Cinnamomum longepaniculatum essential oil self-microemulsion drug delivery system and preparation method thereof

Abstract

The invention discloses a Cinnamomum longepaniculatum essential oil self-microemulsion drug delivery system and a preparation method thereof, the system comprises an oil phase, an emulsifier and a co-emulsifier, the oil phase is Cinnamomum longepaniculatum essential oil; the system is mutually soluble with water in any proportion to form a transparent micro-blue microemulsion. The preparation method of the Cinnamomum longepaniculatum essential oil self-microemulsion drug delivery system adopts 30 emulsifiers and 8 co-emulsifiers, and comprises the following steps: step 1, preliminary screening of the emulsifiers; step 1.1, carrying out compatibility evaluation; step 1.2, carrying out self-emulsification evaluation; step 2, screening of a co-emulsifier; step 2.1, carrying out compatibility evaluation; step 2.2, carrying out self-emulsification evaluation; and step 3, Km value screening. The Cinnamomum longepaniculatum essential oil self-microemulsion drug delivery system provided by the invention has good stability.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of oil camphor essential oil self-microemulsion drug delivery system and its preparation, and particularly relates to an oil camphor essential oil self-microemulsion drug delivery system and a preparation method thereof. BACKGROUND

[0002] Oil camphor essential oil has strong bacteriostatic and bactericidal effects. China is rich in plant resources, with a wide variety of species. Among them, aromatic plant resources account for one-third of the world. At present, more than 150 species have been developed. In the pre-Qin Dynasty, the Book of Songs, the Chu Ci and the Shennong Herbal Medicine of the Han Dynasty recorded that people used internal administration, external application, fumigation and leaching methods for various Chinese medicine aromatic treatments, further proving the application value of aromatic plants (Wang Min 2021). Oil camphor (Cinnamomum longepaniculatum (Gamble) N. Chao ex H. W. Li.) is a evergreen tree of the Lauraceae family, which can grow up to 20 meters high. It is a Chinese endemic tree species, mainly distributed in Yibin, Sichuan. Its leaves contain rich essential oil. Due to seasonal replacement, oil camphor leaves have become a sustainable plant resource. The total area of oil camphor in Yibin is 33,000 hm 2 , accounting for 85% and 65% of China and the world's oil camphor resources, respectively, and has become one of the main economic crops in Yibin (Wu et al. 2022). Oil camphor essential oil has various activities (Cao Mei et al. 2013) (Cong Ying et al. 2016; Du et al. 2014), especially antibacterial (Wei Qin et al. 2006; Wei Qin et al. 2009; Cong Ying 2016) activity. Its main component 1,8-cineole may be the key component of its strong antibacterial activity (da Rocha Neto et al. 2019; Khan et al. 2010), but the hydrophobicity and rapid volatility of essential oil limit its development in the fields of biological medicine, agriculture, chemical industry, etc.

[0003] To solve this key technical problem, the project applicant, based on previous research and pre-experiment results, uses self-microemulsion drug delivery system (SMEDDS) (Chaisri et al. 2024) to establish CLEO-SMEDDS, prolong the volatile time of Cinnamomum longepaniculatum oil, and enhance the bacteriostatic effect, and develop a kind of high-efficiency bacteriostatic, pesticide residue-reducing, environmentally friendly green nano pesticide. The self-microemulsion drug delivery system involved in this project is composed of three parts, namely oil phase, emulsifier and co-emulsifier. Unlike traditional emulsified products, self-microemulsion drug delivery system can be mixed with water at any ratio to form an emulsion (Wang Jiao et al., 2016). It has the advantages of convenient application and slow release, which can prolong the residence time of essential oil in pathogenic bacteria and enhance the sterilization effect of Cinnamomum longepaniculatum oil. CLEO-SMEDDS usually contains one or more hydrophilic cosolvents or co-emulsifiers. After mild stirring, these systems can form O / W (oil-in-water) emulsions immediately after dilution with aqueous media (Friedl et al. 2021; Singh et al. 2009). This system can be easily mixed by simple mixing, which is suitable for large-scale production of industrial production. CLEO-SMEDDS is composed of drugs, oil phase, emulsifier and co-emulsifier, which can overcome the problem of poor water solubility of lipophilic drugs, and exist in the form of oil-in-water in the gastrointestinal tract with a particle size of 100-250 nm (Singh et al. 2009; Chen et al. 2021). In addition, CLEO-SMEDDS can also penetrate the cell wall and cell membrane of bacteria and fungi to quickly enter the microbial body and kill pathogenic bacteria. The establishment of CLEO-SMEDDS system and the revelation of its structure provide a new idea for the development and utilization of natural products. SUMMARY

