CN113209052A - Cannabidiol self-nanoemulsion buccal membrane preparation and preparation method and application thereof - Google Patents
Cannabidiol self-nanoemulsion buccal membrane preparation and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a cannabidiol self-nanoemulsion buccal membrane preparation as well as a preparation method and application thereof. The biological adhesive film comprises a backing film and a biological adhesive film layer adhered on the backing film; the biological adhesion film layer is formed by dispersing cannabidiol in a self-nanoemulsion system, adsorbing the cannabidiol by a solid carrier and then dispersing the cannabidiol in a film-forming polymer, wherein the self-nanoemulsion system comprises an oil phase, a surfactant and a cosurfactant. The cannabidiol self-nanoemulsion membrane preparation enables the cannabidiol to be in a supersaturated dissolution state in an oil phase, the solubility of the cannabidiol in a system is increased, the nano-scale liquid drops formed from the nanoemulsion promote the permeation and absorption of the cannabidiol in buccal mucosa, the onset time of the medicine is shortened, and the bioavailability of the medicine is improved. The cannabidiol self-nanoemulsion buccal membrane preparation can be applied to aspects of epilepsy resistance, pain relief, mental disorder (such as schizophrenia, schizoaffective disorder and delusional disorder), anxiety resistance, depression resistance and the like.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a cannabidiol self-nanoemulsion buccal membrane double-layer preparation as well as a preparation method and application thereof.
Background
Cannabidiol (CBD) is the major chemical component in the medicinal plant cannabis sativa. Unlike addictive Tetrahydrocannabinol (THC), CBD has no neurotoxicity, can block the influence of THC on human nervous system, has various pharmacological actions on nervous system, and has important clinical application value in treating epilepsy, multiple sclerosis, relieving inflammation, pain, anxiety and other psychogenic diseases. A large number of studies show that CBD has obvious antiepileptic and anticonvulsant activities and has fewer side effects compared with the existing antiepileptic drugs.
In 2018, Epidiolex became the first globally approved CBD drug for marketing by the FDA for the treatment of Lennox-Gastaut syndrome (LGS) and Dravet Syndrome (DS) -related seizures in patients aged 2 and over 2. Epidolex is also the only pure CBD formulation product on the market today. Epidiolex was then approved for the treatment of seizures associated with Tuberous Sclerosis (TSC) in patients aged 1 or older.
Epidiolex is an oral, high-purity liquid preparation of CBD extract, which is prepared by dissolving CBD in an organic solvent (using sesame oil as a main solvent) and flavoring it. The product is packaged in a whole bottle, a patient needs to independently measure a certain amount of liquid medicine when taking medicine, and the control of the dosage depends on the patient per se when taking medicine, so that the safety risk exists in clinical medication. In addition, swallowing too much oil can also affect the taste of the drug, causing discomfort to the patient.
Cannabidiol is hardly soluble in water and soluble in organic solvents such as ethanol, methanol, ether, benzene, chloroform and petroleum ether. Therefore, the problems of improving the solubility of cannabidiol and increasing the in vivo absorption and bioavailability of cannabidiol are urgently needed to be solved at present.
Self-nanoemulsion systems are a new technology in the field of pharmaceutical preparations in recent years. Dissolving cannabidiol in one or more of oil, surfactant and cosurfactant to obtain cannabidiol self-nanoemulsion. When the self-nanoemulsion system contacts with water, emulsification is carried out spontaneously to form emulsion drops with micron or nanometer sizes, which are respectively called a self-microemulsion system and a self-nanoemulsion system. Because the drug (API) in the self-nanoemulsion system is already in a dissolved state, compared with the dissolution of solid API, the dissolution process of the API in the self-nanoemulsion system can be directly skipped, the dissolution or permeation rate is higher, and the problems of poor water solubility and low bioavailability of cannabidiol can be effectively solved. Compared with emulsion, the self-emulsifying drug delivery system belongs to a thermodynamic stable system, has more stable physical and chemical properties, is easy to prepare, and can be quickly emulsified to form fine microemulsion under proper temperature and moderate movement of oral cavity or gastrointestinal tract, thereby increasing the solubility, permeability and bioavailability of the drug. However, in actual production and use, the problems of high production cost, inconvenience in transportation and storage, low drug loading and the like exist, and the use of a large amount of surfactant can cause mucosa irritation. Generally, the traditional Chinese medicine composition is encapsulated in a capsule for oral administration, has a single dosage form, and is easy to cause the problems of capsule shell compatibility, drug precipitation, leakage and the like. The liquid self-emulsifying system is solidified in different modes to form a solid self-emulsifying system, so that the stability of the medicine can be obviously improved, the defects of the liquid preparation in the aspects of production, storage and transportation can be effectively overcome, the dosage form selection can be increased, and the application range of the medicine can be enlarged.
So far, there have been some patents for inventions providing a preparation method of a cannabidiol self-emulsifying formulation to improve its bioavailability. Chinese patent CN 109953951A discloses a nano-emulsion containing cannabidiol and a preparation method thereof. Although the self-nanoemulsion system can improve the solubility, dissolution rate and oral bioavailability of cannabidiol, the invention uses an organic solvent (one or more of ethanol, dichloromethane and chloroform) in the preparation process, a large amount of organic solvent is volatilized in industrial production, and the final system has the problem of organic solvent residue. In addition, the dosage of the liquid self-nanoemulsion preparation is not accurate, and the taste of the medicine is affected by the oil phase with too high content. CN 110269840 a discloses a cannabidiol nanoemulsion freeze-dried powder, which enhances the stability and bioavailability of cannabidiol nanoemulsion, but the preparation method described in the patent requires repeated freezing, thawing and hot bath, and the process is too complicated to be suitable for industrial production. CN 110742861 a discloses a cannabidiol solid self-nanoemulsion drug delivery system, which is prepared by adding cannabidiol from a nanoemulsion system into a solid carrier to form self-nanoemulsion soluble powder, and then mixing uniformly to prepare tablets, capsules, pills or granules. Although the preparation method disclosed by the invention effectively overcomes the defects of the self-nano emulsion preparation in the aspects of production, storage, use and the like, when the particle preparation is taken, a large amount of water is still needed for taking, and the preparation method is inconvenient for some groups with dysphagia, such as children, old people and the like.
