CN114558052B - 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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CN114558052B
CN114558052B CN202210214337.7A CN202210214337A CN114558052B CN 114558052 B CN114558052 B CN 114558052B CN 202210214337 A CN202210214337 A CN 202210214337A CN 114558052 B CN114558052 B CN 114558052B
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limonene
nanoemulsion
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oral
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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 to 10 percent of anticancer active substance, 0.1 to 5 percent of synergist, 0.25 to 5 percent of oil phase, 1 to 20 percent of surfactant, 1 to 10 percent 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 oral mucosa diseases including stomatitis and oral ulcer. According to the fourth national oral health epidemiological survey, the incidence rate of oral diseases of people of different ages (3~5, 12 to 15, 35 to 44, 55 to 64 and 65 to 74) in China accounts for 60 to 98 percent (Wang Xing) of the total population (the fourth national oral health epidemiological survey reports R, beijing, people's health publishing agency, 2018), the incidence rate is high, and the oral chronic inflammation which is recurrent 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 medicines mainly take symptomatic medicines for local inflammation diminishing, pain relieving, ulcer healing promotion 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 alterations. The oral cancer has extremely complex inducement, poor prognosis, easy relapse after treatment and no 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, the oral cancer is mostly treated by operation, but the side effect caused by the operation is large, and particularly, the appearance change caused by the operation is difficult to accept by patients. Therefore, the prevention/treatment of early stage oral leukoplakia carcinoma lesions by drugs will gradually become the mainstream of development. The clinical common 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 to 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 C 10 H 16 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.
Glycerol nitrate was reported since Sobrero et al in 1847Sublingual formulations of nitroglycerin were successfully used clinically in 1879 years (Harris D., robinson J.R. Drug delivery via the mucosal 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 prevention of oral cancer by using a local delivery pharmaceutical formulation, oral mucosa is both an effective drug delivery site and a difficulty in absorption due to its unique anatomical structure. 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, which is composed of a continuous gel with a water content of 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 main component content of the tea tree oil used by the invention meets 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 common toxic and side effects of the existing medicaments for preventing oral cancer at home and abroad in different degrees, in addition, the medicament 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 to 10 percent of anticancer active substance, 0.1 to 5 percent of synergist, 0.25 to 5 percent of oil phase, 1 to 20 percent of surfactant, 1 to 10 percent of cosurfactant and the balance of deionized water or distilled water.
Wherein: the anticancer active substance is pure natural extract with 98% contentd-limonene, preferably in a weight percentage of 0.5 to 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 medium 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 is 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 each of limonene and tea tree oil, EL-35 and Tween-80 (6 g of each, namely the mass ratio of 1:1) as mixed surfactants, 1,2-propylene glycol (6 g) as cosurfactants, and MCT, olive oil and soybean oil (all 1 g) as oil phases, mixing the materials, slowly adding 30mL of deionized water dropwise under stirring to prepare the plant-derived essential oil nanoemulsion, and measuring the viscosity of the nanoemulsion, wherein the results are 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 479138DEST_PATH_IMAGE001
Further, the agent-to-oil ratio, i.e., SOR value: the mass of all surfactants (surfactant + cosurfactant) is equal to that of all oil phases (oil phase +)dLimonene + synergist) is 1 to 1, preferably 4:1.
Further, the mass ratio K of the surfactant to the co-surfactant is m The weight ratio is 7.
SOR value and K m The 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 a weight ratio, and stirring for 10 to 120min under the conditions of 100 to 2000r/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 the distilled water into the mixture under the stirring condition, stirring for 30 to 120min after the dripping is finished,preparing the nano emulsion with the grain diameter of 10 to 100nm to obtain the nano emulsion for preventing/stopping the oral precancerous lesiond-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 synergy nano-emulsion composition into a high-pressure homogenizer according to the weight percentage, homogenizing for 10 to 120min under the working pressure of 200 to 1500par to prepare the nano-emulsion with the grain diameter of 10 to 100nm, namely the nano-emulsion for preventing the oral precancerous lesion/preventing the progression of the oral precancerous lesiond-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 lesion (white spot). Therefore, the invention 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 lies in 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 significant synergistic effect on preventing/preventing the progression of oral precancerous lesions.
The invention has scientific and reasonable design and good practical application value.
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FIG. 1 shows normal murine buccal pouch mucosa (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,d-lemonThe alkene synergistic nanoemulsion is applied for 2 times every day, and is applied after the interval of 6 hours when DMBA is applied on the daydThe-limonene synergistic nanoemulsion was used 1 time, and after 15 consecutive weeks, the cheek pouch of the mice was identical to that of the normal group (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 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: 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 main component content meeting international standardization organization (ISO 4730-2017); the oil phase is Medium Chain Triglyceride (MCT); the surfactant is tween-80; the co-surfactant is 1,2-propanediol.
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 main component content meeting international standardization organization (ISO 4730-2017); the oil phase is Medium Chain Triglyceride (MCT); the surfactant is a mixture of Tween-80 and 1:1 of EL-35; the co-surfactant is 1,2-propanediol.
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 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 product.
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 6~8 week-old Chinese mice with the weight of 18-20g, and smearing 0.5% Dimethylbenzanthracene (DMBA) on the right buccal sacs of the Chinese mice by a cotton swab at the 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 composition was applied 2 times a day, with DMBA applied 6 hours apartdThe limonene nanoemulsion composition (the weight 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 example 2) is used for 1 time.
Prevention group-2: 8 pieces of the medicinal liquor are smeared with 0.5 percent DMBA 3 times a week,dthe limonene nanoemulsion synergistic composition is applied for 2 times a day, and is applied after 6 hours on the day when DMBA is applieddLimonene nanoemulsion synergistic composition (example 2) 1 time.
TABLE 2dExperimental results of-limonene nanoemulsion synergistic composition for preventing oral cancer
Figure 52070DEST_PATH_IMAGE002
(2) And (4) experimental conclusion: 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 nanoemulsions.
A Chinese medicinal composition for preventing and treating 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 main component content meeting 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 only specific embodiments of the present invention, but are not limited thereto. Any simple change, equivalent replacement or modification made based on the present invention to solve substantially the same technical problems or achieve substantially the same technical effects are within the scope of the present invention as set forth in the claims.