[0004] Therefore, the present application provides a Cinnamomum longepaniculatum oil self-microemulsion drug delivery system and a preparation method thereof.

[0005] To solve the above technical problems, the present application adopts the following technical solutions:

[0006] A Cinnamomum longepaniculatum oil self-microemulsion drug delivery system, the system composition of which comprises: oil phase, emulsifier and co-emulsifier, wherein the oil phase is Cinnamomum longepaniculatum oil; the system is miscible with water at any ratio to form a transparent blue microemulsion.

[0007] A preparation method of a Cinnamomum longepaniculatum oil self-microemulsion drug delivery system, the screening of the method uses 30 kinds of emulsifiers and 8 kinds of co-emulsifiers, the emulsifiers are marked as No. 1-30, and the co-emulsifiers are marked as No. 1-8, and the method comprises the following steps:

[0008] Step 1: preliminary screening of emulsifiers

[0009] Step 1.1: Compatibility evaluation

[0010] The oil phase and co-emulsifiers in the fixed system were mixed with the oil phase and co-emulsifiers in proportion, respectively, and placed in a test tube. After stirring at room temperature and standing, the compatibility of the oil phase and emulsifiers was observed, and suitable emulsifiers were screened out. The emulsifiers were labeled as EM-19, EM-1, and EM-4 from large to small, and were used for the following self-emulsification evaluation.

[0011] Step 1.2: Self-emulsification evaluation

[0012] The mixtures EM-19, EM-1, and EM-4 without phase separation were added dropwise into deionized water, respectively, and stirred. The emulsification time was measured, and the emulsification was observed. After standing at room temperature, the suitable emulsifier EM-19 was screened out, and the following co-emulsifier screening was carried out.

[0013] Step 2: Co-emulsifier screening

[0014] Step 2.1: Compatibility evaluation

[0015] EM-19 was selected as the emulsifier, and 8 co-emulsifiers were determined and labeled as CEM-1-8. The co-emulsifiers were mixed with the oil phase and emulsifiers in proportion, respectively, and placed in a test tube. After stirring at room temperature and standing, the compatibility of the oil phase and emulsifiers was observed, and it was determined that EM-19 and CEM-1-8 had good compatibility, which could not be screened out. Further screening was carried out by self-emulsification evaluation.

[0016] Step 2.2: Self-emulsification evaluation

[0017] The co-emulsifiers CEM-1-8 were dispersed into deionized water, respectively. The emulsification time was measured, and the emulsification was observed. After standing at room temperature, the suitable co-emulsifiers were screened out, which were milky white and uniform CEM-8, slightly blue and transparent CEM-1, and milky white and uniform CEM-7. The following screening was carried out.

[0018] Step 3: K m value screening

[0019] The direct water titration method was used to draw a pseudo-ternary phase diagram. The fixed emulsifier EM-19 and the co-emulsifiers CEM-8, CEM-1, and CEM-7 were mixed in proportion, respectively, and the K mValue 4:1, 2:1, 3:2, 1:1, 2:3, 1:2, 1:4, mix, marked as A ~ G, and then mixed with oil camphor oil respectively according to 9:1, 8:2, 7:3, 6:4, 5:5, 3:7, 4:6, 2:8, 1:9 ratio, marked as 1 ~ 9, through compatibility evaluation and self emulsifying evaluation, the area connected by the points with visual grade A and B as the index is the self emulsifying area, draw the pseudo ternary phase diagram, calculate the area of the shadow part;

