CN103110582A - Cannabis phenolic compound microemulsion and preparation method thereof - Google Patents

Abstract

The invention relates to the field of pharmaceutical preparations, in particular to a microemulsion containing cannabinol compounds, which comprises the following components in percentage by weight: 0.01-30 wt% of cannabinol compounds; (b) 0.01-30 wt% of an oil phase, wherein the oil phase is selected from one or more of vegetable oil, fatty acid ethyl ester, fatty acid isopropyl ester, fatty acid glyceride or fatty acid polyglycol glyceride; (c) 0.01-60 wt% of surfactant, wherein the surfactant is selected from one or more of polyoxyethylene ether castor oil, polyoxyethylene ether hydrogenated castor oil, poloxamer, fatty acid polyglycolyglyceride, polyoxyethylene sorbitan fatty acid ester or phospholipid; (d) 0.01-40 wt% of cosurfactant, wherein the cosurfactant is one or more of ethanol, propylene glycol, isopropanol, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether, tetrahydrofuran polyglycol ether or glycerol; the balance being water or deionized water.

Description

Cannabis phenolic compound microemulsion and preparation method thereof

technical field

The invention relates to the field of pharmaceutical preparations, in particular to a microemulsion preparation containing plant active ingredients and a preparation method thereof.

Background technique

Microemulsion is a thermodynamically stable, isotropic and transparent dispersion system formed by two immiscible liquids under the action of surfactant molecular interface film. Generally, it is spontaneously formed by oil phase, surfactant, co-surfactant and water phase in an appropriate ratio, with low viscosity and particle size generally in the range of 10-100nm.

Due to the good dispersion of drugs in microemulsions, small particle size, and easy absorption, microemulsions can promote the absorption of drugs and improve the bioavailability of drugs. In addition, the microemulsion has low viscosity, does not cause pain when injected, and does not cause allergic reactions and fat embolism. Moreover, microemulsion is a thermodynamically stable system that can form spontaneously, is easy to prepare, and has good stability.

Studies have confirmed that marijuana contains a variety of cannabinoids. Cannabinol compounds are a class of terpene phenolic compounds, which have been separated into more than 70 species, among which the more important ones are: cannabinol, cannabidiol, tetrahydrocannabinol, cannabinolic acid, cannabidiolic acid, tetrahydrocannabinol cannabinoids, etc. Among them, cannabidiol, tetrahydrocannabinol and cannabinol are the most important and have the highest content, which have anti-inflammatory, analgesic, anti-nausea, anti-tumor, anti-spasmodic, anti-anxiety and other effects.

Contents of the invention

The purpose of the present invention is to provide a new water-based dosage form of cannabinoids to replace other conventionally used dosage forms. The microemulsion of the present invention uses water with rich sources and good environmental compatibility as the dispersed phase, which replaces expensive organic solvents and reduces the amount of surfactants in the formula, thereby avoiding unnecessary ingestion by patients during administration. ingredients.

The core technical problem of microemulsion is the correct application of microemulsion technology and the solution of the storage stability of active ingredients after microemulsion. On the basis of studying the microstructure of the microemulsion, the present invention focuses on screening the oil phase, surfactant and co-surfactant suitable for the microemulsion of cannabinol compounds.

Furthermore, the present invention provides a microemulsion containing cannabinoids, which contains the following components by weight percentage:

(a) 0.01 to 30 wt% cannabinoids;

(b) 0.01-30 wt% oily phase, the oily phase is selected from one or more of vegetable oil, fatty acid ethyl ester, fatty acid isopropyl ester, fatty acid glyceride or fatty acid polyethylene glycol glyceride;

(c) 0.01～60wt% surfactant, said surfactant is selected from polyoxyethylene ether castor oil, polyoxyethylene ether hydrogenated castor oil, poloxamer, fatty acid polyethylene glycol glyceride, polyoxyethylene dehydrated One or more of sorbitol fatty acid esters or phospholipids;

(d) 0.01～40wt% co-surfactant, described co-surfactant is selected from ethanol, propylene glycol, isopropanol, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol mono One or more of ethyl ether, polyglycol ether or glycerin;

The balance is water or deionized water.

In a preferred example, the weight percentages of each component are: 0.2-15 wt% of cannabinol compound, 0.2-15 wt% of oil phase, 0.2-40 wt% of surfactant, 0.2-20 wt% of co-surfactant, and the balance water or deionized water.

In another preferred example, the cannabinoid compound is selected from one or more of cannabinol, cannabidiol or tetrahydrocannabinol.

In another preferred example, the oil phase is selected from one or more of soybean oil, ethyl oleate, isopropyl myristate, caprylic/capric triglyceride, or macrogol glyceride oleate. kind.

