CN118845715A - Cannabidiol composition and its use in treating systemic inflammatory response syndrome - Google Patents

Abstract

The invention discloses a cannabidiol composition in the field of pharmaceutical preparation technology and its use in treating systemic inflammatory response syndrome. The cannabidiol composition includes a barrier layer, an enteric layer and a carrier, and is made by a film coating method; the carrier includes 3-5 parts of cannabidiol, 6-8 parts of non-steroidal anti-inflammatory drugs and 1-3 parts of micellar carriers, and the non-steroidal anti-inflammatory drugs are selected from one of acetaminophen or diclofenac; the use in treating systemic inflammatory response syndrome includes the use of preparing drugs for relieving systemic inflammatory response syndrome and analgesic and antipyretic drugs. The present invention has a perfect structure, and the carrier is made by combining cannabidiol and non-steroidal anti-inflammatory drugs, and the enteric layer and the barrier layer are wrapped outside to reduce the contact between the drug and the stomach wall, so that it is insoluble in the stomach environment and dissolved in the intestinal environment, and the drug side effects are slowed down while improving the anti-inflammatory effect.

Description

Cannabidiol composition and its use in treating systemic inflammatory response syndrome

Technical Field

The present invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a cannabidiol composition and its use in treating systemic inflammatory response syndrome.

Background Art

Cannabidiol (CBD) is an extract of industrial hemp plants, which has many medicinal activities and no psychoactive effects. Since 2700 BC, extracts from the flowers and resins of cannabis plants have been used to treat menstrual disorders, rheumatism, malaria, constipation and mental confusion. In the Middle Ages, doctors used cannabis to treat nausea, vomiting, epilepsy, inflammation pain and fever. In the 19th century, cannabis was widely used as a Western medicine treatment, often as a painkiller. At present, a large number of studies have shown that CBD has multiple pharmacological effects and can play a good pharmacological role in mental illness, cancer, anxiety, inflammation and other diseases. In addition, CBD has also shown the ability to treat acne, slow down the occurrence of skin inflammation, anti-aging, and treat eczema. The most important thing is that CBD shows good safety and tolerability in the human body, which shows that it has broad application prospects in functional foods, cosmetics, pharmaceuticals and other fields.

As a natural polyphenol, CBD has anti-inflammatory effects and has been shown to have certain therapeutic effects on certain inflammatory diseases such as arthritis, synovitis, tendinitis, etc. In addition, studies have shown that cannabidiol can significantly reduce joint swelling, pain levels, immune cell invasion, and synovial thickness, and the effect depends on the dose of CBD.

Regarding systemic inflammatory response syndrome, there are reports that compositions containing cannabidiol may have potential application prospects in treating or alleviating systemic inflammatory response syndrome caused by various exogenous or endogenous factors or reducing the degree of cytokine storm and the damage to tissues and organs caused by it. This may be because cannabidiol can inhibit certain signaling pathways and reduce the release of pro-inflammatory cytokines, thereby reducing the degree of systemic inflammatory response.

By combining cannabidiol and nonsteroidal anti-inflammatory drugs, the drug effect of cannabidiol can be further improved, but cannabidiol and nonsteroidal anti-inflammatory drugs can cause adverse gastrointestinal reactions, and long-term use may lead to gastric and duodenal ulcers, gastrointestinal perforation, and bleeding, so that the traditional solid preparation administration is limited. However, solid preparations, as the most stable drug storage method, have better physical and chemical stability, and are convenient for patients to carry and store, and can be taken at any time as needed. For this reason, it is necessary to propose a cannabidiol composition and its use in the treatment of systemic inflammatory response syndrome.

Summary of the invention

In order to solve the problem that the traditional solid preparations of the above-mentioned cannabidiol composition are limited in administration due to gastrointestinal adverse reactions, the purpose of the present invention is to provide a cannabidiol composition and its use in the treatment of systemic inflammatory response syndrome, by combining cannabidiol and non-steroidal anti-inflammatory drugs to form a carrier, and wrapping an enteric layer and a barrier layer on the outside to reduce the contact between the drug and the stomach wall, so that it is insoluble in the stomach environment but soluble in the intestinal environment, thereby improving the anti-inflammatory effect while reducing the side effects of the drug.

In order to achieve the above-mentioned purpose, the technical scheme of the present invention is as follows: a cannabidiol composition comprises a barrier layer, an enteric layer and a carrier, and is prepared by a film coating method; the carrier comprises cannabidiol, a non-steroidal anti-inflammatory drug and a micellar carrier, the carrier comprises 3-5 parts of cannabidiol, 3-5 parts of non-steroidal anti-inflammatory drugs and 18-30 parts of micellar carriers, and the non-steroidal anti-inflammatory drug is selected from one of acetaminophen or diclofenac.

