Cannabidiol lyophilized orally disintegrating tablet and preparation method thereof

Abstract

The application discloses a kind of cannabidiol freeze-drying oral disintegration tablets and preparation method thereof, belong to the technical field of pharmaceutical preparations.A kind of cannabidiol freeze-drying oral disintegration tablets, the raw material of the oral disintegration tablet includes effective component water-soluble cannabidiol and other auxiliary materials, wherein, water-soluble cannabidiol is 50%-70% by mass percentage;The other auxiliary material is one or more of matrix agent, freeze-drying protective agent, disintegrating agent, binder, lubricant, flavoring agent.The application combines high-pressure homogenization with freeze-drying technology, the obtained oral disintegration tablet is easy to disintegrate, and the particle size after disintegration is smaller, more conducive to absorption, solve the problem that cannabidiol is not easy to absorb in the prior art, and the bioavailability is low.

Description

Technical Field

[0001] This invention belongs to the field of analytical detection methods, specifically relating to a cannabidiol freeze-dried orally disintegrating tablet and its preparation method. Background Technology

[0002] Cannabidiol (CBD) is a non-psychoactive compound extracted from the cannabis plant, possessing various pharmacological activities such as anti-anxiety, anti-epileptic, anti-inflammatory, and antioxidant effects. However, as a typical BCS Class II drug, CBD suffers from severe water solubility issues, with a solubility of only about 0.1528 μg / ml in water and a high log P value of 6.3, classifying it as a highly lipid-soluble compound. This characteristic results in low oral bioavailability of CBD, only 6-13%, severely limiting its end-use applications.

[0003] To address the water solubility issue of CBD, existing technologies primarily employ the following methods: salt formation, altering crystal form, reducing particle size, solid dispersions, solvent systems, cyclodextrin inclusion complexes, microemulsions, and liposomes. Among these, cyclodextrin inclusion complexes can increase CBD solubility by 17-614 times; phospholipid complex technology can increase CBD solubility by 6 times, raising the solubility from 0% to 67.1% within three hours; and nanoemulsion technology can increase oral bioavailability from 6-12% in traditional formulations to 45-60%. However, these technologies still suffer from problems such as low drug loading, complex preparation processes, and poor stability.

[0004] Orally disintegrating tablets (ODTs) are a novel oral dosage form that rapidly disintegrates, disperses, or dissolves in saliva in the oral cavity under anhydrous conditions. They are absorbed through the oral mucosa, avoiding the first-pass effect in the liver and significantly improving bioavailability. They offer advantages such as convenient administration and good patient compliance.

[0005] However, existing cannabidiol orally disintegrating tablets still have the following technical defects: (1) They use traditional fat-soluble CBD, which has low bioavailability; (2) The selection of freeze-drying protectants is inappropriate, which affects product stability; (3) The disintegration time is difficult to control within the range of 30-40 seconds; (4) The preparation process is complex and the cost is high.

[0006] The present invention aims to provide an orally disintegrating tablet prepared by using water-soluble cannabidiol as raw material through a specific formulation combination and freeze-drying technology, which has the advantages of rapid disintegration (30-40 seconds), high bioavailability, and simple preparation process. Summary of the Invention

[0007] To address the problems of poor absorption efficiency and low bioavailability of lipid-soluble CBD in the prior art, this invention provides a cannabidiol freeze-dried orally disintegrating tablet and its preparation method. This invention uses water-soluble cannabidiol as the active ingredient, and through a specific formulation combination and freeze-drying technology, achieves rapid disintegration (30-40 seconds) and high bioavailability, while ensuring stable product quality.

[0008] A cannabidiol freeze-dried orally disintegrating tablet and its preparation method are disclosed. The raw materials of the orally disintegrating tablet include the active ingredient water-soluble cannabidiol and other excipients. The water-soluble cannabidiol accounts for 50%-70% by mass percentage. The other excipients are one or more of the following: matrix agent, freeze-drying protectant, disintegrant, binder, lubricant, and flavoring agent.