In another preferred example, the surfactant is selected from one or more of Cremophor RH40, Poloxamer 188, caprylic/capric macrogolglycerides, Tween80 or phospholipids.

In another preference, the co-surfactant is selected from one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether (Transcutol P) or glycerin.

The present invention also provides a method for preparing a microemulsion containing cannabinoids, comprising first dissolving 0.01 to 30 wt % of cannabinoids in an oil phase accounting for 0.01 to 30 wt % of the total amount of the preparation, and then sequentially adding 0.01 to 30 wt % of cannabinoids 60wt% surfactant, 0.01-40wt% co-surfactant and appropriate amount of water are stirred until homogeneous.

In a preferred example, the weight percentages of each component are: 0.2-15 wt% of cannabinoid compound, 0.2-15 wt% of oil phase, 0.2-40 wt% of surfactant, and 0.2-20 wt% of co-surfactant.

Details of various aspects of the invention are set forth in the ensuing sections. The features, objects and advantages of the present invention will be more apparent from the following description and claims.

Detailed ways

After extensive and in-depth research, the inventor unexpectedly discovered a microemulsion composition containing cannabinoids, an oil phase, a surfactant, a co-surfactant and water. When the contents of the above components are within an appropriate range, the obtained microemulsion composition not only retains the pharmacological activity of the cannabinoid compound, but also has extremely high stability. The microemulsion composition in turn facilitates the absorption and bioavailability of the cannabinoids.

As used in the present invention, cannabinol compounds are a class of terpene phenolic compounds, which have been separated into more than 70 types, including but not limited to: cannabinol, cannabidiol, tetrahydrocannabinol, cannabinolic acid, cannabidiol acid, tetrahydrocannabinolic acid, etc. The preferred cannabinoid compound of the present invention is one or more selected from cannabinol, cannabidiol or tetrahydrocannabinol. The dosage range of the cannabinoid compound of the present invention is 0.01-30wt%, preferably 0.2-15wt%.

oil phase

Studies have shown that the oil phase can not only dissolve hydrophobic drugs, but also promote the transport of drugs in the body, enhance the absorption of the human body, and improve the bioavailability of drugs. The greater the difference in volume between the two phases forming the emulsion, the more stable the emulsion. Within a certain range, the larger the molecular volume of the oil phase, the stronger the solubility of the drug, but the molecular volume of the oil phase is too large to form a microemulsion. In order to increase drug solubility and increase the microemulsion formation area, a short-chain oil phase should be selected. Currently commonly used oil phases are vegetable oil (such as castor oil, soybean oil, peanut oil, olive oil, etc.), ethyl oleate, medium-chain fatty acid triglyceride (GTCC), oleic acid, isopropyl myristate (IPM), etc. Saturated glycerin oleate, triglyceride caprylate and fatty acid esters, etc. Because the fluidity, solubility and self-emulsification of fatty acid esters are better than those of vegetable oils, fatty acid esters are usually the best choice for the oil phase, commonly used are ethyl oleate, ethyl linoleate, and isopropyl myristate (IPM); medium-chain fatty acid triacylglycerol, such as caprylic acid/capric triacylglycerol; long-chain fatty acid triacylglycerol, such as oleic acid/linoleic acid triacylglycerol, etc.

Among them, ethyl oleate is a colorless or light yellow oily liquid, easy to flow like olive oil, and it will not be destroyed by heating at 150°C for several hours. It is often used as a solvent, plasticizer, lubricant and skin penetration accelerator. Medium-chain fatty acid triglycerides (GTCC) are glycerides based on coconut oil fatty acids. Oleic acid, whose scientific name is cis-9-octadecenoic acid, is present in animal and vegetable oils in the form of glycerides together with other fatty acids. Isopropyl myristate (IPM) has excellent penetrating, moisturizing and softening effects. It is often used as an emulsifier and wetting agent, and can replace vegetable oil in the preparation of ointments and creams.

The oil phase of the present invention is selected from one or more of vegetable oil, fatty acid ethyl ester, fatty acid isopropyl ester, fatty acid glyceride or fatty acid polyglycol glyceride, preferably soybean oil, ethyl oleate, isomyristate One or more of propyl ester (IPM), caprylic/capric triacylglycerol (such as Miglycol812), caprylic/capric macrogol glyceride (such as Labrafil M 1944CS). The usage range of the oil phase in the present invention is 0.01-30wt%, preferably 0.2-15wt%.