[0020] Step 4: characterization and stability evaluation

[0021] The optimal system prepared is oil camphor oil CLEO: alkyl glycoside 08: ethanol = 1:5:4 = 10%: 50%: 40%; its characterization and stability evaluation; Fourier infrared spectrometer is used to determine the infrared spectrum of oil camphor oil, alkyl glycoside 08, ethanol and oil camphor oil self-microemulsion drug delivery system, verify the formation of the system; the appearance of oil camphor oil self-microemulsion drug delivery system is observed by transmission electron microscope, and the particle size distribution, Zeta potential and PDI of the system are measured by particle size analyzer; the centrifugal stability, dilution stability and pH stability of the system are investigated by appearance observation, particle size, PDI and Zeta potential.

[0022] Preferably, the 30 kinds of emulsifiers are respectively:

[0023] (1) Tween 80; (2) Span 80; (3) sodium dodecyl sulfate; (4) glycerol monostearate; (5) gum arabic; (6) soluble starch; (7) gelatin; (8) soapnut saponin; (9) casein; (10) sucrose fatty acid ester; (11) sodium lauroyl glutamate; (12) sodium fatty alcohol polyoxyethylene ether sulfate; (13) sodium lauryl polyoxyethylene ether sulfate; (14) fatty acid methyl ester and fatty alcohol ether sulfonate; (15) lauryl betaine; (16) lauryl amidopropyl betaine; (17) cocamidopropyl betaine; (18) fatty acid methyl ester sulfonate; (19) alkyl glycoside 08; (20) alkyl glycoside 10; (21) alkyl glycoside 08 10; (22) alkyl glycoside 08 14; (23) alkyl glycoside 12 14; (24) sodium deoxycholate; (25) poloxamer 188; (26) caprylic capric triglyceride; (27) caprylic capric polyethylene glycol glyceride; (28) polyethylene glycol glyceride oleate; (29) polyoxyethylene castor oil; (30) polyoxyethylene hydrogenated castor oil.

[0024] Preferably, the 8 kinds of co-emulsifiers are respectively:

[0025] (1) ethanol, (2) 1,2-propanediol, (3) glycerol, (4) n-propanol, (5) isopropanol, (6) n-butanol, (7) polyethylene glycol 400, (8) diethylene glycol ether.

[0026] Preferably, in the step 1.1, the CLEO: EM: CEM = 1:5:4 = 10%:50%:40%.

[0027] Preferably, in the step 1.1 and the step 2.1, stirring at room temperature for 20 min, and standing at room temperature for 24 h.

[0028] Preferably, in the step 1.2, each 100 μL of the mixture EM-19, EM-1 and EM-4 without phase separation is dropped into 10 mL of deionized water, and stirred at a speed of 100 r / min at 25°C.

[0029] Preferably, in the step 2.1, the co-emulsifiers are ethanol, 1,2-propanediol, glycerol, n-propanol, isopropanol, n-butanol, polyethylene glycol 400 and diethylene glycol ether, respectively.

[0030] Preferably, in the step 2.1, the CLEO: EM: CEM = 1:5:4 = 10%:50%:40%.

[0031] 10. The preparation method of the CLEO self-microemulsion drug delivery system according to claim 2, wherein in the step 2.2, each 100 μL of CEM-1 to CEM-8 is dispersed into 10 mL of deionized water, and the emulsification time is measured, the emulsification condition is observed, and the system is placed at room temperature for 24 h.

[0032] The present application has the following technical effects compared with the prior art:

[0033] The optimal composition of the CLEO self-microemulsion drug delivery system is CLEO: alkyl polyglycoside 08: ethanol = 1:5:4 = 10%:50%:40%.