[0009] In the above technical solution, the water-soluble cannabidiol is prepared by the following method: cannabidiol is added to molten poloxamer at a mass ratio of 1:6 to 10, and the molten mixture is added to deionized water at a material-to-liquid ratio of 1:10 to 15. Cyclodextrin is added while adding the mixture at a mass ratio of 1:1 to 4. The mixture is stirred until the solution is clear and transparent, and then spray-dried to obtain water-soluble cannabidiol.

[0010] Furthermore, the spray drying heating temperature is 110℃, the air inlet temperature is 67℃, the vacuum degree is -0.03MPa, and the feeding rate is 0.4L / h.

[0011] In the above technical solution, the skeleton agent is one or more of mannitol, xylitol, maltitol, lactitol, erythritol, glucose, or dextran.

[0012] Preferably, the skeleton agent is a mixture of xylitol and mannitol in a mass ratio of 2:1.

[0013] In the above technical solution, the freeze-drying protectant is one or more of mannose, pullulan, gelatin, or carrageenan.

[0014] Preferably, the freeze-drying protectant is pullulan.

[0015] In the above technical solution, the disintegrant is one or more of soluble starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose or croscarmellose.

[0016] Preferably, the disintegrant is a mixture of croscarmellose sodium and croscarmellose polyvinylpyrrolidone in a mass ratio of 2:1.

[0017] In the above technical solution, the adhesive is one or more of starch, pregelatinized starch, sucrose, glucose, methylcellulose, sodium carboxymethylcellulose, gum arabic, gelatin, crospovidone, or sodium alginate.

[0018] Preferably, the adhesive is cross-linked polyvinyl chloride.

[0019] In the above technical solution, the lubricant is one or more of polysorbate 80, poloxamer, or leucine.

[0020] Preferably, the lubricant is leucine.

[0021] In the above technical solution, the flavoring agent is one or more of a sweetener, flavoring agent, or taste masking agent. The sweetener is one or more of sucralose, sodium saccharin, sucrose, acesulfame potassium, steviol glycosides, sorbitol, xylitol, or cyclamate. The flavoring agent is one or more of peppermint flavoring, fruit flavoring, milk flavoring, or vanilla flavoring. The taste masking agent is one or more of sodium sulfate, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutyl-β-cyclodextrin.

[0022] Preferably, the flavoring agent is xylitol.

[0023] Another object of the present invention is to provide a method for preparing the above-mentioned cannabidiol freeze-dried orally disintegrating tablets, comprising the following steps: weighing each raw material in proportion and mixing them evenly, adding purified water, stirring to dissolve, homogenizing under high pressure, quantitatively filling the homogenized liquid into cold aluminum blister packs, pre-freezing, freeze-drying, and obtaining cannabidiol freeze-dried orally disintegrating tablets.

[0024] Furthermore, the mass ratio of the raw material to purified water is 1:5 to 10.

[0025] Furthermore, the high-pressure homogenization pressure is 50-100 MPa, and the homogenization time is 10-15 min.

[0026] Furthermore, the pre-freezing temperature is -196℃ to -150℃, and the pre-freezing time is 15-30 minutes.

[0027] Furthermore, the freeze-drying temperature is -50℃ to -40℃, the drying time is 36 to 48 hours, and the vacuum degree is 5-10 Pa.

[0028] The beneficial effects of this invention are:

[0029] 1. This invention pretreats fat-soluble cannabidiol into water-soluble cannabidiol, thereby increasing the solubility of cannabidiol in water and improving its utilization efficiency.

[0030] 2. By combining high-pressure homogenization and freeze-drying technologies, cannabidiol freeze-dried orally disintegrating tablets were prepared. These tablets rapidly disintegrate in the oral cavity, allowing their active ingredients to be quickly absorbed directly through the oral mucosa. This greatly caters to individuals with swallowing difficulties and expands the product's target population.

