CN114558052A - D-limonene nanoemulsion synergistic composition for preventing oral cancer and preparation method and application thereof - Google Patents

D-limonene nanoemulsion synergistic composition for preventing oral cancer and preparation method and application thereof Download PDF

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CN114558052A
CN114558052A CN202210214337.7A CN202210214337A CN114558052A CN 114558052 A CN114558052 A CN 114558052A CN 202210214337 A CN202210214337 A CN 202210214337A CN 114558052 A CN114558052 A CN 114558052A
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limonene
nanoemulsion
preventing
oral
surfactant
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CN114558052B (en
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王渊
轩瑞晶
焦向英
董晓波
樊卫平
董柯婷
吕原亮
王雪平
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Shanxi Medical University
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Abstract

The invention discloses a method for preventing oral cancerdA limonene nanoemulsion synergistic composition, a preparation method and application. The composition comprises the following components: 0.4-10% of anticancer active substance, 0.1-5% of synergist, 0.25-5% of oil phase, 1-20% of surfactant, 1-10% of cosurfactant and the balance of deionized water or distilled water; wherein the anticancer active substance is pure natural extract with 98% contentd-limonene; the synergist is tea tree oil. The invention discovers and proves for the first time that:dunder the combination of proper scientific matching, limonene and tea tree oil are added with an oil phase and a surfactant to prepare nano emulsion which is used as a medicine for oral local use and has the characteristic of high-efficiency mucous membrane absorption,dthe synergistic nanoemulsion composition consisting of limonene and tea tree oil has a significant synergistic effect on preventing/preventing the progression of oral precancerous lesions.

Description

A Chinese medicinal composition for preventing oral cancerd-limonene nanoemulsion synergistic composition and preparation method and application thereof
Technical Field
The invention belongs to the technical field of natural medicines for inhibiting or preventing cancer cell proliferation, and particularly relates to a medicine for preventing oral cancer or preventing the progression of precancerous lesions of oral cavitydA limonene nanoemulsion synergistic composition, a preparation method and application.
Background
The oral cavity is the main portal for the entry of microorganisms into the human body, and because the internal environment and structure of the oral cavity are suitable for the growth of microorganisms, the oral cavity becomes one of the most complex and huge structures of microbial community in the human body. The research finds that the interaction between oral microflora and the health of human body are closely related. When the microbial ecology in the oral cavity is unbalanced, various oral diseases can be caused, such as stomatitis, oral ulcer and other oral mucosa diseases. According to the fourth national oral health epidemiological survey, the incidence rate of oral diseases of people of different ages (3-5 years, 12-15 years, 35-44 years, 55-64 years and 65-74 years) in China accounts for 60-98% of the total population (Wangxing fourth national oral health epidemiological survey report [ R ]. Beijing: people health publishing agency, 2018), the incidence rate is high, the oral diseases are easy to relapse, and the recurrent oral chronic inflammation can induce the precancerous lesion of oral cancer. Because the etiology is complicated and the pathogenesis is not clear, although various treatment methods exist, no specific medicine exists, and the symptomatic medicine mainly aims at local inflammation diminishing, pain relieving, ulcer healing promoting and the like at present.
Oral cancer is a general term for malignant tumors occurring in the oral cavity, and most of them belong to squamous cell carcinoma, so-called mucosal lesion. The oral cancer has extremely complex inducement, poor prognosis, easy relapse after treatment and no medicine and treatment method with small side effect. Therefore, prevention of oral cancer is more important than treatment. Meanwhile, the development of new oral cancer prevention preparations with high efficiency and small toxic and side effects is more and more urgent and important.