[0034] The system appears as a uniform transparent yellowish liquid, has good dispersibility in 1:500 (v / v) water, and appears as a transparent bluish liquid. The particle size is about 104.23±1.99 nm, the Zeta potential is -30.57±0.55 mV, the PDI is 0.08±0.01, the distribution is uniform, and the system is stable. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 It is a compatibility evaluation diagram of 30 emulsifiers of the present application;

[0036] Figure 2 It is a compatibility evaluation diagram of 8 co-emulsifiers of the present application;

[0037] Figure 3 It is a self-emulsification evaluation diagram of the emulsifiers of the present application;

[0038] Figure 4 Self-emulsification evaluation chart of the co-emulsifier of the application;

[0039] Figure 5 Pseudo ternary phase diagram of different co-emulsifiers of the application;

[0040] Figure 6 Chart of the influence of the content of CLEO on the self-emulsification time of the system of the application;

[0041] Figure 7 Infrared spectrum of the application;

[0042] Figure 8 Transmission electron micrograph of CLEO-SMEDDS of the application;

[0043] Figure 9 Centrifugal stability result chart of the application. DETAILED DESCRIPTION

[0044] The technical solutions in the embodiments of the application will be described clearly and completely below with reference to the drawings in the embodiments of the application. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments of the application. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative work are within the protection scope of the application.

[0045] The application discloses an oil camphor essential oil self-microemulsion drug delivery system, which comprises an oil phase, an emulsifier and a co-emulsifier, wherein the oil phase is oil camphor essential oil; the system is miscible with water in any proportion to form a transparent micro-blue microemulsion.

[0046] The application further discloses a preparation method of the oil camphor essential oil self-microemulsion drug delivery system, wherein 30 kinds of emulsifiers and 8 kinds of co-emulsifiers are used, the emulsifiers are marked as No. 1-30, and the co-emulsifiers are marked as No. 1-8.

[0047] The 30 kinds of emulsifiers are respectively:

[0048] (1) Tween 80; (2) Span 80; (3) sodium dodecyl sulfate; (4) glycerol monostearate; (5) gum arabic; (6) soluble starch; (7) gelatin; (8) soapnut saponin; (9) casein; (10) sucrose fatty acid ester; (11) sodium lauroyl glutamate; (12) sodium fatty alcohol polyoxyethylene ether sulfate; (13) sodium lauryl polyoxyethylene ether sulfate; (14) fatty acid methyl ester and fatty alcohol ether sulfonate; (15) lauryl betaine; (16) lauryl amido propyl betaine; (17) cocamide propyl betaine; (18) fatty acid methyl ester sulfonate; (19) alkyl glycoside 08; (20) alkyl glycoside 10; (21) alkyl glycoside 08 10; (22) alkyl glycoside 08 14; (23) alkyl glycoside 12 14; (24) sodium deoxycholate; (25) poloxamer 188; (26) caprylic capric triglyceride; (27) caprylic capric polyethylene glycol glyceride; (28) polyethylene glycol oleate glyceride; (29) polyoxyethylene castor oil; (30) polyoxyethylene hydrogenated castor oil;

[0049] The compatibility evaluation chart of the 30 emulsifiers is shown in Figure 1

[0050] The 8 co-emulsifiers are respectively:

[0051] (1) ethanol, (2) 1,2-propanediol, (3) glycerol, (4) n-propanol, (5) isopropanol, (6) n-butanol, (7) polyethylene glycol 400, (8) diethylene glycol ether;

[0052] The compatibility evaluation chart of the 8 co-emulsifiers is shown in Figure 2

[0053] Comprising the following steps:

[0054] Step 1: preliminary screening of emulsifiers

[0055] Step 1.1: compatibility evaluation:

[0056] The oil phase and co-emulsifier in the fixed system are mixed with the oil phase and co-emulsifier in proportion, respectively, and the oil camphor oil CLEO: emulsifier EM: co-emulsifier CEM = 1:5:4 = 10%:50%:40%, is placed in a Westlin bottle, stirred at room temperature for about 20 min, and uniformly mixed, and the compatibility of the oil phase and the emulsifier is observed after standing at room temperature for 24 h, and the suitable emulsifiers are screened out from large to small as 19, 28, 14, 1, 4, respectively, marked as EM-19, EM-1, EM-4, and the subsequent self-emulsification evaluation is carried out;