[0031] 3. This invention uses freeze-drying technology, which avoids the component transformation of cannabidiol caused by traditional heat processing methods, ensuring the stability and safety of the product, and providing a new technical path for the industrial upgrading and sustainable development of cannabidiol. Detailed Implementation

[0032] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0033] Example 1

[0034] A method for preparing cannabidiol lyophilized orally disintegrating tablets includes the following steps:

[0035] (1) Preparation of water-soluble cannabidiol: Accurately weigh 65g of poloxamer 407, place it in a 65℃ water bath and heat until melted, add 10g of high-purity cannabidiol powder, stir quickly to dissolve, then add 1000ml of deionized water, transfer to a high-speed mixer and stir at a rate of 8000r / min, while stirring, add 25g of cyclodextrin, and after stirring evenly, spray dry to obtain water-soluble cannabidiol.

[0036] (2) Raw material mixing: Accurately weigh water-soluble cannabidiol, xylitol, mannitol, pullulan, croscarmellose sodium, croscarmellose polyvinylpyrrolidone, croscarmellose and leucine according to the composition in Table 1. After the powder is evenly mixed, it is pulverized and passed through a 50-mesh sieve. Add 1000ml of purified water at a mass ratio (1:10) and stir to dissolve. Homogenize 3 times under 100MPa using a high-pressure homogenizer. Quantitatively fill the homogenized liquid into cold aluminum blister packs.

[0037] (3) Freeze-drying: Place the cold aluminum blister pack in liquid nitrogen and pre-freeze it at -196℃ for 15 minutes to rapidly freeze the pharmaceutical into a solid state. Then place the cold aluminum blister pack in a vacuum freeze dryer and dry it at -50℃ and 10Pa for 48 hours to obtain the product.

[0038] Table 1. Ingredients of Example 1

[0039]

[0040] Example 2

[0041] A method for preparing cannabidiol lyophilized orally disintegrating tablets includes the following steps:

[0042] (1) Preparation of water-soluble cannabidiol: Accurately weigh 65g of poloxamer 407, place it in a 65℃ water bath and heat until melted, add 10g of high-purity cannabidiol powder, stir quickly to dissolve, then add 1000ml of deionized water, transfer to a high-speed mixer and stir at a rate of 8000r / min, while stirring, add 25g of cyclodextrin, and after stirring evenly, spray dry to obtain water-soluble cannabidiol.

[0043] (2) Raw material mixing: Accurately weigh water-soluble cannabidiol, xylitol, mannitol, pullulan, croscarmellose sodium, starch, and leucine according to the composition in Table 1. After the powders are evenly mixed, they are pulverized and passed through a 50-mesh sieve. Add 1000ml of purified water at a mass ratio (1:10) and stir to dissolve. Homogenize three times at 100MPa using a high-pressure homogenizer. Quantitatively fill the homogenized liquid into cold aluminum blister packs.

[0044] (3) Freeze-drying: Place the cold aluminum blister pack in liquid nitrogen and pre-freeze it at -196℃ for 15 minutes to rapidly freeze the pharmaceutical into a solid state. Then place the cold aluminum blister pack in a vacuum freeze dryer and dry it at -50℃ and 10Pa for 48 hours to obtain the product.

[0045] Table 2. Ingredients Table for Example 2

[0046]

[0047] Comparative Example 1

[0048] The preparation method of the cannabidiol freeze-dried orally disintegrating tablets described in this comparative example differs from that in Example 1 in that water-soluble cannabidiol is replaced with cannabidiol, while the other components and operating steps are the same.

[0049] Table 3. Components of Comparative Example 1

[0050]

[0051] Comparative Example 2

[0052] The preparation method of the cannabidiol freeze-dried orally disintegrating tablets described in this comparative example differs from that in Example 1 in that: firstly, water-soluble cannabidiol is replaced with cannabidiol, while the remaining components and operating steps are the same before drying. The drying step is changed to quantitatively loading the homogenized drug solution under high pressure into an aluminum-plastic mold and vacuum drying it at 55°C with a vacuum degree of -0.1 MPa for 48 hours, thus obtaining the product.

