of optimizing prescriptions can try hard to.
Specific embodiment
In order to make those skilled in the art be better understood when the purpose of the present invention, technical scheme and beneficial effects, below It is completely described with attached drawing is illustrated in conjunction with specific embodiments.
Embodiment 1
1, Osthole solubility test in each auxiliary material
It takes different oily phases, surfactant, cosurfactant about 2mL in plug test tube respectively, was added The Osthole bulk pharmaceutical chemicals of amount, be vortexed dispersion, shakes 48h in 37 DEG C of constant temperature oscillation casees, 10000r/min is centrifuged 10min, takes Clear liquid is diluted in right amount with dehydrated alcohol, is then measured solubility of the Osthole in various auxiliary materials, be the results are shown in Table 1.
Solubility of 1 Osthole of table in auxiliary material
As shown in table 1, Osthole ethyl oleate, PGPR, OP, ODO, Labrasol, EL-40, PEG-200, Dissolution in Transcutol HP is higher, thus quasi- these auxiliary materials of selection do further screening.
2, the drafting of ternary phase diagrams
The mass ratio (Km value) of selection surfactant and cosurfactant is respectively 1:1,2:1,3:1,4:1, by oil Mutually weighed respectively with mixed surfactant mass ratio for the ratio precision of 1:9,2:8,3:7,4:6,5:5,6:4,7:3,8:2,9:1 Oily phase, surfactant and cosurfactant mix, water are added dropwise under room temperature, magnetic agitation, until forming clear Micro emulsion.When appearance is no longer clarified, critical amount of water is recorded.By oil, water, mixed surfactant critical point quality percentage Than drawing curve in pseudo-ternary phase diagram, determining microemulsion region.The discovery of auxiliary material screening experiment, PEG-200 and ODO, PGPR, Labrasol be to the optimal cosurfactant of Osthole dissolubility and surfactant, but with dissolution optimum oil phase oleic acid Ethyl ester is hardly at cream.Therefore having chosen to the Transcutol HP that Osthole dissolubility is only second to PEG-200 is to help surface living Property agent and EL-40 be surfactant.Construct pseudo-ternary phase diagram such as Fig. 1, Km=in Km=3:1 in Km=4:1 in a, b, c Km=1:1 in 2:1, d；Sm indicates blended emulsifier；M indicates microemulsion region；G indicates gel area.As seen from the figure when Km=3:1, Microemulsion region is maximum, so the ratio of this experimental selection emulsifier and assistant for emulsifying agent is 3:1.
3, the optimal mixture experiment design optimization formulation of D-
On the basis of ternary phase diagrams, with oily phase (ethyl oleate) quality (X1), the quality (X2) of deionized water and mixture table The mass ratio of face activating agent (EL-40 and Transcutol HP) quality (X3) is investigation factor, with the drugloading rate of Osthole (Y1), gas release (Y2), half foam life period (Y3), partial size (Y4) are evaluation index, with 7.0 statistical software of Design Expert The optimal mixture experiment design optimization formulation of D- is carried out, is shown in Table 2, and weigh oily phase according to ratio shown in table 2, mixed surfactant, go Ionized water, is added excessive Osthole bulk pharmaceutical chemicals and is vortexed and mix, be placed in 37 DEG C, the oscillation of 150r/min constant temperature oscillation case for 24 hours, take Out, 10000r/min is centrifuged 10min, takes supernatant appropriate, dehydrated alcohol is added to dilute, and measures drugloading rate.According to ratio shown in table 2 Weigh gas release and foam half that oily phase, mixed surfactant, deionized water measure each micro emulsion under " 2.2 " guide for method It declines the phase.4 responses are carried out respectively " normalization " handle 4 normalizing values (OD) (Y1, Y2 and Y3 take ODmax, Y4 to take ODmin), on this basis, the weight coefficient for taking each OD value be 0.25 (4 indexs are in par in this experiment, therefore 0.25) weight coefficient is all.Experimental design and it the results are shown in Table 2.