Surfactant

The main function of the surfactant is to reduce the interfacial tension to form an interfacial film and promote the formation of microemulsions. It is characterized by its chemical structure with lipophilic and hydrophilic groups. Surfactants commonly used in the preparation of microemulsion drugs are phospholipids, polyethylene glycol octylphenyl ethers (OP), polysorbates, polyoxyethylene castor oil (CEL) and its derivatives, saponins, and the like. In addition, mixing surfactants can increase the flexibility of the interfacial film and facilitate the formation of microemulsions. This rule has guiding significance for the selection of surfactants in microemulsion systems. Among them, commonly used phospholipid surfactants are soybean phospholipids and egg yolk phospholipids. Soy lecithin is a natural product. It not only has a strong emulsifying effect, but also has nutritional value and medical function. Polyethylene glycol octylphenyl ether (OP) is a light yellow to brown yellow paste, with a melting point of about 85°C, easily soluble in water, 1% aqueous solution with pH 5-7, HLB value 15, and can tolerate 30% Calcium chloride and 50% sulfuric acid aqueous solution are often used as emulsifiers, wetting agents, solubilizers, diffusing agents, etc. to prepare creams, emulsions, suppositories, and suspensions. Polysorbate, the commonly used microemulsion emulsifier is polysorbate 80, which is a light yellow to orange-yellow viscous liquid. It is a non-ionic hydrophilic surfactant and is often used as a solubilizer for injections and a surfactant for other dosage forms. and dispersants. Polyoxyethylene castor oil (CEL) and its derivatives are non-ionic surfactants, which change from light yellow liquid to light yellow paste with the increase of relative molecular weight. Commonly used are polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, etc. Polyoxyethylene castor oil has the functions of emulsification, solubilization, lubrication, emollient, antistatic, decontamination, etc. It is used as emulsifier, solubilizer, lubricant, etc. in pharmaceuticals. Saponins are oligoglycosides of spirosteranes and steroids or triterpenoids similar to their biosources. They exist in most plants and are a natural emulsifier. Saponins have the effect of reducing the surface tension of aqueous solutions. The aqueous solution of saponin produces persistent foam after shaking, and does not disappear due to heating, which can be distinguished from foam produced by other substances.

The surfactant of the present invention is selected from one of polyoxyethylene ether castor oil, polyoxyethylene ether hydrogenated castor oil, poloxamer, fatty acid macrogol glyceride, polyoxyethylene sorbitan fatty acid ester or phospholipid One or more, preferably Cremophor RH40 (polyoxyethylene ether (40) hydrogenated castor oil), poloxamer 188, caprylic/capric macrogol glyceride (Labrasol), Tween 80 (Tween80) or phospholipids one or more of. The dosage range of the surfactant of the present invention is 0.01-60wt%, preferably 0.2-40wt%.

co-surfactant

Co-surfactant is a kind of surface active agent that can change the surface activity and hydrophilic-lipophilic balance of surfactants, participate in the formation of micelles, adjust the polarity of water and oil, water-soluble alcohol can reduce the polarity of water, oil-soluble alcohol Active agent for microemulsion components that increases the polarity of the oil, thereby affecting the phase state and phase properties of the system. Commonly used co-surfactants include short-chain alcohols, organic ammonia, alkyl element acids, mono- and di-alkyl glycerides, and polyoxyethylene fatty acid esters. Among these co-surfactants, alcohols are the most widely used. Alcohols can increase drug loading, increase drug solubility, and form a wide range of microemulsions, such as ethanol, glycerol, PEG400, 1,22 propylene glycol, etc.

Co-surfactant of the present invention is selected from ethanol, propylene glycol, isopropanol, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether (Transcutol), tetrahydrofuran polyethylene glycol One or more of Glycofurol or glycerin, preferably one or more of ethanol, propylene glycol, diethylene glycol monoethyl ether (Transcutol P) or glycerin. The dosage range of the co-surfactant of the present invention is 0.01-40wt%, preferably 0.2-20wt%.

In addition to the above components, the microemulsion of the present invention may also contain one or more other pharmaceutical additives, such as viscosity control agents, fragrances, flavoring agents, antioxidants, preservatives and the like.

The microemulsion of the present invention can be prepared by conventional methods in the art. Firstly, dissolve the cannabinol phenolic compound with the oil phase accounting for the formulation amount, then add surfactant, co-surfactant and water in sequence, and stir until homogeneous.

The microemulsion of the present invention selects suitable oil, surfactant and co-surfactant, does not need to use organic solvent and reduces the dosage of surfactant, and avoids unnecessary ingredients taken by patients during administration. Moreover, the preparation process of the microemulsion of the present invention is simple, does not need to purchase special equipment, saves research and development and production costs, and is suitable for large-scale industrial production.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, ratios, or parts are by weight unless otherwise indicated.

The units in the weight percent in the present invention are well known to those skilled in the art, for example, it refers to the weight of active ingredients contained in 100 weight units of the preparation, and the symbol is "wt%".

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in this patent specification can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.