[0053] Table 4. Components of Comparative Example 2

[0054]

[0055] The performance tests of the orally disintegrating tablets obtained in Examples 1-2 and Comparative Examples 1-2, the sensory evaluation content is shown in Table 5, and the test results are shown in Table 6.

[0056] Table 5 Sensory Evaluation Content Table

[0057]

[0058] Table 6 Test Results

[0059]

[0060] The cannabidiol freeze-dried orally disintegrating tablets prepared by this invention have a delicate taste and no unpleasant odor. The tablets have a good overall appearance and, compared with traditional orally disintegrating tablets, have the characteristics of rapid disintegration time, delicate and comfortable taste, and easy swallowing.

Claims

1. A cannabidiol lyophilized orally disintegrating tablet and its preparation method, characterized in that: The raw material of the orally disintegrating tablets includes the active ingredient water-soluble cannabidiol and other excipients, wherein the water-soluble cannabidiol accounts for 50%-70% by mass percentage, and the other excipients are one or more of the following: matrix agent, freeze-drying protectant, disintegrant, binder, lubricant, and flavoring agent.

2. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The water-soluble cannabidiol is prepared by the following method: Cannabidiol is added to molten poloxamer at a mass ratio of 1:6 to 10. The molten mixture is then added to deionized water at a material-to-liquid ratio of 1:10 to 15. Cyclodextrin is added simultaneously at a mass ratio of 1:1 to 4. The mixture is stirred until the solution is clear and transparent, and then spray-dried to obtain water-soluble cannabidiol.

3. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The skeleton agent is one or more of mannitol, xylitol, maltitol, lactitol, erythritol, glucose, or dextran.

4. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The freeze-drying protectant is one or more of mannose, pullulan, gelatin, or carrageenan.

5. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The disintegrant is one or more of soluble starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose or croscarmellose.

6. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The adhesive is one or more of starch, pregelatinized starch, sucrose, glucose, methylcellulose, sodium carboxymethylcellulose, gum arabic, gelatin, crospovidone, or sodium alginate.

7. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The lubricant is one or more of polysorbate 80, poloxamer, or leucine.

8. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The flavoring agent is one or more of a sweetener, flavoring agent, or taste masking agent, wherein the sweetener is one or more of sucralose, sodium saccharin, sucrose, acesulfame potassium, steviol glycosides, sorbitol, xylitol, or cyclamate; the flavoring agent is one or more of peppermint flavoring, fruit flavoring, milk flavoring, or vanilla flavoring; and the taste masking agent is one or more of sodium sulfate, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, or sulfobutyl-β-cyclodextrin.

9. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claim 1, characterized in that: The orally disintegrating tablets comprise, by weight, the following raw materials: 50-70 parts water-soluble cannabidiol, 10-20 parts matrix agent, 10-15 parts freeze-drying protectant, 10-15 parts disintegrant, 5-10 parts binder, 5-8 parts lubricant, and 4-5 parts flavoring agent.

10. The cannabidiol freeze-dried orally disintegrating tablet and its preparation method according to claims 1-9, characterized in that: Weigh and mix all raw materials thoroughly, add purified water, stir to dissolve, homogenize under high pressure, quantitatively fill into cold aluminum blister packs, pre-freeze with liquid nitrogen, and freeze-dry to obtain cannabidiol lyophilized orally disintegrating tablets; wherein the mass ratio of raw materials to purified water is 1:5-10; the high-pressure homogenization pressure is 50-100 MPa, and the homogenization is performed 3-5 times; the pre-freezing temperature is -196℃ to -150℃, and the pre-freezing time is 15-30 min; the freeze-drying temperature is -50℃ to -40℃, the drying time is 36-48 h, and the vacuum degree is 5-10 Pa.

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