[0057] Step 1.2: self-emulsification evaluation

[0058] ​​Take non-phase separation mixture EM-19, EM-1, EM-4 each 100 μL, respectively, drop into 10 mL deionized water, under the condition of 25 ℃, stirring at 100 r / min, measure the emulsification time, observe the emulsification, room temperature, screen out suitable emulsifier from big to small respectively EM-19, proceed to the next emulsifier screening;

[0059] Among them, the self-emulsifying evaluation diagram of emulsifier is as shown in Figure 3

[0060] Step 2: Screening of co-emulsifiers

[0061] Step 2.1: Compatibility evaluation

[0062] Select EM-19 as emulsifier, and co-emulsifiers are respectively ethanol, 1,2-propanediol, glycerol, n-propanol, isopropanol, n-butanol, polyethylene glycol 400, diethylene glycol ether, which are marked as co-emulsifiers CEM-1~8 respectively. Mix the co-emulsifiers with oil phase and emulsifier in proportion, oil camphor oil CLEO: emulsifier EM: co-emulsifier CEM = 1:5:4 = 10%:50%:40%, place in a shirn bottle, stir at room temperature, observe the compatibility of oil phase and emulsifier after placement, determine that EM-19 and CEM-1~8 have good compatibility, cannot be screened, and further screened by self-emulsifying evaluation;

[0063] Step 2.2: Self-emulsifying evaluation

[0064] Take CEM-1~8 each 100 μL, respectively disperse into 10 mL deionized water, measure the emulsification time under room temperature condition, observe the emulsification, place at room temperature for 24 h, screen out suitable co-emulsifiers CEM-8, CEM-1, CEM-7 respectively, proceed to the next screening;

[0065] Among them, the self-emulsifying evaluation diagram of co-emulsifier is as shown in Figure 4

[0066] Step 3: K m value screening

[0067] Pseudo-ternary phase diagram is drawn by direct water titration method, mix fixed emulsifier EM-19 with co-emulsifiers CEM-8, CEM-1, CEM-7 respectively according to Km value 4:1, 2:1, 3:2, 1:1, 2:3, 1:2, 1:4, marked as A~G, then mix with oil camphor oil according to the proportion 9:1, 8:2, 7:3, 6:4, 5:5, 3:7, 4:6, 2:8, 1:9, marked as 1~9, through compatibility evaluation and self-emulsifying evaluation, the area connected by points with A, B visual grade as the self-emulsifying area, draw the pseudo-ternary phase diagram, calculate the area of the shadow part, the result is as shown in Figure 5 ​​as shown;

[0068] Step 4: characterization and stability evaluation

[0069] The prepared optimal system is CLEO: alkyl glycoside 08: ethanol = 1:5:4 = 10%:50%:40%, which is characterized and evaluated for stability. The infrared spectra of oil camphor essential oil, alkyl glycoside 08, ethanol and oil camphor essential oil self-microemulsion drug delivery system are determined by Fourier infrared spectrometer to verify the formation of the system. The appearance of the oil camphor essential oil self-microemulsion drug delivery system is observed by transmission electron microscope, and the particle size distribution, Zeta potential and PDI of the system are determined by particle size analyzer. The centrifugal stability, dilution stability and pH stability of the system are investigated by appearance observation, particle size, PDI and Zeta potential;

[0070] The state after emulsification (clear and transparent) and emulsification time (<2 min) are used as indicators. With oil phase, emulsifier and co-emulsifier as one vertex, pseudo-ternary phase diagram is drawn by Origin Pro 2021. The emulsification is observed, and the evaluation standard is shown in Table 1. The self-microemulsion that can form microemulsion, uniform and stable is selected, and the area size of self-emulsification region is used as an indicator to select appropriate co-emulsifier. The shadow area is: CEM-1 = 36.51%; CEM-7 = 3.17%; CEM-8 = 20.63%, and the optimal co-emulsifier is CEM-1, i.e. ethanol, which is found by pseudo-ternary phase diagram. Therefore, the Km value proportion with larger emulsification area includes 1:1, 3:2 and 1:2.