Researchers have generally recognized that the appearance of oral leukoplakia, a pre-cancerous lesion, increases the likelihood of oral cancer occurring. At present, surgical treatment is mostly adopted for treating oral cancer, but side effects caused by the surgery are large, and particularly, appearance change caused by the surgery is difficult to accept by patients. Therefore, the prevention/treatment of early stage lesion of oral leukoplakia carcinoma by drugs will gradually become the mainstream of development. The clinical medicines for treating oral leukoplakia comprise vitamin A, retinoids, beta-carotene, vitamin E, selenium, bleomycin, COX-2 inhibitor, certain traditional Chinese medicines and the like, and the substances have the defects of low effective rate, easy toxicity on liver and kidney after long-term administration and the like in the application process. In addition, some researchers research natural extracts such as tea pigment, boswellic acid, salvianolic acid B, epigallocatechin-3-gallate and the like, and prove that the extract has a certain inhibiting effect on oral cancer cells, but the extract has no statistical significance on preventing oral leukoplakia. In addition, the bio-toxicity of some natural extracts is to be further investigated.
d-limonene, chemical name 1-methyl-4-isopropylcyclo-ethylene, molecular formula C10H16The CAS number: 5989-27-5.dLimonene, the most important and widely distributed terpene among natural plants in addition to pinene, is currently recognized by the american Flavor and Extract Manufacturers Association (FEMA) as a GRAS (generally recognized as safe) grade of toxicity and is approved for consumption by the U.S. Food and Drug Administration (FDA), the united states Food and Agriculture Organization (FAO) and World Health Organization (WHO) pairdThe toxicological data of daily ingestion of limonene all attribute it to a high safety food additive raw material.
A great deal of research at home and abroad shows thatdLimonene has inhibiting and reversing effects on various tumors, and has the effect of preventing tumorigenesis. But because ofdLimonene is volatile, highly hydrophobic and unstable, limiting its use.
Since Sobrero et al 1847 reported that nitroglycerin can be absorbed through the oral mucosa into the human blood circulation system, in 1879 sublingual dosage forms of nitroglycerin were successfully used clinically (Harris D., Robinson J.R. Drug delivery via the mucous membranes of the organic cavity [ J.]. J. Pharm. Sci., 1992, 81(1): 1-10). After that, many researchers reported more and more oromucosal drug delivery systems. For the delivery of pharmaceutical formulations by use of topical sitesIn order to prevent oral cancer, oral mucosa is an effective drug delivery site and is difficult to absorb due to the unique anatomical structure of the oral mucosa. The oral mucosa is a tissue lining the surface of the oral cavity, has salivary glands opening on the surface, and consists of epithelial cells, lamina propria and submucosal tissue from outside to inside. The secretions of the epithelial cells of the oral mucosa are the mucus layer, the composition of which is a continuous gel with a water content up to 95%, while the cell membrane is lipophilic. Thus, drugs can pass through the oral mucosa via both intercellular and transcellular pathways. The former favors the passage of hydrophilic drugs and the latter favors the passage of lipophilic drugs.
On the other hand, the fat solubility and the molecular weight of the medicine have certain influence on adhesion administration and absorption of mucous membrane, if the fat solubility of the medicine is larger, the nonionic form is more, the capability of the medicine for penetrating through the oral mucosa is stronger, but the fat solubility of the medicine is too strong, and the medicine is difficult to reach an effective level in saliva; lipid solubility is too weak to be absorbed through the lipid barrier. Thus, the structure of the oral mucosa determinesdLimonene is applied directly to the oral cavity, it is difficult to obtain satisfactory control effect, and it is rationally designeddA dosage form and synergistic complex of limonene suitable for oromucosal absorption appears to be highly desirable.
Tea tree oil is a natural aromatic essential oil extracted from fresh branches and leaves of Melaleuca alternifolia (Melaleuca L.) of Myrtaceae (Myrtaceae), and obtained by steam distillation, and is a mixture of more than 100 different components, and the main types of the essential oil are monoterpene, sesquiterpene and derivatives thereof. The tea tree oil component has difference with tea tree varieties and production batches. The tea tree oil used by the invention has the main component content meeting the requirements of the international organization for standardization (ISO 4730-2017). The tea tree oil has medicinal value in skin penetration promotion, anti-inflammatory, antibacterial, immunity enhancement, and tumor inhibition.
At present, it is related todThe research and the literature of the cancer cell apoptosis induction of the-limonene are more, but the tea tree oil synergy is not founddReports of limonene to prevent precancerous lesions of the oral cavity.