The principle of the basic scheme: When the cannabidiol composition enters the human body orally, the barrier layer protects the enteric layer and the carrier from erosion by gastric acid and digestive enzymes. The drug enters the small intestine and the enteric layer dissolves, at which time the carrier is released. The carrier releases cannabidiol and non-steroidal anti-inflammatory drugs, both of which are absorbed through the active and passive transport mechanisms of the small intestine, reducing the contact between the drug and the stomach, alleviating adverse drug reactions, and improving the absorption effect of the drug.

The beneficial effects of the basic scheme are: through the protection of the barrier layer, the contact between the drug and the stomach can be reduced, and the adverse drug reactions can be alleviated. The enteric layer can ensure the release of cannabidiol and non-steroidal drugs in the small intestine to achieve the best absorption effect. At the same time, the design of the carrier can increase the stability of cannabidiol and improve the bioavailability. The combination of cannabidiol and acetaminophen or diclofenac can produce good synergistic effects. Cannabidiol can relatively reduce the side effects caused by acetaminophen or diclofenac through its anti-inflammatory, analgesic and neuroprotective effects, optimize the therapeutic effect, and enhance the anti-inflammatory effect of non-steroidal drugs.

Furthermore, the barrier layer is located outside the enteric layer and wraps the enteric layer, and the carrier is located inside the enteric layer.

The beneficial effects of the basic solution are: the barrier layer is located at the outermost layer, which can protect the enteric layer and the carrier from erosion by gastric acid and digestive enzymes, while reducing the contact between the drug and the stomach wall, improving the patient's medication experience. As the drug passes through the stomach and enters the small intestine, the pH environment of the small intestine causes the enteric layer to dissolve rapidly, releasing the carrier at this time, and then the cannabidiol and non-steroidal drugs in the carrier are absorbed by the small intestine. The multi-layer structure design allows the drug to be released in the designated part of the small intestine, achieving targeted drug delivery.

Furthermore, sucralfate is selected as the barrier layer, and hypromellose is selected as the enteric layer.

The beneficial effects of the basic solution are: sucralfate as a barrier layer material can react with gastric acid in the stomach to form aluminum salts, neutralize gastric acid, and form a protective film, which can reduce the contact between the drug and the stomach wall and reduce adverse reactions in the stomach. At the same time, the protective film can effectively protect the drug from the erosion of gastric acid and pepsin, so that the drug can pass through the stomach smoothly into the small intestine; Hydroxypropyl methylcellulose is selected as the enteric layer. The solubility of hydropropyl methylcellulose in the pH range of 3-11 remains relatively stable, and the pH value of the stomach is usually less than 3. Hydroxypropyl methylcellulose does not dissolve in the gastric environment, but has good and stable solubility in the intestinal environment, ensuring that the package carrier wrapped in the enteric layer is released in the small intestine to achieve targeted delivery.

Furthermore, cannabidiol and nonsteroidal anti-inflammatory drugs are entrapped in micellar carriers.

The beneficial effects of the basic scheme are: encapsulating the two drugs in the micelle carrier can achieve the co-delivery of the two drugs, simplifying the treatment process, and the micelle carrier can effectively increase the solubility of cannabidiol in water and improve the bioavailability of the drug.

Furthermore, the micelle carrier comprises a hydrophilic block and a hydrophobic block, the hydrophilic block is polyethylene glycol, and the hydrophobic block is polylactic acid.

The beneficial effects of the basic scheme are: polyethylene glycol, as the hydrophilic block of the micelle carrier, has good water solubility, which can increase the solubility of cannabidiol, making the micelle carrier as a whole water-soluble. At the same time, the addition of polylactic acid as a hydrophobic block can protect cannabidiol and non-steroidal anti-inflammatory drugs from various enzymatic and chemical degradation in the human body, thereby improving the stability and activity of the drugs.

Furthermore, the cannabidiol composition is used in the treatment of systemic inflammatory response syndrome, and is used to prepare drugs for relieving systemic inflammatory response syndrome and analgesic and antipyretic drugs.