CN 101862306B provides several methods for preparing oral solid self-emulsifying formulations of poorly soluble drugs. The spray drying method is that the water-soluble solid carrier is dissolved in a proper amount of water, then the self-emulsifying drug release part is dispersed in the water solution of the solid carrier to obtain O/W microemulsion, and finally the O/W microemulsion is prepared by spray drying (the input temperature is more than or equal to 100 ℃). The spray drying method is only suitable for solid carriers (more than or equal to 80 ℃) with higher melting points. The solvent melting method comprises dissolving the self-emulsifying drug-releasing part in appropriate amount of ethanol, adding into heated and melted water-soluble solid carrier (such as PEG, PVP, etc.), stirring, and evaporating to remove ethanol; or dissolving the self-emulsifying drug-releasing part in diluted ethanol solution to form colostrum, removing ethanol and water under reduced pressure, adding the melted water-soluble solid carrier, stirring, rapidly cooling, and drying. The preparation method also introduces a large amount of organic solvent, and the process is complex and is not beneficial to large-scale production.
The traditional oral administration mode has obvious first-pass effect and low bioavailability. The buccal mucosa drug delivery system is a novel drug delivery way developed by replacing the traditional systemic drug delivery way, compared with the traditional oral drug delivery way, the drug can directly enter the blood circulation of human body through the absorption of oral mucosa, thereby avoiding the degradation of gastrointestinal tract enzyme and the first pass effect of liver, achieving effective blood concentration of the drug more quickly, increasing the drug absorption and improving the bioavailability of the drug. Compared with the gastrointestinal absorption administration route, the administration dosage can be reduced, and the related side effects can be reduced; the oral film has proper mechanical properties and is easy to transport and store; has accurate administration dosage and good taste, can improve the medicine taking compliance of patients, and is especially suitable for old people with dysphagia, mental patients and children. CN 104940173B discloses two buccal membrane preparations and a preparation method thereof, wherein the sustained release membrane is prepared by mixing a pharmaceutical active ingredient and various auxiliary materials and then carrying out hot melt extrusion to form a membrane at 160 ℃; the preparation method of the instant membrane comprises the steps of dissolving the active ingredients of the medicine and various auxiliary materials in 80% ethanol solution, and drying at 70 ℃ after coating. Although the film uniformity is ensured to a certain extent by hot-melt extrusion film forming at 160 ℃, the high temperature is often not favorable for the stability of the active ingredients of the medicine, and especially the raw and auxiliary materials sensitive to the temperature are very challenging for the quality control of the prescription process. The other method is to dissolve the raw and auxiliary materials in 80% ethanol, coat the raw and auxiliary materials into a film and dry the film, so that a large amount of ethanol is generated in the preparation process, and on one hand, the problem of organic solvent residue exists, and on the other hand, the production control safety faces a large risk.
The self-emulsifying oral film belongs to the category of a solid self-emulsifying system, no self-emulsifying buccal adhesive film patent report exists at present in China, and only a few self-emulsifying quick-release oral soluble film patent reports exist: for example, CN 108813630A discloses a self-emulsifying film agent which can be directly taken orally and dissolved quickly and a preparation method thereof, and CN 109172547A discloses a self-emulsifying oral instant film agent for pets and a preparation method thereof. Many drugs with strong lipid solubility, good permeability and low oral bioavailability can not be improved or solved from the core problem. CN 1886117B discloses a self-emulsifying gel spray containing cannabidiol and tetrahydrocannabinol (both in approximately equal amounts) for administration via a mucosal surface. The spray takes high-concentration ethanol as a solvent, and also comprises at least one self-emulsifying agent, a cosolvent, a thickening agent and the like (the preferable dosage of the solvent and the cosolvent is more than or equal to 85 percent of the preparation). Sprays tend to cause irritation of the sublingual mucosa and loss of drug when used for sublingual administration, and their use for buccal administration, while avoiding this problem to some extent, is somewhat limiting with respect to device selectivity. When the patient self-administers the spray, the individual administration mode difference possibly causes inaccurate administration dosage and increases the risk of adverse reaction. The application of the spraying agent is limited to a certain extent by the administration dosage and the administration frequency of the spraying agent, and the mouthfeel of the spraying agent and the administration compliance of patients are greatly influenced by a large amount of self-nano emulsion and ethanol contained in the preparation. CN 100594897C provides a similar spray containing cannabinoids for mucosal administration, which, although free of self-emulsifying agents, requires a large amount of ethanol, the proportion of ethanol and propylene glycol being more than 55% of the formulation, and requires a specific spray device to enable the spray to be directed to a specific area of the oral mucosa, which undoubtedly adds significant cost and limitations to the production. US2019350876 a1 discloses a method for preparing a CBD oral soluble film, which comprises dissolving or dispersing CBD in a polymer solution, coating to form a film, and drying. Since CBD is still dispersed in the film in solid form, the rate of dissolution of cannabidiol in gastrointestinal fluids after swallowing is not improved, resulting in still poor bioavailability.
Disclosure of Invention
To date, no patent of pure cannabidiol buccal film formulation has been reported. Based on the physicochemical properties of cannabidiol, the advantages and limitations of the existing cannabidiol preparation patents, and the combination of the advantages of the self-nanoemulsion system and buccal mucosa administration, the invention aims to provide a cannabidiol self-nanoemulsion buccal membrane preparation, and a preparation method and application thereof. The cannabidiol self-nanoemulsion buccal membrane preparation provided by the invention improves the solubility of API, has the advantages of high drug loading, quick response, good permeability, quick absorption and high bioavailability, and has excellent preparation performances such as good flexibility, high tensile strength, moderate thickness, soft mouthfeel, strong stability and the like.
The cannabidiol self-nanoemulsion buccal film preparation comprises the following components in parts by weight: a backing film and a bioadhesive film layer adhered to the backing film;
the biological adhesion film layer is formed by dispersing cannabidiol in a self-nanoemulsion system, adsorbing the cannabidiol by a solid carrier and then dispersing the cannabidiol in a film-forming polymer, wherein the self-nanoemulsion system contains an oil phase, a surfactant and a cosurfactant or cosolvent.