Claims (6)

1. A Chinese medicinal composition for preventing oral cavity precancerous lesion and whitening maculad-a limonene nanoemulsion synergistic composition characterized in that: the composition consists of the following components: 0.5 to 2 percent of anticancer active substance, 0.1 to 1 percent of synergist, 0.25 to 5 percent of oil phase, 1 to 20 percent of surfactant and 1 to 10 percent of cosurfactant, and the components are mixed together, and the mixture is mixed with the water to form a mixture, and the mixture is stirred for a whileThe rest is 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 oil phase is medium chain triglyceride, olive oil or soybean oil; the surfactant is tween-80, tween-60, tween-20, span or polyoxyethylene ether; the cosurfactant is polyethylene glycol, propylene glycol or ethanol;
the agent-oil ratio is 1 to 1, namely the SOR value: the ratio of the mass of all surfactants to the mass of all oil phases;
the mass ratio of the surfactant to the cosurfactant is 7 to 1.
2. The composition of claim 1 for preventing oral precancerous lesionsd-a limonene nanoemulsion synergistic composition characterised in that: the mass ratio of the surfactant to the cosurfactant is 3 to 1.
3. The composition of claim 2 for preventing precancerous oral lesionsd-a limonene nanoemulsion synergistic composition characterised in that: the oil phase is medium 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 cosurfactant is 4:1, the weight 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.
4. A method according to any one of claims 1 to 3 for the prevention of oral precancerous lesionsd-a process for the preparation of a synergistic composition of limonene nanoemulsions characterized in that: the 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 10 to 120min under the conditions of 100 to 2000r/min to obtain a mixture;
(2) Deionized water or distilled water is weighed according to weight ratioSlowly dropping deionized water or distilled water into the mixture under the stirring condition, stirring for 30 to 120min after the dropping is finished, and preparing the nano emulsion with the particle size of 10 to 100nm, namely the nano emulsion for preventing the oral cavity precancerous lesion white spotd-a limonene nanoemulsion synergistic composition product;
alternatively, it is prepared by a high pressure homogenization process: will be provided withdPlacing the materials of the-limonene synergistic nanoemulsion composition into a high-pressure homogenizer according to the weight percentage, homogenizing for 10 to 120min under the working pressure of 200 to 1500par, and preparing the nanoemulsion with the particle size of 10 to 100nm, namely the nanoemulsion for preventing the oral precancerous lesion white spotd-limonene nanoemulsion synergistic composition products.
5. Use of a composition according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention of oral precancerous lesions.
6. Use of a composition according to any one of claims 1 to 3 for the preparation of a mouthwash for the prevention of precancerous lesions in the oral cavity.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106890140A (en) * 2017-03-03 2017-06-27 山西医科大学 D limonene anticancer synergia compositions and preparation method and application
EP3378475A1 (en) * 2017-03-20 2018-09-26 Angeletti, Barbara Composition and kit for the use in the prevention of recurrent onychomycosis

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EP2320921A4 (en) * 2008-07-18 2012-04-04 Novasel Australia Pty Ltd Compositions comprising tea tree oil and methods for the prevention and treatment of cancer
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Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106890140A (en) * 2017-03-03 2017-06-27 山西医科大学 D limonene anticancer synergia compositions and preparation method and application
EP3378475A1 (en) * 2017-03-20 2018-09-26 Angeletti, Barbara Composition and kit for the use in the prevention of recurrent onychomycosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Plants of the Melaleuca Genus as Antimicrobial Agents: From Farm to Pharmacy;Javad Sharifi-Rad;《PHYTOTHERAPY RESEARCH》;20170807;第31卷(第10期);第1475-1497页 *

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