Furthermore, the preparation method of the cannabidiol composition comprises the following steps:

Step 1, preparing the encapsulation carrier: weigh the hydrophilic block and the hydrophobic block of the micelle carrier into a conical flask, add a solvent and ultrasonically dissolve them, then add cannabidiol and non-steroidal anti-inflammatory drugs, continue ultrasonically dissolving, put the solution into a rotary evaporator to remove the solvent until solid particles are formed, and put the solid particles into a blast drying oven until they are completely dried to prepare the encapsulation carrier;

Step 2, coating the enteric layer: the enteric layer material is prepared into an aqueous solution, an emulsifier is added to assist in dissolution, the mixture is stirred evenly and sieved, and a coating machine is used to coat the carrier in step 1 to prepare micropellets;

Step three, coating the barrier layer: dissolve the barrier layer material in propylene glycol to prepare a coating solution, add hot water, stir evenly and sieve, use a coating machine to coat the micropills in step two to obtain a cannabidiol composition.

Furthermore, in step one, the mass ratio of the hydrophilic block and the hydrophobic block of the micelle carrier is 1:1, the mass ratio of cannabidiol to the non-steroidal anti-inflammatory drug is 1:1, the mass ratio of the micelle carrier to the drug is 3:1, the solvent is anhydrous ethanol, and the temperature of the rotary evaporation is 40°C.

Furthermore, in step 2, the mass fraction of the enteric layer aqueous solution is 5%, and the emulsifier is sorbitan oleate.

Furthermore, in step three, the mass fraction of the barrier material coating liquid is 20%, and the mass of the added hot water shall not exceed the mass of the barrier material.

The beneficial effects of the basic scheme are: 1. Through the encapsulation of micellar carriers, the stability of cannabidiol and non-steroidal anti-inflammatory drugs can be improved, and the drugs can be protected from the influence of the external environment. At the same time, the enteric layer can ensure the release of drugs in the intestine, achieve targeted delivery, and improve the bioavailability of drugs. The outermost encapsulation barrier layer can protect the drugs from gastric acid destruction, reduce drug irritation and potential damage to the stomach, and reduce drug-related gastrointestinal side effects.

2. The preparation process is simple to operate. By controlling the concentration of the coating solution and the concentration of the enteric layer aqueous solution, the effective thickness of the barrier layer and the enteric layer can be controlled to achieve control of the drug release rate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a schematic diagram of the structure of a cannabidiol composition according to an embodiment of the present invention.

FIG. 2 is a schematic diagram of a process flow chart of a method for preparing cannabidiol according to an embodiment of the present invention.

DETAILED DESCRIPTION

The following is further described in detail through specific implementation methods:

The reference numerals in the drawings of the specification include: carrier 1, enteric layer 2, barrier layer 3.

Example 1, as shown in FIG1 , comprises a barrier layer 3, an enteric layer 2 and a carrier 1, and is made by a film coating method, wherein the barrier layer 3 is located outside the enteric layer 2 and wraps the enteric layer 2, and the carrier 1 is located inside the enteric layer 2;

The barrier layer 3 is located at the outermost layer, which can protect the enteric layer 2 and the carrier 1 from being eroded by gastric acid and digestive enzymes, and at the same time reduce the contact between the drug and the stomach wall, thereby improving the patient's medication experience. As the drug passes through the stomach and enters the small intestine, the pH environment of the small intestine causes the enteric layer 2 to dissolve rapidly, and the carrier 1 is released at this time, and then the carrier 1 releases the cannabidiol and non-steroidal drugs therein. The multi-layer structure design can release the drug at a designated location in the small intestine, achieve targeted delivery of the drug, and improve the efficacy of the drug. In addition, during the preparation process, the concentration of each layer of coating solution can be controlled to achieve control of the drug release rate.

The barrier layer 3 uses sucralfate, which can react with gastric acid in the stomach to form aluminum salts, forming a protective film to reduce the contact between the drug and the stomach wall; the enteric layer 2 uses hypromellose, which does not dissolve in the stomach environment, but has good and stable solubility in the intestinal environment;

The encapsulating carrier comprises 3 parts of cannabidiol, 3 parts of non-steroidal anti-inflammatory drugs and 18 parts of micelle carriers. Cannabidiol and non-steroidal anti-inflammatory drugs are embedded in the micelle carriers. The micelle carriers are water-soluble carriers as a whole. The micelle carriers include hydrophilic blocks and hydrophobic blocks. The hydrophilic blocks are polyethylene glycol, which has good water solubility and can increase the solubility of cannabidiol. The hydrophobic blocks are polylactic acid, which can protect cannabidiol and non-steroidal drugs from various enzymatic degradation and chemical degradation in the human body, thereby improving the stability and activity of the drugs. The non-steroidal anti-inflammatory drugs are selected from acetaminophen or diclofenac.