Disclosure of Invention
Aiming at the current medicine for preventing oral cancer at home and abroadHas toxic and side effects of different degrees, and adoptsdThe limonene is used for preventing and treating cancer cells, and the problems of low drug effect and poor stability generally exist. The invention aims to provide a medicine for preventing/stopping the progression of oral precancerous lesiondA limonene nanoemulsion synergistic composition, a preparation method and application thereof.
The invention is realized by adopting the following technical scheme:
a Chinese medicinal composition for preventing oral cancerd-a limonene nanoemulsion synergistic composition comprising the following components: 0.4-10% of anticancer active substance, 0.1-5% of synergist, 0.25-5% of oil phase, 1-20% of surfactant, 1-10% of cosurfactant and the balance of deionized water or distilled water.
Wherein: the anticancer active matter is pure natural extract with the content of 98 percentd-limonene, preferably in a weight percentage of 0.5-2%. The synergist is tea tree oil with the main component content meeting the requirements of the international standardization organization (ISO 4730-2017), and the preferable weight percentage is 0.1-1%. The oil phase is chain triglyceride, olive oil or soybean oil; the surfactant is tween-80, tween-60, tween-20, span or polyoxyethylene ether (EL-35), preferably tween-80 and EL-35; the cosurfactant is polyethylene glycol, propylene glycol or ethanol, and preferably 1, 2-propylene glycol.
Experiments prove that the nano emulsion without the oil phase is unstable, the particle size rapidly increases along with the change of time, and the addition of a proper amount of the oil phase in the system can not completely stop the increase of the particle size of the nano emulsion, but can reduce the increase speed of the particle size of the nano emulsion and contribute to the stability of the nano emulsion system, so that a certain amount of the oil phase is added in the formula. The oil phase in the formulation is Medium Chain Triglyceride (MCT), olive oil, soybean oil, etc., preferably MCT, as determined by the following experiment.
Experiment: weighing machined0.5g of limonene and tea tree oil respectively, taking EL-35 and Tween-80 (6 g of each, namely the mass ratio of 1: 1) as mixed surfactants, taking 1, 2-propylene glycol (6 g) as cosurfactant, taking MCT, olive oil and soybean oil (1 g) as oil phases respectively, mixing the materials, slowly adding 30mL of deionized water dropwise under the stirring condition to prepare the plant growth regulatorThe material source essential oil nanoemulsion, and the viscosity measurement is carried out on the nanoemulsion, and the result is shown in table 1. The nanoemulsion containing the oil phase has higher viscosity than a nanoemulsion system without the oil phase, and MCT with better fluidity is selected as the oil phase under the condition that the total mass of the system is the same.
TABLE 1 measurement of the viscosity of different types of oil phase forming nanoemulsions
Figure DEST_PATH_IMAGE001
Further, the agent-to-oil ratio, i.e., SOR value: the mass of all surfactants (surfactant + cosurfactant) and all oil phases (oil phase +)d-limonene + synergist) in a mass ratio of 1:1 to 9:1, preferably 4: 1.
Further, the mass ratio K of the surfactant to the co-surfactant ismIs 7:1 to 1:1, preferably 3:1 to 2:1, and most preferably 3: 1.
SOR value and KmThe values are obtained from a pseudo-ternary phase diagram consisting of the aqueous phase, the total oil phase (oil phase, anticancer active, synergist) and the surfactant (surfactant, co-surfactant).
As described abovedA preparation method of the limonene nanoemulsion synergistic composition comprises the following steps:
(1) firstly, the method is carried outdPlacing limonene, a synergist, an oil phase, a surfactant and a cosurfactant in a container according to the weight ratio, and stirring for 10-120 min under the condition of 100-2000 r/min to obtain a mixture;
(2) after the deionized water or the distilled water is weighed according to the weight ratio, slowly dripping the deionized water or the distilled water into the mixture under the stirring condition, stirring for 30-120 min after dripping is finished, and preparing the nano emulsion with the particle size of 10-100 nm, namely the nano emulsion for preventing the oral precancerous lesion/preventing the oral precancerous lesion from progressingd-limonene nanoemulsion synergistic composition products.