In one aspect of the present invention, the film backing comprises a film-forming polymer selected from the group consisting of: one or more of Eudragit RL100, hydroxypropyl cellulose, hydroxyethyl cellulose and ethyl cellulose.
In one aspect of the invention, the self-nanoemulsion system is present in the cannabidiol self-nanoemulsion buccal film formulation in an amount of about 1-80% w/w, preferably about 3-70% w/w, more preferably about 10-60% w/w. The cannabidiol is dissolved in the self-nanoemulsion system to prepare a film-forming preparation.
The cannabidiol self-nanoemulsion system in the self-nanoemulsion buccal membrane preparation comprises pharmaceutically acceptable oil or oily substances, and the oil phase in the self-nanoemulsion system can be selected from the following components: soybean oil, castor oil, corn oil, olive oil, sesame oil, sunflower oil, peanut oil, long-chain monoglycerides, long-chain triglycerides, medium-chain monoglycerides, caprylic capric triglycerides, caprylic capric monoglycerides, glyceryl monooleate, glyceryl monolinoleate, propylene glycol fatty acid esters, propylene glycol monolaurate, caprylic/capric/succinic triglycerides, vitamin E, fatty acids and fatty acid esters, mineral oil, or any combination thereof.
In one aspect of the present invention, the oil or oily substance has a hydrophilic-hydrophobic balance (HLB value) of about 10 to 15.
In one aspect of the invention, the oil or oily substance is present in the self-nanoemulsion system in an amount of about 5-75% w/w, preferably about 10-60% w/w, more preferably about 15-50% w/w.
The self-nanoemulsion system in the cannabidiol self-nanoemulsion buccal membrane preparation provided by the invention contains a surfactant, and various pharmaceutically acceptable surfactants can be adopted, including a nonionic surfactant, a cationic surfactant, an anionic surfactant, a zwitterionic surfactant or any combination thereof. The surfactant contained in the self-nanoemulsion system is selected from one or more of perfluorooctane sulfonate (PFOS), Sodium Dodecyl Sulfate (SDS), ammonium lauryl sulfate and other alkyl sulfates, sodium dodecyl ether sulfate (SLES) and alkylbenzene sulfonate, Tween20 or 80, span 80 or 85, poloxamer, caprylic/capric macrogol glyceride, polyoxyethylene (35) castor oil ELP, polyoxyethylene ether castor oil, polyoxyethylene ether hydrogenated castor oil, fatty acid macrogol glyceride, polyoxyethylene sorbitan fatty acid ester or phospholipid. The surfactant has a hydrophilic-hydrophobic balance (HLB value) of from about 11 to about 16. .
In one aspect of the invention, the surfactant is present in the self-nanoemulsion system in an amount of about 10-50% w/w, preferably about 20-45% w/w.
In one aspect of the invention, the self-nanoemulsion system of cannabidiol self-nanoemulsion buccal film formulation further comprises a co-surfactant. The cosurfactant can be one or more of ethanol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, 1-hexanol, 2-hexanol, 1-octanol, 2-octanol, fusel oil, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether, tetrahydrofuran polyglycol ether or glycerol.
In yet another aspect of the invention, the co-surfactant is present in the self-nanoemulsion system in an amount of about 3-30% w/w, preferably about 5-40% w/w.
In one aspect of the present invention, the cannabidiol may further comprise a co-solvent in the self-nanoemulsion system of the nanoemulsion buccal film formulation. The cosolvent can be selected from n-propanol, glycerol, diethylene glycol monoethyl ether.
In yet another aspect of the invention, the co-solvent is present in the self-nanoemulsion system in an amount of about 5-50% w/w, preferably about 10-40% w/w.
The solid carrier which can be used in the present invention is various pharmaceutically acceptable solid adsorbent materials, wherein the solid carrier is selected from the group consisting of silica, silicates, magnesium trisilicate, magnesium aluminum silicate (Neusilin), microporous calcium silicate (Florite)TMRE), talcum powder, active carbon, one or more of gas-phase silicon dioxide, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, mannitol, PEG 4000 and PEG 6000. In the invention, the self-nanoemulsion system is adsorbed on a solid carrier and then uniformly distributed in a film-forming polymer, and a biological adhesion film layer is prepared after the film liquid is dried.
In yet another aspect of the present invention, the solid support is present in the bioadhesive membrane layer in an amount of from about 1 to 20% w/w, preferably from about 1 to 15% w/w.
In the present invention, the bioadhesive film layer may further comprise a plasticizer, a pigment and a taste masking agent. The plasticizer is one or more selected from PEG400, glycerol, propylene glycol, etc.
The biological adhesion film layer provided by the invention contains a film-forming polymer, and various pharmaceutically acceptable film-forming high molecular materials can be adopted, including a water-soluble polymer, a water-insoluble polymer or one or more water-soluble polymersA polymer and/or a water insoluble polymer. The film-forming polymer may be selected from the group consisting of polyethylene oxide, pullulan, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, carbomer, polycarbophil, chitosan, polyvinyl alcohol, PVP (povidone) K30, sodium alginate, carrageenan, xanthan gum, gelatin, guar gum, gum arabic, polyacrylic acid, methylmethacrylate copolymers, copolymers of acrylic acid and alkyl acrylates (e.g., copolymers of methacrylic acid and alkyl acrylates)
Polymers) carbopols and combinations thereof.
In one aspect of the invention, the film-forming polymer is present in the bioadhesive film layer in an amount of from about 10% w/w to about 60% w/w.
In one aspect of the invention, the bioadhesive membrane layer comprises a penetration enhancer selected from one or more of ethanol, propylene glycol, a surfactant, oleic acid, laurocapram, menthol, and eucalyptus oil.
In one aspect of the invention, wherein the penetration enhancer is present in the bioadhesive membrane layer from about 0.5% to about 15% w/w, preferably from about 1% to about 10% w/w.