[0071] As shown in Figure 6 When the Km value is 1:1 and 3:2, all systems are less than 1 min, the more CLEO content, the shorter the self-emulsification time, and the relatively less stable system. Therefore, in order to ensure that the system has the largest amount of essential oil and strong stability, centrifugal experiment is carried out, i.e. 10000 rpm, 10 min. The research object is oil phase: emulsifier: co-emulsifier = CLEO: EM: CEM = CLEO: APG08: ethanol. The centrifugal stability, pH stability and temperature stability of the system are investigated by appearance observation.

[0072] Table 1: evaluation of co-emulsifier self-emulsification.

[0073]

[0074] Example 1: Fourier transform infrared spectroscopy (FTIR) determination of surface chemical structure

[0075] The FTIR spectra of Cinnamomum camphora oil, APG08, ethanol and CLEO-SMEDDS were measured using a Fourier transform infrared spectrometer (Nicolet 6700, Thermo Scientific, USA). Data were recorded in the range of 4000-400 cm -1 The samples were prepared in KBr discs using an electric tablet press (2 mg sample dissolved in 200 mg KBr) with a hydraulic press pressure of 25 MPa for 10 s. As shown in Figure 7 The infrared spectrum of the CLEO-SMEDDS system contained the spectral information of Cinnamomum camphora oil, APG08 and ethanol, proving that all the components were present. The successful preparation of CLEO-SMEDDS was verified in terms of chemical composition.

[0076] Example 2: Transmission electron microscopy (TEM) and particle size analysis

[0077] The transmission electron microscopy and particle size analyzer showed that the CLEO-SMEDDS system was spherical, with a particle size of about 104.23 ± 1.99 nm, a zeta potential of -30.57 ± 0.55 mV, a PDI of 0.08 ± 0.01, and a uniform distribution, as shown in Figure 8 .

[0078] Example 3: Stability of Cinnamomum camphora oil self-microemulsion drug delivery system

[0079] (1) Centrifugal stability

[0080] The stable CLEO:APG08:ethanol self-emulsifying system was further investigated for centrifugal stability, i.e. centrifugation at 3000 rpm for 5 min, to visually check whether the mixture was phase-separated or turbid. Based on the layering standard, 6 stable systems were found, namely 1, 2, 10, 19, 28 and 46. The remaining systems had white substances floating on the top layer after centrifugation, which were considered unstable. Analysis found that the 6 stable systems were distributed at the edge of the pseudo-ternary phase diagram, and the composition of CLEO was less than 20% in each system. The self-emulsification time was short. Therefore, the analysis of the instability of other systems found that too much oil phase appeared in the system. Therefore, further verification of dilution stability is needed to determine whether the increasing amount of water can dissolve more and more self-emulsifying systems, making the system more stable.

[0081] Table 2: Pseudo-ternary phase diagram experiment of CLEO:APG08:ethanol self-emulsifying system

[0082]

[0083]

[0084]

[0085]

[0086] (2) Dilution stability (the effect of different dilution multiples on the self-microemulsion)

[0087] Take 100 μL of the self-microemulsion, add purified water at a volume ratio of 1:50, 1:100, 1:300, 1:500, 1:700, 1:900, emulsify at 25°C and 100 r / min, and place for 6 h. Investigate whether the particle size and PDI change after the self-microemulsion is emulsified, diluted at different multiples, and placed for a certain period of time. As shown in Table 3, the particle size first decreases and then increases with the change of the dilution multiple, and the particle size reaches a minimum value (101.70 ± 0.79 nm) at 1:500. However, the PDI of the CLEO-SMEDDS system is less than 0.2 regardless of the dilution, proving that the distribution is uniform and the system is relatively stable. The Zeta potential remains negative, but the Zeta potential significantly increases after 1:500 and the conductivity significantly decreases with the change of the dilution multiple. In order to maintain the overall stability of the system, the system reduces the instability caused by the continuous increase of the dilution multiple through surface structure changes.