As described abovedThe limonene nanoemulsion synergistic composition can also be prepared by a high pressure homogenization process: will be provided withdPutting the materials of the limonene synergistic nano-emulsion composition into a high-pressure homogenizer according to the weight percentage respectively, and workingHomogenizing for 10-120 min under the pressure of 200-1500 par to prepare nano emulsion with the particle size of 10-100 nm, namely the nano emulsion for preventing/preventing the oral precancerous lesion from progressingd-limonene nanoemulsion synergistic composition products.
The inventor proves that the tea tree oil pairdThe-limonene has a synergistic effect, and particularly has a remarkable effect of preventing oral precancerous lesions (white spots). Therefore, the invention is describeddThe limonene nanoemulsion synergistic composition can be used as a medicine for preventing oral cancer or preventing the oral precancerous lesion from progressing, and relates to the application of preparing mouthwash for preventing oral cancer or preventing the oral precancerous lesion in the aspects of oral health care and hygiene.
The significance of the invention is that: the first time of finding and proving is that,dunder the proper combination of scientific matching, the limonene and the tea tree oil are added with an oil phase and a surfactant to prepare the nano emulsion which is used as a medicine for oral local use and has the characteristic of high-efficiency mucous membrane absorption, namely:dthe synergistic nanoemulsion composition consisting of limonene and tea tree oil has a remarkable synergistic effect on preventing/preventing the oral precancerous lesion from progressing.
The invention has scientific and reasonable design and good practical application value.
Drawings
FIG. 1 shows normal buccal mucosa of a mouse (control group).
FIG. 2 shows the buccal mucosa of the hamster after 3 applications of 0.5% DMBA per week for 15 consecutive weeks, with the observation that tissue edema, thickening of the hyperplasia and some of the mice developed precancerous lesions (white spots) (model group).
Figure 3 shows the application of 0.5% DMBA 3 times a week,dthe limonene synergistic nanoemulsion is applied for 2 times a day, and the DMBA is applied on the day after 6 hoursdThe limonene synergistic nanoemulsion was 1 time, and the cheek pouch of the hamster was not different from that of the normal group after 15 consecutive weeks (prevention group-2).
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1: 0.5% effective content of preventableOral precancerous lesion/prevention of progression of oral precancerous lesiond-limonene nanoemulsion synergistic compositions.
A Chinese medicinal composition for preventing and/or inhibiting oral precancerous lesiondThe formula (weight percentage) of the limonene nanoemulsion synergistic composition is as follows:
anti-cancer active substance: 0.4 percent;
a synergist: 0.1 percent;
oil phase: 0.25 percent;
surfactant (b): 2 percent;
cosurfactant: 1 percent;
the rest is: deionized or distilled water.
Wherein the anticancer active substance is 98% pure natural extractd-limonene; the synergist is tea tree oil with the main component content meeting the requirements of the international standardization organization (ISO 4730-2017); the oil phase is Medium Chain Triglyceride (MCT); the surfactant is tween-80; the cosurfactant is 1, 2-propylene glycol.
The preparation method comprises the following steps:
1. firstly, the method is carried outdPlacing limonene, a synergist, an oil phase, a surfactant and a cosurfactant in a container according to a weight ratio, and stirring for 60min under the condition of 1500r/min to obtain a mixture;
2. weighing deionized water or distilled water according to weight ratio, slowly dripping deionized water or distilled water into the mixture under stirring, and stirring for 30min after dripping to obtain the product for preventing/preventing oral precancerous lesiond-limonene synergistic nanoemulsion composition product.
Example 2: 2% effective content of the composition for preventing/preventing oral precancerous lesiond-limonene nanoemulsion synergistic compositions.
A Chinese medicinal composition for preventing and/or inhibiting oral precancerous lesiondThe formula (weight percentage) of the limonene nanoemulsion synergistic composition is as follows:
anti-cancer active substance: 1 percent;
a synergist: 1 percent;
oil phase: 1 percent;
surfactant (b): 9 percent;
cosurfactant: 3 percent;
the rest is: deionized or distilled water.
Wherein the anticancer active substance is 98% pure natural extractd-limonene; the synergist is tea tree oil with the main component content meeting the requirements of the international standardization organization (ISO 4730-2017); the oil phase is Medium Chain Triglyceride (MCT); the surfactant is a 1:1 mixture of Tween-80 and EL-35; the cosurfactant is 1, 2-propanediol.