In yet another aspect of the invention, the cannabidiol has a tensile strength greater than 0.5N/mm from nanoemulsion buccal film formulation2。
In yet another aspect of the present invention, the cannabidiol has a retention time from nanoemulsion buccal film formulation of not less than 15min, preferably 15-720 min.
In yet another aspect of the present invention, the cannabidiol self-nanoemulsion buccal film formulation is far superior to a cannabidiol double-layer buccal adhesive film (common film) in both permeation rate and cumulative permeation rate in permeation experiments. In one aspect of the invention, the permeation model satisfies the sink conditions, the dosing reservoir medium is phosphate buffer (pH 6.8) and the receiving reservoir is predominantly phosphate buffer (pH 7.4).
In yet another aspect of the present invention, the cannabidiol is present in an amount of about 2-80% w/w, preferably about 5-50% w/w, from the nanoemulsion buccal film formulation.
In yet another aspect of the invention, each of the cannabidiol tablets contains about 2-30mg, preferably 2-20mg, from the nanoemulsion buccal film formulation.
In yet another aspect of the present invention, the cannabidiol self-nanoemulsion buccal membrane preparation comprises cannabidiol, caprylic capric acid monoglyceride, polyoxyethylene (35) castor oil, and diethylene glycol monoethyl ether at a mass ratio of 320: 500: 500: 600.
in yet another aspect of the present invention, the formulation of cannabidiol from nanoemulsion buccal film formulation is:
in the present invention, there is also provided a method of preparing a cannabidiol self-nanoemulsion buccal film formulation comprising the steps of:
a. mixing the oil phase, the surfactant, the cosurfactant and/or the cosolvent to obtain a uniform mixture to form a self-nanoemulsion system;
b. adding cannabidiol into the self-nanoemulsion system, and stirring until the cannabidiol is completely dissolved to form a cannabidiol liquid self-nanoemulsion system;
c. swelling, dissolving and dispersing the film-forming polymer in water to form uniform film liquid;
d. c, adding the cannabidiol liquid in the step b into the solution in the step c from the nano-emulsion system under stirring to form a nano-emulsion, adding a solid carrier, and stirring until the mixture is uniformly dispersed; or adding a solid carrier into the cannabidiol liquid self-nanoemulsion system in the step b, fully adsorbing to obtain cannabidiol solid self-nanoemulsion powder, adding the membrane liquid in the step c into the cannabidiol liquid self-nanoemulsion powder, and stirring until the cannabidiol solid self-nanoemulsion powder is uniformly dispersed;
e. then adding a plasticizer, a penetration enhancer, a pigment and a taste masking agent, stirring and dispersing uniformly, standing and degassing, and drying to obtain a biological adhesion film layer;
f. and adhering the biological adhesive film layer to the backing film to form the cannabidiol self-nanoemulsion buccal film preparation with the biological adhesive film layer and the backing film.
In yet another aspect of the present invention, it is preferred that the Eudragit RL100 and the ethanol solution of glycerin are coated on the bioadhesive film layer and dried at room temperature to obtain the cannabidiol self-nanoemulsion buccal film preparation having both the bioadhesive film layer and the backing film.
The cannabidiol self-nanoemulsion buccal membrane preparation can be used for resisting epilepsy, relieving pain, treating mental disorders (such as schizophrenia, schizoaffective disorder and delusional disorder), resisting anxiety, resisting depression and other indications.
The invention screens out the optimal prescription composition of the cannabidiol self-nanoemulsion by adjusting the proportion and the dosage of the oil phase, the surfactant, the cosurfactant and the cannabidiol in the self-nanoemulsion system, and by observing the self-nanoemulsion speed, determining the particle size of emulsion droplets, observing the stability of the self-nanoemulsion system and the like. Then screening and proportioning from the film-forming polymer with larger molecular weight and viscosity, and screening out a prescription which has the advantages of quick hydration, good biological adhesion and meeting the requirement of retention time by observing the characteristics of mechanical property, adhesion, in-vitro retention time and the like of the film agent. Then, by observing the stability of the self-nanoemulsion in the adhesive film, a solid carrier capable of stabilizing the self-nanoemulsion and a prescription with good stability, good film forming property, good mechanical property of the film, good adhesion, stable grain size after redissolution and rapid emulsification of the composite film are screened out.
The composition and the preparation process of the cannabidiol self-nanoemulsion buccal membrane double-layer preparation provided by the invention have innovativeness and controllable release property, and products with different drug-loading rates can be prepared according to different clinical requirements. The specific solid carrier material is adopted in the film preparation to adsorb the self-nanoemulsion system, so that the self-nanoemulsion system can stably exist in an adhesive film, and the proper film-forming material, the self-nanoemulsion system and the solid carrier material and the proper proportion are screened, so that the self-nanoemulsion system and the buccal film can be well combined, the mechanical property of the film preparation is not influenced, and the permeation and the release of the medicine in the self-nanoemulsion system are not influenced. Compared with the Epidolex oral liquid preparation on the market, the cannabidiol self-emulsifying nano-emulsion buccal membrane double-layer preparation provided by the invention contacts a small amount of saliva, the adhesive layer can be quickly hydrated and adhered on the buccal mucosa surface without falling off, then the self-emulsifying nano-emulsion system dispersed in the adhesive layer is quickly self-emulsified to form nano-emulsion droplets under the environment of oral temperature, moisture and slight movement, the nano-emulsion droplets have larger specific surface area due to small particle size and can quickly permeate to the buccal mucosa through larger pores of the swelling membrane layer, the back lining layer ensures the unidirectional release of the medicament, reduces the loss and swallowing of the medicament, and the cannabidiol in the small emulsion droplets in the dissolved state is enhanced in transmucosal absorption and finally shows higher bioavailability. The film agent provided by the invention can be designed into a single layer or a plurality of layers according to the needs, and also can be designed into a quick release and sustained release dosage form, and the drug loading can be adjusted according to the needs of clinical treatment.