1. Experimental Design

The effects of the cannabidiol composition in Example 1 on the survival rate of mice with sepsis, the levels of inflammatory cytokines (including interleukin-1b (IL-1b), interferon-γ (IFN-γ), tumor necrosis factor α (TNF-α) and IL-6), lung tissue pathological changes and immune cell infiltration were observed. The experiment was divided into two parts, using a total of 72 mice.

Survival rate observation experiment:

Thirty-six mice were randomly divided into three groups, with 12 mice in each group.

Groups: model control group, cannabidiol control group, cannabidiol combination experimental group.

Treatment: After cecal ligation and puncture (CLP), 1 mL of 0.9% sodium chloride injection, 20 mg/kg cannabidiol solution, and 20 mg/kg cannabidiol combination solution were administered once every 12 hours for 72 hours.

Observation: The survival rate of mice in each group was recorded 72 hours after CLP.

Specimen collection experiment: The remaining 36 mice were grouped according to the survival rate observation experiment plan.

Corresponding treatment was given 12 hours, 24 hours, and 36 hours after CLP surgery.

The mice were killed 48 hours after surgery, and the levels of inflammatory cytokines, lung pathological changes, and liver immune cell infiltration were detected.

2. Experimental Results

Table 1 Experimental results of each group

As can be seen from the above table, compared with the model group and the cannabidiol control group, the cytokine levels (IL-1b, IFN-γ, TNF-α and IL-6) of the mice in the cannabidiol composition experimental group were significantly reduced, indicating that the cannabidiol composition in Example 1 can effectively inhibit the inflammatory response, and the survival rate of the mice in the cannabidiol composition experimental group was significantly improved to 58.3%, showing that the cannabidiol composition has a significant therapeutic effect on septic mice, and the improvement of lung pathological damage and liver immune cell infiltration further confirms the effectiveness of cannabidiol in the treatment of sepsis (ie, systemic inflammatory response syndrome).

Example 2, substantially as shown in FIG. 2, differs from the above embodiment in that: the method for preparing the cannabidiol composition comprises the following steps:

Step 1, preparing a carrier 1: weighing the hydrophilic block and the hydrophobic block of the micelle carrier in a conical flask, the mass ratio of the hydrophilic block and the hydrophobic block of the micelle carrier is 1:1, adding anhydrous ethanol as a solvent to dissolve it by ultrasound, and then adding cannabidiol and non-steroidal anti-inflammatory drugs. Cannabidiol can be obtained by using the flowers and leaves of female cannabis flowers, crushed and dried by a grinder, and then extracted. The number of cannabidiol used is 3 parts, the mass ratio of the added non-steroidal anti-inflammatory drugs to cannabidiol is 1:1, and the mass ratio of the total amount of micelle carriers to the total amount of encapsulated drugs is 3:1, and ultrasonic dissolution is continued, and the solution is placed in a rotary evaporator to remove the solvent. The temperature of rotary evaporation is 40°C until solid particles are formed, and the solid particles are placed in a blast drying oven until they are completely dried to prepare a carrier 1;

Step 2, coating the enteric layer 2: the enteric layer 2 material is prepared into an aqueous solution, the mass fraction of the enteric layer 2 aqueous solution is 5%, an emulsifier sorbitan oleate is added to assist in dissolution, the mixture is stirred evenly and sieved, and a coating machine is used to coat the carrier in step 1 to prepare micropellets;

Step three, wrapping barrier layer 3: dissolve the barrier layer 3 material in propylene glycol to prepare a coating solution, the mass fraction of the barrier layer 3 material coating solution is 20%, add hot water, the mass of the hot water must not exceed the mass of the barrier material, stir evenly and sieve, use a coating machine to coat the micropills in step 2 to obtain a cannabidiol composition.

1. Experimental Design

A CBD stock solution with a concentration of 1 mg/mL was prepared, and the solution was diluted with anhydrous ethanol to a gradient working solution with concentrations of 0.1, 1, 2, 5, 8 and 10 μg/mL in sequence. The absorbance (A) value was measured at 210 nm using a 10 nm cuvette and an ultraviolet spectrophotometer, and the blank control was anhydrous ethanol. A coordinate system was established with concentration as the independent variable and absorbance as the dependent variable, and a standard curve of CBD was drawn using linear regression fitting. The regression equation was y=0.1586x+0.0451 (R ² =0.9997), and it was known that CBD had a good linear relationship in the range of 0.1-10 μg/mL.

Three CBD solutions of 10 μg/mL, 5 μg/mL, and 1 μg/mL were taken, and the absorbance values were measured at 210 nm using a UV spectrophotometer. Each solution was measured 5 times within one day for precision investigation.