The preparation method comprises the following steps:
1. firstly, the method is todPlacing limonene, a synergist, an oil phase, a surfactant and a cosurfactant in a container according to the weight ratio, and stirring for 60min under the condition of 1000r/min to obtain a mixture;
2. weighing deionized water or distilled water according to weight ratio, slowly dripping deionized water or distilled water into the mixture under stirring, and stirring for 30min after dripping to obtain the product for preventing/preventing oral precancerous lesiond-limonene synergistic nanoemulsion composition products.
As described abovedExperimental methods and results for the limonene nanoemulsion synergistic composition to prevent oral precancerous lesions are as follows:
(1) the experimental method comprises the following steps:
selecting a plurality of Chinese hamster 6-8 weeks old and 18-20 g in weight, and smearing 0.5% Dimethylbenzanthracene (DMBA) on the right buccal pouch of the Chinese hamster with a cotton swab at a frequency of 3 times per week by adopting a smearing method. Atypical hyperplasia occurred at week 5, inflammatory reaction and ulcer occurred at week 9, and precancerous lesion such as leukoplakia and hyperemia appeared in the buccal pouch at week 15. The experiment was carried out in 4 groups, treated as follows, and observed continuously.
Control group: 9 pieces, without any treatment.
Model group: 9 pieces were smeared with 0.5% DMBA 3 times a week.
Prevention group-1: 9 pieces of the medicinal liquor are smeared with 0.5 percent DMBA 3 times a week,dthe limonene nanoemulsion synergistic composition is applied 2 times a day, and the DMBA is applied 6 hours later on the daydThe limonene synergistic nanoemulsion (the mass ratio of the anticancer active substance in the formula is 2%, no synergist is contained, and the ratio of the other components is the same as that in the example 2) is 1 time.
Prevention group-2: 8 pieces of the medicinal liquor are smeared with 0.5 percent DMBA 3 times a week,dthe limonene synergistic nanoemulsion is applied for 2 times a day, and the DMBA is applied on the day after 6 hoursdLimonene synergistic nanoemulsion (example 2) 1 time.
TABLE 2dExperimental results of-limonene nanoemulsion synergistic composition for preventing oral cancer
Figure 313549DEST_PATH_IMAGE002
(2) The experimental conclusion is that: after the cotton swab in the example 2 is smeared on the oral mucosa of the hamster in the experimental process, the mucosa is quickly dried, which indicates that the medicine has high transdermal absorption efficiency, and meanwhile, the result shows that the precancerous lesion of the oral mucosa cannot be prevented by the administration of the example 2 in the form of intragastric lavage, which indicates that the invention provides the applicationdThe limonene nanoemulsion synergistic composition has a large first-pass effect, and is very suitable for oral mucosa local administration. Taken together, this example 2 producesd-limonene nanoemulsion synergistic composition comparable to monocomponentdLimonene nanoemulsion significantly increased the prevention efficacy of oral cancer (as shown in figure 3).
Example 3: effective content of 10% for preventing/preventing oral precancerous lesiond-limonene synergistic nanoemulsion.
A Chinese medicinal composition for preventing and/or inhibiting oral precancerous lesiondThe formula (weight percentage) of the limonene nanoemulsion synergistic composition is as follows:
anti-cancer active substance: 7 percent;
a synergist: 3 percent;
oil phase: 3 percent;
surfactant (b): 17.333 percent;
cosurfactant: 8.667%;
the rest is: deionized or distilled water.
Wherein the anticancer active substance is 98% pure natural extractd-limonene; the synergist is tea tree oil with the main component content meeting the requirements of the international standardization organization (ISO 4730-2017); the oil phase is olive oil; the surfactant is tween-80; the cosurfactant is PEG-400.
The preparation method comprises the following steps: will be provided withdPlacing the materials of the-limonene nanometer emulsion synergistic composition into a high-pressure homogenizer according to the weight percentage, and homogenizing for 30min under the working pressure of 800par to obtain the composition for preventing the oral precancerous lesion/preventing the oral precancerous lesion from progressingd-limonene nanoemulsion synergistic composition products.