The invention creatively provides a cannabidiol self-nanoemulsion buccal mucosa preparation, and the preparation method has the starting point of combining the triple advantages of a self-emulsifying system, a solid preparation and a film agent, overcomes the defects of the traditional liquid self-emulsifying system, adopts a proper adsorption carrier, improves the physicochemical properties of the liquid self-emulsifying system after the liquid self-emulsifying system is solidified, is convenient to stably and uniformly disperse the liquid self-emulsifying system in a film-forming material framework, and can maintain the supersaturated state of active ingredients of the medicament when the preparation forms an emulsion by hydrophilic film-forming polymers such as hydroxypropyl methyl cellulose, povidone and the like, inhibit medicament precipitation and be beneficial to medicament absorption. According to the invention, the preparation of the back lining layer can be dissolved and coated only by using a small amount of ethanol, so that the using amount of ethanol in the production process is greatly reduced, the back lining layer is not contacted with the oral mucosa of a patient, a water-soluble material can be used for preparing the back lining layer according to the requirement, and the selectivity and the flexibility of the preparation process are increased. The patent and the preparation method creatively provide a platform, can prepare various dosage forms containing self-nanoemulsion, and enlarge the clinical application range of the medicine.
Drawings
Figure 1 is a graph of cannabidiol from nanoemulsion and cannabidiol from nanoemulsion buccal mucosa formulation (after reconstitution/hydration) particle size distribution;
figure 2 is the cumulative permeation rate of cannabidiol from nanoemulsion buccal mucosa formulations.
Detailed Description
The present invention will now be described in further detail with reference to the accompanying drawings and embodiments thereof. The following description is only illustrative of the claimed embodiments of the present invention and is not intended to limit the embodiments in any way. The scope of the present invention is defined by the appended claims.
Example 1 apparatus/device and detection method
1. Apparatus and device
High performance liquid chromatography (Agilent, 1260Infinity II), particle size potentiometers (Malvern, Nano ZS90), transdermal diffusion tester (Takay Technology Co., Ltd., TK-12D).
2. Detection method
(1) Establishment of cannabidiol analysis method: high performance liquid chromatography
The instrument comprises the following steps: the cannabidiol and the preparation thereof are separated, analyzed and quantified by using Agilent 1260Infinity II high performance liquid chromatography.
Conditions are as follows:
a chromatographic column: inertsil ODS-35 μm 4.6 x 50mm (UP);
mobile phase: a, water; b, methanol; a, B, 22:78 v/v;
flow rate: 1.0 mL/min; wavelength: 210 nm; sample introduction amount: 20 μ L.
(2) Determining the particle size of emulsion drops in the process of self-nanoemulsion and the particle size of composite membrane after redissolution
The instrument comprises the following steps: malvern Zetasizer (ZEN 3690);
setting parameters: sample RI ═ 1.59; the absorbance is 0.010; the temperature is 25.0 ℃; the viscosity of the solution is 0.8872 cp;
an equilibrium time of 120 s; sample pool Dispsable cuvettes: model DT 001.
(3) Tensile strength measurement
The instrument comprises the following steps: texture analyzer (Stable Micro System, ta.xt.plusc).
Setting parameters:
testing the model: TENSION; pre-test speed: 0.50 mm/sec; testing speed: 0.50 mm/sec; target mode: distance; force: 100.0 g; displacement: 10.000 mm; tension force: 10 percent; trigger force: auto (force).
Measuring mechanical performance parameters such as elongation at break and maximum stress (breaking force) when the film breaks, and calculating the tensile strength according to the cross-sectional area and a formula of the film:
tensile Strength (N/mm)2) Breaking tension (MPa)/initial cross-sectional area of film (mm)2)。
(4) Film thickness measurement
The instrument comprises the following steps: a thickness gauge;
and measuring the thickness of the film, taking five different points to measure the thickness of the film respectively, and calculating the average value of the thicknesses.
Example 2 preparation of cannabidiol from nanoemulsion
1. Screening of oil phase, surfactant and cosurfactant:
solubility determination of cannabidiol in different oils, surfactants and co-surfactants: the selected oil, surfactant and co-surfactant were each placed in 2mL glass bottles, added with excess cannabidiol, sonicated for 2h, sealed and stirred continuously (100rpm) in a shaking incubator (37 ℃) for 72 hours. After centrifugation (3500rpm,20min), the supernatant was filtered through a nylon filter (0.45 μm), diluted with a defined amount of methanol and subjected to HPLC to determine the saturation solubility of cannabidiol in different oils, surfactants and cosurfactants. Cannabidiol as a reference drug. The oils, surfactants and co-surfactants screened include, but are not limited to caprylic capric acid mono-di-glyceride, polyoxyethylene (35) castor oil, diethylene glycol monoethyl ether, medium chain triglycerides, soybean oil, caprylic capric acid polyethylene glycol glyceride, peppermint oil, Tween20, Tween60, Tween80, sesame oil, oleyl alcohol, polyethanol-7-stearate, polyoxyethylene 40 hydrogenated castor oil, PEG400, oleoyl polyoxyethylene glyceride, lauric acid polyethylene glycol glyceride and the like.
2. Prescription screening:
as shown in the following table, according to the measured solubility data, caprylic capric acid mono-diglyceride, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether which have high solubility to cannabidiol and meet the requirement of drug loading are selected, the proportion and the dosage of the components are adjusted, the formation condition of the self-nanoemulsion under different formulas is inspected, the microemulsion area is determined, and the optimal formula meeting the requirement is screened according to the appearance, the emulsification time, the particle size, the stability and the like. The self-nanoemulsion with smaller particle size has larger specific surface area, is easier to quickly emulsify to form micro nano-emulsion drops under certain conditions, and is easier to permeate through physiological barriers such as oral mucosa, small intestinal mucosa and the like. As mentioned above, the self-nanoemulsion formula with the particle size of 20-150 nm is preferred.
The method comprises the following steps:
accurately weighing cannabidiol into a 10mL sample bottle, accurately weighing and sequentially adding caprylic capric acid monoglyceride and capric acid monoglyceride, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether, stirring to fully dissolve, dropwise adding appropriate amount of water under stirring (dropwise adding speed is about 1 drop/second), observing the formation condition of the self-nanoemulsion, and determining the particle size of emulsion droplets.