The optimal mixture experimental designs of 2 D- of table and result
Serial number X1 X2 X3 Y1/(mg·g-1) Y2/cm Y3/min Y4/nm OD value
1 1.30 62.13 36.58 11.10 7.35 5.88 39.77 0.61
2 41.29 39.45 19.26 25.48 6.55 5.27 59.66 0.52
3 1.30 48.25 50.45 19.71 9.27 6.20 43.99 0.72
4 28.52 36.01 35.47 29.88 2.80 3.01 56.85 0.29
5 24.45 63.76 11.79 26.84 2.65 2.37 90.90 0.17
6 17.69 49.94 32.37 21.45 6.47 4.78 74.38 0.43
7 8.81 71.44 19.75 13.55 8.57 6.79 43.54 0.70
8 17.69 49.94 32.37 23.05 7.22 4.54 74.66 0.43
9 24.45 63.76 11.79 26.64 2.70 2.45 68.74 0.19
10 1.30 86.91 11.79 8.63 7.73 4.13 36.67 0.53
11 41.29 8.26 50.45 63.70 6.45 3.43 32.82 0.66
12 41.29 22.30 36.41 32.32 4.10 3.01 58.77 0.31
13 17.69 49.94 32.37 20.52 5.57 4.94 74.51 0.57
14 1.30 86.91 11.79 8.15 7.44 4.20 36.75 0.52
15 21.90 27.64 50.45 38.53 7.45 3.49 83.80 0.41
16 41.29 39.45 19.26 23.34 6.75 5.30 59.75 0.52
ODmax=(Yi- Ymin)/(Ymax- Ymin)
ODmin=(Ymax- Yi)/(Ymax- Ymin)
OD=0.25 × (OD1max+OD2max+OD3max+OD4min)
4, data analysis and formulation optimization
Regression fit and analysis are carried out with 4 kinds of mathematical models using 8.0 experimental design software of Design Expert, to return Returning the P value of model, losing quasi- item, multiple correlation coefficient, adjustment related coefficient and prediction multiple correlation coefficient is overall target, judges and selects Optimal regression model in 4 kinds of mathematical models is taken, the results are shown in Table 3.
3 Regression Analysis Result of table
The multiple correlation coefficient of 4 responses and its OD value is all higher, shows that Regression Model Simulator is preferable, the generation of regression equation Table is good, can Accurate Prediction actual conditions.The regression equation of model of fit:
Y1=-24.59X1+8.11X2+84.22X3+135.68X1X2+137.99X1X3-101.54X 2X3- 332.41X12X2X3-44.57X1X22X3-600.11X1X2X32；
Y2=147.47X1+7.50X2+92.63X3-287.74X1X2-454.99X1X3-162.55X 2X3+ 569.58X1X2X3-161.34X1X2(X1-X2)-125.15X1X3(X1-X3)+103.63X2X3(X2-X3)；
Y3=24.25X1+4.16X2+110.86X3-46.37X1X2-255.87X1X3-204.33X2 X3+ 335.99X1X2X3-23.19X1X2(X1-X2)+126.42X1X3(X1-X3)+153.22X2X3(X2-X3)；
Y4=1642.53X1+36.74X2-1561.40X3-2906.58X1X2-53.16X1X3-321 1.91X2X3- 6.32X1X2X3-2038.03X1X2(X1-X2)-5074.96X1X3(X1-X3)-2338.82X2X3(X2-X3)；
OD=1.36X1+0.51X2+15.20X3-3.13X1X2-30.44X1X3-28.45X2X3+39 .17X1X2X3- 0.88X1X2(X1-X2)+19.23X1X3(X1-X3)+20.52X2X3(X2-X3)。
According to optimum regression equation, Y1, Y2, Y3 and Y4 response are drawn using 8.0 statistical software of Design Expert OD value two dimension contour map, as shown in Figure 2.When ethyl oleate proportion is 1.30%~9.95%, blended emulsifier is 17.69%~27.92%, when water is 65.73%~81.01%, OD value is larger.Optimal prescription is ethyl oleate-polyoxyethylene Castor-oil plant 40- diethylene glycol monoethyl ether-deionized water-Osthole bulk pharmaceutical chemicals (8.13: 14.81: 6.58: 71.44: 1.36). Oily phase, blended emulsifier and Osthole bulk pharmaceutical chemicals are weighed with this ratio, is vortexed and mixes, are placed in 37 DEG C, the vibration of 150r/min constant temperature It swings case oscillation for 24 hours, takes out, 10000r/min is centrifuged 10min, takes supernatant to get Osthole foaming microemulsion.
Embodiment 2
Optimal prescription is pressed in the verifying of optimization formulation, and preparation foaming micro emulsion is repeated 3 times, ratio of adjuvant and test result are shown in Table 4.Each index actual value of result verification prescription shows that the optimal mixture experiment design of D- has standard to micro emulsion proportion close to predicted value True predictability.
The measured value of the optimization verifying prescription of table 4 is compared with predicted value
1, foaming micro emulsion physicochemical property characterization
The micro emulsion prepared by table four is taken to carry out the physics and chemistry such as current potential, partial size, polydispersity coefficient, solubility and drugloading rate to it Matter is characterized.
Appearance: frutus cnidii foaming microemulsion appearance is clear with light blue opalescent liquid.Partial size, polydispersion Coefficient and Zeta potential: the foaming micro emulsion average grain diameter is (43.54 ± 3.43) nm (n=3), average polydispersity coefficient (0.839 ± 0.092) % (n=3), average potential are (- 2.32 ± 0.78) mV (n=3), and particle diameter distribution and Potential distribution are as shown in Figure 3. According to taking appropriate medicine cream to be placed in without spraying device is promoted, utmostly presses once into glass dish, investigate formation of foam power, see Fig. 4.