The product of the invention is mainly used for preventing oral cancer or preventing the progression of precancerous lesions of the oral cavity, can be directly used, and can also be diluted for use according to requirements.
The above are merely exemplary embodiments of the present invention, and are not intended to be limiting. Any simple changes, equivalent substitutions or modifications made based on the present invention to solve the substantially same technical problems or achieve the substantially same technical effects are within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A Chinese medicinal composition for preventing oral cancerd-a limonene nanoemulsion synergistic composition characterised in that: comprises the following components: 0.4-10% of anticancer active substance, 0.1-5% of synergist, 0.25-5% of oil phase, 1-20% of surfactant, 1-10% of cosurfactant and the balance of deionized water or distilled water;
wherein the anticancer active substance is pure natural extract with 98% contentd-limonene; the synergist is tea tree oil.
2. The method of claim 1, wherein the oral cancer is preventedd-a limonene nanoemulsion synergistic composition characterised in that: the oil phase is chain triglyceride, olive oil or soybean oil; the surfactant is tween-80, tween-60, tween-20, span or polyoxyethylene ether; the watch is assistedThe surfactant is polyethylene glycol, propylene glycol or ethanol.
3. A method according to claim 1 or 2 for preventing oral cancerd-a limonene nanoemulsion synergistic composition characterised in that: the weight percentage of the anticancer active matter is 0.5-2%, and the weight percentage of the synergist is 0.1-1%.
4. A method according to claim 3 for preventing oral cancerd-a limonene nanoemulsion synergistic composition characterised in that: the agent-oil ratio is 1: 1-9: 1, namely the SOR value: mass ratio of all surfactants to mass of all oil phases.
5. The method of claim 4, wherein the oral cancer is preventedd-a limonene nanoemulsion synergistic composition characterised in that: the mass ratio of the surfactant to the cosurfactant is 7: 1-1: 1.
6. A method according to claim 5 for preventing oral cancerd-a limonene nanoemulsion synergistic composition characterised in that: the mass ratio of the surfactant to the cosurfactant is 3: 1-2: 1.
7. A method according to claim 6 for preventing oral cancerd-a limonene nanoemulsion synergistic composition characterised in that: the oil phase is chain triglyceride, the surfactant is a mixture of tween-80 and polyoxyethylene ether, and the cosurfactant is 1, 2-propylene glycol;
the weight ratio of the surfactant to the oil is 4:1, the mass ratio of the surfactant to the cosurfactant is 3:1, the weight percentage of the anticancer active substances is 1 percent, and the weight percentage of the synergist is 1 percent.
8. A method of preventing cancer in the oral cavity according to any one of claims 1 to 7d-a process for the preparation of a limonene nanoemulsion synergistic composition, characterised in that: the method comprises the following steps:
(1) firstly, the method is carried outdLimonene, synergist, oil phase, surfactantPlacing the mixture and cosurfactant in a container according to the weight ratio, and stirring for 10-120 min under the condition of 100-2000 r/min to obtain a mixture;
(2) after deionized water or distilled water is weighed according to the weight ratio, slowly dripping the deionized water or distilled water into the mixture under the stirring condition, stirring for 30-120 min after dripping is finished, and preparing the nano emulsion with the particle size of 10-100 nm, namely the nano emulsion for preventing the oral precancerous lesion/preventing the oral precancerous lesion from progressingd-a limonene nanoemulsion synergistic composition product;
alternatively, it is prepared by a high pressure homogenization method: will be provided withdPlacing the materials of the limonene synergistic nano-emulsion composition into a high-pressure homogenizer according to the weight percentage, homogenizing for 10-120 min under the working pressure of 200-1500 par to prepare nano-emulsion with the particle size of 10-100 nm, namely the nano-emulsion for preventing the oral precancerous lesion/preventing the oral precancerous lesion from progressingd-limonene nanoemulsion synergistic composition products.
9. A Chinese medicinal composition for preventing oral cancerdApplication of the limonene nanoemulsion synergistic composition in preparing a medicament for preventing oral precancerous lesion white spots.
10. A Chinese medicinal composition for preventing oral cancerdApplication of the limonene nanoemulsion synergistic composition in preparing mouthwash for preventing oral precancerous lesion white spots.
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