A series of prescription screening including but not limited to the above list is carried out according to the dosage and proportion of each component, and finally S9 is screened out according to appearance, emulsification time, particle size, stability and the like as the optimal prescription of the cannabidiol self-nanoemulsion which meets the requirements, wherein the particle size is 40nm, PDI is 0.18, and Count Rate (kcps) to 370, and S9 is the prescription which meets the requirements of people in all aspects of comprehensive evaluation such as emulsification time (emulsification process is very quick, emulsification is carried out while adding, emulsification is carried out after adding), particle size, particle number, particle size distribution, stability of the nanoemulsion (the particle size is not changed after being placed for one week or being diluted by more than 100 times) and the like.
Example 3 preparation of Single layer buccal adhesive film, double layer buccal adhesive film (blank film without cannabidiol)
Preparation of single layer buccal adhesive film:
hydroxypropyl methylcellulose (HPMC K4M, HPMC K15M, HPMC K100M, HPMC E4M, HPMC E100M), carbomer (971P,934P), polycarbophil, sodium alginate, sodium carboxymethylcellulose (CMC-Na 8000, CMC-Na 12000), polyvinylpyrrolidone (PVP K30, PVP K60, PVP K90) and the like are respectively prepared into a single membrane forming liquid with the mass fraction of 0.5-5%. According to the designed formula (referring to the formula of cannabidiol self-nanoemulsion buccal membrane preparation 1-16, only the film-forming material components in the list are taken, the film-forming material components are not taken, the film-forming material components are mixed according to the quantitative proportion of the content in the formula, the plasticizer is also taken according to the same standard), the film-forming materials with different prescription amounts are uniformly mixed, the plasticizer (glycerol or PEG 400) is added, the mixture is stirred for 30min, then the mixture is kept stand and degassed, and the mixture is dried (60 ℃) for 4 hours to obtain the single-layer buccal adhesive membrane.
Preparation of a double-layer buccal adhesive film:
on the surface of the above-mentioned dried single-layer buccal adhesive film, an ethanol solution of Eudragit RL100 or ethyl cellulose was uniformly spread, and an appropriate amount of glycerin or PEG400 was added, followed by drying at room temperature to prepare a double-layer buccal adhesive film preparation having a backing layer.
Example 4 preparation and evaluation of cannabidiol double-layer buccal adhesive film (common double-layer film), cannabidiol from nanoemulsion Single-layer buccal adhesive film, cannabidiol from nanoemulsion buccal film formulation
1. Preparation of cannabidiol from nanoemulsion double-layer buccal adhesive film (namely, the cannabidiol from nanoemulsion buccal film preparation of the invention, the same below) of cannabidiol (the prescription components are shown in formula 1-16 of the cannabidiol from nanoemulsion buccal film preparation): the method comprises the steps of adding cannabidiol with the quantity listed in the table (cannabidiol self-nanoemulsion buccal membrane preparation 1-16) into caprylic capric acid monoglyceride and diglyceride, polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether (cosurfactant or cosolvent), stirring and dissolving to form a liquid self-nanoemulsion system containing the cannabidiol, then adding a mixed membrane solution of a membrane forming material (a membrane forming polymer is swelled and dissolved in water to form a uniform membrane solution), adding magnesium aluminum silicate, and stirring and dispersing uniformly. Or adding magnesium aluminum silicate into a mixed system of cannabidiol, caprylic/capric acid monoglyceride and/or caprylic/capric acid monoglyceride and polyoxyethylene (35) castor oil and diethylene glycol monoethyl ether (cosurfactant or cosolvent), fully adsorbing to obtain cannabidiol solid self-nanoemulsion powder, adding a film-forming solution (a film-forming polymer is swelled and dissolved in water to form a uniform film solution), and stirring and dispersing uniformly. Further adding taste masking agent (sucralose), pigment, plasticizer (glycerol) and penetration enhancer (propylene glycol), stirring thoroughly, standing for defoaming, and uniformly coating in a culture dish. Heating and drying at 50-60 ℃ to obtain the cannabidiol self-nanoemulsion single-layer buccal adhesive film (biological adhesive film layer). Evenly spraying Eudragit RL100 ethanol solution on the cannabidiol self-nanoemulsion single-layer buccal adhesive film, drying at room temperature to obtain the cannabidiol self-nanoemulsion buccal film preparation, cutting into suitable size, and packaging with polyester/aluminum packaging bags.
2. The cannabidiol double-layer buccal adhesive film (common double-layer film) is prepared by referring to the dosage of the cannabidiol from the nanoemulsion buccal film preparation 1-16 without the self-emulsifying system part (example 9 is referring to the cannabidiol from the nanoemulsion buccal film preparation 2), namely, the cannabidiol is only required to be uniformly dispersed in the film forming solution (without the self-emulsifying system), and the cannabidiol single-layer buccal adhesive film is obtained after standing, degassing and drying. And uniformly spraying an ethanol solution of Eudragit RL100 on the cannabidiol single-layer buccal adhesive film, and drying at room temperature to obtain the cannabidiol double-layer buccal adhesive film (common double-layer film).
The specific formulations are listed in the following table:
cannabidiol self-nanoemulsion buccal membrane preparation 1
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 2
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 3
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 4
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 5
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 6
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 7
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 8
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 9
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 10
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 11
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 12
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 13
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 14
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 15
Used in the recipe but removed during the process.
Cannabidiol self-nanoemulsion buccal membrane preparation 16
Used in the recipe but removed during the process.
Example 5 determination of mechanical Properties of cannabidiol from nanoemulsion buccal film formulations
Measuring mechanical performance parameters such as elongation at break, maximum stress (breaking force) and the like when the film breaks by using a texture analyzer, and calculating the tensile strength according to the cross-sectional area and a formula of the film:
tensile Strength (N/mm)2) Breaking tension (MPa)/initial cross-sectional area of film (mm)2)
Example 6 determination of cannabidiol dissolution time from nanoemulsion buccal film formulations
Film preparations (example 4) of the same size (2 cm. times.2 cm) and different formulations were cut out, and the dissolution time was measured. A stirrer was placed in a beaker containing 100mL of purified water, the test film was clamped on a clamp and placed in a water bath under magnetic stirring (50rpm, 37 ℃) to start timing, the dissolution time of the film adhesive layer was calculated because the backing layer was insoluble in water, and the dissolution time was measured in triplicate and the average value was calculated.