Solubility: blank micro emulsion is mixed with water according to 1g: 50mL, adds excessive Osthole bulk pharmaceutical chemicals, measures snake The solubility of machine tool element in water.As a result the solubility of Osthole in water is 0.43mg/mL, and Osthole bulk pharmaceutical chemicals are in water In solubility be 2.14 μ g/mL, therefore this research optimize microemulsion formulation the solubility of Osthole is at least improved 201 Times.
Drugloading rate: precision weighs drug containing cream 0.1g, is placed in 10mL measuring bottle, adds dehydrated alcohol to dissolve and is diluted to scale, It is measured by chromatographic condition under " 2.1.3 " item.Calculate Osthole drugloading rate be 13.62mg/g.
2, temperature is tested
Precision weigh Osthole foaming micro emulsion it is appropriate, be sealed 10 days under the conditions of 4 DEG C, 25 DEG C, 60 DEG C, respectively at Observing its appearance within 0 day, 5 days, 10 days, whether there is or not changes, and measure medicament contg, partial size, gas release, half foam life period, to investigate sample Product stability, the results are shown in Table 5.As a result illustrate Osthole foaming micro emulsion be stored in 4 DEG C, 25 DEG C, 60 DEG C under the conditions of appearance uniform, Medicament contg, partial size, gas release, half-life period are without significant changes.
5 Osthole of table foaming micro emulsion temperature stability investigates result (n=3)
Present invention foaming microemulsion system significantly improves the solubility and dissolution rate of Osthole, due to Osthole raw material The dissolution of medicine not detected, thus be calculated with the minimum detection limit in this research, and the self-emulsifying prescription that this research optimizes is by snake The solubility of machine tool element at least improves 201 times, achieved the purpose that its solubilising, this for later period Osthole foam micro emulsion into One step preparations shaping provides certain guidance meaning.
Embodiment provided above has carried out further detailed description, institute to the object, technical solutions and advantages of the present invention It should be understood that embodiment provided above is only the preferred embodiment of the present invention, be not intended to limit the invention, it is all Any modification, equivalent substitution, improvement and etc. made for the present invention, should be included in the present invention within the spirit and principles in the present invention Protection scope within.

Claims (5)

  1. The microemulsion 1. a kind of Osthole of mixing optimization foams, it is characterised in that: including Osthole and auxiliary material, wherein auxiliary material Including ethyl oleate, mixed surfactant and deionized water；The mixed surfactant includes Emulsifier EL-60 40 And diethylene glycol monoethyl ether.
  2. The microemulsion 2. a kind of Osthole of mixing optimization according to claim 1 foams, which is characterized in that the auxiliary material In each ingredient mass percent are as follows: ethyl oleate 1.30%~9.95%, mixed surfactant 17.69%~27.92%, Deionized water 65.73%~81.01%.
  3. The microemulsion 3. a kind of Osthole of mixing optimization according to claim 2 foams, which is characterized in that the auxiliary material In each ingredient mass ratio it is as follows:
    Ethyl oleate: polyoxyl 40 hydrogenated castor oil: diethylene glycol monoethyl ether: deionized water=8.13:14.81:6.58: 71.44。
  4. The microemulsion 4. a kind of Osthole of mixing optimization according to claim 3 foams, it is characterised in that: Osthole The mass ratio of foaming each ingredient of microemulsion is as follows:
    Ethyl oleate: polyoxyl 40 hydrogenated castor oil: diethylene glycol monoethyl ether: deionized water: Osthole=8.13: 14.81∶6.58∶71.44∶1.36。
  5. The microemulsion preparation method 5. a kind of Osthole of mixing optimization foams, which comprises the following steps:
    S1, ethyl oleate, polyoxyl 40 hydrogenated castor oil, diethylene glycol monoethyl ether, deionized water are weighed by a certain percentage And Osthole, and sustained-release liquid is made in the mixing that is vortexed；
    S2, above-mentioned sustained-release liquid is placed in 37 DEG C, is vibrated 24 hours in 150 revs/min of constant temperature oscillation case, then taken out；
    S3, it is put into 10000 revs/min of centrifuge and is centrifuged 10 minutes, take supernatant.
CN201910182031.6A 2018-04-27 2019-03-11 A kind of mixing Osthole foaming microemulsion and preparation process Withdrawn CN109700762A (en)

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CN110711177A (en) * 2019-09-23 2020-01-21 山东第一医科大学(山东省医学科学院) Osthole microemulsion and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN110711177A (en) * 2019-09-23 2020-01-21 山东第一医科大学(山东省医学科学院) Osthole microemulsion and preparation method and application thereof
CN110711177B (en) * 2019-09-23 2022-03-25 山东第一医科大学(山东省医学科学院) Osthole microemulsion and preparation method and application thereof

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