The cannabidiol composition prepared in Example 2 was dissolved in anhydrous ethanol, and the absorbance (A) value was measured at 210 nm using a 10 nm cuvette and an ultraviolet spectrophotometer, and its concentration was calculated by the regression equation. Five samples were prepared in parallel.

2. Experimental Results

Table 2 Precision investigation

As shown in Table 2, the precision of determining CBD content using UV spectrophotometry is good, and sample content measurement can be performed.

Table 3 CBD content measurement

It can be seen from Table 3 that the CBD content in the cannabidiol composition has good stability, and the average effective concentration of CBD is 2.72 μg/mL, which reaches the average concentration of commercially available cannabidiol drugs. The cannabidiol composition prepared by this method has good effectiveness.

It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

The above is only an embodiment of the present invention. The common sense such as the known specific structure and characteristics in the scheme is not described in detail here. The ordinary technicians in the relevant field know all the common technical knowledge in the technical field of the invention before the application date or priority date, can obtain all the existing technologies in the field, and have the ability to apply the conventional experimental means before that date. The ordinary technicians in the relevant field can improve and implement this scheme in combination with their own abilities under the enlightenment given by this application. Some typical known structures or known methods should not become obstacles for ordinary technicians in the relevant field to implement this application. It should be pointed out that for those skilled in the art, without departing from the structure of the present invention, several deformations and improvements can be made, which should also be regarded as the protection scope of the present invention, which will not affect the effect of the implementation of the present invention and the practicality of the patent. The protection scope required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims (10)

1. A cannabidiol composition, characterized in that it comprises a barrier layer, an enteric layer and a carrier, and is made by a film coating method; the carrier comprises 3-5 parts of cannabidiol, 3-5 parts of non-steroidal anti-inflammatory drugs and 18-30 parts of micellar carriers, and the non-steroidal anti-inflammatory drug is selected from acetaminophen or diclofenac. 2. The cannabidiol composition according to claim 1 is characterized in that the barrier layer is located outside the enteric layer and wraps the enteric layer, and the carrier is located inside the enteric layer. 3. The cannabidiol composition according to claim 2 is characterized in that: sucralfate is used as the barrier layer and hypromellose is used as the enteric layer. 4. The cannabidiol composition according to claim 3, wherein the cannabidiol and the non-steroidal anti-inflammatory drug are embedded in a micellar carrier. 5. The cannabidiol composition according to claim 4 is characterized in that the micelle carrier comprises a hydrophilic block and a hydrophobic block, the hydrophilic block is polyethylene glycol, and the hydrophobic block is polylactic acid. 6. Use of a cannabidiol composition in the treatment of systemic inflammatory response syndrome, characterized in that it is used to prepare drugs for relieving systemic inflammatory response syndrome and analgesic and antipyretic drugs. 7. The cannabidiol composition according to claim 6, characterized in that: the preparation method of the cannabidiol composition comprises the following steps: Step 1, preparing the encapsulation carrier: weigh the hydrophilic block and the hydrophobic block of the micelle carrier into a conical flask, add a solvent and ultrasonically dissolve them, then add cannabidiol and non-steroidal anti-inflammatory drugs, continue ultrasonically dissolving, put the solution into a rotary evaporator to remove the solvent until solid particles are formed, and put the solid particles into a blast drying oven until they are completely dried to prepare the encapsulation carrier; Step 2, coating the enteric layer: the enteric layer material is prepared into an aqueous solution, an emulsifier is added to assist in dissolution, the mixture is stirred evenly and sieved, and a coating machine is used to coat the carrier in step 1 to prepare micropellets; Step three, coating the barrier layer: dissolve the barrier layer material in propylene glycol to prepare a coating solution, add hot water, stir evenly and sieve, use a coating machine to coat the micropills in step two to obtain a cannabidiol composition. 8. The method for preparing a cannabidiol composition according to claim 7, characterized in that: in step 1, the mass ratio of the hydrophilic block and the hydrophobic block of the micelle carrier is 1:1, the mass ratio of cannabidiol and the non-steroidal anti-inflammatory drug is 1:1, the mass ratio of the total amount of the micelle carrier to the total amount of the encapsulated drug is 3:1, the solvent is anhydrous ethanol, and the temperature of the rotary evaporation is 40°C. 9. The method for preparing a cannabidiol composition according to claim 8, characterized in that: in step 2, the mass fraction of the enteric layer aqueous solution is 5%, and the emulsifier is sorbitan oleate. 10. The method for preparing a cannabidiol composition according to claim 9 is characterized in that: in step 3, the mass fraction of the barrier material coating liquid is 20%, and the mass of the added hot water shall not exceed the mass of the barrier material.