Example 7 in vitro determination of cannabidiol Retention time from nanoemulsion buccal film formulations
The porcine small intestine mucosa is adhered to a glass plate by using a disintegrating device, cannabidiol with different prescriptions is slightly wetted by phosphate buffer solution (PBS pH 6.8) from a nanoemulsion buccal membrane preparation and then lightly pressed on the surface of the small intestine mucosa, and the small intestine mucosa and the buccal mucosa are vertically moved up and down under the conditions of 37 ℃ and 50rpm and are required to be completely submerged in a medium solution during the downward movement. The time for the buccal membranes to slough off the small intestinal mucosa was measured.
According to examples 5 to 7, cannabidiol was measured for mechanical properties, dissolution time and retention time from nanoemulsion buccal film preparations 1 to 16(F1 SNEDDS to F16SNEDDS), and the results are shown in table 1.
As shown in Table 1, formulations containing carbomer or polycarbophil (F5 SNEDDS, F8 SNEDDS, F10 SNEDDS, F11 SNEDDS, F15 SNEDDS) had poor film forming properties and poor appearance, and it was found from the results of the measurements in the table that the film was thick, and the folding endurance, breaking tensile strength, etc. were poor, although the film had a long retention time. And finally selecting F2SNEDDS as an optimal prescription by combining the parameters such as the film thickness, the folding endurance, the elongation at break, the breaking tension, the tensile time, the dissolving time, the retention time and the like and the requirements.
Table 1 cannabidiol determination of mechanical properties, dissolution time and retention time from nanoemulsion buccal film formulations
Example 8 determination of the particle size of cannabidiol after reconstitution/hydration from nanoemulsion buccal film formulations
Drying the cannabidiol self-nanoemulsion buccal membrane preparation prepared according to the formula to form a membrane, then re-dissolving/hydrating the membrane, removing the backing, measuring the particle size of the membrane, comparing the particle size with the particle size of a liquid self-nanoemulsion system containing cannabidiol, and investigating whether the particle size is influenced after the self-nanoemulsion system is combined with a buccal adhesive membrane and in the whole formula process. The results are shown in FIG. 1.
As shown in fig. 1, the particle size distribution of the cannabidiol-containing liquid self-nanoemulsion system (left panel) and the cannabidiol self-nanoemulsion buccal membrane preparation (right panel after redissolution/hydration) are equivalent, and both are 40nm, uniform in dispersion and small in PDI. The results prove that the cannabidiol keeps the particle size of the cannabidiol basically unchanged after the double-layer buccal adhesive film is prepared from the nanoemulsion system, and the cannabidiol is favorable for permeating the double-layer buccal adhesive film from the nanoemulsion system through a mucous membrane tissue to enhance absorption.
Example 9 in vitro permeation evaluation of cannabidiol from nanoemulsion buccal film formulations
The porcine small intestine mucosa is used as an in vitro permeable tissue model, the model is treated and then placed in a Franz diffusion cell, the pH value of a receiving cell is 7.4, the adhesive layer of the cannabidiol self-nanoemulsion buccal membrane preparation is slightly wetted by the phosphate buffer solution with the pH value of 6.8 and then is contacted with the adhesive layer, the cumulative permeability of the cannabidiol in a certain time is investigated, and the cumulative permeability curves of the cannabidiol double-layer buccal adhesive membrane (common membrane) and the cannabidiol self-nanoemulsion buccal membrane preparation are compared, and the result is shown in figure 2.
As shown in fig. 2, comparing the cumulative permeability of cannabidiol from nanoemulsion buccal film formulation (F2 SNEDDS) and cannabidiol double-layer buccal adhesive film (common film) of formula 2 within 600min, it can be seen that cannabidiol rapidly permeates within the initial 15min from nanoemulsion buccal film formulation with a permeability of 0.19%, whereas cannabidiol double-layer buccal adhesive film (common film) is only 0.01, which is nearly 20 times different; within 30min, 45min, 60min, 90min, 120min, 180min, 240min, 360min, 480min and 600min, the difference of the permeation rate of the cannabidiol from the nanoemulsion buccal film preparation and the cannabidiol double-layer buccal adhesive film (common film) is 23 times, 15 times, 10 times, 6 times, 4 times, 2 times, 1.3 times, 0.75 times, 0.6 times and 0.6 times respectively, and the cannabidiol from the nanoemulsion buccal film preparation is far superior to the cannabidiol double-layer buccal adhesive film (common film) in terms of permeation rate and cumulative permeation rate. The cannabidiol dispersed in the common film is not dissolved in water, and can be separated out in the permeation process, and the permeation and dissolution efficiency of the cannabidiol is far inferior to that of the double-layer buccal adhesive film of the self-nano emulsion.
Claims (27)
1. A cannabidiol self-nanoemulsion buccal film formulation comprising: a backing film and a bioadhesive film layer adhered to the backing film;
the biological adhesion film layer is formed by dispersing cannabidiol in a self-nanoemulsion system, adsorbing the cannabidiol by a solid carrier and then dispersing the cannabidiol in a film-forming polymer, wherein the self-nanoemulsion system contains an oil phase, a surfactant and a cosurfactant or cosolvent.
2. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 wherein the backing film comprises a film forming polymer, the film forming polymer being one or more of Eudragit RL100, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose.
3. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1, wherein the formulation, on reconstitution/hydration, forms emulsion droplets having a particle size of from about 10 to 300nm, preferably from 20 to 150 nm.
4. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 wherein the content of cannabidiol self-nanoemulsion system in the cannabidiol self-nanoemulsion buccal film formulation is 10-60% w/w.
5. Cannabidiol self-nanoemulsion buccal film formulation according to claims 1 and 4, characterised in that it comprises self-nanoemulsion system emulsion droplets with a particle size of about 10-300 nm, preferably 20-150 nm.
6. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1, wherein the self-nanoemulsion system comprises an oil phase selected from the group consisting of: soybean oil, castor oil, corn oil, olive oil, sesame oil, sunflower oil, peanut oil, long-chain monoglycerides, long-chain triglycerides, medium-chain monoglycerides, caprylic capric triglycerides, caprylic capric monoglycerides, glyceryl monooleate, glyceryl monolinoleate, propylene glycol fatty acid esters, propylene glycol monolaurate, caprylic/capric/succinic triglycerides, vitamin E, fatty acids and fatty acid esters, mineral oil, or any combination thereof.
7. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 or 6 wherein the oil phase is present in the self-nanoemulsion system in an amount of 15-50% w/w.
8. A cannabidiol self-nanoemulsion buccal membrane formulation as claimed in claim 1, wherein the surfactant included in the self-nanoemulsion system is selected from one or more of perfluorooctanesulfonate, sodium lauryl sulfate, ammonium lauryl sulfate and other alkyl sulfates, sodium lauryl ether sulfate and alkylbenzene sulfonate, tween20 or 80, span 80 or 85, poloxamer, caprylic capric acid macrogol glyceride, polyoxyethylene (35) castor oil ELP, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, fatty acid polyglycolester, polyoxyethylene sorbitan fatty acid ester or phospholipid.
9. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 8 wherein the surfactant is present in the self-nanoemulsion system in an amount of 20-45% w/w.
10. A cannabidiol self-nanoemulsion buccal membrane formulation as claimed in claim 1, wherein the co-surfactant may be selected from one or more of ethanol, propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, 1-hexanol, 2-hexanol, 1-octanol, 2-octanol, fusel oil, polyethylene glycol, dimethyl isosorbide, propylene carbonate, diethylene glycol monoethyl ether, tetrahydrofuran polyglycol ether or glycerol.
11. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 10 wherein the co-surfactant is present in the self-nanoemulsion system in an amount of 5-40% w/w.
12. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 wherein the co-solvent may be selected from n-propanol, glycerol, diethylene glycol monoethyl ether.
13. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 12, wherein the co-solvent is present in the self-nanoemulsion system in an amount of 10-40% w/w.
14. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1, wherein the solid carrier is selected from one or more of silicon dioxide, silicates, magnesium trisilicate, magnesium aluminium silicate, microporous calcium silicate, talc, activated carbon, aerosil, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, mannitol, PEG 4000 and PEG 6000.
15. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 14 wherein the solid carrier is present in the bioadhesive film layer in an amount of 1-15% w/w.
16. The cannabidiol self-nanoemulsion buccal film formulation of claim 1, wherein the bioadhesive film layer further comprises a plasticizer, a pigment, a taste masking agent and a penetration enhancer.
17. The cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 16, wherein the plasticizer is selected from one or more of PEG400, glycerol, propylene glycol and the like.
18. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 16, wherein the penetration enhancer is selected from one or more of ethanol, propylene glycol, surfactant, oleic acid, laurocapram, menthol, eucalyptus oil.
19. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 18 wherein the penetration enhancer is present in the bioadhesive film layer in an amount of 1-10% w/w.
20. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1, wherein the film forming polymer may be selected from the group consisting of polyoxyethylene, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, carbomer, polycarbophil, chitosan, polyvinyl alcohol, PVP (povidone) K30, sodium alginate, carrageenan, xanthan gum, gelatin, guar gum, gum arabic, polyacrylic acid, methylmethacrylate copolymers, copolymers of acrylic acid and alkyl acrylate polycarbophil and combinations thereof.
21. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 wherein the film forming polymer is present in the bioadhesive film layer in an amount of 10-60% w/w.
22. A cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 wherein the content of cannabidiol in the cannabidiol self-nanoemulsion buccal film formulation is 5-50% w/w.
23. A cannabidiol self-nanoemulsion buccal membrane formulation as claimed in claim 1, wherein the cannabidiol self-nanoemulsion buccal membrane formulation comprises cannabidiol, caprylic capric acid mono-diglyceride, polyoxyethylene (35) castor oil, diethylene glycol monoethyl ether in a mass ratio of 320: 500: 500: 600.
24. a cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 23 wherein the cannabidiol self-nanoemulsion buccal film formulation is formulated as:
25. a method of preparing a cannabidiol self-nanoemulsion buccal film formulation comprising the steps of:
a. mixing the oil phase, the surfactant, the cosurfactant and/or the cosolvent to obtain a uniform mixture to form a self-nanoemulsion system;
b. adding cannabidiol into the self-nanoemulsion system, and stirring until the cannabidiol is completely dissolved to form a cannabidiol liquid self-nanoemulsion system;
c. swelling, dissolving and dispersing the film-forming polymer in water to form uniform film liquid;
d. c, adding the solution in the step b into the cannabidiol liquid in the step c from the nano-emulsion system under stirring to form a nano-emulsion, adding a solid carrier, and stirring until the mixture is uniformly dispersed; or adding a solid carrier into the cannabidiol liquid self-nanoemulsion system in the step b, fully adsorbing to obtain cannabidiol solid self-nanoemulsion powder, adding the membrane liquid in the step c into the cannabidiol liquid self-nanoemulsion powder, and stirring until the cannabidiol solid self-nanoemulsion powder is uniformly dispersed;
e. then adding a plasticizer, a penetration enhancer, a pigment and a taste masking agent, stirring and dispersing uniformly, standing and degassing, and drying to obtain a biological adhesion film layer;
f. and coating the biological adhesive film layer on a backing film to form the cannabidiol self-nanoemulsion buccal film preparation with the biological adhesive film layer and the backing film.
26. The method of claim 25 wherein step f comprises applying Eudragit RL100 or an ethanol solution of ethylcellulose and glycerol to the bioadhesive film layer and allowing the solution to evaporate at room temperature to provide the cannabidiol self-nanoemulsion buccal film formulation having both the bioadhesive film layer and the backing film.
27. Use of cannabidiol self-nanoemulsion buccal film formulation as claimed in claim 1 in the manufacture of a medicament for anti-epileptic, analgesic, psychiatric, anxiolytic or antidepressant use.
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