Example 1:

Preparation Process

The raw material cannabidiol is dissolved in soybean oil according to the dosage of the above formula.

Add polyoxyethylene ether (40) hydrogenated castor oil, ethanol, water in sequence, stir evenly, and fill.

The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 2:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 3:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 4:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 5:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Embodiment 6:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Embodiment 7:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Embodiment 8:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Embodiment 9:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 10:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 11:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 12:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 13:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 14:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 15:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 16:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 17:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 18:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 19:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 20:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 21:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 22:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 23:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 24:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 25:

The preparation process is the same as in Example 1. The stability investigation showed that the appearance, particle size and content of the microemulsion obtained in this example had no significant difference before and after the inspection.

Example 26:

The preparation process is the same as in Example 1. The stability investigation shows that the content of the microemulsion obtained in this example has no significant difference before and after the inspection, but the appearance changes significantly, the particle size increases significantly, and the quality of the microemulsion is unstable.

Example 27:

The preparation process is the same as in Example 1. The stability investigation shows that the content of the microemulsion obtained in this example has no significant difference before and after the inspection, but the appearance changes significantly, the particle size increases significantly, and the quality of the microemulsion is unstable.

Example 28:

The preparation process is the same as in Example 1. The stability investigation shows that the content of the microemulsion obtained in this example has no significant difference before and after the inspection, but the appearance changes significantly, the particle size increases significantly, and the quality of the microemulsion is unstable.

Example 29:

The preparation process is the same as in Example 1. The stability investigation shows that the content of the microemulsion obtained in this example has no significant difference before and after the inspection, but the appearance changes significantly, the particle size increases significantly, and the quality of the microemulsion is unstable.

The main technical indicators of the microemulsion containing cannabinol compounds of the present invention prepared by embodiment 1～29 are as shown in table 1:

Various aspects involved in the present invention have been described above. However, it should be understood that, without departing from the spirit of the present invention, equivalent changes and modifications can be made by those skilled in the art, and the changes and modifications also fall within the coverage of the claims of this patent application.

Claims (8)

1. microemulsion that contains cannabinol compounds, it contains following percentage by weight composition:

(a) 0.01～30wt% cannabinol compounds;

(b) 0.01～30wt% oil phase, described oil phase are selected from one or more in vegetable oil, fatty-acid ethyl ester, isopropyl fatty acid ester, fatty glyceride or fatty acid polyethyleneglycol glyceride;

(c) 0.01～60wt% surfactant, described surfactant are selected from one or more in polyoxyethylene ether Oleum Ricini, polyoxyethylene ether castor oil hydrogenated, poloxamer, fatty acid polyethyleneglycol glyceride, polyoxyethylene sorbitan fatty acid ester or phospholipid;

(d) 0.01～40wt% cosurfactant, described cosurfactant is selected from one or more in ethanol, propylene glycol, isopropyl alcohol, Polyethylene Glycol, Isosorbide dimethyl ether, propylene carbonate, TC, Tetrahydrofurfuryl polyethylene glycol ether or glycerol;

Surplus is water or deionized water.

2. microemulsion according to claim 1, it is characterized in that, the percentage by weight of described each composition is: cannabinol compounds 0.2～15wt%, oil phase 0.2～15wt%, surfactant 0.2～40wt%, cosurfactant 0.2～20wt%, surplus is water or deionized water.

3. microemulsion according to claim 1, is characterized in that, described cannabinol compounds is selected from one or more in cannabinol, cannabidiol or tetrahydrocannabinol.

4. microemulsion according to claim 1, is characterized in that, described oil phase is selected from one or more in soybean oil, ethyl oleate, isopropyl myristate, caprylic/capric triglyceride or oleic acid polyethyleneglycol glyceride.

5. microemulsion according to claim 1, is characterized in that, described surfactant is selected from one or more in Cremophor RH40, PLURONICS F87, caprylic/capric polyethyleneglycol glyceride, Tween80 or phospholipid.

6. microemulsion according to claim 1, is characterized in that, described cosurfactant is selected from one or more in ethanol, propylene glycol, TC or glycerol.

7. the preparation method that contains the microemulsion of cannabinol compounds claimed in claim 1, comprise the cannabinol compounds that at first dissolves 0.01～30wt% with the oil phase that accounts for preparation preparation total amount 0.01～30wt%, add successively again the surfactant of 0.01～60wt%, cosurfactant and the suitable quantity of water of 0.01～40wt%, be stirred to homogeneous phase.

8. the preparation method of microemulsion according to claim 7, it is characterized in that, the percentage by weight of described each composition is: cannabinol compounds 0.2～15wt%, oil phase 0.2～15wt%, surfactant 0.2～40wt%, cosurfactant 0.2～20wt%.