[0088] Table 3: Stability of CLEO-SMEDDS at different dilution multiples

[0089]

[0090] (3) pH stability (the effect of different media on the self-microemulsion)

[0091] The pH is selected according to apples, apple tree trunks, and apple tree leaves. Take 100 μL of the self-microemulsion, add media with pH = 4.5, 5.5, 6.5, 7.5, and 8.5 at a volume ratio of 1:100, emulsify (25°C, 100 r / min), and place for 6 h. Investigate whether the particle size and PDI change after the self-microemulsion is emulsified in different media and placed for a certain period of time. As shown in Table 4, the larger the pH, the smaller the particle size, but the PDI is less than 0.2. The larger the Zeta potential, which also proves that the CLEO-SMEDDS system is uniformly distributed and the system is relatively stable. It is indirectly proved that CLEO-SMEDDS can adjust the surface charge and particle size according to different pH microenvironments during the delivery of drugs in plants, so as to maintain the stable structure of the CLEO-SMEDDS system and achieve drug delivery.

[0092] Table 4: Stability of CLEO-SMEDDS at different pH values.

[0093]

[0094] wherein the centrifugal stability results plot is as shown in Figure 9 .

[0095] The above description is only the preferred embodiment of the present application, and does not limit the technical scope of the present application in any way. Any slight modification, equivalent change and modification made according to the technical essence of the present application to the above embodiment are still within the technical scope of the present application.

Claims

1. An oil of Cinnamomum oleum self-microemulsifying drug delivery system characterized by, The system composition comprises: an oil phase, an emulsifier and a co-emulsifier, wherein the oil phase is oil camphor essential oil; the system is soluble with water in any proportion to form a transparent micro-blue microemulsion.

2. A process for the preparation of a self-microemulsifying drug delivery system of oil of Cinnamomum oleifolium, characterized by, The screening of the method adopts 30 kinds of emulsifiers and 8 kinds of co-emulsifiers, the emulsifiers are marked as No. 1-30, and the co-emulsifiers are marked as No. 1-8, and the method comprises the following steps: Step 1: preliminary screening of emulsifiers Step 1.1: compatibility evaluation The oil phase and the co-emulsifier in the fixed system are mixed with the oil phase and the co-emulsifier in proportion, placed in a Schlenk bottle, stirred at room temperature, and then the compatibility of the oil phase and the emulsifier is observed after standing, and the suitable emulsifiers are screened out from large to small as 19, 1 and 4, which are marked as EM-19, EM-1 and EM-4 respectively, and then self-emulsifying evaluation is carried out; Step 1.2: self-emulsifying evaluation The mixture EM-19, EM-1 and EM-4 without phase separation are dropped into deionized water respectively, stirred, the emulsification time is measured, the emulsification situation is observed, and the suitable emulsifier EM-19 is screened out after standing at room temperature, and then co-emulsifier screening is carried out; Step 2: screening of co-emulsifiers Step 2.1: compatibility evaluation EM-19 is selected as the emulsifier, and 8 kinds of co-emulsifiers are determined, which are marked as CEM-1-8 in turn, the co-emulsifiers are mixed with the oil phase and the emulsifier in proportion, placed in a Schlenk bottle, stirred at room temperature, and then the compatibility of the oil phase and the emulsifier is observed after standing, and it is determined that EM-19 and CEM-1-8 have good compatibility and cannot be screened out, and further screening is carried out by using self-emulsifying evaluation; Step 2.2: self-emulsifying evaluation The co-emulsifiers CEM-1-8 are dispersed into deionized water respectively, the emulsification time is measured, the emulsification situation is observed, and the suitable co-emulsifiers are screened out after standing at room temperature, which are milky white and uniform CEM-8, micro-blue and transparent CEM-1, and milky white and uniform CEM-7, and then further screening is carried out; Step 3: K m Value screening The direct water titration method was used to draw the pseudo-ternary phase diagram, and the fixed emulsifier EM-19 was mixed with the co-emulsifiers CEM-8, CEM-1 and CEM-7 respectively according to the K m value 4:1, 2:1, 3:2, 1:1, 2:3, 1:2, 1:4, and marked as A-G, and then mixed with oil camphor oil according to the proportions of 9:1, 8:2, 7:3, 6:4, 5:5, 3:7, 4:6, 2:8 and 1:9, and marked as 1-9. Through compatibility evaluation and self-emulsification evaluation, the area connected by the points with visual grades A and B was the self-emulsification area, the pseudo-ternary phase diagram was drawn, and the area of the shadow part was calculated. Step 4: characterization and stability evaluation The optimal system prepared is oil camphor essential oil CLEO: alkyl glycoside 08: ethanol = 1:5:4 = 10%:50%:40%, and the optimal system is characterized and evaluated for stability; the infrared spectra of oil camphor essential oil, alkyl glycoside 08, ethanol and oil camphor essential oil self-microemulsion drug delivery system are determined by using a Fourier infrared spectrometer to verify the formation of the system; the appearance of the oil camphor essential oil self-microemulsion drug delivery system is observed by transmission electron microscopy, and the particle size distribution, Zeta potential and PDI of the system are measured by using a particle size analyzer; the centrifugal stability, dilution stability and pH stability of the system are investigated by appearance observation, particle size, PDI and Zeta potential.

3. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, The 30 kinds of emulsifiers are as follows: (1) Tween 80; (2) Span 80; (3) sodium dodecyl sulfate; (4) glycerol monostearate; (5) gum arabic; (6) soluble starch; (7) gelatin; (8) soapberry saponin; (9) casein; (10) sucrose fatty acid ester; (11) sodium lauroyl glutamate; (12) sodium fatty alcohol polyoxyethylene ether sulfate; (13) sodium lauryl polyoxyethylene ether sulfate; (14) fatty acid methyl ester and fatty alcohol ether sulfonate; (15) lauryl betaine; (16) lauryl amido propyl betaine; (17) cocamide propyl betaine; (18) fatty acid methyl ester sulfonate; (19) alkyl glycoside 08; (20) alkyl glycoside 10; (21) alkyl glycoside 08 10; (22) alkyl glycoside 08 14; (23) alkyl glycoside 12 14; (24) sodium deoxycholate; (25) poloxamer 188; (26) caprylic capric triglyceride; (27) caprylic capric polyethylene glycol glyceride; (28) oleic acid polyethylene glycol glyceride; (29) polyoxyethylene castor oil; (30) polyoxyethylene hydrogenated castor oil.

4. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, The eight co-emulsifiers are respectively: (1) ethanol, (2) 1,2-propanediol, (3) glycerol, (4) n-propanol, (5) isopropanol, (6) n-butanol, (7) polyethylene glycol 400, (8) diethylene glycol ether.

5. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 1.1, the oil camphor essential oil CLEO: emulsifier EM: co-emulsifier CEM = 1:5:4 = 10%:50%:40%.

6. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 1.1 and the step 2.1, stirring at room temperature for 20 min, and standing at room temperature for 24 h.

7. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 1.2, 100 μL of each of the mixtures EM-19, EM-1, and EM-4 without phase separation was dropped into 10 mL of deionized water, and stirring was carried out at a rate of 100 r / min at 25°C.

8. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 2.1, the co-emulsifiers are respectively ethanol, 1,2-propanediol, glycerol, n-propanol, isopropanol, n-butanol, polyethylene glycol 400, and diethylene glycol ether.

9. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 2.1, the oil camphor essential oil CLEO: emulsifier EM: co-emulsifier CEM = 1:5:4 = 10%:50%:40%.

10. The method for preparing a camphor oil self-microemulsion drug delivery system according to claim 2, characterized in that, In the step 2.2, 100 μL of each of CEM-1 to CEM-8 was dispersed into 10 mL of deionized water, and the emulsification time was measured at room temperature, the emulsification was observed, and standing was carried out at room temperature for 24 h.

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